Inverted formin 2 mutations with variable expression in patients with sporadic and hereditary focal and segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a major cause of end-stage kidney disease. Recent advances in molecular genetics show that defects in the podocyte play a major role in its pathogenesis and mutations in inverted formin 2 (INF2) cause autosomal dominant FSGS. In order to delineate the role of INF2 mutations in familial and sporadic FSGS, we sought to identify variants in a large cohort of patients with FSGS. A secondary objective was to define an approach for genetic screening in families with autosomal dominant disease. A total of 248 individuals were identified with FSGS, of whom 31 had idiopathic disease. The remaining patients clustered into 64 families encompassing 15 from autosomal recessive and 49 from autosomal dominant kindreds. There were missense mutations in 8 of the 49 families with autosomal dominant disease. Three of the detected variants were novel and all mutations were confined to exon 4 of INF2, a regulatory region responsible for 90% of all changes reported in FSGS due to INF2 mutations. Thus, in our series, INF2 mutations were responsible for 16% of all cases of autosomal dominant FSGS, with these mutations clustered in exon 4. Hence, screening for these mutations may represent a rapid, non-invasive and cost-effective method for the diagnosis of autosomal dominant FSGS.

Prednisone dosing per body weight or body surface area in children with nephrotic syndrome: is it equivalent?

The current guidelines recommend a dosage of prednisone of 60 mg/m(2) body surface area per day (BSA PRED) for the initial therapy of nephrotic syndrome (NS). Alternatively, a dosage of 2 mg/kg body weight per day (W PRED) can be used. We hypothesized that the BSA PRED and W PRED are not equivalent and analyzed the differences between BSA PRED calculated with various formulas for body surface area (BSA), W PRED and the dose of prednisone prescribed for our patients. We performed a retrospective chart review of the patients at their initial presentation of NS. Thirty-three children were included, of median age 3.34 years at presentation. The W PRED was significantly lower than BSA PRED (P < 0.05), with a median W PRED:BSA PRED ratio of 0.85 [interquartile range (IQR) 0.8 to 0.9]. The difference between W PRED and BSA PRED decreased proportionally to patients' weights up to 30 kg. No differences were noted between the various BSA formulas using both weight and height for the calculation of BSA. The Bland-Altman analysis showed a proportional error between W PRED and BSA PRED up to the average daily dose of 60 mg, with a mean bias of 0.86 (95% limits of agreement = 0.68 to 1.05). Ten out of the 33 patients (30%) were given a lower than recommended BSA PRED dose by more than 5 mg/day. In conclusion, the dosage of prednisone at 2 mg/kg per day versus 60 mg/m(2) per day is not equivalent for patients with weights <30 kg and/or dose <60 mg/day.

A study of a multi-source feedback system for international medical graduates holding defined licences.

OBJECTIVE: To develop and assess the feasibility and psychometric properties of multi-source feedback questionnaires to monitor international medical graduates practising in Canada under 'defined' licences. METHOD: Four questionnaires (patient, co-worker, colleague and self) were developed and administered in 2 phases through paper-based and telephone or Internet formats. Reliability was assessed with Cronbach's alpha and generalisability coefficient analyses. Validity was established through mean ratings, 'unable to respond' rates and factor analyses. RESULTS: A total of 37 doctors participated in the 2 phases. Overall response rates were 70% for patients, 86% for co-workers, 72% for medical colleagues and 92% for self, with response rates higher for the paper-based format than the Internet and phone formats. The instruments had high internal consistency reliability, with Cronbach's alphas of 0.83 for self-assessment and > 0.90 for the other instruments. The generalisability coefficients were Ep(2) = 0.71 for 25 patients on a 13-item survey, Ep(2) = 0.59 for 8 co-workers on a 13-item survey, and Ep(2) = 0.67 for 8 colleagues on a 21-item questionnaire. The range of mean scores was narrow (between 4 and 5) for all items and all surveys. The factor analyses identified that 2 factors accounted for 70% or more of the variance for the patient and colleague surveys and 60% of the variance for the co-worker survey. CONCLUSION: These data suggest that the instruments have reasonable psychometric properties. Traditional survey methods (i.e. paper-based) yielded better results than Internet or phone methods for this group of doctors.

Enuresis: A maturational lag.

ENURESIS IS NOT A DISEASE, BUT A DISORDER CAUSED BY DELAYS IN THE MATURATION OF THREE PHYSIOLOGICAL PROCESSES: persistence of spontaneous bladder contractions, bladder volume exceeding the nocturnal functional bladder capacity and persistence of elevated sleep/arousal thresholds. Enuresis has been subtyped into two different groups, depending on whether the predominant feature is frequent small voidings (excessive bladder contractions) or large urinary volume (volume-dependent). The clinical pattern demonstrated by the enuretic child depends on the severity of the maturational lag. In practice, a mix of these types is most common.

The Canadian Enuresis Study and Evaluation--short- and long-term safety and efficacy of an oral desmopressin preparation.

OBJECTIVE: To evaluate the long-term (12 months) efficacy and safety of oral desmopressin (DDAVP). MATERIAL AND METHODS: A total of 256 healthy children (6-18 years old) with nocturnal enuresis with a frequency of > or = 10 wet nights during a 4-week observation period were eligible for inclusion in the study. Initially 0.2 mg of DDAVP was given for 14 nights. Those achieving a > 90% reduction in the number of wet nights over the observation period (full responders) began a 12-week continuous treatment period at this dose. The remaining children received 0.4 mg for an additional 14 nights. Those achieving a > or = 50% reduction in the number of wet nights (responders) commenced a 12-week continuous treatment period at this dose. Children with a < 50% reduction in the number of wet nights at this point were withdrawn from the study. Each 12-week treatment period was followed by a treatment-free period of 7-28 days. Children who remained dry during that period were assigned a full response and terminated the trial. Children with > or = 2 wet nights during that period immediately began a new 12-week treatment period at the previous dose. This was repeated for 12 months and thereafter the medication dose was tapered by halving over a 4-week period. RESULTS: A total of 117/236 children who completed the titration period (49.6%; 95% confidence interval 40-57%) responded (> 50% reduction over baseline). Throughout the study their response rate remained constant at approximately 74%. Continuous treatment reduced the median number of wet nights during the observation period from 5.75 to 1.00 per week. A total of 12.4% of children received the 0.2 mg dose and 87.6% the 0.4 mg dose. The proportion of full responses increased over the course of the study from 5.8% to 37.5%. DDAVP was well tolerated: the majority of reported adverse events were mild, although two adverse events leading to withdrawal were reported. CONCLUSIONS: Oral DDAVP provides an effective and well-tolerated means of providing long-term control in children with nocturnal enuresis. Long-term treatment increases the response rate.