The lethal white foal syndrome (LWFS) is a congenital abnormality of overo spotted horses which is a model for human aganglionic megacolon or Hirschsprung disease. Foals with LWFS have an all white, or nearly all white, coat. They also present clinically with an intestinal obstruction that proves fatal within the first few days of life. The LWFS involves both melanocytes and intestinal ganglion cells, and appears to result from a genetic defect involving neural crest cells. This report describes pathologic studies of two recent cases of LWFS. Two different hypothetical models of inheritance of LWFS are presented and discussed.
Context Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. Objective To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. Methods Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. Results Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone–binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. Conclusion SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.
Context Patients with lipodystrophy have dyslipidemia and insulin resistance. Leptin treatment with metreleptin in lipodystrophy decreases insulin resistance and lowers triglycerides without changing high-density lipoprotein. Detailed measurement of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel. We hypothesized that patients with lipodystrophy would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with metreleptin treatment. Objective To characterize the lipoprotein profile in patients with lipodystrophy compared with controls and to evaluate effects of metreleptin treatment. Design, Setting, Patients, and Intervention Patients with lipodystrophy (N = 17) were studied before and after metreleptin for 2 weeks and 6 months and compared with 51 insulin-sensitive sex-matched controls. Main Outcome Measures Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). Results Patients with lipodystrophy had elevated large TRLPs and smaller HDLPs and LDLPs compared with controls. Five patients with lipodystrophy had chylomicrons, compared with zero controls. Metreleptin decreased the size and concentration of TRLPs, eliminated chylomicrons in all but one patient, decreased LDLPs, and increased LDLP size. Metreleptin treatment did not have major effects on HDLPs. Conclusions Patients with lipodystrophy had an atherogenic lipoprotein profile at baseline consistent with elevated CVD risk, which improved after metreleptin treatment. The presence of fasting chylomicrons in a subset of patients with lipodystrophy suggests saturation of chylomicron clearance by lipoprotein lipase.
Background: Black mothers in the United States have shorter breastfeeding (BF) durations and less exclusive breastfeeding (EBF) than others. The factors underlying these disparities require investigation. Methods: Using longitudinal data from a CDC-sponsored birth cohort in Cincinnati, Ohio, we analyzed the factors mediating racial disparity in BF outcomes. Study mothers were enrolled in prenatal clinics associated with two large birth hospitals. Analysis was restricted to racial groups with sufficient numbers in the cohort, non-Hispanic Black (n = 92) and White (n = 113) mothers, followed to at least 6 months postpartum. Results: Black mothers were 25 times more likely to reside in socioeconomically deprived neighborhoods and 20 times more likely to have an annual household income <$50,000/year than White mothers ( p < 0.001). The gap in EBF for 6 weeks was 45 percentage points by racial group (13%-Black mothers versus 58%-White mothers, p < 0.001); in any BF at 6 months was 37 percentage points (28%-Black mothers versus 65%-White mothers, p < 0.001); and in mothers meeting their own intention to BF at least 6 months was 51 percentage points (29%-Black mothers versus 80%-White mothers, p < 0.001). Racial disparity in EBF at 6 weeks was mediated in logistic regression models by inequities in socioeconomic position, maternal hypertension, and BF intention. Racial disparities in BF at 6 months or meeting 6-month BF intention were mediated by inequities in socioeconomic position, maternal obesity, and EBF at 6 weeks. Not all BF disparities could be explained by models used in these analyses. Conclusions: Efforts to lessen BF disparities should address the underlying structural inequities that disproportionately affect Black mothers and children, should incorporate maternal health, and focus on breastfeeding exclusivity and duration. Few Black mothers achieved EBF at 6 weeks, which contributed to disparity in BF duration. Greater attention to Black mother-infant pairs is a public health priority.
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