Free radicals alter ionic calcium levels and membrane phospholipids in cultured rat ventricular myocytes

Oxygen-derived free radicals have been implicated in damage to membrane phospholipids leading to alterations in membrane function. The purpose of this study was to investigate alterations in intracellular ionic calcium (Ca2+) levels and Ca2+ transients, cellular morphology, conjugated diene levels, arachidonate release, and lactate dehydrogenase release resulting from the exposure of cultured neonatal rat ventricular myocytes to a xanthine oxidase catalyzed free radical generating system capable of producing superoxide and hydroxyl radicals. The ability of alpha-tocopherol to prevent alterations due to free radical exposure was investigated. For measurements of Ca2+, myocytes grown on coverslips for 3-4 days were loaded with fura-2/AM and studied by microspectrofluorometry. Control myocytes superfused with a physiological buffer or buffer containing purine and iron-loaded transferrin exhibited Ca2+ transients associated with spontaneous contractions. For control, buffer perfused myocytes (n = 4), the fura-2 340/380 ratios were 0.5 +/- 0.1 (mean +/- S.E.) and 1.6 +/- 0.03 at the minimum and maximum, respectively, of the Ca2+ transient, after 1 h of perfusion. Exposure to the free radical generating solution (n = 14) altered intracellular Ca2+. The 340/380 minimum ratio was 639% of the control value after approximately 30-70 mins with cessation of normal Ca2+ transients. Bleb development was associated with increased Ca2+. Myocytes reperfused with control medium continued to exhibit an elevated minimum fura-2 ratio at 687% of control. Myocytes pretreated with 10 microM alpha-tocopherol (n = 13) for 18-24 h and exposed to free radicals did not exhibit increases in intracellular Ca2+, having a minimum 340/380 ratio of 0.5 +/- 0.1 after 60-90 mins, and although myocytes often ceased contracting, they resumed spontaneous Ca2+ transients with control medium reperfusion and also maintained normal structure. Exposure of myocyte cultures to free radical generating solutions resulted in increased levels of conjugated dienes and increased release of [3H]arachidonate and lactate dehydrogenase compared to control values after 1 h. alpha-Tocopherol treatment attenuated the increase in conjugated diene levels, and the release of [3H]arachidonate and lactate dehydrogenase. Thus, free radicals alter intracellular Ca2+, conjugated dienes and membrane structure indicating their ability to induce altered ionic homeostasis in association with myocardial membrane damage. alpha-Tocopherol decreased free radical mediated injury.     

Primary structure and biological activity of human brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a 27-kDa basic protein of noncovalently linked 13.5-kD subunits related to nerve growth factor and is produced by the central nervous system (CNS). BDNF has been shown to promote the survival of neurons located in or directly connected with the CNS and is likely to function in adjusting the cell number within neuronal populations to the need of this projection field. Here we describe the primary structure of a human BDNF cDNA, the biological activities of pure recombinant human BDNF, and the tissue distribution of rat BDNF. BDNF mRNA can be found in some peripheral tissues as well as in the CNS, and recombinant human BDNF is a potent neurotrophic factor for primary peripheral sensory neurons.     

A comparison of atenolol and nebivolol in isolated systolic hypertension

OBJECTIVES: Some beta-blockers are less effective in reducing central blood pressure than other antihypertensive drugs, which may explain the higher rate of events in subjects randomized to atenolol in recent trials. We hypothesized that nebivolol, a mixed beta-blocker/nitro-vasodilator, would be more effective than atenolol in reducing central blood pressure and augmentation index (AIx). The aim of the present study was to test this in a double-blind, randomized, cross-over study, in a cohort of subjects with isolated systolic hypertension. METHODS: Following a 2-week placebo run-in, 16 never-treated hypertensive subjects received atenolol (50 mg), nebivolol (5 mg) and placebo, each for 5 weeks, in a random order. Seated brachial blood pressure and heart rate were measured. Aortic blood pressure, AIx and pulse wave velocity (PWV) were assessed non-invasively. RESULTS: The placebo-corrected fall in brachial pressure was similar between nebivolol and atenolol, as was the reduction in PWV (mean change +/- SEM: -1.0 +/- 0.3 and -1.2 +/- 0.2 m/s; P = 0.2). However, there was less reduction in heart rate (-19 +/- 2 versus -23 +/- 2 beats/min; P < 0.01) and increase in AIx (+6 +/- 1 versus +10 +/- 1%; P = 0.04), following nebivolol. Aortic pulse pressure was significantly lower (50 +/- 2 versus 54 +/- 2 mmHg; P = 0.02) after nebivolol. N-terminal pro-B-type natriuretic peptide (proBNP) rose on both drugs (100 +/- 33 versus 75 +/- 80 pg/ml; P < 0.01 for both, NS for comparison). CONCLUSIONS: Nebivolol and atenolol have similar effects on brachial blood pressure and aortic stiffness. However, nebivolol reduces aortic pulse pressure more than atenolol, which may be related to a less pronounced rise in AIx and bradycardia. Whether this will translate into differences in clinical outcome requires further investigation.     

The economic payoffs of integrated malaria control in the Zambian copperbelt between 1930 and 1950

It has long been suggested that malaria is delaying the economic development of countries that are most severely affected by the disease. Several studies have documented the economic consequences of malaria at the household level, primarily in communities engaged in subsistence farming. A missing element is the appraisal of the economic impact of malaria on the industrial and service sectors that will probably become the backbone of many developing economies. We estimate the economic effects of integrated malaria control implemented during the colonial period and sustained for 20 years in four copper mining communities of the former Northern Rhodesia (now Zambia). Integrated malaria control was characterized by strong emphasis on environmental management, while part of the mining communities also benefited from rapid diagnosis and treatment and the use of bednets. The programmes were highly successful as an estimated 14,122 deaths, 517,284 malaria attacks and 942,347 work shift losses were averted. Overall, 127,226 disability adjusted life years (DALYs) were averted per 3-year incremental period. The cumulative costs of malaria control interventions were 11,169,472 US dollars (in 1995 US dollars). Because the control programmes were so effective, the mining companies attracted a large reservoir of migrant labourers and sustained healthy work forces. The programmes averted an estimated 796,622 US dollars in direct treatment costs and 5,678,745 US dollars in indirect costs as a result of reduced work absenteeism. Within a few years of programme initiation, Northern Rhodesia became the leading copper producer in Africa, and mining generated the dominant share of national income. Copper production and revenues, which increased dramatically during malaria control interventions, amounted to the equivalent of 7.1 billion US dollars (in 1995 US dollars). Integrated malaria control in copper mining communities was a sound investment. It had payoff for public and occupational health, generally, and without it copper extraction and social and economic development would have been impossible.     

Antibody redesign by chain shuffling from random combinatorial immunoglobulin libraries.

A number of experiments on the shuffling of heavy and light chains from antibodies of defined specificity for the transition-state analogue hapten nitrophenyl phosphonamidate are described. The experiments report on the promiscuity of heavy and light chains in binding antigen and the feasibility of antibody redesign by this shuffling process. The concepts of incestuous and extraclonal promiscuous association are described. Shuffling opens the possibility of generating panels of antibodies with related specificity but of distinct idiotypic composition that may have significance in the use of human monoclonal antibodies in therapy.     

Surgical management of nonhepatic intra-abdominal recurrence of carcinoma of the colon

The role of surgery in the management of intra-abdominal recurrence of colon cancer has not been clearly determined. We reviewed the charts of 28 patients operated upon at our institution for nonhepatic intra-abdominal recurrence of carcinoma of the colon and followed for a median of 10.5 months after reoperation. Total resection of gross disease was possible in 15 patients, who had a median overall actuarial survival of 25.5 months and a disease-free survival of 13 months. Within this group, disease-free survival was significantly prolonged when time to first recurrence was greater than 16 months and when patients had not had a prior operation for recurrent disease (P <0.05). Six patients having a partial resection and seven patients having only a bypass or ostomy had significantly shorter survivals than those in the totally resected group, with median survivals of 8 and 3.5 months, respectively (P <0.05). Operative management of recurrent colon cancer may prolong survival when disease can be eradicated, and palliative operations appear more successful when tumor is resected rather than bypassed.Supported in part by an American Cancer Society Clinical Oncology Fellowship Award (Dr. Gwin).