Biomedical subjects
Publications and source records attributed to E Higgins.
The face of malignant melanoma is changing. The incidence is rising, and the disease is tending to affect a younger age group. Publicity about the disease is intense, and the trend is towards earlier diagnosis. Early diagnosis is essential, as the only effective treatment remains surgical excision, which is curative for thin lesions.
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Five-residue-long deletions centered on Ala63, Ala75, and Glu118 of ribosomal protein L7/L12 gave low mutant yields (5% or less) when the mutant genes were cloned in phage M13mp18 and controlled by the L10 promotor. Deletions of Glu118-Lys120 or Lys120 (the COOH-terminus of L7/L12) gave higher mutant yields, up to 50% with L7/L12 delta Lys120. L7/L12 delta Lys120 was not preferentially found in the S100 and not preferentially removed by LiCl washing, but was preferentially extracted from 70S ribosomes in the presence of 28-35% ethanol in 0.25-0.5 M NH4Cl. It follows that delta Lys120 destabilizes the ribosome-binding domain of ribosomal protein L7/L12 in an ethanol-containing solvent, which raises the question whether Lys120 is part of the ribosome-binding domain of L7/L12 during some step of protein synthesis or whether it is essential to preserve the conformation of the physiological ribosome-binding domain under structurally stressful conditions.
Seventeen patients with chronic psoriasis were given cyclosporin A (CsA) 5 mg/kg per day. Twelve patients cleared within 3 months and their relapse rate, 41% at 6 months, was not significantly different from that previously reported with dithranol or PUVA. This pilot study also suggests that continuing CsA for up to 4 weeks after clinical clearance confers no advantage with regard to relapse. Significant adverse effects on renal function and blood pressure did not occur.
The Wiskott-Aldrich syndrome (WAS) is an X-linked immune deficiency disorder characterized clinically by both lymphocyte and platelet dysfunction. Studies of WAS T lymphocytes have revealed deficient or defective cell surface expression of the highly O-glycosylated leucocyte sialoglycoprotein CD43. To further elucidate the basis for, and functional relevance of, CD43 modifications on WAS lymphocytes, we have studied lymphocytes from two WAS patients with regard to membrane glycoprotein profile and mitogen-induced proliferative responses. CD43 was found to be either absent or altered in size on peripheral blood lymphocytes and lectin-stimulated T cells from both patients. Compared with control cells, the WAS lymphocytes displayed reduced, but measurable proliferative responses to lectins and neuraminidase/galactose oxidase, and virtually no response to periodate, a mitogenic agent which targets sialic acid residues on membrane glycoproteins such as CD43. Analysis of activities of three glycosyltransferases involved in O-glycosylation revealed marked reduction in the level of activity of UDP-N-acetylglucosamine: Gal beta 1-3GalNAc-R beta-1,6-N-acetylglucosamine (beta-1,6-GlcNAc) transferase in one WAS patient and no detectable activity of this enzyme in a second. beta-1,6-GlcNAc transferase activity has recently been shown to increase during T cell activation coincident with changes in the O-linked glycans on CD43. A selective reduction of this glycosyltransferase in WAS lymphocytes suggests that O-linked oligosaccharides may be important to the structure of membrane glycoproteins involved in lymphocyte activation.
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The hypothesis that translation of the ilvD and ilvA genes of Escherichia coli may be linked has been examined in strains in which lacZ-ilvD protein fusions are translated in all three reading frames with respect to ilvD. In these strains, the nucleotide sequence was altered to obtain premature termination of ilvD translation, and in one strain translation termination of ilvD DNA occurred two bases downstream of the ilvA initiation codon. In the wild-type strain, the ilvD translation termination site was located two bases upstream of the ilvA start codon. In each of the mutant strains, expression of ilvA, as determined by the level of threonine deaminase activity, was strikingly lower than in the wild-type strain. The data suggest that expression of ilvD and ilvA is translationally coupled. By inserting a promoterless cat gene downstream of ilvA, it was shown that the differences in enzyme activity were not the result of differences in the amount of ilvA mRNA produced.
Six hundred sixty patients from Downstate and Hackensack Medical Centers were restaged and reviewed to establish correlations with survival using Cox's proportional hazards model. Age, sex, tumor size, and total nodes examined in patients with involved nodes did not correlate with survival. Tumor depth, number of involved nodes, and total nodes examined in patients with uninvolved nodes did correlate with survival. Patients with metastatic invasion into an adjacent organ with uninvolved nodes had an excellent 5 year survival rate compared with patients who had full-thickness invasion into the serosa with uninvolved nodes. These observations need to be confirmed. The relationship of some of these factors to currently used staging systems has also been discussed.
Two young adults, one a native of Libya and one a Sudanese from Saudi Arabia, were referred at different times to the chest service at Westminister Hospital in London with a diagnosis of tuberculosis. They both had neurological deficits due to vertebral lesions. In spite of the fact that neither patient had ever been to North America, diagnoses of North American blastomycosis were established; both patients made remarkable recoveries on amphotericin B therapy.
Metabolic alkalosis is regarded as the "classical" electrolyte abnormality occurring with hypertrophic pyloric stenosis (HPS) but recent experience suggests that atypical electrolyte findings frequently occur and delay establishing the correct diagnosis. The records of 65 infants with HPS treated by pyloromyotomy during the past 4 years were reviewed to determine the serum electrolytes at the initial presentation. The four study groups formed included 8 (12.3%) patients in group A with serum bicarbonate (HCO3) below 18 mEq/L (mean 15.7 +/- 0.5 mEq/L); 19 (29%) in group B with HCO3 between 18 and 25 (22.9 +/- 0.3); 22 (33.8%) in group C with HCO3 between 25 and 30 (27.0 +/- 0.3) and 16 (24.6%) in group D with HCO3 over 30 (34.0 +/- 0.9). Established values for normal HCO3 in neonates is 20.1 +/- 2.5 (mean +/- SD). The mean values in group D for HCO3, potassium (4.0 +/- 0.18 mEq/L), and chloride (88.75 +/- 2.15 mEq/L) were each significantly different (p less than 0.001) from determinations of similar electrolytes in other groups. The duration of vomiting in group D of 10.5 +/- 1.3 days is almost double the time (p less than 0.001) in group A, and was associated with more severe dehydration, predominantly acid urine (pH less than 6), and ketonuria as compared to other groups. No significant difference in other demographic characteristics including the age at presentation, the gestational age, sex distribution, or types of formula used was observed. The results of the study emphasize that serum electrolytes in early HPS may be normal, that HCO3 is significantly lower than established normals for older children, and that the effects of hydrogen-ion loss elevating the serum HCO3 precedes alterations in other serum electrolytes.
A large excess of patients with bladder cancer who have previously been exposed to N-substituted aryl compounds as a result of the production of dyestuff intermediates have the slow phenotype of the enzyme N-acetyltransferase. Among bladder-cancer patients in general, those presenting with T3 or T4 disease or carcinoma-in-situ also show an excess of the slower subtypes. Either N-substituted aryl compounds more frequently produce tumours with this invasive potential if linked with slow acetylation or slow acetylators are more susceptible to tumour production when exposed to some N-substituted aryl compounds. It is suggested that acetylator status could be used to identify susceptible individuals in potentially hazardous occupations.
The therapeutic value of sequential hemi-body irradiation (HBI) as a primary treatment for small-cell lung cancer (SCLC) was compared to 3-drug cyclic chemotherapy (CC) in a group of 64 patients with early and advanced disease. Thirty patients were randomized to receive sequential HBI and 34 to receive CC. All patients received a local radiation boost to the primary lesion. An overall response rate of 87% was obtained in patients treated with sequential HBI and 88% in patients treated with CC. In patients with early disease, the estimated median survival was 43 weeks when treated with HBI and 42 weeks when treated with CC, but in advanced disease the estimated median survival was 15 weeks and 44 weeks respectively. Of the patients with an initial complete response, the estimated median survival was 51 weeks for HBI and 62 weeks for CC. From these observations we suggest that sequential HBI treatment technique with local radiation boost is an efficient method of tumour control in patients with early small-cell lung cancer.
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A prospective clinical evaluation of plasma and urine carcinoembryonic antigen (CEA) in haematuria and urothelial carcinoma is presented. This study, in 325 patients, has shown that plasma CEA is of no value in the differential diagnosis of haematuria, T1 tumours or in the assessment of advanced bladder tumours with metastatic disease. Urinary CEA can be raised in the presence of urothelial carcinoma but is not a reliable diagnostic or prognostic index.
Changes in the respiratory control index (RCI) and ADP:O ratio were found to be related to alterations in the free fatty acids levels of rat liver mitochondria aging in 0.25 M sucrose- Tris buffer at 0 degrees C. Free fatty acid levels increased with time after isolation of mitochondria while a concomitant decrease in the RCI and ADP:O ratio occurred. The changes in free fatty acid levels corresponded with the reported increasing levels of phospholipase A activity in aged mitochondrial preparations. Washing these mitochondria with sucrose buffer containing 1% defatted bovine serum albumin (BSA) counteracted the aging effect on the RCI (E.G., 2.5 to 3.5) and reduced the free fatty acid levels (e.g., 50 to 16 nmol/mg protein). This reversible phenomenon could be repeated several times during the in vitro aging at 0 degrees C. Use of 125I-iodinated BSA showed that approximately 5 microgram BSA/mg mitochondria was adsorbed by the mitochondrial membranes during washing. These results indicate a direct correlation between the level of endogenous fatty acids and the uncoupling of mitochondrial oxidative phosphorylation. The mechanism of counteracting the aging effect by BSA involves the removal of some of the free fatty acids.
Plasma and urinary CEA levels in patients presenting with haematuria have been studied to assess whether they facilitate the differentiation between benign and malignant urothelial conditions. Plasma CEA is of no diagnostic value although, if raised, it may suggest an invasive tumour. Urinary CEA levels are only of value in the absence of urinary infection; even then, only 37% of the cases with overt urothelial tumours had raised titres. A knowledge of the urinary CEA level, therefore, would seem to contribute little to the diagnosis of patients presenting with haematuria and all patients must still be investigated by the conventional techniques of urinary bacteriology, cytology, intravenous pyelography and cystourethroscopy.