MISCELLANEOUS STUDIES


Table of Contents
image Strong mediators of social inequalities in risk of ischaemic heart disease: A six-year follow-up in the Copenhagen male study.
image Curcumin protects bleomycin-induced lung injury in rats.
image Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins.
image Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey .2. Relationships to cardiovascular risk factors and prevalent cardiovascular disease.
image ''Vitamin-CE,'' a novel prodrug form of vitamin E.
image Increased susceptibility of Alzheimer's disease temporal cortex to oxygen free radical-mediated processes.
image Vitamin-C reduces cholesterol-induced microcirculatory changes in rabbits.
image Antioxidant status in patients with uncomplicated insulin- dependent and non-insulin-dependent diabetes mellitus.
image Antioxidant activity of Vitamin-C in iron-overloaded human plasma.
image Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D-3 in cultured human epidermal keratinocytes.
image Novel tocotrienols of rice bran modulate cardiovascular disease risk parameters of hypercholesterolemic humans.
image Plasticity of neuro-endocrine-thymus interactions during aging - A minireview.
image Antiviral therapy of hepatitis C.
image Plasma ubiquinol-10 is decreased in patients with hyperlipidaemia.
image Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection.
image Computational genomic analysis of hemorrhagic fever viruses - Viral selenoproteins as a potential factor in pathogenesis.
image The distribution of Selenium and mortality owing to acquired immune deficiency syndrome in the continental United States.
image Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong.
image Inhibitory effect of selenite and other antioxidants on complement-mediated tissue injury in patients with epidemic hemorrhagic fever.
image Oxidative damage to muscle protein in Duchenne muscular dystrophy.
image Using liquid levodopa in the treatment of Parkinson's disease: A practical guide.
image Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections.
image The neurosteroid pregnenolone sulphate enhances NMDA- induced phasic firing of vasopressin neurones in the rat supraoptic nucleus.

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Strong mediators of social inequalities
in risk of ischaemic heart disease:
A six-year follow-up in the
Copenhagen male study.

Suadicani P Hein HO Gyntelberg F
Int J Epidemiol 1997 JUN;26(3):516-522
Suadicani P, Univ Copenhagen Hosp, Rigshosp 7122,
Dept Occupat Med, Epidemiol Res Unit, Copenhagen Male Study,
DK 2200 Copenhagen N, DENMARK

Objective. Large social inequalities exist in risk of ischaemic heart disease (IHD) in Western populations; inequalities which are only little accounted for by established risk factors. We wished to find out if some newly identified cardiovascular risk factors in concert with established factors might contribute further to the explanation. Design and Setting. A 6-year follow-up in the Copenhagen Male Study. Subjects. Some 2974 males aged 53-75 years (mean 63) without overt cardiovascular disease were included in the study. Potential confounders included were: alcohol, physical activity, smoking, serum lipids, serum cotinine, serum selenium, lifetime occupational exposure to soldering fumes and organic solvents, body mass index, blood pressure, hypertension, use of sugar in hot beverages, use of diuretics, and Lewis phenotypes. Main Outcome Measures. During the 6-year follow-up period (1985/1986-1991), 184 men (6.2%) had a first IHD event. Compared to higher social classes (classes I, II and III), lower classes (classes IV and V) had a significantly (P 0.05) increased risk of IHD; age-adjusted relative risk (RR) with 95% confidence limits was 1.44 (1.1-1.9), P = 0.02. After multivariate adjustment for age, blood pressure, serum lipids, physical activity, and smoking, the RR dropped to 1.38 (1.0-1.9), P = 0.05. Some newly identified risk factors were significantly associated with increased risk of IHD as well as with low social class: a low serum selenium concentration, a low level of leisure time physical activity in midlife, long-term exposure to soldering fumes, and abstention from or a low consumption of wine and strong spirits. After adjustment for these factors also, the RR dropped to 1.12 (P = 0.54). Conclusions. The results of this study suggest that potentially modifiable risk factors associated with lifestyle and working environment are strong mediators of social inequalities in risk of ischaemic heart disease.


Curcumin protects bleomycin-induced
lung injury in rats.

Venkatesan N Punithavathi V Chandrakasan G
Life Sci 1997 JUL 3;61(6):PL51-PL58
Venkatesan N, Univ Edinburgh, Dept Biochem,
Hugh Robson Bldg, George Sq,
Edinburgh EH8 9XD, Midlothian, SCOTLAND

The present study was designed to determine the protective effects of curcumin against bleomycin (BLM)-induced inflammatory and oxidant lung injury. The data indicate that BLM-mediated lung injury resulted in increases in lung lavage fluid biomarkers such as total protein, angiotensin-converting enzyme (ACE), lactate dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), lipid peroxidation (LPO) products, superoxide dismutase (SOD) and catalase. Bleomycin administration also resulted in increased levels of malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) and bronchoalveolar lavage (BAL) cells and greater amounts of alveolar macrophage (AM) superoxide dismutase activity. By contrast, lower levels of reduced glutathione (GSH) were observed in lung lavage fluid, BAL cells and AM. Stimulated superoxide anion and hydrogen peroxide release by AM from BLM rats were found to be higher. Curcumin treatment resulted in a significant reduction in lavage fluid biomarkers. In addition, curcumin treatment resulted in the restoration of antioxidant status in BLM rats. These data suggest that curcumin treatment reduces the development of BLM-induced inflammatory and oxidant activity. Therefore, curcumin offers the potential for a novel pharmacological approach in the suppression of drug or chemical-induced lung injury.


Resveratrol inhibits metal ion-dependent
and independent peroxidation of porcine
low-density lipoproteins.

Belguendouz L Fremont L Linard A
Biochem Pharmacol 1997 MAY 9;53(9):1347-1355
Fremont L, Inra, Lab Nutr & Secur Alimentaire,
Crj, F 78352 Jouy en Josas, FRANCE

Resveratrol, a phytoalexin (3, 4', 5, trihydroxystilbene) present in some red wines, has been reported to inhibit copper-mediated low-density lipoprotein (LDL) oxidation. In this study, we examined the efficiency of this compound in inhibiting metal ion-dependent and independent peroxidation of porcine LDL. At 0.5, 1, or 1.5 mu M, transresveratrol prolonged the lag time preceding the onset of conjugated diene formation in a dose-dependent manner, with a slope of the propagation phase 5-ford greater in the presence of Cu SO4 (5 mu M) than in the presence of the free radical generator, AAPH [2, 2'-azobis (2-amidinopropane) dihydrochloride] (1 mM). At 1 mu M, transresveratrol prolonged the lag time 3.4- and 1.4-fold in the presence of copper and AAPH, respectively. Isomerisation into cisresveratrol significantly lowered the chelating capacity, but did not alter the free radical scavenging capacity. As compared to flavonoids and trolox, transresveratrol showed a much higher ability to prolong the lag time in copper, but not in AAPH-catalyzed oxidation. The kinetics of generation of degradative products in the presence of copper confirmed the strongest protective effects of transresveratrol, because the formation of thiobarbituric acid reactive substances and hydroperoxides was almost completely inhibited at 200 min. By contrast, transresveratrol was less potent than flavonoids (but more than trolox) as a scavenger of free radicals. Our data show that, like flavonoids, resveratrol protects LDL against peroxidative degradation by both chelating and free radical scavenging mechanisms. However, transresveratrol, which is by far the most potent chelator of copper, does not chelate iron. It might contribute to the protective effects of wine polyphenols by removing copper from LDL particles and arterial tissue and, thereby, delaying the consumption of flavonoids and endogenous antioxidants.


Epidemiology of coagulation factors,
inhibitors and activation markers:
The Third Glasgow MONICA Survey 2
Relationships to cardiovascular risk
factors and prevalent cardiovascular disease.

Woodward M Lowe GDO Rumley A
TunstallPedoe H Philippou H Lane DA Morrison CE
Br J Haematol 1997 JUN;97(4):785-797
Lowe GDO, Univ Glasgow, Royal Infirm, Dept Med,
10 Alexandra Parade, Glasgow G31 2ER, Lanark, SCOTLAND

Coagulation factor activity (fibrinogen, VII, VIII and IX), coagulation inhibitor activity (antithrombin, protein C, protein S), and coagulation activation markers (prothrombin fragment F1, 2; thrombin-antithrombin complexes) were measured in 746 men and 816 women aged 25- 74 years, randomly sampled from the north Glasgow population in the Third MONICA Survey. After age- adjustment, significant associations with cardiovascular risk factors were observed. Serum cholesterol and triglyceride were associated with increases in factors VII and IX, as well as antithrombin, protein C and protein S; and with increased fibrinogen and factor VIII in women. Apart from factor VIII (related to blood pressure in men, but not in women), similar associations were observed for blood pressure and body mass index. Smoking status and/or smoking markers were related to fibrinogen, factor IX, antithrombin and protein S. Alcohol intake was related to protein S, and inversely to fibrinogen and antithrombin in men. Low social class was associated with fibrinogen, factor VIII, factor IX, and with antithrombin, protein S, and low protein C in men. Serum Vitamin-C was associated inversely with coagulation factors and coagulation inhibitors. The only associations of activation markers were with low serum Vitamin-C, and with alcohol consumption and low social class in men. Prevalent cardiovascular disease was associated only with fibrinogen. These associations of coagulation factors and inhibitors with cardiovascular risk factors are plausibly relevant to thrombotic risk in cardiovascular disease. In general, 'worse' Values of risk factors are associated with increased plasma levels of both coagulation factors and inhibitors, without significant increase in coagulation activation markers. However, the association of lower serum Vitamin-C with increased coagulation activation markers is of potential therapeutic interest.


''Vitamin-CE,'' a novel prodrug
form of vitamin E.

Rosenau T Habicher WD
Chem Pharm Bull Tokyo 1997 JUN;45(6):1080-1084
Habicher WD, Dresden Univ Technol, Inst Organ Chem,
Mommsenstr 13, D 01062 Dresden, GERMANY

Reaction of 5a-bromo-alpha-tocopherol with ascorbic acid produces 5a-tocopheryl ascorbate which is designated ''Vitamin-CE.'' This novel tocopherol derivative represents an interesting prodrug form of alpha-tocopherol (vitamin E) that is stable un der acidic conditions, but regenerates finely dispersed vitamin E in basic media. The reaction mechanism of the base-induced decomposition of Vitamin-CE involves elimination of ascorbate and production of an ortho-quinone methide intermediate that oxidize s ascorbate, and is reduced to vitamin E. Kinetic experiments showed the reaction to proceed in the pH range of 8 to 11 under physiological conditions. Tissue culture measurements demonstrated that vitamin E generated from the novel derivative is absorbed at much higher rates than conventional preparations and can even be absorbed under simulated conditions of malabsorption where there Is no uptake of conventional vitamin E medications.


Increased susceptibility of Alzheimer's
disease temporal cortex to oxygen
free radical-mediated processes.

McIntosh LJ Trush MA Troncoso JC
Free Radical Biol Med 1997;23(2):183-190
McIntosh LJ, Stanford Univ, Dept Biol Sci,
Stanford,CA 94305 USA

Reactive oxygen-mediated processes are thought to contribute to the pathogenesis of Alzheimer's disease (AD). To investigate this hypothesis we studied autopsy tissue from Il pairs of AD cases and control individuals matched for age, postmortem delay, and tissue storage time. The temporal neocortex, which is severely involved by AD pathology, and the cerebellum, which is spared, were analyzed for tissue markers of lipid peroxidation (LPO). The average chemiluminescence formed from bond breakage in tissue homogenates during a 3-h incubation, without the presence of catalysts such as metal ions or ascorbate, was significantly increased in the AD temporal cortex to 130% of matched controls. Basal tissue content of LPO products (thiobarbituric acid reactive substances-TBARs) was not different between groups. However, TBARs were significantly elevated in AD temporal cortex to 135% of control after the incubation. In contrast, in the cerebellum there was no difference between AD and control tissue, indicating a disease-specific tissue effect. Because the use of oral antioxidants have received considerable attention in the last few years, the results seen in the testing of an AD patient who took daily vitamin E supplements for 4 years is particularly interesting. The time course for CL reactivity in the temporal cortex was considerably delayed compared to all other samples. This observation is consistent with the hypothesis that antioxidants within tissue will quench ROS- mediated reactions. This study indicates that there is increased susceptibility to ROS in the AD temporal cortex that may contribute to the pathogenesis of the disease. Furthermore, our observations suggest that oral antioxidant supplementation may be protective against LPO in the human brain.


Vitamin-C reduces cholesterol-induced
microcirculatory changes in rabbits.

Freyschuss A Xiu RJ Zhang J Ying XY Diczfalusy
U Joestrand T Henriksson P Bjorkhem I
Arterioscler Thromb Vasc Biol 1997 JUN;17(6):1178-1184
Bjorkhem I, Huddinge Univ Hosp, Karolinska Inst,
Dept Med Lab Sci & Technol,
Div Clin Chem, S 14186 Huddinge, SWEDEN

The microcirculation was studied for 10 weeks in untreated rabbits (n=12) and in rabbits treated with Vitamin-C in their drinking water (0.5 g/d, n=6), a 1% cholesterol diet (n=12), or a combination of the two treatments (n=11). The studies were performed by direct intravital microscopic imaging of the conjunctiva of both eves to evaluate blood flow velocity, microvessel diameter, and microhemorheologic conditions. As we reported previously, changes occurred in all of the aforementioned variables as a consequence of cholesterol feeding. After 3 and 6 weeks of feeding, there was a marked and significant (P.0001) decrease in blood flow velocity in third-order arterioles. Which was accompanied by stasis and erythrocyte aggregation in the smaller conjunctival vessels. When cholesterol treatment was combined with Vitamin-C, blood flow was almost identical to that of controls and significantly (P.0001) higher than that of rabbits treated with cholesterol alone. All other changes were also significantly reduced by the addition of Vitamin-C treatment to the cholesterol diet. Cholesterol-treated rabdeveloped macroscopic arterial lesions that were not significantly reduced by Vitamin-C treatment. Neither circulating oxysterol levels nor atheromas were reduced by Vitamin-C treatment, which also had no significant effect on lipid or circulating vitamin E levels. We have previously shown that the lipid-soluble antioxidant BHT is able to prevent both cholesterol-induced microcirculatory changes and the development of arterial lesions in rabbits. This phenomenon is compatible with a critical oxidation step occurring in the lipid phase that is common to both processes. The finding that microcirculatory changes can be prevented by a water-soluble antioxidant is compatible with a role for water-soluble oxidants in this context. The possibility is discussed that Vitamin-C might also be important for the microcirculation in humans.


Antioxidant status in patients with
uncomplicated insulin- dependent and
non-insulin-dependent diabetes mellitus.

Maxwell SRJ Thomason H Sandler D Leguen
C Baxter MA Thorpe GHG Jones AF Barnett AH
Eur J Clin Invest 1997 JUN;27(6):484-490
Maxwell SRJ, Leicester Royal Infirm, Div Clin Pharmacol,
Clin Sci Bldg, Leicester LE2 7LX, Leics, ENGLAND

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical-scavenging antioxidant activity of serum from 28 patients with insulin-dependent diabetes mellitus and 24 patients with noninsulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non-diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2 +/- 11.3 vs. 427.5 +/- 19.2 mu mol L-1; P 0.001). This was attributable to lower urate (209.4 +/- 10.4 vs. 297.1 +/- 16.7 mu mol L-1; P 0.001) and Vitamin-C levels (63.6 +/- 6.0 vs. 87.5 +/- 4.9 mu mol L-1; P 0.01). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age- matched control subjects (433.8 +/- 25.4 vs. 473.9 +/- 30.2 mu mol L-1; NS), reflecting lower urate (299.5 +/- 19.4 vs. 324.8 +/- 21.4 mu mol L-1; NS) and Vitamin-C levels (38.6 +/- 5.7 vs. 58.5 +/- 5.3 mu mol L-1; P 0.05). Multiple regression analysis showed that urate, Vitamin-C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.


Antioxidant activity of Vitamin-C in
iron-overloaded human plasma.

Berger TM Polidori MC Dabbagh A Evans PJ Halliwell
B Morrow JD Roberts LJ Frei B
J Biol Chem 1997 JUN 20;272(25):15656-15660
Frei B, Boston Univ, Sch Med, Whitaker Cardiovasc Inst,
Evans Mem Dept Med, 80 E Concord St, W 507,
Boston,MA 02118 USA

Vitamin-C (ascorbic acid, AA) call act as an antioxidant or a pro-oxidant in vitro, depending on the absence or the presence, respectively, of redox-active metal ions. Some adults with iron-overload and some premature infants have potentially redox-active, bleomycin-detectable iron (BDI) in their plasma, Thus, it has been hypothesized that the combination of AA, and BDI causes oxidative damage in vivo. We found that plasma of preterm infants contains high levels of AA and F-2-isoprostanes, stable lipid peroxidation end products. However, F-2-isoprostane levels were not different between those infants with BDI (138 +/- 51 pg/ml, n = 19) and those without (126 +/- 41 pg/ml, n = 10), and the same was true for protein carbonyls, a marker of protein oxidation (0.77 +/- 0.31 and 0.68 +/- 0.13 nmol/mg protein, respectively). Incubation of BDI- containing plasma from preterm infants did not result in detectable lipid hydroperoxide formation (less than or equal to 10 nM cholesteryl ester hydroperoxides) as long as AA concentrations remained high. Furthermore, when excess iron was added to adult plasma, BDI became detectable, and endogenous AA was rapidly oxidized. Despite this apparent interaction between excess iron and endogenous AA, there was no detectable lipid peroxidation as long as AA was present at >10% of its initial concentration. Finally, when iron was added to plasma devoid of AA, lipid hydroperoxides were formed immediately, whereas endogenous and exogenous AA. Delayed the onset of iron-induced lipid peroxidation in a dose- dependent manlier. These findings demonstrate that in iron- overloaded plasma, AA acts an antioxidant toward lipids. Furthermore, our data do not support the hypothesis that the combination of high plasma concentrations of AA and BDI, or EDI alone, causes oxidative damage to lipids and proteins in vivo.


Retinoic acid modulates the anti-proliferative
effect of 1,25-dihydroxyvitamin D-3 in
cultured human epidermal keratinocytes

Segaert S Garmyn M Degreef H Bouillon R
J Invest Dermatol 1997 JUL;109(1):46-54
Bouillon R, Katholieke Univ Leuven, Legendo,
Gasthuisberg 0&N, 9TH Floor, Herestr 49, B 3000 Louvain, BELGIUM

Both 1,25-dihydroxyvitamin D-3 (VD) and retinoids have potent effects on keratinocyte proliferation, Parallelism in their action as steroid hormones, which involves interaction of their receptors, and in their therapeutic efficacy for hyper-proliferative skin diseases provides a rationale to investigate their combined action on proliferation in pre-confluent human epidermal keratinocyte cultures. As shown by [H-3]thymidine incorporation, all-trans retinoic acid (atRA) at subpharmacologic concentrations and 9-cis retinoic acid (9cRA) diminished the anti-proliferative effect of VD, Pre- incubation of the cells with the retinoids clearly enhanced this effect, Cell-cycle analysis revealed G1 arrest upon VD treatment that was attenuated by retinoic acid (RA). Moreover, Northern and Western blot analysis demonstrated that retinoic acid opposed VD-induced accumulation of transforming growth factor-beta 1, p21(WAF1), and p27(KIP1). Finally, retinoic acid reduced VD-elicited hypophosphorylation of the retinoblastoma protein. AtRA at micromolar concentrations conversely potentiated most of the aforementioned VD-dependent actions. In addition, atRA and 9cRA (but not VD) caused a rapid, sustained reduction of RXR alpha protein. VD receptor protein was induced by VD regardless of the presence of RA. In conclusion, RA modulates VD-dependent effects at different levels of keratinocyte proliferation. This could have implications for the use of combinations of both drugs for skin diseases.


Novel tocotrienols of rice bran modulate
cardiovascular disease risk parameters
of hypercholesterolemic humans.

Qureshi AA Bradlow BA Salser WA Brace LD
J Nutr Biochem 1997 MAY;8(5):290-298
Qureshi AA, Adv Med Res, 8251 Raymond Rd, Madison,WI 53719 USA

Tocotrienols inhibit cholesterol synthesis by post- transcriptionally suppressing beta-hydroxy-beta- methylglutaryl-coenzyme A reductase activity. A double blind, 12-week study was performed to investigate the effect of a novel tocotrienol-rich fraction (TRF25; obtained by molecular distillation from specially processed rice bran oil) on cardiovascular disease risk factors of hypercholesterolemic human subjects (serum total cholesterol >5.69 mmol/L). After acclimation to an alcohol-free regimen (baseline) participants were assigned to the National Cholesterol Education Program (NCEP) Step- 1 diet (saturated fat 19%, total fat 30% of total calories and cholesterol 7.76 mmol/L). The participants were evaluated after 4 weeks of exposure to the NCEP Step- 1 diet; one group of 21 participants was continued on the NCEP Step-1 diet for 4 weeks receiving an additional 1.2 gm corn oil (placebo group) and a second group of 20 received 200 mg TRF25 dissolved in 1.0 gm corn oil (TRF25 group). Serum total cholesterol and LDL-cholesterol levels of all the participants, stable during the baseline phase of the study, decreased 5% and 8%, respectively, during the 4- week NCEP Step-1 diet. Placebo continuing on the NCEP Step- 1 diet for an additional 4 weeks experienced additional but modest decreases in serum total cholesterol (2%) and LDL-cholesterol (3%), yielding significant (P 0.05) decreases when compared with the baseline values. These responses confirm the cholesterol-lowering action of a low fat, low cholesterol diet. Participants receiving TRF25 had 12% and 16% reductions (P 0.05) in total cholesterol and LDL-cholesterol levels during the 4-week experimental phase; during the two phases (NCEP Step-1 diet plus treatment) the serum total cholesterol and LDL-cholesterol levels of these participants were decreased (P 0.05) by 17% and 24%, respectively. TRF25-mediated decreases in Apo B, Lp(a), platelet factor 4 and thromboxane B-2 (15%, 17%, 14%, and 31%, respectively) were significant (P 0.05). There was no change in the levels of HDL-cholesterol and apolipoprotein A-I by this treatment. The treatments also resulted in remarkable increases in the levels of LDL- bound antioxidants, especially tocotrienols, which have substantially greater antioxidant activity than vitamin E.


Plasticity of neuro-endocrine-thymus
interactions during aging - A minireview.

Fabris N Mocchegiani E Provinciali M
Cell Mol Biol 1997 JUN;43(4):529-541
Fabris N, Italian Natl Res Ctr Aging, Gerontol Res Dept,
Ctr Immunol, I 60100 Ancona, ITALY

Thymic regrowth and reactivation of thymic endocrine activity may be achieved even in old animals by different endocrinological or nutritional manipulations. In particular: a) intrathymic transplant pf pineal gland or treatment with melatonin; b) implantation of a growth hormone secreting tumor cell line or treatment with exogenous growth hormone; c) castration or treatment with exogenous LH-RH; d) treatment with exogenous thyroxine or triiodothyronine, and e) nutritional interventions such asArginineor zinc supplementation. These data strongly support the idea that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine- thymus interactions and that it is the disruption of such interactions in old age which is responsible for most of age-associated dysfunctions. With regard to the mechanisms involved in hormone-induced thymic reconstitution, it is, at present, difficult to draw any definitive conclusion. The effect of GH, thyroid hormones and LH-RH may be due to the presence on thymic epithelial cells, supposed to produce thymic peptides, of the specific hormone receptors. Melatonin or pineal derived factors may as well act through specific receptors but experimental demonstration is still lacking. The role of zinc, whose turnover is usually reduced in old age, is of quite wide- range: from the reactivation of zinc-dependent enzymes, required for both cell proliferation and apoptosis, to the reactivation of thymulin, a zinc-dependent thymic hormone. The role of zinc may be even more crucial. According to recent preliminary data obtained both in animal and in man, it appears that the above reported endocrinological manipulations, capable of restoring thymic activity in old age, may act also by normalizing the altered zinc pool.


Antiviral therapy of hepatitis C.

Schalm SW Brouwer JT
Scand J Gastroenterol 1997;32:46-49
Schalm SW, Erasmus Univ Rotterdam, Hosp Dijkzigt,
Dept Hepatogastroenterol, Room Ca 326,
NL 3015 Gd Rotterdam, NETHERLANDS

Background: Chronic hepatitis C can be treated with interferon therapy, but persistent viral clearance is only achieved in 20% of patients. Which patients have a high chance of viral clearance and what other treatment might enhance the effectivity of interferon therapy are reviewed. Methods: Data from published randomized trials on interferon mono-therapy, ribavirin mono-therapy and combination therapy of interferon-ribavirin and interferon- ursodeoxycholic acid are analysed separately and in a meta- analysis of individual data. Results: Interferon mono- therapy leads to viral clearance in only 10% of patients with genotype 1 and in less than 10% in cirrhosis; patients with plasma HCV RNA detectable at 3 weeks of therapy have only 2% chance of viral clearance. Prolongation of therapy reduces relapse in treatment responders. Interferon-ribavirin combination therapy appears to enhance the efficacy 2-3 fold without increasing toxicity. Conclusions: The benefit-risk/cost ratio of interferon mono-therapy can be improved by selection of patients, monitoring plasma HCV RNA at 4 weeks, and prolonging therapy to 12 months in responders with genotype 1. Interferon-ribavirin combination is promising for its enhanced efficacy.


Plasma ubiquinol-10 is decreased in
patients with hyperlipidaemia.


Kontush A Reich A Baum K Spranger T Finckh
B Kohlschutter A Beisiegel U
Atherosclerosis 1997 FEB 28;129(1):119-126
Kontush A, Univ Hamburg, Hosp Eppendorf, Biochem Lab,
Med Kern & Poliklin, Martinistr 52,
Pav 39, D 20246 Hamburg, GERMANY

Ubiquinol-10, the reduced form of ubiquinone-10 (coenzyme Q(10)), is a potent lipophilic antioxidant present in nearly all human tissues. The exceptional oxidative lability of ubiquinol-10 implies that it may represent a sensitive index of oxidative stress. The present study was undertaken to assess the hypothesis that the level of ubiquinol-10 in human plasma can discriminate between healthy subjects and patients who are expected to be subjected to an increased oxidative stress in vivo. Using a newly developed method, we measured plasma ubiquinol-10 in 38 hyperlipidaemic patients with and without further complications, such as coronary heart disease, hypertension: or liver disease, and in 30 healthy subjects. The oxidizability of plasma samples obtained from hyperlipidaemic patients was found to be increased in comparison with control subjects, suggesting that the patients were subjected to a higher oxidative stress in vivo than the controls. Plasma ubiquinol-10, expressed as a percentage of total ubiquinol-10 + ubiquinone-10 or normalized to plasma lipids, was lower in the patients than in controls (P = 0.001 and 0.008, respectively). The proportion of ubiquinol-10 decreased in the order young controls > aged controls > hyperlipidaemic patients without complications > hyperlipidaemic patients with complications (P = 0.003). A negative correlation was found between the proportion of ubiquinol-10 and plasma triglycerides. The hyperlipidaemic patients with hypertension had a lower proportion of ubiquinol-10 than subjects without. When the study population was divided into smokers and non-smokers, plasma ubiquinol-10 was found to be reduced amongst smokers, independently of whether it was expressed as a percentage of total ubiquinol-10 + ubiquinone-10 (P = 0.006) or normalized to plasma lipids (P = 0.009). These data suggest that the level of ubiquinol-10 in human plasma may represent a sensitive index of oxidative stress in vivo especially indicative of early oxidative damage. Measuring plasma ubiquinol-10 can be proposed as a practical approach to assess oxidative stress in humans.


Serum selenium versus lymphocyte
subsets and markers of disease progression
and inflammatory response in human
immunodeficiency virus-1 infection.

Look MP Rockstroh JK Rao GS Kreuzer KA Spengler U Sauerbruch T
Biol Tr Elem Res 1997 JAN;56(1):31-41
Look MP, Univ Bonn, Dept Gen Internal Med,
Sigmund Freud Str 25, D 53105 Bonn, GERMANY

Serum selenium levels were determined cross-sectionally in 57 HIV-infected patients who were classified according to the Centers for Disease Control (CDC) 1993 classification system. Mean serum selenium levels were lower in CDC stage II (58.7 +/- 12.2 mu g/L; p 0.01; n = 18) and stage III (47.6 +/- 11.3 mu g/L; p 0.01; Il = 19) HIV-infected patients, than in healthy subjects (80.6 +/- 9.6 mu g/L; n = 48) and stage I patients (73.6 +/- 16.5 mu g/L; n = 20). Serum selenium levels were positively correlated with CD4 count, CD4/8 ratio, hematocrit, and serum albumin (r = 0.42; r = 0.39; r = 0.48; and r = 0.45; p 0.01, respectively) and inversely with serum levels of thymidine kinase (r = -0.49; p 0.01; n = 49) and beta 2- microglobulin (r = -0.46; p 0.001; n = 49). In addition, serum selenium levels in 20 randomly selected AIDS-free individuals (CDC I: r = 10; CDC II: n = 10) were inversely correlated with serum concentrations of interleukin-8 (IL- 8) and soluble tumor necrosis factor receptors (sTNFR) types I and II. There was no correlation with serum immuneglobulin A and total serum protein levels. The results show that the progressive deprivation of serum selenium in HIV-infection is associated with loss of CD4(+)-cells and with increased levels of markers of disease progression and inflammatory response.


Computational genomic analysis of
hemorrhagic fever viruses -
Viral selenoproteins as a potential
factor in pathogenesis.

Ramanathan CS Taylor EW
Biol Tr Elem Res 1997 JAN;56(1):93-106
Taylor EW, Univ Georgia, Computat Ctr Mol Struct; Design,
Athens,GA 30601 USA

A number of distinct viruses are known as hemorrhagic fever viruses based on a shared ability to induce hemorrhage by poorly understood mechanisms, typically involving the formation of blood clots (''disseminated intravascular coagulation''). It is well documented that selenium plays a significant role in the regulation of blood clotting via its effects on the thromboxane/prostacyclin ratio, and effects on the complement system. Selenium has an anticlotting effect, whereas selenium deficiency has a proclotting or thrombotic effect. It is also well documented that extreme dietary selenium deficiency, which is almost never seen in humans, has been associated with hemorrhagic effects in animals. Thus, the possibility that viral selenoprotein synthesis might contribute to hemorrhagic symptoms merits further consideration. Computational genomic analysis of certain hemorrhagic fever viruses reveals the presence of potential protein coding regions (PPCRs) containing large numbers of in-frame UGA codons, particularly in the -1 reading frame. Ln some cases, these clusterings of UGA codons are very unlikely to have arisen by chance, suggesting that these UGAs may have some function other than being a stop codon, such as encoding selenocysteine. For this to be possible, a downstream selenocysteine insertion element (SECIS) is required. Ebola Zaire, the most notorious hemorrhagic fever virus, has a PPCR with 17 UGA codons, and several potential SECIS elements can be identified in the viral genome. One potential viral selenoprotein may contain up to 16 selenium atoms per molecule. Biosynthesis of this protein could impose an unprecedented selenium demand on the host, potentially leading to severe lipid peroxidation and cell membrane destruction, and contributing to hemorrhagic symptoms. Alternatively, even in the absence of programmed selenoprotein synthesis, it is possible that random slippage errors would lead to increased encounters with UGA codons in overlapping reading frames, and thus potentially to nonspecific depletion of SeC in the host.


The distribution of Selenium and mortality
owing to acquired immune deficiency
syndrome in the continental United States.

Cowgill UM
Biol Tr Elem Res 1997 JAN;56(1):43-61
Cowgill UM, Univ Colorado, Dept EPO Biol,
POB 1327, Carbondale,CO 81623 USA

A hypothesis has been proposed that Selenium (Se) concentration in the environment as measured by its uptake by alfalfa, which sorbs Se from the soil in proportion to what is present, exerted an apparent effect on incidence of (acquired immune deficiency syndrome) AIDS such that AIDS' mortality within the conterminous United States was lower where the Se quantity in the soil was high than where the amount was low. The object of this study was to test this hypothesis for statistical significance and to discover whether the apparent pattern of AIDS mortality in relation to Se distribution holds true with respect to all ages, both races (Black and White), and both genders. The statistical analysis employed was analysis of variance. Age-specific data as well as age-adjusted data were subject to statistical analysis. Ages where AIDS mortality rates per 100,000 were greatest were in the range from 25- 54 yr for low-, medium-, and high-Se areas of the US. Black mortality owing to AIDS showed highly statistically significant results for the three Se regions, both genders, and six age groups, whereas White mortality was not as significantly affected by Se. A hypothesis is proposed that the Black population during the last decade or so has been less migratory than the White population. Thus, their food supply and hence its Se content have been more stable than that of the White population, which is more prone to consume imported foods of unknown Se content and be more migratory. A second hypothesis is advanced that suggests that medical care is not equally available to the poor and especially poor Blacks. Black men and women die at a greater death rate than do Whites. This implies that a lack of medical care is the true cause. This article suggests that a pattern exists between the geographical distribution of Se using alfalfa as a dietary guide and AIDS' mortality such that an inverse relationship persists between Se quantity in an area and AIDS' mortality in the same area.


Protective role of selenium against hepatitis
B virus and primary liver cancer in Qidong.

Yu SY Zhu YJ Li WG
Biol Tr Elem Res 1997 JAN;56(1):117-124
Yu SY, Chinese Acad Med Sci, Inst Canc,
Peking Union Med Coll,
Beijing 100021, PEOPLES R CHINA

High rates of hepatitis B virus (HBV) infection and primary liver cancer (PLC) are present in Qidong county. Epidemiological surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as HBV infection. Four-year animal studies showed that dietary supplement of Se reduced the HBV infection by 77.2% and liver precancerous lesion by 75.8% of ducks, caused by exposure to natural environmental etiologic factors. An intervention trial was undertaken among the general population of 130,471. Individuals in five townships were involved for observation of the preventive effect of Se. The g-yr follow-up data showed reduced PLC incidence by 35.1% in selenized table salt supplemented vs the nonsupplemented population. On withdrawal of Se from the treated group, PLC incidence rate began to increase. However, the inhibitory response to HBV was sustained during the 3-yr cessation of treatment. The clinical study among 226 Hepatitis B Surface Antigen (HBsAg)-positive persons provided either 200 mu g of Se in the form of selenized yeast tablet or an identical placebo of yeast tablet daily for 4 yr showed that 7 of 113 subjects were diagnosed as having PLC in the placebo group, whereas no incidence of PLC was found in 113 subjects supplemented with Se. Again on cessation of treatment, PLC developed at a rate comparable to that in the control group, demonstrating that a continuous intake of Se is essential to sustain the chemopreventive effect.


Inhibitory effect of selenite and other
antioxidants on complement-mediated
tissue injury in patients with
epidemic hemorrhagic fever.

Hou JC
Biol Tr Elem Res 1997 JAN;56(1):125-130
Hou JC, Chinese Acad Med Sci, Inst Basic Med Sci,
Beijing 100730, PEOPLES R CHINA

Results on the inhibitory effect on complement activation by sodium selenite, sodium glycyrrhizin, and a selenium- glycyrrhizin compound in hemorrhagic fever patients are presented.


Oxidative damage to muscle protein in
Duchenne muscular dystrophy.

Haycock JW MacNeil S Jones P Harris JB Mantle D
Neuroreport 1996 DEC 20;8(1):357-361
Haycock JW, Univ Sheffield, No Gen Hosp, Ctr Clin Sci, Dept Med,
Herries Rd, Sheffield S5 7AU, S Yorkshire, ENGLAND

THE hypothesis that reactive free radical species (ROS) may contribute to the pathogenesis of Duchenne muscular dystrophy (DMD) has been suggested previously, but experimental data obtained in support of the above have to date proved inconclusive. The recent discovery that nitric oxide synthase (required for muscle relaxation) is associated with the sarcolemmal protein dystrophin normally and that both proteins are absent in DMD has heightened interest in the potential role of ROS in this disorder . We therefore investigated oxidative damage to proteins in the quadriceps femoris muscle by quantifying protein carbonyl levels in six patients with DMD and six normal controls. In DMD, the mean protein carbonyl level in the quadriceps femoris muscle was increased by 211% (p < 0.005) compared with the normal control subjects. The data thus support the hypothesis for the role of ROS induced protein oxidation of muscle cell damage in DMD.


Using liquid levodopa in the treatment
of Parkinson's disease: A practical guide.


Kurth MC
Drug Aging 1997 MAY;10(5):332-340
Kurth MC, 222 W Thomas, Suite 401,
Phoenix,AZ 85013 USA

Many patients with Parkinson's disease develop both involuntary movements from, and a critical dependency on, levodopa therapy as their disease progresses. This results in a narrow therapeutic window in which blood concentrations of levodopa can achieve optimal control of parkinsonian symptoms. The short half-life of levodopa, combined with loss of intraneuronal storage capacity for levodopa as the disease progresses, results in patients experiencing marked motor fluctuations complicated by medication-induced dyskinesias. When given in tablet form, the dosage of levodopa (which is usually combined with a decarboxylase inhibitor such as carbidopa or benserazide) often cannot be titrated adequately, and the drug may become unpredictable in its ability to relieve parkinsonian symptoms. A solution of levodopa and carbidopa, stabilised using ascorbic acid, offers a means of delivering a titrated amount of levodopa at regular intervals. Solutions pass through the stomach faster than solids, affording more rapid symptomatic relief in some patients with Parkinson's disease.


Ribavirin therapy in bone marrow
transplant recipients with viral
respiratory tract infections.

Sparrelid E Ljungman P EkelofAndstrom E Aschan
J Ringden O Winiarski J Wahlin B Andersson J
Bone Marrow Transplant 1997 MAY;19(9):905-908
Sparrelid E, Huddinge Univ Hosp, Div Infect Dis, I 73,
S 14186 Huddinge, SWEDEN

Treatment with ribavirin was instituted in 12 allogeneic and one autologous bone marrow transplant (BMT) recipients with proven respiratory syncytial virus (RSV), influenza B virus or parainfluenza virus infections. RSV was diagnosed in six cases, influenza B virus in four and parainfluenzavirus in three patients. Ribavirin was given orally or intravenously (15-20 mg/kg/day in three divided doses) and in nine cases with the addition of ribavirin inhalations (6 g/day). Three patients required ventilator support. Three out of seven patients with pneumonia, including one patient with RSV who developed pulmonary infiltrates 10 days after the start of therapy, died despite treatment with ribavirin (two RSV, one influenza B). Multiple etiological agents were found in the fatal cases. The clinical condition improved in 10 of 13 patients during therapy. No serious adverse effects of systemic ribavirin were noticed. Two patients had reversible signs of hemolysis but only one patient required more erythrocyte transfusions than expected after BMT. Obstructive respiratory distress was often observed (6/9 patients receiving ribavirin inhalation therapy), which resulted in discontinuation of aerosolized therapy in four cases. Time to engraftment (WBC 0.2 x 10(9)/l) did not differ from other non-treated BMT patients. We conclude that ribavirin is well tolerated both orally and intravenously and it may, if instituted before development of hypoxia, reduce morbidity and mortality of RSV, influenza B and parainfluenza in this group of patients.


The neurosteroid pregnenolone sulphate
enhances NMDA- induced phasic firing of
vasopressin neurones in the rat supraoptic nucleus.

Wakerley JB Richardson CM
Neurosci Lett 1997 APR 25;226(2):123-126
Wakerley JB, Univ Bristol, Sch Med Sci, Dept Anat,
Neuroendocrine Res Grp, Bristol BS8 1TD, Avon, ENGLAND

The effect of the neurosteroid pregnenolone sulphate (PS) on N-methyl-D-aspartate (NMDA)-induced phasic firing of supraoptic vasopressin (VP) neurones was studied in rat hypothalamic slices in vitro. In VP neurones which were induced to fire phasi cally by continuous perifusion with NMDA (9-30 mu M), addition of 100 mu M PS to the incubation medium significantly increased overall spike frequency, with a rise in both proportion of time active and intraburst firing rate. A similar effect was seen dur ing picrotoxin block of GABAergic transmission. No significant change in NMDA-induced phasic firing was observed with 100 mu M dehydroepiandrosterone sulphate. VP neurones became silent in the absence of NMDA, and under these conditions PS had no effect.