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PubMed2001

Genome-wide analysis of the general stress response in Bacillus subtilis.

Bacteria respond to diverse growth-limiting stresses by producing a large set of general stress proteins. In Bacillus subtilis and related Gram-positive pathogens, this response is governed by the sigma(B) transcription factor. To establish the range of cellular functions associated with the general stress response, we compared the transcriptional profiles of wild and mutant strains under conditions that induce sigma(B) activity. Macroarrays representing more than 3900 annotated reading frames of the B. subtilis genome were hybridized to (33)P-labelled cDNA populations derived from (i) wild-type and sigB mutant strains that had been subjected to ethanol stress; and (ii) a strain in which sigma(B) expression was controlled by an inducible promoter. On the basis of their significant sigma(B)-dependent expression in three independent experiments, we identified 127 genes as prime candidates for members of the sigma(B) regulon. Of these genes, 30 were known previously or inferred to be sigma(B) dependent by other means. To assist in the analysis of the 97 new genes, we constructed hidden Markov models (HMM) that identified possible sigma(B) recognition sequences preceding 21 of them. To test the HMM and to provide an independent validation of the hybridization experiments, we mapped the sigma(B)-dependent messages for seven representative genes. For all seven, the 5' end of the message lay near typical sigma(B) recognition sequences, and these had been predicted correctly by the HMM for five of the seven examples. Lastly, all 127 gene products were assigned to functional groups by considering their similarity to known proteins. Notably, products with a direct protective function were in the minority. Instead, the general stress response increased relative message levels for known or predicted regulatory proteins, for transporters controlling solute influx and efflux, including potential drug efflux pumps, and for products implicated in carbon metabolism, envelope function and macromolecular turnover.

Bacillus subtilis↗
PubMed1982

Comparative discriminative stimulus effects of 5-methoxy-N,N-dimethyltryptamine and LSD.

Rats were trained to discriminate injections of either 5-OMe DMT (1.5 mg/kg) or LSD (0.096 mg/kg) from saline in a two-lever drug discrimination task. After stable discrimination performances were attained (greater than 85%) in each group, dose-response generalizations between the two groups of animals were examined. The results revealed that the 5-OMe DMT-stimulus response generalized to LSD and that the LSD-stimulus response generalized to 5-OMe DMT. Furthermore, both the 5-OMe DMT-stimulus and the LSD-stimulus could be significantly attenuated by the serotonin antagonist BC-105. However, the pattern of the dose-related antagonism by BC-105 was different between the drug stimuli. It was concluded that while the discriminative stimulus effects of 5-OMe DMT and LSD may be mediated via a common serotonergic system, the receptor interaction of these agents within that pharmacological system may be somewhat different.

Animals↗
PubMed1976

Changes in responses of medial pontomedullary reticular neurons during repetitive cutaneous, vestibular, cortical, and tectal stimulation.

1. In cats anesthetized with chloralose, responses of medial pontomedullary reticular neurons to stimulation of the body surface, vestibular nerves, superior colliculi, pericruciate cortices, cerebral peduncles, and spinal cord were studied at different stimulus rates. Raising the rate from 1/10 s to between 1/4 s and 2/s caused a significant decrement or increment in the response of most neurons tested. Response decrement typically began near the beginning of the higher frequency stimulus sequence and increased throughout the sequence. Response increment usually began somewhat later, rose to a peak, and then declined. Recovery from response decrement or increment usually occurred within 30-60 s at a 1/10 s stimulus rate.2. Measurements of response latency and of changes occurring in the initial and longer latency portions of responses indicated that all components of a response typically decreased or increased in parallel. Background spontaneous activity did not change during response decrements, but sometimes increased during response increment.3. Where changes could be detected, response decrement usually developed more rapidly when a sequence of repetitive stimulation was repeated.4. Response decrement was most pronounced at the highest stimulation rates and lowest stimulus intensities. Response increment was usually maximal at a stimulus rate of 1/s: at lower rates less increment occurred; at higher rates responses began to exhibit decrement.5. Response changes varied with the type of stimulus applied. Response decrements predominated when the body surface, vestibular nerves, or ipsilateral superior colliculus were stimulated. Approximately equal amounts of response increment and decrement were produced by repetitive stimulation of the cerebral peduncles and contralateral superior colliculus. Stimulation of the surface of the pericruciate cortex or of the spinal cord usually produced a long-lasting response increment.6. Generalization of response decrement and increment was observed in cases where trains of stimuli at a rate of 2/s applied to one point produced changes in the response to stimulation of another point which was tested once per 10 s and where single-shock stimulation of the first point was without effect on the test response. Generalization of response decrement occurred most often when two nearby points were stimulated. Generalization of response increment appeared to spread widely between distant cutaneous points and stimuli of different kinds.7. The response decrement and increment observed in medial pontomedullary reticular neurons displayed most of the parametric features of behavioral habituation and sensitization (8, 33) and therefore appear to represent neural analogs of these latter phenomena. The properties of response decrement suggest that it may occur to a large extent within afferent pathways leading to medial reticular neurons...

Animals↗
PubMed1990

Human auditory steady-state response during general anesthesia.

The 40-Hz auditory steady-state evoked response (ASSR) is a sinusoidal electrical response of the brain to periodically presented auditory stimuli. It was recorded during anesthesia in 10 elective surgical patients to evaluate its usefulness as a measure of the level of consciousness. The anesthetic agents used were thiopental, fentanyl, and isoflurane with or without nitrous oxide. Recordings were carried out during the period before induction and during induction, surgical anesthesia, emergence, and recovery from anesthesia. The level of consciousness was measured with an auditory stimulus detection task. The electroencephalogram (EEG) was also recorded for comparison with the ASSR. The following indices were analyzed: total EEG power, relative power in the beta, alpha, theta, and delta frequency bands, and the median and spectral edge frequency. The amplitude of the ASSR was reduced significantly at the end of the induction period and decreased below noise levels during surgical anesthesia. It increased significantly during emergence and recovery. The amplitude during recovery remained significantly smaller than the preinduction values. The changes of the ASSR paralleled those of the level of consciousness. The EEG measurements were distorted by the presence of muscle artifacts that were prominent during emergence and recovery. The amplitude of the ASSR appears to provide a more reliable indicator of the level of consciousness than the EEG.

Adult↗
PubMed1988

Effects of low dose perioperative interferon on the surgically induced suppression of antitumour immune responses.

General surgical procedures are followed by a period of generalized immunosuppression that may favour the deposition of metastases seeded at operation in patients with malignant disease. In an attempt to prevent the suppression of host-antitumour immune mechanisms following surgery we have studied the immunological effects of low-dose perioperative interferon-alpha (r-HuIFN alpha). Patients were randomly allocated pre-operatively to the control (n = 15) or treatment group (n = 15). Patients in the treatment arm received a 1-week course of subcutaneous recombinant human interferon-alpha 2a (Roferon-A) at a dose of 2 megaunits daily starting on the evening before surgery. Natural killer cell, lymphokine activated killer cell cytotoxicities and endogenous interleukin 2 production were measured 1 day before surgery and on the first, third, fifth and tenth postoperative days. Treatment with r-HuIFN alpha did not prevent the postoperative impairment of interleukin 2 production or lymphokine activated killer cell cytotoxicity. However it prevented the fall in natural killer cell activity normally observed following surgery. This may have important consequences in controlling metastatic dissemination of tumour in this vulnerable period.

Antibody Formation↗
PubMed1999

Robust regression for clustered data with application to binary responses.

Generalized estimating equations (GEE) can be highly influenced by the presence of unusual data points. A generalization of the GEE procedure, which yields parameter estimates and fitted values that are resistant to influential data, is introduced. Resistant generalized estimating equations (REGEE) include weights in the estimating equations to downweight influential observations or clusters. Influential observations are downweighted according to their leverage or residual in an example of correlated binary regression applied to 137 urinary incontinent elderly patients from 38 medical practices.

Aged↗
PubMed1992

Dissociation between the effects of benzodiazepine receptor agonists on behavioral vigilance and responsitivity.

The effects of benzodiazepine receptor (BZR) full agonists chlordiazepoxide and midazolam, and the partial agonist beta-carboline ZK 91,296 on the rat's performance in a simple reaction time paradigm were examined. This task required the animals to respond to a rarely and unpredictably occurring brief (50 ms) visual stimulus. Non-parametric measures of signal sensitivity and response bias derived from signal-detection theory were used as a basis for the dissociation between the effects of these drugs on attentional abilities and general responsivity. The dose-dependent effects of midazolam (0.1-3.13 mg/kg) on signal sensitivity and general responsivity occurred in parallel. In contrast, the effects of chlordiazepoxide (1.56-12.5 mg/kg) on signal sensitivity were largely independent from effects on response bias. The partial agonist ZK 91,296 (0.39-25 mg/kg) in general had little effect on performance. The effects of the highest doses of chlordiazepoxide and midazolam were reversed by the co-administration of the BZR antagonist Ro15-1788 (15 mg/kg). Additionally, extension of the stimulus presentation time to 500 ms decreased the magnitude of the effect of chlordiazepoxide on signal sensitivity. These results support the hypothesis that BZR agonist-induced disruption of attentional abilities is not necessarily confounded by effects on general responsivity or sedation, and thus may represent a discrete pharmacological property of BZR-agonists.

Animals↗
PubMed2004

[The practice guideline 'Dementia' (second revision) from the Dutch College of General Practitioners; a response from the perspective of general practice].

With growing numbers of older adults in the population, the number suffering from dementia will increase. The general practitioner has to try to determine the difference between Alzheimer's disease and vascular dementia on the one hand, and fronto-temporal dementia and dementia with Lewy bodies on the other hand, while also considering the therapeutic options now and in the future. Support for patients and their family is the responsibility of the general practitioner, who must also consider the patient's driving proficiency and the wishes for euthanasia of the demented older adult. The revised version of the practice guideline 'Dementia' of the Dutch College of General Practitioners is well suited to the work of the general practitioner. It is advisable to read the practice guideline several times and in such cases not only to use the summary card but the entire practice guideline.

Dementia↗
PubMed1979

HLA-D locus typing in ankylosing spondylitis and Reiter's syndrome.

HLA-D typing of 44 patients with ankylosing spondylitis (AS) and 31 patients with Reiter's syndrome (RS) did not show increased frequency of any particular Dw allele in either population of patients as compared to controls. Such studies also allowed each patient's general response to be compared with other general responses within each experiment. Contrary to reports of diminished lymphocyte responses in AS patients, hyperresponsiveness in both AS and RS patients was found.

Alleles↗
PubMed2005

Induction of myocardial connective tissue growth factor in pacing-induced heart failure in pigs.

AIMS: Connective tissue growth factor (CTGF) is a secreted, heparin-binding, and extracellular matrix associated protein shown to stimulate many of the cellular events underlying fibrosis. Previous investigations have revealed that myocardial CTGF is substantially induced in ischaemic heart failure, particularly in the ischaemic and peri-ischaemic region. The purpose of the present study was to investigate to what extent myocardial induction of CTGF is a general response to congestive heart failure (CHF) and to what extent CTGF is a decisive effector of fibrosis. METHODS: Experimental heart failure in pigs was induced by rapid pacing at 220-240 beats min(-1) for 3 weeks (CHF pigs; n = 12). RESULTS: The CHF pigs exhibited significant left ventricular (LV) dilatation, reduced contractility, and increased cardiac filling pressures. Northern blot analysis demonstrated that myocardial CTGF mRNA levels in CHF pigs were fivefold higher (P < 0.05) than those in control pigs (n = 10). Similar elevations of immunoreactive CTGF (sixfold; P < 0.05) were observed in myocardial tissue samples prepared for Western blot analysis. Immunohistochemical analysis of myocardial tissue sections revealed predominant expression in interstitial and perivascular fibroblasts and endothelial cells. Myocardial procollagen alpha1(I) mRNA levels were also significantly elevated (sixfold; P < 0.05) in CHF pigs compared with controls, whereas myocardial tissue contents of collagen were not statistically different between the groups. CONCLUSION: Induction of myocardial CTGF in heart failure is not just a response to ischaemia, but rather a general response to evolving heart failure. Yet, induction of myocardial CTGF was clearly not a sufficient effector of fibrosis.

Animals↗
PubMed2003

Chill induction of the SigB-dependent general stress response in Bacillus subtilis and its contribution to low-temperature adaptation.

A variety of environmental and metabolic cues trigger the transient activation of the alternative transcription factor SigB of Bacillus subtilis, which subsequently leads to the induction of more than 150 general stress genes. This general stress regulon provides nongrowing and nonsporulated cells with a multiple, nonspecific, and preemptive stress resistance. By a proteome approach we have detected the expression of the SigB regulon during continuous growth at low temperature (15 degrees C). Using a combination of Western blot analysis and SigB-dependent reporter gene fusions, we provide evidence for high-level and persistent induction of the sigB operon and the SigB regulon, respectively, in cells continuously exposed to low temperatures. In contrast to all SigB-activating stimuli described thus far, induction by low temperatures does not depend on the positive regulatory protein RsbV or its regulatory phosphatases RsbU and RsbP, indicating the presence of an entirely new pathway for the activation of SigB by chill stress in B. subtilis. The physiological importance of the induction of the general stress response for the adaptation of B. subtilis to low temperatures is emphasized by the observation that growth of a sigB mutant is drastically impaired at 15 degrees C. Inclusion of the compatible solute glycine betaine in the growth medium not only improved the growth of the wild-type strain but rescued the growth defect of the sigB mutant, indicating that the induction of the general stress regulon and the accumulation of glycine betaine are independent means by which B. subtilis cells cope with chill stress.

Adaptation, Physiological↗
PubMed1975

Depression in lymphocyte response to general mitogens by owl monkeys infected with Herpesvirus saimiri.

The effect of Herpesvirus saimiri (HVS) infection on the response of owl monkey lymphocytes to general mitogens was examined during the development of neoplastic disease. The reactivity of the lymphocytes was then correlated with the clinical condition of the infected monkeys and the content of virus rescued from the peripheral blood lymphocytes (PBL). Eight monkeys developed lymphoma which, in six monkeys, was accompanied by lymphocytic leukemia. All animals that died of HVS-induced neoplasia consistently showed a lack of mitogenic response to phytohemagglutinin and concanavalin A. The response to pokeweed mitogen, while always reduced, was generally less markedly affected than the response to the other two mitogens. Lymphocytes from five of the leukemic animals demonstrated an elevated level of spontaneous DNA synthesis in culture late in the disease. This increased spontaneous DNA synthesis tended to correlate with the rescue of HVS from the PBL as demonstrated by the infective center assay. Although mitogenic hyporesponsiveness corresponded with HVS rescue from PBL in six of nine monkeys, the impairment of normal lymphocyte responsiveness sometimes preceded virus recovery.

Animals↗
PubMed1994

Response-specific inhibition during general facilitation of defensive responses in Aplysia.

Siphon responses of Aplysia have been used to examine the neural basis of nociceptive behavioral inhibition. The authors tested the response specificity and functional significance of this inhibition. Video analysis showed that strong tail-nerve shock decreased the duration of siphon constriction evoked by weak siphon shock. Tail-nerve shock also caused the appearance of a novel flaring response to the test stimulus, which resembled the siphon response to tail-nerve shock. Novel flaring responses were expressed to both mechanical and electrical siphon stimuli. Tailshock facilitated another defensive response, inking, during the period of inhibited siphon constriction. Tailshock also facilitated tail contractions evoked by weak contralateral tail stimulation during this period. These results indicate that inhibition is not generalized across defensive responses and is specific to siphon responses that interfere with directed ink ejection toward an injured site.

Animals↗
PubMed1994

Autonomic responsivity in generalized social phobia.

To determine whether patients with generalized social phobia exhibit evidence of abnormal autonomic nervous system (ANS) functioning, 15 non-depressed, medication-free subjects with DSM-IV social phobia (generalized type) and 15 healthy control subjects participated in a series of autonomic function tests. Generalized social phobics exhibited increased blood pressure responsivity to Valsalva and exaggerated vagal withdrawal in response to isometric exercise, but normal cardiovascular responsivity to all other tasks. Plasma norepinephrine and epinephrine levels were also normal. Studies with larger sample sizes and the use of specific neuropharmacologic probes seem warranted to further delineate a role for autonomic dysfunction in the pathophysiology of this disorder.

Adult↗
PubMed1997

Cloning and sequencing of a 35.7 kb in the 70 degree-73 degree region of the Bacillus subtilis genome reveal genes for a new two-component system, three spore germination proteins, an iron uptake system and a general stress response protein.

In the framework of the international project aimed at sequencing the Bacillus subtilis (Bs) genome, a 35.7-kb chromosome segment around the pel locus has been cloned and sequenced. This region (35,745 bp; 70 degrees-73 degrees of the genetic map) contains two partial and 38 complete orfs. A homology search for the products deduced from the 39 orfs revealed that 26 of them exhibit significant similarity to known proteins, e.g. germination proteins, sodium-alanine symporter, PTS system, methionine amino peptidase, 2-oxoglutarate/malate translocater, pectate lyase, general stress response protein, RNA helicase, iron uptake and two-component systems.

Bacillus subtilis↗
PubMed1997

Placebo response in generalized anxiety: its effect on the outcome of clinical trials.

The development of new treatments for generalized anxiety disorder increasingly has been sabotaged by a high placebo-response rate. As a consequence, and in contrast to the surge of approvals for new antidepressants, only one new anxiolytic has been approved by the U.S. Food and Drug Administration in the past 15 years. This article presents a brief review of factors that contribute to the placebo response in treatment studies of generalized anxiety. Since anxiety is a normal emotion that is sensitive to a variety of life stresses, it is particularly difficult to achieve the primary goal of a clinical trial, which is to extract the "signal" of a drug effect from the "noise" of background fluctuations in symptoms. Data from the published literature and from the authors' research unit concerning placebo-response trends are reviewed.

Anti-Anxiety Agents↗
PubMed1992

Effects of high-probability requests on the acquisition and generalization of responses to requests in young children with behavior disorders.

The failure to respond to requests in young children often is maintained by the reactions of the adults that encounter this behavior. This failure to respond to requests has been identified as a primary reason for the children's exclusion from community, social, and instructional opportunities. Numerous interventions that target the failure to respond have consisted of punishment and reinforcement procedures. More recently, antecedent interventions have focused on changing the context in which a request is delivered. In the current study, high-probability requests were provided as an antecedent to delivering a low-probability request. The requests were delivered by multiple trainers in an attempt to produce generalized appropriate responding to adults who did not use the high-probability sequence. Results showed an immediate increase in appropriate responding in 2 children when the intervention was delivered. In addition, when the intervention was implemented by more than one adult, spontaneous increases in responding also were observed toward adults who had never implemented the request sequence. Improvements in responding to requests were maintained after the intervention was discontinued.

Aggression↗