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M Paul

Publications and source records attributed to M Paul.

At least 91 records · Page 5Linked to original sources
PubMed2001

A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential.

Neuroendocrine (NE) cells may be involved not only in growth and differentiation of the normal prostate but also in carcinogenesis and progression of prostate adenocarcinoma (Pca), including development of androgen resistance. However, the exact pathophysiology of NE cells in Pca remains poorly understood. Here we describe a transgenic model of Pca with progressive NE differentiation. Seven lines of transgenic mice with the rat prostate-specific large probasin promoter linked to the SV40-large T antigen (Tag) that develop prostatic neoplasia have been established. In this study, one of the seven lines (12T-10) was characterized by examination of 52 mice aged from 2-12 months. With advancing age, low-grade prostatic intraepithelial neoplasia, high-grade prostatic intraepithelial neoplasia, microinvasion, invasive carcinoma, and poorly or undifferentiated carcinoma with NE differentiation appeared in the prostates in sequential order. Whereas Tag is expressed uniformly in prostate epithelium, only an increasing subset of cells in prostatic intraepithelial neoplasia showed NE differentiation by chromogranin immunostaining. Frankly invasive carcinoma developing subsequently showed occasional definitive glandular differentiation (adenocarcinoma) and particularly undifferentiated carcinoma with NE histological features similar to those observed in NE carcinomas in humans. The NE carcinomas occurred in the dorsolateral and ventral lobes and were generally androgen receptor negative. Twenty-one of 32 (66%) mice aged > or = 6 months and 15 of 17 (88%) mice aged > or = 9 months developed metastatic tumors, as confirmed by histology and/or Tag immunohistochemistry. Metastases occurred at the later time points, with metastasis to regional lymph nodes, liver, and lung being particularly common. Metastases showed histological features of NE differentiation, as confirmed by chromogranin immunostaining and electron microscopy. An athymic nude mouse that received a s.c. implant of a primary NE tumor developed Tag-positive metastatic tumors with similar NE differentiation. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified identical protein profiles between the primary NE tumor and lesions in the extraprostatic organs. Hence, in the 12T-10 large probasin promoter-Tag mouse, high-grade prostatic intraepithelial neoplasia develops progressively greater NE differentiation and progresses to invasive adenocarcinoma and NE carcinoma, with a high percentage of metastases. The predictable progression through these stages will allow testing of therapeutic interventions as well as possible further delineation of the role of NE cells in Pca progression.

Adenocarcinoma↗
PubMed2001

Photo amidoglycosylation of an allal azidoformate. Synthesis of beta-2-amido allopyranosides.

[figure: see text] Photolysis of an allal C-3 azidoformate provoked intramolecular nitrene insertion into the glycal C=C unit and allowed direct incorporation of alcohol nucleophiles as beta-disposed substituents at C-1. The 2-amido allopyranoside products were elaborated via N-acylation and selective oxazolidinone hydrolysis, providing N-Boc-protected 2-amino sugars and simplifying stereochemical assignments. Synthesis of the potentially labile allal azidoformate was achieved via reaction of the corresponding carbonyl imidazolide with trimethylsilyl azide, facilitated by dibutyltin oxide.

Amides↗
PubMed2001

Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-alpha-linked-acidic dipeptidase (NAALADASE).

In this study we examined the effect of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and GPI 5693, selective inhibitors of the enzyme N-Acetylated-alpha-Linked-Acidic Dipeptidase (NAALADase; glutamate carboxypeptidase II; EC no. 3.4.17.21), which cleaves glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG), on the conditioned place preference (CPP) response to cocaine in male rats. The i.p. administration of 15 mg/kg of cocaine produced a significant CPP response. The acquisition and expression of the CPP response to cocaine was blocked by the i.p. administration of 100 mg/kg of 2-PMPA and the p.o. administration of 30 mg/kg of GPI 5693. In contrast, neither 2-PMPA nor GPI 5693 produced a CPP or conditioned place aversion response when administered alone. Furthermore, neither 2-PMPA or GPI 5693 altered the expression of the CPP response to food. These results indicate that NAALADase inhibitors block the incentive motivational value of cocaine, suggesting that such agents may be of use in treating cue-induced craving in cocaine addicts.

Animals↗
PubMed2001

Extracellular matrix proteins in cardiac fibroblasts derived from rat hearts with chronic pressure overload: effects of beta-receptor blockade.

Left ventricular hypertrophy (LVH) is accompanied by progressive accumulations of extracellular matrix proteins. They are produced predominantly by cardiac fibroblasts that surround the cardiac myocytes. The aim of this study was to emphasize the role of a combined approach using both in vivo and in vitro studies to elucidate the effects of carvedilol on cardiac remodeling. We therefore used an established model of supravalvular aortic banding and cardiac fibroblasts. LVH was induced by banding of the ascending aorta. Male Wistar rats were allocated to four groups: sham-operated, sham+carvedilol, aortic stenosis (AS), and AS+carvedilol. Treatment time was four weeks. Fibroblasts were isolated from the entire left ventricle of sham and AS rats. Carvedilol/metoprolol/prazosin were added (0.1, 1.0 and 10 microM; 24 h). In addition, interferon- gamma was applied for 24 h (10, 100 and 1000 IU). AS rats revealed increased LV weights (+27%) and cardiomyocyte widths as compared to sham-operated rats (1.6-fold, P<0.01). Carvedilol reduced LVH by 20%. This finding was accompanied by a decrease of laminin, fibronectin, collagen I and III in vivo. Collagen I/III and fibronectin were increased in fibroblasts of AS v sham rats (P<0.0001, each). Carvedilol reduced collagen I, III and fibronectin by 40/60/35% (0.1 microM; P<0.001) irrespective of LVH. Carvedilol had no effects on collagen IV and laminin. Carvedilol dose-dependently reduced the proliferation rate by 20% at 0.1 microM(P<0.0001). Metoprolol and prazosin had no effect on the expression of extracellular matrix proteins and on the proliferation of the cells of either origin. Interferon- gamma blunted the proliferation rate of cultured fibroblasts and lead to a significant decrease in extracellular matrix deposits. These results indicate that the effects of carvedilol may be due to the antiproliferative or antioxidative properties of this unselective beta-adrenergic receptor antagonist. These changes of the extracellular matrix represent a new mechanism of carvedilol that may contribute to the observed beneficial effects in congestive heart failure.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2001

*NO and oxyradical metabolism in new cell lines of rat brain capillary endothelial cells forming the blood-brain barrier.

To investigate the relevance of *NO and oxyradicals in the blood-brain barrier (BBB), differentiated and well-proliferating brain capillary endothelial cells (BCEC) are required. Therefore, rat BCEC (rBCEC) were transfected with immortalizing genes. The resulting lines exhibited endothelial characteristics (factor VIII, angiotensin-converting enzyme, high prostacyclin/thromboxane release rates) and BBB markers (gamma-glutamyl transpeptidase, alkaline phosphatase). The control line rBCEC2 (mock transfected) revealed fibroblastoid morphology, less factor VIII, reduced gamma-glutamyl transpeptidase, weak radical defence, low prostanoid metabolism, and limited proliferation. Lines transfected with immortalizing genes (especially rBCEC4, polyoma virus large T antigen) conserved primary properties: epitheloid morphology, subcultivation with high proliferation rate under pure culture conditions, and powerful defence against reactive oxygen species (Mn-, Cu/Zn-superoxide dismutase, catalase, glutathione peroxidase, glutathione) effectively controlling radical metabolism. Only 100 microM H2O2 overcame this defence and stimulated the formation of eicosanoids similarly as in primary cells. Some BBB markers were expressed to a lower degree; however, cocultivation with astrocytes intensified these markers (e.g., alkaline phosphatase) and paraendothelial tightness, indicating induction of BBB properties. Inducible NO synthase was induced by a cytokine plus lipopolysaccharide mixture in all lines and primary cells, resulting in *NO release. Comparing the cell lines obtained, rBCEC4 are stable immortalized and reveal the best conservation of properties from primary cells, including enzymes producing or decomposing reactive species. These cells can be subcultivated in large amounts and, hence, they are suitable to study the role of radical metabolism in the BBB and in the cerebral microvasculature.

Animals↗
PubMed2001

Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy.

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.

Angiotensin II↗
PubMed2001

Functional characterization of the human prion protein promoter in neuronal and endothelial cells.

Human prion diseases such as Creutzfeld-Jakob disease and kuru are of major medical and biological importance because of their fatal course, epidemic potential, and unique pathophysiology. Endogenous expression of the normal cellular prion protein (PrP(C)) is necessary for infection and prion replication. However, knowledge of human PrP(C) gene regulation is rudimentary. We therefore cloned1543 bp of the 5' untranslated and promoter region of the PrP gene. Using transient transfection assays, the full-length promoter and serial deletion mutants subcloned in a luciferase reporter vector were analyzed in neuronal (KELLY) and endothelial (EA.hy926) cell lines, which both express PrP(C) as shown by RT/PCR. Analysis of promoter constructs in KELLY cells indicated two activating regions at -131/-284 and -1303/-1543, relative to the 3'-terminal end of exon 1, and also two repressing elements at -254/-567 and -567/-909 in neuronal cells. In EA.hy926 cells, activating elements were identified at -131/-284 and -284/-567, and one repressing region was localized at -567/-909. In addition, transcriptional start sites were determined by 5'-RACE reaction and RNase protection assay, revealing one major transcriptional start site located at -47 (in KELLY cells), -53 (in human thalamus) and at about -55 (in EA.hy926 cells).

5' Untranslated Regions↗
PubMed2001

Excess mortality in women with hospital-acquired bloodstream infection.

PURPOSE: We examined the outcomes of bloodstream infection in men and in women and whether any sex-related differences were explained by underlying disorders, severity of disease, or clinical management. SUBJECTS AND METHODS: Using a prospectively collected database, we compared in-hospital mortality in men and women. We used multivariable logistic regression analysis to test whether sex-related differences could be due to potential confounders. RESULTS: Of 4250 patients with bloodstream infections, 1750 (41%) had hospital-acquired infections. The overall case fatality was 31% (625 of 2032) in women and 29% (631 of 2218, P = 0.1) in men. However, 43% (325/758) of the women with hospital-acquired infections died, compared with 33% (327/992) of the men (P = 0.0001). In a multivariate analysis, female sex was associated with greater mortality in patients with hospital-acquired infections (odds ratio = 1.7; 95% confidence interval: 1.1 to 2.6). The excess mortality in women was mainly seen in patients with major underlying disorders (fatality rate of 45% [234 of 525] in women vs. 32% in men [234 of 743, P = 0.0001). CONCLUSIONS: Mortality in women with hospital-acquired bloodstream infections is substantially greater than in men. The excess mortality was concentrated in women with severe underlying disorders, suggesting that sepsis might have accentuated differences in the outcome of underlying disorders in women.

Adult↗
PubMed2001

First trimester surgical abortion practices: a survey of National Abortion Federation members.

The objective of this study was to survey first trimester surgical abortion practices of North American providers. A survey was mailed to the 310 active member clinics of the National Abortion Federation, the professional organization of abortion providers in North America. The 236 respondents (76%) comprising the study group provided approximately 30% and 33% of all first trimester abortions in the US and Canada, respectively. Of the 529 practitioners who perform most abortions at the clinics, 68% are obstetrician-gynecologists, and 18% are family physicians; 51% are at least 50 years old. The majority of respondents (156 of 236, 66%) confirm gestational age with ultrasonography. Of the 202 clinics that favor one method of anesthesia, 58% use local cervical block with or without oral pre-medication, 32% combine local anesthesia with intravenous sedation, and 10% use general anesthesia. Most clinics open the cervix with tapered dilators (207 of 233, 89%), evacuate the uterus by using curved rigid plastic cannulas (157 of 229, 69%) and an electric vacuum source (191 of 233, 82%), and explore the uterus with a metal curette following aspiration (133 of 232, 57%). A large majority of respondents examine the uterine aspirate on-site (91%), prescribe antibiotics (91%), and offer oral contraceptives (95%) when requested. Although variations exist, surgical techniques and postoperative practices are quite uniform among clinics. Local anesthesia is presently the most frequent method of pain control. Ultrasonographic dating before abortion is common practice. The "graying" of skilled practitioners raises concerns about the future availability of abortion.

Abortion, Legal↗
PubMed2001

Evidence that the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei to inhibit maternal behavior in rats.

The maternal behaviors shown by a rat that has given birth are not shown by a virgin female rat when she is first presented with young. This absence of maternal behavior in virgins has been attributed to the activity of a neural circuit that inhibits maternal behavior in nulliparae. The medial amygdala and regions of the medial hypothalamus such as the anterior and ventromedial hypothalamic nuclei have previously been shown to inhibit maternal behavior, in that lesions to these regions promote maternal responding. Furthermore, we have recently shown that these and other regions, such as the principal bed nucleus of the stria terminalis, the ventral lateral septum, and the dorsal premammillary nucleus, show higher pup-induced Fos-immunoreactivity in non-maternal rats exposed to pups than during the performance of maternal behavior, indicating that they too could be involved in preventing maternal responsiveness. The current study tested whether the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei in a neural circuit that inhibits maternal behavior, as well as to see what other brain regions could participate in this circuit. Bilateral excitotoxic lesions of the medial amygdala, or of the anterior/ventromedial hypothalamic nuclei, promoted maternal behavior. Unilateral medial amygdala lesions caused a reduction of pup-induced Fos-immunoreactivity in the anterior/ventromedial hypothalamic nuclei in non-maternal rats ipsilateral to the lesion, as well as in the principal bed nucleus of the stria terminalis, ventral lateral septum, and dorsal premammillary nucleus. Finally, unilateral medial amygdala lesions paired with contralateral anterior/ventromedial hypothalamic nuclei lesions promoted maternal behavior, although ipsilateral lesion placements were also effective.Together, these results indicate that the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei in a neural circuit that inhibits maternal behavior, and that the principal bed nucleus of the stria terminalis, ventral lateral septum, and dorsal premammillary nucleus could also be involved in this circuit.

Amygdala↗
PubMed2001

The genetics of coronary heart disease.

Coronary heart disease (CHD) is one of the major causes of morbidity and mortality in westernized countries, and the contribution of genetics to CHD has already been demonstrated by twin studies. In the context of pathophysiologically relevant regulatory systems, various groups of candidate genes are involved in cardiovascular pathophysiology, which emphasizes the need for so-called 'high-throughput techniques' for the detection of polymorphisms. In view of genetic variability, we need to define realistic and clear-cut genotype-phenotype relationships. This may be achieved by using in vitro and in vivo studies to evaluate the potential functionalities of identified polymorphisms and by creating appropriate tools to provide relevant phenotypes. The identification of relevant genes and genetic variants involved in the different pathophysiological steps leading to CHD may considerably improve our understanding of the mechanisms of the disease course. This may help to identify high-risk individuals and groups or subgroups in whom specific therapeutic interventions are indicated or necessary, leading to individually adapted clinical management.

Journal Article↗
PubMed2001

Cover design for radioactive and AMD-producing mine waste in the Ronneburg area, eastern Thuringia.

At the former uranium mining site of Ronneburg, large scale underground and open pit mining for nearly 40 years resulted in a production of about 113,000 tonnes of uranium and about 200 million cubic metres of mine waste. In their present state, these materials cause risks to human health and strong environmental impacts and therefore demand remedial action. The remediation options available are relocation of mine spoil into the open pit and on site remediation by landscaping/contouring, placement of a cover and revegetation. A suitable vegetated cover system combined with a surface water drainage system provides long-term stability against erosion and reduces acid generation thereby meeting the main remediation objectives which are long-term reduction of radiological exposure and contaminant emissions and recultivation. The design of the cover system includes the evaluation of geotechnical, radiological, hydrological, geochemical and ecological criteria and models. The optimized overall model for the cover system has to comply with general conditions as, e.g. economic efficiency, public acceptance and sustainability. Most critical elements for the long-term performance of the cover system designed for the Beerwalde dump are the barrier system and its long-term integrity and a largely self-sustainable vegetation.

Environmental Monitoring↗
PubMed2001

Chronic beta-blocker therapy improves outcome and reduces treatment costs in chronic type B aortic dissection.

OBJECTIVES: To compare the medical treatment of chronic type B aortic dissection with beta-blockers versus other antihypertensive treatments in terms of their requirement for surgical intervention and treatment costs. METHODS: Case records of the 130 patients treated for aortic dissection type B in this unit between 1988 and 1997 were reviewed. Seventy-eight of 130 patients with chronic dissection have received isolated medical treatment. Seventy-one of 78 patients were discharged alive. Fifty-one of 71 received beta-blocker treatment, 20/71 were treated with other antihypertensive drugs. RESULTS: Surgery for aortic dissection became necessary in 20/71 patients (28%) during follow-up (mean, 4.2 years): 10/51 in the beta-blocker group and 9/20 in the other antihypertensive drug group. The freedom from subsequent aortic operation was 80 and 47%, respectively (P=0.001). Indications for emergency surgery were increased aortic diameter (79%), symptomatic aortic aneurysm (11%), and renal artery hypoperfusion (5%). The median hospitalization time during follow-up (dissection-related) was 2 days for patients who received beta-blockers and 16 days for patients who received other antihypertensive drug treatments (P=0.001). The cost of treatment/patient per year amounted to 644 and 12748 euros, respectively. CONCLUSIONS: A substantial proportion of patients with chronic type B dissection who receive initial medical management will later need surgery. Long-term treatment with beta-blockers reduces the progression of aortic dilatation, the incidence of subsequent hospital admissions, as well as the incidence of late dissection-related aortic procedures and the cost of treatment. Patients with chronic type B dissection need, in addition to frequent follow-up of aortic diameter, continuous treatment with beta-blocking agents.

Adrenergic beta-Antagonists↗
PubMed2001

Enhancing photosynthesis with sugar signals.

Photosynthesis has long been a target in the quest to maximize crop productivity to feed burgeoning populations. Recent evidence suggests that improved photosynthetic performance can be most easily achieved by modifying sugar-signalling mechanisms that control the expression of genes for whole pathways and processes that determine photosynthetic capacity and source-sink balance, rather than by directly targeting individual 'key' enzymes. Here, we highlight recent progress and support for the hypothesis that genetic modification of trehalose metabolism through its interaction with sugar-signalling pathways can enhance photosynthetic capacity.

Carbohydrate Metabolism↗
PubMed2001

Comparison of the dot immunobinding assay and two enzyme-linked immunosorbent assay kits for the diagnosis of liver cystic echinococcosis.

The dot immunobinding assay for the detection of hydatid antigen-specific antibodies (HA-DIA) was evaluated in patients with liver cystic and alveolar echinococcosis in comparison to two commercial ELISA kits. In 30 patients, E. granulosus infection (CE) was confirmed by histopathology or by the presence of parasite protoscoleces and/or hooks or specific antigen 5 (Ag5) in cyst fluid samples obtained by the fine needle aspiration biopsy (FNAB). Infection of E. multilocularis (AE) was diagnosed in two patients by the detection of specific anti-Em2(plus) ELISA and -Em18 Western blot antibodies and finally confirmed by histopathology. The HA-DIA using bovine hydatid antigens showed a high sensitivity in serum samples from CE patients; specific antibodies were found in 29 of 30 CE patients (96.7%). One negative result has been observed in a patient 2.6 years after radical surgery with a subsequent albendazole chemotherapy. The Echinococcosis ELISA(R) (Dialab Diagnostic) was positive in 23 CE cases (76.7%). The correlation between the HA-DIA and the Echinococcosis ELISA(R) was statistically significant. By contrast, Echinococcus granulosus IgG ELISA(R) (Bordier Affinity Products) gave positive results in only 12 of 30 CE patients (40.0%). Sera from two AE patients were high positive in all three methods analysed in our study. In non-endemic areas, due to the between-strains variations and differences in cyst immunogenic activity, related to the natural history of the parasite, a choice of an optimal method for a diagnosis of liver cystic echinococcosis has been discussed.The high diagnostic sensitivity and a faster one-step procedure, in comparison to traditional enzyme immunoassays, make the HA-DIA a very useful method for the diagnosis of CE in non-endemic areas, especially in a case of small or degenerating lesions and sterile echinococcal cysts with a low immunogenicity. The positive serology for CE frequently requires additional differentiation with E. multilocularis-specific antibodies.

Journal Article↗
PubMed2001

Inducible nitric oxide synthase in the myocard.

Recognition of significance of nitric oxide synthases (NOS) in cardiovascular regulations has led to intensive research and development of therapies focused on NOS as potential therapeutic targets. However, the NOS isoform profile of cardiac tissue and subcellular localization of NOS isoforms remain a matter of debate. The aim of this study was to investigate the localization of an inducible NOS isoform (NOS2) in cardiomyocytes. Employing a novel immunocytochemical technique of a catalyzed reporter deposition system with tyramide and electron microscopical immunocytochemistry complemented with Western blotting and RT-PCR, we detected NOS2 both in rat neonatal and adult cultured cardiomyocytes and in the normal myocard of adult rats as well as in the human myocard of patients with dilative cardiomyopathy. NOS2 was targeted predominantly to a particulate component of the cardiomyocyte--along contractile fibers, in the plasma membrane including T-tubules, as well as in the nuclear envelope, mitochondria and Golgi complex. Our results point to an involvement of NOS2 in maintaining cardiac homeostasis and contradict to the notion that NOS2 is expressed in cardiac tissue only in response to various physiological and pathogenic factors. NOS2 targeting to mitochondria and contractile fibers suggests a relationship of NO with contractile function and energy production in the cardiac muscle.

Animals↗
PubMed2001

Allelic distribution of HLA-B*5 in HLA-B5-positive Israeli patients with Behçet's disease.

In order to investigate the sub-typing of the B5 antigen in Israeli (Jewish and Arabic) patients with Behçet's disease (BD) allele-specific genotyping of B51 and B52 alleles was performed in Israeli BD patients and healthy controls. Among the HLA-B51-positive BD patients, B*5101 was found to be the predominant allele, identified in 62% of all BD patients and 78% of Jewish BD patients. HLA-B*5101 was also the predominant allele in HLA-B51-positive healthy controls. HLA-B*5108 and B*5104 alleles were identified in 23% and 15% of B51-positive BD patients, respectively. The HLA-B*5201 allele was identified in all HLA-B52-positive patients and controls. Our study suggests that both HLA-B*5101 and HLA-B*5201 are the dominant alleles of HLA-B5 in Israeli BD patients.

Alleles↗