Thermoelectricity in polymer composites due to fluctuation-induced tunneling.

Transport in heavily-doped polymer composites, characterized by localized charge regions, is examined in light of the recent interest in polymers for thermoelectric applications. The developed fundamental transport theory describes carrier tunneling between charged localizations by taking into account thermally induced fluctuations of the applied potential. A range of characteristic behaviors corresponding to experimental data are described. Deviations from the Wiedemann-Franz law are also identified. This novel theory enables the determination of factors dominating the transport in polymers and a comparison to tunneling without thermal fluctuations is also provided. The obtained asymptotic expressions for the conductivity, Seebeck coefficient, and carrier thermal conductivity are particularly useful for elucidating possible routes for thermoelectric transport control and optimization.

Low-fat oxidation may be a factor in obesity among men with schizophrenia.

OBJECTIVE: Obesity associated with atypical antipsychotic medications is an important clinical issue for people with schizophrenia. The purpose of this project was to determine whether there were any differences in resting energy expenditure (REE) and respiratory quotient (RQ) between men with schizophrenia and controls. METHOD: Thirty-one men with schizophrenia were individually matched for age and relative body weight with healthy, sedentary controls. Deuterium dilution was used to determine total body water and subsequently fat-free mass (FFM). Indirect calorimetry using a Deltatrac metabolic cart was used to determine REE and RQ. RESULTS: When corrected for FFM, there was no significant difference in REE between the groups. However, fasting RQ was significantly higher in the men with schizophrenia than the controls. CONCLUSION: Men with schizophrenia oxidised proportionally less fat and more carbohydrate under resting conditions than healthy controls. These differences in substrate utilisation at rest may be an important consideration in obesity in this clinical group.

Modification, validation and implementation of a protocol for post-thyroidectomy hypocalcaemia.

Introduction The management of post-thyroidectomy hypocalcaemia should facilitate early discharge, and reduce risks of hypocalcaemia, readmission and treatment related hypercalcaemia. This paper describes the implementation, evaluation and revision a protocol for the optimal management of this condition. Methods Day 1 parathyroid hormone (PTH) measurements in addition to calcium measurements were commenced following review of the unit's outcomes and literature on post-thyroidectomy hypocalcaemia. Outcomes from a three-year cohort of patients undergoing thyroid surgery helped amend this protocol (revision 1) to reduce biochemical tests, stipulate the need, nature and dose of vitamin D/calcium supplements, and encourage early discharge. This was further validated over seven months to assess compliance, episodes of hyper and/or hypocalcaemia after discharge, readmissions and need for treatment changes. Further revisions were made (revision 2) and implemented. Results The temporary and long-term postoperative hypocalcaemia rates were 29.1% and 3.2% respectively. Repeat calcium measurements on the first day altered management in only 1.4% of cases. The revised protocol was adhered to in 90% of cases. One patient had hypocalcaemia (due to non-compliance) and one had hypercalcaemia. Revision 2 involved reducing the dose of calcium. Conclusions This is a good example of a unit protocol for post-thyroidectomy hypocalcaemia being developed and modified on the basis of the literature and local experience. Day 1 PTH and calcium levels determine the need for treatment and frequency of follow-up visits, facilitate early discharge, reduce risk of over and/or undertreatment, and are good indicators of permanent hypocalcaemia.

Geographic Information Systems to Assess External Validity in Randomized Trials.

INTRODUCTION: To support claims that RCTs can reduce health disparities (i.e., are translational), it is imperative that methodologies exist to evaluate the tenability of external validity in RCTs when probabilistic sampling of participants is not employed. Typically, attempts at establishing post hoc external validity are limited to a few comparisons across convenience variables, which must be available in both sample and population. A Type 2 diabetes RCT was used as an example of a method that uses a geographic information system to assess external validity in the absence of a priori probabilistic community-wide diabetes risk sampling strategy. METHODS: A geographic information system, 2009-2013 county death certificate records, and 2013-2014 electronic medical records were used to identify community-wide diabetes prevalence. Color-coded diabetes density maps provided visual representation of these densities. Chi-square goodness of fit statistic/analysis tested the degree to which distribution of RCT participants varied across density classes compared to what would be expected, given simple random sampling of the county population. Analyses were conducted in 2016. RESULTS: Diabetes prevalence areas as represented by death certificate and electronic medical records were distributed similarly. The simple random sample model was not a good fit for death certificate record (chi-square, 17.63; p=0.0001) and electronic medical record data (chi-square, 28.92; p<0.0001). Generally, RCT participants were oversampled in high-diabetes density areas. CONCLUSIONS: Location is a highly reliable "principal variable" associated with health disparities. It serves as a directly measurable proxy for high-risk underserved communities, thus offering an effective and practical approach for examining external validity of RCTs.

The use of electronic medical records for recruitment in clinical trials: findings from the Lifestyle Intervention for Treatment of Diabetes trial.

BACKGROUND: The use of the electronic medical record (EMR) system in recruitment in clinical trials has the potential for providing a very reliable and cost-effective recruiting methodology which may improve participant recruitment in clinical trials. We examined a recruitment approach centered on the use of the EMR, as well as other traditional methods, in the Lifestyle Intervention for Treatment of Diabetes (LIFT Diabetes) trial. METHODS: LIFT Diabetes is a randomized controlled trial designed to investigate the effects of two contrasting interventions on cardiovascular disease risk: a community-based intensive lifestyle program aimed at achieving weight loss and a clinic-based enhanced diabetes self-management program. Eligible participants were overweight/obese (body mass index, BMI ≥25 kg/m2) patients with type 2 diabetes who were aged 21 years or older. Recruitment strategies included the use of the EMR system (primary), direct referrals, media advertisements, and community screenings. RESULTS: A total of 1102 telephone screens were conducted, resulting in randomization of 260 participants (61.5 % from EMR, mean age 56.3 years, 66.2 % women, 48.1 % non-Hispanic blacks) over a 21-month period, with a yield of 23.6 %. Recruitment yields differed by recruitment method, with referrals having the highest yield (27.5 %). A history of cardiovascular disease was the main health reason for exclusion from the study (16.5 %). An additional 8.9 % were excluded for BMI <25 kg/m2 (<27 kg/m2 for insulin users), 5.4 % could not exercise, 5.2 % had an HbA1c >11 %, and 34.9 % were excluded for other non-medical reasons. Exclusion criteria did not appear to differentially affect enrollment in terms of race or ethnicity. CONCLUSIONS: Future clinical studies should tailor their recruitment strategies based on the participant demographics of interest. Efficient methods such as using the EMR system and referrals should be prioritized over labor-intensive, low-yielding methods such as community screenings and mass mailings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01806727 . Registered on 5 March 2013.

Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia.

OBJECTIVE: A pyridinium metabolite (HPP+) of the neuroleptic drug haloperidol has been identified in rats and in the urine of patients. The purpose of this study was to measure the steady-state blood and plasma concentrations and daily urinary excretion of HPP+ in patients treated with haloperidol. METHODS: HPP+ was measured by HPLC with fluorescence detection. The chromatograms also revealed the presence of a previously unknown pyridinium species, which was identified in urine by liquid chromatography/mass spectrometry/mass spectrometry as 4-(4-chlorophenyl)-1-4-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP+). Concentrations of RHPP+ were then measured by HPLC. RESULTS: The steady-state concentrations of HPP+ or RHPP+ in blood and plasma from 34 patients were virtually identical. The plasma concentrations of each metabolite were related to the daily dose of haloperidol and to its plasma concentrations. Nonlinearity in the elimination of RHPP+ was suggested by the increase in the ratio between RHPP+ and HPP+ plasma concentrations with dose or steady-state concentrations of haloperidol. The concentrations of RHPP+ in plasma and urine generally exceeded those of HPP+; the ratio between them in plasma ranged from 0.9 to 14.1. The daily urinary excretion of HPP+ and RHPP+ accounted for 0.40% +/- 0.18% and 2.3% +/- 1.4% of the haloperidol dose, respectively. The renal clearance of each species was 4.5 +/- 2.5 and 11.3 +/- 5.3 L/hr, respectively. CONCLUSIONS: The presence of these pyridinium species in humans raises the concern that they may be neurotoxic in a manner similar to the dopaminergic pro-neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Effects of tamoxifen and protein kinase C inhibitors on hyperthermic cell killing.

The effects of the anti-estrogen, tamoxifen, and the protein kinase C inhibitor, 1-(5-isoquinolinylsulfonyl)2-methylpiperazine (H7), on hyperthermic cytotoxicity were studied. Three cell lines were used, a human colon cancer cell line (HT-29), a human mammary carcinoma cell line (MCF-7), and Chinese hamster V79 lung fibroblasts. With all three cell lines, tamoxifen at concentrations greater than 7.5 microM during heating or with a 3-hr exposure prior to heating significantly sensitized cells to heat. When cells were preincubated with 10-20 microM tamoxifen for 1-2 hr at 37 degrees C prior to heat treatment, washed free of extracellular tamoxifen, heated to generate thermoresistance, and examined 18 hr later for thermoresistance, tamoxifen treated HT-29 and MCF-7 cells were significantly more heat sensitive than thermotolerant controls not previously exposed to tamoxifen. In contrast, the degree of induced thermoresistance of V79 cells was unchanged after tamoxifen treatment. H7, but not its structural analogue and low affinity protein kinase C inhibitor, HA1004, also sensitized cells to heat. Neither H7 nor HA1004 had any apparent effect on the degree of heat-induced thermoresistance in the three cell lines tested.

Endocytosis in different lifestyles of protozoan parasitism: role in nutrient uptake with special reference to Toxoplasma gondii.

A fundamental property of any eukaryotic cell is endocytosis, that is the ability to take up external fluid, solutes and particulate matter into membrane-bound intracellular vesicles by various mechanisms. Toxoplasma gondii is an intracellular protozoan parasite of the phylum Apicomplexa with a wide geographical and host range distribution. Significant progress in studying the cell biology of this parasite has been accomplished over the last few years. Only recently endocytic compartments and endocytic trafficking have come to a closer dissection in T. gondii. In this review, we discuss the evidence for an endocytic compartment and present a model for an endocytic pathway in Toxoplasma against a background of endocytosis in kinetoplastida and the extensive insights gained from mammalian and yeast cells.

Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms.

In patients taking haloperidol (HP), circulating concentrations of reduced haloperidol (RHP increase disproportionately to the dose or concentration of the parent drug. In the current study, we tested the hypothesis that the nonlinearity is due to preferential saturation of the reoxidation of RHP to HP, and two factors that could amplify the nonlinearity-concentration-dependent binding of RHP by plasma proteins, or by red blood cells. In 25 patients with schizophrenia who were taking HP, the unbound fraction of HP (0.085 +/- 0.016) and RHP (0.244 +/- 0.026) in plasma, and the blood:plasma ratio for each compound were independent of their concentration. Thus, saturable binding of RHP to plasma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal fractions, respectively. Because ketone reductase-catalysed formation of RHP is stereospecific, we examined each enantiomer of RHP separately. The Vmax for the oxidation of the S(-) and R(+) RHP enantiomers in four livers was 0.23 +/- 0.15 and 0.60 +/- 0.32 mumol/g protein per min (mean +/- SD), respectively. The Km was 110 +/- 40 and 70 +/- 10 microM, respectively. In contrast, HP reductase activity displayed greater capacity and was not saturable. The rate of production of RHP at a HP concentration of 122 microM (the limit of HP solubility) in the same livers was 2.6 +/- 0.7 mumol/g protein per min. Despite the observed nonlinearity between the enzymatic pathways in vitro, RHP concentrations in vivo are 2-3 orders of magnitude lower than the Km for oxidation of each enantiomer of RHP.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of haloperidol and reduced haloperidol in the plasma and blood of patients on depot haloperidol.

We developed a sensitive HPLC assay to measure haloperidol (HA) and its metabolite, reduced haloperidol (RH), in plasma and whole blood. The conditions under which HA might be converted to RH during collection and analysis of blood were examined. Provided the blood was kept at 0 degrees C, erythrocyte ketone reductase activity was insignificant. The solid phase extraction method did not generate RH. We studied ten patients taking 25-400 mg/month of HA decanoate and one patient for 4 weeks after the daily oral dose of 120 mg HA was ceased. In the patients on depot HA, the plasma and blood concentrations of HA were not significantly different (P greater than 0.1). For the first time, RH was detected in plasma patients on depot drug, but only in three cases. In contrast, RH was present in the blood of eight of these patients. The accumulation of RH in red blood cells was also evident in the patient on oral HA, in whom the mean ratio of RH concentrations in whole blood to plasma was 3.6 +/- 1.1. Plasma concentrations of HA correlated highly with total neuroleptic activity measured by a radioreceptor assay. Compared to plasma, analysis of concentrations of HA and RH in blood has the advantages of greater sensitivity, of using smaller volumes of blood and of avoiding the efflux of HA and RH during separation of plasma and red cells.

Cytotoxic hyperthermia and Ca2+ homeostasis: the effect of heat on Ca2+ uptake by nonmitochondrial intracellular Ca2+ stores.

The effect of cytotoxic hyperthermia on Ca2+ transport by intracellular, nonmitochondrial Ca2+ stores of the human colon cancer cell line, HT-29, was studied using cells permeabilized with saponin. Saponin treatment permitted equilibration of the cytosol with a defined extracellular medium consisting of an intracellular-like ionic composition, ATP and an ATP-regenerating system, and Ca2+/EGTA buffers to adjust the free [Ca2+]. Under the conditions employed, ATP-dependent Ca2+ uptake in saponin-permeabilized cells was demonstrated to be exclusively due to nonmitochondrial Ca2+ stores, e.g., endoplasmic reticulum or calciosomes. Heat treatment for 120 min at 44.5 degrees C sufficient to kill 80% of the cells inhibited ATP-dependent Ca2+ uptake by 50% in terms of rate and total Ca2+ accumulated. With cells made thermotolerant by either arsenite or heat treatment 24 h prior to challenge heating, ATP-dependent Ca2+ uptake was resistant to a second equivalent heat dose. Efflux of Ca2+ from saponin-permeabilized cells when measured at 37 degrees C was unaffected by a prior heat treatment (44.5 degrees C for 120 min).

Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia.

Impaired olfactory identification has been reported in samples of schizophrenic patients. Little is known about the associations between these impairments and neuropsychological deficits, neurological deficits and olfaction-related symptoms. Forty-six subjects (37 men and 9 women) with schizophrenia were examined with the University of Pennsylvania Smell Identification Test (UPSIT), a selection of neuropsychological tests and standardised neurological and symptom evaluations. Eighty-five per cent of the subjects scored below the published norms' 10th percentile on the UPSIT. Stepwise multiple regression found that WAIS-R Information score and Wisconsin Card Sort Test Failure to Maintain Set score (WCST-FMS) were the only significant predictors of the UPSIT percentile scores, accounting for 41% of the variance. Neurological signs did not contribute to the prediction of impaired olfactory identification. Although 26% of subjects reported olfactory hallucinations, there was no association between this symptom and olfactory impairment. The results suggest that general knowledge or general intelligence may have some influence on olfactory identification in subjects with schizophrenia; however, olfactory identification deficit could not be explained by gross impairments of sustained attention, memory or conceptual ability.

Chirality of reduced haloperidol in humans.

In vitro, cytosolic human ketone reductases catalyse the stereospecific (i.e. >99%) formation of S(-) reduced haloperidol (RHP) from haloperidol (HP). Whether this situation is reflected in patients taking the drug is unknown. In this study in nine patients taking HP, only 73.2+/-18.2% of the RHP excreted in urine was the S(-) enantiomer. Thus, enzymes other than cytosolic ketone reductases must be responsible for the formation of the minor enantiomer.

Mianserin-induced up-regulation of serotonin receptors on normal human platelets in vivo.

The antidepressant, mianserin, is a serotonin receptor (5-HT2) antagonist and produces down-regulation of 5-HT2 and 5-HT1c receptors in the cerebral cortex of rats. In preparation for testing the validity of platelets as a model system for changes in 5-HT2 receptors during antidepressant drug treatment, mianserin (40 mg daily), was given to five human volunteers for five days, and platelets were collected on days 0, 1, 6, and 8. 5-HT2 receptor affinity and density were measured by specific binding of 125I-LSD, with and without an excess of spiperone. 5-HT uptake site affinity and density were determined by 3H-paroxetine binding, with and without an excess of fluoxetine. Platelet serotonin content was measured using high pressure liquid chromatography and electrochemical detention. Platelet 5-HT2 receptor density was increased and the ligand affinity was decreased during mianserin administration. In contrast, platelet 5-HT content was not altered significantly by mianserin administration, nor was platelet uptake site density and ligand affinity.

Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem.

We have shown in patients taking the antipsychotic drug haloperidol (HP) that two pyridinium metabolites (HPP+ and RHPP+) are present in blood and urine in nM concentrations. These metabolites are structurally analogous to MPP+, the neurotoxic metabolite of the well-known parkinsonian-producing protoxin, MPTP. In this study we measured the concentrations of HPP+ and RHPP+ in seven regions of the brain (putamen, substantia nigra, globus pallidus, caudate, hippocampus, cerebellum and occipital cortex) obtained at post-mortem from three patients who were taking HP before death. Blood, urine, and bile from one patient were analysed as well. HPP+ was present in all regions (except for substantia nigra in one patient and globus pallidus in another); the amount/g ranged from 1.6-8.3 pMol but there was no preferential sequestration of the metabolite in dopaminergic regions. Similarly, RHPP+ was present relatively uniformly in all regions; the amount/g ranged from 1.1-7.6 pMol. The concentrations of HPP+ and RHPP+ in one patient were 24 and 13 nM in blood, 660 and 230 nM in urine, and 13.0 and 1.4 microM in bile, respectively. The presence of these pyridinums in brain adds another important piece of information to the case that, at least for HP, metabolite-induced neurotoxicity could contribute to the extrapyramidal side-effects in patients receiving long-term therapy.

Choosing negative symptom instruments: issues of representation and redundancy.

Assuming that the negative syndrome in schizophrenia may be multidimensional, this study examines how conclusions about the structure of negative symptoms may be influenced by the particular rating scale used, the level of data reduction used (such as total, subscale and individual item scores), and also the type of data analyses used to compare scales. Forty-seven subjects with RDC schizophrenia were rated on three instruments: the negative symptom subscale of the BPRS (BPRS-WR); the negative symptom subscale of the PANSS (PANSS-NS); and the SANS. Comparisons were made of different levels of data reduction and different methods of analysis, which included bivariate correlation, bi-multivariate canonical correlation and redundancy analysis. We found that while the total scores from all three scales were highly correlated and therefore highly redundant, both the individual items and subscale scores from the SANS contained information independent of the BPRS-WR, and also, to a lesser extent, of the PANSS-NS. When the BPRS-WR was correlated with either the SANS or the PANSS-NS, one strong canonical variate (CV) emerged, on which all or most items loaded, particularly the affective items. When the SANS and PANSS-NS were correlated, this component again emerged along with three less strong but interpretable components. When examining the non-symmetrical redundancy, we found that the BPRS-WR variates explained 40% of the SANS variance, while conversely the SANS variates explained 80% of the BPRS-WR variance. The PANSS-NS variates were found to explain 58% of the SANS variance, while the SANS variates explained 85% of the PANSS-NS variance. Finally, the PANSS-NS variates explained 79% of the BPRS-WR variance, while conversely the BPRS-WR variates explained 54% of the PANSS-NS variance. AH three scales appear to measure a single general 'affective' component of the negative syndrome, while the PANSS-NS and the SANS also cover additional components which identify cognitive, anergic and social dimensions. This extra information is lost, however, if inappropriate data reduction and/or statistical analyses are used. The fact that the three instruments predicted the various dimensions of the negative syndrome to different degrees suggests that the best choice of a negative scale depends on the type of information required. Nevertheless, further examination of how negative symptom scales cover the multi-dimensional nature of the negative syndrome is required.

Toxicity and bioaccumulation of pentachlorophenol in broiler chickens.

Hubbard-Hubbard broiler chickens were fed graded levels (0, 1, 10, 100, and 1000 ppm) of pentachlorophenol (PCP) containing less than .0023% octachlorodibenzo-p-dioxin (OCDD) for 8 weeks. Tissue samples for PCP, OCDD, and pentachloroanisole (PCA) were cleaned up via gel permeation chromatography and analyzed by gas chromatography employing electron capture detection. Kidney weights were significantly increased by the 100 ppm and 1000 ppm PCP diet. Weights of all other organs including the body weights were significantly lowered by the 1000 ppm PCP diet. Except for the control group, histopathologic examination of the liver revealed bile duct proliferation and some fatty changes in all of the 6-week-old birds. Examination of the brain, liver, gizzard, pancreas, intestine, proventriculus, spleen, kidney, lung, and heart revealed no histopathological lesions in the treated or control birds. Significant linear relationships were found between PCP accumulation in tissues and the concentration of dietary PCP. Accumulation of PCP was greatest in the kidney followed by liver, heart, leg, breast, gizzard, and fat. The high residue levels in the kidney and liver may reflect principal routes of elimination and metabolism. Following a 5 week withdrawal of PCP from the diet, PCP residues were still present in the adipose tissue of all treated birds. Residue levels in the kidney and liver were reduced at the first and third week of withdrawal, but a continuous decline was interrupted by a slight elevation in residue level at the fifth week of withdrawal from the chemical.

Approaches to measuring quality of life and their relevance to mental health.

OBJECTIVES: This paper describes the 'sociological' and health-related approaches to the measurement of quality of life and aims to describe their major findings, shortcomings and potential uses with mental health problems. METHOD: The literature is selectively reviewed to illustrate the major developments and conclusions. RESULTS: Despite the lack of an accepted definition of quality of life, sociological approaches have repeatedly shown in general populations, the mentally ill and the elderly that subjective assessments are more influential in determining expressions of happiness, wellbeing and life satisfaction than are the objective circumstances of a person's life. This supports the use of subjective judgements as the basis for quality-of-life determinations.. CONCLUSIONS: The quality-of-life approaches can help to answer a broad range of questions of interest to psychiatry. Health-related quality-of-life approaches are potentially useful methods of demonstrating the impact of mental illness and the benefit of interventions. Further work is required to determine whether the commonly used measures are sensitive to change.

The distribution of adipose tissue in female in-patients receiving psychotropic drugs.

Of 51 long-term female in-patients receiving psychotropic drugs, 62% were overweight or obese, and 73% were centrally obese to a degree which could be dangerous to their health. The patients also had waist: hip ratios which were significantly higher than expected for their age and obesity (P < 0.01).

Two cases of papillary carcinoma of the thyroid associated with psychosis and violence.

Two cases are described in which serious violent acts occurred during the course of a psychotic illness and in which papillary carcinoma of the thyroid was later diagnosed. Several possible explanations are examined, including a suggestion that neuroendocrine changes reportedly associated with violence may have allowed existing thyroid cancers to grow so as to become clinically apparent.