Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

The importance of body fat distribution as a predictor of metabolic aberrations was evaluated in 9 nonobese and 25 obese, apparently healthy women. Plasma glucose and insulin levels during oral glucose loading were significantly higher in women with predominantly upper body segment obesity than in women with lower body segment obesity. Of the former group, 10 of 16 subjects had diabetic glucose tolerance results, while none of the latter group was diabetic. Fasting plasma triglyceride levels were also significantly higher in the upper body segment obese women. The site of adiposity in the upper body segment obese women was comprised of large fat cells, while in the lower body segment obese subjects, it was formed of normal size cells. In both types of obesity, abdominal fat cell size correlated significantly with postprandial plasma glucose and insulin levels. Thigh fat cell size gave no indication as to the presence of metabolic complications. Thigh adipocytes were also resistant to epinephrine-stimulated lipolysis, presumably due to an increase in alpha-adrenergic receptors. Thus, in women, the sites of fat predominance offer an important prognostic marker for glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. This association may be related to the disparate morphology and metabolic behavior of fat cells associated with different body fat distributions.

No abstract

A possible role for increased androgenic/estrogenic activity in the pathogenesis of upper body fat localization and its accompanying cellular and metabolic characteristics was examined. Eighty healthy, nonhirsute, premenopausal, caucasian women with a wide range of body fat topography [waist to hips girth ratio (WHR), 0.64 to 1.02] and obesity level (percentage of ideal body weight, 92-251%) were studied. Increasing androgenicity, as reflected by a decrease in plasma sex hormone-binding globulin capacity and an increase in the percentage of free testosterone, was accompanied by 1) increasing WHR, this relationship being independent of and additive to that of obesity level; 2) increasing size of abdominal, but not femoral, adipocytes; 3) increasing plasma glucose and insulin levels, both basally and in response to oral glucose loading; and 4) diminished in vivo insulin sensitivity, as revealed by increasing steady state plasma glucose levels at comparable plasma insulin levels, attained by the infusion of somatostatin, insulin, and glucose. No association was found between total plasma testosterone, androstenedione, dehydroepiandrosterone sulfate, or estradiol concentrations and WHR, fat cell size, or metabolic profiles. We, therefore, propose that in premenopausal women, a relative increase in tissue exposure to unbound androgens may be responsible in part for localization of fat in the upper body, enlargement of abdominal adipocytes, and the accompanying imbalance in glucose-insulin homeostasis.

Nitric oxide (NO) is detectable in the exhaled air of human subjects, and its concentration is increased in patients with asthma. We have investigated the origin of the increase in exhaled NO in asthmatic patients by using different expiratory maneuvers and by direct sampling from the upper and lower respiratory tracts. Exhaled NO was measured by a chemiluminescence analyzer. Concentrations of NO measured during expiration against the resistance of the analyzer with exhaled flow of 1 L/min, were 78 +/- 3 ppb in normal subjects (n = 46) and significantly elevated in patients with asthma (301 +/- 26 ppb, n = 30, p < 0.001). Values of exhaled NO were lower when measured during unobstructed expiration with a flow of 5 L/min with sampling from a side-arm (7 +/- 1 ppb), but again were elevated in patients with asthma (46 +/- 6 ppb, p < 0.001). Breath-holding for 20 s resulted in an initial peak of NO, but end-expiration values similar to the unobstructed expiration. The concentration of NO in the nose was considerably greater than in expired air (996 +/- 39 ppb) and was elevated in patients with asthma (1,390 +/- 71 ppb, p < 0.002). Direct sampling from trachea and right middle lobe bronchus via a fiberoptic bronchoscope gave similar values in five normal and 15 asthmatic subjects to the values recorded during unobstructed expiration, and there was a good correlation between values in expired air and direct sampling (trachea r = 0.91, right middle lobe r = 0.87, p < 0.001). We conclude that exhaled NO measured in an unobstructed breath reflects concentrations in the lower respiratory tract, but that breath-holding or expiration against resistance is contaminated by residual NO derived from the upper respiratory tract. We also provide evidence that the elevated levels of exhaled NO in asthmatic patients are derived predominantly from the lower respiratory tract.

The concentration of nitric oxide (NO) is increased in the exhaled air of asthmatic patients and may reflect cytokine-mediated inflammation in the airways. We investigated whether allergen-induced inflammation causes an elevation in the level of exhaled NO. Of 25 patients who underwent allergen challenge, 16 developed dual early and late responses, whereas eight had a single early response. In the patients with a dual response, the maximal fall in FEV1 during the late response was 26.8 +/- 4.2% at 9 h and there was a significant increase in the level of exhaled NO (maximal increase of 59.4 +/- 9.8%) 10 h after challenge. There was a significant relationship between the size of the late response and the increase in exhaled NO (r = 0.75, p < 0.01). In patients who have a single early response, there was no significant increase in exhaled NO, with the exception of a single time point at 21 h. In five patients given a control challenge with methacholine there was no change in exhaled NO. There was no increase in exhaled NO after inhaled histamine in any of the patient groups. We conclude that the late asthmatic response to allergen is associated with elevated exhaled NO concentrations and that this provides further evidence that exhaled NO may reflect allergic inflammation in asthmatic airways, and may be a useful marker in monitoring asthma and its response to anti-inflammatory treatments. Whether endogenously produced NO plays a pathophysiologic role in the late response remains to be determined.

No abstract

To determine whether plasma exchange was of additional benefit in patients treated with oral immunosuppressive drugs for focal necrotizing glomerulonephritis (without anti-GBM antibodies), we performed a randomized controlled trial with stratification for renal function on entry. Forty-eight cases were analyzed, 25 in the treatment group (plasma exchange, prednisolone, cyclophosphamide and azathioprine) and 23 in the control group (drug therapy only). There was no difference in outcome in patients presenting with serum creatinine less than 500 mumol/liter (N = 17), or greater than 500 mumol/liter but not on dialysis (N = 12), all but one of whom had improved by four weeks. However, patients who were initially dialysis-dependent (N = 19) were more likely to have recovered renal function (P = 0.041) if treated with plasma exchange as well as drugs (10 of 11) rather than with drugs alone (3 of 8). Long-term follow-up showed that improvement in renal function was generally maintained. The results of this trial confirm that focal necrotizing glomerulonephritis related to systemic vasculitis responds well to immunosuppressive drugs when treatment is started early, and suggest that plasma exchange is of additional benefit in dialysis-dependent cases.