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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-1beta, IL-8, and TNF-alpha. 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.

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.

Unlabelled: The current experiment examined the effects of exogenous testosterone (T) on spermatogenesis in rats with spinal cord injury (SCI) and their relationship with the cellular distribution of a cyclic AMP-responsive element modulator (CREM) in testicular cells. Implantation of T-filled Silastic capsules (TCs, 1-20 cm) resulted in dose-dependent, biphasic changes in testicular T levels and spermatogenesis in SCI rats. However, dose responsiveness of spermatogenesis to exogenous T in SCI rats differed from that in sham control rats. Specifically, implantation of 2-cm TCs enhanced the effects of SCI on spermatogenesis, resulting in total regression of the seminiferous epithelium. Although 3-cm TCs maintained complete spermatogenesis in sham control rats, this regimen failed to support complete spermatogenesis in SCI rats. Although complete spermatogenesis was maintained in SCI rats given 5-20-cm TC implants, various abnormalities persisted. Cellular distribution of CREM remained normal in SCI rats but was altered in those SCI rats that received 3- or 5-cm TC implants. Such effects were associated with reduced CREM proteins in testicular tissues. These results were consistent with altered cAMP signaling and its regulation in testicular cells after SCI and provided possible mechanistic explanations for the effects of SCI on spermatogenesis., Conclusion: SCI resulted in changes in the responsiveness of spermatogenesis to exogenous T. These effects were associated with altered cAMP/CREM signaling in testicular cells. Further studies, including a study of the relationship between serum T levels and normalcy of sperm functions and the role of neural-endocrine interactions in mediating the effects of SCI on spermatogenesis and sperm function, are needed so that therapeutic regimens can be designed for clinical use.

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.

Our previous studies demonstrated various abnormalities in spermatogenesis after spinal cord injury (SCI) in cord-transected rats. In this study, we examined whether abnormalities in spermatogenesis in SCI rats were related to the degree of SCI. We used spinal cord-contused (SCC) rats as a model. Adult male Sprague-Dawley rats were subjected to various degrees of cord contusion caused by the weight of a rod dropped from different heights (12.5, 25, 50, and 75 mm) using a New York University IMPACTOR. Testicular histology revealed persistent complete spermatogenesis in all SCC rats 4, 8, or 14 weeks after cord contusion regardless of the extent of SCI. Northern blot complementary DNA (cDNA) hybridization revealed transient but significant decreases in the levels of Sertoli cell-specific transcripts in SCC rats. In addition, levels of messenger RNA (mRNA) transcripts for germ cell-specific transition protein-2 and protamine-1 were consistently decreased in these rats. Such effects were related to the height of the weight drop and were associated with reduced levels of mRNA for cyclic adenosine monophosphate (cAMP) responsive element modulator (CREM). These results demonstrated specific effects of SCI on spermiogenesis and were consistent with altered cAMP signaling in testicular cells after SCI. Sperm motility was also significantly decreased in SCC rats and was related to the height of weight drop. Normal sperm motility recovered only in those rats injured by weight drop from 12.5- and 25-mm heights. In summary, current results demonstrate persistent abnormalities in spermiogenesis and sperm motility in rats that suffered spinal cord contusion by weight drop. Such effects were related to the height of the weight drop and thus to the extent of SCI.

Introduction: Earlier studies demonstrated that the effects of spinal cord injury (SCI) on spermatogenesis were associated with altered Sertoli cell responses to treatment with follicle-stimulating hormone (FSH) and/or testosterone (T). Because of the importance of the cyclic adenosine 3',5'-monophosphate (cAMP) signal pathway in hormonal actions on Sertoli cells and spermatogenesis, the purpose of this study was to determine whether cAMP signaling in testicular cells is altered after SCI., Methods: Rats with SCI were treated with FSH, T, or FSH + T for 7 or 14 days. Northern blot cDNA hybridization was used to measure testicular levels of Sertoli and germ cell-specific transcripts encoded by genes that contain cAMP responsive element (CRE) and/or steroid hormone responsive element (HRE). Cellular distribution of CRE modulator (CREM) was determined by immunohistochemistry., Results: Treatment of sham control rats with FSH or T + FSH for 2 weeks resulted in decreases in mRNAs for CREM and CRE binding protein (CREB). Concomitantly, levels of mRNA for Sertoli cell inhibin alpha and germ cell-specific protamine 1 (Pm-1), transition protein 2 (TP-2), and lactate dehydrogenase C (LDHC) were all reduced. In contrast, identical FSH and/or T treatments resulted in increases in levels of CREM and CREB mRNAs in the testes of SCI rats; these effects were associated with similar changes in mRNAs for inhibin alpha, Pm-1, TP-2, and LDHC. The effects of SCI on CREM expression were corroborated by similar changes in its distribution in testicular cells., Conclusion: SCI is associated with changes in FSH and/or T regulation of cAMP/CRE and HRE signaling in testicular cells. These effects may mediate the effects of SCI on spermatogenesis.

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), alpha-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 microg/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., (Copyright 2002 S. Karger AG, Basel)

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.

To date, the search for the clock component that is both necessary and sufficient for generation of circadian rhythms has relied primarily on experimental interventions such as lesions and transplantation of fetal SCN. While these approaches have been fruitful, lesions disrupt adjacent host tissue and fiber pathways, and donor tissue is likewise subject to trauma during harvest and transplantation. The current investigation has used congenitally anophthalmic (eyeless) mice to ask whether VIP-IR SCN neurons are necessary and sufficient for generation of circadian rhythms. In this animal model, arrhythmic mice occur naturally, together with their rhythmic littermates. We have combined recording of wheel-running activity with light microscopic immunocytochemistry for vasoactive intestinal polypeptide (VIP) and cytoarchitectural analysis of the suprachiasmatic nuclei (SCN) in rhythmic and arrhythmic anophthalmic mice. Our data provide the first definitive evidence that the presence of VIP neurons in the SCN is not sufficient for generation of circadian locomotor rhythms.

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.

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.

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.

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., (Copyright 2001 S. Karger AG, Basel)

Exposure of rats to inescapable stressors (IS) results in persistent elevations in plasma corticosterone (CORT), which are selective to the trough of the circadian rhythm. Although affective disorders (depression, anxiety) in humans are also characterized by persistent hypothalamic-pituitary-adrenal axis (HPAA) activation, the predominant measure of HPAA activation in clinical studies is 24-h urinary cortisol. To facilitate interspecies comparisons regarding the persistent effects of stress on HPAA activity, we compared the effects of IS on plasma and urinary CORT in rats. Male Sprague-Dawley rats were exposed to three 2-h sessions of IS (40, 2.0 mA tailshocks) or remained in their home cages. The 24-h urine samples were collected daily from 2 days prior to stress to 5 days after stressor cessation, then weekly for 3 weeks. In addition, plasma samples were obtained at 08:00 (trough) and 20:00 hours (peak) for the first 3 days after stressor cessation and weekly for 3 weeks thereafter. Consistent with our earlier work, plasma CORT elevations were apparent in the trough, but not the peak samples for 3 days after stressor cessation. The 24-h urinary CORT levels were elevated during stressor exposure, and remained elevated for 3 days after stressor cessation. Persistent stress-induced urinary CORT elevations in rats are reminiscent of the clinical HPAA abnormalities described for major depression and affective disorders.

Many researchers have studied acute responses to stress in animals and how they are modified by prior stressor exposure, but relatively few have examined whether responses to stressors might last for prolonged periods of time. We have previously demonstrated that trough plasma corticosterone levels in rats are elevated for three to five days after single or repeated exposures to mild restraint and inescapable tailshock. The current study measured other aspects of the adrenal axis, and activity in other neuroendocrine systems, 24 hours after one or three consecutive exposures to the same stress paradigm. The data indicated persistent activation of the adrenal axis and prolactin levels, whereas the thyroid and reproductive hormone axes were inhibited after either one or three stress sessions. These changes are remarkable in that one would have expected acute responses to even intense stressors to have ended within hours after the end of the stressor. It will be important to understand the interactions among these responding neuroendocrine systems and to know how long such persistent changes last. Finally, it will be critical to understand the relative contributions of neuroendocrine and psychological factors in maintaining these persistent neuroendocrine changes after exposure to intense stressors.

The detrimental effects of spinal cord injury (SCI) on spermatogenesis in the rat can be attenuated by exogenous testosterone (T) but enhanced by exogenous follicle-stimulating hormone (FSH). These results suggest that T-dependent cellular events may be involved in testicular injury after SCI and that such events may be associated with modification of FSH effects on Sertoli cell function. The current study compared the responses of Sertoli cells to exogenous T and FSH after SCI or sham surgery using steady-state levels of Sertoli cell protein mRNA transcripts as markers of responsiveness. Rats underwent sham surgery or SCI and then were treated for 7 or 14 days with T-filled silastic capsules (2 x 5 cm) and/or daily injections of 0.1 units of porcine FSH. Vehicle-treated control rats received 5-cm empty capsules and daily injections of saline vehicle. Two weeks after sham surgery, levels of mRNA for the androgen receptor (AR), FSH receptor (FSHR), androgen-binding protein (ABP), or sulfated glycoprotein (SGP)-2 in the testis were unaffected by T or FSH alone. Testosterone alone, however, significantly decreased transferrin (Trf) mRNA levels in the testis (P: < 0.01). The combination of T and FSH treatments resulted in significant decreases in levels of the above transcripts (P: < 0.05; P: < 0.01). Seven days after SCI, the testes of vehicle-treated SCI rats had higher levels of AR and SGP-2 mRNA than did those of sham control rats (P: < 0.01); such effects were transient and disappeared by Day 14 post-SCI. Testosterone treatment of SCI rats for 7 days resulted in decreases in mRNA levels for AR and Trf in the testes (P: < 0.01) but increased testicular levels of mRNAs for FSHR and SGP-2 in SCI rats. Follicle-stimulating hormone treatment for 7 days prevented the increase in AR mRNA that was seen in the testis of untreated SCI rats and increased levels of ABP and SGP-2 mRNAs in SCI rats (P: < 0.01). Follicle-stimulating hormone treatment of SCI rats did not affect FSHR mRNA levels by itself, but it blocked the stimulatory effect of T on FSHR and SGP-2 mRNAs. Fourteen days after SCI, testicular AR mRNA levels were not affected by T alone, but they increased in those rats that received FSH with or without concurrent T treatments (P: < 0.05). In contrast to their effects in sham control rats, T or FSH alone or in combination resulted in significant increases in testicular levels of ABP, SGP-2, and FSHR mRNAs (P: < 0.05). At this time, Trf mRNA in the testis of SCI rats was also suppressed by T (P: < 0.05), as it did in sham control rats, but Trf mRNA was increased by the FSH (P: < 0.01) that had inhibited this transcript in the testes of sham control rats. The effects of FSH on the Sertoli cell transcripts in SCI rats were either attenuated or blocked when T was given concurrently. In addition, testicular and serum T levels in those SCI rats that received FSH (alone or in combination with T) for 14 days were significantly increased, an effect that was not seen after sham surgery. These findings demonstrate that hormonal regulation of both Sertoli and Leydig cells was altered during the acute phase of SCI. Such changes may modify the functions of both cell types, thereby affecting the endocrine and/or paracrine microenvironment within the seminiferous epithelium. These effects could impair the functional capacity of Sertoli cells and contribute to impairment of spermatogenesis after SCI.

In the rat, regression of spermatogenesis during the chronic stages of spinal cord injury (SCI) occurs in the presence of normal function of the pituitary-testis hormone axis, thus suggesting that nonendocrine mechanisms might be involved. The current study examined whether disruption of neural input to the testis contributes to the cascade that leads to the regression of spermatogenesis. Four weeks after denervation of the superior spermatic nerve (SSN), testis weight was 25% lower (p < 0.01) than that of the contralateral sham-operated testis. Defects in spermatogenesis including phagocytosis of mature spermatids, vacuolization of spermatid nuclei, delayed spermiation and incomplete cellular associations were observed in >60% of the tubules. In the remaining 30-40% of tubules, the seminiferous epithelium was severely regressed. While cutting the inferior spermatic nerve (ISN) alone did not affect spermatogenesis significantly, it enhanced the effect of SSN denervation on both spermatogenesis and testis weight (p < 0.01). Spermatogenesis was totally regressed in the SSN/ISN-denervated testes. At this time, quantitatively normal spermatogonial proliferation was maintained in SSN- or ISN-denervated testes. Twelve weeks after surgery, regression of the seminiferous epithelium characterized by absence of proliferating spermatogonia, while undifferentiating spermatogonia were present, was observed in all SSN-denervated testes. At this time, regression of the seminiferous epithelia also occurred in >30% of the tubules in ISN-denervated testes. At both times, serum follicle-stimulating hormone, luteinizing hormone and testosterone levels were normal and >60% of normal testicular testosterone concentrations were maintained in the denervated testes. These results indicate that disruption of neural input to the testis is not a cause for the decrease in spermatogonial proliferation during the acute phase of SCI, but may contribute to the chronic effects of SCI on spermatogenesis., (Copyright 2000 S. Karger AG, Basel)

Objective: The objective of this study was to examine whether inappropriate cardiovascular responses to stressors may underlie symptoms in Gulf War veterans with chronic fatigue., Methods: Psychophysiological stress testing was performed on 51 Gulf War veterans with chronic fatigue (using the 1994 case definition of the Centers for Disease Control and Prevention) and 42 healthy veterans. Hemodynamic responses to cold pressor, speech, and arithmetic stressors were evaluated using impedance cardiography., Results: Veterans with chronic fatigue had diminished blood pressure responses during cognitive (speech and arithmetic) stress tests due to unusually small increases in total peripheral resistance. The cold pressor test, however, evoked similar blood pressure responses in the chronic fatigue and control groups. Low reactivity to cognitive stressors was associated with greater fatigue ratings among ill veterans, whereas an opposite relation was observed among healthy veterans. Self-reported neurocognitive decline was associated with low reactivity to the arithmetic task., Conclusions: These results suggest a physiological basis for some Gulf War veterans' reports of severe chronic fatigue. A greater deficit with responses processed through cerebral centers, as compared with a sensory stimulus (cold pressor), suggests a defect in cortical control of cardiovascular function. More research is needed to determine the specific mechanisms through which the dissociation between behavioral and cardiovascular activities identified in this study may be contributing to symptoms in Gulf War veterans.

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 x 2 (stress x 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.

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.

The purpose of this study was to determine whether Gulf War Illness (GWI) can be explained by the presence of psychiatric disorders as assessed by DSM-III-R. To reduce the heterogeneity amongst Persian Gulf War veterans with GWI (PGV-F), only those were studied who presented with severe fatigue as a major complaint and also fulfilled clinical case definitions for Chronic Fatigue Syndrome, Idiopathic Chronic Fatigue, and/or Multiple Chemical Sensitivity. A total of 95 Registry PGVs were examined; 53 presented with GWI and 42 did not report any post-war health problems (PGV-H). All subjects were assessed for the presence of DSM-III-R Axis I psychiatric disorders. Compared to PGV-Hs, 49% of PGV-Fs had similar post-war psychiatric profiles: either no, or only one, psychiatric disorder was diagnosed. Psychiatric profiles of the remaining 51% of PGV-Fs were significantly different from PGV-Hs in that most of these veterans suffered from multiple post-war psychiatric diagnoses. The presence of psychiatric disorders as assessed by DSM-III-R criteria cannot explain symptoms of Gulf War Illness among all Persian Gulf veterans with severe fatiguing illness.

Autonomic evaluation using the heart rate spectrum is sensitive to changes in breathing parameters, but few studies using this technique have controlled both the rate and depth of breathing. Fewer still have also measured or controlled inspiration and expiration times, or end-tidal carbon dioxide. This study describes the development of a digital instrument that can be used to alter tidal volume, ventilation rate and the time of inspiration and expiration with paced breathing visual templates displayed on a computer monitor. The digital instrument runs during data acquisition and displays the ventilatory signal from the subject superimposed on the paced breathing templates. Thus, adjustment of ventilatory parameters is achieved by matching the actual breathing signal to the target template. By regulating the ventilation rate and the tidal volume, end-tidal carbon dioxide could be increased or decreased in small increments. This instrument provided ventilatory control to investigate the effects on the heart rate spectrum of breathing depth, ventilation rate, end-tidal carbon dioxide and the time of expiration.

Causes of poor semen quality following spinal cord injury (SCI) are not known. One possible reason, based upon studies that reported improved semen quality in SCI men after several induced ejaculations, is delayed epididymal sperm transport. Our study was designed to establish baseline epididymal sperm transport values in the Sprague Dawley rat and evaluate effects of SCI on this process. Spermatozoa protamine was labeled with tritiated arginine, and the rats were sacrificed various times after injection. Each epididymis was divided into six equal sections from proximal to distal. Sperm tails were dissolved with 8 molar (M) urea in the presence of 2 mM dithiothreitol (DTT); sperm heads were collected by centrifugation (3,000 rpms, 10 min.). The radioactivity in sperm heads from each section was counted and expressed as counts per million sperm heads. To account for different rates of labeled arginine incorporation, the percentage of counts per million sperm heads in each section was calculated relative to the total number of counts in all six sections. Our results showed there was an orderly progression of sperm through the epididymis. It took 8 days for labeled sperm to enter the epididymis and 28 days to peak in the caudal (tail) section in non-SCI rats. Stasis was present 10 days after T-9 SCI in rats compared with transport in sham controls. This was evidenced by a significant increase in the percentage of labeled sperm in proximal sections of the epididymis (sections 1, 2, and 4) in T-9 transected animals (p < 0.01). If similar stasis occurs in SCI men, it could obviously contribute to poor semen quality. However, it remains to be determined how long this stasis persists after SCI in rats.

Although it is more common to study the effects of light on circadian systems, nonphotic stimuli can also influence and entrain circadian clocks. Because anophthalmic mice (ZRDCT-AN) have a genetic mutation that prevents the development of the eyes, they do not respond to light or entrain to light-dark cycles. Thus, entrainment of anophthalmic mice requires a nonphotic zeitgeber (entraining stimulus). In the current study we attempted to entrain sighted and anophthalmic mice of the same strain, using restricted access to an unlocked running wheel as the zeitgeber. First, free-running rhythms were established. The running wheels were then locked, and unlocked only from 0930-1130 h each day. Finally, a postentrainment free run was measured. In one group of animals, body temperature and general activity were measured using a Minimitter telemetry system. In another, general activity was measured by a sensitive force plate beneath the cage. Running-wheel activity was recorded in both groups. The force plate proved satisfactory for observing the behavior of the circadian system during wheel locking, and preferable to the temperature transmitters for long-term studies because the battery life of the mouse temperature transmitters was limited. Both sighted and anophthalmic mice were able to entrain to restricted wheel access, although not all animals responded. Mice that did not entrain showed either no effect of wheel locking or exhibited masking.

Background: Some research immunologists have suggested that major depression amd chronic fatigue syndrome (CFS) are characterized by immune activation. To test this hypothesis, we compared immunological function in patients with major depression and in patients with CFS who developed major depression after the onset of CFS to that of sedentary healthy controls., Methods: Subjects completed the Centers for Epidemiological Study-Depression (CES-D) questionnaire and allowed venisection. We performed flow cytometric analysis on 13 groups of white blood cells and used a reverse transcriptase PCR method to assay m-RNA of eight cytokines., Results: CES-D scores were high in both patient groups and did not differ significantly. We found no evidence for immune activation in either patient group. Instead the data suggested immunological downregulation in depression., Limitations: Not all the subjects in the two patient groups were off antidepressants., Conclusions: The data indicate that immune activation is not necessary in depression--either alone or with CFS.

The study was an examination of the effects of spinal cord injury (SCI) on spermatogenesis and Sertoli cell functions in adult rats with Sertoli cell-enriched (SCE) testes. The effects of SCI on the seminiferous epithelium were characterized by abnormalities in the remaining spermatogenic cells during the first month after SCI. Three days after SCI, serum testosterone levels were 80% lower, while serum FSH and LH levels were 25% and 50% higher, respectively, than those of sham control SCE rats. At this time, the levels of mRNA for androgen receptor (AR), FSH receptor (FSH-R), and androgen-binding protein (ABP) were normal whereas those for transferrin (Trf) had decreased by 40%. Thereafter, serum testosterone levels increased, but they remained lower than those of the sham control rats 28 days after SCI; and serum FSH and LH levels returned to normal. The levels of mRNA for AR, ABP, and Trf exhibited a biphasic increase 7 days after SCI and remained elevated 28 days after SCI. FSH-R mRNA levels were also elevated 90 days after SCI. Unexpectedly, active spermatogenesis, including qualitatively complete spermatogenesis, persisted in > 40% of the tubules 90 days after SCI. These results suggest that the stem cells and/or undifferentiated spermatogonia in SCE testes are less susceptible to the deleterious effects of SCI than the normal testes and that they were able to proliferate and differentiate after SCI. The presence of elevated levels of mRNA for Sertoli cell FSH-R and AR, as well as of that for the Sertoli cell proteins, in the SCE testes during the chronic stage of SCI suggests a modification of Sertoli cell physiology. Such changes in Sertoli cell functions may provide a beneficial environment for the proliferation of the stem cells and differentiation of postmeiotic cells, thus resulting in the persistence of spermatogenesis in these testes.

This study was conducted to evaluate the immunological response to an exhaustive treadmill exercise test in 20 female chronic fatigue syndrome patients compared to 14 matched sedentary controls. Venipuncture was performed at baseline and 4 min, 1 hr, and 24 hr postexercise. White blood cells were labeled for monoclonal antibody combinations and were quantified by FACsan. Cytokines were assayed utilizing quantitative RT/PCR. No group difference was seen in VO2peak (28.6 +/- 1.6 vs 30.9 +/- 1.2 ml.kg-1.min-1; P > 0.05). However, 24 hr after exercise the patients' fatigue levels were significantly increased (P < 0.05). The counts of WBC, CD3+ CD8+ cells, CD3+ CD4+ cells, T cells, B cells, natural killer cells, and IFN-gamma changed across time (P's < 0.01). No group differences were seen for any of the immune variables at baseline or after exercise (P's > 0.05). The immune response of chronic fatigue syndrome patients to exhaustive exercise is not significantly different from that of healthy nonphysically active controls.

Our previous studies have demonstrated that impaired spermatogenesis during the acute phase of spinal cord injury (SCI) is preceded by a transient (but significant) suppression of serum FSH, LH, and testosterone (T) concentrations. It is hypothesized that hormonal deprivation may impair Sertoli cell function, leading to the loss of spermatogonia, degeneration of spermatogenic cells, and eventual regression of the seminiferous epithelium. The current study examined the efficacy of exogenous T and FSH in the maintenance of spermatogenesis and Sertoli cell functions in SCI rats. Implantation of T capsules (TC, 2 x 5 cm) attenuated some of the spermatogenic lesions and maintained qualitatively complete spermatogenesis in all SCI rats 4 weeks after the surgery. In contrast, daily injections of 0.1 U of FSH alone, or in combination with TC implants, paradoxically enhanced the regression of spermatogenesis in SCI rats. At this time, the numbers of Aal, A1, and B spermatogonia and preleptotene spermatocytes in SCI rats have decreased by 25-30%. Though not prevented by TC implants, the decrease in Aal and A1 spermatogonia was attenuated by FSH alone but was further enhanced when FSH-treated rats also received TC implants. The intratesticular T concentration in untreated and FSH-treated SCI rats was not different from that of sham control rats, but it decreased by more than 95% in those SCI rats given TC implants alone. These results demonstrate that impairment of spermatogenesis during the acute phase of SCI is not related to the availability of FSH and/or T. Northern blot analysis revealed an increase in androgen receptor messenger RNA (mRNA) in the testis of SCI rats; this increase was prevented by TC implants but persisted when FSH was also given. In contrast, the levels of FSH-receptor, androgen binding protein, and transferrin mRNA were not affected by SCI but were significantly higher in those SCI rats given FSH alone or in combination with TC. TC implants alone suppressed mRNA levels of transferrin in testes of SCI rats, without concomitant change in those for FSH-receptor and ABP. The changes in Sertoli cell responses to FSH and T, and perhaps other hormones, may alter signal events elicited by these hormones, thus contributing to abnormal epithelial environments and regression of spermatogenesis. Maintenance of spermatogenesis in SCI rats by exogenous T suggests the feasibility of using exogenous hormones to impede the detrimental effects of SCI on spermatogenesis. This approach may have clinical applicability for the preservation of spermatogenic functions in SCI men.

The purpose of this study was to evaluate immune function through the assessment of lymphocyte subpopulations (total T cells, major histocompatibility complex [MHC] I- and II-restricted T cells, B cells, NK cells, MHC II-restricted T-cell-derived naive and memory cells, and several MHC I-restricted T-cell activation markers) and the measurement of cytokine gene expression (interleukin 2 [IL-2], IL-4, IL-6, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) from peripheral blood lymphocytes. Subjects included two groups of patients meeting published case definitions for chronic fatigue syndrome (CFS)-a group of veterans who developed their illness following their return home from participating in the Gulf War and a group of nonveterans who developed the illness sporadically. Case control comparison groups were comprised of healthy Gulf War veterans and nonveterans, respectively. We found no significant difference for any of the immune variables in the nonveteran population. In contrast, veterans with CFS had significantly more total T cells and MHC II+ T cells and a significantly higher percentage of these lymphocyte subpopulations, as well as a significantly lower percentage of NK cells, than the respective controls. In addition, veterans with CFS had significantly higher levels of IL-2, IL-10, IFN-gamma, and TNF-alpha than the controls. These data do not support the hypothesis of immune dysfunction in the genesis of CFS for sporadic cases of CFS but do suggest that service in the Persian Gulf is associated with an altered immune status in veterans who returned with severe fatiguing illness.

Troops in the Persian Gulf War have registered complaints consistent with CNS dysfunction that emerged after returning from the Gulf. A common experience among Persian Gulf War veterans was exposure to pyridostigmine bromide (PB) for prophylaxis against nerve gas exposure. To determine whether PB causes emergent CNS dysfunction, Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats were given PB for 7 consecutive days in their drinking water. The WKY, but not the SD, rats exhibited a delayed-onset, persistently exaggerated startle response. The WKY rats exhibited exaggerated startle responses that appeared 15 days after the end of PB treatment and were still evident 22 days after the end of treatment. Both the duration and the magnitude of the exaggerated startle responses were related to the dosage of PB. The PB-treated rats exhibited normal short-term and long-term habituation. However, exaggerated startle responses were related to the development of enhanced short-term sensitization. Treating the rats for a second time, 7 weeks after the end of the first PB treatment, induced an exaggerated startle response that appeared sooner and dissipated faster than was evident after the first PB treatment. Inasmuch as the WKY rat has inherently low butyrylcholinesterase activity, a scavenger for PB, these results suggest that prophylactic PB may influence CNS function in individuals with low butyrylcholinesterase activity. Elaboration of the factors that mediate enhanced sensitization in the WKY rat may provide insight into some of the complaints registered by veterans of the Persian Gulf War.

Circadian rhythms are generated by the suprachiasmatic nuclei (SCN) and synchronized (entrained) to environmental light-dark cycles by the retinohypothalamic tract (RHT), a direct pathway from the retina to the suprachiasmatic nuclei. In anophthalmic mice, the optic primordia are resorbed between embryonic days 11.5 and 13, before retinal ganglion cells emerge. Thus the retinohypothalamic tract, which is the primary "zeitgeber" for circadian rhythms in sighted animals, never forms, and there is no retinal or photic input to the circadian system. We have used wheel running activity, a highly consistent and reliable measure of circadian rhythmicity in rodents, to establish the properties of endogenous locomotor rhythms of anophthalmic mice. We have identified three subpopulations of anophthalmic mice: a) rhythmic with strong stable circadian period but significantly increased period length; b) rhythmic with unstable circadian period; and c) arrhythmic. Future correlation of locomotor rhythms with properties of the suprachiasmatic nuclei in these mice will clarify the relationship between generation and properties of circadian rhythms and the neuroanatomical, neurochemical, and molecular organization of the circadian clock.

Chronic fatigue syndrome, which can occur after acute infection and last for years, is characterized by severe and persistent fatigue. Others have reported decreases in mouse running activity following infection and have suggested this may provide an animal model for studying chronic fatigue. Voluntary running is a highly motivated activity in mice, which will often run 5-7 mi/day in our laboratory. Following 2 weeks of acclimation to running wheels with food and water available ad lib, female BALB/c mice received 0.2-mL tail vein injections of killed Brucella abortus (BA) or saline vehicle. Subsequently the effects on voluntary running and grooming behavior were determined. Injection of BA caused an immediate large decrease in running and a lack of grooming. Vehicle injections produced no changes in behavior. After the first several days of reduced running behavior, levels of running and grooming slowly returned back to normal over the next 2-4 weeks, with substantial individual differences in the rate of recovery. The pattern of running during recovery was intriguing in that BA mice first ran at normal levels just after the lights went out, but they stopped after only 1-2 h. As recovery proceeded, they gradually increased the duration of the running bout during the night. Because this model uses voluntary exertion and the ability to run for longer periods of time characterizes recovery, the model may be a good one for studying the biologic underpinnings of chronic fatigue.

Recently, we reported that changes in spermatogenesis in adult rats during acute phase (within 2 weeks) of spinal cord injury (SCI) were associated with a suppression of pituitary-testis hormone axis, and these effects mimic those that occur after hormone deprivation. In this study, we examined the long-term (>4 weeks) effects of SCI on spermatogenesis and its recovery. Results of this study reveal that while serum follicle stimulating hormone, luteinizing hormone, and testosterone levels in SCI rats recovered within 1 month after the injury, their spermatogenesis continued to regress. By 3 months, spermatogenesis in 70% of SCI rats has totally regressed, characterized by the absence of proliferating spermatogonia; these effects could not be prevented by an otherwise effective regimen of testosterone treatment. Sertoli cells in the regressed seminiferous tubules exhibited unusual behavior, characterized by the formation of multiple cell layers and/or aggregates that extended into the tubular lumen. Active spermatogenesis was observed in nine of the 19 SCI rats by 6 months, seven of which had complete spermatogenesis, but with persisting abnormalities. These results demonstrate that SCI results in total, but reversible, regression of spermatogenesis. Failure to prevent such effects by an otherwise effective exogenous testosterone regimen suggests that non-endocrine factors are involved in the SCI effects on spermatogenesis. The unusual Sertoli cell localization in the regressed testes may have been triggered by the loss of proliferating spermatogonia and may be involved in subsequent spermatogenic recovery.

The purpose of this study was to determine if Gulf War veterans with complaints of severe fatigue and/or chemical sensitivity (n = 72) fulfill case definitions for chronic fatigue syndrome (CFS) and/or multiple chemical sensitivity (MCS) and to compare the characteristics of those veterans who received a diagnosis of CFS (n = 24) to a group of non-veterans diagnosed with CFS (n = 95). Thirty-three veterans received a diagnosis of CFS with 14 having MCS concurrently; an additional six had MCS but did not fulfill a case definition for CFS. The group of fatigued veterans receiving a diagnosis of CFS was comprised of significantly fewer women and fewer Caucasians than the civilian group, and significantly fewer veterans reported a sudden onset to their illness. Veterans with CFS had a milder form of the illness than their civilian counterparts based on medical examiner assessment of the severity of the symptoms, reported days of reduced activity, and ability to work. Since CFS in veterans seems less severe than that seen in civilians, the prognosis for recovery of veterans with this disorder may be better.

Cardiomyopathic hamsters (CMH) develop heart disease early in life which leads to congestive heart failure and death as these hamsters age. We have previously shown that living in constant light or other non-24-h light-dark (LD) cycles can increase longevity in these hamsters, and the current experiment examined potential mechanisms for this effect. Thus, CMH were orchidectomized, pinealectomized, or given melatonin treatment and then placed on either 1:23 or 1:23.6 LD cycles. Orchidectomy had no effect on longevity in either LD cycle, but in 1:23.6 it did lead to death with a greater degree of heart failure. On the other hand, pinealectomy of 1:23 CMH led to changes in life span similar to those produced by placing the hamsters in 1:23.6. Moreover, melatonin implant treatment of CMH in 1:23.6 led to changes in life span that were similar to those caused by life in 1:23, at least over the first half of the survival curves. Thus, it appears that the pineal gland and melatonin may be involved in mediating the effects of non-24-h LD cycles, whether these effects are beneficial or detrimental. In addition, the testes and testosterone appear to have no role in mediating these effects. These data suggest that inhibition, rather than stimulation, of pineal function might be beneficial for those with congestive heart failure, but further experiments are necessary to clarify when during the disease process potential treatments might be helpful.

The prostate is one of the male accessory sex glands that produce fluid components of the seminal plasma. In addition to androgen, a normal innervation of the prostate is believed to be important for maintaining normal function of the prostate. Previously we noted that, in the rat, the weight of the prostate decreased following surgically induced spinal cord injury (SCI). This observation suggests that growth, and possibly function, of the prostate may be compromised after SCI. To explore this possibility, we examined the effects of SCI on the androgen-related biochemical properties and morphology of the prostate in the rat at various times after surgically induced SCI. SCI resulted in an acute decrease in prostate weight and an increase in steady state level of mRNA for testosterone-repressed prostate message 2 (TRPM 2) during the first 2 weeks postinjury. These changes perhaps relate to an increase in cell death or a decrease in secretory activity due to an acute suppression of serum testosterone after the injury. Concomitantly, there was a transient, but significant, decrease in the steady state level of androgen receptor (AR) mRNA in the prostate during the first 2 weeks after SCI, an indication of an altered autoregulation of AR by its own ligand. Despite the fact that growth of the prostate, as indicated by weight increase, in SCI rats resumed 2 weeks postinjury, prostate weights were persistently lower in SCI rats than sham-operated controls for at least 3 months. Furthermore, prostate TRPM 2 mRNA levels remained elevated throughout the recovery period even after a normal prostate weight had been restored. In addition, a decrease in the height of ventral prostate epithelial cells was noted in SCI rats 28 and 90 days postinjury. These results demonstrate a prolonged effect of SCI on prostate function. These findings and our unreported observation of persistently smaller seminal vesicles in the same groups of SCI rats suggest that functions of male accessory sex glands may also be compromised after SCI. These changes may affect biochemical properties of the secretory products of these glands and may provide some explanation for the reported changes in the composition of the seminal plasma and abnormal sperm motility seen in the semen of SCI men.

Objective: Our previous work showed that stress sensitized the vessels of cardiomyopathic hamsters (CMHs), but only hamsters in the lesion-forming period of their life. We hypothesized that we would find an interaction between stressor intensity and microvascular vulnerability., Method: Male CMHs at ages of 1.5, 2.5, and 3.5 months were stressed with supine immobilization for five consecutive days. Stressor intensity was manipulated by immobilizing groups of CMHs at room temperature for 0 minutes, 15 minutes, 30 minutes, 1 hour, or 2 hours. CMHs were anesthetized and sacrificed 5 days after stress, and their hearts were perfused using a modified Langendorff system. Body weight changes and baseline coronary vascular resistance (CVR) were recorded, and CVR was also measured after coronary artery infusion of arginine vasopressin (AVP)., Results: Stress produced no effect on coronary vasculature in 1.5-month-old CMHs. In 2.5-month-old CMHs, only the two highest-intensity stressors enhanced coronary reactivity to AVP. In 3.5-month-old CMHs, higher-intensity stressors produced a marginal AVP-induced increase in CVR; but this marginal increase was significantly lower than the increases seen with the two highest-stressor intensities in the 2.5-month-old CMHs., Conclusion: The stress-induced coronary hyperreactivity to AVP seen in 2.5-month-old CMHs diminished when microvascular vulnerability was lower in 3.5-month-old CMHs. For 1.5-month-old CMHs, the resting CVR was extremely high, so that the addition of stress produced no further increase. Thus, stressor intensity interacted with microvascular vulnerability to alter the consequences of stress.

In previous experiments we have shown that hamsters with inherited heart disease--cardiomyopathic hamsters (CMHs)--live longer if they spend their lives in an environment devoid of time cues. The purpose of this experiment was to test the several hypotheses by which life in constant light could extend life in CMHs. To do this, CMHs were allowed to spend their lives in one of six different lighting conditions: constant light, LD 12:12, LD 23:1, LD 1:23, LD 1:23.2, and LD 1:23.6. The only schedule to produce a significant extension of life was LD 1:23.6; in contrast to LD 1:23.2, this schedule is photostimulatory. Of the hypotheses tested to evaluate the life-enhancing effects of constant light, support was found for only the one stating that non-24-h LD regimens are health enhancing. Although some evidence was found relating testicular size to life span, dissociations between these variables indicate that testicular function does not play an overriding role in modulating the phototherapeutic effects.

Our earlier work showed that stress had progressively more serious consequences in a hamster model of congestive heart failure as the magnitude of heart failure worsened. Based on that study, we hypothesized that the intensity of the stressor used might play an important part in determining this outcome as well as in influencing coronary reactivity to arginine vasopressin (AVP). Cardiomyopathic (2.5, 6.5, and 10 months) hamsters (CMHs) were stressed with a 2-hr period of supine immobilization for five consecutive days. Stressor intensity was increased by exposing the hamsters to progressively longer periods at 4 degrees C: the low stress group was never put in the cold; the moderate stress group was exposed to cold for 1 hr, and the high stress group for 2 hr. CMHs were anesthetized and sacrificed 5 days after stress, and their hearts were perfused using a modified Langendorff system. Maximum +/- dP/dt, developed pressure, ventricular relaxation time, (T), and coronary vascular resistance (CVR) were recorded, and CVR was also measured following coronary infusion of AVP. Stressor intensity had no effect on cardiac mechanics in 2.5-month CMHs. In 6.5-month CMHs, only the high-intensity stressor impaired ventricular mechanics (decreased maximum +/- dP/dt and developed pressure, increased T; P < 0.05), while low and moderate stress produced no effects. In 10-month CMHs, stress at all intensities exacerbated ventricular dysfunction (decreased maximum +/- dP/dt and developed pressure; P < 0.05). These results support our first hypothesis that stressor intensity interacts multiplicatively with severity of the underlying disease to influence the course of heart failure. However, our second hypothesis was not supported, because stress-regardless of intensity-affected reactivity of the coronary vasculature to AVP only in 2.5-month CMHs. A further test of the relation of stressor intensity and coronary vascular reactivity requires study of additional groups of CMHs during the period of their disease characterized by coronary vasospasm.

Because of recent interest in the effects of physical exercise on immunologic function, we decided to use state-of-the-art methods to evaluate cytokines in the peripheral blood leukocytes (PBLs) of 7 men before and after a maximal treadmill stress test. Change in cytokine gene expression was quantified from PBLs using a reverse transcriptase polymerase chain reaction assay (RT-PCR). In contrast to reports on serum levels or using in vitro testing, direct gene expression of TNF-alpha decreased after the stress test (p < 0.008). However, the 47% decrease was relatively small and of questionable biological significance. Levels of IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-10, and INF-gamma did not change.

Objectives: Because cardiomyopathic hamsters (CMHs) in the lesion-forming period of their disease are more susceptible to the lethal effects of stress than older CMHs, we tested the hypothesis that different pathophysiological effects of stress may occur: coronary vasospasm in younger CMHs and congestive heart failure in older ones., Methods: CMHs aged 2.5 and 6.5 months were stressed with 2 h supine cold immobilization for 5 consecutive days. Three, 5 and 7 days after stress, the hearts were excised and perfused using a modified Langendorff system. Maximum +/- dP/dt, developed pressure, ventricular relaxation time (Tau) and coronary vascular resistance (CVR) were recorded and CVR was also measured following coronary infusion of arginine vasopressin (AVP)., Results: Stress produced ventricular dysfunction (decreased maximum +/- dP/dt, developed pressure, and increased Tau) in older CMHs (P < 0.05) but not in younger CMHs. Baseline CVR in younger CMHs was significantly higher than in older CMHs (P < 0.01) and AVP infusion produced a bigger increase in CVR in younger stressed CMHs than in either younger nonstressed or older stressed CMHs (P < 0.05)., Conclusion: The younger CMH heart exhibits greater resting vascular tone and stress produces coronary vasoconstriction that is consistent with coronary spasm. In contrast, the older CMH experiences a decrease in cardiac function which remains 7 days after stress and indicates an exacerbation of CHF from the mild form existing prior to stress. The lethal effects of stress may occur because of the activation of different pathological processes in younger and older CMHs.

Posttraumatic stress disorder (PTSD) may occur in humans exposed chronically to stressors or after a single exposure to a traumatic event. A distinguishing feature of patients with PTSD is an exaggerated startle response, evident long after the traumatic event. We have observed similar abnormalities in our animal model of a chronic stress state. Rats exposed to 3 days (3DS) of our stress regimen (2-hr sessions of 40, 2 mA tailshocks) have exhibited a consistent pattern of persistent physiological and behavioral abnormalities including an exaggerated startle response several days after stressor cessation. In contrast, rats exposed to a single stress session (1DS) have exhibited many, but not all, of the persistent abnormalities displayed by 3DS rats. The present experiment compared the startle responding of 3DS and 1DS rats 4, 7, and 10 days after stressor cessation. Consistent with previous work, stressed rats exhibited elevated basal plasma corticosterone (CORT) levels the first day poststressor. These CORT levels were sensitive to the number of stressor exposures with higher CORT levels in 3DS rats than in 1DS rats. As for startle responding, the 1DS rats exhibited an exaggerated startle response 7 days poststressor, whereas startle sensitization was apparent 10 days poststressor in 3DS rats. Thus, the appearance of an exaggerated startle response after stressor cessation appears to be related to the number of stress session exposures. These animal models, the 3DS and 1DS rats, may be useful to gain insight into the neurobehavioral changes associated with PTSD.

The present study has combined recording of circadian locomotor rhythms with light microscopic immunocytochemistry for vasoactive intestinal polypeptide (VIP) in the suprachiasmatic nucleus (SCN) of congenitally anophthalmic mice. These mice, which never develop retinae or optic nerves and do not perceive light, are thus in constant darkness. Our data show a circadian rhythm in expression of VIP in the SCN of anophthalmic mice--expression is maximal during late subjective night/early subjective day and minimal in late subjective day/early subjective night. These observations support the hypothesis that expression of VIP is related to regulation of circadian rhythms by the SCN.

For 5 days, rats were exposed to shocks that were signalled by a light 0, 33, 66, or 100% of the time. Basal hormone levels and responses to a light-shock pair were measured daily. Greater predictability was associated with higher basal plasma corticosterone and norepinephrine levels indicative of chronic stress. Habituation of the corticosterone response was also less in the groups with greater predictability. However, predictability did not affect plasma prolactin or epinephrine responses. Because the endocrine systems responded differently, it is unlikely that the changes were due to a unitary process. Greater predictability appeared to be more stressful in this paradigm. Both associative and nonassociative factors have major roles in determining the hormonal responses to repeated presentation of stressors.