Respiratory function in facioscapulohumeral muscular dystrophy 1.

To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant facioscapulohumeral muscular dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of facioscapulohumeral muscular dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences.

A model for perception-based identification of sensitive skin.

BACKGROUND: With high prevalence of sensitive skin (SS), lack of strong evidence on pathomechanisms, consensus on associated symptoms, proof of existence of 'general' SS and tools to recruit subjects, this topic attracts increasing attention of research. OBJECTIVE: To create a model for selecting subjects in studies on SS by identifying a complete set of self-reported SS characteristics and factors discriminatively describing it. METHODS: A survey (n = 3058) was conducted, comprising questions regarding socio-demographics, atopy, skin characteristics, personal care, degree of self-assessed SS and subjective and objective reactions to endogenous and exogenous factors. Exploratory factor analysis on 481 questionnaires was performed to identify underlying dimensions and multivariate logistic regression to find contributing variables to the likelihood of reporting SS. RESULTS: The prevalence of SS was found to be 41%, and 56% of SS subjects reports a concomitant atopic condition. The most discriminative were the eliciting factors toiletries and emotions, and not specific skin symptoms in general. CONCLUSION: Triggers of different origins seem to elicit SS, it is not defined by concomitant skin diseases only, suggesting existence of 'general' SS. A multifactorial questionnaire could be a better diagnostic than a one-dimensional provocative test.

A pilot study on the Psoriasis Area and Severity Index (PASI) for small areas: Presentation and implications of the Low PASI score.

BACKGROUND: The Psoriasis Area and Severity Index (PASI) is not able to measure small affected areas in a body region which is important for assessing the performance of high-effective treatment. OBJECTIVE: To present the Low PASI score, show the difference between the classic PASI and the Low PASI, evaluate the inter-observer agreement of both scores, and compare the two scores within investigators. METHODS: Cross-sectional study. Two investigators independently assessed the classic PASI and the Low PASI in 10 patients with mild-to-moderate plaque psoriasis. Differences in outcome between the two scores were calculated. Intra-class correlation coefficients (ICC) were used to determine the inter-observer agreement and to compare measurements of the two scores within both investigators. Prediction limits of 95% for the errors in measurements were provided. RESULTS: In both investigators, Low PASI was mean 1.71 and 1.76, whereas the classic PASI was mean 4.14 and 4.33. The inter-observer agreement (ICC) was excellent for both investigators in both scores (ICC classic PASI = 0.95 and Low PASI = 0.87). CONCLUSION: The Low PASI score allows more possible scores at lower levels of psoriasis extent (affected areas lower than 10% in a body region) compared to the classic PASI. This new score may lead to a more precise analysis of treatment responses and may have important clinical implications.

Methotrexate in pediatric plaque-type psoriasis: Long-term daily clinical practice results from the Child-CAPTURE registry.

BACKGROUND: Evidence on effectiveness and safety of methotrexate (MTX) in pediatric psoriasis is scarce. OBJECTIVES: To study the effectiveness and safety of MTX in pediatric plaque-type psoriasis and its influence on quality of life (Qol) in daily clinical practice. METHODS: Subset analysis of prospectively collected data extracted from the Child-CAPTURE registry, a single center, longitudinal, long-term, observational daily practice cohort of pediatric psoriasis patients. A maximum dose between 0.14 and 0.63 mg/kg once weekly was prescribed in 25 children. Primary endpoints were percentages of patients with ≥ 75% improvement in the Psoriasis Area and Severity Index (PASI) at week 12 and 24. RESULTS: PASI75 was achieved in 4.3% and 33.3% of patients at week 12 and 24, whereas 40% and 28.6% reached PASI 75 at week 36 and 48. Median PASI and body surface area decreased from 10.0 (range 3.8-42.4) and 11.0 (range 3.5-72.0) at baseline to 4.3 (range 0-19.8) and 2.6 (range 0.0-39.6) at week 24, respectively. Physician Global Assessment improved significantly from 3.0 to 1.2 at week 24. A significant decrease in Children's Dermatology Life Quality Index from 9.0 to 3.8 at week 24 was found. Most reported adverse events were severe nausea (n = 5), infections requiring antibiotics (n = 5) and tiredness (n = 4). CONCLUSIONS: MTX shows a positive effect on PASI scores, improves Qol and has a reasonable safety profile.

Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement.

To better understand postural and movement disabilities, the pattern of total body muscle fat infiltration was analyzed in a large group of patients with facioscapulohumeral muscular dystrophy. Additionally, we studied whether residual D4Z4 repeat array length adjusted for age and gender could predict the degree of muscle involvement. Total body computed tomography scans of 70 patients were used to assess the degree of fat infiltration of 42 muscles from neck to ankle level on a semi-quantitative scale. Groups of muscles that highly correlated regarding fat infiltration were identified using factor analysis. Linear regression analysis was performed using muscle fat infiltration as the dependent variable and D4Z4 repeat length and age as independent variables. A pattern of muscle fat infiltration in facioscapulohumeral muscular dystrophy could be constructed. Trunk muscles were most frequently affected. Of these, back extensors were more frequently affected than previously reported. Asymmetry in muscle involvement was seen in 45% of the muscles that were infiltrated with fat. The right-sided upper extremity showed significantly higher scores for fat infiltration compared to the left side, which could not be explained by handedness. It was possible to explain 29% of the fat infiltration based on D4Z4 repeat length, corrected for age and gender. Based on our results we conclude that frequent involvement of fat infiltration in back extensors, in addition to the abdominal muscles, emphasizes the extent of trunk involvement, which may have a profound impact on postural control even in otherwise mildly affected patients.

Increased incidence of squamous cell carcinoma of the skin after long-term treatment with azathioprine in patients with auto-immune inflammatory rheumatic diseases.

BACKGROUND: Auto-immune inflammatory rheumatic diseases (AIRD) are often successfully treated with the immunosuppressant azathioprine for years. Treatment with azathioprine has been proven to increase the risk of non-melanoma skin cancer (NMSC) in transplant patients and possibly in patients with inflammatory bowel disease as well. Little is known about the risk of NMSC in AIRD patients treated with azathioprine. OBJECTIVES: The aim of this study is to determine the incidence of NMSC in patients with AIRD treated with azathioprine for at least 1 year, as compared with the general Dutch population. METHODS: Data were extracted from a historical cohort of patients with AIRD in a tertiary care centre. We compared the incidence to an age-matched control population and analysed risk factors for NMSC with univariate logistic regression. RESULTS: Fifty-nine patients were analysed. No patients were diagnosed with basal cell carcinoma and four patients with a single squamous cell carcinoma (SCC). Patients with SCC had a higher cumulative dose of azathioprine (≥ 500 g: OR 30.0 [95% CI 2.6-345.1]) and longer treatment duration (≥ 11 years: OR 13.5 [95% CI 1.3-143.6]). The risk of SCC compared with the general Dutch population was increased (standardized incidence ratio of 16.0 [95% CI 0.3-31.7]). CONCLUSIONS: In this cohort of patients with AIRD treated with azathioprine for at least 1 year, the risk of SCC was increased, as compared with the general population. An individual cumulative dose of at least 500 g azathioprine and a treatment duration of at least 11 years were quantified as risk factors.

Chromatin remodelling initiation in spermatids: differences among human males.

During the last phase of spermatogenesis, called spermiogenesis, the nucleosome-based chromatin structure is replaced by a protamine-based DNA packaging. Not much is known about the chromatin remodelling involved in humans and animals. Here, we have investigated initiation of chromatin remodelling over seven probands of which five were diagnosed with non-obstructive azoospermia (NOA) and two with obstructive azoospermia (OA) (failed vaso-vasostomy patients with proven fertility prior to vasectomy, Johnsen scores ≥9). Chromatin remodelling was studied evaluating the presence of nucleosomes, histone H3, pre-protamine 2 and protamine 1. This approach was feasible since the local initiation of nucleosome eviction in the sub acrosomal domain, which was visible in alkaline nuclear spread preparations. The patterns of nucleosome and H3 loss were largely congruent. Nucleus wide incorporation of protamine 1 could already be observed at the late round spermatid stage. Both for nucleosome loss and for protamine 1 incorporation, there was distinct variation within and between probands. This did not relate to the efficiency of sperm production per meiocyte. Pre-protamine 2 was always confined to the subacrosomal domain, confirming the role of this area in chromatin remodelling.

Prognostic value of decreased tongue strength on survival time in patients with amyotrophic lateral sclerosis.

Decreased tongue strength (TS) might herald bulbar involvement in patients with amyotrophic lateral sclerosis (ALS) well before dysarthria or dysphagia occur, and as such might be prognostic of short survival. The purpose of this study was to investigate the prognostic value of a decreased TS, in addition to other prognostic factors, such as site of onset, bulbar symptoms, bulbar signs, age, sex, maximum phonation time, time from symptoms to diagnosis, and gastrostomy, for survival time in patients with ALS. TS was measured in four directions in 111 patients who attended the diagnostic outpatient motor neuron clinic of our university hospital. Of these patients, 54 were diagnosed with ALS. TS was considered abnormal if the strength in minimally one direction was at least two standard deviations below the reference values obtained from comparable age category and sex-groups of healthy controls (n = 119). Twenty of the patients with ALS had a decreased TS. Multivariable analysis showed that, in addition to age, TS was an independent prognostic factor for survival time in patients with ALS.

Normal height and weight in a series of ambulant Duchenne muscular dystrophy patients using the 10 day on/10 day off prednisone regimen.

Prednisone treatment delays the progressive course of Duchenne muscular dystrophy. The aim of this study was to determine the influence of the 10 day on/10 day off treatment on height and weight. We retrospectively reviewed the growth and weight charts of Duchenne patients born between 1988 and 2006 (patients between 4 and 9 years old, being able to walk in the home situation). Forty-seven patients were eligible for further analysis and divided into two groups: 33 patients treated with prednisone and 14 non-prednisone treated patients. Results of a median follow-up of 57 months (range 27-146) are described. By using linear mixed models this study demonstrates that height and body mass index in prednisone-treated patients with 10/10 regimen are not significantly different compared to untreated patients. We cautiously conclude that the alternating prednisone regimen has no apparent side effects on weight and height in the ambulatory phase of Duchenne muscular dystrophy.

Risk factors for short- and long-term complications after groin surgery in vulvar cancer.

BACKGROUND: The cornerstone of treatment in early-stage squamous cell carcinoma (SCC) of the vulva is surgery, predominantly consisting of wide local excision with elective uni- or bi-lateral inguinofemoral lymphadenectomy. This strategy is associated with a good prognosis, but also with impressive treatment-related morbidity. The aim of this study was to determine risk factors for the short-term (wound breakdown, infection and lymphocele) and long-term (lymphoedema and cellulitis/erysipelas) complications after groin surgery as part of the treatment of vulvar SCC. METHODS: Between January 1988 and June 2009, 164 consecutive patients underwent an inguinofemoral lymphadenectomy as part of their surgical treatment for vulvar SCC at the Department of Gynaecologic Oncology at the Radboud University Nijmegen Medical Centre. The clinical and histopathological data were retrospectively analysed. RESULTS: Multivariate analysis showed that older age, diabetes, 'en bloc' surgery and higher drain production on the last day of drain in situ gave a higher risk of developing short-term complications. Younger age and lymphocele gave higher risk of developing long-term complications. Higher number of lymph nodes dissected seems to protect against developing any long-term complications. CONCLUSION: Our analysis shows that patient characteristics, extension of surgery and postoperative management influence short- and/or long-term complications after inguinofemoral lymphadenectomy in vulvar SCC patients. Further research of postoperative management is necessary to analyse possibilities to decrease the complication rate of inguinofemoral lymphadenectomy; although the sentinel lymph node procedure appears to be a promising technique, in 50% of the patients an inguinofemoral lymphadenectomy is still indicated.

Robot-assisted versus total laparoscopic radical hysterectomy in early cervical cancer, a review.

OBJECTIVE: The aim of this study was to review current literature on total laparoscopic (TLRH) and robot-assisted radical hysterectomy (RRH) with pelvic lymphadenectomy in the treatment of early stage cervical cancer by analyzing data published in individual case series in order to compare surgical and oncological outcomes. METHODS: Up to January 2010, 27 studies were identified that met the inclusion criteria, together with our own unpublished data of patients, accounted for 342 RRH patients and 914 TLRH patients. RESULTS: There was no statistical difference between the methods in terms of age, BMI or prior abdominal surgery. Estimated mean operative time, blood loss and number of lymph nodes retrieved did not statistically differ between the RRH and TLRH method. Less blood transfusions were needed in patients treated by RRH (5.4%) versus TLRH (9.7%, p<0.05). Both methods were similar in respect to adjuvant chemo- or (chemo)radiation and recurrence rate. When complications were prioritized to severity, major post-operative complications where more frequent in RRH patients (9.6%) than in TLRH patients (5.5%, p<0.05). The length of hospital stay was significantly shorter in RRH compared to TLRH treatment (3.3 versus 6.2days respectively; p:0.04). CONCLUSIONS: Robot-assisted and total laparoscopic radical hysterectomy appears to be equally adequate and feasible. RRH studies had small patient populations and further experience beyond the learning curve phase may improve operative time and complication rate. Both minimal invasive techniques should be investigated in a randomized manner.

Factors influencing success of pelvic organ prolapse repair using porcine dermal implant Pelvicol.

OBJECTIVE: To evaluate factors influencing pelvic organ prolapse (POP) recurrence after repair surgery with a porcine dermal collagen implant (Pelvicol). STUDY DESIGN: From December 2003 to August 2005, 78 patients with mainly stage 3 pelvic organ prolapse by the Pelvic Organ Prolapse Quantification (POP-Q) system underwent vaginal repair using porcine dermal implant. Assessments were made preoperatively and at 6 weeks and one year follow-up. These included physical examination with POP-Q, Incontinence Impact Questionnaire, Urogenital Distress Inventory and the Defaecatory Distress Inventory and questions from the Patient Global Impression of Improvement. Data were recorded on changes in functional status, mesh erosion and adverse events. Procedural success was defined as POP-Q stage 0/1. RESULTS: 71 patients returned for one year follow-up. The overall cure rate was 74.6%. The chance of a successful operation in the younger group was significantly higher than in the older group (OR: 7.5; 95% CI 1.38, 40.69), but this effect is lower and no longer significant after adjusting for compartment (post, anterior, post+anterior) (adjusted OR: 5.5; 95% CI 0.92, 32.6). CONCLUSIONS: A low complication rate and satisfactory overall results were observed in a group of women after POP repair surgery with Pelvicol. Whether these results are better or worse than with conventional surgery or non-resorbable mesh implantation is unclear and can only be determined in a randomized controlled trial. There was a strong tendency towards better results in the younger women than in the older women, but the reason for this phenomenon is unclear.

Karyotyping, congenital anomalies and follow-up of children after intracytoplasmic sperm injection with non-ejaculated sperm: a systematic review.

BACKGROUND: For men with azoospermia, it is possible to father their own progeny by intracytoplasmic sperm injection (ICSI) with epididymal or testicular sperm. Some studies show that children born after assisted reproductive technology (ART) are at increased risk of birth defects, other studies suggest that there is no extra concern about ICSI children conceived with epididymal or testicular sperm. METHODS: Studies about the karyotypes of fetuses, congenital anomalies and the follow-up of the children born after ICSI with non-ejaculated sperm were identified by means of a systematic literature search. RESULTS: Eight relevant studies were identified; two studies reported karyotype, five reported malformations and one reported follow-up of children after ICSI. In total, there were 55 out of 1973 (2.8%) abnormal karyotypes in the ICSI with ejaculated sperm group, 0 out of 31 in the ICSI with epididymal sperm group and 5 out of 191 (2.6%) in the ICSI with testicular sperm group. Major malformations were found in 543 out of 12 377 (4.4%) in the ICSI with ejaculated sperm group, 17 out of 533 (3.2%) in the ICSI with epididymal sperm group and 31 out of 670 (4.6%) in the ICSI with testicular sperm group. CONCLUSIONS: Although there were no statistical differences, the study groups were small and heterogenic, with a number of potential biases. We therefore recommend a standardized methodology of follow-up studies after ART, with well-defined groups of ICSI with ejaculated sperm, ICSI with epididymal sperm and ICSI with testicular sperm, and a control group of naturally conceived children.

Toxicity testing of human assisted reproduction devices using the mouse embryo assay.

Systems to assess the toxicity of materials used in human assisted reproduction currently lack efficiency and/or sufficient discriminatory power. The development of 1-cell CBA/B6 F1 hybrid mouse embryos to blastocysts, expressed as blastocyst rate (BR), is used to measure toxicity. The embryos were divided into control and test groups, and were exposed to either control medium or to a potentially toxic test medium. Inferences on toxicity were based on differences in BR between the two groups. The mouse embryo assay followed a stratified (mouse), randomized (embryo), and balanced (equal number of embryos per group and per mouse) design. The number of embryos needed was calculated using power analysis. The basal BR of the hybrid strain was determined in a historical population. Sixty-nine mouse embryos per group were required to detect toxic materials with sufficient sensitivity and to account for the considerable inter-mouse variation in blastocyst development. Fifty-two samples, divided over batches of seven different products were tested before use in the study IVF centre and five of these were found to be toxic. This test system, presented as the Nijmegen mouse embryo assay (NMEA), can be used to detect embryo-toxic materials in daily IVF practice, and this report may provide a starting point for standardization.

Young adults and acceptance of the human papillomavirus vaccine.

OBJECTIVES: To determine whether young Dutch adults had ever heard of human papillomavirus (HPV) and whether they would accept vaccination, and to assess the factors influencing their decision. STUDY DESIGN: Cross-sectional survey. METHODS: Six hundred participants aged 18-25 years were recruited from two university departments and one non-university technical college. RESULTS: One hundred and six (17.7%) participants had heard of HPV and 536 (94%) had heard of cervical carcinoma. Women had significantly more knowledge of cervical carcinoma than men. A medical education, knowledge of HPV, knowledge of cervical cancer and knowledge of the cervical screening programme were not significantly associated with acceptance of HPV vaccination, whereas gender and age did show a significant relationship. In total, 61% of the female participants and 48% of the male participants were willing to accept a 'catch-up' HPV vaccination. CONCLUSIONS: This study found that average knowledge levels of HPV and cervical cancer were low. Despite this lack of knowledge, a small majority of the study population would accept a 'catch-up' HPV vaccination. Women and younger participants were significantly more willing to accept HPV vaccination. However, in these subgroups, acceptance of HPV vaccination seems to be affected by other, still unidentified, factors. These factors could be evaluated in a more qualitative orientated study. An educational campaign is needed to cover knowledge about HPV and cervical carcinoma, and beliefs and behaviours associated with the acceptance of vaccination.

Prognostic factors for recurrence in patients with FIGO stage I and II, intermediate or high risk endometrial cancer.

BACKGROUND: The aim of this study was to determine predictors for loco-regional or distant recurrence of disease in a subgroup of intermediate or high risk stage I and II endometrial cancer. METHODS: A retrospective analysis of 295 patients with histopathological stage I and II, intermediate or high risk endometrial cancer is reported. The following factors were studied: stage, grade, age, histologic diagnosis, lymphadenectomy, lymphovascular space invasion, and adjuvant radiotherapy. The Log-Rank test was used for statistical analyses and the Kaplan-Meyer method was used for time-to-event analysis. Multivariate analysis was also performed. RESULTS: Thirty-four (11.5%) patients developed a recurrence; 20 (59%) developed loco-regional recurrence, and 14 (41%) developed distant recurrence. In 20 women (59%), recurrence appeared within 3 years of surgery, and the actuarial survival at 3 years after recurrence was 29%. Multivariate analysis showed that for recurrence, age >60 years was a significant unfavourable prognostic factor (p < 0.05). CONCLUSIONS: We found low rates of recurrence in patients with early stage intermediate or high risk endometrial cancer. Only age was identified as an independent significant predictor for recurrence.

Vermindering van diagnostiek en overbehandeling bij RS-virus-bronchiolitis na geprotocolleerde behandeling.

PURPOSE: Evaluating the guideline 'Diagnosis and treatment of respiratory syncytial (RS) virus bronchiolitis' on the number of chest X-rays, C-reactive proteïn (CRP) counts, leukocyte counts, and antibiotic prescriptions in infants admitted to hospital with RS bronchiolitis. DESIGN: Retrospective 'before-after' cohort study. LOCATION: Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. PATIENTS: Infants admitted with proven RS virus infection. METHODS: Guidelines, including sound restriction of performance of X-rays, CRP and leukocytes, were introduced in February 2003. Data from infants admitted with RS virus infection during 1997- 1999 (cohort A) were compared with those admitted from 2003- April 2006 (cohort B)Results: There were 155 infants in cohort A and 170 in cohort B. Implementation of guidelines led to significant reductions of CRP and leukocyte determinations: 49.0% and 48.2%, respectively (both p<0.001) and X-rays: 30.3% (p=0.020). Numbers of antibiotic prescriptions decreased with 55% (p<0.001). The chance of antibiotic prescription increased significantly when X-rays (OR=5.2), CRP (OR=5.4), or leukocytes (OR=4.2) were done. After implementation of the guidelines, the median stay in hospital decreased significantly from 8.0 to 6.0 days (p<0.001; ranges 1-13 days and 2-23 days, respectively). Performing X-ray, CRP or leukocytes, or antibiotic prescription did not significantly alter the total duration of hospital stay. CONCLUSION: Implementation of the guidelines led to significant decreases in numbers of X-rays, CRP and leukocytes determinations, and antibiotic prescriptions. Our data support the restrictive use of chest X-rays, CRP and leukocyte determinations in infants, admitted to hospital with RS virus bronchiolitis.

Morbidity and mortality in first-degree relatives of C282Y homozygous probands with clinically detected haemochromatosis compared with the general population: the HEmochromatosis FAmily Study (HEFAS).

BACKGROUND: Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking. METHODS: Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality. RESULTS: A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p<0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control. CONCLUSION: In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.