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Biomedical subjects

M Roth

Publications and source records attributed to M Roth.

At least 199 records · Page 11Linked to original sources
PubMed1993

Biochemical and anatomical redistribution of tau protein in Alzheimer's disease.

We have developed assays that distinguish tau protein incorporated into the core structure of the paired helical filament (PHF) from non-PHF tau protein in brain tissue, whether soluble or insoluble. The PHF content was 19-fold greater in Alzheimer's disease cases compared with cognitively intact controls, and in temporal cortex the difference was 40-fold. There was a threefold decrease in soluble tau protein in Alzheimer's disease cases compared with normal age-matched controls, the decrease being greatest in frontal cortex. The PHF content was closely correlated with the number of tau-immunoreactive dystrophic neurites in plaques and throughout the neuropil, whereas counts of neurofibrillary tangles were poorer predictors of PHF content. beta-Amyloid deposits correlated neither with PHF content nor with neurofibrillary pathology. These findings suggest that Alzheimer's disease is characterized by a substantial redistribution of available tau protein from free to PHF-incorporated fractions and that PHF accumulation may be important in neurites as well as tangles in predicting the extent of cognitive impairment in Alzheimer's disease.

Adult↗
PubMed1992

Manidipine regulates the transcription of cytokine genes.

Manidipine, a Ca(2+)-channel blocker, at concentrations that lower elevated blood pressure, modulates the transcription rates of cytokine genes in the mesangial cells of humans that had been stimulated with platelet-derived growth factor BB isomer; although the transcription for mRNA of interleukin 1 beta and granulocyte/monocyte colony-stimulating factor was inhibited, the transcription of mRNA for interleukin 6 was enhanced. Additionally, the induction of c-fos, c-jun, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase transcription was inhibited by manidipine. We conclude that manidipine, at nanomolar concentrations, is efficacious in modulating gene transcriptions that are involved in proinflammatory changes of mesangial cells. Thus, manidipine, at pharmacological concentrations that are one to two orders of magnitude lower than those required for inhibition of agonist- or depolarization (K+)-induced vasoconstriction, causes changes in the activity of the genes that code for inflammatory mediators.

Calcium↗
PubMed1992

Evidence for continuous stimulation of interleukin-6 production in Crohn's disease.

Increased serum concentrations of acute-phase proteins can be found in active inflammatory bowel disease. Because interleukin 6 (IL-6) is one of the main mediators of acute-phase protein synthesis by the liver, the serum concentrations of IL-6 and the acute-phase proteins C-reactive protein, alpha 1-antitrypsin, and alpha 1-acid glycoprotein were determined in 70 patients with Crohn's disease (CD) and 23 patients with ulcerative colitis (UC). Disease activities were determined by established clinical activity indices. Serum IL-6 concentrations were significantly (P less than 0.005) increased in patients with CD (mean +/- SEM, 6.8 +/- 0.9 U/mL) compared with patients with UC (mean, less than 4 U/mL) and healthy controls (mean, less than 4 U/mL). Of patients with CD, 68.5% had serum IL-6 concentrations of greater than or equal to 4 U/mL, compared with 21.7% of patients with UC and 0% of healthy controls. There was a tendency toward higher serum IL-6 concentrations in patients with active CD than in patients with inactive disease. However, these differences were not statistically significant. There was no correlation between IL-6 serum concentrations and clinical activity indices, possibly because of the short circulatory lifetime and rapid hepatic clearance of IL-6 from the portal venous blood. In contrast to serum IL-6, acute-phase proteins, which have a longer circulatory lifetime, were significantly correlated with clinical activity indices. Only the follow-up of individual patients with initially highly active disease showed a further increase in IL-6 levels during acute exacerbations of the inflammatory process. The results show that most patients with even moderately active CD have significantly increased serum concentrations of IL-6, most probably reflecting a continuous stimulation of IL-6-producing cells.

Acute Disease↗
PubMed1992

Cell cultures from cryopreserved human lung tissue.

To assess gene induction in primary human fibroblasts, we have developed a method for cryopreservation of lung biopsies in liquid nitrogen. Fresh biopsies (n = 10) were chopped into 5 x 5 mm pieces and transferred into an ice-cold freezing medium. Biopsies were kept on ice for 15 min, followed by further cooling of the tissue to -70 degrees C. With this method, lung biopsies were preserved for more than 1 year before they were used for generating cell cultures. There was no significant difference in the biological responsiveness of fibroblasts generated from immediately cultured lung biopsies compared with those from cryopreserved tissue. The doubling rate of fibroblasts from fresh tissue was 23.6 +/- 1.1 hr; compared to 23.5 +/- 1.5 hr for fibroblasts generated from cryopreserved tissue. PDGF-BB enhanced de novo synthesis of DNA 100 times, in both the immediately cultured fibroblasts and those generated from cryopreserved biopsies. Macrophages, dendritic cells and endothelial cells could also be recovered from cryopreserved lung tissue. This method permits long-term storage of lung tissue and the possibility of establishing primary cell lines from the same tissue at later times without appreciable changes in their cellular biological characteristics.

Cell Cycle↗
PubMed1992

The properties of the nervous system and the two-growth-types (egg-sperm) concept of carcinogenesis.

Some common morphological and functional features of the sperm and of the neuroblast (above all the resistance of the egg once fertilized to penetration of further sperms and of the embryonic cell once innervated to additional innervation) point to their developmental relationship, viz. to continued existence of the sperm, following temporary disappearance and genetic interaction within the egg, in the form of a neuroblast. The egg and the sperm would thus give origin to the two basic growth types of the vertebrate body, viz. the cellular-divisional (of the non-nervous tissues) related to the egg and the neural-extensive originating in the sperm and characterized by sprouting of processes even several decimeters long from a single nerve cell body. The nervous system, in addition to its intricate functions, represents an extremely dense feltwork of nervous trunks, branches and fibres, the 'nervous skeleton' (6), the product of the extensive neural growth which is 'stuffed' with the products of the cellular divisional proliferation of the other, non-nervous tissues. The absence of nerves (or of normal nerves) within the malignant tumours points to cellular 'escape' from the limiting confines of the nervous skeleton as the biological cause of malignancy: the 'escaped' cells pursue the one-growth type way of life instead of the normal two-growth-types way, viz. they revert back towards the egg-condition and acquire embryonic features. Introduction of neuroblasts into the malignant tumour aimed at re-establishment of its nervous skeleton should convert the malignant lesion into a benign one.

Animals↗
PubMed1992

Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: results of the rt-PA-APSAC patency study (TAPS)

Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and anisoylated plasminogen streptokinase activator (APSAC) in myocardial infarction has been proved to reduce mortality. A new front-loaded infusion regimen of 100 mg of rt-PA with an initial bolus dose of 15 mg followed by an infusion of 50 mg over 30 min and 35 mg over 60 min has been reported to yield higher patency rates than those achieved with standard regimens of thrombolytic treatment. The effects of this front-loaded administration of rt-PA versus those obtained with APSAC on early patency and reocclusion of infarct-related coronary arteries were investigated in a randomized multicenter trial in 421 patients with acute myocardial infarction. Coronary angiography 90 min after the start of treatment revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3) in 84.4% of 199 patients given rt-PA versus 70.3% of 202 patients given APSAC (p = 0.0007). Early reocclusion within 24 to 48 h was documented in 10.3% of 174 patients given rt-PA versus 2.5% of 163 patients given APSAC. Late reocclusion within 21 days was observed in 2.6% of 152 patients given rt-PA versus 6.3% of 159 patients given APSAC. There were 5 in-hospital deaths (2.4%) in the rt-PA group and 17 deaths (8.1%) in the APSAC group (p = 0.0095). The reinfarction rate was 3.8% and 4.8%, respectively. Peak serum creatine kinase and left ventricular ejection fraction at follow-up angiography were essentially identical in both treatment groups. There were more bleeding complications after APSAC (45% vs. 31%, p = 0.0019).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The disposition of a human relaxin (hRlx-2) in pregnant and nonpregnant rats.

The pharmacokinetics and tissue distribution of a human relaxin were investigated after intravenous (iv) bolus administration to pregnant or nonpregnant rats. Human gene-2 relaxin (hRlx-2) serum concentrations after iv bolus administration were described as the sum of three exponentials. The pharmacokinetics were comparable in pregnant and nonpregnant rats. The serum clearance (CL) was 7.4-10.2 ml/min/kg at doses of 46-93 micrograms/kg and was linear in this range. The half-lives were 1.1-2.0, 15.1-16.4, and 53.7-67.9 min, respectively. The volume of the central compartment (Vc) was 48-79 ml/kg and the volume of distribution at steady state (Vss) was 271-336 ml/kg. Increasing the dose to 463 micrograms/kg increased the dose-corrected area under the serum concentration-time curve and significantly decreased CL and Vss. The distribution of radioactivity in the tissues of pregnant rats was followed after iv bolus dosing with hRlx-2 internally labeled with 35S-cysteine. Comparison of the extent of organ uptake of radiolabel after 35S-hRlx-2 or 35S-cysteine administration suggested that the kidneys were the principal site of uptake; the liver was of secondary importance. In perfusion experiments utilizing livers isolated from pregnant or nonpregnant rats, 36-52% of the dose of hRlx-2 was cleared from the perfusate in 2 hr. These studies showed that the pharmacokinetics of hRlx-2 in rats appeared to be unaffected by pregnancy and suggested that the kidneys and liver both play a role in the elimination of hRlx-2.

Animals↗
PubMed1992

Value of endoscopic retrograde cholangiopancreatography in determining the cause but not course of acute pancreatitis.

We have recently shown that ERCP is the most useful technique for detecting a biliary origin of acute pancreatitis and can be done without side effects. We now report on a second series of 50 patients with acute pancreatitis in whom ERCP, computed tomography (CT), ultrasound (US), and clinical and laboratory assessment were performed within the first 24 to 48 hours of hospitalization. A score for ERCP, CT and US was used to assess the severity of the disease. Patients were followed up until discharge or death and their condition classified according to outcome as mild (less than or equal to 1 complication), severe (greater than 1 complication) or fatal. ERCP was superior in detecting choledochal stones (ERCP 100%, US 25%, CT 50%) and dilated intrahepatic ducts (ERCP 75%, US 75%, CT 37%) but not gallbladder stones (ERCP 70%, US 100%, CT 60%). When the ERCP severity score was calculated there was no relevant difference between patients thereafter having a mild course (0.66 +/- 0.91, range 0-3), a severe course (1.3 +/- 0.80, range 0-3), or a fatal outcome (1.0 +/- 1.1, range 0-3). In contrast, the CT score was different in all three groups (mild: 3.0 +/- 1.9; severe: 5.3 +/- 3.2; lethal: 6.3 +/- 3.1) as was the US score (mild: 1.5 +/- 1.3; severe: 3.2 +/- 2.3; lethal: 4.4 +/- 1.4). It is concluded from these results that ERCP is of value in defining the origin of acute pancreatitis. When a biliary origin is detected this can lead to immediate treatment using endoscopic sphincterotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

The efficacy of reversible monoamine oxidase inhibitors in depressive illness.

The introduction of selective and reversible inhibitors of MAO-A (RIMA) has led to the re-examination of new MAO inhibitors in psychiatry. This paper reviews three controlled trials comparing moclobemide with imipramine and clomipramine. According to the data presented, moclobemide is as effective as imipramine and clomipramine in treating endogenous depression. Moreover, in a comparison with clomipramine, in patients with endogenous depression, moclobemide led to an earlier improvement in symptoms. A separate trial of moclobemide and clomipramine in outpatients with non endogenous depression found a comparable time of onset of clinical effect. Patients treated with moclobemide also showed greater tolerance after six and 12 weeks of treatment than patients treated with clomipramine. The three trials discussed found the RIMA compounds to be free of any serious adverse effects and generally better tolerated than the tricyclic compound with which they were compared.

Antidepressive Agents, Tricyclic↗
PubMed1992

[Constrictive pericarditis--surgery with or without heart-lung machine?].

In patients suffering from constrictive pericarditis, the best hemodynamic results can be achieved by total mobilization of the heart and complete resection of the pericardium. Among 72 patients operated upon from 1969 to 1991, the use of extracorporeal circulation became necessary only twice. Therefore, we suggest the use of heart lung machine only in patients with bad myocardial function or in patients who need correction of additional diseases. Routine use of extracorporeal circulation is not mandatory.

Diagnosis, Differential↗
PubMed1992

[A new type of ANCA in sera of patients with ulcerative colitis: effects of therapy and disease severity on serum titer].

Sera of 108 patients with chronic inflammatory bowel disease (IBD) and 13 control sera were screened for antibodies against neutrophil cytoplasmic antigens (ANCA) by an indirect immunofluorescence test. 37 out of 64 sera (58%) from patients with ulcerative colitis (UC) produced a fine granular and perinuclear ANCA staining pattern (p-ANCA) clearly different from the typically diffuse and granular cytoplasmic ANCA fluorescence (c-ANCA) seen in active Wegener's granulomatosis (WG). Only 1 of the 44 sera from patients with Crohn's disease and none of the control sera showed positive p-ANCA reactions. Only 1 of the 64 CU sera was positive for antinuclear antibodies, and another one showed a positive reaction in the anti-proteinase-3 ELISA which is specific for WG. Antibodies against myeloperoxidase were negative in the CU sera. 31 out of the 37 p-ANCA-positive sera (84%) were obtained from patients with high disease activity. p-ANCA titers became negative after long-term steroid therapy and after complete colectomy. These preliminary data suggest that ANCA screening may be of value in differentiating IBD and in monitoring disease activity and drug effects in UC patients.

Adult↗
PubMed1992

Domestic violence--the medical community's legal duty.

During the last decade, domestic violence has been identified as one of the major causes of emergency room visits by women. As many as 30% of the women who are seen by emergency room physicians exhibit at least one or more symptoms of physical abuse. Unfortunately, the vast majority of these cases go unreported due to a lack of awareness on the part of physicians and other health care providers regarding the law, actual reporting procedures, and potential liability. This article addresses both the medical community's legal liability and the results of a January 1992 survey conducted by the Jefferson County Medical Society and University of Louisville. This survey evaluated local physicians' awareness of the statutory requirements imposed on the medical community when treating suspected victims of domestic violence. According to this survey of 215 physicians, only 29% were aware that Kentucky law requires physicians and other health care practitioners to report to the Cabinet for Human Resources any suspected abuse, neglect, or exploitation of an adult. Furthermore, the Jefferson County Medical Society survey reported that only 24% of the physicians polled had ever filed a domestic violence report on behalf of a patient. In an effort to compare the physicians' knowledge of other domestic violence issues, the physicians were also questioned regarding the issue of child abuse. Over 80% of physicians surveyed were aware of the Kentucky statute which requires a physician to report child abuse, and greater than 60% of those physicians surveyed had filed a complaint with a local or state agency. Domestic violence is now being publicly recognized as a social problem with far-reaching consequences.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1991

Inflammatory mediators in chronic inflammatory bowel diseases.

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) of unknown etiology. They are characterized by an activation of intestinal mononuclear cells. Cytokines play a crucial role in the regulation of the functions of these cells. An increased synthesis of the cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha), which are primarily synthesized by activated monocytes/macrophages has been described in patients with IBD. The synthesis of interleukin-2 (IL-2) and of interferon gamma (IFN gamma), which are produced by lymphocytes, on the other hand, has been found to be decreased. The published data are, however, not quite consistent. In patients with IBD there is not only a stimulation of the local cytokine production in the gut. The blood levels and the synthesis of the cytokines IL-1, IL-6 and TNF alpha by peripheral blood mononuclear cells are also increased, in particular in patients with Crohn's disease. Drugs, which are commonly used for the treatment of IBD impair the synthesis of these cytokines in monocytes/macrophages.

Colitis, Ulcerative↗
PubMed1991

Ca(2+)-channel blockers modulate expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and low density lipoprotein receptor genes stimulated by platelet-derived growth factor.

The effects of Ca(2+)-channel blockers (amlodipine, nifedipine, nitrendipine, and verapamil) on expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.88) and low density lipoprotein receptor (LDL-R) genes stimulated by recombinant platelet-derived growth factor BB isomer (PDGF-BB) were evaluated in human skin fibroblasts. The drugs enhanced expression of the LDL-R protein on the plasma membrane of the cells; in contrast, they inhibited expression of the HMG-CoA reductase gene. In addition, PDGF-BB-dependent stimulation of transcription of c-fos mRNA was inhibited also by the Ca(2+)-channel blockers. We conclude that PDGF-BB-dependent activation of the two genes is inhibited effectively by the Ca(2+)-channel blockers, at therapeutic concentrations, although they are unable to lower systemic cholesterol levels at these concentrations; however, they do modify responses of the two genes that are involved crucially in regulation of cellular cholesterol homeostasis.

Amlodipine↗
PubMed1991

Structure of the detergent phase and protein-detergent interactions in crystals of the wild-type (strain Y) Rhodobacter sphaeroides photochemical reaction center.

Rhodobacter sphaeroides (strain Y) reaction center (RC) crystals were grown in the presence of n-octyl beta-glucoside (beta-OG). In order to determine the structure of the detergent phase in these crystals, low-resolution neutron diffraction experiments were performed at different contrasts obtained by varying the H2O/D2O ratio in the solvent. From the contrast variation data and from the RC atomic coordinates determined by X-ray diffraction [Arnoux, B., Ducruix, A., Reiss-Husson, F., Lutz, M., Norris, J., Schiffer, M., & Chang, C. H. (1989) FEBS Lett. 258, 47-50], a model was obtained for the structure of the detergent phase in the crystal. The detergent forms a ring-shaped micelle surrounding the most hydrophobic part of the transmembrane alpha helices of the RC. Each detergent ring is connected to two next-neighbor rings by intermicellar bridges. The detergent phase is organized thus in infinite zigzag chains parallel to the b axis of the P2(1)2(1)2(1) unit cell. The main interactions between beta-OG molecules and the RC molecules are hydrophobic and are localized at the level of the transmembrane alpha helices. This interaction replaces the phospholipid-protein interaction existing in vivo in the membrane and, to some extent, also the light harvesting complex-protein interaction. Secondary hydrophilic interactions are found between a few of the charged residues of the H subunit and the hydrophilic surface of the detergent ring from a neighboring RC molecule. A comparison with a previous study on Rhodopseudomonas viridis crystals [which grow in the presence of lauryldimethylamine N-oxide (LDAO) and belong to a different space group] [Roth, M., Lewit-Bentley, A., Michel, H., Deisenhofer, J., Huber, R., & Oesterhelt, D. (1989) Nature 340, 659-661] shows a quasi identity of shape and position of the beta-OG and LDAO rings around the transmembrane alpha helices. The secondary interactions, involving in both cases the external surface of the H subunit, differ because of the different molecular packing in the two space groups. The role and structural requirements of the detergent in the crystallization process are discussed.

Algorithms↗