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Biomedical subjects

J T Alexander

Publications and source records attributed to J T Alexander.

At least 19 recordsLinked to original sources
PubMed1998

Hypothalamic serotonin in control of eating behavior, meal size, and body weight.

Serotonin (5-HT) has been implicated in the control of eating behavior and body weight. Stimulants of this monoamine reduce food intake and weight gain and increase energy expenditure, both in animals and in humans. This article reviews evidence that supports a role for hypothalamic serotonergic receptor mechanisms in the mediation of these effects. A variety of studies in rodents indicate that, at low doses, 5-HT or drugs that enhance the release of this neurotransmitter preferentially inhibit the ingestion of carbohydrate, more than fat or protein. This phenomenon is mediated, in part, by 5-HT receptors located in various medial hypothalamic nuclei. A negative feedback loop exists between the consumption of this macronutrient and the turnover of 5-HT in the hypothalamus. That is, carbohydrate ingestion enhances the synthesis and release of hypothalamic 5-HT, which in turn serves to control the size of carbohydrate-rich meals. A model is described that proposes the involvement of circulating hormones and glucose in this feedback process. These hormones, including insulin, corticosterone, and the adipose tissue-derived hormone, leptin, have impact on serotonergic function as well as satiety. This model further suggests that 5-HT exerts its strongest effect on appetite at the start of the natural feeding cycle, when carbohydrate is normally preferred. Clinical studies provide evidence that is consistent with the proposed model and that implicates 5-HT in disturbances of eating and body weight disorders.

Animals↗
PubMed1998

Hypothalamic galanin: control by signals of fat metabolism.

The peptide, galanin (GAL), is known to stimulate eating behavior, reduce energy expenditure and affect the release of metabolic hormones. Further, the activity of this peptide in the hypothalamus is modulated, in turn, by these hormones as well as by the ingestion of nutrients. The focus of this investigation is on signals related to nutrient metabolism that may also affect GAL production and, through these neurochemical events, control the ingestion of specific nutrients. Three experiments were performed in normal-weight male, Sprague-Dawley rats. In Experiment 1, the impact of food deprivation (24 and 48 h) was examined. Experiment 2 tested the effects of the compound, 2-deoxy-D-glucose (2-DG, 200 and 400 mg/kg), which blocks glucose utilization, whereas Experiment 3 studied mercaptoacetate (MA, 200 and 600 micromol/kg), which blocks fatty acid oxidation. Eating behavior was examined in some rats, whereas hypothalamic GAL activity was measured in others using radioimmunoassay, immunohistochemistry and in situ hybridization. Both food deprivation and MA (600 micromol/kg), but not 2-DG, affected GAL in the hypothalamus, in one specific area. This is the anterior parvocellular region of the paraventricular nucleus (aPVN), which has a dense concentration of GAL-containing neurons and terminals. GAL gene expression and peptide immunoreactivity in this area is enhanced by food deprivation; in contrast, it is reduced by injection of MA. Other hypothalamic sites with dense concentrations of GAL-containing neurons or fibers are unaffected by food deprivation or MA, and the antimetabolite 2-DG has no impact on GAL in any area. Behavioral measurements indicate that these shifts in GAL activity are accompanied by specific changes in eating behavior. Food deprivation which enhances aPVN GAL produces a marked increase in fat ingestion, whereas MA which reduces aPVN GAL causes a specific reduction in fat ingestion along with a stimulation of protein intake. In contrast, 2-DG preferentially enhances ingestion of carbohydrate. These findings suggest a possible relationship between GAL activity in the aPVN and the metabolic and behavioral processes of fat metabolism and ingestion.

Animals↗
PubMed1998

Neuropeptide Y in relation to carbohydrate intake, corticosterone and dietary obesity.

Neuropeptide Y (NPY) is known to stimulate eating behavior and to be related to behavioral patterns of carbohydrate ingestion. The present report investigates this relationship further to: (1) characterize the specific NPY projection activated in different dietary paradigms; (2) understand associated changes in circulating hormones that may mediate dietary effects on NPY neurons; and (3) determine whether endogenous NPY in conditions with macronutrient diets can be linked to body fat. Male albino Sprague-Dawley rats were tested in two feeding paradigms, one in which the rats were given a choice of the macronutrients, carbohydrate, fat or protein, or the other involving a single diet varying in carbohydrate of fat content. These studies consistently demonstrated a close association between the ingestion of carbohydrate and NPY levels, specifically in the arcuate nucleus (ARC) and medial portion of the paraventricular nucleus (PVN) of the hypothalamus. In addition to revealing increased NPY activity in animals that naturally select high carbohydrate when given a choice of macronutrients, a single diet with 65% carbohydrate (10% fat), compared to a control diet with 45% carbohydrate (30% fat), significantly potentiates NPY gene expression and NPY-immunoreactivity, as determined by in situ hybridization and immunohistochemistry. A further lowering of carbohydrate to 15% has little effect on NPY. Studies of medial hypothalamic fragments in vitro also reveal enhanced NPY release from hypothalamic tissue taken from rats maintained on high-carbohydrate diet. Together with NPY, circulating corticosterone (CORT) levels are also highest in a high-carbohydrate condition and positively correlated with NPY in the ARC. An association between NPY and adiposity in these dietary conditions is indicated by significantly higher levels of NPY in the medial PVN in rats with high body fat, whether consuming a high-carbohydrate of high-fat diet. This evidence, linking NPY to carbohydrate intake and circulating CORT, suggests a role for this peptide in glucose homeostasis that is normally exhibited under conditions when carbohydrate stores are low. Disturbances in this homeostatic process, associated with hyperinsulinemia and higher levels of NPY, become evident with only a moderate rise in body fat on a high-carbohydrate as well as high-fat diet.

Adipose Tissue↗
PubMed1998

A cadaveric and clinical evaluation of endoscopically assisted zygomatic fracture repair.

An endoscopic method of malar arch repair without a bicoronal incision has been recently described. To determine the effectiveness of this new technique, a cadaver study was performed to evaluate the capacity of this technique to (1) restore the anatomic position of a fractured malar arch, (2) rigidly fixate the arch, and (3) avoid injury to the frontal branch of the facial nerve. The technique of endoscopically assisted fracture repair was then applied to a clinical series of consecutive patients presenting with displaced zygomatic fractures with comminution at the malar arch. All cadaveric specimens repaired with this endoscopic technique demonstrated anatomic reduction and rigid fixation of the arch without disruption of the frontal branch of the facial nerve. In all clinical cases, four-point rigid plate fixation (zygomaticofrontal, infraorbital, malar arch, and zygomaticomaxillary buttress) was achieved endoscopically with limited access incisions. All clinical cases demonstrated excellent skeletal restoration of the zygoma on postoperative computed tomography scans. On clinical examination, facial symmetry and normal facial nerve function were observed in all patients after operation.

Cadaver↗
PubMed1998

Behavioral and endocrine traits of obesity-prone and obesity-resistant rats on macronutrient diets.

Patterns of eating behavior, body weight gain, and hormone changes were examined in normal-weight albino Sprague-Dawley rats on macronutrient diets. These diets consisted of either three separate jars with pure macronutrients, fat, carbohydrate and protein, from which to choose, or a single diet with different concentrations of fat and carbohydrate. Similar patterns on the choice-diet and single-diet paradigms were observed. During the first 7-10 days on these diets but not subsequently, the rats consuming a fat-rich diet exhibit significant hyperphagia, an increase in both total and fat intake that produces higher body weight gain. Compared with a 10% fat diet, a 30% fat diet is associated with a decline in insulin and corticosterone (CORT) levels, whereas a 60% fat diet produces an increase in circulating glucose. Levels of glucose are positively correlated with fat intake, and together these measures are consistently related to body fat. These relationships are most strongly expressed in rats that consume a fat-rich diet with >30% fat. Whereas insulin levels are also positively related to body fat, CORT is inversely related in these normal-weight subjects. In animals consuming a high-fat diet, a clear separation can be seen between "obesity-prone" (OP) rats with 100% greater body fat than "obesity-resistant" (OR) rats. The OP rats, which consume 15% more total calories, have significantly higher insulin and glucose levels. In animals that consume a diet with >30% fat, it is the OP but not the OR rats that exhibit a positive relation between fat intake, glucose levels, and body fat and reveal an additional association between carbohydrate intake, insulin, and body fat. Thus these rats on macronutrient diets exhibit distinct traits that relate behavior to hormone disturbances and adiposity and distinguish subjects that are prone vs. resistant to obesity.

Adipose Tissue↗
PubMed1998

Gonadal steroids and hypothalamic galanin and neuropeptide Y: role in eating behavior and body weight control in female rats.

The neuropeptides, galanin (GAL) and neuropeptide Y (NPY), based on studies in male rodents, are believed to have a role in controlling energy balance, both nutrient ingestion and metabolism. Whereas these peptides are also involved in reproduction, little is known about their specific function in energy balance in females. In rats consuming lab chow or macronutrient diets, measurements across the estrous cycle were taken of hypothalamic GAL and NPY, using RIA and immunohistochemistry; of the circulating hormones, estradiol, progesterone, and LH; and also of food intake and body weight. Levels of GAL and NPY peak during the proestrous phase of the female cycle when circulating estradiol and progesterone also rise. As previously reported for GAL, this peak is detected in two areas, the medial preoptic area (MPOA; +110%; P < 0.05) and the external zone of the median eminence (+57%; P < 0.05). In addition, this proestrous peak is seen in the paraventricular nucleus (PVN), specifically the anterior parvocellular portion (+35%; P < 0.05). Similarly, NPY rises during proestrous in the medial region of the PVN (+21%; P < 0.05) in addition to the MPOA (+78%; P < 0.05) and arcuate nucleus (+35%; P < 0.05). This peak in peptide levels is accompanied by an increase in caloric intake in rats receiving the lab chow diet and a specific increase in preference for fat in rats receiving macronutrient diets. Animals showing a preference for a fat-rich diet exhibit higher levels of GAL in the MPOA as well as the PVN and median eminence and also of NPY specifically in the MPOA. These peptides in the MPOA are similarly enhanced in animals with greater body fat, independent of diet. This evidence suggests that in the female rat, both GAL and NPY in the MPOA may contribute to the overeating and increased weight gain that occur during a fat-rich diet.

Animals↗
PubMed1994

Galanin-containing neurons in the paraventricular nucleus: a neurochemical marker for fat ingestion and body weight gain.

The physiological function of the peptide galanin (Gal) remains to be established. It is known to exist in high concentrations within the hypothalamus and to modulate the secretion of specific hormones, as well as to potentiate food consumption. Our study provides evidence for an essential function of neuronal Gal, within a specific hypothalamic area, in stimulating the behavioral process of fat ingestion and body weight gain. Through analyses of peptide levels via RIA and of gene expression via in situ hybridization, a close positive association is established between Gal in the paraventricular nucleus (PVN), particularly its midlateral region, and fat ingestion. No such relationship is detected for Gal in other brain areas or between PVN Gal and ingestion of carbohydrate or protein, supporting the behavioral and anatomical specificity of this relationship. Through PVN injection studies with antisense oligonucleotides to Gal mRNA, a dramatic decline in fat ingestion and body weight suggests that endogenous Gal contributes to the natural appetite for fat. Thus, Gal in the PVN is identified as a neurochemical marker for fat ingestion and, consequently, body weight gain.

Analysis of Variance↗
PubMed1994

Hypothalamic neuropeptide Y and its gene expression: relation to light/dark cycle and circulating corticosterone.

The hypothalamic neuropeptide Y (NPY) system, along with levels of circulating corticosterone (CORT), were examined in rats at different times across the light/dark cycle. Tissue samples were taken from the mediobasal hypothalamus (MBH), which contains the primary hypothalamic NPY cell group of the arcuate nucleus (ARC), and the mediodorsal (MDH) hypothalamus, which contains the paraventricular and dorsomedial nuclei that receive a dense NPY innervation from the ARC. In these dissections, measurements of NPY mRNA and peptide levels were taken using a solution hybridization/nuclease protection assay procedure and radioimmunoassay. The results demonstrate that (i) NPY mRNA levels in the MBH, but not MDH, vary significantly in relation to the light/dark cycle, showing a sharp rise 4-6 h before dark onset, sustained high levels over the next 3-4 h and then, a sharp decline 1 h before dark onset; (ii) this rise in NPY mRNA in the MBH before dark onset, while associated with stable levels of MBH NPY during this time, is followed 2-4 h later, around dark onset, by a rise in NPY peptide levels of the MDH simultaneous to a decrease in NPY levels of the MBH; (iii) levels of circulating CORT shift dramatically across the light-dark cycle, exhibiting an increase from basal levels (< 0.3 microgram/dl) to 5 micrograms/dl approximately 4 h before dark onset, a further rise that peaks at 26 micrograms/dl around dark onset, and then a significant decline to 16 micrograms/dl at 2 h after dark onset; and (iv) there exists a positive relationship between CORT and NPY mRNA or peptide levels in the MBH during the 4-6 h before dark onset, while in the MDH, a positive relationship between this steroid and NPY peptide levels is obtained at dark onset. It is proposed that these rhythms, involving a predark rise in CORT and NPY gene expression leading to a peak in CORT and peptide levels at dark onset, are active in stimulating feeding behavior, particularly carbohydrate ingestion, which predominates at that time.

Adrenocorticotropic Hormone↗
PubMed1994

Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion.

Neuropeptide Y (NPY), which is synthesized in neurons of the arcuate nucleus (ARC) that project to different hypothalamic nuclei, is known to have potent effects on eating behavior and hormone secretion after hypothalamic administration. To test the hypothesis that endogenous NPY is essential for the normal expression of these responses, the present study used to unmodified antisense oligodeoxynucleotides (ODNs) to disrupt the synthesis of NPY in the ARC and to examine the impact of this disturbance on nutrient intake, as well as on circulating levels of insulin and the adrenal steroids, corticosterone and aldosterone. Brain-cannulated rats maintained on macronutrient diets were given daily, bilateral injections, over a 4-day period, of NPY antisense ODNs, sense ODNs or saline into the ARC. The NPY antisense ODNs produced a significant decline (-33% relative to sense ODNs and -40% relative to saline, P < 0.05) in NPY levels in this nucleus, without causing any direct neural damage. Peptide levels in other hypothalamic areas, namely, the paraventricular nucleus and medial preoptic nucleus, were not significantly affected. In association with this reduction in ARC NPY, the antisense-treated animals exhibited a significant decrease in feeding behavior measured during the first 90 min of the natural feeding cycle, as well as over the 24-h period. In the 90-min interval, both carbohydrate and fat intake were suppressed by 65-70% (P < 0.05, relative to both saline and sense ODNs control scores).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1993

Meal patterns and macronutrient intake after peripheral and PVN injections of the alpha 2-receptor antagonist idazoxan.

Studies with idazoxan (IDA), a specific alpha 2-noradrenergic receptor antagonist, demonstrate effects on feeding behavior opposite to those observed with norepinephrine in the paraventricular nucleus (PVN) and peripheral injection of the alpha 2 agonist clonidine. Administration of IDA, both intraperitoneally (IP) and into the PVN at the onset of the nocturnal feeding cycle, caused a dose-related, selective suppression of carbohydrate intake 90 min after injection. To characterize further the impact of this antagonist on macronutrient intake, we examined in IDA-injected animals the macrostructure of feeding using computer-assisted analyses of meal patterns. Both IP and PVN administration of IDA produced a selective suppression of carbohydrate intake, primarily during the first meal of the feeding cycle. This effect occurred through significant reductions in meal size, diet composition, feeding time, and feeding rate for this nutrient. Idazoxan administration into the PVN continued to decrease carbohydrate intake in the next two meals and reduced the satiating impact of this nutrient. In contrast to this immediate change in carbohydrate intake, PVN IDA reduced protein intake after a latency of 4 h. although fat intake was suppressed only after a latency of 7 h. An increase in total meal number and a decrease in the average meal size across the 12-h dark cycle were seen after PVN IDA administration. These results, showing effects of peripheral and PVN-injected IDA on carbohydrate intake, suggest a possible physiological role of endogenous PVN alpha 2-noradrenergic receptors in modulating natural patterns of carbohydrate feeding at the onset of the dark period.

Adrenergic alpha-Antagonists↗
PubMed1993

Effects of serotonin and the serotonin blocker metergoline on meal patterns and macronutrient selection.

Serotonin [5-hydroxytryptamine(5-HT)] in the paraventricular nucleus (PVN) of rats has a suppressive effect on feeding behavior and causes a selective decrease in carbohydrate ingestion, specifically at the onset of the natural (dark) feeding period. Studies conducted here provide further evidence for this phenomena, showing a similar dose-related decrease in carbohydrate ingestion at dark onset after PVN injection of 5-HT or of the agonists, d-norfenfluramine or fluoxetine, which act through endogenous 5-HT. To further characterize the effects of this indoleamine on the macrostructure of feeding, a computer-automated data acquisition system was used to analyze macronutrient feeding patterns in freely feeding animals maintained on the pure diets of protein, carbohydrate, and fat. Results indicate that PVN administration of 5-HT at dark onset decreases intake of the carbohydrate nutrient by decreasing meal size, feeding time, and feeding rate for this nutrient and increasing the satiating effect of carbohydrate. These effects, which occur specifically during the first meal after injection, are opposite those seen after peripheral administration of the 5-HT receptor antagonist, metergoline. This drug stimulates feeding through a selective increase in carbohydrate intake, characterized by an increase in meal size, percent composition, and feeding time for this nutrient and a decrease in the satiety ratio for carbohydrate. These results implicate the serotonergic system in the termination of carbohydrate-rich meals that are prevalent during the early hours of the natural feeding cycle.

Animals↗
PubMed1993

Pregnancy and discogenic disease of the spine.

Low back pain is common during pregnancy and is of moderate or severe intensity in about one fourth of all pregnancies. The etiology is multifactorial but in most cases is related to the physical and physiologic changes brought about by pregnancy. For most women, the pain resolves spontaneously, although they remain at higher risk for increased LBP in future pregnancies and for the development of symptomatic disc disease in later life. Many of the common treatments for LBP are contraindicated or must be modified in this setting. Neurologically symptomatic herniated discs are rare during pregnancy, yet, when indicated, pregnant women can safely undergo surgery.

Diagnosis, Differential↗
PubMed1992

A simple method of removing residual intrathoracic air post-thoracotomy in children.

A simple and effective method of aspirating residual intrathoracic air is described. This method can be used when air leaks or persistent fluid accumulations are not expected. This technique may be easily adapted for use in older children or adults when similar circumstances are present. Standard postoperative monitoring, including serial roentgenogram of the chest, should be used to verify appropriate pulmonary re-expansion.

Air↗
PubMed1989

The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model.

Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 +/- 14.6 and 35.8 +/- 6.0, respectively, mean +/- standard error of the mean) were larger (p less than 0.05) than in control animals (61.4 +/- 6.4 and 14.6 +/- 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

Animals↗
PubMed1989

The effect of intravenous interleukin-2 on brain water content.

Parenteral treatment with interleukin-2 (IL-2) is effective against certain advanced cancers outside the central nervous system. Prior to commencement of Phase II trials in patients with brain tumors, the neurological and neuroradiological features of 10 patients treated with intravenous administration of repeated doses of IL-2 were studied. Three patients had malignant gliomas, and seven patients had extracranial cancer without evidence of intracranial metastasis. All were treated with intravenous doses of 10(5) U/kg three times daily for up to 5 days. The patients with gliomas received cranial computerized axial tomography (CT) scans before IL-2 therapy was initiated and during the later stages of treatment. The patients with extracranial cancer underwent T2-weighted magnetic resonance (MR) imaging before and later during therapy. After two to 11 doses of IL-2, the patients with gliomas had marked neurological deterioration that was associated with a mild to marked increase in peritumoral edema and mass effect visible on CT scans. With cessation of treatment and appropriate supportive care, all returned to their pretreatment state. The patients with extracranial cancer were either neurologically unchanged or underwent minor transient changes in mental status (lethargy and confusion). In these patients, the MR signal intensity was quantified and compared in eight anatomic regions of interest. In six of the seven patients, there were increases in gray and white matter signal intensity consistent with increased cerebral water content. The percentage changes (means +/- standard error of the means) were 12.6% +/- 7.3% in the gray matter and 17.0% +/- 6.2% in the white matter. This study demonstrates that treatment with a high parenteral dose of IL-2 is not tolerated by patients with gliomas due to increased cerebral edema. In patients with extracranial cancer but no brain disease, parenteral IL-2 induces an increase in the cerebral water content of both gray and white matter.

Brain Chemistry↗
PubMed1987

Introduction.

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Historiography↗