Localization of fluorescein-labeled antinucleoside antibodies in glomeruli of patients with active systemic lupus erythematosus nephritis

Renal tissues from two groups of patients were studied with fluorescein-labeled (Fl-) antibodies (Abs) to immunoglobulins, complement, and antibodies prepared in rabbits against BSA conjugate of 5-methyluridine (T) and cytidine (C), the latter two of which react specifically with denatured DNA. The first group consisted of 13 SLE patients, and the second consisted of 53 patients with non-SLE nephropathies. The data obtained from the two groups of patients were used for comparison, and they showed the following:(a) Fl-Abs to immunoglobulins and complement were bound in the glomeruli of tissues from all patients with active SLE glomerulonephritis characterized by deposits of foreign material in glomerular capillary walls (GCW). The fluorescent pattern was granular, corresponding to the distribution of the glomerular deposits, as seen by electron microscopy. Fl-Abs reactive with thymine and cytosine were bound in the GCW of eight of the nine patients with active SLE glomerulonephritis and showed the same granular distribution. The capacity of these latter Fl-Abs to stain the GCW was removed by absorption with the homologous antigen or denatured DNA.(b) Fl-Abs to immunoglobulins, complement, and pyrimidine bases of DNA did not react with the GCW of two SLE patients without clinical and histologic evidence of glomerulonephritis or with the sclerotic glomeruli of two uremic patients with chronic "burned out" lupus nephritis.(c) The glomeruli of 47 of the 53 patients with other nephropathies bound Fl-Abs to immunoglobulins and complement to some extent, and in 26, the localization appeared as marked as in the patients with active SLE glomerulonephritis. Fl-Abs reactive with thymine and cytosine were bound in the GCW of only one of the renal tissues from the 53 non-SLE patients. In the remaining 52, no binding was seen.(d) The findings are consistent with the hypothesis that antigen-antibody complexes, formed by denatured DNA, specific antibody, and complement, are present in the deposits of foreign material accumulated in the GCW of patients with active SLE glomerulonephritis, and that they may contribute to the pathogenesis of this renal disease.     

S-T segment elevation during exercise: Electrocardiographic and arteriographic correlation in 38 patients

The clinical significance and underlying mechanisms of S-T segment elevation during exercise were evaluated by correlating the exercise-induced S-T elevation with the coronary arteriograms and left ventriculogram in 38 patients. Of these, 37 (97 percent) showed significant coronary artery disease; 71 percent of these had proximal lesions. Of 27 patients with old myocardial infarction manifested in the electrocardiogram at rest, 25 had significant coronary artery disease and a ventricular aneurysm. All 11 patients with no previous myocardial infarction in the electrocardiogram at rest had significant coronary artery disease but only 2 (18 percent) had a ventricular aneurysm. One patient had a ventricular aneurysm without coronary artery disease. The sites of S-T elevation correctly localized the area of ventricular aneurysm of 30 (91 percent) of 33 instances and the area of the compatible diseased vessels in 38 (95 percent) of 40 instances.Our data suggest that (1) S-T elevation during exercise in the absence of a pattern of previous myocardial infarction in the electrocardiogram at rest indicates significant proximal coronary artery disease without ventricular aneurysm, whereas in the presence of such a pattern it is indicative of both ventricular aneurysm and significant proximal coronary artery disease; (2) the sites of S-T elevation accurately identify the location of ventricular aneurysm and the compatible diseased vessels; and (3) ischemia and abnormal wall motion may independently or additively underlie the mechanism for S-T elevation during exercise.     

Studies in the distribution of body fat. II. Longitudinal effects of change in weight

Information on the effects of age, sex, obesity and weight change on the fat distribution pattern has not been systematically reported. As an index of body fat distribution, the waist hip circumference ratio (WHR) was computed in 370 men and 177 women aged 22-86 years, participants of the Baltimore Longitudinal Study of Aging. For cross-sectional analysis, initial data on the participants were analyzed; for longitudinal study, the changes in the measurements related to weight change during a 5-year follow-up were analyzed. From cross-sectional analysis: (1) waist circumference is larger in men than in women and increases progressively with age; (2) hip circumference shows no consistent age or sex differences; (3) thus, the well known sex differences in WHR are totally attributable to differences in waist circumference; (4) increases in WHR with age occur in both men and women. From longitudinal analysis of weight change: (1) changes in waist and hip circumferences are correlated directly with changes in weight in both sexes, but there are large differential sex effects; (2) in men, waist changes dominate; (3) in women, waist and hip changes are nearly the same; (4) thus, weight changes in men have large effects on the WHR, while in women changes in WHR are very small. Men, as a group, have a more dangerous fat distribution pattern than women, but men as a group will show a more beneficial pattern of change in WHR with weight control than women.     

Local resistance to oxidative stress by overexpression of copper-zinc superoxide dismutase limits neointimal formation after angioplasty.

PURPOSE: To examine the effects of oxidative stress on neointimal hyperplasia through local overexpression of human copper-zinc superoxide dismutase (Cu-Zn SOD). METHODS: The left common femoral arteries (CFA) of 18 New Zealand white rabbits were subjected to balloon overdilation injury. Each dilated CFA was then incubated with either a nonviral (buffer) or viral (adenovirus overexpressing beta-galactosidase) control or an adenovirus overexpressing Cu-Zn SOD. Animals were then sacrificed at 3, 7, or 28 days (3 arteries per group per time point) and the treated CFA segments were harvested for analysis of esterase-positive inflammatory cells and extracellular matrix elements. The intima-to-media ratio (I/M) was measured to assess the degree of neointimal formation. RESULTS: At 3 days, local SOD levels in the Cu-Zn SOD-treated group were significantly elevated relative to both controls (p<0.01). Significant reductions in lipid peroxidation byproducts were also seen in the SOD group relative to viral and nonviral controls (p<0.05). Mean I/M at 28 days was 0.582+/-0.088 for the nonviral control group versus 0.565+/-0.133 for the viral control group. The SOD-treated group had a significant reduction relative to both controls: 0.259+/-0.045 (p<0.05). Statistically significant reductions in I/M were also demonstrated in the SOD group relative to control groups at 7 days (p<0.05). The SOD-treated group demonstrated significant preservation of elastin relative to controls, as well as a significant reduction in esterase-positive granulocytes relative to controls (p<0.05). CONCLUSIONS: Direct buffering of oxidative stress in balloon-injured vessels can significantly alter postinjury response and limit neointimal hyperplasia.     

Direct observation of hygiene in a Peruvian shantytown: not enough handwashing and too little water

Objective To document frequency of hygiene practices of mothers and children in a shantytown in Lima, Peru. Methods Continuous monitoring over three 12‐h sessions in households without in‐house water connections to measure: (i) water and soap use of 32 mothers; (ii) frequency of interrupting faecal‐hand contamination by washing; and (iii) the time until faecal‐hand contamination became a possible transmission event. Results During 1008 h of observation, 55% (65/119) of mothers’ and 69% (37/54) of children’s faecal‐hand contamination events were not followed within 15 min by handwashing or bathing. Nearly 40% (67/173) of faecal‐hand contamination events became possible faecal‐oral transmission events. There was no difference in the time‐until‐transmission between mothers and children (P = 0.43). Potential transmission of faecal material to food or mouth occurred in 64% of cases within 1 h of hand contamination. Mean water usage (6.5 l) was low compared to international disaster relief standards. Conclusions We observed low volumes of water usage, inadequate handwashing, and frequent opportunities for faecal contamination and possible transmission in this water‐scarce community.     

Nerve growth factor receptors: identification of distinct classes in plasma membranes and nuclei of embryonic dorsal root neurons.

Two classes of receptors for 125I-labeled nerve growth factor in chick embryonic dorsal root neurons have been observed. One type is associated with the plasma membrane (or microsomal fraction) and can be completely solubilized by Triton X-100. These receptors display the nonsaturable binding isotherms and curvilinear Scatchard plots previously reported for nerve growth factor receptors in whole cells. The second class of binding sites is located in the nucleus, firmly bound to chromatin. These receptors are not solubilized by detergent, show saturable binding, and yield linear Scatchard plots of the type associated with a single class of binding sites of high affinity. The presence of the two receptor types suggests a bimodal mechanism of action for nerve growth factor.     

Increased collagen deposition and diastolic dysfunction but preserved myocardial hypertrophy after pressure overload in mice lacking PKCepsilon

Overexpression and activation of protein kinase C-epsilon (PKCepsilon) results in myocardial hypertrophy. However, these observations do not establish that PKCepsilon is required for the development of myocardial hypertrophy. Thus, we subjected PKCepsilon-knockout (KO) mice to a hypertrophic stimulus by transverse aortic constriction (TAC). KO mice show normal cardiac morphology and function. TAC caused similar cardiac hypertrophy in KO and wild-type (WT) mice. However, KO mice developed more interstitial fibrosis and showed enhanced expression of collagen Ialpha1 and collagen III after TAC associated with diastolic dysfunction, as assessed by tissue Doppler echocardiography (Ea/Aa after TAC: WT 2.1+/-0.3 versus KO 1.0+/-0.2; P<0.05). To explore underlying mechanisms, we analyzed the left ventricular (LV) expression pattern of additional PKC isoforms (ie, PKCalpha, PKCbeta, and PKCdelta). After TAC, expression and activation of PKCdelta protein was increased in KO LVs. Moreover, KO LVs displayed enhanced activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), whereas p42/p44-MAPK activation was attenuated. Under stretch, cultured KO fibroblasts showed a 2-fold increased collagen Ialpha1 (col Ialpha1) expression, which was prevented by PKCdelta inhibitor rottlerin or by p38 MAPK inhibitor SB 203580. In conclusion, PKCepsilon is not required for the development of a pressure overload-induced myocardial hypertrophy. Lack of PKCepsilon results in upregulation of PKCdelta and promotes activation of p38 MAPK and JNK, which appears to compensate for cardiac hypertrophy, but in turn, is associated with increased collagen deposition and impaired diastolic function.     

Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry

Background

Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US.