The Influence of α-Tocopherol on Serum Biochemical Markers During Experimentally Induced Pleuritis in Rats Exposed to Dioxin

Toxicity of dioxins is wide ranging. Amongst the organs, the liver is the most susceptible to damage by dioxins. Damage caused to liver cells results in promoting inflammatory processes. The aim of this work was to evaluate whether high doses of tocopherol will change the inflammatory response, monitored by biochemical indicators, by improving liver function in rats exposed to tetrachlorodibenzo-p-dioxin (TCDD). The study was conducted on a population of female Buffalo rats. The animals were divided into the following groups: Control Group A—representing physiological norms for the studied diagnostic indicators; Control Group B—subjects were administered a 1% ceragenin solution to induce pleuritis; Study Group 1—where rats were administered α-tocopherol acetate for 3 weeks, after which pleuritis was induced; Study Group 2—rats were administered a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), while 3 weeks later, pleuritis was induced; and Study Group 3—rats were administered a single dose of TCDD and next, were administered α-tocopherol acetate for 3 weeks, followed by pleuritis induction. The results clearly show that administering tocopherol in the course of inflammation causes changes to the distribution and ratio of in the serum protein fractions, including acute phase proteins. The latter proteins are indicative to the improvement in liver function and linked to protein synthesis and stimulation of the antibody-mediated immunity. Moreover, in the course of inflammation caused by exposure of rats to TCDD, tocopherol significantly affected the acute phase protein concentration.     

Failure and efficacy of insulin therapy in insulin dependent (type I) diabetic patients

Summary In order to determine the degree of metabolic control (HbA_1c [normal<5.8%], mean blood glucose [MBG], glucosuria and lipids) and the prevalence of late diabetic complications in insulin-dependent diabetic patients treated by conventional insulin therapy both patients of a diabetes center (DC: n=130; age 37.1±1.4 years) and a rural area (RA: n=73; age 38.4±2.4 years) were examined within their local setting. Eighty such insulin-dependent diabetic patients were also taught a technique of near normal glycemic insulin substitution (NIS), which separates basal from prandial insulin replacement and instructs the patients to immediately correct self-controlled (3.8±0.1/day) aberrant blood glucose values. None of the groups on conventional insulin therapy was able to achieve satisfactory metabolic control or to avoid late diabetic complications, but rural patients were even worse off (BG 240±10 mg/dl; HbA_1c 8.7±0.2% [normal: 3/73=4%]) than those of the DC (MBG 191±5 mg/dl; HbA_1c 7.1±0.2% [normal: 27/130=21%]), while the prevalence of late diabetic complications was almost identical (RA/DC: neuropathy 22%/25%; retinopathy 41%/38%; macroangiopathy 15%/13%; but proteinuria 14%/5.4%). Metabolic control was improved by NIS with twice daily injections of basal (long acting) and separately of prandial (regular) insulin (total: 4.8±0.1 injections/day; MBG 130±2 mg/dl; HbA_1c 5.8±0.1% [normal: 41/80=51%]. We conclude (1) that conventional insulin therapy just prevents metabolic catastrophe but in more than 79% of insulin-dependent diabetic patients lacks the ability to provide good metabolic control, while (2) NIS, a more physiological form of insulin therapy, improves this deplorable situation 5- to 12.4-fold. Presented in part at the 20th Annual Meeting of the European Association for the Study of Diabetes, London, England, September 12–15, 1984. Supported in part by a grant (#01/0086) of the?sterreichische Forschungsgemeinschaft, and by Novo-Austria. The study was made possible by the generous cooperation of the following general practitioners: Drs I. Avancini, U. Brandl, H. Dabringer, P. Erhart, G. Freerk, F. Geiger, W. Günther, W. J?ger, A. K?hle, R. Lanner, K. Lhotta, F. Menhart, J. Mühlburger, G. Offer, M. Pesendorfer, F. Pistoja, R. Reiger, W. Reiter, K. Schartner, H.J. Somavilla, K. Somavilla, C. Steiger, H. Stocker, J. Tummer, H. Trojer. R. Unterweger, and G. Weg.     

Competitive NMDA-Receptor Antagonists, LY 235959 and LY 233053, Enhance the Protective Efficacy of Various Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 [(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-quinoline-3-carboxylic acid; 50.5 mgikg] or LY 233053 [cis-(±)-4–[(2H-tetrazol-5–yl) methyl] piperidine-2-carboxylic acid; 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, Freiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Results: Both LY 235959 and LY 233053 (=0.5 and 5 mg/kg, respectively) did not influence the electroconvul sive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydan-toin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.     

Effect of acute and chronic treatment with milnacipran potentiates the anticonvulsant activity of conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice

Rationale  

Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs.     

Can general cardiovascular risk evaluation facilitate the assessment of fitness for work and contribute to the reduction of cardiovascular incidents among seamen and fishermen? Article for discussion

Apart from accidents and work related injuries caused by external factors, being the primary cause of death at sea and repatriation of seamen and fishermen from ship to hospital on shore, acute cardiovascular incidents are the main internal causes of their death, both at sea and on land, as well as of long lasting sick leave and disability. In the regulations on health requirements for persons working on sea-going ships and in inland navigation (orders of the Ministry of Health 1993, 1996, 2003, guidelines (39), EU directives and other national regulations) and in the register of diseases and conditions disqualifying from such an employment (EU directive, annex to the order of the Ministry of Health 1993, European Commission (32,33), ILO/WHO guidelines, cardiovascular diseases are only generally mentioned. The minimal scope of examinations is recommended for seafarers in age up to 50 years, and for older seafarers, but without the assessment of their occupational risk. This gives rise to ambiguities in interpretation at the time of issuing their health certificates, and also in judicature when analyzing cause-and-effect relationship between the occurrence of an acute cardiovascular incident during the ship's voyage and conditions of the work at sea. Principles, possibilities and benefits are discussed in this paper, which may be expected from the general assessment of cardiovascular diseases risk at the time of the health assessment for the work at sea. The risk forecasting, health certification and the question of choosing primary preventive methods are included in this presentation.     

Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae

Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane.     

Diabetes and work at sea: has everything been already settled? Article for discussion

Along with increased worldwide incidence of diabetes, the frequency of its occurrence among persons employed on seagoing vessels has also grown (12). According to the current regulations, persons treated with insulin are not admitted to work at sea, and those treated with oral drugs have a markedly limited access to such a work. This may lead to concealing the fact of being a diabetic, thus enhancing the existing hazards. Current improved methods of glycemia self-control and treatment of diabetes have radically improved vital abilities of diabetics. Having this in mind, a question arises whether the binding regulations on the fitness of diabetics for work at sea should be verified.