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Index to Abstracts from AACFS Conference October 1998


Abstracts of Papers Presented at
The Bi-Annual Research Conference of the
American Association for
Chronic Fatigue Syndrome (AACFS)

October 10-11, 1998 -- Cambridge, Massachusetts

Session 6: Physiology

Co-chairs: Wilhelmina Behan, M.D., and Benjamin H. Natelson, M.D.
October 11, 1998 -- 8:45 am-11:00 am

1. Levels of activity and fatigue after extreme exercise in Chronic Fatigue Syndrome (CFS)
E. Bazelmans, G. Bleijenberg, H. Folgering, J.W.M. van der Meer
2. The symptoms of Chronic Fatigue Syndrome are related to abnormal ion channel function
Peter O. Behan, Abhijit Chaudhuri, Walter S. Watson, John Pearn
3. Identifying physical activity patterns in Chronic Fatigue Syndrome using actigraphic assesssment
S.P. van der Werf, G. Bleijenberg, J.B. Prins, J.H.M.M. Vercoulen, J.W.M. van der Meer
4. RNase L dysfunction disorder (R.E.D.D.) in CFS
K. De Meirleir, P. De Becker, B. Van Steenberge, C. Bisbal, T. Salehzada, B. Lebleu, C.V. Herst
5. Characterization of RNase L dysfunction in peripheral blood mononuclear cell extracts from patients with Chronic Fatigue Syndrome
Susan B. Horvath, Daniel L. Peterson, and Robert J. Suhadolnik
6. The effect of exercise on gait in patients with Chronic Fatigue Syndrome
L. Paul and L. Wood
7. CFS severity is related to reduced stroke volume and diminished blood pressure responses to mental stress
Arnold Peckerman, John J. LaManca, Sharon L. Smith and Benjamin H. Natelson
8. Cardiovascular responses during a cognitive stressor before and after exercise in Chronic Fatigue Syndrome vs. Sedentary healthy subjects
S.A. Sisto, J.J. LaManca, A. Peckerman, B. Natelson
9. Patterns of orthostatic intolerance and abnormalities in heart rate variability suggest autonomic dysfunction in Chronic Fatigue Syndrome during adolescence
Julian M. Stewart, Amy Weldon, Karl Li, Nina Arlievsky, Jose Munoz


Levels of activity and fatigue after extreme exercise in Chronic Fatigue Syndrome (CFS)

Authors: E. Bazelmans, G. Bleijenberg, H. Folgering, J.W.M. van der Meer; Dutch Fatigue Research Group, Depts. of Medical Psychology, Pulmonology, and Internal Medicine, University Hospital Nijmegen, the Netherlands

Objective: The role of physical activity as a perpetuating factor in CFS is an important one. CFS patients often complain that a burst of activity makes them even more fatigued than they already are, and that they need prolonged rest in order to recover to their previous level of fatigue. One hypothesis is that this is due to physiological deconditioning. Another hypothesis is that this represents a cognitive behavioral problem: CFS patients presume that they need prolonged rest and sleep.

Methods: In the present study, 26 CFS patients and 24 healthy controls participated. They were all given a fatigue diary (registrating self-observed fatigue and muscle pain) and an actometer (an apparatus registrating the degree of movement), to keep for 2 weeks. In the middle of these 2 weeks, an ergometer test with climbing effort took place to induce extreme activity.

Results: None of the CFS patients or healthy controls suffered from physiological deconditioning. The fatigue diaries show that CFS patients report being more fatigued and experience more muscle pain at the day of the exercise test, and are still more fatigued one day thereafter, compared to the period before the exercise test. CFS patients are not less active the days after the exercise test, compared to the period before. No differences in the level of fatigue, muscle pain, or actometer scores before and after the excercise test are found for the healthy controls.

Conclusion: The data show that CFS patients do not suffer from physiological deconditioning. Being more fatigued and less active after extreme exercise seems to be a cognitive behavioral problem. These findings have implications for the cognitive behavior therapy programs in CFS.

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The symptoms of Chronic Fatigue Syndrome are related to abnormal ion channel function

Authors:Peter O. Behan*, Abhijit Chaudhuri*, Walter S. Watson**, John Pearn***
*University Department of Neurology, Institute of Neurological Sciences and
**Department of Nuclear Medicine, Southern General Hospital, Glasgow (UK),
***Department of Child Health, University of Queensland, Brisbane (Australia).

Objective: Many symptoms of chronic fatigue syndrome (CFS), including severity of fatigue, are periodic, fluctuant and are inducible by physical and mental activities. Chest pain is a common symptom of CFS-like patients with syndrome X, an ion channel disorder. Symptoms in CFS such as fatigue, myalgia and headache bear striking resemblance with neurological disorders that affect ion channel function, such as periodic paralysis and familial hemiplegic migraine. Maintenance of normal transmembrane ionic equilibrium is an active, energy-dependent process, and constitutes an important share of the resting energy expenditure (REE). We wanted to compare and contrast the clinical profile of CFS patients with other neurological disorders that are known to affect ion channel function, and estimate REE in CFS. We also studied the myocardial perfusion in CFS by thallium201 SPECT scans to compare the results with Syndrome X.

Methods:: All patients who fulfilled the modified CDC criteria for CFS were included in our studies. For investigations that required the administration of radiopharmaceuticals (e.g. cardiac-thallium201 SPECT scans), patients between the age of 18 - 65 years were recruited after informed consent. A comparable group of healthy, sedentary volunteers were tested as controls in the REE study.

Results: Fatigue was fluctuant in most patients with CFS. This was induced or worsened by physical activities (exercise), mental stress and chemicals that affect ion channel function (e.g. alcohol, quinine and anaesthetics). Significant perfusion defects were observed in the cardiac-thallium201 SPECT scans in 70% of CFS patients, similar to that described in patients with syndrome X. In a separate study, a significant number of CFS patients were found to have elevated REE as compared to the controls using total body potassium (TBK) as the refererence (REE TBK).4

Conclusion: Abnormal thallium201-cardiac SPECT scans in CFS similar to those described in syndrome X suggest a common mechanism for both these conditions. An abnormality of membrane ion channel function is considered the underlying mechanism in syndrome X. Increased REETBK; in a subgroup of CFS patients suggests that some CFS patients spend more energy in maintaining essential body function at the expense of the energy available for other physical activities. Since 30% of REE is expended to maintain physiological ion gradients in normal health, cell membranes that leak ions increase REETBK Elevated REE and abnormal cardiac perfusion scans in CFS provide the first objective and indirect support to our hypothesis that symptoms in CFS could be the result of an acquired abnormality of the voltage or ligand-gated ion channels. It is possible that such alteration of transmembrane ion traffic could affect normal receptor sensitivity to neurochemicals and neurohormones such as acetylcholine, serotonin or other monoamines, accounting for the neuroendocrine abnormalities previously documented in CFS.

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Identifying physical activity patterns in Chronic Fatigue Syndrome using actigraphic assesssment

Authors: S.P. van der Werf, G. Bleijenberg, J.B. Prins, J.H.M.M. Vercoulen, J.W.M. van der Meer; Dutch Fatigue Research Group, Depts. of Medical Psychology and Internal Medicine, University Hospital Numegen, the Netherlands

Objective: Chronic Fatigue Syndrome (CF S) patients often describe themselves as being significantly less physical active as compared to the time before they suffered from CFS. In previous studies of our research group, we recorded motor-activity by ankle-worn motion sensing devices (actometer). This device uses a piezo-electric sensor and yields highly reliable and valid data on human physical activity. Results showed that CFS patients had, on average, reduced physical activity levels as compared to healthy controls (Vercoulen, et al., 1997). Nevertheless, clinical observations and other research findings indicate that there may be subtypes of activity patterns in CFS. Our goal was to define and operationalize such subtypes of motor-activity with the use of a behavioral measure as the actometer. We tried to identify extreme activity patterns and developed parameters to describe intra-individual activity patterns in more detail.

Method: Actigraphic data over a 12-day period were collected from 277 CFS patients. Active and inactive patients were defined as those subjects whose average daily actometer scores exceeded (active) or stayed below (passive) a CFS-normative actometerscore in at least eleven of the twelve assessment days. The CFS sample was accordingly divided into three groups: permanently inactive, varying activity pattern, and permanently rather active. To describe intra-individual variability in activity, we compared the intensity and duration of active and inactive periods within subjects.

Results:Using this new method we subtyped 24% of the patients as permanently inactive, 15% as rather active, and the remaining patients (61%) as varying active. Self-reported disability in mobility differed significantly across the three groups. The inactive group, as compared to the very active group, reported more strongly that they avoided physical activity in order to prevent fatigue. These fmdings validated the usefulness of subtyping physical activity. Futhermore, in contrast to active patients, inactive patients were characterized by longer inactive periods after activity peaks.

Conclusion: This study shows that it is possible to use actometer results to subtype physical activity patterns in CFS. In cognitive behavioral therapy, changing the activity pattern is an important therapeutic aim. Therefore, this subtyping may have implications for treatment strategies. Preliminary results indeed indicate that inactive patients benefit less from standard cognitive behavioral therapy. Inactive patients may need an other approach (see paper, Prins).

References:
Vercoulen J, Bazelmans E, Swanink C, et al. (1997) Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. Journal of Psychiatric Research 31, 661-673.

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RNase L dysfunction disorder (R.E.D.D.) in CFS

AuthorsK. De Meirleir*, LCLI, I. Campine+*, P. De Becker, B. Van Steenberge*, C. Bisbal**, T. Salehzada**, B. Lebleu**, C.V. Herst*
*Department of Human Physiology, Free University of Brussels, Brussels, Belgium
**Institute of Molecular Genetics, Montpellier University, Montpellier, France + I.Campine is supported by funds from the Foundation for Scientific Research, Belgium (F.W.O.).

NOTE: The paper that was actually presented at the meetings had more information in it concerning the relationship between R.E.D.D. and the experimental drug Ampligen. As soon as I get a copy of the paper, or an abstract, I will upload it here or provide it on another website with a hyperlink. If anyone has a copy of the paper that was presented, or has a good set of notes, I would appreciate it if you could share a copy with me. Thanks -- Mary Schweitzer, at schweit2@ix.netcom.com.

Objective: The unknown aetiology and absence of biochemical markers in CFS are a major problem in this disorder. Activation of immune responses and infection by several viruses have been suggested in several studies. Recent work by Suhadolnik et al. has demonstrated increased levels of 2-5' A oligonucleotides, 2'-5'A Synthetase and RNase L activity in mononuclear cell pellets from CFS patients, as well as a low molecular form of RNase L in severely disabled CFS patients. This work was designed to explore the specificity and sensitivity of the presence of the LMW RNase L in CFS.

Methods: Mononuclear cell pellets (PBMC) of 57 patients and 18 controls were studied. The technique used to detect the RNase L molecular weight is described by Charachon et al (Biochemistry 29:2550-2556, 1990). This technique is different from the one described by the one used by Suhadolnik et al. (Clin Inf Dis, 18 (Suppl 1), 5 96-104, 1994). An RLI binding study was also performed.

Results: A low molecular weight (LMW) 2'-5'A binding polypeptide (37 kDa) was found in 50 out of 57 PBMC pellets of the CFS patients, versus 4 out of 18 healthy individuals. Both sensitivity and specificity of the LMW RNase L in relationship to CFS are high. The 37kDa 2'-5'A binding polypeptide binds RLI.

Conclusion: The presence of a 37 kDa 2'.-5'A binding polypeptide in the PBMC pellets of CFS patients may objectively contribute to distinguish CFS patients from healthy individuals. These observations could provide the basis for the development of a biochemical assay for the differential diagnosis of CFS and for follow up of its clinical evolution.

Supported by grants from ARC and the CFIDS Association to Bernard Lebleu.

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Characterization of RNase L dysfunction in peripheral blood mononuclear cell extracts from patients with Chronic Fatigue Syndrome

Authors: Susan B. Horvath*, Daniel L. Peterson**, and Robert J. Suhadolnik* *Temple University School of Medicine, Philadelphia, PA; **Sierra Internal Medicine Associates, Incline Village, NV.

Objective: This laboratory has previously demonstrated a statistically significant dysregulation in the 2',5'-oligoadenylate (2-5A) synthetase / RNase L pathway in peripheral blood mononuclear cell (PBMC) extracts from individuals with Chronic Fatigue Syndrome (CFS)1,2. In CFS PBMC, the 2-5A synthetase is present predominantly in its activated form and levels of biologically active 2-5A and RNase L activity are elevated compared to healthy controls. We recently discovered the presence of a novel low molecular weight (LMW) RNase L (37 kDa) in CFS PBMC3. Characterization of the 2-5A binding site for the LMW RNase L compared to the 80 kDa RNase L by equilibrium binding studies, isotope competition, and competition with p3A3 was completed to determine the regulation of RNase L activity.

Methods: CFS subjects who met the 1994 CDC criteria for CFS and age and sex-matched control subjects were selected from Incline Village, NV. PBMC extracts from individuals with CFS and non-CFS controls were prepared as described.1,2 Identification of RNase L in PBMC extracts was as described.3 Isotope competition experiments were completed with unlabeled pApAp(8-azidoA) plus [32P]pApAp(8-azidoA). Photolabeled/immunoprecipitated RNase L was resolved by SDS-PAGE and quantitated as described.3 Competition of binding between [32P]pApAp(8-azidoA) and p3A3 was determined as described for isotope competition experiments. Saturation of 2-5A binding was determined by incubating [32P]pApAp(8-azidoA) (0-5 x 10-7 M) with PBMC extracts as described.3

Results: In isotope competition experiments, 100-fold excess unlabeled pApAp(8-azidoA) prevented the binding of [32P]pApAp(8-azidoA) to LMW RNase L in PBMC extracts from individuals with CFS and the 80 kDa RNase L in PBMC extracts from non-CFS individuals. When equal concentrations of [32P]pApAp(8-azidoA) and p3A3 were incubated simultaneously with a PBMC extract containing only 80 kDa RNase L or only LMW RNase L, authentic 2-5A completely competed out the binding of [32P]pApAp(8-azidoA). Equilibrium binding studies between 2-5A and 80 kDa RNase L in PBMC extracts from non-CFS controls revealed a Kd of 42 nM; the Kd for LMW RNase L in PBMC extracts from CFS patients was determined to be 7 nM.

Summary: Competition experiments with [32P]pApAp(8-azidoA) and pApAp(8-azidoA) or p3A3 demonstrated that the 2-5A photoprobe is specific for the 2-5A binding site. The 6-fold difference in Kd between the 80 kDa and the LMW RNase L suggests that the LMW RNase L is responsible for the elevated RNase L activity observed in CFS PBMC.

This research was funded in part by research grants from the CFIDS Association of America and NIH (RO1 A138378).

1. R.J. Suhadolnik et al., Clinical Infectious Diseases 18:S96-S104 (1994) 2. R.J. Suhadolnik et al., In Vivo 8: 599-604 (1994)
3. R.J. Suhadolnik et al., Journal of lnterferon & Cytokine Research 17: 377-385 (1997)

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The effect of exercise on gait in patients with Chronic Fatigue Syndrome

Authors: L. Paul and L. Wood, Division of Physiotherapy and Department of Biological Science, Glasgow Caledonian University, Glasgow, Scotland.

Objective: Gait is a central component of normal function. Dynamic walking requires sensory input from the visual, vestibular and proprioceptive systems as well as adequate muscle strength, general flexibility and appropriate neuromuscular timing. Symptoms of Chronic Fatigue Syndrome (CF S), including muscle fatigue and dysequilibrium, may therefore alter the sufferer's gait. Anecdotal evidence suggests that even minor activity can exacerbate the symptoms of CFS. This may further affect the indiviuals' gait pattern. The aim of the study was to investigate the effect of exercise on specific gait parameters in CFS subjects and controls.

Methods: Eleven CFS subjects and eleven sedentary age and sex matched controls took part in the study. Gait was examined on an instrumented walkmat which recorded the subjects step length and time, time of single and double support, velocity and cadence. Gait was assessed before each subject completed 15 minutes of exercise on a cycle ergometer. Subjects cycled at 90% of their predicted work rate at their anaerobic threshold based on age, sex and weight. Heart rate and Rating of Perceived Exertion (RPE) were recorded every minute during the test. Gait assessment was repeated immediately following the exercise period, then at 20 minute intervals for the subsequent hour and reassessed 24 hours later.

Results: Analysis of variance suggested that pre-exercise subjects with CFS took smaller steps with both the right (59.15cm) and left (59.74cm) legs when compared to control subjects (right=70. 15cm, left=69.34cm) (p=0.006 and 0.008 respectively). In addition the time for each step was increased in CFS subjects (right=57s, left=0.56s) compared to controls (right=0.5ls, left=0.50s) (right p=0.017, left p=0.014). The relative velocity of gait was significantly reduced in CFS subjects (0.64ms-1) compared to controls (0.84ms[-1])( p=0.002).Similarly, cadence was also significantly reduced in CFS subjects (106 steps/mm) compared to controls (120 steps/mm) (p=0.011). Double support time was not statistically different between the two groups (subjects 0.19s and controls 0.16s) (p=0.066). For both groups, CFS and controls, there was no difference in any of the gait parameters following exercise. The heart rate response at the end stage of the exercise test was not significantly different between CFS subjects and controls, however the RPE of the CFS group was significantly greater than the controls (p=0.0005).

Conclusions: CFS subjects have a 'normal' heart rate response during exercise although they perceive the workload to be significantly greater. A number of gait parameters were altered in the CFS group compared to the controls (step distance, step time, velocity and cadence). Gait analysis, therefore, may prove to be a valid outcome measure in the evaluation of treatment intervention in this group of patients. Gait was not adversely affected by exercise thus the results of this study do not support anecdotal evidence, from CSF sufferers, that activity can adversely affect functional abilities, as assessed by changes in gait pattern. Further studies in progress, using three dimensional motion analysis of gait, may provide more specific information on the kinetics of the gait pattern in CFS subjects.

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CFS severity is related to reduced stroke volume and diminished blood pressure responses to mental stress

Authors:Arnold Peckerman, John J. LaManca, Sharon L. Smith, and Benjamin H. Natelson; NJ CFS Research Center, University of Medicine and Dentistry of New Jersey

Objective: One plausible hypothesis of the pathophysiology of chronic fatigue syndrome (CFS) is a disorder of circulation. The present study examined whether cardiovascular homeostasis at rest and centrally-mediated hemodynamic responses to behavioral challenges are altered in CFS.

Methods: Twenty-one patients fulfilling CDC criteria for CFS (18 women and 3 men) and 25 matched sedentary controls were evaluated in supine, standing, and sitting postures (resting homeostasis), and during the cold pressor test and simulated public speaking (stress responsivity). The measured responses, in addition to blood pressure and heart rate, included impedance cardiography-derived stroke volume and cardiac output. Patients with CFS were rated for illness severity on a 6-point scale using the New Jersey CFS diagnostic system.

Results: As a group, patients with CFS displayed a similar cardiovascular functional status on most of the parameters. However, an observation was made that in patients with CFS, a lower stroke volume was highly predictive (r = -.72, p < .001) of illness severity. When divided into severe (N = 11) and less-than-severe (N = 10) groups, the severe CFS patients were found to have a lower stroke volume and cardiac output (p < .05) relative to a more moderate CFS group across three different postures. In response to the speech task, the less severe CFS group displayed attenuated blood pressure responses relative to a healthy control group (p < .05). A reduced blood pressure response to speech stressor in less severe CFS patients was attributable to a smaller increase in total peripheral resistance. In contrast, cardiovascular responses to the cold pressor test were not significantly different

Conclusion: These findings suggest the possibility of a low flow circulatory state in the most severe cases of CFS. In patients with a less severe form of CFS, a diminished blood pressure response to a cognitive-behavioral (speech presentation), but not to an aversive-sensory (the cold pressor test) stressor may indicate a defect in the higher cortical modulation of cardiovascular autonomic control. In this latter group, situations may arise where a demand for blood flow to the brain may exceed the supply with a possibility of ischemia and a decrement of function.

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Cardiovascular responses during a cognitive stressor before and after exercise in Chronic Fatigue Syndrome vs. Sedentary healthy subjects

Authors: S.A. Sisto, J.J. LaManca, A. Peckerman, B. Natelson

Objectives: Patients with Chronic Fatigue Syndrome (CFS) complain of cognitive difficulties that worsen after exertion. The purpose of this study was to determine if patients with CFS have similar cardiovascular responses during a cognitive test battery before and after exercise compared to sedentary healthy controls.

Methods: The CFS group consisted of 19 patients who fulfilled the 1988 CDC criteria for CFS. The control (CON) group included 20 sedentary healthy individuals matched with the CFS group for age, sex, and socio-economic background. The cognitive test battery (CTB) included the Stroop (3 parts), the symbol digit modalities test, an oral trail-making test and a subtraction task. Beat-by-beat blood pressure (Finapres) and electrocardiogram were recorded continuously while the subjects performed the CTB pre-, post-, and 24 hours after a maximal treadmill exercise test to exhaustion.

Results: Repeated measures analysis of variance procedure was used to evaluate the cardiovascular effects over the three test intervals. The CFS group demonstrated a significantly lower change in systolic blood pressure (p = 0.009) compared to the sedentary healthy group. Interactions indicated that the systolic blood pressure changed differently during the CTB (p = 0.0001) and across the three CTB test intervals (p = 0.005). The CFS group also had significantly lower heart rate responses during the CTB (p = 0.007).

Conclusions: Patients with CFS demonstrate a hyporesponsiveness to a cognitive stressor before exercise. Exercise produces the expected attenuation of the cardiovascular responses in the healthy group, but not for the CFS patients. Since CFS patients have lower systolic blood pressure and heart-rate responses compared to their healthy counterparts, they may not be able to exhibit the expected range of response to either cognitive or exercise stressor. This hyporesponsiveness may, in part, be responsible for CFS patients reporting detrimental effects of periods of psychological stressors or excess physical exertion.

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Patterns of orthostatic intolerance and abnormalities in heart rate variability suggest autonomic dysfunction in Chronic Fatigue Syndrome during adolescence

Authors:Julian M. Stewart, Amy Weldon, Karl Li, Nina Arlievsky, Jose Munoz

Objective: To determine the frequency and nature of orthostatic intolerance in the chronic fatigue syndrome (CFS) in adolescents and to delineate its relation to autonomic dysfunction assessed by measurements of heart rate variability.

Methods: We investigated supine baseline time and frequency domain indices of heart-rate variability, and the heart-rate and oscillometric blood pressure responses to head-up tilt (HUT) in 26 adolescents aged 11-19y with CFS, compared to responses in 26 adolescents referred for the evaluation of simple faint, and to responses in 13 normal healthy control children of similar age. After 30 min supine, HRV indices were determined and patients were tilted to 80° for 40 min or until syncope occurred. Time domain indices included RR interval, SDNN, RMSSD, pNN50. An autoregressive model was used to calculate power spectra. LFP (.04-.l5Hz), HFP (.15-.4OHz), and TP (.0l-.4OHz) were compared.

Results: 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt fall in blood pressure and heart-rate associated with loss of consciousness. One CFS patient had a normal HUT.25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities and edema indicated venous pooling in many of these. None of the control or simple faint patients experienced comparable acral or tachycardic findings. All time domain indices of HRV were decreased compared with either healthy control or syncopal control patients. LFP, HFP and TP were markedly depressed for CFS patients. HR and BP reponse during tilt and corresponding baseline spectral data are shown in the figure.

Conclusion: We conclude that chronic fatigue syndrome in adolescents is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS has heart-rate and blood pressure suggesting the orthostatic tachycardia syndrome and HRV abnormalities consistent with a partial autonomic defect. Such a defect may contribute to symptomatology in these patients.

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