Methodological problems in the study of classical aversive conditioning of adrenocortical responses

The present studies were conducted to demonstrate classical aversive conditioning of a corticosterone stress response in male rats. In the first experiment animals exposed to an odor which had previously preceded tube restraint stress had significantly higher plasma corticosterone levels than animals which were probed with a novel odor, or animals in which stress was followed, rather than preceded, by the odor. Careful consideration of corticosterone responses obtained on different days during training made it impossible to conclude unequivocally that learning had occurred. A second experiment was designed specifically to deal with the problems raised by the first, but we were again unable to show rigorously that learning had taken place. However, with data and paradigms comparable to our own, other researchers have prematurely concluded that aversive visceral conditioning can occur. It is suggested that the methodological considerations raised in the present studies could also be important for interpreting other experiments. Given the classical importance ascribed to learning components in many psychosomatic pathologies, future experiments are necessary to determine if stress responses can be classically conditioned, but they must be more rigorously designed than in the past.     

可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成

为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C₃烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ～Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。     

Adrenocortical and behavioral responses to repeated stressors: toward an animal model of chronic stress and stress-related mental illness

Research in chronic stress has been hampered by the absence of an operational definition for that condition. To explore possible criteria for chronic stress, we repeatedly exposed rats to 2 hr of tail shock per day. After several days, we found elevated prestress corticosterone levels and abnormal behavior, including decreased food consumption, fear-like suppression of activity immediately before stress, greater hesitancy to drop from a suspended wire, and decreased exploratory behavior in a novel environment. A less intensely stressed group of rats also had elevated prestress corticosterone levels, but not the abnormal behaviors that persisted in shocked rats after the stress sessions were discontinued. We propose that abnormalities in both adrenocortical function and behavior are a better marker for chronic stress than abnormalities in either of these systems alone. The animal model we have described may be useful for studying factors that contribute to development of chronic stress or PTSD.     

A somatostatin analogue decreases embryonic loss following superovulation in rats by normalizing insulin-like growth factor-I action in the uterus

This study was designed to determine whether the somatostatin analogue, octreotide, could prevent embryonic loss by normalizing increased uterine insulin-like growth factor-I (IGF-I) action related to hyperoestrogenaemia following superovulation. Superovulated immature and oestradiol-17beta-treated adult rats were infused with 100 or 300 microg/ml of octreotide respectively, or injected daily with 1 or 10 microg of octreotide from day 1 to day 3 of pregnancy. On day 3, embryos were collected from the oviducts and uteri. Uterine luminal fluid was subjected to embryo culture. The amounts of uterine IGF-I and IGF binding proteins (IGFBP) were determined by radioimmunoassay and ligand binding assay respectively. Octreotide infusion normalized uterine IGF-I action following superovulatory and oestradiol-17beta treatment, by reducing IGF-I concentrations and increasing IGFBP concentrations. Octreotide infusion increased the number of normal embryos by 2.7-fold and 1.7-fold in superovulated and oestradiol-17beta- treated rats respectively, and reversed the detrimental effects of uterine luminal fluid on embryonic development caused by superovulatory and oestradiol-17beta treatment. Daily injections with octreotide had similar but reduced effects in all parameters examined in both treatment groups. In conclusion, octreotide may reduce embryonic loss, at least in part, by normalizing IGF-I action following superovulation.      

Humoral indices of stress in rats

Rats, bearing chronic venous cannulas, were subjected to 30 sec of constant current grid shock at 1 of 6 intensities (0, 0.25, 0.5, 1, 2, 4 mA), after being allowed to acclimate to the test chamber overnight. Blood, sampled before and after shock, was assayed for epinephrine, norepinephrine and corticosterone. Peak levels of both catecholamines increased in a stepwise fashion (i.e., monotonically) with increasing magnitude of stress, as reflected by current intensity of foot shock. Plasma corticosterone did not increase monotonically but instead showed similar increases in the 5 groups of rats that actually received shock. These data support earlier work which indicate that plasma corticosterone is not a sensitive index of stress; this is probably the case because of the relatively narrow range of responsiveness of the adrenal cortex to ACTH. In contrast, both plasma catecholamines appear to satisfy some of the requisites for a sensitive visceral index of stress.     

Detection of immunologically significant factors for chronic fatigue syndrome using neural-network classifiers

Neural-network classifiers were used to detect immunological differences in groups of chronic fatigue syndrome (CFS) patients that heretofore had not shown significant differences from controls. In the past linear methods were unable to detect differences between CFS groups and non-CFS control groups in the nonveteran population. An examination of the cluster structure for 29 immunological factors revealed a complex, nonlinear decision surface. Multilayer neural networks showed an over 16% improvement in an n-fold resampling generalization test on unseen data. A sensitivity analysis of the network found differences between groups that are consistent with the hypothesis that CFS symptoms are a consequence of immune system dysregulation. Corresponding decreases in the CD19(+) B-cell compartment and the CD34(+) hematopoietic progenitor subpopulation were also detected by the neural network, consistent with the T-cell expansion. Of significant interest was the fact that, of all the cytokines evaluated, the only one to be in the final model was interleukin-4 (IL-4). Seeing an increase in IL-4 suggests a shift to a type 2 cytokine pattern. Such a shift has been hypothesized, but until now convincing evidence to support that hypothesis has been lacking.     

Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise

OBJECTIVE: The purpose of this study was to compare the cardiovascular responses of patients with chronic fatigue syndrome (CFS) to healthy control subjects when performing stressful cognitive tasks before and after strenuous exercise. METHOD: Beat-by-beat blood pressure and electrocardiogram were recorded on 19 women with CFS and 20 healthy nonexercising (ie, sedentary) women while they performed cognitive tests before, immediately after, and 24 hours after incremental exercise to exhaustion. RESULTS: Diminished heart rate (p <.01) and systolic (p <.01) and diastolic (p <.01) blood pressure responses to stressful cognitive testing were seen in patients with CFS when compared with healthy, sedentary controls. This diminished stress response was seen consistently in patients with CFS across three separate cognitive testing sessions. Also, significant negative correlations between self-ratings of CFS symptom severity and cardiovascular responses were seen (r = -0.62, p <.01). CONCLUSIONS: Women with CFS have a diminished cardiovascular response to cognitive stress; however, exercise did not magnify this effect. Also, the data showed that the patients with the lowest cardiovascular reactivity had the highest ratings of CFS symptom severity, which suggests that the individual response of the patient with CFS to stress plays a role in the common complaint of symptoms worsening after stress.     

Cardiovascular stress responses and their relation to symptoms in Gulf War veterans with fatiguing illness

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.     

A prospective trial of short‐fractionation radiotherapy for the palliation of liver metastases

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty‐eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty‐two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high‐dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53?66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well‐tolerated treatment achieves useful palliation.