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Biomedical subjects

J Cleary

Publications and source records attributed to J Cleary.

At least 19 recordsLinked to original sources
PubMed2005

Parenteral antioxidant treatment preserves temporal discrimination following intrahippocampal aggregated Abeta(1-42) injections.

There is evidence that oxidative stress may play a role in the neuropathology of Alzheimer's disease (AD). This study used an aggregated beta-amyloid (Abeta) injection model of AD in the rat, and a recycling conjunctive schedule of food reinforcement to examine the effects of bilateral intrahippocampal injections of aggregated Abeta(1-42) (5.0 microl/side) on temporal discrimination, and the efficacy of the antioxidant alpha-tocopherol (150 mg/kg daily p.o.) in alleviating these effects. The results indicated that bilateral intrahippocampal injections of aggregated Abeta(1-42) detrimentally affected temporal discrimination from five-day block 31-35 post-injections until the end of the study (90 days post-injections). Daily treatment with alpha-tocopherol improved temporal discrimination under the recycling conjunctive schedule following aggregated Abeta(1-42) injections from the five-day block 61-65 days until the end of the study.

Amyloid beta-Peptides↗
PubMed2002

Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated Abeta(1-42) injections in the rat.

It has been suggested that inflammatory processes may play a role in the development of Alzheimer's disease (AD), and that nonsteroidal anti-inflammatory drug treatments may provide protection against the onset of AD. In the current study male Wistar rats were trained in two-lever operant chambers under an alternating lever cyclic-ratio ratio (ALCR) schedule. When responding showed no trends, subjects were divided into groups. One group was bilaterally injected into the CA3 area of the hippocampus with 5 microl of aggregated beta-amyloid (Abeta) suspension, and one group was bilaterally injected into the CA3 area of the hippocampus with 5 microl of sterile saline. Subgroups were treated twice daily with 0.1 ml (40 mg/kg) ibuprofen administered orally. The results indicated that chronic administration of ibuprofen protected against detrimental behavioural effects following aggregated Abeta injections. Withdrawal of ibuprofen treatment from aggregated Abeta-injected subjects produced a decline in behavioural performance to the level of the non-treated aggregated Abeta-injected group. Ibuprofen treatment reduced the numbers of reactive astrocytes following aggregated Abeta injection, and withdrawal of ibuprofen resulted in an increase of reactive astrocytes. These results suggest that induced inflammatory processes may play a role in AD, and that ibuprofen treatment may protect against some of the symptoms seen in AD.

Alzheimer Disease↗
PubMed2001

RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes.

Myelopoiesis and lymphopoiesis are controlled by haematopoietic growth factors, including cytokines, and chemokines that bind to G-protein-coupled receptors (GPCRs). Regulators of G-protein signalling (RGSs) are a protein family that can act as GTPase-activating proteins for G(alphai)- and G(alphaq)-class proteins. We have identified a new member of the R4 subfamily of RGS proteins, RGS18. RGS18 contains clusters of hydrophobic and basic residues, which are characteristic of an amphipathic helix within its first 33 amino acids. RGS18 mRNA was most highly abundant in megakaryocytes, and was also detected specifically in haematopoietic progenitor and myeloerythroid lineage cells. RGS18 mRNA was not detected in cells of the lymphoid lineage. RGS18 was also highly expressed in mouse embryonic 15-day livers, livers being the principal organ for haematopoiesis at this stage of fetal development. RGS1, RGS2 and RGS16, other members of the R4 subfamily, were expressed in distinct progenitor and mature myeloerythroid and lymphoid lineage blood cells. RGS18 was shown to interact specifically with the G(alphai-3) subunit in membranes from K562 cells. Furthermore, overexpression of RGS18 inhibited mitogen-activated-protein kinase activation in HEK-293/chemokine receptor 2 cells treated with monocyte chemotactic protein-1. In yeast cells, RGS18 overexpression complemented a pheromone-sensitive phenotype caused by mutations in the endogeneous yeast RGS gene, SST2. These data demonstrated that RGS18 was expressed most highly in megakaryocytes, and can modulate GPCR pathways in both mammalian and yeast cells in vitro. Hence RGS18 might have an important role in the regulation of megakaryocyte differentiation and chemotaxis.

Amino Acid Sequence↗
PubMed2001

Thermodynamic basis for sequence-specific recognition of ssDNA by an autoantibody.

11F8 is a sequence-specific DNA binding monoclonal autoantibody previously isolated from an autoimmune lupus-prone mouse [Stevens, S. Y., and Glick, G. D. (1999) Biochemistry 38, 560-568]. This antibody, like many other lupus anti-DNAs, localizes to kidney tissue and eventually leads to renal damage through a process that first involves the binding of DNA antigens. A series of experiments were conducted to investigate the thermodynamic and structural basis by which this antibody discriminates between specific, noncognate, and nonspecific sequences. Sequence-specific binding occurs with a minimal dependence on the polyelectrolyte effect along with a favorable binding enthalpy reflecting the presence of base stacking and contacts to DNA bases. This favorable binding enthalpy apparently is derived from desolvation at the binding interface and is consistent with recent models of the nonclassical hydrophobic effect. Noncognate recognition is also driven by the nonclassical hydrophobic effect, but is accompanied by highly unfavorable entropies that are responsible for reduced affinity relative to the high-affinity consensus sequence. Nonspecific recognition is driven completely by the polyelectrolyte effect involving extensive electrostatic interactions with the phosphate backbone. Collectively, the data demonstrate the ability of 11F8 to adapt its mode of binding to the available DNA surface and provide a thermodynamic model for sequence-specific recognition of single-stranded DNA. The salient features of this model employ the paradigms invoked to explain protein.dsDNA, protein.RNA, and antibody.antigen binding.

Animals↗
PubMed2001

Responding to SUPPORT: an academic medical center examines its end-of-life care practices. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

The purpose of this exploratory study was to examine the end-of-life (EOL) care rendered to patients and families within a large midwestern academic medical center during a recent one-year period. An investigator-developed audit tool was used to review the final hospitalization records of 100 patients. Data were collected regarding demographic variables, final hospitalization, medical diagnoses and histories, and documented end-of-life care. Major findings included a majority of deaths occurring within medical services on critical care units, a frequent short length of stay, a majority of Do Not Resuscitate or Withdrawal of Support orders being written 1-3 days prior to death, an unstable health status prior to admission, and presence of at least one significant chronic illness in the past medical history. Findings are being used to address EOL care related issues within the institution.

Academic Medical Centers↗
PubMed2001

Tracing functionally identified neurones in a multisynaptic pathway in the hamster and rat using herpes simplex virus expressing green fluorescent protein.

Using a genetically modified herpes simplex virus encoding green fluorescent protein we sought to establish if this viral modification could be used in transneuronal tracing studies of the sympathetic nervous system. The herpes simplex virus encoding green fluorescent protein was injected into the adrenal medulla of three hamsters and six rats. After a suitable survival period, neurones in the sympathetic intermediolateral cell column of the thoracolumbar spinal cord, rostral ventral medulla and paraventricular nucleus of the hypothalamus were clearly identified by the presence of a green fluorescence in the cytoplasm of the neurones of both species. Thus, herpes simplex virus encoding green fluorescent protein labelled chains of sympathetic neurones in the hamster and rat and therefore has the potential to be used in transneuronal tracing studies of autonomic pathways in these species.

Animals↗
PubMed2000

Single-blind randomised controlled trial of chemonucleolysis and manipulation in the treatment of symptomatic lumbar disc herniation.

This single-blind randomised clinical trial compared osteopathic manipulative treatment with chemonucleolysis (used as a control of known efficacy) for symptomatic lumbar disc herniation. Forty patients with sciatica due to this diagnosis (confirmed by imaging) were treated either by chemonucleolysis or manipulation. Outcomes (leg pain, back pain and self-reported disability) were measured at 2 weeks, 6 weeks and 12 months. The mean values for all outcomes improved in both groups. By 12 months, there was no statistically significant difference in outcome between the treatments, but manipulation produced a statistically significant greater improvement for back pain and disability in the first few weeks. A similar number from both groups required additional orthopaedic intervention; there were no serious complications. Crude cost analysis suggested an overall financial advantage from manipulation. Because osteopathic manipulation produced a 12-month outcome that was equivalent to chemonucleolysis, it can be considered as an option for the treatment of symptomatic lumbar disc herniation, at least in the absence of clear indications for surgery. Further study into the value of manipulation at a more acute stage is warranted.

Adolescent↗
PubMed2000

Varied duration of congenital hypothyroidism potentiates perseveration in a response alternation discrimination task.

The behavior of five groups of rats (seven rats per group) made hypothyroid for varying lengths of time and one group of seven normal control rats was assessed under forced alternation fixed-ratio (FR1, FR3, FR5 and FR10), alternating lever cyclic-ratio (ALCR) and progressive-ratio (PR3) schedules of reinforcement. Hypothyroidism was produced by adding methimazole (MMI) to the drinking water of pregnant dams from embryonic day E16 to postnatal day P25. Four groups were given replacement thyroxine (T4) injections beginning at specific time points (P1, P7, P13, and P19). There were no differences in behavioral performance between control and experimental groups under the FR schedule, which indicates that the animals' sensorimotor abilities were intact. Under the forced ALCR schedule, all groups reached criteria similarly. However, under the choice lever ALCR schedule, control animals and those which received T4 replacement from early on (P1, P7, P13 groups) performed well and all had reached criteria by 11 sessions. In contrast, animals which did not receive any T4 replacement or received it late (P19 group) took longer to reach criteria and 5/14 animals had not reached criteria at all by 20 sessions. This deterioration in performance was paralleled by an increase in perseverative behavior as evidenced by an increased frequency of pressing the wrong lever when alternation of lever was required. This suggests that congenital hypothyroidism results in increased perseveration leading to a decrease in learning when a discrimination between correct and incorrect operanda is made available.

Animals↗
PubMed2000

Dorsal thoracic cord compression from a spinal angiolipoma: case report and brief comment.

Angiolipomas are benign tumors usually found in the forearms of young adults. To the best of our knowledge only 63 cases of spinal angiolipomas have been reported in the literature up until 1999 (MEDLINE 1966-1999). We report a case of a spinal angiolipoma causing dorsal cord compression in a 44-year-old woman presenting with subacute lower limb paresthesias, in the absence of sensory or motor findings, which mimicked multiple sclerosis by history. Operative intervention was curative.

Adult↗
PubMed1999

Congenital hypothyroidism impairs response alternation discrimination behavior.

The behavior of six congenitally hypothyroid and six normal control rats was assessed under forced alternation fixed-ratio, alternating lever cyclic-ratio (ALCR) and progressive-ratio schedules of reinforcement. Hypothyroidism was produced by adding methimazole (MMI) to the drinking water of pregnant dams from embryonic day 16 to postnatal day 25. There were no differences in behavioral performance between MMI-treated and control animals under the fixed-ratio and progressive ratio schedules. There were also no differences in circulating triiodothyronine levels between groups at the end of the study. Under the ALCR schedule, when alternation of responding was forced during the first three cycles but both levers (choice) were presented during the last three cycles (correct lever active), the entire control group reached a competency criteria in nine sessions. In contrast, only two MMI-treated animals reached criteria after 17 sessions, and the remaining four MMI-treated animals did not reach criteria by 30 sessions of training. These results suggest that congenital hypothyroidism impairs learning when a discrimination between correct and incorrect operanda is made available.

Animals↗
PubMed1999

Delayed behavioral effects following intrahippocampal injection of aggregated A beta (1-42).

Beta amyloid protein (A beta) is the major extracellular component of Alzheimer's disease (AD) plaques. In the current study, A beta (1-42) was aggregated in vitro using a method which produces A beta aggregates similar to those found in the AD brain. Twelve male Sprague-Dawley rats were trained in two-lever operant chambers under an alternating lever cyclic-ratio (ALCR) schedule. When performance was stable on the ALCR schedule, six subjects were injected (bilaterally into the CA3 area of the dorsal hippocampus) with 5.0 microliters aggregated A beta in suspension, and the remaining six subjects were injected with 5.0 microliters sterile water. Behavioral testing resumed 5 days after surgery and continued for 90 days post-injection. Aggregated A beta injection did not affect the number of lever switching errors made in a daily session but did affect the number of incorrect lever response perseverations. After approximately 30 days post-injection, aggregated A beta injection detrimentally affected ability to track the changing parameters of the schedule, and decreased the efficiency by which subjects obtained reinforcers. From approximately day 50 post-injection onward, A beta-injected subjects demonstrated significantly higher numbers of incorrect lever response perseverations than did sterile water-injected subjects. These effects appeared to be central rather than peripheral, as A beta injection did not decrease running response rates under the ALCR schedule. The delayed onset of behavioral effects seen in this and other behavioral studies may be a result of a cascade of potentially harmful responses induced through glial activation following aggregated A beta injection.

Amyloid beta-Peptides↗
PubMed1999

Left atrial myxomas presenting with right hand weakness.

A 63-year-old man with multiple left atrial myxomas presenting with right hand weakness is described. Two-dimensional echocardiography obtained during the evaluation for his stroke showed a large left atrial mass. At surgery, two separate left atrial myxomas were excised. Pathology confirmed the diagnosis. Although left atrial myxomas are uncommon, they should be included in the differential diagnosis of stroke, especially in patients who present without cardiovascular or cerebrovascular risk factors. The absence of cardiac symptoms and signs does not rule out a cardiac myxoma.

Central Nervous System Diseases↗
PubMed1998

Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients.

BACKGROUND: Patients with cancer frequently experience episodes of acute pain, i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is usually treated with short-acting oral opioids, most of which provide some relief after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been shown to provide meaningful pain relief within 5 minutes in patients following surgery. We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of OTFC for cancer-related breakthrough pain. METHODS: Patients who were 18 years of age or older, receiving the equivalent of at least 60 mg oral morphine or at least 50 microg transdermal fentanyl per day for chronic cancer-related pain, and experiencing at least one episode of breakthrough pain per day were studied. After titration to an effective OTFC dose, subjects were given 10 randomly ordered treatment units (seven OTFC units and three placebo units) in the form of identical lozenges. If acceptable pain relief was not achieved within 30 minutes, subjects were instructed to take their previous breakthrough pain medication (i.e., rescue medication). Pain intensity, pain relief, and use of rescue medication were evaluated at 15-minute intervals over a 60-minute period. RESULTS: Eighty-nine of 92 patients who received the randomized treatment were assessable (i.e., treated with at least one unit of OTFC and one unit of placebo). OTFC produced significantly larger changes in pain intensity and better pain relief than placebo at all time points (two-sided P<.0001). Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95% confidence interval = 1.51-3.26; two-sided P<.0001). CONCLUSIONS: OTFC appears effective in the treatment of cancer-related breakthrough pain.

Administration, Oral↗
PubMed1998

Intrahypothalamic discriminative stimulus effects of neuropeptide Y.

Neuropeptide Y (NPY) is one of the most ubiquitous neurotransmitters in the CNS and has been implicated in a variety of psychological and physiological functions. The current study investigated whether intrahypothalamic (I.H.) administrations of NPY were behaviorally discriminable from saline injections. Rats were trained to differentially respond based on whether they received I.H. injections of NPY (0.5 microg/0.5 microl) or saline (0.5 microl 0.9% NaCl). Subjects demonstrated discriminative control (85% correct in 8 out of 10 consecutive sessions) after a mean of 32 sessions. The ability of subjects to discriminate I.H. NPY from saline was dose dependent, with the lowest NPY dose tested (0.03 microg/0.5 microl) generalizing to saline. The opioid antagonist naloxone blocked the discrimination of NPY when administered I.P. (3.0 mg/kg) or I.H. (50 microg/0.5 microl).

Animals↗
PubMed1997

Anticipation in schizophrenia: biology or bias?

Anticipation is a genetic phenomenon wherein age of disease onset decreases and/ or severity increases in successive generations. Anticipation has been demonstrated for several neuropsychiatric disorders with expanding trinucleotide repeats recently identified as the underlying molecular mechanism. We report here the results of an analysis of anticipation performed with multiplex families segregating schizophrenia. Thirty-three families were identified through the NIMH Genetics Initiative that met the following criteria: had at least two affected members in successive generations and were not bilineal. Affectation diagnoses included schizophrenia, schizoaffective disorder-depressed, and psychosis NOS. Additional analyses included the Cluster A personality disorders. Three indices of age of onset were used. Disease severity was measured by several different indices. Four sampling schemes as suggested by McInnis et al. were tested, as well as additional analysis using pairs ascertained through the parental generation. Anticipation was demonstrated for age of onset, regardless of the index or sampling scheme used (P<0.05). Anticipation was not supported for disease severity. Analyses that took into account drug use and diminished fecundity did not affect the results. While the data strongly support intergenerational differences in disease onset consistent with anticipation, they must be viewed cautiously given unavoidable biases attending these analyses.

Age of Onset↗
PubMed1997

Naloxone administration following operant training of sucrose/water discrimination in the rat.

The suppression of food intake observed following naloxone administration has often been ascribed to palatability or taste. Unfortunately, many confounds become apparent when attempts are made to isolate such factors in the investigation of ingestive behaviors. In the present study, rats (two groups) were trained to discriminate either a 10% or 5% sucrose solution from water (0.1 ml). These mildly food deprived subjects (95% of free-feeding weight) were trained to press the appropriate lever in a two-lever operant chamber following sampling of sucrose or water; successful responding was reinforced by delivery of a 45 mg grain food pellet. Following random exposure to reduced sucrose concentrations tested under extinction, a sucrose concentration gradient (1.0, 0.5, 0.1, 0.05, 0.01 and 0.005% sucrose solution) was established for both training groups under i.p. saline administration. Data collected under i.p. saline were then compared to those collected following random i.pf1p4loxone administration (3.0, 1.0, 0.3 and 0.1 mg/kg). No significant differences were observed between the sucrose concentration gradients obtained under saline and those obtained under naloxone, suggesting that the anorectic effect of naloxone is not primarily determined by discrimination of sweet taste.

Animals↗
PubMed1997

Serum anticholinergic activity and behavior following atropine sulfate administration in the rat.

Anticholinergic agents such as atropine and scopolamine have long been suggested to produce delirium-like states in humans and experimental animals. Evidence for an anticholinergic mechanism in the pathogenesis of human delirium has accumulated, leading to studies of the behavioral effects of the anticholinergic drug atropine in animals. The current study addresses the adequacy of animal models of delirium in terms of sensitivity, specificity and pharmacological relevance. A multiple fixed-ratio fixed-interval reinforcement schedule was used to test the effects of relatively low doses of atropine on behavior in rats. Additionally, total serum anticholinergic activity (SAA) was measured under dose and time course conditions identical to those used in the behavioral study. Atropine reduced high and low rates of responding in a dose-dependent manner, and SAA increased in a dose dependent manner. SAA at atropine doses of 0.1 mg/kg to 1.0 mg/kg was similar to that found in delirious humans. These behavioral and serum level data suggest that relatively low doses of atropine, substantially below those used in previous attempts to model delirium using rats, may be more pharmacologically relevant to delirium and may minimize non-specific peripheral effects of this drug.

Animals↗