Impact of late-onset Pompe disease on participation in daily life activities: evaluation of the Rotterdam Handicap Scale.

With the recent approval of enzyme replacement therapy for Pompe disease, insight into the social consequences of this disorder becomes even more relevant. The aim of this study was to measure the impact of late-onset Pompe disease on participation in daily life activities and to evaluate the applicability of the Rotterdam Handicap Scale (RHS) for use in Pompe disease. Two hundred fifty-seven adult patients from different countries participated in the study. The mean RHS score was 25.9+/-6.5 on a scale of 9-36. Individual item scores were lowest for 'domestic tasks indoors', 'domestic tasks outdoors', and 'work/study'. The mean RHS score differed significantly between patients with and without respiratory support (22.9 vs. 28.5, p<0.001) and patients with and without a wheelchair (20.9 vs. 29.5, p<0.001). No differences in RHS score were found between countries. The RHS showed good internal consistency and excellent Test-retest reliability. A ceiling effect of 8% was present. We conclude that the RHS seems suitable for this patient population and that Pompe disease has a large impact on the participation in daily life activities, in particular on the ability of patients to fulfil their work or study.

Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement.

The aim of this study was to identify immunobiological subgroups in 133 infant acute lymphoblastic leukemia (ALL) cases as assessed by their immunophenotype, immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement pattern, and the presence of mixed lineage leukemia (MLL) rearrangements. About 70% of cases showed the pro-B-ALL immunophenotype, whereas the remaining cases were common ALL and pre-B-ALL. MLL translocations were found in 79% of infants, involving MLL-AF4 (41%), MLL-ENL (18%), MLL-AF9 (11%) or another MLL partner gene (10%). Detailed analysis of Ig/TCR rearrangement patterns revealed IGH, IGK and IGL rearrangements in 91, 21 and 13% of infants, respectively. Cross-lineage TCRD, TCRG and TCRB rearrangements were found in 46, 17 and 10% of cases, respectively. As compared to childhood precursor-B-ALL, Ig/TCR rearrangements in infant ALL were less frequent and more oligoclonal. MLL-AF4 and MLL-ENL-positive infants demonstrated immature rearrangements, whereas in MLL-AF9-positive leukemias more mature rearrangements predominated. The immature Ig/TCR pattern in infant ALL correlated with young age at diagnosis, CD10 negativity and predominantly with the presence and the type of MLL translocation. The high frequency of immature and oligoclonal Ig/TCR rearrangements is probably caused by early (prenatal) oncogenic transformation in immature B-lineage progenitor cells with germline Ig/TCR genes combined with a short latency period.

Course of disability and respiratory function in untreated late-onset Pompe disease.

Fifty-two untreated patients with late-onset Pompe disease completed questionnaires about their clinical condition and level of handicap at baseline and at 1-year (n = 41) and 2-year follow-ups (n = 40). During this period, declines in functional activities, respiratory function, handicap, and survival were recorded on a group level. This study illustrates the progressiveness of late-onset Pompe disease and indicates the need for close clinical follow-up of both children and adults with this disorder.

Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients.

Late-onset Pompe's disease (acid maltase deficiency, glycogen storage disease type II) is a slowly progressive myopathy caused by deficiency of acid alpha-glucosidase. Current developments in enzyme replacement therapy require detailed knowledge of the kind and severity of symptoms and the natural course of the disease in the patient population. A detailed questionnaire covering the patients' medical history and current situation was developed and information was gathered from 54 Dutch patients. The mean age of the participants was 48.6 +/- 15.6 years. The first complaints started at a mean age of 28.1 +/- 14.3 years and were mostly related to mobility problems and limb-girdle weakness. Fifty-eight percent of the adult patients indicated the presence of mild muscular symptoms during childhood. Twenty-eight percent of the patients waited >5 years for the final diagnosis after the first visit to a physician for disease-related complaints. At the time of questionnaire completion, 48% of the study population used a wheelchair and 37% used artificial ventilation. Movements such as rising from an armchair, taking stairs or getting upright after bending over were difficult or impossible for more than two-thirds of the respondents. The age at onset, the rate of disease progression and the sequence of respiratory and skeletal muscle involvement varied substantially between patients. Seventy-six percent of the participants indicated being troubled by fatigue and 46% by pain. This survey has mapped the age at onset, presenting symptoms, heterogeneity in progression and range of disease severity in a large group of Dutch patients. We conclude that early manifestations in childhood require proper attention to prevent unnecessary delay of the diagnosis. The follow-up of patients with late-onset Pompe's disease should focus on respiratory and limb-girdle muscle function, the capacity to perform daily activities, and the presentation of fatigue and pain.

Heparin as a risk factor for perigraft seroma complicating the modified Blalock-Taussig shunt.

OBJECTIVE: The purpose of this study was to determine the risk factors associated with the occurrence of perigraft seromas complicating systemic-to-pulmonary polytetrafluoroethylene grafts. METHODS: Clinical and perioperative variables were reexamined, blinded for the outcome variable perigraft seroma, in 60 patients undergoing 67 consecutive graft procedures in a 3.5-year period. RESULTS: Eight cases of perigraft seroma were diagnosed in six patients. Univariate analysis revealed age (p = 0.02), a diagnosis of pulmonary atresia with ventricular septal defect and systemic-pulmonary collaterals (p = 0.001), reimplantation of collaterals during the procedure (p < 0.001), and intravenous heparin administered after operation (p < 0.0001) as risk factors for symptomatic perigraft seroma. Multivariable analysis defined heparin as the only significant factor associated with symptomatic perigraft seroma. Consolidation of the upper lobe on chest radiograph, ipsilateral to the shunt, directly after operation (p = 0.01), but especially 8 to 10 days after operation (p < 0.0001), or the need for prolonged drainage of pleural fluid (p < 0.0001) were correlated with the occurrence of perigraft seroma. Perigraft seroma led to four early rethoracotomies in three patients and to accelerated corrective surgery in three cases. Consolidation and absent perfusion of lung segments persisted in two patients. CONCLUSIONS: Our data suggest that the use of heparin leads to an increased risk of perigraft seroma, complicating systemic-pulmonary polytetrafluoroethylene grafts. Prolonged pleural drainage and/or postoperative consolidation of the upper lobe indicate the development of symptomatic perigraft seroma. Treatment is controversial and results are unpredictable. Expectative management seems to be justified so long as permitted by the clinical condition.

Hepatitis C virus genotypes: epidemiological and clinical associations. Benelux Study Group on Treatment of Chronic Hepatitis C.

In a cohort of 292 chronic hepatitis C patients living in the Benelux countries the relationship between viral genotype and geographical origin, route of transmission, clinical characteristics and severity of liver disease was analyzed. HCV-RNA isolates could be classified by the Line Probe Assay (LiPA) as 1a, 1b, 2, 3, 4 or 5 in 286 (98%) cases. Patients of European origin were predominantly infected with HCV subtype 1b (164/254, 65%, CI 58-70%), as were patients of Asian origin (7/13, 54%). Patients originating from Surinam (South America) had predominantly type 2 (9/10, 90%), whereas Africans were mainly infected with type 4 (7/9, 77%). Blood transfusion was the mode of transmission in 142 (50%) patients, intravenous drug abuse (IVDA) in 40 (14%), occupational needle accident or tattoo in 11 (4%); no obvious source of infection was found in 93 (33%). In patients infected by blood transfusion, subtype 1b was predominant (70%, CI 61-77%), whereas subtypes la and 3 were predominant in those infected by IVDA (25% and 45%, respectively, p<0.001). Cirrhosis was observed in 68 (24%) patients; in multivariate analysis, factors independently related to cirrhosis were: the duration of infection, age and prior hepatitis B. No significant relationship was found between the severity of fibrosis or liver inflammation and the HCV (sub)types. In summary, in this large cohort of patients in the Benelux countries the hepatitis C virus (sub)type present was clearly related to the country of origin and the route of transmission, but not to the severity of liver disease.

Long-term pulmonary sequelae in children with congenital diaphragmatic hernia.

Neonates with congenital diaphragmatic hernia (CDH) often suffer from respiratory insufficiency due to lung hypoplasia and pulmonary hypertension. Artificial ventilation is frequently required, and this leads to a high incidence of bronchopulmonary dysplasia. Long-term follow-up studies have shown persisting airway obstruction. To evaluate the long-term pulmonary sequelae in CDH, we studied 40 CDH patients of age 7 to 18 yr (median 11.7 yr) and 65 age-matched controls without CDH and lung hypoplasia who underwent similar neonatal treatment. Mild airway obstruction was found in both groups with more peripheral airway obstruction in CDH patients than in control subjects. Both groups had normal TLC and single-breath carbon monoxide diffusion capacity (DLCO). CDH patients had increased residual volume (RV) and RV/TLC compared with controls. Increased airway responsiveness to methacholine (MCH) was common but bronchoconstriction to inhaled metabisulfite (MBS) was rare both in CDH and control subjects. We conclude that this group of CDH patients has minor residual lung function impairment. Mild airway obstruction and increased airway responsiveness to inhaled MCH but not to MBS suggest that structural changes in distal airways are involved and not autonomic nerve dysfunction. Both artificial ventilation in the neonatal period and residual lung hypoplasia seem important determinants of persistent lung function abnormalities in CDH patients.

The prognostic influence of neuroendocrine cells in prostate cancer: results of a long-term follow-up study with patients treated by radical prostatectomy.

The distribution of immunohistochemically defined neuroendocrine (NE) cells in benign, pre-cancerous and neoplastic prostatic tissues and the prognostic value of these cells in prostate cancer were studied in the radical prostatectomy specimens of 90 patients from whom complete long-term follow-up data were available. The tissue blocks containing all the different Gleason patterns observed in a particular tumor were selected and immunostained. Since chromogranin B stained only a few cells compared to chromogranin A (CgA), NE cells were only defined by their reactivity with CgA. A semi-quantificative CgA score was assessed for all distinct pathological areas. Cox's regression model was used to analyze the influence of final TNM classification (TNM, 1992), Gleason sum score (GSS), age and CgA score on the probability of progression and tumor-specific death. NE cells were demonstrated in all normal prostatic tissues and in most hyperplastic and intra-epithelial neoplastic lesions. CgA staining was seen in 78% of the tumors. CgA scores were not related with Gleason growth patterns, GSS or TNM classification and had no prognostic value. The independent prognostic variables in Cox's regression model were: GSS and pT stage for progression and GSS for tumor-specific survival. Theoretically, NE cells could influence tumor behavior and this discrepancy suggests the need for experimental studies to investigate the role of NE cells in the normal and neoplastic prostate.