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acute exacerbations of copd are characterized by a change in cough , sputum production , and respiratory symptoms from baseline that cause the patient to seek medical attention and involve increasing the dose and/or frequency of existing bronchodilator therapy .
systemic corticosteroids are also recommended in patients with more advanced copd that may require hospitalization .
exacerbations may be mild , necessitating only outpatient therapy such as antibiotics and/or systemic steroids but often may be severe enough to require hospitalization and admission to the intensive care unit .
therefore , prevention of exacerbations is one of the most important goals of chronic obstructive pulmonary disease ( copd ) management ( global initiative for chronic obstructive lung disease 2005 ) because of the impact on patients daily activities and health - related quality of life ( hrqol ) , with these effects lasting for several weeks or months ( haughney and gruffydd - jones 2004 ) .
frequent exacerbations also lead to a poorer recovery in terms of improvement in health status ( haughney and gruffydd - jones 2004 ) .
furthermore , the frequency of acute exacerbation has a significant impact on the accelerated decline of lung function ( donaldson et al 2002 ) and also on healthcare costs ( haughney and gruffydd - jones 2004 ) .
consequently , strategies for preventing copd exacerbations may have an important effect on the natural course , cost of management , and mortality in copd ( martinez and anzueto 2005 ) . in recent years
, several large - scale clinical trials in copd have analyzed the exacerbation - preventing aspects of different treatments ( niewoehner 2004 ; solr 2005 ) .
these include inhaled bronchodilators , inhaled corticosteroids ( icss ) , and a limited number of antimicrobial strategies .
however , most antimicrobial strategies have been used therapeutically in the form of antibiotic treatment during an established exacerbation , apart from vaccinations against influenza and pneumococci , which can protect from these infections which are particularly dangerous for copd patients ( cazzola et al 2005 ) .
long - acting 2-agonists ( labas ) have both bronchodilator and non - bronchodilator properties , whereas icss are potent anti - inflammatory agents ( cazzola and dahl 2004 ) .
it is , therefore , obvious that labas and icss treat different aspects of copd ( cazzola and dahl 2004 ) .
labas are central in the symptomatic control of copd ( american thoracic society / european respiratory society 2005 ) , whereas conflicting results have been reported with icss ( barnes 2000 ; calverley 2000 ) .
this may reflect the fact that the inflammation in copd is poorly suppressed by corticosteroids , with small reduction in inflammatory cells , cytokines , or proteases in induced sputum even with oral corticosteroids ( barnes 2004 ) , although there are some subgroups of patients ( eg , those with eosinophilia ) who respond very well ( chanez et al 1997 ) .
nonetheless , findings from several clinical studies have shown that treatment with icss improve expiratory airflow and reduce symptoms and the rate of exacerbations associated with copd ( alsaeedi et al 2002 ) , and , moreover , reduce all - cause mortality in copd ( sin et al 2005 ) .
icss in relatively high doses ( eg , budesonide 800 g / day or fluticasone propionate 1 mg / day ) reduce exacerbations by 20%30% and improve the health status of copd patients by a similar amount compared with placebo ( man and sin 2005 ) .
in particular , a meta - analysis of six trials , which evaluated the long - term effects ( 6 months ) of icss in stable copd and provided information about total exacerbations , demonstrated that icss reduce exacerbation rates in copd by nearly one third relative to placebo ( relative risk [ rr ] , 0.70 ; 95% ci , 0.580.84 ) ( alsaeedi et al 2002 ) . in the isolde ( inhaled steroid in obstructive lung disease in europe ) study ,
the major benefit of therapy was seen in those whose lung function was less than 50% of predicted ; however , the number of patients having at least one exacerbation per year was reduced with icss irrespective of baseline lung function ( jones et al 2003 ) .
a convincing demonstration of the effectiveness of these agents in copd patients has come from the cope study ( an investigation of copd in the department of pulmonology , enschede , the netherlands ) ( van der valk et al 2002 ) .
this study showed that the discontinuation of therapy with icss was associated with a more rapid onset and a higher risk of recurrence of exacerbations , and with a significant deterioration in aspects of hrqol , in the majority of patients .
however , 40% of subjects in the cope study experienced no untoward effect from the withdrawal of icss .
this finding indicates that there is an urgent need to identify which subgroups of copd patients respond well to prolonged icss therapy . in any case , a recent article that has reviewed the diverse approaches to data analysis used in the randomized trials of icss in the treatment of copd and their meta - analysis , has concluded that the reports that icss reduce copd exacerbation rates are the result of improper statistical analysis techniques ( suissa 2006 ) .
the only two studies that used the correct statistical approach found insignificant effects with these drugs .
it is not a surprise , therefore , that the evaluation of a cohort of newly treated copd patients formed from the administrative databases of saskatchewan health documented that icss do not seem to be beneficial in preventing the risk of a first exacerbation of copd ( de melo et al 2004 ) .
interestingly , a recent paper has documented that immortal time bias can not account for the risk reduction associated with icss exposure in observational studies ( kiri et al 2005 ) .
this finding is strengthened by the observed relationship between increased regularity of icss prescriptions and reductions in event rates .
although labas have been shown to reduce exacerbation rates of copd , the magnitude of the effect appears modest at best .
published trials reveal that salmeterol is the only laba with a significant effect on the rate of exacerbations . in a 1-year study comparing salmeterol with placebo ,
salmeterol significantly reduced the mean number of exacerbations per patient by 20% and the mean number of exacerbations requiring oral corticosteroids per patient by 29% ( calverley et al 2003a ) . recently
, it has been documented that the addition of salmeterol to existing treatment in patients with a history of copd exacerbations and poor reversibility of airflow obstruction reduces exacerbations in patients who comply with treatment ( stockley et al 2006 ) .
on the contrary , formoterol , in twice daily doses , failed to show such an effect in two other trials ( calverley et al 2003b ; szafranski et al 2003 ) , although a subsequent study has documented that it can influence exacerbation surrogates , for example bad days
salmeterol has been shown in several model systems to reduce inflammatory cell activation , to reduce formation of edema and to enhance edema clearance , and to mitigate epithelial damage induced by bacteria ( rennard 2004 ) .
whether these effects have any clinical importance remains to be determined , but they may account for its ability to reduce frequency of exacerbations of copd .
formoterol may have similar non - bronchodilator effects ; however , studies are needed to document these effects .
combining two therapies that possess different modes of action could be expected to have a greater benefit in the management of copd .
there is an exciting possibility that the potential benefit in combining icss and labas might be due to a synergistic interaction .
however , the basic molecular mechanism of such an interaction has still to be fully identified .
recent in vitro and in vivo evidence suggest a mechanistic interaction at the molecular level between icss and labas .
corticosteroids have been shown to up - regulate the 2-adrenoceptor in the human airways , which in turn may provide more receptors for 2-agonists to activate ( mak et al 1995 ; baraniuk et al 1997 ) . at the same time , labas may potentiate the molecular mechanism of corticosteroid actions by increasing the nuclear translocation of glucocorticoid receptors ( grs ) and thus causing an additive or sometimes synergistic suppression of inflammatory mediator release ( eickelberg et al 1999 ; korn et al 2001 ; pang and knox 2000 , 2001 ) . similar interactions between icss and labas in vivo are a likely explanation for the effects seen in the study of barnes and coworkers ( 2006 ) documenting that the combination of inhaled salmeterol and fluticasone propionate significantly reduced the absolute numbers of biopsy ( cd45 ) leukocytes , cd8 cells , and cd4 cells together with decreases in cells expressing genes for the proinflammatory mediators ifn- and tnf-. in the complementary airway compartment sampled by induced sputum , combination treatment significantly reduced sputum differential neutrophils and total eosinophils . furthermore , in vitro studies suggest that the addition of a laba to an ics may counter some of the potential negative effects of the corticosteroid ( tse et al 2003 ) or alternatively , some of those elicited by laba ( seeto et al 2003 ) .
in addition to the complementary interaction of labas and icss at the molecular level , the delivery of these medications together in a single device may also help simplify treatment regimens and improve patient adherence ( cazzola and dahl 2004 ) .
it is widely recognized that adherence to treatment of chronic obstructive airways diseases declines as the regime becomes more complicated , either by increasing the number of medications and/or the number of daily doses ( coutts et al 1992 ; chapman et al 2000 ) . as a result , improved compliance would be expected to occur through the use of a single combination inhaler simply because of the reduction in the number of medications and actuations required with such a regime . in particular
, it would be expected that the use of combination therapy should improve compliance with ics therapy as its use is linked with laba therapy , which patients are more likely to take because of the greater symptomatic benefit . because of the above effects , it is not unexpected that long - term use of icss with labas may be associated with a reduction in copd exacerbations ( cazzola and dahl 2004 ) .
however , the capacity of both icss and labas to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration - dependent manner without altering the bacterial tropism for mucosa , and to preserve ciliated cells , is important in this context ( dowling et al 1999 ) .
icss and labas , when administered together at low concentrations , exhibited a synergistic effect with respect to the preservation of ciliated cells , showing a trend toward reduced damage and a significant preservation of the number of ciliated cells compared with either agent alone at the same concentrations .
this result may have clinical significance as it is thought that ciliated cells are the most sensitive to damage by bacterial infection ( tsang et al 1994 ) .
it is well - known that airway colonization and chronic infection contribute to progressive pulmonary damage in copd patients via the action of proinflammatory substances in what is known as the vicious circle theory ( wilson 1991 ) .
recently , the synergistic effects of salmeterol and fluticasone in human rhinovirus - induced proinflammatory cytokine production have also been documented ( edwards et al 2006 ) .
rhinoviruses are implicated in many acute exacerbations of copd , perhaps by inducing proinflammatory cytokines ( seemungal et al 2001 ) .
combining two therapies that possess different modes of action could be expected to have a greater benefit in the management of copd .
there is an exciting possibility that the potential benefit in combining icss and labas might be due to a synergistic interaction .
however , the basic molecular mechanism of such an interaction has still to be fully identified .
recent in vitro and in vivo evidence suggest a mechanistic interaction at the molecular level between icss and labas .
corticosteroids have been shown to up - regulate the 2-adrenoceptor in the human airways , which in turn may provide more receptors for 2-agonists to activate ( mak et al 1995 ; baraniuk et al 1997 ) . at the same time , labas may potentiate the molecular mechanism of corticosteroid actions by increasing the nuclear translocation of glucocorticoid receptors ( grs ) and thus causing an additive or sometimes synergistic suppression of inflammatory mediator release ( eickelberg et al 1999 ; korn et al 2001 ; pang and knox 2000 , 2001 ) . similar interactions between icss and labas in vivo are a likely explanation for the effects seen in the study of barnes and coworkers ( 2006 ) documenting that the combination of inhaled salmeterol and fluticasone propionate significantly reduced the absolute numbers of biopsy ( cd45 ) leukocytes , cd8 cells , and cd4 cells together with decreases in cells expressing genes for the proinflammatory mediators ifn- and tnf-. in the complementary airway compartment sampled by induced sputum , combination treatment significantly reduced sputum differential neutrophils and total eosinophils . furthermore , in vitro studies suggest that the addition of a laba to an ics may counter some of the potential negative effects of the corticosteroid ( tse et al 2003 ) or alternatively , some of those elicited by laba ( seeto et al 2003 ) .
in addition to the complementary interaction of labas and icss at the molecular level , the delivery of these medications together in a single device may also help simplify treatment regimens and improve patient adherence ( cazzola and dahl 2004 ) .
it is widely recognized that adherence to treatment of chronic obstructive airways diseases declines as the regime becomes more complicated , either by increasing the number of medications and/or the number of daily doses ( coutts et al 1992 ; chapman et al 2000 ) . as a result , improved compliance would be expected to occur through the use of a single combination inhaler simply because of the reduction in the number of medications and actuations required with such a regime . in particular
, it would be expected that the use of combination therapy should improve compliance with ics therapy as its use is linked with laba therapy , which patients are more likely to take because of the greater symptomatic benefit .
because of the above effects , it is not unexpected that long - term use of icss with labas may be associated with a reduction in copd exacerbations ( cazzola and dahl 2004 ) .
however , the capacity of both icss and labas to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration - dependent manner without altering the bacterial tropism for mucosa , and to preserve ciliated cells , is important in this context ( dowling et al 1999 ) .
icss and labas , when administered together at low concentrations , exhibited a synergistic effect with respect to the preservation of ciliated cells , showing a trend toward reduced damage and a significant preservation of the number of ciliated cells compared with either agent alone at the same concentrations .
this result may have clinical significance as it is thought that ciliated cells are the most sensitive to damage by bacterial infection ( tsang et al 1994 ) .
it is well - known that airway colonization and chronic infection contribute to progressive pulmonary damage in copd patients via the action of proinflammatory substances in what is known as the vicious circle theory ( wilson 1991 ) .
recently , the synergistic effects of salmeterol and fluticasone in human rhinovirus - induced proinflammatory cytokine production have also been documented ( edwards et al 2006 ) .
rhinoviruses are implicated in many acute exacerbations of copd , perhaps by inducing proinflammatory cytokines ( seemungal et al 2001 ) .
the efficacy of combination therapy with icss and labas delivered via a single inhaler to copd patients has repeatedly been documented ( table 1 ) . in particular , the impact on acute exacerbations of long - term treatments with combined therapy is shown in figures 1 and 2 , and table 2 .
it is very important to also mention that the definition of exacerbation and the patient population enrolled in these studies are not uniform ( table 3 ) , and these facts have to be taken in consideration when analyzing their results . in a multicenter , randomized , placebo - controlled study , hanania et al ( 2003 ) compared the efficacy and safety of fluticasone propionate ( 250 g ) and salmeterol ( 50 g ) , when administered twice daily together in a single device for 6 months , with that of placebo and the individual agents alone in patients with copd .
this study was unable to observe significant differences among treatment groups in the number of exacerbations or the time to first exacerbation .
however , this study was of short duration and was designed and powered to evaluate the treatment effect on fev1 , which was the primary measure of efficacy , rather than to evaluate the rates of exacerbations . in a study with a similar design but evaluating the higher dose formulation of this combination therapy , fluticasone propionate ( 500 g ) with salmeterol ( 50 g ) twice daily given for 6 months ( mahler et al 2002 ) , there were no statistically significant differences between treatment groups in time to exacerbation .
this study also demonstrated no difference in the number of participants who exacerbated once ( placebo : 8.8% ; salmeterol : 5.6% ; fluticasone : 10.1% ; fluticase / salmeterol combination [ fsc ] : 8.5% ) , but no p values were presented .
also this study was of short duration and was designed and powered to evaluate the treatment effect on fev1 , which was the primary measure of efficacy , rather than to evaluate the rates of exacerbations .
the tristan study ( calverley et al 2003a ) , a randomized controlled trial over 1 year of combination treatment with salmeterol ( 50 g ) and fluticasone ( 500 g ) administered together in a single device twice daily versus each of the components alone and versus placebo , enrolled patients with a baseline fev1 before bronchodilation that was 25%70% of that predicted . in this study , the rate of exacerbations requiring medical intervention , defined as a worsening of copd symptoms that required treatment with antibiotics or oral corticosteroids , or both , fell by 25% in the combination group and by 20% and 19% in the salmeterol and fluticasone groups , respectively , compared with placebo .
in particular , there was a significant difference in the mean exacerbation rate per participant per year in favor of the combination therapy when compared with placebo ( fsc : 0.97 vs placebo : 1.30 , p<0.0001 ) , but , interestingly , differences among the three active treatment arms were small and not statistically significant .
the treatment effect was more pronounced in patients with severe disease ( ie , a baseline fev1 < 50% of predicted ) , who showed a 30% reduction with combination therapy compared with placebo , compared with a 10% reduction in patients who had a baseline fev1 greater than 50% of predicted .
however , this beneficial effect was also seen for exacerbations treated with oral corticosteroids , which have conventionally been thought to be more severe episodes . the combination therapy was associated with an approximate 39% reduction in the number of this type of exacerbations compared with placebo ( 0.46 vs 0.76 exacerbations per year , p<0.0001 ) but , again , the differences between fsc and salmeterol or fluticasone were not significant .
it is worth mentioning that the tristan was longer , but still based on fev1 .
hence , the ability to observe exacerbation differences may have been helped by study duration . in a study using a design similar to that of the tristan study but including patients with an fev1 below 50% predicted , szafranski et al ( 2003 ) compared the effects of two inhalations twice daily of either budesonide / formoterol combination ( bfc ) 160/4.5 g ( delivered dose ) in a single inhaler , budesonide 200 g ( metered dose ) , formoterol 4.5 g , or placebo for 12 months . data from this study
demonstrate a significant reduction in the number of severe exacerbations by 24% in the bfc group vs placebo , 23% vs formoterol , and 11% vs budesonide .
this reflects a mean reduction in the mean annual exacerbation rates of 0.42 ( 95% ci 0.140.70 ) , 1.841.42 exacerbations per year when combination therapy was used . compared with placebo ,
both bfc and budesonide significantly reduced the number of oral steroid courses used in association with exacerbations ( 31% and 29% , respectively , compared with 3% for formoterol vs placebo ) .
in addition , bfc significantly reduced the number of oral steroid courses compared with formoterol ( 28% ) .
mild exacerbations were also significantly reduced on bfc when compared with placebo ( 62% ) and budesonide ( 35% ) , but not with formoterol ( 15% ) . in another study investigating bfc ,
calverley et al ( 2003b ) studied patients who initially received formoterol alone ( 9 g delivered dose twice daily ) and a short course of oral prednisolone ( 30 mg once daily ) for 2 weeks before randomization .
the patients were subsequently randomized to twice daily inhaled bfc 320/9 g ( delivered dose ) , budesonide 400 g ( metered dose ) , formoterol 9 g , or placebo for 12 months , bfc prolonged time to first exacerbation requiring medical intervention , defined as a need for antibiotics and/or oral corticosteroids and/or hospitalization due to respiratory symptoms , compared with all other treatments .
hazard rate analysis showed that the risk of having an exacerbation while being treated with bfc was reduced by 22.7% , 29.5% , and 28.5% vs budesonide , formoterol , and placebo , respectively .
the exacerbation rate with bfc was reduced compared with placebo ( 23.6% ) and formoterol ( 25.5% ) but not with budesonide alone ( 13.6% ) .
furthermore , bfc prolonged the time to first course of oral corticosteroids after randomization ; risk reductions were 32.7% and 33.8% vs budesonide and formoterol , respectively , and 42.3% vs placebo .
bfc also reduced the rate of oral corticosteroid courses by 28.2% , 30.5% , and 44.7% vs budesonide , formoterol , and placebo , respectively ; budesonide alone reduced the number of oral corticosteroid courses compared with placebo but formoterol did not .
data of three large studies ( calverley et al 2003a , 2003b ; szafranski et al 2003 ) that have examined the effects of a combination of laba and ics on the risk of developing exacerbation in copd have shown that the patients receiving combination therapy were less likely to report an exacerbation than those receiving the laba alone .
nevertheless , a recent cochrane review ( nannini et al 2004 ) concluded that there were conflicting results when the different combination therapies were compared with the single components alone . in particular , the results of the studies showed that bfc and fsc were effective and reduced the frequency of exacerbations compared with dummy medication to a level of three quarters of the previous rates , with one exacerbation prevented every 24 years in the participants in the clinical trials . when the combination treatment was compared with one of the component drugs given as single treatments , bfc was better than its component laba at preventing the frequency of exacerbations , but fsc did not show a significant advantage over laba .
recently , two different reviews ( halpin 2005 ; cazzola 2006 ) , which have evaluated the applicability and clinical relevance of number needed to treat ( nnt ) analysis for determining the effectiveness of combination therapies against copd exacerbations , have calculated that for every 100 patients treated with bfc for 1 year , between 42 and 47 exacerbations requiring medical intervention would be prevented vs laba therapy alone , whereas for every 100 patients treated with fsc for 1 year , only 7 exacerbations would be prevented vs laba alone ( table 2 ) .
it should be noted , however , that the nnt value relating to fsc should be interpreted with caution as there was no significant difference between fsc and salmeterol alone ( p=0.345 for treatment ratios for combination vs salmeterol therapy ) .
this means that the hypothetical 95% ci would include infinity and that an nnt of infinity should be more appropriately applied to the difference between the two treatments , which indicates no true net clinical benefit of fsc over salmeterol alone . in any case ,
in a recent study investigating the effect withdrawal of fluticasone from patients with severe copd ( fev1 < 50% predicted ) using fsc ( cosmic study ) for 3 months , wouters et al ( 2005 ) demonstrated an acute and sustained decrease in fev1 , increase in symptoms , and an increase in mild exacerbations in patients treated with salmeterol alone compared with those who continued treatment with fsc over the one year of the study .
the conflicting findings between the results of the different studies may be accounted for by dissimilar study designs . in particular ,
definitions of exacerbation that have been used in the examined studies have been rather different ( table 3 ) .
for example , in mahler s study ( mahler et al 2002 ) , exacerbation was defined by treatment ( mild = increased use of salbutamol ; moderate = use of either oral antibiotics and/or corticosteroids ; severe = hospitalization ) . in the szafranski s study ( szafranski et al 2003 ) ,
the definition of mild exacerbation was a day with 4 inhalations of reliever medication above the mean run - in use , whereas that of severe exacerbation was a requirement for oral steroids and/or antibiotics and/or hospitalization due to respiratory symptoms . in the tristan study ( calverley et al 2003a )
, exacerbations were defined a priori as a worsening of copd symptoms that required treatment with antibiotics or oral corticosteroids , or both .
pauwels et al ( 2004 ) correctly highlighted that considerable heterogeneity in the aetiology and manifestation of copd exacerbations makes identification and quantification of defining symptoms extremely difficult .
however , with the emergence of a number of drugs designed or developed specifically to treat copd and associated exacerbations , the absence of a uniform definition is a significant issue .
in fact , the choice of definition can significantly affect study outcomes , with varying criteria likely to result in different levels of demonstrated treatment success .
furthermore , emerging data confirm that exacerbation is a term not easily understood by patients , who prefer to use simpler words such as crisis
it is also interesting to stress that there was some difference in the patient populations enrolled in the studies described above .
patients enrolled in the tristan study ( calverley et al 2003a ) had to have suffered from at least one episode of acute copd symptom exacerbation per year in the previous 3 years , and at least one exacerbation in the year immediately before trial entry that required treatment with oral corticosteroids , antibiotics , or both . in the szafranski study ( szafranski et al 2003 ) , patients had to have suffered from at least one severe ( use of oral corticosteroids and/or antibiotics and/or hospitalization due to respiratory symptoms ) copd exacerbation within 212 months before the first clinic visit .
moreover , the mean pre - trial fev1 was 45% predicted in the tristan study ( calverley et al 2003a ) and 36% predicted in the szafranski s study ( szafranski et al 2003 ) . moreover , the mean total exacerbation rate per patient per year under placebo was 1.30 in the tristan study ( calverley et al 2003a ) and 1.9 in the szafranski study ( szafranski et al 2003 ) .
this differences indicate that the szafranski s study ( szafranski et al 2003 ) probably enrolled patients with more severe disease or , at least , with a higher possibility of suffering from acute exacerbation .
in fact , also in the calverley study ( calverley et al 2003b ) , the mean pre - trial fev1 was 36% predicted and the mean total exacerbation rate per patient per year under placebo was 1.80 .
as correctly highlighted by calverley et al ( 2003b ) , the more severe disease in the patients enrolled in bfc studies is the likely explanation of the greater number of episodes that they observed compared with other studies , a difference that increased the power of the study to detect an effect of treatment .
it is also important to highlight that the authors of the three studies did not report the number of exacerbations in the year before the enrolment in the studies .
this is a real lack of information because , as recently documented by donaldson et al ( 2003 ) , annual exacerbation frequency remains constant over time . as rabe ( 2003 ) stated in his editorial comment on the calverley paper ( calverley et al 2003b ) , the data of the combination therapy trials in copd seem to indicate that patients experiencing more severe exacerbations benefit the most from combination therapy , whereas , if the definition of a ( mild ) exacerbation for clinical trials also includes aggravation of symptoms , such as in the paper by szafranski et al ( 2003 ) , the relative effect of a long - acting bronchodilator might be more pronounced .
this clearly highlights the importance of definitions of exacerbations for clinical trials and calls for studies comparing the effect of maximal bronchodilation with , for example , the combination of labas with long - acting anticholinergics ( lamas ) in copd with mild and severe exacerbations as an outcome . in effect
, some studies are documenting the clinical value of combining a laba with a lama in copd ( cazzola et al 2004 ; van noord et al 2005 , 2006 ) , although the information of the impact of such a type of combination on exacerbations is still lacking . borrowing jones opinion ( jones 2004 ) , we believe that there are a number of possible mechanisms to account for the apparent additive effect of inhaled combination therapy with icss and labas in preventing exacerbations and to explain the discrepancies observed between the studies .
it is likely that : ( 1 ) the individual drugs were not at the top of their dose response curve for this outcome ; ( 2 ) they have different , and additive , mechanisms of action , which can also be linked to the specific compound ; or ( 3 ) the different agents were preventing different types of exacerbation .
jones ( 2004 ) has highlighted that an operational definition based upon a worsening of symptoms and the treatment required ( moderate exacerbations are those that can be treated with oral corticosteroids and/or antibiotics , severe exacerbations are those requiring hospital admission ) does not identify the type of exacerbation .
this emphasizes again the importance for the need of a uniform definition of copd exacerbation for clinical trials in order to reach more solid conclusions .
whatever the case may be , it must be emphasized that a treatment regimen with administration of an ics and laba in a single inhaler prolongs the time to a first copd exacerbation , compared with treatment with the single components in patients with an fev1 < 50% predicted ( calverley et al 2003b ) .
intriguingly , this finding has been observed with bfc ( calverley et al 2003b ) , but not with fsc ( calverley et al 2003a ) . the prolonged time to first exacerbation may delay the deterioration of the disease and help maintain health status and patient well - being .
it is an important outcome because it indicates that following aggressive treatment of an acute exacerbation with an oral corticosteroid , therapy with an ics / laba combination may better control the disease than treatment with bronchodilator alone . in particular , as highlighted by calverley ( 2004 ) , combining treatments is certainly something to be considered in patients who have reported exacerbations on a regular basis but have not yet received ics or laba therapy in combination , although there are concerns about the increased risk of side - effects and cost of using laba / ics therapy in copd .
data of three large studies ( calverley et al 2003a , 2003b ; szafranski et al 2003 ) that have examined the effects of a combination of laba and ics on the risk of developing exacerbation in copd have shown that the patients receiving combination therapy were less likely to report an exacerbation than those receiving the laba alone .
nevertheless , a recent cochrane review ( nannini et al 2004 ) concluded that there were conflicting results when the different combination therapies were compared with the single components alone . in particular , the results of the studies showed that bfc and fsc were effective and reduced the frequency of exacerbations compared with dummy medication to a level of three quarters of the previous rates , with one exacerbation prevented every 24 years in the participants in the clinical trials . when the combination treatment was compared with one of the component drugs given as single treatments , bfc was better than its component laba at preventing the frequency of exacerbations , but
recently , two different reviews ( halpin 2005 ; cazzola 2006 ) , which have evaluated the applicability and clinical relevance of number needed to treat ( nnt ) analysis for determining the effectiveness of combination therapies against copd exacerbations , have calculated that for every 100 patients treated with bfc for 1 year , between 42 and 47 exacerbations requiring medical intervention would be prevented vs laba therapy alone , whereas for every 100 patients treated with fsc for 1 year , only 7 exacerbations would be prevented vs laba alone ( table 2 ) .
it should be noted , however , that the nnt value relating to fsc should be interpreted with caution as there was no significant difference between fsc and salmeterol alone ( p=0.345 for treatment ratios for combination vs salmeterol therapy ) .
this means that the hypothetical 95% ci would include infinity and that an nnt of infinity should be more appropriately applied to the difference between the two treatments , which indicates no true net clinical benefit of fsc over salmeterol alone . in any case ,
in a recent study investigating the effect withdrawal of fluticasone from patients with severe copd ( fev1 < 50% predicted ) using fsc ( cosmic study ) for 3 months , wouters et al ( 2005 ) demonstrated an acute and sustained decrease in fev1 , increase in symptoms , and an increase in mild exacerbations in patients treated with salmeterol alone compared with those who continued treatment with fsc over the one year of the study .
the conflicting findings between the results of the different studies may be accounted for by dissimilar study designs .
in particular , definitions of exacerbation that have been used in the examined studies have been rather different ( table 3 ) .
for example , in mahler s study ( mahler et al 2002 ) , exacerbation was defined by treatment ( mild = increased use of salbutamol ; moderate = use of either oral antibiotics and/or corticosteroids ; severe = hospitalization ) . in the szafranski s study ( szafranski et al 2003 ) , the definition of mild exacerbation was a day with 4 inhalations of reliever medication above the mean run - in use , whereas that of severe exacerbation was a requirement for oral steroids and/or antibiotics and/or hospitalization due to respiratory symptoms . in the tristan study ( calverley et al 2003a )
, exacerbations were defined a priori as a worsening of copd symptoms that required treatment with antibiotics or oral corticosteroids , or both .
pauwels et al ( 2004 ) correctly highlighted that considerable heterogeneity in the aetiology and manifestation of copd exacerbations makes identification and quantification of defining symptoms extremely difficult .
however , with the emergence of a number of drugs designed or developed specifically to treat copd and associated exacerbations , the absence of a uniform definition is a significant issue .
in fact , the choice of definition can significantly affect study outcomes , with varying criteria likely to result in different levels of demonstrated treatment success .
furthermore , emerging data confirm that exacerbation is a term not easily understood by patients , who prefer to use simpler words such as crisis
it is also interesting to stress that there was some difference in the patient populations enrolled in the studies described above .
patients enrolled in the tristan study ( calverley et al 2003a ) had to have suffered from at least one episode of acute copd symptom exacerbation per year in the previous 3 years , and at least one exacerbation in the year immediately before trial entry that required treatment with oral corticosteroids , antibiotics , or both . in the szafranski study ( szafranski et al 2003 ) , patients had to have suffered from at least one severe ( use of oral corticosteroids and/or antibiotics and/or hospitalization due to respiratory symptoms ) copd exacerbation within 212 months before the first clinic visit .
moreover , the mean pre - trial fev1 was 45% predicted in the tristan study ( calverley et al 2003a ) and 36% predicted in the szafranski s study ( szafranski et al 2003 ) .
moreover , the mean total exacerbation rate per patient per year under placebo was 1.30 in the tristan study ( calverley et al 2003a ) and 1.9 in the szafranski study ( szafranski et al 2003 ) .
this differences indicate that the szafranski s study ( szafranski et al 2003 ) probably enrolled patients with more severe disease or , at least , with a higher possibility of suffering from acute exacerbation .
in fact , also in the calverley study ( calverley et al 2003b ) , the mean pre - trial fev1 was 36% predicted and the mean total exacerbation rate per patient per year under placebo was 1.80 .
as correctly highlighted by calverley et al ( 2003b ) , the more severe disease in the patients enrolled in bfc studies is the likely explanation of the greater number of episodes that they observed compared with other studies , a difference that increased the power of the study to detect an effect of treatment .
it is also important to highlight that the authors of the three studies did not report the number of exacerbations in the year before the enrolment in the studies .
this is a real lack of information because , as recently documented by donaldson et al ( 2003 ) , annual exacerbation frequency remains constant over time . as rabe ( 2003 ) stated in his editorial comment on the calverley paper ( calverley et al 2003b ) , the data of the combination therapy trials in copd seem to indicate that patients experiencing more severe exacerbations benefit the most from combination therapy , whereas , if the definition of a ( mild ) exacerbation for clinical trials also includes aggravation of symptoms , such as in the paper by szafranski et al ( 2003 ) , the relative effect of a long - acting bronchodilator might be more pronounced .
this clearly highlights the importance of definitions of exacerbations for clinical trials and calls for studies comparing the effect of maximal bronchodilation with , for example , the combination of labas with long - acting anticholinergics ( lamas ) in copd with mild and severe exacerbations as an outcome . in effect
, some studies are documenting the clinical value of combining a laba with a lama in copd ( cazzola et al 2004 ; van noord et al 2005 , 2006 ) , although the information of the impact of such a type of combination on exacerbations is still lacking . borrowing jones opinion ( jones 2004 ) , we believe that there are a number of possible mechanisms to account for the apparent additive effect of inhaled combination therapy with icss and labas in preventing exacerbations and to explain the discrepancies observed between the studies .
it is likely that : ( 1 ) the individual drugs were not at the top of their dose response curve for this outcome ; ( 2 ) they have different , and additive , mechanisms of action , which can also be linked to the specific compound ; or ( 3 ) the different agents were preventing different types of exacerbation .
jones ( 2004 ) has highlighted that an operational definition based upon a worsening of symptoms and the treatment required ( moderate exacerbations are those that can be treated with oral corticosteroids and/or antibiotics , severe exacerbations are those requiring hospital admission ) does not identify the type of exacerbation .
this emphasizes again the importance for the need of a uniform definition of copd exacerbation for clinical trials in order to reach more solid conclusions .
whatever the case may be , it must be emphasized that a treatment regimen with administration of an ics and laba in a single inhaler prolongs the time to a first copd exacerbation , compared with treatment with the single components in patients with an fev1 < 50% predicted ( calverley et al 2003b ) .
intriguingly , this finding has been observed with bfc ( calverley et al 2003b ) , but not with fsc ( calverley et al 2003a ) . the prolonged time to first exacerbation may delay the deterioration of the disease and help maintain health status and patient well - being .
it is an important outcome because it indicates that following aggressive treatment of an acute exacerbation with an oral corticosteroid , therapy with an ics / laba combination may better control the disease than treatment with bronchodilator alone . in particular , as highlighted by calverley ( 2004 ) , combining treatments is certainly something to be considered in patients who have reported exacerbations on a regular basis but have not yet received ics or laba therapy in combination , although there are concerns about the increased risk of side - effects and cost of using laba / ics therapy in copd . | acute exacerbations of copd can complicate the course of the disease in patients with severe airway obstruction .
reduction of exacerbations is an important clinical outcome in evaluating new therapies in copd .
combination therapies with long - acting -agonists and inhaled corticosteroids have now been approved for use .
three 1-year randomized clinical trials , which studied the effect of combining a long - acting 2-agonist with an inhaled corticosteroid in copd , documented that exacerbation frequency was lower with therapy than placebo .
combination therapy had a similar effect to its monocomponents in the trial evaluating salmeterol / fluticasone combination .
however , when patients with more severe copd were studied using a combination of budesonide and formoterol , a clear improvement was seen in the overall exacerbation rates compared with the use of a long - acting 2-agonist alone . | [
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reverse shoulder prosthesis is an excellent surgical option for patients with certain shoulder pathologies , of which rotator cuff arthropathy is one .
one area where we are gaining a greater understanding is that of managing acromial pathology .
recent studies are showing that not all acromial pathology is a contraindication to reverse shoulder arthroplasty ; in both pre- and post - operative patients , small lateral fractures of the acromion can be treated non - operatively or fixed surgically with a tension band technique .
overall , results comparable to that of reverse arthroplasty can be achieved with either of these treatment options .
however , fractures at the base of the acromion or of the scapular spine present a different problem . in these types of fractures , a larger length of deltoid muscle is detached , and therefore defunctioned . in reverse shoulder arthroplasty , in order to achieve a stable shoulder , the deltoid must be tensioned a great deal .
this in turn causes a deforming force and distraction at the fracture site , making for a poor healing potential . also , as the reverse shoulder prosthesis relies on the deltoid muscle to move the arm , if the deltoid is detensioned or improperly tensioned , this will lead to poor functional capacity .
we present a case of treatment of a fracture at the base of the acromion using a 90/90 plating construct that healed in a good position .
a 71-year - old right - handed woman presented with a 2-year history of right shoulder pain and dysfunction , which began abruptly when lifting a heavy load . at the initial evaluation ,
her range of motion was limited , particularly in active abduction as she achieved only 45 degrees in this plane . a cuff arthropathy ( hamada grade 3 )
was diagnosed and the decision was taken to proceed with reverse shoulder arthroplasty . to complete the pre - operative assessment ,
a ct scan was performed which confirmed there was no acromial pathology involved . a reverse shoulder prosthesis and a biceps tenodesis
was carried out ( delta xtend , depuy , warsaw , in , usa ) through a deltopecoral approach [ figure 1 ] .
the patient 's right arm was immobilized in a sling and the range of motion exercises were started 6 weeks after arthroplasty [ figure 1a ] .
five months after surgery , she sustained a blow to the right shoulder but sought medical attention 1 month later , at her scheduled follow - up visit .
radiographs showed a displaced fracture at the base of the acromion [ figure 1 ] .
this showed that both the humeral and glenoid components were well fixed and the only pathology was the fracture .
antero - posterior radiographs showing the patient 's right shoulder immediately after reverse shoulder arthroplasty ( a ) and after fracture , 5 months later ( b ) .
the post - operative image shows no pre - existing acromial pathology she was taken to the operating room and her previous incision was extended into a sabre incision to better expose the acromion .
two small fragment ( 3.5 mm ) locking plates ( synthes , west chester , pa , usa ) were used in a 90/90 configuration ; one was a fragment specific clavicular plate and the other a reconstruction plate .
the fragment specific clavicular plate was applied on the superior edge of the scapular spine in a compression mode .
a second reconsrtuction plate was applied from the posterior acromion to the posterior cortex of the scapular spine , in the infraspinatus fossa .
fixation was solid , but in order to protect the construct , the patient was placed in an abduction brace for 6 weeks .
eighteen months after fracture fixation , the patient was satisfied with the clinical result [ figure 2 ] .
she was capable of 125 degrees of abduction , 160 degrees of forward flexion , 85 degrees of external rotation in adduction , and 60 degrees of internal rotation .
her quickdash score was 29.5 ( compared to 82.5 pre - op ) and constant score was 69 on the affected side compared to 85 on the left side , for a good functional outcome .
a medline search using the key words [ acromion fracture ] , [ scapula fracture ] , [ reverse arthroplasty ] was performed .
we then sought to classify and separate the cases by location ; there were 30 cases of fractures at the base of the acromion , and scapular spine . when our case is added , we have a total of 31 cases .
results are summarized in table 1 . in brief , of the 30 more proximal cases , 21 were treated non - operatively in a sling , 7 were treated with open reduction and open fixation and one with revision of the prosthesis . of those treated non - operatively , and for whom results are published , fourteen had a non - union , four had a malunion and in two cases , it was unclear whether union was achieved . for patients receiving fixation of the fracture , there was one non - union , two repeat fixations , and one patient required removal of the fixation .
the patient who had a revision of the prosthesis had a malunion of the acromion .
results of the literature review . in the fracture location column , the fracture description provided by the authors is presented .
although recent studies have shown that good outcomes may be achieved with non - surgical management of lateral acromial fractures , the same does not hold true for basal acromial fractures .
the likely reason for this is that with fractures at the base of the acromion , a large length of the deltoid is defunctioned and the deltoid muscle is essential to the functioning of the reverse shoulder prosthesis .
previously described techniques , such as tension band fixation achieved poor functional results for fractures at the base of the acromion .
we postulate that this is because the fixation method is insufficient to withstand the forces generated by the deltoid muscle a tension band can neutralize forces parallel to the axis of the band but in the case of the deltoid , force vectors are generated in different directions .
it also allows for compression along the fracture site and resists motion in all directions .
good screw purchase can be achieved by angling the screws either toward the scapular spine or the coracoid .
the locking option enables good fixation and improves cut - out strength in osteopenic or osteoporotic bone .
in addition to the stable fixation achieved with this technique , we further recommend immobilization of the affected shoulder using a sling and an abduction pillow to detension the deltoid , thus at least partially removing the distractive forces at the fracture site . also essential to achieving a good functional result
we thus also recommend a program of range of motion exercises followed by strengthening exercises to maximize functional capabilities . based on results from previous studies ,
fractures of the tip were those of the most lateral or anterior portion of the acromion .
fractures of the body of the acromion are those medial to the tip of the acromion and lateral to the beginning of the scapular base .
the scapular base is the lateral border of the scapular spine , which is smooth and round . in our nomenclature ,
fractures at the scapular base are termed fractures at the base of the acromion as functionally , this zone connects the acromion to the rest of the scapula and this term avoids confusion with any more medially occurring fractures .
coronal ( a ) and axial ( b ) representations of the proposed classification scheme for acromial fractures associated with revere arthroplasty we propose the above mentioned classification system as it provides a nomenclature for acromial fractures that is descriptive and is based on the anatomy and functionality of the scapula . as the results from the review of the literature indicate , the more medial the fracture , the worse the prognosis with non - operative treatment .
thus , this classification system may be used to predict outcomes and determine treatment offered .
it differs from other classification systems ( crosby ) in that it further subclassifies more medial fractures , which are the more ominous fractures . as more research is carried out in this field | fractures of the acromion and scapula are known to occur after reverse shoulder arthroplasty .
we present a case of a fracture at the base of the acromion 5 months after arthroplasty treated successfully with dual plating of the acromion .
eighteen months after fracture fixation , the patient had 160 degrees of active forward flexion , a quickdash of 29.5 , a constant score of 69 and she was satisfied with the result . a concomitant review of the literature produced , in addition to our patient , 56 cases .
these were used to produce a classification system , based on bony and functional anatomy as follows .
tip fractures are of the most lateral or anterior portion of the acromion , those of the body of the acromion are medial to the tip but lateral to the beginning of the scapular base
. fractures at the scapular base are termed fractures of the base of the acromion and those more medial to that , fractures of the scapular spine .
the functional results of these case series demonstrated poorer functional outcomes for more medial fractures .
as future research in this domain increases , clarity on the nomenclature of these fractures will allow for prognostication and treatment based on fracture location as well as comparison between studies . | [
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besides its classical role in calcium and bone homeostasis , vitamin d is considered a potent immunomodulator that can affect the pathogenesis of several autoimmune diseases .
our aim is to evaluate the effect of vitamin d correction to a patient with new onset graves disease ( gd ) with an underlying vitamin d deficiency .
we describe the effect of vitamin d3 on untreated graves disease with vitamin d deficiency .
a healthy saudi woman in her 40s sought consultation with a three - month history of palpitation .
she denied any history of heat intolerance , weight loss , menstrual irregularity or sweating .
. physical examination revealed a mild diffusely enlarged and non - tender thyroid gland with no bruit .
the initial thyroid function test , which was done in an outside hospital , revealed a tsh , 0.01 miu / l ; ft4 , 22.5
vitamin d 25-oh level was done in our hospital and showed a result of 26.0 nmol / l with a tsh , 0.013 miu / l ; ft4 , 16.7
tc-99 m thyroid scintigraphy demonstrated an enlarged thyroid gland with increased radiotracer trapping and heterogeneous distribution .
the patient was given only oral cholecalciferol 4000 iu per day since november 2012 ( prescribed by an outside hospital ) then from may 2013 onwards she was given 50,000 iu per month .
follow - up laboratory exams revealed improved vitamin d levels as well as tsh and ft4 .
vitamin d deficiency may exacerbate the onset and/or development of gd and correction of the deficiency may be able to reverse it .
however , further prospective clinical studies will be needed to define the role of vitamin d treatment in gd .
more recently , vitamin d has been shown to be a modulator in both innate and adaptive immunity.1 there is a well - established link between vitamin d deficiency and various autoimmune diseases , including type 1 diabetes mellitus ( t1 dm ) , systemic lupus erythematosus ( sle ) , rheumatoid arthritis ( ra ) , inflammatory bowel disease ( ibd ) , and multiple sclerosis ( ms ) .
furthermore , it has been found that the supplementation of vitamin d can prevent the onset and/or development of different kinds of autoimmune disorders in human beings and animal models.2 in addition , it has been shown that the prevalence of vitamin d deficiency is common in patients with graves disease ( gd),3 and is associated with higher thyroid volume.4 in our case report , we evaluated the effect of vitamin d correction to a patient with new onset gd with an underlying vitamin d deficiency .
a healthy saudi woman in her 40s sought consultation with a 3 months history of palpitation .
she denied any history of heat intolerance , weight loss , menstrual irregularity , diarrhea , or sweating .
there was no personal or family history of thyroid disease and no specific medication history .
physical examination revealed a mild diffusely enlarged and non - tender thyroid gland with no bruit .
the initial thyroid function test , which was done in an outside hospital , revealed a tsh , 0.01 miu / l ; ft4 , 22.5
vitamin d 25-oh level was done in our hospital and showed a result of 26.0 nmol / l with a tsh , 0.013 miu / l ; ft4 , 16.7
anti - thyroid antibodies showed a tg , 17.1 iu / ml ; tpo , 0.19 iu / ml with a positive tsh receptor antibody .
tc-99 m thyroid scintigraphy demonstrated an enlarged thyroid gland with increased radiotracer trapping and heterogeneous distribution ( fig .
the patient was given only oral cholecalciferol 4000 iu per day since november 2012 ( took it from an outside hospital ) then from may 2013 onwards she was given 50,000 iu per month .
the serial thyroid function tests , vitamin d levels , and titer autoantibodies are summarized in table 1 .
follow - up laboratory exams revealed improved vitamin d levels as well as tsh and ft4 .
written informed consent was obtained from the patient for the publication of this case and accompanying images .
it has become apparent that multiple factors contribute to the etiology of gd , including genetic and environmental factors .
these activated t cells in turn increase the secretion of thyroid - specific autoantibodies from b cells .
the prevalence of vitamin d deficiency was reported to be common in patients with gd.3 whether vitamin d deficiency has a causal relationship with gd remains a controversial issue .
misharin et al.5 observed that vitamin d deficiency was found to modulate graves hyperthyroidism induced in balb / c mice by thyrotropin receptor immunization . in this study ,
balb / c mice on a vitamin d deficient diet were more likely to develop persistent hyperthyroidism than other mice receiving adequate vitamin d supply . in another study ,
combination treatment with methimazole and vitamin d3 ( 1,25 ( oh)2d ) in patients with gd has more rapid euthyroidism achievement compared with patients receiving methimazole alone.6 in addition , vitamin d supplementation has been shown to inhibit inflammatory responses in human thyroid and t cells.7 interestingly , vitamin d deficiency is found to be associated with higher thyroid volume in patients with newly onset gd.4 it has been recently discovered that vitamin d - receptor gene and vitamin d - binding protein gene polymorphisms are associated with gd.8,9
our present case supports the current literature and strongly suggests that vitamin d deficiency may exacerbate the onset and/or development of gd and correction of which may be able to reverse it .
however , further prospective clinical studies will be needed to define the role of vitamin d treatment in gd . | objectivebesides its classical role in calcium and bone homeostasis , vitamin d is considered a potent immunomodulator that can affect the pathogenesis of several autoimmune diseases .
our aim is to evaluate the effect of vitamin d correction to a patient with new onset graves disease ( gd ) with an underlying vitamin d deficiency.methodwe describe the effect of vitamin d3 on untreated graves disease with vitamin d deficiency.resultsa healthy saudi woman in her 40s sought consultation with a three - month history of palpitation .
she denied any history of heat intolerance , weight loss , menstrual irregularity or sweating .
she has a history of chronic muscle aches and pains . physical examination revealed a mild diffusely enlarged and non - tender thyroid gland with no bruit .
she had no signs of graves ophthalmopathy . in laboratory examinations ,
the initial thyroid function test , which was done in an outside hospital , revealed a tsh , 0.01 miu / l ; ft4 , 22.5
pmol / l and ft3 , 6.5 pmol / l .
vitamin d 25-oh level was done in our hospital and showed a result of 26.0 nmol / l with a tsh , 0.013 miu / l ; ft4 , 16.7
pmol / l ; and ft3 , 3.8 pmol / l .
tsh receptor antibody was positive .
tc-99 m thyroid scintigraphy demonstrated an enlarged thyroid gland with increased radiotracer trapping and heterogeneous distribution .
the patient was given only oral cholecalciferol 4000 iu per day since november 2012 ( prescribed by an outside hospital ) then from may 2013 onwards she was given 50,000 iu per month .
follow - up laboratory exams revealed improved vitamin d levels as well as tsh and ft4 .
she eventually improved both clinically and biochemically with a satisfactory outcome.conclusionvitamin d deficiency may exacerbate the onset and/or development of gd and correction of the deficiency may be able to reverse it .
however , further prospective clinical studies will be needed to define the role of vitamin d treatment in gd . | [
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] |
nigella sativa l. ( ns ) is a vegetal specie of the ranunculaceae family , commonly known as black cumin seed , neguilla or ajemuz , that is widely cultivated in the mediterranean region .
its seeds have played an important role over the years in ancient islamic system of herbal medicine and in spain , where they have been traditionally used in folk medicine .
ns seeds have shown several therapeutic effects such as prevention of cancer , antihypertensive effect , anti - inflammatory , analgesic , and antihistaminic actions .
the volatile oil from this plant presents a relaxant action on different smooth muscles and tracheal muscles of guinea pigs .
there is evidence of anticonvulsant and antioxidant effects against pentylenetetrazol - induced kindling in mice .
. likewise , aqueous extract of this plant suppresses penicillin - induced epileptic activity in rats .
this anticonvulsant effect is a consequence of selectively altering the monoamine level in different brain regions . in recent works , histopathological changes of neurodegeneration in the frontal cortex and brain stem in neurons after exposition to toluene have been observed [ 15 , 16 ] .
the administration of ns extract and thymoquinone ( major component from ns volatile oil ) causes morphologic improvement over apoptosis and indicates that ns therapy is useful as a potential treatment of neurodegeneration prevention .
ns seeds composition includes nutritional components such as carbohydrates ( glucose , xylose , rhamnose , and arabinose ) , vitamins as thiamine , riboflavin , pyridoxine , niacin and folic acid , mineral elements , and proteins .
the ns seeds are also a source of calcium , iron and potassium , alkaloids ( nigellidine , nigellimine , and nigellicine ) , 36%38% fixed oil and 0.4%2.5% essential oil . the fixed oil is mainly composed of unsaturated and essential fatty acids ( linoleic acid , followed by oleic acid ) whereas the volatile oil has been shown to contain 18.424% thymoquinone and 46% monoterpenes such as p - cymene and pinene [ 5 , 20 ] .
thimoquinone , as indicated above , is thought to be the main active component of ns seeds and suppresses itself epileptic seizures in rats , while a monodesmosidic triterpene saponin , -hederin , has also been isolated from the extract of ns seeds and proved to exert antitumoral activity .
three flavonoid glycosides and triterpene saponins were also identified from nigella sativa , together with four phospholipid classes : phosphatidylcholine phosphatidylethanolamine , phosphatidylserine , and phosphatitdylinositol [ 24 , 25 ] . in previous studies we demonstrated that aqueous and methanolic extracts of ns seeds exert a potent sedative and depressive effect on cns and induce analgesia .
the effect on cns resulted in a significant reduction of spontaneous motility , a decrease in normal body temperature and significant analgesic action against hot - plate and pressure tests .
body temperature reduction can be interpreted as an index of alteration of various central neurotransmitters ; anxiety and sedation are mainly mediated by the gaba - a receptor in the cns . since depressant action was confirmed specially for the methanolic extract , we decided to study whether the addition of this methanolic dry extract in cortical neurons culture could exert any influence on the secretion of the excitatory amino acids aspartate ( asp ) and glutamate ( glu ) , and the inhibitory amino acids gaba and glycine ( gly ) , as well as the presence of these amino acid neurotransmitters in the extract .
we also considered its effect on the amino acids secretion when stimulated by a depolarizing agent and its effect on cultured neurons viability .
the viability of the cultured neurons after exposition to ns extract concentrations 2.5 , 25 , and 250 g / ml during 15 and 60 minutes are shown in figure 1 .
results are expressed as a percentage with respect to control value ( 100% viability ) .
the amino acids gaba , gly , glu , and asp were measured in ns methanolic extract by hplc .
the results are expressed as pmoles / mg of ns extract ( table 1 ) .
the results showed gly as the most abundant , followed by gaba , glu , and asp , respectively .
the amino acids content in the extract was subtracted from the total amino acid content measured in the cellular medium after neuronal stimulation with ns extract so we can state that the final amino acids content in cell culture is a direct consequence of cell release .
the release of the four amino acids after stimulation with the chosen nontoxic concentrations of ns extract ( 2.5 , 25 , and 250 g / ml ) showed a diminished secretion response that was statistically significant ( p < .05 for gly and glu ; p < .01 for gaba ; p < .001 for asp ) after 15 minutes of incubation with respect to control ( neuronal cells stimulated with normal locke medium during the same period of time and considered as 100% secretion ) ( figures 2 , 3 , 4 , and 5 ) .
gly and asp release was reduced in a dose dependent manner ; glu and gaba showed a tendency to retrieve control values , although their secretion was lower than control .
this fall of aminoacids release is greater for higher extract concentration except for glu and gaba , which showed a tendency to recuperation to control values at the same time ( figure 2 ) .
the hplc analysis revealed the same behavior for all the amino acids , with the exception of gaba , after treatment with ns extract during 60 minutes .
the increased presence of this amino acid was statistically significant for 25 and 250 g / ml ns extract . in order to know the response to a depolarizing agent ,
cortical neurons were stimulated with ns extract at the indicated concentrations , during 15 and 60 minutes previous to depolarization with 60 mm kcl ( figures 6 and 7 ) .
the neurons treated with ns extract during 15 minutes and subsequently stimulated with kcl showed a dose - dependent decrease in amino acids secretion with respect to control value ( neuronal cells stimulated with locke medium ) , which was considered as 100% . the observed behaviour was more relevant for glu and asp at 25 and 250 g / ml than for gaba and gly under the same conditions ( figure 6 ) .
measurement of secretion mediated by kcl during 60 minutes revealed an inhibition of the liberation of these neurotransmitters .
in this case , only gaba and glu were released in a dose - dependent manner ( figure 7 ) .
the aim of the study was to determine the effects of ns methanolic extract on the release of neurotransmitter amino acids by measuring their concentrations in the culture media using hplc precolumn derivatization technique .
three concentrations of ns extract ( 2.5 , 25 , and 250 g / ml ) and two time points ( 15 and 60 min ) for the determination of the effects were used .
this is a preliminary study which shows that exposure of the cultured neurons have a modulatory effect on the release and contents of these aminoacids .
the 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide ( mtt ) assay was employed to estimate the cells viability when neurons were treated with ns extract .
the three concentrations of dry methanolic extract used in our study did not affect cellular respiratory capacity at any of the two periods of time considered .
these results allowed us to consider the adequate approach to the study of amino acid secretion in the conditions selected and to confirm the innocuous characteristics of the chosen extract concentrations .
our previous in vitro findings support the hypothesis that the sedative and depressive effects of nigella sativa ( ns ) observed in vivo , could be based on changes of inhibitory / excitatory amino acids levels .
several authors attribute the sedative effects of different plant extracts ( valeriana officinalis l. , scutellaria lateriflora l. ) [ 27 , 28 ] to its endogenous gaba concentration , although they also hypothesize that there exist other components of the vegetal extracts with benzodiazepine - like effects that may account for their in vivo effects .
the aim of our research was to determine whether these substances that are present in the ns extract could mediate the specific effects previously observed in vivo through the secretion of asp , glu , gaba , and gly .
first of all , the presence and content of the four amino acids in the extract was analyzed by hplc , showing a major presence of inhibitory amino acids ( gly and gaba ) ( table 1 ) .
then , the cell amino acids release was assayed after addition of several concentrations of ns extract to cultured neurons during two different periods of time ( 15 and 60 minutes ) .
the aim of this approach was to observe whether neuronal secretion could be modified depending on the exposition time .
high secretion of gaba was observed after 60 minutes ' contact with ns extract at 25 and 250 g / ml . this time is close to the one that allowed the maximum effect in our in vivo study , close to 40 minutes . under these conditions ,
similar results have been observed when high gaba concentrations are present in an aqueous extract of valeriana officinalis root which induced in vitro liberation of [ h]gaba in rat synaptosomes by reversal of the gaba carrier and inhibition of its reuptake .
both plants are widely prescribed as sedative / anxiolytic ones . as the gaba presence in the methanolic extract of ns
was confirmed with our results , it is possible to assume that a high level of gaba in the medium during cellular incubation and a longer period of exposition at this one could exert the same effect above described .
recent findings suggest that ns protects from induced generalized epilepsy in rats by selectively altering the monoamine level in different brain regions .
this study pointed that ns possibly facilitates the inhibitory activity of the gabaergic system through a competitive agonist action in the benzodiazepine ( bzd ) site of the gaba receptor as well as the involvement of dopaminergic and noradrenergic system .
the confirmed presence of gaba in the methanolic extract could be directly related to its conduct over the gaba receptor and this could explain the potent sedative and depressive effect on cns as previously reported . moreover , the important presence of gly in the extract could be also related to its inhibitory action .
the binding of both neurotransmitters to their receptors on the neuronal membrane induces hyperpolarization that could be responsible for a significantly lower secretion of amino acids with respect to control values .
in addition to this , our results showed a decrease in neuronal excitatory activity derived from a diminished asp and glu secretion , specially the second one .
our results show the behavior of the cortical neurons and confirm what we expected from the previous study performed in vivo .
likewise the methanolic extract composition is able to mediate in the neuronal amino acids release . in this case , the ns extract had an influence on neuronal transmission because it modifies the neurotransmitter amino acids release .
depolarization of neuronal cells by application of high k+ concentration ( 60 mm kcl ) induced a diminished amino acid release in both periods of time assayed .
this diminished release was similar to nondepolarizing secretion except for gaba which also diminished its secretion .
although multiple mechanisms of neurotransmitter release evoked by elevated extracellular k+ may be involved [ 29 , 30 ] , we consider that the effect of ns extract over neuronal cells produces a drop in the transmission and is responsible for of the inhibitory effect indicated above .
a possible action of ns extract over l - type calcium channels or an opening on potassium channels had been suggested by others authors [ 3135 ] , and it could contribute to the relaxant activities of this plant .
furthermore , its possible effect over these channels could persist even after the extract was eliminated from the medium before depolarization .
with respect to gaba secretion , the only amino acid which differs in its behavior with respect to nondepolarizing liberation , the diminished secretion may derivate from the membrane transporter - reversal for gaba above suggested . in our study , we have considered the possibility that the gaba carrier had been previously affected by the presence of ns extract during 15 or 60 minutes , inhibiting gaba reuptake and favouring its liberation from neurons .
other authors have concluded that extracellular k+ ( 50 mm kcl ) provokes gaba release by reversal transporter of gaba . in our case
, we observed a diminished liberation that could be justified by the previous loss of cellular gaba content as the neurons had been treated with the ns extract . in conclusion , this study suggests a sedative effect of ns methanolic extract by modification of neurotransmitter amino acids release , because the ns extract may induce an important release of gaba and gly in the cultured neurons medium and therefore , exert an increase in the agonist action over their receptors .
the results explain the sedative and depressive effects observed in vivo by an increase in inhibitory amino acids at the synaptic terminals .
even more , this effect is complemented with a possible decrease of excitatory transmission , as it has been demonstrated in vitro and could contribute to inhibitory response .
minimum essential eagle 's medium ( emem ) was obtained from bio - whittaker , and foetal bovine serum ( fbs ) and horse serum ( hs ) were procured from sera - lab ( sussex , england )
. standards of glutamate , aspartate , gaba and glycine were purchased from sigma ( st . louis , mo , usa ) .
reagents and solvents for hplc were triethylamine from sigma ( st . louis , mo , usa ) , acetic acid and methanol ultra gradient grade from merck ( darmstadt , germany ) .
distilled water used for the preparation of buffers and standards was deionized with milli - q purification system .
syringe filters millex - gv were obtained from millipore ( milford , ma , usa ) .
membrane filters ( 0.45 m pore size ) from tecknochroma ( barcelona , spain ) were used for filtration of the mobile phase and samples .
cell proliferation kit ii ( xtt ) , colorimetric determination , was purchased from roche diagnostics gmbh ( mannheim , germany ) .
, usa ) coupled with a photodiode array detector shimadzu spd-10a ( izasa , madrid , spain ) was used for the amino acids isolation and quantification . the analytical system consisted of a waters ods spherisorb 150 4.6 mm i.d . ; 5 m packed column ( teknokroma , barcelona , spain ) as stationary phase , preceded by a guard column spherisorb rp-18 , 5 m , 4 mm 4 mm .
a microplate fluorescence reader fl600-biotek spectrofluorimeter was used for the quantification of cell viability at 492 nm .
seeds of nigella sativa l. were supplied by the medicinal and aromatic plants research institute of egypt ( el cairo , egypt ) .
herbarium samples were authenticated by a taxonomist and a voucher specimen was deposited in the herbarium of the faculty of pharmacy , universidad complutense de madrid , with voucher number maf 161043 .
the methanolic extract of the plant was prepared according to ( science and technology program for development ) cyted protocol for vegetal species from countries that are included in this program .
brain neurons were obtained from foetal rat brains of 19 days of gestation as previously described with minor modifications .
isolated neurons were suspended in eagle 's minimum essential medium ( emem ) containing 0.3 g / l glutamine , 0.6% glucose , 5% phosphate buffered saline ( pbs ) , 5% horse serum ( hs ) , 100 u / ml penicillin and 100 g / ml streptomycin .
cells , at a density of 1 10 cells / well , were placed on plastic petri dishes of 24 wells , treated with 10 g / ml poly - l - lysine to aid attachment .
the plates were incubated in a humidified incubator in an atmosphere of 5% co2/95% air at 37c . after 72 hours ,
nonneuronal cells ( contaminating glial cells ) were mitotically inhibited by exposure to cytosine arabinoside .
the incubation medium was replaced by fresh medium to which cytosine arabinoside was added to a final concentration of 10 m .
after 3 days , this medium was replaced by fresh medium and experiments were carried out using cultures ranging from 1015 days .
cell purity was checked by both cells staining with cresyl violet to identify neurons and with the specific antiglial fibrillary acidic protein ( gfap ) antibody to identify glial cells .
cortical neurons , after 7 days in culture , were detached from the culture plates with trypsin solution ( 0.25% trypsin and 0.02% edta in dulbecco 's buffered saline without calcium and magnesium ) and then the cells were fixed ( during 30 min ) with 2% p - formaldehyde .
after two washes with 1 ml of pbs , the cells were treated ( during 1 h ) with anti - gfap antirabbit ( at dilution of 1/500 ) .
subsequently , the cells were washed with pbs and treated with antirabbit conjugated igg fitc , at 1/100 , for 30 min .
the glial cells in the cultures were 8.3 3.6% of the total ( neural + glial cells ) .
this assay is used as an index of cell survival or cellular respiratory capacity - based on method of mossmann and improved by weislow et al . and roehm et al . .
the tetrazolium assay is based on the mitochondrial dehydrogenases ( md ) activity and their inactivation after cell death . in live cells ,
mtt is reduced to a highly water - soluble orange colored product , formazan dye .
neuronal cells were seeded in 96-multiwell plates at a density of 36 10 cells / well ( in 200 l medium ) and kept in the incubator until 8090% confluence .
after this , the medium was removed and the cells were washed twice with pbs and the ns extract previously dissolved in pbs was added to the wells and incubated for 15 minutes or 1 hour .
after each one of the treatment periods ( 15 or 60 min ) , the medium was removed and incubated with mtt solution ( final concentration 0.3 mg / ml ) , according to the kit specifications .
after 2 h incubation at 37c in a humidified atmosphere , orange dye solution was spectrophotometrically quantified using an elisa plate reader at 492 nm .
the amount of orange formazan formed , as monitored by the absorbance , directly correlates to the number of living cells .
hplc analysis of amino acids was performed by a previously described method with minor modifications and with the equipment and conditions that were previously developed for the amino acids determination .
prior to hplc amino acid secretion analysis cells were washed twice , at 10 min intervals , with 1 ml of locke medium . after removing the medium ,
cells were stimulated for 15 min or 1 hour at 37c with 250 l fresh locke medium ( control cells ) or with 250 l of locke medium containing the dry methanolic extract of ns seeds at different concentrations ( 2.5 , 25 and 250 g / ml ) .
after stimulation , the wells medium ( supernatant s1 ) was taken for amino acid valuation and cells were then stimulated with 250 l of 60 mm kcl for 15 min .
after this , the cells secretion ( supernatant s2 ) was removed for their valuation and cells were lysated with 250 l of distilled water for total intracellular amino acids content determination .
the different supernatants obtained , s1 and s2 , as well as the cell lysated , were lyophilized for their dansylation .
the content of the four amino acids present in the methanolic extract was also determined by hplc analysis under the same conditions and these results were subtracted from the total amino acids content in cellular medium in presence of ns extract ( s1 ) in order to obtain cellular secretion value itself .
the results were calculated as the amino acid release into the incubation medium with respect to the total amino acid content .
these results were expressed as a percentage of secretion with respect to control experiments that were considered as 100% .
data are presented as means sem of four separated experiments from different cell cultures , each one performed in triplicate with different batches of neuronal cells . |
nigella sativa l. ( ns ) has been used for medicinal purposes since ancient times . this
study aimed to investigate the cytotoxicity of ns dry methanolic extract on cultured
cortical neurons and its influence on neurotransmitter release , as well as the presence of
excitatory ( glutamate and aspartate ) and inhibitory amino acids ( gamma - aminobutyric
acid gaba and glycine ) in ns extract .
cultured rat cortical neurons were exposed to
different times and concentrations of ns dry methanolic extract and cell viability was
then determined by a quantitative colorimetric method .
ns did not induce any toxicity .
the secretion of different amino acids was studied in primary cultured cortical neurons
by high - performance liquid chromatography ( hplc ) using a derivation before injection
with dansyl chloride .
ns modulated amino acid release in cultured neurons ; gaba was
significantly increased whereas secretion of glutamate , aspartate , and glycine were
decreased .
the in vitro findings support the hypothesis that the sedative and depressive
effects of ns observed in vivo could be based on changes of inhibitory / excitatory amino
acids levels . | [
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pheochromocytomas are rare catecholamine producing tumors arising from chromaffine cells in the sympatho adrenal system .
its prevalence is estimated at 0.1% to 0.6% . they secrete various catecholamines , predominantly norepinephrine , and epinephrine to small extent .
these catecholamines are responsible for the manifestations with sustained or paroxysmal symptoms . diagnosis is established by measuring metanephrines in the urine or blood .
localization of the tumor is done using computed tomography ( ct ) or magnetic resonance imaging ( mri ) scans .
thrombosis of the inferior vena cava ( ivc ) has comparable etiological factors to lower limb deep venous thrombosis .
hypercoagulability related to hematological or neoplastic abnormalities , venous stasis secondary to extraluminal pressure from tumors or inflammatory processes , and vessel injury due to trauma have all been implicated as primary mechanism in the pathophysiology of ivc thrombosis .
however , its association with pheochromocytoma in indian subjects has not been reported till date .
a 48-year - old man was admitted to our hospital with complaints of headache , sweating , anxiety , dizziness , nausea and vomiting .
the patient was 164 cm tall and weighed 57 kg . on physical examination , there were no caf au lait spots or neurofibromas .
hematological analysis confirmed normocytic anemia with hemoglobin 11.3 gm / dl , a raised erythrocyte sedimentation rate ( esr ) ( 130 mm fall in the first hour ) , while the total and differential leukocyte counts were normal .
biochemical parameters such as liver and kidney functions , and serum electrolytes , calcium , phosphorous , alkaline phosphatase and d - dimer were within normal limits .
the endocrinological evaluation revealed increased urine catecholamines and urinary vanillyl mandelic acid ( vma ) [ table 1 ] .
baseline biochemical parameters of the patient abdominal ct revealed a well defined , heterogenous mass lesion of size 7.6 5.3 4.8 cms with attenuation score of 35 hu at the upper pole of right kidney without any calcifications [ figure 1 ] .
there was no involvement of renal vein , hepatic veins and veins of lower limbs demonstrated by doppler ultrasound .
magnetic resonance imaging ( mri ) revealed intraluminal thrombus extending proximally up to the confluence of hepatic veins immediately inferior to the right atrium without distal extension to femoral veins bilaterally [ figure 2 ] .
an ivc venogram via the right jugular vein demonstrated multiple filling defects indicating occlusion of the ivc inferior to the right atrium [ figure 3 ] .
there was simultaneous enlargement of distal part of ivc . computed tomography of the abdomen- showing a well defined , heterogeneously enhancing mass lesion of size 7.6 5.3 4.8 cm at the upper pole of right kidney without any calcifications .
the left adrenal gland appeared to be normal t2-weighted axial magnetic resonance imaging demonstrating the mass ( predominantly high signal ) between the inferior vena cava and right kidney ( black arrow ) compressing the overlying inferior vena cava ( white arrow ) ivc venogram showing multiple filling defects indicating occlusion of the inferior vena cava inferior to the right atrium .
there is distal enlargement of inferior vena cava a diagnosis of ivc thrombosis with pheochromocytoma was established , and surgical treatment was planned .
alpha receptor blocking therapy with prazosin was instituted , followed by blocker , after testing for adequacy of blockade .
the patient was treated conservatively with subcutaneous low molecular weight heparin followed by oral warfarin .
after 2 weeks , hypertension was well controlled and the remaining symptoms disappeared . with adequate blood pressure control ,
biopsy of the specimen revealed a typical organoid or zellballen pattern with no cytoplasmatic inclusion , pleomorphism , cytological alterations or necrosis ; and , the mitotic index was low [ figure 4 ] . during the postoperative period ,
the patient 's blood pressure remained normal . a 24-hour urine specimen collected for metanephrine and vma , revealed levels within normal limits . at present , the patient is asymptomatic , requires no medications , and is employed as an engineer .
mri imaging demonstrated resolution of the thrombosis and return of patency of the ivc at 4 months [ figure 5 ] . the typical growth pattern of nests of tumor cells ( zellballen ) surrounded by a discontinuous layer of sustentacular cells and fibrovascular stroma in the biopsy specimen of the patient in the study .
blood vessels surrounding tumor nests are composed of round to oval cells t2-weighted axial magnetic resonance imaging comparable in position and image acquisition to figure 2 demonstrating complete resolution of inferior vena cava thrombosis ( white arrow ) after 4-months of oral anticoagulation therapy
two aspects render our case unusual : 1 ) the coexistence of pheochromocytoma with ivc thrombosis 2 ) though there are case reports citing the association between malignant pheochromocytoma and ivc thrombus , to our sincere belief ; this is the first such report citing this uncommon association from india .
although the lifetime incidence of venous thrombosis is 0.1% , it still remains a rare condition especially in patients below 30 years of age .
predisposing factors include alterations in blood flow [ stasis ] , injury to the vascular endothelium and abnormalities in the constitution of blood hypercoagulability ( virchow 's triad ) .
endothelial damage is invariably an acquired phenomenon , whereas hypercoagulability may result from both congenital and acquired risk factors ( especially in the peri - operative period ) .
the classical presentation of ivc thrombus varies according to the level of the thrombosis with up to 50% of patients presenting with bilateral lower extremity swelling and dilatation of superficial abdominal vessels . whilst some patients remain asymptomatic ,
lower back pain , nephrotic syndrome , hepatic engorgement , cardiac failure and pulmonary embolus have also been described .
tsuji et al . reported a series of 10 patients where 40% were pyrexic at presentation , with an associated elevation in d - dimer levels and inflammatory markers ( white cell count , c - reactive protein ) .
our patient had no lower limb , liver or kidney involvement , and this might be ascribed to the partial occlusion of ivc .
we could not explain normal d - dimer levels in the backdrop of such a large thrombus in our patient .
ct scan with contrast enhanced images and mri scan are used to localize adrenal pheochromocytoma .
meta - iodobenzylguanidine ( mibg ) and positron emission tomography ( pet ) scanning ( gallium- dota - toc / noc and dopa - pet perform better than fdg- pet ) are largely reserved for extraadrenal paraganglioma , or very large tumors to rule out metastasis .
heterogeneity , high hounsfield density on ct ( > hu ) , marked enhancement with intravenous contrast and delayed contrast washout ( < 60 % at 10 minutes ) , high signal intensity on t2 weighted mri , cystic and hemorrhagic changes point to pheochromocytoma , adrenocortical carcinoma or metastasis .
however , pheochromocytoma with lipid degeneration can result in low attenuation scores ( < 10 hu ) and > 60% washout at delayed ct scanning .
benign adrenal incidentalomas are characterized by size < 5 cm , sharp margins , smooth contours , lack of demonstrable growth on serial examinations , attenuation scores < 10 hu , and > 60% washout at delayed ct scanning . in our patient , ct scan revealed nonhomogenous mass of hu 35 without any calcification .
histologically , pheochromocytomas are capsulated and are composed of round or polygonal epithelioid / chief cells arranged in characteristic compact cell nests ( zellballen ) or trabecular patterns .
the chief cells have centrally located nuclei with finely clumped chromatin , and a moderate amount of eosinophilic , granular cytoplasm .
tumors of higher grade are characterized by a progressive loss in the relationship between chief cells and sustentacular cells , and a decrease in the number of sustentacular cells . in our patient , typical zellballen pattern was found .
presence of markers like chromogranin a ( cga ) , neuron specific enloase , synaptophsyin serve as additional tools to confirm the neuroendocrine nature of the chief cells .
the only reliable clue to the presence of a malignant pheochromocytoma is local invasion or distant metastases , which may occur as long as 20 years after resection .
benign on pathologic examination , long term follow - up is indicated in all patients to confirm that impression .
other markers for malignancy are absent or weak expression of inhibin / activin- beta b subunit , and presence of succinate dehydrogenase b ( sdh b ) subunit is seen . in absence of any invasion , we considered the mass in our patient to be benign . the simultaneous occurrence of pheochromocytoma and ivc thrombosis is reported sporadically .
ivc thrombosis in this case could be because of : 1 ) local compression leading to alteration in blood flow and stasis 2 ) sustained hypertension leading to vascular endothelial injury and hypercoagulability , 3 ) association of pheochromocytoma with systemic lupus erythematous and behcet 's disease might explain the triggering of an autoimmune phenomenon leading to a hypercoagulable state , and 4 ) an underlying anatomic abnormality or coagulation disorder .
it also could be a chance association between these 2 conditions . in our case ,
recent advances in the utilization of ultrasound , ct and mri imaging as well as endovascular procedures have resulted in an increase in detection rates of ivc anomalies , as well as an increase in the incidental discovery of such abnormalities during unrelated investigations , therapeutic endovascular or surgical procedures .
contrast venography remains the standard for diagnosis of ivc thrombosis with a low false - positive rate , and the advantage of access for immediate treatment if required .
however , it is an invasive procedure associated with a 2%-10% incidence of post - procedural deep venous thrombosis ( dvt ) .
duplex ultrasound scanning has become an accurate non - invasive method of diagnosing ivc thrombosis and is often the first - line investigative modality .
however , duplex usg is operator dependant and can be limited by body habitus or the presence of bowel gas and may occasionally fail to identify any ivc anomaly .
ct imaging is a rapid non - invasive method which can accurately diagnose and assess the extent of thrombus as well as delineate any associated abdominal or pelvic abnormality .
mri imaging is now replacing ct as the optimal investigative tool avoiding radiation and giving more accurate delineation of thrombus as well as any ivc anomaly .
mri is also used to follow - up patients to determine morphological changes in the thrombus following therapy .
management of patients with coexisting pheochromocytoma and ivc thrombosis needs operative resection of the adrenal mass and medical / interventional management of ivc thrombosis .
the goals of operation include 1 ) removal of the tumor with postoperative normotension , and 2 ) ivc luminal restoration and anticoagulation .
minimally invasive techniques are being increasingly used for resection of adrenal tumors and to treat renal artery lesions .
our patient was subjected to laparoscopic adrenalectomy after adequate preoperative blood pressure control by blockers , followed by blockers .
treatment options in the case of ivc thrombus without anatomical variance include anticoagulation , mechanical thrombectomy , systemic thrombolytic therapy , transcatheter regional thrombolysis , pulse - spray pharmacomechanical thrombolysis and angioplasty .
there is no specific literature describing the ideal duration of anticoagulation in these instances ; however , case evidence identifies a trend toward treatment for a minimum of one year with the interplay of hypercoagulability disorders needing to be factored into any decision .
surgical reconstruction of the ivc and bypass of an aberrant section are both recognized modalities reserved for the most severe cases and are associated with morbidity and mortality risk .
endovascular stent placement in combination with angioplasty is recommended in the cases of residual stenosis and chronic ivc occlusion . in the case of ivc thrombus
associated with an aberrant ivc , with no other predisposing factors , treatment involves anti - coagulation .
the duration of this treatment is widely debated with no extensive literature to provide an evidence based approach .
dean et al . took a view , which is quite similar to that of ours , that a caval anomaly is a permanent risk factor for venous stasis and thrombosis and that anticoagulant treatment should be lifelong . since our patient had no anatomic abnormality or any other predisposing factors , we decided to give the treatment for 4 months only and stopped it then after documenting radiologic luminal restoration .
though cases of renal artery stenosis , renal artery aneurysm and inferior vena cava thrombosis have been described , we found the uncommon association with ivc thrombosis in an indian patient .
ct or preferably mri imaging are required to delineate ivc anatomy and ascertain proximal extent of the thrombus .
although invasive therapeutic modalities exist , long - term and commonly life - long anticoagulation is often required .
pheochromocytoma does not seem to have any effect on the outcome of the coexisting ivc thrombosis . | pheochromocytomas have been described in association with vascular abnormalities like renal artery stenosis .
a 48-year - old man was admitted to our hospital with the complaints of headache , sweating , anxiety , dizziness , nausea , vomiting and hypertension . for last several days , he was having a dull aching abdominal pain .
abdominal computed tomography ( ct ) revealed the presence of a left adrenal pheochromocytoma .
an inferior vena cava ( ivc ) venogram via the right jugular vein demonstrated occlusion of the ivc inferior to the right atrium .
surgical removal of pheochromocytoma was done , followed by anticoagulant treatment for ivc thrombosis , initially with subcutaneous low molecular weight heparin , and then with oral warfarin , resulting in restoration of patency . to the best of our knowledge ,
the occurrence of pheochromocytoma in ivc thrombosis has not been reported so far from india .
possible mechanisms of such an involvement are discussed . | [
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] |
in recent years , core training has been widely studied since it has been considered a pivotal issue in health , rehabilitation and sports performance ( hibbs et al . , 2008 ) .
however , the definition of the core varies with the interpretation of the literature ( hibbs and thompson , 2008 ) .
anatomically , the core region has been described as the area bounded by the abdominal muscles in the front , by paraspinal and gluteal muscles in the back , by diaphragm on the top and by pelvic floor and girdle musculature at the bottom ( richardson et al . , 1999 ) .
the core represents the connection between lower and upper limbs and should be considered as a functional unit in which different muscles interact , even if not located in the thoraco - lumbar region ( such as shoulders and pelvic muscles )
. however , literature concerning core training sometimes fails to distinguish between concepts of core stability and core strength .
faries and greenwood ( in hibbs and thompson , 2008 ) formulated the following clear definitions : core stability refers to the ability to stabilize the spine as a result of muscle activity , while core strength refers to the ability of muscles contractions to produce and transfer force as a result of muscle activity . since strength and motor control are complementary qualities , the core training programmes can target mainly , but not exclusively , at muscle strengthening and/or motor control of core musculature .
motor control training seems to require low intensity stabilization exercises focused on efficient integration of low threshold recruitment of local and global muscle systems .
conversely , core strength training seems to require high intensity and overload training of the global muscle system .
vezina and hubley - kozey ( 2000 ) suggested that core stability programmes should include muscle activation below 25% of maximum voluntary contraction ( mvc ) , while core strength training should include activation higher than 60% of mvc to result in strength benefits .
the available evidence suggests that to adequately train the core muscles in athletes , strength and conditioning specialists should focus on implementing multi - joint full body exercises , rather than core - specific exercises ( martuscello et al . , 2013 ) .
exercises involving the full body linkage such as plank exercises , have been advocated to the capacity of transmitting force through the body linkage ( schoenfeld et al . , 2014 ) .
training with labile systems has been documented to offer unique opportunities for linkage training challenges ( mcgill et al . , 2015 ) .
several studies examined core muscle activation during the execution of various exercises on stable and unstable surfaces ( for a review see : behm et al . , 2010 ) .
the use of unstable surfaces contacting the subject s feet or hands is becoming popular in strength training .
instability can be obtained through the use of many devices and techniques including , but not limited to , unstable platforms such as bosu or swiss balls .
more recently , suspension training systems have been added to the list of instability training devices . in suspension training , lower or upper limbs
many core directed exercises are designed with such a device , creating a wide variety of challenges .
these exercises consist of multi - planar and multijoint movements , and are executed with complex techniques .
it is important to quantify the muscle contraction intensity since it is a key factor in establishing training effects induced by this sort of exercises .
although considerable research has examined more traditional means of instability training ( behm and drinkwater , 2010 ) , little previous research has evaluated the effects of suspension training on muscle activation . in particular , some studies focused on core - directed exercises ( atkins , 2014 ; byrne et al . , 2014 ; czaprowski et al . , 2014 ; mok et al . , 2014 ; snarr and esco , 2014 ) , whereas others investigated the effect of the application of suspension system on core muscle activity in push exercises ( calatayud et al . , 2014
further investigation of these exercise approaches is needed to understand their influence on muscle activation and joint load levels .
the primary purpose of this study therefore , was to examine differences in core muscle activation across four full - body linkage exercises using a suspension training system .
these exercises were chosen from a spectrum of whole body linkage exercises focused on the anterior core musculature executed in instable conditions , including a roll - out , bodysaw , pike , and knee - up .
although the selected exercises were mainly focused on anterior slings , we wanted to provide a comprehensive view of core muscle activation by monitoring rectus abdominis , internal and external oblique , and paraspinal muscles . it was hypothesized that significant differences would be found in core muscles among exercises .
the second aim of the study was to determine which of these exercises would reach the threshold of 60% of mvc , expected to be high enough to increase muscle strength .
it was hypothesized that the four exercises would elicit muscle activity in excess of 60% of mvc in the rectus abdominis , i.e. the muscle on which the main focus was put considering the selected exercises .
seventeen healthy participants were recruited ( age 27.32.4 years , body height 1725 cm , body mass 69.29.3 kg ) .
all participants were physically active , declaring three practice sessions per week of resistance training .
inclusion criteria for study participation were as follows : no past or present neurological or musculoskeletal trunk or limb pathology , no cardiorespiratory disease , no history of abdominal , shoulder or back surgery , and no psychological problems .
participants were instructed to refrain from performing strenuous physical activity in the 24 hours preceding all experimental sessions .
the study was previously approved by the research ethics committee of the department of medical sciences , university of turin .
the surface electromyographic ( emg ) signals were obtained from six trunk muscles with concentric bipolar electrodes ( code , spes medica , battipaglia , italy ) . before the placement of the electrodes , the skin was slightly abraded with adhesive paste and cleaned with water in accordance to seniam recommendation for skin preparation ( hermens et al . , 2000 ) .
the electrodes were placed according to the instructions described in previous methodological works ( beretta piccoli et al . , 2014 ; boccia and rainoldi , 2014 ) lower rectus abdominis : on the lower part of the rectus abdominis , 3 cm lateral to the midline ; upper rectus abdominis : on the upper part of the rectus abdominis , 3 cm lateral to the midline ; external oblique : 14 cm lateral to the umbilicus , above the anterior superior iliac spine ( asis ) ; internal oblique : 2 cm lower with respect to the most prominent point of the asis , just medial and superior to the inguinal ligament ; lower erector spinae : 2 cm lateral to the l5-s1 ; upper erector spinae : 6 cm lateral to the l1-l2 .
the electrodes were placed only on the left ( randomly chosen ) side of the body ; the reference electrode was positioned on the wrist .
the signal of a biaxial electrogoniometer ( sg 150 , biometrics ltd , gwent , uk ) positioned at the level of the shoulders ( for the roll - out and bodysaw ) or the hips ( for the pike and knee - tuck ) , depending on which joint was more involved during the exercise , was used as a trigger to highlight exercise repetitions .
the emg signals were synchronized with the electrogoniometer signal , amplified ( emg - usb , ot bioelettronica , torino , italy ) , sampled at 2048 hz , bandpass filtered ( 3-db bandwidth , 10 - 450 hz , 12 db / oct slope on each side ) , and converted to digital data by a 12-bit a / d converter .
samples were visualized during acquisition and then stored in a personal computer using ot biolab software ( version 1.8 , ot bioelettronica , torino , italy ) for further analysis .
the participants recruited were instructed with regard to the correct technique of suspension exercise and the mvc procedure during the first experimental session conducted one week before the measurement session .
the participants were asked to refrain from physical activity 24 hours before the measurements . during the measurement session
, participants performed 4 exercises with the use of suspension straps ( trx suspension trainer ; fitness anywhere lcc , san francisco , ca , usa ) in random order .
the exercises were selected based on a previous study ( behm and drinkwater , 2010 ) that indicated them as important in developing core strength . at the beginning of the measurement session
, three mvc exercises were performed twice for 5 s , with 2 min rest between them .
the following standardized exercises ( ng et al . , 2002 ) were used to activate maximally the trunk muscles ( figure 1 ) : upper rectus abdominis ( ura ) and lower rectus abdominis ( lra ) : body supine with hips and knees flexed 90 , with feet locked .
participants flexed the trunk ( i.e. crunch execution ) against resistance at the level of the shoulders;external oblique ( eo ) and internal oblique ( io ) : side - lying with the hip at the edge of the bench and feet locked by a second operator .
participants performed side - bend exercise against resistance at the level of the shoulder;lower erector spinae ( les ) and upper erector spinae ( ues ) : prone position with asis at the edge of the bench and feet locked by a second operator .
upper rectus abdominis ( ura ) and lower rectus abdominis ( lra ) : body supine with hips and knees flexed 90 , with feet locked .
participants flexed the trunk ( i.e. crunch execution ) against resistance at the level of the shoulders ; external oblique ( eo ) and internal oblique ( io ) : side - lying with the hip at the edge of the bench and feet locked by a second operator .
participants performed side - bend exercise against resistance at the level of the shoulder ; lower erector spinae ( les ) and upper erector spinae ( ues ) : prone position with asis at the edge of the bench and feet locked by a second operator .
standardized exercises used to maximally activate trunk muscles : lower rectus abdominis and upper rectus abdominis ( left ) ; internal oblique and external oblique ( middle ) ; lower erector spinae and upper erector spinae ( right ) .
participants were required to achieve a range of motion with the correct technique execution and to maintain a neutral position of the spine and pelvis in each exercise .
a certified strength and conditioning coach monitored the exercise performance to ensure that the exercise was properly executed considering its technique .
each exercise was repeated three times and lasted 6 s. a metronome set at 30 beats per minute was used to ensure proper timing ( with 4 beats for each repetition ) : 2 s from the initial position to the final position ( concentric phase ) ; 2 s of maintenance ( isometric phase ) ; and 2 s returning to the starting position ( eccentric phase ) .
the exercises were performed with 3 min of rest in - between to allow complete recovery .
the random order of the exercises allowed to mitigate the effects of cumulative fatigue on emg estimates .
the following exercises were used ( figure 2 ) : roll - out : participants assumed an inclined standing position while placing each hand on the strap handles , with elbows and wrists placed below the shoulders , arms perpendicular to the floor and shoulders flexed approximately 45 ; they then performed a shoulder flexion moving the hands forward;bodysaw : participants assumed a prone position , they placed elbows below the shoulders , both forearms touching the floor , while placing each foot on the strap handle ; participants then flexed the shoulders and extended the elbows pushing the body backwards;pike : participants assumed a push - up position with the feet in strap handles , then they flexed hips to approximately 90 , while keeping the knees fully extended;knee - tuck : participants assumed a push - up position while placing each foot in the strap handle , then they flexed both hips and knees to approximately 90 , bringing the knees forward .
roll - out : participants assumed an inclined standing position while placing each hand on the strap handles , with elbows and wrists placed below the shoulders , arms perpendicular to the floor and shoulders flexed approximately 45 ; they then performed a shoulder flexion moving the hands forward ; bodysaw : participants assumed a prone position , they placed elbows below the shoulders , both forearms touching the floor , while placing each foot on the strap handle ; participants then flexed the shoulders and extended the elbows pushing the body backwards ; pike : participants assumed a push - up position with the feet in strap handles , then they flexed hips to approximately 90 , while keeping the knees fully extended ; knee - tuck : participants assumed a push - up position while placing each foot in the strap handle , then they flexed both hips and knees to approximately 90 , bringing the knees forward .
initial and final positions of each exercise : 1 ) roll - out ; 2 ) bodysaw ; 3 ) pike ; 4 ) knee - tuck .
the average rectified value ( arv ) of emg signals was computed off - line with numerical algorithms using non - overlapping signal epochs of 0.5 s ( hibbs et al . , 2011 ) .
the mean value of arv over the two repetitions was calculated for each muscle and normalized with respect to the maximum arv obtained during the correspondent mvc .
the normality assumption of the data was evaluated with the shapiro - wilk test ; homoscedasticity and autocorrelation of the variables were assessed using the breusch - pagan and durbin - watson tests .
the differences between exercises ( pike bodysaw knee - tuck roll - out ) and between muscles ( lra ura eo io les ues ) were compared with the 2-way analysis of variance ( anova ) . for the purpose of this report
statistical analyses were conducted using the r statistical package ( version 3.0.3 , r core team , foundation for statistical computing , vienna , austria ) .
all participants managed to complete each exercise trial and thus , were included in the data analysis .
figure 3 shows the box plots of the activation values ( % of mvc ) of each muscle during the four exercises . muscle activation ( median , ir )
figure 3each box plot shows the muscle activation ( as percentage of maximum voluntary contraction ) during exercise .
table 1muscle activation ( median , ir ) expressed as percentage values of electromyographic amplitude normalized to maximum voluntary contraction .
results of the two - way anova after tukey multiple comparisons are reported as symbols ; p < 0.01.lower rectus abdominisupper rectus abdominisexternal obliqueinternal obliquelower erector spinaeupper erector spinaepike57 ( 36 ) 41 ( 48 ) 55 ( 21)23 ( 20)12 ( 7)9 ( 4)bodysaw100 ( 42 )
57 ( 52)59 ( 33)32 ( 20)4 ( 3)8 ( 6)knee - tuck54 ( 50 )
44 ( 41 ) 42 ( 7 ) 18 ( 26)8 ( 5)6 ( 5)roll - out140 ( 89 )
67 ( 78 )
71 ( 44 ) 40 ( 31)9 ( 5)11 ( 6)indicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the pikeindicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the bodysawindicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the knee - tuckindicates statistically significant difference betweenthe indicated exercise ( explained in row ) with respect to the roll - out each box plot shows the muscle activation ( as percentage of maximum voluntary contraction ) during exercise .
muscle activation ( median , ir ) expressed as percentage values of electromyographic amplitude normalized to maximum voluntary contraction .
results of the two - way anova after tukey multiple comparisons are reported as symbols ; p < 0.01 .
indicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the pike indicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the bodysaw indicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the knee - tuck indicates statistically significant difference between the indicated exercise ( explained in row ) with respect to the roll - out the normalized
lra activity was 140% ( ir , 89% ) of mvc during the roll - out , 100% ( ir ,
42% ) of mvc during the bodysaw , 57% ( ir , 36% ) of mvc during the pike
and 54% ( ir , 50% ) of mvc during the knee - tuck .
the normalized lra
values were significantly higher ( p < 0.01 )
during the roll - out and bodysaw compared to the pike and knee - tuck .
the roll - out exercise showed significantly greater activation
( p < 0.01 ) than the bodysaw .
the
normalized ura activity was 67% ( ir , 78% ) of mvc during the roll - out ,
57% ( ir , 52% ) of mvc during the bodysaw , 41% ( ir , 48% ) of mvc during
the pike and 44% ( ir , 41% ) of mvc during the knee - tuck .
the
normalized ura values were significantly higher ( p
< 0.01 ) during the roll - out compared to the pike and
knee - tuck .
the normalized eo activity was 71% ( ir , 44% ) of mvc
during the roll - out , 59% ( ir , 33% ) of mvc during the bodysaw , 55%
( ir , 21% ) of mvc during the pike and 42% ( ir , 7% ) of mvc during the
knee - tuck .
the normalized eo values were significantly higher
( p < 0.01 ) during the roll - out compared to
the knee - tuck .
the normalized io activity was 40% ( ir , 31% ) of
mvc during the roll - out , 32% ( ir , 20% ) of mvc during the bodysaw , 23%
( ir , 20% ) of mvc during the pike and 18% ( ir , 26% ) of mvc during the
knee - tuck . during all exercises the normalized io values were not
significantly higher ( p < 0.01 ) .
the
normalized les activity was 9% ( ir , 5% ) of mvc during the roll - out ,
4% ( ir , 3% ) of mvc during the bodysaw , 12% ( ir , 7% ) of mvc during the
pike and 8% ( ir , 5% ) of mvc during the knee - tuck . during all
exercises the normalized les values were not significantly higher
( p < 0.01 ) .
the normalized ues
activity was 11% ( ir , 6% ) of mvc during the roll - out , 8% ( ir , 6% ) of
mvc during the bodysaw , 9% ( ir , 4% ) of mvc during the pike and 6%
( ir , 5% ) of mvc during the knee - tuck . during all exercises the
normalized ues values were not significantly higher
( p < 0.01 ) .
table 2 shows the estimate
( difference of means ) at 95% of the confidence interval after tukey
multiple comparisons ; in this case only exercise
factor was considered .
estimate
at 95% of the confidence interval after tukey multiple comparisons
with the exercise factor considered .
the estimate
shows the difference of means ( % of maximum voluntary contraction ) . indicates the statistical significance of the adjusted p - value .
the roll - out exercise showed significantly ( p < 0.01 ) higher
activation compared to the bodysaw ( 16% , ci 8 - 23% ) , pike ( 26% , ci
18 - 33% ) and knee - tuck ( 29% , ci 21 - 37% ) .
pike and knee - tuck exercises
showed significantly higher activation compared to the bodysaw of 10%
( 28% ) and 13% ( 6 - 21% ) .
suspension training has become
increasingly popular as a training tool . despite this popularity ,
relatively little research exists on the effects of such training on
muscle activation magnitude .
the first objective of the study was to
investigate the activation differences of four exercises ( roll - out ,
bodysaw , pike and knee - tuck ) to better characterize suspension
training .
our findings indicate that suspension exercises could be an
effective strategy to reach high to very high activation of abdominal
muscles such as the rectus abdominis and external oblique . to
facilitate comparisons between exercises and previous studies
, we
categorized muscle activation into four levels according to previous
studies , with < 21% as low , 2140% as moderate ,
4160% as high , and > 60% as very high ( escamilla et al . ,
2010 ) .
exercises used in the present study provide a range of
medium to high intensity exercises through which participants or
athletes can progress during a training or rehabilitation programme
( blanchard and
glasgow , 2014 ) ( figure 2 ) .
roll - out exercise
was the most challenging for core musculature , followed by bodysaw ,
pike and knee - tuck exercises ( table 2 ) .
the roll - out showed
the highest activation of rectus abdominis and oblique muscles
compared to other exercises .
although lra showed much greater
activation in roll - out and bodysaw compared to pike and knee - tuck
exercises , the other muscles showed smaller differences .
these
findings could suggest that in the exercises characterized by
shoulder flexion ( such as roll - out and bodysaw ) , the increased
requirement of core stability was reflected more by the lower rectus
abdominis . according to vezina and hubley - kozey
( 2000 ) , the exercises that generate muscle activity greater
than 60% of mvc might be more conducive to developing muscular
strength .
the rectus abdominis ( both parts ) and eo reached activation
higher than 60% of mvc ( or very close to that threshold , 55% ) in the
roll - out and bodysaw ; consequently these exercises can be considered
suitable for strength training of these muscles .
although in the
knee - tuck and pike , the rectus abdominis and eo did not reach the
threshold of 60% , they presented high activation levels ( 41 - 60% mvc ) .
while strengthening of the core is important , an activation level
below 60% might be beneficial in increasing muscle endurance within
the core . since the core muscles are primarily composed of type i
fibres ( haggmark and thorstensson ,
1979 ) , muscular endurance should also be a major concern when
designing strength and conditioning programmes ( vezina and hubley - kozey ,
2000 ) . due to large demand for muscle activation , all the
proposed exercises might be appropriate for extremely fit individuals
in the latter stages of a progressive abdominal strengthening or
rehabilitation programme .
this is an expected
result as all exercises focused on anterior abdominal wall muscles .
this finding confirms that in the herein selected whole - body linkage
exercises , the activation of core muscles can be mainly focused on
abdominal muscles while keeping the paraspinal muscles involved with
low intensity .
although no direct comparison can be made
between the selected suspension exercises compared to previously
reported similar exercises , it is possible to highlight the following
differences .
we can compare only the activation of the rectus
abdominis , since for oblique muscles we used a different
normalization exercise than the other three studies .
plank exercises
are frequently included in spine stabilization programmes as a means
of improving motor control for spine stabilization .
when plank
exercises are performed on stable or unstable support surfaces , the
reported activation level of the rectus abdominis and eo ranges from
low to moderate ( garcia - vaquero et al . , 2012 ) .
when executed in suspension condition , rectus abdominis muscles also
showed moderate activation ( byrne and bishop , 2014 ) .
only
when the planks were performed with a similar technique ( instability
on lower limb and shoulder flexion ) was the activation similar to
that reported here , which was very high for the rectus abdominis
( mcgill and
andersen , 2015 ) .
therefore , we can assume that our exercises
were more challenging than an isometric plank in a stable
condition .
in the roll - out , we found very high activation of
lra ( 140% ) and ura ( 67% ) .
these levels were higher than previously
reported values obtained during the execution of the roll - out with the
swiss - ball ( about 50 - 60% for rectus abdominis ) ( escamilla and lewis , 2010 ;
marshall and
desai , 2010 ) and similar to the values reported with the use
of the power wheel , being very high for ura ( 76% ) and lra ( 81% )
( escamilla et
al . , 2006 ) .
in the pike , we found high activation of lra ( 57% )
and ura ( 41% ) .
the values reported for the pike executed with the
swiss ball ( escamilla and lewis , 2010 ) and
power wheel ( escamilla and babb , 2006 ) were
similar for ura ( swiss ball 47% ; power wheel 41% ) and lra ( swiss ball
55% ; power wheel 53% ) . in the knee - tuck , we observed high activation
of lra ( 54% ) and ura ( 44% ) . otherwise , the values reported for the
knee - tuck executed with the swiss ball ( escamilla and lewis , 2010 ) and
power wheel ( escamilla and babb , 2006 ) were
lower for both ura ( swiss ball 32% ; power wheel 41% ) and lra ( swiss
ball 35% ; power wheel 45% ) .
our findings suggest that the two
parts of the rectus abdominis can be activated differently according
to the needs of the motor task ( kibler et al . , 2006 ) .
this
finding could be explained by the possibility to ( voluntary or
involuntary ) modulate the activation ratio between rectus abdominis
parts in order to achieve the best control of the core region .
this
could be justified by the metameric innervation of rectus abdominis
muscles ( duchateau et al . , 1988 ) ,
although this issue is still controversial ( monfort - panego et al . , 2009 ) .
however , lra muscles were generally more active than ura because of
confounding methodological factors .
mvcs of the lra and ura in fact
were estimated by a standardized exercise to activate maximally the
trunk muscles : it could be argued that the same exercise fully
activated ura whereas it failed to fully activate lra .
hence , the emg
amplitude recorded during mvc was not the maximum achievable .
consequently , throughout experimental exercises , lra seemed
relatively more active than ura because its reference value of mvc
was underestimated .
, arv estimates of
emg signals exceeded the mvc reference values ( arv higher than 100% ) .
this inconsistency might be due to incomplete activation during mvc
( as in the case of the lower rectus abdominis ) and other confounding
factors related to emg technique ( relative shift of muscle belly with
respect to electrodes occurring in dynamic tasks and different
activation between isometric and dynamic tasks , among others ) . as widely reported , variability of muscular activation between
participants was high .
this suggests that performing these exercises ,
some individuals might produce more or less activation than the
average activity indicated here .
although 17 individuals participated
in this research , the differences in their fitness level and exercise
experience could have affected the performance of the exercises and
the resulting activation levels .
crosstalk between muscles was
minimized by using an innovative detection system based on
concentric - ring electrodes which had been reported as having higher
spatial selectivity compared to the traditional detection systems and
reducing the problem of crosstalk from nearby muscles ( farina and cescon ,
2001 ) .
findings from this study , based on
electromyographic analysis , showed that roll - out exercise was the
most challenging .
moreover , roll - out and bodysaw exercises executed in
suspension activated the rectus abdominis and external oblique
muscles at intensities higher than , or very close to , 60% of the
maximum voluntary contraction . based on these findings
, we can assume
that roll - out and bodysaw exercises can be used to adequately
strengthen the antero - lateral , superficial aspect of the core region ,
and thus they can be considered core strength exercises .
these
findings appear to have particular relevance for well - trained
individuals given the high demand imposed by these exercises . | abstracta quantitative observational laboratory study was conducted to characterize and classify core training exercises executed in a suspension modality on the base of muscle activation . in a prospective single - group repeated measures design
, seventeen active male participants performed four suspension exercises typically associated with core training ( roll - out , bodysaw , pike and knee - tuck ) .
surface electromyographic signals were recorded from lower and upper parts of rectus abdominis , external oblique , internal oblique , lower and upper parts of erector spinae muscles using concentric bipolar electrodes . the average rectified values of electromyographic signals were normalized with respect to individual maximum voluntary isometric contraction of each muscle .
roll - out exercise showed the highest activation of rectus abdominis and oblique muscles compared to the other exercises .
the rectus abdominis and external oblique reached an activation higher than 60% of the maximal voluntary contraction ( or very close to that threshold , 55% ) in roll - out and bodysaw exercises .
findings from this study allow the selection of suspension core training exercises on the basis of quantitative information about the activation of muscles of interest .
roll - out and bodysaw exercises can be considered as suitable for strength training of rectus abdominis and external oblique muscles . | [
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] |
acute mountain sickness ( ams ) occurs during exposure to high altitude ( ha ) and is a clinical syndrome characterised by headache , insomnia , malaise , and gastrointestinal symptoms .
it is common , developing in 1030% at 25003000 meters and in up to 60% of those ascending to around 4500 meters .
it causes significant morbidity and is a challenging clinical condition in remote environments . a biochemical marker of ams , particularly one available as a point - of - care test ( poc ) , could have widespread clinical utility .
the pathophysiology of ams is not clearly understood but involves alterations in fluid balance , endothelial function , vascular permeability , inflammation , and oxidative stress .
the renal response to ha is an important factor in acclimatization , and ha exposure leads to renal arteriole constriction and relative hypoxia [ 3 , 4 ] . despite the relative renal hypoxia ,
ngal ( neutrophil gelatinase - associated lipocalin ) is a 25 kda peptide , part of the lipocalin family of small soluble proteins .
it is produced in a number of human tissues , notably the distal nephron but also in the lung ngal rises rapidly in the nephron in response to a renal insult and an ngal 150 ng / ml following acute kidney injury ( aki ) is predictive of acute renal failure ( arf ) well before creatinine has risen .
ngal is also an acute - phase protein , has a role in inflammation [ 8 , 9 ] , and is upregulated in the lung during inflammation [ 5 , 10 , 11 ] .
ngal is also known to rise in conditions associated with oxidative stress [ 12 , 13 ] , and oxidative stress has been implicated in ams [ 14 , 15 ] .
we therefore hypothesised that ngal would increase at ha secondary to these various stimuli and that the magnitude of any increase might relate to the presence of ams .
we therefore studied a combined cohort of trekkers from 2 expeditions to ha . in order to clarify the relative contribution of ams , hypoxia or exercise to ngal levels
, we also studied a cohort pre- and postexercise at near sea level , and a further cohort exposed to acute normobaric hypoxia .
the potential role of inflammation in stimulating ngal was assessed by the measurement of highly sensitive c - reactive protein ( hscrp ) in a subset of participants .
all study protocols were approved by the ministry of defence research ethics committee , whitehall , uk , and satisfied the requirements of the declaration of helsinki . in all studies informed ,
thirty - two subjects participating in a defence medical services ( dms ) trekking expedition ( trek 1 ) in the khumbu region of nepal were studied .
blood samples were taken from the antecubital fossa at 3 study altitudes : on day 2 at 3400 m , day 6 at 4270 m , and day 10 at 5150 m ( following ascent to everest base camp at 5364 m ) . all samples in this study
were collected immediately following a day trekking ( posttrek ) to the study altitude .
twenty subjects from a further dms expedition ( trek 2 ) to nepal were also studied .
blood samples were again taken at 3 study altitudes : on day 2 ( 3400 m ) , day 6 ( 4270 m ) , and day 10 ( 5150 m ) ( following ascent to kala patthar ( kp ) , 5643 m ) .
samples in this study were again collected immediately following a day trekking ( posttrek ) .
additional samples were taken at rest in kathmandu ( kat ) at 1300 m and at rest the next morning at the 3 study altitudes .
as serving members of the military , all subjects were able to fulfil the fitness criteria of their relevant service .
this broadly includes an age - adjusted ability to run 1.5 miles in under approximately 11 minutes and to perform an age - adjusted number of sits - ups and push - ups within two blocks of 2 minutes .
fourteen subjects underwent a 3-hour exposure to normobaric hypoxia ( fio2 11.6% , equivalent to 4800 m altitude ) in a hypoxic chamber .
this exposure included a 5-minute step test ( step height of 25 cm , 1 complete step every 2 seconds ) at 95 minutes .
a group of 22 subjects had ngal assayed at rest and after exercise at sl in the uk following ascent from sea level to 1085 m over 6 hours ( an equivalent gain in altitude and duration of exercise similar to that experienced on a trekking day in nepal ) .
two subjects from trek 2 were part of the sl exercise group , but data collection occurred several months apart .
ngal was analysed in the field on a biosite triage point of care monitor ( alere ltd , stockport , uk ) using a triage ngal test kit .
the triage ngal test is a point - of - care , fluorescence - based immunoassay used which gives a rapid ( 15 minutes ) quantitative measurement of ngal in a range from 60 to 1,300 ng / ml .
oxygen saturation ( digitally on warm hands at rest ) was measured using a nellcor np-20 pulse oximeter ( covidian , ma , usa ) during trek 1 + 2 and in the hypoxic chamber study at the same time as blood samples were taken . during trek 1 + 2 ,
twice - daily ams scores were assessed using the lake louise score ( lls ) questionnaire .
the lls allocates a score of 0 to 3 ( symptom not present to severe ) for symptoms of ams ( headache , gastrointestinal symptoms , fatigue / weakness , dizzy / light - headedness , and difficulty sleeping ) .
a score of 3 or more in the presence of headache is consistent with ams , a score of 6 or more with severe ams .
the commercially available , highly sensitive , immunoturbidimetric assay ( roche diagnostics ) was used to measure crp in trek 2 at the same time points as ngal .
mg / l and a between - run coefficient of variation between 2.5 and 5.7% . for statistical calculations ,
the software package spss 14.0 was used . for subjects with a ngal below the limit of detection of the assay ( 60 ng / ml ) ,
a value of 60 ng / ml was assigned for the purposes of statistical analysis .
all data were tested for gaussian distribution using the kolmogorov - smirnov test and shapiro wilks statistic . for the analysis of dependent variables that were normally distributed , changes were tested by student 's paired t - test . for independent variables that were normally distributed ,
a within - subjects anova was performed to investigate any serial changes in ngal with ascent at rest and post - trek . a two - way mixed anova with either resting or after trek ngal at each study altitude as the within - subjects factor and the presence of ams ( according to the ll score at multiple altitudes ) as the between - subjects factor
if the mauchly sphericity test was significant , then p values were expressed after multiplication by the greenhouse - geisser epsilon .
correlation analyses for normally distributed data were performed by calculating the pearson coefficient of correlation .
a p value < 0.05 ( two - sided ) was considered significant . as the ascent profile and route were closely matched in trek 1 and trek 2 , data were combined and analysed as a whole . taking medication ( acetazolamide , dexamethasone )
had no apparent effect on ngal values , and therefore these subjects ( n = 11 ) were not excluded from the analysis .
demographic data for the field study ( trek 1 + 2 ) , the controls , and the hypoxic chamber study are shown in table 1 . in the 22 subjects ascending to 1085 m in the uk
, there was no significant ( p = 0.084 ) rise in ngal following exercise : resting sl ngal was 64 11 ( ng / ml , mean sd , range 60104 ) and postexercise ngal was 71 14 ( ng / ml , mean sd , range 60100 ) . of the 52 subjects ,
spo2 ( % , mean sem ) dropped from 97 2 at kat ( 1300 m ) to 84 5 and 79 7 at 4270 and 5150 m , respectively ( p < 0.001 ) .
there was a moderate inverse correlation between ngal and spo2 at 5150 m ( r = 0.477 , p = 0.001 ) ( figure 1 ) with a weaker inverse correlation between ngal and spo2 at 4270 m ( r = 0.340 , p = 0.019 ) .
within the subjects , anova demonstrated a significant change in ngal with ascent both at rest ( p = 0.007 ) and after trek ( p = 0.001 ) ( figure 2 ) .
spo2 ( % , mean sem ) dropped from 99 0.4 at baseline to a nadir of 79 5 ( p < 0.001 ) . despite an equivalent drop in spo2 to
that seen in trek 1 + 2 , ngal ( ng / ml , mean sd , range ) showed no change between baseline and 180 minutes : 63 26 ( 2980 ) versus 67 25 ( 2784 ) , p = 0.538 . in trek 2 , serum creatinine { mol / l , mean sem , ( range ) , ( p value versus baseline at kat ) } was 78 2 ( 6395 ) at baseline ; at 3400 , 4270 and 5150 m it was 87 3 ( 72120 ) ( p = 0.001 ) ; 84 2 ( 72104 ) ( p < 0.001 ) ; and 94 5 ( 76142 ) ( p < 0.001 ) .
according to their ll scores at the highest study altitude ( 5150 m ) , there were 23 subjects with no ams , 16 subjects with mild ams , and 7 subjects with severe ams .
there was a significant difference between ngal depending on the presence or absence of ams at 5150 m ( figure 3 ) with higher values in those with ams and severe ams . a two - way mixed anova revealed a significant change ( p = 0.003 ) in resting ngal with ascent and an interaction with ams at 4270 m ( p = 0.017 ) and 4910 m ( p = 0.002 for change in ngal , p = 0.027 for interaction with ams ) .
hscrp was ( mean sem , range ) : 1.6 0.4 ( 0.337.53 ) at baseline ; at 3400 m , 4270 m , and 5150 m post - trek : 7 2.9 ( 0.7847.93 ) ( p = 0.002 versus baseline ) ; 25.7 8.1 ( 0.58104 ) ( p < 0.001 versus baseline ) ; 9 3.2 ( 0.5644.62 ) ( p = 0.003 versus baseline ) . at 3400 m , 4270 m , and 5150 m at rest : 6.2 2.9 ( 1.8725.1 ) ( p = 0.001 versus baseline ) ; 21.6 5.7 ( 0.4983.9 ) ( p < 0.001 versus baseline ) ; and 5.8 2.1 ( 0.5426.59 ) ( p = 0.012 versus baseline ) .
ngal at 5150 m , after trek was moderately correlated with hscrp at 5100 m after exercise ( rho 0.526 , p = 0.036 ) .
this is the first report to describe an association between ngal and both the presence and severity of ams at ha .
the significant novel findings are that ngal rises in response to sustained hypobaric hypoxia but not acute normobaric hypoxia or near sl exercise and that this rise is related to ams at 5150 m. the rise in ngal following trekking ( by day 2 at 3400 m ) was to the levels normally associated with the subsequent development of arf ( > 150 ng / ml ) , but this did not occur .
although creatinine rose significantly with altitude , the rise was very modest , and we suspect that a combination of factors other than a simple renal insult is responsible for the increase in ngal at ha .
our data suggest an inverse correlation between spo2 and ngal at 5150 m ( and to a lesser extent at 4270 m ) . although no such correlation was found at 3400 m , this may still suggest that prolonged renal hypoxia could be a significant drive to ngal release .
in addition to renal hypoxia , we suspect that other factors may also contribute to the rise in ngal at ha . the significantly greater ngal in those with severe or mild ams versus those without at 5150
indeed , ngal is an acute - phase protein with a role in inflammation [ 8 , 10 , 11 ] .
exercise stimulates an immune response , and hypoxia is also known to cause a response in immune and endothelial cells with inflammatory markers such as hscrp increasing with ha [ 1922 ] .
consistent with this , we saw a significantly higher hscrp at all altitudes compared to baseline .
limited data have suggested hscrp may be associated with ams but we did not demonstrate any evidence to support this .
there was a weak correlation between hscrp and ngal at 5150 m but this can not explain the rise in ngal as a whole .
ngal also rises with oxidative stress [ 9 , 12 ] which is increased by exercise , and ha - induced oxidative stress has been implicated in ams . as such , it is interesting to note that we found a higher ngal following trekking and in those with ams at the highest altitude . in an attempt to clarify the relative influence of exercise and hypoxia on ngal , we measured ngal before and after exercise of a similar duration ( 6 hrs ) and similar incremental altitude ( 1085 m ) as that experienced daily in nepal and also in a hypoxic chamber . in neither scenario did ngal rise .
this may reflect inadequate duration or severity of stimulus but may also reflect that the ngal response is not due to exercise or hypoxia alone but is multifactorial involving hypoxia , oxidative stress , an inflammatory response , and other , as yet unidentified , stimuli .
we also acknowledge limitations such as a lack of serum markers of oxidative stress and a lack of resting ngal data in trek 1 .
in addition , we did not measure ngal at sl before departure to nepal , although the ngal recorded as a baseline at kat ( 1300 m ) ( 68 ng / ml ) was no different to those recorded at sl in the uk ( 63 and 64 ng / ml ) .
we also acknowledge the fact that although we measured creatinine in trek 2 , we did not continue to monitor it after the cessation of trekking . as a consequence of creatinine rising more slowly in response to a renal insult than ngal ,
in conclusion , there are several interesting and novel findings that are worthy of further exploration .
ngal rises in response to prolonged hypobaric hypoxia ; marked increases in ngal may occur without concomitant arf and the degree of ngal rise at ha is associated with the presence or absence of ams .
the fact that ngal does not appear to rise secondary to acute normobaric hypoxia or exercise in isolation suggests that the rise at ha and relation with ams may have common pathways , perhaps related to prolonged hypoxia and an inflammatory response . with the huge and increasing popularity of recreational sports undertaken at both moderate and high altitude
assessment of ngal takes a matter of minutes using poc testing , and its use in identifying ams requires further evaluation . | acute mountain sickness ( ams ) is a common clinical challenge at high altitude ( ha ) . a point - of - care biochemical marker for ams could have widespread utility .
neutrophil gelatinase - associated lipocalin ( ngal ) rises in response to renal injury , inflammation and oxidative stress .
we investigated whether ngal rises with ha and if this rise was related to ams , hypoxia or exercise .
ngal was assayed in a cohort ( n = 22 ) undertaking 6 hours exercise at near sea - level ( sl ) ; a cohort ( n = 14 ) during 3 hours of normobaric hypoxia ( fio2 11.6% ) and on two trekking expeditions ( n = 52 ) to over 5000 m. ngal did not change with exercise at sl or following normobaric hypoxia . during the trekking expeditions ngal levels ( ng / ml , mean sd , range ) rose significantly ( p < 0.001 ) from 68 14 ( 60102 ) at 1300 m to 183 107 ( 65519 ) ; 143 66 ( 60315 ) and 150 71 ( 60357 ) at 3400 m , 4270 m and 5150 m respectively .
at 5150 m there was a significant difference in ngal between those with severe ams ( n = 7 ) , mild ams ( n = 16 ) or no ams ( n = 23 ) : 201 34 versus 171 19 versus 124 12 respectively ( p = 0.009 for severe versus no ams ; p = 0.026 for mild versus no ams ) . in summary ,
ngal rises in response to prolonged hypobaric hypoxia and demonstrates a relationship to the presence and severity of ams . | [
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] |
from may 1 through july 30 , 2007 , a total of 29 cases of locally acquired cyclospora infection were reported in british columbia ( figure 1 ; table 1 ) .
an initial investigation was conducted around the 6 laboratory - confirmed case - patients reported in the last 2 weeks of may and the first week of june ( phase 1 ) .
no common exposure was reported , and case reports subsided . during the last week of june , case reports resumed , and phase 2 of the investigation was initiated .
a total of 19 confirmed and 4 probable cases were identified with symptom onsets during june 28july 20 , 2008 .
average time from symptom onset to positive laboratory result was 17 days ( range 631 days ) . confirmed and probable cases of cyclosporiasis ( n = 29 ) , by date of onset , british columbia , canada , may august 2007 . *
laboratory - confirmed cases were reported to public health by medical diagnostic laboratories and specimens forwarded for confirmation to the public health reference laboratory .
oocysts included shape ( spherical ) , size ( 810 m in diameter ) , oocyst wall ( well - defined ) , internal contents with refractile globules , autofluorescence , and modified acid - fast or safranin staining ( 1 ) . during phase 2 , a total of 17 confirmed case - patients were interviewed with hypothesis - generating questionnaires about items eaten in the 2 weeks before symptom onset .
the instrument included questions about restaurant history with meal details ; grocery stores frequented ; and yes / no questions about > 70 fruits and vegetables , 8 herbs , and 16 mixed foods ( e.g. , salsa , pesto ) previously implicated in outbreaks of foodborne disease .
frequently reported foods were compared with population controls from canadian ( waterloo , ontario ) and american ( oregon ; us foodborne diseases active surveillance network [ foodnet ] ) published food consumption surveys ( 35 ) .
although such measurements may be limited by the timing of questionnaire administration and the recall period considered , they can be useful comparators during the hypothesis - generating stages of an investigation . by the end of phase 2 , strawberries , cilantro , and sweet basil
garlic and red peppers also were commonly eaten by case - patients ; however , population comparisons were unavailable .
eighty - eight percent of case - patients reported having eaten romaine lettuce ; 85% of controls in the waterloo survey ( 4,5 ) had eaten lettuce of any type , and romaine lettuce consumption was much less commonly reported in the foodnet survey ( 3 ) ( table 2 ) .
a formal case control study was considered premature in the early stages of phase 2 because no strong hypothesis emerged from early interviews and comparisons to population controls .
we further explored the plausibility of various hypotheses through a combination of methods described below that allowed room for additional hypotheses to emerge or existing hypotheses to strengthen as cases accrued .
* case - patients were 17 persons with laboratory - confirmed cases interviewed during phase 2 ( june 24july 21 , 2007 ) .
us foodnet , foodborne diseases active surveillance network ; na , not applicable . detailed questionnaires asked whether foods were eaten in a restaurant or were store - bought and about type of packaging and method of preparation ( because c. cayetanensis is heat - sensitive ) ( 6 ) .
we reinterviewed early case - patients using the second questionnaire and interviewed later case - patients using both questionnaires . in phase 1 ,
garlic eaten at restaurants by all 4 persons with confirmed infections were traced back to different suppliers ; only 1 case - patient ate raw garlic in a restaurant .
three case - patients also reported eating cooked garlic at home ; cooking would have inactivated the pathogen . early and proactive collaboration with cfia involved a general assessment of the country of origin and distribution patterns for frequently eaten foods . according to cfia records ,
romaine lettuce and red peppers sold during the exposure period were not imported from a known cyclospora - endemic country and were widely distributed in canada and the united states .
comm . ) . because interviews , population control comparisons , and product distribution limited suspected foods to strawberries , cilantro , and basil , we began preliminary traceback of all 3 suspected items . environmental health officers and regional cfia staff
interviewed grocery store owners , restaurant managers , and distributors to trace produce to its supplier .
local strawberries eaten by case - patients from 3 small markets were traced back to 2 local farms in geographically separate regions of british columbia .
cilantro eaten by case - patients was traced to 2 suppliers ; both supplied home - grown rather than imported produce .
of 14 case - patients with confirmed basil exposures , 4 ( 57% ) ate only organic basil supplied by distributor a. additionally , 4 ( 29% ) reported multiple basil exposures , including exposure to organic basil from distributor a ( figure 2 ) . in british columbia , organic basil enjoys a smaller market share than the conventional product .
traceback of basil eaten by persons with confirmed cyclosporiasis ( n = 14 ) , british columbia , canada , may
august 2007 . in phase 2 , 12 ( 71% ) of 17 case - patients reported shopping at grocery c. records of any grocery store purchases for the households of 8 consenting case - patients were obtained through grocery c s savings card program ; other case - patients were not cardholders .
all purchase histories were requested for 1 month before symptom onset to account for the typical incubation period plus product shelf life .
records from 3 ( 38% ) case - patients showed purchases of the same organic basil supplied by distributor a. two case - patients had bought organic basil on the same day at the same location .
of the remaining 5 case - patients who recalled purchasing organic basil but whose consumer card records did not confirm it , 2 had not used their cards for large portions of the incubation period .
we collected supplier information for organic basil during a visit to the distribution warehouse and local farm site of distributor a. the remaining 2 ( 14% ) case - patients with basil exposure previously unlinked to distributor a were confirmed through trace - forward from distributor a. the first had eaten organic basil at a smaller market supplied by distributor a under another trade name .
the second had eaten conventional basil from a grocery store supplied by distributor a. distributor a confirmed using organic basil to supplement conventional basil shipments when supply was low .
late summer outbreaks of cyclosporiasis in british columbia are unusual ; distributor a confirmed that imported product was used throughout the summer in 2007 because of a poor local growing season .
all case - patients in phase 2 who recalled basil exposure ( 82% ) could have been exposed to organic basil from distributor a. once this common vehicle was identified , cfia conducted a full traceback of organic basil by using formal documentation including invoices , shipment numbers , and airway bills . the suspected imported basil was no longer available for testing .
using distributor a invoices , we identified a specific shipment of organic basil imported from 1 of 2 mexican supplier farms , and cfia notified mexican authorities .
the mexican farm was located in a region previously linked to cyclosporiasis outbreaks ( r. cardinal , cfia , pers .
detailed interviews , modified traceback of several suspected items , and information about product distribution and market share led to organic basil as a primary hypothesis .
food regulators could pinpoint a specific shipment and trace it to its origin because consumer cards provided the exact purchase dates for basil that case - patients could not recall .
overall , the approach used in this investigation increased the work load typically requested of team members during foodborne outbreaks .
however , this combination of investigative methods successfully identified a single vehicle during a community cyclosporiasis outbreak where a common menu was not available . | investigations of community outbreaks of cyclosporiasis are challenged by case - patients poor recall of exposure resulting from lags in detection and the stealthy nature of food vehicles .
we combined multiple techniques , including early consultation with food regulators , traceback of suspected items , and grocery store loyalty card records , to identify a single vehicle for a cyclosporiasis outbreak in british columbia , canada , in 2007 . | [
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brucellosis is a zoonotic disease mostly transmitted to humans through consumption of unpasteurized dairy products and can lead to a systemic disease with any organ involvement . in this report , we describe a case of brucellosis - induced avascular necrosis of the hip .
brucellosis was diagnosed through serological tests , and avascular necrosis of the femoral head was confirmed by pelvic mri .
the patient was treated with a combination of antimicrobial treatments and referred to the orthopedic service for total hip arthroplasty .
brucellosis may present with unusual manifestations and should be always taken into consideration , particularly in endemic areas .
brucellosis is a zoonotic disease mostly transmitted to humans through consumption of unpasteurized dairy products of infected animals ( 1 ) .
it is a serious public health problem particularly in endemic areas , and is accompanied by .
the disease is endemic in iran and has a high prevalence in lorestan province , central iran ( 3 ) .
brucellosis is a systemic disease that may involve any organ in the body ( 4 ) .
osteoarticular involvements including arthritis , spondylitis , osteomyelitis , tendonitis , and bursitis occur frequently and are reported in 3085% of patients with brucellosis ( 5 ) .
the involvement of the large peripheral joints is usually manifested as monoarthritis ( 1 ) . although the hip joints involvement may happen in brucellosis , brucellosis - induced avascular necrosis of the hip
, we describe a case of brucellosis that complicated by avascular necrosis of the femoral head .
the patient was a 50-year - old rural farmer and rancher who presented with groin pain for six months before admission .
he reported no history of trauma , underlying diseases , and steroids and alcohol use . over the previous six months
, he had experienced symptoms including .fever , night sweats , weakness , fatigue , anorexia , and weight loss of 10 kg .
the patient was visited by a local therapist ; in addition there was a delay in timely referral due to his addiction to opium .
the groin pain was his most severe complaint on admission so that he could not bear his weight on the right leg .
the physical examinations on admission showed stable vital signs , there was no organomegaly , and the right hip was in flexion and external rotation position so that any active and passive motion increased the pain .
the results of laboratory study were as follows : complete blood count ( cbc ) : nl , liver function test ( lft ) : nl , rheamatic factor ( rf ) : neg , antinuclear antibody ( ana ) : neg , blood culture : neg , elevated erythrocyte sedimentation rate ( esr ) , c - reactive protein ( crp ) : positive , and standard agglutination test for brucellosis : positive ( table 1 ) .
pelvic radiography and magnetic resonance imaging ( mri ) were administered showing avascular necrosis of right femoral head ( fig . 1 , 2 ) .
the patient was subsequently treated with standard antibrucellosis regimen : streptomycine 1gr / d i m for three weeks , doxycycline 100mg / bid po , and rifampin 600mg / d po .
.despite the improvement in the patient s general condition and laboratory evidence showing infection control , the patient was suffered from right groin pain and limitation of motion in the hip joint .
although osteoarticular involvements , especially arthritis in the large peripheral joints , are among the most common manifestations of brucellosis , no joint destruction has been reported in many studies ( 5 ) . despite few reports on the permanent joint complications of brucellosis - induced peripheral joint arthritis , hip joints pyogenic infection has a poor prognosis , particularly if treatment is delayed ( 6 ) .
delays in diagnosis and treatment of brucellosis - induced hip arthritis could lead to complications including dislocation and avascular necrosis of the femoral head ( 4 ) .
although aspiration and examination of the joint fluid were not performed due to lack of synovial effusion on admission , considering the positive serological tests for brucellosis and concurrent avascular necrosis of the femoral head on mri , it seems that the delay in diagnosis and treatment of brucellosis in this patient had led to avascular necrosis of the femoral head .
finally , the following questions arise : was avascular necrosis caused by increased intra - articular pressure related to the infection or due to direct involvement of the femoral head by the organism ?
since brucellosis is a systemic infection with a broad clinical spectrum ranging from asymptomatic forms to deaths in severe cases , this disease should be taken into considerations when dealing with any patient with various and nonspecific symptoms in endemic areas with extension of the clinical signs of brucellosis .
moreover , early diagnosis and long - term treatment and follow - up are of great importance in brucellosis . | backgroundbrucellosis is a zoonotic disease mostly transmitted to humans through consumption of unpasteurized dairy products and can lead to a systemic disease with any organ involvement . in this report , we describe a case of brucellosis - induced avascular necrosis of the hip .
brucellosis was diagnosed through serological tests , and avascular necrosis of the femoral head was confirmed by pelvic mri .
the patient was treated with a combination of antimicrobial treatments and referred to the orthopedic service for total hip arthroplasty .
brucellosis may present with unusual manifestations and should be always taken into consideration , particularly in endemic areas . | [
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, more than 9000 articles related to sids were published and over 100 sids explanations appeared in medical hypotheses .
sids occurs when an infant dies suddenly , unexpected by history , and without a cause found at forensic autopsy or thorough death - scene investigation . in the past four decades several multifactor models
three inter - related causal spheres of influence model in which any two of these three could cause sids : ( 1 ) subclinical tissue damage ( 2 ) deficiency in postnatal development of reflexes and responses , and ( 3 ) environmental factors .
filiano and kinney also proposed a triple risk model but required three risk factors , similar to emery 's , to act simultaneously and described them as ( 1 ) vulnerable infant ; ( 2 ) critical development period ; and ( 3 ) environmental stressors .
these and other models do not , however , address the mathematical character of sids .
this paper addresses each characteristic factor of sids that must be explained : the gender distribution ; the age distribution ; the effect of prone and supine sleep positions ; the seasonal variation ; risk factors of anemic apnea , respiratory infection , and neurological prematurity , and links them together with other causes of respiratory deaths as a proposed unifying theory .
this paper uses data on infant live births and deaths as reported by the u.s .
the sids data are given by international classification of diseases ( icd ) for 19791998 as 9icd and for 19992005 as 10icd .
although technically a sids diagnosis requires an autopsy without causal findings , not all these sids were autopsied and the percentage of sids without autopsy in the us has decreased monotonically from 1979 to the present day .
however , cdc lists sids for all autopsied and nonautopsied cases without distinction . in the case of an interracial parentage
consequently the cause of death and race of sids will have measurement error involved which will increase the chi - square 1 d.f .
test statistics ( 1 ) of comparisons between predicted and observed sids numbers and races , above those for tabulated p - values that assume the variance is from sampling error only
. therefore although p - values are presented they may give incorrect implications for rejection of hypotheses if they fall < p = .05 .
we therefore rely upon the overall consistency of age and gender data to support our mathematical construct of sids .
a characteristic male fraction is associated with sids . because of difficulty in detecting congenital anomalies and other subtle causes of death in < 28-day neonates , postneonatal sids
the cdc reports there were 62,933 male and 40,952 female postneonatal sids during 1979 to 2005 for a male fraction of 0.606 .
figure 1 shows the male fraction of us postneonatal sids of all races over this period fluctuating slightly about the mean value of 0.606 as the sids rate decreased markedly from the discovery that the prone sleep position was a major sids risk factor which was followed by a back - to - sleep campaign in 1992 .
naeye et al . first hypothesized that the male excess in infant mortality could be x - linked .
mage and donner [ 810 ] showed that this excessive male fraction could be related to an unknown x - linked gene locus with a dominant allele ( a ) protective against sids , perhaps by providing enzymatic activity to allow anaerobic oxidation to take place in respiratory control neurons of the brainstem during transient periods of cerebral anoxia .
the corresponding recessive allele ( a ) , with frequency q , would not provide this protection and could allow critical cerebral neurons to die of anoxia , and sids to occur when the dominant allele a is not present . for xy males and
xx females the recessive allele frequency ( q ) can be determined from ( 1a ) and ( 1b ) , as the ratios of susceptible infants
( 1a)fmmm = q2fbq mb ,
( 1b)q = fm / fbmm / mb ,
where fm and mm are postneonatal female and male sids and fb and mb are female and male live birth rates , respectively , so q represents the female postneonatal sids rate divided by the male postneonatal sids rate per 1000 live births .
the global average male fraction of 0.612 for autopsied postneonatal sids is higher than the 0.606 us male fraction for total autopsied and nonautopsied sids , perhaps due to false positive sids that have a lower male fraction . with a 5% average male excess live birth rate ,
when stratified by race , we obtain from the cdc us 19792005 total postneonatal sids and birth data there is a white male fraction of 0.622 , black male fraction of 0.570 , and other races combined = 0.594 . using ( 1b ) , q white = 0.639 , q black = 0.779 , and for other races combined q = 0.724 . such variation in allele fraction between races along with the establishment of hardy - weinberg equilibrium
is expected for each racial grouping from genetic drift over a long period of time . by necessity
we accept here the cdc racial designations and neglect the presence of interracial infants . in our genetic analysis
we assume that all sids infants have only the recessive allele ( a ) and require their probability of genetic susceptibility pg to equal 1 . to support this genetic mechanism , we note in table 1 that other causes of respiratory deaths in infancy have a statistically similar male fraction to 0.606 for postneonatal us sids when all races are combined .
not all of these cdc reported cases were autopsied , and false positive sids occur from infanticide by gentle suffocation that is virtually indistinguishable from sids at autopsy , so statistical testing assuming no autopsy error may not be cause for rejection at p = 0.05 .
rds , also known as hyaline membrane disease , had a male fraction of 0.610 .
bronchopulmonary dysplasia had a male fraction of 0.613 . with the discovery that the prone position is a risk factor , there is a trend to parse postneonatal sids into true sids and subcategories .
two such alternatives to sids are accidental suffocation and strangulation in bed and unknown ill - defined unspecified - causes which had male fractions of 0.593 and 0.597 , respectively .
. suffocations by inhalation of food or other foreign object ( siffo ) in infancy had a male fraction of 0.600 very close to 0.606 ( p = 0.52 ) for all postneonatal sids .
the risk factors for infant inhalation of food or other object are morsel size , rounded shape , and slippery surface , like a grape .
however , types of infant food , and mode and manner of preparation are identical for males and females , so these risk factors are independent of gender .
we hold that all this tabulated male fraction similarity of order 0.61 is strong evidence of a common x - linked recessive susceptibility to the same terminal mechanism of cerebral anoxia .
furthermore , the virtually identical male fraction of 0.6053 compared to 0.6057 for sids occurs for these same siffo icd codes combined for all children ages 1 to 14 years in the us from 1979 to 2005 , with 2,324 male and 1,515 female ( p = 0.98 ) .
when broken into ages 14 , 59 , and 1014 years none of these groups are rejected .
the implications of this consistent male fraction from infancy through adolescence is emphasized in the later discussion section .
the siffo + igc data for the next cdc age group of 1519 years with a higher male fraction is not shown here because higher teenage male alcohol consumption is a new positive bias factor ( 496 male , 277 female : male fraction = 0.642 ) .
the male fractions in 19791998 of all us infant deaths by all icd 9 chapters and for 19992005 in their icd 10 equivalents are shown in table 2 .
these data show the well - known male excess in virtually all icd classes of infant death , with only the neoplasms showing no male or female excess as expected from a purely random initiation process as the 5% us male live birth excess corresponds to a male fraction of 105/205 = 0.5122 .
( 1 ) the differing male fractions for most of these disease classes are essentially similar between the two periods 19791998 and 19992005 .
this suggests that there is something physiological involved that provides the apparent characteristic excess male risk for each such class of cause of death .
for example , certain conditions arising in the perinatal period with some 350 000 deaths covered by icd9 and 100 000 covered by icd10 have male fractions of 0.566 and 0.567 , respectively .
( 2 ) the approximately 0.61 male fractions of table 1 for respiratory causes shown are found as expected for the congenital anomalies of the respiratory system ( 0.602 icd9 and 0.579 icd10 ) and diseases of the respiratory system ( 0.587 icd9 and 0.581 icd10 ) .
what is surprising is that the male fraction of mortality from diseases of the digestive system in infancy is similar to that from respiratory causes , 0.588 in 9icd and 0.601 in 10icd . in the uk from 1979 to 2006 other diseases of the digestive system
( not ulcer - appendicitis - hernia - obstruction - chronic liver disease - cirrhosis ) were 458 male and 329 female for a male fraction of 0.581 similar to the us data .
we speculate that a linkage between the mechanism for the similar male fraction from digestive disease as sids may be from digestive causes such as malabsorption of iron and glucose in celiac disease and insufficient vascularization that would limit uptake and transport of glucose , respectively .
this could lead to hypoglycemia that is a known risk factor for sids and sudden death [ 15 , 16 ] . in the older infant , the resistance to hypoxia is much less than for the neonate , reflecting the diminished stores of glycogen and therefore limited substrate for anaerobic metabolism .
an enzyme , such as glucose-6-phosphate dehydrogenase ( g6pd ) could play a role as its x - linked gene locus is at xq28 and it has a great multiplicity of alleles that are associated in their deficiency with nonspherocytic hemolytic anemia , and anemia is a likely risk factor for sids .
g6pd catalyzes initiation of glucose oxidation via the hexose - monophosphate pathway that may be a critical requirement for neuronal survival during cerebral anoxia .
there could be more complicated x - linked processes such as requiring two ( or more ) independent x - linked alleles with probabilities q1 and q2 , with probability of simultaneous presence ( q = q1q2 ) that would equal the qvalues listed above for a single x - linked allele . alternatively ,
a gene locus such as g6pd could have many recessive alleles ( q1 , q2 , q3 , ) that are nonprotective of sids that could sum up to the q values listed above for the same risk of sids ( q = q1 + q2 + q3 + ) .
we have chosen a single - gene x - linkage process for simplicity of discussion , and note that any genome - wide association study required to test our model can test for all possibilities .
the age distribution of sids is unique : any viable hypothesis for the cause of sids must account for its characteristic age distribution . .
raring first noted that the unique and characteristic age distribution of sids appeared to follow a 2-parameter lognormal model .
mage reviewed the sids age literature and in a meta - analysis of 15 global sids age data sets obtained the distribution of some 20 000 ages of sids shown in figure 2 . in construction of figure 2 , 1-month is < 28 days of life .
age data in weeks of life were divided by 4.33 to convert to months and the althoff data from cologne reported as age within midmonth intervals ( e.g. , 1.52.5 month ) were plotted to estimate the corresponding integer month intervals ( e.g. , 1 - 2 months and 2 - 3 months ) for pooling with the other monthly sids data .
the total of 19,949 sids includes 194 sids deaths that are predicted to occur after 1-year in these 15 cohorts by use of an exponential fit to monthly data intervals 5 to 12 that was then extrapolated and summed from 13 to 41 months .
these data in figure 2 were fit by a 4-parameter lognormal distribution , also known as the johnson sb distribution , shown as ( 2 ) .
here dp(m ) is the probability of sids occurring between ages m and m + dm in months , median = 3.1 months and standard deviation = 0.6617 , as fit by maximum likelihood
( 2)dp(m)dm=(22)1[(m+0.31)1 + ( 41.2m)1 ] exp [ log e2([(m+.31)(41.2)]/[(41.2m)(+.31)])/22 ]
.
equation ( 2 ) can be interpreted as a sum of products of three age dependent terms , denoted as pn , pi , and pa . let pn = 1/(m + 0.31 ) represent a risk factor of neurological prematurity leading to delays in development of respiratory reflexes and responses , that decreases with increasing age .
neurological prematurity is a risk factor that is maximal at birth and decreases as the infant physically matures .
kinney has found that an important subset of sids appears to have a deficiency in serotonin receptors that is hypothesized as a causal factor of those sids .
let pi = 1/(41.2 m ) represent an infection risk factor that increases with increasing age .
secondary sids , that have findings of low - grade respiratory infection at autopsy that of itself is insufficient to cause death .
risk of such infection increases with age as infants lose passively acquired maternal immunoglobulin ( igg ) and they have increased exposure to pathogens as they have more contacts both within and without their immediate family . us dhhs linked birth and death certificate data for 19952004 show , in table 3 , that the rate of sids increases monotonically with live birth order ( lbo ) .
it has been suggested that older school - age siblings may be an important respiratory infection vector .
we assume here that the infant lives with two parents , all older siblings survived to the time of sids death , and no adoption of the sids infant or older siblings took place . for lbo
6 we assume only 5 siblings have contact with the infant . let the probability of a family member not carrying a respiratory infection communicable to the infant at any time = p. for infants with family size = 2 parents + ( lbo 1 ) siblings the probability of not having an infection vector present is equal p. the probability of an exposure to at least one carrier is then 1 p. by least squares analysis we found p = 0.9 with a scaling factor of 2.5 , so we model the rate of sids per 1000 = 2.5 ( 1 .
infant anemia has not been considered directly as a risk factor for sids per se , because accurate hemoglobin [ hb ] levels can not be determined after death due to rapid hb breakdown resulting in the mottled and reddened areas known as livor mortis .
a study in mice shows how hb is already significantly decreased in the first postmortem hour . because the exact time of sids during sleep is not known it would be impossible to correct for the variable amount of hb lost between the instant of sids death and autopsy .
there is , however , indirect evidence suggesting a relationship between anemia and sids : the peak incidence of sids coincides with the nadir [ of hb ] in the physiological anemia of infancy .
anemia does contribute to apnea and apparent life - threatening events ( altes ) from causing longer cyanotic breath - holding spells [ 2932 ] that are risk factors for sids , leading to the apnea hypothesis .
[ 3 , 32 ] . therefore anemia is treated by us as a risk factor for sids .
let pa = exp [ log e ( [ ( m + 0.31)/( + 0.31)]/[(41.2
m)/(41.2 )])/(2 ) ] , as found in the johnson sb model as ( 2 ) , represent an anemia - cum - apnea risk factor rising from 0 at birth , reaching a peak at the median ( = 3.1 months ) and decreasing to zero at 41.2 months .
anemia in infancy may be defined relatively as any value for the hemoglobin [ hb ] less than two standard deviations ( < 2 ) below the mean for age , or absolutely as less than a fixed value , such as 13.5 g / dl which is the 2 level below mean cord blood hb and mean hb at 1 week .
infant physiological anemia is a risk factor that is virtually zero at birth due to placental transfusion during labor and at birth hb concentration in the blood can reach + 2 of 23.7 g / dl .
we propose that this high at birth hb phenomenon accounts for the relative protection from sids during the first week of life . in the following weeks
, total hb decreases rapidly as fetal hemoglobin ( hbf ) is removed faster than it can be replaced by adult hemoglobin ( hba ) .
a nadir in total hb occurs at or about 2 months of age for a term infant that corresponds to the 63rd day mode of the sids sb age distribution [ 18 , 21 ] .
table 4 shows the 2 hb g / dl level ( lowest 2.5% of all infants ) . by definition ,
approximately 25 in 1000 term infants have a hb value below the 2 value shown , and preterm infants will fall under this value with a higher frequency , perhaps related to their increased risk of sids . of those 25 in 1000 , the one with the lowest hb would be at the highest risk of apnea and therefore sids . if physiological anemia is considered as a hb deficit from a fixed level of 13.5 g / dl , that could , combined with apnea , cause transient hypoxia and inability to meet neuronal oxygen demand in the brainstem of sids susceptible infants .
if so , it could correspond , as shown in table 4 , to the rise - and - fall factor pa modeled from the johnsonsbdistribution as ( 2 ) fit to figure 2 .
the presence of respiratory infection as a risk factor fits the characteristic of sids of a seasonal dependency , maximizing in the winter and minimizing in the summer , that has been associated with wide seasonal temperature changes .
mage showed that in hawaii , a semitropical us state with only narrow seasonal change in mild temperatures , that 384 sids varied seasonally with calendar day ( t ) between 1979 and 2002 as a cosine function shown as ( 3 ) where the maximum sids rate is predicted to occur on january 30th ( t = 30 ) :
( 3)mortality on day t=0.810 + 0.241 [ 1+cosine2(t30)365.25],0<t<365.25 .
this equation may be interpreted to show that in hawaii , 23% of sids have a seasonal infection component ( 0.241/1.051 ) and that 77% of sids occur at a constant rate due to other physiological factors such as anemia and neurological prematurity that have no known seasonality .
the winter flux of infection vector would come via visitors from the us mainland and japan , so the authors expect that the proportion of seasonal infections and sids may be larger in temperate zones of the us with colder winter temperatures than found in hawaii .
there has been a tendency for the winter peak to be reduced since the start of the back - to - sleep campaign that may be due to the lessening of the hypoxia caused by low - grade seasonal respiratory infection when sleeping supine [ 38 , 39 ] .
the pre-1992 lognormal form of the age distribution of sids [ 40 , 41 ] remained the same during the change of preferred sleep position from prone to supine .
pollack found the age distributions of us sids between 1989 and 1999 were virtually unchanged in the two cohorts .
he reported that the stability of this distribution is remarkable when one considers the large decline in sids incidenceas shown in figure 1 .
malloy and freeman also found little change in age distribution for us sids between 1992 and 1999 ( p = 0.025 ) .
the derivation and its explanation for this consistency is aided by a venn diagram shown as figure 3 .
let a prone sleeping infant be susceptible to sids in both the pg pa pn and pg pa pi areas of figure 3 even if missing the pi or pn risk factors , respectively .
note that the sum of pg pa pn + pg pa pi represents two overlapping areas on the venn diagram because the central segment ( pg pa pn pi ) is counted twice .
let the probability of a prone sleeping child = pp and that of a supine sleeping child = ps . for simplicity we include the side sleeping position with the prone , and we require pp + ps = 1 .
then the probability of dying of sids at age m while prone ( ppsids ) is written as ,
( 4)ppsids = pp pg pa ( [ pn+pi]pnpi ) .
one can then write the probability of supine sids ( pssids ) as ,
( 5)pssids = ps pg pa pn pi .
combining ( 4 ) and ( 5 ) we get the total probability of sids ( psids ) as
( 6)psids = pp pg pa ( pn+pi)+(pspp ) pg pa pn pi .
we then note that the sum of pn + pi has a similar mathematical form as pn pi as follows :
( 7a)pn+pi=1(m + 0.31)+1(41.2m)=[(41.2m)+(m+0.31)][(m+0.31 ) ( 41.2m ) ] ,
( 7b)pn+pi=41.5[(m+0.31)(41.2m ) ] ,
( 7c)pn pi=1[(m+0.31)(41.2m ) ] .
thus the mathematical form for the age distribution of both supine sids and prone sids can be represented by the same relationship of c pa/[(m + 0.31 ) ( 41.2 m ) ] , where c is a constant , which implies that , in terms of relative probability at different values of m , ( 7b ) and ( 7c ) are the same .
this is consistent with the report that there were similar frequencies of pathological findings in both supine and prone sids confirming that the mode and cause of sids death is apparently the same for both sleep positions .
this derivation shows how the venn diagram and johnson sbage distribution predict that supine and prone sids have the same age distribution , with lower rates for the supine sids .
this corresponds to the supine requirement to have all 4 risk factors ( pg pa pn pi ) as opposed to only 3 risk factors ( pa pg pi or pa pg pn ) that can allow a prone sids to happen more readily .
factors that make the prone sleep position a risk factor for sids are rebreathing of exhaled breath with reduced oxygen and increased carbon dioxide and the finding that presence of a fan in the infants sleep environment , that disperses exhaled breath , decreases the sids rate .
other hypotheses than the x - linkage hypothesis of naeye et al . for the male excess in sids and other causes of infant respiratory mortality have appeared in the literature [ 4547 ] .
the mechanism behind the excess perimortality rate in male infants is not known . a genetic factor leading to reduced tolerance
analyzed amniotic fluid and showed the male fetus developed pulmonary surfactants slower than the female fetus and suggested that this deficit at birth may cause the male excess in infant respiratory distress syndrome ( rds ) that matches that of sids .
this is not likely because the measured deficit should decrease with maturity as the infant ages , but cdc reports that the male fraction of rds between 28 and 364 days [ 0.617 ] is greater than the male fraction [ 0.604 ] on the first day of life when the deficit is maximal .
patterson et al . found in their sids cases that males had a larger deficiency in serotonin receptors in the brainstem than females and suggested that this may be related to the male excess in sids . as for the male surfactant deficit cited above , a greater male serotonin - receptor deficit at birth should decrease with infant maturity , but the 0.606 male fraction of sids between 28 and 364 days is also greater than the 0.548 male fraction for 06 days ( which may partially be related to false positive sids from undiscovered infanticide or subtle congenital anomalies ) .
l'hoir et al . found in their study in the netherlands that male infants were placed to sleep in the prone position more often than females , and were more likely to turn prone from a side sleeping position than females , and suggested that this may be related to the male sids excess .
however , as shown in figure 1 , the sids male fraction remained essentially the same as the recommended sleep position in the us changed from prone ( pre-1992 ) to supine ( post-1992 ) , even though the sids rate dropped by a factor of three from 1979 to 2005 .
furthermore , any other hypothesized cause for sids that suggests that the sids male excess in mortality is related to a male underdevelopment relative to the female can not explain the fact that virtually exactly the same male fraction of 0.605 occurs for siffo between 1 and 14 years as the 0.600 in the first year of life shown in table 1 .
the risk factors for siffo in children are independent of gender because food in the us is not chosen or prepared differently for males and females . types of food that are most often recovered from the upper airway at infant autopsy are raw carrot and apple , round and slippery items such as hotdog pieces without skin removed , candy , nuts , and grapes [ 4951 ] .
foreign objects swallowed by children over 1 year of age are often balloons and small coins such as pennies .
although the rates of siffo decrease with age , as dentition and swallowing control develop , and the types of food items eaten by children change as they go from infancy to 14 years of age ( e.g. , chewing gum is often inhaled ) , the male excess remains the same up to 14 years .
as opposed to sids that predominantly occurs during sleep , siffo predominantly occurs while the infant is awake or being fed , and immediate first aid is attempted that is successful in approximately 99% of all cases [ 52 , 53 ] . yet , assuming equal siffo risks for males and females , more males than females can not be resuscitated in exactly the same proportion as dying in sids .
virtually all other risk factors posited for sids are either independent of gender ( e.g. , parental smoking or autosomal genetic conditions ) or are inoperative for siffo between 1 and 14 years of age except the possible x - linkage . an obvious potential cause of an infant male excess for any icd class may be due to an androgen excess in the male .
we discussed this previously and showed that during the first year of life , the sids male fraction remains relatively constant while the male serum testosterone is slightly higher than the female 's at birth , peaks for three months during the first six months to aid testicular descent , and falls back towards zero for the second six months of life , so an androgen interaction is not a likely factor . as in any epidemiology study , there is always a finite probability that these data are the result of happenstance and coincidence , known as sampling error , and that next year 's data may be cause for rejection of the developments presented .
we have shown how all characteristic properties of sids , its gender , age , and seasonal distributions , along with the observed risk factors of apnea , respiratory infection , and neurological prematurity , can be tied to each other mathematically .
these relationships presented here explain how the supine position reduces the rate of sids and why it does not change the gender distribution or the form of the age distribution from those of sids occurring predominantly in the prone position .
because all sids risk factors except the hypothesized x - linkage are independent of gender , we propose that equal numbers of males and females , per equal numbers of live births , are at risk of having potentially fatal risk factors that we previously defined here as pa , pi , and pn .
approximately 2/3 of all males and 4/9 of all females have a genetic risk factor pg that is necessary to cause sids but not sufficient by itself
infants with the protective allele and the three other risk factors ( see figure 3 ) may be among the cohort of those presenting with apparent life - threatening episodes ( altes ) that do not then or later progress to sids .
it is proposed that sids may occur for those genetically susceptible infants when repeated transient coincidences of factors reduce the oxygen supply ( apnea , anemia , rebreathing exhaled breath , etc . ) during a period of increased oxygen demand ( low grade respiratory infection raising body temperature )
. if the infant has a residual neurological prematurity , auto resuscitation by the gasp reflex may be delayed causing acute cerebral anoxia that may cause some respiratory - drive neurons in the brainstem to die ( emery 's subclinical tissue damage ) . when a sufficient number of such neurons die
, the next sleep with identical risk factors causing anoxia may reduce the number of functioning neurons below a minimum critical requirement so auto resuscitation is impossible .
the protected infant with an x - linked dominant allele ( a ) could switch over from aerobic oxidation to anaerobic oxidation to keep those critical neurons alive during the same transient anoxic conditions so that autoresuscitation could occur . in summary
, the quadruple risk model presented here , with factors developed from pre-1994 gender data and from pre-1992 sids age data , predicts the age and gender distributions for post-1992 data as shown . the factors determining the age distribution mesh with the medical literature 's findings of the risk factors for sids .
should the genetically susceptible infant pass through infancy unscathed , the genetic susceptibility to cerebral anoxia can still penetrate in childhood if anoxic circumstances arise as shown by the identical us postneonatal sids male fraction of 0.606 occurring in us children aged 1 to 14-years suffocating from inhalation of food or other foreign objects .
so , in the absence of any other plausible explanation in the medical literature for the same siffo male excess from birth to 14 years of age as sids , a common x - linkage remains as the only possibility . furthermore there was a 45% excess adult male completion rate of suicide attempts by coal - gas inhalation in paris between 1949 and 1962 ( completions of 58% male versus 40% female ) . in conclusion , although modern thought is now that sids is a composite of independent and different causes of death , they all appear to have the same male fraction .
we reason that all those different causes of death lead to the same cerebral anoxia that may result in respiratory failure from the absence of an x - linked dominant allele that supports anaerobic oxidation in respiratory control neurons of the brainstem .
proof of this unifying mechanism must await genetic testing to identify , if correct , the unknown recessive x - linked allele that is exclusively present in all these icd codes with the statistically similar male excess of sids . | the sudden infant death syndrome ( sids ) has four distinctive characteristics that must be explained by any theory proposed for it .
( 1 ) a characteristic male fraction of approximately 0.61 for all postneonatal sids in the us ; ( 2 ) a distinctive lognormal - type age distribution arising from zero at birth , mode at about 2 months , median at about 3 months , and an exponential decrease with age going towards zero beyond one year ; ( 3 ) a marked decrease in sids rate from the discovery that changing the recommended infant sleep position from prone to supine reduced the rate of sids , but it did not change the form of the age or gender distributions cited above ; ( 4 ) a seasonal variation , maximal in winter and minimal in summer , that implies subsets of sids displaying evidence of seasonal low - grade respiratory infection and nonseasonal neurological prematurity . a quadruple - risk model is presented that fits these conditions but requires confirmatory testing by finding a dominant x - linked allele protective against cerebral anoxia that is missing in sids . | [
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This repository contains model predictions generated by AutoTrain for the following task and dataset:
- Task: Summarization
- Model: google/bigbird-pegasus-large-arxiv
- Dataset: scientific_papers
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