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Biomedical subjects

M Schachter

Publications and source records attributed to M Schachter.

At least 73 records · Page 4Linked to original sources
PubMed1997

Calcium antagonists and atherosclerosis.

Calcium channel blockers (CCBs) have several properties which may have beneficial effects on the development of atherosclerosis. These include inhibition of vascular smooth muscle cell (SMC) proliferation and migration; inhibition of calcium influx into the vascular wall; reduction of extracellular matrix synthesis; promotion of uptake and breakdown of low-density lipoproteins; protection of lipoproteins from oxidative modification; maintenance of endothelial cell function; inhibition of platelet activation; and reduction of blood pressure. Although some of these effects are only seen at high drug concentrations, the great majority of reports indicate that CCBs can attenuate atherogenesis in animal models, notably the cholesterol-fed rabbit. Several clinical trials have now attempted to determine the efficacy of these drugs in human atheromatous disease. The outcome of these studies, including the International Nifedipine Trial of Antiatherosclerotic Therapy (INTACT), the Montreal Nicardipine Trial, and the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS), are summarized in this review, in the context of trials currently in progress. The emerging evidence suggests that an antiatherosclerotic action can be demonstrated in patients but the extent and clinical importance of this effect have yet to be fully established.

Animals↗
PubMed1997

Vascular smooth muscle cell migration, atherosclerosis, and calcium channel blockers.

Calcium channel blockers have been studied widely for their potential ability to retard or even reverse atherosclerosis. Several potential cellular mechanisms have been proposed, including interactions with vascular smooth muscle cells: migration, inhibition of proliferation, or both. This paper reviews some of the signaling events involved in smooth muscle cell migration, including changes in intracellular calcium, and the inhibition of cell migration by calcium channel blockers. Finally, there is a discussion of preliminary experiments on human vascular smooth muscle cell migration using amlodipine.

Amlodipine↗
PubMed1997

Differential effects of lovastatin on mitogen induced calcium influx in human cultured vascular smooth muscle cells.

1. In this study the effect of lovastatin, an inhibitor of cholesterol and isoprenoid synthesis, on the rises in intracellular calcium concentration ([Ca2+]i) induced by platelet derived growth factor BB (PDGF-BB), angiotensin II (AII), low density lipoproteins (LDL) and foetal calf serum (FCS) was examined in human cultured vascular smooth muscle cells (VSMC) from saphenous vein. Changes in [Ca2+]i were measured in cell suspensions by the Ca2+ sensitive probe, fura 2. 2. Incubation with lovastatin for 24-26 h markedly reduced the peak rise and sustained phase of [Ca2+]i elevation in response to PDGF-BB but the responses to AII, LDL and FCS were unaffected. Further experiments showed that lovastatin pretreatment inhibited PDGF-BB induced Ca2+ influx but not intracellular Ca2+ release. This inhibition could be overcome by co-incubation with mevalonic acid. 3. Pretreatment of cells with the heterotrimeric G protein inhibitor pertussis toxin for up to 24 h completely abolished AII-induced [Ca2+]i rises but the response to PDGF-BB was unaffected. 4. The tyrosine kinase inhibitor genistein largely abolished PDGF-BB-induced [Ca2+]i elevation but had no significant effect on AII-induced responses. 5. Pre-incubation with lovastatin had no effect on the level of tyrosine phosphorylation of PDGF-beta receptors (as measured by Western blot) in response to the PDGF-BB ligand. 6. PDGF-BB elicits Ca2+ influx via a tyrosine kinase-dependent mechanism distinct from the heterotrimeric G protein coupled pathway utilized by AII. Lovastatin most likely acts by inhibition of isoprenylation (via blockade of isoprenoid synthesis) of an intermediate molecule involved in PDGF-BB-induced Ca2+ influx.

Calcium↗
PubMed1997

Inhibition of proliferation by heparin and expression of p53 in cultured human vascular smooth muscle cells.

Human vascular smooth muscle cells (HVSMC) cultured from restenotic lesions are resistant to inhibition of proliferation by heparin. We examined if altered expression of p53 protein might be related to this phenomenon. HVSMC were cultured from saphenous vein and p53 protein levels examined using immunocytochemistry, and by immunoprecipitation with antibodies specific for wild-type or mutant conformations followed by SDS PAGE and immunoblotting. Inhibition of proliferation by heparin was measured in 14-day growth assays. Elevated levels of p53 were found in five out of 41 HVSMC strains. The accumulated p53 protein was not precipitated by a mutant conformation-specific anti-p53 antibody in any of the five strains. In one of the five positive strains there was concomitant human cytomegaloviral infection. No significant difference was found between efficacy of heparin in the p53-positive and -negative strains. Furthermore heparin had no detectable effect on p53 protein levels. Although aberrant levels of p53 are detectable in a minority of HVSMC strains, these data do not support a role for altered p53 expression in resistance to the growth inhibitory effects of heparin in these cells.

Cell Division↗
PubMed1997

Endotoxin related early neutrophil activation is associated with outcome after thoracoabdominal aortic aneurysm repair.

BACKGROUND: Thoracoabdominal aortic aneurysm (TAAA) repair is associated with high mortality rates, especially in patients who develop postoperative renal and pulmonary impairment. Organ damage during TAAA repair may be mediated by activated polymorphonuclear neutrophils (PMNs) during a systemic inflammatory response. The association between intraoperative neutrophil activation and postoperative outcome was studied after TAAA surgery. METHODS: Perioperative PMN activation (surface CD11b expression by flow cytometry), plasma endotoxin, plasma endotoxin core antibody, tumour necrosis factor (TNF), and interleukin 1 (IL-1) levels were measured in 21 patients undergoing TAAA repair. RESULTS: Intraoperative PMN CD11b expression was significantly greater in the 11 patients who developed pulmonary and renal complications than in those who made an uneventful recovery (P = 0.0009). In addition, CD11b expression during visceral reperfusion was preceded by a rise in plasma endotoxin level and a fall in antibody level (reflecting binding by absorbed endotoxin) which was significantly greater in patients who developed complications (P = 0.031 and P = 0.001 respectively). Plasma endotoxin level correlated with CD11b expression (r = 0.828, P = 0.001). There were no significant differences in intraoperative plasma levels of TNF and IL-1, or aortic cross-clamp times and blood transfusion volumes between the complicated and uncomplicated repairs. CONCLUSION: Intraoperative neutrophil activation is a marker for the development of postoperative complications after TAAA reconstruction and is associated with endotoxin absorption.

Acute-Phase Reaction↗
PubMed1996

Estrogen biosynthesis--regulation, action, remote effects, and value of monitoring in ovarian stimulation cycles.

OBJECTIVE: To review current knowledge regarding estrogen biosynthesis, its regulation and action, specifically concerning local as opposed to remote effects of this hormone, and to examine the effectiveness and prognostic value of monitoring hormone concentrations and endometrial response in cycles of controlled ovarian hyperstimulation. DATA IDENTIFICATION AND SELECTION: Studied that relate specifically to estrogen biosynthesis, enzymatic pathways, estrogen receptor physiology, and the clinical aspects of estrogen monitoring were identified through literature and Medline searches. RESULTS: Folliculogenesis is the basic unit of ovarian activity, which has a dual purpose: oocyte maturation and steroid production. Steroidogenic granulosa and theca cells cooperate under gonadotropin control to produced estrogens by stimulating synthesis of steroidogenic enzyme messenger RNAs. Steroid synthesis is amplified further by local growth factors and follicular cell multiplication. Estrogen synthesis is directed by FSH, and only small amounts of LH are needed to amplify the follicular estrogenic potential. However, the growth of preovulatory follicles can proceed without LH, under FSH regulation only, even in the presence of low peripheral estrogen levels. Oocyte maturation and fertilization may proceed independently of ambient estrogen levels, leading to the assumption that estrogen exerts a minimal autocrine-paracrine function. The notable effect of follicular estrogen production is to promote adequate receptive endometrium for embryo implantation. Clinical treatment cycles may be monitored more effectively by evaluating end-organ response to estrogen rather than by evaluating absolute serum E2 concentrations or sonographic follicular measurements. CONCLUSION: Follicular estrogen production is regulated by a complex set of signals that synergize to produce optimal steroidogenesis. Most importantly, the effect of estrogen is truly an endocrine effect, as it prepares the endometrium for implantation. Therefore, the goal of effective treatment and monitoring strategies should focus on direct assessment of the biologic activity of estrogen as it optimizes endometrial receptivity in anticipation of subsequent implantation.

Animals↗
PubMed1996

Radioligand-binding analysis of human prostatic alpha-1 adrenoreceptor density following transurethral microwave therapy.

OBJECTIVE: To determine the effects of single-session transurethral microwave treatment (TUMT) on human prostatic alpha-1 adrenoreceptor density in patients with symptomatic bladder outlet obstruction caused by benign prostatic hyperplasia. PATIENTS AND METHODS: Radioligand-binding assays using 3H-prazosin were performed on prostatic tissue obtained from 25 patients, 10 of whom had received a single TUMT whilst the remaining 15 patients had not, and acted as controls. Prostatic tissue was obtained by cold-punch biopsy immediately before transurethral resection of the prostate from 20 patients (10 following microwave treatment and 10 controls) and from a further five patients at the time of retropubic prostatectomy; these five patients again had undergone TUMT. There were no statistically significant differences in several variables between the groups except for the weight of resected tissue, which was greater for the patients undergoing retropubic prostatectomy. Differences in the maximum receptor density (Bmax) and dissociation constant (Kd) were analysed statistically using the Mann-Whitney U-test because the data were non-parametric. RESULTS: Binding was saturable and a single class of high-affinity binding sites was identified in all cases. In the control group, the mean and 95% confidence interval (CI) alpha-1 adrenoreceptor density (Bmax) was 96.4 (82.7-110.1) fmol/mg and the mean (95% CI) dissociation constant (Kd) was 0.56 (0.37-0.74) nmol/l. In those patients who had undergone TUMT, the mean Bmax was significantly lower at 71.3 (58.6-84.7) fmol/mg (P < 0.02) but the Kd of 0.56 (0.20-1.14) mmol/L was identical to that in the control group. CONCLUSIONS: Single-session TUMT, using a non-irrigated catheter, causes a significant reduction in prostatic alpha-1 adrenoreceptor density in the region of the prostate subjected to maximum beating. This may represent one possible mechanism of action by which microwave treatment exerts its beneficial effects.

Aged↗
PubMed1996

Effect of angiotension II on the expression of the early growth response gene c-fos and DNA synthesis in human vascular smooth muscle cells.

OBJECTIVES: The aims of this study were to characterize the angiotensin II receptor subtype present on vascular smooth muscle cells from human saphenous vein and to assess the effect of angiotensin II on the expression of the early growth response gene c-fos and on DNA synthesis. METHODS AND RESULTS: Using radioligand binding studies, we have defined the angiotensin II receptors present on these cells as being predominantly of the AT1 subtype. Angiotensin II increased peak intracellular calcium levels by 126 +/- 16 nmol/l (mean +/- SEM) in 17/49 cultures. Angiotensin II induced c-fos expression in a concentration-dependent manner only in cultures that exhibited an intracellular calcium transient in response to stimulation with angiotensin II. The induction of c-fos was inhibited by the selective AT1 antagonist losartan in accordance with the binding studies. Angiotensin II stimulated DNA synthesis with a maximal increase of 66.4% +/- 20.5% over serum-free levels at 1 nmol/l (mean +/- SEM, n = 6, P < 0.05). DNA synthesis declined with increasing angiotensin II concentration, falling to control values at 1 mumol/l, suggesting that a growth-inhibitory influence may counter-balance the stimulatory effect that is observed at lower concentrations. CONCLUSION: Vascular smooth muscle cells from human saphenous vein possess predominantly AT1 receptors and in response to angiotensin II show an induction of c-fos and a modest increase in DNA synthesis.

Angiotensin II↗
PubMed1996

Enhanced tissue polyamine content in the spontaneously hypertensive rat.

1. Endogenous polyamines play a key role in mediating cellular growth and differentiation. Hypertension is associated with structural modifications of the circulatory system, a process that may be facilitated by polyamines. In this study, we examined whether there are elevated polyamine concentrations in the cardiovascular tissues of spontaneously hypertensive rats (SHR) relative to Wistar-Kyoto (WKY) rats. We also determined the chronic effect of 2% difluoromethylornithine (DFMO; a polyamine biosynthesis inhibitor) on tissue polyamines and hypertension. 2. SHR and WKY rats were treated with either 2% DFMO or drug-free drinking water; blood pressure was measured on alternate days and tissue polyamines were analysed at the end of the study. 3. We found that spermidine and spermine concentrations were markedly raised in the ventricles, resistance vessels and liver of the SHR, in comparison with corresponding tissues of WKY rats. DFMO did not affect SHR resistance vessel and liver polyamines, although spermidine in the ventricles was reduced. The blood pressure of neither SHR nor WKY rats was affected by DFMO. 4. In conclusion, this study shows for the first time a raised concentration of polyamines in the resistance vasculature of the SHR, in relation to their normotensive counterparts. The inability of DFMO to significantly reduce tissue polyamines in this study is in contrast to the effectiveness of 2% DFMO in other hypertension models, suggesting that polyamine homeostasis in this model may be stringently regulated.

Animals↗
PubMed1996

Hypogonadotropic patients with ultrasonographically detected polycystic ovaries: endocrine response to pulsatile gonadotropin-releasing hormone.

To characterize the endocrine response during induction of ovulation in patients with hypogonadotropic hypogonadism and ultrasound findings of polycystic ovary, we performed a retrospective analysis of 22 treatment cycles with pulsatile gonadotropin-releasing hormone (GnRH) in such patients and of 17 treatment cycles in similar patients with ultrasonographically normal ovaries. Of the 21 patients studies, 11 had an ultrasound finding of polycystic ovaries and ten had ovaries that appeared normal. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol levels, number of follicles of diameter > 12 mm (by ultrasound), and ovulation and conception rates were measured. Patients with hypogonadotropic hypogonadism and ultrasound-diagnosed polycystic ovary had pretreatment endocrine status similar to those with normal ovaries, but had much higher baseline ovarian volume. Ovulation induction with pulsatile GnRH induced much higher serum LH concentrations in the former group despite similar FSH levels. This difference preceded any change in estradiol levels. The former group consistently recruited significantly more follicles during pulsatile GnRH treatment. However, ovulation and conception rates were (non-significantly) higher in the latter group. In conclusion, this study characterized a subgroup of hypogonadotropic patients with ovarian morphology, volume and response to ovulation induction similar to in patients with polycystic ovary syndrome. When treated with pulsatile GnRH, those with polycystic ovary significantly hypersecreted LH before their estradiol level changed significantly. The primary lesion in polycystic ovary syndrome seems to be in the ovary, with pituitary hypersecretion of LH secondary to disturbed ovarian feedback signalling.

Estradiol↗
PubMed1996

Depletion of resistance vessel polyamines attenuates angiotensin II induced blood pressure rise in rats.

Vascular structural changes in hypertension are proposed to contribute to raised peripheral resistance. Endogenous polyamines (putrescine, spermidine and spermine) have an essential role in cellular growth and may be required in vascular restructuring. We have previously shown raised polyamines in resistance vessels in response to angiotensin II (angII) infusion in the rat and here we examined whether polyamine depletion influences the hypertensive process. Wistar-Kyoto rats were infused with either angII or saline by osmotic minipump, and maintained on either 2% difluoromethylornithine (DFMO; polyamine synthesis inhibitor) or water for 12 days. AngII significantly increased tail-cuff blood pressure (bp), resistance vessel spermidine and spermine concentration, and media:lumen ratios. DFMO attenuated both the rise in bp (p < 0.05) and vascular spermidine (p < 0.05) in the angII infused rats but vascular structure was apparently unaffected on day 12. In conclusion, raised concentration of resistance vessel spermidine may be a necessary component of the ang II pressor effect.

Angiotensin II↗
PubMed1996

Recurrent mucinous adenocarcinoma of the ovary presenting as an inguino-labial hernia.

We report a case of a 65-year-old woman who nine years previously had undergone total abdominal hysterectomy and bilateral salpingoophorectomy for a large ovarian cyst. During surgery the cyst had ruptured and some mucinous material had been spilled intraabdominally. Histopathological studies demonstrated the cyst to be a mucinous adenocarcinoma of low malignant potential. Appendectomy had also been performed due to an enlarged appendix, which proved to be a mucocoele. The patient had been lost to subsequent follow-up. Her current presenting symptom was a giant inguino-labial hernia of 25 cm diameter with two small skin perforations leaking a gelatinous discharge. Subsequent laparotomy and inguinal exploration have disclosed herniated small intestine with an attached metastatic multicystic mucinous adenocarcinoma. This case represents a case of borderline mucinous adeno-carcinoma-pseudomyxoma peritonei recurring in a unique pattern as a huge inguino-labial hernia, and serves to emphasize the possible consequences of spillage of ovarian cyst contents during surgery.

Adenocarcinoma, Mucinous↗
PubMed1995

The impact of external cephalic version on the rate of vaginal and cesarean breech deliveries: a 3-year cumulative experience.

The authors have reviewed the impact of their practice of external cephalic version (ECV) at term, with respect to success rate, factors associated with successful version and the effect of this protocol on the overall breech and cesarean breech rate. Two hundred and forty-nine parturients identified as having a breech presenting fetus after the 36th gestational week over a 3-year period, after excluding contraindicated cases, were offered a trial of ECV, with the use of ritodrine tocolysis. ECV was effected by one operator, using the minimally effective force necessary. Successful ECV was achieved in 196 attempts (78.7%). No deleterious effects in fetuses or mothers were noted. Of successfully turned fetuses, 78% eventually had a vaginal vertex delivery. Parity, birthweight and amount of amniotic fluid were found to have a significant effect on the success rate of ECV, whereas gestational age at version or placental location were not found to have a significant effect on success rate. Introduction of the ECV protocol effected a significant decrease in breech presentation at term, from 3.9 to 2.4% (P < 0.01), which can be translated into a decrease of 5.5% in the overall cesarean section rate. The authors conclude that ECV is a safe and effective procedure, in properly selected cases. Institution of a screening protocol to identify breech presentation after 36 weeks, and utilizing ECV where possible, may lead to a significant reduction in the breech delivery rate, and may prevent serious infant morbidity.

Amniotic Fluid↗