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the medical records of a consecutive series of patients who had undergone a decompressive laminectomy procedure for spinal stenosis from january 2007 to march 2010 by a single fellowship - trained spine surgeon were reviewed .
this review involved detailed review of hospital charts , operative reports , consultations , and preoperative / postoperative office notes .
when this review revealed cases of postoperative urinary retention , personal interviews of patients were then conducted .
the diagnosis of postoperative ces was made when the following were present : saddle numbness , loss of anal sphincter tone ( although not necessarily bowel incontinence ) , urinary retention , and abnormal cystometrogram showing neurogenic bladder . from each patient record , the following data were obtained : age , gender , date of birth , preoperative diagnosis , surgical procedure , date of procedure , level(s ) of decompression and/or fusion , postoperative urinary retention , consultation findings , progress notes , and preoperative questionnaire .
all patients received a preoperative magnetic resonance imaging study ( sagittal and axial t1- and t2-weighted sequences ) and/or computed tomography , which demonstrated a spinal stenosis .
a total of 14 cases of postoperative urinary retention were found and of those , five cases of postoperative ces were detected for an incidence of 8.0% and 2.8% , respectively . in regards to the five postoperative ces cases , one patient was male and four were female , with a range in age from 38 to 84 years ( mean age , 61 years ) .
all five patients who developed postoperative ces improved over a 3- to 9-month period , but none completely resolved .
of the nine cases of postoperative urinary retention that were not diagnosed as ces , five resolved spontaneously over 2 to 6 weeks ; the remaining four were diagnosed as having mechanical urinary problems ( e.g. , enlarged prostate or prolapsed bladder ) that required surgical treatment . on a preoperative questionnaire ,
the same operation technique was used in all five ces patients , and there was no trend noted in the specifics of the surgery .
the spinous processes of the affected levels were removed . bilateral laminectomy and foraminotomy were performed at the effected levels . at the conclusion of decompression , each nerve root was followed out to the foramen and appeared adequately decompressed . at this point , facet joints at the affected levels were removed with a rongeur .
the transverse processes of affected levels were decorticated with a rongeur , and bone from the bone bank was packed along the decorticated areas across the facet joints into the gutters between the affected levels . spinal cord and
nerve monitoring showed no changes at the end of the procedure for all five patients .
anal sphincter monitoring at the time of surgery was not predictive in those patients who developed ces .
the same operation technique was used in all five ces patients , and there was no trend noted in the specifics of the surgery .
bilateral laminectomy and foraminotomy were performed at the effected levels . at the conclusion of decompression ,
each nerve root was followed out to the foramen and appeared adequately decompressed . at this point ,
the transverse processes of affected levels were decorticated with a rongeur , and bone from the bone bank was packed along the decorticated areas across the facet joints into the gutters between the affected levels . spinal cord and
nerve monitoring showed no changes at the end of the procedure for all five patients .
anal sphincter monitoring at the time of surgery was not predictive in those patients who developed ces .
in the current study , five patients developed postoperative ces after decompression surgery for spinal stenosis .
previously , the cause of postoperative ces after decompression surgery has been shown to be caused by inadequate decompression , unsuspected stenosis at a more proximate level , malpositioning of a fat graft , a retained surgical sponge , and a compressive hematoma.1
6
9 these were not the causes of postoperative ces in the current study .
ces is traditionally accepted to be the result of a compressive neuropathy . yet , in the situation where ces arises in a postoperative setting where no compressive source is identified , as in the current study , the compressive neuropathy definition can fall short .
previously , it has been put forth that tension , not compression , and the subsequent ischemic effects on spinal cord microcirculation are a more descriptive analysis of the precursors to ces.10
11 in 1977 , murphy emphasized that the extrusion of disc material in the lumbar region puts tension , rather than compression , on the nerve root , which can likely precipitate ces.11
furthermore , it is has been shown that there is an area of hypovascularity below the tip of the conus medullaris , which would be very vulnerable to dural tension of nerve roots at mid to lower lumbar levels , thus potentially inducing root ischemia , precipitating ces.1
12 dural tension affecting this area of hypovascularity could be caused by spinal stenosis , as well as retropulsion of disc material in mid to lower lumbar levels .
we propose that , in the five cases of postoperative ces presented herein , that the source of dural tension on lumbosacral nerve roots , as described above , was expansion of the decompressed dura .
the tension on the lumbar sacral nerve roots would further compromise an area that already is hypovascular , inducing root ischemia and ultimately ces (
figs . 1
and
2
) .
this would also explain why further decompression in three of the five patients was not effective at improving their symptoms of ces and would also explain the presence of postoperative ces where no other compressive etiology could be elucidated .
this hypothesis would also explain why anal sphincter monitoring was not predictive of ces in these patients because we believe that the syndrome occurs after surgery .
( a ) preoperative diameter ( arrow ) of dura on cross - sectional magnetic resonance imaging .
( b ) postoperative diameter ( large arrow ) of dura on computed tomography .
it is also possible that these patients were predisposed to root ischemia secondary to dural tension of lumbosacral nerve roots .
table 1
shows that four of the five patients with postoperative ces had comorbidities that can compromise microvasculature , such as diabetes , hypertension , and antiphospholipid syndrome . finally , it is important to note that a majority of the patients in this study who did experience postoperative urinary retention ( including the subgroup of those who were diagnosed with ces ) did not initially disclose to their physician or surgeon their symptoms .
thus we feel that these symptoms of postoperative urinary retention and other symptoms of ces are likely underreported by patients in general and is likely reflective of why the incidence in the current literature is lower than what was found in the current study .
our study demonstrates that postoperative ces as a complication of decompression surgery for spinal stenosis occurs at an incidence 2.8% , which is more common than the literature suggests .
it is theorized that the cause of postoperative ces after decompressive surgery for spinal stenosis , where no other compressive source can be identified , is the result of dural tension on lumbosacral nerve roots , secondary to dural expansion following decompression , resulting in root ischemia .
unfortunately , our study demonstrates that once this complication occurs , though it may improve , it will not fully resolve . in this | cauda equina syndrome following decompression for spinal stenosis appears to occur more commonly than the literature suggests .
a large series of spinal stenosis decompressions was reviewed .
based on these findings , a theory is put forth as to the cause of this complication .
one hundred seventy - five cases of decompression for spinal stenosis done over a 2.5-year period were reviewed .
follow - up was 1year to 2 years and 4 months .
there were 14 cases of postoperative urinary retention , for an incidence of 8% .
of those , five were ultimately diagnosed with cauda equina syndrome , for an incidence of 2.8% .
of the nine cases that were not diagnosed as cauda equina syndrome , five resolved spontaneously over 2 to 6 weeks .
the remaining four were diagnosed as having mechanical urinary problems ( e.g. , prostate or prolapsed bladder ) that required surgical treatment .
anal sphincter monitoring at the time of surgery was not predictive in those patients who developed cauda equina syndrome .
all patients who developed cauda equina syndrome improved over 3 to 9 months , but none completely resolved .
three cases underwent further decompression with no apparent improvement .
cauda equina syndrome occurs in 2.8% of decompressions for spinal stenosis . | Methods
Results
Surgical Technique
Discussion
Conclusions | [
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the sequencing of the entire human genome in 2003 has led to a series of unrealized opportunities for public health benefit , many of which rest on accurate genetic risk interpretation and adoption of protective behavior . by 2006 , direct - to - consumer genetic testing and feedback was available through 24 internet - based companies , many of which did not require physician or genetic counseling followup to ensure accurate interpretation of test findings .
recent general population surveys indicate high levels of risk misinterpretation even among highly educated general population subgroups [ 46 ] . to date
, the few studies that have examined outcomes associated with direct - to - consumer genetic testing have found no remarkable increases in distress , screening , or behavior change [ 79 ] , yet it is unclear whether these findings may be due to risk misinterpretation , or lack of consideration of diverse elements of risk , including family history .
first - degree relatives ( fdrs ) of cancer patients may be among the first to pursue cancer genetic susceptibility testing through direct - to - consumer channels , given their heightened risk salience . among fdrs , interpretation of negative findingsthe absence of an identified higher risk genetic risk variant may present a particular challenge , because most of those tested will receive negative findings due to low population prevalence of risk mutations and common risk variants , and because it is unclear how negative genetic findings may be interpreted in the context of other relevant risk factors such as family history .
larusse and colleagues compared women 's interpretation of genetic versus family history risk assessment negative findings
( identical 29% lifetime estimates of developing alzheimer 's disease ) and found that those who received genetic risk feedback reported lower perceived risk and lower anxiety about developing the disease than those who received family history risk assessment .
accordingly , genetic test results indicating negative or uncertain findings may prove to be more salient and impactful than family history information , increasing the probability of diverse risk interpretations and continued information seeking [ 12 , 13 ] , variations in recall of test findings , and justifications for continued risk behavior . to closely examine message interpretation and behavioral intentions given plausible genetic risk feedback
melanoma is an ideal study context given the established genetic ( high - risk mutations , as well as more common genetic variants ) and environmental ( ultraviolet radiation exposure ) risks for this common cancer , and the need to enhance early detection and risk reduction strategies in melanoma fdrs .
this study employed an experimental pre - post design to assess message interpretation ( aim i ) and behavioral intentions ( sun protection and skin screening , aim ii ) associated with receipt of hypothetical risk feedback modeled on varied prototypic melanoma genetic risk feedback in melanoma fdrs .
melanoma fdrs ( n = 139 ) participated in the study . with the approval of each patient 's physician , 426 melanoma patients ( english fluent , age 18 )
were approached at their postsurgical followup appointments at memorial sloan - kettering 's ( msk ) gastric and mixed tumor service by a research study assistant ( rsa ) who described the study , provided a brochure , and requested patients ' assent to contact their eligible fdrs by telephone .
most patients ( 74% ) stated initial willingness to refer an fdr when they were approached in clinic , and 66% of patients provided us with adequate referral information ( name , relation to the patient , and telephone and contact information ) for us to contact their fdr .
of the 280 fdrs who were referred , 50% participated ( n = 139 ) , 44% were unavailable by telephone after five attempts to reach them , and 6% refused participation .
those fdrs who participated did not differ in gender from those who did not participate .
study questionnaires were completed either by telephone or in clinic if the fdr was accompanying the patient .
the sample was 70% female , 97% non - hispanic white , highly educated ( 71% had a college degree ) and mostly ( 78% ) comprised daughters , sons , and mothers ; all included participants were unrelated to each other .
few ( 8% ) had more than one family member with melanoma ; 14% had a personal melanoma history .
half ( 54% ) had a sun - sensitive phenotype indicating skin prone to burning ( skin type i / ii ; ) .
the study used a 3 by 2 experimental design where feedback type and risk level of the scenarios were varied , and participants were randomized to one of the six conditions .
for feedback type , mutation feedback was modeled on inherited mutations in cdkn2a ( gene encoding p16 ) , an identified tumor suppressor gene , that has been linked to hereditary melanoma ( melanoma diagnosed in a family with two or more affected relatives ; ) .
gene - environment feedback was modeled on the melanocortin receptor gene ( mc1r ) , which interacts with sun exposure to heighten population melanoma risk .
nongenetic feedback was based on a nongenetic melanoma risk assessment that includes factors such as mole number .
risk level was varied by whether the findings were positive ( test identified higher risk genetic marker / nongenetic risk information ) or negative .
the following elements recommended by persky and colleagues were used to increase the accuracy of testing outcomes , including verbal elements to increase verbal immediacy of the scenario , use of a request to imagine they are having the test , the use of second person ( you ) , a test administrator ( nurse ) , a description of the test context in concrete terms , a description of each new test as immediately available , inclusion of detail about the tests ( blood test , the heritability of melanoma , and the bases on which risk is determined for each test type ) , the use of a brief , relatively low text - dense scenario description , and finally random assignment to condition and slow , verbal presentation by the rsa .
think hard about how you would feel and what you would think in this situation .
imagine that you learn from your doctor that there is a new test that will provide information about a person 's risk of developing melanoma .
[ this genetic test involves giving a blood sample that is tested for a gene mutation that places a person at increased risk for developing melanoma / this genetic test involves giving a blood sample that is tested for a common genetic difference that makes someone more susceptible to the negative effects of sunlight and sunburn / this test involves a brief series of questions about whether you have had skin cancer before , freckling and number of large moles , how sun - sensitive you are , and sunburn history .
] you know that as a close family member of someone who has had melanoma , that your risk is already increased , regardless of your test results .
[ a nurse takes a sample of blood from you for this purpose ( deleted for non - genetic feedback ) ] .
think hard about how you would feel and what you would think in this situation .
imagine that you learn from your doctor that there is a new test that will provide information about a person 's risk of developing melanoma .
[ this genetic test involves giving a blood sample that is tested for a gene mutation that places a person at increased risk for developing melanoma / this genetic test involves giving a blood sample that is tested for a common genetic difference that makes someone more susceptible to the negative effects of sunlight and sunburn / this test involves a brief series of questions about whether you have had skin cancer before , freckling and number of large moles , how sun - sensitive you are , and sunburn history .
] you know that as a close family member of someone who has had melanoma , that your risk is already increased , regardless of your test results .
[ a nurse takes a sample of blood from you for this purpose ( deleted for non - genetic feedback ) ] .
accordingly , we assessed absolute verbal likelihood of developing melanoma ( how likely is it that you will develop melanoma in the future ?
would you say your chance of getting melanoma is assessed on a 5-point scale , very low to very high ) and comparative likelihood of developing melanoma compared to same age and sex others ( compared to the average person your age , would you say that you are assessed on a 3-point scale , less likely to get melanoma , about as likely to get melanoma , or more likely to get melanoma ) .
current self - reported sun protection practices ( use of sunscreen , shirts , hats , shade seeking , and sunglasses when outside on a sunny summer day for more than an hour ) were assessed on separate 5-point scales , never to always , .
history of healthcare provider skin cancer screening and skin self - examination ( history of prior screening , no history of prior screening ) was also assessed .
accordingly , we assessed absolute verbal likelihood of developing melanoma ( how likely is it that you will develop melanoma in the future ?
would you say your chance of getting melanoma is assessed on a 5-point scale , very low to very high ) and comparative likelihood of developing melanoma compared to same age and sex others ( compared to the average person your age , would you say that you are assessed on a 3-point scale , less likely to get melanoma , about as likely to get melanoma , or more likely to get melanoma ) .
current self - reported sun protection practices ( use of sunscreen , shirts , hats , shade seeking , and sunglasses when outside on a sunny summer day for more than an hour ) were assessed on separate 5-point scales , never to always , .
history of healthcare provider skin cancer screening and skin self - examination ( history of prior screening , no history of prior screening ) was also assessed .
scenario interpretation was assessed two ways through a multiple - choice item ( see table 1 ) and by a second administration of the same perceived skin cancer risk questions that were assessed at pretest .
intentions for future sun protection practices ( use of sunscreen , shirts , hats , shade seeking , and sunglasses when outside for more than one hour on separate 5-point scales , never to always , and healthcare provider and self - screening intentions ( intend , not intend ) as well as basic demographic and skin type information ) were assessed .
scenario interpretation was assessed two ways through a multiple - choice item ( see table 1 ) and by a second administration of the same perceived skin cancer risk questions that were assessed at pretest .
intentions for future sun protection practices ( use of sunscreen , shirts , hats , shade seeking , and sunglasses when outside for more than one hour on separate 5-point scales , never to always , and healthcare provider and self - screening intentions ( intend , not intend ) as well as basic demographic and skin type information ) were assessed . to assess message interpretation ( aim i ) ,
multiple - choice responses are reported descriptively , and via pre - post melanoma perceived risk assessed with a 3 by 2 analyses of covariance ( ancova ) , with vignette type and vignette risk level as the independent variables , controlling for pretest perceived risk . to assess anticipated sun protection behavioral intentions ( aim ii ) ,
hierarchical linear modeling ( hlm ; ) was employed to examine sun protection ( intended use of sunscreen , shirts , hats , shade seeking , and sunglasses on separate 5-point scales , never to always ) given the presumed correlation between outcomes , treating study i d as the sole random effect .
statistical evidence was evaluated by the type - iii test of wald statistic , using the mixed procedure in the spss statistical package ( v.18 ) . for the dichotomous outcome of skin examination ( intend / not intend screening ) , a generalized estimating equation ( gee ; ) was used to examine intended skin cancer screening ( by healthcare provider as well as skin self - examination ) . statistical evidence in the gee was evaluated by the generalized score tests for type iii contrasts using the sas statistical package ( v9.2 ) .
the independent variables in the hlm and gee models were vignette type , vignette risk level , and an interaction between vignette type and risk level .
we did not include pretest sun protection behaviors in the hlm , nor pretest skin cancer screening in the gee models because of sample size limitations .
randomization was balanced , as indicated by the lack of significant pretest differences in participants ' reported sun protection behaviors and skin cancer screening across participants randomized to different experimental conditions .
there were no significant differences across conditions in whether participants reported a sun - sensitive phenotype , whether they had one or more family members with melanoma , nor whether they had a prior personal melanoma history .
positive feedback was interpreted more consistently than negative feedback across all feedback types ( see table 1 ) . of those who received mutation - positive feedback , two - thirds ( 67% )
those who received mutation negative findings had more diverse interpretations only one - third ( 38% ) equated their risk to others with a family history of melanoma , yet 33% reported that their risk was decreased , and 25% reported that their risk did not differ from that of the general population .
most of those who received positive gene - environment feedback ( 70% ) interpreted their results to mean that their melanoma risk was increased , but of those who received negative gene - environment feedback , 30% reported that their risk was decreased , and 30% reported that their risk was similar to the general population .
most of those who received positive feedback ( 70% ) interpreted their results to mean that their melanoma risk was increased , but of those who received negative feedback , 41% reported that their risk was decreased , and 32% reported that their risk was similar to the general population .
interestingly , compared to those who received negative gene environment and nongenetic feedback , more who received positive gene environment and nongenetic feedback interpreted their findings to mean that their risk was not different from others with a melanoma family history .
interpretations that melanoma was either ruled out , or inevitable , were almost nonexistent , with the only three participants who reported certainty that they would get melanoma all having received mutation - positive feedback . to examine the effect of feedback type ( mutation , gene environment , nongenetic ) and risk level ( positive or negative findings ) on perceived melanoma risk , two 3 by 2 ancovas ( feedback type by risk level , controlling for pretest perceived risk ) were used .
main effects for risk level for both verbal absolute risk and comparative risk were found , f(1,132 ) = 59.22 , p < 0.0001 ; f(1,132 ) = 37.37 , p < 0.0001 , respectively , such that those who received positive findings had significantly heightened anticipated perceived risk for all types of feedback ; those who received negative findings had significantly reduced anticipated perceived risk for all types of feedback . there were no significant main effects for feedback type ( mutation , gene environment , nongenetic ) nor any significant interactions ( all ps > 0.60 ; see figure 1 ) .
intentions for all sun protection , wald f(1 , 134.27 ) = 3703.72 , p < 0.0001 and skin cancer screening , gee : (1 ,
n = 139 ) = 5.09 , p = 0.02 , were higher among those receiving positive versus negative feedback .
feedback type was not a significant predictor in either the mixed model ( p = 0.37 ) or the gee ( p = 0.18 ) , and there were no significant interactions ( p = 0.74 and p = 0.30 , resp . ) .
figure 2 depicts both pretest ( self - reported behavior ) and posttest ( intended changes in behavior ) findings . those who received positive versus negative feedback showed higher levels of intending to maintain consistent ( often or always ) sunscreen use such that they reported high pretest sunscreen use and high posttest intentions for sunscreen use .
for example , 67% who received positive feedback intended to maintain consistent sunscreen versus 59% of those who received negative feedback .
positive feedback led to higher intentions to adopt consistent ( often or always ) shade seeking , such that those who did not report consistent shade seeking at pretest reported that they intended to adopt it at posttest .
those who received positive versus negative feedback showed higher levels of intending to maintain healthcare provider screening , as well as increased intentions to adopt skin self - examination .
findings regarding intended use of shirts , hats , and sunglasses are not shown but followed the same pattern .
this study found that the positive versus negative dimension of the prototypic melanoma risk feedback consistently influenced melanoma fdrs ' melanoma risk perceptions as well as behavioral intentions .
those study participants receiving positive feedback anticipated higher - risk perceptions compared to pretest levels ; those participants receiving negative feedback anticipated lower - risk perceptions compared to pretest levels as evaluated in aim i. similarly , as evaluated in aim ii , anticipated intentions for protective behaviors ( such as use of sunscreen and shade - seeking ) and screening ( provided by a health - care provider , as well as self - screening ) increased more among those who received positive risk feedback , confirming the theoretical connection between increased risk judgments and intentions to self - protect .
recent studies have documented that individuals at moderate cancer risk are not highly sensitive to low - penetrance genetic quantitative risk magnitude and pictorial information [ 2931 ] and that findings regarding whether a test was positive or negative may be more salient than the exact percentage risk feedback . indeed , genetic risk feedback necessarily contains two dimensions : first , whether a genetic mutation or risk variant is identified or not ; second , what quantitative risk level the genetic mutation or variant confers .
this may be because the easily understood gist is the presence or absence of the risk - conferring gene mutation or variant
. it may be that the risk level is only salient to those who have already been identified to have a risk - conferring genetic factor present . for those receiving negative feedback , or feedback
that a risk - conferring genetic factor is not present , it may be most important for them to integrate their findings with other relevant personal risk information .
we found that negative feedback led to more varied interpretations than positive feedback , with over half of those receiving negative feedback interpreting their feedback as either decreased melanoma risk , or as risk similar to the general population .
it is possible that some of those receiving negative feedback may have discounted their family history despite the clarity with which this information was presented either defensively , or because of a recency effect since hypothetical genetic feedback findings were presented subsequent to the family history risk statement .
this is of potential concern given that early adopters of genetic testing outside the high - risk clinic are likely to include those with family disease histories who may be more motivated to use their genetic test findings to minimize their concerns than to amplify them .
some who received positive feedback did not interpret their risk to exceed that of others with a melanoma family history , as this was a more common interpretation among those who received positive ( versus negative ) gene environment or nongenetic feedback .
suggestions for careful presentation of negative findings include prominent repetition of reminders about other relevant risk factors , including family history , after genetic test findings are conveyed , as well as consideration of whether different types of risk information can and should be integrated in genetic risk calculations .
most importantly , we advocate for the careful evaluation of message interpretation and comprehension prior to the use of these messages in direct - to - consumer contexts .
the use of scenarios is a widely used research strategy to examine decision - making processes associated with genetic testing .
it is possible that the brevity of prototypic feedback may have impeded interpretations of negative findings , in particular .
another limitation involved the fact that 14% of our fdr participants also had a personal melanoma history , which was an additional source of risk heterogeneity in our sample .
however , our results clearly showed that those who received positive feedback both increased their risk perceptions and showed higher intentions for behavior change , supporting relatively accurate interpretations of the positive versus negative feedback dimension .
a strength of our study involved the use of first - degree family members of melanoma patients who are at actual increased melanoma risk based on their family history , as well as the fact that changes in risk judgments led to changes in intended behavior change predicted by major health behavior theories .
our findings need to be confirmed in actual testing situations , with larger samples that will allow stratification across skin type , sun exposure histories , strength of family history , and whether individuals have a personal melanoma history , with longitudinal followup of actual sun protection and skin cancer screening adoption . in conclusion ,
much remains to be learned regarding the translational behavioral potential of human genomics , especially outside of the high - risk setting where extensive genetic counseling will be unavailable or not required .
our study casts a spotlight on the need to conduct further research on those who receive negative genetic feedback , who may be relieved about their findings and yet discount other important cancer risk factors . | little is known about how individuals might interpret brief genetic risk feedback .
we examined interpretation and behavioral intentions ( sun protection , skin screening ) in melanoma first - degree relatives ( fdrs ) after exposure to brief prototypic melanoma risk feedback . using a 3 by 2 experimental pre - post design where feedback type ( high - risk mutation , gene environment , and nongenetic ) and risk level ( positive versus negative findings ) were systematically varied , 139 melanoma fdrs were randomized to receive one of the six scenarios .
all scenarios included an explicit reminder that melanoma family history increased their risk regardless of their feedback .
the findings indicate main effects by risk level but not feedback type ; positive findings led to heightened anticipated melanoma risk perceptions and anticipated behavioral intentions . yet
those who received negative findings often discounted their family melanoma history .
as such , 25% , 30% , and 32% of those who received negative mutation , gene - environment , and nongenetic feedback , respectively , reported that their risk was similar to the general population .
given the frequency with which those who pursue genetic testing may receive negative feedback , attention is needed to identify ideal strategies to present negative genetic findings in contexts such as direct to consumer channels where extensive genetic counseling is not required . | 1. Background
2. Methods
3. Results
4. Discussion | [
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growth is the result of biologic processes by means of which living matter normally gets larger and it is not uniform throughout the life .
adolescence is a period during which the rate of growth acceleration reaches a peak velocity and then decelerates until adulthood is achieved .
this pattern can be found in all individuals , but there are marked individual variations in the initiation , duration , rates and amount of growth during this period of life .
one of the objectives of orthodontic treatment during adolescence , in cases with skeletal discrepancies is to take advantage of the patient 's growth changes .
maturational status can have a considerable influence on diagnosis , treatment goals , treatment planning and the eventual outcome of orthodontic treatment .
this is especially true when treatment considerations are based strongly on the facial growth such as the use of extra oral traction , functional appliances , selection of orthodontic retention and orthognathic surgery .
the maturity status of a child is best estimated relative to specific stages of physiologic maturity than chronological age , being not a reliable indicator .
the technique for assessing skeletal maturity consists of visual inspection of the developing bone , their initial appearance and their subsequent ossification related changes in shape and size .
various areas of the skeleton have been used like frontal sinus , the foot , the ankle , the hip , the elbow , the hand - wrist and the cervical vertebrae .
it is a routine procedure for the orthodontist to take both hand - wrist radiograph for assessing the skeletal maturation and cephalometric radiograph to analyze skeletal morphology and direction of growth patterns .
cervical vertebral analysis for the assessment of skeletal maturity is correlating and is as reliable as hand - wrist radiographic method of assessment .
a series of investigations performed in different parts of the world have confirmed the validity of the cervical vertebral maturation ( cvm ) method , mostly by comparing it with the hand
hagg and taranger have described five stages of mp3 ( middle phalanx of the middle finger ) growth , based primarily on epiphyseal changes for the assessment of skeletal maturity .
they are mp3 - f , mp3 - fg , mp3 - g , mp3 - h , mp3 - i stages .
rajagopal and kansal have added an additional bone stage between mp3 - h and mp3 - i , which they called the mp3 -hi stage .
the modified six stages of mp3 can be easily compared with that of cvmi , which can be recorded on a standard periapical x - ray film and dental x - ray machine . considering the above
, the objective of the present study is to determine the ossification events of the mp3 could be used to assess skeletal age with precision comparable to that of 6 cvmi stages and to assess the reliability of dental radiographic film for the assessment of skeletal maturity status .
the aim of this study was to determine whether the six modified mp3 stages described by rajagopal and kansal could be correlated with the six stages of cervical vertebrae maturation indices ( cvmi ) , as described by hassel and farman . to evaluate the feasibility of recording mp3 stages using standard dental radiographic film for assessment of skeletal maturity . to assess the correlation among the chronological age , cervical vertebral maturity indicators and mp3 maturity stages .
the subjects were selected randomly from the departments of orthodontics and dentofacial orthopedics , pedodontics and oral medicine and radiology of narayana dental college and hospital , nellore .
a sample of 200 subjects ( 100 males and 100 females ) of nellore , indian origin boys aged between 10 to 19 years and girls aged between 8 to 16 years were selected for the study [ table 1 ] .
all potential participants were explained the need and design of the study and the benefits if undergoing through clinical and radiographic investigations .
individuals who agreed to undergo this procedure were instructed to read and sign the consent form .
percentage of growth estimation in correlation with mp3 and cervical vertebrae maturation stages the samples were a mixed one consisting of patients with normal occlusion , malocclusion and those undergoing orthodontic treatment .
patients presenting with congenital or acquired malformations affecting cervical vertebrae or hand wrist.patients presenting with developmental alterations of cervical vertebrae or hand - wrist bone .
patients presenting with congenital or acquired malformations affecting cervical vertebrae or hand wrist . patients presenting with developmental alterations of cervical vertebrae or hand - wrist bone .
villa sistemi medicali , rotograph plus [ figure 1 ] , satelec dental radiographic machine [ figure 2 ] and 10 inches rigid cassette , fuji radiographic films , kodak iopa films and lead apron with thyroid shield were used .
36- micron matte acetate sheet , 0.5 mm diameter lead pencil and x- ray viewer . in this
study the radiographs of left hand middle phalanx of third finger - mp3 [ figure 3 ] and lateral cephalogram [ figure 4 ] were taken under ideal conditions .
once skeletal maturation was assessed from the mp3 radiograph , the lateral cephalogram was taken and three parts of the cervical vertebrae were traced .
they were dens odontoid process , the body of the third cervical vertebrae ( c3 ) and the body of the fourth cervical vertebrae ( c4 ) .
these areas were selected because c3 and c4 could be visualized even when a thyroid protective collar was worn during radiation exposure .
the method used by rajagopal and kansal was used to compare the modified mp3 stages [ figure 5 and table 1 ] with that of the cervical vertebrae as growth indicator .
radiograph of left hand middle phalanx of third finger lateral cephalogram machine correlation of cervical vertebrae with mp3 skeletal maturation stages
villa sistemi medicali , rotograph plus [ figure 1 ] , satelec dental radiographic machine [ figure 2 ] and 10 inches rigid cassette , fuji radiographic films , kodak iopa films and lead apron with thyroid shield were used .
36- micron matte acetate sheet , 0.5 mm diameter lead pencil and x- ray viewer .
36- micron matte acetate sheet , 0.5 mm diameter lead pencil and x- ray viewer .
in this study the radiographs of left hand middle phalanx of third finger - mp3 [ figure 3 ] and lateral cephalogram [ figure 4 ] were taken under ideal conditions .
once skeletal maturation was assessed from the mp3 radiograph , the lateral cephalogram was taken and three parts of the cervical vertebrae were traced .
they were dens odontoid process , the body of the third cervical vertebrae ( c3 ) and the body of the fourth cervical vertebrae ( c4 ) .
these areas were selected because c3 and c4 could be visualized even when a thyroid protective collar was worn during radiation exposure . the method used by rajagopal and kansal
was used to compare the modified mp3 stages [ figure 5 and table 1 ] with that of the cervical vertebrae as growth indicator .
radiograph of left hand middle phalanx of third finger lateral cephalogram machine correlation of cervical vertebrae with mp3 skeletal maturation stages
age and gender distribution of the study population [ table 2 ] . age and gender distribution of study population the study population consists of 100 ( 50% ) males and 100 ( 50% ) females in the age range from 8 to 19 years .
comparison of cvmi vs. mp3 among the study population : table 3 represents the comparison between mp3 and cvmi scores among the study population irrespective of age groups and gender .
comparison of mp3 versus cervical vertebrae maturation indices among the study population comparison of cvmi vs. mp3 among males .
table 4 represents the comparison between cvmi and mp3 among males irrespective of age group .
comparison of mp3 versus cervical vertebrae maturation indices among males comparison of cvmi vs. mp3 among females .
table 5 represents the comparison between cvmi and mp3 among females irrespective of age group .
comparison of mp3 versus cvmi among females comparison of cvmi vs. mp3 among 8 - 9 years age group in study population [ figure 6 ] .
the cvmi and mp3 among 8 - 9 years age in study population irrespective of gender had a cvmi score 1 , 18 subjects ( 100.00% ) were showing mp3 - f stage .
with cvmi score 2 , 1 subject ( 25.00% ) was showing mp3 - f stage and 3 subjects ( 75.00% ) were showing mp3 fg stage .
comparison of cvmi versus mp3 among 8 - 9 years age group in study population comparison of cvmi vs. mp3 among 10 - 11 years age group in study population [ figure 7 ] .
the cvmi and mp3 among 10 - 11 years age in study population irrespective of gender had a cvmi score of 1 , 8 subjects ( 88.88% ) were showing mp3 f stage and 1 subject was showing mp3 - fg stage .
comparison of cvmi versus mp3 among 10 - 11 years age group in study population comparison of cvmi vs. mp3 among 12 - 13 years age group in study population [ figure 8 ] .
the cvmi and mp3 among 12 - 13 years age in study population irrespective of gender had a cvmi score of 1 , 2 subjects ( 100.00% ) were showing mp3 - f stage .
comparison of cvmi versus mp3 among 12 - 13 years age group in study population comparison of cvmi vs. mp3 among 14 - 15 years age group in study population [ figure 9 ] .
the cvmi and mp3 among 14 - 15 years age in study population irrespective of gender had a cvmi score of 1 , 1 subject ( 100.00% ) was showing mp3 - f stage .
comparison of cvmi versus mp3 among 14 - 15 years age group in study population comparison of cvmi vs. mp3 among 16 - 17 years age group in study population [ figure 10 ] .
the cvmi and mp3 among 16 - 17 years age in study population irrespective of gender had a cvmi score 5 , 4 subjects ( 100.00% ) were showing mp3 - hi stage .
with the cvmi score 6 , 2 subjects ( 7.14% ) were showing mp3 - hi stage and 26 subjects ( 92.85% ) were showing mp3 - i stage .
comparison of cvmi versus mp3 among 16 - 17 years age group in study population comparison of cvmi vs. mp3 among 18 - 19 years age group in study population [ figure 11 ] .
the cvmi and mp3 among 18 - 19 years age in study population irrespective of gender had a cvmi score 5 , 1 subject ( 100.00% ) was showing mp3 - hi stage . with
the cvmi score 6 , 1 subject ( 5.26% ) was showing mp3 - hi stage and 18 subjects ( 94.73% ) were showing mp3 - i stage .
optimal effectiveness in the use of orthodontic or orthopedic appliances has been associated with skeletal maturation .
functional appliances have shown to be more effective when used at peak mandibular growth rate rather than earlier .
chronologic age is an inaccurate indicator of the stages of development through adolescence to adulthood .
dental age has a significantly low correlation with biological age.[41012 ] growth prediction based on the appearance of secondary sexual characteristics requires a long observation period and frequent physical examinations .
the skeletal maturity of the bones of the hand - wrist and cervical vertebrae , on the other hand , is closely related to that of the craniofacial region development .
the skeletal maturity indices are good reliable predictors of sexual and somatic maturity as well .
a sample of 200 subjects ranging from 10 to 19 years for boys and 8 to 16 years for girls was taken to assess the stages of skeletal maturation through cervical vertebrae as well as mp3 stages .
two successive cvmi - mp3 groups were combined ; it was considered that mp3 anatomic characters were unique to each of these groupings .
a very good kappa correlation value of 0.82 [ table 3 ] was found in the study population between cvmi and mp3 stages hassel and farman - rajagopal and kansal analysis .
similar results were found in a previous study in which there was a high correlation between cvmi and mp3 scores .
there was 90.9% similarity in mp3 - f stage and with a cvmi score of 1 , 88.5% similarity in mp3 - fg stage and with a cvmi score of 2 , 75.0% similarity in mp3 - g stage and with a cvmi score of 3 , 100.0% similarity in mp3 - h stage and with a cvmi score of 4 , 71.4% similarity in mp3 - hi stage and with a cvmi score of 5 , 97.1% similarity in mp3 - i stage and with a cvmi score of 6 .
kappa value 0.72 [ table 4 ] is slightly lower when compared to females 0.91 [ table 5 ] .
females are more in the advanced maturity stages as compared to males , indicating that faster maturation occurs in females as compared to males . however , the difference in the smi and cvmi scores between males and females are statistically not significant . the findings of this study showed that the agreement strength of cvmi versus mp3 among 8 - 9 years age group in the study population as in [ figure 6 ] was very good which means 95.45% in the sample size in the population coincided by cvmi and mp3 .
similarly the agreement strengths of cvmi versus mp3 among 10 - 11 , 12 - 13 age group was very good i.e. , 0.8 and 0.86 [ figures 7 and 8 ] , whereas 14 - 15 , 16 - 17 , and 18 - 19 years age groups showed good agreement 0.74 , 0.64 and 0.64 [ figures 911 ] .
from the present study , the following conclusions are made
there was a good concordance between six stages of cvmi ( hassel and farman ) and the six stages of mp3 ( rajagopal and kansal).physiological maturity was earlier in females than in males when compared to the individuals of opposite sex of same chronological age.chronological age was not a valid predictor of assessing the skeletal maturity because of significant variations in the distribution of cvmi and mp3 stages with respect to individual chronological age distribution .
there was a good concordance between six stages of cvmi ( hassel and farman ) and the six stages of mp3 ( rajagopal and kansal ) .
physiological maturity was earlier in females than in males when compared to the individuals of opposite sex of same chronological age .
chronological age was not a valid predictor of assessing the skeletal maturity because of significant variations in the distribution of cvmi and mp3 stages with respect to individual chronological age distribution .
hence , mp3 indicator can be a better choice of predicting skeletal maturity of an individual because of its simplicity , reliability and reduced radiation exposure to an individual .
there is a need for further study with a larger sample size and longitudinal study methodology , as this can show a better correlation between cvmi and mp3 than the observations made in this study . to conclude , chronological age of an individual
can not be a reliable method of predicting the skeletal maturity and any kind of dentofacial orthopedics should be instituted at an early age in females when compared to males , because skeletal maturity is earlier in females .
therefore , any method that might help to identify growth acceleration or deceleration is helpful . | objective : evaluation of skeletal maturity in human individuals is an important aspect in orthodontics and dentofacial orthopedics because , growth guidance and fundamental structural changes are essential for treatment of skeletal discrepancies in all the three planes . among various growth assessment methods ,
cervical vertebra maturation stages and hand wrist have been correlated with the individual growth changes during puberty .
the purpose of this study is to determine correlation of the cvm index with the modified median phalanx index ( mp3 ) as described by rajagopal and kansal.materials and methods:200 subjects ( 100 males and 100 females ) of nellore , indian origin boys aged between 10 to 19 years and girls of 8 to 16 years were selected for the study .
the subjects are selected randomly from patients visiting the departments of orthodontics and dentofacial orthopedics , pediatric dentistry and oral medicine and radiology at narayana dental college and hospital .
nellore .
radiographs of left hand mp3 and lateral cephalogram were taken.results:cohen's kappa statistic was used to assess the agreement between the two measurements based on categorical variables.conclusions:there was a good concordance between 6 stages of cvmi ( hassel and farman ) and the 6 stages of mp3 ( rajagopal and kansal ) .
physiological maturity was earlier in females than in males when compared to the individuals of opposite sex of same chronological age .
chronological age was not a valid predictor of assessing the skeletal maturity because of significant variations in the distribution of cvmi and mp3 stages with respect to individual chronological age distribution . | INTRODUCTION
MATERIALS AND METHODS
Equipment used in the study
Processing
Calibration device
Radiographic evaluation
RESULTS
DISCUSSION
CONCLUSION | [
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smith - lemli - opitz syndrome is an autosomal recessively inherited disorder with equal preponderance in males and females .
a severe defect in cholesterol biosynthesis has been identified leading to abnormally low plasma cholesterol levels and elevated levels of the cholesterol precursor 7-dehydrocholesterol ( 7-dhc ) , the result of deficiency of 7-dehydrocholesterol reductase ( dhcr7 ) .
the clinical manifestations are the result of the reduced cholesterol , which is needed in many important biological processes and the accumulation of the toxic precursors of cholesterol as described above .
we describe a 4-month - old boy with clinical and biochemical profile suggestive of smith - lemli - opitz syndrome .
a 4-month - old male child , born of a non - consanguineous marriage , was referred in view of failure to thrive .
he was born at 7 months gestation by caesarean section in view of oligohydramnios , had a weak cry at birth , and had a birth weight of 2.1 kg .
mother had hypothyroidism and was on thyroid supplements for past 5 years . at 4 months of age
physical examination revealed failure to thrive ( weight = 3.6 kg , < 5 centile ; length = 57 cm , < 5 centile ) , microcephaly , hypertelorism , prominent forehead , large and low - set ears , bulbous nose , long philtrum , micrognathia [ figures 1 and 2 ] , right postaxial polydactyly , long fingers [ figure 3 ] , left lower limb oligodactyly [ figure 4 ] , and deep sacral dimple .
other systems were normal . on investigation , hemoglobin was 6.7 gm / dl and white cell count was 30,800/cu.mm ( 73% polymorphs , 25% lymphocytes ) .
blood urea nitrogen was 14 mg / dl and creatinine was 0.7 mg / dl .
usg abdomen showed right - sided hydronephrosis and a dilated pelvicalyceal system on the left side .
echocardiography revealed moderate - sized ostium secundum atrial septal defect ( asd ) with left - to - right shunt and mild pulmonary hypertension . in view of renal and cardiac anomalies with dysmorphic features ,
he was suspected to have smith - lemli - opitz syndrome and serum cholesterol levels were done , which were low ( 94 mg / dl [ normal = 150 - 250 mg / dl ] ) .
he was advised genetic testing but could not do the same due to non - affordability .
microcephaly , large and low - set ears , bulbous nose , retromicrognathia large forehead , hypertelorism , large and prominent philtrum polydactyly of right upper limb oligodactyly of left lower limb
prevalence of smith - lemli - opitz syndrome has been estimated to be 1 in 20000 .
smith - lemli - opitz syndrome , first described in 1964 , has been described in only one patient from india .
the abnormality in cholesterol biosynthesis appears to explain much of the clinical phenotype of these children .
the abnormalities include growth failure in form of moderately small at birth with subsequent failure to thrive ; moderate - to - severe mental deficiency with variably altered muscle tone ( 10% have iq of 50 - 70 ) ; microcephaly with narrow frontal area ; slanted or low - set ears ; ptosis of eyelids ; broad nasal tip with anteverted nares ; micrognathia ; simian crease ; syndactyly of second and third toes ; and post - axial polydactyly of hand and less often feet .
genitourinary abnormalities may include hypospadias , cryptorchidism , micropenis , bifid scrotum , upper tract anomalies , ureteropelvic junction obstruction , hydronephrosis , renal cystic dysplasia , renal duplication , renal agenesis , and reflux in 57% patients .
cardiac defects are seen in 50% , particularly endocardial cushion defect , hypoplastic left heart , asd , patent ductus arteriosus , and membranous ventricular septal defect . similarly , our patient had facial dysmorphism with cardiac and renal anomalies and delayed milestones .
patients may have seizures , central nervous system malformations , eye abnormalities , cleft palate , macrostomia , bifid tongue , sensorineural hearing loss , hypoplasia of thymus , adrenal enlargement , inguinal hernia , hepatic dysfunction , deep sacral dimple , rectal atresia , pyloric stenosis , cholestatic liver disease , malrotation of the gut , diaphragmatic hernia , anal stenosis , hirschsprung 's disease , and short neck occasionally .
affected children are sociable , have better receptive than expressive language , and may be mechanically adept .
behavioral characteristics of autism and self - injurious and aggressive behavior are common . treatment in form of dietary trials
are under way in view of cholesterol deficiency being the major reason for the various manifestations of the syndrome .
cholesterol supplementation in the food is being evaluated as this would lead to decreased precursors of cholesterol , i.e. , 7-dhc by feed - back inhibition .
doses of cholesterol from 20 - 300 mg / kg / day have been tried in some of the studies .
3-hydroxy-3-methylglutaryl coenzyme a ( hmg - coa ) reductase inhibitors ( statins ) have recently been studied as potential therapy for smith - lemli - opitz syndrome .
interestingly , in contrast to the effects in healthy individuals , statins do not appear to lower plasma cholesterol levels in many of those with smith - lemli - opitz syndrome .
prenatal diagnosis can be done at 16 weeks of gestation on an affected fetus on the basis of reduced amniotic fluid cholesterol and elevated 7-dehydrocholesterol with undetectable amniotic fluid unconjugated estriol . | smith - lemli - opitz syndrome is an autosomal recessively inherited disorder .
a severe defect in cholesterol biosynthesis has been identified leading to abnormally low plasma cholesterol levels and elevated levels of the cholesterol precursor 7-dehydrocholesterol , the result of deficiency of 7-dehydrocholesterol reductase .
we describe one such child with smith - lemli - opitz syndrome .
this child had clinical features similar to smith - lemli - opitz syndrome like facial dysmorphism and cardiac and renal anomalies with failure to thrive . | Introduction
Case Report
Discussion | [
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low- and high - power lasers have been used in oral surgery , endodontics , periodontics , and restorative dentistry among other specialties .
low - level laser therapy ( lllt ) is a promising treatment option for open wounds , and it has been examined on a clinical basis for treatment of rheumatoid arthritis , pain management , healing of atrophic ulcers , healing of indolent wounds , bone formation , and burns .
instead , the photon energy causes photochemical , photophysical , or photobiological effects in cells and tissue .
it has been demonstrated that the effects of low - intensity lasers on biologic tissues are processed in different ways , through the mitotic activity induction of the epithelial cells , modification of the capillary density , stimulation of the local microcirculation , and increase of the in vitro and in vivo collagen synthesis .
it increases mitochondrial function , adenosine triphosphate ( atp ) , rna , and protein synthesis .
this interaction leads to increased oxygen consumption and membrane potential and enhanced synthesis of nadh and atp .
it consequently increases the cellular metabolism , possibly increasing the wound healing and accelerating the inflammatory process .
however , the most common cause is physiologic or ethnic as a result of excessive melanin deposition by melanocytes , which in turn depends on the activity of enzyme tyrosinase .
several techniques including mechanical , surgical , electrosurgical , cryosurgical , free gingival grafts and lasers have been used .
scalpel surgery for depigmentation is a time - tested technique and remains the gold standard .
the purpose of using lllt as a part of postoperative therapy is to provide patients with the highest quality of healthcare .
one of the possible mechanisms behind the therapeutic effects of lllt is the interaction of photons from laser irradiation at optimal doses ( therapeutic window ) with specific receptors in the mitochondria .
the aim of the present study is to evaluate and compare the effects of lllt after depigmentation procedure .
this study had a double - blinded , placebo - controlled , and split - mouth design .
it included 12 patients in which 15 test sites and 15 control sites ( total 30 sites ) were treated for gingival hyperpigmentation .
inclusion criteria were the presence of melanin pigmentation associated with maxillary and mandibular anterior region .
patients with any systemic illness such as uncontrolled hypertension , uncontrolled diabetes mellitus , pregnancy , and smoking were excluded from the study . sites extending from distal of the right canine to the midline and distal of the left canine to the midline of the maxilla or the mandible of the permanent dentition in each patient
the patients were instructed for proper oral hygiene habits , and complete oral prophylaxis and root planing were performed 2 weeks before the surgical procedure .
the patients who were esthetically cautious and exhibited excellent maintenance after phase 1 therapy were carefully chosen to be included in the study .
the procedure was done under local anesthesia 2% lignocaine with adrenaline , which was infiltrated in proximity of the site being operated at .
after completion of the surgical process and bleeding stasis , any of the symmetrical surgical sites was randomly assigned for lllt using a defocused diode laser at 1 mm distance for 5 min .
the diode laser used had a wavelength of 810 nm with power setting at 1 w at continuous mode . to prevent the scattering of light to the opposite side , stents were prepared preoperatively using putty impression material .
lllt procedure was repeated each day until 7 day and photographs were taken on the 3 , 7 , and 15 day using the same stent at control site [ figure 1 ] . clinical procedure and low - level laser therapy application .
( a ) preoperative ; ( b ) intra - operative ; ( c ) low level laser therapy on test site ; ( d ) post - operative day 3 ; ( e ) post - operative day 7 ; ( f ) post - operative day 15 all patients were instructed to take paracetamol 500 mg after surgery and continue for 2 days only in case of pain .
after every laser exposure , the surgical site was coated with plaque disclosing solution ( erythrosine in 1:50 dilution according to manufacturer 's recommendation ) for 30 s and then rinsed off .
a photograph of the surgical site was taken using a digital slr camera ( nikon d5100 slr , usa ) , which was placed at 30 cm distance .
the photographs were taken at 55 mm zoom , 1/100 shutter speed , f 14 aperture size , and iso 4000 with a ring flash .
the accuracy of the imaging software was estimated by measuring surface areas of shapes of known mathematical areas .
actual measurements were also made of the patient 's teeth to avoid any discrepancy in the size of image .
a layer of the photograph was cut using the cutting tool in the imaging software , and the disclosing agent color was selected .
the expansion tool of the software then calculated the same color in the whole layer and calculated the area in pixels .
pixel dimension was then converted into millimeter square using a reference object dimension in the software [ figure 2 ] .
( a ) test site - day 3 ; ( b ) test site - day 7 ; ( c ) test site - day 15 ; ( d ) control site - day 3 ; ( e ) control site - day 7 ; ( f ) control site - day 15 the surface area analysis was performed by one of the authors ( vg ) who were blinded to the treatment techniques and to the test and control sites to assure an unbiased determination . the visual analog scale ( vas )
the vas consisted of a scale with values ranging from 0 to 10 , with the left end by the descriptor no pain and at the right end by
scores between 1 and 3 were considered slight pain , scores between 3 and 6 were considered moderate pain , and scores between 6 and 10 were recorded as severe pain . statistical package for
social sciences version 16 ( armonk , new york , usa ) was used for the statistical analysis . the unpaired t - test
this study had a double - blinded , placebo - controlled , and split - mouth design .
it included 12 patients in which 15 test sites and 15 control sites ( total 30 sites ) were treated for gingival hyperpigmentation .
inclusion criteria were the presence of melanin pigmentation associated with maxillary and mandibular anterior region .
patients with any systemic illness such as uncontrolled hypertension , uncontrolled diabetes mellitus , pregnancy , and smoking were excluded from the study . sites extending from distal of the right canine to the midline and distal of the left canine to the midline of the maxilla or the mandible of the permanent dentition in each patient
the patients were instructed for proper oral hygiene habits , and complete oral prophylaxis and root planing were performed 2 weeks before the surgical procedure .
the patients who were esthetically cautious and exhibited excellent maintenance after phase 1 therapy were carefully chosen to be included in the study .
the procedure was done under local anesthesia 2% lignocaine with adrenaline , which was infiltrated in proximity of the site being operated at .
after completion of the surgical process and bleeding stasis , any of the symmetrical surgical sites was randomly assigned for lllt using a defocused diode laser at 1 mm distance for 5 min .
the diode laser used had a wavelength of 810 nm with power setting at 1 w at continuous mode . to prevent the scattering of light to the opposite side , stents were prepared preoperatively using putty impression material .
lllt procedure was repeated each day until 7 day and photographs were taken on the 3 , 7 , and 15 day using the same stent at control site [ figure 1 ] . clinical procedure and low - level laser therapy application .
( a ) preoperative ; ( b ) intra - operative ; ( c ) low level laser therapy on test site ; ( d ) post - operative day 3 ; ( e ) post - operative day 7 ; ( f ) post - operative day 15 all patients were instructed to take paracetamol 500 mg after surgery and continue for 2 days only in case of pain .
after every laser exposure , the surgical site was coated with plaque disclosing solution ( erythrosine in 1:50 dilution according to manufacturer 's recommendation ) for 30 s and then rinsed off .
a photograph of the surgical site was taken using a digital slr camera ( nikon d5100 slr , usa ) , which was placed at 30 cm distance .
the photographs were taken at 55 mm zoom , 1/100 shutter speed , f 14 aperture size , and iso 4000 with a ring flash .
the accuracy of the imaging software was estimated by measuring surface areas of shapes of known mathematical areas .
actual measurements were also made of the patient 's teeth to avoid any discrepancy in the size of image .
a layer of the photograph was cut using the cutting tool in the imaging software , and the disclosing agent color was selected .
the expansion tool of the software then calculated the same color in the whole layer and calculated the area in pixels .
pixel dimension was then converted into millimeter square using a reference object dimension in the software [ figure 2 ]
( a ) test site - day 3 ; ( b ) test site - day 7 ; ( c ) test site - day 15 ; ( d ) control site - day 3 ; ( e ) control site - day 7 ; ( f ) control site - day 15 the surface area analysis was performed by one of the authors ( vg ) who were blinded to the treatment techniques and to the test and control sites to assure an unbiased determination .
the visual analog scale ( vas ) was used to evaluate the subjective pain level experienced by each patient .
the vas consisted of a scale with values ranging from 0 to 10 , with the left end by the descriptor no pain and at the right end by
scores between 1 and 3 were considered slight pain , scores between 3 and 6 were considered moderate pain , and scores between 6 and 10 were recorded as severe pain .
statistical package for social sciences version 16 ( armonk , new york , usa ) was used for the statistical analysis . the unpaired t - test
postoperative complications such as swelling , bleeding , or edema were observed in only one patient on the test site and all patients used analgesics for 3 days . at day 3 ,
test site showed 1.26 0.23 mm and control site showed 1.45 0.21 mm stain uptake by the tissue which was statistically significant . at day 7 and day 15 , the test sites exhibited 1.24 0.30 mm and 1.12 0.25 mm stain uptake , whereas the control site at day 7 and day 15 showed 1.37 25 mm and 1.29 0.28 mm staining , respectively . at day 7 and day 15 , the values were higher at control sites but were not statistically significant [ table 1 and graph 1 ] .
comparison of surface area of stain uptake in test and control site comparison of surface area of stain uptake in test and control site all the patients were satisfied by the treatment outcome . at day 3 , the mean vas score was 4.43 0.76 for the test site and 5.21 0.58 for the control site . at day 7 , the mean vas score was 1.93 0.73 for the test site and 2.21 0.89 for the control site .
there was no statistically significant difference in the vas scores of both the groups . at day 15 , the patients had no pain on either of the sites .
at day 3 , test site showed 1.26 0.23 mm and control site showed 1.45 0.21 mm stain uptake by the tissue which was statistically significant . at day 7 and day 15 , the test sites exhibited 1.24 0.30 mm and 1.12 0.25 mm stain uptake , whereas the control site at day 7 and day 15 showed 1.37 25 mm and 1.29 0.28 mm staining , respectively . at day 7 and day 15 , the values were higher at control sites but were not statistically significant [ table 1 and graph 1 ] .
comparison of surface area of stain uptake in test and control site comparison of surface area of stain uptake in test and control site all the patients were satisfied by the treatment outcome .
at day 3 , the mean vas score was 4.43 0.76 for the test site and 5.21 0.58 for the control site . at day 7 , the mean vas score was 1.93 0.73 for the test site and 2.21 0.89 for the control site .
there was no statistically significant difference in the vas scores of both the groups . at day 15 , the patients had no pain on either of the sites .
healing of periodontal tissue after surgical treatment has long been a subject of the study .
the use of lllt for oral and periodontal purposes has been the subject of numerous in vitro and in vivo studies . in this clinical trial ,
the wounds were assessed after depigmentation over 15 days to clarify whether lllt with diode laser could or could not improve the healing process and postsurgical patient comfort . within the limitations of this study , the findings revealed that lllt promotes wound healing after depigmentation procedure until the 3 day in humans . on the 7 and 15 day , the difference in healing was not statistically significant .
the wound healing mainly includes fibroblasts , keratinocytes , and immune cells . within a few days following surgery ,
epithelial cells start to migrate over the wound surface from the margins , whereas fibroblasts proliferate and lay a new connective tissue underneath the epithelial seal . during this period ,
cytokines and growth hormones expressed by the immune cells such as neutrophils and macrophages orchestrate the wound healing process .
previous studies suggest that lllt application may accelerate wound healing by increasing the motility of human keratinocytes and promoting early epithelization , by increasing fibroblast proliferation and matrix synthesis and by enhancing neovascularization .
it has also been shown that the expression of fibroblast growth factors by macrophages and fibroblasts is increased after lllt application .
another effect of lllt on wound healing is to increase the revascularization rate as it is known that successful wound healing following periodontal surgery is strongly influenced by the revascularization rate . a study by ozcelik et al .
has shown that lllt may enhance epithelization and improve wound healing after gingivectomy and gingivoplasty operations .
the basic principle of lllt is based on the biostimulation or the biomodulation effect , which consists of the fact that irradiation at a specific wavelength is able to alter cellular behavior .
this effect is achieved by acting on the cellular mitochondrial respiratory chain or on membrane calcium channels .
this action subsequently promotes an increase in cell metabolism and proliferation . in the present study
, there was a significant difference in the uptake of the plaque disclosing solution on the 3 day , but this difference was not significant on the 7 and 15 day . a possible explanation for this could be that surface epithelialization completes in 25 days though complete epithelialization occurs in about 1 month .
this result is in contrast with a study ozcelik et al . , who found that lllt applied sites after gingivectomy procedures have significantly lower stained surface areas on the 3 , 7 , and 15 day .
first , the small sample size of the study may affect the reproducibility of our results , and , therefore , these results should be interpreted with caution .
second , healing after a depigmentation operation is a rapid and simple process , which is usually uneventful even when diverse techniques are used .
in addition , although an image - analyzing program was used to determine the stained gingival surface , this method is still strongly operative sensitive .
therefore , further clinical , histological , and/or immunohistological studies with larger study populations including diverse clinical conditions are required to evaluate the exact benefits of lllt on gingival healing and to correlate the clinical alterations with the findings at the cellular level .
within the limitations of this study , the findings revealed that lllt promotes wound healing after depigmentation procedure until the 3 day . on the 7 and 15 day , the difference in healing was not statistically significant . | aim : the aim of the present study is to evaluate and compare the effects of low - level laser therapy ( lllt ) on wound healing after depigmentation procedure.materials and methods : in this study , 12 patients with bilateral melanin hyperpigmentation were treated with surgical stripping using a blade .
after completion of the surgical process and bleeding stasis , any of the symmetrical surgical sites was randomly assigned for lllt ( test site ) using a defocused diode laser at 1 mm distance for 5 min .
after every laser exposure , the surgical site was coated with plaque disclosing solution ( erythrosine ) on the 3rd , 7th , and 15th day .
a photograph of the surgical site was taken using a digital slr camera , which was placed at 30 cm distance at 55 mm zoom , 1/100 shutter speed , f 14 aperture size , and iso 4000 with a ring flash .
the area of the stained parts of the photographs was evaluated using image analysis software.results:at day 3 , test site showed 1.26 0.23 mm2 and control site showed 1.45 0.21 mm2 stain uptake by the tissue which was statistically significant . at day 7 and day 15 , the test sites exhibited 1.24 0.30 mm2 and 1.12 0.25 mm2 stain uptake , whereas the control site showed 1.37 25 mm2 and 1.29 0.28 mm2 staining , respectively , which were not statistically significant.conclusion:within the limitations of this study , the findings revealed that lllt promotes wound healing after depigmentation procedure until the 3rd day . on the 7th and 15th day , the difference in healing was not statistically significant . | INTRODUCTION
MATERIALS AND METHODS
Study population
Clinical procedures and low-level laser therapy application
Surface area determination
Visual analog scale score determination
Statistical analysis
RESULTS
Surface area evaluation
Visual analog scale score evaluation
DISCUSSION
CONCLUSION
Financial support and sponsorship
Conflicts of interest | [
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phacomatosis cesioflammea , earlier called as phacomatosis pigmentovasularis ( ppv ) type ii is a rare condition characterized by the coexistence of dermal melanocytosis ( mongolion spot or nevus of ota ) and nevus flammeus .
klippel trenaunay syndrome ( kts ) manifests as asymmetric overgrowth of a limb and soft tissue associated with vascular malformation ( nevus flammeus ) and varicosities .
a 30-year - old male presented with extensive vascular changes on the trunk and limbs and pigmentary changes on the face .
cutaneous examination showed extensive nevus flammeus affecting almost the entire back , crossing the midline and extending to the buttocks and left lower limb [ figure 1a and b ] .
similar discrete lesions were present over the flanks and lateral aspect of the chest [ figure 2 ] .
there was bilateral bluish - grey pigmentation over the face along the ophthalmic and maxillary division of the trigeminal nerve consistent with nevus of ota [ figure 3a ] .
the sclera , nasal mucosa and palate also showed patchy bluish - grey pigmentation bilaterally [ figure 3a and b ] .
soft tissue hypertrophy of the left lower limb was seen in association with nevus flammeus and varicose veins over the left leg .
a difference of 3 cm was noted in the circumference of both lower legs at the mid - calf region .
radiological examination of the left lower limb showed soft tissue swelling without evidence of bony changes .
color doppler of the affected limb showed varicosities of short saphenous vein with incompetence of the perforators .
also , there was no history of similar pigmentary or vascular lesions in any of his family members .
( a ) showing extensive nevus flammeus over the back , crossing the midline and extending to the buttocks and left lower limb ( b ) showing hypertrophy of left lower limb with nevus flammeus and varicose veins showing nevus flammeus over the flanks and lateral aspect of the chest ( left side ) ( a ) showing nevus of ota over the face bilaterally .
note the prominent pigmentation of sclera bilaterally ( b ) showing bluish - grey pigmentation over the palate and nasal mucosa bilaterally
ppv is a rare disorder that exhibits an association of a widespread vascular nevus with pigmentary nevus .
the term phacomatosis was originally used to characterize some neuro - cutaneous syndromes , but is now mainly applied to genetically determined diseases characterized by the presence of two or more different nevi such as ppv .
each type involves a nevus flammeus with an additional nevus , and is further divided into subtypes a and b. subtype a has cutaneous involvement only while subtype b has extracutaneous involvement .
cutis marmorata telangiectasia congenital ( cmtc ) with mongolian spot have been reported as type v , a distinct variant of ppv . in 2005
, happle proposed a newer and simplified classification scheme for ppv including three different categories [ table 1 ] .
phacomatosis cesioflammea ( blue spots with nevus flammeus , traditional type iia / iib ) , phacomatosis spilorosea ( nevus spilus with pale pink telangiectatic nevus , traditional type iiia / iiib ) and phacomatosis cesiomarmorata ( blue spots with cutis marmorata telangiectasia congenita , traditional type v )
. he also added a category of unclassifiable forms that can not be included into the rest of the three groups .
the traditional type i was dropped in this classification as it was extremely rare and virtually non - existent .
vidaurri - de la cruz et al . in a series of 24 consecutive cases of ppv
it has been proposed that the combination of vascular and pigmentary anomalies arise as a result of twin spotting phenomenon .
two different recessive mutations could be present on each chromosome of the same pair , on different loci ; one each for pigmented and vascular lesions . during embryogenesis , some somatic crossing over could occur with a mitotic recombination , resulting in homozygous cell population in different areas leading to pigmented and vascular nevi .
kts manifests as a triad of capillary malformations , congenital varicose veins and hypertrophy of underlying tissue .
the association of phacomatosis cesioflammea with kts in our patient is indeed interesting and rare . | a 30-year - old indian male presented with bilateral nevus of ota , extensive nevus flammeus over the trunk and left lower limb with soft tissue hypertrophy and varicosities affecting the left lower limb .
he was otherwise in good general health .
a diagnosis of phacomatosis cesioflammea or phacomatosis pigmentovasularis type ii with klippel trenaunay syndrome was made .
the case is being reported on account of its rarity . | INTRODUCTION
CASE REPORT
DISCUSSION | [
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small cell carcinomas ( scc ) are malignancies deriving from neuroendocrine tissue and although the gastrointestinal tract contains the largest population of neuroendocrine cells , these malignancies are rare . through amine precursor uptake and decarboxylation system ,
neuroendocrine cells are capable of synthetizing , storing and secreting a variety of neuroamines , neuropeptides and related substances .
small cell neoplasia most commonly originates in the lung but also other sites such as skin , thymus , kidney , breast , ovary , uterus , urinary bladder , hepatobiliary tree , pancreas , and salivary glands ( extrapulmonary small cell carcinoma , epscc ) .
more specifically , the colorectal scc accounts for 0.2% to 1.5% of all colonic cancers and is considered to be an aggressive neoplasm with rapid growth and early spread carrying poor prognosis .
the chemosensitivity of the epscc is reported to be similar to small cell lung cancer ( sclc ) with similar chemotherapeutic agents .
a 51-year - old fit gentleman presented with a short history of pelvic discomfort , perianal pain and bleeding per rectum .
the patient was non - smoker and the only comorbidity was hypertension - induced cardiomegaly .
1 ) confirmed a large rectal mass extending from the anorectal junction to the mid rectum with multiple enlarged perirectal and mesorectal lymph nodes .
immunohistochemistry revealed that tumour cells were negative for cytokeratin , lca ( lymphoid marker ) and s100 but positive for cd56 ( neural cell adhesion molecule , ncam ) and chromogranin , consistent with a diagnosis of small cell ( neuroendocrine ) carcinoma ( fig .
3 ) . staging ct scan and bone scan excluded any metastatic spread beyond the pelvis .
the case was discussed in the colorectal multidisciplinary meeting and was felt to be inoperable at the time and the recommendation was to treat with a combination of chemotherapy and radiotherapy .
the patient was commenced on chemotherapy ( august 2005 ) consisting of alternate cycles of cyclophosphamide 800 mg / m day 1 + liposomal doxorubicin 50 mg / m day 1 + vincristine 1.4 mg / m day 1 ( cav ) and carboplatin auc 5 day 1 ( 600 mg ) + etoposide 100 mg / m i.v .
day 1 , day 2 and day 3 ( ep ) repeated every 3 weeks for 6 cycles .
following completion of chemotherapy , the patient received consolidation radiotherapy to the pelvis to a dose of 30 gy/10#. a restaging ct scan of chest / abdomen / pelvis in january 2006 demonstrated good partial response with minimal residual rectal disease ( thickening ) and no distant metastasis .
( 100 mg / m ) 3 weeks on and 1 week off for further 6 cycles .
a repeat ct at this stage confirmed unchanged appearance of rectal wall thickening and no new findings ( fig .
this resulted in the patient receiving further 6 cycles of carboplatin and etoposide repeated at 4 weekly intervals .
subsequent ct scan ( december 2006 ) again revealed unchanged appearance of rectal wall , which on sigmoidoscopy appeared normal .
one year after completion of treatment , a ct / pet scan ( december 2007 ) confirmed no residual active disease in the pelvis or elsewhere .
last ct scan from june 2009 confirmed no evidence of recurrence and the patient remains well and free of disease on clinical examination 4.5 years after completion of treatment ( 6 years after diagnosis ) .
epscc initially described by duguid and kennedy in 1930 has been increasingly recognised as a distinct entity from that of lung scc with a different biological behaviour and prognosis .
more specifically , the scc of the gastrointestinal tract is a rare entity and typically presents at advanced stage .
we present this case for its rarity and to share our positive experience in terms of outcome from treatment .
most available literature on this condition exists in the form of case reports and retrospective studies and therefore , much remains to be uncovered about the natural history and the optimal treatment of the disease .
the neuroendocrine differentiation of the tumour is usually demonstrated by immunochemical methods or electron microscopy .
positive immunoreactivity to at least 2 neuroendocrine markers is required , which in our case were cd56 and chromogranin .
the disease staging is evaluated in a similar fashion to the one used for scc of the lung and is essentially divided into 2 major groups : limited disease or extensive disease , purely based on the ability to cover the whole disease in an acceptable radiotherapy portal . in a retrospective study of 64 cases in the united states ( 2004 ) ,
the leading location for epscc was colon and rectum with a median age at presentation of 55 years and slight male predominance .
the median survival ranged from 612 months for treated patients and in weeks for untreated patients .
another retrospective study of 24 patients from korea reported a median overall survival of 15.3 months and a 3-year survival rate of 30% .
studies up to date have invariably shown dismal prognostic outcomes for epscc as the disease is universally fatal and the 5-year survival rate as low as 13% .
some suggest only local treatments using surgery or radiotherapy and others suggest multimodality approach or chemotherapy alone .
one study on 54 patients with limited disease epscc reported an unfavourable outcome with local therapy alone ( median disease - free survival of 56 months ) . in another evaluation of 81 patients with epscc , the majority with limited disease , the combination of chemotherapy and radiation therapy was found to be as effective as surgery
our treatment approach was unique , as we employed sequential chemoradiation followed by maintenance chemotherapy resulting in a long - term disease - free survival .
we know from sclc experience that these patients do respond to combined modality treatment initially but usually present with relapse fairly quickly . in the above study of 81 patients , the median time to relapse following
another study of 16 patients with reported rectal scc had only 3 long - term survivors who were alive 5 years after the time of diagnosis and as expected , all of them had limited disease . with our limited experience , we recommend aggressive multimodality treatment of limited - stage extrapulmonary sclc and consideration for maintenance chemotherapy after initial good response in young and fit patients to transform initial response into a long - term disease control and possibly cure . | we present a rare case of small cell carcinoma of the rectum presenting with rectal bleeding and discomfort in a fit 51-year - old gentleman .
our patient was treated with a combination of chemotherapy and radiotherapy and remains alive and free of disease 6 years after diagnosis .
our patient experience and review of the literature is presented highlighting the uncertainties regarding the biological behaviour and management . | Introduction
Case Report
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amyloidosis is the term for diseases that share a common feature of extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues.1 the classification of amyloidosis is based on the nature of precursor plasma proteins that form the fibril deposits.2 the most common form is primary amyloidosis , also known as light chain amyloidosis .
the structural subunits of amyloid proteins in light chain ( al ) amyloidosis are made up of fragments of monoclonal immunoglobulin heavy chains or light chains.3 the extracellular deposits interfere with organ function and may lead to premature death .
the most common presentations are unexplained nephrotic syndrome , cardiomyopathy , hepatomegaly , and peripheral neuropathy.4 clinically significant pulmonary amyloidosis is uncommon despite the fact that amyloid deposition in the lung parenchyma is a common histological finding in this condition.6 isolated amyloid deposition in the pulmonary vasculature , without clinically significant parenchymal involvement , is a histological finding that occurs to some extent in all systemic forms.7 however , pulmonary hypertension is rarely reported in these cases .
the subject of this report is a patient with amyloidosis al type who presented with severe pulmonary hypertension without an apparent cardiac or parenchymal lung involvement .
a 73-year - old woman presented with a 2-month history of progressive exertional dyspnea , increasing leg edema , and abdominal distention .
two years before admission , the patient presented with symptomatic anemia and was diagnosed as having al type amyloidosis .
she received 1 course of chemotherapy with prednisone and chlorambucil , which were stopped because of severe pancytopenia without any additional chemotherapeutic treatments thereafter .
the patient was tachypneic ( respiratory rate of 25/minute ) and tachycardic ( 120 beats / minute ) .
easily detectable purpuric rash was noted around her eyes . elevated jugular venous pressure of 11 cm , prominent ascites , and leg edema grade 3
auscultation of the heart revealed an accentuated pulmonic component of the second heart sound and a grade 3/6 systolic murmur over the left sternal border .
arterial blood gas analysis on room air revealed a po2 of 58 mmhg , pco2 of 30 mmhg , and ph = 7.5 .
further laboratory workup revealed normocytic anemia ( hb = 10 gr / dl ) , thrombocytopenia of 60,000/mm , white blood cells ( wbc ) of 9,500/mm , mild impairment of renal functions ( creatinine = 1.1 mg / dl , urea = 60 mg / dl ) , albumin = 3.5 gr / dl , globulin = 3 gr / dl , hypercalcemia of 11.5 mg / dl , and a high lactate dehydrogenase of 607 u / l ( normal value
serum protein electrophoresis showed a 16.3 g / l monoclonal spike in the gamma fraction and serum immunoelectrophoresis demonstrated increased igg level with monoclonal lambda chain peak .
bone marrow biopsy confirmed a diagnosis of multiple myeloma with plasma cells comprising 70% of the marrow elements .
electrocardiogram showed sinus tachycardia with right bundle branch block and prominent r waves in the right anterior leads ( v13 ) .
a transthoracic echocardiogram revealed severe pulmonary hypertension with an estimated systolic pulmonary arterial pressure of 90 mmhg and moderate tricuspid regurgitation , but good left ventricular function ( ejection fraction = 66% ) .
no signs of left to right shunt and no echocardiographic signs of restrictive cardiomyopathy or cardiac amyloidosis were found .
perfusion lung scan which revealed nonhomogenous perfusion without segmental perfusion defects that was interpreted as low probability of pulmonary embolism .
a high resolution computed tomography ( ct ) [ high - resolution computed tomography ( hrct ) ] angiogram of the chest did not demonstrate evidence of pulmonary embolism or signs of interstitial or other lung diseases .
lung functions are summarized in table 2 and were interpreted as normal spirometry with decreased diffusing capacity of the lung for carbon monoxide ( dlco ) .
serologic testing for hiv was negative and no clinical findings or laboratory markers suggesting collagen vascular disease were detected .
doppler ultrasound of the portal vein and liver scan did not show signs of portal hypertension or chronic liver disease .
based on the absence of significant pulmonary parenchymal lung findings in hrct , and findings in pulmonary function tests that are consistent with pulmonary hypertension , and the risk of lung biopsy in severe pulmonary hypertension , we decided to avoid this procedure . in light of the patient s refusal to undergo right heart catheterization ,
because of the absence of a secondary condition causing pulmonary hypertension , the most likely cause was deposition of amyloid in the pulmonary vasculature
. it should be noted , however , that this was merely a diagnosis of exclusion .
the patient was treated with nifedipine and diuretics with subsequent clinical improvement in signs and symptoms of right heart failure and slight lowering of the pulmonary hypertension , with an estimated pulmonary artery pressure of 84 mmhg in echocardiogram .
, she received 10 additional courses of prednisone and chlorambucil which were replaced by dexamethasone and cyclophosphamide .
six months after the first admission , the patient presented with worsening dyspnea , cough , and leg edema .
based on a presumptive diagnosis of pneumonia , treatment with antibiotics , supplemental oxygen and diuretics were initiated .
she died because of progressive respiratory failure refractory to treatment and died on the seventh hospital day .
we present a case of al type amyloidosis in association with severe pulmonary hypertension , which raises two issues : the relationship of pulmonary hypertension to pulmonary amyloidosis and the role of amyloid deposition and vascular dysfunctions .
systemic light - chain deposition due to plasma cell dyscrasias usually causes restrictive cardiomyopathy due to cardiac amyloidosis and manifests by signs and symptoms of diastolic ventricular dysfunction .
doppler evaluation of ventricular function is essential to rule out cardiac amyloidosis and the absence of characteristic findings of cardiac amyloidosis in echocardiography , as in the present case , has a negative predictive value of 88%.5 hence , the possibility of cardiac amyloidosis as a main cause of right heart failure in this case is low .
pulmonary amyloidosis rarely causes symptoms despite the fact that it is commonly found in autopsy.6 various classifications of pulmonary amyloidosis have been proposed based upon the site of amyloid deposition .
it is classified as tracheobronchial or parenchymal , the latter being further classified radiographically either as solitary / multiple nodules or as a diffuse alveolar septal pattern.6,7 amyloid involvement of the pulmonary vasculature is a histological finding that occurs at least , to some extent , in all systemic forms8 ; however , pulmonary hypertension is only rarely reported .
pulmonary arterial hypertension is defined as sustained elevation of the pulmonary arterial pressure to more than 25 mmhg at rest or to more than 30 mmhg with exercise , with left ventricular end - diastolic pressure of less than 15 mmhg.9 pulmonary arterial hypertension encompasses idiopathic pulmonary hypertension , pulmonary arterial hypertension in the setting of collagen vascular disease , portal hypertension , congenital left - to - right intracardiac shunts , and infection with human immunodeficiency virus ( hiv).10 our patient was diagnosed as having multiple myeloma ( mm ) with amyloidosis .
all reported cases were related to thalidomide treatment,1113 which is irrelevant to our case . as mentioned previously , deposition of amyloid in the pulmonary vasculature
amyloid deposition in blood vessel walls can result in endothelial dysfunction and eventually lead to pulmonary arterial hypertension .
the pathologic mechanisms that cause pulmonary arterial hypertension probably involve vasoconstriction , smooth muscle cell and endothelial cell proliferation , and thrombosis .
this suggests the presence of perturbations in the normal relationships between vasodilators and vasoconstrictors , growth inhibitors and mitogenic factors , and antithrombotic and prothrombotic determinants .
these homeostatic imbalances are probably consequences of pulmonary endothelial cell dysfunction or injury.14 vasculopathy secondary to amyloid deposition can result in flow abnormalities and ischemia .
vascular involvement has been described in 8890% of patients with al amyloidosis.15,16 despite the frequent histological vascular involvement , clinical expression secondary to amyloid vasculopathy is infrequent .
described an abnormal response of endothelial - dependent vasodilatation in the coronary arteries to acetylcholine infusion in patients with amyloidosis.17 in addition , 2-amyloid was shown to enhance the vasoconstriction induced in aortic rings by phenylephrine and endothelin.18 hence , amyloid deposition in blood vessel walls can result in systemic endothelial dysfunction .
it is possible that similar mechanisms operate in the pulmonary circulation causing pulmonary hypertension . to the best of our knowledge ,
, 8 patients with pulmonary hypertension and amyloidosis without cardiac or parenchymal lung involvement have been reported in the literature.1923 the main clinical and laboratory findings in these reports and those of our patient are summarized in table 1 .
the median age of the patients at diagnosis of amyloidosis was 67 13 , while the median age at the diagnosis of pulmonary hypertension was 1 year higher ( 68 13 ) .
seven patients had al amyloidosis , 1 patient had aa type amyloidosis secondary to untreated familial mediterranean fever , and 1 patient had 2 microglobulin amyloidosis secondary to hemodialysis treatment . from the available echocardiographic data ( 6 out of 9 patients ) , no evidence of cardiac amyloidosis was found .
the median left ventricular ejection fraction was 66% , while all patients had right ventricular dilatation with depressed function .
the diagnosis of pulmonary hypertension secondary to deposition of amyloid in the pulmonary vasculature was confirmed by a lung biopsy in 5 cases .
follow - up data shows rapid clinical deterioration in most of the patients , with a median time until death of 73 days after the diagnosis of pulmonary hypertension . in comparison , the mean survival of patients with primary pulmonary hypertension without therapy is 23 years,24 while that of patients with al amyloidosis is 12 months.1table 1features of patients with pulmonary hypertension and amyloidosis agesextype of pulmonary amyloidosis*cardiac amyloidosissymptomstypeage at diagnosis of amyloidosisage at diagnosis of phtnestimated pap ( mmhg)multiple myelomatime to death ( d)191falveolar septalnhfal9191n265fpartial alveolar septalnd , hfal6565.539y41361f
nd , cp , hfaa fmf484862n618ab2mncurrent case-973f nd , hfal717390y240cp chest pain , d dyspnea , hf heart failure , n no , phtn pulmonary hypertension , y yes.*diagnosis was made by lung biopsy or by autopsy in cases 12 , 67.cardiac amyloidosis was ruled out by echocardiography in cases 25 and 9 and by autopsy histological examination in cases 1 , 6 , and 7.table 2results of pulmonary function tests actualpredictedpercent ( % ) act/ prefev1 ( l)1.341.7875.4fvc ( l)1.682.1777.6fev1/fvc ( % ) 7975dlco3.736.5357.1 features of patients with pulmonary hypertension and amyloidosis cp chest pain , d dyspnea , hf heart failure , n no , phtn pulmonary hypertension , y yes . * diagnosis was made by lung biopsy or by autopsy in cases 12 , 67 .
cardiac amyloidosis was ruled out by echocardiography in cases 25 and 9 and by autopsy histological examination in cases 1 , 6 , and 7 .
results of pulmonary function tests in summary , we present a woman with amyloidosis who developed dyspnea and right heart failure and was diagnosed with pulmonary hypertension , most probably secondary to pulmonary vascular involvement by amyloid fibrils .
dyspnea and right heart failure are not uncommon in patients with amyloidosis and are usually the consequence of cardiac and pulmonary amyloidosis . pulmonary hypertension due to deposition of amyloid in the pulmonary vasculature is uncommon ; nevertheless , it should be considered as a possibility in unexplained pulmonary hypertension in patients with amyloidosis . | only a limited number of patients with amyloidosis and pulmonary hypertension have been reported in the literature .
we report a 73-year - old female with al type amyloidosis who developed respiratory insufficiency and right heart failure because of severe pulmonary hypertension .
there were no signs of cardiac involvement with amyloid or findings consistent with interstitial lung disease .
previous reports of pulmonary hypertension without an apparent parenchymal lung or myocardial involvement with amyloidosis are summarized .
pulmonary hypertension due to deposition of amyloid in the pulmonary vasculature is an uncommon finding ; however , it should be considered in cases of unexplained pulmonary hypertension in patients with amyloidosis . | INTRODUCTION
CASE REPORT
DISCUSSION | [
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parkinson 's disease ( pd ) is a progressive neurodegenerative disorder affecting 1 - 2% of the elderly population .
in addition to the well - known motor problems of pd patients , that are related to nigrostriatal dopamine deficits , also nonmotor symptoms are common . these symptoms strongly affect quality of life of pd patients as they include autonomic dysfunction , sleep problems , cognitive and neuropsychiatric changes [ 25 ] , all changes unrelated to degeneration of the substantia nigra ( sn ) .
apart from dopaminergic cell loss , the deposition of -synuclein is a prominent neuropathological hallmark of pd . according to the staging concept described by braak
this coincides with the occurrence of nonmotor symptoms and can be observed already in early stages of pd , that is , in incidental lewy body disease ( ilbd ) .
moreover , -synuclein can activate microglial cells , and neuroinflammatory responses are indeed important pathological features of pd [ 810 ] .
accumulation of -synuclein has been reported in the hippocampus ( hc ) , which may contribute to the cognitive and depressive changes that represent prominent nonmotor symptoms in pd [ 11 , 12 ] ( figure 1 ) . of interest ,
the hc is also one of the few brain regions where stem cells reside . in the hippocampal subgranular zone ( sgz ) ,
stem cells undergo proliferation before they migrate through the granular cell layer ( gcl ) , where they eventually become newborn , functional neurons that contribute to network function .
in addition to this unique process of adult neurogenesis , which is largely confined to the dg , stem cells in the hc can proliferate and respond to neurodegenerative conditions .
for instance , overexpression of -synuclein in pd models induces aberrant differentiation of neural progenitors and alters cellular plasticity in the hippocampus [ 1315 ] . also striatal deafferentiation , or the loss of dopaminergic neurons , affects both neurogenesis and proliferation in the hc .
in addition , several parkinson - related pathogens induce degeneration of human neural stem cells ( nscs ) or reduce neurogenesis .
stimulation of cellular plasticity on the other hand , for example through exercise , antidepressant treatment or high frequency stimulation , reverses impairments in neurogenesis in pd models and may even benefit pd patients [ 21 , 22 ] .
the discovery that the human brain contains stem cells has instigated extensive research into their proliferative responses during neurodegeneration and into their potential for brain repair .
in related animal models for alzheimer 's disease ( ad ) , changes in cellular plasticity and proliferation appear to depend on the extent of pathology and the severity of the disorder .
regarding pd , stem cells and related cellular plasticity markers are also altered in relevant animal models [ 2426 ] , but only few studies exist on proliferative changes in human pd brain , most of which have focused on the sn [ 27 , 28 ] and subventricular zone ( svz ) [ 29 , 30 ] . in the human sn and svz , discrepant results have been obtained between different studies , and this topic remains subject of debate [ 26 , 29 , 3134 ] . thus far , little attention has been paid to cellular proliferative changes in the human hc , a brain region relevant for nonmotor symptoms in pd , like cognitive and depressive changes . moreover , besides proliferation of nscs , glial cells within the cns may also proliferate in response to neuropathological changes .
indeed , in the ad hippocampus or in experimental multiple sclerosis , for example , proliferation of cns resident microglia has been observed [ 35 , 36 ] .
here , we first studied proliferative changes in prodromal and established cases of pd and , given the differential -synuclein deposition , we include both the ca ( nonneurogenic ) and the dg ( neurogenic ) subregions .
as activated microglial cells are present in the hc in pd and implicated in pd pathogenesis [ 9 , 37 ] , we also questioned whether microglial cells proliferate in these conditions .
we selected hippocampal tissue of well - established and neuropathologically confirmed pd patients ( braak pd stages 46 ) , matched control subjects ( braak pd stage 0 ) , and incidental lewy body disease ( ilbd ) cases ( braak pd stages 13 ) ( figure 1 ) . as these latter cases lacked clinical symptoms of pd during their lives and did not receive dopaminergic medication , but displayed a neuropathological braak -synuclein deposition at autopsy , they can be considered a presymptomatic and prodromal state of pd . to assess cell proliferation
, we used the well validated marker minichromosome maintenance protein 2 ( mcm2 ) [ 38 , 39 ] and colabeled it with the microglial marker iba1 to investigate to what extent cell proliferation in the hc is accounted for by microglia .
human postmortem hippocampal tissue was obtained from the netherlands brain bank ( nbb , amsterdam , the netherlands ) . in compliance with all local ethical and legal guidelines , informed consent for brain autopsy and the use of brain tissue and clinical information for scientific research
fourteen clinically diagnosed and neuropathologically verified pd patients ( braak pd stages 46 ) were selected as well as six clinically healthy controls without neurological or psychiatric disease , that displayed some pd -synuclein pathology at autopsy ( braak pd stages 13 ) and were classified as ilbd cases . for the control group , nine healthy subjects without neurological or psychiatric disease and without any -synuclein pathology ( braak pd stage 0 ) were included .
the three groups were matched for gender and age ; age of the control subjects ranged from 62 to 92 years , in the ilbd cases from 56 to 91 , and in the pd patients from 59 to 96 .
also braak neurofibrillary tangles ( nft ) and amyloid - beta ( a ) plaques scores were matched between control subjects , ilbd cases , and pd patients , ruling out any possible difference in proliferation due to differences in ad pathology .
the clinicopathological data of the patients and the braak staging for pd and ad of all donors is summarized in table 1 .
braak scores for ad and pd neuropathology were provided by the nbb and had been obtained after careful neuropathological evaluation of disease - relevant brain areas by experienced neuropathologists .
the density and distribution of lbs / lns , nft , and a plaques were determined using classic bodian staining and immunohistochemistry for -synuclein ( clone km51 , novacastra , bioconnect bv ) and hyperphosphorylated tau ( clone at8 , pierce , rockford , il ) and a ( clone 6f/3d , dako , dakocytomation bv ) , respectively . at autopsy ,
brain regions were dissected and immersion - fixed in 4% formaldehyde for four weeks , after which they were embedded in paraffin . from the paraffin blocks that contained the hc ,
10-micrometer ( m ) sections were cut on a microtome , mounted , and dried in a stove overnight at 37c before immunohistochemical analysis .
sections were mounted on positively charged glass slides ( menzel - glaser superfrost plus , braunschweig , germany ) .
various markers are available to identify cell proliferation or specific phases of the cell cycle in human postmortem brain tissue [ 3942 ] . of these ,
the minichromosome maintenance protein 2 ( mcm2 ) is involved in the control of dna replication and commonly used in cancer research as a reliable marker for detecting dividing and slowly cycling putative stem cells in situ [ 38 , 43 , 44 ] .
mcm2 expression starts in early g1 and is maintained throughout the cell cycle , also in cells that proliferate without actually synthesizing dna , and is thus present in higher numbers than , for example , the short - lived proliferation marker ki-67 [ 38 , 45 , 46 ] . moreover , the majority of the cells that express mcm2 coexpress the immature neuronal marker doublecortin and mcm2 was therefore also used to study cellular plasticity in comparable tissues .
various tests to validate and confirm specificity of mcm2 and related markers have been performed by us and others before [ 38 , 46 , 47 ] , for example , on samples of young rat brain and human colon , that were processed and embedded in the exact same way as the human brain tissue used in the current study [ 39 , 41 ] .
sections were heated in a stove for one hour at 56c , before they were deparaffinized in xylene and rehydrated through a graded series of ethanol ( 100% , 96% , 90% , and 70% , resp . ) and tbs . for subsequent antigen retrieval
, sections were rinsed in 10 mm tris buffer ( ph 9.0 ) containing 1 mm edta ( tris - edta ) and afterwards placed in preheated tris - edta buffer in a steamer at 9099c for 30 minutes .
after pretreatment , the sections were allowed to regain room temperature ( rt ) , rinsed in tris - buffered saline ( tbs , ph 7.6 ) , and incubated for 20 min in tbs containing 0.3% h2o2 and 0.1% sodium azide to block endogenous peroxidase activity .
nonspecific binding was blocked with 5% nonfat dried milk in tbs containing 0.5% triton ( tbs - t , ph 7.6 ; blocking solution ) for 30 min at rt .
subsequently , sections were incubated overnight at 4c with mouse anti - mcm2 ( bm28 , bd transduction lab 610700 , mouse 1:600 ) .
sections were then washed in tbs and incubated for 2 hr at rt in biotinylated goat anti - mouse iggs ( 1:400 ; jackson immunoresearch laboratories inc . , west grove , pa , usa ) followed by hrp - labeled avidin - biotin complex ( abc complex , 1:400 ; vector laboratories , burlingame , ca , usa ) in tbs - t for 1 hr at rt .
after dehydration in graded ethanol solutions , sections were cleared in xylene and coverslipped in entellan ( merck ) . for double - immunofluorescent labeling of microglial cells and mcm2 expression , iba1 ( wako chemicals , 019 - 19741 , rabbit , 1:300 ) and mcm2 ( 1:1000 ) were used .
sections were pretreated with tris - edta ( ph 9.0 ) and primary antibodies were diluted in the blocking solution , as indicated above .
after an overnight incubation at 4c , the sections were washed and subsequently incubated for 2 h at rt with donkey anti - rabbit alexa fluor 488 labeled donkey anti - rabbit iggs ( iba1 ) and biotinylated goat anti - mouse iggs ( mcm2 ) ( 1:400 , jackson immunoresearch , west grove , pa , usa ) , followed by abc complex ( 1:800 ) for 1 h and biotinylated tyramide enhancement in tbs for 20 min .
hereafter , sections were incubated with alexa fluor 594 labeled streptavidin ( 1:800 , jackson immunoresearch , west grove , pa , usa ) .
after washing , sections were coverslipped with vectashield and examined using a confocal microscope ( leica tsc - sp2-aobs ; leica microsystems , wetzlar , germany ) . for standardization purposes ,
hippocampal sections were collected only around the anterior to midlevel of the hc of every subject and only when large dentate gyrus ( dg ) and cornu ammonis ( ca ) subregions were both present .
furthermore , mcm2-positive cells were included in the subsequent analysis only when they displayed a clearly immature , mitotic , and/or migratory morphology , and were located in an isolated manner ( figure 2 ) .
semiquantification was performed by assessing the numbers of mcm2-positive cells present in the five main hc grey matter regions , that is dg , ca4 , ca3 , ca2 , and ca1 , at a 10x magnification and then expressed per surface area ( region of interest , roi , 1 mm ) using cell olympus soft imaging solutions gmbh software ( tokyo , japan ) .
statistical analyses were performed using the spps package version 20.0 ( statistical product and service solutions , chicago , il , usa ) .
the mean and standard deviation of the number of mcm2-positive cells were calculated for each group and within each subject for all the different subregions of the hc .
the data did not meet criteria for normal distribution ; thus statistical analyses were performed using nonparametric tests .
statistical analysis was executed with the nonparametric kruskal - wallis test to examine main group effects between controls , ilbd , and pd patients .
results were considered significant if they fell below an alpha of p 0.016 , after bonferroni correction . within the same cases , statistical analyses for the different subregions of the hc
were performed with the nonparametric related samples friedman 's analysis to examine main region effects , followed by paired wilcoxon tests as post hoc tests .
results were considered significant if they fell below an alpha of p 0.02 , family wise error- ( fwe- ) corrected .
this critical value was established with sisa ( http://www.quantitativeskills.com/sisa/calculations/bonhlp.htm ) , which uses the mean correlation between variables ( r = 0.65 ) that are mutually correlated ( i.e. , number of mcm2-positive cells ) for the alpha correction and allows one to perform a less stringent correction than the bonferroni method for multiple comparisons .
in the pyramidal layer and dg of the hc of all three patient groups , generally low numbers of mcm2-positive cells were found that displayed morphology typical for proliferating cells , such as a doublet shape and small size ( figure 2 and figures 5(b ) , 5(e ) , and 5(h ) ) . except for a significant main effect in the number of mcm2-positive cells between the hippocampal subregions within the control group ( figure 3(a ) ; p = 0.034 , related samples friedman 's analysis ) , no significant differences were found between the subregions within each of the 2 different patient groups ( figures 3(b ) and 3(c ) ) .
further analysis revealed a trend towards an increase in the dg compared to the ca3 , ca4 , and ca1 within the control group ( figure 3(a ) ; resp .
, p = 0.043 , p = 0.043 , and p = 0.08 ; nonparametric mann - whitney u test , significance reached at alpha of p 0.02 , fwe - corrected ; ctr dg mean = 2.45 1.03 ; ctr ca3 mean = 0.31 0.21 ; ctr ca4 mean = 0.35 0.25 ; ctr ca1 mean = 0.93 0.56 ) . taking all data together revealed a significant increase in the number of mcm2-positive cells in the total hippocampal grey matter ( ca1-ca4 , dg combined ) in the ilbd cases compared to control subjects ( figure 4(a ) ; p = 0.004 ; nonparametric mann - whitney u test , significance reached at alpha p 0.016 , bonferroni - corrected ; ctr mean = 5.21 2.23 ; ilbd mean = 45.24 25.29 ; pd mean = 26.51 9.25 ) .
when analyzing the subregions separately , a significant main group effect was found for ca3 and ca4 between control subjects , ilbd cases , and pd patients ( resp .
, p = 0.006 , p = 0.16 ; nonparametric independent samples kruskal - wallis analysis ) .
further analysis revealed there was a significant increase in the number of mcm2-positive cells in the ca3 and ca4 of the ilbd cases compared to the ca3 and ca4 of control subjects ( figures 4(d ) and 4(e ) ; resp .
, p = 0.001 , p = 0.003 ; nonparametric mann - whitney u test , significance reached at alpha p 0.016 , bonferroni - corrected ; ctr ca3 mean = 0.31 0.21 ; ctr ca4 mean = 0.35 0.25 ; ilbd ca3 mean = 13.05 8.77 ; ilbd ca4 mean = 4.95 1.67 ) and a trend towards an increase in the numbers of mcm2-positive cells in the other three hippocampal subregions of the ilbd cases compared to the control subjects ( figures 4(b ) , 4(c ) , and 4(f ) ; ca1 p = 0.097 ; ca2 p = 0.082 ; dg p = 0.191 ; ctr ca1 mean = 0.93 0.56 ; ctr ca2 mean = 1.17 0.62 ; ctr dg mean = 2.45 1.03 ; ilbd ca1 mean = 5.88 3.17 ; ilbd
ca2 mean = 14.82 9.58 ; ilbd dg mean = 6.45 4.04 ) .
no significant differences were found between pd patients and control or ilbd cases in total hc or within any of the subregions ( figure 4 ) . to determine
whether microglia are proliferating , double immunofluorescence and confocal microscopical analysis revealed that the majority of mcm2-positive cells colocalized with iba1-positive microglia ( representative examples are shown in figure 5 ) .
of each patient group , 3 cases were double stained for iba1 and mcm2 and the percentage coexpression was determined . in the control subjects ,
mcm2-positive cells were rare in the ca regions but always colocalized with iba1 ( 100% ) .
in ilbd cases , the highest number of mcm2-positive cells was present in the ca subregions .
an average of 14 positive mcm2 cells were counted , of which an average of 13 were iba1 positive , yielding 93% coexpression . in pd patients ,
an average of 6 positive mcm2 cells were counted , of which on average 5 were iba1 positive , that is , 83% . in the dg , overall less mcm2-positive cells were counted ; however , the percentages of colocalization with iba1 were similar to ca regions .
in general , quantification revealed > 90% of the mcm2-positive cells in the hc to be microglia in control subjects , ilbd cases , and pd patients ( representative examples are shown in figures 5 and 6 ) .
we studied proliferating cells in the hc of control subjects , ilbd cases , and established pd patients . using mcm2 as marker
, no difference was observed in the amount of proliferating cells between control subjects and pd patients .
however , in the presymptomatic ilbd cases , a clear increase in mcm2-positive cells was found .
interestingly , over 90% of the mcm2-positive cells were colabeled with iba1 , indicating that microglial cells are the main proliferating cells in the hc of ilbd cases and pd patients . in control subjects ,
the low number of mcm2-positive proliferating cells observed in the hc is consistent with the low rates of hippocampal proliferation and neurogenesis found before in the aged rodent , primate , and human hc and in comparable pd brain tissue [ 30 , 41 , 4851 ] . within the control group ,
mcm2-positive cells were increased in the dg compared to other hippocampal regions ( figure 3(a ) ) , which was of interest as most proliferation was beforehand expected to occur in this subregion .
interestingly , the differences between the dg and other subregions were no longer present in the ilbd and pd groups , with higher numbers of proliferating cells in all subregions ( figures 3(b ) and 3(c ) ) , suggesting that the disease process has triggered additional proliferative responses also outside the dg , and in fact throughout the hc . when total counts in the combined hc were compared between the three cohorts , significant increases in proliferation were found in the ilbd cases , but no difference was present between the pd group relative to the control group ( figure 4(a ) ) .
this was unexpected as , based on experimental studies , lowered dopamine levels were expected to reduce hippocampal proliferation .
also the increase in ilbd cases was unexpected as no clinical symptoms were present in this cohort ( yet ) and although not quantified , their dopamine levels are assumed to be unaltered . however , there is also some dat - spect data that reflects a decrease of striatal dopamine levels and nigral degeneration already in the premotor stage of pd [ 5254 ] .
whether these cases can be readily compared to our ilbd cases remains to be answered .
subdividing the different hc subregions revealed that the significant increase in the entire hc in ilbd was mainly due to the ca3 and ca4 and to a lesser extent to the ca2 subregion ( figures 4(c ) , 4(d ) , and 4(e ) ) .
since ilbd can be considered a presymptomatic state of pd , this result suggests that an early and disease - related induction of proliferation occurs in the hc .
neurons that attempt to reenter the cell cycle , there are no indications that proliferation in the ca subregions will actually give rise to new neurons .
also the current morphology , consistent with a proliferative phenotype , and the localization of the mcm2 cells , that is , closely apposed to a pyramidal neuron and thus suggestive of a satellite cell ( figure 2 , arrowhead ) , hinted that proliferation in nonneurogenic subregions likely reflects that of a nonneuronal cell type , for example , microglia . to confirm this , we used immunofluorescent colabeling of mcm2 with iba1 and established that almost all proliferating cells in the pd hc represent microglia .
the increase in ilbd cases relative to control subjects and pd patients suggests that proliferation of microglia occurs early in pd , prior to actual deposition of -synuclein . in most pd cases , neuronal populations in the hc show
accumulation of -synuclein [ 56 , 57 ] which may activate the brain 's immune system through microglia activation .
it is still debatable whether neuronal -synuclein inclusions ( lewy bodies / lewy neurites ) cause microglial activation and/or neuronal death , or whether lbs / lns act as protective
containers and that it is the extracellular -synuclein oligomers and fibrils that are toxic and activate microglia . on
the other hand , neurons containing -synuclein inclusions could communicate with microglia and activate them by neuron to glia signaling . indeed ,
while different microglial phenotypes are present in the sn , hc , and ob in pd , their functional role and hence the implications of microglia proliferation for pd etiology remain elusive [ 37 , 5961 ] .
transgenic mice overexpressing wild - type -synuclein develop -synuclein inclusions shortly after birth but show unchanged cell proliferation in their svz and hc at later ages [ 14 , 62 , 63 ] .
in related prion disease models , proliferation of microglial cells is considered important in their turnover [ 64 , 65 ] and to a larger extent to account for the expansion of the resident microglia population during , for example , prion disease development . a related study on ad mouse models found changes in proliferation and microglia to coincide in time with increases in amyloid plaque load , suggesting that the accumulation of aberrant proteins like amyloid , and possibly also of -synuclein , may trigger microglial proliferation . while in vitro studies
had already demonstrated that the aggregated form of -synuclein can trigger microglial activation [ 10 , 68 ] , the hc of ilbd cases is largely devoid of -synuclein depositions , and a role for soluble forms or -synuclein oligomers can thus not be excluded .
-synuclein oligomers can , for example , activate microglia via toll - like receptor-2 ( tlr2 ) and thereby stimulate proinflammatory cytokine production [ 69 , 70 ] .
in agreement , in a separate study , we found tlr2 expression to be upregulated in microglia in the hc of ilbd cases .
in addition to increasing the cell population , an alternative , more speculative , interpretation of proliferation in microglia could be phagocytosis of -synuclein .
the release of -synuclein and the subsequent uptake by neighboring neurons or glia suggest possibilities for cell - to - cell transfer and propagation that was recently proposed as conceptual model for proteinopathies [ 71 , 72 ] and is consistent with the spatiotemporal progression of pd neuropathology over the brain .
interestingly , neuron - to - glia transmission is accompanied by microglia activation [ 26 , 74 ] and could thus underlie some of the proliferative changes observed in microglia in our current study .
for instance , -synuclein secreted by neurons is released into the extracellular space and can be taken up by microglia and phagocytosed .
several forms of -synuclein have been found to induce microglial activation [ 10 , 75 , 76 ] .
similar to amyloid - beta , such secreted proteins can be sensed by microglia through toll - like receptors that could lead to the activation of inflammatory response genes and their proliferation [ 61 , 69 , 71 , 7779 ] .
another possibility is that proliferative changes reflect altered calcium signaling that was , for example , found to be dysregulated in microglia in close vicinity to amyloid plaques in ad brain .
these options are still speculative , and ongoing phagocytosis of -synuclein inside microglia is technically difficult to visualize in postmortem human brain but may provide a possible explanation for the microglial proliferation we observed .
our current hippocampal data are in contrast with a previous study on proliferation in the svz in pd and pd models , indicating that cell proliferation in the svz , and possibly also in the dg , may be under dopaminergic control [ 16 , 29 , 81 , 82 ] .
these authors used nestin and beta tubulin as markers and found significant reductions in proliferation in the hc of 3 pd patients and 5 pd patients with dementia , which they compared to 3 controls .
although different markers were used , we did not find any indication for a reduction in proliferation in the hc our cohorts , together comprising 20 patients and 9 controls .
another study on the svz failed to find differences in the proliferative capacity between controls and pd patients too . while followed by an interesting debate [ 32 , 33 ] , this also suggested that proliferating progenitor cells are at least not reduced in pd .
the methodological limitations that exist for visualization of neuronal proliferation in human postmortem brain [ 8388 ] do not seem to hold explicitly for microglia proliferation .
mcm2 can thus be used as a marker to determine also nonneuronal cell proliferation in human postmortem material . in conclusion ,
the increase in numbers of proliferating cells in the hc of ilbd cases , a prodromal state of pd , but not in clinically established pd patients , indicates an early response to developing pathology in the pd hc . as almost all of the proliferating cells in the hc
are microglia , this implies that neuroinflammatory processes may play an important role in ongoing pd pathology . | besides dopamine - deficiency related motor symptoms , nonmotor symptoms , including cognitive changes occur in parkinson 's disease ( pd ) patients , that may relate to accumulation of -synuclein in the hippocampus ( hc ) .
this brain region also contains stem cells that can proliferate .
this is a well - regulated process that can , for example , be altered by neurodegenerative conditions .
in contrast to proliferation in the substantia nigra and subventricular zone , little is known about the hc in pd .
in addition , glial cells contribute to neurodegenerative processes and may proliferate in response to pd pathology . in the present study , we questioned whether microglial cells proliferate in the hc of established pd patients versus control subjects or incidental lewy body disease ( ilbd ) cases as a prodromal state of pd .
to this end , proliferation was assessed using the immunocytochemical marker minichromosome maintenance protein 2 ( mcm2 ) .
colocalization with iba1 was performed to determine microglial proliferation .
mcm2-positive cells were present in the hc of controls and were significantly increased in the presymptomatic ilbd cases , but not in established pd patients .
microglia represented the majority of the proliferating cells in the hc .
this suggests an early microglial response to developing pd pathology in the hc and further indicates that neuroinflammatory processes play an important role in the development of pd pathology . | 1. Introduction
2. Material and Methods
3. Results
4. Discussion | [
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in the natural history of chronic obstructive pulmonary disease ( copd ) , exacerbations have a significant impact on mortality,1 especially in those who require hospital admission .
indeed , exacerbations become more frequent and more severe as the severity of copd increases.2 although exacerbations have multiple causes , an infectious etiology is by far the most frequent , with figures up to 78% for hospital - admitted copd patients.3 bacterial infections account for one - half of the acute episodes , while respiratory viruses are identified in more than one - quarter , with rhinovirus ( rv ) and influenza being the most commonly detected viral pathogens .
microbiological studies have identified change in sputum color and purulence as good surrogate markers for bacterial infection,4,5 while the detection of viruses in exacerbations is only marginally associated with the appearance of changes in the characteristics of sputum.6,7 both respiratory bacteria and viruses are able to produce major local and systemic inflammatory responses , and biomarkers such as c - reactive protein ( crp ) have been extensively studied and used as an alternative test to diagnose bacterial infections in both copd and pneumonia.8,9 likewise , in stable copd , crp levels have been examined as a marker of bacterial colonization and/or subclinical infection10 but in studies of exacerbated copd patients , including viral etiology , they have proven unable to distinguish virus - associated exacerbations from others.7 in fact , a recent study by clark et al demonstrated a higher level of crp in exacerbations due to viruses than in those with positive cultures for bacteria.11 few studies have evaluated the usefulness of crp as a predictor of the severity of acute episodes . studies that have suggested that high crp levels are a marker of exacerbation in copd have not demonstrated its value for the identification of episodes severe enough to require admission.12 in severe copd outpatients , studies of crp are scarce , and the relationship between microorganisms and the severity of exacerbations is not fully understood .
the aim of the present study was to identify the causative microorganism ( either bacterium or virus ) in anthonisen type i
we evaluated the systemic inflammatory response as measured by crp blood levels and assessed their impact on the severity of the episode , measured as the need for hospital admission .
outpatients from a severe copd cohort regularly attending a respiratory diseases day care unit for scheduled and exacerbation visits from 200514,15 were the target population for the present study .
patients included in the cohort had scheduled visits and received education on self - care of the disease and a personal action plan , with unscheduled visits when exacerbation symptoms appeared , as described elsewhere.14 inclusion criteria for the study were a baseline forced spirometry showing a forced expiratory volume in 1 second ( fev1 ) < 50% of the reference value and the report of three or more exacerbations in the previous year .
age < 40 years , previous diagnosis of asthma , cystic fibrosis , cancer , bronchiectasis diagnosed from a previous chest x - ray , and chronic treatment with oral corticosteroids , immunosuppressive drugs , or long - term systemic or inhaled antibiotic therapy were exclusion criteria for the study .
ethical permission for the study was obtained from the sabadell hospital ethics committee and written informed consent was given by each participant on enrollment . at baseline , smoking history ,
severity of the disease , body - mass , airflow obstruction , dyspnea , and exercise index,16 comorbidities ( charlson comorbidity index),17 and use of long - term home oxygen therapy was recorded .
copd was defined as a post bronchodilator ratio of fev1 to forced vital capacity of < 0.7 according to the global initiative for chronic obstructive lung disease ( gold ) criteria , in a patient with a smoking habit of > 10 pack - years.18 a computed tomography scan was obtained as part of the patient s baseline characterization in order to identify undiagnosed bronchiectasis , grading its extension in accordance with previously reported criteria.14 participants from the severe copd cohort underwent the same scheduled clinical controls performed by the same team of pulmonologists at the respiratory daycare unit .
they received regular treatment with long - acting beta - agonists , anticholinergics , and inhaled corticosteroids in accordance with current guidelines,18 and attended the unit for unscheduled visits when acute symptoms appeared .
exacerbations suffered by patients from the severe copd cohort participating in the study were the target for the present study .
episodes that required an unscheduled visit at the unit and met more than two anthonisen s criteria13 between january 2005 and march 2008 were considered for the study . in all episodes ,
acute symptoms were recorded , together with fever , respiratory rate ( rr ) , and upper respiratory symptoms ( nasal congestion , increased rhinorrhea , or sore throat ) .
blood analyses , including blood counts , renal function , electrolytes , crp levels , and arterial gases , were performed in all exacerbations , and a spontaneous sputum sample was obtained before the administration of antibiotics .
decisions regarding treatment and admission were left to the discretion of attending physicians , and were taken in accordance with international guidelines.18,19 exacerbations were considered severe in the presence of criteria for hospital admission.20 episodes in which prior antibiotic or corticosteroids were administered ( < 5 days ) were excluded from the final analysis.21 spontaneous sputum samples were collected from each exacerbation and processed within 60 minutes of collection .
washington criteria were used for the identification and selection of samples representative of bronchial secretions.22 sputum samples graded murray iv v were cultured for potentially pathogenic microorganisms ( ppms ) in selective media according to standard methods , and cultures were considered positive when ppms were recovered.23 briefly , samples were vortexed for 3060 seconds after homogenization with sputolysin and 10 l of the solution obtained was cultured using a calibrated loop in blood agar , blood agar with nalidixic acid , chocolate agar , and mcconkey agar plates .
all plates were incubated in a 5% carbon dioxide incubator at 35c ( macconkey agar under aerobic conditions ) and read at 18 and 48 hours .
gram - negative and gram - positive bacteria recognized as agents causing respiratory infections , such as haemophilus influenzae , haemophilus parainfluenzae , streptococcus pneumoniae , moraxella catarrhalis , pseudomonas aeruginosa , staphylococcus aureus , and enterobacteriaceae , were considered as ppms.24 the number of colony forming units per milliliter of sputum was calculated from the number of colonies obtained and the dilution of the sputum .
viral dna / rna was extracted from 200 l of respiratory clinical samples previously liquefied with sputasol ( oxoid limited , basingstoke , uk ) in a 37c water bath for 20 minutes .
then , dna / rna was extracted using qiamp minelute virus spin procedure on the qiacube ( qiagen , hilden , germany ) obtaining 50 l of nucleic acid elute . a multiplex retrotranscriptase - nested polymerase chain reaction ( rt - pcr )
assay was used for simultaneous detection of parainfluenza virus ( 1 , 2 , 3 , 4ab ) , human coronavirus 229e and oc43 , enterovirus , rv , influenza virus a , b , c , respiratory syncytial virus ( rsv ) , and adenovirus following the procedure described by coiras et al.25 data were analyzed using graphpad prism version 7.0 ( graphpad software inc . , san diego , ca , usa ) and pasw statistics version 21 ( spss inc . , chicago , il , usa ) .
results for categorical variables were expressed as absolute and relative frequencies , and continuous variables were expressed as mean values and standard deviations ( sds ) or median and interquartile ranges ( iqrs ) when distribution was non - normal . we used a generalized estimating equation ( gee ) logistic model with an exchangeable within - patient correlation structure and robust standard errors to account for individual patients with multiple exacerbations .
the gee logistic regression model was used to analyze factors associated with hospital admission . in the model we included all patient - related covariates that were judged a priori to be clinically relevant and those with a p - value < 0.1 .
correlations between pairs of predictors were examined to ensure the absence of multicollinearity in the model .
at baseline , smoking history , severity of the disease , body - mass , airflow obstruction , dyspnea , and exercise index,16 comorbidities ( charlson comorbidity index),17 and use of long - term home oxygen therapy was recorded .
copd was defined as a post bronchodilator ratio of fev1 to forced vital capacity of < 0.7 according to the global initiative for chronic obstructive lung disease ( gold ) criteria , in a patient with a smoking habit of > 10 pack - years.18 a computed tomography scan was obtained as part of the patient s baseline characterization in order to identify undiagnosed bronchiectasis , grading its extension in accordance with previously reported criteria.14 participants from the severe copd cohort underwent the same scheduled clinical controls performed by the same team of pulmonologists at the respiratory daycare unit .
they received regular treatment with long - acting beta - agonists , anticholinergics , and inhaled corticosteroids in accordance with current guidelines,18 and attended the unit for unscheduled visits when acute symptoms appeared .
exacerbations suffered by patients from the severe copd cohort participating in the study were the target for the present study .
episodes that required an unscheduled visit at the unit and met more than two anthonisen s criteria13 between january 2005 and march 2008 were considered for the study . in all episodes ,
acute symptoms were recorded , together with fever , respiratory rate ( rr ) , and upper respiratory symptoms ( nasal congestion , increased rhinorrhea , or sore throat ) .
blood analyses , including blood counts , renal function , electrolytes , crp levels , and arterial gases , were performed in all exacerbations , and a spontaneous sputum sample was obtained before the administration of antibiotics .
decisions regarding treatment and admission were left to the discretion of attending physicians , and were taken in accordance with international guidelines.18,19 exacerbations were considered severe in the presence of criteria for hospital admission.20 episodes in which prior antibiotic or corticosteroids were administered ( < 5 days ) were excluded from the final analysis.21
spontaneous sputum samples were collected from each exacerbation and processed within 60 minutes of collection .
washington criteria were used for the identification and selection of samples representative of bronchial secretions.22 sputum samples graded murray iv v were cultured for potentially pathogenic microorganisms ( ppms ) in selective media according to standard methods , and cultures were considered positive when ppms were recovered.23 briefly , samples were vortexed for 3060 seconds after homogenization with sputolysin and 10 l of the solution obtained was cultured using a calibrated loop in blood agar , blood agar with nalidixic acid , chocolate agar , and mcconkey agar plates .
all plates were incubated in a 5% carbon dioxide incubator at 35c ( macconkey agar under aerobic conditions ) and read at 18 and 48 hours .
gram - negative and gram - positive bacteria recognized as agents causing respiratory infections , such as haemophilus influenzae , haemophilus parainfluenzae , streptococcus pneumoniae , moraxella catarrhalis , pseudomonas aeruginosa , staphylococcus aureus , and enterobacteriaceae , were considered as ppms.24 the number of colony forming units per milliliter of sputum was calculated from the number of colonies obtained and the dilution of the sputum .
viral dna / rna was extracted from 200 l of respiratory clinical samples previously liquefied with sputasol ( oxoid limited , basingstoke , uk ) in a 37c water bath for 20 minutes .
then , dna / rna was extracted using qiamp minelute virus spin procedure on the qiacube ( qiagen , hilden , germany ) obtaining 50 l of nucleic acid elute .
a multiplex retrotranscriptase - nested polymerase chain reaction ( rt - pcr ) assay was used for simultaneous detection of parainfluenza virus ( 1 , 2 , 3 , 4ab ) , human coronavirus 229e and oc43 , enterovirus , rv , influenza virus a , b , c , respiratory syncytial virus ( rsv ) , and adenovirus following the procedure described by coiras et al.25
data were analyzed using graphpad prism version 7.0 ( graphpad software inc . , san diego , ca , usa ) and pasw statistics version 21 ( spss inc . ,
results for categorical variables were expressed as absolute and relative frequencies , and continuous variables were expressed as mean values and standard deviations ( sds ) or median and interquartile ranges ( iqrs ) when distribution was non - normal .
we used a generalized estimating equation ( gee ) logistic model with an exchangeable within - patient correlation structure and robust standard errors to account for individual patients with multiple exacerbations .
the gee logistic regression model was used to analyze factors associated with hospital admission . in the model we included all patient - related covariates that were judged a priori to be clinically relevant and those with a p - value <
0.1 . correlations between pairs of predictors were examined to ensure the absence of multicollinearity in the model .
one hundred eighteen patients from the severe copd cohort met the inclusion criteria for the study .
the study population was predominantly male , with a mean ( sd ) age of 69 ( 8) years , and over half of the cases were classified as gold iv .
a total of 386 sputum samples were obtained during exacerbations meeting 2 anthonisen criteria in the follow - up period , with a median exacerbation rate of 1.70 ( iqr 0.902.66 ) episodes per year .
a single exacerbation was reported in 44 patients , whereas 24 presented two and the remaining 50 presented three or more .
six episodes were excluded from further analysis due to corticosteroid treatment and/or antibiotic treatment in the last 5 days before the current episode . of the remaining 380 episodes , 227 ( 60% ) were community - managed , with oral antibiotics and/or corticosteroids ( 96.5% and 59% , respectively ) , while 153 episodes ( 40% ) were considered severe and required hospital admission . from a total of 380 sputum samples collected , full microbiological analyses were possible from 265 exacerbations providing samples valid for analysis according to murray
washington criteria and harboring enough material to perform rt - pcr ( figure 1 ) .
pathogenic bacteria were cultivated from 167 ( 63% ) of the episodes , with h. influenzae ( n=66 ) , s. pneumoniae ( n=28 ) , m. catarrhalis ( n=28 ) , and p. aeruginosa ( n=28 ) being the most frequently recovered species . in 96 samples ( 36% ) , viruses were detected ; rv was the most common ( 56 ) followed by parainfluenzae ( 17 ) , influenza virus ( 9 ) , coronavirus ( 7 ) , rv ( 5 ) , and adenovirus ( 2 ) .
viruses were identified from 45 of the 98 samples with negative cultures for bacteria ( 45.9% ) and from 51 of the 167 exacerbations with cultures showing bacterial infection ( 30.5% ) , which were accordingly considered as coinfections . in these episodes , the relationships between bacterial type and viruses detected did not show statistical significance ( p=0.9 ) .
rvs were present at all times of year , while parainfluenza , influenza , and rsv were predominately isolated in fall or winter ( figure 2 ) .
median crp levels from the 265 episodes with full microbiological analyses were higher in cases with positive cultures for bacteria ( 58.3 mg / l , iqr 21.0128.2 ) than in episodes only positive for viruses ( 37.3 mg / l , iqr 18.679.1 ) and cases negative for any microorganism ( 36.4 mg / l , iqr 10.893.7 ) ( p<0.014 ) . in bacterial infections , crp reached the highest levels in exacerbations due to s. pneumoniae ( 74.1 , iqr 42.0220.7 ) and h. influenza ( 74.5 , iqr 23.9167.9 ) in comparison with episodes related to p. aeruginosa ( 45.2 , iqr 11.170.1 ) or infections due exclusively to viruses ( 37.3 , iqr 18.679.1 ) ( table 2 ) .
crp was not related with bacterial load except for s. pneumoniae , in which a significant correlation was observed ( figure 3 ) .
episodes due to s. pneumoniae also reported fever ( 15 , 56% ) and required hospital admission ( 17 , 60.7% ) more frequently than other microorganisms ( p=0.061 and 0.002 , respectively ) .
self - reported upper airway symptoms were similar across the groups ( table 2 ) .
in the 380 exacerbations studied , significant differences in crp levels were found between community - attended episodes ( 37.3 mg / l , iqr 12.882.7 ) and hospitalized episodes ( 67.4 mg / l , iqr 27.0189.0 ) .
other markers of exacerbation severity such as rr , sao2 , pao2 , and paco2 were also associated with the need for hospital admission ( table 3 ) . the increase in crp
was significantly associated with increases in rr and leukocytes , and a fall in sao2 ( rho = 0.143 ; p=0.012 , rho = 0.270 ; p<0.01 and rho = 0.185 ; p<0.01 , respectively ) . in the gee model for assessing the influence of inflammatory response on exacerbation severity , crp emerged as predictive , along with long - term oxygen therapy and baseline hypercapnia . when adjusted for clinical variables and comorbidities , both basal hypercapnia and crp remained in the model , with a fourfold risk of hospital admission when the crp level was > 100 mg / l ( table 4 ) .
one hundred eighteen patients from the severe copd cohort met the inclusion criteria for the study .
the study population was predominantly male , with a mean ( sd ) age of 69 ( 8) years , and over half of the cases were classified as gold iv .
a total of 386 sputum samples were obtained during exacerbations meeting 2 anthonisen criteria in the follow - up period , with a median exacerbation rate of 1.70 ( iqr 0.902.66 ) episodes per year .
a single exacerbation was reported in 44 patients , whereas 24 presented two and the remaining 50 presented three or more .
six episodes were excluded from further analysis due to corticosteroid treatment and/or antibiotic treatment in the last 5 days before the current episode . of the remaining 380 episodes , 227 ( 60% ) were community - managed , with oral antibiotics and/or corticosteroids ( 96.5% and 59% , respectively ) , while 153 episodes ( 40% ) were considered severe and required hospital admission .
from a total of 380 sputum samples collected , full microbiological analyses were possible from 265 exacerbations providing samples valid for analysis according to murray
washington criteria and harboring enough material to perform rt - pcr ( figure 1 ) .
pathogenic bacteria were cultivated from 167 ( 63% ) of the episodes , with h. influenzae ( n=66 ) , s. pneumoniae ( n=28 ) , m. catarrhalis ( n=28 ) , and p. aeruginosa ( n=28 ) being the most frequently recovered species . in 96 samples ( 36% ) , viruses were detected ; rv was the most common ( 56 ) followed by parainfluenzae ( 17 ) , influenza virus ( 9 ) , coronavirus ( 7 ) , rv ( 5 ) , and adenovirus ( 2 ) .
viruses were identified from 45 of the 98 samples with negative cultures for bacteria ( 45.9% ) and from 51 of the 167 exacerbations with cultures showing bacterial infection ( 30.5% ) , which were accordingly considered as coinfections . in these episodes , the relationships between bacterial type and viruses detected did not show statistical significance ( p=0.9 ) .
rvs were present at all times of year , while parainfluenza , influenza , and rsv were predominately isolated in fall or winter ( figure 2 ) .
median crp levels from the 265 episodes with full microbiological analyses were higher in cases with positive cultures for bacteria ( 58.3 mg / l , iqr 21.0128.2 ) than in episodes only positive for viruses ( 37.3 mg / l , iqr 18.679.1 ) and cases negative for any microorganism ( 36.4 mg / l , iqr 10.893.7 ) ( p<0.014 ) . in bacterial infections , crp reached the highest levels in exacerbations due to s. pneumoniae ( 74.1 , iqr 42.0220.7 ) and h. influenza ( 74.5 , iqr 23.9167.9 ) in comparison with episodes related to p. aeruginosa ( 45.2 , iqr 11.170.1 ) or infections due exclusively to viruses ( 37.3 , iqr 18.679.1 ) ( table 2 ) .
crp was not related with bacterial load except for s. pneumoniae , in which a significant correlation was observed ( figure 3 ) .
episodes due to s. pneumoniae also reported fever ( 15 , 56% ) and required hospital admission ( 17 , 60.7% ) more frequently than other microorganisms ( p=0.061 and 0.002 , respectively ) .
self - reported upper airway symptoms were similar across the groups ( table 2 ) .
in the 380 exacerbations studied , significant differences in crp levels were found between community - attended episodes ( 37.3 mg / l , iqr 12.882.7 ) and hospitalized episodes ( 67.4 mg / l , iqr 27.0189.0 ) .
other markers of exacerbation severity such as rr , sao2 , pao2 , and paco2 were also associated with the need for hospital admission ( table 3 ) . the increase in crp
was significantly associated with increases in rr and leukocytes , and a fall in sao2 ( rho = 0.143 ; p=0.012 , rho = 0.270 ; p<0.01 and rho = 0.185 ; p<0.01 , respectively ) . in the gee model for assessing the influence of inflammatory response on exacerbation severity , crp emerged as predictive , along with long - term oxygen therapy and baseline hypercapnia . when adjusted for clinical variables and comorbidities , both basal hypercapnia and crp remained in the model , with a fourfold risk of hospital admission when the crp level was > 100 mg / l ( table 4 ) .
in a well - characterized cohort of severe copd patients with anthonisen type i ii exacerbations , systemic inflammation , as measured by crp , was associated with a bacterial etiology ( mainly s. pneumoniae or h. influenzae ) , and with bacterial load when s. pneumoniae was the causative agent .
crp , additionally , was a good predictor of the severity of the exacerbations ; patients with crp levels > 100 mg / l presented a fourfold increase in hospitalization .
thus , crp emerges as a good biological marker for the identification of severe exacerbations in copd patients with advanced disease , mainly related to bacterial infections due to s. pneumoniae and h. influenzae .
the prevalence of infection in severe copd outpatients in our study was 80% , with figures > 60% for bacteria and ~40% for viruses , one - half of them as coinfections with pathogenic bacteria .
these data are similar to those obtained in other studies that have focused on patients requiring hospitalization due to the severity of the episode,26,27 suggesting that this etiologic pattern characterizes severe copd exacerbations .
h. influenzae was the most frequently recovered bacteria in the present study and was the cause of one - quarter of the exacerbations , followed by s. pneumoniae , m. catarrhalis , and p. aeruginosa . consistent with other reports , rvs were the most frequently detected virus in our study , in 30% of the cases as a coinfection with pathogenic bacteria.27,6 crp levels in peripheral blood were clearly related to the etiology of the exacerbation in the study population , with the highest figures for s. pneumoniae and h. influenzae and a statistically significant relationship between bacterial load and blood levels of this inflammatory marker for s. pneumoniae .
the systemic impact of this ppm has been assessed in patients with pneumonia ; it is related to severity and prognosis9,28 and is determined by a host
pathogen interaction favored by the c - polysaccharide of the pneumococcal cell wall.29 the inflammatory power of h. influenzae in the bronchial tree is well known and has been related to microbial load,10 but the systemic effect of this ppm has been studied only marginally .
the present results confirm that bronchial infections due to h. influenzae have a clear systemic effect in severe copd patients , as measured by crp levels in peripheral blood , equivalent to the effect found in s. pneumoniae - related exacerbations .
this finding is clinically significant , because h. influenzae is the most prevalent cause of exacerbation in these patients ; infections by h. influenzae and s. pneumoniae were the cause of nearly one - half of the episodes .
our results are at odds with those of previous studies that have reported higher levels of serum crp in patients with virus - induced exacerbations.6,11 the differences are probably due to the characteristics of the episodes reported here , consisting of exacerbations that appear in the follow - up of a cohort of severe copd outpatients .
previous studies have focused on severe exacerbations requiring hospitalization and have thus missed milder episodes that may be partially related to viruses and probably evolve with lower crp levels .
unfortunately , as previously reported,7 crp levels were unable to predict etiology due to the overlapping of levels between the different microorganisms . in our study ,
crp levels were clearly related to the need for hospitalization ; with crp > 100 mg / l , the probability of admission rose more than fourfold .
these high crp figures were mainly related to bacterial infections by s. pneumoniae and h. influenzae .
this relationship did not depend on the covariates assessed and supports a role for this inflammatory marker in the management of exacerbations appearing in severe copd outpatients ; however , in previous studies , it did not prove valuable in predicting outcome.12,30 our study suggests similarities with pneumonia in relation to the significance of crp for the management of these entities .
in fact , a cutoff > 100 mg / l has been associated with adverse outcomes28 and demonstrated a predictive ability for selecting patients requiring intensive care unit ( icu ) admission.31 similar values of crp have been reported in copd exacerbations for selecting patients requiring icu admission , although the number of patients included ( n=64 ) was too small to draw conclusions.32 our study also underlined the importance of baseline hypercapnia as a marker of severity in acute episodes , in agreement with previous studies that have associated this abnormality with survival.33 baseline hypercapnia doubled the risk of hospital admission and it seems reasonable to think that it identified a subgroup of more frail patients , at least in our cohort . in two studies with exacerbated copd patients,34,35 the addition of arterial blood gas parameters ( oxygen and carbon dioxide partial pressures and ph )
did not improve the prediction of mortality during hospitalization , but was closely related with need for admission .
participants were from a severe copd population regularly attending a respiratory daycare unit , and our results can not be extrapolated to the copd population as a whole .
even though we used a gee approach to overcome this problem , we can not rule out a possible over - representation of a particular subset of patients who may be more susceptible to specific microorganisms .
finally , infections with uncommon respiratory viruses such as metapneumovirus and bocavirus were not evaluated in our study , and the true prevalence of virus infection may therefore be slightly underestimated .
in conclusion , this study demonstrated a high prevalence of bacterial infection , mainly due to h. influenzae , s. pneumoniae , m. catarrhalis , and p. aeruginosa in exacerbations appearing in severe copd outpatients .
systemic inflammation identified through crp blood levels was higher in bacterial infections , mainly when h. influenzae and s. pneumoniae were the cause , and high figures for this inflammatory biomarker were related to the severity of the episode .
the findings suggest that crp blood levels may be a useful biomarker in the management of exacerbations appearing in these severe patients . | backgroundc - reactive protein ( crp ) measurement has proven valuable for detecting exacerbations , but its usefulness in predicting etiology remains controversial . likewise , its potential value as a marker of severity , which is well established in patients with pneumonia , remains unproven in chronic obstructive pulmonary disease ( copd ) exacerbations.methodsa cohort study of 118 patients with severe copd and acute infectious exacerbations were included and followed up over 1 year .
episodes of exacerbations meeting anthonisen s criteria type i ii were evaluated , analyzing the etiology and inflammatory response as measured by crp in blood.resultsa total of 380 episodes were recorded .
full microbiological analysis was available in 265 samples .
haemophilus influenzae was the most commonly isolated bacteria and rhinovirus the most common virus .
median crp levels from the 265 episodes were higher in the cases with positive cultures for bacteria ( 58.30 mg / l , interquartile range [ iqr ] 21.028.2 ) than in episodes only positive for viruses ( 37.3 mg / l , iqr 18.679.1 ) and cases negative for any microorganism ( 36.4 mg / l , iqr 10.893.7 ) ( p<0.014 ) .
h. influenzae and streptococcus pneumoniae reached the highest crp levels of 74.5 mg / l ( iqr 23.9167.9 ) and 74.1 mg / l ( iqr 42.0220.7 ) , respectively . in
the 380 exacerbations studied , 227 ( ~60% ) were community - managed , while 153 ( ~40% ) required hospital admission . in the multivariate analysis to assess the influence of inflammatory response on exacerbation severity , baseline hypercapnia ( odds ratio [ or ] : 2.70 , 95% confidence interval [ ci ] : 1.464.9 ) and crp levels > 100 mg / l ( or : 4.23 , 95% ci : 2.128.44 ) were independent predictors after adjustment for baseline characteristics.conclusioncrp level was higher in bacterial infections , especially when h. influenzae and s. pneumoniae were isolated .
crp values > 100 mg / l were associated with a fourfold increased risk of hospital admission .
therefore , crp blood levels may be a useful biomarker in the management of exacerbations appearing in patients with severe disease . | Introduction
Materials and methods
Clinical variables
Sputum samples
Statistical analysis
Results
Patient characteristics
Microbiology
CRP levels and etiology of exacerbations
CRP and exacerbation severity
Discussion
Limitations
Conclusion | [
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however ,
many such patients , particularly those with severe chronic obstructive pulmonary disease ,
have a high risk of postoperative pulmonary complications1 .
there is growing interest in the use of non - pharmacological
interventions after lung resection or during cancer care , such as radiation therapy and
chemotherapy .
pulmonary rehabilitation ( pr ) has been proposed to decrease the risk of
postoperative pulmonary complications2 .
it
is necessary to develop a home - based exercise program to improve the function of patients
and prevent postoperative pulmonary complications because the out - patient period is longer
than the in - patient period .
however , previous studies have focused mainly on pr for
in - patients or only hospital workers , such as doctors , nurses , physical therapists , and
respiratory therapists , provided the pr .
few studies on education programs for caregivers ,
which are the main supporters of home - based exercise programs during the outpatient period ,
have been conducted .
the aim of this study was to evaluate the effects of a pr education
program for caregivers on pulmonary function and pain in patients with lung cancer after
lung resection .
the subjects comprised patients hospitalized within the department of thoracic surgery of a
national university hospital between march and november 2013 who had not previously partaken
in a pulmonary rehabilitation education program for caregivers and were scheduled for lung
resection .
this study was approved by the national university hospital of health science
human ethics committee ; all subjects provided written informed consent prior to
participation . during the hospital
stay for the surgery , all 50 subjects received the same
general management ( typical care ) and were randomly divided into an experimental group ( n =
25 ) and a control group ( n = 25 ) .
three subjects dropped out of the experimental group , and
six dropped out of the control group during the 4-week study due to application of the
exclusion criteria .
therefore , the study was completed with 22 subjects in the experimental
group and 19 in the control group .
patients with other cardiopulmonary diseases , a
congenital chest deformity , or rib fractures were excluded .
after surgery , patients who
received additional chemotherapy that weakened their body function were also excluded , as
were those who did not attend the weekly pr education program .
the assessments of subjects
were performed by a physical therapist who was blinded to any information about the groups .
the control group received the entire typical care program , including pain management ,
general education for postoperative care , incentive spirometer use training , mobilization of
the upper limbs and trunk , and nebulizer use instructions from the department of thoracic
surgery .
the experimental group partook in the pr education program for caregivers once per
week for 30 min , under the direction of a physical therapist instructor .
the pr education
program included instruction regarding splint cough , airway clearance techniques , diaphragm
breathing , segmental breathing , exercises for upper and lower extremities , walking
exercises , and stair exercises .
the instructor demonstrated the procedures to caregivers ,
and then the caregivers practiced with their patients while the instructor observed .
cambridge , uk ) . forced
vital capacity ( fvc ) and forced expiratory volume in 1 sec ( fev1 ) were measured in
accordance with the american thoracic society guidelines3 .
data were encoded and
analyzed using spss for windows ver . 12.0 ( spss ,
the homogeneity of the general characteristics
between the two groups was analyzed by test and independent t - test .
the
differences in the changes between the two groups before the experiment and at 2 weeks
( baseline ) and 6 weeks after surgery ( 4 weeks ) were assessed by repeated - measures analysis
of variance .
the average age , height , weight , and bmi of subjects were 60.22 10.89 , 163.01 8.77 cm ,
61.39 11.35 kg , and 23.01 3.34 , respectively .
pulmonary function ( fvc and fev1 ) in the
experimental group increased significantly compared with that in the control group ( p <
0.01 ) ( table 1table 1.comparison of pulmonary function and painmean ( sd)controlexperimentalfvcbaseline1.89 ( 0.45)1.90 ( 0.47)4 weeks2.00 ( 0.44)2.30 ( 0.44)fev1baseline1.63 ( 0.43)1.71 ( 0.37)4 weeks1.62 ( 0.42)1.95 ( 0.36)vasbaseline3.15 ( 2.13)3.54 ( 2.09)4 weeks2.73 ( 1.82)2.23 ( 1.60)p<0.01 ) .
vas scores at 4 weeks and baseline differed significantly , but no
differences were observed over time or among groups ( table 1 ) .
filaire et al.5 reported that the
fev1/fvc ratio did not change , but the inspiratory and expiratory reserve volume decreased
rapidly by ~40% in the acute stage after lung resection in 31 patients with lung cancer
( mean age , 59 10 years ) .
varela et al.6
showed that fev1 decreased rapidly 1 day after surgery and then recovered slowly during the
next 6 days , but it did not reach the previous level .
our results were similar , as the
fev1/fvc ratio at baseline was 0.86 in the control group and 0.90 in the experimental group .
however , the change in fvc differed before and after the experiment , as that in the
experimental group increased by 21.1% compared with 5.8% in the control group .
this was
believed to be caused by the short study period ( 4 weeks ) and the fact that each group
received a different intervention .
in contrast , a pilot study by spruit et al.7 , applied an 8-week pr exercise program to
inpatients who had undergone lung resection for lung cancer : all pulmonary functions , with
the exception of fev1 , differed significantly , including functional exercise capacity .
it
would appear that the pr education program for caregivers , designed to improve pulmonary
function ( fvc and fev1 ) , was responsible for these differences : the previous study had
focused on strengthening and aerobic exercises , such as walking .
the pulmonary
rehabilitation education program for caregivers had a positive effect on pulmonary function
in patients with lung cancer following lung resection .
in a previous study , the pain score
( vas ) of patients who had undergone lung resection was 3.3 immediately after surgery , 2 at 2
weeks , and 1.5 at 6 weeks after surgery8 .
in our study ,
the vas revealed significantly decreased pain in both groups , but no
difference was observed between the two groups . | [ purpose ] the purpose of this study was to evaluate the effects of a pulmonary
rehabilitation education program for caregivers on patients who underwent lung resection
surgery .
[ subjects ] subjects who underwent lung resection by visual assisted thoracotomy
( vats ) were selected and divided into a control group of 19 and an experimental group of
22 .
[ methods ] the experimental group received a pulmonary rehabilitation education program
for caregivers , while the control group received typical care for 4 weeks .
this study
assessed the subjects 2 weeks ( baseline ) and 6 weeks after surgery ( 4 weeks ) .
the forced
vital capacity ( fvc ) and forced expiratory volume in 1 sec ( fev1 ) were measured to
evaluate pulmonary function . a visual analogue scale ( vas )
was utilized to evaluate pain .
[ results ] pulmonary function ( fvc and fev1 ) increased more in the experimental group
compared with the control group .
furthermore , vas scores were lower in the experimental
group compared with the control group .
[ conclusion ] a pulmonary rehabilitation education
program for caregivers had a positive effect on pulmonary function in patients with lung
cancer after lung resection . | INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION | [
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unintentional injuries are the most important causes of morbidity and mortality in 15 year - old children , responsible for 750,000 annual mortalities and 400 million severe injuries / year ( 1 - 3 ) . a total of 16 million injured children are admitted to emergency units in the united states each year , 30,000 of which suffer permanent defects ( 4 ) .
the frequency of unintentional injury - induced mortality is very high in iran , and has been reported to be 48 cases in 100,000 general population .
it makes up 12% of the total annual mortalities and 82.6% of injury deaths in iran .
unintentional home injuries of children are on the rise and have become an important social problem ( 6 , 7 ) .
4 million preschool children suffer from such injuries annually , most important causes of which are falls , poisoning , and burns ( 8) .
the most important risk factors reported for home injury include living in unsafe homes , low socioeconomic status , and mothers low knowledge and inappropriate attitudes ( 9 - 14 ) .
a study performed in 14 european countries has shown that the most important obstacle for adopting preventive measures is the inability of mothers to take continuous care of their children , followed by poor knowledge about factors involved in injuries ( 21 ) .
several studies have evaluated the role of parents preventive measures in decreasing the incidence of home injuries ( 15 - 17 ) .
using pm can decrease the incidence of home injuries in some cases , but not in others .
for example , the results of a review study showed that application of pm , reduces the incidence of poisoning in children to a great degree ( 18 ) .
however , the results of two other studies showed that , these measures have varying effects or no effect on reducing the incidence rate of falls and burns in children ( 19 , 20 ) .
many researches have placed great emphasis on motivations and obstacles faced by mothers to adopt pm . however , the exact role of the majority of these factors is still unknown .
although valuable efforts have been made to recognize such factors , the results have been different and even contradictory due to cultural , social , regional and even methodological differences ( 17 , 18 , 20 ) .
based on the above - mentioned , the present study aims to evaluate the contributing factors of unintentional home injury prevention in preschool victims presented to the emergency department .
study design and setting
this prospective cross sectional study was carried out from march 2011 to february 2012 in imam hossein and shohadaie - hafte - tir hospitals , tehran , iran .
the subjects consisted of the mothers of all the preschool children , who had sustained unintentional home injuries , and had been admitted to the emergency departments of the studied hospitals . mothers not interested in taking part in the study were excluded .
the protocol of the study was approved by ethics committee of shahid beheshti university of medical sciences .
data collection and setting :
data were collected using a questionnaire , which consisted of the following sections : a : demographic data , socioeconomic status of mothers , history of unintentional injuries during the previous three weeks , and the condition of the current injury ( type , cause , and site of injury ) .
b : 7 questions on the knowledge of mothers about home injuries of preschool children ( scores ranged from 0 to 7 ) .
c : 12 questions on mothers attitude ( scores ranged from 0 to 12 ) .
d : 15 questions on adoption of preventive strategies ( a score of 2 was given to
always , 1 to sometimes and 0 to never , scores ranged from 0 to 30 ) .
the median of scores gained by the study population was used as a classification cut - point , which is a customary technique for classification of groups ( 21 - 23 ) .
finally , mothers were divided into two groups ( poor and good ) based on their application of pm status .
the questionnaire was designed under the supervision of two emergency medicine specialists and one epidemiologist .
it was given to 20 mothers in a pilot study , and its reliability was confirmed using cronbach s alpha coefficient ( = 0.78 ) . if the participants could not read or write , the questionnaire was completed by the aid of an oral interview .
data were collected after each child received standard treatment so that the mother s anxiety about her child s health would not affect data collection .
the population size was determined , based on previous studies ( 24 ) , where p = 0.6 , = 0.05 , and d = 0.07 .
a population size of at least 188 subjects was calculated but 230 mothers were evaluated , which increased the study power to 96% .
stata 11.0 statistical software program was used for data analysis . after descriptive analysis of data ,
the relationship between studied variables and application of pm was evaluated by chi - squared and fisher s exact tests .
subsequently , the significant factors , determined by chi - squared test , were entered into the backward multivariate logistic regression model .
then the odds ratio ( or ) was determined at a 95% confidence interval ( ci ) .
the mean and the standard deviation ( sd ) of their age was 29.4 5.2 years .
the most common home injury was falls with 145 ( 63.04% ) cases and the most common locations of accidents was living rooms , with 85 ( 36.96% ) cases .
the status of pm application was poor in 101 ( 43.91% ) cases and good in 129 ( 56.09% ) .
57 ( 24.78% ) mothers had poor knowledge and 134 ( 58.26% ) had inappropriate attitudes towards home injury pm .
table 1 presents the relationship of the mother s characteristic and application of preventive measure status . in addition , the relationship of injury characteristics and application of preventive measure status is summarized in table 2 .
multivariate logistic regression analysis showed that daily absence of mother 8 hours ( or = 9.2 ; 95% ci : 2.235.46 ; p = 0.002 ) , having at least 3 children ( or = 7.2 ; 95% ci : 1.132.9 ; p = 0.04 ) and a history of a home injury during the previous 3 weeks ( or = 8.3 ; 95% ci : 2.141.3 ; p = 0.001 ) were predictive factors of poor preventive measure application status by mothers .
however , high knowledge level ( or = 0.05 ; 95% ci : 0.0020.32 ; p = 0.002 ) and appropriate attitudes ( or = 0.12 ; 95% ci : 0.030.51 ; p = 0.01 ) resulted in adoption of proper pm by mothers .
the results of the present study showed that only 56.09% of mothers whose children had sustained home injuries had applied proper pm .
mothers characteristics including poor knowledge , inappropriate attitudes , absence from the house 8 hours , having more than 3 children , and history of child home injuries during the previous 3 weeks were independent predictive factors of poor preventive measure application status .
the results of 14 european studies showed that the majority of mothers believed that the most important obstacle for adopting pm was lack of constant care .
lack of knowledge about factors involved in injuries was the second most common cause in this regard ( 24 ) .
relationship of the mothers characteristics with application of preventive measures status the relationship of injury characteristics and application of preventive measure status apart from knowledge , mothers appropriate attitudes have an important role in adoption of pm . in the present study ,
therefore , in addition to mothers knowledge , appropriate attitudes also influence implementation of pm .
the results of a study by vladutiu et al . showed that parents appropriate attitudes have a direct relationship with improvement in preventive behaviors ( 25 ) .
several studies have placed great emphasis on the role of educational status in improving mothers attitudes and performance in relation to the adoption of pm against home injuries .
for example , eldosoky et al . showed that educated mothers ( university or college education ) and mothers with high socioeconomic status have better preventive behaviors ( 26 ) .
in addition , tomruk et al . showed that higher education improves mothers knowledge and attitudes regarding prevention of home injuries ( 27 ) .
the major limitation of such studies is ignoring the co - linearity of mothers knowledge and her educational status .
therefore , educational status is a cofactor for knowledge level . in three studies by eldosoky et al .
, this weakness is evident because in these studies mothers knowledge was not included as a factor in multivariate regression analysis . to confirm this hypothesis , vladutiu et al . demonstrated that when the relationship between preventive behaviors and mothers characteristics ( such as attitudes and knowledge ) are evaluated , age , educational status , income or the condition of the house ( rented or owned ) have no effect on preventive behaviors ( 25 ) .
the number of children in the family significantly influences mothers preventive behaviors . a study by gielen et al
. showed that mothers with at least 3 children exhibit poorer preventive behaviors ( 28 ) .
this decrease in the adoption of pm is attributed to the short duration of time allocated by mothers to their children s care . a mother with three children dedicates less time to education , upbringing , and even care of each child , compared to a mother with one child or two children . finally , it is suggested that programs be prepared in order to improve and increase mothers pm .
after implementation of such measures , a decrease in child home injuries can be expected .
informing mothers of the consequences of serious accidents such as falls , burns , drowning , and poisoning might encourage parents to adopt measures that are more effective .
first , it was a cross sectional study , so no inference can be made about causal relationships between variables .
second , the results are based on self - reported data ; respondents may have over - reported their injury prevention measures due to social desirability bias .
the results of the present study showed that only 56.09% of mothers whose children had sustained home injuries had applied proper pm .
mothers characteristics including poor knowledge , inappropriate attitudes , absence from the house 8 hours , having more than 3 children , and history of child home injuries during the previous 3 weeks were independent predictive factors of poor preventive measure application status .
this project was supported by a research grant from safety promotion and injury prevention research center .
all authors passed four criteria for authorship contribution based on recommendations of the international committee of medical journal editors . | introduction : different factors such as parents knowledge and attitudes regarding preventive measures ( pm ) have a great role in reducing children unintentional home injuries .
the present study aims to evaluate the contributing factors of unintentional home injury prevention in preschool victims presented to the emergency department .
methods : the subjects consisted of all the mothers of preschool children who were presented to the emergency department of imam hossein and shohadaie - hafte - tir hospitals , with unintentional home injuries , from march 2011 to february 2012 .
the participants were divided into two groups according to implementation of preventive measures status .
the significant confounding factors of pm application was determined by chi - squared test and entered into the backward multivariate logistic regression model .
results:230 mothers with the mean age of 29.4 5.2 years were evaluated .
225 ( 97.83% ) of them were still married , 74 ( 32.17% ) had high school education or higher , 122 ( 53.04% ) were homemakers , and 31 ( 13.49% ) worked outside the home for at least 8 hours daily .
high level of knowledge ( or = 0.05 ; 95% ci : 0.0020.32 ; p = 0.002 ) , appropriate attitude ( or = 0.12 ; 95% ci : 0.030.51 ; p = 0.01 ) , having at least three children ( or = 7.2 ; 95% ci : 1.132.9 ; p = 0.04 ) , daily absence of mother for at least 8 hours ( or = 9.2 ; 95% ci : 2.235.46 ; p = 0.002 ) , and a history of home injury during the previous 3 weeks ( or = 8.3 ; 95% ci : 2.141.3 ; p = 0.001 ) were independent factors which influenced application of preventive measures . conclusion : increasing mothers knowledge level and improving their attitudes were facilitating factors and mothers absence from the house for more than 8 hours a day and having at least 3 children were obstacles to application of preventive measures .
in addition , a history of same injury during the previous 3 weeks increased the risk of repeated event . | Introduction:
Methods:
Results:
Discussion:
Conclusion:
Conflict of interest:
Funding support:
Authors contributions: | [
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while violence remains the third most common cause of spinal cord injury ( sci ) in the united states , only 1% of scis occurs from stab wounds.1 non - missile injuries , namely stabbings , are more common in developing countries where access to firearms is limited.2,3 in a large series from south africa , 25% of scis were reported to result from penetrating injuries not due to firearms , of which 84.2% were caused by stabbing.4 commonly used weapons include knives , ice picks , screwdrivers , and bicycle spokes . to our knowledge ,
no case of sci caused by a fall onto a nail has been reported in the english - language literature . here
we present a patient who developed complete sci after his thoracic spinal cord was transected by a nail .
the causative mechanism , diagnostic tools , and review of the literature on non - missile sci are discussed .
a detailed history and physical examination were performed along with a careful review of the patient 's medical records .
plain x - rays and magnetic resonance imaging ( mri ) were performed to help determine the etiology of the patient 's injury .
a literature review was also conducted to assess the incidence of similar mechanism of sci .
a 6-year - old boy was initially evaluated in the emergency department in mulago hospital , kampala , uganda , after he fell from a tree . at the scene of the fall
it was then discovered that he had landed on a nail , which was upright in a piece of wood .
the nail penetrated his body at about the t8 vertebra and was found buried in the soft tissue ; it was removed shortly after .
the patient was then admitted to the spine ward at mulago hospital where he was examined 12 days later by a team of visiting surgeons . on examination
the patient had 0/5 motor strength in the lower extremities , symmetrical areflexia , and hypoesthesia below the t8 level .
clinically , his american spinal injury association ( asia ) score was a with a t8 level .
after the initial neurological assessment , the team believed further imaging to evaluate the cord integrity and rule out a surgically correctable cause of paralysis would be in order .
an mri scan of the thoracic spine revealed a complete transection of the spinal cord at the t8 vertebra ( fig .
3 ) . there was no evidence of infection , tumor , or epidural abnormalities that could have otherwise accounted for the patient 's symptoms .
the mri confirmed the diagnosis that the boy suffered a spinal cord transection from the penetrating injury , namely the nail .
a detailed discussion was conducted with the patient and his family concerning the prognosis and the fact that it would be unlikely for him to independently walk again .
also discussed was the role of nonoperative management , namely aggressive rehabilitation , bowel , and bladder care . ap x - rays of the thoracic spine .
t8 vertebra ( arrow ) . digital photograph of the patient back highlighting the healed nail puncture wound .
t8 vertebra ( arrow ) . a t2 mri scan of the thoracic spine .
the white arrow indicates the nail tract and the resultant spinal cord ( black arrow ) transection .
the mechanism of sci differs between developed and developing countries . in the united states scis are typically due to motor vehicle injuries ( 42.1% ) , falls ( 26.7% ) , violence ( 15.1% ) , sporting injuries ( 7.6% ) , and unknown events ( 8.6%).1 the latter is more common in the pediatric population and when this occurs it is called sci without radiographic abnormality ( sciwora).5 in addition , scis in juvenile patients are most often a result of motor vehicle injuries and falls from heights.6 in developing countries , including south africa , where there is a lack of access to firearms , the primary cause of sci was a penetrating injury from a sharp object of which 84.2% resulted from stabbing .
most injuries caused hemi - section of the spinal cord with incomplete neurological deficits.4 there are numerous case reports of sci caused by nonviolent penetrating injuries .
a recent case described sci as a result of penetration from an epidural needle.7 another case report documented sci from a glass fragment.8 most pencil injuries have been reported to occur in or around the orbital region,9,10 with the exception of one report of sci from pencil impalement.11 although craniofacial and both upper and lower extremities injury caused by nail impalement have been reported,12 to the best of our knowledge , no case of sci , especially complete transection has been described in the english - language literature . in this case
the sci was believed to occur in the following manner : the nail transected the spinal cord via a path through skin , thoracolumbar fascia , either lateral to the spinal process or directly through the t8/t9 interspinous ligaments ; then through the lamina or interlaminar space , and finally through the spinal cord .
it is also postulated that the nail interrupted the posterior blood supply to the cord as well as damaging the artery of adamkiewicz , which generally enters the spinal cord through t8 and t12 levels to supply the anterior part of the spinal cord.13 in cases with suspected sci due to impalement , plain x - rays are recommended to detect the level of lesion and penetration into the spinal canal .
an mri is recommended for further evaluation of the spinal cord and surrounding soft tissue and the relation between the object and the spinal cord .
the surprising aspect of this case was the absence of any other morbidity , such as infection or cerebrospinal fluid leak . in summary , we report a rare case of a complete sci caused by cord transaction by a nail . to our knowledge
the editors have selected this case to continue the discussion on spinal cord injury ( sci ) in emerging countries with limited medical infrastructure .
we have received diverse opinions on our question of how much and what type of spine reconstructive surgery to do in developing countries as delivered by short - term visiting surgeons .
so many opinions , in fact , that we have collected these and plan to create a special focus issue on this topic in the future .
there is little doubt about the acute care needs of this patient , both the commentator and the presenting authors agree .
the much bigger questions arise regarding the long - term prospects of this t8 asia a paraplegic boy .
what form of rehabilitation support is the patient receiving , what bowel / bladder care program
will he be a candidate for fusion surgery when he develops the expected neuromuscular paralytic curve ?
what does his decubitus prophylaxis look like ? what is he doing scholastically and what is his eventual life expectancy ?
in developed countries , patients with mid - thoracic sci can achieve near normal life expectancy at reasonable annual healthcare costs .
societal protections , such as afforded by the americans with disabilities act , are priceless for the life quality of many patients , especially those with sci .
this again raises the question of the responsibility of visiting surgeons . aside from bringing surgical expertise to the developing countries are they engaged in creating a rehabilitation medicine community or knowledge transfer , for instance , through the use of internet communications ?
should this be part of a visiting spine surgeon 's portfolio , or should this be left to others to care for ?
chief of spine surgery seattle children 's hospital the authors present a case in which a 6-year - old child in uganda fell from a tree and suffered a complete spinal cord injury ( sci ) .
a nail was found embedded in the soft tissue directly over the t8 midline and had been removed before presentation .
the mri showed complete cord transection at the t8 level , which was believed to have occurred from penetrating injury at this level from the nail .
the mri is consistent with the proposed mechanism , and not with a transection due to sciwora , fracture , or dislocation from the fall .
the combination of lack of soft- tissue coverage in this child , and larger interlaminar space in children may have contributed to this occurrence . in developed countries ,
pediatric scis are most commonly caused by motor vehicle injuries , falls , sports injuries , or penetrating trauma from firearms . in developing countries where firearms are less readily available , penetrating injuries from stabbings with sharp instruments are more common causes , and they most often result in incomplete sci syndromes , such as brown - sequard.1 neither the authors nor this reviewer could find a report of sci caused by nail penetration in the english - language literature .
although many other implements have been reported including acupuncture needles , broken glass fragments , chopsticks , migrated k - wires from clavicle fracture fixation , stingray spine , and a senegalese tiger tooth .
local wound debridement and prophylactic antibiotics for 24 hours are appropriate.2 indications for surgery from a non - missile penetrating injury include evidence of progressive neurological deficit , spinal cord compression from hematoma or bony fragment , or persistent spinal fluid leak .
late instability is rare , and treatment should focus as it did on appropriate rehabilitation . | study design : case report.objective : to describe a case of spinal cord transection in a 6-year - old child.background information : non - missile injury of the spinal cord is not common and its incidence varies according to the country . in addition , to our knowledge , there are no published reports of spinal cord injury ( sci ) from a penetrating nail . here , we report the case of a child who developed complete sci because of cord transection by a nail.methods : a detailed history and physical examination were performed along with careful review of the patient 's medical records .
in addition , a review of the literature was conducted to assess the incidence and treatment of similar injuries.case description : a 6-year - old boy was admitted to the hospital after falling from a tree and landing on a nail .
his physical examination revealed an emaciated child with multiple decubitus ulcers , lying on his side in bed .
visible was a well - healed posterior puncture wound at the t8 vertebral level .
on neurological examination , the patient had 0/5 muscle strength in his lower extremities , symmetrical areflexia , and hypoesthesia below the t8 level .
plain x - ray of the thoracolumbar spine was normal .
magnetic resonance imaging revealed a transected spinal cord at the t8 vertebra , consistent with his nail puncture wound.discussion : this report describes an unusual case of a complete sci in a pediatric patient caused by penetrating trauma from a nail .
to our knowledge , this is the first case to report on complete sci due to trauma from a nail . | Introduction
Methods
Report of a Case
Discussion
Editorial Perspective
Commentary | [
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