Calcium Channels in Vascular Smooth Muscle.

Calcium (Ca2+) plays a central role in excitation, contraction, transcription, and proliferation of vascular smooth muscle cells (VSMs). Precise regulation of intracellular Ca2+ concentration ([Ca2+]i) is crucial for proper physiological VSM function. Studies over the last several decades have revealed that VSMs express a variety of Ca2+-permeable channels that orchestrate a dynamic, yet finely tuned regulation of [Ca2+]i. In this review, we discuss the major Ca2+-permeable channels expressed in VSM and their contribution to vascular physiology and pathology.

Mobilization without immune depletion fails to restore immunological tolerance or preserve beta cell function in recent onset type 1 diabetes.

Granulocyte colony-stimulating factor (G-CSF) has been used to restore immune competence following chemoablative cancer therapy and to promote immunological tolerance in certain settings of autoimmunity. Therefore, we tested the potential of G-CSF to impact type 1 diabetes (T1D) progression in patients with recent-onset disease [n = 14; n = 7 (placebo)] and assessed safety, efficacy and mechanistic effects on the immune system. We hypothesized that pegylated G-CSF (6 mg administered subcutaneously every 2 weeks for 12 weeks) would promote regulatory T cell (Treg) mobilization to a degree capable of restoring immunological tolerance, thus preventing further decline in C-peptide production. Although treatment was well tolerated, G-CSF monotherapy did not affect C-peptide production, glycated haemoglobin (HbA1c) or insulin dose. Mechanistically, G-CSF treatment increased circulating neutrophils during the 12-week course of therapy (P < 0·01) but did not alter Treg frequencies. No effects were observed for CD4(+) : CD8(+) T cell ratio or the ratio of naive : memory (CD45RA(+)/CD45RO(+)) CD4(+) T cells. As expected, manageable bone pain was common in subjects receiving G-CSF, but notably, no severe adverse events such as splenomegaly occurred. This study supports the continued exploration of G-CSF and other mobilizing agents in subjects with T1D, but only when combined with immunodepleting agents where synergistic mechanisms of action have previously demonstrated efficacy towards the preservation of C-peptide.

Synthetic porcine secretin is highly accurate in pancreatic function testing in individuals with chronic pancreatitis.

The secretin stimulation test is the most sensitive and specific test for pancreatic function. It is usually performed using biologically derived porcine secretin. Several shortages of biologic porcine secretin have occurred in the past few years. The aim of this study was to compare synthetic porcine secretin to biologic porcine secretin in pancreatic function testing in subjects with chronic pancreatitis. Twelve patients with a previously abnormal secretin stimulation test were enrolled. After an overnight fast, each patient underwent a secretin stimulation test on 2 consecutive days using 1 CU/kg biologic porcine secretin or 0.2 [microg/kg synthetic porcine secretin in a randomized fashion. The peak bicarbonate concentration in duodenal juice was used as a measure of pancreatic function. The peak bicarbonate concentration (mean +/- SD) obtained by using biologic porcine secretin and synthetic porcine secretin were 70 +/- 25 mEq/L and 68 +/- 31 mEq/L, respectively (p = 0.58, paired t test; R = 0.964). The accuracy of synthetic porcine secretin in diagnosing pancreatic insufficiency was 100% when compared with biologic porcine secretin. We conclude that synthetic porcine secretin is highly accurate and safe in pancreatic function testing. The 100% purity, excellent diagnostic accuracy, and ready availability make synthetic porcine secretin an attractive choice for secretin stimulation testing.

ADAPT: Association for Drug Abuse and Prevention and Treatment.

AIDS: The Association for Drug Abuse Prevention and Treatment (ADAPT) is a harm reduction, needle exchange, and street outreach program in New York. The program director, Mike Cintron, describes how the program works and its goals. The program is anonymous, and there are no statistics kept on the percentage of participants who are HIV-positive. The program moves to a variety of sites throughout the city and works closely with other agencies to insure the best possible care for their clients.^ieng

Long-term effects of ovariectomy and aging on the rat skeleton.

The long-term skeletal effects of ovariectomy and aging were studied in female Sprague-Dawley rats sacrificed at 270, 370, and 540 days after bilateral ovariectomy (OVX) or sham surgery at 90 days of age. The proximal tibia was processed undecalcified for quantitative bone histomorphometry. For continuity, data from these late time points were combined with previously published data from earlier time points (0-180 days). A biphasic pattern of cancellous bone loss was detected in the proximal tibial metaphysis of OVX rats. An initial, rapid phase of bone loss out to 100 days was followed by an intermediate period of relative stabilization of cancellous bone volume at the markedly osteopenic level of 5-7%. After 270 days, a slow phase of bone loss occurred during which cancellous bone volume declined to 1-2%. Both the initial, rapid phase and the late, slow phase of bone loss in OVX rats were associated with increased bone turnover. In control rats, cancellous bone volume remained constant at 25-30% out to 270 days (12 months of age), then decreased to approximately 10% by 540 days (21 months of age). This age-related bone loss was also associated with increased bone turnover. It is interesting to note that the proximal tibial growth plates were closed in approximately a quarter of the control rats by 15-21 months of age. Our data indicate that a slow rate of bone loss and increased bone turnover persist in OVX rats during the later stages of estrogen deficiency. Therefore, the development of osteopenia is coincident with increased bone turnover in OVX rats as well as in aged, control rats.

Temporal relationship between bone loss and increased bone turnover in ovariectomized rats.

To characterize osteopenic changes in ovariectomized (OVX) rats as a function of time, female Sprague Dawley rats (240 g body weight, 90 days old) were subjected to bilateral ovariectomy or sham surgery and killed at various times from 14-180 days postovariectomy. The proximal tibial metaphysis was processed undecalcified for quantitative bone histomorphometry. Osteopenia and increased indices of bone resorption and formation were detected in OVX rats as early as 14 days. Longitudinal bone growth was also significantly increased by ovariectomy at 14 days, but returned to control levels at all later times. In OVX rats, osteopenia became progressively more pronounced with time up to 100 days postovariectomy, after which trabecular bone volume appeared to stabilize at the markedly reduced level of 5%. Changes in osteoclast surface, osteoblast surface, and fluoro-chrome-based indices of bone formation in OVX rats followed a similar time course. The maximal increase in these parameters occurred during the first several months postovariectomy followed by a gradual decline toward control levels. Our results indicate that the initial rapid phase of bone loss in OVX rats is coincident with the maximal increase in bone turnover. At later times postovariectomy, bone loss and bone turnover both subside. These findings emphasize the close temporal association between the development of osteopenia and increased bone turnover in OVX rats.

Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats.

Female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX) or sham surgery (control). Groups of ovariectomized (OVX) and control rats were injected daily with low, medium, or high doses of 17 beta-estradiol (10, 25, or 50 micrograms/kg BW, respectively). An additional group of OVX and control rats was injected daily with vehicle alone. All rats were killed 35 days after OVX, and their proximal tibiae were processed undecalcified for quantitative bone histomorphometry. Trabecular bone volume was markedly reduced in vehicle-treated OVX rats relative to that in control rats (12.1% vs. 26.7%). This bone loss was associated with a 2-fold increase in osteoclast surface and a 4-fold increase in osteoblast surface. The bone formation rate, studied with fluorochrome labeling, was also significantly elevated in vehicle-treated OVX rats (0.111 vs. 0.026 micron3/micron2.day). In contrast, treatment of OVX rats with the three doses of estradiol resulted in normalization of tibial trabecular bone volume and a decline in histomorphometric indices of bone resorption and formation. Our results indicate that estrogen treatment provides complete protection against osteopenia in OVX rats. The protective mechanism involves estrogenic suppression of bone turnover. These findings are consistent with the skeletal effects of estrogen therapy in postmenopausal women.

Effect of body weight on osteopenia in ovariectomized rats.

Bilateral ovariectomies or sham surgeries were performed in female Sprague Dawley rats that were 78 days of age and weighed an average of 210 g. Food was available ad libitum to the control rats and to a group of ovariectomized rats (obese OVX). The food consumption of a second group of ovariectomized rats (weight-matched OVX) was restricted to match their body weights to those of the control rats. All rats were sacrificed at 14 weeks postovariectomy. Radioimmunoassay of terminal serum estradiol confirmed the success of ovariectomy. The estradiol concentration in control rats was 24.9 +/- 20.2 pg/ml, whereas the hormone was undetectable (less than 10 pg/ml) in both groups of OVX rats. The final body weights of control and weight-matched OVX rats were nearly identical (approximately 260 g). In contrast, obese OVX rats weighed significantly more than both of the above groups (approximately 320 g, P less than 0.001). The proximal tibia and lumbar vertebra were processed undecalcified for quantitative bone histomorphometry. Tibial trabecular bone volume (TBV) was determined to be 17.6 +/- 4.5%, 7.9 +/- 5.3%, and 3.6 +/- 3.1% for the control, obese OVX, and weight-matched OVX groups, respectively. Tibial TBV for both OVX groups was significantly less than the control value (P less than 0.001). The difference in tibial TBV between obese OVX and weight-matched OVX rats was also statistically significant (P less than 0.02). Histologic indices of bone resorption and formation were indicative of increased bone turnover in the proximal tibia of both OVX groups.(ABSTRACT TRUNCATED AT 250 WORDS)