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Biomedical subjects

A Levy

Publications and source records attributed to A Levy.

At least 55 records · Page 3Linked to original sources
PubMed2001

Angiotensin II-induced transcriptional activation of the cyclin D1 gene is mediated by Egr-1 in CHO-AT(1A) cells.

Cyclin D1 protein expression is regulated by mitogenic stimuli and is a critical component in the regulation of G(1) to S phase progression of the cell cycle. Angiotensin II (Ang II) binds to specific G protein-coupled receptors and is mitogenic in Chinese hamster ovary cells stably expressing the rat vascular Ang II type 1A receptor (CHO-AT(1A)). We recently reported that in these cells, Ang II induced cyclin D1 promoter activation and protein expression in a phosphatidylinositol 3-kinase (PI3K)-, SHP-2-, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)-dependent manner (Guillemot, L., Levy, A., Zhao, Z. J., Béréziat, G., and Rothhut, B. (2000) J. Biol. Chem. 275, 26349-26358). In this report, transfection studies using a series of deleted cyclin D1 promoters revealed that two regions between base pairs (bp) -136 and -96 and between bp -29 and +139 of the human cyclin D1 promoter contained regulatory elements required for Ang II-mediated induction. Mutational analysis in the -136 to -96 bp region provided evidence that a Sp1/early growth response protein (Egr) motif was responsible for cyclin D1 promoter activation by Ang II. Gel shift and supershift studies showed that Ang II-induced Egr-1 binding involved de novo protein synthesis and correlated well with Egr-1 promoter activation. Both U0126 (an inhibitor of the MAPK/ERK kinase MEK) and wortmannin (an inhibitor of PI3K) abrogated Egr-1 endogenous expression and Egr-1 promoter activity induced by Ang II. Moreover, using a co-transfection approach, we found that Ang II induction of Egr-1 promoter activity was blocked by dominant-negative p21(ras), Raf-1, and tyrosine phosphatase SHP-2 mutants. Identical effects were obtained when inhibitors and dominant negative mutants were tested on the -29 to +139 bp region of the cyclin D1 promoter. Taken together, these findings demonstrate that Ang II-induced cyclin D1 up-regulation is mediated by the activation and specific interaction of Egr-1 with the -136 to -96 bp region of the cyclin D1 promoter and by activation of the -29 to +139 bp region, both in a p21(ras)/Raf-1/MEK/ERK-dependent manner, and also involves PI3K and SHP-2.

Androstadienes↗
PubMed2001

Prophylaxis against organophosphate poisoning by sustained release of scopolamine and physostigmine.

Protection efficacy of continuous prophylactic administration of physostigmine and scopolamine against sarin-induced toxicity was evaluated previously in guinea pigs. The present study in large animals used Beagle dogs, that serve as an animal model with cholinergic sensitivity similar to that of humans. Pretreatment with physostigmine salicylate and scopolamine hydrochloride at dose rates of 2.5 and 1 microg x kg(-1) x h(-1), respectively, was administered via Alzet mini-osmotic pumps. At the time of exposure, the physostigmine salicylate concentration in plasma was 0.7 ng x ml(-1) and the scopolamine hydrochloride concentration was ca. 0.2 ng x ml(-1), both of which are levels known to be well tolerated in humans. Whole-blood cholinesterase inhibition was 15-20%. This regimen conferred full protection against 2.5 x LD50 i.v. of sarin. Albeit the high-dose exposure, cholinergic toxicity symptoms were mild with no convulsions. About 11-14 min following poisoning the treated animals started to walk and 15-20 min following exposure full recovery was observed and the dogs behaved normally. With higher dose rates of physostigmine salicylate and scopolamine hydrochloride, at plasma concentrations of 2.1 and 0.6 ng x ml(-1), respectively, treated dogs regained normal posture 6-10 min after exposure.

Animals↗
PubMed2001

Monoclonality of endocrine tumours: What does it mean?

It is believed and hoped that clonality assignment of tumours predicts long-term behaviour, narrows the search for the putative pathogenic event or events, identifies the extent of involvement of surrounding and distant tissues and assesses the completeness of surgical clearance. It should define optimal therapeutic strategies, such as gene therapy, and the most fruitful directions for research. Because the histological characteristics that are central to establishing prognosis in most neoplasms are of limited value in endocrine tumours, the benefits of interpretation of clonality are potentially even more valuable and far-reaching in these tissues. So, can clonality be accurately defined and, if it can, can the distinction between a polyclonal expansion of cells that are simply 'obeying orders' and the presumed progeny of a single anarchic mutant be usefully made? This review comes to the conclusion that the answer is 'probably not'.

Animals↗
PubMed2001

Enhanced visualization processing: effect on workflow.

RATIONALE AND OBJECTIVES: Soft-copy viewing of digital radiographs allows for image processing to improve visualization of anatomy and lesions, but it can take more time than film-based viewing. Enhanced visualization processing (EVP) was developed to increase the latitude of an image without reducing the vital contrast, potentially reducing the need for the radiologist to manipulate images. This study examined the influence of processing radiographic images with EVP on workflow in a picture archiving and communications system (PACS). MATERIALS AND METHODS: Portable computed radiographic chest images were obtained and processed either with EVP or without. A security camera with a videocassette recorder was positioned above the PACS workstation. Four radiologists reviewed the images during their normal work schedule. The current diagnostic image was used to determine if the case contained EVP or non-EVP images. The videotapes of the sessions were reviewed to determine diagnostic viewing times and how zoom and/or window and level manipulation was used. RESULTS: Viewing time was significantly longer for the non-EVP than the EVP cases. The difference occurred with all readers. Window and level manipulation was used on 35% of the EVP and 41% of the non-EVP images. Zoom was used on 64% of the EVP and 69% of the non-EVP images. Average time spent using zoom and window and level manipulation was significantly shorter with the EVP than with the non-EVP images. CONCLUSION: EVP of chest images displayed on PACS monitors significantly improved workflow as measured by viewing time. EVP decreased use of window and level manipulation and zooming and the amount of time each one was used.

Humans↗
PubMed2001

VIP receptor antagonists and chemotherapeutic drugs inhibit the growth of breast cancer cells.

The effects of vasoactive intestinal peptide (VIP) antagonists on breast cancer cells were investigated. (N-stearyl, norleucine17)VIP hybrid ((SN)VIPhyb) inhibited specific 125I-VIP binding to MCF7, SKBR3, T47D ZR75-1 and MDA-MB231 cells with high affinity (IC50 values of 0.03-0.06 microM). (SN)VIPhyb, 1 microM, inhibited the ability of 10 nM VIP to cause elevation of cAMP and to increase c-fos mRNA. Micromolar concentrations of (SN)VIPhyb inhibited the proliferation of MDA-MB231 or MCF7 cells using a MTT and clonogenic assay. Using a MTT assay, (SN)VIPhyb enhanced the ability of taxol and doxorubicin to inhibit breast cancer growth. Using nude mice bearing MDA-MB231 xenografts, VIPhyb potentiated the ability of taxol to inhibit proliferation. The results indicate that VIP receptor antagonists increase the ability of chemotherapeutic drugs to kill breast cancer cells.

Amino Acid Sequence↗
PubMed2001

Differences in arginine vasotocin gene transcripts and cortisol secretion in trout with high or low endogenous melanin-concentrating hormone secretion.

Previous studies on trout suggest that melanin-concentrating hormone (MCH) acts at both hypothalamic and pituitary levels to restrain the release of adrenocorticotropic hormone and hence cortisol during stress. Using in situ hybridization, the present work examined whether high rates of MCH secretion were associated with changes in the synthesis of arginine vasotocin (AVT), one of the corticotropin secretogogues. It also examined whether high endogenous MCH secretion restrains cortisol secretion during intense as well as mild stress, and how exogenous MCH affects the rise in plasma cortisol following injection stress. Trout were reared in black- or white-coloured tanks for 1 year or more to achieve maximal differences in MCH secretion. Following a mild stress, cortisol secretion was greater in black-reared fish with low MCH secretion which is in line with previous findings but, following a more severe stress, plasma cortisol concentrations were similar in the two groups. Injection of MCH into black-adapted fish restrained the stress-induced rise in plasma cortisol concentration during the first hour but did not affect final cortisol values. In two separate experiments, AVT mRNA levels were significantly lower in the hypothalamus of black-reared fish. Possible explanations for this include a greater negative-feedback restraint by cortisol, which is likely to rise higher in black-adapted fish during the moderate, daily stresses of aquarium life; or the possibility that exposure to a white background may be psychologically stressful, stimulating AVT transcription. The possibility that MCH directly stimulates AVT transcription cannot be excluded but seems less likely. The results suggest that while MCH may restrain the release of hypothalamo-pituitary stress hormones under moderately stressful conditions, it does not restrain AVT synthesis.

Animals↗
PubMed2001

Lack of effect of protein deprivation-induced intrauterine growth retardation on behavior and corticosterone and growth hormone secretion in adult male rats: a long-term follow-up study.

To further define the neuroendocrine consequences of intrauterine growth retardation (IUGR), we have used a rat model of maternal protein restriction throughout pregnancy to examine the pattern of corticosterone and GH secretion under basal conditions and in response to psychological stress in male offspring at 4, 9, and 18 months of age. The findings were correlated with studies of behavioral activity. Despite a consistent reduction in birth weight and failure of catch-up growth, there were no significant differences in GH secretory profiles between IUGR and control rats at any age. We were unable to demonstrate a difference in the number, amplitude, length, or area of corticosterone secretory pulses between control and IUGR animals; although again, there was a significant decrease with age. The mean peak plasma concentration of corticosterone in response to a noise stress also declined with age but was unaffected by IUGR. There were no consistent, statistically significant differences in behavioral responses between normal control and IUGR animals or between groups of animals at different ages. These results do not, therefore, support the presence of major functional abnormalities in either GH or corticosterone secretory responses in adult male rats subjected to IUGR.

Aging↗
PubMed2001

Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures.

Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pituitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined changes in trophic activity within the rat anterior pituitary gland following dexamethasone withdrawal and re-treatment. Treatment of adrenalectomised, male Wistar rats with dexamethasone results in a discrete, highly significant burst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethasone withdrawal, calculated total anterior pituitary cell populations remain below that seen in untreated adrenalectomised controls. Repeated exposures to dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the amplitude of apoptotic bursts induced by second and third dexamethasone exposures are similar but smaller than that induced by initial exposure, it appears that the very first exposure to dexamethasone deletes a subset of anterior pituitary cells that are either not restored at all, or are only replaced very slowly. The reduced proportion of corticotrophs contributing to the increase in mitotic index after dexamethasone withdrawal corroborates this. Although continued cell turnover within the pituitary predicts that the absolute cellular deficit would diminish with time, the effects seen may contribute to the delayed recovery of pituitary axis function following cessation of glucocorticoid treatment.

Adrenalectomy↗
PubMed2001

Scopolamine bioavailability in combined oral and transdermal delivery.

Transdermal therapeutic system scopolamine (TTS-S) is effective in preventing motion sickness for 72 h. However, by this route a prophylactic effect is obtained 6 to 8 h postapplication. By the oral route, scopolamine is effective within 0.5 h for a period of 6 h. To achieve safe as well as effective protection against seasickness during the first hours of a voyage until the TTS-S patch takes effect, the pharmacokinetics of scopolamine was investigated after patch application in combination with oral tablets, 0.6 mg, 0. 3 mg, or placebo. Subjects were 25 naval-crew volunteers, randomly divided into three groups: group 1 (n = 9), TTS-S patch + 0.6 mg of scopolamine per os (p.o.); group 2 (n = 8), TTS-S patch + 0.3 mg of scopolamine p.o.; and group 3 (n = 8), TTS-S patch + placebo tablet. Blood samples were collected before treatment and 0.5, 1, 1.5, 2.5, 3.5, 6, 8, and 22 h post-treatment, and were analyzed for scopolamine levels using radioreceptor assay. Significantly higher plasma scopolamine levels were found in group 1 at 0.5, 1, 1.5, and 2.5 h, and in group 2 at 1 and 1.5 h post-treatment, compared with group 3. Thereafter, plasma levels did not differ significantly between the groups. In all subjects of group 1 and seven subjects (88%) of group 2, therapeutic levels (>50 pg/ml) were measured during the first 2.5 h, compared with only two subjects (25%) of group 3 (P < 0.05). Heart rate, blood pressure, visual accommodation, performance test results, and subjective complaints of adverse effects did not differ significantly. The combination of transdermal and oral scopolamine (0.3 or 0.6 mg) provides the required plasma levels to prevent seasickness, starting as early as 0.5 h post-treatment, with no significant adverse effects.

Accommodation, Ocular↗
PubMed2001

An animal model for studying therapeutic drugs against post-traumatic stress disorder.

An animal model for the evolvement of post-traumatic stress disorder (PTSD) was developed by simulating the hormonal consequences of prolonged stress via the continuous administration of corticosterone by subcutaneously implanted sustained-release pellets. Behavioral, morphological, and biochemical effects were recorded and analyzed. This model has shown cognitive deficits as well as hippocampal damage in the rat similar to those found in PTSD patients. The model was also used to test a therapeutic treatment against stress-induced brain damages. Concomitant treatment with the L-type calcium channel blocker, nimodipine, protected young rats from corticosterone-induced morphological brain changes but not cognitive impairments. The proposed animal model may be useful for testing the efficacy of various neuroprotective drugs. Development of an effective drug treatment for use after a traumatic event and through the trauma period might prevent permanent brain damage and the development of PTSD.

Animals↗
PubMed2001

Domestic violence: prevalence among women in a primary care center--a pilot study.

BACKGROUND: Domestic violence is a prevalent problem with serious consequences, including the risk of death. The lifetime prevalence ranges from 21 to 34%, with 8-14% of them reporting abuse in the previous year. The incidence seen in primary care practice is about 8%. Despite this high rate, domestic violence is under-diagnosed in primary care. OBJECTIVES: To estimate the prevalence of domestic violence among women visiting a primary care center, to characterize them and to evaluate a screening tool. METHODS: A brief anonymous questionnaire (in Hebrew and Russian) for self-completion was used as a screening tool. During October 1998 we distributed the questionnaires in a primary care clinic in Beer Sheva to all women aged 18-60 years whose health permitted their participation. A woman was considered at high risk for domestic violence when she gave a positive answer to at least one of the three questions related to violence. The risk factors for domestic violence were calculated by odds ratio with 95% confidence intervals. RESULTS: The response rate was 95.7%. We found 41 women (30.8%) at high risk for violence. Women preferred talking about this issue with their family physician. Women at highest risk were older than 40 years, had emigrated from the former Soviet Union during the last 10 years, were living alone, and were unemployed. None of the women visited the Domestic Violence Center during the study period and 2 months thereafter. Only three women tore off the Center's address and phone number attached to the questionnaire. CONCLUSIONS: The anonymous questionnaire was well accepted and had a high compliance rate. Its disadvantages are that respondents must be literate and that it permits the woman to continue with her "secret-keeping" behavior. A high prevalence of domestic violence among women visiting a primary care clinic should convince family physicians to be more active in diagnosing the problem accurately among their patients, providing treatment and preventing further deterioration and possible danger. Further effort should be directed at improving the clinic staff's ability to detect domestic violence among patients, and at developing management programs in the health system to help combat domestic violence.

Adult↗
PubMed2000

Hospital readmissions. We'll meet again.

A 12-month study of emergency medical admissions at one trust suggests most readmissions could not be avoided. The re-admission rate within 28 days was 10 per cent, of which 5 per cent were found to be preventable. Readmissions were higher among smokers, men and people living in hostels. The study found no evidence of increased readmissions in winter.

Adolescent↗
PubMed2000

The protein-tyrosine phosphatase SHP-2 is required during angiotensin II-mediated activation of cyclin D1 promoter in CHO-AT1A cells.

Angiotensin II (Ang II) binds to specific G protein-coupled receptors and is mitogenic in Chinese hamster ovary (CHO) cells stably expressing a rat vascular angiotensin II type 1A receptor (CHO-AT(1A)). Cyclin D1 protein expression is regulated by mitogens, and its assembly with the cyclin-dependent kinases induces phosphorylation of the retinoblastoma protein pRb, a critical step in G(1) to S phase cell cycle progression contributing to the proliferative responses. In the present study, we found that in CHO-AT(1A) cells, Ang II induced a rapid and reversible tyrosine phosphorylation of various intracellular proteins including the protein-tyrosine phosphatase SHP-2. Ang II also induced cyclin D1 protein expression in a phosphatidylinositol 3-kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)-dependent manner. Using a pharmacological and a co-transfection approach, we found that p21(ras), Raf-1, phosphatidylinositol 3-kinase and also the catalytic activity of SHP-2 and its Src homology 2 domains are required for cyclin D1 promoter/reporter gene activation by Ang II through the regulation of MAPK/ERK activity. Our findings suggest for the first time that SHP-2 could play an important role in the regulation of a gene involved in the control of cell cycle progression resulting from stimulation of a G protein-coupled receptor independently of epidermal growth factor receptor transactivation.

Angiotensin II↗
PubMed2000

Interplay of Twisting and Folding in Overcrowded Heteromerous Bistricyclic Aromatic Enes.

Fluorenylidenexanthenes 5-7 were synthesized by 2-fold extrusion diazo-thione couplings. 7 exhibited yellow crystals and purple (560 nm) solutions. (1)H NMR of 5 and 7 indicated subtle equilibria twisted (t) right harpoon over left harpoon anti-folded (a) major/minor conformations. (13)C DNMR of 6 gave DeltaG(c)(double dagger)(enantiomerization/inversion) = 26.5 kJ/mol and DeltaG(c)(double dagger)(E,Z-topomerization) = 82.0 kJ/mol. PM3 calculations of 5 revealed minima a, t, ts (twisted/syn-folded), DeltaDeltaH(f) degrees = 0.0, 14.1, 15.6 kJ/mol, and transition states [t-ts], [a-ts], [t( perpendicular)], [a-a], DeltaDeltaH(f) degrees = 16.3, 17.4, 82.2, 99.3 kJ/mol.

Journal Article↗
PubMed2000

Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer.

HYPOTHESIS: Neoadjuvant therapy has the potential to induce regression of high-risk, locally advanced cancers and render them resectable. Preoperative chemoradiotherapy is proposed as a testable treatment concept for locally advanced pancreatic cancer. DESIGN: Fourteen patients (8 men, 6 women) with locally advanced pancreatic cancer were surgically explored to exclude distant spread of disease, to perform bypass of biliary and/or gastric obstruction, and to provide a jejunostomy feeding tube for long-term nutritional support. A course of chemotherapy with fluorouracil and cisplatin plus radiotherapy was then initiated. Reexploration and resection were planned subsequent to neoadjuvant therapy. MAIN OUTCOME MEASURES: Tumor regression and survival. INTERVENTIONS: Surgically staged patients with locally advanced pancreatic cancer were treated by preoperative chemotherapy with bolus fluorouracil, 400 mg/m2, on days 1 through 3 and 28 through 30 accompanied by a 3-day infusion of cisplatin, 25 mg m2, on days 1 through 3 and 28 through 30 and concurrent radiotherapy, 45 Gy. Enteral nutritional support was maintained via jejunostomy tube. RESULTS: Of 14 patients who enrolled in the protocol and were initially surgically explored, 3 refused the second operation and 11 were reexplored; 2 showed progressive disease and were unresectable and 9 (81%) had definitive resection. Surgical pathologic stages of the resected patients were: Ib (2 patients), II (2 patients), and III (5 patients). Pancreatic resection included standard Whipple resection in 1 patient, resection of body and neck in 1 patient, and extended resection in 6 patients (portal vein resection in 6, arterial resection in 4). One patient who was considered too frail for resection had core biopsies of the pancreatic head, node dissection, and an interstitial implant of the tumorous head. Pathologic response: 2 patients had apparent complete pathologic response; 1 patient had no residual cancer in the pancreatectomy specimen, the other patient who had an iridium 192 interstitial implant had normal core biopsies of the pancreatic head. Five patients had minimal residual cancer in the resected pancreas or microscopic foci only with extensive fibrosis, and 2 patients had fully viable residual cancer. Lymph node downstaging occurred in 2 of 4 patients who had positive peripancreatic nodes at the initial surgical staging. There was 1 postoperative death at 10 days. Sepsis, prolonged ileus, and failure to thrive were major complications. In the definitive surgery group the median survival was 19 months after beginning chemoradiotherapy and 16 months after definitive surgery. The absolute 5-year survival was 11% of 9 patients, 1 is surviving 96 months (with no evidence of disease) after chemoradiotherapy and extended pancreatic resection including resection of the superior mesenteric artery and the portal vein for stage III cancer. In the nonresected group the mean survival was 9 months (survival range, 7-12 months) after initiation of chemoradiotherapy. CONCLUSION: A pilot study of preoperative chemoradiotherapy with infusional cisplatin and radiation induced a high rate of clinical pathologic response in patients with locally advanced pancreatic cancer and merits further study in these high-risk patients.

Adult↗