Clinical outcome measures are important tools to monitor patient improvement during treatment as well as to document changes for research purposes. The short-form Bournemouth questionnaire for neck pain patients (BQN) was developed from the biopsychosocial model and measures pain, disability, cognitive and affective domains. It has been shown to be a valid and reliable outcome measure in English, French and Dutch and more sensitive to change compared to other questionnaires. The purpose of this study was to translate and validate a German version of the Bournemouth questionnaire for neck pain patients.German translation and back translation into English of the BQN was done independently by four persons and overseen by an expert committee. Face validity of the German BQN was tested on 30 neck pain patients in a single chiropractic practice. Test-retest reliability was evaluated on 31 medical students and chiropractors before and after a lecture. The German BQN was then assessed on 102 first time neck pain patients at two chiropractic practices for internal consistency, external construct validity, external longitudinal construct validity and sensitivity to change compared to the German versions of the Neck Disability Index (NDI) and the Neck Pain and Disability Scale (NPAD).Face validity testing lead to minor changes to the German BQN. The Intraclass Correlation Coefficient for the test-retest reliability was 0.99. The internal consistency was strong for all 7 items of the BQN with Cronbach α's of .79 and .80 for the pre and post-treatment total scores. External construct validity and external longitudinal construct validity using Pearson's correlation coefficient showed statistically significant correlations for all 7 scales of the BQN with the other questionnaires. The German BQN showed greater responsiveness compared to the other questionnaires for all scales.The German BQN is a valid and reliable outcome measure that has been successfully translated and culturally adapted. It is shorter, easier to use, and more responsive to change than the NDI and NPAD. Musculoskeletal problems are extremely common in our population, especially neck pain and its associated disability . The theClinical outcome measures such as self-report questionnaires are useful in monitoring patient improvement during treatment. The vast majority of disease-specific instruments have been developed in English- speaking countries . The mosNeck pain, similar to low back pain is a multidimensional experience, best described by the biopsychosocial model that includes pain, disability, cognitive and affective domains . HoweverIn order to use the BQN in a German speaking patient population it is not enough to just translate the items well linguistically, because that does not guarantee similar measurement properties . The queAs the BQN is only available in English, French and Dutch ,11,12, tEthics approval for this study was obtained by the Canton of Zürich ethics review board (KEK-ZH-Nr.2010-0252/5).The translation and cross cultural adaptation were based on the guidelines of Beaton, Bombardier et al. . The entTwo translators (T1 and T2) translated independently the questionnaire from English into German. Both T1 and T2 had German as their mother language but were also fluent in English. One of the translators (T1) is a chiropractor in Switzerland (clinician) and the second (T2) is a Swiss librarian (linguist). They both provided a written report.The two independent translated versions TV1 and TV2 were revised by consensus agreement to TV1-2 by the original translators, and overseen by the expert committee.The agreed TV1-2 version was then back translated by two independent translators (BT1 and BT2). Both back translators had English as their first language but were fluent in German. BT1 and BT2 were both chiropractors from Canada working in the German speaking part of Switzerland for several years. They were blinded to the original version of the Bournemouth questionnaire. Their two versions of the back translation (BTV1 and BTV2) were submitted to the committee.An expert committee reviewed all reports and agreed by consensus to a pre-final version of the German Bournemouth questionnaire. This team of 8 people was made up of methodologists, health professionals, language professionals, and translators. The original developer of the English version of the BQN also participated in an advisory capacity.The pre-final form of the BQN was tested on a sample of 30 patients in a chiropractic practice in Zürich, Switzerland for face validity. The neck pain patients were asked to complete the questionnaire after having treatment. Afterwards the questionnaire was discussed with the patient item by item and they were asked to explain their understanding of the meaning of each question. The patients were also asked if they had any problems with the format, instructions, response scales or layout of the questionnaire.A written report on the face validity of the questionnaire was sent to the expert committee. Each member of the committee also made a written report. Minor changes were agreed and the pre-final form was modified to include these changes with consensus. This version then became the final German version of the BQN for validation testing  ,13,16. TExternal construct validity shows the extent to which the BQN's scores concord with the scores of other instruments measuring the same theoretical hypotheses of the concepts under consideration . This waThe sensitivity to change over time of the three questionnaires was assessed with the standardized response mean (SRM). The average change in scores for each scale was divided by the standard deviation of the score changes ,17.From the 128 chiropractic patients presenting with a new episode of neck pain who completed all three baseline (pre-treatment) questionnaires, 102 also provided complete 4 week post-treatment data for these same three questionnaires. Of the 102 patients included in the study, 38 were male and 64 were female with a mean age of 39.3 years (SD = 13.0). There was no significant age difference between the genders. The mean total score for the German BQN at baseline was 33.14 (SD = 15.8) or 47% of the maximum score. For the NDI the mean baseline score was 14.14 (SD = 8.0) or 28% of the maximum score and for the NPAD the mean baseline score was 35.28 (SD = 21.1) or 35% of the maximum score.The ICC results from the 31 students and chiropractors participating in the test-retest reliability study indicated acceptable agreement (.91 - .99) for all scales and the total scores  is a relatively new, short form multidimensional instrument developed from the biopsychosocial model and includes question items on pain, disability, cognitive and affective domains . CurrentThe 6-step translation and cross cultural adaptation process after Beaton, Bombardier et al.  was usedWhen using outcome measures such as questionnaires, it is important that the instrument is appropriate for the patient population and setting in which it is used. Although content validity was not specifically evaluated in this study, as it was already established in the original English version , it woulAnother possible interpretation of the previous results is that the NDI is more suited to an acute patient population. Patients are asked to fill out the NDI according to how they feel 'right now' as opposed to the BQN which asks them 'over the past week'. Consequently the NDI may be more suitable for patients whose complaint started within the past few days and the BQN for patients whose pain complaint began possibly a minimum of 5 to 7 days previously. On review, the NPAD would seem to fit in between the NDI and BQN as patients are not given clear instructions (with the exception of pain intensity) as to what time frame to use in order to answer the questions.Similar to previous studies, the internal consistency of the BQN indicated that all of the 7 questionnaire items were acceptable and well above the 0.2 Cronbach α cut-off point achieving a 0.79 for total pre-treatment scores and 0.82 for total post-treatment scores ,13. ThesThe standardized response means (SRM) identified that the BQN is more sensitive to change in this patient population compared to the NDI and NPAD. This corresponds to similar results by Bolton and Humphreys  who compWhen comparing the SRMs in terms of the sensitivity for each subscale for the 3 questionnaires, it is interesting to note that all seven of the scales (questions) for the BQN are more sensitive than the NPAD or NDI. One possible reason is that the NDI asks patients to respond to each item as they are at present. As patients' pain experience is known to fluctuate, patients' pain experience today may not be representative of their overall neck pain experience . The BQNAs mentioned previously, no specific evaluation of content validity of the German version of the BQN was done since it had been established in the English version. Ideally this should have been included in this study in spite of the fact that previous papers reporting on the translation and validation of the BQ into other languages had not included this step ,13. CurrThis study confirms that the BQN is a valid, reliable and responsive questionnaire for use in chiropractic patients presenting with neck pain in the German language. Its advantages are that it is short (only 7 questions), more responsive to change and therefore easy to use in the practice or research setting. The results of this study reaffirm that the NDI and NPAD are suitable outcome measures for use in neck pain patients.The authors declare that they have no competing interests.MS: Data acquisition, drafting and revising the manuscript, interpretation of data. CP: Concept and design of the study, analysis and interpretation of data, drafting of results section, revising manuscript. BKH: Concept and design of the study, drafting manuscript discussion section, revising manuscript. All authors read and approved the final version of the manuscript.Appendix. Final German version of the BQN for validation testing.Click here for file


By definition, patients with unresponsive wakefulness syndrome (UWS) do not experience pain, but it is still not completely understood how far their brain can process noxious stimuli. The few positron emission tomography studies that have examined pain processing did not yield a clear and consistent result. We performed an functional magnetic resonance imaging scan in 30 UWS patients of nontraumatic etiology and 15 age- and sex-matched healthy control participants (HC). In a block design, noxious electrical stimuli were presented at the patients' left index finger, alternating with a resting baseline condition. Sixteen of the UWS patients (53%) showed neural activation in at least one subsystem of the pain-processing network. More specifically, 15 UWS patients (50%) showed responses in the sensory-discriminative pain network, 30% in the affective pain network. The data indicate that some patients completely fulfilling the clinical UWS criteria have the neural substrates of noxious stimulation processing, which resemble that in control individuals. We therefore suppose that at least some of these patients can experience pain. Pain is defined as an unpleasant sensory and emotional experience, associated with real or potential tissue damage  and inclIn individuals with preserved consciousness, both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) reveal a well-formed network of interrelated brain regions responding to pain stimuli, the so-called pain matrix. The pain matrix entails two main subsystems : the latThe unresponsive wakefulness syndrome   is a sta15O-radiolabeled water PET to study cortical processing of noxious stimulation of the median nerve and found significant brain activations in the midbrain, contralateral thalamus, and S1 in each of the 15 examined UWS patients. However, the activated primary cortex was functionally disconnected from secondary, higher order integrative brain regions. Similar results were obtained in two other PET studies with a medium-size sample . Thirty UWS patients fulfilling the inclusion criteria underwent the fMRI examination  as well as 15 healthy participants   .n = 25), subarachnoid or intracerebral hemorrhage (n = 4) and encephalitis (n = 1). Patients' morphologic information provided by T1-weighted scans was assessed using a scale developed by All patients were of nontraumatic etiology, including hypoxic encephalopathy  .Twenty-six patients underwent a CRS-R examination within the first week of their stay and then every 2 weeks. Within the week before the MR scan, another CRS-R score was determined, which went into our analysis.In four patients, the standardized examination according to the CRS-R was not possible. They had to be transported over a long distance and were directly brought to the scanning center. All of them were chronic patients. Their diagnoses have been verified by their attending physicians.Exclusion criteria for healthy participants were the history of head trauma, neurological diseases, or any chronic illness. Exclusion criteria for all participants were any contraindication to fMRI. The participants' legal guardians gave written informed consent. The study was approved by the ethical committee of the University of Tuebingen and conducted in accordance with the Declaration of Helsinki.An alternating block design  was performed. Each block consisted either of 60 noxious stimuli (1/sec) or a 60-sec baseline rest interval. The nociceptive experience was elicited by an electrical stimulus  at the left index finger using the DS7A HV Constant Current Stimulator from Digitimer. The HC group evaluated the electrical stimuli as moderately painful  on a visual analogue scale (VAS) from 0 (no pain) to 10 (worst pain imaginable). The moderate pain stimulation was used for ethical reasons. Another group of 16 healthy individuals , who did not participate in the fMRI experiment, additionally evaluated the valence  and arousal  of the same stimuli.The examination was always accompanied by a physician. The patient's vital signs  were monitored continuously.Blood oxygenation level-dependent (BOLD) images were obtained at two imaging centers  in order to avoid unnecessary patient transportation. In Bad Aibling, where 22 patients were examined, data were collected using a 1.5 Tesla MRI scanner  system equipped with a 12-channel head coil. Changes in BOLD T2*-weighted MR signal were measured using a gradient echo-planar imaging (EPI) sequence . A T1-weighted anatomical image was additionally acquired for each subject to allow anatomical localization . In Tuebingen, imaging was performed on a 3 T Siemens Trio scanner. After a T2*-weighted acquisition , anatomical images were obtained using the MP-RAGE sequence .Magnetic resonance imaging scans of the 15 healthy subjects were acquired in Bad Aibling using the above-mentioned 1.5 T Siemens Symphony MR Scanner and the same imaging parameters.http://www.fil.ion.ucl.ac.uk/spm/software/spm8/). Preprocessing included realignment, coregistration, segmentation, and spatial normalization . Then, a Gaussian filter of 8-mm full width at half maximum was applied to smooth the data spatially.Image processing and statistical analysis were conducted using Statistical Parametric Mapping  version t-tests for each group  separately. The probability threshold was set at P < 0.05, corrected for family-wise errors (FWE) for whole-brain analysis.For the statistical analysis of regional differences in brain activation, painful stimulation and resting condition were input into the categorical general linear model design at the subject level . ContrasP < 0.05 (FWE corrected) was used.In addition, region of interest (ROI) analyses were performed for pain-related brain areas on the individual level, such as the ACC, insula, S1, S2, thalamus, and cerebellum using automated anatomical labeling masks  and the For comparison between UWS and HC, several chi-squared tests were applied. Their significance was corrected by the number of the tests using the Bonferroni–Holm correction procedure .As can be seen in The data presented in As can be seen in n = 4) tended to demonstrate significant activations in the sensory-discriminative network more often than chronic patients . The same trend for the affective network only approached significance (P = 0.069).Acute and subacute patients  and with the number of activated regions . None of the patients showed a CRS-R motor subscore higher than 2 (else the diagnosis would be different from UWS).The CRS-R motor subscore, which reflects motor reaction to nociceptive stimulation  was significantly negative related with a general absence/presence of brain activation in the regions of the pain network  and in the higher and lower order structures .Compared with UWS patients, HC subjects showed significantly more frequent activation in the sensory and the affective part of the pain matrix , the S2 , the S1 , the thalamus , and the posterior insula  were significantly more frequently activated in HC subjects than UWS patients. No significant group difference was found in the cerebellum  and in the ACC .Looking at the individual brain areas demonstrated that the anterior insula , although the average rating of the pain intensity was 3.93 (SD = 1.28) on a VAS . Another more probable explanation from our point of view is the age of the HC patients: those healthy participants who do not show any activation in the affective part of the pain matrix were 18 years older on average. The correlation between age and BOLD signal in HC is 0.7, whereas there is no correlation between VAS score and BOLD in HC, and between age and BOLD signal in UWS patients. It is known that the subjective threshold of pain experience increases with age .The inability to experience pain (or any other subjective feeling) is a central part of the definition of the UWS. Despite this definition, not only patients' relatives but also many health professionals believe that UWS patients can perceive pain. In several studies using PET, pain-related activations in UWS patients were observed exclusively in the primary sensory part of the pain matrix, indicating that higher order processing of noxious stimuli was lacking e.g. , 2008. IThe present data indicate clear individual differences in pain responsiveness of UWS patients. While no pain-related activation was found in 14 patients, the others did respond to noxious stimuli. Fifteen UWS patients showed activation in the sensory-discriminative part of the pain matrix and nine patients (30%) showed even affective pain-related responses. In 15 patients, higher order pain control areas  were also involved. Moreover, about one-third of the UWS patients had pain-related responses in both, the sensory and affective parts of the pain matrix, thus replicating the PET findings of The somatosensory cortex receives noxious input from the thalamus and contains neurons that code spatial, temporal, and intensity of noxious somatosensory stimuli , charactThe CRS-R motor subscore was significantly and inversely correlated with a general absence/presence of brain activation in the pain network and with the number of activated regions. At first sight, this result is surprising, as one might have expected a positive correlation between brain activation in the pain matrix and the clinical reaction to noxious stimuli. However, absent motor reaction to pain stimulation does not necessarily mean the absence of pain perception. Perception of pain, more precisely the sensory afference, and the visible motor reaction, thus the motor efference, are two different and independent pathways and can be impaired separately from each other. In fact, our findings emphasize that the clinical examination of UWS patients is difficult and might miss some patients who are actually more conscious than they seem . This faOf course, diagnosis of consciousness remains a philosophical problem, not just a neurological one. An increase of brain activity in some brain areas cannot strongly prove the presence of subjective experience. However, given pain-related changes in such brain structures as anterior insula and ACC, which are related to emotional awareness and autonomic regulation of pain , we findBy definition, subjective threshold of pain perception and pain tolerance cannot be obtained in UWS patients. Therefore, and primarily for ethical reasons, rather moderate noxious stimuli were applied in the present experiment. We cannot rule out that they were weaker than in the comparable PET studies, which would partially explain the differences in results.Moreover, to avoid long, uncomfortable, and exhausting transportation, the patients were examined at two different imaging centers with different scanners. Although the results obtained with the 1.5 T and the 3 T scanners are not substantially different, a replication study in which all patients are measured with the same scanner is desirable.Furthermore, Importantly, these limitations may be supposed to decrease, rather than enhance, the pain responsiveness of the patients. The fact that the present experiment was strongly biased toward false-negative findings underscores the importance of positive ones. If stimuli of such low intensity, perhaps additionally masked by the scanner noise, activated large portions of the brain pain matrix in one third of our UWS sample, one can suppose that in a real and severe pain event  the brain activation might be even more pronounced. From a practical point of view, therefore, a conclusion from the present data may be drawn that the medical staff should carefully examine UWS patients for any clinical sign or potential source of pain and treat them appropriately, assuming in the case of doubt that pain is subjectively experienced unless strong evidence for the opposite is obtained.The brain responses to pain were contrasted to the rest condition only. As a next step, it would be interesting to compare brain responses to painful and nonpainful  somatosensory stimuli. The present, rather plain design was selected to provide the comparability with the previous PET studies of UWS patients, in which the same design was employed.This is the first fMRI study on pain processing in a larger group of patients in UWS. Significant indications of pain processing were found in at least half of UWS patients, and about one-third UWS patients showed even activations in both sensory and affective pain networks. The findings stress the need for elaborated pain management in patients with disorders of consciousness.


The lumbar plexus block provides excellent analgesia after hip and knee surgery. One approach to the three major nerves  of the lubar plexus is the fascia iliaca compartment block, first described by Dalens and colleagues. Using this blind approach, complete nerve block in the distribution of the lumbar plexus may be achieved only in 38% of cases. Ultrasound-guided regional techniques offer a number of advantages including real-time needle guidance and direct observation of local anesthetic spread within tissue planes.We hypothesized that real-time UFIB could be successfully performed in the ED and would provide an excellent adjunct or alternative to repeat doses of IVMS for pain control in patients with HFx. The study was conducted at University Hospital, Birmingham, where we see about 90,000 patients every year. All patients with confirmed femoral (neck/shaft) fractures and pain score >7 were included in the study. Patients with local wounds, or suspected significant pelvic injury were excluded. A combination of 15 ml lignocaine 1% and 15 ml bupvivcaine 0.25% was used. VAS (0 to 10), pain on movement of the leg and patient satisfaction were used to assess the outcome. The assessments were made before the FIB, at 15 minutes, 30 minutes and 45 minutes.A convenience sample of 19 patients was enrolled in this study. The compartment block was placed by three mergence ultrasound trainers. The mean age was 58.5 years. There were 13 females and six males. The mean pain score was 9.5 at time 0. The mean pain score had improved to 5.5 at 15 minutes, 4.5 at 30 minutes and 3 at 45 minutes, respectively. The patient satisfaction was scored 4.5 on a scale of 1 to 5 where 5 was the most satisfied. No patient required any further analgesia up to 90 minutes and no issues were raised about the pain or discomfort upon patient transfer. We have no documented complications or side effects.FIB is now widely used by non-anaesthetic trainees to combat pain in preoperative care due to its safe landmarks. Our results have shown that it can be used safely and effectively for pain management in hip fracture by emergency physicians, who are trained in the technique, on the shop floor.


Background. The Allergy Lateral Flow Assay (ALFA) is a novel rapid assay for the detection of sIgE to allergens. The objective of this study is the evaluation of ALFA for the detection of sIgE to bee venom (BV) and wasp venom (WV) in insect venom allergic patients. Methods. Specific IgE to BV and WV was analyzed by ALFA, ALLERG-O-LIQ, and ImmunoCAP in 80 insect venom allergic patients and 60 control sera. Sensitivity and specificity of ALFA and correlation of ALFA and ImmunoCAP results were calculated. Results. The sensitivity/specificity of ALFA to the diagnosis was 100%/83% for BV and 82%/97% for WV. For insect venom allergic patients, the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.79 for BV and 0.80 for WV. However, significant differences in the negative control groups were observed. Conclusion. ALFA represents a simple, robust, and reliable tool for the rapid detection of sIgE to insect venoms. Reliable diagnosis of insect venom allergy is based on the combination of patient's history, skin testing (SPT) and laboratory tests for the detection of specific IgE (sIgE) –4. Dermatophagoides pteronyssinus (d1), Alternaria alternata (m6), birch pollen (t3) [Apis mellifera (BV) and wasp, Vespula vulgaris and germanica (WV) were characterized and prepared for use with ALFA. The objective of this study was the evaluation of ALFA, for the detection of sIgE to bee venom (BV) and wasp venom (WV) in a well-defined cohort of patients. Sera were also analyzed by ImmunoCAP  and ALLERG-O-LIQ (Dr. Fooke Laboratorien GmbH). The correlation between methods was calculated, and agreement between ALFA and the diagnosis ) was determined.The methodology for the measurement of sIgE has evolved during the recent years , 6. Latelen (t3) , and alslen (t3) . In contlen (t3) , which eSera of four groups were analyzed as follows.A)(n = 12) or wasp (n = 28) venom with agreement of patient's history, sIgE against the given venom by ImmunoCAP and skin test. Mean age 41.8 y (SD 14.96 y). 23 (57.5%) males, 17 (42.5%) females. 3 (7.5%) Patients presented with anaphylactic reactions grade 1 , 23B) to bee and wasp venom, determined by ImmunoCAP, patient's history and skin test. Mean age 42.25 y (SD 17.5 y). 20 (50%) males, 20 (50%) females. 4 (10%) Patients presented with anaphylactic reactions grade 1 , 27C)(n = 30). Mean age 33.5 y (SD 15.75 y). 16 (53.34%) males, 14 (46.67%) females. 19 (63.34%) patients presented with atopic dermatitis, 12 (40%) patients with allergic rhinoconjunctivitis, and 7 (23.34%) with allergic asthma (some patients presented with two or three manifestations). None of the patients were under immunosuppressive medication or specific immunotherapy. Atopic individuals  without history of insect venom allergy (D)(n = 30). None of the patients were under immunosuppressive medication or specific immunotherapy. Mean total IgE was 35.60 kU/L (range 2–99.3 kU/L). Non atopic individuals without history of insect venom allergy , poμg/mL)  were performed. If negative, intradermal tests at 1 μg/mL were added as recommended by the position paper of the EAACI Interest Group on Insect Venom Hypersensitivity [In patients with insect venom allergy, skin prick tests with increasing concentrations of BV and WV  were assayed for sIgE to BV and WV by ALFA, ALLERG-O-LIQ, a reversed-type, quantitative, WHO 75/502 calibrated immunoassay [All sera in this study n = 40 were aunoassay , which mP-values (1-tailed Student's t-test), and Receiver Operating Characteristic analysis were performed with GraphPad Prism Ver. 5.01.Spearman correlation, When compared to the diagnosis  comparative receiver operating characteristic analysis of groups A and B revealed area under the curve values for ALFA of 0.97 (BV) and 0.91 (WV).In monosensitized patients (group A only), 12/12 BV allergic patients and 23/28 WV allergic patients were positive in ALFA using a cut-off value for ALFA of 10.0 RU, corresponding to a sensitivity of 100% for BV and 82% for WV. Similar results were obtained by ALLERG-O-LIQ. In ALLERG-O-LIQ 12/12 BV allergic patients and 24/28 WV allergic patients were found positive .For groups A and B high agreement between ALFA, ALLERG-O-LIQ, and skin tests of up to 92% was observed (data not shown). Using atopic  and nonatopic (group D) sera as controls, the specificity of ALFA for the detection of sIgE to BV was calculated as 83% and for sIgE to WV as 97% .P < 0.0001) for BV and 0.80 (P < 0.0001) for WV (data not shown). Correlation of ALFA to ImmunoCAP for each group revealed a more defined picture. For the detection of sIgE to BV the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.72 (P < 0.0001) for group A, 0.86 (P < 0.0001) for group B, 0.07 (ns) for group C, and 0.18 (ns) for group D (P < 0.0001) for group A, 0.84 (P < 0.0001) for group B, 0.25 (ns) for group C, and 0.31 (P < 0.05) for group D  the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.79  but poor quantitative agreement for the control groups, especially for BV (groups C and D). This seems to be caused by a surprisingly high number of positive ImmunoCAP results in the control groups, in particular in the group of atopic individuals  with high total IgE-a finding that has been described before for different allergens , 16. In Since sIgE to CCDs (cross-reactive carbohydrate determinants) can be responsible for major cross-reactivity of glycosylated allergens , sIgE to CCDs could also account for the high rate of BV ImmunoCAP positives in the atopic negative controls (Group C). However analyzing CCD reactivity by ImmunoCAP showed that only less than 50% of the ImmunoCAP BV positive sera also displayed CCD reactivity (data not shown). This suggests that the high rate of BV positive results by ImmunoCAP in atopic patients  with strongly elevated total IgE levels  cannot be explained by CCD reactivity but rather may reflect nonspecific IgE binding due to the solid phase architecture of the ImmunoCAP assay system.Recently recombinant allergens have been introduced into the in vitro diagnostic of insect venom allergy. In particular for dissecting true double sensitization from cross-reactivity recombinant allergens seems to be of great relevance –19. SincDetection of sIgE to bee and wasp venom by ALFA shows in the present study a good discrimination between sera of bee or wasp allergic patients and control sera with a comparable performance to the ALLERG-O-LIQ and ImmunoCAP system. Noteworthy ALFA detected no sIgE to BV in WV allergic patients and vice versa. In case of specificity, a high degree of correlation was found for ALFA and ALLERG-O-LIQ, whereas differing results were obtained using the ImmunoCAP system.We conclude that the Allergy Lateral Flow assay together with the novel scanner-based system represents a versatile and reliable tool for the measurement of sIgE to insect venom allergens meeting the growing demand for digital documentation of laboratory results. Further studies with more allergens  are mandatory to further proof the applicability of the ALFA test system.


The most dominant feature in chronic pancreatitis is intense abdominal pain. Changes in spinal and/or supraspinal central nervous system pain processing due to visceral nociceptive input play an important role in this pain. How altered pain processing is related to disease stage still needs study.Sixty chronic pancreatitis patients were compared to 15 healthy controls. Two subgroups of pancreatitis patients were defined based on the M-ANNHEIM severity index of chronic pancreatitis; i.e. moderate and severe. Pain detection and tolerance thresholds for pressure and electric stimuli were measured in six selected dermatomes . In addition, the conditioned pain modulation response to cold pressor task was determined. These measures were compared between the healthy controls and chronic pancreatitis patients. Severe pancreatitis patients showed lower pain thresholds than moderate pancreatitis patients or healthy volunteers. Healthy controls showed a significantly larger conditioned pain modulation response compared to all chronic pancreatitis patients taken together.The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes, i.e. central sensitization, may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis. Intense upper abdominal pain is common in chronic pancreatitis patients and is the most important predictor of health-related quality of life. Answering questions like “How do chronic pancreatitis patients process pain and how does altered pain processing relate to their pain experience?” is fundamental for the design of new therapeutic strategies. In human experimental pain models basic pain mechanisms can be explored by quantitative sensory testing (QST), electroencephalography or MRI. QST is increasingly used to study pain mechanisms in painful conditions. At present, comprehensive comparisons between chronic pancreatitis patients at different disease stages and compared with a healthy population regarding pain processing are not available. Such observations related to disease progression may also be of clinical value for other chronic painful disorders e.g. ulcerative colitis and Crohn’s disease The objective of this study is to investigate the difference in pain sensitivity and modulation between healthy subjects and chronic pancreatitis patients using QST to determine 1) pressure pain thresholds, 2) electric pain thresholds and 3) CPM response. Our hypothesis is that pain in chronic pancreatitis is accompanied by alterations in pain processing, and that this is influenced by disease stage The study was approved by the responsible Ethical Committees in both countries  and all patients provided written informed consent. Patients were recruited for an investigator initiated double-blind, placebo-controlled, parallel-group study of increasing doses of pregabalin conducted in the Netherlands  and Denmark  and a diagnosis of chronic pancreatitis based on The Mayo Clinic diagnostic criteria. A healthy control group was recruited in Denmark for comparison with our chronic pancreatitis group. The controls did not have any active disease and no history of a medical condition that could interfere with our pain measurements. Measurements were performed in females in the same phase of the menstrual cycle. Informed consent was provided by all healthy controls.2 probe , at each of the following sites on the dominant body side: lower neck (C5 dermatome), sternum (T4 dermatome), pancreatic site  and ventral (T10BACK dermatome)), hip region (L1 dermatome) and knee (L4 dermatome).QST took place using a standard temporal test sequence. The pancreatic and more distant dermatomes were chosen to permit observation of segmental and spreading hyperalgesia respectively. The upper abdominal area  was chosen to detect segmental hyperalgesia because dorsal horn neurons receiving painful stimuli from this skin area also receive nociceptive stimuli from the pancreas (i.e. pancreatic area). To examine spreading and generalized hyperalgesia we chose 2 dermatomes  near the pancreatic area (dermatomes T4 and L1) and 2 dermatomes more distant  from the pancreatic area (dermatomes C5 and L4). The more distant areas were chosen to act as a control area likely unaffected by pancreatic nociceptive input because the nociceptive pathways from these areas are well-separated from those coming from the pancreas at both peripheral and spinal levels.Two thresholds were measured: pressure pain detection threshold (pPDT) and pressure pain tolerance threshold (pPTT).Thresholds to electric constant current skin stimulation  were measured on the same sites as for pressure stimulation. Two thresholds were measured: electric pain detection threshold (ePDT) and electric pain tolerance threshold (ePTT).The conditioned pain modulation  paradigm was carried out to test the ability of the patient to generate descending inhibitory modulation. We formed two groups of patients based on ‘the M-ANNHEIM severity index of chronic pancreatitis’ which is a validated clinical disease stage classification for chronic pancreatitis. We divided the patients in two groups based on their score, namely: ≤10 points, moderate chronic pancreatitis group (including: minor and increased severity level) and >10 points, severe chronic pancreatitis group (including: advanced and marked severity level).The study was powered to detect a difference in average daily pain scores of 25% between groups during the 3 weeks of study treatment. We determined that a study with 30 patients per group was needed to provide a power of 90% with the use of a 2-sided significance level of 0.05. Hence, the sample size was set at 64 patients to allow for possible dropouts.We performed statistical analysis using the Statistica for Windows Software Package . All results are given as means with standard deviations or 95% confidence intervals as appropriate. We analyzed QST results using a mixed model two-way ANOVA with one between subjects factor  and one within subjects factor . We analyzed CPM results using a one-way ANOVA with one between subjects factors . Post hoc analysis was performed using Fisher’s least significant difference test.From October 2008 to May 2010 a total of 236 patients diagnosed with chronic pancreatitis in the last five years in one of both hospitals were screened and 64 patients were randomized; the study was completed without any incident. The majority of patients not meeting inclusion criteria were pain free, had passed away or were no longer being treated in either of the hospitals. From those 64 patients, four patients were excluded due to a new pain condition  that would interfere with their QST measurements . All patFor pPDT, there were significant differences between groups overall . Post-hoc analysis showed overall significantly lower thresholds for the severe chronic pancreatitis group compared to healthy controls (p = 0.001) and moderate pancreatitis group (p = <0.001). As expected, thresholds were significantly different according to dermatome of measurement . A significant interaction was found for SITE and GROUP  . Post-hoFor pPTT there were no significant thresholds differences between groups overall, but only a trend . Thresholds in the different dermatomes again significantly differed . A significant interaction between SITE and GROUP (F = 3.27 and p = <0.001) was seen . HoweverePDT thresholds differed significantly according to dermatome  and groups overall . Post hoc analysis for GROUP showed overall significantly lower thresholds for the severe chronic pancreatitis group compared to healthy controls (p = 0.007) and for the severe chronic pancreatitis group compared to the moderate chronic pancreatitis group (p = 0.03). There was also a significant interaction between SITE and GROUP  . Post hoFor ePTT thresholds differed significantly for GROUP , with again a significant post-hoc analysis for overall lower thresholds for the severe chronic pancreatitis group compared to healthy controls (p = 0.02) and for the severe chronic pancreatitis group compared to the moderate chronic pancreatitis group (p = 0.02). Thresholds differed significantly for SITE . The interaction between SITE and GROUP was not significant  .The baseline pressure pain tolerance thresholds for dermatome L4 were not significantly different between groups . Chronic pancreatitis patients and healthy controls showed an increase in thresholds after the cold pressor task. The moderate chronic pancreatitis patients tolerated the cold pressor task for 66±59 sec and the severe chronic pancreatitis patients for 36±27 sec vs. healthy controls with 180±1 sec – which was significantly different overall (F = 52.2 and p<0.0001). Post hoc analysis was only significant for the healthy controls vs. the two pancreatitis groups (p<0.0001).The effect of CPM was smaller in the patient groups compared to the controls, but the difference between groups was not significant . When all pancreatitis patients were taken together and compared to healthy controls, there was a significant difference .Our study confirms that patients with chronic pancreatitis show signs of central sensitization, manifest as lower pain thresholds compared to healthy controls. Our results suggest that patients with more severe disease exhibit more central sensitization. We were unable to demonstrate a relation between disease stage and effectiveness of inhibitory pain modulation.Peripheral nociception at the site of the pancreas spreads via ascending pathways of the spinal cord to supraspinal structures including the cortex. The effect of endogenous feedback systems on nociceptive input can be measured using the conditioned pain modulation (CPM) paradigm, which reflects effects of descending control from the brain on second-order neurons in the spinal cord. Both peripheral and central pain signaling are potentially sensitized in chronic pancreatitis. Several studies provide evidence for peripheral visceral nerve damage in chronic pancreatitis. The findings concerning variations in supraspinal central sensitization in relation to disease stage suggest implications regarding treatment approaches in chronic pancreatitis. Firstly, it has been demonstrated that degree of hyperalgesia in neuropathic pain patients is inversely related to analgesic efficacy of opioids. Our results support the hypothesis that patients with more severe disease exhibit more central sensitization. This hypothesis is further supported by other studies regarding relationships between disease severity, degree of central sensitization and therapeutic effect. For CRPS, a clear relationship between degree of central sensitization and disease progression has been demonstrated. A limitation of this study is the relatively small size of the two chronic pancreatitis disease stage subgroups. Nevertheless, even the present explorative study provides evidence of significant differences between healthy controls and a validated classification of pancreatitis disease stages. A better-powered study might have provided more robust and significant evidence across all the modalities and individual dermatomes we measured in our study.Sensitization of neurons and the extent of sensitization could be different between different tissues (skin vs. deeper tissues) and dermatomes. This might explain the differences between electric pain thresholds  and pressure pain thresholds (a stimulus of deeper tissues) in different dermatomes.The healthy control group is slightly younger than the pancreatitis group. However, the impact of aging on pain processing remains controversial, some studies described an increase of pain thresholds during aging A further important limitation of this study is that it is only cross-sectional. For definitive answers, a larger and longitudinal study will need to be performed. In this study only QST measurements were performed. Combining QST with EEG measurements or brain imaging would provide more detailed data on changes in the central nervous system in relation to pain processing on which to base more effective therapeutic strategies in the future. The M-ANNHEIM classification is at the moment the most comprehensive classification system for different stages of chronic pancreatitis and various degrees of clinical severity. In our study the classification proved simple, objective and accurate to apply The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis and may have important implications for its treatment. More research is needed to further characterize the link between disease severity and progression and its relationship to altered pain processing and treatment in chronic pancreatitis and other chronic pain disorders.


Objective. To date, there is still no consensus on the treatment of spinal degenerative disease. Current surgical techniques to manage painful spinal disorders are imperfect. In this paper, we aimed to evaluate the prospective results of posterior transpedicular dynamic stabilization, a novel surgical approach that skips the segments that do not produce pain. This technique has been proven biomechanically and radiologically in spinal degenerative diseases. Methods. A prospective study of 18 patients averaging 54.94 years of age with distant spinal segment degenerative disease. Indications consisted of degenerative disc disease (57%), herniated nucleus pulposus (50%), spinal stenosis (14.28%), degenerative spondylolisthesis (14.28%), and foraminal stenosis (7.1%). The Oswestry Low-Back Pain Disability Questionnaire and visual analog scale (VAS) for pain were recorded preoperatively and at the third and twelfth postoperative months. Results. Both the Oswestry and VAS scores showed significant improvement postoperatively (P < 0.05). We observed complications in one patient who had spinal epidural hematoma. Conclusion. We recommend skipping posterior transpedicular dynamic stabilization for surgical treatment of distant segment spinal degenerative disease. The most frequent clinical problem of the adult spine is back pain. It is known that 60–80% of the population will have back pain at some point in their lives that may affect their general health, daily activities, and their working capacity. It is assumed that back pain only has a defined pathology in 15% of patients . Those aRetrospective clinical studies have demonstrated that the lumbar fusion can lead to an acceleration in pathologic changes of the adjacent motion segment . The queThis study included 18 patients averaging 54.94 years of age; there were 10 females and 8 males. Our selection criteria for this procedure included any neurogenic, radicular pain and/or chronic low-back pain that was resistant to any conservative treatment and neurological deficit. The level of provocative pain was determined by discography in cases where the source of pain was not confirmed by clinical and radiological findings . RadioloThe Oswestry Disability Index (ODI) and the visual analog scale (VAS) were used for preoperative and postoperative subjective patient evaluations.Preoperative and postoperative values (VAS and ODI) were compared with the Wilcoxon ranked sum test. P < 0.05, Wilcoxon test). The preoperative mean VAS score was 7.28, the 3-month postoperative mean VAS score was 2.50, and the 12-month postoperative mean VAS score was 1.33 .Oswestry scale and VAS scale values were compared between the following groups: preoperative and 3-month postoperative, preoperative and 12-month postoperative, 3-month postoperative and 12-month postoperative. We observed significant changes between the groups. The preoperative mean Oswestry scale score was 68.00, the 3-month postoperative mean Oswestry scale score was 23.89, and the 12-month postoperative mean Oswestry scale score was 14.00. This decrease in the mean Oswestry scale score as the postoperative time increased was significant  significantly improved patient outcome compared to decompression alone –48. HoweSurgeons advocating fusion without instrumentation indicate that this process gives a little chance to adjacent segment degeneration, and this concept is supported by various studies. Fischgrund et al. reported a randomized study comparing decompressive laminectomy and arthrodesis with or without spinal instrumentation. After a 2-year followup period, the authors concluded that successful fusion did not influence the patients' outcomes . ConsideLumbar arthrodesis for the management of an unstable spine has dramatically increased over the last few decades. The purpose of spinal instrumentation is to increase fusion, but it is obvious that fusion with very long segment instrumentation is being tried, especially for different segment degenerative disorders. In our study, we adopted a surgical approach that only targeted unstable degenerated and pain-producing segments. Using this approach, we applied neural decompression by a minimally invasive approach that resulted in very little disruption of tissue integrity, discectomy by sparing ligamentum flavum, and decompression by hemilaminectomy in stenosis . We prov


Neuropathic pain is commonly associated with cancer. Current treatments include combination opioid and adjuvant therapies, but no guidelines are available for dose escalation strategies. This phase II study compared the efficacy and tolerability of two dose escalation strategies for oxycodone and pregabalin combination therapy.Patients (N = 75) with oncological neuropathic pain, previously untreated with pregabalin, were recruited in 5 Italian institutions between 2007 and 2010. Patients were randomised to two different dose escalation strategies  oxycodone at a fixed dose with increasing pregabalin doses;  pregabalin at a fixed dose with increasing oxycodone doses. Patients were evaluated from daily diaries and follow-ups at 3, 7, 10, and 14 days after beginning treatment with a numerical rating scale (NRS), neuropathic pain scale (SDN), and well-being scale (ESAS). The primary endpoint was a ≥1/3 reduction in pain (NRS); secondary endpoints included the time to analgesia and adverse effects. The study had a 90% probability of detecting the best strategy for a true difference of at least 15%.More patients in arm A (76%) than arm B (64%) achieved ≥1/3 overall pain reduction even after controlling for baseline factors . Group A reported fewer side effects than group B; constipation 52.8% vs. 66.7%; nausea: 27.8% vs. 44.4%; drowsiness: 44.4% vs. 55.6%; confusion: 16.7% vs. 27.8%; itching: 8.3% vs. 19.4%.Both strategies effectively controlled neuropathic pain, but according to the adopted selection design arm A is preferable to arm B for pain control.NCT00637975ClinicalTrials.gov  Neuropathic pain is a common symptom in patients with cancer. Among patients with oncological pain, at least 1/3 is diagnosed with neuropathic pain Previously, a meta-analysis on the role of opioids in treating benign neuropathic pain showed that some opioids, particularly oxycodone, are more effective than other agents Gatti et al. demonstrated the effectiveness and tolerability of pregabalin combined with oxycodone in treating non-cancer pain in a large cohort of patients Previous studies have demonstrated that genetic variations in pain-related receptors, transporters, and metabolising enzymes were related to opioid efficacy. The most interesting genes discovered were the mu and kappa opioid receptors To our knowledge, no previous studies have investigated different dose escalation strategies in a combination therapy for neuropathic pain. In current clinical practice, this decision is typically made empirically by individual physicians, based on personal experience.The present prospective study aimed to evaluate two different dose escalation strategies for combining pregabalin with oxycodone in treating patients with neuropathic pain caused by neoplasms. We also examined genetic SNPs as a potential basis for differences in drug responses.The protocol for this trial and supporting CONSORT checklist are available as supporting information; see This research has been approved by the Ethics Committee of Fatebenefratelli and Oftalmico Hospital in Milan and has been conducted according to the Declaration of Helsinki Principles. Five Italian institutions participated in the trial from September 2007 to December 2010. The protocol was approved by the ethics committees of each participating centre and written informed consent was obtained from all participants. The study is registered at Clinicaltrial.gov .Patients with cancer pain were enrolled when they had a clinical diagnosis of cancer and pain with a neuropathic component. Neuropathic pain was identified by the physician as burning pain, shooting or lancinating pain episodes, dysesthesia, or allodynia.The inclusion criteria were at least 18 years of age; pain that occurred within the 24-h period preceding the screening visit and was rated ≥4 on a NRS  Chemotherapy crossover was not allowed in the 3 weeks before screening or throughout the study. Radiotherapy was not allowed on the lesion that caused the neuropathic pain. Hormone therapy that had been started before trial entry could be continued, but the dose could not be changed during the study.Patients were randomly assigned by a computer-generated scheme to receive one of two dose escalation strategies. (Arm A) Patients received oxycodone controlled release (CR), 20 mg/day, plus increasing doses of pregabalin, starting at 50 mg/day. (Arm B) Patients received pregabalin, 50 mg/day, plus increasing doses of oxycodone, starting at 20 mg/day .On the day of the screening visit, seven days before treatment start (−7 days), a titration phase began with the administration of normal-release morphine. On the day that treatment started (day 0), eligible patients were randomly allocated to Arm A or Arm B. After randomisation, patients were observed for 14 days. Pain and tolerability were recorded daily in a patient diary and evaluated by a physician at 3, 7, 10, and 14 days.When the prior 24-hour pain scores, taken at specified time points, were ≥4 and no side effects were reported, the patients received a dose escalation, according to the randomisation arm. In Arm A, the dose of pregabalin was increased by 50 mg up to a maximum dose of 300 mg. In Arm B, oxycodone CR was increased in increments less than fifty percent of the previous dose. Rescue doses with normal release morphine were permitted, but they had to be recorded in the patient’s daily diary.During the 24-hour period preceding the randomisation visit, average pain intensity was assessed on a 0 to 10 NRS The somatic component, mainly due to bone metastases, was also clinically evaluated by the physician and recorded on the clinical chart.Allodynia, defined as pain in response to non-painful stimulation, was assessed by asking the patient to describe the location of a referred pain, and gently stroking the area with a cotton swab. The pain was recorded as present or absent.At the screening visit (day -7), patients were instructed on how to complete a daily pain diary, which included the average intensity of global pain, evaluated with the NRS, and any concomitant medications. The patient was also required to record the number of daily breakthrough pain episodes (BTP) and the use of rescue analgesic doses. At each follow-up visit , pain was re-assessed by the physician with the SDNs, and ESAS interviews were performed.The primary endpoint was overall analgesia, defined as a reduction of pain intensity by at least 1/3 (NRS). Secondary endpoints were reductions in BTP episodes and neuropathic pain (SDN) and an improvement in patient well-being (ESAS).Drug safety was assessed by evaluating the type, frequency, and intensity of any reported adverse events according to the Common Terminology Criteria for Adverse Events Version 4.02 (CTCAE 4.02) OPRK1) and mu 1 (OPRM1) OPRK1 polymorphisms  and one OPRM1 polymorphism (rs1799971) were genotyped with TaqMan SNP Genotyping assays . PCR was carried out in 384-well plates, prepared with an automatic liquid handling system . The PCR-amplified DNA fragments were analysed with Allelic Discrimination Sequence Detection Software .Within the main study, there was an optional ancillary study aimed to detect a possible correlation between selected genes and the drug response. A subset of 50 out of 76 patients from five Italian institutions participated in the ancillary study, from September 2007 to December 2010. The candidate genes included, in addition to others, the opioid receptors, kappa 1  and reductions in BTP episodes, allodynia, somatic pain, and side effects were reported in terms of absolute and relative frequencies or medians and ranges, according to the type of data . Since the randomised selection design is not powered for formal comparisons between arms, the differences between the two groups were analysed only for exploratory purposes with the χA multivariate analysis was performed and adjusted for the presence of a somatic component.From September 2007 to November 2010, 75 patients were randomised in 5 Italian centres. Thirty-eight (50.7%) were assigned to arm A and 37 (49.3%) were assigned to arm B.The trial implementation profile is shown in Demographic characteristics of patients and baseline pain characteristics are reported in Reduction of at least 33% of the baseline pain was achieved in 26 (76.5%) patients in arm A vs. 23 (63.9%) patients in arm B . The median NRS score for pain was 6 (range 4–9) in arm A and 5 (range 2–9) in arm B. The result was confirmed in a multivariate analysis, after adjustments for gender, the presence of a somatic pain component, and the initial pain score . Analgesia was achieved in arm A with a mean dose of 100 mg of pregabalin and in arm B with a mean dose of 60 mg of oxycodone. The median time to achieve analgesia was 10 days (95% CI: 5–14 days) in arm A and 11 days (95% CI: 5–18 days) in arm B. Activity outcome is summarised in The frequency of the use of rescue doses of analgesics for BTP was similar between groups: arm A, 10 patients (29.4%); arm B, 8 patients (28.6%); p = 0.59.The well-being of patients, based on the ESAS scale and SDN item distributions was not statistically different between the study arms.Unexpectedly, distinct toxicity profiles for each study arm could not be found . In factOPRK1 and OPRM1 genes were correlated to the activity and/or toxicity of the combination of pregabalin and oxycodone. We found no significant correlations. Moreover, the distributions of the different genotypes were similar in the two groups.We analysed DNA samples from 50 patients to determine whether the The aim of this phase two study was to assess two different dose escalation strategies for the treatment of neuropathic pain in an oncological setting. The study was designed according to the Simon selection design in order to select the best strategy for a subsequent phase 3 trial. Regarding tolerability, we confirmed the data available in the literature, which showed that the combination of oxycodone and pregabalin was effective and safe OPRK1 and OPRM1 SNPs. Unfortunately, our data were not sufficiently powered to determine genetic influences on drug response. Nevertheless, the distributions of these genotypes were equivalent between the groups studied. This allowed us to exclude the possibility that the clinical differences observed between the two randomised groups were influenced by differences in mu and kappa receptor genes. Our analysis indicated that the genes identified by rs1051660, rs1799971, and rs7815624 had no interactions with the results. However, the rs702764 polymorphism showed an odds ratio of 1.8; thus, in future large scale studies, it might be interesting to analyse the role of this polymorphism in the response to combination therapy.The response to neuropathic pain treatment and the incidence of side effects are different for each patient. This variability may be explained by the specific characteristics of individual patients. Thus, we selected and evaluated potential polymorphisms in two key genes involved in the opioid response with genetic analyses of the The treatment of neuropathic pain remains an open issue. Active research should be conducted to find more effective and personalised treatments. This paper could lead to a phase III study that would compare the strategy of oxycodone plus pregabalin at increasing doses with a conventional treatment, like gabapentin plus morphine, as published by Caraceni and colleagues Protocol S1Trial protocol.(DOC)Click here for additional data file.Checklist S1CONSORT checklist.(DOC)Click here for additional data file.


There is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the descending pain inhibitory network in age-matched FM patients and healthy controls (HC).We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus.p < .001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients.FM patients required significantly less pressure (kPa) to reach calibrated pain at 50 mm on a 0–100 visual analogue scale (Patients with FM displayed less connectivity within the brain’s pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation. FM is a common pain disorder, estimated to affect 2 to 4 % of the population, out of which 80 % are women . This muAccumulated evidence indicates that pain dysregulation within the central nervous system plays an important role in the development and maintenance of FM. For instance, brain imaging studies suggest that FM is associated with 1) augmented brain responses to experimental pain stimuli ,9; 2) chRecently, several fMRI studies have significantly enhanced our understanding of the intrinsic functional connectivity underlying pain perception ,26, painIn this study we used connectivity analyses of fMRI data to investigate the functional connectivity of the rACC and thalamus during pressure-evoked pain, in both healthy controls and FM patients. Previous neuroimaging studies in FM found altered cerebral activity during evoked pain ,9,22, suen passant findings of intracranial anomalies, leaving 83 patients for matching with healthy controls. A total of 14 healthy female controls were available, aged 24 to 48 years, mean age 34 (SD = 8.6). Due to the relatively large number of patients, each healthy control could be age-matched with two FM patients . In cases where there were more than two patients with the same age, the two patients with the most similar duration of FM symptoms were chosen. The study was performed in accordance with the Helsinki Declaration and was approved by the local Ethical Committee at each of the three participating sites. All patients and healthy controls gave written informed consent. Parts of the present dataset were used in 2 previous publications; see Jensen et al. 2010 [A total of 42 female subjects  were analyzed in the present study. Patients were recruited as part of a pharmacological multicenter study (EudraCT # 2004-004249-16). All three sites – one in England, Sweden and Germany, respectively - also performed the experiment in healthy controls, consecutively recruited throughout the study. A total of 92 female FM patients aged 25 to 55 years, mean age 44 (SD = 8.2) were enrolled. Of the 92 patients 9 were excluded from fMRI analyses due to image artifacts or al. 2010  where alal. 2010 , where 1All subjects were first screened and then scheduled for one behavioral session and one fMRI session on two adjacent days. On day one, subjects were familiarized with the equipment that was used to evoke experimental pain, calibrated for subjective pain ratings and asked to fill out self-report questionnaires. FMRI scanning was performed on day two.All subjects were right-handed. The study protocol required that all medications that could influence pain perception, including psychopharmacological medications, were washed out. Patients had to withdraw from all central nervous system acting therapies, including antidepressants, anticonvulsants, mood stabilizers, opioids, and narcotic patches, and to discontinue treatment with transcutaneous electrical nerve stimulation, biofeedback, tender and trigger point injections, acupuncture, and anesthetics. Required periods off medication were dependent on the actual pharmacological characteristics to ensure complete washout. All analgesics were prohibited during the study, except for paracetamol, dipyrone and nonsteroidal anti-inflammatory agents (NSAIDs), which were used as rescue medications. The rescue medications had to be prescribed at the lowest available dose and for the shortest period of time necessary to manage the patient’s acute pain. Use of any analgesic or narcotic drug had to be discontinued 48 hours prior to the assessments of pain sensitivity. Zolpidem was allowed for treatment of insomnia. Exclusion criteria included the following: severe psychiatric illness (including severe melancholic depressive episode); serious suicide risk; history or behavior that would prohibit study compliance; history of substance, drug, or alcohol abuse; heavy cigarette smoking (> 25 cigarettes/day); presentation of an intracranial anomaly; significant cardiovascular, pulmonary, gastrointestinal, hepatic, or renal disease; history of autoimmune disease; current systemic infection; active cancer  or current cancer therapy; unstable endocrine disease; severe sleep apnea; or pregnancy or breastfeeding. FM patients were mainly recruited from primary care and were diagnosed according to the 1990 American College of Rheumatology criteria [2 hard rubber probe, has been proven effective in several previous publications [Calibration of pain and stimulations during fMRI were performed using a laptop-controlled tool that delivered pressure to the right thumbnail. This specially designed tool, which consists of a plastic piston that applies pressure via a 1 cmications ,31,32. CImages were collected using three different 1.5 Tesla scanners: in London a General Electric HDx scanner was used, in Stockholm a General Electric Twinspeed Signa Horizon, and in Cologne a PHILIPS scanner was used. Multiple T2*-weighted single-shot gradient echo EPI sequences were used to acquire blood oxygen level dependent (BOLD) contrast images. The following parameters were used: repetition time: 3000 ms (35 slices acquired), echo time: 40 ms, flip angle: 90 degrees, field of view: 24 × 24 cm, 64 × 64 matrix, 4 mm slice thickness with 0.4 mm gap and sequential image acquisition order. In the scanner, cushions and headphones were used to reduce head movement and dampen scanner noise. Placing a blank screen in front of the patient’s field of view from inside the scanner minimized visual distraction during scans.Two types of stimulations were used during the functional scans: individually calibrated painful pressure, representing each subject’s 50 mm VAS, and a non painful pressure perceived as light touch, representing 0 mm VAS. All stimulations were randomly jittered over the scanning time, preventing subjects from anticipating the onset time and event type. The time interval between consecutive events was randomized with a mean stimulus onset asynchronicity (SOA) of 15 seconds (range 10–20 seconds). The total duration of the scans was approximately 35 minutes. Before scanning, subjects were instructed to focus on the pressures on the thumb and not to use any distraction or coping techniques.3.In addition to the functional scans, high-resolution T1-weighted structural images were acquired in coronal orientation for anatomical reference purposes and screening for cerebral anomalies. Parameters were: Spoiled Gradient Recalled 3D sequence, repetition time: 24 ms, echo time: 6 ms, flip angle 35 degrees with a voxel size of 0.9 × 1.5 × 0.9 mmThe scanning procedure was standardized between sites by the use of written manuscripts for the oral instructions as well as practical training for all investigators involved in the study. In order to ensure calibrated experimental procedures and scanner settings, several visits were done at the three sites by a central coordinator.The day before fMRI-scanning, all patients used a 0–100 mm VAS to rate their average clinical pain during the previous week and their current pain. Additionally, patients completed the Fibromyalgia Impact Questionnaire (FIQ); a 20-question questionnaire that assesses the overall symptom severity in patients with FM . A high The differences between FM patients and healthy controls regarding age and pressure pain sensitivity were assessed using two independent samples t-tests (two-tailed). A polynomial regression was used to determine each individual’s representation of VAS 50 mm, built on the 15 ratings from the randomized series of thumb pressures. The SPSS statistics software, version 18, was used for statistical analyses of behavioral data.http://www.fil.ion.ucl.ac.uk/spm/). Two separate one-sample t-tests were performed for the rACC and thalamus, assessing the connectivity between the seeds and the rest of the brain in FM patients (n = 28) and healthy controls (n = 14), respectively. Differences in rACC and thalamus connectivity between FM patients and healthy controls were assessed by two separate two-sample t-tests. The two seeds used in this study were 1) the rACC, centered at x = 8, y = 46, z = 4  with a 2 mm radius, and 2) the thalamus, centered at x = −14, y = −34, z = 12 MNI with a 2 mm radius. The coordinates were based on the results from a previous publication where we compared the pain-evoked fMRI signal in FM patients and healthy controls [The connectivity fMRI analyses were performed in line with the methods previously described by our group ,27,34 ancontrols .p < .005, uncorrected, with a minimum cluster size of 20 contiguous voxels. For all other brain regions, a threshold of voxel-wise p < .05, corrected for multiple comparisons, was used.According to our hypothesis and previous studies of the DPMS , the PAGt-test validated that there was no significant difference in age between the two groups . In accordance with our previous findings, the sensitivity to pressure was significantly higher in FM patients, represented by lower amounts of pressure required to evoke pain at 50 mm VAS   was age-matched with two FM patients (n = 28). A two-sample 4 was aget-test for FM patients only (n = 28), demonstrated significant functional connectivity between the seed located in the rACC and the contralateral rACC and medial prefrontal cortex (MPFC), an area which was predefined as an ROI. Also, there was significant connectivity between the rACC and the precuneus and occipital cortex  revealed that, compared to FM patients, the rACC of healthy controls had significantly higher connectivity to the left amygdala, bilateral hippocampi, and the brainstem .A one-sample only n = 8, demonsonly n = 8, demonst-test for FM patients only, demonstrated significant functional connectivity between the seed located in the thalamus and the contralateral thalamus. A one-sample t-test for healthy controls revealed significant functional connectivity between the seed region in the thalamus and the contralateral thalamus as well as the orbitofrontal cortex (OBFC). In a direct comparison between healthy controls and FM patients (two sample t-test), the thalamus showed significantly higher connectivity to the OBFC in healthy controls. There were no significant regions outside of the predefined ROI’s and no regions showed higher thalamus connectivity in FM patients, compared to controls. For all thalamic connectivity results, see Table A one-sample In this study, we investigated the differences in functional brain connectivity between FM patients and matched healthy controls during intermittent application of pressure pain. The results revealed that healthy controls had higher rACC connectivity to the bilateral hippocampi, amygdala, brainstem and RVM; regions highly involved in the descending modulation of pain. Additionally, we found that healthy controls displayed higher connectivity between the thalamus and the OBFC, a cortical region that plays an important role in endogenous modulation of pain and emotions . Hence, In a previous study, we found that patients with FM failed to recruit the rACC during evoked pressure pain . Using tThe role of the hippocampus in pain modulation is less explored but we speculate that the connectivity between the rACC and the hippocampus is likely related to the aversive drive and motivational dimension of pain ,55. For In addition to the functional connectivity between the rACC, hippocampus and PAG, control subjects showed significantly higher connectivity between the rACC and bilateral amygdalae, a limbic structure with direct projections to the PAG . PreviouIn one of our previous studies , includiThere is increasing evidence for altered thalamic function in pain patients with chronic pain such as neuropathic pain ,59 and FThe OBFC has been proposed to be involved in sensory integration, reward processing, decision-making and expectation . A meta-Due to the uneven number of FM patients and healthy controls available for this study, we chose to match each healthy control (n = 14) with two FM patients (n = 28). We estimate that the benefit of increasing our power by matching two patients per control, instead of one, is larger than the risk of getting unfair variance estimations for the two groups.In the present study, we used subjectively calibrated pressure stimuli during fMRI scans, leading to matched levels of experienced pain in FM patients and controls. As a result, the pressure needed to evoke pain was significantly different for FM patients and controls and could possibly affect some aspects of our results. It is possible, but unlikely, that certain parts of the central nervous system can detect information about absolute stimulus magnitudes and thereby confound the comparison between FM patients and controls.In summary, our study indicates that FM patients display less functional connectivity between areas involved in pain inhibition compared to healthy controls during intermittent pressure pain administration. Our results suggest tha the dysfunction of the DPMS, a crucial homeostatic modulator of pain, plays an important role in maintenance of FM pain. These results may translate into clinical implications by using the functional connectivity of DPMS as an objective measure of pain dysregulation.The authors declare that they have no competing interests.EC, RHG, MI, EK, YM, FP, OV, SCRW participated in the design of the study. EC, SC, PF, MI, KBJ, EK, HM, YM FP, OV, SCRW coordinated the study and performed the data collection. Data analysis and expertise on analyses was contributed by PF, RLG, RHG, MI, KBJ, EK, JK, RL, HM, FP, SCRW. The manuscript was drafted by EC, SC, PF, RLG, RHG, MI, KBJ, EK, JK, RL, HM, FP, SCRW. All authors read and approved the final manuscript.


For many years, the CD instrumentation has been regarded as the standard device for the surgical correction of adolescent idiopathic scoliosis (AIS). Nevertheless, scientific long-term results on this procedure are rare. Therefore, we conducted a retrospective follow-up study of patients treated for AIS with CD instrumentation and spondylodesis.A total of 40 patients with AIS underwent CD instrumentation in our department within 3 years and between 1990 and 1992. For the retrospective analysis, first all the patient documents were reviewed, and pre-/postoperative X-ray images as well as those at the latest follow-up were analysed. Furthermore, it was attempted to conduct a clinical survey using the SRS-24 questionnaire, which was sent to the patients after a preceding announcement on the phone.Radiologically, the frontal main curvature was improved from a preoperative angle of 69.2° to a postoperative angle of 35.4°, and the secondary curvature was improved from a preoperative angle of 42.6° to a postoperative angle of 20.5°. The latest radiological follow-up at average 57.4 months post surgery showed an average loss of correction of 9.6° (main curvature) and 4.6° (secondary curvature), respectively.Within the first 30 days post surgery, 3 out of 40 patients (7.5%) received early operative revision for the dislocation of hooks or rods.At an average of 45.7 months (range 11 to 142 months), 19 out of 40 patients  received late operative revisions: The reasons were late infection  with the development of fistulae (7 cases) or putrid secretion (3 cases), which was resolved with the complete removal of instrumentation after all. The average time until revision was 35.5 months (range 14 to 56 months) after CD instrumentation. Furthermore, complete implant removal was necessary in 8 out of 40 patients (20%) for late operate site pain (LOSP). The average time until removal of instrumentation was 62.7 months (range 18 to 146 months) post surgery; and one patient received partial device removal for prominent instrumentation 11 months post surgery. Altogether, only 22 out of 40 CD instrumentations (55%) were still in situ.in situ.After an average period of 14.3 years post surgery, it was possible to follow-up 14 out of 40 patients (35%) using the SRS-24 questionnaire. The average score was 93 points, without showing significant differences between patients with or without their instrumentation Retrospectively, we documented for the first time a very high revisions rate in patients with AIS and treated by CD instrumentation. Nearly half of the instrumentation had to be removed due to late infection and LOSP. The reasons for the high rate of late infections with or without fistulae and for LOSP were analysed and discussed in detail. For the surgical treatment of adolescent idiopathic scoliosis (AIS), various anterior and posterior procedures and instrumentations were developed. With regard to posterior procedures, two different well-known instrumentations must be distinguished:With the development of the Harrington rod, a long-With the development and introduction of a novel double-rod instrumentation by Cotrel and Dubousset about 25 years later, the disBetween March 1990 and September 1992, a total of 42 consecutive patients with AIS underwent surgical correction with CD instrumentation  in both planes (with the patients standing on cassettes that were 36 inches long) were then analysed with regard to the following parameters: curve patterns were classified by the method based on King-Moe and ScolAt the time of the empirical data collection, after an average period of 14.3 years (range 189 to 159 months) post surgery, it was attempted to contact the patients via telephone in order to conduct a clinical evaluation using the SRS-24 questionnaire. Due to various reasons , it was only possible to assess 14 out of 40 patients (35%).For statistical analysis, SPSS Version 8 software for Windows was used for the statistical analysis, and P values of ≤ 0.05 were considered significant. Descriptive statistics were used to determine the means, standard deviations (SD), and ranges. Comparisons between the variables were performed using the Student’s t test and the Kruskal-Wallis test.The demographic data included 40 patients , with an average age at the time of surgery of 16.0 years (range 13 to 21 years). According to the SRS terminology there were 23 right thoracic, 10 double major curves, 4 thoracolumbar, and 3 left thoracic curves. According to the King-Moe classification[In the frontal plane, the mean preoperative primary curve was 69.2° (range 50° to 100°). Postoperatively, the primary curve was 35.4° (range 13° to 70°), giving a correction rate of 48.8%. At the most recent follow-up evaluation, the Cobb angle of the curve was 41.6°, giving a final correction rate of 39.9%. The mean preoperative secondary curve was 42.6° (range 21° to 73°). Postoperatively, the secondary curve was 20.5° (range 2° to 46°), giving a correction rate of 51.9%. At the most recent follow-up evaluation, the Cobb angle of the curve was 25.1°, giving a final correction rate of 41.1%. The frontal balance, as determined by the mediolateral offset of the C7 vertebral body centre in relation to CSVL, was 14.6 mm on average, postoperatively, and 3 out of 40 patients (7.5%) had frontal imbalance of more than 20 mm offset (range 25 to 36 mm), postoperatively. Apical translation (apex of primary curve to CSVL) measured 63.5 mm pre-, 30.9 mm postoperatively and 37.3 mm at the final follow-up, giving a final correction rate of 41.3%. In the sagittal plane, the average preoperative thoracic kyphosis angle (T5 to T12) curve was 22.4° (range 2° to 63°). Postoperatively, the thoracic kyphosis angle measured 23.6°, only one patient had thoracic hyperkyphosis of more than 40°. Moreover, the average preoperative lumbar lordosis angle (L1 to S1) curve was 57.3° (range 30° to 87°). Postoperatively, the lumbar lordosis angle measured 54.9° (range 30° to 78°).There was no direct or indirect operative mortality. Furthermore, there was no permanent neurological complication. In one case, surgical correction was stopped incompletely because of massive bleeding, and then the correction was successfully concluded 14 days later.According to the medical files, 21 out of 40 patients (52.5%) received one or more operative revisions, for a total of 23 surgical revisions:Within the first 30 days post surgery, 3 out of 40 patients (7.5%) received early operative revision for the dislocation of hooks or rods.At an average of 45.7 months (range 11 to 142 months), 19 out of 40 patients  received late operative revisions.At this occasion, we documented the revision rate of the highest significance , not in the first year of introduction but rather for 1992, the third and last year of application. Despite thorough data analysis, we could not find any explanations for this.The reasons were late infection  with the development of fistulae (7 cases) or putrid secretion (3 cases), which was resolved with the complete removal of instrumentation after all. We documented 5 out of 7 fistulae at the distal end of the instrumentation. The average time until revision was 35.5 months (range 14 to 56 months) after CD instrumentation. There were no bacteriological findings of any pathogens after a maximum time of cultivation of 48 hours.Furthermore, complete implant removal was necessary in 8 out of 40 patients (20%) for late operate site pain (LOSP). No infections or non-unions were detected intraoperatively, but there was a partial implant loosening in the caudal section of the implant in 6 cases, including corrosion in 2 out of 6 cases and broken cranial transverse connectors in 2 other cases. The average time until removal of instrumentation was 62.7 months (range 18 to 146 months) postoperatively.Moreover, one more patient received partial device removal for prominent instrumentation 11 months postoperatively.Therefore, only 22 out of 40 CD instrumentations (55%) were still in situ.The statistical analysis showed only tendency but no significant influence for the distal end of the instrumentation: 8 out of 16 patients (50%) with instrumentation including lumbar level 4 or 5 received implant removal for infection or LOSP. On the other side, 10 out of 24 patients (41.7%) with distal end of instrumentation until lumbar level 1, 2 or 3 received implant removal. This difference was not statistically significant (p > 0.05). Moreover, the statistical analysis showed no significant influences for the removal of instrumentation compared to patients with instrumentation still in situ (18 versus 22 patients) for e.g. sex, type of curve , or other demographic parameters.in situ (average 96.4 points) and the 9 patients after the removal of the instrumentation (average 91.5 points).Only 14 out of 40 patients (35%) completed the SRS-24 questionnaire after a mean of 14.3 years postoperatively. In the SRS-24 questionnaire, the total score averaged 93.3 points out of a maximum 120 points (min. 71 to max. 106 points) at the follow-up. The analysis of the questionnaire showed no significant differences between the 5 patients with instrumentation still The retrospective study (Evidence Level 4) was primarily aiming at assessing the clinical and radiological long-term results of AIS patients after dorsal CD instrumentation. For this, it was initially possible to include all of the 40 consecutive patients who had undergone surgical procedures in our spine department during a period of 3 years. Compared to other so-called monocentric studies, this number of cases seems somewhat small in total; however, it may be considered sufficient when taking into account the follow-up period-16. SurpTherefore, a more detailed discussion is required:First of all, it must be emphasised that all surgical procedures had been conducted following strict and standardised aseptic criteria in a modern operation room with a laminar flow section, and that single-shot antibiotic prophylaxis had been given and repeated, respectively, if required. Furthermore, our previously published data from 1993 to 1996 had demonstrated clearly better results with regard to infection rates. MoreoveAfter an average postoperative period of 57.4 months, the latest x-ray images showed a minor loss of correction – of both main and secondary curvatures – that was similar to the results demonstrated in other study.However, compared to other studies-22, empiIt must be emphasised from a historical point of view that, prior to the introduction of CD instrumentation, the surgeons had been trained in the use of the Harrington rod for many years  – however, this system is not consistent with the philosophy and usage of the CD. Nevertheless, no “learning curve” with significantly increased complication rates has been seen during the first year of introduction. In contrast, the highest revision rate  was seen in 1992, which was the third and last year of application. Despite thorough data analysis, we could not find any explanations for this.Propionibacterium acnes is a specific pathogen; however, detection requires a particular agar and a incubation period of up to 14 days. This might be an explanation for the fact that this pathogen was not identified in any of our cases with clinically manifest late infections, since all the specimens had been incubated for a routine period of only up to 48 hours at the time of surgery. Furthermore, proprietary unpublished study results show that the intraoperative detection of Propionibacterium acnes in the surgical wound significantly increases with the duration of surgery.Over time, 40 procedures were performed by 4 different surgeons, which is a basic deviation when compared to other studies,17,19, bIn our study group, we had 8 patients with back pain without clinical evidence of pseudarthrosis or manifest infections at the time of surgical revision/complete implant removal. Cook et al. documentin situ mainly had a good quality of life post surgery. We finally summarised the clinical results of other studies investigating CD instrumentation in TableAfter an average period of 14 years post surgery, it was not possible to encourage more patients to participate in a clinical follow-up, despite intense effort. However, this is in accordance with other clinical results after long-term follow-up. There wRetrospectively, we documented for the first time a very high revisions rate in patients with AIS and treated by CD instrumentation. This high rate of surgical revisions has not yet been documented in the literature. Nearly half of the instrumentation had to be removed due to late infection and LOSP. The reasons for the high rate of late infections with or without fistulae and for LOSP were analysed and discussed in detail.The authors declare that they have no competing interests.FJM has contributes in conception and design and acquisition of data, analysis and interpretation of data, drafting the manuscript and revising it critically; HG has contributed in conception and design of data, drafting the manuscript and given the final approval of manuscript. Both authors read and approved the final manuscript.


Treatosthesis . RecentlPrimary end-points include: pain relief, improvement in the range of motion, activities of daily living, and enhancement of shoulder strength referring to the Constant Score  recordedSince September 2012 we have implanted the Biodegradable InSpace Balloon in 10 patients  affected by an irreparable massive rotator-cuff tear. All patients were preoperatively assessed by physical examination, RX and RMN examinations. Prospective postoperative assessment of symptoms and complications and/or device-related adverse events were recorded with prospective determination of the Constant Score as well as at hospital discharge, 1, 3 and 6 weeks, 3 and 6 months postoperatively. All operations were performed with the patient in a beach-chair position under general anesthesia. This device has been inserted arthroscopically, using 3 arthroscopic ports  in the subacromial space. After subtotal removal of the subacromial bursa, the tear was debrided and the rotator cuff was assessed by grasping the edges of the tendons with an arthroscopic clamp, in an attempt to draw it to the footprint region. A decision was made to insert the balloon when it was deemed that the rotator cuff tear was irreparable. During the postoperative period the patients have followed a rehabilitation program which consisted in immobilizing the arm with a 4 week brace and, after that, in an active/passive motor physical therapy. The patients were taught simple motor exercises to do at home in order to hasten the rehabilitation process and were advised avoiding heavy activities during the first three months after the surgery.There was a significant reduction of pain score and night pain one week following balloon implantation. This improvement increased progressively throughout the whole duration of follow-up. Patients reported significant improvement in their daily living activities the sixth week after surgery. The range of motion also showed significant improvement 8 weeks later the surgery.In all measurable parameters, once reached significance, the improvement was maintained throughout the follow-up period. All patients were satisfied with the results and showed significant functional improvements just a few time after the surgery. No postoperative complications showed up.This study has shown efficacy and a very high clinical safety profile of the InSpaceTM device in a small group of patients with massive irreparable rotator cuff tears. The insertion of the device was associated with significant early improvement in subjective pain scores and a decrease in reported night pain. The total Constant Score showed statistically significant improvement as did scores of activities of daily living and range of motion. It’s a simple non-invasive surgery, technically esay to replicate with preliminary encouraging results. This procedure represents a valid surgical option in order to postpone more invasive operations.