Differential effects of endothelin-1 on the vasorelaxant properties of benzopyran and non-benzopyran potassium channel openers.

1. The effects of endothelin-1 (ET-1) on the vasorelaxant properties of structurally different potassium channel openers (PCOs), BRL-38227, Ro 31-6930, SDZ PCO 400, EMD-52692, RP-49356 and pinacidil, were studied. 2. All PCOs evoked concentration-related relaxations of ET-1 (10 nM) or KCl (20 mM) contracted rat isolated aortic rings denuded of endothelium. BRL-38227, EMD 52692, SDZ PCO 400 and Ro 31-6930 were 11-42 times less potent in relaxing contractions to ET-1 than KCl. In contrast, this differential potency was not observed with RP-49356 or pinacidil. 3. BRL-38227 (0.06-3.0 microM), RP-49356 (0.3-3.0 microM) and pinacidil (0.3-3.0 microM) displaced KCl concentration-response curves to the right of controls, without modifying the maximum response. A subcontractile concentration of ET-1 (0.1 nM) prevented the inhibitory effects of low concentrations of BRL-38227 (0.06-0.1 microM) on KCl responses, but failed to modify those to RP-49356, pinacidil or high concentrations of BRL-38227 (0.3-3.0 microM). The inhibitory effects of BRL-38227 (0.1 microM) were also not changed by ET-3 (1.0 nM) or angiotensin II (0.1 nM). 4. In anaesthetized spontaneously hypertensive rats (SHR), cumulative bolus intravenous administrations of BRL-38227 (1-1000 micrograms kg-1, i.v.), Ro 31-6930 (1-1000 micrograms kg-1, i.v.), RP-49356 (10-1000 micrograms kg-1, i.v.) or nitrendipine (0.1-30 micrograms kg-1, i.v.) produced dose-dependent falls in diastolic blood pressure (DBP).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta/A4 deposits and their relationship to senile plaques in Alzheimer's disease.

The density and spatial pattern of immunostained beta/A4 deposits and mature senile plaques (SP) stained by the Glees method were compared in Alzheimer's diseased brain. Thirty-seven percent of the variance in Glees SP density in a tissue could be explained by beta/A4. Both lesions were clustered with the beta/A4 clusters often larger than the Glees SP clusters. Beta/A4 and Glees SP cluster size were not correlated in a tissue. The size of Glees SP clusters was positively correlated with SP density but no correlation could be detected for beta/A4. Hence, the density and spatial pattern of beta/A4 deposits in most tissues did not predict the development of Glees SP.     

The adequacy of prenatal care and incidence of low birthweight among the poor in Washington State and British Columbia.

OBJECTIVES. The purpose of this study was to examine differences in adequacy of prenatal care and incidence of low birthweight between low-income women with Medicaid in Washington State and low-income women with Canadian provincial health insurance in British Columbia. METHODS. A population-based cross-sectional study was done by using linked birth certificates and claims data. RESULTS. Overall, the adjusted odds ratio for inadequate prenatal care in Washington (comparing women with Medicaid with those with private insurance) was 3.2. However, the risk varied by time of Medicaid enrollment relative to pregnancy (2.0, 1.0, 2.7, 6.3; for women who enrolled prior to pregnancy, during the first trimester, during the second trimester, or during the third trimester, respectively). In British Columbia, the adjusted odds ratio for inadequate care (comparing women receiving a health premium subsidy with those receiving no subsidy) was 1.5 for women receiving a 100% subsidy and 1.2 for women receiving a 95% subsidy. The risk for low birthweight followed a similar trend in both regions, but there was no association with enrollment period in Washington. CONCLUSIONS. Overall, the risk for inadequate prenatal care among poor women was much greater in Washington than in British Columbia. Most of the difference was due to Washington women's delayed enrollment in Medicaid. In both regions, the poor were at similar risk for low birthweight relative to their more affluent counterparts.     

The use of the Ilizarov technique in the correction of limb deformities associated with skeletal dysplasia.

The skeletal dysplasias are a unique and heterogeneous group of disorders with skeletal manifestations including deformity, disproportion, and short stature. The purpose of this article is to describe the use of the Ilizarov technique in the management of these orthopedic problems in 15 patients with skeletal dysplasias. The technique is particularly appropriate in those patients requiring correction of angular deformity and limb lengthening. The greatest number of complications were encountered in those patients undergoing extended limb lengthening. Nevertheless, all patients achieved their preoperative goals.     

A quantitative study of the pathological changes in cortical neurons in sporadic Creutzfeldt–Jakob disease

The frequency of morphological abnormalities in neuronal perikarya was studied in the cerebral cortex in cases of sporadic CJD (sCJD) and in elderly control patients. Three hypotheses were tested, namely that the proportion of neurons exhibiting abnormal morphology was increased: (i) in sCJD compared with control patients; (ii) in sCJD, in areas with significant prion protein (PrP) deposition compared with regions with little or no PrP deposition; and (iii) when neurons were spatially associated with a PrP deposit compared with neurons between PrP deposits. Changes in cell shape (swollen or atrophic cell bodies), nuclei (displaced, indistinct, shrunken or absent nuclei; absence of nucleolus), and cytoplasm (dense or pale cytoplasm, PrP positive cytoplasm, vacuolation) were commonly observed in all of the cortical areas studied in the sCJD cases. The proportion of neurons exhibiting each type of morphological change was significantly increased in sCJD compared with age‐matched control cases. In sCJD, neuronal abnormalities were present in areas with little PrP deposition, but at significantly lower frequencies compared with areas with significant densities of PrP deposits. Abnormalities of cell shape, nucleus and the presence of cytoplasmic vacuolation were increased when the neurons were associated with a PrP deposit, but fewer of these neurons were PrP‐positive compared with neurons between deposits. The data suggest significant neuronal degeneration in the cerebral cortex in sCJD in areas without significant PrP deposition and a further phase of neuronal degeneration associated with the appearance of PrP deposits.     

Incidence of histologic types of uterine sarcoma in relation to menstrual and reproductive history

To determine whether the occurrence of one or more histologic types of uterine sarcoma is related to events in a woman's reproductive life, a population-based case-control study was conducted. One-hundred sixty-seven women newly diagnosed with uterine sarcoma among residents of 6 geographic regions were compared to 208 women selected at random from the same populations with regard to histories of menstruation, pregnancy and childbearing, and breast feeding, as reported during a telephone interview. Compared to women whose menstrual periods began at age 13, women whose menses began earlier were at increased risk of leiomyosarcoma (OR = 2.0, 95% CI 0.9, 4.3); other histologic types were less strongly associated with early age at menarche. Women with leiomyosarcoma and endometrial stromal sarcoma, but not malignant mixed Müllerian tumors, tended to have ceased menstruating 2-3 years later than controls. None of the histologic types was clearly related to parity or to age at first live birth, but each was inversely related to age at last live birth. Associations were observed between leiomyosarcoma and histories of an induced abortion (OR = 4.2, 95% CI 1.2, 14.2) and of breast feeding after a live birth (OR = 0.5, 95% CI 0.3, 1.0); these relationships were not observed for other morphologic variants. These results suggest possible similarities and differences in menstrual and reproductive risk factors among histologic types of uterine sarcoma, and between these malignancies and the more common breast, endometrial and ovarian carcinomas.     

Elaboration of neutral proteoglycanase by growth-plate tissue cultures

This report describes the properties of a neutral protease that was synthesized and secreted into medium by intact cartilaginous growth plate in tissue culture. Bovine cartilaginous growth plate was grown for seven days in tissue culture, during which time the chondrocytes remained viable and metabolically active as determined by quantitation of trypan-blue exclusion and incorporation of 3H-cytidine. Protease activity, assayed by viscometry using proteoglycan monomer from cartilage as a substrate, was absent on day 1 but was present at high levels on days 2 through 5. The protease activity did not require activation and was highest at neutral and alkaline pH. Protease activity was abolished by twenty-millimolar EDTA but was unaffected by pepstatin, iodoacetate, and soybean trypsin inhibitor. In contrast to the high levels of activity of neutral protease that were present in tissue cultures of the intact growth plate, no protease activity could be detected when chondrocytes from the cartilaginous growth plate were grown in cell culture, even after sonication of the cells or activation with aminophenyl mercuric acetate or trypsin. Since hypertrophic chondrocytes probably do not survive the disruption of tissue that is involved in establishing cell cultures, these observations suggest that neutral protease is probably released into the medium by the hypertrophic chondrocytes that are present in the cultures of cartilaginous growth-plate tissue. It appears that the organization of the growth plate in tissue culture, as well as the maturation of proliferating chondrocytes into hypertrophic chondrocytes in tissue culture, may be required for synthesis of the neutral protease and its extracellular secretion by hypertrophic chondrocytes.