Four separate initiation sites for neural tube (NT) fusion have been demonstrated recently in mice and other experimental animals. We evaluated the question of whether the multisite model vs. the traditional single-site model of NT closure provided the best explanation for neural tube defects (NTDs) in humans. Evidence for segmental vs. continuous NT closure was obtained by review of our recent clinical cases of NTDs and previous medical literature. With the multi-site NT closure model, we find that the majority of NTDs can be explained by failure of fusion of one of the closures or their contiguous neuropores. We hypothesize that: Anencephaly results from failure of closure 2 for meroacranium and closures 2 and 4 for holoacranium. Spina-bifida cystica results from failure of rostral and/or caudal closure 1 fusion. Craniorachischisis results from failure of closures 2, 4, and 1. Closure 3 non-fusion is rare, presenting as a midfacial cleft extending from the upper lip through the frontal area ("facioschisis"). Frontal and parietal cephaloceles occur at the sites of the junctions of the cranial closures 3-2 and 2-4 (the prosencephalic and mesencephalic neuropores). Occipital cephaloceles result from incomplete membrane fusion of closure 4. In humans, the most caudal NT may have a 5th closure site involving L2 to S2. Closure below S2 is by secondary neurulation. Evidence for multi-site NT closure is apparent in clinical cases of NTDs, as well as in previous epidemiological studies, empiric recurrence risk studies, and pathological studies. Genetic variations of NT closures sites occur in mice and are evident in humans, e.g., familial NTDs with Sikh heritage (closure 4 and rostral 1), Meckel-Gruber syndrome (closure 4), and Walker-Warburg syndrome (2-4 neuropore, closure 4). Environmental and teratogenic exposures frequently affect specific closure sites, e.g., folate deficiency (closures 2, 4, and caudal 1) and valproic acid (closure 5 and canalization). Classification of NTDs by closure site is recommended for all studies of NTDs in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Results indicate that the use of family history to determine the need for cholesterol screening in children would have (1) missed many with moderate dyslipidemia and (2) failed to detect a substantial number with likely genetic dyslipidemias that would require pharmacologic treatment. The use of universal cholesterol screening would identify all children with severe dyslipidemia, allowing for proper intervention and follow-up and leading to the prevention of future atherosclerotic disease.

A controlled trial of cyclosporine in patients diagnosed with progressive membranous nephropathy (MGN) was carried out to determine whether cyclosporine (D) would be more effective than placebo (P) in reducing the rate of deterioration in renal function. Patients (N = 64) with MGN were placed on a restricted protein diet (< or = 0.9 g/kg) and followed closely for 12 months (Part 1). Patients at high risk of progression based on an absolute loss in creatinine clearance (CCr) of > or = 8 ml/min and persistent nephrotic range proteinuria (Pr) were selected and randomly assigned to either (D) (N = 9) or (P) (N = 8) for 12 months (Part 2). No differences in the two groups were noted at entry. After 12 months, the improvement in CCr slope in ml/min/month was significantly greater in the D patients (D + 2.1 vs. P + 0.5, mean difference 1.6; 95% CI 0.3 to 3.0, P < 0.02). This improvement was maintained in six of eight D (75%) over a mean follow-up period of 21 months. Daily Pr also improved with D (by month 3, D - 4.5 g/day vs. P + 0.7 g/day, P = 0.02) and was sustained in six of eight (75%) D patients. When Pr was expressed as a function of their concurrent CCr, the D versus P patients' time to halving was faster (P = 0.02) and absolute number higher (4/9 D vs 0/8 P). In the D group a trend towards worse hypertension and an increase in the number of transient rises in serum creatinine were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

We conducted a prospective randomized study in which patients with biopsy-confirmed idiopathic membranous nephropathy were assigned to receive either a six-month course of prednisone given on alternate days (45 mg per square meter of body-surface area; n = 81) or no specific treatment (n = 77). The mean duration of follow-up was 48 months. Patients in the prednisone group (median age, 46 years) entered with a mean disease duration of 15 months, a median creatinine clearance of 1.2 ml per second per 1.73 m2 (range, 0.25 to 2.6), and a median rate of urinary protein excretion of 6.8 g per day (0.3 to 26). The annual change in the corrected creatinine clearance at six months did not differ between the prednisone group and the control group (0.10 vs. 0.06 ml per second; P = 0.8), or at the last follow-up evaluation (-0.07 vs. -0.02 ml per second; P = 0.2; 95 percent confidence interval on the difference, -0.03 to 0.13). The proportion of patients with complete remission of proteinuria was also similar in the groups at 6 and 12 months and after a mean of 48 months. Outcomes were similar in the two groups with respect to progression to renal failure (3 vs. 4 patients), death (3 vs. 1 patient), complete remission of proteinuria at 36 months (16 vs. 19 patients), and a decline of 25 percent or more in the creatinine clearance at 60 months (32 vs. 25 percent of patients). A multivariate analysis, which adjusted for differences at entry in sex distribution, urinary protein excretion, and creatinine concentration, as well as other prognostic variables, failed to provide an explanation for the lack of effect of prednisone. We conclude that a six-month course of therapy in which prednisone is given on alternate days is of no benefit to patients with idiopathic membranous nephropathy.

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