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Biomedical subjects

J Herbert

Publications and source records attributed to J Herbert.

At least 19 recordsLinked to original sources
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

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

Memory retrieval by 18--30-month-olds: age-related changes in representational flexibility.

Deferred imitation was used to trace changes in memory retrieval by 18-30-month-olds. In all experiments, an adult demonstrated 2 sets of actions using 2 different sets of stimuli. In Experiments 1A and 1B, independent groups of infants were tested immediately or after a 24-hr delay. Each infant was tested with 1 set of stimuli from the original demonstration and 1 set of stimuli that was different. Recall of the target actions when tested with different stimuli increased as a function of age, particularly after a delay. In Experiment 2, infants were provided with a unique verbal label for the stimuli during the demonstration and the test. The verbal label facilitated performance by 24-month-olds tested with different stimuli but had no effect on performance by 18-month-olds. One hallmark of memory development appears to be an age-related increase in the range of effective retrieval cues for a particular memory.

Age Factors↗
PubMed1999

C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction.

Myocardial infarction in humans provokes an acute phase response, and C-reactive protein (CRP), the classical acute phase plasma protein, is deposited together with complement within the infarct. The peak plasma CRP value is strongly associated with postinfarct morbidity and mortality. Human CRP binds to damaged cells and activates complement, but rat CRP does not activate complement. Here we show that injection of human CRP into rats after ligation of the coronary artery reproducibly enhanced infarct size by approximately 40%. In vivo complement depletion, produced by cobra venom factor, completely abrogated this effect. Complement depletion also markedly reduced infarct size, even when initiated up to 2 h after coronary ligation. These observations demonstrate that human CRP and complement activation are major mediators of ischemic myocardial injury and identify them as therapeutic targets in coronary heart disease.

Acute Disease↗
PubMed1999

Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures.

Glucocorticoids are toxic to hippocampal neurons. We report here that the steroid dehydroepiandrosterone protects neurons of primary hippocampal cultures against the toxic effects of corticosterone. Corticosterone (20-500 nM) added for 24h to primary cultures of embryonic day 18 rat hippocampus resulted in significant neurotoxicity. Dissociated cells were grown for at least 10 days, initially in serum-containing medium, but serum was removed before adding steroids for 24 h. Neurotoxicity was measured by counting the number of cells stained either for beta-tubulin III or glial fibrillary acidic protein. Corticosterone-induced toxicity was prevented by co-treatment of the cultures with dehydroepiandrosterone (20-500 nM). Dehydroepiandrosterone on its own had little effect, though the highest concentration used (500 nM) was mildly toxic. Immunohistochemical studies on the nuclear translocation of a range of stress-activated protein kinases showed that stress-activated protein kinases 1, 2, 3 and 4 were all translocated by 10 min exposure to corticosterone (100 nM). Dehydroepiandrosterone (100 nM) attenuated the translocation of stress-activated protein kinase 3, but not the others. These experiments show that dehydroepiandrosterone has potent anti-glucocorticoid actions on the brain, and can protect hippocampal neurons from glucocorticoid-induced neurotoxicity. This protective action may involve stress-activated protein kinase 3-related intracellular pathways, though direct evidence for this has still to be obtained.

Animals↗
PubMed1999

Central serotonin depletion modulates the behavioural, endocrine and physiological responses to repeated social stress and subsequent c-fos expression in the brains of male rats.

Intraspecific confrontation has been used to study effect of depleting central serotonin on the adaptation of male rats to repeated social stress (social defeat). Four groups of adult male rats were used (serotonin depletion/sham: stressed; serotonin depletion/sham: non-stressed). Central serotonin was reduced (by 59-97%) by a single infusion of the neurotoxin 5,7-dihydroxtryptamine (150 microg) into the cerebral ventricles; levels of dopamine and noradrenaline were unaltered (rats received appropriate uptake blockers prior to neurotoxic infusions). Sham-operated animals received solute only. Rats were then either exposed daily for 10 days to a second larger aggressive male in the latter's home cage, or simply transferred to an empty cage (control procedure). Rats with reduced serotonin failed to show the increased freezing behaviour during the pre-defeat phase of the social interaction test characteristic of sham animals. There was no change in the residents' behaviour. Core temperature increased during aggressive interaction in sham rats, and this did not adapt with repeated stress. By contrast, stress-induced hyperthermia was accentuated in serotonin-reduced rats as the number of defeat sessions increased. Basal core temperature was unaffected by serotonin depletion. Heart rate increased during social defeat, but this did not adapt with repeated stress; serotonin depletion had no effect on this cardiovascular response. Basal corticosterone was increased in serotonin-depleted rats, but the progressive reduction in stress response over days was not altered. C-fos expression in the brain was not altered in control (non-stressed) rats by serotonin reduction in the areas examined, but there was increased expression after repeated social stress in the medial amygdala of 5-HT depleted rats. These experiments show that reduction of serotonin alters responses to repeated social stress in male rats, and suggests a role for serotonin in the adaptive process.

5,7-Dihydroxytryptamine↗
PubMed1999

Multiple immediate-early gene expression during physiological and endocrine adaptation to repeated stress.

This study had three objectives: (i) to determine whether there were individual differences in the activation and adaptation of a range of immediate-early genes to repeated restraint stress, (ii) to monitor physiological responses (endocrine, cardiovascular and core temperature) and their adaptation with repeated presentations of the stressor, and (iii) to determine whether any of these indices were altered by dehydroepiandrosterone, an anti-glucocorticoid steroid known to be reduced in humans by stress. Four groups of male rats were implanted subcutaneously with either dehydroepiandrosterone or control (paraffin) pellets. They were then subjected to either a single or 14 days of restraint (60 min/day) or transferred to the testing room (unstressed). Repeatedly stressed animals and their controls were also implanted with intra-abdominal telemetric transmitters to record heart rate and core temperature. Protein products for c-fos,fos-b, c-jun and jun-b were displayed by immunocytochemistry. Areas examined included the ventrolateral septum, hypothalamic paraventricular nucleus, amygdala, locus coeruleus and nucleus of the solitary tract. Acute restraint increased Fos immunoreactivity in all of the areas examined, with the exception of the medial amygdala. The pattern of induction for Fos-B and Jun-B was similar, while c-Jun was only increased in the septum (though constitutive levels were high in most structures compared to the other proteins examined). After 14 days of restraint, immediate-early gene immunostaining was reduced in all of the areas examined, though the extent of adaptation depended on the area and immediate-early gene. In the forebrain, Fos expression adapted in the paraventricular nucleus, amygdala and septum, whereas Fos-B and c-Jun adapted incompletely in the septum. In contrast, Jun-B behaved like Fos. In the brainstem, Fos, Fos-B and Jun-B expression adapted in the nucleus of the solitary tract (but not the locus coeruleus). Corticosterone levels were still raised above baseline, but the response was blunted compared to acute stress. There was marked stress-induced hypothermia which did not adapt during the restraint session, but this returned to baseline during restraint after about five days. In contrast, stress-induced tachycardia did not change during repeated restraint. Dehydroepiandrosterone implants had no clear-cut effects on any immunostaining following acute stress, though there was a trend towards lessened adaptation of the Fos response in the septum after steroid treatment. Dehydroepiandrosterone also did not affect the cardiovascular or endocrine responses to repeated restraint. These experiments show that adaptation of the expression of multiple immediate-early genes occurs during repeated restraint, but in a site-specific pattern in the brains of male rats.

Adaptation, Physiological↗
PubMed1999

Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity.

Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis. SAP may therefore participate in handling of chromatin exposed by cell death. Here we show that mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease. The SAP-/- mice also have enhanced anti-DNA responses to immunization with extrinsic chromatin, and we demonstrate that degradation of long chromatin is retarded in the presence of SAP both in vitro and in vivo. These findings indicate that SAP has an important physiological role, inhibiting the formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and regulating its degradation.

Animals↗
PubMed1999

Leber's hereditary optic neuropathy mitochondrial DNA mutations at nucleotides 11778 and 3460 in multiple sclerosis.

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) can be difficult to distinguish from optic neuritis seen in multiple sclerosis (MS). About half of the LHON patients harbor a mutation at nucleotide (nt) 11778 in the mitochondrial (mt) DNA. In addition, mutations at nt-3460 and nt-14484 have been associated with LHON. An association of LHON and MS has been suspected for decades, and, recently, the LHON nt-11778 and nt-3460 mtDNA mutations have been found in several patients with MS or MS-like disease. We attempted to determine which MS patients should be evaluated further for LHON mutations. METHODS: We screened 103 clinically definite MS patients (age range from 18 to 72 years, 27 men and 76 women) for the LHON nt-11778 and nt-3460 mtDNA mutations. RESULTS: Neither mutation was identified in the patients. CONCLUSIONS: Our findings confirm previous reports which found that both LHON mutations are rare in unselected MS patients. The reports to date suggest that MS patients with peripapillary teleangiectasia typical of LHON, with relatives harboring LHON or with early severe bilateral optic neuropathy, particularly if female, should be further evaluated for LHON mutations.

Adolescent↗
PubMed1999

Low levels of transthyretin in the CSF of depressed patients.

OBJECTIVE: Transthyretin plays an important role in the transport and distribution of thyroid hormone in the central nervous system (CNS). This study replicated and extended to patients with nonrefractory depressive illness a pilot study indicating that patients with refractory major depression have significantly lower levels of CSF transthyretin than do healthy comparison subjects. METHOD: Lumbar punctures were performed in drug-free subjects with DSM-III-R major depression (N = 18), DSM-III-R bipolar disorder, depressed phase (N = 1), and healthy comparison subjects (N = 24). CSF concentrations of transthyretin, determined by a quantitative dot-immunobinding assay, of the depressed patients and comparison subjects were compared by analysis of covariance (ANCOVA). The relationship between CSF transthyretin levels and Hamilton Depression Rating Scale scores was determined in a subset of the depressed patients. RESULTS: CSF concentrations of transthyretin were significantly lower in the depressed patients than in the comparison subjects by ANCOVA. Within the depressed group there was no significant overall correlation between CSF transthyretin levels and Hamilton depression scale scores, but there was a significant inverse correlation in male depressed patients (N = 8) between CSF transthyretin concentrations and Hamilton depression scores. CONCLUSIONS: Lower CSF transthyretin concentrations in depressed patients may reflect either a stable trait in this population or a state change secondary to depression or other factors. Lower CSF transthyretin concentrations may result in altered CNS thyroid hormone homeostasis. Such alteration could account for certain mood and neurovegetative symptoms of depression and might contribute to failure of standard antidepressant treatment.

Adult↗
PubMed1999

A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium.

We have obtained a current profile of multiple sclerosis York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. Patients with relapsing disease were more likely to be employed and have private forms of insurance, whereas patients with progressive types of disease were more likely to have government-supported insurance to cover medical expenses.

Adult↗
PubMed1998

Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo.

The binding of 125I-factor Xa to human aortic smooth muscle cell (SMC) monolayers was studied. At 4 degreesC, 125I-factor Xa bound to a single class of binding sites with a dissociation constant value of 3.6+/-0.7 nM and a binding site density of 11,720+/-1,240 sites/cell (n = 9). 125I-factor Xa binding was not affected by factor X, thrombin, or by DX9065, a direct inhibitor of factor Xa, but was inhibited by factor Xa (IC50 = 5.4+/-0.2 nM; n = 9) and by antibodies specific for the effector cell protease receptor 1 (EPR-1), a well-known receptor of factor Xa on various cell types. A factor X peptide duplicating the inter-EGF sequence Leu83-Leu88-(Gly) blocked the binding of 125I-factor Xa to these cells in a dose-dependent manner (IC50 = 110+/-21 nM). Factor Xa increased phosphoinositide turnover in SMCs and when added to SMCs in culture was a potent mitogen. These effects were inhibited by DX9065 and by antibodies directed against EPR-1 and PDGF. Increased expression of EPR-1 was identified immunohistochemically on SMCs growing in culture and in SMCs from the rabbit carotid artery after vascular injury. When applied locally to air-injured rabbit carotid arteries, antibodies directed against EPR-1 (100 mug/ artery) strongly reduced myointimal proliferation 14 d after vascular injury (65-71% inhibition, P < 0.01). DX9065 (10 mg/kg, subcutaneous) inhibited myointimal proliferation significantly (43% inhibition, P < 0.05). These findings indicate that SMCs express functional high affinity receptors for factor Xa related to EPR-1, which may be of importance in the regulation of homeostasis of the vascular wall and after vascular injury.

Animals↗
PubMed1998

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity.

DHEA, together with DHEAS, is the most abundant steroid in the blood of young adult humans. Levels in humans decline with age and during certain types of illness or stress. We have found that DHEA(S) can prevent or reduce the neurotoxic actions in the hippocampus of the glutamate agonists N-methyl-D-aspartic acid (NMDA) both in vitro and in vivo or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid in vitro. Pre-treatment with DHEA (10-100 nM for 6-8 h) protected primary hippocampal cultures from embryonic day 18 (E18) embryos against NMDA-induced toxicity (0.1, 1, 10, and 50 mM). DHEA added either with NMDA (1 mM) or 1 h later had lesser, but still significant, protective actions. DHEAS also reduced NMDA-induced toxicity (1 mM), although the lowest effective dose of DHEAS (100 nM) was higher than that of DHEA (10 nM). DHEA (100 nM) protected cultured neurons against the neurotoxic actions of either AMPA (25 microM) or kainic acid (1 mM) as well. In vivo, s.c. pellets of DHEA, which resulted in plasma levels that resembled those in young adult humans, protected hippocampal CA1/2 neurons against unilateral infusions of 5 or 10 nmol of NMDA. Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults, these results suggest that decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage.

Animals↗
PubMed1998

Effects of intracerebroventricular dizocilpine (MK801) on dehydration-induced dipsogenic responses, plasma vasopressin and c-fos expression in the rat forebrain.

This study determines the interaction between glutamate receptors and dehydration-induced drinking, vasopressin (AVP) release, plasma osmolality and c-fos expression in the brain of conscious rats. The NMDA receptor antagonist dizocilpine (100 nmol infused into the cerebral ventricles) suppressed drinking following either 22 h water deprivation or intragastric injection of hypertonic saline (1.5 M), attenuated the increased plasma vasopressin induced by dehydration, but had no effects on peripheral hyperosmolality caused by either water deprivation or injections of hypertonic saline. Dizocilpine had no inhibitory effects on feeding after 24 h food deprivation. Dizocilpine also suppressed c-fos expression induced by dehydration in the median preoptic nucleus (MPN), the supraoptic and paraventricular nuclei (SON and PVN), but did not influence c-fos expression in the subfornical organ (SFO). The non-NMDA receptor antagonists CNQX (400 nmol) or DNQX (60 nmol) affected neither the animals' drinking nor c-fos expression induced by dehydration. Double staining showed that suppression of c-fos expression following dizocilpine occurred in the NMDA R1 receptor containing neurons in the hypothalamus. These results suggest that the NMDA-type glutamate receptors may be involved in dehydration induced dipsogenic and neuroendocrinological responses. They complement our earlier findings that dizocilpine also attenuates drinking and c-fos expression following intraventricular infusions of angiotensin II.

Animals↗