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Biomedical subjects

J McCarthy

Publications and source records attributed to J McCarthy.

At least 37 records · Page 2Linked to original sources
PubMed2002

Mental health services and young people with intellectual disability: is it time to do better?

BACKGROUND: There is evidence that the mental health needs of children with disabilities are inadequate. The aim of the present study was to determine the extent of specialist health service use during adolescence by a group of individuals with intellectual disability (ID) and mental health problems. METHOD: The study population consisted of 80 young people with ID, who were examined in childhood and adolescence for psychiatric and behaviour disorder. These young people were interviewed again in early adult life for the presence of psychiatric and behaviour disorder. Evaluation questionnaires were used during the follow-up study to assess service use from adolescence. RESULTS: The key finding was that the great majority (64%) of subjects with persistent challenging behaviour from childhood into adult life and those with an established childhood psychiatric disorder received no specialist mental health care. CONCLUSIONS: The development of mental health services for this vulnerable group with complex psychiatric and behaviour disorders has been poor for a number of reasons, including lack of recognition at the primary care level and insufficient numbers of trained professionals within specialist services.

Adolescent↗
PubMed2001

Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction.

BACKGROUND: Recent advances in high-throughput genomics technology have expanded our ability to catalogue allelic variants in large sets of candidate genes related to premature coronary artery disease. METHODS AND RESULTS: A total of 398 families were identified in 15 participating medical centers; they fulfilled the criteria of myocardial infarction, revascularization, or a significant coronary artery lesion diagnosed before 45 years in men or 50 years in women. A total of 62 vascular biology genes and 72 single-nucleotide polymorphisms were assessed. Previously undescribed variants in 3 related members of the thrombospondin protein family were prominent among a small set of single-nucleotide polymorphisms that showed a statistical association with premature coronary artery disease. A missense variant of thrombospondin 4 (A387P) showed the strongest association, with an adjusted odds ratio for myocardial infarction of 1.89 (P=0.002 adjusted for covariates) for individuals carrying the P allele. A variant in the 3' untranslated region of thrombospondin-2 (change of thymidine to guanine) seemed to have a protective effect against myocardial in individuals homozygous for the variant (adjusted odds ratio of 0.31; P=0.0018). A missense variant in thrombospondin-1 (N700S) was associated with an adjusted odds ratio for coronary artery disease of 11.90 (P=0.041) in homozygous individuals, who also had the lowest level of thrombospondin-1 by plasma assay (P=0.0019). CONCLUSIONS: This large-scale genetic study has identified the potential of multiple novel variants in the thrombospondin gene family to be associated with familial premature myocardial infarction. Notwithstanding multiple caveats, thrombospondins specifically and high-throughput genomic technology in general deserve further study in familial ischemic heart disease.

Adult↗
PubMed2001

Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain.

Palatable food stimulates neural systems implicated in drug dependence; thus sugar might have effects like a drug of abuse. Rats were given 25% glucose solution with chow for 12 h followed by 12 h of food deprivation each day. They doubled their glucose intake in 10 days and developed a pattern of excessive intake in the first hour of daily access. After 30 days, receptor binding was compared to chow-fed controls. Dopamine D-1 receptor binding increased significantly in the accumbens core and shell. In contrast, D-2 binding decreased in the dorsal striatum. Binding to dopamine transporter increased in the midbrain. Opioid mu-1 receptor binding increased significantly in the cingulate cortex, hippocampus, locus coeruleus and accumbens shell. Thus, intermittent, excessive sugar intake sensitized D-1 and mu-1 receptors much like some drugs of abuse.

Animals↗
PubMed2001

Ischemic and pharmacological preconditioning in Girardi cells and C2C12 myotubes induce mitochondrial uncoupling.

Pharmacological uncoupling of mitochondrial oxidation from phosphorylation promotes preconditioning-like cardioprotection in the isolated rat heart. We hypothesized that modest mitochondrial uncoupling may be a critical cellular event in orchestrating preconditioning. Human-derived Girardi cells and murine C2C12 skeletal myotubes were preconditioned using simulated ischemia, adenosine, and diazoxide. Cell viability after 6 hours of simulated ischemia was measured using lactate dehydrogenase release and propidium iodide uptake. Mitochondrial inner membrane potential (DeltaPsim) was investigated by flow cytometry, cellular ATP by recombinant firefly-luciferase bioluminescence, and cellular oxygen consumption using oximetry. Preconditioning enhanced cell viability with attenuation of lactate dehydrogenase release (>/=30%, P<0.05 versus ischemic controls) and a reduction in propidium iodide uptake by >/=26% versus ischemic controls after simulated ischemia in both cell lines. In Girardi cells, preconditioning induced the following phenotype immediately before index ischemia: (1) decreased DeltaPsim (JC-1: simulated ischemia 90+/-3%, adenosine 82+/-7%, diazoxide 87+/-4%, versus control 100%, P<0.05); (2) attenuation in cellular ATP levels (CTL 0.21+/-0.03 nmol/L ATP/microg protein, simulated ischemia 0.12+/-0.02, adenosine 0.15+/-0.02, diazoxide 0.11+/-0.02, P<0.05); and (3) enhanced cellular oxygen consumption (control 2.3+/-0.1 nmol/L oxygen/min/1x10(6) cells, simulated ischemia 3.1+/-0.1, adenosine 3.1+/-0.3, diazoxide 2.6+/-0.2, P<0.05). Cytoprotection, mitochondrial depolarization, and enhanced oxygen consumption were attenuated by the putative mitochondrial K(ATP)-channel antagonist 5-hydroxydecanoate. The uncoupled phenotype in response to preconditioning was similarly observed in C2C12 myotubes. The present study suggests that modest mitochondrial uncoupling represents a unifying cellular response which may be important in directing preconditioning-mediated cytoprotection.

Adenosine↗
PubMed2001

Regulation of Akt/PKB activation by tyrosine phosphorylation.

Activation of Akt/PKB by growth factors requires multiple phosphorylation events. Phosphorylation of Thr(308) and Ser(473) of Akt by its upstream kinase(s) or autophosphorylation is critical for optimal activation of its kinase activity. Here, we present evidence that tyrosine phosphorylation is required for Akt activation. Epidermal growth factor treatment induces tyrosine phosphorylation of Akt in COS1 and PC3M cells, which is abrogated by PP2, a selective inhibitor for Src family tyrosine kinases. Elevated Akt activity is observed in v-Src transformed NIH3T3 cells, which is accompanied with increased tyrosine phosphorylation of Akt. Akt activity induced by growth factors is significantly reduced in SYF cells lacking Src, Yes, and Fyn, which can be restored by introducing c-Src, but not the kinase-inactive Src, back to these cells. Furthermore, we have identified two tyrosine residues near the activation loop of Akt that are important for its activation. Substitution of these residues with phenylalanine abolishes Akt kinase activity stimulated by growth factors. These two YF mutants fail to block Forkhead transcription factor activity in 293 cells and are unable to prevent apoptosis induced by matrix detachment. Our data suggest that, in addition to phosphorylation of Thr(308) and Ser(473), tyrosine phosphorylation of Akt may be essential for its biological function.

Amino Acid Sequence↗
PubMed2001

Shifting visuo-spatial attention in a virtual three-dimensional space.

The present investigation, with a virtual reality set-up, aimed to study attentional orienting within a three-dimensional visual world. Near and far stimuli were used. Half of the subjects were provided with a virtual representation of their body, whereas half were not. Results showed a different distribution of attentional resources in the two conditions, suggesting a dissociation between attentional systems controlling the proximal and the distal visual space. In particular, attention was focused close to the subject's body when a virtual representation of it was present, whereas attention was focused away from the body when a virtual representation of the body was not present.

Attention↗
PubMed2001

Isolation and characterization of 2S cocoa seed albumin storage polypeptide and the corresponding cDNA.

The amine pool of cocoa is known to be an essential component for the development of the typical cocoa flavor. To better understand and to produce an intense in vitro cocoa flavor, identification of the polypeptides that are the source of the amine flavor precursor pool is essential. Chromatographic analysis of the polypeptide profile of unfermented cocoa resulted in identification of a novel storage polypeptide of M(r) 8515. The N-terminal sequence of the first 34 residues of the purified polypeptide shows similarity to 2S storage albumins of cotton and Brazil nut and sweet protein, Mabinlin. To identify the corresponding cDNA of the putative cocoa 2S albumin, 18 randomly chosen clones from the cDNA library of immature Theobroma cacao seed mRNA were sequenced, and a full-length cDNA clone encoding a protein harboring the N-terminal sequence of the novel polypeptide was selected. The open reading frame of the clone encodes a polypeptide of M(r) 17125. Comparison of the translated amino acid sequence of the precursor protein or the mature polypeptide against the Swiss-Prot and TrEMBL databases shows high sequence similarity (>52%) and identity (>38%) to many plant 2S albumins. Tryptic peptide mass fingerprinting of the purified polypeptide by high-performance liquid chromatography-electrospray ionization mass spectrometry shows 10 masses that match the expected tryptic peptides of the deduced sequence. Together with the published work on plant 2S albumin processing, the results presented here suggest that post-translational processing yields a 73-residue polypeptide (residue positions 78-150) corresponding to the 9 kDa subunit of the mature cocoa 2S albumin protein.

Amino Acids↗
PubMed2001

Developmental variation of sugars, carboxylic acids, purine alkaloids, fatty acids, and endoproteinase activity during maturation of Theobroma cacao L. seeds.

The changes of mono- and oligosaccharides, carboxylic acids, purine alkaloids, and fatty acid composition, and of aspartic endoproteinase activity, were analyzed during seed development in two varieties of cacao (Theobroma cacao). The majority of the components examined either decreased or accumulated steadily in concentration during the second half of bean development. Sucrose is the major sugar in the mature embryo, whereas fructose and glucose are at higher concentrations in the endosperm tissue. Considerable amounts of malate are found in the endosperm, whereas citrate is the dominant carboxylic acid in the embryo. A major change in the fatty acid composition occurs in the young embryo when the proportion of stearic acid increases rapidly at the expense of linoleic acid, which is reduced from about 18 to 3%. Theobromine is the dominant purine alkaloid (ca. 80%), and caffeine appears only toward the end of seed maturity. Aspartic endoproteinase activity increases rapidly during embryo expansion, reaching a maximal activity before final maturity. The results are discussed in conjunction with physiological changes in developing seeds, and the potential contributions of the compounds analyzed for cocoa quality.

Aspartic Acid Endopeptidases↗
PubMed2001

TNF alpha is required for hypoxia-mediated right ventricular hypertrophy.

Hypoxia has been shown to activate the pleiotropic cytokine TNFalpha in the lung. TNFalpha in turn, is known to induce pulmonary vasoconstriction. Additional effects of this cytokine in hypoxia mediated cardiopulmonary remodeling are poorly understood. To further evaluate the role of TNFalpha in chronic hypoxia we exposed TNFalpha null (TNFalpha-/-) and wild-type mice to three weeks of hypobaric hypoxia (10% O2). Equivalent erythocytosis (Hematocrit increased by > 40%) developed in both genetic backgrounds. In contrast, right ventricular systolic pressure increased in response to three weeks of hypoxia in the wild-type mice (> or = 75%), yet was unaltered in the TNFalpha-/- mice. Concomitantly right ventricular hypertrophy was attenuated in the TNFalpha-/- mice (35 +/- 5% increase) when compared to wild-type mice (124 +/- 6% increase p < 0.001, n > or = 20). Interestingly in both strains the lung wet weights increased to a similar degree in response to hypoxia. In conclusion, our data demonstrate that TNFalpha is an integral autocoid in chronic hypoxia mediated right ventricular hypertrophy. Moreover, additional components of cardiopulmonary remodeling may be regulated by TNFalpha signaling as suggested by the negligible right ventricular systolic pressure response to hypoxia in the absence of TNFalpha.

Animals↗
PubMed2001

Psychopathology and young people with Down's syndrome: childhood predictors and adult outcome of disorder.

There is a scarcity of follow-up studies into adult life of psychiatric disorder in young people with intellectual disability. The key aims of the present study were: (1) to determine the outcome of psychopathology present in childhood in individuals with Down's syndrome (DS); and (2) to look at childhood predictors of adult psychiatric disorder. Fifty-two young people with DS were identified from a sample of 193 subjects examined in childhood and adolescence for psychiatric and behaviour disorder. These young adults were interviewed for the presence of psychiatric disorder. No significant relationship was found between childhood mental disorder and psychiatric disorder in adult life for those individuals with DS. Early childhood factors of psychiatric disorder, challenging behaviour and family environment, except social background, did not predict adult psychopathology in young people with DS. Childhood disorder in individuals with DS has a good early prognosis with little evidence of continuity of the disorder into adult life.

Adolescent↗
PubMed2001

Restraint practices in Australasian emergency departments.

OBJECTIVE: The objective of this study was to estimate the use of restraint techniques and evaluate restraint policies and training in Australasian emergency departments METHOD: A survey of 116 Australasian emergency departments was conducted to determine the type, indications/contraindications, training, policies, documentation and audit requirements for restraint. RESULTS: The overall estimated rate of patient restraint is 3.3 episodes per 1000 presentations. The commonest indications for restraint are violence or threatened violence (52%), psychosis (32%) and acute brain syndrome (10%). Major contraindications are medical instability, risk of harm to staff in applying restraint and the availability of alternatives to restraint. Chemical restraint is used in all emergency departments surveyed. The commonest agents used are haloperidol (93%), midazolam (82%) and diazepam (59%). At least one benzodiazepine and one major tranquilliser are used in 97% of emergency departments. Manual restraint (87%) is frequently used as a prelude to chemical or, less frequently, mechanical restraint (69%). Seclusion restraint is used in 23% of Australasian emergency departments. Formal training is most commonly undertaken for chemical restraint, being used in 33% of departments surveyed. Less than half of the departments have written policies guiding the use of restraint, and only 11% audit their use of restraint. A specific form for restraint documentation is used in only one emergency department. CONCLUSIONS: Patient restraint is a common procedure in Australasian emergency departments. There is little formal training in, or documentation or audit of, restraint practices in Australasian emergency departments, despite the important clinical, occupational health and medical legal issues associated with the use of restraint.

Antipsychotic Agents↗
PubMed2001

Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model.

OBJECTIVE: To determine whether levosimendan, a calcium sensitiser that facilitates the activation of the contractile apparatus by calcium, improves myocardial contractile function during severe ischaemia and reperfusion without exacerbating the incidence of arrhythmias. DESIGN: Pigs were pretreated orally twice daily for 10 days with 0.08 mg/kg levosimendan or placebo. On day 11 the left main coronary artery was ligated for 30 minutes, followed by 30 minutes of reperfusion. A bolus dose of levosimendan, 11.2 microg/kg intravenously, or placebo was given 30 minutes before coronary ligation, followed by a continuous infusion of 0.2 microg/kg/min levosimendan or placebo for the remainder of the experiment. RESULTS: During the ischaemic period, cardiac output was higher in the levosimendan group than in the placebo group (mean (SD): 2.6 (0.5) v 2.0 (0.2) l/min, p < 0.05) and systemic vascular resistance was lower (2024 (188) v 2669 (424) dyne.s(-1).cm(-5), p < 0.005). During reperfusion, cardiac output and contractility (LV(max)dP/dt (pos), 956 (118) v 784 (130) mm Hg/s, p < 0.05) were increased by levosimendan. The incidence of ischaemic ventricular fibrillation and tachycardia was similar in the two groups but there were more arrhythmic events (ventricular tachycardia and ventricular fibrillation) in the levosimendan treated group (8/12 levosimendan v 1/9 control p = 0.05). CONCLUSIONS: Levosimendan improved cardiac output and myocardial contractility during coronary artery ligation and reperfusion. However, it increased the number of arrhythmic events during ischaemia in this model of in vivo regional ischaemia.

Animals↗
PubMed2000

Assessing the risks of exposures to multiple chemicals with a common mechanism of toxicity: how to cumulate?

The Food Quality Protection Act (FQPA) of 1996 requires the U.S. EPA to consider the "cumulative effects" of pesticides and other substances that have a "common mechanism of toxicity." Several different methods for combining the exposures to estimate the risk of groups of common mechanism chemicals with different potencies and exposure characteristics are critically evaluated. These are the hazard index (HI), toxicity equivalence factor (TEF), and combined margin of exposure (MOE(T)) procedures as well as the point of departure index (PODI) and cumulative risk index (CRI) methods that are the reciprocals of the HI and MOE(T) approaches, respectively. Each of these methods ideally requires, at a minimum, the availability of in vivo toxicology data for the same toxicological endpoint in the same animal species. Furthermore, all assume that the effects of the individual components in the mixture are independent in nature (i.e., are additive rather than synergistic or antagonistic) and that the dose-response functions for all compounds have a similar slope. The point of departure (POD), preferably the dose corresponding to a given effect level (e.g., the ED(10)), can be used as a measure of the relative potency of the different chemicals in the group. If appropriate exposure and toxicology data are available, and the chemicals in the group have a common uncertainty factor (UF), all the procedures yield a numerically identical result. The fact that different chemicals in the group often have different UFs raises issues for all summation procedures and, in the case of the TEF approach, the UF of the index chemical selected dictates the final result of the assessment. A major distinction between the different methods for addition is the point in the process at which uncertainty is considered. The HI and CRI approaches are problematic because they require application of policy-driven UFs (in the form of RfDs) at that stage of the process where exposure should be expressed in terms of potency. In contrast, the PODI and MOE(T) approaches require application of a single group UF(G) at the end of the risk assessment process although they will also accommodate the application of data-based adjustments earlier in the analysis. Importantly, both the PODI and the MOE(T) approaches allow policy- and data-driven UFs to be separated and thus make the process more transparent; these should be considered the methods of choice for cumulative risk assessment. Assignment of a single group UF is somewhat different from developing an UF for a single chemical and the total weight of evidence available in the group database can be used to advantage to reduce the UFs that need to be applied to the group. This larger database can also be used to refine the PODs for individual members of the group. It is important to emphasize that there remains a great deal of scientific uncertainty about how to proceed with cumulative risk assessment as described in the FQPA. The serious difficulties associated with defining "common mechanism of toxicity" and "concurrent exposure" combined with the current paucity of data and methodology required to conduct cumulative risk assessment suggest that the procedure is not yet ready for use in pesticide regulation.

Algorithms↗
PubMed2000

Preferential loss of visceral fat following aerobic exercise, measured by magnetic resonance imaging.

The aim of this study was to use whole-body magnetic resonance imaging (MRI) together with biochemical and anthropometric measurements to study the influence of regular moderate exercise with no dietary intervention on adipose tissue distribution in nonobese healthy women. We found significant decreases in both total (28.86+/-2.24 vs. 27.00+/-2.27 liters, P < 0.05) and regional fat depots (visceral fat: 1.68+/-0.21 vs. 1.26+/-0.18 liters, P < 0.01) using whole-body MRI despite no significant change in body weight, body mass index, or the waist-to-hip ratio. Interestingly, no changes in body fat content were found using anthropometry or impedance. There was a significant increase in high density lipoprotein cholesterol (1.58+/-0.06 vs. 1.66+/-0.08 mmol/L P < 0.02) following exercise although there were no changes in other blood lipids such as triglycerides. In summary, moderate aerobic exercise over a period of 6 mon resulted in a preferential loss in visceral fat in nonobese healthy women, and this may help to explain some of the health benefits associated with regular and moderate physical activity.

Adipose Tissue↗
PubMed2000

In vivo evaluation of the effects of continuous exercise on skeletal muscle triglycerides in trained humans.

Magnetic resonance spectroscopy (1H MRS) and imaging (MRI) were used to investigate the effects of a bout of moderate prolonged exercise on intra (IMCL)- and extramyocellular lipid (EMCL) utilization in the soleus, tibialis anterior, and gastrocnemius muscles of five trained human subjects. MRI and 1H MRS measurements were obtained before and after a 90 min run on a calibrated treadmill at a velocity corresponding to 64 +/- 1.5% of each subjects' maximal rate of oxygen consumption. There were significant decreases in IMCL following exercise in the tibialis (pre: 22.37 +/- 4.33 vs. post: 15.16 +/- 3.25 mmol/kg dry wt; P < 0.01) and soleus (pre: 36.93 +/- 1.45 vs. post: 29.85 +/- 2.44 mmol/kg dry wt; P < 0.01) muscles. There was also a decrease in the gastrocnemius muscle, although this did not reach the level of significance (pre: 33.78 +/- 5.35 vs. post: 28.48 +/- 5.44 mmol/kg dry weight; P < 0.10). No significant changes were observed in EMCL or subcutaneous fat. In conclusion, this study showed that IMCL were significantly utilized in the tibialis and soleus muscles of aerobically endurance-trained humans. The absence of significant utilization of IMCL in the gastrocnemius may reflect differences in fiber type and/or intensity of contraction for each muscle group.

Adult↗