Biomedical subjects
Publications and source records attributed to V Thomas.
A 64-year-old female with the cancer family syndrome suffered from multiple malignant melanomas and a malignant fibrous histiocytoma. She has shown unusually long survival which is a feature of these patients.
Fifty patients with colonic tuberculosis are reported in whom a colonoscopic diagnosis confirmed by histological examination was possible in 40. Bacteriological studies did not increase the diagnostic yield. Abdominal pain was the most common symptom (90%) and an abdominal mass the most common abnormal physical finding (58%). A nodular mucosa with areas of ulceration was the usual colonoscopic finding. Ileocaecal disease was found in 16, ileocaecal and contiguous ascending colon disease in 14, segmental colonic tuberculosis in 13, ileocaecal disease and non-confluent involvement of another part of the colon in five, and pancolitis in two patients. This report emphasises that colonoscopy is a useful procedure for diagnosing colonic tuberculosis and that segmental colonic tuberculosis is not uncommon.
Cilofungin (LY-121019) is a fungicidal cell wall-active 1,3-beta-glucan synthetase inhibitor with a short plasma half-life and saturable nonlinear plasma pharmacokinetics. To optimize the in vivo efficacy of this compound, we studied the effects of its linear and nonlinear pharmacokinetics during continuous versus intermittent intravenous infusion of cilofungin in the treatment of experimental disseminated candidiasis in persistently granulocytopenic rabbits. Six groups of rabbits were studied, untreated controls (n = 32) and five cilofungin dosage regimen groups consisting of the following: 25 mg/kg of body weight intravenously twice daily (VLoINT) (n = 9); 50 mg/kg twice daily (LoINT) (n = 9); 90 mg/kg twice daily (HiINT) (n = 11); 5 mg/kg/h for 18 h/day (LoCI) (n = 7); and 10 mg/kg/h for 18 h/day (HiCI) (n = 7). All regimens achieved plasma concentrations exceeding the MIC for Candida albicans (0.25 microgram/ml). In vitro timed kill assays found that the fungicidal activity and rate of kill by cilofungin above the MIC for C. albicans was concentration dependent. At the lower dosage regimens (VLoINT, LoINT, and LoCI), cilofungin followed linear plasma pharmacokinetics, whereas at higher doses (HiCI and HiINT), nonlinear kinetics consistent with a saturated elimination pathway(s) were observed. Only HiCI and HiINT produced a 10(3)- to 10(4)-fold reduction in CFU per gram in candidiasis of the brain (P less than or equal to 0.001). HiCI and HiINT also significantly reduced infection in the choroid (P less than or equal to 0.05). All regimens, except VLoInt, significantly (P less than or equal to 0.01) reduced tissue infections in lung, liver, spleen, and kidney. However, only the regimens with nonlinear saturation kinetics (HiCI and HiINT) produced a 10(6) reduction in the spleen and a > 10(5) reduction of C. albicans in the kidney and liver. A simple doubling of the dosage from LoCI to HiCI resulted in tissue concentrations that were 10 times higher and a 10(2)- to 10(4)-fold-greater antifungal effect. There was a direct correlation (r2 = 0.83) between tissue concentrations of cilofungin and antifungal activity. Thus, continuous and intermittent infusion dosage regimens that elicit nonlinear saturation plasma pharmacokinetics of cilofungin were associated with increased antifungal activity against experimental disseminated candidiasis.
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A simple covalent enzyme-linked immunoassay procedure (CELIA) is described for the routine determination of free and immune complex-bound antibodies in sera. Assays for the latter could not have been performed by adsorption ELISA due to the high ionic strength of the reassociating buffer. For the measurement in human sera of free naturally occurring IgG and IgM antibody directed against the hapten spermine, polycarboxystyrene microtiter plates with covalently coupled spermine were used. For the determination of immune complex-bound antipolyamine IgG and IgM antibody titers, serum was first dissociated at pH 2.3 in tubes and then reassociated at pH 8.1 in the wells of a microtiter plate containing covalently bound spermine. The reactivity of anti-spermine antibodies was increased from 2- to 13-fold after dissociation and reassociation compared to that of non-dissociated area. The apparent reaction constant (Rapp.) of free IgG antibodies to spermine in the sera of 19 bronchopulmonary patients with cancer differed significantly from Rapp. values of IgG antibodies having this specificity in ten other patients with non-malignant disease.
The coupling of viral antigens from parainfluenza virus (PIV-1), cytomegalovirus (CMV) and human immunodeficiency virus (HIV-1) to chemically functionalized polystyrene plates has permitted us to develop a covalent enzyme-linked immunoassay (CELIA) for measuring the titers of free antibody (Ab) and immune complex (IC) bound Ab directed against each of these viruses. The method was first validated for experimentally produced IC (PIV-anti-PIV) and then applied to the analysis of IC in human sera. In the case of a renal transplant patient with CMV viremia whose free Ab titers were less than 100, the method unambiguously permitted the IC bound anti-CMV titers to be determined. In the case of a survey for HIV-1 Ab, it also allowed us to identify a sub-group of seropositives with IC anti-HIV. In view of the ease and rapidity with which CELIA can be performed, this technology should enable determinations of IC bound Ab of defined specificity to be undertaken routinely in seroepidemiological surveys.
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To investigate the potential use of SCH-39304 for the prevention and treatment of disseminated candidiasis in granulocytopenic patients, we studied its in vivo antifungal activity as preventive, early, and late treatments in three models (acute, subacute, and chronic) of disseminated candidiasis in persistently granulocytopenic rabbits. SCH-39304 was an effective as amphotericin B alone and fluconazole alone for the prevention of disseminated candidiasis. SCH-39304 alone and fluconazole alone were as effective as amphotericin B plus flucytosine for early treatment of subacute disseminated candidiasis. When treatment was delayed for 5 days to establish chronic disseminated candidiasis, SCH-39304 was less effective than amphotericin B plus flucytosine. In comparison with different treatment regimens, SCH-39304 was more effective in early and preventive treatment. Thus, SCH-39304 was comparable to treatment control regimens in prevention and early treatment of subacute disseminated candidiasis. SCH-39304 also was most effective in granulocytopenic rabbits with disseminated candidiasis when used for prevention or early treatment.
Polyclonal anti-idiotypic antibodies (anti-Ids)(fim) developed against idiotypes on antibodies (Ab-1s) that specifically bind structural, organelle fimbrial proteins of Escherichia coli were able to modulate immune function in anti-Id(fim)-immunized mice. Proliferation or suppression of splenic lymphoid cell responses by polyclonal anti-Ids in tissue culture appeared to be dose dependent. Anti-Ids were able to induce a dose-dependent T-cell-mediated immunity specific for type 1 fimbrial antigen(s) in immunized animals when assessed in vitro, but they failed to elicit in vivo positive ear-swelling skin reactions. Anti-Ids were unable to induce protective immunity against an in vivo infectious challenge with E. coli in anti-Id-immunized adult animals, but they stimulated a specific, secondary antibody response in anti-Id-challenged mice. Anti-Ids stimulated the development of anti-anti-Ids (Ab-3s) specifically binding a fimbrial antigen(s) and revealed the presence of antibody idiotypes binding E. coli adhesin proteins in the 27- to 29-kilodalton range. Results suggest discrete, but subtle, immunomodulatory effects of the anti-Ids and potential vaccinoid properties capable of stimulating a specific humoral and cellular response in vivo.
A double blind, randomised, placebo controlled clinical trial was carried out in endoscopically proved chronic duodenal ulcer patients to compare the efficacy of sucralfate and ranitidine. Sucralfate 1 g four times daily and ranitidine 150 mg twice daily were found to be equally effective in inducing ulcer healing (73.1% and 82.1% respectively) during the 6-week treatment period. The rate of recurrence of the ulcer within six months after the initial treatment (84.2% and 82.6%) was also comparable in the sucralfate and ranitidine groups. Sucralfate and ranitidine are equally effective in ulcer healing and prevention of ulcer relapse.
The hemin moiety of horseradish peroxidase (donor:hydrogen-peroxide oxidoreductase, EC 1.11.1.7) was removed and the apoprotein reconstituted with the fluorescent protoporphyrin IX. Steady-state and time-resolved fluorescence properties of the HRP(desFe) adduct were examined; the multifrequency phase and modulation method was utilized for lifetime and dynamic polarization studies. The emission spectrum of HRP(desFe) had maxima at 633 and 696 nm. The lifetime of this emission was characterized by a single exponential decay of 16.87 ns at 22 degrees C. Debye rotational relaxation times for HRP(desFe) were determined using both static (Perrin plot) and dynamic (differential phase and modulation fluorometry) methods; these two approaches gave values of 96 and 86 ns, respectively. A spherical protein of HRP's molecular weight and partial specific volume would be expected to have a Debye rotational relaxation time, at 22 degrees C, in the range of 50 to 60 ns, depending upon the extent of hydration. Hence our results indicate that HRP(desFe) is asymmetric; the global rotational relaxation times observed are consistent with those of a prolate ellipsoid with an axial ratio of 3:1.
Time-resolved fluorescence studies on the emission of NADH bound to porcine heart mitochondrial malate dehydrogenase [S)-malate:NAD+ oxidoreductase, EC 1.1.1.37), in the presence and absence of saturating levels of hydroxymalonate, were carried out. The lifetime of NADH bound in the ternary complex was determined to be 9.5 ns compared to 1.74 ns as reported in the literature. Steady-state and dynamic polarization data indicated a Debye rotational relaxation time in the range of 106-109 ns for the dimeric enzyme. This value is significantly larger than that calculated for a spherical protein and is consistent with the asymmetric dimer found by crystallographic studies.
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An ever increasing number of drugs prescribed in the treatment of asthma are presented as aerosols, so that patients may be requested to inhale many puffs every day. In this study, the opinion of asthmatic patients was sought and their behaviour towards aerosols during attacks and in long-term treatment was recorded by means of a questionnaire. The answers confirmed that asthmatics liked aerosols and found them usually effective, but 60% of these patients exceeded the stated dose, and if the drug failed to bring the expected relief, 30% waited 24 hours before calling for a doctor. In long-term treatments, 80% of the patients studied said that 10 puffs a day were a nuisance, and 12% were switched to another treatment for that reason. These results are very important. Doctors should reinforce the patients' education and limit the number of daily puffs they prescribe to obtain better compliance of asthmatics with their treatment.
We investigated whether salbutamol (S) and ipratropium bromide (IB) exerted a true additive bronchodilator effect in asthma. In fifteen selected chronic asthmatics, individual cumulative dose-response curves to S and IB were performed on two separate days (linear regression of bronchodilator response (delta FEV1) between 20 and 80% of maximal response, versus log dose), and the dose of S equipotent to the IB dose giving the maximal bronchodilator effect (IBopt) was calculated by interpolation of each S curve. On two other days, each patient received IBopt or the equipotent S dose followed by an additional 400 micrograms S. On day 1 or 2, FEV1 reached 220 +/- 410 ml and 2410 +/- 380 ml (p less than 0.05) after the maximal dose of IB and S respectively. On day 3 or 4 after pretreatment by IB or S an additional 400 micrograms S gave a further increase, which was similar in both series (315 and 320 ml, respectively). FEV1 after combination treatment reached 238 +/- 350 ml and was not significantly different from the maximal effect of S (2440 +/- 290 ml). We conclude that S and IB exert a true pharmacological additive effect, since the combination effect is as great as the maximal effect of the most potent drug (S) and greater than the maximal effect of IB, and that the same additional dose of S gives the same increase after equipotent doses of S and IB.
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