Research topics:  General Articles and Research Overviews, Immune System Research, Viral Research, Cardiac Research, Exercise Research, Muscle Research, Metabolic Research, Neurological and Cognitive Research, Genetic Research, Neuroendocrine Research, and Miscellaneous Research.

Seronegative Sjogren's syndrome manifested as a subset of chronic fatigue syndrome. Nishikai M, Akiya K, Tojo T, Onoda N, Tani M, Shimizu K. British Journal of Rheumatology 1996; 35: 471-474.

Abstract: We determined the extent to which chronic fatigue syndrome (CFS) patients with sicca symptoms fulfil the diagnostic criteria for Sjogren's syndrome (SS). Three sets of diagnostic criteria for SS, formulated by the Japanese, Europeans and Fox, were used. One-third of the CFS patients with sicca symptoms fulfilled the diagnostic criteria for SS. However, they were 'seronegative', differing from the ordinary primary SS.

Vagal tone is reduced during paced breathing in patients with the chronic fatigue syndrome. Sisto SA, Tapp W, Drastal S, Bergen M, DeMasi I, Cordero D, Natelson B. Clinical Autonomic Research 1995; 5(3): 139-43.

Abstract: Patients with chronic fatigue syndrome (CFS) often complain of an inability to maintain activity levels and a variety of autonomic-like symptoms that make everyday activity intolerable at times. The purpose of the study was to determine if there were differences in vagal activity at fixed breathing rates in women with CFS. Twelve women with the diagnosis of CFS between the ages of 32 and 59 years volunteered for the study. Healthy women, who were between the ages of 30 and 49, served as controls. Full signal electrocardiograph and respiratory signals were collected during a paced breathing protocol of three fixed breathing rates (8, 12 and 18 breaths/min) performed in the sitting and standing postures. Vagal activity was analyzed by means of heart rate spectral analysis to determine the subject's response to specific breathing rates and postures. Heart rate variability was used as a non-invasive method of measuring the parasympathetic component of the autonomic nervous system. Using this method, although there was significantly less vagal power in the sitting versus the standing postures for both groups, the overall vagal power was significantly lower (p < 0.034) in the CFS group versus healthy controls. Vagal power was also significantly lower (p < 0.01 to p < 0.05) at all breathing rates in both postures except while standing and breathing at 18 breaths/min. Knowledge of the differences in vagal activity for CFS patients may allow stratification for the analysis of other research variables.

Red blood cell magnesium and chronic fatigue syndrome. Cox IM, Campbell MJ, Dowson D. Lancet 1991; 337: 757-60.

Abstract: The hypothesis that patients with chronic fatigue syndrome (CFS) have low red blood cell magnesium and that magnesium treatment would improve the wellbeing of such patients were tested in a case-control study and a randomised, double-blind, placebo-controlled trial, respectively. In the case-control study, 20 patients with CFS had lower red cell magnesium concentrations than did 20 healthy control subjects matched for age, sex, and social class (difference 0.1 mmol/l, 95% confidence inteval [Cl] 0.05 to 0.15) In the clinical trial, 32 patients with CFS were randomly allocated wither to intramuscular magnesium sulphate every week for 6 weeks (15 patients) or to placebo (17). Patients treated with magnesium claimed to have improved energy levels, better emotional state, and less pain, as judged by changes in the Nottingham health profile. 12 of the 15 treated patients said they had benefited from treatment, and in 7 patients energy score improved from the maximum to the minimum. By contrast, 3 of the 17 patients said that they felt better (difference 62%, 95% CI 35 to 90), and 1 patient had a better energy score. Red cell magnesium returned to normal in all patients on magnesium but in only 1 patient on placebo. The findings show that magnesium may have a role in CFS.

Amantadine and L-carnitine treatment of chronic fatigue syndrome. Plioplys AV, Plioplys S. Neuropsychobiology 1997; 35(1): 16-23.

Abstract: Carnitine is essential for mitochondrial energy production. Disturbance in mitochondrial function may contribute to or cause the fatigue seen in Chronic Fatigue Syndrome (CFS) patients. Previous investigations have reported decreased carnitine levels in CFS. Orally administered L-carnitine is an effective medicine in treating the fatigue seen in a number of chronic neurologic diseases. Amantadine is one of the most effective medicines for treating the fatigue seen in multiple sclerosis patients. Isolated reports suggest that it may also be effective in treating CFS patients. Formal investigations of the use of L-carnitine and amantadine for treating CFS have not been previously reported. We treated 30 CFS patients in a crossover design comparing L-carnitine and amantadine. Each medicine was given for 2 months, with a 2-week washout period between medicines. L-Carnitine or amantadine was alternately assigned as fist medicine. Amantadine was poorly tolerated by the CFS patients. Only 15 were able to complete 8 weeks of treatment, the others had to stop taking the medicine due to side effects. In those individuals who completed 8 weeks of treatment, there was no statistically significant difference in any of the clinical parameters that were followed. However, with L-carnitine we found statistically significant clinical improvement in 12 of the 18 studied parameters after 8 weeks of treatment. None of the clinical parameters showed any deterioration. The greatest improvement took place between 4 and 8 weeks of L-carnitine treatment. Only 1 patient was unable to complete 8 weeks of treatment due to diarrhea. L-Carnitine is a safe and very well tolerated medicine which improves the clinical status of CFS patients. In this study we also analyzed clinical and laboratory correlates of CFS symptomatology and improvement parameters.

Trial of a selective acetylcholinesterase inhibitor, galanthamine hydrobromide, in the treatment of chronic fatigue syndrome. Snorrason E, Geirsson A, Stefansson K. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 35-54.

Abstract: The purpose of the study was to search for a means of diminishing the plight of patients with chronic fatigue syndrome (CFS) and to test the hypothesis that central to the pathogenesis of CFS is a cholinergic defect. Forty-nine patients who fulfilled consensus criteria for CFS were treated with the acetylcholinesterase inhibitor, galanthamine hydrobromide. Thirtynine patients finsihed the study according to the protocol with 43% reporting 50% improvement whereas patients in the placebo group reported only 10% improvement in the same parameters of CFS. The improvement of patients on galanthamine was in most cases gradual and reached significance for the group only after four to eight weeks. The improvement was stable, and no patients who reported over 50% improvement on galanthamine relapsed to a pretrial level of any symptom. One of the most surprising effects was the dramatic improvement of sleep disturbances that occurred in most patients on this medication: more than 60% of the patients who finished the study reported over 70% improvement in sleep deficit. If the subjective report by patients can be proved by objective means, this would be the first demonstration of a drug that can be used to correct a sleep disturbance that also influences a specific stage in normal sleep. The most common adverse effect of galanthamine, as given in this study, was nausea that was dose-dependent and reversible. Galanthamine hydrobromide is relatively safe and appears to be an effective medication against many symptoms of CFS. But the positive results of this study have to be interpreted cautiously because of methodological limitations of this trial. First, this study was originally organized as a double-blind, placebo-controlled trial but was changed to an optional crossover after two weeks of treatment. Also, the adverse effects of the active drug in 30% of patients could compromise the double-blind. With these limitations in mind, it is nevertheless tempting to conclude that this study lends an indirect support to our hypothesis that a cholinergic deficit may play a role in the pathogenesis of the syndrome.

Therapy of chronic fatigue syndrome. Uchida A. Nippon Rinsho 1992; 50(11): 2679-2683.

Abstract: Chronic fatigue syndrome (CFS) is characterized by unexplained, debilitating fatigue or easy fatigability lasting longer than six months. While a number of clinical trials have been performed in CFS patients, there is currently no established therapy for CFS. Treatment with acyclovir of CFS patients is ineffective. Intravenous immunoglobulin therapy appears to be effective, though the results are controversial. Antidepressants might help the associated depression and anxiety but not other symptoms. Trials with magnesium have improved the well-being of patients. Restoration of NK activity by biological response modifiers, such as sizofirann, resulted in restoration of NK cell activity and recovery from CFS. Taken together, immunological abnormalities may be involved in CFS, and its restoration may produce clinical benefit in CFS.

Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Vercoulen JH, Swanink CM, Zitman FG, Vreden SG, Hoofs MP, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G. Lancet 1996; 347: 858-61.

Abstract: BACKGROUND: No somatic treatment has been found to be effective for chronic fatigue syndrome (CFS). Antidepressant therapy is commonly used. Fluoxetine is recommended in preference to tricyclic agents because it has fewer sedative and autonomic nervous system effects. However, there have been no randomised, placebo-controlled, double-blind studies showing the effectiveness of antidepressant therapy in CFS. We have carried out such a study to assess the effect of fluoxetine in depressed and non-depressed CFS patients. METHODS: In this randomised, double-blind study, we recruited 44 patients to the depressed CFS group, and 52 to the non-depressed CFS group. In each group participants were randomly assigned to receive either fluoxetine (20 mg once daily) or placebo for 8 weeks. The effect of fluoxetine was assessed by questionnaires, self-observation lists, standard neuropsychological tests, and a motion-sensing device (Actometer), which were applied on the day treatment started and on the last day. FINDINGS: The two groups were well matched in terms of age, sex distribution, employment and marital status, and duration of CFS. There were no significant differences between the placebo and fluoxetine-treated groups in the change during the 8-week treatment period for any dimension of CFS. There was no change in subjective assessments of fatigue, severity of depression, functional impairment, sleep disturbances, neuropsychological function, cognitions, or physical activity in the depressed or the non-depressed subgroup. INTERPRETATION: Fluoxetine in a 20 mg daily dose does not have a beneficial effect on any characteristic of CFS. The lack of effect of fluoxetine on depressive symptoms in CFS suggests that processes underlying the presentation of depressive symptoms in CFS may differ from those in patients with major depressive disorder.

The ocular signs and symptoms of chronic fatigue syndrome. Caffery BE, Josephson JE, Samek MJ. Journal of the American Optometric Association 1994; 65(3): 187-91.

Abstract: BACKGROUND: Chronic Fatigue syndrome (CFS) is a relatively newly defined clinical entity that affects multiple systems including the ocular system. These effects have not been well documented. METHODS: 25 consecutive CFS patients were evaluated and the ocular signs and symptoms were described. RESULTS: Significant ocular symptoms were present in all 25 patients. The most common clinical findings were abnormalities of the preocular tear film and ocular surface (19 patients) and reduced accommodation for age (18 patients). CONCLUSIONS: CFS affects the ocular system in many ways. Eye care practitioners should pay particular attention to accommodative needs, ocular surface disease and tear film dysfunction when examining these patients. Further research into the pathophysiology of these ocular findings may lead to a better understanding of the pathophysiology of CFS.

Selective impairment of auditory processing in chronic fatigue syndrome: a comparison with multiple sclerosis and healthy controls. Johnson SK, DeLuca J, Diamond BJ, Natelson BH. Perceptual and Motor Skills 1996; 83: 51-62.

Abstract: The most consistent deficit observed in individuals with Chronic Fatigue Syndrome has been in efficiency of information processing. To examine the possibility of a modality-specific impairment, the present study examined subjects with Chronic Fatigue Syndrome, multiple sclerosis, and healthy controls on an auditory-versus visual-paced serial-addition test. 20 subjects with Chronic Fatigue Syndrome, 20 subjects with clinically definite Multiple Sclerosis, and 20 sedentary healthy controls were compared. One-half of the subjects in each group were administered the Paced Auditory Serial Addition Test and the other half were administered the Paced Visual Serial Addition Test. The group with Chronic Fatigue Syndrome was differentially impaired on the auditory relative to the visual processing task. The group with Multiple Sclerosis was equally impaired on both versions of the task. The results are discussed within the framework of Baddeley's model of working memory.

Survey of the ocular manifestations of chronic fatigue syndrome [Abstract]. Potaznick W, Kozol N. Clinical Infectious Diseases 1994; 18(Supp 1): S87.

Abstract: Chronic fatigue and immune dysfunction syndrome (CFIDS) is a disease presenting with systemic, sensory, cognitive, and psychological manifestations. Ocular symptomatology is reported in the visual, functional, perceptual, and pathological aspects of the visual system. The purpose of the research was to evaluate ocular symptoms in patients with CFIDS. One hundred and ninety CFIDS patients [155 females, 35 males; mean age of 41 years (range 15 to 72)] and 198 healthy controls [133 females, 65 males; mean age of 42 years (range 8 to 89)] were surveyed via written questionnaire. Evaluation of data showed statistical significance at levels ranging from 0.0001 to 0.007 for all but one symptom surveyed. It appears that the ocular symptoms of CFIDS are genuine. Further research is needed to determine the etiology and appropriate treatment of this disease.

Ocular manifestations of chronic fatigue and immune dysfunction syndrome. Potaznick W, Kozol N. Optometry and Vision Science 1992; 69(10): 811-4.

Abstract: Chronic fatigue and immune dysfunction syndrome (CFIDS) is a disease presenting with systemic, sensory, cognitive, and psychological manifestations. Ocular symptomatology is reported in the visual, functional, perceptual, and pathological aspects of the visual system. The purpose of the research was to evaluate ocular symptoms in patients with CFIDS. One hundred and ninety CFIDS patients [155 females, 35 males; mean age of 41 years (range 15 to 72)] and 198 healthy controls [133 females, 65 males; mean age of 42 years (range 8 to 89)] were surveyed via written questionnaire. Evaluation of data showed statistical significance at levels ranging from 0.0001 to 0.007 for all but one symptom surveyed. It appears that the ocular symptoms of CFIDS are genuine. Further research is needed to determine the etiology and appropriate treatment of this disease.

Sensory and cognitive event-related potentials in myalgic encephalomyelitis. Prasher D, Smith A, Findley L. Journal of Neurology Neurosurgery and Psychiatry 1990; 53: 247-53.

Abstract: Myalgic Encephalomyelitis (ME) is a form of post viral fatigue syndrome resulting in myalgia and fluctuating fatiguability. Symptoms reflecting central nervous system dysfunction are common and include muscle weakness, headache, sensory disturbances, poor short term memory and impairment of concentration. In view of the fact that sensory and cognitive disturbances are experienced by many patients objective evidence was sought with multi-modality sensory evoked potentials and auditory event-related cognitive potentials in a group of ME patients both with and without the enteroviral antigen, VP1 test positive. The auditory brainstem, median nerve somatosensory and pattern reversal checkerboard visual potentials were normal for all 37 patients tested. In contrast to the sensory potentials significant differences in the mean latencies of the cognitive potential N2 and P3 were found. Reaction times were also significantly prolonged but the performance in terms of error was not significantly affected. No significant difference emerged in any of the parameters for the VP1 test. P3 was abnormal in latency or amplitude in 36% of the VP1 positive patients for the frequency discrimination task and 48% for the more difficult duration discrimination task. The abnormalities indicate attentional deficits in some patients and slower speed of information processing in others. The prolonged latencies observed in these patients have not been observed in patients with depression in many other studies.

Vestibular function test anomalies in patients with chronic fatigue syndrome. Ash-Bernal R, Wall C 3rd, Komaroff AL, Bell D, Oas JG, Payman RN, Fagioli LR. Acta Oto-Laryngologica 1995; 115(1): 9-17.

Abstract: Chronic fatigue syndrome (CFS) is distinguished by the new onset of debilitating fatigue that lasts at least 6 months, concomitant with other symptoms to be described later. Many CFS patients complain of disequilibrium, yet the exact type of the balance dysfunction and its function and its location (peripheral vs. central) have not been described. Herein we report results of vestibular function testing performed on 11 CFS patients. These results revealed no predominant pattern of abnormalities. Patients typically performed below average in dynamic posturography testing, with a significant number of falls in the tests requiring subjects to depend heavily on the vestibular system. One patient had abnormal caloric testing, while 3 had abnormally low earth vertical axis rotation (EVA) gains at the higher frequencies tested. As a group, the average gain of EVA was significantly lower than normals in the 0.1 - 1.0 Hz range (p < 0.05). In earth horizontal axis rotation, the CFS group had a higher than normal bias value for the optokinetic (OKN) and eyes open in the dark conditions (p < 0.05), but had normal scores during visual vestibular reflex testing. Five of the 11 subjects had an abnormal OKN bias build up over the course of the run, equal to or actually exceeding the 60 degrees/s target velocity by as much as 14 degrees/s. Altogether, these results are more suggestive of central nervous system deficits than of peripheral vestibular disfunction.

Vestibular nucleus projections to the parabrachial nucleus in rabbits: implications for vestibular influences on the autonomic nervous system. Balaban CD. Experimental Brain Research 1996; 108(3): 367-381.

Abstract: Acute vestibular dysfunction and motion sickness are characterized by autonomic effects such as pallor, nausea, and vomiting. Previous anatomic and physiologic studies suggest that one potential mediator of these effects may be light, direct vestibular nuclear projections to the nucleus tractus solitarius and the dorsal motor nucleus of the vagus nerve. This study presents evidence for relatively dense, direct projections from the vestibular nuclei to the parabrachial nucleus. Male albino rabbits received injections of Phaseolus vulgaris leucoagglutinin into the vestibular nuclei. The tracer was visualized immunocytochemically with standard techniques. Anterogradely labeled axons were traced bilaterally from the vestibular nuclei to the parabrachial nuclear complex, where they terminated around somata in the Kolliker-Fuse nucleus, external medial parabrachial nucleus, medial parabrachial nucleus, and lateral parabrachial nucleus. Less dense terminations were observed in the ventrolateral aspect of the medullary reticular formation, the subtrigeminal nucleus, lateral tegmental field, and nucleus ambiguus. These findings have several important implications. First, they suggest that vestibular input converges directly at brain stem levels with visceral sensory input in both nucleus of the solitary tract and the parabrachial complex. Second, they suggest that vestibular input influences brain stem autonomic outflow via two parallel pathways: (1) direct, light projections to the nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve, and ventrolateral medullary reticular formation; and (2) denser projection to regions of the parabrachial nucleus that project to these brain stem regions. Finally, since the parabrachial nucleus regions that receive vestibular input also project to the hypothalamus and the insular and infralimbic prefrontal cortex, the parabrachial nucleus may serve as an important relay and integrative structure for the cognitive impairment and vegetative symptoms associated with motion sickness, vestibular dysfunction, and responses to altered gravitational environments.

Fundamental immune mechanisms of the brain and inner ear. Harris JP, Ryan AF. Otolaryngology and Head and Neck Surgery 1995; 112(6): 639-53.

Abstract: Because of the blood-brain and blood-labyrinthine barriers, the brain and inner ear were once thought to be immunoprivileged sites. Although these barriers provide protection from inflammatory damage to the delicate structures of the organs, both sites have since been shown to be capable of active immune responses when appropriately stimulated. In the inner ear, perisacular tissue around the endolymphatic sac hosts resident lymphocytes and serves as a site of immunosurveillance. Lymphocytes also enter the inner ear from the circulation, and in the cochlea this occurs via the spiral modiolar vein. Immune responses can protect the labyrinth from infection, but they can also cause bystander injury. Moreover, the cochlea can itself become the target of immune responses that damage hearing. Such autoimmune sensorineural hearing loss can be site specific, with the primary manifestation of the disorder being hearing loss and dysequilibrium. Some of these cases can be diagnosed by antibody or lymphocyte responses to inner ear antigens. Alternately, systemic autoimmune disorders can result in inner ear dysfunction as part of a broader spectrum of disease. Both forms of immune-mediated inner ear dysfunction may respond to immunosuppressive therapies, including steroids, cytotoxic agents, and plasmapheresis.

Properties of sympathetic reflexes elicited by natural vestibular stimulation: implications for cardiovascular control. Yates BJ, Miller AD. Journal of Neurophysiology 1994; 71(6): 2087-2092.

Abstract: 1. To study the properties of vestibulosympathetic reflexes we recorded outflow from the splanchnic nerve during natural vestibular stimulation in multiple vertical planes in decerebrate cats. Most of the animals were cerebellectomized, although some responses were recorded in cerebellum-intact preparations. Vestibular stimulation was produced by rotating the head in animals whose upper cervical dorsal roots were transected to remove inputs from neck receptors; a baroreceptor denervation and vagotomy were also performed to remove visceral inputs. 2. The plane of head rotation that produced maximal modulation of splanchnic nerve activity (response vector orientation) was measured at 0.2-0.5 Hz. The dynamics of the response were then studied with sinusoidal (0.05- to 1-Hz) stimuli aligned with this orientation. 3. Typically, maximal modulation of splanchnic nerve outflow was elicited by head rotations in a plane near pitch; nose-up rotations produced increased outflow and nose-down rotations reduced nerve discharges. The gains of the responses remained relatively constant across stimulus frequencies and the phases were consistently near stimulus position, like regularly firing otolith afferents. Similar response dynamics were recorded in cerebellectomized and cerebellum-intact animals. 4. The splanchnic nerve responses to head rotation could be abolished by microinjections of the excitotoxin kainic acid into the medial and inferior vestibular nuclei, which is concordant with the responses resulting from activation of vestibular receptors. 5. The properties fo vestibulosympathetic reflexes recorded from the splanchnic nerve support the hypothesis that the vestibular system participates in compensating for posturally related changes in blood pressure.

Vestibular influences on the autonomic nervous system. Yates BJ. Annals of the New York Academy of Science 1996; 781: 458-73.

Abstract: Considerable evidence exists to suggest that both sympathetic and respiratory outflow from the central nervous system are influenced by the vestibular system. Otolith organs that respond to pitch rotations seem to play a predominant role in producing vestibulo-sympathetic and vestibulo-respiratory responses in cats. Because postural changes involving nose-up pitch challenge the maintenance of stable blood pressure and blood oxygenation in this species, vestibular effects on the sympathetic and respiratory systems are appropriate to participate in maintaining homeostasis during movement. Vestibular influences on respiration and circulation are mediated by a relatively small portion of the vestibular nuclear complex comprising regions in the medial and inferior vestibular nuclei just caudal to Deiters' nucleus. Vestibular signals are transmitted to sympathetic preganglionic neurons in the spinal cord through pathways that typically regulate the cardiovascular system. In contrast, vestibular effects on respiratory motoneurons are mediated in part by neural circuits that are not typically involved in the generation of breathing.