The genetic basis of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Familial clustering of cases suggests that genetic factors play an important part in its aetiology. A number of studies of families with several cases of PCOS have produced results suggesting an autosomal dominant trait. Detailed analysis of a large number of affected families has, however, cast some doubt about the mode of inheritance. An autosomal dominant trait remains possible but a more complex aetiology seems more likely. The results of our recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved. We review evidence for an important role for the insulin gene minisatellite in the aetiology of anovulatory PCOS and for the gene coding for P450 cholesterol side chain cleavage (CYP11a) in the mechanism of excessive androgen secretion in women with polycystic ovaries. We propose that the heterogeneity of clinical and biochemical features in PCOS can be explained by the interaction of a small number of key genes with environmental, particularly nutritional, factors.      

Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia.

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.     

Correlated changes in feeding behavior on selection for large and small body size in mice

An automated method was used to record the temporal pattern of feeding of lines of mice selected over 15 generations for high and low body weight (L-mice and S-mice, respectively). Both L-mice and S-mice eat in meals concentrated during the night, and meal frequency is similar in the two lines, but L-mice consume much larger meals, each made up of many more separate feeding bouts. The outbred strain from which the selected lines were derived has a similar basic pattern of feeding in meals, which becomes like that of L-mice when the animal's thermogenic metabolic rate is high, and like that of S-mice when it is low, suggesting that the differences between the feeding patterns of the two selected lines are a secondary consequence of alterations in whole body metabolic rate.     

Preliminary experience with a cuffed ePTFE graft for hemodialysis vascular access

The purpose of this study was to determine graft patency and blood flow rates in recipients of a new cuffed ePTFE graft (Venaflo graft) used for hemodialysis access. A pilot study was conducted with 12 (7 men, 5 women) consecutive patients (age range, 36-76 yr; mean, 65 yr). All patients were recipients of a new cuffed PTFE graft placed for hemodialysis access. Seven were high risk because of a prior history of clotted hemodialysis accesses (1-6; mean, 3.3). Blood flow rates were determined by ultrasound dilution technique at 3 month intervals. One year and 2 year overall graft patency rates were 90.9% and 68.2%, respectively. One graft (high risk, six prior grafts) was lost to thrombosis in the first year; two grafts (one high risk, four prior grafts) were lost to thrombosis in the second year of follow-up. No graft thrombosis resulted from stenosis at the graft-vein anastomosis. Blood flow rates ranged from 550 to 2,110 ml/min (mean, 1,086 ml/min; n = 8) when first measured 3 months after graft placement. Similar flow rates were observed at 12 months (mean, 1,043 ml/min; n = 7) and 24 months (mean, 1,014 ml/min; n = 4) in grafts available for comparison. Dialysis flow rates in excess of 350 ml/min were possible with all patent grafts. A cuffed ePTFE graft provided stable blood flow and satisfactory graft patency during 2 years of follow-up, even in high risk patients with a prior history of vascular access thrombosis.     

Lung dendritic cells are primed by inhaled particulate antigens, and retain MHC class II/antigenic peptide complexes in hilar lymph nodes for a prolonged period of time

Intratracheal (IT) administration of heat-killed Listeria monocytogenes (HKL) results in an influx of macrophage and dendritic cell (DC) precursors into the lung interstitium. Low-density, FcR+, interstitial lung cells isolated from rats instilled 24 hr before with HKL or vehicle alone, were > 90% Mar1+. After culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF) for 3 days, up to 24% of the loosely adherent cells were DC that stimulated allogeneic T-cell proliferation in an mixed lymphocyte reaction (MLR) assay. After only an overnight incubation with GM-CSF, however, the capacity of interstitial Mar1+ cells to stimulate HKL immune T-cell proliferation without exogenous antigen was low. By contrast, when DC were isolated as major histocompatibility complex (MHC) class II+ cells from rat lungs at 1, 3, 7 and 14 days after HKL instillation and cultured overnight with GM-CSF, their antigen presentation capacity without added exogenous antigen was robust, but declined over the 2-week period. Interestingly, hilar lymph node DC maintained their HKL antigen-presenting capacity for up to 2 weeks after instillation of HKL. Following IT administration of PKH-26 labelled HKL, fluorescent or immunolabelled organisms were detected in OX62+ DC in airway epithelium, lung interstitium and hilar lymph nodes in situ and in MHC class II+ DC isolated from these sites. We conclude that newly immigrated Mar1+ lung DC precursors, while efficient in endocytosing particulate antigens, are incapable of eliciting a significant proliferative response from HKL-sensitized T cells. By contrast, MHC class II+ DC isolated from lungs and incubated overnight with GM-CSF induce vigorous antigen-specific T-cell proliferation. Antigen-loaded lung DC in hilar lymph nodes maintain their antigen presentation capacity for up to 2 weeks.     

Accessory cells of the lung. II. Ia+ pulmonary dendritic cells display cell surface antigen heterogeneity

In earlier studies, we had determined that class II (Ia) major histocompatibility complex (MHC) antigen expression in the normal rat lung was limited to dendritic cells and type II alveolar cells. In order to characterize the Ia+ pulmonary dendritic cells of the lung parenchyma, Lewis rat lungs were dissected free of their major airways, enzymatically digested, and serially subjected to density centrifugation on bovine serum albumin, overnight adherence, and immunopanning with a murine anti-rat monoclonal antibody (anti-OX-6) that reacts specifically with class II (Ia) MHC antigens. The purified Ia+ pulmonary cells displayed the morphologic and functional features of dendritic accessory cells, including extended cell processes, absence of nonspecific esterase staining, minimal phagocytosis of latex beads, rapid clustering with T lymphocytes, and co-stimulation of T-cell mitogen responses. Detailed immunophenotyping by cytofluorimetry and immunohistology showed that the purified dendritic cells were Ia (OX-6)+, CD45R (OX-1)+, CD45Rb (OX-22)-, ICAM-1+, and OX-43-. As many as 50% of the cells bound heat-aggregated IgG, while a smaller percentage expressed the CD43 sialophorin antigens (W3/13) expressed by a variety of blood-derived cells, and/or the OX-41 and RMA macrophage antigens. We conclude that Ia+ dendritic cells of lung are heterogeneous with respect to their expression of surface membrane differentiation antigens and may prove to be functionally distinct with respect to their accessory activities.     

Human cytomegalovirus causes productive infection and neuronal injury in differentiating fetal human central nervous system neuroepithelial precursor cells

OBJECTIVES: To study the effect of cell differentiation on the vulnerability of human neural cell types to human cytomegalovirus (HCMV) infection. STUDY DESIGN/METHODS: Primary cultures of human fetal neuroepithelial stem cells and differentiating neuroepithelial precursor cells were infected with HCMV strain AD169. Infectious virus production, apoptosis, and viral-associated cytopathic effects then were examined over a 5-day period. RESULTS: HCMV established productive infection in these cells, generating 10-fold amplification of infectious virus. There was no significant difference in the percentage of apoptotic cells in HCMV-infected versus mock-infected cultures. HCMV antigen and specific cytopathic effects were observed in differentiating astrocytes and neurons, although HCMV antigen was 2-fold more frequent among postmitotic neurons. CONCLUSIONS: Neuroepithelial precursor cells and differentiating astrocytes and neurons are permissive to cytopathic HCMV infection, suggesting that the fetal human central nervous system is vulnerable to HCMV-induced neuronal injury at its earliest stages of development.