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Biomedical subjects

R A Wise

Publications and source records attributed to R A Wise.

At least 19 recordsLinked to original sources
PubMed2006

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease.

BACKGROUND: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. METHODS: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. RESULTS: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p < 0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for > or =5 year mortality. CONCLUSIONS: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Adult↗
PubMed2005

Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice.

RATIONALE: The rewarding effects of lateral hypothalamic brain stimulation, various natural rewards, and several drugs of abuse are attenuated by D1 or D2 dopamine receptor (D1R or D2R) antagonists. Much of the evidence for dopaminergic involvement in rewards is based on pharmacological agents with limited or "relative" selectivity for dopamine receptor subtypes. Genetically engineered animal models provide a complementary approach to pharmacological investigations. OBJECTIVES: In the present study, we explored the contribution of dopamine D2Rs to (1) brain stimulation reward (BSR) and (2) the potentiation of this behavior by morphine and amphetamine using D2R-deficient mice. METHODS: Wild-type (D2Rwt), heterozygous (D2Rhet), and D2R knockout (D2Rko) mice were trained to turn a wheel for rewarding brain stimulation. Once equivalent rate-frequency curves were established, morphine-induced (0, 1.0, 3.0, and 5.6 mg/kg s.c.) and amphetamine-induced (0, 1.0, 2.0, and 4.0 mg/kg i.p.) potentiations of BSR were determined. RESULTS: The D2Rko mice required approximately 50% more stimulation than the D2Rwt mice did. With the equi-rewarding levels of stimulation current, amphetamine potentiated BSR equally across the three genotypes. In contrast, morphine potentiated rewarding stimulation in the D2Rwt, had no effect in the D2Rhet, and antagonized rewarding stimulation in the D2Rko mice. CONCLUSIONS: D2R elimination decreases, but does not eliminate, the rewarding effects of lateral hypothalamic stimulation. After compensation for this deficit, amphetamine continues to potentiate BSR, while morphine does not.

Amphetamine↗
PubMed2005

Neuroadaptations of total levels of adenylate cyclase, protein kinase A, tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area do not correlate with expression of sensitized or tolerant locomotor responses to cocaine.

Neuroadaptations induced by high-dose cocaine treatment have been hypothesized to persist after the cessation of drug treatment and mediate the expression of sensitization and tolerance to cocaine. We looked for evidence of these neuroadaptations in rats receiving more modest behaviorally effective cocaine treatments. Rats were exposed to either a sensitizing regimen of seven once-daily injections of 15 mg/kg cocaine or a tolerance-producing regimen involving a continuous infusion of the same daily dose. We assessed enzyme activity levels of protein kinase A and adenylate cyclase, and protein levels of tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area. Only protein kinase A activity levels were altered by cocaine treatment, but this alteration persisted for only 7 days, whereas a sensitized locomotor response was still evident at 21 days. Although behavioral tolerance to cocaine was seen the day after the termination of treatment, none of the molecular measures was altered on this or any other day. Thus, although increased protein kinase A activity can temporarily modulate sensitized responses to cocaine, alterations in total levels of the molecules assessed in our study do not correlate with the expression of sensitized or tolerant locomotor responses to cocaine.

Adaptation, Physiological↗
PubMed2001

Striatal hyperthermia associated with arousal: intracranial thermorecordings in behaving rats.

Humans and experimental animals show strong increases in body temperature in response to a variety of stimuli presumed to have stress as their common denominator. To assess the brain's role in this 'emotional' hyperthermia, temperatures were continuously recorded in dorsal and ventral striatum and in deep temporal muscle of freely moving rats exposed to different arousing and mild stress stimuli (placement in the test cage, 20-s sound stimulation, i.v. saline injection, 3-min social interaction with conspecific, and 3-min tail-pinch). The stimuli caused brain hyperthermia of differing degrees but similar pattern, in both the dorsal and ventral striatum. Ventral striatum had approximately 0.4 degrees C higher basal temperature than dorsal striatum, each of these brain temperatures was higher than that in deep temporal muscle. Maximal increases in brain temperature ( approximately 0.8-1.2 degrees C for 20-40 min) occurred upon placement in the test cages, during tail-pinch and during social interaction, all of which were accompanied by behavioral activation. These increases developed with short onset latencies (up to 5-15 s) and always preceded increases in muscle temperature. Significant but smaller increases in brain temperature ( approximately 0.2 degrees C for 4-6 min) were detected after sound stimulation and i.v. saline injection that induced minimal changes in behavior and no change in muscle temperature. Thus, it appears that brain hyperthermia can be triggered by quite different arousing or stressful stimuli that disturb an organism's homeostasis and demand adaptive responding. Although the exact mechanisms of local heat production in brain tissue remain to be confirmed, neuronal activation appears to be the primary triggering force behind changes in brain temperature that are sufficient to affect body temperature. Because most neural processes are temperature-dependent, change in local temperature may result in dramatic modulation of the efficiency of neural processes in situations critical for life-support and during adaptive behavior.

Acoustic Stimulation↗
PubMed2001

The effect of anthropometric and socioeconomic factors on the racial difference in lung function.

African-Americans have lower lung function than whites. However, the relative contributions of body habitus and socioeconomic factors are unknown. To address this question, we analyzed data from 1242 white (806 women, 436 men) and 1084 African-American (696 women, 388 men) asymptomatic, nonsmoking adult participants of the third National Health and Nutrition Examination Survey (NHANES III). African-Americans were poorer, had larger FEV(1)/FVC and body mass index (BMI), but lower sitting height, FEV(1) and FVC than whites. Cross-sectional regression analyses using spirometric, anthropometric, and socioeconomic data were performed separately by sex to investigate racial differences in lung function. Sitting height accounted for 35-39% of the race difference in both sexes. Poverty index accounted for about 7.5% and 2.5% of the racial difference in women and men, respectively, whereas the effect of education accounted for about 2% in women and 4.7% in men. With further adjustment for BMI, we could account for only about half of the racial difference in FEV(1) and FVC. We conclude that the racial difference in lung function is only partially explained by a shorter upper body segment in African-Americans. Although low socioeconomic indicators are related to lower lung function, they explain only a small proportion of this racial difference.

Adult↗
PubMed2001

Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: possible role for dendritically released dopamine.

This study was designed to assess the involvement of D1 dopamine actions in the ventral tegmental area (VTA) on intravenous cocaine self-administration. Rats were trained to self-administer intravenous injections of cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR-1) schedule or a progressive ratio (PR) schedule of reinforcement and then were tested under the influence of bilateral VTA injections of the D1 dopamine receptor antagonist SCH 23390 or the 5-HT2 receptor antagonist ketanserin. SCH 23390 increased cocaine self-administration on the FR-1 schedule but decreased it on the PR schedule. Injections of ketanserin were ineffective, as were injections of SCH 23390 in a site 1 mm dorsal or 1 mm rostral to the effective VTA site. These data suggest a role for dendritically released dopamine, presumably acting through D1 receptors located on the axons of GABAergic or glutamatergic inputs to the VTA, in the effectiveness of cocaine reward.

Animals↗
PubMed2001

Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation.

Rewarding hypothalamic brain stimulation is thought to depend on trans-synaptic activation of high-threshold (and thus rarely directly depolarized by rewarding stimulation) dopaminergic fibers of the medial forebrain bundle. We used in vivo microdialysis and high-performance liquid chromatography coupled with electrochemical or fluorometric detection to investigate the concurrent release of dopamine and glutamate in the nucleus accumbens septi and in the ventral tegmental area, as a function of lateral hypothalamic self-stimulation.Self-stimulation at a variety of stimulation frequencies and pulse widths increased levels of dopamine and its primary metabolites, dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens. Lateral hypothalamic self-stimulation also induced significant increases in ventral tegmental area dopamine and metabolite levels, and the percentage increase of dopamine was higher in this region than in the nucleus accumbens. Local perfusion with the dopamine uptake inhibitor nomifensine (10 microM) increased dopamine levels in the nucleus accumbens about three-fold and potentiated the increase of dopamine levels induced by self-stimulation. Nomifensine perfusion also induced a delayed decrease in nucleus accumbens glutamate levels, and self-stimulation did not modify this effect of the drug. Local perfusion with the D2-type dopamine receptor antagonist raclopride significantly increased both basal and self-stimulation induced dopamine release in the nucleus accumbens. Neither nomifensine nor raclopride perfusion significantly affected the maximal rates of self-stimulation. Perfusion with tetrodotoxin (2 microM) into nucleus accumbens significantly decreased basal and prevented stimulation-induced increases in accumbens dopamine levels but only slightly decreased the rate of self-stimulation. In contrast, perfusion of tetrodotoxin (0.5 microM) into the ventral tegmental area decreased basal and blocked stimulation-induced increases in both nucleus accumbens and ventral tegmental area dopamine levels; this treatment also blocked or strongly inhibited self-stimulation. While it had no effect on glutamate levels in the nucleus accumbens, lateral hypothalamic self-stimulation induced a significant and tetrodotoxin-sensitive increase in glutamate levels in the ventral tegmental area. Taken together, the present results indicate that, across a broad range of stimulation parameters, rewarding lateral hypothalamus stimulation causes major and persistent activation of the mesolimbic dopamine system, and suggest descending glutamatergic fibers in the medial forebrain bundle as a candidate for the directly activated descending pathway in lateral hypothalamus brain stimulation reward.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

The effect of gender on the relationship between body fat distribution and lung function.

Although abdominal obesity, as measured by waist-to-hip ratio (WHR), has long been recognized as a risk factor for metabolic and cardiovascular diseases, little is known about the effect of WHR on pulmonary function, especially in women. In this study of 1094 men and 540 women (18-102 years) from the Baltimore Longitudinal Study of Aging (BLSA), we examined the effect of WHR on forced expiratory volume in 1 s (FEV(1)). Cross-sectional analyses, after accounting for body mass index (BMI) and other variables, showed a strong inverse association of WHR with FEV(1) in men (beta = -1.338, P=.0001) but not in women. Furthermore, larger values of WHR were associated with greater reductions of forced vital capacity (FVC) in men (beta = -1.383, P =.0005) compared to women (beta = -0.679, P =.02). Thus, body fat distribution has independent effects on lung function that are more prominent in men than women.

Adolescent↗
PubMed2001

Novelty-evoked elevations of nucleus accumbens dopamine: dependence on impulse flow from the ventral subiculum and glutamatergic neurotransmission in the ventral tegmental area.

In vivo microdialysis in freely moving rats was used to monitor novelty-evoked elevations in extracellular dopamine in the nucleus accumbens septi (NAS) and to examine the role of the ventral subiculum of the hippocampus and glutamatergic transmission in the ventral tegmental area (VTA) on these elevations. Exposure to novel stimuli evoked investigatory activity and increased nucleus accumbens dopamine. Unilateral injections of the sodium channel blocker tetrodotoxin (0.16 ng/0.5 microL) into the ventral subiculum ipsilateral to the dialysed NAS abolished novelty-evoked elevations in dopamine. Injections of tetrodotoxin into the contralateral VS did not prevent novelty-evoked elevations in nucleus accumbens dopamine. Unilateral perfusion (via microdialysis) of the ionotropic glutamate receptor antagonists kynurenic acid (1 mM) into the ipsilateral but not the contralateral VTA blocked novelty-evoked elevations in nucleus accumbens dopamine. Neither unilateral injections of tetrodotoxin nor unilateral perfusion of kynurenic acid disrupted investigatory behaviour. These data indicate that phasic elevations in nucleus accumbens dopamine evoked by exposure to unconditioned novel stimuli are dependent on impulse flow from the hippocampus and glutamatergic transmission in the VTA.

Animals↗
PubMed2001

Equal sensitivity to cocaine reward in addiction-prone and addiction-resistant rat genotypes.

Rat genotypes tentatively identified as addiction-prone or addiction-resistant on the basis of alcohol preference and locomotor responsiveness to novelty--Lewis versus Fischer strains and Nijmegen high versus low responder lines--differed in time to develop intravenous cocaine self-administration habits, but did not differ in sensitivity to the ability of cocaine reward to summate with lateral hypothalamic brain stimulation reward. Moreover, rats from the Nijmegen low-responder line that initiated self-administration came to do so compulsively and to the same degree as did the Nijmegen high-responder rats. Thus the differences between both sets of genotypes appeared to reflect differences in reactions to the testing situation more than differences in reaction to the reinforcing drug per se.

Alcohol Drinking↗
PubMed2001

Primary pulmonary hypertension is not associated with scleroderma-like changes in nailfold capillaries.

STUDY OBJECTIVES: To determine whether primary pulmonary hypertension (PPH) is associated with scleroderma-like changes in nailfold capillaries. DESIGN: Blinded, prospective, case-control study. SETTING: University medical centers in Baltimore, MD. PATIENTS: Thirty-seven patients with PPH, 15 patients with scleroderma, and 13 healthy control subjects. MEASUREMENTS: Subjects underwent nailfold capillary videomicroscopy of the fourth digits of both hands. Capillary images were evaluated by two blinded, trained graders according to standardized criteria for the presence of scleroderma nailfold changes. RESULTS: The prevalence of scleroderma-associated nailfold changes in patients with PPH (1 of 37 patients) was dramatically lower than that in patients with scleroderma (9 of 15 patients; p < 0.0001). The distribution of nailfold grades for the PPH patients was indistinguishable from that of the healthy control subjects. CONCLUSION: PPH is not associated with scleroderma-like vasculopathy of nailfold capillaries.

Adult↗
PubMed2000

Intravenous self-administration of methamphetamine-heroin (speedball) combinations under a progressive-ratio schedule of reinforcement in rats.

The i.v. self-administration by rats of a polydrug combination of methamphetamine and heroin was explored. The rewarding efficacy of a range of methamphetamine doses (0.0625-2.0 mg/kg/injection) alone or in combination with heroin (12.5 microg/kg/injection) was compared using a progressive-ratio (PR) schedule of reinforcement. Breaking points (BP) for one group of rats were determined at each dose of methamphetamine-alone and for another group at each of the same methamphetamine doses plus the heroin dose. The methamphetamine-heroin combination was associated with higher BPs than methamphetamine alone at all doses of methamphetamine. These data demonstrate that methamphetamine-heroin combinations (speedballs) produce a greater rewarding effect than the identical doses of methamphetamine alone and suggest that enhanced reward may underlie the popularity of speedball abuse.

Animals↗
PubMed2000

Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.

BACKGROUND: Lung inflammation (alveolitis) may cause lung fibrosis in scleroderma. OBJECTIVE: To determine whether cyclophosphamide treatment is associated with retention of lung function and improved survival in scleroderma patients with alveolitis. DESIGN: Retrospective cohort study. SETTING: Johns Hopkins and University of Maryland Scleroderma Center. PATIENTS: 103 patients with scleroderma who had bronchoalveolar lavage or lung biopsy. INTERVENTION: Cyclophosphamide therapy. MEASUREMENTS: 1) Serial measurement of forced vital capacity (FVC) and carbon monoxide diffusing capacity and 2) survival. RESULTS: During a median follow-up of 13 months after bronchoalveolar lavage or biopsy, patients with alveolitis who did not receive cyclophosphamide therapy experienced a decrease in FVC (mean difference, -0.28 L [95% Cl, -0.41 to -0.16 L] and -7.1% of the predicted value [Cl, -10.9% to -4.0%]). Carbon monoxide diffusing capacity also decreased in these patients (mean difference, -3.3 x mmol min(-1) x kPa(-1) [Cl, -4.6 to -2.1 mmol x min(-1) x kPa(-1)] and -9.6% of the predicted value [Cl, -16.7% to -2.4%]). During a median follow-up of 16 months, patients with alveolitis who received cyclophosphamide were more likely to have a good outcome (stabilization or improvement) in FVC (relative risk, 2.5 [Cl, 1.5 to 4.1]) and diffusing capacity (relative risk, 1.5 [Cl, 1.0 to 2.2]). These patients also had improved survival; the median survival rate was 89% (25th, 75th percentiles, 84%, 94%) compared with 71% (25th, 75th percentiles, 55%, 86%) in untreated patients (P = 0.01, log-rank test). CONCLUSIONS: The presence of lung inflammation identifies patients with scleroderma who are more likely to have worsening lung function. Lung function outcomes and survival are improved in patients with alveolitis who receive cyclophosphamide.

Biopsy↗
PubMed2000

Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area.

Dual-probe microdialysis (with HPLC and electrochemical detection) in freely moving rats and single-unit recording in anesthetized rats were used to study the extent to which impulse flow through the ventral tegmental area (VTA) contributes to elevations in nucleus accumbens (NAS) dopamine (DA) evoked by stimulation of the ventral subiculum (VS). During perfusion of artificial extracellular fluid into the VTA, injections of 0.74 microgram of the excitatory amino acid NMDA into the VS elevated accumbens DA to >150% of basal values. During intra-VTA perfusion of either 1 microM tetrodotoxin (which blocks impulse flow) or 1 mM kynurenic acid (which blocks excitatory glutamate receptors), injections of NMDA into the VS failed to elevate accumbens DA. Thus, increased impulse flow through VTA DA neurons, mediated by excitatory glutamate inputs to this region, appears critical for VS stimulation to elevate NAS DA. Increased impulse flow through VTA DA neurons was confirmed using single-unit recording in anesthetized rats. Intra-VS NMDA injections increased the firing rates of 45% (14 of 31), decreased the firing rates of 13% (4 of 31), and had no effect on 42% (13 of 31) of VTA DA neurons. Increases in firing rates were evident within 15 min of NMDA injections, a time at which VS NMDA injections elevate accumbens DA in awake animals. The results of the present experiments identify the VTA as a critical site through which outputs from the VS modulate NAS dopaminergic neurotransmission.

Animals↗
PubMed2000

Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine).

RATIONALE: It has been inferred from indirect tests that MK-801, an NMDA receptor antagonist, blocks sensitization to amphetamine and to morphine. These inferences were made from studies where behavioral scores were not recorded after each drug treatment in the sensitization protocol. OBJECTIVES: We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after each of several treatments with MK-801 and amphetamine or morphine. METHODS: Each male Long Evans rat was administered intraperitoneal injections of MK-801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously by photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamine or saline as the second injection and on days 1-10, 13, 16 and 32 for rats receiving morphine or saline as their second injection (with no testing or treatment on intervening days). RESULTS: The animals treated in the amphetamine condition and animals treated in the morphine condition all showed progressively greater locomotion and stereotypy over the first 5 (amphetamine) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK-801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamine or morphine was given in the absence of MK-801 (days 8 and 13 for amphetamine and morphine rats, respectively), there was no expression of the sensitized response; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. The sensitized response was still expressed, in animals tested in the appropriate drug condition, after a 2-week period in which no drugs were given, confirming that the changes underlying this form of sensitization were long-lasting and thus probably a consequence of some form of synaptic plasticity. CONCLUSIONS: Our data provide evidence that behavioral sensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the failure of expression of sensitization seen when MK-801 is withdrawn from a given psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather than dependency on some essential function of NMDA receptor activation.

Amphetamine↗
PubMed2000

Fos expression following self-stimulation of the medial prefrontal cortex.

Self-stimulation of the medial prefrontal cortex and medial forebrain bundle appears to be mediated by different directly activated fibers. However, reward signals from the medial prefrontal cortex do summate with signals from the medial forebrain bundle, suggesting some overlap in the underlying neural circuitry. We have previously used Fos immunohistochemistry to visualize neurons activated by rewarding stimulation of the medial forebrain bundle. In this study, we assessed Fos immunolabeling after self-stimulation of the medial prefrontal cortex. Among the structures showing a greater density of labeled neurons in the stimulated hemisphere were the prelimbic and cingulate cortex, nucleus accumbens, lateral preoptic area, substantia innominata, lateral hypothalamus, anterior ventral tegmental area, and pontine nuclei. Surprisingly, little or no labeling was seen in the mediodorsal thalamic nucleus or the locus coeruleus. Double immunohistochemistry for tyrosine hydroxylase and Fos showed that within the ventral tegmental area, a substantial proportion of dopaminergic neurons did not express Fos. Despite previous suggestions to the contrary, comparison of the present findings with those of our previous Fos studies reveals a number of structures activated by rewarding stimulation of both the medial prefrontal cortex and the medial forebrain bundle. Some subset of activated cells in the common regions showing Fos-like immunoreactivity may contribute to the rewarding effect produced by stimulating either site.

Animals↗