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Biomedical subjects

N Muller

Publications and source records attributed to N Muller.

At least 19 recordsLinked to original sources
PubMed2000

Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins.

Homocamptothecin (hCPT) is an E-ring modified camptothecin (CPT) analogue bearing a methylene spacer between the alcohol and carboxyl functions of the CPT lactone. Combining pronounced inhibitory activity of topoisomerase I (Topo I) with enhanced plasma stability, hCPT constitutes an attractive template for the elaboration of new anticancer agents. Fluorinated hCPT analogues, prepared in enantiomerically pure form, were assayed by their stimulation of Topo I-mediated DNA cleavage. Translation into cytotoxicity against tumor cells was evaluated on HT29 human colon adenocarcinoma and on the multidrug resistant lung and bladder tumor cell lines, A549 and T24r. Good correlation is observed between the ability of the drugs to stimulate Topo I-mediated DNA cleavage and the respective 50% inhibitory concentrations (IC(50) values) of the HT29, A549, and T24r cell growth. Fluorine substitution in the A-ring of hCPT was found to have a pronounced influence on biological activity, providing several compounds which are up to 100-fold more potent than CPT in terms of IC(50). Among these, 10,11-difluoro-hCPT has been selected for further development.

Antineoplastic Agents↗
PubMed1999

Nephrotic syndrome in Namibian children.

BACKGROUND AND OBJECTIVES: Patterns of nephrotic syndrome vary between regions and countries, and influence approaches to management. In the mid-1970s the University of Stellenbosch became involved in providing tertiary care to Namibia, including a paediatric nephrology service. The aim of this study was to document the clinical, pathological and outcome features of nephrotic syndrome in Namibian children. SUBJECTS: Seventy black Namibian children with nephrotic syndrome were managed from 1975 to 1988. Sixty-eight renal specimens (67 biopsies and 1 autopsy specimen) were evaluated. RESULTS: Twenty-nine of the 70 children (41.4%) were hepatitis B virus (HBV) carriers, of whom 25 (86.2%) were male. Of the 29, 26 had predominantly membranous glomerulonephritis (MGN), 1 mesangiocapillary glomerulonephritis (MCGN), and 1 focal segmental glomerulosclerosis (FSGS); 1 child in advanced renal failure was not biopsied. Five children (7.4%) showed minimal change disease (MCD), 11 (16.2%) FSGS and 15 (22.1%) diffuse mesangial proliferative glomerulonephritis (DMP). The remaining 10 children showed diffuse glomerulosclerosis (6), MCGN (3) and endocapillary proliferative GN (1). Four of the 5 children with MCD went into remission on immunosuppressive treatment. Of the 15 with DMP, 4 improved spontaneously and only 1 of those treated did not improve. Only 2 of those with FSGS improved on treatment. The children with HBV-associated MGN and MCGN were offered symptomatic rather than specific treatment. Thirteen children presented with degrees of chronic renal failure. Eight are known to have died, 3 of relentless nephrotic syndrome and 4 (of whom 3 were HBV carriers) of end-stage renal failure. One child died of penicillin anaphylaxis. CONCLUSIONS: The pattern of nephrotic syndrome in black Namibian children differed greatly from the non-African pattern elsewhere in that MCD was uncommon and HBV-associated GN was the most common single group. The most frequent pattern of HBV-associated GN was MGN with some mesangiocapillary features showing marked male predominance. MCD and DMP were potentially treatable and could only be identified by biopsy. HBV carrier rates exert a major influence on the proportions of morphological subgroups of nephrotic syndrome in children. As these HBV carrier rates alter in future due to the influence of vaccination and urbanisation, the relative size of nephrotic subgroups seems likely to alter.

Adolescent↗
PubMed1998

Efficient simulation of coherence transfer pathway selection by phase cycling and pulsed field gradients in NMR

The selection of well-defined coherence transfer pathways is an essential feature of all but the simplest NMR and EPR pulse sequences. This selection can be achieved by phase cycling and by pulsed field gradients. The properties of the RF-pulses (flip angle, offset effects, inhomogeneity) and transport phenomena (diffusion, flow) in conjunction with gradients cause a weighting of the different coherence transfer pathways. We present a method by which the selection process can be simulated efficiently and visualized easily. In its basic form it involves straightforward matrix manipulations without reference to the density matrix and the particular spin system. This method is implemented in a MATLAB program, called CCCP (Complete Calculation of Coherence Pathways). Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

The glycyl radical enzyme TdcE can replace pyruvate formate-lyase in glucose fermentation.

Mutants of Escherichia coli unable to synthesize a functional pyruvate formate-lyase (PFL) are severely impaired in their capacity to grow by glucose fermentation. In a functional complementation assay designed to isolate the pfl gene from Clostridium butyricum, we fortuitously identified a gene that did not encode a PFL but nonetheless was able to complement the phenotypic defects caused by an E. coli pfl mutation. The clostridial gene encoded a basic 14. 5-kDa protein (TcbC) which, based on amino acid similarity and analysis of immediately adjacent DNA sequences, was part of a transposase exhibiting extensive similarity to the product of the site-specific transposon Tn554 from Staphylococcus aureus. Our studies revealed that the clostridial TcbC protein activated the transcription of the E. coli tdcABCDEFG operon, which encodes an anaerobic L-threonine-degradative pathway. Normally, anaerobic synthesis of the pathway is optimal when E. coli grows in the absence of catabolite-repressing sugars and in the presence of L-threonine. Although anaerobic control of pathway synthesis was maintained, TcbC alleviated glucose repression. One of the products encoded by the tdc operon, TdcE, has recently been shown to be a 2-keto acid formate-lyase (C. Hesslinger, S. A. Fairhurst, and G. Sawers, Mol. Microbiol. 27:477-492, 1998) that can accept pyruvate as an enzyme substrate. Here we show that TdcE is directly responsible for the restoration of fermentative growth to pfl mutants.

Acetyltransferases↗
PubMed1997

Internal rotation of mutually interacting methyl groups: A 13C NMR study

The overall and intramolecular rotational diffusion behavior of 1,3, 7,10-tetramethylbenzo[c]cinnoline was determined from longitudinal 13C NMR relaxation and 1H-13C NOE measurements in dilute chloroform solution. The four methyl groups in this compound represent three different situations of sterical hindrance. One pair of methyl groups is in close mutual sterical contact, forming the ends of an open six-membered ring. Assuming completely anisotropic overall molecular tumbling combined with a 120 degrees jump model for the internal methyl rotations the jump rates of methyl groups were evaluated and compared to earlier results on different sterically hindered compounds, in particular with respect to a potential cogwheel-like intermethyl interaction. To characterize intermethyl interactions in different sterical situations, a new gauge-the "methyl interaction volume"-is introduced. Implications for correlated rotational diffusion of methyl groups are discussed. Copyright 1997 Academic Press. Copyright 1997Academic Press

Journal Article↗
PubMed1997

Giardia lamblia infections in B-cell-deficient transgenic mice.

In the present study, we infected B-cell (and antibody-)-deficient transgenic mice with the Giardia lamblia clone GS/M-83-H7. These animals were inhibited in intestinal anti-Giardia immunoglobulin A (IgA) production and could not resolve the parasite infection, and antigenic diversification within the respective parasite populations occurred in an unusually slow manner. These findings indicate an important immunological function of local IgA antibodies which promotes antigenic variation of the parasite and is involved in control of the parasite infection.

Animals↗
PubMed1996

Pregnancy in partially remitted hepatitis B-associated membranous glomerulonephritis.

Hepatitis B-associated glomerulonephritis is a relatively common cause of nephrotic syndrome in endemic areas affecting especially male children. When this disease affects girls or women, both the glomerular disease and the hepatitis B carrier state could affect subsequent pregnancies. This may be the first reported case of such a pregnancy. In this patient the partially remitted renal disease and the reduced infectivity of the hepatitis B carrier state decreased the influence of the disease on the pregnancy.

Carrier State↗
PubMed1995

Cryptogenic organizing pneumonia. A report of 25 cases and a review of the literature.

Cryptogenic organizing pneumonia (COP), also known as bronchiolitis obliterans organizing pneumonia (BOOP), is an uncommon lung disease characterized by the presence of granulation tissue within the alveolar ducts and alveoli. Because of the limited published literature on this topic and limited information on outcome we reviewed our own experience over an 8-year period and also critically evaluated the literature. We reviewed all cases of COP diagnosed from 1985 through 1992 at Vancouver General Hospital: 25 patients (14 male, 11 female) aged 20-77 years (mean, 49 yr, SD +/- 17 yr). Nine patients had myeloproliferative disorder, including 6 who had allogenic bone marrow transplants; 2 patients had connective tissue disease; and 14 patients had no underlying disease (idiopathic). Data retrieved retrospectively from clinical records included demographics, risk factors, symptoms, chest radiographs, computerized tomograms, lung function tests, therapy prescribed, and response to therapy. Symptoms included dyspnea and cough (n = 15) (60%), cough only (n = 10) (40%), and fever (n = 15) (60%). Twenty-two patients were diagnosed by open lung biopsy and 3 by transbronchial biopsy. Lung imaging showed bilateral patchy airspace consolidation or nodular opacities as the main finding in 22 patients. Pulmonary function tests showed a combined restrictive and obstructive pattern. All patients received prednisone therapy except 1 patient whose idiopathic findings resolved completely with minimal treatment. Eight patients died, including 4 of the 9 patients with myeloproliferative disorder--2 from a combination of respiratory failure due to COP and graft-versus-host disease. One of 2 patients with connective tissue disease died, and 3 of 14 patients with idiopathic COP died. COP is an uncommon condition but should be considered in patients with bilateral airspace disease, especially those who fail to respond to antibiotics for presumed pneumonia. Although pulmonary function tests and CT scan findings in conjunction with the clinical features usually suggest the diagnosis, definite confirmation usually requires either open lung biopsy or transbronchial biopsy. Histologic confirmation of the diagnosis is particularly warranted as therapy with corticosteroids is usually needed for a number of months. The prognosis is excellent with idiopathic cases but more guarded especially when COP is associated with lymphoproliferative or connective tissue disease.

Adrenal Cortex Hormones↗
PubMed1994

Anti-inflammatory properties of IL-1 in carrageenan-induced paw oedema.

To evaluate any inhibitory effect of a single dose of human recombinant interleukin-1 beta (hrIL-1 beta) on the severity of carrageenan-induced oedema in rats (a commonly used model of acute inflammation), we first injected 0.1 ml of carrageenan (0.2%, 0.5%, or 2%) to induce mild, moderate, or severe inflammation, respectively into the right rear footpad. Then we promptly injected the interleukin (0.02, 0.2, or 2 micrograms) subcutaneously into the flank. The initial rapid increase in volume of the injected paw (within 2 h of the subplantar injection) was independent of the dose of carrageenan, whereas the increase in volume by 6 to 10 h was dose-dependent. All doses of HrIL-1 beta inhibited the carrageenan-induced swelling at the 6th hour. In the moderate and severe carrageenan-induced oedemas, the higher dose of HrIL-1 beta induced a delayed inflammation peaking at 10 h instead at 6 h.

Animals↗
PubMed1994

Representation of affinity in the case of co-operativity in protein-ligand binding.

We have already proposed a "Global Association Function" to represent the global affinity of proteins to a drug; it was first applied in the case of independent binding sites. In this paper, we show that this same function can also be used to assess interactions between sites by varying the number of interacting sites and their co-operativity level. The resulting curves in two application cases are given together with the corresponding Scatchard plot: i) in a system with one single class of identical and interacting sites, ii) in a system with two classes of sites in which either primary or secondary are interacting; unexpectedly, in this latter case we also observed that sometimes positive co-operativity occasionally resulted in a concave-up Scatchard plot which is unusually admitted. In addition, as described in one example, our function is assumption free; this might be an advantage over usual methods, such as discrete parameter methods, because they require additional and empirical hypotheses on their related binding model.

Binding Sites↗
PubMed1994

Binding sites of fluorescent probes on human serum albumin.

Human serum albumin is known to have two major and selective drug binding sites, termed sites I and II. The fluorescent probes, dansylamide and dansylsarcosine selectively interact with sites I and II, respectively. However, the binding site of the fluorescent probe dansylglycine on human serum albumin is not clear from the literature. This study investigated whether dansylglycine interacts tightly with site I or II. Spectrofluorimetric titrations (quenching and complex) and circular dichroism measurements were performed to determine the binding characteristics of dansylglycine to human serum albumin. Modification in probe fluorescence was described by fluorescence titrations to be a result of competitive displacement by ligands. The pattern of displacement of this probe by several ligands whose primary binding sites are exactly known, enabled the identification of its specific binding site. The fluorescence of dansylglycine is only extensively changed when ligands of site II are added, suggesting that it strongly interacts with the benzodiazepine/indole binding site on human serum albumin.

Binding Sites↗
PubMed1994

HIV-associated nephropathy--an initial presentation in an HIV-positive patient.

The lesions of HIV-associated nephropathy occur in patients with AIDS, AIDS-related complex and in individuals clinically asymptomatic for HIV infection. We report on a 35-year-old black South African woman who presented with nephrotic syndrome and renal failure. The renal biopsy appearance suggested HIV infection and this was subsequently verified. This finding emphasises the possibility that otherwise asymptomatic patients presenting with renal disease may be HIV-positive.

Adult↗
PubMed1993

Direct high-performance liquid chromatographic resolution of the enantiomers of tiaprofenic acid using immobilized human serum albumin.

Resolution of racemic tiaprofenic acid (TA) has been performed using immobilized human serum albumin as the stationary phase. The eluent was phosphate buffer-acetonitrile-n-octanoic acid (90:10:0.015, v/v). Detection was achieved at 305 nm. The pharmacokinetics of the enantiomers were studied following oral administration into humans and after subcutaneous injection in rats. Plasma concentrations of (+)-TA were much greater than those of (-)-TA. For the rat, the pharmacokinetic parameters between (-)-TA and (+)-TA were all statistically different (p < 0.005).

Administration, Oral↗
PubMed1993

Hyaluronidase degradation of hyaluronic acid from different sources: influence of the hydrolysis conditions on the production and the relative proportions of tetra- and hexasaccharide produced.

1. Hyaluronic acid (HA) can be digested with a Streptomyces hyaluronidase. 2. The rate of production and the ratio of tetrasaccharide (T) and hexasaccharide (H), studied by HPLC, varied with the temperature and duration of hydrolysis. 3. The rates of production and the respective amounts of the two oligosaccharides depended on the rheological properties of the HA from different sources. 4. A close relationship was found between the initial rate of hydrolysis and the intrinsic viscosity of the HA (eta i). 5. Our data suggest that enzymatic degradation at a given pH value, temperature, and duration of hydrolysis is dependent on the conformation of HA. 6. Moreover, under given conditions, the relative proportions of the two oligosaccharides depend on the eta i and may also reflect the degree of hydrolysis of the substrate.

Chromatography, High Pressure Liquid↗