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Biomedical subjects

M Stoll

Publications and source records attributed to M Stoll.

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

Domino reaction of 1,3-bis(trimethylsilyloxy)-1,3-dienes with oxalyl chloride: general and stereoselective synthesis of gamma-alkylidenebutenolides

The Lewis acid catalyzed cyclization of oxalyl chloride with 1,3-bis(trimethylsilyloxy)-1,3-dienes 3, derived from 1,3-dicarbonyl compounds 1, provides a new and general approach for the synthesis of gamma-alkylidenebutenolides 4, a pharmacologically and synthetically important class of substances. A variety of butenolides were efficiently prepared in good yields and with very good regio- and stereoselectivities. An up-scaling of the reaction was possible. The use of the Lewis acid trimethylsilyl-trifluoromethanesulfonate (TMSOTf) proved to be superior to other activation conditions. Sterically undemanding gamma-alkylidenebutenolides could be prepared alternatively by reaction of the corresponding 1,3-dicarbonyl dianions with N,N'-dimethoxy-N,N'-dimethylethanediamide (2d). In contrast to the dianion method, the Lewis acid catalyzed reaction also facilitated the cyclization of sterically hindered, base-labile, cyclic and functionalized substrates. From a methodology viewpoint, the dianion reaction represents the first cyclization of a bis-Weinreb amide and the first cyclization of an oxalic acid-synthon with an ambident dianion. The TMSOTf-catalyzed reactions are both the first cyclizations of 1,3bis(trimethylsilyloxy)-1,3-dienes with a C2 dielectrophile and the first cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes with a carboxylic acid dichloride or a related dielectrophile.

Journal Article↗
PubMed2000

Genetically defined risk of salt sensitivity in an intercross of Brown Norway and Dahl S rats.

A genetic segregation analysis was performed to identify genes that cosegregate with arterial blood pressure traits reflective of salt sensitivity. A population of 113 F2 male rats was derived from an intercross of inbred SS/JrHsd/Mcw (Dahl salt-sensitive) and BN/SsN/Mcw (Brown Norway) rats. Rats were maintained on an 8% salt diet from the age of 9 to 13 wk, and arterial pressure was measured for 3 h daily during the 4th wk of high salt intake in unanesthetized rats using implanted arterial catheters. At the end of the 3rd day of high-salt pressure recordings, the arterial pressure response to salt depletion was determined 1.5 days following treatment with Lasix and a low-sodium (0. 4%) diet. A genome-wide scan using 265 polymorphic simple sequence length polymorphism (SSLP) markers found that seven arterial pressure phenotypes determined at different times and circumstances, and representing two distinct indexes of salt sensitivity, mapped to the same region of rat chromosome 18. The trait of salt sensitivity was strongly influenced by the presence of SS alleles in this region of chromosome 18, and those rats which were homozygote SS/SS exhibited a significantly greater reduction of mean arterial pressure following sodium depletion (29 +/- 2 mmHg) than homozygote BN/BN (17 +/- 3 mmHg) or heterozygotic (22 +/- 2 mmHg) rats. This region of rat chromosome 18 corresponds to the long arm of human chromosome 5 and a region of human chromosome 18 that has been linked to hypertension in humans. Given the unlikely chance of these different blood pressure traits mapping to the same region, we believe these data provide evidence that this region of rat chromosome 18 plays an important role in salt-induced hypertension.

Alleles↗
PubMed2000

[Public health economic aspects of antiretroviral therapy. Can we afford to do less?].

In Germany, politically motivated economic considerations are becoming even more important. In this connection, scientific research into the health system is not limited merely to a consideration of costs, but utilizes the same methods and conceptual models as economic research in general to investigate defined problems. The reduction of illness-related loss of production and quality of life to monetary units in the models used, often stimulates critical discussions of the ethical permissibility of such an approach. Public discussion of such models then makes it possible to justify rationally founded allocation decisions and to expose and thus prevent hidden forms of rationing. The medically successful concept of long-term administration of highly active antiretroviral combination treatment (HAART) was first considered by numerous studies to be cost-effective solely on the basis of the saving of inpatient treatment costs--a stance that in the light of the life-shortening HIV infection should not be thought to be only basis for the decision. Owing to a lack of experience with the long-term prognosis under HAART, it is difficult to assess indirect costs for HIV infection. An assessment of the quality of life in the symptom-free stages of HIV infection depends largely on coping strategies, so that the results of studies on quality of life measurement under antiretroviral treatment must not lightly be interpreted as a function of a given therapeutic strategy. Given the high costs of HIV infection to the economy, the marked reluctance to provide the necessary funding for research in the area of epidemiological monitoring, specific preventive measures and vaccination strategies is to be regretted.

Anti-HIV Agents↗
PubMed2000

[Osteonecrosis: a rare complication of HIV infection. Association with certain risk factors].

Osteonecrosis is a rare complication of HIV infection. The presumptive cause of the aseptic osteonecrosis is a disturbed blood supply to the bone. Most cases of osteonecrosis are associated with numerous risk factors, such as use of steroids, alcohol abuse, coagulopathies or metabolic derangements. Since conventional X-rays appear unremarkable, early forms often go unrecognized or are diagnosed late. Methods of establishing the diagnosis are NMR and three-phase skeletal scintigraphy. The pathogenesis of osteonecrosis in HIV infection is unclear. So far, about 30 cases have been reported in the literature. Since a number of these cases had no classical risk factors, it is assumed that the HIV infection itself is the causative agent. In other patients anticardiolipin antibodies, which are considered to be a risk factor, are found. Other HIV patients with aseptic osteonecrosis have elevated blood lipids; changes in blood fats have long been established as a risk factor in osteonecrosis. Furthermore, an association of osteonecrosis with proteinase inhibitor-induced metabolic lipid disorders was reported. Whether the risk for osteonecrosis in treatment with proteinase inhibitors actually is raised, or whether the association is a coincidence needs further investigation. We would recommend that in HIV patients with typical symptoms--in particular when classical risk factors are present--osteonecrosis be included in the differential diagnostic considerations.

Adult↗
PubMed2000

[Lipodystrophy and metabolic disorders in anti-HIV therapy].

For the effective treatment of HIV infection, combinations of antiretroviral drugs that, at various points of attack, prevent viral replication are used. After the introduction of HIV-1 specific protease inhibitors, various metabolic complications and changes in body habitus manifesting as abnormal fat distribution were observed in HIV patients. These side effects, initially assigned class-specifically to the protease inhibitors, have, however, also been frequently seen under other drug combinations. Changes to body habitus as a result of fat redistribution have mostly been designated as lipodystrophy syndrome, but are now increasingly being recognized as highly heterogeneous abnormalities. Furthermore, the disturbances of glucose and fat metabolism may occur completely independently of phenotypic habitus changes. The result is that both the suspected pathophysiological relationships and the therapeutic consequences are becoming even more complex. This paper summarizes the current state of investigations into the side effects of antiretroviral therapy and their clinical consequences.

Anti-HIV Agents↗
PubMed2000

Reconstitution of NK cell activity in HIV-1 infected individuals receiving antiretroviral therapy.

We studied natural immunity mediated by natural killer (NK) cells in 62 HIV-1 infected individuals, 54 HIV-1 infected individuals receiving highly active antiretroviral therapy (HAART) for more than one year and 8 HIV-1 infected individuals without antiretroviral therapy. 22 individuals had a complete suppression of viral replication characterized by viral load values <50 copies/ml, whereas 32 individuals presented with persistent viral replication. The 8 untreated patients had an indication to start antiretroviral treatment. Lytic activity of NK cells was measured in a 51chromium release assay. In patients with persistent viral replication under HAART NK cell activity was significantly decreased compared to patients with effective control of HIV viremia. Patients with complete suppression of HIV replication displayed a similar NK activity to healthy control persons. Differences in antibody-dependent cellular cytotoxicity (ADCC) were not observed. Further studies will investigate whether decreased NK cell activity is a reason for or the consequence of persistent viral replication.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2000

Immune reconstitution syndromes in human immuno-deficiency virus infection following effective antiretroviral therapy.

Effective antiretroviral therapy leads to rapid decrease in plasma HIV-1 RNA, frequently followed by an increase in CD4 T-helper cell counts. The improvement of immune function during highly active antiretroviral therapy has important impact on natural history of AIDS-related opportunistic disorders. Here we describe cases of unusual clinical inflammatory syndromes in CMV retinitis, hepatitis C, and atypical mycobacteriosis in HIV-1 infected patients associated with the initiation of antiretroviral therapy. Pathogenetic implications and therapeutic management of these new immunopathologic syndromes are discussed.

AIDS-Related Opportunistic Infections↗
PubMed2000

[Deficits in socioeconomic and psychosocial support of HIV-positive women].

Despite increasing numbers of heterosexually transmitted HIV-infected women and high numbers of female i.v.-drug users within HIV-infected population the subject of HIV-infection in women has been of low interest during the past years in Germany. This prospective study investigated the economic, social and psychological situation with regard to the special situation of this group. While there was no difference in clinical parameters we found a worse economic situation of HIV-positivity in women. Concerning the psychosocial situation there were few differences, but HIV-infected women sought help by voluntary workers more often. Specific education and socioeconomic support of HIV-infected women are conditions for the success of antiretroviral therapy of HIV-infection which has recently become more demanding and complex.

Adolescent↗
PubMed2000

Hormonal changes induced by partial rootzone drying of irrigated grapevine.

Partial rootzone drying (PRD) is a new irrigation technique which improves the water use efficiency (by up to 50%) of wine grape production without significant crop reduction. The technique was developed on the basis of knowledge of the mechanisms controlling transpiration and requires that approximately half of the root system is always maintained in a dry or drying state while the remainder of the root system is irrigated. The wetted and dried sides of the root system are alternated on a 10-14 d cycle. Abscisic acid (ABA) concentration in the drying roots increases 10-fold, but ABA concentration in leaves of grapevines under PRD only increased by 60% compared with a fully irrigated control. Stomatal conductance of vines under PRD irrigation was significantly reduced when compared with vines receiving water to the entire root system. Grapevines from which water was withheld from the entire root system, on the other hand, show a similar reduction in stomatal conductance, but leaf ABA increased 5-fold compared with the fully irrigated control. PRD results in increased xylem sap ABA concentration and increased xylem sap pH, both of which are likely to result in a reduction in stomatal conductance. In addition, there was a reduction in zeatin and zeatin-riboside concentrations in roots, shoot tips and buds of 60, 50 and 70%, respectively, and this may contribute to the reduction in shoot growth and intensified apical dominance of vines under PRD irrigation. There is a nocturnal net flux of water from wetter roots to the roots in dry soil and this may assist in the distribution of chemical signals necessary to sustain the PRD effect. It was concluded that a major effect of PRD is the production of chemical signals in drying roots that are transported to the leaves where they bring about a reduction in stomatal conductance.

Plant Growth Regulators↗
PubMed2000

New target regions for human hypertension via comparative genomics.

Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for "candidate hypertension loci in humans" based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics.

Animals↗
PubMed2000

Identification of regulated genes in rat heart after myocardial infarction by means of differential mRNA display.

In order to testify the hypothesis that unknown mechanisms are involved in the process of cardiac remodeling after myocardial infarction (MI), we employed differential display reverse transcription-polymerase chain reaction (DDRT-PCR) as our primary inspection tool. An animal model of MI was established by ligation of the left anterior descending coronary artery (LAD) in rat. Fifty upregulated candidate cDNA fragments were obtained in the right ventricle (RV) of the heart six weeks after MI. Eight cDNA fragments isolated from DD denaturing gel were extracted and reamplified, cloned into pCR II vector and sequenced. A Genbank search of these clones showed that three of them have a high homology with known genes not previously associated with cardiac remodeling, i.e., mouse interleukin-4 receptor gene, rat ferritin mRNA, and T-cell receptor beta chain V beta 5. The remaining clones have no similarity to known sequences. These data suggest that certain genes which were not previously being associated with cardiac hypertrophy are turned on during the process of cardiac remodeling after MI.

Animals↗
PubMed2000

Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed?

Since the introduction of HIV-1 protease inhibitors as components of antiretroviral drug combination regimens, the clinical course of HIV disease and opportunistic infections has changed dramatically. Besides the favourable virological, immunological and clinical impact of highly active antiretroviral therapy (HAART), several adverse drug reactions have been observed in patients with HIV receiving therapy. Particularly, peripheral lipodystrophy, central adiposity, dyslipidaemia and insulin resistance have been described with a prevalence of up to 80% in patients infected with HIV, and attributed to almost all components of HAART. Hyperlipidaemia is characterised by an increase of low and very low density lipoprotein-cholesterol as well as apolipoproteins B and E. Several studies strongly suggest that there are either multiple syndromes or a variety of factors inducing different changes that influence the ultimate phenotype. Similarities between HIV-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis suggest the pathophysiological involvement of, for example, nuclear factors like lamin A/C and drug-induced mitochondrial dysfunction. Moreover, there is some evidence that cytokines and hormones impair fat and glucose homeostasis in patients with HIV receiving HAART. Three years after the first description of HIV therapy-associated abnormal fat redistribution, there is still an ongoing discussion about the case definition, diagnostic procedure and treatment options for both body shape changes and metabolic disturbances. Regarding therapy, there is a major concern about possible complex pharmacological interactions and overlapping adverse effects between HAART and, for example, lipid-lowering therapy. In addition, the likely contribution of both nucleoside analogue reverse transcriptase inhibitors and protease inhibitors to the development of abnormal fat redistribution in patients with HIV limits options of changing to alternative effective antiretroviral drug combinations. Thus, the occurrence of hyperlipidaemia, maturity onset diabetes mellitus, and marked changes in body habitus resulted in important social and clinical consequences such as an increased risk of atherosclerosis. It also sheds new light on the use of protease inhibitors regarding risk factors for the initial treatment decision. In this article, we discuss the features, pathogenesis and treatment options for body fat redistribution and metabolic disturbances associated with HAART in HIV-1 infection.

Animals↗
PubMed1999

Immunologic and virologic studies in long-term nonprogressors with HIV-1 infection.

BACKGROUND: It is not known whether clinical latency in long-term nonprogressors (LTNP) with HIV-1 infection is due to a strong HIV-1 specific immune response of the host or to virologic factors. - METHODS: Peripheral blood mononuclear cells (PBMC) of 6 LTNP were analyzed for their phenotype, proliferation rates, natural killer (NK) cell activity, antibody dependent cellular cytotoxicity (ADCC), and CCR5 chemokine receptor genotype. Furthermore sequence analyses of the HIV-1 gene were performed. - RESULTS: Phenotypic analyses of lymphocyte subsets revealed increased CD8+ as well as HLA-DR+ expressing cells in LTNP and patients with progressive disease (PRO). Proliferation assays in LTNP and PRO showed a reduction of stimulation by polyclonal mitogens (PHA, ConA, PWM) of up to 60%. NK activity was within normal ranges in LTNP but reduced in PRO. 1 LTNP exhibited heterozygosity for CCR5-D32. A mutant HIV nef gene was not discovered by PCR in any of the LTNP. HIV-V3 loop PCR in 5 LTNP revealed the HIV-1B (NSI) subtype. In 2 patients further sequence analyses of the HIV-1 genome showed homozygous mutations in the Sp1 and NF-kB binding sites. CONCLUSION: The non-progression of HIV-1 infection in some LTNP seems to be due to single mutations in the viral genome resulting in a less replicative HIV-1 subtype or to a mutant chemokine receptor leading to a reduced HIV-1 entry into CD4+ cells. NK cell activity might be an additional contributing factor in controlling viremia.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors.

OBJECTIVES: To evaluate metabolic abnormalities, beta-cell function, lipid profile and vascular risk factors in HIV patients on protease inhibitors (PI). DESIGN: Prospective cross-sectional study. METHODS: Thirty-eight HIV-1-infected patients receiving at least one PI were compared with 17 PI-naive HIV patients in an oral glucose tolerance test (OGTT). Serum glucose, insulin, proinsulin, and C-peptide were determined. The fasting lipid pattern was analysed using electrophoresis and the assessment of apolipoproteins including lipoprotein (a). Fibrinogen, homocysteine, and anticardiolipin antibodies were also assessed. RESULTS: Twenty-seven (71%) of the PI-treated group had detectable hyperlipidaemia. Isolated hypertriglyceridaemia was present in 12 patients (44%), two (7%) of them had type V and 10 (37%) subjects had type IV hyperlipidaemia (Frederickson classification). Type IIb hyperlipidaemia defined as an increase of both very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) was found in 10 (36%) subjects, and five (18%) patients presented with isolated hypercholesterolaemia (type IIa). PI treatment was associated with significant higher fasting cholesterol, triglycerides, LDL and VLDL levels. Apolipoprotein B and E concentrations were significantly increased in patients receiving PI. Elevated concentrations of lipoprotein (a) (> 30 mg/dl) were detected in six (16%) of the hyperlipidaemic patients on PI. Eighteen (46%) patients on PI had impaired oral glucose tolerance and five (13%) had diabetes. Although four (24%) of the PI-naive patients were glucose intolerant, none had diabetes. Fasting concentrations and secretion response of insulin, proinsulin, and C-peptide to glucose ingestion was significantly increased in the PI-treated group suggesting a beta-cell dysfunction in addition to peripheral insulin resistance. Beta-cell abnormalities were associated with the abnormal lipid pattern and PI treatment. CONCLUSION: Combination drug regimens including PI are accompanied by impaired glucose tolerance, hyperproinsulinaemia as an indicator for beta-cell dysfunction, and lipid abnormalities proved to be significant risk factors for coronary heart disease. Moreover, PI may have an impact on the processing of proinsulin to insulin.

Adult↗
PubMed1999

Human papillomavirus testing in primary screening for cervical cancer of human immunodeficiency virus-infected women, 1990-1998.

OBJECTIVE: Women infected with the human immunodeficiency virus (HIV) have an increased risk of cervical neoplasia while the value of cytologic screening is limited due to a high prevalence of inflammatory disease. The study was conducted to determine whether testing for human papillomavirus (HPV) DNA could improve primary screening for cervical cancer of these patients. METHODS: One hundred thirty-eight HIV-infected women were examined between 1990 and 1998. Ninety-four patients with a total of 279 women-years were eligible for incidence evaluation. Colposcopy, cytology, and HPV DNA testing with the hybrid capture I assay were performed at each visit. RESULTS: Seventeen cases of high-grade cervical neoplasia were diagnosed at study entry and 13 developed CIN II or CIN III during follow-up. The hybrid capture I assay detected 94.1% of prevalent and 100% of incident high-grade neoplasia, while the corresponding sensitivity of Pap smears using CIN I or worse as the referral criteria was 82.3% for prevalent and 69.2% for incident high-grade neoplasia. Eleven of 13 patients who progressed to histologically confirmed CIN II/III tested positive for HPV DNA at study entry compared with 5/13 women presenting with any degree of cytologic atypia at recruitment. The Pap smears of 36/94 women remained normal throughout the study while 54/94 patients remained negative for high-risk HPV types. CONCLUSION: Hybrid capture I identified high-grade cervical neoplasia more accurately than the Pap smear and appeared to be beneficial for primary cervical cancer screening in HIV-infected women.

Adult↗
PubMed1999

Emotionally evoked changes in cerebral hemodynamics measured by transcranial Doppler sonography.

The cerebral representation of emotions has previously been investigated by the study of patients with local brain damage, experiments with selective stimulation of only one hemisphere, and more recently by imaging techniques such as positron-emission tomography or magnetic resonance imaging measuring local cerebral blood flow. We investigated the mean flow velocity (FVmean) in the middle cerebral artery (MCA) by transcranial Doppler sonography during emotional stimulation with video scenes in 24 healthy test persons. The videos consisted of an erotic scene and a violent scene shown in contrast to a calming scene. Blood pressure, heart rate, and breathing frequency were monitored continuously by noninvasive measurement. FVmean increased during the erotic scene to 108.5+/-11.9% (P < 0.05) of the baseline value in the right MCA and to 109.0+/-10.6% (n.s.) in the left MCA. During the violent scene FVmean reached 109.0+/-8.7% (P < 0.05) on the right side and 108.1+/-13.0% (n.s.) on the left side. The FVmean time course showed a close relationship to the video sequence. During scenes involving great tension FVmean showed a plateaulike state and peaked during sudden actions. Blood pressure, heart rate, and respiratory rate showed no significant changes. However, we observed a tendency towards lower heart rates (lowest value 94.5+/-13.6%) during the erotic scene and two peaks (103.2+/-13.3%, 104.8+/-16.8%) coinciding with sudden violent actions. The significant increase in FVmean in the right MCA supports the theory of a right hemisphere dominance for the processing of emotions.

Adult↗