Biomedical subjects

J P Cleary

Publications and source records attributed to J P Cleary.

At least 19 recordsLinked to original sources

PubMed2005

Centrally administered orexin A increases motivation for sweet pellets in rats.

RATIONALE: Centrally administered orexin A induces both feeding and locomotion in rats. Thus, the feeding response following orexin A administration may be secondary to general increases in activity rather than a specific motivation to eat. OBJECTIVE: The aim of the study is to determine whether orexin A increases the motivation to eat. METHODS: The effect of orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol) on breakpoint was determined in male Sprague-Dawley rats with rostro-lateral hypothalamic cannulae under a progressive ratio of five schedule (PR5). The effect of orexin A (0, 31.25, 125, and 500 pmol) on pressing rate under a fixed ratio (20) schedule was obtained to analyze the time course of orexin-A-induced pressing. The effect of 24-h food deprivation on breakpoint under PR5 and the effect of orexin A (125 pmol) on free feeding (sweet pellets) and on open-field locomotor activity (0, 100, 500, and 1,000 pmol) were also tested. RESULTS: Orexin A significantly augmented free feeding of sweet pellets, open-field locomotor activity, rate of pressing (FR20 schedule), and breakpoint (PR5 schedule), although compared to 24-h deprivation, the effect of orexin A on breakpoint was mild. However, there was a differential dose response relationship and time course of stimulation between orexin A's effects on locomotion and lever pressing. CONCLUSION: These data indicate that infusion of orexin A enhances free feeding by enhancing and possibly prolonging motivation to eat.

Animals↗

PubMed2005

The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention.

Burgeoning evidence suggests that soluble oligomers of Abeta (amyloid beta-protein) are the earliest effectors of synaptic compromise in Alzheimer's disease. Whereas most other investigators have employed synthetic Abeta peptides, we have taken advantage of a beta-amyloid precursor protein-overexpressing cell line (referred to as 7PA2) that secretes sub-nanomolar levels of low-n oligomers of Abeta. These are composed of heterogeneous Abeta peptides that migrate on SDS/PAGE as dimers, trimers and tetramers. When injected into the lateral ventricle of rats in vivo, these soluble oligomers inhibit hippocampal long-term potentiation and alter the memory of a complex learned behaviour. Biochemical manipulation of 7PA2 medium including immunodepletion with Abeta-specific antibodies and fractionation by size-exclusion chromatography allowed us to unambiguously attribute these effects to low-n oligomers. Using this paradigm we have tested compounds directed at three prominent amyloid-based therapeutic targets: inhibition of the secretases responsible for Abeta production, inhibition of Abeta aggregation and immunization against Abeta. In each case, compounds capable of reducing oligomer production or antibodies that avidly bind Abeta oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers.

Alzheimer Disease↗

PubMed2001

Early high-frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation in very low birth weight infants: a pilot study of two ventilation protocols.

OBJECTIVE: To evaluate the feasibility of conducting a prospective, randomized trial comparing early high-frequency oscillatory ventilation (HFOV) to synchronized intermittent mandatory ventilation (SIMV) in very low birth weight (VLBW) premature infants. This pilot study evaluated two ventilator management protocols to determine how well they could be implemented in a multicenter clinical trial. Although this pilot study was not powered to detect differences in outcome, we also collected outcome data. DESIGN: Prospective, multicenter, randomized pilot study. SETTING: Seven tertiary-level intensive care nurseries with previous experience with both HFOV and flow-triggered SIMV. PATIENTS: Fifty infants weighing 501 to 1200 g, less than 4 hours of age, who had received one dose of surfactant and required ventilation with mean airway pressure > or =6 cm H2O and F(I)O2 > or =0.25, and had an anticipated duration of ventilation greater than 24 hours. INTERVENTIONS: Patients were stratified by birth weight and prenatal steroid status, then randomized to either HFOV or SIMV with tidal volume monitoring. Ventilator management for patients in both study arms was strictly governed by protocols that included optimizing lung inflation and blood gases, weaning strategies, and extubation criteria. MEASUREMENTS: Data were collected using the tools planned for the larger collaborative study. Protocol compliance was closely monitored, with successive changes in the protocol made as necessary to improve clarity and increase compliance. The incidence of major neonatal adverse outcomes was recorded. MAIN RESULTS: Data are presented for 24 HFOV and 24 SIMV infants (two infants, twins, were withdrawn from the study at parent's request). Nineteen of the 24 HFOV infants and 20 of the 24 SIMV infants survived to 36 weeks corrected age. Age at final extubation for survivors was 16+/-16 (mean+/-SD) days for HFOV infants and 24+/-24 days for SIMV infants. At 36 weeks corrected age, 14 of the 19 HFOV survivors were extubated and in room air, whereas 5 required supplemental oxygen. In comparison, 6 of the 20 SIMV survivors were extubated and in room air, whereas 14 required supplemental oxygen. Grade III/IV IVH and/or periventricular leukomalacia occurred in 2 HFOV and 2 SIMV patients. Overall compliance with the ventilator protocols was 82% for the SIMV protocol, and 88% for the HFOV protocol. CONCLUSIONS: The preliminary outcome data supports conducting the large randomized trial, which began in July of 1998. The protocols for the ventilator management of VLBW infants, both with HFOV and with SIMV were easily implemented and consistently followed, and are presented here.

Age Factors↗

PubMed2001

Collaboration between an internal medicine residency program and a federally qualified health center: Norwalk Hospital and the Norwalk Community Health Center.

In 1999, Norwalk Hospital and an independent, community-based board collaboratively developed the Norwalk Community Health Center (the NCHC). The objectives of the affiliation were to (1) create a new, free-standing, high-quality community health center, (2) optimize grant and clinical revenue, (3) create an ideal venue for ambulatory care training for residents, and (4) replace the traditional and increasingly inefficient hospital-based primary care clinics. The hospital transferred all of its primary care clinical activity to the new community health center and provides an ongoing financial subsidy of the NCHC operations via a forgivable loan. In exchange, the NCHC granted Norwalk Hospital 24% of the seats on its board of directors and purchases all primary care provider services from the hospital. For adult medicine, the contract providers are exclusively Norwalk Hospital internal medicine residents and faculty. Contract charges are based not upon actual staffing but upon a standard formula relating full-time-equivalent providers to patient visits. The new 10,000 square-foot NCHC contains 2,500 square feet of additional integrated space, rented from the NCHC by Norwalk Hospital, which supports the residency education program. The NCHC opened in April 1999 and received FQHC status in November 1999. Adult medicine volume increased 30%, from 36.8 daily visits in the old hospital-based clinics to 48.0 at the NCHC. Resident and patient satisfaction are high. The NCHC now receives cost-based visit reimbursement from Medicaid and has received $1.8 million in state, federal, and local grants.

Adult↗

PubMed2001

Naloxone's effect on meal microstructure of sucrose and cornstarch diets.

The opioid receptor antagonist naloxone decreases consumption of high-sucrose diets but does not reduce cornstarch diet intake in energy-restricted rats. Sucrose-fed rats eat at a much higher rate, consuming more food than cornstarch-fed rats. We examined meal microstructure using an automated weighing system in food-restricted rats eating either a high-sucrose or high-cornstarch diet. Sucrose-fed rats exhibited a higher rate of eating during their first meal compared with cornstarch-fed rats (0.34 vs. 0.20 g/min, respectively). However, naloxone did not reduce eating rate in either group. Naloxone decreased the size of the first meal in both diet groups by shortening the length of the meal. Naloxone's anorectic effect was more potent in the sucrose-fed rats. These results indicate that naloxone's heightened anorectic effect on sucrose diet consumption is not "rate dependent." Naloxone's anorectic actions may be modulated by two conditions, the sensory properties of food and the energy state of the animal. Thus the elevated anorectic potency of naloxone in energy-restricted sucrose-fed rats may reflect actions on neural systems that mediate orosensory and/or postingestive signals.

Animals↗

PubMed2001

Medical management of a large aortic thrombus in a young woman with essential thrombocythemia.

Aortic thrombus formation is rare in the patients with essential thrombocytosis (ET); therefore, no guidelines for its management have been established. Embolism from ET-associated large vessel thrombi is potentially lethal and has been managed surgically in a few reported cases. We describe herein a 45-year-old black woman with ET found to have a 3.5-cm, pedunculated intra-aortic thrombus at the thoracoabdominal junction. How to treat this potentially devastating aortic thrombus was a management dilemma. We believed, based on the patient's diagnosis of ET and the histology of similar thrombi in 1 reported series, that the aortic thrombus was a "white thrombus" consisting primarily of aggregated platelets with a minimal fibrin network and almost no entrapped erythrocytes. The patient was treated with aspirin, 325 mg daily, as a platelet antiaggregating agent and hydroxyurea, 1,500 mg daily, to reduce the platelet count to less than 450 x 10(9)/L. The thrombus resolved without severe thromboembolic events. To our knowledge, this is the first reported case of a large intra-aortic thrombosis associated with ET that has been successfully managed with medical therapy alone.

Aorta, Abdominal↗

PubMed2001

Amyloid beta-peptide1-40 increases neuronal membrane fluidity: role of cholesterol and brain region.

There is increasing evidence of an interaction between cholesterol dynamics and Alzheimer's disease (AD), and amyloid beta-peptide may play an important role in this interaction. Abeta destabilizes brain membranes and this action of Abeta may be dependent on the amount of membrane cholesterol. We tested this hypothesis by examining effects of Abeta1-40 on the annular fluidity (i.e., lipid environment adjacent to proteins) and bulk fluidity of rat synaptic plasma membranes (SPM) of the cerebral cortex, cerebellum, and hippocampus using the fluorescent probe pyrene and energy transfer. Amounts of cholesterol and phospholipid of SPM from each brain region were determined. SPM of the cerebellum were significantly more fluid as compared with SPM of the cerebral cortex and hippocampus. Abeta significantly increased (P < or = 0.01) annular and bulk fluidity in SPM of cerebral cortex and hippocampus. In contrast, Abeta had no effect on annular fluidity and bulk fluidity of SPM of cerebellum. The amounts of cholesterol in SPM of cerebral cortex and hippocampus were significantly higher (P < or = 0.05) than amount of cholesterol in SPM of cerebellum. There was significantly less (P < or = 0.05) total phospholipid in cerebellar SPM as compared with SPM of cerebral cortex. Neuronal membranes enriched in cholesterol may promote accumulation of Abeta by hydrophobic interaction, and such an interpretation is consistent with recent studies showing that soluble Abeta can act as a seed for fibrillogenesis in the presence of cholesterol.

Amyloid beta-Peptides↗

PubMed2000

Urethral obstruction and bilateral ureteral hydronephroses secondary to fecal impaction.

We present a case report of the first adult woman reported to suffer from both urethral obstruction and bilateral ureteral hydronephroses secondary to fecal impaction. The work-up suggested that hypothyroidism might be the cause for fecal impaction. Urinary tract obstruction caused by hypothyroidism-induced fecal impaction has never been reported. Fecal impaction should be considered as one of the causes for urinary tract obstruction.

Aged↗

PubMed1999

Discriminative stimulus effects of morphine: central versus peripheral training.

While it is well known that rats can discriminate a peripheral injection of morphine from a saline injection, to our knowledge no one has trained rats to discriminate a direct brain-site injection of morphine from saline. In the present series of studies, one group of rats was trained to discriminate morphine (0.3 microgram) from saline injected into the perifornical area of the hypothalamus (PFA), a process that took rats about 37 sessions to learn. A dose response generalization curve for PFA-injected morphine (0.01, 0.03, 0.1, and 0.17 microgram) was generated in which the two highest doses of morphine generalized to the morphine-appropriate training stimulus. Intraperitoneal (i.p.) injection of 3 mg/kg, but not 1 mg/kg morphine, resulted in morphine-appropriate responding in the PFA morphine-trained rats. A second group of rats was trained to discriminate i.p. injections of 3 mg/kg morphine from injections of saline. A dose-response generalization test for i.p.-injected morphine (0.3, 0.56, 1.0, and 1.7 mg/kg) was conducted in which the 0.17 mg/kg dose of morphine generalized to the morphine-appropriate training stimulus. Generalization tests using PFA-injected morphine doses (0.17, 0.56, 1.0, and 3.0 microgram) failed to result in morphine-appropriate responding in the i.p. morphine-trained rats. Naloxone administered into the PFA (50 microgram) or the periphery (3 mg/kg, i.p.) blocked morphine discrimination in the PFA-trained rats. However, when naloxone was injected into the PFA (50 microgram) together with i.p. morphine (3 mg/kg) in animals trained using i.p. injections, the antagonist failed to block morphine-appropriate responding. Thus, while peripheral injection of morphine generalized to the discriminative stimulus effects of morphine produced under PFA-injection training, the opposite effects were not noted.

Analgesics, Opioid↗

PubMed1999

The effect of naloxone on food-motivated behavior in the obese Zucker rat.

We assessed differences in food reinforced behavior between obese and lean Zucker rats with a progressive ratio schedule 3 (PR3) in which a subject emitted three additional lever-presses each time a reinforcer was delivered. The number of responses required for a reinforcer eventually exceeded its value, termed the "break point", a sensitive measure of food motivated behavior. Break points were higher in obese rats than lean controls for grain pellets (27.5 versus 9.5, P = 0.01) but not for sweet pellets (51.6 versus 38.5, P = 0.31). We determined if naloxone (0.01-3.0 mg/kg, SC), which reduces free food intake in obese Zucker rats, affects food motivated behavior in obese Zuckers and lean controls. Naloxone reduced break points in both obese and lean rats to a similar extent when working for either grain pellets or sweet pellets. Under free-access feeding conditions, naloxone again decreased pellet intake similarly in the obese and lean Zucker rats. Naloxone appeared to decrease free-access pellet consumption to a greater extent than break point in both groups. These results show that (1) obese rats exhibit higher levels of performance for food than lean rats only when working for the less valued grain pellet, (2) naloxone reduces both break points and free-access pellet consumption independent of genotype, and (3) naloxone appears to decrease food more effectively in rats given free access to food than in rats working for food.

Animals↗

PubMed1999

Effects of neuropeptide Y on the discriminative stimulus and antinociceptive properties of morphine.

Previous research indicates that opioid receptor blockade diminishes the effects of neuropeptide Y (NPY) on feeding and memory. Conversely, NPY attenuates naloxone-precipitated morphine withdrawal. The present study evaluated the effects of NPY on the discriminative stimulus and antinociceptive effects produced by the prototypical mu opioid, morphine. Rats were trained to discriminate 5.6 mg/kg morphine (IP) from saline using a standard two-lever, food-reinforced, drug discrimination procedure. Across a range of doses (3.0, 5.0, and 10 microg), intracerebroventricular (ICV) injection of NPY failed to substitute for, antagonize, or potentiate the discriminative stimulus effects of morphine. A warm-water tail-withdrawal procedure was used to examine the antinociceptive effects of morphine and NPY, alone and in combination. NPY (3.0 and 10 microg, ICV) failed to alter tail-withdrawal latencies from 52 degrees and 56 degrees C water, whereas morphine (1.0-30 mg/kg, IP) produced a dose-related increase in latencies at both water temperatures. A 10-microg dose of NPY also failed to alter the antinociceptive effects of morphine. This study does not support the idea that the discriminative stimulus and antinociceptive effects of morphine are dependent on an NPYergic pathway.

Analgesics, Opioid↗

PubMed1999

Cytomegalovirus pneumonitis as an initial presentation in an HIV-infected patient.

Human immunodeficiency (HIV) infection often presents with an unusual symptom complex. Although cytomegalovirus (CMV) is a frequent opportunistic infection in the late stage of acquired immunodeficiency syndrome (AIDS), CMV pneumonitis as an initial manifestation of HIV infection is not documented in the medical literature. We report a previously healthy patient with bilateral interstitial pulmonary infiltrates who was found to have CMV pneumonitis; only later was HIV virus infection diagnosed. Cytomegalovirus is a frequently isolated pathogen from respiratory secretions in AIDS patients. The role of CMV as a sole pulmonary pathogen is controversial. After exclusion of other pathogens, CMV was demonstrated by histological changes and viral culture in our case. This case indicates that pulmonary infiltrates presenting as the first manifestation of HIV infection can be caused by CMV infection.

AIDS-Related Opportunistic Infections↗

PubMed1998

Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo.

To determine the stability of beta-amyloid peptide (Abeta) and the glial and neuronal changes induced by Abeta in the CNS in vivo, we made single injections of fibrillar Abeta (fAbeta), soluble Abeta (sAbeta), or vehicle into the rat striatum. Injected fAbeta is stable in vivo for at least 30 d after injection, whereas sAbeta is primarily cleared within 1 d. After injection of fAbeta, microglia phagocytize fAbeta aggregates, whereas nearby astrocytes form a virtual wall between fAbeta-containing microglia and the surrounding neuropil. Similar glial changes are not observed after sAbeta injection. Microglia and astrocytes near the injected fAbeta show a significant increase in inducible nitric oxide synthase (iNOS) expression compared with that seen with sAbeta or vehicle injection. Injection of fAbeta but not sAbeta or vehicle induces a significant loss of parvalbumin- and neuronal nitric oxide synthase-immunoreactive neurons, whereas the number of calbindin-immunoreactive neurons remains unchanged. These data demonstrate that fAbeta is remarkably stable in the CNS in vivo and suggest that fAbeta neurotoxicity is mediated in large part by factors released from activated microglia and astrocytes, as opposed to direct interaction between Abeta fibrils and neurons.

Amyloid beta-Peptides↗

PubMed1997

Amyloid beta-peptides increase annular and bulk fluidity and induce lipid peroxidation in brain synaptic plasma membranes.

Amyloid beta-peptides (A beta) may alter the neuronal membrane lipid environment by changing fluidity and inducing free radical lipid peroxidation. The effects of A beta(1-40) and A beta(25-35) on the fluidity of lipids adjacent to proteins (annular fluidity), bulk lipid fluidity, and lipid peroxidation were determined in rat synaptic plasma membranes (SPM). A fluorescent method based on radiationless energy transfer from tryptophan of SPM proteins to pyrene and pyrene monomer-eximer formation was used to determine SPM annular fluidity and bulk fluidity, respectively. Lipid peroxidation was determined by the thiobarbituric acid assay. Annular fluidity and bulk fluidity of SPM were increased significantly (p < or = 0.02) by A beta(1-40). Similar effects on fluidity were observed for A beta(25-35) (P < or = 0.002). Increased fluidity was associated with lipid peroxidation. Both A beta peptides significantly increased (p < or = 0.006) the amount of malondialdehyde in SPM. The addition of a water-soluble analogue of vitamin E (Trolox) inhibited effects of A beta on lipid peroxidation and fluidity in SPM. The fluidizing action of A beta peptides on SPM may be due to the induction of lipid peroxidation by those peptides. A beta-induced changes in neuronal function, such as ion flux and enzyme activity, that have been reported previously may result from the combined effects of lipid peroxidation and increased membrane fluidity.

Amyloid beta-Peptides↗

PubMed1997

Role of carbohydrate type on diet selection in neuropeptide Y-stimulated rats.

We tested whether carbohydrate source (corn starch, sucrose, Polycose) influences the choice between a high-fat and high-carbohydrate diet in spontaneously feeding rats and in rats stimulated to eat by neuropeptide Y (NPY) administration or food deprivation. Rats were tested under three diet options: 1) a high-fat diet versus a high-corn starch diet; 2) a high-fat diet versus a high-sucrose diet, and 3) a high-fat diet versus a high-Polycose diet. During daily and stimulated feeding rats ate more of the high-carbohydrate diet than the fat diet when the source of carbohydrate was sucrose or Polycose; however, when corn starch was provided as the carbohydrate source rats ate more of the high-fat diet. Food-deprived rats increased intake of both the high-fat and the high-carbohydrate diets, with the proportion of energy ingested from each of the diets resembling that noted during 3 days of spontaneous feeding. NPY-injected rats ate more of both the high-fat and high-carbohydrate diets during diet options 1 and 3, but not during option 2 when the high-sucrose and high-fat diets were offered concurrently. In that case, rats did not significantly increase their intake of the high-fat diet. Although carbohydrate source and NPY administration each influenced diet selection, altering the source of carbohydrate had a more marked effect.

Animals↗

PubMed1996

Potency of naloxone's anorectic effect in rats is dependent on diet preference.

Modulation of feeding behavior by neuropeptide Y (NPY) and opioids is well established, but the possibility that these neural influences provoke specific appetites, NPY for carbohydrate and opioids for fat, has also been considered. In other studies, intake of standard chow after NPY stimulation can be blocked by naloxone, indicating an interaction between these systems in the regulation of feeding. The present experiments examined the nature of NPY-opioid interactions in diet selection. Rats were administered NPY and naloxone concurrently, then chose between high-fat and high-carbohydrate diets. Subcutaneous administration of naloxone (0.01-0.3 mg/kg) potently reduced intake of the preferred diet, but not the nonpreferred diet. A similar pattern of selection was seen in a separate experiment where the same doses of naloxone were administered after 24-h food deprivation. These data support the idea that the opioid system mediates the "rewarding" aspects of feeding.

Animals↗

PubMed1995

Triazolam in Alzheimer's disease: pilot study on sleep and memory effects.

We examined the effects on sleep and memory of a nighttime dose of triazolam, 0.125 mg, in seven subjects with Alzheimer's disease (AD) who were reported by caregivers to be frequently up at night. Subjects were admitted to an intermediate care hospital ward for the 8-day ABA design protocol (placebo baseline-drug-placebo washout). Drug or placebo was given each evening at 2100 h. Sleep was assessed with a wrist-worn activity monitor. Memory was evaluated using a computerized delayed-matching-to-sample (DMTS) task administered at 0800 and 2130 h. Triazolam had no significant effects on total sleep time at night, latency to sleep onset, number of arousals, or time asleep during the day. DMTS performance was significantly worse at night compared to morning during baseline, but there were no significant drug effects. Our results suggest the standard geriatric dose of triazolam, 0.125 mg, may not be an effective hypnotic in AD patients with disrupted sleep, but neither does it substantially worsen the recent memory deficits of AD.

Aged↗

PubMed1995

Improved oxygenation during synchronized intermittent mandatory ventilation in neonates with respiratory distress syndrome: a randomized, crossover study.

In a randomized, crossover study, we compared arterial partial pressure of oxygen and of carbon dioxide between consecutive periods of conventional and synchronized intermittent mandatory ventilation (SIMV). We studied spontaneously breathing infants with an endotracheal tube in place. The infants were < 12 hours of age, had a diagnosis of respiratory distress syndrome, and had an arterial/alveolar oxygen ratio of < 0.25. The infants had a mean birth weight of 1077 gm and gestational age of 28 weeks. The mean rate of asynchrony on intermittent mandatory ventilation (IMV) was 52% (range, 36% to 76%), and on SIMV was < 1%. Infants were randomly assigned to IMV or SIMV as their initial ventilator mode and underwent ventilation for four 15-minute periods, and crossed over to the alternate mode after each period. Ventilator settings and the fraction of inspired oxygen were not changed between modes. At the end of each period, arterial blood gas measurements were obtained; 26 paired comparisons were made between modes. The mean arterial partial pressure of oxygen was significantly higher during SIMV than during IMV (mean, 61.5 vs 53.3 mmHg; p < 0.01). The mean arterial partial pressure of carbon dioxide was slightly lower during SIMV than during IMV (mean, 42.7 vs 41.3 mm Hg; p < 0.05). The improvement in oxygenation demonstrated with SIMV may allow a reduction in ventilator pressure or oxygen exposure in this group of infants, who are at risk of having complications of ventilation.

Carbon Dioxide↗