Objective: Two groups of Gulf War era veterans, one exhibiting blurred vision, balance problems/dizziness, tremors/shaking, and speech difficulty and a second group with post-traumatic stress disorder (PTSD), but not the neurologic syndrome, were assessed for organophosphate-detoxifying enzyme paraoxonase/arylesterase (PON1) and its Q/R isoforms, butyrylcholinesterase (BuChE) and its U/A isoforms and cytokines. Methods: Defibrinated peripheral blood was evaluated for enzymes and cytokines. Results: Trends toward elevation of Th2 cytokines interleukin-4 (IL-4) and IL-13 were observed in subjects with neurologic syndrome. Neither the activities nor isoforms of the enzyme, the neurologic symptoms, nor PTSD had any relationship to wartime deployment to the theater of combat. Conclusion: The negative outcomes described above suggest that exposure to organophosphates or other agents normally detoxified by PON1 and BuChE may not have contributed significantly to neurologic components of Gulf War Illness.

BACKGROUND Some think chronic fatigue syndrome (CFS) and fibromyalgia (FM) are variants of the same illness process. This would imply that CFS patients with and without comorbid FM have similar biological underpinnings. To test this, we compared serotonergic-based responses, plasma prolactin (PRL), and self-reported measures of fatigue to intravenous infusion of tryptophan among patients with CFS alone, CFS + FM, and healthy controls. METHODS Men and women with CFS alone or CFS + FM and healthy subjects, none with current major depressive disorder (MDD), were given 120 mg of L-tryptophan per kg lean body mass intravenously (i.v.). Before and after tryptophan infusion, blood samples were collected, and plasma PRL, tryptophan, and kynurenine concentrations were determined. RESULTS Women with CFS alone, but not CFS + FM, showed upregulated plasma PRL responses compared with controls. There were no differences among groups of men. Plasma tryptophan and kynurenine concentrations did not differ among groups. CONCLUSIONS These results indicate that women with CFS alone have upregulated serotonergic tone that is not seen in those with comorbid FM. The lack of effect in men suggests a mechanism that might explain, in part, the increased prevalence of CFS in women. The data support the interpretation that CFS in women is a different illness from FM.

We examined the pattern of cytokine secretion across the 24-hr day for women with widespread pain and tenderness having the diagnosis of fibromyalgia (FM) and matched healthy controls. Subjects were given time to habituate to being in a clinical research laboratory environment and then were sampled for cytokines without their being disturbed for a 24-hr period including an 8-hr sleep period. Cytokine levels were uniformly low but characterized by bursts of secretion. Bursting occurred either in singlets or in doublets with a range from 88 to 131 mins between doublet bursts. There was an element of synchronization of these bursts with most occurring at the beginning of sampling. FM patients showed a shift to increased IL-10 in the nighttime compared to controls. The relation between this anti-inflammatory cytokine to the pro-inflammatory cytokines studied also differed between groups: FM patients showed an increased ratio of IL-10 burst amplitude to that of pro-inflammatory cytokines IL-1β, IL-8, and TNF-α. We interpret this to indicate a skew away from the normal balance favoring pro-inflammatory cytokines in controls toward one favoring an anti-inflammatory response in FM. These changes toward anti-inflammatory predominance in FM may explain their common complaint of disturbed sleep because these cytokines are known to disrupt sleep.

OBJECTIVE:To assess whether differences in negative affect (NA) and chemical intolerance (CI) affect responses to chemical mixtures and stress in a controlled experimental model. METHODS:Participants were 130 nonsmoking, healthy women, recruited from a university community. Participants completed the Positive and Negative Affect Scale and the Chemical Odor Intolerance Index. In separate sessions 1 week apart, they were exposed to volatile organic compounds (VOCs), VOCs with ozone (VOCs+O3), and ambient or filtered air with a 1-minute spike of VOCs (masked clean air). During each session, half of the participants performed a videotaped speech stressor and half performed simple arithmetic. Before, during, and after each session, salivary cortisol samples were collected, and subjects completed neurobehavioral tests and used a ratio scale to rate physical, cognitive, and anxiety symptoms. RESULTS:Relative to low NA or low CI, neither the high NA nor the high CI groups reported significantly more symptoms in response to any exposure condition. High NA subjects reported more anxiety symptoms in response to the speech stressor but did not have higher cortisol than low NA subjects. High NA subjects, however, were more distressed by the experimental conditions than were low NA subjects. Low NA subjects reported more severe anxiety in the VOCs+O3 with psychological stress condition. CONCLUSIONS:Subjects high in NA were more anxious after a stressor but were not more physically symptomatic in response to increasing chemical exposures. A disposition toward high or low CI did not result in a differential symptomatic response to controlled chemical exposures.

ABSTRACT Arguments exist as to the cause of chronic fatigue syndrome (CFS). Some think that it is an example of symptom amplification indicative of functional or psychogenic illness, while our group thinks that some CFS patients may have brain dysfunction. To further pursue our encephalopathy hypothesis, we did spinal taps on 31 women and 13 men fulfilling the 1994 case definition for CFS and on 8 women and 5 men serving as healthy controls. Our outcome measures were white blood cell count, protein concentration in spinal fluid, and cytokines detectable in spinal fluid. We found that significantly more CFS patients had elevations in either protein levels or number of cells than healthy controls (30 versus 0%), and 13 CFS patients had protein levels and cell numbers that were higher than laboratory norms; patients with abnormal fluid had a lower rate of having comorbid depression than those with normal fluid. In addition, of the 11 cytokines detectable in spinal fluid, (i) levels of granulocyte-macrophage colony-stimulating factor were lower in patients than controls, (ii) levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls, and (iii) IL-10 levels were higher in the patients with abnormal spinal fluids than in those with normal fluid or controls. The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process.

Objective: A significant proportion of Gulf War veterans (GWVs) report chemical sensitivity, fatigue, and unexplained symptoms resulting in ongoing disability. GWVs frequently recall an association between diesel and petrochemical fume exposure and symptoms during service. The purpose of the present study among GWVs was to evaluate the immediate health effects of acute exposure to chemicals (diesel vapors with acetaldehyde) with and without stress. Methods: In a single, controlled exposure to 5 parts per million (ppm) diesel vapors, symptoms, odor ratings, neurobehavioral performance, and psychophysiologic responses of 12 ill GWVs (GWV-I) were compared with 19 age- and gender-matched healthy GWVs (GWV-H). Results: Relative to baseline and to GWV-H, GWV-I reported significantly increased symptoms such as disorientation and dizziness and displayed significantly reduced end-tidal CO2 just after the onset of exposure. As exposure increased over time, GWV-I relative to GWV-H reported significantly increased symptoms of respiratory discomfort and general malaise. GWV-I were also physiologically hyporeactive in response to behavioral tasks administered during but not before exposure. Conclusions: Current symptoms among GWV-I may be exacerbated by ongoing environmental chemical exposures reminiscent of the Gulf War. Both psychologic and physiologic mechanisms contribute to current symptomatic responses of GWV-I.

Abstract Objective: To develop a spinal cord injury (SCI) animal model for the study of bladder stones and compare this model with a non-SCI animal model. Methods: Small pieces of catheters were implanted into the bladders of Sprague-Dawley rats as a nidus for bladder stone formation. Three weeks later, the rats underwent an SCI surgery (SCI transection or sham SCI). Control rats had SCI surgery, but no catheters were implanted into their bladders. Main Outcome Measures: Bladder stone number, weight, and composition were determined in two groups of SCI and sham SCI animals: Group A (recent spinal shock: 2 weeks post-SCI/sham SCI surgery) and Group B(out of spinal shock: 3 weeks to 3 months post-SCI/sham SCI surgery). AX2 test was used to compare the incidence of bladder stones in SCI vs sham SCI animals. AStudent t test was used to compare the weight of bladder stones in the 2 groups. Results: Group A(recent spinal shock): Of the 20 SCI rats, 8 (40%) had stones. None of the sham SCI rats with implanted catheters (n = 5) had stones (0%). Group B(out of spinal shock): All 6 of the SCI rats with implanted catheters had stones (100%). Of the 10 sham SCI animals with implanted catheters, 3 (30%) had stones. Stones were more common in the SCI rats than in the sham SCI rats (X2., = 4.9, P < 0.05). The mean weight of the bladder stones in SCI rats (42.2 ± 16.3 mg) was greater than that in sham SCI rats (5.4 ± 1.5 mg) (P < 0.01). Group C (controls: SCI surgery, but no catheter implanted): At 3 weeks post-SCI, control rats had no stones (n = 7); control rats at 3 months post-SCI also had no stones (n = 9). Stone composition in the 3 sham SCI animals was calcium apatite (90%) and calcium oxylate (10%). In the 14 SCI rats, 10 had struvite stones (1 00%), 1 had struvite (70%) and carbonate apatite (30%) stones, 1 had brushite (100)% stones, and 2 had carbonate apatite (>90%) stones. Conclusion: Bladder stones occurred earlier and more frequently and attained a larger size in SCI rats with catheters compared with sham SCI rats with catheters. There were no stones in SCI rats without catheter implants, even at 3-month follow-up. The bladder stone composition in SCI rats was similar to that in humans with SCI. The Sprague-Dawley rat model appears to be an excellent animal model for the study of bladder stones following SCI. J Spinal Cord Med. 2003;26:65-68

Abnormal cardiovascular stress responses have been reported in Gulf War veterans with chronic fatigue. However, many of these veterans also suffer from posttraumatic stress disorder (PTSD), which could potentially explain the reported abnormalities. To test this hypothesis, 55 Gulf veterans (GVs) with chronic fatigue syndrome (CFS) or idiopathic chronic fatigue (ICF) were stratified into groups with (N=16) and without (N=39) comorbid PTSD, and were compared to healthy Gulf veterans (N=47) on cardiovascular responses to a series of stressors. The CFS/ICF with PTSD group had lower blood pressure responses to speech and arithmetic tasks, and more precipitous declines and slower recoveries in blood pressure after standing up than the controls. Similar trends in the CF/ICF group without PTSD were not significant, however. Both CFS/ICF groups had blunted increases in peripheral vascular resistance during mental tasks. However, only the veterans with comorbid PTSD had diminished cardiac output responses to the mental stressors and excessive vasodilatory responses to standing. Symptoms of posttraumatic stress were significant predictors of hypotensive postural responses, but only in veterans reporting a significant exposure to wartime stress. We conclude that comorbid PTSD contributes to dysregulation of cardiovascular responses to mental and postural stressors in Gulf veterans with medically unexplained fatiguing illness, and may provide a physiological basis for increased somatic complaints in Gulf veterans with symptoms of posttraumatic stress.

Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to have central cholinesterase inhibition properties under certain conditions (such as when ingested with other chemical compounds or following a high level of stress). Here we tested if stressing rats, using an intermittent 1 hr tailshock protocol, affected the degree of brain acetylcholinesterase (AChE) inhibition caused by a subsequent single injection of PB (2.0 mg/kg) or neostigmine bromide (NB, 0.32 mg/kg), another peripheral carbamate cholinesterase inhibitor. Stressed rats treated with PB had lower levels of AChE activity in the basal forebrain/striatum, but not in other brain areas. Stressed rats treated with NB did not show basal forebrain/striatum AChE activity changes but did show minor reductions of AChE activity in the cortex and cerebellum. These results confirm that prior stress can change the characteristic actions of certain peripherally acting drugs, thus possibly leading to unexpected central nervous system effects. Possible causes for these effects are discussed.

Study design: Randomized control. Objective: To examine the effects of testosterone replacement therapy (TRT) on skeletal muscle 11 weeks after complete SCI. Setting: Athens, Georgia USA. Methods: Soleus (SOL), gastrocnemius (GA), tibialis anterior (TA), vastus lateralis (VL) and triceps brachii (TRI) muscles were taken from twelve young male Charles River rats 11 weeks after complete SCI (T-9 transection, n=8) or sham surgery (n=4). Rats received either TRT (two 5 cm capsules, n=4) or empty capsules (n=8) implanted at surgery. Muscle samples were sectioned and fibers analyzed qualitatively for myosin ATPase and quantitatively for succinate dehydrogenase (SDH), α-glycerol-phosphate dehydrogenase (GPDH) and actomyosin ATPase (qATPase) activities using standard techniques. Results: SCI decreased average fiber size (49±4%) in affected muscles and the percentage of slow fibers in SOL (93±3% to 17±2%). In addition, there was a decrease in SDH and an increase in GPDH and qATPase activities across the four hind-limb muscles of the SCI animals. Fiber size in the TRI was increased (31±2%) by SCI while enzyme activities were not altered. Average fiber size across the four hind limb muscles was decreased by only 30% in TRT SCI animals and their SOL contained 39±2% slow fibers. TRT also attenuated changes in enzyme activities. There was no effect of TRT on the TRI relative to SCI. Conclusions: TRT was effective in attenuating alterations in myofibrillar proteins during 11 weeks of SCI in affected skelatal muscles. Sponsorship: Supported by a grant from The National Institutes of Health (HD-33738) and HD-37645 to KV, and HD-39676 to GAD.

Vaginocervical stimulation (VS) significantly elevated the concentration of oxytocin (OT) in spinal cord superfusates of 8 intact urethane-anesthetized rats measured 10–15 min after VS (median [interquartile range]: 1.7 [1.00–3.37] pg/ml) compared to that measured 10–15 min before VS (1.1 [1.01–1.40] pg/ml). When VS was administered once (n = 8), it produced a 55% increase over baseline values; when administered a second time 45 min later (n = 6), it produced only a 22% increase over pre-VS values. The effects of estrogen on the VS-induced release of OT were then investigated using ovariectomized rats that were treated either with estradiol benzoate (EB; 10 µg/100 g bw) (n = 6) or with an oil vehicle (n = 6) subcutaneously for 3 days. The EB treatment significantly elevated the basal levels of OT released into spinal cord superfusates above vehicle control levels. Within 5–10 min after the onset of VS, OT concentrations in the superfusates were significantly higher in EB-treated than in vehicle-treated rats. The vehicle-treated rats did not show a significant elevation in OT concentration following VS. To rule out the possibility that the posterior pituitary gland was the source of this OT, the effect of hypophysectomy (HYPOX) was assessed on the VS-induced release of OT into spinal cord superfusates and plasma. The concentration of OT in spinal cord superfusates of both the HYPOX (n = 5) and intact rats (n = 6) increased significantly from 5.8 [4.4–6.5] pg/ml pre-VS to 7.9 [6.7–10.3] pg/ml immediately after VS, and from 4.4 [3.8–5] pg/ml pre-VS to 5.1 [4.6–5.7] pg/ml immediately after VS, respectively. There was no significant difference in baseline levels of OT in cerebrospinal fluid between the two groups. By contrast, plasma OT levels, while significantly elevated in response to VS from 3.42 [2.9–5.34] pg/ml baseline to 7.25 [5.33–15.77] pg/ml in the intact group, failed to respond significantly to VS in the HYPOX group (n = 5). The present findings provide evidence of a direct estrogen-dependent release of OT within the spinal cord in response to VS, presumably via descending oxytocinergic neurons.

Exposure to inescapable stress elicits persistent effects on the physiology and behavior of rats. Elevated basal plasma corticosterone concentrations have been observed for several days after cessation of stress. In this study, we measured hormonal concentrations in multiple axes at multiple levels, 24 h after one or three consecutive exposures to the same stress paradigm. The data indicated persistent activation of plasma corticosterone and prolactin concentrations, whereas plasma triiodothyronine, thyroxine, luteinizing hormone, and growth hormone concentrations were inhibited after either one or three stress sessions. In addition, we isolated the effects of restraint/tail shock per se from the effects of being moved and exposed to other stressed rats, and from the effects of reduced feeding produced by our stress protocol. The data clearly indicated that the stress paradigm, rather than exposure to stressed rats or decreased nutrient intake, is necessary to induce the persistent physiologic changes we observe after stressor exposures.

Elevated basal plasma corticosterone concentrations have been observed for several days after the cessation of severe stress. In the present study, we examined whether or not the acute plasma corticosterone response to stress is necessary to elicit increased basal plasma corticosterone concentrations the following day. Pretreatment with metyrapone (100 m a g , intraperitoneal)1 h before inescapable stress (40 2mA tail shocks delivered over a 1-h period) (IS)blocked the acute plasma corticosterone response to IS. However, elevated basal plasma corticosterone concentrations still emerged the next day. These results suggest that the corticosterone response to stress, and its attendant feedback, are not necessary to produce persistent hypothalamic-pituitary-adrenal axis (HPAA) activation.

Annals of the New York Academy of SciencesVolume 933, Issue 1 p. 310-314 Central Nervous System Effects from a Peripherally Acting Cholinesterase Inhibiting Agent: Interaction with Stress or Genetics Kevin D. Beck, Corresponding Author Kevin D. Beck Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USAd Address for correspondence: Richard J. Servatius, Neurobehavioral Unit (127A), Veterans Affairs New Jersey Health Care System, East Orange, NJ 07018. Voice: 973-676-1000, x3678; fax: 973-395-7111. rjs@njneuromed.orgSearch for more papers by this authorGuanping Zhu, Guanping Zhu Department of Neuroscience, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USASearch for more papers by this authorDawn Beldowicz, Dawn Beldowicz Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USASearch for more papers by this authorFrancis X. Brennan, Francis X. Brennan Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USASearch for more papers by this authorJohn E. Ottenweller, John E. Ottenweller Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USA Department of Neuroscience, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USASearch for more papers by this authorRoberta L. Moldow, Roberta L. Moldow Department of Biology, Seton Hall University, South Orange, New Jersey 07079, USASearch for more papers by this authorRichard J. Servatius, Corresponding Author Richard J. Servatius Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USA Department of Neuroscience, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USAd Address for correspondence: Richard J. Servatius, Neurobehavioral Unit (127A), Veterans Affairs New Jersey Health Care System, East Orange, NJ 07018. Voice: 973-676-1000, x3678; fax: 973-395-7111. rjs@njneuromed.orgSearch for more papers by this author Kevin D. Beck, Corresponding Author Kevin D. Beck Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USAd Address for correspondence: Richard J. Servatius, Neurobehavioral Unit (127A), Veterans Affairs New Jersey Health Care System, East Orange, NJ 07018. Voice: 973-676-1000, x3678; fax: 973-395-7111. rjs@njneuromed.orgSearch for more papers by this authorGuanping Zhu, Guanping Zhu Department of Neuroscience, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USASearch for more papers by this authorDawn Beldowicz, Dawn Beldowicz Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USASearch for more papers by this authorFrancis X. Brennan, Francis X. Brennan Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USASearch for more papers by this authorJohn E. Ottenweller, John E. Ottenweller Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USA Department of Neuroscience, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USASearch for more papers by this authorRoberta L. Moldow, Roberta L. Moldow Department of Biology, Seton Hall University, South Orange, New Jersey 07079, USASearch for more papers by this authorRichard J. Servatius, Corresponding Author Richard J. Servatius Neurobehavioral Unit, Veterans Affairs New Jersey Health Care System, East Orange, New Jersey 07018, USA Department of Neuroscience, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USAd Address for correspondence: Richard J. Servatius, Neurobehavioral Unit (127A), Veterans Affairs New Jersey Health Care System, East Orange, NJ 07018. Voice: 973-676-1000, x3678; fax: 973-395-7111. rjs@njneuromed.orgSearch for more papers by this author First published: 25 January 2006 https://doi.org/10.1111/j.1749-6632.2001.tb05833.xCitations: 15Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume933, Issue1THE ROLE OF NEURAL PLASTICITY IN CHEMICAL INTOLERANCEMarch 2001Pages 310-314 RelatedInformation

Chronic fatigue (CF) is one of the most common conditions reported by Gulf War veterans. This study evaluated female sexual dysfunction (FSD) in veterans with or without complaints of CF. Subjects were screened for medical and psychiatric causes of CF. They included 22 healthy subjects and 26 with fatiguing symptoms. FSD was reported by 10% of controls and by 60% of the fatigued ( p < .002) while 19% versus 81% ( p < .001) noted decreased libido. FSD was more prevalent in fatigued veterans than in the controls. This relationship was not mediated by an Axis I diagnosis. This appears to be the first report of sexual dysfunction in CF.

An important question for researchers interested in long-term consequences of military service is the health outcome of symptomatic Persian Gulf War Veterans. From an original group of 76 Gulf War Veterans who received the diagnosis of severe fatiguing illness, we attempted to get 58 veterans to return to our center for a second evaluation. Thirteen returned. Two had recovered by the time of revisit, but the rest remained ill; however, only one was so ill as to be unable to work. The data suggest that the medical consequences of serving in the Persian Gulf are not transient. The difficulty in getting veterans to return to our center suggests potential problems in the proposed nation-wide longitudinal health outcome study of Persian Gulf War Veterans.

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by severe, unexplained fatigue and postexertional exacerbation of symptoms. We examined basal endocrine function in a group of CFS patients and a carefully matched group of sedentary controls. The subjects then completed a graded, maximal exercise test on a treadmill, and additional blood samples were drawn 4 min and a day after the end of exercise. There were no differences in basal hormone levels before exercise. Plasma adrenocorticotropin, epinephrine, prolactin and thyrotropin responses 4 min after exercise were lower in the CFS group, but the growth hormone response may have been exaggerated, and the plasma norepinephrine response was similar to that in controls. The next day, there were no differences in hormone levels between the groups, which suggests that long-term changes in endocrine function are unlikely to be a cause of the prolonged fatigue that occurs in CFS patients after a bout of exertion.

Elevated basal plasma corticosterone concentrations have been observed for several days after the cessation of severe stress. In the present study, we examined whether or not the acute plasma corticosterone response to stress is necessary to elicit increased basal plasma corticosterone concentrations the following day. Pretreatment with metyrapone (100 mg/kg, intraperitoneal) 1 h before inescapable stress (40 2mA tailshocks delivered over a 1-h period) (IS) blocked the acute plasma corticosterone response to IS. However, elevated basal plasma corticosterone concentrations still emerged the next day. These results suggest that the corticosterone response to stress, and its attendant feedback, are not necessary to produce persistent hypothalamic-pituitary-adrenal axis (HPAA) activation.

The fact that many patients with chronic fatigue syndrome (CFS) have an infectious like sudden onset to their illness has led to the hypothesis that CFS is a medical illness. If CFS were, on the other hand, a psychiatric disorder related to symptom amplification, one would expect illness onset to occur randomly over the calendar year. This study tested that hypothesis with 69 CFS patients whose illness was on the more severe side of the illness spectrum; all patients reported sudden illness onset with the full syndrome of sore throat, fatigue/malaise, and diffuse achiness developing over no longer than a 2-day period. Date of illness onset was distinctly nonrandom. It peaked from November through January and was at its lowest from April through May. These data support the hypothesis that an infectious illness can trigger the onset of CFS.

Pyridostigmine bromide (PB) is a reversible, peripherally active inhibitor of acetylcholinesterase (AChE) activity, and is recommended by the military as a pretreatment against potential nerve gas exposure. Recent evidence suggests that exposure to inescapable stressors allows PB to cross the blood–brain barrier, and thereby affect central AChE activity in mice. Here, we evaluated the functional impact of a stress/PB treatment interaction on acoustic startle responding and plasma butyrylcholinesterase (BuChE) activity in male Sprague–Dawley rats. To model the treatment protocol used by the military, PB was delivered in the drinking water of rats for 7 consecutive days. The morning after the start of PB treatment, and for the next 6 days, half the rats were exposed to 1 h of supine restraint stress. We therefore employed a 2 × 2 (stress × PB treatment) between-groups design. Exposure to supine stress alone induced a persistent decrease in plasma BuChE activity. Further decreases in BuChE activity were not observed in rats exposed to supine restraint and PB treatment. Exposure to stress also induced an exaggerated startle response, evident on the last day of stress and 24 h after stressor cessation. Treatment with PB alone produced an exaggerated startle response over the same time period, albeit to a lesser degree. Although treatment with PB concurrent with stress did not produce further changes in either BuChE activity or acoustic startle responding, stress-induced alterations in drinking behavior (and thereby the dose of PB ingested) may have affected these results. Persistent stress-induced reductions in BuChE activity may increase the risk of adverse reactions to cholinomimetics.