Biomedical subjects

R B Harris

Publications and source records attributed to R B Harris.

At least 37 records · Page 2Linked to original sources

PubMed2000

Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin.

Limonene has demonstrated efficacy in preclinical models of breast and colon cancers. The principal sources of d-limonene are the oils of orange, grapefruit, and lemon. The present case-control study was designed to determine the usual citrus consumption patterns of an older Southwestern population and to then evaluate how this citrus consumption varied with history of squamous cell carcinoma (SCC) of the skin. In this Arizona population, 64.3% and 74.5% of the respondents reported weekly consumption of citrus fruits and citrus juices, respectively. Orange juice (78.5%), orange (74.3%), and grapefruit (65.3%) were the predominant varieties of citrus consumed. Peel consumption was not uncommon, with 34.7% of all subjects reporting citrus peel use. We found no association between the overall consumption of citrus fruits [odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.73-1.32] or citrus juices (OR = 0.97, 95% CI = 0.71-1.31) and skin SCC. However, the most striking feature was the protection purported by citrus peel consumption (OR = 0.66, 95% CI = 0.45-0.95). Moreover, there was a dose-response relationship between higher citrus peel in the diet and degree of risk lowering. This is the first study to explore the relationship between citrus peel consumption and human cancers. Our results show that peel consumption, the major source of dietary d-limonene, is not uncommon and may have a potential protective effect in relation to skin SCC. Further studies with large sample sizes are needed to more completely evaluate the interrelationships between peel intake, bioavailability of d-limonene, and other lifestyle factors.

Adult↗

PubMed2000

Tea intake and squamous cell carcinoma of the skin: influence of type of tea beverages.

Differences in tea drinking habits are likely to vary by populations and could contribute to the inconsistencies found between studies comparing tea consumption and cancer risk. A population-based case-control study was used to evaluate how usual tea consumption patterns of an older population (n = 450) varied with history of squamous cell carcinoma (SCC) of the skin. A detailed tea questionnaire was developed to assess specific tea preparation methods and patterns of drinking. In this southwestern United States population, black tea was the predominant variety of tea consumed. We found no association between the broad definition of any tea consumption and skin SCC. However, the adjusted odds ratios (ORs) for hot and iced black tea intake were 0.63 [95% confidence interval (CI), 0.36-1.10] and 1.02 (95% CI, 0.64-1.63), respectively. Controls were more likely to report usually drinking strong hot tea (OR, 0.74; 95% CI, 0.53-1.03) with increased brewing time (P for trend = 0.03). Adjusting for brewing time, the association between skin SCC and hot black tea consumption suggests a significantly lower risk in consumers of hot tea compared to nonconsumers (OR, 0.33; 95% CI, 0.12-0.87). This is one of the first studies to explore the relation between different types of tea consumption and occurrence of human cancers. Our results show that tea concentration (strength), brewing time, and beverage temperature have major influences on the potential protective effects of hot black tea in relation to skin SCC. Further studies with increased sample sizes are needed to evaluate the interrelationships between preparation techniques, tea type, and other life-style factors.

Adult↗

PubMed1999

The effects of paradoxical sleep deprivation and valine on spatial learning and brain 5-HT metabolism.

We have previously reported that rapid eye movement sleep deprivation (REMSD), induced by the flower pot technique, causes a deficit in reference spatial memory and increases rates of serotonin (5-HT) metabolism in the brain. In this study we used increased concentrations of dietary valine to inhibit tryptophan (TRP) transport across the blood-brain barrier in an attempt to modify the REMSD-induced increase of 5-HT metabolism. Rats were fed either a control diet or the same diet supplemented to 2% by weight valine, and were allocated to one of three experimental groups: cage control (CC), stress tank control (TC), or REMSD. Reference and working spatial memory of all rats was tested in a Morris water maze on Days 2, 3, and 4. REMSD produced a significant decrement in reference memory on Days 2 and 4, independent of dietary condition. The valine diet had a detrimental effect on the reference memory of TC rats on Day 2 but not Day 4. Measurements made on Day 4 indicated that the valine diet decreased brain TRP only in the CC rats. In contrast, the valine diet did not prevent increases in brain TRP or 5-HT metabolism in REMSD rats, and increased hypothalamic and brain stem TRP concentrations and the hippocampal 5-HIAA/5-HT ratio in TC rats. These results indicate that dietary valine does not prevent REMSD-induced changes in spatial memory or serotonin metabolism, although it does reduce brain TRP in nonstressed rats.

Animals↗

PubMed1999

Neuroautoantibody immunoreactivity in relation to aging and stress in apolipoprotein E-deficient mice.

Progressive disruption of both the neuroendocrine and immune systems has been correlated with age-associated pathogenesis in patients with Alzheimer's disease and in mice lacking apolipoprotein E (ApoE). In this study, we examined neuroautoimmune and neuroendocrine activities in relation to aging and stress in ApoE-deficient mice. An elevated level of autoantibodies against brain antigens was found in sera from ApoE-deficient mice compared to that of wild-type mice as early as 7-8 weeks of age. However, there was no significant difference between the two genotypes at this age in the effect of stress on serum corticosterone or autoantibody titers. Higher titers of autoantibodies were observed in approximately 12-week-old ApoE-deficient mice, especially in those exposed to chronic stress. Based on Western analysis, sera from ApoE-deficient mice showed a strong immunoreactivity with approximately 78 kDa and approximately 40 kDa brain abundant polypeptides, approximately 58 kDa non-brain tissue abundant antigen, and others of approximately, 80-82 kDa in both the brain and non-brain tissues. Immunofluorescence confocal microscopy showed that the major cellular components recognized by the autoimmune sera from ApoE-deficient mice were associated with neuronal cell nuclei and fiber-like structures in different regions of the brain, including the frontal cortex, lateral cortex and hippocampus. These results suggest that neuroautoimmunity associated with the aging process and exposure to chronic stress may be involved in early development of neurodegeneration in mice with ApoE-deficiency.

Aging↗

PubMed1999

Using the Internet to teach melanoma management guidelines to primary care physicians.

The aim of this study was to determine whether a brief Internet-based education programme could improve physicians' abilities to manage pigmented skin lesions. A pre-test-post-test assessment was used of subjects' knowledge of skin cancer, confidence in their management abilities and actual ability to recommend appropriate treatment for 20 hypothetical patients with pigmented skin lesions. The setting was the general medicine service of an academic medical centre. Seventeen volunteer medical students, house officers and faculty members took part in the study. Following the pre-test, subjects completed a 1-hour computer-based educational programme, distributed via the Internet, presenting a guideline for recognizing and managing potentially malignant pigmented skin lesions. The guideline was based on the ABCD rule and the Glasgow seven-point checklist. The educational programme had a positive effect on the subjects' overall skin cancer knowledge and had significantly positive effects on their confidence and ability to apply the management guideline. Based on the guideline criteria, the subjects made the correct management decision on the clinical scenarios 63.2% of the time before the programme and 74.1% of the time after the programme (P = 0.002). We were able to teach melanoma management guidelines to physicians and medical students using a brief, interactive computer programme distributed via the Internet. Such an approach is more cost-effective than classroom teaching and could be used to improve the clinical skills of practising physicians to recognize and manage early melanomas. This approach to distributed learning could also be used to teach other clinical guidelines to physicians.

Adult↗

PubMed1999

Fatty acid oxidation affects food intake by altering hepatic energy status.

Inhibition of fatty acid oxidation stimulates feeding behavior in rats. To determine whether a decrease in hepatic fatty acid oxidation triggers this behavioral response, we compared the effects of different doses of methyl palmoxirate (MP), an inhibitor of fatty acid oxidation, on food intake with those on in vivo and in vitro liver and muscle metabolism. Administration of 1 mg/kg MP selectively decreased hepatic fatty acid oxidation but did not stimulate food intake. In contrast, feeding behavior increased in rats given 5 or 10 mg/kg MP, which inhibited hepatic fatty acid oxidation to the same extent as did the low dose but in addition suppressed fatty acid oxidation in muscle and produced a marked depletion of liver glycogen. Dose-related increases in food intake tracked dose-related reductions in liver ATP content, ATP-to-ADP ratio, and phosphorylation potential. The findings suggest that a decrease in hepatic fatty acid oxidation can stimulate feeding behavior by reducing hepatic energy production.

Adenosine Diphosphate↗

PubMed1999

Prevention of stress-induced weight loss by third ventricle CRF receptor antagonist.

We previously reported that rats exposed to repeated restraint (3 h/day for 3 days) experience temporary hypophagia and a sustained reduction in body weight compared with nonrestrained controls. Studies described here determined the involvement of central corticotropin-releasing factor (CRF) receptors in the initiation of this chronic response to acute stress. In experiment 1, Sprague-Dawley rats were fitted with cannulas in the lateral ventricle and infused with 50 micrograms of alphahCRF-(9-41) or saline immediately before restraint on each of the 3 days of restraint. The receptor antagonist inhibited hypophagia and weight loss on day 1 of restraint but not on days 2 and 3. In experiment 2, 10 micrograms of alphahCRF-(9-41) or saline were infused into the third ventricle immediately before each restraint. The receptor antagonist totally blocked stress-induced hypophagia and weight loss. These results demonstrate that CRF receptors located in or near the hypothalamus mediate the acute responses to stress that lead to a permanent change in the hormonal or metabolic processes that determine body weight and body composition.

Animals↗

PubMed1999

Sustained effects of repeated restraint stress on muscle and adipocyte metabolism in high-fat-fed rats.

Repeated restraint stress 3 h/day for 3 days in rats causes a temporary hypophagia but a sustained weight loss. We investigated whether poststress changes in peripheral tissue metabolism contributed to these responses. One day after the last restraint, insulin sensitivity, measured by oral glucose tolerance test, was improved in restrained rats. Restraint and pair-fed rats weighed less than controls, but body fat content was the same in all groups. Muscle glucose uptake, measured in vitro, was not changed by treatment, whereas in vitro adipocyte glucose uptake was substantially inhibited only in restrained rats. Adipocytes from restrained rats had elevated rates of fatty acid oxidation but not fatty acid esterification, indicating a shift in energy supply from glucose to fatty acids. Five days after the last restraint, the reduced weight of restrained and pair-fed rats resulted from loss of both lean and fat tissue. These results demonstrate that restraint caused sustained, tissue-specific changes in metabolism that may contribute to changes in body composition and body weight of the rats.

Adipose Tissue↗

PubMed1999

Does beta(3)-adrenoreceptor blockade attenuate acute exercise-induced reductions in leptin mRNA?

We investigated the effect of a single bout of exercise on leptin mRNA levels in rat white adipose tissue. Male Sprague-Dawley rats were randomly assigned to an exercise or control group. Acute exercise was performed on a rodent treadmill and was carried out to exhaustion, lasting an average of 85.5 +/- 1.5 min. At the end of exercise, soleus muscle and liver glycogen were reduced by 88% (P < 0.001). Acutely exercised animals had lower (P < 0.05) leptin mRNA levels in retroperitoneal but not epididymal fat, and this was independent of fat pad weight. To test the hypothesis that beta(3)-adrenergic-receptor stimulation was involved in the downregulation of leptin mRNA in retroperitoneal fat, a second experiment was performed in which rats were randomized into one of four groups: control, control + beta(3)-antagonist, exercise, and exercise + beta(3)-antagonist. A highly selective beta(3)-antagonist (SR-59230A) or vehicle was given by gavage 30 min before exercise or control experiment. Exercise consisted of 55 min of treadmill running, sufficient to reduce liver and muscle glycogen by 70 and 80%, respectively (both P < 0.0001). Again, acute exercise reduced leptin mRNA in retroperitoneal fat (exercise vs. control; P < 0.05), but beta(3)-antagonism blocked this effect (exercise + beta(3)-antagonist vs. control + beta(3)-antagonist; P = 0.42). Unexpectedly, exercise increased serum leptin. This would be consistent with the idea that there are releasable, preformed pools of leptin within adipocytes. We conclude that beta(3)-receptor stimulation is a mechanism by which acute exercise downregulates retroperitoneal adipose tissue leptin mRNA in vivo.

Adipose Tissue↗

PubMed1999

Parabiosis between db/db and ob/ob or db/+ mice.

Genetically obese C57B1/6J-m db/db mice were parabiosed with either lean male db/+ or obese female ob/ob mice. Male db/db mice had lower serum leptin than females, and this was reflected in the amount of protein that crossed the parabiotic union into their partners. Eighteen days post operation, ob/ob partners of db/db mice had increased body temperature, lost 50% body weight and 60% body fat, but maintained carcass protein. The db/+ partners of db/db mice had a normal gut content and (by implication) food intake, did not raise their body temperature, but lost significant amounts of both lean and fat tissue during 25 days of parabiosis. The differences between the db/+ and ob/ob partners of db/db mice may be caused by leptin inhibiting growth of male mice, but not of female mice that are on a slower growth curve, or by the excess lipid in ob/ob mice sparing body protein. The db/db partners of ob/ob mice lost a small amount of body fat, but carcass protein was increased by 30%, compared with their controls. These results imply that leptin stimulated release of a circulating growth factor, possibly through activation of the long-form leptin receptor, in ob/ob partners of db/db mice.

Animals↗

PubMed1999

Development of heparin antagonists with focused biological activity.

Heparin, a complex glycosaminoglycan, has long been used to temporarily render the blood incoagulable during extracorporeal circulation, cardiovascular surgery, and other arterial interventions. But bleeding complications are especially common when the arterial tree is violated, occurring in as many as 10-15% of cases. For cardiovascular surgery and many related interventions, protamine has long been the standard antagonist when acute and complete neutralization of heparin s anticoagulant effect is necessary. Protamine s efficacy is related in part to its total net cationic charge, but unfortunately so is its toxicity. For these reasons, there is renewed interest in developing heparin antagonists which will replace the use of protamine. At Commonwealth Biotechnologies, Inc., we have used a rationale design approach for the preparation of a family of low molecular weight helix peptides which bind heparin with high affinity. For each of the new compounds, we have assessed their ability to bind heparin using isothermal titration calorimetry and circular dichroism spectrometry and have examined potential complexes formed with the anticoagulant pentasaccharide unit of heparin using molecular modeling techniques. The biological potencies of these compounds were assessed in ex vivo experiments where their ability to compete with antithrombin for binding heparin was determined. The best of the compounds, designated HepArrestTM, is highly effective in reversing heparin-mediated and HepArrest is a safer drug than protamine because of reduced adverse hemodynamic side effects compared with those associated with protamine. HepArrest binds low molecular weight heparins and causes reversal of anticoagulation by low molecular weight heparins, as determined by activated partial thromboplastin time, thrombin time, or factor Xa neutralization assays. These highly promising preclinical results indicate that HepArrest is a novel heparin neutralizing agent that may well fill a substantial unmet need for vascular surgeons and cardiac anesthesiologists who perform coronary artery bypass grafts and several other major vascular surgeries, as well as for cardiologists and interventional radiologists.

Animals↗

PubMed1998

The role of CRF2 receptors in corticotropin-releasing factor- and urocortin-induced anorexia.

The experiments presented in this study were designed to assess corticotropin-releasing factor (CRF) receptor subtype mediation of CRF- and urocortin (UCN)-induced decrease in food intake. Male Sprague-Dawley rats were treated with antisense and sense oligonucleotides (ON) to CRF2 receptor mRNAs for 36 h and then received an intracerebroventricular (i.c.v.) injection of CRF, UCN (3 micrograms) or saline. Antisense treatment significantly attenuated CRF- and UCN-induced suppression in food intake and HPA activation. Administration of CRF1 receptor antagonist did not affect the decrease in food intake or activation of the HPA axis induced by i.c.v. infusion of 3 micrograms CRF. The data suggest that down-regulation of CRF2 receptors selectively attenuates CRF- and UCN-induced anorexia and hypothalamo-pituitary-adrenocortical activation in rats.

Animals↗

PubMed1998

Acute and chronic effects of leptin on glucose utilization in lean mice.

Experiments described here show that in vivo glucose uptake is impaired in mice given 30 micrograms leptin by intraperitoneal injection 2 hours before an oral glucose tolerance test (GTT). When mice were infused for 7 days with 10 micrograms/day leptin, the 4-fold increase in circulating leptin caused a transient hypophagia, a sustained weight loss and significantly inhibited insulin release in response to an oral GTT. Adipocytes from these mice were not insulin responsive whereas insulin-stimulated muscle and liver glycogen synthesis were increased. In contrast, leptin added to 2 hour in vitro incubations had an insulin-like effect on muscle glucose utilization and augmented insulin stimulation of adipocyte lipid synthesis. Thus, normal mice treated chronically with leptin develop tissue specific changes in insulin sensitivity and compensate for inhibition of glucose-stimulated insulin release. The contrasting response to acute leptin exposure suggests these changes are not a direct effect of the protein.

Adipocytes↗

PubMed1998

Apolipoprotein-E deficiency results in an altered stress responsiveness in addition to an impaired spatial memory in young mice.

It has been suggested that Alzheimer's disease (AD) is associated with an altered neurotrophic function of apolipoprotein-E (ApoE) and abnormal neuroendocrine activities. In the present study we investigated stress responsiveness of ApoE-deficient mice. Firstly, two sessions of restraint were introduced, 20 min per day for two (session 1) and three (session 2) consecutive days. In session 1, there was no difference between genotypes in open-field activity in response to restraint stress. In session 2, spatial memory was assessed in a Morris Water Maze 'Place Learning Set' task immediately following stress. Restraint stress caused a significant impairment of spatial memory in wild-type mice. The non-restraint ApoE-deficient mice showed a severe impairment of spatial memory similar to that of the restrained wild-type mice. Restraint stress had no obvious effect on spatial memory in ApoE-deficient mice until the third day of testing, when there was a decrease in reference memory compared with their non-restraint controls. In addition, the first session of restraint stress had an inhibitory effect on food intake in wild-type but not ApoE-deficient mice, and a longer-lasting effect on body weight in the wild-type than ApoE-deficient mice. ApoE-deficient mice showed a weaker corticosterone response to the initial restraint stress and a slower descending rate in serum corticosterone level during a 30-min post-stress period than their wild-type controls. However, higher baseline levels and stronger corticosterone responses were observed in ApoE-deficient mice than in wild-type mice when exposed to repeated restraint stress. The expression of ApoE mRNA was upregulated in the hypothalamus in wild-type mice exposed to repeated restraint stress. Taken together, these results demonstrate that ApoE deficiency causes a memory impairment and an altered stress responsiveness in mice.

Analysis of Variance↗

PubMed1998

Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets.

Exposure to the moderate stressor of 3-h restraint for 3 consecutive days causes a temporary drop in food intake but a permanent reduction in body weight in adult rats. Young rats did not show the same response. Food intake of adult rats exposed to repeated restraint was significantly lower than that of controls for 4 days after the end of stress, and there was no rebound hyperphagia. Body weight remained significantly lower for at least 40 days after stress. When the rats were fed a high-fat diet of 80% chow and 20% vegetable shortening (48% kcal fat, 16% protein), lean body mass accounted for all of the weight loss in stressed rats. When the experiment was repeated with a purified high-fat diet containing corn oil and coconut oil as the source of fat (41% kcal fat, 16% protein), weight loss consisted of both lean and fat tissue. There were no sustained changes in single time point measures of corticosterone, insulin, or leptin that could account for the reduced body weight in these rats.

Aging↗

PubMed1998

A leptin dose-response study in obese (ob/ob) and lean (+/?) mice.

This experiment determined the amount of leptin required to correct different abnormalities in leptin-deficient ob/ob mice. Baseline food intakes and body weights of lean (+/?) and obese (ob/ob) C57B1/6J mice were recorded for 7 days. An Alzet miniosmotic pump was placed in the peritoneal cavity of each mouse and delivered 0, 1, 2, 5, 10, or 42 microg/day human leptin for 7 days. In ob/ob mice, 2 microg leptin/day reduced food intake and body weight, and increased hypothalamic and brain stem serotonin concentrations. All fat pads were reduced 35-40% by 10 microg leptin/day, and liver weight, lipid, and glycogen decreased. Serum insulin and glucose were reduced in all leptin-treated ob/ob mice, and levels were normalized by 10 microg/day leptin. Low rectal temperatures of ob/ob mice were corrected by 10 and 42 microg/day leptin. These doses also increased brown adipose tissue uncoupling protein expression. The only responses in lean mice were a transient reduction in food intake and weight loss with 10 or 42 microg/day leptin. This study shows enhanced leptin sensitivity in ob/ob mice and suggests that increased temperature and sympathetic activity are indirect responses to high concentrations of protein.

Animals↗

PubMed1997

Failure to change exploration or saccharin preference in rats exposed to chronic mild stress.

Chronic mild stress (CMS) exposes animals to unpredictable stressors. Reduced consumption of sucrose or saccharin solutions by CMS rats has been used as a putative measure of anhedonia, typical of depression. Our objective was to determine whether saccharin consumption and preference and suppression of exploratory and rearing behaviors in the open field were reliable indicators of CMS-induced behavioral depression. In Experiment 1, male Wistar rats subjected to 6 weeks of CMS consumed significantly less food and gained less weight than controls. CMS did not effect saccharin intake, or preference, measured in a two-bottle test with water. CMS rats exposed to a novel open field showed increased exploration and rearing. In a second test, performed immediately after a novel stress of restraint, there were no differences in exploratory or rearing behavior of CMS and control rats. In Experiment 2, CMS was reduced to 3 weeks and rats were single or group housed in their home cages. Open field activity of CMS rats was similar to that in Experiment 1. Saccharin preference of CMS rats was significantly suppressed when tested after 24 hours of water deprivation, but was not different from controls after 5 hours of water deprivation. In the final experiment Sprague Dawley rats behaved the same as Wistar rats in the CMS paradigm. Therefore, the CMS protocol used in these experiments did not induce behaviors indicative of depression but did cause a mild anorexia and weight loss. Saccharin intake of CMS rats was dependent upon their dehydration state and could not be attributed to stress-induced anhedonia.

Animals↗

PubMed1997

High molecular weight kininogen peptides inhibit the formation of kallikrein on endothelial cell surfaces and subsequent urokinase-dependent plasmin formation.

A sequence of 31 amino acids (S565-K595) in domain 6 of the light chain of high molecular weight kininogen (HK) has previously been shown to be responsible for the binding of plasma prekallikrein (PK) or kallikrein. To find effective peptides that might block binding between HK and PK on cell surfaces, a new series of synthetic peptides has now been prepared that incorporates portions of this binding domain sequence. For mapping the minimal sequence within HK, these new peptides were tested for their ability to compete with HK for binding PK in a cell-free system and on human umbilical vein endothelial cells (HUVEC). In the former, at pH 7.4, the kds for binding between kallikrein and either D567-K595, S565-P594, D567-S593, or D567-T591 were all similar to that for the binding of S565-K595 (0.2 to 0.4 micromol/L), but those for the binding of D568-K595, W569-K595, and D567-P589 were an order of magnitude greater (kd = 2 to 5 micromol/L). D567-S586, the shortest chain length of the N- and C-terminal truncation sequences tested, does not effectively compete with kininogen for kallikrein binding (kd = 100 micromol/L). These results imply that D567-T591, a 25-residue peptide (HK25c), contains sufficient structural information for binding kallikrein in solution. D567-T591 also is the minimum structural sequence to block binding of kallikrein to HUVEC-bound HK (IC50 = 50 nmol/L) and to inhibit PK activation to kallikrein on the cell surface (IC50 = 80 nmol/ L). In addition, D567-T591 also inhibits the generation of kallikrein-activated urokinase, which activates plasminogen to plasmin (IC50 = 100 nmol/L). Thus, HK-derived peptides may be useful compounds for modulating excessive fibrinolysis and hypotension in sepsis and multiple trauma.

Amino Acid Sequence↗