Electrical transport properties of single wall carbon nanotube/polyurethane composite based field effect transistors fabricated by UV-assisted direct-writing technology.

We report on the fabrication and transport properties of single-walled carbon nanotube (SWCNT)/polyurethane (PU) nanocomposite microfiber-based field effect transistors (FETs). UV-assisted direct-writing technology was used, and microfibers consisting of cylindrical micro-rods, having different diameters and various SWCNT loads, were fabricated directly onto SiO2/Si substrates in a FET scheme. The room temperature dc electrical conductivities of these microfibers were shown to increase with respect to the SWCNT concentrations in the nanocomposite, and were about ten orders of magnitude higher than that of the pure polyurethane, when the SWCNT load ranged from 0.1 to 2.5 wt% only. Our results show that for SWCNT loads ≤ 1.5 wt%, all the microfibers behave as a FET with p-type transport. The resulting FET exhibited excellent performance, with an I(on)/I(off) ratio of 105 and a maximum on-state current (I(on)) exceeding 70 µA. Correlations between the FET performance, SWCNTs concentration, and the microfiber diameters are also discussed.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

A novel, non-substrate-based series of glycine type 1 transporter inhibitors derived from high-throughput screening.

The synthesis and structure-activity relationships (SAR) of a series of indane and tetralin inhibitors of the type 1 glycine transporter, derived from a high-throughput screening (HTS) hit, are described. Key modifications that reduced the 5HT1B receptor affinity of the HTS hit and the P450 2D6 inhibition of subsequent analogues are delineated. While these modifications led to potent and selective GlyT1 inhibitors, HERG affinity and human microsomal clearance remain an issue for this series of compounds.

Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.

Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile.

Ziprasidone is a novel antipsychotic agent with a unique combination of pharmacological activities at human receptors. Ziprasidone has high affinity for human 5-HT receptors and for human dopamine D(2) receptors. Ziprasidone is a 5-HT(1A) receptor agonist and an antagonist at 5-HT(2A), 5-HT(2C) and 5-HT(1B/1D) receptors. Additionally, ziprasidone inhibits neuronal uptake of 5-HT and norepinephrine comparable to the antidepressant imipramine. This unique pharmacological profile of ziprasidone may be related to its clinical effectiveness as a treatment for the positive, negative and affective symptoms of schizophrenia with a low propensity for extrapyramidal side effects, cognitive deficits and weight gain.

Urinary calcium excretion in healthy Thai children.

The objective of this study was to determine age-specific reference values for urinary calcium/creatinine ratios (UCa/Cr) of children in southern Thailand. Non-fasting urine samples were collected from a random population of 488 healthy children (282 males, 206 females) ranging in age from 17 days to 15 years. Samples were divided into six groups by age. Subjects whose calcium levels exceeded the 95th percentile within each age group were classified as having hypercalciuria. Pyuria, hematuria, proteinuria, urinary sodium, and potassium levels in children with normal UCa/Cr were compared with levels in children with high UCa/Cr. The 95th percentiles for UCa/Cr (mg/mg) by age were: <6 months, 0.75; 6 months to <12 months, 0.64; 12 months to <2 years, 0.40; 2 years to <5 years, 0.38; 5 years to <10 years, 0.29; and 10 years to <15 years, 0.26. Pyuria, hematuria, and proteinuria were no more prevalent in the 22 children with hypercalciuria than in children with normal urinary calcium levels. Urinary sodium/creatinine ratios (UNa/Cr) and urinary sodium/potassium ratios (UNa/K) were correlated with UCa/Cr (r=0.41, P<0.0001 and r=0.24, P<0.0001, respectively). Urinary potassium/creatinine ratios (UK/Cr) were not (r=0.05, P>0.1)). Children with high UCa/Cr ratios also had higher UNa/Cr and UNa/K (5.6+/-7.1 vs. 2.6+/-1.5, P<0.001 and 5.4+/-2.3 vs. 2.5+/-0.23, P<0.05, respectively). The study established reference values for random, non-fasting UCa/Cr for healthy Thai children and indicated that urinalysis is not a good indicator of hypercalciuria.

Sequence variants of the sarco(endo)plasmic reticulum Ca(2+)-transport ATPase 3 gene (SERCA3) in Caucasian type II diabetic patients (UK Prospective Diabetes Study 48).

AIMS/HYPOTHESIS: Type II (non-insulin-dependent) diabetes mellitus is a common heterogeneous metabolic disorder of largely unknown genetic aetiology. The sarco(endo)plasmic reticulum Ca(2+)-transport ATPase (SERCA) plays an important part in the glucose-activated beta-cell Ca(2+) signalling that regulates insulin secretion. Impaired function and expression of SERCA have been shown in islets of Langerhans from diabetic animal models and have also been associated with beta-cell apoptosis. Thus, the SERCA3 encoding gene is a plausible candidate for a primary pancreatic beta-cell defect. METHODS: In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients. RESULTS: We found four rare missense mutations [Exon 4: Gln(108)-->His (CAG-->CAT), Exon 14: Val(648) -->Met (GTG-->ATG) and Arg(674)-->Cys (CGC--> TGC), and Exon 15: Ile(753)-->Leu (ATC-->CTC)]. The patients with Gln(108)-->His, Val(648)-->Met and Arg(674)-->Cys mutations, which may affect the E1P-E2P transition of SERCA3 during its enzyme cycle, had normal body weight with marked hyperglycaemia and beta-cell dysfunction. That is an unusual phenotype only found in 6 % of the Type II diabetic patients recruited for the UK Prospective Diabetes Study. In addition, five silent polymorphisms, six intron variants and two polymorphisms in the 3' untranslated region of exon 22 were found with similar frequency in diabetic and control subjects. CONCLUSION/INTERPRETATION: Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999) 42: 1240-1243].

School performance and weight status of children and young adolescents in a transitional society in Thailand.

OBJECTIVE: To study the association between current or previous weight status and school performance among children and young adolescents of Hat Yai municipality, southern Thailand. DESIGN: Cross-sectional and longitudinal study. SETTING: Primary and secondary schools of Hat Yai municipality, southern Thailand. SUBJECTS: 1207 grades 3-6 and 587 grades 7-9 students. MEASUREMENTS: Body mass index (BMI, kg/m2) calculated from weight and height measurement of subjects in 1992 and 1994; parental education level and occupation, and monthly income, by questionnaire performed in 1992; grade-point-average (GPA) and grades of mathematics and Thai language from the school records of final examinations in 1994. RESULTS: Overweight subjects (BMI value > 85th percentile of the NHANES-I data for age and gender) in grades 7-9 had a mean GPA 0.20 point (95% confidence internal (CI) = 0.04, 0.37) lower than that of the normal weight children after controlling for gender, age, school and grade. They were twice more likely to have low grades (lower than 2 on the scales of 0-4) of mathematics and Thai language than normal weight children. There were no associations between GPA or individual subject grades and previous BMI status in 1992. Children in grades 7-9 who became overweight over the two years, had a mean GPA of 0.48 point lower than those who did not become overweight (95% CI = 0.12, 0.84). In grades 3-6 subjects, however, becoming overweight had no effect on GPA and individual subject scores. CONCLUSIONS: Our study showed that being overweight and becoming overweight during adolescence (grades 7-9) was associated with poor school performance, whereas such an association did not exist in children (grades 3-6).

Growth pattern and age at menarche of obese girls in a transitional society.

Childhood obesity is an increasing problem in a transitional society such as Thailand. To study physical growth and puberty in obese children, a cross-sectional survey of growth and age at menarche was carried out in schoolgirls aged between 8 and 16 years old. The 3,120 girls were divided into two groups based on weight-for-height criteria. Girls with weight-for-height between 80 and 120% were classified as normal stature (2,625; 84.1%) and those more than 120% were obese (495; 15.9%). Using probit analysis, age at menarche in obese girls was 0.9 year earlier than normal stature girls (11.5 years vs 12.4 years). At age 12, obese girls were reaching menarche 2.8 times more when compared with the normal stature girls. In terms of growth pattern, obese girls were taller and grew faster during the prepubertal period, and then reached their final height earlier than the normal stature girls (13 years vs 15 years). The final height in obese girls was significantly shorter (153.0 cm and 155.0 cm, p = 0.01). We conclude that: 1) obese girls grow faster, have earlier menarche and then stop growing earlier, and 2) obese girls tend to be shorter as adults, compared with normal stature girls.

Evaluation of various models of hyaluronan kinetics for assessment of liver function.

The purpose of this study of various models of hyaluronan kinetics has been to find the most appropriate model for estimation of parameters which characterize liver endothelial cell function. Five theoretical models for serum hyaluronan distribution and elimination were evaluated by computer analysis of serial measurements of the mass concentration of hyaluronan in serum following an intravenous bolus dose. Three of the models were based on one-compartment distribution of intravenously injected hyaluronan. Model 1A, with assumed first-order elimination, was found to be compatible with measured data and had identifiable parameters. Model 1B, with assumed non-linear Michaelis-Menten kinetics, was also found to be compatible but the Michaelis-Menten constant (K(m)) was not well determined. In model 1C, with non-linear Michaelis-Menten elimination kinetics, K(m) was set to a fixed value of 340 micrograms l-1, and the remaining parameters were well determined and the model was found to be compatible. Two models with an assumed two-compartment distribution of intravenously injected hyaluronan, were not acceptable due to unidentified parameters not discriminating between patients and healthy persons. In conclusion, model 1C, with one-compartment distribution and non-linear Michaelis-Menten kinetics, best fulfilled the criteria of validity and was accepted for further evaluation of clinical materials.

Djenkol beans as a cause of hematuria in children.

BACKGROUND: Djenkolism is djenkol bean poisoning, characterized by acute renal failure, urinary obstruction and spasmodic pain. The effects of djenkol bean consumption on the urinary tract without overt symptoms and long-term outcome are not established. This paper examines the association between djenkol bean ingestion and urine abnormalities in school children. METHOD: 609 school children aged 7-11 years in five urban Hat-Yai schools were interviewed, and had their urine analyzed. All children included in the study had normal blood pressure for age, no illness (including respiratory tract symptoms) and were not taking medication. RESULTS: 78% of the children had a history of eating djenkol bean and of these 31% had done so in the past 24 h. Children with hematuria were almost four times (crude odds ratio = 3.7) as likely to have a history of eating djenkol beans as those with normal urine. Crystaluria and pyuria were not significantly more common among those eating the beans. The risk of having hematuria did not change with increasing consumption, or time since last eaten, or type of preparation even after adjustment for sex and age. CONCLUSION: Djenkol bean consumption may be defined as one of the probable causes of hematuria in the area where the djenkol tree grows.

Incidence and risk factors for carbohydrate intolerance in Thai infants with acute diarrhea: an outpatient-based study.

Until recently, information concerning carbohydrate intolerance complicating acute infantile diarrhea of outpatients in Thailand has been lacking. This prospective study was undertaken to determine the incidence and risk factors of secondary carbohydrate intolerance in outpatients. Of 197 well-nourished infants with acute diarrhea who were seen at the outpatient department of Songklanagarind Hospital between July 1991 and June 1992, 62 infants (31.3%) had carbohydrate intolerance, and 7 of the 62 (3.5%) also had acquired monosaccharide intolerance. The clinical characteristics that predicted infants with carbohydrate intolerance were : a low bodyweight relative to the length, dehydration (OR 4.55, 95% CI 1.1.5-17.9), the presence of mucus in diarrheal stools (OR 2.79, 95% CI 1.23-6.32) and rotavirus infection (OR 3.49, 95% CI 1.20-10.18).

Risk factors for cardiovascular disease in obese and normal school children: association of insulin with other cardiovascular risk factors.

OBJECTIVE: To investigate the level of insulin and other known cardiovascular risk factors in school children and their association with obesity. DESIGN: Cross-sectional study. SUBJECTS: 123 normal and 116 obese school children categorized by weight-for-height, mean age: 10.2 and 10.5 years old respectively. MEASUREMENTS: Family histories of diseases by questionnaires; blood pressure (BP) and waist and hip circumferences by measurements; fasting blood for glucose, insulin, total cholesterol, HDL-cholesterol and triglycerides. RESULTS: The numbers of boys in the normal and obese group were 65 and 58, those of the girls, 53 and 63 respectively. The obese group was more likely to have family histories of obesity, high blood pressure and diabetes; had significantly greater waist-hip-ratio (WHR), higher systolic and diastolic BP, lower HDL-cholesterol, higher triglyceride and fasting insulin levels (with fasting blood sugar in the normal range) than the normal weight group. In a crude analysis, insulin levels were positively correlated with obesity, systolic BP, WHR, age and triglycerides and negatively associated with male gender and HDL-cholesterol. After adjustment using multiple regression, only obesity status, age, gender and triglycerides still remained significantly associated with insulin level. Limitation of utilizing family disease history report for identification of children at risk was discussed. CONCLUSION: These findings suggest that risk to coronary heart disease and hypertension through insulin resistance already operates in school-aged children.

Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity.

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.

Ages at thelarche and menarche: study in southern Thai schoolgirls.

Ages at thelarche and menarche have been studied by a status quo method in 3,029 Thai schoolgirls in Hat Yai municipality. The median ages at thelarche and menarche estimated by probit analysis are 9 years 11 months, and 12 years 5 months, respectively. Declining in ages of thelarche and menarche is observed and can be explained by improvement in nutritional status and higher living standards.

Goiter in Thai schoolchildren: study in Hat Yai, southern Thailand.

Examination for goiter was performed in 6,035 schoolchildren (2,899 girls, 3,136 boys), aged 8-17 years, from primary and secondary schools in Hat-Yai municipality, Songkhla province. Goiter was detected in 355 children (combined prevalence 6%; 232 or 8% in girls, 123 or 4% in boys). Of the 355 children with goiter, 214 (60%; 148 girls, 66 boys) participated in the study, and had blood drawn for free thyroxine (FT4), triiodothyronine (T3), thyroid stimulating hormone (TSH), and thyroid antibodies. All had urine collected for iodine excretion. The diagnoses of goiter were as follows: simple goiter in 192 (89.8%; 129 girls, 63 boys); juvenile autoimmune thyroiditis in 18 (8.4%; 16 girls, 2 boys); Graves' disease in 2 girls (0.9%); thyroid adenoma in 1 boy (0.45%), and ectopic thyroid in 1 girl (0.45%). Acquired hypothyroidism was found in 4 out of 18 children with juvenile autoimmune thyroiditis (22.2%). Iodine deficiency disorder was not evident in children examined shown by high urinary iodine excretion of more than 50 mcg/gm creatinine (mean 298, range 70-630). In conclusion, simple goiter is a common occurrence in children and adolescents in Southern Thailand. Juvenile autoimmune thyroiditis should be identified and differentiated from simple goiter as it is the most common cause of acquired hypothyroidism. Iodine deficiency is not evident in Southern Thailand, at least in the urban areas of a large city.

Effects of serotoninergic agents on downregulation of beta-adrenoceptors by the selective serotonin reuptake inhibitor sertraline.

The results of the present study show that the down-regulation of beta-adrenoceptors of rat brain, induced by subacute administration of sertraline, is facilitated when this selective serotonin reuptake inhibitor was co-administered with the serotonin releaser, norfenfluramine, or the serotonin terminal autoreceptor antagonist, methiothepin. The respective drug combination produced a reduction in Bmax of [3H]dihydroalprenolol binding to cortical membranes of treated rats at a dose of the releaser, release enhancer, or sertraline, which was ineffective when administered alone. In a similar manner, the 5-HT1A agonists, gepirone and 8-OH-DPAT, were found to facilitate the downregulation of beta-adrenoceptors induced by sertraline. The 5-HT1B agonist, 3-trifluoromethylphenylpiperazine, and the 5-HT2 antagonist, ritanserin, showed neither facilitation nor antagonism of sertraline, but the 5-HT3 antagonist, ondansetron, attenuated the decrease of Bmax of [3H]dihydroalprenolol binding elicited by sertraline. Agents that putatively increase the serotoninergic activity facilitated the down-regulation of beta-adrenoceptors induced by sertraline, suggesting that the enhancement of serotonin transmission, expected of the selective serotonin reuptake inhibitor itself, may play a role in this effect of sertraline. Whether the downregulation of brain beta-adrenoceptors by sertraline plays any role in its antidepressant activity cannot be deduced from these experiments.

Hepatic extraction of hyaluronic acid in porcine peritonitis.

The hepatic extraction of hyaluronic acid (HA) was studied in porcine fecal peritonitis in two groups of animals given various amounts of volume substitution. There was a progressive decrease in hepatic blood flow (QH) and a corresponding increase in the plasma concentration of HA in arterial blood over a 5-hour observation period, less pronounced in animals given more volume substitution. While hepatic clearance of HA decreased, the extraction ratio over the liver was not altered. The extracted amount of HA, which at steady state reflects the turnover of HA, was also unchanged. There was a significant correlation between QH and arterial HA concentration (r = 0.57; p < 0.05). The data suggest that the arterial HA concentration in sepsis reflects QH rather than an altered ability of the liver to eliminate HA.

Kinetics of circulating hyaluronan in humans. 4.

The elimination of intravenously injected hyaluronan (HA) from the blood was investigated in 12 healthy volunteers. Three consecutive 30 min infusions of HA were given, separated by 90 min washout periods. Blood samples were taken before, during and after each infusion and the plasma HA concentration was determined. The deposition of HA was modelled according to a Michaelis-Menten kinetic model which included natural synthesis of HA. Km and Vmax was estimated to 0.34 +/- 0.13 microgram ml-1 and 3.48 +/- 0.97 microgram min-1 kg-1 b.w., respectively. The endogenous input was calculated to be 24 +/- 11 micrograms min-1 and was found to correlate to the age of the subjects (P < 0.05). As the baseline HA concentration was 0.031 +/- 0.21 microgram ml-1, the rate of elimination was linear in the normal concentration range. The calculated Vd was about 75% higher than a weight-estimated plasma volume. The total amount of HA excreted by the kidneys during the study period was 394 +/- 77 micrograms, which corresponded to approximately 1.7% of the total input of HA into the circulation during the experiment.