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Biomedical subjects

M Schachter

Publications and source records attributed to M Schachter.

At least 55 records · Page 3Linked to original sources
PubMed2000

p53, p21(WAF1/CIP1), and MDM2 involvement in proliferation and apoptosis in an in vitro model of conditionally immortalized human vascular smooth muscle cells.

Using an in vitro model of a conditionally immortalized cell line, we investigated how human vascular smooth muscle cells (VSMCs) are affected by the expression of simian virus 40 (SV40) large T antigen (LT antigen), which binds to cell cycle regulators, such as the tumor suppressor protein p53. Cells were obtained after infection of saphenous vein-derived VSMCs with a nonreplicative retroviral vector containing a temperature-sensitive (ts) mutant of SV40 LT antigen and were shown to have maintained some characteristics and responses of VSMCs. Under permissive temperature conditions (36 degrees C), the increased rate of cell proliferation was shown to be associated with expression of LT antigen and with LT-antigen binding to and inactivation of p53. p53 inactivation failed to block apoptosis induced by serum withdrawal or by UV irradiation. Downregulation of LT-antigen expression at the nonpermissive temperature (39 degrees C) was shown to be associated with growth arrest, increased expression of the cell cycle inhibitor p21(WAF1/CIP1), increased MDM2-promoter activity, and differential expression of MDM2 gene products, suggesting that p53-induced transcription/transactivation may be involved in VSMC cell cycle control but not necessarily apoptosis. The established SMC line HVTs-SM1 may be a useful model for the study of processes involved in myointimal hyperplasia and cellular aging, as well as for the study of cell cycle control in general.

Actins↗
PubMed2000

p53, p21(WAF1/CIP1), and MDM2 involvement in the proliferation and apoptosis in an in vitro model of conditionally immortalized human vascular smooth muscle cells.

Using an in vitro model of a conditionally immortalized cell line, we have investigated how human vascular smooth muscle cells (VSMCs) are affected by the expression of simian virus 40 (SV40) large T antigen (LT antigen), which binds to cell cycle regulators such as the tumor suppressor protein p53. Cells were obtained after infection of saphenous vein-derived VSMCs with a nonreplicative retroviral vector containing a temperature-sensitive mutant of SV40 LT antigen and were shown to have maintained some characteristics and responses of VSMCs. Under permissive-temperature conditions (36 degrees C), the increased rate of cell proliferation was shown to be associated with expression of LT antigen and with LT antigen binding to and inactivation of p53. p53 inactivation failed to block apoptosis induced by serum withdrawal or UV irradiation. Downregulation of LT antigen expression at a nonpermissive temperature (39 degrees C) was shown to be associated with growth arrest, increased expression of the cell cycle inhibitor p21(WAF1/CIP1), increased murine double minute-2 promoter activity, and differential expression of murine double minute-2 gene products, suggesting that p53-induced transcription/transactivation may be involved in VSMC cycle control but not necessarily in apoptosis. The established SMC line HVTs-SM1 may be a useful model for study of the processes involved in myointimal hyperplasia and cellular aging, as well as for the study of cell cycle control in general.

Antigens, Polyomavirus Transforming↗
PubMed2000

Erectile dysfunction and lipid disorders.

Epidemiological studies have shown that elevated serum cholesterol and reduced high density lipoprotein (HDL) cholesterol levels are associated with an increased risk of erectile dysfunction (ED). This is another example of the link between ED and atherosclerosis. Whether correcting a dyslipidaemic profile will result in a reduced risk of developing ED has not been established. Similarly, it is not known if such an intervention will improve symptoms in patients with established ED. The situation is further complicated by the likelihood that one of the rarer side-effects of fibrates and statins is ED. There is a need for appropriately designed trials to establish if intervening with statins or fibrates is beneficial on a short- or long-term basis for the treatment or prevention of ED.

Adult↗
PubMed1999

Characterization of [3H]-heparin binding in human vascular smooth muscle cells and its relationship to the inhibition of DNA synthesis.

1. The glycosaminoglycan heparin inhibits vascular smooth muscle cell (VSMC) proliferation and migration, but the mechanism of its antiproliferative action remains unclear. Heparin has been reported to bind to high affinity cell surface sites on animal VSMC before undergoing receptor mediated endocytosis resulting in signal transduction into the cytoplasm and modulation of genes involved in proliferation. In this study, we have characterized the binding of [3H]-heparin to human saphenous vein-derived VSMC and examined whether there is any relationship between the affinity of [3H]-heparin binding and the inhibitory effect of heparin and its structural analogues on DNA synthesis. 2. At 4 degrees C [3H]-heparin binding to human VSMC occurred in a specific, time and concentration-dependent manner and was not influenced by the removal of calcium ions. Binding of the ligand appeared to occur to the cell surface and was both saturable and reversible. Kinetic and steady state data indicated a single class of binding sites. 3. The pharmacology of [3H]-heparin binding was examined in displacement studies using unlabelled heparin and structural analogues. A comparison of the rank potencies of heparin, heparan sulphate fraction II, low molecular weight heparin and trehalose octasulphate showed that there was a marked discrepancy between their estimated affinities in the binding assays and their effect on DNA synthesis. 4. In summary, we have characterized the heparin binding site on human saphenous vein-derived VSMC. Our findings suggest that the action of heparin and its analogues on DNA synthesis does not simply reflect an interaction with the cell-associated heparin binding site defined in these studies, but may also be determined by the internalization and metabolism of the glycosaminoglycan(s).

Anticoagulants↗
PubMed1999

Low dose indapamide plus perindopril combination effects on cardiovascular structure and function in genetic hypertension.

1. Although the fixed combination preparations of thiazide and angiotensin-converting enzyme inhibitor are gaining wide acceptance in clinical practice, data on the basic pharmacology of the combinations are relatively limited. The long-term structural and functional effects of a fixed low dose (0.24 + 0.76 mg/kg per day) combination of indapamide + perindopril (I + P,S5590) is spontaneously hypertensive rats (SHR) were examined in the present study. 2. Male SHR (10-12 weeks) were treated with I + P or vehicle for 8 weeks. The blood pressure and heart rate were monitored by weekly measurements. At the end of the treatment period, left ventricular, aortic and intramyocardial coronary arteriole structures were assessed. Contractile and relaxant properties of mesenteric arteries were determined by wire-myography. 3. Indapamide + perindopril combination caused a significant lowering of both systolic (P < 0.001) and diastolic (P < 0.001) blood pressures. Left ventricle plus septum:bodyweight ratio (P < 0.001), aortic medial cross-sectional area (P < 0.05) and media:lumen ratios (P < 0.005) were all significantly reduced by I + P treatment. In contrast, the effect of I + P on intramyocardial coronary vascular structure did not reach statistical significance. There was some improvement in endothelium-independent vasorelaxation of mesenteric vessels but contractile responses to noradrenaline and calcium were unaffected by treatment. 4. In summary, a low dose I + P combination treatment of SHR partly normalizes both systolic and diastolic blood pressures. Cardiac and larger vessel hypertrophy was reversed but intramyocardial coronary arteriole structure was not as readily regressed by the end of the study.

Animals↗
PubMed1999

Isolated recurrent torsion of the Fallopian tube: case report.

We report a rare clinical case of recurrent isolated torsion of the Fallopian tube. An 18 year old woman presented with acute right lower quadrant pain, nausea and vomiting. Torsion of the Fallopian tube was detected by laparoscopy and detorsion was performed. Two years later, a second similar episode of pelvic pain recurred. Having in mind the first episode, diagnosis was facilitated and detorsion was performed in accordance with the patient's wishes. However, the dilemma of ideal management of recurrent cases of torsion of the same tube remains open for discussion. The possibility of torsion of the Fallopian tube and recurrent torsion of the tube, although rare, should be considered in any patient with acute onset of lower abdominal pain.

Adolescent↗
PubMed1999

Birth of a healthy neonate following the intracytoplasmic injection of testicular spermatozoa from a patient with Klinefelter's syndrome.

Klinefelter's syndrome is one of the known causes of azoospermia or cryptoazoospermia, and it may present in non-mosaic (47,XXY) or mosaic (47,XXY/46,XY) form. The likelihood of finding spermatozoa in the ejaculate or testicular tissue of patients with mosaic Klinefelter's syndrome is low, and with the non-mosaic form, even lower. We describe a patient with non-mosaic Klinefelter in whom initially non-motile spermatozoa were derived from searching the ejaculate. Ten mature oocytes were injected, but none was fertilized. Subsequently, testicular biopsy was undertaken in order to collect spermatozoa for oocyte injection. Fifteen motile sperm cells were found and injected. Nine oocytes were fertilized and cleaved; three embryos were transferred into the uterine cavity. The woman conceived and following a normal pregnancy delivered a healthy child. Genetic analysis of the neonate disclosed a normal 46,XY karyotype. Non-motile spermatozoa in the ejaculate did not prove their fertilization potential, but their presence did not exclude finding motile, fertile spermatozoa in the testicular tissue in a non-mosaic Klinefelter patient. This report is further evidence that normal spermatozoa with fertilization potential are produced in the testes of patients with Klinefelter's syndrome.

Adult↗
PubMed1999

Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration.

This study aimed to compare the efficacy of micronized progesterone administered as luteal support following ovulation induction for in-vitro fertilization (IVF)- embryo transfer in cycles using gonadotrophin-releasing hormone agonist, either orally (200 mgx4/day) or vaginally (100 mgx2/day) and to characterize the luteal phase hormonal profile during such treatments. A total of 64 high responder patients requiring intracytoplasmic sperm injection due to male factor infertility were prospectively randomized into two treatment groups. Patients treated orally or vaginally were comparable in age (31.9 +/- 6.1 versus 30.6 +/- 5.2; mean +/- SD), number of oocytes retrieved (17 +/- 8.2 versus 18 +/- 7.0), and number of embryos transferred (3.1 +/- 1.2 versus 2.7 +/- 0.9) per cycle. Following low dose vaginal treatment, a significantly higher implantation rate (30.7 versus 10.7%, P < 0.01), but similar clinical pregnancy rate (47.0 versus 33.3%) and ongoing pregnancy rate (41.1 versus 20.0%) was observed, compared with oral treatment. In conception cycles, luteal serum progesterone and oestrogen concentrations did not differ between the treatment groups. In non-conception cycles, late luteal progesterone concentrations were significantly lower following vaginal treatment. As low dose micronized progesterone administered vaginally is simple, easy and well tolerated, it could be recommended as the method of choice for luteal support, especially for high responder patients at risk for ovarian hyperstimulation syndrome.

Administration, Intravaginal↗
PubMed1999

Inhibition of carbonic anhydrase accounts for the direct vascular effects of hydrochlorothiazide.

Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (KCa) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because KCa channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pHi) were measured simultaneously with 2', 7'-bis(2-carboxyethyl)-5(6)'-carboxyfluorescein (BCECF-AM). Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16+/-8% relaxation) compared with hydrochlorothiazide (74+/-12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of KCa channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Hydrochlorothiazide and the inhibitors of carbonic anhydrase failed to relax tone induced by a depolarizing potassium solution. Acetazolamide and hydrochlorothiazide increased pHi by 0.27+/-0.07 and 0.21+/-0.04, respectively, whereas bendroflumethiazide had a much smaller effect: 0.06+/-0.03. The rise in pHi induced by any agent was not inhibited by charybdotoxin. The vasorelaxant effect of hydrochlorothiazide is shared by other inhibitors of carbonic anhydrase. Inhibitors of carbonic anhydrase, but not bendroflumethiazide, cause intracellular alkalinization, which is associated with KCa channel opening. These data suggest that the vasodilator effect of thiazide diuretics results primarily from inhibition of vascular smooth muscle cell carbonic anhydrase, which results in a rise in pHI, leading to KCa channel activation and vasorelaxation.

Animals↗
PubMed1999

Moxonidine: a review of safety and tolerability after seven years of clinical experience.

Centrally acting antihypertensive drugs, or sympatholytics, (reserpine, methyldopa and clonidine) have a long history of efficacy but are now little used in most countries. One of the most important reasons for this is relatively poor tolerability compared to many newer agents. In the case of clonidine there is also the potential danger of rebound hypertension. The most prominent adverse effects have been dry mouth, sedation, dizziness and oedema. These reactions, especially the first two, are thought to be associated with activation of central nervous system and salivary gland alpha2-adrenergic receptors. In the last 15 years it has become possible to produce drugs with selective agonist effect on another class of brainstem receptors, the imidazoline I1-receptors, which appear to have modulate sympathetic activity and blood pressure without affecting alertness or salivary flow: however, they still have some action on alpha2-receptors. Moxonidine and rilmenidine are moderately selective imidazoline agonists which have been in clinical use for several years in many European countries. Trial evidence and postmarketing surveillance indicate that moxonidine may cause dry mouth or sedation in a minority (<10%) of patients, significantly less than with the older drugs. There is no significant incidence of oedema and unexpected or idiosyncratic adverse effects are extremely rare. Moxonidine may improve aspects of glucose and lipid metabolism. In conclusion, moxonidine is a safe as well as an effective antihypertensive, with considerably improved patient tolerability compared to the older sympatholytics.

Antihypertensive Agents↗
PubMed1998

Vein graft stenosis and the heparin responsiveness of human vascular smooth muscle cells.

BACKGROUND: Vascular smooth muscle cell (VMSC) proliferation is an essential component of myointimal hyperplasia, which is implicated in the failure of 30% to 50% of vascular interventions, such as coronary angioplasty and peripheral vein grafting. We have shown that cells derived from stenotic lesions in infrainguinal vein grafts were significantly more resistant than controls to growth inhibition by heparin. METHODS AND RESULTS: In a prospective study, we correlated antiproliferative responses to heparin in vitro with graft patency after 1 year. Sixty-two patients with infrainguinal vein grafts were entered into a graft surveillance program for > or = 1 year. At operation, saphenous vein segments were explanted for VSMC culture. Cell proliferation in response to fetal calf serum was later determined in the presence and absence of heparin. In 35 cell cultures, including 13 from the above-mentioned patients, [3H]heparin binding was also estimated. VSMCs from patients with patent grafts were significantly more sensitive to growth inhibition by heparin than cells from patients with stenoses (median, 54% versus 20.9%, P<0.001), and [3H]heparin binding was strongly correlated with inhibition of proliferation (r=0.81). CONCLUSIONS: Responsiveness to heparin in cultured VSMCs is a strong predictor of outcome for infrainguinal vein grafts, and reduced sensitivity to heparin is correlated with decreased heparin binding. Relative resistance to the antiproliferative action of heparin may be a marker for aberrant regulation of VSMC growth.

Adult↗
PubMed1998

Visceral ischemia and neutrophil activation in sepsis and organ dysfunction.

BACKGROUND: It has previously been shown that a rise in intraoperative neutrophil CD11b expression during supracoeliac cross-clamping is a marker for subsequent development of postoperative organ dysfunction. Prolonged visceral ischemia and increased aneurysm extent are associated with higher risks of morbidity and mortality after TAAA repair. This study investigates the relationship between visceral ischemia and neutrophil activation in sepsis and organ dysfunction following visceral reperfusion. METHOD: Fifty-one patients undergoing supracoeliac cross-clamping, 5 patients undergoing suprarenal clamping, and 8 patients undergoing infrarenal clamping for repair of aortic aneurysms were studied. Perioperative neutrophil CD11b expression was measured by flow cytometry. RESULTS: There was significant correlation between visceral clamp time and intraoperative CD11b expression. More extensive aneurysms resulted in increased visceral clamp times and CD11b expression. There were no differences between bypass and non-bypass-assisted surgery with regard to neutrophil expression. There were increased clamp time in patients who developed severe sepsis and postoperative organ dysfunction. Differences in preoperative levels of CD11b expression were observed between groups and high levels of preoperative CD11b expression were observed in patients who died intraoperatively, in type II patients who went on to develop severe sepsis and organ failure, and in patients who developed multiple organ failure rather than single organ failure. CONCLUSION: Longer periods of visceral ischemia are associated with higher levels of intraoperative CD11b expression, severe sepsis, and organ failure. High preoperative levels of CD11b may identify an "at-risk" subset of patients.

Adolescent↗
PubMed1998

Transvaginal drainage of ascites as an alternative to abdominal paracentesis in patients with severe ovarian hyperstimulation syndrome, obesity, and generalized edema.

OBJECTIVE: To describe an alternative technique for transvaginal drainage of ascites in a case of severe ovarian hyperstimulation syndrome (OHSS), generalized edema, and obesity. DESIGN: Case report. SETTING: A university-based hospital IVF and Reproductive Medicine Unit. PATIENT(S): A patient hospitalized with severe OHSS after IVF-ET in whom drainage of large amounts of ascitic fluid was necessary. INTERVENTION(S): Ultrasonographic transvaginal insertion of a wire guide through a standard IVF needle into the Douglas pouch. Placement of a "peel-away" set on the wire, which was replaced with a "pigtail" indwelling catheter. MAIN OUTCOME MEASURE(S): Amount of drained ascitic fluid. RESULT(S): Ascitic fluid was drained efficiently, leading to improvement of the patient's condition. CONCLUSION(S): Transvaginal ultrasonography-guided insertion of a pigtail catheter through the Douglas pouch is an efficacious procedure when the abdominal approach for decompression of ascites is difficult.

Adult↗
PubMed1998

Safety and tolerability of moxonidine in the treatment of hypertension.

Classical centrally acting antihypertensive agents lower blood pressure by reducing excessive sympathetic tone; however, their clinical use is limited by an adverse effect profile resulting from alpha2-adrenoceptor agonism. Moxonidine is a new centrally acting agent showing selective agonism of imidazoline I1 receptors, but very little alpha2-adrenoceptor agonism. The safety and tolerability of moxonidine was reviewed over an 8-year period (1989 to 1997), including 74 clinical trials and an estimated 370000 patient-years of exposure. Dry mouth and somnolence were the most frequently reported adverse events, followed by headache and dizziness. In phase II to IV controlled studies in patients with hypertension (n = 1460), the incidence of dry mouth was 8 to 9%, somnolence 5 to 8% and headache 6%, as recorded by spontaneous reporting; the percentage of patients discontinuing treatment because of adverse events did not exceed 4%. Subgroup analyses revealed no differences in adverse events related to age or gender. Moxonidine did not exacerbate concomitant conditions such as diabetes mellitus or chronic obstructive pulmonary disease, or interact pharmacokinetically with concurrent medications such as hydrochlorothiazide, digoxin and glibenclamide (glyburide). Coadministration of moxonidine with lorazepam resulted in small additional impairments in tasks requiring attention. A similar distribution of adverse events was observed in uncontrolled studies (n = 1058). The incidence and severity of dry mouth and somnolence were found to decrease with increasing exposure to moxonidine over a period of up to 2 years. Serious adverse events were rare in all trials and could not be attributed to administration of moxonidine. Post-marketing surveillance of the adverse effect profile of moxonidine detected 2 additional adverse effects: nausea and allergic skin reactions. The safety profile of moxonidine, combined with proven antihypertensive efficacy, suggests that it may have an important role to play in the management of mild-to-moderate hypertension.

Antihypertensive Agents↗
PubMed1997

The pathogenesis of atherosclerosis.

The hypothesis that atherosclerosis is a 'response to injury' is now generally accepted. This paper briefly reviews factors that can damage the vascular endothelium plus the formation of fatty streak lesions, thrombogenic surfaces, fibrous plaques and complex advanced lesions of atherosclerosis.

Arteriosclerosis↗