Abstracts for Citations - Veterans Affairs



Abstracts for Citations

For citations entered from PubMed that contained abstracts.

1. Institute of Medicine, Gulf War Veterans: Treating Symptoms and Syndromes. Committee on Identifying Effective Treatments for Gulf War Veterans' Health Problems. Editors Bernard M. Rosof and Lyla M. Hernandez. 2001, Washington, D.C.: National Academy Press. 152.

2. Moher, D., et al. Does the inclusion of grey literature influence the estimates of intervention effectiveness reported in meta-analyses? [abstract]. in Research Seminar Series, UCLA Division of General Internal Medicine/Health Services Research and the Clinical Scholars Program. June 2000. 2000. Los Angeles.

Background: Including only a subset of all available evidence in a meta-analysis may introduce biases and threaten its validity. This is particularly likely if the subset of included studies differ from those not included, as may be the case for published and grey literature. We set out to examine whether exclusion of grey literature, compared to its inclusion in meta-analysis, provides different estimates of the effectiveness of interventions evaluated in randomized trials. Methods: From a random sample of 135 meta-analyses, we identified and retrieved 33 publications that included both grey and published primary studies. The 33 publications contributed 41 separate meta-analyses from several disease areas. General characteristics of the meta-analyses and associated studies and outcome data at the trial level were collected. We explored the effects of the inclusion of grey literature on the quantitative results using logistic regression analyses. Findings: Thirty-three percent of the meta-analyses were found to include some form ofgrey literature. The grey literature, when included, accounts for between 4.5% and 75% of the studies in a meta-analysis. On average, the published literature, compared to the grey literature, yielded significantly larger estimates of the intervention effect by 12% [ROR = 1.12; 95%CI: 1.01, 1.23]. Excluding abstracts (i.e. only including unpublished studies, conference proceedings, graduate theses, book chapters, company reports and applications) from the analysis further compounded the exaggeration [ROR = 1.38, 95%CI: 1.15, 1.64]. The exclusion of grey literature from a meta-analysis may increase the likelihood of a biased result. Interpretations: This study provides evidence that the exclusion of grey literature from meta-analyses can lead to exaggerated estimates of intervention effectiveness. In general, meta-analysts should attempt to identify, retrieve and include all literature, grey and published, that meets pre-defined inclusion criteria.

3. Collins, J.F., et al., The antibiotic treatment trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics. Control Clin Trials, 2002. 23(3): p. 333-53. Many veterans who were deployed to the Persian Gulf during the 1990-1991 Gulf War developed multiple unexplained symptoms such as pain, fatigue, and neurocognitive problems. This constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI). Although there is no proven explanation for the cause of GWVI, one fairly widespread explanation is systemic Mycoplasma fermentans infection. The Antibiotic Treatment Trial of GWVI is a randomized placebo-controlled trial to determine whether a 1-year course of doxycycline treatment in deployed Gulf War veterans with GWVI and testing as Mycoplasma species positive will improve their overall functional status as measured by the Physical Component Summary of the SF-36V questionnaire. The study of a multisymptom illness such as GWVI is complicated by the nonspecific nature of the illness, the unknown etiology, and the lack of a widely accepted outcome measure. The presumption of mycoplasma infection raises concerns regarding the methodology for determination of mycoplasma infection, the choice of treatment, and the duration of treatment. However, such a presumption allows the formulation of a clear testable hypothesis that can be tested with treatments with known rates of adverse events and known activity against Mycoplasma species. This paper describes the major issues faced by the investigators during planning, the study design, the patient screening results, and the baseline characteristics of the study patients. There were 2712 patients screened for study entry at 26 Department of Veterans Affairs and two Department of Defense medical centers. Of these, 491 met all study entry criteria and were randomized to either 1 year of doxycycline (200 mg/day) or 1 year of placebo. All patients were seen monthly during treatment and at 6 months after the end of treatment. Study patients had a mean age of 41 years and were mostly male (86%), white (64%), married (68%), and employed full-time (71%).

4. Hilborne, L. and B. Golomb, A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 1: Infectious Diseases, . 1998, RAND: Washington, DC.

5. Hyman, E.S., Urinary sediment examination and Gulf War Syndrome. Am J Med Sci, 1998. 316(6): p. 411-3.

6. Nicolson, G.L. and N.L. Nicolson, Diagnosis and treatment of mycoplasma infections, . 1995.

7. Nicolson, G.L. and N.L. Nicolson, The isolation, purification, and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes. Methods Mol Genetics, 1994. 5: p. 281-298.

8. Rea, W.J., et al., Reduction of chemical sensitivity by means of heat depuration, physical therapy and nutritional supplementation in a controlled environment. J Nutritional Medicine, 1996. 6.

9. Kilburn, K.H., R.H. Warsaw, and M.G. Shields, Neurobehavioral dysfunction in firemen exposed to polycholorinated biphenyls (PCBs): possible improvement after detoxification. Arch Environ Health, 1989. 44(6): p. 345-50. Fourteen firemen exposed to polychlorinated biphenyls (PCBs) and their byproducts generated in a transformer fire and explosion had neurophysiological and neuropsychological tests 6 mo after the fire. They were re-studied 6 wk later after undergoing 2-3 wk of an experimental detoxification program consisting of medically supervised diet, exercise, and sauna. A case-control comparison with firemen matched from the same department, but who did not participate in controlling the transformer fire, had shown significant impairment of memory for stories, visual images, and digits backwards. Cognitive function was impaired for block design, identifying embedded figures, and design association and recognition using Culture Fair. Making of trails and choice reaction time, which measured cognitive function and perceptual motor speed, were also impaired. These signs of protracted neurobehavioral impairment were attributed to PCBs and heat-produced byproducts. No relationship, however, was found between the firemen's serum or fat levels of PCBs as Arochlor 1248 and their type or degree of neurobehavioral impairment. Retesting following the detoxification program showed significantly improved scores on: three memory tests, block design, trails B, and embedded figures. Thus, there was significant reversibility of impairment after the detoxification interval. However self-appraisal scores for depression, anger, and fatigue--which were initially elevated--and for vigor--which was reduced--did not change across this interval.

10. Folkers, K. and J.L. Nilsson, [Coenzyme Q regarded as a vitamin]. Nord Med, 1970. 83(16): p. 489-93.

11. Bargossi, A.M., et al., Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int J Clin Lab Res, 1994. 24(3): p. 171-6. Ubiquinone is a carrier of the mitochondrial respiratory chain which regulates oxidative phosphorylation: it also acts as a membrane stabilizer preventing lipid peroxidation. In man the quinone ring originates from tyrosine, while the formation of the polyisoprenoid lateral chain starts from acetyl CoA and proceeds through mevalonate and isopentenylpyrophosphate; this biosynthetic pathway is the same as the cholesterol one. We therefore performed this study to evaluate whether statins (hypocholesterolemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase) modify blood levels of ubiquinone. Thirty unrelated outpatients with primary hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 3-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, and at 45 and 90 days: total plasma cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Apo A1, Apo B and CoQ10 in plasma and in platelets. In the S group, there was a marked decrease in total cholesterol low-density lipoprotein-cholesterol and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of plasma CoQ10 (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg).(ABSTRACT TRUNCATED AT 250 WORDS).

12. England, J.D., et al., Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors--simvastatin and pravastatin [letter]. Australian and New Zealand Journal of Medicine, 1995. 25(4): p. 374-5.

13. Barbiroli, B., et al., Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cellular and Molecular Biology, 1997. 43(5): p. 741-9.

14. Chen, R.S., C.C. Huang, and N.S. Chu, Coenzyme Q10 treatment in mitochondrial encephalomyopathies. Short-term double-blind, crossover study. European Neurology, 1997. 37(4): p. 212-8.

15. Folkers, K. and R. Simonsen, Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies. Biochimica et Biophysica Acta, 1995. 1271(1): p. 281-6.

16. Kuz'menko, I.V., et al., [Efficiency of ubiquinone and p-oxybenzoic acid in prevention of E-hypovitaminosis-induced development of muscular dystrophy]. Ukr Biokhim Zh, 1981. 53(5): p. 73-9. It is shown that E-hypovitaminosis-induced muscular dystrophy in rabbits is accompanied by a sharp decrease in the body mass, an increase in the urine creatine-index, a decrease in the vitamin E and ubiquinone contents in the liver and skeletal muscle tissues. In the myocardium mitochondria a decrease in the vitamin E content and an increase in the ubiquinone content are observed. The activity of NADH-cytochrome c-, NADH-ubiquinone- and succinate-ubiquinone-reductase also varies in mitochondria of the studied tissues. In myocardium organellas a direct dependence is found between the content of ubiquinone, NADH- and succinate-ubiquinone-reductase activity and an inverse one-between its content and the activity of the NADH-cytochrome c-reductase system. It is established that p-oxybenzoic acid as well as vitamin E prevents development of muscular dystrophy and causes changes analogous in direction in the activity of the ubiquinone-dependent enzymic systems of mitochondria. Ubiquinone-9 is less efficient in preventing the development of muscular dystrophy.

17. Shimomura, Y., et al., Protective effect of coenzyme Q10 on exercise-induced muscular injury. Biochem Biophys Res Commun, 1991. 176(1): p. 349-55. The effect of coenzyme Q10 administration on exercise-induced muscular injury was examined in rats. Coenzyme Q10-treated and control rats were exercised by 90 min of downhill treadmill running. A part of the animals in both groups were killed immediately after exercise and the others were 40 h postexercise. After the exercise bout, serum creatine kinase and lactate dehydrogenase activities were elevated in the control rats, but not in the coenzyme Q10-treated rats. These enzyme activities in the latter increased to the similar level of the former 40 h postexercise. The muscle coenzyme Q10 content increased by the coenzyme Q10 treatment. These results suggest that the coenzyme Q10 treatment protected skeletal muscles against injury caused during exercise, but not against damage related with inflammatory processes after exercise.

18. Kamikawa, T., et al., Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol, 1985. 56(4): p. 247-51. The effects of coenzyme Q10(CoQ10) on exercise performance were studied in 12 patients, average age 56 years, with stable angina pectoris. The study involved a double-blind, placebo-controlled, randomized, crossover protocol, using multistage treadmill exercise tests. CoQ10(150 mg/day in 3 daily doses) was administered orally for 4 weeks, tended to reduce anginal frequency from 5.3 +/- 4.9 to 2.5 +/- 3.3 attacks for 2 weeks and nitroglycerin consumption from 2.6 +/- 2.8 to 1.3 +/- 1.7 tablets for 2 weeks compared with patients receiving the placebo, but the reduction was not statistically significant. Exercise time increased from 345 +/- 102 seconds with placebo to 406 +/- 114 seconds during CoQ10 treatment (p less than 0.05). The time until 1 mm of ST-segment depression occurred increased from 196 +/- 76 seconds with placebo to 284 +/- 104 seconds during CoQ10 treatment (p less than 0.01). During the exercise test, ST-segment depression, heart rate and pressure-rate product at the same and at the maximal workload showed no significant difference between patients after placebo and CoQ10 administration. The average CoQ10 plasma concentration increased from 0.95 +/- 0.48 microgram/ml to 2.20 +/- 0.98 microgram/ml after CoQ10 treatment. This increase was significantly related to the increase in exercise duration (r = 0.68, p less than 0.001). Only 1 patient had a loss of appetite, but continued therapy. This study suggests that CoQ10 is a safe and promising treatment for angina pectoris.

19. Alleva, R., et al., Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection. FEBS Lett, 2001. 503(1): p. 46-50. Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to alpha-tocopheryl succinate (alpha-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to alpha-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by alpha-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents.

20. Di Giovanni, S., et al., Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology, 2001. 57(3): p. 515-8. Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.

21. Fernandez-Ayala, D.J., et al., Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. Antioxid Redox Signal, 2000. 2(2): p. 263-75. Coenzyme Q10 (CoQ10) is a component of the antioxidant machinery that protects cell membranes from oxidative damage and decreases apoptosis in leukemic cells cultured in serum-depleted media. Serum deprivation induced apoptosis in CEM-C7H2 (CEM) and to a lesser extent in CEM-9F3, a subline overexpressing Bcl-2. Addition of CoQ10 to serum-free media decreased apoptosis in both cell lines. Serum withdrawal induced an early increase of neutral-sphingomyelinase activity, release of ceramide, and activation of caspase-3 in both cell lines, but this effect was more pronounced in CEM cells. CoQ10 prevented activation of this cascade of events. Lipids extracted from serum-depleted cultures activated caspase-3 independently of the presence of mitochondria in cell-free in vitro assays. Activation of caspase-3 by lipid extracts or ceramide was prevented by okadaic acid, indicating the implication of a phosphatase in this process. Our results support the hypothesis that plasma membrane CoQ10 regulate the initiation phase of serum withdrawal-induced apoptosis by preventing oxidative damage and thus avoiding activation of downstream effectors as neutral-sphingomyelinase and subsequent ceramide release and caspase activation pathways.

22. Kagan, T., et al., Coenzyme Q10 can in some circumstances block apoptosis, and this effect is mediated through mitochondria. Ann N Y Acad Sci, 1999. 887: p. 31-47. The mitochondrial component coenzyme Q10 (CoQ10) has been used for many years as a dietary supplement intended to promote good health by trapping free radicals, thus preventing lipid peroxidation and DNA damage. We have tested its use as a generic anti-apoptotic compound and have found that its ability to protect against apoptosis varies depending on both cell type and mode of cell death induction. We have further established that this protection may be mediated by its effect on mitochondrial function and viability. We provide additional evidence that CoQ10's protective effect on mitochondrial membrane potential does not always result in altered mitochondrial enzyme activity and neither does it guarantee survival. These observations open the way for further investigations into the mechanisms involved in mitochondrial control of apoptosis.

23. Mosca, L., et al., Modulation of apoptosis and improved redox metabolism with the use of a new antioxidant formula. Biochem Pharmacol, 2002. 63(7): p. 1305-14. Oxidative stress is involved in the pathogenesis of a wide spectrum of diseases, implicating that strategies directed at counterbalancing oxidative processes could have a role in clinical medicine. There is also an evidence that oxidative stress acts as a major determinant of apoptotic cell death. Many studies have reported favourable effects of antioxidant formulas on several parameters of the oxidant-antioxidant balance, but none of them has focused whether antioxidant formulas could modulate apoptosis. We investigated in 20 healthy individuals the effect of supplementation with a formula containing alpha-tocopherol, alpha-lipoic acid, coenzyme Q(10), carnitines, and selenomethionine, on plasma oxidant status and peroxide levels, erythrocyte antioxidant enzymes, lymphocyte apoptosis, and generation of ROS at the mitochondrial level. Control subjects received only carnitines or an incomplete formula with alpha-tocopherol, alpha-lipoic acid, coenzyme Q(10), and selenomethionine. Supplementation with the complete formula resulted in a significant increase in the plasma antioxidant status that was mirrored by a decrease in blood peroxide levels and a reduced generation of ROS at the mitochondrial level. This was associated with a significant decrease in the frequency of peripheral blood lymphocytes, with either CD4 or CD8 phenotype, undergoing apoptosis. Less consistent results were found when either incomplete formula was used. Our study suggests that supplementation with antioxidant formulas can modulate the process of apoptosis under in vivo conditions. The clinical potential of this strategy in the treatment of diseases with an elevated commitment to apoptosis should be explored.

24. Schults, C.W., et al., Effects of coenzyme Q10 in early Parkinson disease. Evidence of slowing of the functional decline. Archives of Neurology, 2002. 59(10): p. 1541-50. Background: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression.

Objective: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD.

Design: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. Setting: Academic movement disorders clinics. Patients: Eighty subjects with early PD who did not require treatment for their disability. Interventions: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d.Main Outcome Measure:  The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. Results: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was .09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P = .04). Conclusions: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.

25. Haley, R.W., et al., Brain abnormalities in Gulf War syndrome: Evaluation with 1H MR spectroscopy. Radiology, 2000. 215: p. 807-817. PURPOSE: To test for neuronal brain damage in the basal ganglia and brainstem in Gulf War veterans by using magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: Twenty-two Gulf War veterans with one of three factor analysis-derived syndromes (case patients); 18 well veterans matched for age, sex, and education level (control subjects); and six Gulf War veterans with syndrome 2 from a different population (replication sample) underwent long echo time (272 msec) proton (hydrogen 1) MR spectroscopy on a 4 x 2 x 2-cm voxel in the basal ganglia bilaterally and a 2 x 2 x 2-cm voxel in the pons. Syndromes 1-3 are described as "impaired cognition," "confusion-ataxia," and "central pain," respectively. RESULTS: The N-acetylaspartate-to-creatine (NAA/Cr) ratio, which reflects functional neuronal mass, was significantly lower in the basal ganglia and brainstem of Gulf War veterans with the three syndromes than in those structures of the control subjects (P =.007). The finding was corroborated in the replication sample (P =.002). Veterans with syndrome 2 (the most severe clinically) had evidence of decreased NAA/Cr in both the basal ganglia and the brainstem; those with syndrome 1, in the basal ganglia only; and those with syndrome 3, in the brainstem only. CONCLUSION: Veterans with different Gulf War syndromes have biochemical evidence of neuronal damage in different distributions in the basal ganglia and brainstem.

26. Sinzinger, H., P. Schmid, and J. O'Grady, Two different types of exercise-induced muscle pain without myopathy and CK -elevation during HMG-Co-enzyme-A-reductase inhibitor treatment. Atherosclerosis, 1999. 143(11): p. 459-460.

27. Muller, D.P., J.K. Lloyd, and O.H. Wolff, Vitamin E and neurological function: abetalipoproteinaemia and other disorders of fat absorption. Ciba Found Symp, 1983. 101: p. 106-21. Evidence that vitamin E is important for normal neurological function in humans is presented. First, in abetalipoproteinaemia early therapy with vitamin E delays and may prevent the development of the neurological complications, and in patients with established lesions treatment can arrest or reverse the neuropathy. Second, in other chronic disorders of fat absorption with severe vitamin E deficiency, neurological manifestations which are very similar to those described in untreated abetalipoproteinaemia can be improved by vitamin E. Vitamin E supplementation is therefore advisable for all patients with chronic fat malabsorption who have low serum vitamin E concentration. Serum vitamin E concentrations should also be measured in patients with spinocerebellar disorders, whatever the aetiology.

28. Muller, D.P.R., J.K. Lloyd, and A. Bird, Long-term management of abetalipoproteinemia. Possible role for vitamin E. Arch Dis Child, 1977. 52: p. 209-14.

29. Iannaccone, S.T. and R.J. Sokol, Vitamin E deficiency in neuropathy of abetalipoproteinemia. Neurology, 1986. 36(7): p. 1009.

30. Hegele, R.A. and A. Angel, Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy. Can Med Assoc J, 1985. 132(1): p. 41-4. A 16-year-old girl, one of dizygotic twins, presented in 1976 complaining of a 1-year history of a lack of coordination and an inability to run. The results of biochemical tests confirmed the diagnosis of classic abetalipoproteinemia. In addition to the recognized neurologic features of this disorder, she had a reduced evoked motor unit potential and markedly elevated serum levels of muscle enzymes, which suggested myositis. The serum vitamin E level was markedly decreased. Oral therapy with vitamin E, 800 mg daily, was begun, and in 1981 the dosage was increased to 3200 mg daily. Over the 7 years of follow-up she improved clinically, there was an increase in the evoked motor unit potential, the serum levels of some of the muscle enzymes decreased to normal, and the serum and tissue vitamin E levels increased significantly. It was concluded that treatment with high doses of vitamin E was responsible for the arrest of the usually progressive neuropathy and myopathy.

31. Azizi, E., et al., Abetalipoproteinemia treated with parenteral and oral vitamin A and E and with medium chain triglycerides. Acta Pediatr Scand, 1978. 67: p. 797-801.

32. Morris, M.C., et al., Vitamin E and cognitive decline in older persons. Archives of Neurology, 2002. 59(7): p. 1125-1132.

33. Veltkamp, R. and J.F. Toole, Hyperbaric oxygen--a neuroprotective adjuvant for hyperacute ischemic stroke? Journal of the Neurological Sciences, 1997. 150(1): p. 1-2.

34. Clifton, G.L., Hypothermia and hyperbaric oxygen as treatment modalities for severe head injury. New Horizons, 1995. 3(3): p. 474-8. Abstract: Moderate systemic hypothermia has been shown to improve neurologic outcomes in both fluid-percussion and cortical contusion models of experimental brain injury. Based upon initial clinical work, it was concluded that at temperatures < 32 degrees C, patients with severe brain injury were at increased risk of ventricular arrhythmias, and that rapid rewarming immediately postinjury predisposed to intracranial pressure increases. Subsequent clinical studies of moderate hypothermia (32 degrees C) for 24- to 48-hr duration with slow rewarming in human brain injury showed indications of neurologic improvement and a low incidence of hypothermia-related complications. Based upon the strengths of both laboratory and clinical data, a multicenter (nine centers), randomized, prospective trial testing moderate systemic hypothermia in patients with severe brain injury has been organized. This trial, funded by National Institutes of Health, National Institute of Neurological Disorders and Stroke, began on October 20, 1994. Five hundred patients are to be treated in an intent-to-treat protocol using standard management at normothermia versus standard management at hypothermia. The trial is designed to detect an absolute shift of 12% in the percentage of patients achieving satisfactory outcome (good recovery/moderate disability) at a power of 85% at 6 months postinjury. The efficacy of hyperbaric oxygen administered every 8 hrs for 1-hr duration for a 2-wk period has also been tested in patients after severe brain injury. While the mortality rate was reduced in the treated group, the percentage of favorable outcomes was unchanged. Further studies are in progress.

35. Nighoghossian, N. and P. Trouillas, Hyperbaric oxygen in the treatment of acute ischemic stroke: an unsettled issue. Journal of the Neurological Sciences, 1997. 150(1): p. 27-31. Abstract: Therapy for acute ischemic stroke can be approached in two basic ways: first, by an attempt to restore or improve blood flow in an occluded vascular territory and, second, via therapy directed at the cellular and metabolic targets. As local anoxia and energy failure are the initiating cellular stage in ischemia, the inhalation of oxygen at increased atmospheric pressures might be effective. Treatment of acute focal cerebral ischemia with hyperbaric oxygen (HBO) has been reported in animals and humans. In general, the results of research in animals have suggested a promising role for the use of HBO. More than 400 cases of human ischemic stroke treated with HBO have been reported. In about half of the cases, improvement in status has been claimed on clinical or electroencephalographic grounds. In fact, the effectiveness of HBO in most disease processes other than carbon monoxide poisoning and decompression sickness is a subject of major ongoing debate. This short review will attempt: (1) to recall some early experiments involving HBO in the treatment of acute ischemia: (2) to point out some conflicting results regarding the role of HBO on cellular and metabolic disorders; and (3) to determine the possibility of a future role for HBO therapy in acute ischemic stroke.

36. Nighoghossian, N., et al., Hyperbaric oxygen in the treatment of acute ischemic stroke. A double-blind pilot study. Stroke, 1995. 26(8): p. 1369-72. Abstract: BACKGROUND AND PURPOSE: The effects of hyperbaric oxygen (HBO) therapy on humans are uncertain. Our study aims first to outline the practical aspects and the safety of HBO treatment and then to evaluate the effect of HBO on long-term disability. METHODS: Patients who experienced middle cerebral artery occlusion and were seen within 24 hours of onset were randomized to receive either active (HBO) or sham (air) treatment. The HBO patients were exposed daily to 40 minutes at 1.5 atmospheres absolute for a total of 10 dives. We used the Orgogozo scale to establish a pretreatment functional level. Changes in the Orgogozo scale score at 6 months and 1 year after therapy were used to assess the therapeutic efficacy of HBO. In addition, we used the Rankin scale and our own 10-point scale to assess long term-disability at 6 months and 1 year. Two sample t tests and 95% confidence intervals were used to compare the mean differences between the two treatment groups. Student's two-tailed test was used to compare the differences between pretherapeutic and posttherapeutic scores at 6 months and 1 year in the two treatment groups. RESULTS: Over the 3 years of study enrollment, 34 patients were randomized, 17 to hyperbaric treatment with air and 17 to hyperbaric treatment with 100% oxygen. There was no significant difference at inclusion between groups regarding age, time from stroke onset to randomization, and Orgogozo scale scores. Neurological deterioration occurred during the first week in 4 patients in the sham group, 3 of whom died; this worsening was clearly related to the ischemic damage. Treatment was also discontinued for 3 patients in the HBO group who experienced myocardial infarction, a worsening related to the ischemic process, and claustrophobia. Therefore, 27 patients (13 in the sham group and 14 in the HBO group) completed a full course of therapy. The mean score of the HBO group was significantly better on the Orgogozo scale at 1 year (P < .02). However, the difference at 1 year between pretherapeutic and posttherapeutic scores was not significantly different in the two groups (P < .16). Moreover, no statistically significant improvement was observed in the HBO group at 6 months and 1 year according to Rankin score (P < .78) and our own 10-point scale (P < .50). CONCLUSIONS: Although the small number of patients in each group precludes any conclusion regarding the potential deleterious effect of HBO, we did not observe the major side effects usually related to HBO. Accordingly, it can be assumed that hyperbaric oxygen might be safe. We hypothesize that HBO might improve outcome after stroke, as we detected an outcome trend favoring HBO therapy. A large randomized trial might be required to address the efficacy of this therapy.

37. Berrouschot, J., et al., [Hyperbaric oxygen therapy (HBO) after acute focal cerebral ischemia]. Nervenarzt, 1998. 69(12): p. 1037-44. Abstract: For a large number of patients with stroke no therapeutic option can be offered, even after approval of thrombolytic therapy for treatment of acute ischemic stroke in the US. In cerebral ischemia local anoxia and energy failure lead to further cellular damage and finally to complete stroke. All therapeutic concepts try to salvage structurally intact tissue which is at risk for irreversible damage (so-called penumbra). Hyperbaric oxygen (HBO) treatment has been reported in animal models of cerebral ischemia, and in a few clinical reports. In general, the results of these studies have been promising. This review focuses on the clinical perspective of HBO therapy and summarizes both the clinical and experimental data available on HBO therapy following ischemic stroke.

38. Krakovsky, M., et al., Effect of hyperbaric oxygen therapy on survival after global cerebral ischemia in rats. Surgical Neurology, 1998. 49(4): p. 412-6. Abstract: BACKGROUND: Hyperbaric oxygenation (HBO) has been considered for many years for the treatment of severe brain ischemia. However, its efficacy has not been proven. The aim of this study was to shed light on this question. METHODS: Acute global cerebral ischemia was induced in 18 rats using the four-vessel occlusion model. Regional cerebral blood flow (CBF) was determined by laser-Doppler flowmetry using a flexible 1 mm fiberoptic probe. Two stainless steel screws were used to measure the spontaneous electrical activity from the contralateral hemisphere. After ischemia monitored by laser-Doppler flowmetry and ECoG, the animals were divided into two groups: (1) control animals that breathed air at atmospheric pressure and (2) rats exposed to HBO at three atmospheres absolute pressure (ATA) for 1 hour. Survival time and rate were recorded for both groups of animals for 14 days. RESULTS: The survival rate in the study group was significantly higher (45%) than in the control group (0%). In the animals that did not survive the 14-day period, those exposed to HBO survived longer than the control animals (59.8+/-9.1 hour versus 17.9+/-2.7 hours, p < 0.05). CONCLUSION: This investigation demonstrates that HBO administered after global cerebral ischemia can increase survival in a rat stroke model.

39. Jain, Textbook of Hyperbaric Medicine. 1999.

40. . ms/mscenter/index.html, Treating Multiple Sclerosis (MS) with Hyperbaric Oxygen Therapy (HBO). 2000.

41. Heuser, G. and J.M. Uszler, Hyperbaric oxygenation for cerebral palsy. Lancet, 2001. 357(9273): p. 2053-4.

42. O'Donnell, P., et al., The magnetic resonance imaging appearances of the brain in acute carbon monoxide poisoning. Clinical Radiology, 2000. 55(4): p. 273-80. AIMS: To describe the magnetic resonance imaging (MRI) appearances of the brain in acute carbon monoxide poisoning, the commonest cause of accidental poisoning in Europe and the U.S.A. To attempt to correlate the imaging findings with patient outcome as an aid to prognosis. MATERIALS AND METHODS: Brain MRI was performed on 19 consecutive patients, who had sustained acute carbon monoxide poisoning, as soon as possible after their referral to the regional Hyperbaric Unit at the Royal Hospital, Haslar. All patients were unconscious on arrival, and had received at least one treatment with hyperbaric oxygen by the time of first MR. The imaging findings were analysed independently by two experienced MR radiologists, with a third radiologist arbitrating on discrepant results. RESULTS: Thirteen male and six female patients, age range 21-70 years (mean 38.7 years) underwent MR an average of 35.6 h (range 6-126 h) following presentation at the referring centre. MR (at 0.5T) revealed abnormalities in the following areas: globus pallidus (n = 12); other basal ganglia [ n = 5: entire lentiform (globus pallidus and putamen), putamen alone, caudate nucleus, thalamus]; white matter (n = 6: periventricular, subcortical, other); cerebral cortex (n = 5), either localized or general; medial temporal lobe in the region of the hippocampus (n = 4). The majority of the patients with hyperintensity in the region of the hippocampus (n = 3) had no other area of cortical involvement. Two patients showed abnormalities in the cerebellum. Normal appearances were seen on the initial MR in seven patients. CONCLUSION: The appearances of the brain following acute CO poisoning are varied, and have previously been the subject of case reports or small studies, most of which have have addressed the delayed sequelae of this condition. This study, the first large series undertaken in the acute phase, confirms that, although the globus pallidus is the commonest site of abnormality in the brain, the effects of CO poisoning are widespread. The extent of damage correlates with clinical outcome, and therefore aids management and prognosis.

43. Stuppaeck, C.H., et al., Akathisia induced by necrosis of the basal ganglia after carbon monoxide intoxication. Movement Disorders, 1995. 10(2): p. 229-231.

44. Albin, R.L., Basal ganglia neurotoxins. Neurologic Clinics,, 2000. 18(3): p. 665-80. The epidemiology, clinical features, pathology, and mechanisms of action of basal ganglia neurotoxins are reviewed. Manganese, cyanide, hydrogen sulfide, methanol, carbon monoxide, 3-nitropropionic acid, MPTP, and annonaceae alkaloids are discussed. The probable mechanism of action for almost all basal ganglia neurotoxins is inhibition of mitochondrial function with destruction of the pallidum and putamen. MPTP produces selective loss of dopaminergic neurons because of selective uptake of a toxic metabolite in dopaminergic neurons. The basis for selective vulnerability of the putamen and pallidum is unknown.

45. Kao, C.H., et al., HMPAO brain SPECT in acute carbon monoxide poisoning. Journal of Nuclear Medicine, 1998. 39(5): p. 769-72. Technetium-99m-hexamethylpropylene amine oxime (HMPAO) brain images with fanbeam SPECT, in combination with surface three-dimensional display, were used to detect basal ganglion and cerebral cortex anomalies in the acute phase of carbon monoxide (CO) poisoning. METHODS: Ten patients, aged 16-29 yr, with acute CO poisoning and no past history of neurologic disorders were enrolled in this study. After oxygen treatment, all 10 patients were investigated using 99mTc-HMPAO brain images with fanbeam SPECT and surface three-dimensional display. Meanwhile, 6 of 10 patients also received a brain CT scan. RESULTS: CT scan findings were negative in all 6 patients. Fanbeam SPECT demonstrated unilateral or bilateral hypoactivity of basal ganglia in 6 patients. Local hypoactivity anomalies were found in the brain cortex of 7 patients, using surface three-dimensional display of the brain. Only 2 of 10 patients had normal 99mTc-HMPAO brain images. CONCLUSION: This study suggests that, in comparison with traditional brain imaging techniques, 99mTc-HMPAO brain imaging with fanbeam SPECT in combination with surface three-dimensional display is a better tool for early detection of regional cerebral anomalies in acute CO poisoning.

46. Weaver, L., et al., Carboxyhemoglobin half-life in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure. Chest, 2000. 117(3): p. 801-8. STUDY OBJECTIVES: There are large reported differences for the carboxyhemoglobin (COHb) half-life (COHb t(1/2)) in humans breathing 100% atmospheric O(2) following CO inhalation in tightly controlled experiments compared to the COHb t(1/2) observed in clinical CO poisoning (range, 36 to 131 min, respectively). Other reports have suggested that the COHb t(1/2) may be affected by gender differences, age, and lung function. We wished to test the hypothesis that the COHb t(1/2) might also be influenced by CO poisoning vs experimental CO exposure, by a history of loss of consciousness (LOC), concurrent tobacco smoking, and by PaO(2). The purpose of the present study was to measure the COHb t(1/2) in a cohort of CO-poisoned patients and to determine if those listed factors influenced the COHb t(1/2). DESIGN: Retrospective chart review from 1985 to 1995. We calculated the COHb t(1/2) of CO-poisoned patients who were treated with high-flow supplemental atmospheric pressure O(2) delivered by nonrebreather face mask or endotracheal tube. SETTING: Hyperbaric medicine department of a tertiary-care teaching hospital. PATIENTS: Of 240 CO-poisoned patients, 93 had at least two COHb measurements > 2% (upper limit of normal) with recorded times of the measurements, permitting calculation of the COHb t(1/2). RESULTS: The COHb t(1/2) was 74 +/- 25 min (mean +/- 1 SD) with a range from 26 to 148 min. By stepwise multiple linear regression analysis, the PaO(2) influenced the COHb t(1/2) (R(2) = 0.19; p < 0.001), whereas the COHb t(1/2) was not influenced by gender, age, smoke inhalation, history of LOC, concurrent tobacco smoking, degree of initial metabolic acidosis (base excess), or initial COHb level. CONCLUSIONS: The COHb t(1/2) of 93 CO-poisoned patients treated with 100% O(2) at atmospheric pressure was 74 +/- 25 min, considerably shorter than the COHb t(1/2) reported in prior clinical reports (approximately 130 +/- 130 min) and was influenced only by the patient's PaO(2).

47. Golomb, B.A., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 2: Pyridostigmine Bromide. 1999, Santa Monica, CA: RAND. 385.

48. Cecchine, G., et al., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 8: Pesticides. 2000, Santa Monica, CA: RAND. 182.

49. Augerson, W., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Volume 5: Chemical and Biological Warfare Agentsw. 2000, Washington, D.C.: RAND.

50. Nicolson, G.L., N.L. Nicolson, and M. Nasralla, Mycoplasmal infections and fibromyalgia/chronic fatigue illness (Gulf War Illness) associated with deployment to Operation Desert Storm. International Journal of Medicine, 1998. 1: p. 80-89.

51. Duerksen, S., Infection may hold clue to Gulf ills: Bacteria being found in many ailing vets, in San Diego Union Tribune. 2000. p. B1.

52. Fukuda, K., et al., Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Jama, 1998. 280(11): p. 981-8. CONTEXT: Gulf War (GW) veterans report nonspecific symptoms significantly more often than their nondeployed peers. However, no specific disorder has been identified, and the etiologic basis and clinical significance of their symptoms remain unclear. OBJECTIVES: To organize symptoms reported by US Air Force GW veterans into a case definition, to characterize clinical features, and to evaluate risk factors. DESIGN: Cross-sectional population survey of individual characteristics and symptoms and clinical evaluation (including a structured interview, the Medical Outcomes Study Short Form 36, psychiatric screening, physical examination, clinical laboratory tests, and serologic assays for antibodies against viruses, rickettsia, parasites, and bacteria) conducted in 1995. PARTICIPANTS AND SETTING: The cross-sectional questionnaire survey included 3723 currently active volunteers, irrespective of health status or GW participation, from 4 air force populations.The cross-sectional clinical evaluation included 158 GW veterans from one unit, irrespective of health status. MAIN OUTCOME MEASURES: Symptom-based case definition; case prevalence rate for GW veterans and nondeployed personnel; clinical and laboratory findings among veterans who met the case definition. RESULTS: We defined a case as having 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155 GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness was not associated with time or place of deployment or with duties during the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases, 86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical examination, laboratory, or serologic findings identified cases, veterans who met the case definition had significantly diminished functioning and well-being. CONCLUSIONS: Among currently active members of 4 Air Force populations, a chronic multisymptom condition was significantly associated with deployment to the GW. The condition was not associated with specific GW exposures and also affected nondeployed personnel.

53. May, K.P., et al., Sleep apnea in male patients with the fibromyalgia syndrome. Am J Med, 1993. 94(5): p. 505-8. PURPOSE: Fibromyalgia is a common pain syndrome that is often associated with sleep disturbances. The most characteristic pattern noted on formal sleep study is alpha-wave intrusion on delta-wave sleep. This nonrestorative sleep pattern may be endogenous, or caused by any of a number of sleep disturbances. Our goal was to determine the frequency of sleep apnea and its relationship to a nonrestorative sleep pattern in our patients with fibromyalgia syndrome. PATIENTS AND METHODS: All new fibromyalgia patients seen in the Rheumatology Clinic at Fitzsimons Army Medical Center were screened using history and physical examination for suspicion of sleep apnea. When this condition was suspected, the patients underwent formal polysomnography to delineate any sleep disturbance. RESULTS: Four of 92 women, and 13 of 25 men with the new diagnosis of fibromyalgia syndrome underwent polysomnography. Of the women, 2.2% (2 of 92) had significant sleep apnea at formal evaluation; both were obese and had obstructive findings. In contrast, 44% (11 of 25) of the men had significant sleep apnea. CONCLUSIONS: Sleep apnea is not a significant cause of fibromyalgia symptoms in females. In male patients with fibromyalgia, sleep apnea was observed in a large percentage. Fibromyalgia may be a marker for occult sleep apnea in males.

54. Molony, R.R., et al., Sleep, sleep apnea and the fibromyalgia syndrome. J Rheumatol, 1986. 13(4): p. 797-800. A patient who presented with primary fibromyalgia syndrome (PFS) was found to have sleep apnea. Since frequent wakening and nonrestorative sleep are prominent clinical complaints in both disorders, we hypothesized an etiologic relationship. A subsequent clinical survey of 11 additional sleep apneics revealed that 3 (27%) fulfilled proposed criteria for PFS. This was significantly greater than local and literature reported studies of nonrheumatologic patients and was comparable to reported prevalence of fibromyalgia in rheumatologic referral populations. A blinded sleep physiology study of 7 patients with PFS revealed a significantly increased percentage of transitional sleep and increased frequency of miniarousals/h, but no significant evidence of occult sleep apnea compared to matched normal controls. The frequent arousals of sleep apnea may be associated with fibromyalgia in some patients but do not explain the sleep disorder of PFS.

55. Alvarez Lario, B., et al., Fibromyalgia syndrome: overnight falls in arterial oxygen saturation. Am J Med, 1996. 101(1): p. 54-60. PURPOSE: Sleep alterations and muscular changes suggesting hypoxia have been reported in fibromyalgia syndrome (FS) pathophysiology. We tested the hypothesis that patients with FS show falls in the oxygen saturation of hemoglobin in arterial blood (SaO2%) during sleep. PATIENTS AND METHODS: Overnight SaO2% was measured by digital pulse oximetry in 28 randomly selected women who met 1990 American College of Rheumatology criteria for the diagnosis of FS and 15 similar controls. Considering the results of pulse oximetry and in order to evaluate the possible presence of a sleep apnea syndrome (SAS) as the reason for the nocturnal desaturations, the Epworth Sleepiness Scale (ESS) was mailed to the patients and controls. Patients and controls who had a score higher than 10 on the ESS underwent a polysomnographic study. RESULTS: Patients with FS showed lower overnight minimum SaO2% (86.8 +/- 1.3 versus 90.7 +/- 0.9 in controls, P < 0.05), greater number of desaturations (8.3 +/- 1.8 versus 2.7 +/- 0.8 in controls, P < 0.05) and more desaturations/hour (1.3 +/- versus 0.4 +/- 0.1 in controls, P < 0.05), more night minutes in SaO2% < 92% (56.3 +/- 12.9 versus 9.1 +/- 3.8 in controls, P < 0.01) and more minutes in SaO2% < 90% (14.7 +/- 3.7 versus 2.4 +/- 1.0 in controls, P < 0.05). There were no differences between patients with FS and controls in ESS scores. Five patients (19.2%) in the FS group and 2 (15.4%) in the control group had ESS scores higher than 10. One patient had 1 control subject showed on apnea-plus-hypopnea index higher than 5 (13 and 9, respectively) in polysomnographic study. CONCLUSIONS: Patients with FS showed small overnight falls in SaO2% and spent more time during the night in SaO2% below 92% and 90% than did the control group. These alterations that, as a whole, are not due to the presence of an associated SAS could be important in FS musculoskeletal pathophysiology.

56. Plantamura, A., J. Steinbauer, and J. Eisinger, [Sleep apnea and fibromyalgia: the absence of correlation does not indicate an exclusive central hypothesis]. Rev Med Interne, 1995. 16(9): p. 662-5. Fibromyalgia (FM) is a chronic painful syndrome characterized by widespread aching and points of tenderness, changed perception of pain and reduced brain serotonin. Abnormal EEG patterns have been reported in this condition. A study of FM occurrence in subjects with sleep abnormalities demonstrated by polysomnography was performed. Fifty patients (group 1:29 with sleep apnea and group 2:21 with poor sleep without sleep apnea) and 31 control subjects (without any sleep abnormalities) were submitted to the same clinical research of FM (ACR criteria). There was one 1 FM in group 1 (3.4%), one FM in group 2 (4.7%), and one FM in control group (3.2%). Sleep abnormalities and particularly sleep apnea are not significantly associated with FM. Other pathophysiological factors than central mechanisms are probably involved in the pathogenesis of FM.

57. Alvarez Lario, B., et al., Lack of association between fibromyalgia and sleep apnoea syndrome. Ann Rheum Dis, 1992. 51(1): p. 108-11. To determine whether sleep disorders can cause a fibromyalgia syndrome, 30 patients with sleep apnoea syndrome were studied. All presented an important reduction in deep sleep stages (-93.1 (SD 17.9)% of stage IV and -77.2 (45.7)% of stage III) and frequent episodes of wakening ('arousals'), factors which are involved in fibromyalgia. One patient (3%) met the criteria for fibromyalgia; the estimated prevalence of fibromyalgia for patients attending a general medical clinic is 6%. No significant correlation was found between the number of points which were tender upon pressure and the various sleep parameters studied. It is concluded that sleep disorders alone are not able to produce a fibromyalgia syndrome.

58. Jennum, P., et al., Sleep and other symptoms in primary fibromyalgia and in healthy controls. J Rheumatol, 1993. 20(10): p. 1756-9. OBJECTIVE. To evaluate sleep architecture and self-reported complaints in patients with fibromyalgia (FS). Forty patients and 10 age standardized healthy controls were included. All participants were women. METHODS. All patients and controls underwent a clinical examination and gave answers to a questionnaire. Polysomnography was done in 20 patients and in all controls. RESULTS. The percent arousal time and arousal index were higher (p < 0.05 and < 0.01, respectively) among FS compared to controls, but no other differences were found in sleep architecture. Ten of the patients with FS and 2 controls showed an apnea-hypoapnea index above 5/h (NS). The arousal time and arousal index were higher in patients with apnea-hypoapnea index > or = 5 compared to controls with apnea-hypoapnea index < 5 [mean (SD)] [arousal time: 4.5 (3.2) vs 0.7 (0.7), p < 0.001, arousal index: 14.9 (10.8) vs 2.4 (3.7), p < 0.001]. In patients with FS with apnea-hypoapnea index < 5 the arousal time was higher (2.0 (1.2), p < 0.05) and arousal index marginally higher (5.6 (3.2), p = 0.07) compared to the controls. No other differences were found in sleep structure. Insomnia (difficulties falling asleep, maintaining sleep, early morning awakening), tiredness, mood, cognitive disturbances and muscular pain were all reported more commonly by patients with FS than controls. A subdivision of the patients with FS into those with apnea-hypoapnea index < 5 and apnea-hypoapnea index > or = 5 did not change these findings. CONCLUSION. We conclude, that patients with FS show minor polysomnographic findings, with a higher occurrence of arousals. The arousals were in part explained by respiratory abnormalities. Patients with FS have several complaints, including insomnia. Some of these may relate to sleep fragmentation. Controlled studies are a requirement in investigations of sleep disorders in fibromyalgia.

59. Harding, S.M., Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci, 1998. 315(6): p. 367-76. Fibromyalgia (FM) patients report early morning awakenings, awakening feeling tired or unrefreshed, insomnia, as well as mood and cognitive disturbances; they may also experience primary sleep disorders including sleep apnea. Longitudinal studies have demonstrated the chronic nature of these disturbances in patients with FM. A distinct relationship exists between poor sleep quality and pain intensity. Polysomnographic findings during sleep in these patients include an alpha frequency rhythm, termed alpha-delta sleep anomaly, which is also seen in normal controls during stage 4 sleep deprivation; deep pain induced during sleep in normal controls also causes this anomaly. Sleep architecture is altered in FM patients showing an increase in stage 1, a reduction in delta sleep, and an increased number of arousals. Before prescribing pharmacologic compounds aimed at modifying sleep, adequate pain control and sleep habits should be achieved; tricyclic antidepressants, trazadone, zopiclone, and selective serotonin reuptake inhibitors, however, may be required. More research is needed to elucidate the cellular and molecular mechanisms involved in the sleep disturbances occurring in patients with FM.

60. Fischler, B., et al., Sleep anomalies in the chronic fatigue syndrome. A comorbidity study. Neuropsychobiology, 1997. 35(3): p. 115-22. Polysomnographic findings were compared between a group of patients with the chronic fatigue syndrome (CFS; n = 49) and a matched healthy control (HC) group (n = 20). Sleep initiation and sleep maintenance disturbances were observed in the CFS group. The percentage of stage 4 was significantly lower in the CFS group. A discriminant analysis allowed a high level of correct classification of CFS subjects and HC. Sleep-onset latency and the number of stage shifts/hour contributed significantly to the discriminant function. The presence of these anomalies as well as the decrease in stage 4 sleep were not limited to the patients also diagnosed with fibromyalgia or with a psychiatric disorder. No association was found between sleep disorders and the degree of functional status impairment. The mean REM latency and the percentage of subjects with a shortened REM latency were similar in CFS and HC.

61. Paiva, T., et al., The relationship between headaches and sleep disturbances. Headache, 1995. 35(10): p. 590-6. The relationship between headaches and sleep disturbances is complex and difficult to analyze. Both symptoms may have causal relations, or may be associated in the same patient with mutual reinforcements. We studied 25 patients presenting with morning or nocturnal headaches. Standard headache diagnosis and polysomnography were performed. After polysomnography, the diagnoses were reevaluated. The main headache entities were cluster, chronic paroxysmal hemicrania, migraine, tension, combined headache, and chronic substance abuse headache. For each group, headache, sleep data, and changes in diagnosis are discussed. The diagnosis was changed in 13 patients; the final diagnoses were periodic movements of sleep, fibromyalgia syndrome, and obstructive sleep apnea. The diagnoses of cluster headache and chronic paroxysmal hemicrania were not modified by polysomnography. The migraine and tension headache groups had a relative male preponderance, and the diagnosis was changed in approximately half of the patients. This was also observed in combined headaches. Patients who had chronic substance abuse headaches had mainly insomnia, which in some cases, was relieved by stopping medication. Data were also analyzed in terms of simple models linking headache and sleep disturbances. Such an approach allowed the identification of several modes of mutual interaction. In summary, morning or nocturnal headaches are frequent indicators of a sleep disturbance and their presence might justify polysomnography, and the use of simple clinical models may be useful for understanding the complex relationship between headache and sleep.

62. Jelkmann, W., Use of recombinant human erythropoietin as an antianemic and performance enhancing drug. Curr Pharm Biotechnol, 2000. 1(1): p. 11-31. The glycoprotein hormone erythropoietin is an essential viability and growth factor for the erythrocytic progenitors in the bone marrow. Tissue hypoxia is the main stimulus for the synthesis of the hormone in the kidneys and the liver. Endogenous erythropoietin and recombinant human erythropoietin (rHu-EPO) are similar with respect to their biological and chemical properties except for some microheterogeneities in their 4 carbohydrate chains. Generic products and alternatives to rHu-EPO are in development. Renal anemia can be corrected by rHu-EPO in a dose-dependent and predictable way without major side effects apart from a possible increase in arterial blood pressure. The optimal target hematocrit still needs to be defined. There are rare reports of antibody formation towards rHu-EPO in humans. Patients suffering from non-renal anemias may also benefit from the prescription of rHu-EPO. The drug has been approved for treatment of tumor patients with platinum-induced anemia. The cost-effectiveness and medical justification of the administration of rHu-EPO in tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still a matter of debate. In surgical patients, the pharmacological application of rHu-EPO can increase the yield of blood units in autologous blood donation programs and lower the severity and duration of postoperative anemia, if applicated some days prior to surgery. While rHu-EPO is a godsend in medical practice, its abuse as an performance enhancing drug by athletes in endurance sports is an unethical and potentially dangerous procedure. Unequivocal methods for detection of rHu-EPO doping still need to be established.

63. Green, D., et al., Recombinant human erythropoietin: effect on the functional performance of anemic orthopedic patients. Arch Phys Med Rehabil, 1996. 77(3): p. 242-6. OBJECTIVE: To determine whether rapid correction of anemia improves the functional and cognitive performance of postoperative orthopedic patients. DESIGN: A randomized, double-blind, placebo-controlled clinical trial. SETTING: A rehabilitation institute. PATIENTS: Persons having orthopedic surgery at least 2 weeks previously, and a hemoglobin concentration < 10g/dL. INTERVENTIONS: Recombinant human erythropoietin (rH-EPO) or the EPO vehicle for up to 8 weeks. All patients received ferrous sulfate. MEASUREMENTS: Blood counts were performed at weekly intervals, and functional and cognitive tests at baseline and weeks 4 and 8. RESULTS: In patients receiving vehicle only, hemoglobin levels increased from a mean of 9.0 at baseline to 11.0 at 4 weeks and 11.7 at 8 weeks; corresponding values for rH-EPO were 8.8 (p = NS), 12.6 (p = .02), and 13.5 (p = .01). However, functional improvement in dressing, toileting, and mobility was similar between groups, and the results of neuropsychological tests showed no trends favoring rH-EPO. CONCLUSIONS: Although hemoglobin increases more rapidly in anemic orthopedic patients treated with rH-EPO, equally rapid functional improvement occurs in those who receive only iron therapy.

64. Ekblom, B., Blood doping and erythropoietin. The effects of variation in hemoglobin concentration and other related factors on physical performance. Am J Sports Med, 1996. 24(6 Suppl): p. S40-2.

65. Hengemihle, J.M., et al., Chronic treatment with human recombinant erythropoietin increases hematocrit and improves water maze performance in mice. Physiol Behav, 1996. 59(1): p. 153-6. Erythropoietin is a glycoprotein produced endogenously in the kidney, which stimulates red blood cell production. We evaluated the effects of chronic treatment with recombinant human erythropoietin (epoetin alfa: EPO) on the performance of 6-month-old male C57BL/6J mice in a spatial learning task, the Morris water maze. Mice were treated with either EPO (1.5 U injected SC every other day) or vehicle (PBS also injected SC every other day). Results indicated that the treatment had no effect on maze performance after 8 weeks, but after 19 weeks the EPO-treated mice showed better performance compared to controls as measured by mean distance (centimeters) to reach the goal platform. The improved performance in EPO-treated mice at 19 weeks was accompanied by an increased hematocrit. After 32 wk of EPO-treatment, the hematocrit returned to baseline levels even though the size and density of the red blood cells were increased.

66. Verbrugge, D.J. and L.T. Goodnough, The effect of recombinant human erythropoietin treatment on the endurance performance of Sprague-Dawley rats. Scand J Clin Lab Invest, 1994. 54(1): p. 55-9. Mild increases in haematocrit (Hct) have been shown to enhance aerobic performance, but the effects of more severe increases have not been studied. Recombinant human erythropoietin (rHuEPO), which can cause substantial increases in haematocrit, was used to study the effects of induced severe polycythemia on aerobic endurance performance. Sixteen Sprague-Dawley rats were aerobically trained on motorized running wheels. After 5 weeks, the baseline aerobic endurance of each animal was determined by measuring the running time to exhaustion (RTE). Then each rat was randomly assigned to an experimental group (EXP) which received 600 U kg-1 rHuEPO every 3 days, or a placebo group (PLC). Haematocrit and animal mass were monitored for 3 weeks while training and treatment continued, and then the RTE was determined a second time. Results indicated that the rats in the treatment group had a significantly higher Hct (62.2% vs. PLC value of 47.3%, p < 0.001), but did not have a different RTE (75 min vs. PLC value of 73 min, p > 0.05) when compared to the placebo group. The change in the Hct compared to the change in RTE for each animal showed an inverse relationship (r = -0.8212), indicating that greater increases in rHuEPO induced polycythemia resulted in a decreased performance level. We conclude that rHuEPO-induced severe polycythemia was not accompanied by an increase in aerobic endurance in this animal model.

67. Martin, G.R., et al., Recombinant erythropoietin (Epogen) improves cardiac exercise performance in children with end-stage renal disease. Pediatr Nephrol, 1993. 7(3): p. 276-80. To determine the effects of anemia in children with end-stage renal disease, we studied cardiac performance before and 1 and 6 months after recombinant erythropoietin (Epogen). Children with end-stage renal disease were included if they had significant anemia [hematocrit (Hct) < 30%]. Epogen 50 U/kg was given subcutaneously or intravenously three times per week until the Hct was > or = 33%. Echocardiography, cardiac output (acetylene rebreathing), and treadmill (modified Bruce) tests were performed. Boys (9) and girls (9), 11.9 +/- 5.6 years, were given Epogen and the Hct increased (from 21.7 +/- 2.7% to 33.4 +/- 2.1%, P = 0.001). Heart rate decreased (P = 0.04) and stroke volume did not change. Blood pressure did not change. Cardiac thickness, chamber dimensions, left ventricular wall stress, velocity of circumferential fiber shortening, and indices of diastolic function were normal and did not change after Epogen. Exercise time increased (from 10.3 +/- 1.9 to 11.2 +/- 1.9 min, P = 0.01) after 1 month of Epogen. Resting oxygen consumption (VO2) decreased (from 7.8 +/- 1.8 to 6.9 +/- 1.4 ml/min per kg, P = 0.01) 1 month after Epogen and peak exercise VO2 did not change after Epogen. There were no differences in exercise tests between the 1 and 6 month measurements. Exercise tolerance improves after the short-term correction of anemia and there is no further improvement after long-term correction.

68. McMahon, L.P., et al., Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin. Nephrol Dial Transplant, 1992. 7(12): p. 1199-206. Physical performance and haemodynamic parameters at rest and with exercise were compared in a prospective, cross-over fashion in 12 anaemic haemodialysis patients (Hb 6.4 +/- 0.5, mean +/- SEM) at two levels of haemoglobin (Hb 9 and 12 g/dl) before and after long-term treatment with recombinant human erythropoietin (rHuEpo). Patients were divided into two groups and measurements made prior to treatment, upon reaching, and after 4 months at the first target Hb (9 g/dl group A, 12 g/dl group B), and after 4 months at the alternative target Hb. Tests included an exercise radionuclide ventriculogram, Doppler echocardiogram, and respiratory function exercise test. Compared to pretreatment, there was a significant reduction in resting pulse rate (P < 0.001), and in pulse rate (P < 0.001) and arterial lactate (P < 0.01) concentrations at specified levels of exercise. Work capacity improved 60% (P < 0.001), and left ventricular mass fell by 26% (P < 0.001). Although cardiac output (CO) during and after exercise was reduced (P < 0.05), resting CO, cardiac index, stroke volume and ejection fraction (rest and exercise) were not significantly altered. There appeared little benefit in having the higher target Hb: no significant difference could be found between target levels for almost any measure. In addition, despite marked improvement from pretreatment levels, performance parameters were still below those of non-uraemic age-matched controls. These results demonstrate the beneficial but incomplete effect of rHuEpo on resting and exercise-related factors, and suggest that most improvement is achieved with modest increments in haemoglobin.

69. Adamson, J.W. and D. Vapnek, Recombinant erythropoietin to improve athletic performance. N Engl J Med, 1991. 324(10): p. 698-9.

70. Braumann, K.M., et al., Improved physical performance after treatment of renal anemia with recombinant human erythropoietin. Nephron, 1991. 58(2): p. 129-34. The physical performance of 12 anemic patients on renal dialysis was investigated following treatment of renal anemia with recombinant human erythropoietin (rhEPO; 40-120 U/kg, 3 times a week). Exercise intensity at a heart rate of 130 beats/min (PWC130) on a bicycle ergometer was assessed before rhEPO treatment, after reaching the target hematocrit (73 +/- 18 days), and in the maintenance phase (211 +/- 53 days). Hemoglobin concentrations measured at these time points were 7.3 +/- 1.2, 11.9 +/- 1.5, and 12.1 +/- 1.4 g/dl, respectively. PWC130 rose from 77 +/- 27 to 104 +/- 37 and 104 +/- 51 W, respectively. Aerobic threshold (i.e. blood lactic acid concentration of 2 mmol/l) shifted to higher workloads indicating improved muscle oxygen supply.

71. Scott, W.C., The abuse of erythropoietin to enhance athletic performance. Jama, 1990. 264(13): p. 1660.

72. Huppmann, M., et al., [Erythropoietin therapy in renal anemia. Effect on ergospirometry performance parameters]. Wien Med Wochenschr Suppl, 1989. 104: p. suppl 48-50.

73. Bocker, A., et al., Effect of erythropoietin treatment on O2 affinity and performance in patients with renal anemia. Contrib Nephrol, 1988. 66: p. 165-75.

74. Corey-Bloom, J. Ginkgo biloba slows cognitive decline in patients with multiple sclerosis. in Annual Meeting of the American Academy of Neurology. 2002. Denver, CO.

75. Joint National Committee, The Sixth Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC VI). Arch Intern Med, 1997. 157: p. 2413-2446.

76. Matsubayashi, K., et al., Postural dysregulation in systolic blood pressure is associated with worsened scoring on neurobehavioral function tests and leukoaraiosis in the older elderly living in a community. Stroke, 1997. 28(11): p. 2169-73. BACKGROUND AND PURPOSE: Postural hypotension, which occurs frequently in community-living, apparently healthy elderly adults, is usually asymptomatic. However, the relation between postural changes in blood pressure and quantitative higher cerebral function or silent brain lesions remains unclear. We examined the association of exaggerated postural changes in systolic blood pressure with cognitive and quantitative neurobehavioral functions and with brain lesions on MRI in the community-dwelling older elderly. METHODS: The study population consisted of 334 community-dwelling elderly adults, aged 75 years or older (mean age, 80 years). Postural changes in systolic blood pressure (SBP) were assessed using an autosphygmomanometer (BP-203 I). By the difference between the mean of two measurements of SBP at standing and at supine position (dSBP = SBP at upright-SBP at supine position), we divided the subjects into three groups: (1) 20 subjects with postural hypotension (d-SBP < or = -20 mm Hg), (2) 29 subjects with postural hypertension (dSBP > or = 20 mm Hg), and (3) 285 subjects with postural normotension (20 < dSBP < 20 mm Hg). We defined the former two groups as the postural dysregulation group. Scores in four neurobehavioral function tests (Mini-Mental State Exam. Hasegawa Dementia Scale Revised, computer-assisted visuospatial cognitive performance score, and the Up and Go Test) and activities of daily living were compared among the three groups. Brain lesions on MRI, including number of lacunes and periventricular hyperintense lesions, were compared among 15 age- and sex-matched control subjects with postural hypotension, 15 with postural hypertension, and 30 with postural normotension. RESULTS: Twenty subjects (6.0%) exhibited postural hypotension and 29 (8.7%) postural hypertension. Scores in neurobehavioral functions and activities of daily living were significantly lower in the postural dysregulation group (both postural hypotension and hypertension groups) than in the postural normotension group. The postural dysregulation group exhibited significantly more advanced periventricular hyperintensities than the normotension group. CONCLUSIONS: Asymptomatic community dwelling elderly individuals with postural hypotension as well as those with postural hypertension had poorer scores on neurobehavioral function tests and more advanced leukoaraiosis demonstrated on MRI than those without exaggerated postural changes in SBP.

77. Korten, A.E., et al., Health, cognitive, and psychosocial factors as predictors of mortality in an elderly community sample. Journal of Epidemiology and Community Health, 1999. 53(2): p. 83-88. STUDY OBJECTIVE: To examine whether cognitive and psychosocial factors predict mortality once physical health is controlled. DESIGN: A prospective study of community dwelling elderly. Mortality was assessed over a period of 3-4 years after the baseline assessment of predictors. The data were analysed using the Cox proportional hazards model. SETTING: Canberra and Queanbeyan, Australia. PARTICIPANTS: A sample of 897 people aged 70 or over and living in the community, drawn from the compulsory electoral roll. RESULTS: For the sample as a whole, the significant predictors of mortality were male sex, poor physical health, poor cognitive functioning, and low neuroticism. Men had an adjusted relative risk of mortality of 2.5 compared with women. For the male sub-sample, poor self rated health and a poor performance on a speeded cognitive task were significant predictors, while for women, greater disability, low systolic blood pressure, and a low score on a dementia screening test were the strongest predictors. CONCLUSIONS: Mortality was predicted by physical ill health and poor cognitive functioning. Psychosocial factors such as socioeconomic status, psychiatric symptoms, and social support did not add to the prediction of mortality, once sex, physical health, and cognitive functioning were controlled. Mortality among men was more than twice that of women, even when adjusted for other predictors.

78. Guo, Z., et al., Blood pressure and performance on the Mini-Mental State Examination in the very old. Cross-sectional and longitudinal data from the Kungsholmen Project. American Journal of Epidemiology, 1997. 145(12): p. 1106-1113. The authors examined the association of blood pressure with cognitive function as assessed by the Mini-Mental State Examination (MMSE) in a community-based Swedish cohort of 1,736 people aged 75-101 years. Age, sex, education, antihypertensive medication use, heart disease, and stroke were considered as covariates. Multiple linear regression analysis indicated that both systolic and diastolic blood pressure, measured in 1987-1989, were positively and significantly related to baseline MMSE score; baseline systolic pressure was also positively and significantly related to follow-up MMSE score, measured after an average period of 40.5 months among subjects who were not taking antihypertensive medication at baseline. Furthermore, in the nontreated group, multiple logistic regression showed that individuals with a baseline systolic pressure less than 130 mmHg had an odds ratio of 1.88 (p = 0.05) for follow-up cognitive impairment (MMSE score < 24) compared with those whose systolic pressure was 130-159 mmHg. An increased but not statistically significant risk of cognitive impairment was associated with high blood pressure (systolic pressure > or = 180 mmHg or diastolic pressure > or = 95 mmHg) only in persons taking antihypertensive medication at baseline. Subjects with systolic pressure of 160-179 mmHg tended to be at lower risk of cognitive impairment. These results may support the view that a certain blood pressure level, particularly a systolic pressure of at least 130 mmHg, is important to the maintenance of cognitive functioning in the very old. They also suggest that severe hypertension that is not well controlled (systolic pressure > or = 180 mmHg or diastolic pressure > or = 95 mmHg) is still a threat to cognitive function in this age group. However, the use of blood pressure measurements made at a single visit and the relatively short follow-up period should be considered when interpreting these results.

79. Guo, Z., et al., Occurrence and progression of dementia in a community population aged 75 years and older: relationship of antihypertensive medication use. Archives of Neurology, 1999. 56(8): p. 991-6. OBJECTIVE: To examine whether antihypertensive medication use can affect the occurrence and progression of dementia. SUBJECTS AND METHODS: In a community cohort of 1810 persons aged 75 years and older, 225 prevalent cases of dementia were detected. Among the 1301 persons without dementia, 224 incident cases of dementia were identified during an average period of 3 years. Among the 225 prevalent cases of dementia, 79 were suitable for the analysis of cognitive decline. Information on drug use was collected for the 2 weeks preceding the baseline interview. RESULTS: Subjects taking antihypertensive medication (n = 651, 83.9% of whom took diuretics) had a lower prevalence of dementia than those not taking antihypertensive medication (P or =75 years with initially good cognition. Cognitive performance was indexed with the Mini-Mental State Examination (MMSE) on two occasions, 3 years apart. The average decline in MMSE score was 0.4 points per year. However, 23.4% of the participants lost more than 10% of their baseline MMSE scores. Women declined more rapidly than men. Baseline advanced age, lower education, and stroke predicted the greater decline in women. It appears that the relation of lower education and stroke with cognitive decline was more pronounced in men, but age did not predict cognitive decline in men. In addition, there was a correlation between systolic pressure reduction and cognitive decline in women, which was not accounted for by other factors. In summary, although the cognitive ability is generally spared longitudinally, in terms of the entire population, a considerable proportion of individuals show substantial decline that is related to several factors such as advanced age, female gender, lower education, stroke, and systolic pressure reduction.

81. Guo, Z., et al., Low blood pressure and incidence of dementia in a very old sample: dependent on initial cognition. Journal of the American Geriatrics Society, 1999. 47(6): p. 723-6. OBJECTIVE: To examine whether initially low blood pressure is related to the incidence of dementia. DESIGN: A population-based prospective study. SETTING: The Kungsholmen district of Stockholm, Sweden PARTICIPANTS: Three hundred four nondemented subjects aged 75 to 96 years at baseline. MEASUREMENTS AND MAIN RESULTS: After an average of 3 years, 81 dementia cases were identified (67 with Alzheimer's disease cases). Compared with individuals with baseline systolic pressure of 141 to 179 mm Hg, those with systolic pressure < or = 140 mm Hg had a significantly higher risk of dementia (relative risk (RR) = 1.9, 95% confidence interval (CI), 1.2-3.2) and Alzheimer's disease (RR = 2.2, 95% CI, 1.2-3.8). However, the RR in relation to systolic pressure < or = 140 mm Hg was 1.3 (0.8-2.2) for all dementia and 1.5 (0.8-2.6) for Alzheimer's disease, when the baseline Mini-Mental State Examination (MMSE) score was included in the model as a dichotomous variable (< 24 vs > or = 24). Baseline MMSE < 24 significantly predicted the occurrence of dementia (RR = 6.9; 95% CI, 4.3-11.1). Systolic pressure < or = 140 mm Hg was significantly related to MMSE score < 24 at baseline. CONCLUSIONS: These data suggest that low blood pressure may be an early correlate of a dementing process although a causative effect cannot be definitely ruled out.

82. Kario, K., et al., Autonomic nervous system dysfunction in elderly hypertensive patients with abnormal diurnal blood pressure variation: relation to silent cerebrovascular disease. Hypertension, 1997. 30(6): p. 1504-10. To investigate the relationships among diurnal blood pressure (BP) variations and autonomic nervous system dysfunction, we assessed heart rate variability (HRV) using power spectral analysis of the 24-hour RR interval in 51 asymptomatic elderly hypertensive patients with various patterns of nocturnal BP fall. The extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low-frequency power (LF)/high-frequency power (HF) ratios (a relative index of sympathetic nervous system activity), while the nondippers without nocturnal BP fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index of parasympathetic nervous activity), when compared with dippers with appropriate nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the nondippers, and both were markedly higher than that (6.3%) in the dippers (both P ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download