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Biomedical subjects

J Hastings

Publications and source records attributed to J Hastings.

At least 19 recordsLinked to original sources
PubMed2001

Noradrenaline synthesis, release and vesicular transport in the rat brain following subarachnoid haemorrhage.

The present study was designed to estimate the release of noradrenaline, and to evaluate the efficiency of noradrenaline vesicular transport, as indicated from measures of dihydroxyphenylglycol (DHPG), and synthesis in the medulla and hypothalamus following subarachnoid haemorrhage in rats. Subarachnoid haemorrhage was induced by the injection of homologous blood into the cisterna magna (n = 11). Sham operated animals served as controls (n = 11). Three days following subarachnoid haemorrhage, medulla and hypothalamus were dissected and placed in an in vitro superfusion system. Exposure to K(+) (50 mM) for 2 min served as a stimulus for the release of the neurotransmitter noradrenaline, its precursor (dihydroxyphenylalanine [DOPA]) and intraneuronal metabolite, DHPG. Basal noradrenaline overflow from both the medulla and hypothalamus were similar in the two groups of rats but basal DOPA overflow from the medulla was significantly reduced in the subarachnoid haemorrhage animals (0.97 +/- 0.15 vs. 1.97 +/- 0.38 pg/10 min/mg, p < 0.01). Administration of K(+) induced the release of noradrenaline, the response from the medulla in the subarachnoid haemorrhage group being attenuated (p < 0.01) compared with the sham operated animals (174% and 240%, respectively). K(+) induced a similar release of noradrenaline from the hypothalamus in both groups of rats (239% in sham animals and 283% in the subarachnoid haemorrhage group). The overflow of DHPG from both the hypothalamus and medulla was similar in both groups of animals. Our results suggest that the diminution in noradrenaline release from the medulla occurs as a result of a reduction in the rate of noradrenaline synthesis and release.

Animals↗
PubMed2001

Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects.

OBJECTIVES: We sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects. BACKGROUND: Although the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown. METHODS: We assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 +/- 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose. RESULTS: Low dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 +/- 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 +/- 1 mm Hg (p < 0.001) and mean arterial pressure by 6 +/- 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover; however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 +/- 120 to 564 +/- 115 pmol/min), but was reduced in patients with CHF (976 +/- 133 to 656 +/- 127 pmol/min, p < 0.01). CONCLUSIONS: Our results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.

Chronic Disease↗
PubMed2001

Sympathetic nervous system and insulin resistance: from obesity to diabetes.

As the world faces an obesity "epidemic," the mechanisms by which overweight is translated into insulin resistance, hypertension, and diabetes need to be better understood. Although the processes of transition remain uncertain, overactivity of the sympathetic nervous system appears pivotal. In obesity, there is stimulation of sympathetic outflow to the kidneys, evident in increased rates of spillover of noradrenaline into the renal veins, and to skeletal muscle vasculature, demonstrated with microneurography. The cause is unclear, but possibly involves the stimulatory action of leptin released from adipose tissue, or from within the brain, for which there is recent evidence in human obesity. The high renal sympathetic tone contributes to hypertension development by stimulating renin secretion and through promoting renal tubular reabsorption of sodium. Neurally mediated skeletal muscle vasoconstriction reduces glucose delivery and uptake in muscle. Impairment of glucose uptake by skeletal muscle is a hallmark of insulin resistance syndromes. Pharmacologic sympathetic nervous suppression within the central nervous system with imidazoline receptor-binding agents such as rilmenidine is a logical therapeutic approach for lowering blood pressure (BP) in patients with essential hypertension, in whom sympathetic activity is often increased. In addition, drugs of this class appear to have the capacity to favorably modify insulin sensitivity, which has particular relevance in the treatment of hypertensive diabetic patients. In the hypertension accompanying maturity onset obesity, with recent recommendations from advisory bodies setting lower goal BP, and with these lower targets often being reached only with combinations of antihypertensive agents, it is advisable that all drugs used in combination therapy have a favorable or at least a neutral effect on insulin resistance.

Antihypertensive Agents↗
PubMed2001

Sympathetic nerve biology in essential hypertension.

1. Although the importance of sympathetic nervous activation in the pathogenesis of essential hypertension is well documented, the exact pathophysiology of the sympathetic nervous dysfunction present remains to be delineated. There are several possible explanations for the increased spillover of noradrenaline from the kidneys and heart to plasma, a key piece of evidence supporting the neurogenic basis of essential hypertension, in addition to the obvious one of an increased rate of sympathetic nerve firing. 2. The possibility that there may be an increase in the density of sympathetic innervation in human hypertension, well documented in the spontaneously hypertensive rat, is currently under investigation by us. 3. Adrenaline cotransmission is present in the cardiac sympathetic nerves of patients with essential hypertension, presumptive evidence of their exposure to high levels of stress and a possible basis for the observed increase in cardiac noradrenaline spillover, through presynaptic augmentation of noradrenaline release. 4. Phenotypic evidence exists also of faulty noradrenaline reuptake into the sympathetic nerves of the heart in essential hypertension, an abnormality that would amplify the sympathetic neural signal by impairing removal of noradrenaline from the synaptic cleft.

Aging↗
PubMed1999

Portal glucose infusion increases hepatic glycogen deposition in conscious unrestrained rats.

It has been demonstrated in the conscious dog that portal glucose infusion creates a signal that increases net hepatic glucose uptake and hepatic glycogen deposition. Experiments leading to an understanding of the mechanism by which this change occurs will be facilitated if this finding can be reproduced in the rat. Rats weighing 275-300 g were implanted with four indwelling catheters (one in the portal vein, one in the left carotid artery, and two in the right jugular vein) that were externalized between the scapulae. The rats were studied in a conscious, unrestrained condition 7 days after surgery, following a 24-h fast. Each experiment consisted of a 30- to 60-min equilibration, a 30-min baseline, and a 120-min test period. In the test period, a pancreatic clamp was performed by using somatostatin, insulin, and glucagon. Glucose was given simultaneously either through the jugular vein to clamp the arterial blood level at 220 mg/dl (Pe low group) or at 250 mg/dl (Pe high group), or via the hepatic portal vein (Po group; 6 mg. kg(-1). min(-1)) and the jugular vein to clamp the arterial blood glucose level to 220 mg/dl. In the test period, the arterial plasma glucagon and insulin levels were not significantly different in the three groups (36 +/- 2, 33 +/- 2, and 30 +/- 2 pg/ml and 1.34 +/- 0.08, 1. 37 +/- 0.18, and 1.66 +/- 0.11 ng/ml in Po, Pe low, and Pe high groups, respectively). The arterial blood glucose levels during the test period were 224 +/- 4 mg/dl for Po, 220 +/- 3 for Pe low, and 255 +/- 2 for Pe high group. The liver glycogen content (micromol glucose/g liver) in the two Pe groups was not statistically different (51 +/- 7 and 65 +/- 8, respectively), whereas the glycogen level in the Po group was significantly greater (93 +/- 9, P < 0.05). Because portal glucose delivery also augments hepatic glycogen deposition in the rat, as it does in the dogs, mechanistic studies relating to its function can now be undertaken in this species.

Animals↗
PubMed1999

Isolation and characterization of novel human immunodeficiency virus integrase inhibitors from fungal metabolites.

We have identified a series of novel inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase by randomly screening natural product extracts using an in vitro biochemical assay designed to identify inhibitors of integrase-catalysed strand transfer. Equisetin recovered from the fungus Fusarium heterosporum and a novel enantiomeric homologue of equisetin from Phoma sp. were isolated as inhibitors of HIV-1 integrase in vitro. Two additional analogues, a novel decalin derivative, integric acid, and oteromycin were also discovered to be inhibitors of integrase. Equisetin and related compounds inhibit 3' end-processing and strand transfer as well as disintegration catalysed by either the full-length enzyme or the truncated integrase core domain (amino acids 50-212). These compounds also inhibit strand transfer reactions catalysed by stable complexes assembled in vitro and integration reactions catalysed by pre-integration complexes isolated from HIV-1-infected cells. The compounds described in this report are structurally novel and mechanistically distinct from many previously described inhibitors of HIV-1 integrase. These results demonstrate the utility of using an appropriately configured assay to identify compounds that are effective post-assembly and the potential of isolating novel integrase inhibitors from complex natural product extracts.

Base Sequence↗
PubMed1997

Equivalent inhibition of half-site and full-site retroviral strand transfer reactions by structurally diverse compounds.

In vitro assay systems which use recombinant retroviral integrase (IN) and short DNA oligonucleotides fail to recapitulate the full-site integration reaction as it is known to occur in vivo. The relevance of using such circumscribed in vitro assays to define inhibitors of retroviral integration has not been formerly demonstrated. Therefore, we analyzed a series of structurally diverse inhibitors with respect to inhibition of both half-site and full-site strand transfer reactions with either recombinant or virion-produced IN. Half-site and full-site reactions catalyzed by avian myeloblastosis virus and human immunodeficiency virus type 1 (HIV-1) IN from virions are shown to be equivalently sensitive to inhibition by compounds which inhibit half-site reactions catalyzed by the recombinant HIV-1 IN. These studies therefore support the utility of using in vitro assays employing either recombinant or virion-derived IN to identify inhibitors of integration.

Animals↗
PubMed1994

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds.

Synthesis of influenza virus mRNA is primed by capped and methylated (cap 1, m7GpppXm) RNAs which the virus derives by endonucleolytic cleavage from RNA polymerase II transcripts in host cells. The conserved nature of the endonucleolytic processing provides a unique target for the development of antiviral agents for influenza viruses. A series of 4-substituted 2,4-dioxobutanoic acid compounds has been identified as selective inhibitors of this activity in both influenza A and B viruses. These inhibitors exhibited 50% inhibitory concentrations in the range of 0.2 to 29.0 microM for cap-dependent influenza virus transcription and had no effect on the activity of other viral and cellular polymerases when tested at 100- to 500-fold higher concentrations. The compounds did not inhibit the initiation or elongation of influenza virus mRNA synthesis but specifically inhibited the cleavage of capped RNAs by the influenza virus endonuclease and were not inhibitory to the activities of other nucleases. Additionally, the compounds specifically inhibited replication of influenza A and B viruses in cell culture with potencies comparable to the 50% inhibitory concentrations obtained for transcription.

Animals↗
PubMed1992

Osteoporosis in spinal cord injury: using an index of mobility and its relationship to bone density.

This study was undertaken to improve quantification of the extent of osteoporosis that accompanies spinal cord injuries (SCI) of various types, using single photon densitometry. In this study, we evaluated subjects with complete and incomplete SCI to determine whether there is a correlation between mobility and bone density. We created an index to rank the various levels of mobility among SCI subjects. Mobility index parameters ranged from 1, for complete immobility, to 9, for the full mobility of the uninjured control population. Incomplete SCI subjects (motor and/or sensory) ranked from 2 to 8 on the mobility scale. We also attempted to define clearly the mechanism of osteoporosis in those with predominantly unilateral SCI (Brown-Sequard syndrome). Using single photon absorptiometry (SPA), we found a strong correlation between our mobility index and observed bone density. These observations clearly show that osteoporosis is affected by the subject's level of physical activity. These observations also support the hypothesis that SCI individuals benefit from efforts to maintain a standing posture with some regularity. This effort to improve bone density slows the development of osteoporosis, a process that results in physical impairments in the SCI population.

Absorptiometry, Photon↗
PubMed1990

Parenteral nutrition supplemented with short-chain fatty acids: effect on the small-bowel mucosa in normal rats.

When enteral nutrition is excluded from animals maintained solely with total parenteral nutrition (TPN), atrophy of the intestinal mucosa is observed. Short-chain fatty acids (SCFAs) are produced in the colon by the fermentation of dietary carbohydrates and fiber polysaccharides and have been shown to stimulate mucosal-cell mitotic activity in the intestine. This study compared the effects of an intravenous and an intracecal infusion of SCFAs on the small-bowel mucosa. Rats received standard TPN, TPN with SCFAs (sodium acetate, propionate, and butyrate), TPN with an intracecal infusion of SCFAs, or rat food. After 7 d jejunal and ileal mucosal weights, DNA, RNA, and protein were determined. Standard TPN produced significant atrophy of the jejunal and ileal mucosa. Both the intracecal and intravenous infusion of SCFAs significantly reduced the mucosal atrophy associated with TPN. The intravenous and intracolonic infusion of SCFAs were equally effective in inhibiting small-bowel mucosal atrophy.

Animals↗
PubMed1988

Characteristics of male spouse abusers consistent with personality disorders.

Researchers and clinicians have tended to minimize the role of psychological characteristics of male spouse abusers, which has restricted the selection of potentially appropriate treatment interventions. A review of clinical literature on psychological characteristics of male batterers, including some studies incorporating psychometric testing, suggests that many of the characteristics of batterers are consistent with DSM-III criteria for personality disorders. Several authors have defined subtypes of batterers, which can be associated with specific types of personality disorders. Treatment programs for male spouse abusers should address the specific problems presented by patients with personality disorders, including alcohol-abusing batterers, a particularly difficult group to treat.

Alcoholism↗
PubMed1986

Electrothermal debracketing. Part II. An in vivo study.

Part I of this study described the procedure of electrothermal removal of brackets (ETD) that were bonded on human teeth. The temperature generated at the pulpal wall due to ETD was significantly lower than an established primate threshold. Part II of the study investigated the histologic features of the pulp after ETD. There was some cellular modification that corresponded to placement of the extraction forceps, but there was no evidence of cellular pathosis or modification due to ETD. The data in Parts I and II of this study suggest that ETD is a physiologically acceptable alternative to conventional debracketing techniques.

Adolescent↗
PubMed1986

Electrothermal debracketing. Part I. An in vitro study.

The contemporary techniques of bracket removal require shearing or compression forces. The force necessary to separate the bracket from the tooth is sufficient to cause deformation of the bracket and, in some cases, is capable of damaging the tooth. An alternative to conventional bracket removal is electrothermic debracketing (ETD). ETD is the technique of removing bonded brackets from enamel surfaces with a cordless battery device that generates heat. The heat is transferred to the bracket by a blade that is placed in the bracket slot. The bracket is firmly held by a thumb-activated lock-on arm of the ETD unit. When the heat applied to the bracket is transferred to and deforms the adhesive-bracket interface, the bracket can be gently lifted from the enamel surface without distortion of the bracket or excessive force to the underlying enamel. Part I of this study measured the in vitro rise in temperature at the pulpal wall when ETD is used. These data are correlated with established primate threshold temperatures that have been reported to cause pulpal pathosis. All ETD procedures in the sample elicited pulpal wall temperatures that were significantly below the primate baseline. When water spray was used in conjunction with ETD, the mean ultimate increase in pulpal wall temperature was less than 1 degree C.

Dental Bonding↗