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Carlijn Campman,1 Dirk van Ranst,2 Jan Willem Meijer,2 Margriet Sitskoorn1 1Department of Cognitive Neuropsychology, Tilburg University, Tilburg, 2Pulmonary Rehabilitation Center ‘Schoondonck’, Revant, Breda, the Netherlands Purpose: COPD is associated with cognitive impairment. These impairments should be diagnosed, but due to time- and budget-reasons, they are often not investigated. The aim of this study is to examine the viability of a brief computerized cognitive test battery, Central Nervous System Vital Signs (CNSVS), in COPD patients. Patients and methods: Patients with COPD referred to tertiary pulmonary rehabilitation were included. Cognitive functioning of patients was assessed with CNSVS before pulmonary rehabilitation and compared with age-corrected CNSVS norms. CNSVS is a 30 minute computerized test battery that includes tests of verbal and visual memory, psychomotor speed, processing speed, cognitive flexibility, complex attention, executive functioning, and reaction time. Results: CNSVS was fully completed by 205 (93.2%, 105 females, 100 males) of the total group of patients (n=220, 116 females, 104 males). Z-tests showed that COPD patients performed significantly worse than the norms on all CNSVS cognitive domains. Slightly more than half of the patients (51.8%) had impaired functioning on 1 or more cognitive domains. Patients without computer experience performed significantly worse on CNSVS than patients using the computer frequently. Conclusion: The completion rate of CNSVS was high and cognitive dysfunctions measured with this screening were similar to the results found in prior research, including paper and pen cognitive tests. These results support the viability of this brief computerized cognitive screening in COPD patients, that may lead to better care for these patients. Cognitive performance of patients with little computer experience should be interpreted carefully. Future research on this issue is needed. Keywords: CNS vital signs, cognitive function, computerized cognitive testing, neuropsychological assessment, viability

D van Ranst, WA Stoop, JW Meijer, HJ Otten, IG van de PortRevant, Pulmonary Rehabilitation Center "Schoondonck," Breda, the NetherlandsBackground: Pulmonary rehabilitation (PR) is an important treatment option for chronic obstructive pulmonary disease (COPD) patients and might contribute to a reduction in exacerbation and exacerbation-related hospitalization rate.Methods: In this prospective study, all COPD patients that completed a comprehensive pulmonary rehabilitation program (PRP) between June 2006 and December 2012 were included. Self-reported exacerbation and hospitalization frequency 1 year before PR was retrospectively recorded. During the year following PR, exacerbation and hospitalization frequency was recorded with questionnaires.Results: For 343 patients, complete information on exacerbation and hospitalization rate was obtained. The mean number of exacerbations decreased significantly after participating in a PRP by 1.37 exacerbations/year (95% confidence interval 1.029 to 1.717) from 4.56±3.26 exacerbations in the year preceding PR to 3.18±2.53 in the year following PR (P

Dirk van Ranst1, Henk Otten1,2, Jan Willem Meijer1, Alex J van 't Hul1,31Revant, Pulmonary Rehabilitation Center 'Schoondonck', Breda, 2Erasmus Medical Center, Department of Pulmonary Diseases, Erasmus University, Rotterdam, 3VU Medical Center, Department of Pulmonary Diseases, VU University, Amsterdam, The NetherlandsIntroduction: Effects of pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) patients with severely impaired health status are poorly documented since these patients are usually excluded from clinical trials. This retrospective, observational study aims to study the impact of disease on health status and the effects of PR on COPD patients referred to a tertiary center for PR in The Netherlands.Methods: Between June 2006 and June 2010, 437 patients with COPD were allocated to our intensive, comprehensive PR program. Patients participated in this interdisciplinary program for 12 weeks for a weekly average of 20–25 hours. Before and directly after, several measures of physical performance and health-related quality of life were determined.Results: At baseline, most patients (75%) had a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage of III-IV. Peak exercise performance on a cycle ergometer was on average reduced to 43 ± 29 Watt, and health-related quality of life was significantly impaired, with a total score on the St George's Respiratory Questionnaire (SGRQ) of 66. Health-care utilization in the year preceding PR was very high. After rehabilitation, all outcome measures improved statistically significantly (P < 0.001). Exercise performance measured with the 6 minute walking distance test improved clinically significantly in 68% of the patients, whereas 75% of the patients showed a clinically meaningful improvement in quality of life as measured with the SGRQ. Multiple regression analysis revealed that 19% of the variation in responses on the 6 minute walking distance test and the SGRQ could be explained on the basis of baseline characteristics.Conclusion: The present study provides data to indicate that COPD patients may substantially benefit from rehabilitation in a tertiary pulmonary rehabilitation center, despite a severely impaired health status and high level of health-care utilization, in which prior treatment in primary and secondary care have failed to improve health status. Individual rehabilitation responses can only partially be predicted on the basis of baseline characteristics. Consequently, no firm conclusions can be drawn from this study with respect to the selection of candidates that could be deemed eligible for this rehabilitation program when entering the program.Keywords: BODE index, 6MWDT, HRQL, SGRQ, pulmonary rehabilitation

Digital pathology with whole-slide imaging (WSI) has a large potential to make the process of expert consultation and expert panel diagnosis more rapid and more efficient. However, comparison with the current methods is necessary for validation of the technique. In this study, we determined if digital assessment of whole-slide images of hematopathology specimens with a focus on the assessment of lymphoma can be used for consultation and panel diagnostics. Ninety-three histological specimens with a suspicion for lymphoma were assessed both with conventional microscopy and digital microscopy with a wash out period between assessments. A consensus diagnosis was based on full concordance between the pathologists or, in case of discordances, was reached at a joint session at a multi-headed microscope. In 81% of the cases, there was a full concordance between digital and light microscopical assessment for all three pathologists. Discordances between conventional microscopy and digital pathology were present in 3% of assessments. In comparison with the consensus diagnosis, discordant diagnoses were made in 5 cases with digital microscopy and in 3 cases with light microscopy. The reported level of confidence and need for additional investigations were similar between assessment by conventional and by digital microscopy. In conclusion, the performance of assessment by digital pathology is in general comparable with that of conventional light microscopy and pathologists feel confident using digital pathology for this subspecialty.

Background: Free-living walking activity and its contributing factors in ambulatory people with stroke is poorly investigated. Objective: Evaluating free-living walking activity and identifying factors associated with free-living walking activity. Methods: In this cross-sectional study, participants wore an accelerometer to measure their level of walking activity. They also completed the Berg Balance Scale (BBS) and the Timed Up and Go test for functional balance, the Falls Efficacy Scale, the 10-Metre Walk Test and the Geriatric Depression Scale to investigate the relation between the performance tests and walking activity. Results: The 38 analyzed participants were on average 62 (±11.4) years old and 66 (IQR 64.8) months post stroke. They took an average of 3048.3 ± 1983.1 steps, had 123.3 ± 61.3 walking bouts a day and walked for 32.5 ± 18.2 min a day. Their average speed was 90.3 ± 13.8 steps a minute. The multivariate linear analysis showed that the BBS was the only determinant that was significantly related to all outcomes, except walking bouts. Conclusion: Free-living walking activity levels in ambulatory people with chronic stroke are low. The BBS is an independent significant predictor of free-living walking activity.Implications for rehabilitationFree-living walking activity can be expressed in different outcomes measured by accelerometry.Free-living walking activity levels in ambulatory people with chronic stroke are low, therefore support to sustain walking in the own environment should be part of the rehabilitation program after stroke.Balance is an important related factor to free-living walking activity which needs attention during rehabilitation after stroke.

Objective: To evaluate the association between falls and functional status after stroke., Design: Secondary analysis of data from the randomized controlled FIT-Stroke trial. Outcomes were measured at the time of discharge from inpatient rehabilitation (t0) and after 12 weeks (t1). Between t0 and t1, all patients attended an outpatient rehabilitation program that included the FIT-Stroke intervention., Setting: Nine centers for rehabilitation medicine., Participants: Outpatients after stroke (N=250) with mild cognitive impairments (Mini-Mental State Examination [MMSE] score ≥24), discharged home after inpatient rehabilitation and able to walk 10m independently., Interventions: Not applicable., Main Outcome Measures: The primary outcome was the change in Stroke Impact Scale (SIS)-16 score. The independent variable was ≥1 falls after stroke. The outcome was corrected for type of outpatient rehabilitation (group allocation), severity of hemiplegia (Motricity Index [MI]), and cognition (MMSE) at baseline using multiple regression analysis., Results: Complete data were available for 199 patients, with a mean age of 58±10 years, MMSE score of 28.1±2, and MI score of 130±43. Fifty-five patients (28%) reported falls during the 12 weeks after discharge from inpatient rehabilitation. Falls were significantly associated with less improvement in functional status as assessed with the SIS-16 (P=.009)., Conclusions: Almost 30% of this stroke population with minor cognitive deficits and moderate to high mobility scores reported falls during the 12 weeks of outpatient rehabilitation. Falls were negatively associated with self-reported functional status measured by the change in SIS-16 score. Therefore, it is important to identify patients with high risk of falls and implement strategies to reduce falls., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Naive and central memory T lymphocytes (T N and T CM ) can infiltrate the inflamed gut mucosa in inflammatory bowel disease (IBD) patients. Homing of these subsets to the gut might be explained by ectopic formation of tertiary lymphoid organs (TLOs), containing high endothelial venules (HEVs). We aimed to evaluate the presence of HEVs and TLOs in inflamed intestinal mucosa of newly diagnosed, untreated IBD patients in relation to the presence of T N and T CM lymphocytes. IBD patients (n = 39) and healthy controls (n = 8) were included prospectively. Biopsy samples of inflamed and normal intestine, respectively, were analysed by immunohistochemistry for lymphocytes (CD3/CD20), blood vessels (CD31) and peripheral lymph node addressin (PNAd) expression (MECA-79). T N and T CM lymphocyte subsets were identified by flow cytometric immunophenotyping. A higher number of HEVs was found in the inflamed colon of patients with ulcerative colitis [median 3·05 HEV/mm 2 ; interquartile range (IQR) = 0-6·39] and ileum of Crohn's disease patients (1·40; 0-4·34) compared to healthy controls (both 0; P = 0·033). A high density of colonic HEVs (HEV high ) was associated with increased infiltration of T N and T CM in the inflamed gut (median 87%; IQR = 82-93% of T cell population), compared to HEV low patients (58%; 38-81%; P = 0·003). The number of colonic follicles was higher in HEV high patients (median 0·54/mm 2 ; IQR 0·28-0·84) compared to HEV low patients (0·25/mm 2 ; 0·08-0·45; P = 0·031) and controls (0·31/mm 2 ; 0·23-0·45; P = 0·043). Increased homing of T N and T CM lymphocytes to inflamed gut tissue in IBD patients might be facilitated by ectopic formation of extrafollicular HEVs and TLOs in a subgroup of patients., (© 2016 British Society for Immunology.)

Objective: Within the asthma population, difficult asthma (DA) is a severe condition in which patients present with frequent exacerbations, hospitalizations and emergency room visits. The identification and treatment of psychopathology is included in the management of DA. Psychopathology is supposed to predispose patients to DA or vice versa; psychopathology may develop as a consequence of DA. We reviewed the available literature on empirical findings regarding psychopathology in adult patients with DA., Methods: Studies in English language journals using MEDLINE, Cochrane and PsycINFO databases, were retrieved by an electronic search published from 1990 till July 2014., Results: Literature on psychopathology in DA is scarce. The search identified 16 articles of which only 6 articles were specifically about psychopathology in adult patients with DA. Almost half of the patients with DA had evidence of psychopathology at both syndrome and symptom level. Moreover, psychopathology appeared to be related to frequent exacerbations in patients with DA., Conclusions: This literature review suggests a high prevalence of psychopathology of patients with DA, although it remains unclear whether psychopathology occurs more often in DA compared to "stable asthma". More research is needed on a possible role of psychopathology on clinical signs and symptoms in DA.

Aims: Current immunohistochemical methods to study the expression of multiple proteins in a single tissue section suffer from several limitations. In this article, we report on sequential immunohistochemistry (S-IHC), a novel, easy method that allows the study of numerous proteins in a single tissue section, while requiring very limited optimization., Methods and Results: In S-IHC, a tissue section is stained for multiple antibodies, with intermediate scanning of the section and elution of chromogen and antibodies. Overlays are made of the digital images, allowing assessment of multiple proteins in the same tissue section. We used S-IHC to study nine nodular lymphocyte-predominant Hodgkin lymphomas (NLPHLs) and 10 T-cell-rich and histiocyte-rich diffuse large B-cell lymphomas (T/HRBCLs) for expression of cyclin D1, CD20, and CD68. We observed cyclin D1 expression in single tumour cells in 44% of NLPHLs and 60% of T/HRBCLs. Comparison of S-IHC with classic single immunohistochemical staining revealed discrepancies in eight cases (42%), demonstrating the difficulty of differentiating tumour cells from histiocytes on morphological grounds, and stressing the additional value of S-IHC., Conclusions: For research and diagnostic purposes, S-IHC is a promising technique that assesses the expression of numerous proteins in single tissue sections with complete architectural information, allowing phenotypic characterization of single cells., (© 2014 John Wiley & Sons Ltd.)

Objective: According to screening studies, celiac disease (CD) is prevalent in Western Europe. Actual prevalence tends to be much lower. The width of this actual gap is determined by the balance between disease symptoms and the "case-finding" capabilities of the healthcare system. Therefore, we conducted a nationwide study to determine the temporal trends in the incidence in the Netherlands including a focus on demographic aspects., Materials and Methods: We performed a nationwide search in the Dutch Pathology Registry (PALGA) to identify all biopsy-proven cases of CD in five different years between 1995 and 2010. Furthermore, demographic profiles and socioeconomic status (SES) of patients were studied., Results: The overall incidence of CD increased from 2.72 (confidence interval [CI] 2.46-2.99) in 1995 to 6.65 (CI 6.27-7.06) per 100,000 inhabitants in 2010. No significant regional differences were noticed. In men, rates increased from 2.28 (CI 1.95-2.65) to 4.71 (CI 4.25-5.20) per 100,000 in 2010. In women, the increase was from 3.27 (CI 2.88-3.70) to 8.66 (CI 8.04-9.31) per 100,000 in 2010. A trend toward leveling of incidence was observed from 2008 to 2010. Patients diagnosed during childhood live in areas with a higher SES compared with patients diagnosed at adult age., Conclusion: The incidence of biopsy-proven CD in the Netherlands increased almost threefold between 1995 and 2010. In areas with a higher SES, relatively more children were diagnosed.

Background: Chronic obstructive pulmonary disease (COPD) is a common disease with considerable consequences for patients' daily lives. The Clinical COPD Questionnaire (CCQ) was designed to measure these consequences in daily practice. Although the CCQ is widely used, its original structure has never been tested., Aims: This study examines the psychometric properties of the CCQ with regard to its latent structure in a sample of primary care patients with COPD., Methods: Two cross-sectional studies were conducted; in study 1 (N=243) exploratory analyses, including exploratory factor analysis (EFA) and Mokken scale analysis, were performed to explore the latent structure of the CCQ. In study 2 (N=244), confirmatory factor analysis (CFA) was conducted to evaluate the model fit of the structure found in study 1., Results: Both EFA and Mokken scale analysis revealed a structure of two dimensions ('general impact' α=0.91 and 'cough' α=0.84). This structure, however, was not confirmed in study 2, nor was the original structure. However, subsequently removing items that violated the assumption of a normal response distribution did result in an excellent model fit with two dimensions measuring 'dyspnoea' and 'cough' (CFA: comparative fit index (CFI) 0.98; normed fit index (NFI) 0.97; root mean squared error of approximation (RMSEA) 0.08 (0.04))., Conclusions: In primary care, factor analyses on the CCQ revealed a two-component structure measuring 'general impact', and 'cough'. A shortened and more specific version of the CCQ could be regarded as a useful instrument to screen for exacerbations by measuring dyspnoea, coughing and producing phlegm.

Abstract Correct histological classification of malignant lymphomas is important but has always been a difficult challenge. Since 2001 the World Health Organization (WHO) classification has been used, which should make it easier to define distinct disease entities. The purpose of this study was to evaluate the usefulness of a panel of expert hematopathologists in reviewing the diagnosis of malignant lymphomas and to examine whether the discordance between primary and panel diagnoses has declined throughout the years. All patients with a primary malignant lymphoma diagnosed between 2000-2001 and 2005-2006 were identified through the population based cancer registry. All diagnoses were reviewed by a panel of three expert pathologists. In 2000-2001, 344 patients were included, and in 2005-2006, 370 patients. The overall discordance rate decreased from 14% in 2000-2001 to 9% in 2005-2006 (p = 0.06). We were able to identify lymphoma subgroups with the highest discordance rates and lowest discordance rates (mantle cell lymphoma and classical Hodgkin lymphoma), which remained unchanged throughout the years. Based on these results we would propose to review all cases of malignant lymphoma with the exception of mantle cell lymphoma and classical Hodgkin lymphoma, when the initial pathologist has no doubt about the diagnosis.

Several conditions can mimic the clinical presentation of inflammatory breast cancer. Three women presented with a swollen, red and painful breast which turned out to be inflammatory breast cancer after being treated as infectious mastitis. Non-puerperal bacterial mastitis may be confused with inflammatory breast cancer, leading to potentially preventable delays in diagnosis and treatment. The skin changes in inflammatory breast cancer are caused by tumour emboli within the dermal lymphatics, and not by infiltration of inflammatory cells as is suggested by the nomenclature. Patients who are treated for suspected mastitis without clinical improvement in one week should be referred to outpatient care in the surgery department to exclude underlying malignancy.

In February 2014 an update of a systematic review was published on the effectiveness of physical therapy after stroke. This review shows that the quality and quantity of the scientific basis for physical therapy interventions in rehabilitation after stroke have increased significantly, which confirms the relevance of physical therapy in multidisciplinary stroke care. As far as physical therapy is concerned, implementation of the results of this review and organisation or reorganisation of care so that it is accessible to all patients is a major challenge. We propose that the general practitioner should be given a central role in the care of patients during the chronic phase after stroke.

Objective: COPD-guidelines recommend regular evaluation of both the degree of airway obstruction and health-status to provide adequate treatment. Numerous health-status questionnaires have been developed of which the 'Clinical-COPD-Questionnaire' and the 'COPD-Assessment-Test' are best known; although highly recommended, both have several limitations regarding structure, content, and/or methodological qualities. In the present study a new COPD-specific instrument was developed to measure impairment: the 'Patient-centred-COPD-Questionnaire' (PCQ)., Methods: Six focus groups with COPD patients and (lung) health care providers from primary, secondary and tertiary (rehabilitation) care were formed to discuss aspects of COPD most relevant to patients' daily lives. Eighty candidate items were derived for explorative factor analyses (EFA) to test their psychometric properties (study I, n=541). These resulted in an 18-item scale that was further explored by confirmatory factor analyses (CFA) and construct and concurrent validity assessment (study II, n=412)., Results: EFA in study I suggested a reliable three component solution ('shortness of breath', 'acceptance of COPD' and 'confidence in care'). In study II this model was confirmed with CFA, and significant and clinically relevant correlations were found between the PCQ subscales, and other COPD specific and general health questionnaires. Furthermore, multivariate analyses of covariance revealed that more severely ill patients reported more impairment., Conclusions: The PCQ is a questionnaire with three dimensions to assess the impact of COPD on daily life that is easy to complete. For the first time, a dimension referring to 'confidence in care' is included in a tool that assesses COPD-related impairment., (© 2013.)

Background: Routine duodenal biopsies during upper gastrointestinal endoscopy (UGE) have been suggested to be useful in detecting coeliac disease (CD). However results from previous studies are not conclusive. The aim of this study is to investigate the diagnostic yield and cost-effectiveness of routine duodenal biopsy during UGE., Methods: In this retrospective single-centre study, we studied 6442 patients undergoing first-time UGE at the Rijnstate Hospital, Arnhem, the Netherlands, from January 2009 to December 2010. All UGE reports were analysed for indication, duodenal intubation, and endoscopic aspect of duodenal mucosa. Endomysium and tissue transglutaminase antibody titre, when present, were scored as positive or negative. CD was defined as Marsh 3a or higher. Costs of duodenal biopsies and pathology analysis were calculated. Comparisons were done with T-tests for continuous data and Chi-square tests for categorical data., Results: Forty-one patients had newly diagnosed CD; 34 of these 41 patients had definite indications for biopsy prior to UGE, e.g. positive serology or symptoms. Thus, routine duodenal biopsies identified seven patients as having CD, who otherwise would not have been biopsied. The number needed to biopsy was therefore 577, spending more than v 30,000 per case., Conclusions: We do not recommend routine duodenal biopsy to screen for coeliac disease because of the high number needed to biopsy as well as high costs.

Background: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN) in breast cancer patients. Previously, we reported that ultra-staging led to more axillary lymph node dissections (ALND). The question was, whether ultra-staging is effective in reducing the risk of regional relapse., Methods: From January 2002 to July 2003, 541 patients from 4 hospitals were prospectively registered when they underwent a SN biopsy. In hospitals A, B, and C, 3 levels of the SN were examined pathologically, whereas in hospital D at least 7 additional levels were examined. Patients with a positive SN, including isolated tumor cells, underwent an ALND. This analysis focuses on the 341 patients with a negative SN. Primary endpoint was 5-year regional recurrence rate., Results: In hospital D 34% of the patients had a negative SN as compared to 71% in hospitals A, B, and C combined (p < 0.001). At 5 years follow-up, 9 (2.6%) patients had developed a regional lymph node relapse. In hospital D none of the patients had a regional recurrence, as compared to 9 (2.9%) cases of recurrence in hospitals A, B, and C., Conclusion: The less intensified SN pathology protocol appeared to be associated with a slightly increased risk of regional recurrence. The absolute risk was still less than 3%, and does not seem to justify the intensified SN pathology protocol of hospital D., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background. Long-term splinting, using static orthoses to prevent contractures, is widely accepted in stroke patients with paresis of the upper limb. A number of stroke patients complain about increased pain and spasticity, which leads to the nonuse of the orthosis and a risk of developing a clenched fist. Objectives. Evaluating long-term use of static hand-wrist orthoses and experienced comfort in chronic stroke patients. Methods. Eleven stroke patients who were advised to use a static orthosis for at least one year ago were included. Semistructured telephone interviews were conducted to explore the long-term use and experienced comfort with the orthosis. Data were analyzed using descriptive statistics. Results. After at least one year, seven patients still wore the orthosis for the prescribed hours per day. Two patients were unable to wear the orthosis 8 hours per day, due to poor comfort. Two patients stopped using the orthosis because of an increase in spasticity or pain. Conclusions. These pilot data suggest that a number of stroke patients cannot tolerate a static orthosis over a long-term period because of discomfort. Without appropriate treatment opportunities, these patients will remain at risk of developing a clenched fist and will experience problems with daily activities and hygiene maintenance.

Purpose: To evaluate tolerance of a new dynamic hand-wrist orthosis and effectiveness on the prevention of progressive wrist contracture and spasticity after stroke., Method: Chronic stroke patients (N = 6) with upper limb spasticity, who had not been able to endure a static orthosis, were provided with a custom-made dynamic orthosis. Tolerance of the orthosis was evaluated by the daily wearing time, and self-reported pain and spasticity. Effectiveness was measured by contracture of wrist and finger flexor muscles, upper limb spasticity and use of spasticity treatment. Outcome measures were collected at time of fitting of the dynamic orthosis (baseline) and after three and six months., Results: Five patients could endure the dynamic orthosis without discomfort for 6 hours daily during the 6-month period. Self-reported spasticity and pain decreased significantly (p < 0.05) compared to wearing the static orthosis. In comparison to baseline, the maximum passive wrist extension increased significantly from -29° to -12° (p < 0.05). Although, no significant change in spasticity was measured, the use of Botulinum Toxin injections decreased for two patients., Conclusions: The majority of the included chronic stroke patients tolerated the new dynamic orthosis for at least 6 hours daily and the use significantly reduced wrist contractures in a 6-month period.

Objective: The purpose of this study was to assess, with histopathologic control, the use of open-system 1-T (1)H MR spectroscopy for the evaluation of hepatic steatosis in morbidly obese patients undergoing gastric bypass surgery., Subjects and Methods: Patients underwent (1)H MR spectroscopy (MRS) for the assessment of steatosis before and 3 months after surgery. Liver biopsy was performed during surgery. Hepatic steatosis was expressed as the ratio of fat peak area to cumulative water and fat peak areas. Histopathologic percentage of steatosis was graded as none (0-5%), mild (5-33%), moderate (33-66%), or severe (> 66%). The accuracy of (1)H-MRS and Spearman correlation coefficient were calculated. Differences between groups were assessed with the Wilcoxon signed rank and Mann-Whitney tests., Results: The study included 38 patients (median age, 45.5 years; median body mass index, 47.7). Before surgery, median steatosis measured with (1)H-MRS was 5.8%. The accuracy of (1)H-MRS was 89% (32/36), and the (1)H-MRS findings correlated with the histopathologic assessment of steatosis (r = 0.85, p < 0.001). With (1)H-MRS, no steatosis was discriminated from mild steatosis (p = 0.011), mild was discriminated from moderate steatosis (p < 0.001), and moderate was discriminated from severe steatosis (p = 0.021). Three months after surgery, steatosis had decreased to 3.1% (p < 0.001). The prevalence of hepatic steatosis measured with (1)H-MRS decreased from 53% to 32%., Conclusion: In the care of morbidly obese patients undergoing assessment of hepatic steatosis and changes in steatosis after gastric bypass surgery, (1)H-MRS with an open 1-T MRI system is feasible. Measurements of hepatic fat with (1)H-MRS are accurate and correlate with clinical and histopathologic results.

Background: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (CRC). KRAS mutation analysis is usually performed on primary tumour tissue because metastatic tissue is often not available. However, controversial data are available on the concordance of test results between primary tumours and corresponding metastases. We assessed the concordance of KRAS mutation status in a study of 305 primary colorectal tumours and their corresponding liver metastases., Methods: Patients with histologically confirmed CRC who underwent surgical resection of the primary tumour and biopsy or surgical resection of the corresponding liver metastasis were included. KRAS mutation analysis was performed for codons 12 and 13., Results: KRAS mutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), we found a discordance between primary tumour and metastasis: 5 primary tumours had a KRAS mutation with a wild-type metastasis, 1 primary tumour was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a different KRAS mutation., Conclusion: We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6-98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7-4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis.

Purpose: An intervention for persons with neuromuscular diseases (NMD) or multiple sclerosis (MS) who experienced severe fatigue was developed which aimed at educating participants in maintaining a balance between capacity and load in their daily activities. This pilot study evaluated the results of this intervention., Methods: Persons with NMD or MS who experienced severe fatigue were included. Outcome measures were: fatigue (Fatigue Severity Scale), health-related quality of life (HRQoL; SF-36) and self-efficacy (ALCOS-16). Changes in scores between the start of the intervention (T0) and 3 months post-intervention (T1) were tested with the Wilcoxon tests in the complete group and in subgroups (gender, education, high/low self-efficacy)., Results: Forty-three persons participated. Significant improvements of HRQoL were found for the domains role-physical, mental health and general health perceptions. Subgroup analyses showed more improvement in males (fatigue, role-physical, vitality, bodily pain, general health perceptions), participants with lower education (role-physical, vitality) and participants with low self-efficacy at T0 (self-efficacy, mental health, general health perceptions) than in females, participants with higher education and participants with higher initial self-efficacy., Conclusion: This pilot-study provides preliminary evidence for the effectiveness of a group educational intervention in improving HRQoL without increasing fatigue in persons with NMD and MS.

Purpose: We determined the potential value of protein profiling of tissue samples by assessing how precise this approach enables discrimination of B-cell lymphoma from reactive lymph nodes, and how well the profiles can be used for lymphoma classification., Experimental Design: Protein lysates from lymph nodes (n=239) from patients with the diagnosis of reactive hyperplasia (n=44), follicular lymphoma (n=63), diffuse large B-cell lymphoma (n=43), mantle cell lymphoma (n=47), and chronic lymphocytic leukemia/small lymphocytic B-cell lymphoma (n=42) were analysed by SELDI-TOF MS. Data analysis was performed by (i) classification and regression tree-based analysis and (ii) binary and polytomous logistic regression analysis., Results: After internal validation by the leave-one-out principle, both the classification and regression tree and logistic regression classification correctly identified the majority of the malignant (87 and 96%, respectively) and benign cases (73 and 75%, respectively). Classification was less successful since approximately one-third of the cases of each group were misclassified according to the histological classification. However, an additional mantle cell lymphoma case that was misclassified as chronic lymphocytic leukemia/small lymphocytic B-cell lymphoma initially was identified based on the protein profile., Conclusions and Clinical Relevance: SELDI-TOF MS protein profiling allows for reliable identification of the majority of malignant lymphoma cases; however, further validation and testing robustness in a diagnostic setting is needed., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To associate the short-term effects of the Handmaster orthosis on disabling symptoms of the affected upper extremity with long-term Handmaster orthosis use after stroke., Design: Historic cohort study., Patients: Patients with chronic stroke., Methods: The Modified Ashworth Scale (0-5) for wrist (primary outcome) and elbow flexor hypertonia, visual analogue scale (0-10) for pain, oedema score (0-3), and passive range of wrist flexion and extension (pROM, degrees) were assessed prior to Handmaster orthosis prescription (T0), after 6 weeks try-out (T1) and a subsequent 4 weeks withhold period (T2). Long-term use was evaluated using a questionnaire. Non-parametric analyses and predictive values were used for statistical analyses., Results: Of the 110 included patients 78.2% were long-term Handmaster orthosis users. Long-term users showed significant short-term (T0-T1) improvements on all impairment scores and a significant relapse of wrist and elbow Modified Ashworth Scale (T1-T2). Non-users showed significant short-term effects on elbow Modified Ashworth Scale and visual analogue scale only. Positive predictive values of short-term effects for long-term use varied between 75% and 100%, with 85% (95% confidence interval (CI) 0.72-0.93) for wrist Modified Ashworth Scale. Negative predictive values were low (11-27%)., Conclusion: Short-term Handmaster orthosis effects were generally beneficial for hypertonia, pain, oedema, and pROM, especially in long-term users. Short-term beneficial effects were highly predictive for long-term use, but not for non-use.

We examined the validity of immunohistochemistry for mismatch repair (MMR) proteins in colorectal cancer specimens to identify patients at risk for Lynch syndrome (hereditary nonpolyposis colorectal cancer) and patients with sporadic microsatellite instable colorectal cancer. This was assessed by observer agreement for and accuracy of interpretation of immunohistochemistry. Seven pathologists from 5 different pathology laboratories evaluated 100 molecularly defined colorectal cancers stained for MLH1, PMS2, MSH2, and MSH6. Two of the pathologists were experienced in interpretation of immunohistochemistry for MMR proteins. After evaluation of a subset of 20 cases, a discussion meeting was organized, after which pathologists evaluated all 100 cases. Staining patterns were interpreted as aberrant, normal, or indefinite. In 82% of tumors, 5 or more pathologists reached the same interpretation, which was considered the consensus diagnosis. Consensus was reached slightly less frequently in microsatellite instable than in stable tumors, and interobserver variation was moderate to substantial (kappa: 0.49-0.79). More microsatellite instable tumors showed an indefinite staining pattern compared with microsatellite stable tumors. Three out of 7 pathologists, including the 2 experienced pathologists, did not miss a microsatellite instable tumor. Each pathologist found at least 1 tumor with an aberrant staining pattern, whereas consensus was a normal staining pattern and the tumor was microsatellite stable. We conclude that, if restricted to experienced pathologists, immunohistochemistry is a valid tool to identify patients at risk for Lynch syndrome and patients with sporadic microsatellite instable colorectal cancer. An indefinite or aberrant staining result has to be followed by molecular microsatellite instability analysis to confirm the presence of a defective DNA MMR system.

Objective: Diabetic polyneuropathy (PNP) has been proposed to be a primary disorder of sensory nerves. At an early stage motor nerve conduction velocity (MNCV) and muscle strength remain preserved due to compensatory mechanisms (axonal sprouting, reinnervation). We evaluated the use of invasive muscle fiber conduction velocity (MFCV) measurements as a method to detect muscle fiber denervation atrophy, as an early sign of motor axonal loss in diabetes mellitus (DM)., Methods: Twelve selected male patients (8 type 1, 4 type 2; mean age 35.8 years, SD 10.6), without any sign of micro- or macroangiopathy, were studied by systematic clinical and neurophysiological testing including MFCV estimation., Results: Hand-held dynamometry was normal in all subjects. There were no signs of recent denervation by concentric needle EMG in any of the patients. Sensory nerve conduction velocity (SNCV) was abnormal in 6 subjects, MFCV in 6 subjects (5 had also low SNCV). The ratio of fastest/slowest muscle fibers in MFCV was correlated to SNCV of sural nerve (-.59, p < .05), but not to MNCV., Conclusions: Half of the clinically asymptomatic DM subjects showed sensory involvement together with MFCV abnormalities, despite normal needle EMG and force., Significance: MFCV estimation offers a sensitive method in detecting early signs of motor axonal dysfunction in DM.

Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant literature. A 64-yr-old woman with bulbar ALS for 6 mos was treated for disabling sialorrhoea. She had moderate dysphagia, but she was able to swallow. The submandibular and parotid glands were injected transcutaneously, under ultrasound guidance, with botulinum toxin (Dysport), 80 U on each side. Four days later, her bulbar function rapidly deteriorated, resulting in complete aphagia and anarthria on the fifth day. A PEG catheter was placed. Although according to the literature this treatment can be made safer by cautiously increasing the dosage and injecting the parotid glands first, BTX should not be the first-line treatment of sialorrhoea in ALS; comparative studies of BTX, amitryptiline, scopolamine, and radiation should be performed first.

Background: Spastic hemiplegia is a common feature after stroke, which can result in a clenched fist deformity with secondary hygienic problems and pain. Operative treatment can improve these problems, although literature about its long-term effects is lacking., Purpose: To determine whether Superficialis-to-Profundus tendon (StP-) transfer procedure leads to permanent improvement of hygiene and reduction of pain in patients with clenched fist due to spastic hemiplegia following stroke., Method: Patients who underwent a StP-transfer in 2003-2005 were evaluated on skin condition, upper extremity joint mobility, resting position and muscle tone and with VAS scores on hygiene maintenance and pain in the hand., Results: Six patients (mean age 54 years; duration after stroke 10 years) were included. Indications to operate were hygienic problems only (3) or combined with pain (3). The average follow-up period was 19 months. After 6 weeks of post-operative splinting, no standard follow-up was applied. Serious post-operative complications were not reported. At follow-up no hygienic problems were present and pain was decreased in all except one patient. All hands could passively be fully opened. In resting position, flexion was seen in the MCP-joints (60-90 degrees). Muscle tone was raised in flexors of the wrist and fingers and m. adductor pollicis (Ashworth 1-2). Given the same pre- and post-operative circumstances, all patients would agree to have the surgery over again., Conclusion: Even 19 months after the StP-transfer for clenched fist, all operated hands could still be fully opened and there was a permanent improvement of hygiene and pain reduction.

Background: Estimates of the diagnostic performance of serologic testing and HLA-DQ typing for detecting celiac disease have mainly come from case-control studies., Objective: To define the performance of serologic testing and HLA-DQ typing prospectively., Design: Prospective cohort study., Setting: University hospital., Patients: Patients referred for small-bowel biopsy for the diagnosis of celiac disease., Interventions: Celiac serologic testing (antigliadin antibodies [AGA], antitransglutaminase antibodies [TGA], and antiendomysium antibodies [EMA]) and HLA-DQ typing., Measurements: Diagnostic performance of serologic testing and HLA-DQ typing compared with a reference standard of abnormal histologic findings and clinical resolution after a gluten-free diet., Results: Sixteen of 463 participants had celiac disease (prevalence, 3.46% [95% CI, 1.99% to 5.55%]). A positive result on both TGA and EMA testing had a sensitivity of 81% (CI, 54% to 95.9%), specificity of 99.3% (CI, 98.0% to 99.9%), and negative predictive value of 99.3% (CI, 98.0% to 99.9%). Testing positive for either HLA-DQ type maximized sensitivity (100% [CI, 79% to 100%]) and negative predictive value (100% [CI, 98.6% to 100%]), whereas testing negative for both minimized the negative likelihood ratio (0.00 [CI, 0.00 to 0.40]) and posttest probability (0% [CI, 0% to 1.4%]). The addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, did not change test performance compared with either testing strategy alone., Limitation: Few cases of celiac disease precluded meaningful comparisons of testing strategies., Conclusions: In a patient population referred for symptoms and signs of celiac disease with a prevalence of celiac disease of 3.46%, TGA and EMA testing were the most sensitive serum antibody tests and a negative HLA-DQ type excluded the diagnosis. However, the addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, provided the same measures of test performance as either testing strategy alone.

The gene family of serine protease inhibitors of the Kazal type (SPINK) are functional and positional candidate genes for celiac disease (CD). Our aim was to assess the gut mucosal gene expression and genetic association of SPINK1, -2, -4, and -5 in the Dutch CD population. Gene expression was determined for all four SPINK genes by quantitative reverse-transcription polymerase chain reaction in duodenal biopsy samples from untreated (n=15) and diet-treated patients (n=31) and controls (n=16). Genetic association of the four SPINK genes was tested within a total of 18 haplotype tagging SNPs, one coding SNP, 310 patients, and 180 controls. The SPINK4 study cohort was further expanded to include 479 CD cases and 540 controls. SPINK4 DNA sequence analysis was performed on six members of a multigeneration CD family to detect possible point mutations or deletions. SPINK4 showed differential gene expression, which was at its highest in untreated patients and dropped sharply upon commencement of a gluten-free diet. Genetic association tests for all four SPINK genes were negative, including SPINK4 in the extended case/control cohort. No SPINK4 mutations or deletions were observed in the multigeneration CD family with linkage to chromosome 9p21-13 nor was the coding SNP disease-specific. SPINK4 exhibits CD pathology-related differential gene expression, likely derived from altered goblet cell activity. All of the four SPINK genes tested do not contribute to the genetic risk for CD in the Dutch population.

Alpha-I antitrypsin (AIAT) is an acute-phase protein that is produced in liver cells. AIAT deficiency is a hereditary disease which is defined by the hepatic production of an abnormal protein that can not be released into the plasma. This leads to deficiency of plasma AIAT and subsequently to an impaired protection against proteases, resulting in pulmonary disease. Accumulation of the abnormal protein in hepatocytes can lead to liver damage. Serum level measurement, phenotyping and liver biopsy can be used for establishing the diagnosis. Homozygous AIAT deficiency can cause neonatal hepatitis; in adults end-stage liver disease, cirrhosis and hepatocellular carcinoma can develop. There are strong arguments to consider heterozygous AIAT deficiency as an important co-factor in the aetiology of chronic liver disease. Studies have shown that AIAT heterozygosity can be considered a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma. The accumulation of AIAT in the hepatocytes occurs more profoundly in a diseased liver, and as a consequence it affects the natural course of the liver disease. Therapeutic options include augmentation therapy (infusion of purified human plasma AIAT) in pulmonary disease; in end-stage liver disease liver transplantation is an option. For the future, other interventions such as gene therapy or strategies to inhibit polymerisation are promising.

Aim: To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patients., Methods: A total of 104 consecutive patients with Hashimoto's thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies)., Results: Of 104 patients with Hashimoto's thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or -DQ8) was present in all the five and 53 patients with Hashimoto's thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassified into euthyroidism in ten (5%; 95% CI 2-9), subclinical hypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto's thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves' disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis., Conclusion: The data from a Dutch population confirm the association between Hashimoto's thyroiditis and coeliac disease. Screening patients with Hashimoto's thyroiditis for coeliac disease and vice versa is recommended.

Background: In this multi-institutional prospective study, we evaluated whether we could identify risk factors predictive for non-sentinel lymph node (non-SN) metastases in breast cancer patients with a positive sentinel lymph node (SN)., Methods: In this multi-institutional study, 541 eligible breast cancer patients were included prospectively., Results: The occurrence of non-SN metastases was related to the size of the SN metastasis (P = .02), primary tumor size (P = .001), and lymphovascular invasion (P = .07). The adjusted odds ratio was 3.1 for SN micro-metastasis compared with SN isolated tumor cells, 4.0 for SN macro-metastasis versus SN isolated tumor cells, 3.1 for tumor size (>3.0 cm compared with 3.0 cm, and with vessel invasion., Conclusion: We identified three predictive factors for non-SN metastases in breast cancer patients with a positive SN: size of the SN metastasis; primary tumor size; and vessel invasion. We were not able to identify a specific group of patients with a positive SN in whom the risk for non-SN metastases was less than 5%.

Background & Aims: Refractory celiac disease (RCD) may be subdivided into RCD types I and II with phenotypically normal and aberrant intraepithelial T-cell populations, respectively. In RCD II, transition into enteropathy-associated T-cell lymphoma (EATL) is seen frequently. We have evaluated the effect of cladribine (2-CDA), a purine analogue inducing T-cell depletion, on clinical, histopathologic, and immunologic parameters, as well as the toxicity and side effects in a group of RCD II patients., Methods: Between 2000 and 2005, 17 patients were included (8 men, 9 women). All patients had a clonal rearrangement of the T-cell receptor gamma gene and immunophenotyping showed an aberrant T-cell population lacking surface expression of CD3, CD8, and T-cell receptor alphabeta, in the presence of expression of surface CD103 and intracytoplasmic CD3. Treatment consisted of 2-CDA (0.1 mg/kg/day) intravenously for 5 days, given in 1-3 courses every 6 months depending on the response., Results: All patients tolerated 2-CDA without serious side effects. Six patients (35.8%) showed a clinical improvement (weight gain, improvement of diarrhea, and hypoalbuminemia). In 10 patients (58.8%) a significant histologic improvement and in 6 patients (35.2%) a significant decrease in aberrant T cells was seen. Seven patients (41.1%) developed EATL and died subsequently. One patient died of progressive refractory state with emaciation., Conclusions: Treatment with 2-CDA in RCD II is feasible, well tolerated, and can induce clinical and histologic improvement as well as a significant decrease of aberrant T cells in a subgroup of patients, albeit it does not prevent EATL development. However, the earlier reported potential risk of precipitating an overt lymphoma should be taken into consideration.

Background: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN). At present, therefore, various hospitals use different SN pathology protocols of which the effect has not been fully elucidated. We hypothesized that differences between hospitals in SN pathology protocols affect subsequent surgical treatment strategies., Methods: Patients from four hospitals (A-D) were prospectively registered when they underwent an SN biopsy. In hospitals A, B, and C, three levels of the SN were examined pathologically, whereas in hospital D, at least seven additional levels were examined. In the absence of apparent metastases with hematoxylin and eosin examination, immunohistochemical examination was performed in all four hospitals., Results: In total, 541 eligible patients were included. In hospital D, more patients were diagnosed with a positive SN (P < .001) as compared with hospitals A, B, and C, mainly because of increased detection of isolated tumor cells. This led to more completion axillary lymph node dissections in hospital D (66.3% of patients (P < .0001), compared with 29.0% in hospitals A, B, and C combined). Positive non-SNs were detected in 13.9% of patients in hospital D, compared with 9.7% in hospitals A, B, and C (P = .70). That is, in 52.4% of patients in hospital D, a negative completion axillary lymph node dissection was performed, compared with 19.3% of patients in hospitals A, B, and C combined., Conclusions: Differences in SN pathology protocols between hospitals do have a substantial effect on SN findings and subsequent surgical treatment strategies. Whether ultrastaging and, thus, additional surgery can offer better survival remains to be determined.

Background & Aims: Celiac disease (CD) is a common gluten-sensitive enteropathy associated with human leukocyte antigen (HLA)-DQ2 and HLA-DQ8. The aim of this study was to determine if a particular HLA-DQ subtype predisposes to complications such as refractory CD with (RCD II) or without aberrant T cells (RCD I), and enteropathy-associated T-cell lymphomas (EATL)., Methods: Molecular HLA-DQ typing was performed on 43 RCD I, 43 RCD II, and 30 EATL patients, and compared with age-matched groups of 121 patients with histologically defined uncomplicated CD and 183 healthy controls. All individuals were Dutch Caucasians and were at least 21 years of age., Results: HLA-DQ2 was present in 79% of RCD I, 97.7% of RCD II, and 96.6% of EATL patients. The differences were significant when compared with 28.9% in controls but not with 91.7% in uncomplicated CD. Homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCD II, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls. HLA-DQ8 was present in 10.7% of CD, 16.2% of RCD I, 9.3% of RCD II, and 6.6% of EATL patients vs 20.2% of controls., Conclusions: Homozygosity for HLA-DQ2 is associated with RCD II and EATL. Early identification of HLA-DQ2 homozygous CD patients may help to recognize CD patients at risk for developing these severe complications.

Objective: To develop a hierarchical scale that measures activity limitations in walking in patients with lower-extremity disorders who live at home., Design: Cross-sectional study., Setting: Orthopedic workshops and outpatient clinics of secondary and tertiary care centers., Participants: Patients (N=981; mean age +/- standard deviation, 58.6+/-15.4 y; 46% men) living at home, with different lower-extremity disorders: stroke, poliomyelitis, osteoarthritis, amputation, complex regional pain syndrome type I, and diabetic and degenerative foot disorders., Interventions: Not applicable., Main Outcome Measures: (1) Fit of the monotone homogeneity model, indicating whether items can be used for measuring patients; (2) fit of the double monotonicity model, indicating invariant (hierarchical) item ordering; (3) intratest reliability, indicating repeatability of the sum score; (4) robustness, addressing the clinimetric properties within subgroups of patients; and (5) differential item functioning, addressing the validity of comparisons between subgroups of patients., Results: Thirty-five of 41 dichotomous items had (1) good fit of the monotone homogeneity model (coefficient H=.50), (2) good fit of the double monotonicity model (coefficient H(T)=.33), (3) good intratest reliability (coefficient rho=.95), (4) satisfactory robustness (within subgroups of patients defined by age, sex, and diagnosis), and (5) some differential item functioning (6 items in amputees compared with nonamputees)., Conclusions: A hierarchical scale, with excellent scaling characteristics, was developed to measure activity limitations in walking in patients with lower-extremity disorders who live at home. The measurements should be interpreted cautiously when making comparisons between amputees and nonamputees.

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.

Objective: Several national and international scoring systems are used to diagnose diabetic polyneuropathy (PNP). The variety in these scores and the lack of data on validity and predictive value has led to a comparison and validation of the scores with clinical standards for PNP to determine the most powerful measurement for screening., Research Design and Methods: Three matched groups were selected: 24 diabetic patients with neuropathic foot ulcers, 24 diabetic patients without PNP or ulcers, and 21 control subjects without diabetes. In all participants the scores from the International Consensus on the Diabetic Foot (ICDF) and the Dutch Nederlandse Diabetes Federatie-Centraal Beleids Orgaan (NDF/CBO) were tested. The Diabetic Neuropathy Symptom score, the Diabetic Neuropathy Examination score, Heart Rate Variability, the Nerve Conduction Sum score, and a San Antonio Consensus sum score were obtained as clinical standards. Reproducibility was tested in a separate study (13 patients)., Results: The construct validity and discriminative power of the ICDF and NDF/CBO scores were comparable, although monofilaments (NDF/CBO) scored lower. The predictive value was good for all scores, with the best results being obtained for the tuning fork (NDF/CBO). Reproducibility of the NDF/CBO scores (monofilaments and tuning fork) was high., Conclusions: The characteristics of the scores of tests recommended by ICDF and NDF/CBO are comparable. The single use of the 128-Hz tuning fork produces results similar to the extended scores of the ICDF and much better than those of monofilaments on validation and for predictive value. For screening we therefore advise the use of the tuning fork alone.

Background: Small colonic lesions which are identified during endoscopy are usually difficult to locate intra-operatively. Endoscopic tattoo of the colon seems the most efficient method, however it does fail in some cases to identify the lesion peroperatively. We studied this method to evaluate its efficacy., Methods: Nineteen patients were tattooed during colonoscopy with "India ink" (drawing ink Rotring ). These patients had lesions in which difficulties were anticipated when retracing them again during colorectal surgery. Seventeen patients underwent colonic surgery. One patient underwent laparoscopic polypectomy and the other TEM (Transanal Endoscopic Microsurgery)., Results: The visibility of the "India ink" peroperatively and afterwards during histological examination were evaluated. The tattoos were visible in 68.4 % patients intraoperatively. Histopathological macroscopic examination of the specimens showed ink in 73.6 % patients. In 31.5 % patients the tattoo could not be recognised peroperatively., Conclusions: Endoscopy assisted tattooing of the colon has been reported to be a safe method to landmark lesions in the colon. In the majority of our patients the tattoo was obvious during surgery. Endoscopic tattoo seems an efficient technique in identifying small colonic lesions intraoperatively.

Patients with coeliac disease (CD), particularly those who are undiagnosed or do not adhere to a strict gluten free diet (GFD), are prone to develop complications. Malignant complications are the most serious and should be suspected when expected responses to GFD are not achieved or sustained. Lymphomas, mostly T-cell type, and other malignant tumours, particularly carcinoma of the small bowel, less frequently of stomach and oesophagus, are associated with CD. Loss of response to a gluten free diet (refractory coeliac disease) and ulcerative jejunitis are two recently described complications of CD that may progress to an Enteropathy-Associated T-cell Lymphoma (EATL). Coeliac disease-related lymphoma most often appears at extra-nodal sites, essentially the small bowel, although one have to realise that T-cell lymphomas arising in sites outside the small bowel could be related to coeliac disease. Workup of an EATL must include immunehistology and if necessary T-cell flow cytometry and T-cell rearrangement. Adequate imaging with CT and PET-scanning is mandatory.

Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-gamma), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-gamma, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-gamma gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission.

Background and Aims: The causative molecular pathways underlying the pathogenesis of coeliac disease are poorly understood. To unravel novel aspects of disease pathogenesis, we used microarrays to determine changes in gene expression of duodenal biopsies., Methods: cDNA microarrays representing 19 200 genes were used to compare gene expression profiles of duodenal biopsies from 15 coeliac disease patients with villous atrophy (Marsh III) and seven control individuals with normal biopsies (Marsh 0). In addition, the specific effect of gluten was studied by comparing the expression profiles of Marsh III lesions of seven patients exposed to gluten with four patients on a gluten free diet., Results: Comparing Marsh III with Marsh 0 lesions identified 109 genes that differed significantly (p<0.001) in expression levels between patients and controls. A large number of these genes have functions in proliferation and differentiation pathways and might be important for correct development of crypt-villous units. Alterations in these pathways may lead to the characteristic hyperplasia and villous atrophy seen in coeliac disease. The analyses also revealed 120 differentially expressed genes (p<0.005) when comparing patients on a gluten free diet with those exposed to gluten. These genes further strengthen our observation of increased cell proliferation in the presence of gluten., Conclusions: Our study provides new candidate genes in the pathogenesis of coeliac disease. Based on our results, we hypothesise that villous atrophy in coeliac disease patients is due to failure in cell differentiation. These genes are involved in pathways not previously implicated in coeliac disease pathogenesis and they may provide new targets for therapy.

Microscopic colitis (MC) is viewed as an umbrella term applicable to both lymphocytic and collagenous colitis. The first case was published in 1976, a new entity with chronic watery diarrhea with lymphocytic colitis, with or without a subepithelial collagen deposition. Patients are usually middle-aged women, and the pathogenesis is unknown. The response to steroids and the female predominance underlines an autoimmune disease. Up to 40% NSAID's and Lanzoprazole-induced MC are well-known. Biopsies during sigmoidoscopy in unexplained diarrhea must be standard. Treatment is empirical. The most important step is to ban all NSAID's and other MC inducing agents. Immunosuppressive treatment must be considered. However the disease has a benign course and sometimes is selflimiting.

The major genetic susceptibility to coeliac disease is contributed by the human leukocyte antigen (HLA) region. The primary association is with the HLA-DQ2 molecule, encoded by the DQA1*05 and DQB1*02 alleles, which is expressed by over 90% of patients. The aim of our study was to perform an extensive scan of the entire HLA region to determine whether there is evidence for the presence of additional HLA susceptibility genes for coeliac disease in the Dutch population, acting independently of DQ2. In all, 16 microsatellite markers and the DQA1 and DQB1 genes were genotyped in simplex cis DQ2-positive coeliac disease families and cis DQ2-positive control families. Allele frequencies of markers on phase-known DQ2-positive haplotypes transmitted to patients were compared to a combined group of DQ2-positive nontransmitted and control haplotypes, thereby controlling for the DQ2 contribution. No significant differences at any of the marker loci were detected, suggesting that DQ2 is the major HLA risk factor for coeliac disease. Individuals homozygous for DQ2 or heterozygous for DQA1*05-DQB1*02/DQA1*0201-DQB1*02 were found to be at five-fold increased risk for development of coeliac disease (P<10(-8)). This risk seems to be conferred by the presence of a second DQB1*02 allele next to one DQA1*05-DQB1*02 haplotype, independently of the second DQA1 allele.