Search PubMed⌕ Search

Biomedical subjects

J Herbert

Publications and source records attributed to J Herbert.

At least 37 records · Page 2Linked to original sources
PubMed2001

Corticosterone modulates autonomic responses and adaptation of central immediate-early gene expression to repeated restraint stress.

We have tested the role of elevated corticosterone in modulating the responses to either a single (acute) or chronic (repeated daily) restraint stress. Male rats were adrenalectomised, and received subcutaneous corticosterone pellets that resulted in either low (ca. 60 ng/ml) or higher (ca. 130-150 ng/ml) levels of plasma corticosterone. They were also implanted with telemetric transmitters relaying heart rate and core temperature. Control rats were unoperated and untreated. In the first experiment, rats were exposed to daily (60 min) restraint stress for 9 days whereas in the second experiments, rats were only exposed to a single restraint stress. Heart rate and core temperature were recorded every 10 min during each stress session. Brains were removed 1 h after the end of the final stress, and stained immunocytochemically for Fos, Fos-b. Plasma corticosterone was measured by radioimmunoassay. Control rats showed marked tachycardia, peaking at about 10 min and declining thereafter (habituation). This pattern did not change significantly across the 9 days of repeated stress. Rats with low dose corticosterone replacement showed a different pattern: maximal heart rate responses were similar, but elevated heart rate persisted during the period of stress. This effect was most marked on the first exposure to restraint. In contrast, high dose replacement rats showed similar heart rate responses to controls. Restraint stress induced a transient hypothermia, which in control rats was reduced during repeated stress (adaptation). High dose corticosterone resulted in accelerated adaptation of this response. As expected, an acute stress increased Fos expression in a range of limbic structures including the lateral septum, lateral preoptic area, bed nucleus of the stria terminalis, and three divisions of the hypothalamic paraventricular nucleus and in the raphe, locus coeruleus and solitary nucleus of the brainstem. After 9 days, there was no longer increased Fos expression in any of these areas. There was no effect of corticosterone treatment on Fos expression after an acute stress, and following repeated stress the low dose group showed increased expression in the lateral preoptic area only. Results with Fos-b were quite different. The effects of an acute stress in control animals was similar to that observed for Fos. Corticosterone had no effects on Fos-b expression after a single stress. Following repeated stress, there were still elevations of Fos-b (compared to controls) in the lateral septum, and in the basolateral and medial amygdala. Rats receiving low dose corticosterone showed increased Fos-b expression following 9 days stress in the lateral septum and in the dorsal and medial parts of the paraventricular nucleus compared to either control, stressed rats or those receiving the higher corticosterone dose and repeated stress. From these results we suggest that persistently elevated corticosterone acts to reduce ('shut-off') stress-induced responses as assessed both by the reaction of the autonomic system and by the expression of immediate-early genes in the brain. However, there are marked differences in the relations between corticosterone and the parameters measured in our experiments. In particular, there are distinctions between Fos and Fos-b both in the way they adapt to repeated restraint stress, and the effect corticosterone has on this adaptive process.

Adaptation, Physiological↗
PubMed2001

Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation.

Dehydroepiandrosterone (DHEA) is a steroid that shows a marked age-related decline in humans. Previous research suggests potential for DHEA replacement in old age to enhance cognition and well-being. We conducted a clinical trial to test these hypotheses in a non-clinical sample of 46 men aged 62-76. Participants received either 50 mg DHEA daily for 13 weeks, followed by placebo for 13 weeks, or the reverse, in a randomised double-blind cross-over trial design. Levels of salivary cortisol and DHEA were measured at 0800 h and 2000 h prior to each assessment session. Cognition was assessed with tests of speed, attention and episodic memory. Well-being was measured with questionnaires of mood and perceived health. Mood questionnaires were completed at the assessment session as well as concurrently with saliva sampling.A correlational analysis of baseline behavioural data with hormonal data, controlling for age, revealed that higher morning DHEA was associated with lower confusion (r=-0.33; P=0.04), while higher evening DHEA was associated with lower anxiety (r=-0.35; P=0.03) and lower current negative mood in the morning (r=-0.37; P=0.03). Conversely, higher morning cortisol and a morning cortisol/DHEA ratio were associated with higher anxiety (r=0.35; P=0.03), (r=0.46; P=0.004), general mood disturbance (r=0.32; P=0.046), (r=0.32; P=0.04) and higher current negative mood in the evening (r=0.37; P=0.03), (r=0.38; P=0.03). A higher morning cortisol/DHEA ratio was also associated with higher confusion (r=0.39; P=0.01) and lower visuo-spatial memory performance (r=-0.39; P=0.01). Unexpectedly, higher evening cortisol was associated with faster choice reaction time (r=-0.33; P=0.04). These findings are consistent with an impairing effect of high cortisol on episodic memory and mood in older men, which may be attenuated by DHEA. When treatment effects were analysed, no significant effects of DHEA were observed on any of the trial outcomes, providing no support for benefits of DHEA supplementation for cognition or well-being in normal older men in the shorter-term.

Affect↗
PubMed2001

Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis.

The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6-/- mice did not, however, suffer spontaneous bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6-/- mice resembled that of patients with platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis.

Animals↗
PubMed2001

Corticosterone differentially modulates expression of corticotropin releasing factor and arginine vasopressin mRNA in the hypothalamic paraventricular nucleus following either acute or repeated restraint stress.

Exposing rats to repeated restraint stress induces well-characterized adaptations in the expression of either corticotropin-releasing factor (CRF) or arginine-vasopressin (AVP) mRNA in the parvocellular neurons of the hypothalamic paraventricular nucleus (PVN). The effects of regulating corticosterone levels on this adaptation was studied in male rats. In intact rats, acute restraint stress increased the expression of CRF mRNA whilst AVP mRNA expression was no different to control. Repeated exposure resulted in habituation of CRF expression, whereas AVP mRNA increased above that seen in either non stressed or acutely stressed animals. In adrenalectomised rats with replacement pellets of corticosterone that replicated blood levels approximating to the daily trough (mean levels 37--65 ng/mL), basal CRF expression levels were raised, but the response to acute stress was still observed. However, the habituation seen in normal animals that had been repeatedly stressed was prevented, so that CRF mRNA levels continued to be raised after repeated stress. By contrast, the AVP response to both acute and repeated stress was unaltered in these low-dose corticosterone-treated rats compared with controls. Higher dose pellets, which resulted in blood levels around those of the daily maximum (mean 118--141 ng/mL) had the opposite effects. There was no change compared to intact rats in the expression of CRF mRNA following either acute or repeated stress, but the expected increase in AVP following repeated restraint was prevented. These experiments show that corticosterone has important modulating effects on the adaptive pattern of both CRF and AVP mRNA expression in the parvocellular PVN. The 'set-point' of corticosterone differs; for CRF, experiencing higher levels is necessary for subsequent adaptation to repeated restraint to occur, whereas for AVP a return to lower levels is necessary to allow this peptide to respond to repeated stress.

Acute Disease↗
PubMed2001

Interferon beta-1a in children with multiple sclerosis is well tolerated.

BACKGROUND: Multiple sclerosis is a chronic demyelinating disease rare in children. Currently marketed disease modifying therapies are limited to adults. OBJECTIVE: To determine the tolerability of interferon beta-1a (IFNB-1 a) 30 mcg injected intramuscularly once a week in children with clinically definite relapsing-remitting multiple sclerosis (RRMS). DESIGN/METHODS: A standardized questionnaire was sent to neurologists in the United States to determine the tolerability of IFNB-1 a in patients younger than 16 years. RESULTS: Tolerability data were available for 9 of 33 children who were reported to initiate IFNB-1 a. Mean age on initiating treatment was 12.7 years (range 8 - 15) and mean duration of therapy was 17 months (range 5 - 36). No patient discontinued therapy due to an adverse event. CONCLUSIONS: Preliminary data indicate that weekly intramuscular injections of IFNB-1 a are well tolerated.

Adjuvants, Immunologic↗
PubMed2001

Possible role of cortisol and dehydroepiandrosterone in human development and psychopathology.

BACKGROUND: The characteristics of adrenal hormone secretion change markedly during infancy. Disturbances in basal levels may precipitate psychological dysfunction and are associated with psychopathology in young people. AIMS: To relate three aspects of behavioural endocrinology: developmental changes in cortisol and dehydroepiandrosterone (DHEA), the role of these hormones in the psychopathology of young people, and the action of these steroids in the brain. METHOD: A selective review from the human developmental, psychiatric and neurosciences literature. RESULTS: There are developmentally mediated changes in brain sensitivity following excess exposure to cortisol. This may result in impairments of mental and behavioural function. DHEA and gonadal steroids may modulate the actions of cortisol. CONCLUSIONS: Steroid hormones contribute to shaping behavioural function during early development and act as risk factors for psychopathology.

Brain↗
PubMed2001

Low compliance with national standards for cardiovascular emergency preparedness at health clubs.

There is heightened concern that older adults and individuals with occult or known heart disease are exercising at fitness facilities that do not provide adequate cardiovascular screening and emergency procedures, as outlined in contemporary recommendations. To evaluate adherence to these standards, we surveyed 122 randomly chosen fitness clubs in Ohio (53% response rate; n = 65) that included > 110,000 total members. Special programs for older adults, cardiac patients, or both, were offered at 52% of these clubs. More than one fourth of the clubs (28%) failed to employ pre-entry screening to identify members with signs, symptoms, or history of cardiovascular disease, even though 17% reported one or more cardiovascular emergencies (ie, acute myocardial infarction, sudden cardiac death, or both) in their facility during the past 5 years. Moreover, a majority of the clubs (53%) had no written emergency response plan and 92% failed to conduct emergency response drills as described in published national standards. Only 3% of the centers reported having automated external defibrillators. These findings indicate that staff at public fitness facilities must work to identify members with signs, symptoms, or history of cardiovascular disease and prepare for prompt and appropriate responses to cardiovascular emergencies as described in contemporary national recommendations. Such risk management procedures may reduce exercise-related cardiovascular events among the escalating number of moderate-to-high-risk adults who are being mainstreamed into health and fitness facilities.

Cardiovascular Diseases↗
PubMed2000

Role of serum amyloid P component in bacterial infection: protection of the host or protection of the pathogen.

Serum amyloid P component (SAP) binds to Streptococcus pyogenes, and we show here that it also binds to Neisseria meningitidis, including a lipopolysaccharide (LPS)-negative mutant, and to rough variants of Escherichia coli. Surprisingly, this binding had a powerful antiopsonic effect both in vitro and in vivo, reducing phagocytosis and killing of bacteria. Furthermore, SAP knockout mice survived lethal infection with S. pyogenes and rough E. coli J5, organisms to which SAP binds. The susceptibility of SAP(-/-) mice was fully restored by injection of isolated human SAP. However, SAP(-/-) mice were more susceptible than wild-type animals to lethal infection with E. coli O111:B4, a smooth strain to which SAP does not bind, suggesting that SAP also has some host defense function. Although SAP binds to LPS in vitro, SAP(-/-) mice were only marginally more susceptible to lethal LPS challenge, and injection of large amounts of human SAP into wild-type mice did not affect sensitivity to LPS, indicating that SAP is not a significant modulator of LPS toxicity in vivo. In contrast, the binding of SAP to pathogenic bacteria enabled them to evade neutrophil phagocytosis and display enhanced virulence. Abrogation of this molecular camouflage is thus potentially a novel therapeutic approach, and we show here that administration to wild-type mice of (R)-1-[6-(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine -2- carboxylic acid, a drug that inhibits SAP binding, significantly prolonged survival during lethal infection with E. coli J5.

Animals↗
PubMed2000

Altered salivary dehydroepiandrosterone levels in major depression in adults.

BACKGROUND: The authors sought to examine whether levels of dehydroepiandrosterone are abnormal in depression. METHODS: Three groups of subjects aged 20-64 were studied: 44 major depressives, 35 subjects with partially or completely remitted depression, matched as far as possible for age and drug treatment, and 41 normal control subjects. Dehydroepiandrosterone and cortisol in saliva were determined from specimens taken at 8:00 AM and 8:00 PM on 4 days. RESULTS: The mean age of the three groups did not differ. Dehydroepiandrosterone was lowered at 8:00 AM and 8:00 PM compared with control subjects. Values for the remitted group were intermediate. Dehydroepiandrosterone levels at 8:00 AM correlated negatively with severity of depression and were not related to drug treatment or smoking, but decreased with age (as expected). Cortisol was elevated in depression in the evening. The molar cortisol/dehydroepiandrosterone ratio also differentiated those with depression from the control group. CONCLUSIONS: Lowered dehydroepiandrosterone levels are an additional state abnormality in adult depression. Adrenal steroid changes are thus not limited to cortisol. Because dehydroepiandrosterone may antagonize some effects of cortisol and may have mood improving properties, these findings may have significant implications for the pathophysiology of depression.

Adult↗
PubMed2000

Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being.

BACKGROUND: In view of the theoretical rationale for beneficial effects of DHEA and DHEAS in aging and dementia, we believe it is timely to undertake a thorough investigation of well-conducted studies in this area. This will provide a basis for confirmation of any effect of DHEA/S administration in humans, in large-scale and properly controlled trials, which would evaluate effective dosage, acceptable route and duration of administration and side effect profiles. This is especially pertinent at this time as DHEA is currently being sold in large quantities in health food stores, particularly in the USA. In some cases the recommended dose is different for men and women (50mg/day for men and 25mg/day for women) and the basis for this recommendation needs to be explored. OBJECTIVES: To establish whether administration of DHEA, or its sulphate, DHEAS, improves psychological well-being and/or improves cognitive function or reduces the rate of decline of cognitive function in older adults or in individuals with dementia. SEARCH STRATEGY: All available electronic databases, hand searched journals, personal communications and conference abstracts were searched for randomised controlled trials of DHEA in well-being and cognition. The total yield from searching was 415 and the detailed breakdown is given in the body of this review. SELECTION CRITERIA: All relevant randomised controlled trials of DHEA or DHEAS were considered for inclusion in the review. Studies where groups are matched, rather than randomised, were also considered. DATA COLLECTION AND ANALYSIS: Data for the specified outcomes were independently extracted by two reviewers (FAH & JvN) and cross-checked. Any discrepancies were discussed and resolved. Where possible and appropriate, data were pooled and the mean differences estimated. MAIN RESULTS: The published DHEA trials fall into 2 categories: 1. four German studies in which DHEA was administered for a period of two weeks or less; 2. a USA study in which DHEA was administered for three months. Well-being was assessed in both sets of studies and a significant improvement was reported in the longer duration USA study, while no effect was reported in the shorter duration studies. The USA study used an open-ended questionnaire for self-assessment of well-being and stated that 67% of men and 82% of women reported enhanced well-being on DHEA compared with placebo. There was no significant change on an analogue measure of libido. The German studies assessed mood and well-being with a number of standardised scales and reported no significant effects of DHEA on any of them. Only the German studies examined performance on cognitive tests, i.e. memory, verbal fluency, speed of processing, etc. They reported no significant benefit of DHEA. REVIEWER'S CONCLUSIONS: The data at present offer limited support for improvement in a sense of well-being following DHEA treatment. This effect was reported only in the longer-term study which used a crude measure of well-being. The data offer no support at present for an improvement in memory or other aspects of cognitive function following DHEA treatment, although cognitive function was only measured in the short-duration trials. In view of the growing public enthusiasm for DHEA supplementation, particularly in the USA, it is clear that high-quality trials need to be undertaken in older adults, in which (a) the duration of DHEA treatment is in excess of two weeks, (b) the number of participants is large enough to detect effects if they exist, and (c) the outcome measures include validated scales for assessment of mood and well-being, and objective tests of cognitive function. Recently, studies of DHEA supplementation in clinical depression and Alzheimer's Disease have been completed in the USA. As soon as the results are available these studies will be reviewed. Currently, two trials (in France and the USA) in normal elderly are in progress.

Adult↗
PubMed2000

Stochastic host-parasite interaction models.

We contribute to the discussion of causes and effects of aggregation (overdispersion) of macroparasite counts, focussing particularly upon the effects of clumped infections and parasite-induced host mortality. The simple nonlinear stochastic model for the evolution of the parasite load of a single host, investigated in Isham (1995), is extended to allow three parasite stages (larval, mature and offspring), and to allow durations of these stages to be non-exponentially distributed. As in the earlier work, exact algebraic results are possible, providing insight into the aggregation mechanisms, as long as the only source of interaction between host and parasites is an excess host mortality linearly related to the parasite load. Results are obtained on the distribution of parasite load and on host survival. In particular, although parasite-induced host mortality is usually thought of as a process that reduces parasite aggregation (Anderson and Gordon 1982), it is shown that, for this model, parasite-induced host mortality cannot cause the index of dispersion to fall below unity. Host heterogeneity and disease control are also discussed. An approximation based on moment assumptions appropriate to a specially-constructed multivariate negative binomial distribution is proposed. This approximation, which is applicable to other processes, and an alternative based on the multivariate normal distribution are compared with exact results.

Animals↗
PubMed2000

c-fos expression, behavioural, endocrine and autonomic responses to acute social stress in male rats after chronic restraint: modulation by serotonin.

The effects in male rats of serotonin depletion (using the neurotoxin 5,7-dihydroxytryptamine) on the cross-sensitization of an acute social stress (defeat by a larger resident male) by previous repeated restraint stress (10 days, 60 min per day) was studied. Previous restraint increased freezing responses during social defeat in sham-operated rats, but this was not observed in those with depleted serotonin (83% or more in different regions of the brain). In contrast, neither heart rate (tachycardia) nor core temperature responses (hyperthermia) were accentuated in previously restrained rats (i.e. neither showed heterotypical sensitization), and neither adapted to repeated restraint (there is a hypothermic core temperature response during restraint). Corticosterone levels, which did adapt, nevertheless did not show accentuated responses to social defeat in previously restrained rats, though samples could only be taken 60 min after defeat. c-fos expression in the central nucleus of the amygdala 60 min after social defeat was increased by previous restraint. No other areas examined in the hypothalamus (e.g., paraventricular nucleus) or brainstem (e.g., solitary nucleus) showed differences related to previous restraint. Serotonin depletion reduced the expression of c-fos in the frontal cortex, lateral preoptic area, medial amygdala, central gray, medial and dorsal raphe, and locus coeruleus after social stress, but this was not altered by previous restraint. These results show that serotonin depletion has selective effects on the cross-sensitization of responses in previously stressed rats to a heterotypical stressor.

5,7-Dihydroxytryptamine↗
PubMed2000

Tuberculosis drug resistance in England and Wales. How much is 'home-grown'?

The fact that a substantial proportion of tuberculosis drug resistance (especially multidrug resistance) is due to transmission of resistant strains or treatment failure in the UK underlines the need to strengthen control in this country. Early identification and effective treatment of cases (including measures to support adherence and appropriate use of initial treatment regimes involving at least four drugs in those at risk of isoniazid resistance) would help to control the problem [1].

Antitubercular Agents↗
PubMed2000

First-episode major depression in adolescents. Affective, cognitive and endocrine characteristics of risk status and predictors of onset.

BACKGROUND: There is little information on whether patterns of steroids precede and are associated with depressive onset. AIMS: To establish whether there is an association between salivary cortisol and/or dihydroepiandrosterone (DHEA) levels and depression independent of psychosocial risk. METHOD: Two subgroups of adolescents in the community at high (n = 181) and low (n = 65) risk for psychopathology were interviewed for recent psychiatric disorder at entry and again at 12 months. Salivary samples (08.00 and 20.00 h) for hormone estimations and self-reports on current mood and cognitive style were obtained at both assessments. RESULTS: Neither hormone was associated with risk status, current mood or cognitive style at entry. Of 31 onsets of major depression that occurred over the next 12 months, 30 came from the high-risk group but were not associated with any particular pattern of risk. Increased negative mood and feelings and DHEA (08.00 h) hypersecretion at entry were associated with subsequent major depression. CONCLUSIONS: Both negative mood and feelings and alterations in adrenal steroid function precede the onset of first-episode major depression in adolescents. Variation in levels of hormones may arise from more distal origins than recent life events and current ongoing difficulties.

Adolescent↗
PubMed2000

Recent life events, cortisol, dehydroepiandrosterone and the onset of major depression in high-risk adolescents.

BACKGROUND: It is not clear whether cortisol or dehydroepiandrosterone (DHEA) hypersecretion increases the risk for major depression in the presence of undesirable life events. AIMS: To determine whether there is a specific pattern of psychoendocrine factors that predicts the onset of major depressive disorder. METHOD: 180 adolescents (73 boys, 107 girls) at high risk for psychopathology were assessed for cortisol, DHEA, depressive symptoms, life events and psychiatric disorder at entry and 12 months later. RESULTS: Major depression was predicted for both genders by the additive effects of: higher depressive symptoms; personal disappointments and losses only in the month before onset; one or more daily levels of cortisol at 08.00 h or DHEA at 20.00 h greater than the 80th percentile of the daily mean. CONCLUSIONS: A subgroup of adolescents may carry a physiological risk for major depression which may be either of genetic and/or earlier psychosocial origin.

Adolescent↗
PubMed2000

Morning cortisol as a risk factor for subsequent major depressive disorder in adult women.

BACKGROUND: Whether individual differences in cortisol contribute to subsequent major depressive disorder (MDD) is unknown. AIMS: To determine whether premorbid levels of salivary cortisol and dehydroepiandrosterone (DHEA) were associated with subsequent MDD and how these related to psychosocial factors known to increase the risk for MDD. METHOD: Adult women (n=116) were recruited from general practices. None was currently depressed; 83 were 'psychosocially vulnerable' to MDD, 33 were not. Salivary steroids (cortisol and DHEA at 08.00 h and 20.00 h), recent life events, current mood and social support were assessed at entry. Onset of MDD was recorded during 13 months' follow-up. RESULTS: There were no associations between salivary cortisol or DHEA and recent life events or vulnerability. Twenty-eight onsets of MDD occurred during the follow-up period. This was associated with: severe adverse life events and difficulties during the follow-up period; mean morning cortisol levels at entry; and the presence of any of three vulnerability factors. CONCLUSIONS: Individual differences in morning salivary cortisol levels may represent an independent risk factor for subsequent MDD. The origin of these differences in cortisol is not yet understood.

Adolescent↗
PubMed2000

Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial.

Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are adrenal precursors of steroid biosynthesis and centrally acting neurosteroids. Glucocorticoid and mineralocorticoid deficiencies in Addison's disease require life-long hormone replacement, but the associated failure of DHEA synthesis is not corrected. We conducted a randomized, double blind study in which 39 patients with Addison's disease received either 50 mg oral DHEA daily for 12 weeks, followed by a 4-week washout period, then 12 weeks of placebo, or vice versa. After DHEA treatment, levels of DHEAS and Delta(4)-androstenedione rose from subnormal to within the adult physiological range. Total testosterone increased from subnormal to low normal with a fall in serum sex hormone-binding globulin in females, but with no change in either parameter in males. In both sexes, psychological assessment showed significant enhancement of self-esteem with a tendency for improved overall well-being. Mood and fatigue also improved significantly, with benefit being evident in the evenings. No effects on cognitive or sexual function, body composition, lipids, or bone mineral density were observed. Our results indicate that DHEA replacement corrects this steroid deficiency effectively and improves some aspects of psychological function. Beneficial effects in males, independent of circulating testosterone levels, suggest that it may act directly on the central nervous system rather than by augmenting peripheral androgen biosynthesis. These positive effects, in the absence of significant adverse events, suggest a role for DHEA replacement therapy in the treatment of Addison's disease.

Addison Disease↗