Biomedical subjects
R Thomas
Publications and source records attributed to R Thomas.
A phase I and pharmacokinetic study of trimetrexate using a 24-hour continuous-injection schedule.
Trimetrexate (TMTX) is an analog of methotrexate and a potent inhibitor of the enzyme dihydrofolate reductase. In this phase I study, TMTX was given intravenously to 32 patients as a constant infusion over 24 hours every 28 days. The maximum-tolerated dose of TMTX was 200 mg/m2, with myelosuppression as the dose-limiting toxicity. Other toxicities included nausea and vomiting, stomatitis, erythema and phlebitis at the site of infusion, rash and skin hyperpigmentation, and elevated serum hepatic enzymes. Two drug-related deaths occurred secondary to leukopenia and sepsis. Twenty-six patients were evaluable for antitumor response. Twenty-one patients had progressive disease, while three patients had disease stabilization. There were two partial responses observed--one in a patient with breast cancer and a second in a patient with nasopharyngeal carcinoma. TMTX pharmacokinetics were studied in 15 patients. The drug had a mean terminal half-life of 13 hours. Steady-state was not achieved during the 24-hour infusions. Only 6% of the parent compound was excreted unchanged in the urine, and CSF levels averaged less than 2% of simultaneously measured plasma levels. A dose of 150 mg/m2 is recommended for phase II trials of TMTX using this 24-hour infusion schedule.
Acute renal failure following collective intoxication by Cortinarius orellanus.
Twenty-six young men with no previous medical history all ingested mushroom soup, exclusively made with Cortinarius orellanus. They were hospitalized 10-12 days after the incident. On admission, 12 patients presented with acute tubulointerstitial nephritis with acute renal failure; 8 required haemodialysis. In addition to symptomatic treatment, 9 patients were given corticosteroids. In this group of 12 patients, 8 recovered rapidly, and the other 4 suffered from chronic renal failure for several months. In the other group of 14 patients, initial leukocyturia was observed in 12 cases, although renal function remained normal during a one-year follow-up. Hepatic acetylation and hydroxylation tests performed after 6 months in 22 patients did not provide any explanation for the strong individual sensitivity to the renal toxicity of this fungus.
The effect of chloroquine and hyperthermia on murine neuroblastoma.
A number of reports suggest that hyperthermia is an effective adjunctive treatment modality in management of neural crest tumors. Recent studies have demonstrated a synergistic effect of induced hyperthermia when coupled with chloroquine in an in vitro model. This study examines the effect of chloroquine and hyperthermia in an in vivo murine neuroblastoma model. Forty-seven Ajax white mice (weighing 20 to 30 g) received a subaxillary tumor burden (C-1300 murine neuroblastoma) per trochar (1.25 x 10(6) cells). The tumor was then incubated for 9 days. Mice were then divided into four groups: group 1, controls (n = 15); group 2, hyperthermia (n = 12); group 3, chloroquine (n = 10); and group 4, chloroquine with hyperthermia (n = 10). Hyperthermia was induced with 40 to 69 mW/cm2 at 2,450 MHz microwave radiation for 4 minutes to achieve a temperature of 41.5 degrees C for 10 of 14 treatment days. Chloroquine was administered intraperitoneally at a dose of 40 mg/kg body weight for 10 of 14 treatment days. Mice were weighed and tumor size was determined daily. Animals were killed on day 21 and postmortem examination was performed, with tumors graded histologically. Animal weight, tumor weight, and tumor size were similar for all groups (P greater than .05). Mortality was 6% in group 1, 25% in group 2, 50% in group 3, and 40% in group 4 (P less than .05). Rate of tumor metastases was also statistically different from controls: group 1, 0%; group 2, 60%; group 3, 90%; and group 4, 90% (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Evaluation of combined commercial enzyme-linked immunosorbent assay for detection of rota and adenoviruses for automation.
219 stools were examined by direct electron microscopy (EM), culture and 'combined' commercial enzyme-linked immunosorbent assay kits (CELISA). The specificity of the combined ELISA for rotavirus was 100% as compared with EM, and 100% for adenovirus when both culture in addition to EM were carried out. ELISA appeared to be more sensitive than EM for both viruses. There was no cross-reaction between the 2 'combined' antisera. This technique may be useful for automation of viral diagnosis with ELISA using a 'panel' of selected viruses for a variety of specimens.
Genes and development: molecular and logical themes.
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A waterborne outbreak of leptospirosis among United States military personnel in Okinawa, Japan.
A waterborne outbreak of leptospirosis occurred among US military personnel during September 1987, on the island of Okinawa, Japan. Micro-agglutination titres for leptospiral antigen of greater than or equal to 200 were detected in hospitalized adult males averaging 22.5 years of age with symptoms compatible with leptospirosis. Epidemiological findings revealed two case clusters distinguished by time and place of exposure. The overall attack rates among recreational swimmers and combat skills training participants were 467/1000 (7/15) and 183/1000 (15/82), respectively. Swallowing of water differentiated individuals with laboratory-confirmed infection from those with no infection, while water immersion alone did not appear to result in leptospiral infection. Additionally, subnormal rainfall may have contributed to the risk of exposure associated with this outbreak.
Effect of dietary nucleosides on growth and maturation of the developing gut in the rat.
Dietary nucleoside (DN) as a precursor for nucleic acid synthesis may be important for rapidly dividing cells, since gut epithelial cells have limited capacity for de novo purine and pyrimidine synthesis. We evaluated in a controlled blinded study the effect of added nucleosides, 0.8% by weight, given for 2 weeks, on gut growth and maturation in 20 weanling rats. Mucosal protein and DNA in the proximal intestinal segment were 50% and 77% higher, respectively, in the DN-supplemented group (n = 10; p less than 0.05). Villus height based on cell count was 25% greater in the DN group (p less than 0.05). Maltase activity was significantly greater in proximal, middle, and distal intestinal segments, and the largest increase, 87%, was seen in the proximal gut mucosa. The maltase/lactase ratio was also higher in this segment. Increases in sucrase were less prominent. Lactase was minimally affected. The pattern of change in disaccharidase activity suggests that DN may enhance gut growth and maturation of the intestine in the weanling rat, the effects being more pronounced in the proximal segment. Diets free of nucleosides and nitrogenous bases may have adverse effects on the gut.
Characterization of gentamicin-resistant respiratory-deficient (res-) variant strains of Staphylococcus aureus.
Exposure of sensitive cells of Staphylococcus aureus to concentrations of gentamicin higher than the minimal inhibitory concentration, results in the recovery of low level resistant strains with a greatly altered phenotype (variants). Because the phenotypic alteration in these strains is so great the expected diagnostic characterization of these variants as S. aureus is obscured. Starting with a genetically-marked parent strain, a comprehensive cytological, physiological, morphological, genetic and biochemical analysis of the variants isolated from it was carried out. The genetic lineage of the variants to the parent was also established by DNA/DNA hybridization. Variants result from mutations in the hemin biosynthesis locus, the effect of which is to disrupt the synthesis of components of the electron transport system, lipid synthesis and selected nucleotide synthesis. Thus the strains are defective in aerobic and anaerobic respiration, (res-), in active transport of aminoglycosides (which confers low level resistance), export of characteristic exo-enzymes, and in cell wall composition and structure.
Determination of terbinafine in nail samples during systemic treatment for onychomycoses.
A combination of alkali treatment and proteinase K digestion was used to solubilize nail samples from patients with onychomycosis treated orally with terbinafine. The samples were extracted and the levels of terbinafine and its metabolite measured by high-pressure liquid chromatography. The results showed a relatively rapid penetration of terbinafine into normal nail plate, suggesting that diffusion via the nail plate is the primary route of entry into this tissue. The levels of terbinafine achieved in nail samples exceeded the range of MICs for dermatophytes at the earliest time point (4 weeks) tested in 50% of patients and remained stable, without accumulation, during periods of treatment of up to 3 months.
The conservative management of choroidal melanoma.
The results of 32 choroidal melanomas managed by observation, Iodine-125 scleral plaques and local surgical excision are presented. Initially, 12 patients were managed by observation, and of these three continued to be managed by observation alone. Fifteen patients were managed with Iodine-125 scleral plaques and followed for an average of 15 months. The tumour regressed in 11, remained the same in three, and recurred in one case. The final visual acuity remained within two Snellen lines of that recorded preoperatively in 10 patients. Fourteen patients underwent local excision with an average follow-up of 31 months. These cases, in general, had larger tumours. The final visual acuity was within two Snellen lines of the preoperative vision in four patients. Five eyes required enucleation at a later date. Four of the five enucleations occurred earlier in the series. The management of choroidal melanoma remains controversial. Various methods of conservative treatment are described and the indications for conservative management by observation, scleral plaque and local excision are discussed.
Inactivation of human immunodeficiency virus type 1 in tissue culture fluid and in genital secretions by the spermicide benzalkonium chloride.
We have shown that the spermicidal agent benzalkonium chloride can exert a direct inhibitory effect on the viral reverse transcriptase activity of human immunodeficiency virus type 1 (HIV-1) when utilized at concentrations of 0.05% and higher. Exposure of HIV-1 to this disinfectant at concentrations of more than 0.05% was able to completely destroy viral infectivity, as assessed on susceptible target cells. We have further shown that HIV-1, which is present in both seminal and genital secretions, can be inactivated in such fluids by direct exposure to benzalkonium chloride.
Vasopressin mediates alpha 1-adrenergic stimulation of adrenocorticotropin secretion.
In conscious rats bearing venous and cerebroventricular cannulae, central administration of the alpha 1-adrenergic agonist methoxamine stimulated the secretion of ACTH, and the effect was reduced by the alpha 1-antagonist prazosin. Methoxamine was more potent in stimulating ACTH secretion when injected icv than peripherally, suggesting that the stimulant alpha 1-adrenoceptors are located in the brain rather than in the periphery. In order to investigate the relative roles of hypothalamic CRF-41 and vasopressin as mediators of the stimulant effects of alpha 1-adrenoceptors on ACTH secretion, we examined the effects of equipotent doses of antagonists to CRF-41 and vasopressin on the ACTH responses to methoxamine. The effect of methoxamine was reduced by the vasopressin antagonist dPTyr(Me) arginine vasopressin but not by the CRF-41 antagonist alpha-helical CRF-9-41, suggesting that vasopressin is more important than CRF-41 in mediating the effects of alpha 1-adrenoceptors on ACTH secretion. However, the combination of the two antagonists caused a reduction in the ACTH response to methoxamine that was greater than that of the vasopressin antagonist alone. This suggested that CRF-41 plays some role in this response, possibly by enhancing the activity of vasopressin in a synergistic manner. These two hypothalamic peptides seem to account for most of the ACTH releasing activity of alpha 1 adrenoceptor activation.
Myocardial preservation: a comparison of oxygenated crystalloid and blood cardioplegia.
The purpose of this experiment was to compare myocardial protective effect after global ischemia using oxygenated crystalloid (CCcO2) and an oxygenated blood (BCcO2) cardioplegic solutions. Post-ischemic ventricular performance was studied in 2 equal (n = 7) groups of dogs subjected to 120 min of global ischemia induced at average myocardial temperatures of 8 degrees C in the CCcO2 group and 18 degrees C in the BCcO2 group. Left ventricular (LV) function included analysis of LV systolic function (global and regional function), LV diastolic function (chamber and myocardial stiffness) and LV relaxation was measured by sonomicrometry and Millar micrometers. Data were processed with a Dec PDP-11/23 computer. In vitro oxygen content (Vol%) measured 3.2 +/- 1.0 (CCcO2) and 9.5 +/- 0.3 (BCcO2). Percent recoveries of LV global function (LVSP, loop area, % shortening, LV dp/dt, mean VCF and E max) in the CCcO2 group were approximately the same as those in the BCcO2 group. There were no significant differences in LV regional function (loop area and % shortening) after ischemia between the two groups. The chamber and myocardial stiffness after ischemia in the CCcO2 group were almost the same as the baseline values. Values in the BCcO2 group were reduced significantly compared to the baseline level. There were significant differences in post-ischemic chamber and myocardial stiffness between the two groups. Post-ischemic maximum negative LV dp/dt in both groups decreased significantly compared to the baseline values. However, the time constant and diastolic interval after ischemia in both groups were approximately the same as the baseline values. We conclude that there were no significant differences in myocardial protective effect between the CCcO2 and BCcO2 groups, and both methods preserved the ischemic myocardium well.
Intracardiac epithelial cyst in association with an atrioventricular canal defect.
An epithelial cyst within the heart is an uncommon occurrence. Cysts associated with cardiac malformations are very rare. We present a case of an epithelial cyst in the interatrial septum of a premature infant in association with a persistent atrioventricular canal defect.
Isolated complete denervation of the flexor pollicis longus.
Isolated complete denervation of the flexor pollicis documented by electromyography has not been reported. We report a healthy 26-year-old man who sustained a gunshot wound at the base of his left index finger. He reported ipsilateral flexor pollicis longus (FPL) paralysis one week later, after undergoing surgical exploration of the radial digital artery and nerve supplying the left index finger under axillary block anesthesia. Forearm pronation and distal interphalangeal flexion of the second through fifth digits were normal. Electromyographic findings revealed complete isolated denervation of the FPL. This represents a lesion involving the branch or branches of the anterior interosseous nerve to the FPL. The etiology was postulated to be either a direct injury secondary to intravenous catheter placement or an unusual presentation of neuralgic amyotrophy.
[Anti-basement-membrane antibody mediated, rapidly progressive, glomerulonephritis. Diagnostic and therapeutic strategy based on a retrospective study of 14 cases].
Fourteen cases of anti-GBM antibody-induced RPGN were evaluated retrospectively in terms of renal function improvement and therapeutic risks. Nine men and 5 women (mean age: 55.3 years) were observed over a 9 year period; in three patients, hemoptysis was associated with renal disease (Goodpasture's syndrome). Most of these patients had received combinations of steroid therapy (ST), immunosuppressive drugs (IS) and plasma exchanges (PE). Age, duration of symptoms prior to diagnosis, initial renal function, therapeutic modalities and complications were assessed according to renal outcome: 9 patients (group A, "non-responders") remained on dialysis irrespective of the treatment administered; 5 patients (group B, "responders") recovered renal function. Complications, especially infections, were twice as frequent in group A. Two of the 4 recorded deaths were related to the disease or the treatment. Analysis of clinical and pathological values at the time of entry into the study for both groups indicated that oliguria/anuria, serum creatinine greater than 500 mumol/l and greater than 50% crescents, when associated, were factors predictive of poor renal outcome; in these patients, dialysis may be required except in cases of pulmonary hemorrhage. In all other patients, treatment with ST, IS and PE is recommended. Active hemoptysis necessitates pulse steroids or PE; if absent, further tests (carbon monoxide uptake, bronchoalveolar lavage, lung biopsy) are indicated before use of aggressive therapy.
[Valproic acid: association of a fatal acute hepatitis and pancreatitis].
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