Evidence for alteration of the vitamin D-endocrine system in obese subjects.

Serum immunoreactive parathyroid hormone (PTH) is increased in obese as compared with nonobese subjects and declines with weight loss. To determine whether alteration of the vitamin D-endocrine system occurs in obesity and whether ensuing secondary hyperparathyroidism is associated with a reduction in urinary calcium, a study was performed in 12 obese white individuals, five men and seven women, and 14 nonobese white subjects, eight men and six women, ranging in age from 20 to 35 yr. Body weight averaged 106 +/- 6 kg in the obese and 68 +/- 2 kg in the nonobese subjects (P less than 0.01). Each of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium and 900 mg of phosphorus. Whereas mean serum calcium, serum ionized calcium, and serum phosphorus were the same in the two groups, mean serum immunoreactive PTH (518 +/- 48 vs. 243 +/- 33 pg/ml, P less than 0.001), mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] (37 +/- 2 vs. 29 +/- 2, P less than 0.01), and mean serum Gla protein (33 +/- 2 vs. 24 +/- 2 ng/ml, P less than 0.02) were significantly higher, and mean serum 25-hydroxyvitamin D (25-OHD) (8 +/- 1 vs. 20 +/- 2 ng/ml, P less than 0.001) was significantly lower in the obese than in the nonobese men and women. Mean urinary phosphorus was the same in the two groups, whereas mean urinary calcium (115 +/- 10 vs. 166 +/- 13 mg/d, P less than 0.01) was significantly lower, and mean urinary cyclic AMP (3.18 +/- 0.43 vs. 1.84 +/- 0.25 nM/dl GF, P less than 0.01) and creatinine clearance (216 +/- 13 vs. 173 +/- 6 liter/d, P less than 0.01) were significantly higher in the obese than in the nonobese individuals. There was a significant positive correlation between percentage of ideal body weight and urinary cyclic AMP (r = 0.524, P less than 0.01) and between percentage of ideal body weight and serum immunoreactive PTH (r = 0.717, P less than 0.01) in the two groups. The results provide evidence that alteration of the vitamin D-endocrine system in obese subjects is characterized by secondary hyperparathyroidism which is associated with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D. The reduction of serum 25-OHD in them is attributed to feedback inhibition of hepatic synthesis of the precursor by the increased serum 1,25(OH)2D.     

Hypertension in blacks

The major differences that have been recognized between black and white hypertensives are primarily epidemiologic, with hypertension being more prevalent, having an earlier onset, and having more severe sequelae in the black population. The cause of the problem in both black and white people remains obscure, but it appears that a difference in sodium handling may contribute to the particular hemodynamic and hormonal profile of black hypertensives. Salt sensitivity, expanded plasma volume and low renin levels have been the hallmark of the black hypertensive. Complications such as stroke and left ventricular hypertrophy remain the major sequelae of this disease in blacks. Finally, a current study confirmed the improved efficacy of antihypertensive therapy in blacks to diuretics and calcium channel blockers and a somewhat lower efficacy profile to angiotensin converting enzyme inhibitors and beta blockers, although the latter classes of agents have shown better response in blacks than previously thought.     

Evidence for activation of the coagulation system in migraine with aura

Migraine with aura has been shown to be an independent risk factor for stroke. Although the precise mechanism of migraine-related stroke is not known, risk factors for hypercoagulability have been found in migraineurs. Prothrombin factor 1.2 (F1.2) is a cleavage product of prothrombin. Elevated plasma F1.2 has been shown to be a sensitive and a specific marker of ongoing thrombin generation, and thus may serve as an indicator of hypercoagulability. In this study we determined plasma F1.2 levels in 35 patients with migraine (22 with aura and 13 without aura) and in 24 healthy age- and sex-matched volunteers. Elevated F1.2 levels were found in 11 of 22 (50%) patients with migraine with aura (1.25-3.5 nmol/l). None of the patients with migraine without aura nor any of the healthy volunteers had elevated plasma F1.2 levels (normal < 1.1 nmol/l). We conclude that prothrombin F1.2 levels are elevated in a significant number of patients with migraine with aura but not in patients with migraine without aura. This finding suggests that there is activation of the clotting system in certain patients with migraine with aura.     

Evidence for in vivo upregulation of the intestinal vitamin D receptor during dietary calcium restriction in the rat.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] increases intestinal calcium absorption through events that include binding of 1,25(OH)2D3 to the intracellular vitamin D receptor. In vitro studies using mammalian cell cultures reveal an increase in vitamin D receptor content after exposure to 1,25(OH)2D3. To test the hypothesis that 1,25(OH)2D3 increases enterocyte vitamin D receptor content in vivo, male rats were fed either a normal calcium diet (NCD, 1.2% Ca) or low calcium diet (LCD, 0.002% Ca). After 21 d LCD increased serum 1,25(OH)2D3 levels (27 +/- 3 vs. 181 +/- 17 pg/ml, P less than 0.001) and increased transepithelial mucosal to serosal calcium fluxes (Jms) across duodenum (65 +/- 21 vs. 204 +/- 47 nmol/cm2.h, NCD vs. LCD, P less than 0.01) and jejunum (23 +/- 3 vs. 46 +/- 4, P less than 0.007). No change in serosal to mucosal calcium fluxes (Jsm) were observed. LCD increased 1,25(OH)2D3 receptor number threefold in duodenum (32.9 +/- 6.7 vs. 98.7 +/- 13.7 fmol 1,25(OH)2D3/mg protein) and jejunum (34.1 +/- 9.5 vs. 84.9 +/- 7.7) without a change in the receptor affinity for 1,25(OH)2D3 (Kd is 0.17 +/- 0.06 vs. 0.21 +/- 0.02 nM for NCD and LCD duodenum, respectively). Duodenal polyadenylated vitamin D receptor mRNA determined by Northern blot analysis did not increase appreciably during LCD, suggesting that upregulation in vivo may not be due primarily to increased receptor synthesis. The results of this study indicate that under physiologic conditions as during chronic dietary calcium restriction, increased intestinal vitamin D receptor content accompanies increased calcium active transport. Upregulation of the vitamin D receptor by 1,25(OH)2D3 may result primarily from posttranslational processes that decrease degradation of the receptor with increased receptor synthesis responsible for a negligible portion of the accumulation.     

Frequency of PLA1 in blacks

Racial frequencies of platelet-specific antigens in racial groups other than whites have not been studied. The prevalence of PLA1 was determined in white and black blood donors. Two hundred forty-two of 243 blacks were PLA1-positive (99.6%), compared with 242 of 250 whites (96.8%) (p = 0.021). This black population has the highest frequency of PLA1 yet reported.     

Perspectives on the status of elder blacks in America

The purpose of this paper is to describe the daily existence of Black elders in America and to describe those factors which influence both the lifestyle and longevity of this group as well as some strategies for change. The author concludes with a challenging question for America.     

Cephalosporin-induced alteration in hepatic glutathione redox state. A potential mechanism for inhibition of hepatic reduction of vitamin K1,2,3-epoxide in the rat.

Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second- and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal gamma-carboxylation of a synthetic pentapeptide. Since MTT is a thiocarbamide, a type of compound that can increase oxidation of glutathione, the present studies were carried out to determine whether alterations in hepatic glutathione redox state might interfere with vitamin K metabolism. Dose-related increases in biliary efflux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MTT or MTT-containing antibiotics to rats. This finding suggested that these compounds could alter the hepatic glutathione redox state in vivo. Microsomal reduction of vitamin K epoxide occurred in the presence of 100 microM dithiothreitol (DTT), but was inhibited by preincubation with GSSG at concentrations as low as 10 microM. At higher concentrations of DTT (1.0 mM) inhibition by GSSG persisted, but higher concentrations were required, suggesting that the thiol/disulfide ratio, rather than the absolute concentration of GSSG was important. By contrast, GSSG did not effect microsomal gamma-carboxylation of a pentapeptide, using either vitamin K1 or its hydroquinone as a cofactor. These findings suggest a novel mechanism for the hypoprothrombinemia occurring after administration of MTT-containing antibiotics.     

The probability of exclusion of the HLA-A,B system in North American whites and blacks in parentage tests

The value of the HLA-A,B system in excluding a man falsely accused of paternity, the power of exclusion (A), was examined by four different methods. Methods to define A were: analysis of artificially created false trios, calculation of the proportion of all exclusion cases (corrected for unexcluded men who were not fathers) in which the HLA system showed evidence of an exclusion, derivation from individual Random Man Not Excluded (RMNE) values, and derivation from individual Paternity Index (PI) values. The false trios were limited within the same ethnic group (whites and blacks) so that no mixed ethnic matings were considered. It was assumed that all of the men in the artificial trios were not fathers. Twenty-one percent of the observed exclusions were based on A locus markers, 36 percent on B locus markers, and 43 percent on both A and B markers. Among 510 false white trios, the man was excluded in 476 cases, yielding a power of exclusion (A) for whites of 93.3 percent. One hundred thirty men were excluded in 140 black artificial trios, giving a value of 92.9 percent for A in blacks. Similar values, 94.4 percent for whites and 93.6 percent for blacks, were derived from the proportion of all exclusions detected by the HLA system. A was also derived by computer analysis on the same cases with formulas that use RMNE and PI values. These results also agreed. This concordance by all four methods enhanced the validity of the A values of about 93 to 94 percent for both whites and blacks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of mammalian cell lysis mediated by peptide defensins. Evidence for an initial alteration of the plasma membrane.

Defensins induce ion channels in model lipid bilayers and permeabilize the membranes of Escherichia coli. We investigated whether similar membrane-active events occur during defensin-mediated cytolysis of tumor cells. Although defensin-treated K562 targets did not release chromium-labeled cytoplasmic components for 5-6 h, they experienced a rapid collapse (within minutes) of the membrane potential, efflux of rubidium, and influx of trypan blue. Defensin treatment also blunted the subsequent acidification response induced by nigericin, thereby further supporting the notion of enhanced transmembrane ion flow during exposure. These initial effects on the plasma membrane were not sufficient for subsequent lysis; a second phase of injury was required which involved the continued presence of defensin. The rapid membrane permeabilization phase was inhibited by azide/2-deoxyglucose, cytochalasin B, and increased concentrations of extracellular potassium and was unaffected by actinomycin-D, cycloheximide, and varying the calcium concentration. In contrast, the second phase was unaffected by cytochalasin B, inhibited by azide/2-deoxyglucose, enhanced by actinomycin D and cycloheximide, and varied with calcium concentration. These results indicate the initial adverse effect of defensins on mammalian cells occurs at the cell membrane. It is possible that the second phase of injury is mediated intracellularly by defensin that has been internalized through this leaky membrane.     

Evidence for the involvement of the Ss protein of the mouse in the hemolytic complement system

A significant within-strain correlation has been demonstrated between the levels of Ss and hemolytic complement (C) activity in two Ss-high strains. Mouse serum specifically depleted of Ss by absorption with F(ab')2 fragments of anti-Ss had negligible C activity. In control experiments, Ss-specific antigen-antibody complexes formed with F(ab')2 fragments did not fix rabbit C, and bovine serum albumin-specific antigen-antibody complexes formed with F(ab')2 fragments did not fix mouse C. Therefore the removal of C activity by anti-Ss [F(ab')2] was apparently not due to C fixation. These results suggest that the Ss protein is a necessary component of the C system.     

Evidence for the involvement of cerebral renin-angiotensin system (RAS) in stress analgesia

Studies concerning variations of the central renin-angiotensin system (RAS) during immobilization stress in rats have shown a significant increase in renin-like activity in the hypothalamus and fronto-parietal cortex, together with a definite decrease in the hypophysis and pineal gland. The resultant stress analgesia is blocked by the previous administration of naloxone and saralasin (angiotensin II antagonist). The intracerebral administration of renin and angiotensin II produces an increase in latencies to thermoalgesic stimuli; this is reduced, as is immobilization stress, by naloxone and saralasin. Both chemical hypophysectomy obtained by dexamethasone pretreatment as well as surgical epiphysectomy block the stress-induced analgesia. The experimental data obtained argue in favour of the participation of the cerebral RAS in stress analgesia through the indirect mechanism of release of opioid peptides.     

Evidence of oxidative stress in the renal cortex of diabetic rats: favourable effect of vitamin E

The aim of this study was to determine whether there are any disturbances of red/ox balance in the renal cortex of rats during the course of experimental diabetes. In the renal cortex of rats with streptozotocin-induced diabetes, the activity of superoxide dismutase (SOD) isoenzymes, glutathione peroxidase (GSH-Pox). glutathione S-transferase (GST) and glutathione reductase (GSH-RED) was measured in the 5th, 10th and 15th weeks of diabetes. Free radical cell damage was assessed on the basis of malonyldialdehyde (MDA) concentration. The influence of lipophilic antioxidant vitamin E on these analytes was also studied. An increase in MDA concentration in the 10th and 15th weeks of diabetes correlated significantly with plasma glucose concentration (r=0.47; p<0.001). Moreover, MDA concentration was influenced by time (+); p<0.001, diabetes (+); p<0.001, vitamin E (-) p<0.001 (ANOVA). Plasma creatinine concentration in rats was elevated by diabetes (p<0.001), whereas vitamin E decreased the concentration (p<0.05). Vitamin E lowered the activity of GSHPox (p<0.001) and GST (p<0.01) (ANOVA). Our results indicate that during experimental diabetes, disturbances of red/ox balance lead to disturbance in renal function manifested as increased creatinine blood concentration. We suggest that oral supplementation of vitamin E protects the renal cortex of rats during experimental diabetes.     

Evidence of oxidative stress in the renal cortex of diabetic rats: favourable effect of vitamin E

The aim of this study was to determine whether there are any disturbances of red/ox balance in the renal cortex of rats during the course of experimental diabetes. In the renal cortex of rats with streptozotocin-induced diabetes, the activity of superoxide dismutase (SOD) isoenzymes, glutathione peroxidase (GSH-Pox), glutathione S-transferase (GST) and glutathione reductase (GSH-RED) was measured in the 5th, 10th and 15th weeks of diabetes. Free radical cell damage was assessed on the basis of malonyldialdehyde (MDA) concentration. The influence of lipophilic antioxidant vitamin E on these analytes was also studied. An increase in MDA concentration in the 10th and 15th weeks of diabetes correlated significantly with plasma glucose concentration (r = 0.47; p < 0.001). Moreover, MDA concentration was influenced by time (+); p < 0.001, diabetes (+); p < 0.001, vitamin E (-) p < 0.001 (ANOVA). Plasma creatinine concentration in rats was elevated by diabetes (p < 0.001), whereas vitamin E decreased the concentration (p < 0.05). Vitamin E lowered the activity of GSHPox (p < 0.001) and GST (p < 0.01) (ANOVA). Our results indicate that during experimental diabetes, disturbances of red/ox balance lead to disturbance in renal function manifested as increased creatinine blood concentration. We suggest that oral supplementation of vitamin E protects the renal cortex of rats during experimental diabetes.