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Biomedical subjects

M Weiss

Publications and source records attributed to M Weiss.

At least 271 records · Page 15Linked to original sources
PubMed1997

Recognition of acute cardiac allograft rejection from serial integrated backscatter analyses in human orthotopic heart transplant recipients. Comparison with conventional echocardiography.

BACKGROUND: Previous studies showed that moderate and severe acute cardiac rejection (AR) but not mild AR is associated with significant myocardial acoustic changes. This study examines whether serial measurements of end-diastolic two-dimensional integrated backscatter (2D-IB) enhance the diagnostic potential of ultrasonic tissue analysis in AR. METHODS AND RESULTS: Serial endomyocardial biopsies, conventional echocardiograms, and parasternal long-axis radiofrequency signals for determination of posterior wall and septal 2D-IB were performed in 52 transplant patients. Histology showed no AR in 155 biopsy samples, AR grade 1A in 25, AR grade 1B/2 in 27, and AR grade 3A/3B in 13. Whereas no significant 2D-IB changes occurred between AR-free studies and during AR grade 1A, posterior wall and septal 2D-IB increased during AR grade 1B/2 from -47.80 +/- 4.36 to -42.97 +/- 5.11 dB and from -36.72 +/- 7.45 to -32.52 +/- 7.98 dB (P < .001 and P < .05, respectively) and during AR grade 3A/3B from -47.96 +/- 4.74 to -38.25 +/- 5.32 dB and from -37.92 +/- 5.87 to -31.01 +/- 4.62 dB (P < .001 and P < .01, respectively). Changes in posterior wall and septal 2D-IB were greater during AR grade 3A/3B than during AR grade 1B/2 (P < .01 and P < .05). Increases of 1.5 dB in posterior wall or septal 2D-IB indicated AR grades > or = 1B with sensitivities of 88% and 83% and specificities of 89% and 85%; posterior wall and septal 2D-IB increases of 5.5 and 3.8 dB identified AR grades > or = 3A with sensitivities of 92% and 79% and specificities of 90% and 84%. Although a weak inverse correlation between posterior wall and septal 2D-IB changes and posterior wall and septal thickening (r = .41 and r = .39, both P < .001) and fractional diameter shortening (r = .35, P < .001) was found, significant 2D-IB increases also occurred in some rejecting patients with unaltered contraction. CONCLUSIONS: Increases in end-diastolic posterior wall and septal 2D-IB in serial studies permit reliable identification not only of moderate and severe AR but also of mild AR. Because 2D-IB increase significantly more in AR with myocyte damage than without such damage, an estimate of AR severity appears feasible. Significant myocardial acoustic changes during AR may occur independently of changes in contractile performance.

Acute Disease↗
PubMed1997

BTKbase, mutation database for X-linked agammaglobulinemia (XLA)

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 368 entries from 318 unrelated families showing 228 unique molecular events. In addition to mutations the database lists also some polymorphisms and site-directed mutations. Each patient is given a unique patient identity number (PIN). Information is provided regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites forming arginine residues. These hot spots have generally pyrimidines 5'and purines 3'to the mutated cytosine. A decreased frequency of missense mutations was found in the TH, SH3 and the upper lobe of the kinase domain. The putative structural implications of all the missense mutations are given in the database showing 228 unique molecular events, including a novel missense mutation causing an R28C substitution as previously seen in the Xid mouse.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1997

Partial restoration of scintigraphically assessed cardiac sympathetic denervation in newly diagnosed patients with insulin-dependent (type 1) diabetes mellitus at one-year follow-up.

Diabetic neuropathy is thought to comprise a reversible metabolic and an irreversible structural component of neuronal abnormality. To investigate whether the cardiac sympathetic denervation recently described in newly diagnosed, but metabolically stabilized, diabetic patients without myocardial perfusion abnormalities reflects transient or permanent sympathetic abnormalities, 123-I-metaiodobenzylguanidine (123-I-MIBG) scintigraphy was performed in 16 patients with insulin-dependent (Type 1) diabetes mellitus (IDDM) 1 year after initial assessment and diagnosis. All patients had been treated with an intensified insulin therapy for 1 year. HbA1c had fallen from 11.5 +/- 2.0% to 6.3 +/- 0.9% (p < 0.001). The global myocardial 123-I-MIBG uptake (score 1-6) had improved in 7 patients at 1 year, remained unchanged in 7, and deteriorated in 2 patients. Regionally, the myocardial uptake score of the posterior and septal regions had improved significantly (p < 0.01, p = 0.02) with a mean uptake score in the groups of 3.8 +/- 1.1 and 3.4 +/- 1.2 at diagnosis versus 2.6 +/- 0.5 and 2.5 +/- 0.9 at 1 year. Myocardial uptake scores of the anterior, lateral, and apical regions had also improved in 7, 6, and 9 patients, but the mean changes of these scores did not reach significance. The study demonstrates that scintigraphically assessed cardiac sympathetic denervation in newly diagnosed, but metabolically stabilized, IDDM patients is partially reversed with improved metabolic control after 1 year of intensified insulin therapy. We suggest that even in the early stage of IDDM, cardiac sympathetic dysfunction is composed of reversible and irreversible neuronal abnormalities.

3-Iodobenzylguanidine↗
PubMed1997

Signal generation in a non-EU country.

One of the most important objects of post-marketing surveillance is the early detection of serious, unknown and unexpected adverse events. As spontaneous reported adverse events vary considerably in their signal-generating value the Swiss Drug Monitoring Center SANZ implemented an early signal detection system in 1991. With a set of screening criteria the individual case reports are automatically checked by the system and read into a signal file. Subsequently these potential signals are processed to quantify the signal generating value of the particular case. According to the screening criteria 2072 (53%) of the reported cases were considered as potential signals. After validating and quantifying their signal value 27% (565) were drug-related and unlabelled, 8% (173) were also rated as serious. On the basis of these cases 114 labelling changes were made. Some of the most interesting cases are discussed. This computer-assisted early signal generation model in a small country with 7 million inhabitants has a high detectability of new, rare, serious and quality of life affecting adverse drug reactions (ADRs). These newly detected ADRs must be interpreted in cognizance of the limitations and restrictions of spontaneous reporting and do not allow pharmacoepidemiologic conclusions.

Journal Article↗
PubMed1997

On the validity of the dispersion model of hepatic drug elimination when intravascular transit time densities are long-tailed.

The dispersion model with mixed boundary conditions uses a single parameter, the dispersion number, to describe the hepatic elimination of xenobiotics and endogenous substances. An implicit a priori assumption of the model is that the transit time density of intravascular indicators is approximately by an inverse Gaussian distribution. This approximation is limited in that the model poorly describes the tail part of the hepatic outflow curves of vascular indicators. A sum of two inverse Gaussian functions is proposed as an alternative, more flexible empirical model for transit time densities of vascular references. This model suggests that a more accurate description of the tail portion of vascular reference curves yields an elimination rate constant (or intrinsic clearance) which is 40% less than predicted by the dispersion model with mixed boundary conditions. The results emphasize the need to accurately describe outflow curves in using them as a basis for determining pharmacokinetic parameters using hepatic elimination models.

Animals↗
PubMed1997

Safety of a low-dosage Filgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with an inflammatory process.

OBJECTIVE: To evaluate the effect and safety of a low dose Filgrastim treatment in surgical intensive care patients. DESIGN: Prospective, clinical study. SETTING: Surgical intensive care unit (ICU) in a university hospital. PATIENTS: Ten patients with the systemic inflammatory response syndrome (SIRS) and ten patients with sepsis were included in the study. INTERVENTIONS: Filgrastim was given intravenously at 1.0 microgram/kg for 3 days, followed by 0.5 microgram/kg for 4 days. MEASUREMENTS AND RESULTS: Filgrastim treatment increased leukocyte counts and plasma levels of G-CSF. Cytokine levels (IL-6 and IL-8) decreased in the first 3 days of treatment. None of the SIRS patients developed sepsis or multiple organ failure and none of the patients died. In the sepsis group four patients died. No adverse side effects were observed, especially no attenuation of lung injury. CONCLUSIONS: Low-dosage Filgrastim treatment in ICU patients is safe. Whether the observed changes of the inflammatory response can be attributed to Filgrastim has to be clarified in further randomized trials.

Cytokines↗
PubMed1997

Pharmacokinetics and tissue distribution of idarubicin and its active metabolite idarubicinol in the rabbit.

A three-compartment model was fitted to idarubicin data in a NONMEM pooled-data approach. Clearance (CL) of 221.7 ml/min was relatively high, and drug distribution was rapid (CLD = 248.3 ml/min) and extensive [steady-state volume of distribution (Vss) 24 1]. The area under the concentration-time curve (AUC) of idarbicinol was 8 times that of idarubicin. Concentrations of idarubicin (idarubicinol) measured in the myocardium at 24 h after i.v. administration of idarubicin were 20 (5) times those determined in plasma. Tissue concentrations of idarubicinol were up to 400 times those of idarubicin, indicating that the active metabolite contributes significantly to the overall drug action.

Animals↗
PubMed1997

Higher prevalence and greater severity of coronary disease in short versus tall men referred for coronary arteriography.

The incidence of myocardial infarction is higher in short individuals than in tall ones. To test whether the prevalence and severity of coronary disease is greater in short than in tall individuals, we compared a group of short men (height < [mean height - one SD]) to a group of tall men (height > [mean height + one SD]) drawn from a sample of 1046 consecutive men referred for coronary arteriography. Short men had a higher frequency of > or = 50% diameter stenosis; more diseased vessels (1.61 +/- 1.09 vs 1.15 +/- 1.11, p = 0.0004); a higher frequency of three-vessel disease (26.8% vs 16.1%, p = 0.04); and more total occlusions (40.1% vs 27.3%, p = 0.03). By multivariate analysis, height independently predicted > or = 50% lesions in the right coronary artery (p = 0.01) and left anterior descending artery (p = 0.06); three-vessel disease (p = 0.04); total occlusion (p = 0.04); and the number of diseased vessels (p = 0.005). This higher prevalence and greater severity of coronary disease may explain the higher incidence of and deaths caused by myocardial infarction previously reported in short men.

Aged↗
PubMed1997

Electrophysiological evidence for agonist properties of flumazenil, a benzodiazepine receptor antagonist, in rat hippocampus slices.

The purpose of this study was to determine the ability of the putative benzodiazepine antagonist flumazenil to modulate the excitatory synaptic responses recorded from rat hippocampus slices. The benzodiazepine agonist clonazepam was demonstrated to depress the CA1 population spike. This effect was attributed to an enhancement of GABA efficacy after its electrically-elicited release from local inhibitory circuitry. As an unexpected effect, flumazenil failed to antagonize this depressing effect. Moreover, flumazemil was observed to significantly depress, on its own, the magnitude of the evoked response to the activation of the excitatory afferents. This intrinsic depressant activity of flumazenil suggests that flumazenil acts 'in vitro' as an agonist at the benzodiazepine receptors, and is consistent with some previously reported atypical effects of flumazenil 'in vivo'.

Animals↗
PubMed1997

For doctors' eyes only: medical records in two Israeli hospitals.

"Scientific" and "craft" representations of medical diagnosis can be regarded as complementary discursive systems used by physicians in order to legitimate and monopolize their professional power. This paper examines the medical record as a context for the interplay of these two discourses. During interviews conducted with 78 Israeli physicians, 94% have refused to give patients access to their medical records. This refusal is discussed vis-à-vis a reading of the actual contents of medical records, which are shown to contain many errors, inconsistencies and ambiguities. The paper concludes by offering an alternative, anthropological model for medical records as fieldnotes.

Adult↗
PubMed1997

On the degree of solute mixing in liver models of drug elimination.

One of the fundamental differences between various liver models regards the underlying assumptions on the intrahepatic mixing process. A model-independent method for the evaluation of the departure from the perfectly mixed system is proposed which is based on an application of the relative entropy concept to hepatic transit time distributions of intravascular markers. This approach provides a measure of the distance between two probability distributions. Available data measured in isolated perfused livers indicate that sinusoidal solute mixing is nearly optimal. The suggestion of maximum mixedness in the liver may explain the discrepancy between the apparent validity of the venous equilibrium model and the physiological irrelevance of the underlying well-stirred assumption. In terms of the dispersion model the results are in accordance with the model equation obtained for mixed boundary conditions.

Entropy↗
PubMed1997

Errors in clearance estimation after bolus injection and arterial sampling: nonexistence of a central compartment.

In conventional pharmacokinetics monotonic decreasing drug disposition curves are usually assumed after bolus injection. For arterial sampling starting about 1 min after dosing the resulting neglect of the initial concentration peak leads to a relative overestimation of clearance which may be approximated by the percentage of systemic drug extraction. This error can be avoided by administering the drug as a short-term infusion.

Body Fluid Compartments↗
PubMed1997

Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma.

AIMS: We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. METHODS: A bolus of injectate containing [51Cr] labelled red blood cells, [14C]-sucrose and [3H]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [51Cr] or beta [14C and 3H] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). RESULTS: The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. CONCLUSIONS: The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.

Aged↗
PubMed1997

Cholesterol 7 alpha-hydroxylase activity in hypothyroidism and hyperthyroidism in humans.

Alterations of serum cholesterol levels are well recognized findings in hypothyroidism and hyperthyroidism. It remains unclear, whether thyroid hormones may affect serum concentrations of cholesterol through changes in the activity of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the catabolic conversion of cholesterol to bile acids. We determined serum concentrations of the bile acid precursor 7 alpha-hydroxy-4-cholesten-3-one, which reflects cholesterol 7 alpha-hydroxylase activity in the liver, in 19 patients with hypothyroidism and in 10 patients with hyperthyroidism before and after treatment, respectively. In patients with hypothyroidism, serum concentrations of cholesterol and LDL-cholesterol decreased by 33% (p < 0.0005) and 39% (p < 0.0005), respectively, after replacement therapy with thyroid hormones. In contrast, serum concentrations of 7 alpha-hydroxy-4-cholesten-3-one (21.7 +/- 15.8 ng/ml vs 24.5 +/- 18.1 ng/ml before treatment, n.s.) as well as serum HDL-cholesterol were unchanged during substitution therapy. In patients with hyperthyroidism, serum concentrations of cholesterol and LDL-cholesterol increased by 27% (p < 0.01) and 39% (p < 0.01) after antithyroid treatment, respectively. Again, serum concentrations of 7 alpha-hydroxy-4-cholesten-3-one did not change significantly during treatment (15.8 +/- 12.6 ng/ml vs 14.7 +/- 8.1 ng/ml before treatment, n.s.). These findings indicate that in humans, thyroid hormones influence serum lipid concentrations by other mechanisms than by affecting the activity of cholesterol 7 alpha-hydroxylase.

Adenoma↗
PubMed1997

Pre- and postmeiotic expression of male germ cell-specific genes throughout 2-week cocultures of rat germinal and Sertoli cells.

The present study was aimed at examining, by reverse transcription polymerase chain reaction, the expression of germ cell-specific genes in cocultures of Sertoli cells with either pachytene spermatocytes (PS) or round spermatids (RS). In situ hybridization studies showed that the mRNAs encoding phosphoprotein p19 and the testis-specific histone TH2B were specifically expressed in PS whereas those encoding the transition proteins TP1 and TP2 were specific to RS. This resulted in p19:TP1 and TH2B:TP2 ratios that were much higher in PS fractions than in RS fractions prepared by elutriation. When PS or RS were seeded on Sertoli cell monolayers in bicameral chambers, both the number and the viability of the cells decreased during the coculture. However, both parameters were equal to, or higher than, 60% after 2 wk. In PS-Sertoli cell cocultures, the ratios of p19:TP1 and TH2B:TP2 decreased dramatically during the second week of culture; this was due not only to a decrease in the levels of p19 and TH2B mRNAs but also to an enhancement in the relative amounts of TP1 and TP2 as compared to the amounts present on the first day of the coculture. Conversely, both ratios remained low in RS-Sertoli cell cocultures; this was due to a decrease in the levels of the four mRNAs studied during the coculture period. DNA flow cytometry studies showed the occurrence of a haploid cell population (1C) in PS-Sertoli cell cocultures from Day 2 onward, together with a decrease in the tetraploid cell population (4C). No such changes were observed in Sertoli cell-only cultures. By contrast, the haploid population decreased 3-fold during the first week in RS-Sertoli cell cocultures. Immunocytochemical studies demonstrated further that 5-bromo-2'-deoxyuridine-labeled PS of stages V-VIII were able to differentiate into RS under the present coculture conditions. Hence, although clearly imperfect, the present coculture system should help to clarify the local regulations governing spermatogenesis and should allow easier study of spermatogenic cell gene expression.

Animals↗