Comparison of 6-s-cis- and 6-s-trans-locked analogs of 1alpha,25-dihydroxyvitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are preferred for genomic biological responses

The hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] generates biological responses via both genomic and rapid, nongenomic mechanisms. The genomic responses utilize signal transduction pathways linked to a nuclear receptor (VDRnuc) for 1alpha,25(OH)2D3, while the rapid responses are believed to utilize other signal transduction pathways that may be linked to a putative membrane receptor for 1alpha,25(OH)2D3. The natural seco steroid is capable of facile rotation about its 6,7 single carbon bond, which permits generation of a continuum of potential ligand shapes extending from the 6-s-cis (steroid like) to the 6-s-trans (extended). To identify the shape of conformer(s) that can serve as agonists for the genomic and rapid biological responses, we measured multiple known agonist activities of two families of chemically synthesized analogs that were either locked in the 6-s-cis (6C) or 6-s-trans (6T) conformation. We found that 6T locked analogs were inactive or significantly less active than 1alpha,25(OH)2D3 in both rapid responses (transcaltachia in perfused chick intestine, 45Ca2+ influx in ROS 17/2.8 cells) and genomic (osteocalcin induction in MG-63 cells, differentiation of HL-60 cells, growth arrest of MCF-7 cells, promoter transfection in COS-7 cells) assays. In genomic assays, 6C locked analogs bound poorly to the VDRnuc and were significantly less effective than 1alpha,25(OH)2D3 in the same series of assays designed to measure genomic responses. In contrast, the 6C locked analogs were potent agonists of both rapid response pathways and had activities equivalent to the conformationally flexibile 1alpha,25(OH)2D3; this represents the first demonstration that 6-s-cis locked analogs can function as agonists for vitamin D responses.     

Long-term function (6 years) of islet allografts in type 1 diabetes

Eight type 1 diabetic patients, ages 29-41 years, with mean diabetes duration of 23 years (range 18-29 years) received islet transplants from 1 to 5 donors. Seven patients had stable kidney allografts 1-11 years before the islet transplant, and one patient had a simultaneous islet-kidney allograft. Patients' blood glucose control was poor as reflected by the mean +/- SD HbA1c of 9.1 +/- 1.7% before transplant. Of the first three patients, two (1 and 3) achieved insulin independence for 36 and 38 days, respectively. Two recipients rejected their islet grafts within 1 month (2 and 8) and therefore were excluded from analysis. The HbA1c and insulin requirement of the six remaining patients who had persistent islet function for more than 60 days was significantly reduced from 9.3 +/- 1.9 to 6.4 +/- 1.0% (P = 0.002) and from 0.75 +/- 0.15 to 0.35 +/- 0.12 U x kg(-1) x day(-1) (P < 0.001), respectively. The two patients with the longest graft survival (4 and 6) achieved a normalization or near-normalization of their HbA1c levels during 6 years in the absence of severe episodes of hypoglycemia. As demonstrated by a decline in C-peptide response during Sustacal challenge tests over a 6-year period, there was a diminution of islet allograft function over time, despite persistence of normal or near normal HbA1c. We concluded that transplantation of allogeneic islets with an islet mass comparable with whole or segmental pancreas transplants in type 1 diabetic patients can result in long-term islet allograft function; further, we concluded that, in conjunction with small dosages of exogenous insulin, a functioning islet allograft can result in near-normalization of blood glucose levels and significant improvement in HbA1c. The occurrence of severe hypoglycemic episodes observed for patients in the Diabetes Control and Complications Trial was not observed in recipients with functioning islet transplants, despite the continuous need for exogenous insulin therapy to sustain normal HbA1c over the 6-year follow-up. The significant improvement in metabolic control observed for the patients described in this study, and the potential to significantly decrease or halt the progression of diabetic complications, support the continued application of islet allotransplantation as a treatment modality for type 1 diabetic patients.     

Hostility, cigarette smoking and alcohol consumption in the general population

Hostility has been associated with coronary heart disease, and hostility may affect coronary risk through its influence on risk factors such as cigarette smoking and alcohol consumption. The objective of this study was to determine relationships between hostile personality, cigarette smoking and alcohol consumption in the general population. The Edinburgh Artery Study comprises a cross-sectional survey of 1592 men and women aged 55-74 years sampled from age-sex registers of 10 general practices throughout the city. The Bedford-Foulds Personality Deviance Questionnaire was used to elicit extrapunitiveness (including hostile thoughts), dominance (including hostile acts) and intropunitiveness. Social class, age and deprivation score were controlled for in multivariate analyses. The hostile thoughts scale emerged as a significant independent predictor of alcohol consumption in men and women (P < or = 0.01), and the models accounted for 4-9% of the variance in alcohol consumption. Hostile acts were independently predictive of smoking in men (P < or = 0.001), with the model accounting for 5% of the variance in smoking. Hostile thoughts were independently predictive of smoking in women (P < or = 0.001), and the model accounted for 4% of the variance in their smoking. We conclude that hostility may affect coronary risk through its influence on lifestyle-related coronary risk factors, although in future further elucidation of hostility type and standard measurement of hostility are necessary.     

Retinoid X receptor expression in the normal pituitary and clinically ''non-functioning'' pituitary tumours

Nasal chondromesenchymal hamartoma is the suggested appellation for a tumefactive process of the nasal passages and contiguous paranasal sinuses in seven children with a detectable mass in the nose. With the exception of one patient who was 7 years of age at diagnosis, the others were 3 months of age or less upon recognition of the mass. Two children were diagnosed in the first 2 weeks of life. Imaging studies showed a complex solid and cystic mass or masses filling the nasal cavity and extending into the ethmoid sinuses in most cases. Erosion of the surrounding bone, including the cribriform plate, resulted in an intracranial component in the four cases. Surgical resection was the treatment of choice despite its technical difficulties that often necessitated a combined intranasal and intracranial approach. Residual disease with continued growth in one case was the clinical outcome in two children, and the remaining five patients have not experienced any further difficulties. The piecemeal fragments of tissue disclosed a collage of histologic features, but the basic morphologic elements were well-demarcated nodules of cartilage with some variation in the cellular density and maturation of the chondrocytes, a myxoid to spindle cell stroma, focal osteoclastlike giant cells in the stroma, and erythrocyte-filled spaces resembling those of the aneurysmal bone cyst. Two of the tumors were less polymorphous or complex in their spectrum of histologic features. These nasal masses have similarities to the so-called chest wall hamartoma or mesenchymal hamartoma of the chest wall in terms of the clinical presentation in infancy and the basic cartilaginous character of both entities. There is a degree of presumption in the designation of these nasal and chest wall tumors as hamartomas because the pathogenesis has not been established for either entity.     

Reference ranges for serum prostate-specific antigen in black and white men without cancer

OBJECTIVES: To determine the age- and race-specific prostate-specific antigen (PSA) distributions in healthy men in central South Carolina and to compare these to data from other studies. METHODS: Two thousand ninety-two black men aged 40 to 69 years and white men aged 50 to 69 years from the general population in 11 counties of central South Carolina participated in a prostate cancer educational program. Seventy-two percent of the participants were black-about double the proportion in the general population-and 63% of the men (1319 of 2092) subsequently obtained a PSA determination from their own physician. The distribution of serum PSA was compared with distributions from the Olmsted County study and from the Walter Reed Army Medical Center/Center for Prostate Disease Research study. RESULTS: Older men without cancer had higher PSA levels. Regression analyses yielded an associated increase of about 3.3% per year. Reference ranges for normal PSA in men without cancer (based on their sample 95th percentiles) were zero to 1.9, 3.8, and 5.7 ng/mL in black men aged 40 to 49, 50 to 59, and 60 to 69 years, and zero to 2.7 and 4.9 mg/mL in white men aged 50 to 59 and 60 to 69 years, respectively. CONCLUSIONS: Reference ranges for normal serum PSA levels should take into account the population from which they are derived and to which they will be applied. Reference ranges that are useful in the general population can differ from those that are appropriate in a hospital setting. For the general population in central South Carolina, reference ranges for serum PSA levels are lower than previously published reference ranges, particularly among black men.     

Decreased erythrocyte Na+,K(+)-ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonoliguric hyperkalemia

To determine whether a shift of potassium ions from the intracellular space to the extracellular space accounts, in part, for the hyperkalemia seen in extremely low birth weight infants, we examined potassium concentration in serum and erythrocytes from extremely low birth weight infants with hyperkalemia (n = 12) or with normokalemia (n = 27). In addition, to determine whether the shift of potassium was associated with low sodium-potassium-adenosinetriphosphatase (Na+,K(+)-ATPase) activity, we studied the activity of ATPase in the last 16 infants enrolled in the study. Fluid intake and output were measured during the first 3 days of life. Infants were considered to have hyperkalemia if the serum potassium concentration was 6.8 mmol/L or greater. Blood was obtained daily for intracellular sodium and potassium levels by means of lysis of erythrocytes. The remaining erythrocyte membranes were frozen and analyzed for Na+,K(+)-ATPase activity. There were significantly lower intracellular potassium/serum potassium ratios in the infants with hyperkalemia for each day of the 3-day study (p < 0.001). In the hyperkalemic group, there was lower Na+,K(+)-ATPase activity than in the infants with normokalemia (p = 0.006). Low Na+,K(+)-ATPase activity was associated with lower intracellular potassium/serum potassium ratios (p = 0.006), higher serum potassium values (p = 0.02), and lower intracellular potassium concentration (p = 0.009). The urinary data demonstrated that there was no difference in glomerulotubular balance between the two groups. We conclude that nonoliguric hyperkalemia in extremely low birth weight infants may be due, in part, to a shift of potassium from the intracellular space to the extracellular space associated with a decrease in Na+,K(+)-ATPase activity.