A longitudinal study of the association between the GNB3 C825T polymorphism and metabolic disturbance in bipolar II patients treated with valproate.

This longitudinal study aimed to investigate the associations between the polymorphisms of guanine nucleotide-binding protein subunit ß-3 (GNB3) C825T and metabolic disturbance in bipolar II disorder (BP-II) patients being treated with valproate (VPA). A 100 BP-II patients received a 12-week course of VPA treatment, and their body weight and metabolic indices were measured. At baseline, the GNB3 C825T polymorphisms were associated with the triglyceride level (P=0.032) in BP-II patients. During the VPA treatment course, the polymorphisms were not only associated with body mass index (BMI) and waist circumference (P-values=0.009 and 0.001, respectively), but also with total cholesterol, triglyceride, low-density lipoprotein and leptin levels (P-values=0.004, 0.002, 0.031 and 0.015, respectively). Patients with the TT genotype had a lower BMI, smaller waist circumference, and lower levels of lipids and leptin than those with the CT or CC genotypes undergoing the VPA treatment course.

Increased expression of the lncRNA BANCR and its prognostic significance in human osteosarcoma.

Long noncoding RNAs (lncRNAs) play important roles in the formation and progression of many types of human malignancies. The aim of our study was to investigate the expression and biological functions of the lncRNA BRAF-activated noncoding RNA (BANCR) in human osteosarcoma. BANCR expression was quantified by real-time PCR in human osteosarcoma cell lines and tissues. We analyzed the association between BANCR levels and clinicopathological factors and patient prognosis. MTT, flow cytometric, and transwell invasion assays were performed to observe the effects of BANCR on MG-63 cell biological behaviors. BANCR overexpression was observed in osteosarcoma cell lines and clinical specimens. Increased BANCR expression was significantly associated with large tumor size, positive distant metastasis, and advanced clinical stage. High BANCR expression in osteosarcoma was an independent predictor of poor survival. Downregulation of BANCR inhibited MG-63 cell proliferation and invasion and promoted cell apoptosis in vitro. These findings suggested that BANCR may act as a tumor promoter in osteosarcoma and could serve as a potential therapeutic target for this disease.

Correlation of plasma brain-derived neurotrophic factor and metabolic profiles in drug-naïve patients with bipolar II disorder after a twelve-week pharmacological intervention.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of bipolar disorder (BD) and metabolic syndrome. We investigated the correlation between plasma BDNF with mood symptoms and metabolic indices in patients with BD-II over a 12-week pharmacological intervention. METHOD: Drug-naïve patients with BD-II (n=117) were recruited. Metabolic profiles [cholesterol, triglyceride, HbA1C, fasting serum glucose, body mass index (BMI)] and plasma BDNF wtrun "tblautotrun "tblsctrun "tbl_contere measured at baseline and 2, 8, and 12 weeks after beginning medication. To adjust within-subject dependence over repeated assessments, multiple linear regressions with generalized estimating equation methods were used. RESULTS: Seventy-six (65.0%) patients completed the intervention. Plasma BDNF levels were significantly associated with BMI (P=9.6E-5), low-density lipoprotein (P=0.034) and total (P=0.001) cholesterol, but not with the Hamilton Depression Rating Scale-17 and Young Mania Rating Scale scores over the 12-week treatment. CONCLUSION: We found initial evidence of a positive correlation between plasma BDNF levels and BMI, low-density lipoprotein and total cholesterol in drug-naïve patients with BD-II. The specific function of BDNF in regulating and maintaining peripheral metabolic health requires additional investigation.

P300 waveform and dopamine transporter availability: a controlled EEG and SPECT study in medication-naive patients with schizophrenia and a meta-analysis.

BACKGROUND: Reduced P300 event-related potential (ERP) amplitude and latency prolongation have been reported in patients with schizophrenia compared to healthy controls. However, the influence of antipsychotics (and dopamine) on ERP measures are poorly understood and medication confounding remains a possibility. METHOD: We explored ERP differences between 36 drug-naive patients with schizophrenia and 138 healthy controls and examined whether P300 performance was related to dopamine transporter (DAT) availability, both without the confounding effects of medication. We also conducted a random effects meta-analysis of the available literature, synthesizing the results of three comparable published articles and our local study. RESULTS: No overall significant difference was found in mean P300 ERP between patients and controls in latency or in amplitude. There was a significant gender effect, with females showing greater P300 amplitude than males. A difference between patients and controls in P300 latency was evident with ageing, with latency increasing faster in patients. No effect of DAT availability on P300 latency or amplitude was detected. The meta-analysis computed the latency pooled standardized effect size (PSES; Cohen's d) of -0.13 and the amplitude PSES (Cohen's d) of 0.48, with patients showing a significant reduction in amplitude. CONCLUSIONS: Our findings suggest the P300 ERP is not altered in the early stages of schizophrenia before medication is introduced, and the DAT availability does not influence the P300 ERP amplitude or latency. P300 ERP amplitude reduction could be an indicator of the progression of illness and chronicity.

Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity.

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease.

Essential role for polyamine biosynthesis in thyroxine stimulated pancreatic development in neonatal rats.

Administration of thyroxine to rat pups leads to precocious development of the pancreas. The role of ornithine decarboxylase (ODC) and polyamines in thyroxine-induced pancreatic maturation was examined. Rat pups (aged 5 days) were given daily subcutaneous injection of thyroxine (0.1 micrograms/g body wt.) until the day before death. Serial ODC activities were measured in pancreatic homogenates after 1, 2, 3, 4, 5, 6, 7 and 10 days of thyroxine treatment. There was a biphasic induction of ODC activities by thyroxine: an early peak appeared on day 2 of treatment followed by a decrease on day 4; a second peak was evident on day 5 and then a decrease to control values by day 7. Significant increases in tissue concentrations of putrescine and spermidine were observed concomitant with two peaks of ODC activity. Pancreatic amylase concentration, DNA and protein also showed a significant increase after thyroxine treatment. Difluoromethyl ornithine (DFMO), a specific ODC inhibitor, given orally (8% in drinking water) to nursing dams at postnatal day 5 for 5 days caused an 83% inhibition of pancreatic ODC activity in thyroxine-treated pups when compared to thyroxine-treated pups not exposed to DFMO. Concomitantly, the thyroxine-induced increases in pancreatic weight, protein and amylase activity were suppressed. Our results suggest that increases in ODC activities and polyamine levels are critical intermediary steps in the precocious induction of pancreatic development by thyroxine.

Short-term effect of epidermal growth factor (EGF) on sodium and glucose cotransport of isolated jejunal epithelial cells.

This study was undertaken to assess the short-term effects of EGF on sodium and glucose uptake, glucose metabolism and Na+/K(+)-ATPase activity in isolated enterocytes of rats. Jejunal cells exposed to EGF had a significantly greater total uptake of sodium compared to controls after 6 min. Kinetic analysis of glucose transport across BBMV's demonstrated similar Km values but a significant increase of the Vmax in vesicles prepared from cells first exposed to EGF as compared to controls. EGF was also associated with a significant increase in glucose metabolism of jejunal enterocytes after 15 min. The activity of Na+/K(+)-ATPase increased in jejunal enterocytes exposed to EGF. The increase in Na+/K(+)-ATPase activity of the cells following EGF exposure was not accompanied by an increase in immunodetectable total or assembled Na+/K(+)-ATPase protein. EGF's effect on enzyme activity was abolished by removing NaCl from the incubation solution, and by preincubating the enterocytes with phlorizin prior to addition of EGF. Preincubation with amiloride did not inhibit the effect of EGF on Na+/K(+)-ATPase. The results confirm that EGF promotes uptake of both sodium and glucose by the jejunal mucosal cells, and suggest the effect of EGF on glucose and sodium is mediated through the brush-border membrane glucose-sodium transporter. The increase in Na+/K(+)-ATPase activity that occurs with EGF appears to be secondary to a rise in intracellular Na+ concentration. The short-term effects of EGF on glucose and sodium transport by the small intestine may have potential therapeutic implications.

Regulation of rat pancreatic glucocorticoid receptors by thyroxine during development.

The effect of T4 on the development of pancreatic glucocorticoid receptors was studied in normal and adrenalectomized rat pups. Daily injection of T4 (0.1 microgram/g BW) to intact pups starting 3 days before death at 10, 15, and 20 days of age resulted in a precocious increase in pancreatic glucocorticoid-binding capacities. Intact pups made hypothyroid by propylthiouracil feeding exhibited lower glucocorticoid-binding capacities in their pancreata. Scatchard analysis demonstrated an increase in the number of glucocorticoid-binding sites in the pancreata of T4-treated intact rats compared to that in normal intact rats. In hypothyroid groups the number of glucocorticoid-binding sites was much lower than that in normal intact rats. The Kd values, however, were unchanged in hypothyroid, hyperthyroid, and control groups. Rat pups who underwent adrenalectomy at 12 days of age had undetectable plasma corticosterone levels and showed an increase in their pancreatic glucocorticoid-binding capacity 3 days after operation. Replacement of corticosterone resulted in a binding level similar to that in the sham-operated group. However, injection of T4 alone to adrenalectomized pups led to a further increase in pancreatic glucocorticoid-binding capacity above that due to adrenalectomy alone. When both T4 and corticosterone were given together to adrenalectomized pups their pancreatic glucocorticoid-binding capacities increased to levels above those in the adrenalectomized group, but lower than those in pups receiving T4 alone. Our results suggest that T4 modulates the development of rat pancreatic glucocorticoid receptors and, at least in part, acts via pathways independent of adrenal function.

The lower limits of dexamethasone window in Chinese depressives.

BACKGROUND: Previous studies have shown wide variation in plasma dexamethasone (DEX) concentrations following a standard 1-mg dexamethasone suppression test (DST), and significantly lower DEX concentrations in DST nonsuppressors compared with suppressors, suggesting that DEX pharmacokinetics/bioavailability is an important variable associated with DST nonsuppression. METHODS: To determine the effect of plasma DEX levels on the DST in Chinese depressives, we measured plasma DEX and post-DEX cortisol levels at 4:00 PM in a group of 50 depressed outpatients, 28 anxiety outpatients, and 33 normal subjects during the course of 1-mg oral overnight DST. RESULTS: We found a significant difference in the plasma DEX levels between DST nonsuppressors and suppressors in the depression group and overall subject population, and a significant negative correlation between the plasma DEX and cortisol levels in the depression, anxiety, and total groups. Within a DEX "window", the DST performance was enhanced, whereas the relationships between plasma DEX and post-DEX cortisol levels remained equally strong. CONCLUSIONS: Our findings support a relationship between plasma DEX and post-DEX cortisol levels, a relationship that might be superimposed on the hypothalamic-pituitary-adrenal axis. Comparing our "window" range with those of previous studies, we suggest that Chinese depressives may have lower limits of plasma DEX window, and that ethnicity may be an intervening variable in both DST response and pharmacokinetics of DEX.

CSF neurochemical study of tardive dyskinesia.

Twenty-three inpatients who met DSM-III criteria for schizophrenia were selected for cerebrospinal fluid (CSF) neurochemical study of tardive dyskinesia (TD). Ten inpatients had tardive dyskinesia, and the remaining 13 patients without TD served as controls. There were no intergroup differences in sex, age, duration of neuroleptic treatment, or in total amount of neuroleptics received between the TD and the control groups. Cerebrospinal fluid was collected by lumbar puncture, and concentrations of homovanillic acid (HVA), MHPG, 5-hydroxyindoleacetic acid (5-HIAA), and acetylcholinesterase (AChE) activity were measured. The concentrations of MHPG (TD 11.56 +/- 3.48 ng/ml versus control 14.20 +/- 3.86 ng/ml), 5-HIAA (45.27 +/- 9.77 ng/ml versus 40.34 +/- 13.77 ng/ml), and HVA (38.26 +/- 18.31 ng/ml versus 31.40 +/- 7.83 ng/ml), and the activity of AChE (TD 7.95 +/- 5.21 mmol/g.hr versus control 12.89 +/- 8.04 mmol/g.hr) showed no significant differences between the two groups, but the ratios of HVA/AChE (t = 2.21, p = 0.05), 5-HIAA/AChE (t = 2.62, p = 0.02), MHPG/HVA (t = -2.16, p = 0.04), and MHPG/5-HIAA (t = -2.48, p = 0.02) were statistically different. The results indicated that TD might involve an imbalance of dopamine-acetylcholine, noradrenalin-dopamine, noradrenalin-serotonin, and serotonin-acetylcholine.

Plasma free 3-methoxy-4-hydroxyphenylglycol predicts response to fluoxetine.

This study was designed to investigate the relationship between platelet serotonin (5-HT) and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) measures in depressed outpatients obtained from the same patient with unipolar depression during the pretreatment period and subsequent response to 6 weeks of treatment with either fluoxetine or maprotiline. Compared to the nonresponder group, the fluoxetine responders showed significantly higher pretreatment levels of MHPG, but no difference in pretreatment 5-HT levels. There were no significant differences in either 5-HT or MHPG levels between maprotiline responders and nonresponders. As to posttreatment levels, there were no between-group differences in 5-HT or MHPG between responders and nonresponders to either fluoxetine or maprotiline. When the relationships between changes in 5-HT or MHPG levels and treatment response were examined, 5-HT values showed a marked decrease in both fluoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fluoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatment levels of plasma free MHPG appear to predict response to fluoxetine.

The dopamine D4 receptor gene (DRD4) is not associated with alcoholism in three Taiwanese populations: six polymorphisms tested separately and as haplotypes.

The dopaminergic system has been implicated in alcoholism but studies at the dopamine D2 receptor gene (DRD2), one of the five dopamine receptors, have not given a consistent picture of an association with alcoholism. We have now studied the dopamine D4 receptor gene (DRD4) using six polymorphisms, both separately and as haplotypes. Three groups of alcoholics from Taiwan (Atayal, Ami, and Han) diagnosed as having severe alcohol dependence using DSM-III-R criteria, together with nonalcoholics matched for gender, ethnic group, and geographic origin, were typed by polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism (RFLP) for all six polymorphisms. Three out of six markers are polymorphic in all three Taiwanese populations. Although the prevalence rates of alcoholism are remarkably different, no highly significant association of this locus with alcoholism was observed in any of the three groups whether the analysis considered genotype distributions or allele frequencies at the three polymorphic markers considered individually and as haplotypes. Neither is there any obvious pattern in the data that covaries with or hints at a relationship with the very different prevalences of alcoholism in the groups studied. Especially because the powerful, multi-site haplotype analysis was not statistically significant in any of the population samples, we conclude that there is no association of the DRD4 locus with alcoholism in Taiwanese populations.

No association between alcoholism and multiple polymorphisms at the dopamine D2 receptor gene (DRD2) in three distinct Taiwanese populations.

This study examined whether there is evidence for an association between alcoholism and the alleles of the TaqI A, TaqI B, and short tandem repeat polymorphisms (STRP), both individually and as haplotypes, at the dopamine D2 receptor gene (DRD2) in males of three populations from Taiwan. We studied 46 Chinese Han (21 alcoholics and 25 nonalcoholics), 42 Atayal (21 alcoholics and 21 nonalcoholics), and 40 Ami (20 alcoholics and 20 nonalcoholics). Alcoholism was diagnosed according to DSM-III-R criteria and all individuals in the alcoholic groups were severely affected. Significant linkage disequilibrium occurs for the three polymorphic sites in all three populations. No significant association was observed between any of the three polymorphisms at the DRD2 locus, tested individually and as haplotypes, and alcoholism in the three subject groups. We conclude that no association exists between genetic variation at the DRD2 locus and alcoholism in Chinese Han, Atayal, and Ami males.

Abnormalities of brain structure and density in schizophrenia.

Quantitative and qualitative measures of brain morphology were derived through CT scans using computer-assisted methodology in patients with schizophrenia or schizo-affective psychosis and headache controls. Schizophrenics had significantly higher density of white matter, together with greater right vs. left asymmetry in density of white matter than controls. Schizophrenics tended to have larger widths of cortical sulci than headache patients. In our sample of schizophrenics, however, no significant differences were found on measures of lateral ventricle (LV) width, LV area, VBR, or other measures of ventricular size compared to headache controls. There were no differences between CT scan measures taken in patients with schizophrenia vs. schizo-affective psychosis.

The specificity of the dexamethasone suppression test in endogenous depressive patients.

The purpose of this study was to evaluate the specificity of the dexamethasone suppression test (DST) for endogenous depression. Between July 1983 and June 1985 we collected 51 cases of endogenous depression (including 16 bipolar disorder, depressed, and 35 major depression with melancholia), 36 cases of schizophrenia (including 14 with depression and 22 without depression), 19 cases of borderline disorder with depression, 16 cases of dysthymic disorder, and 20 normal volunteers. The sensitivity of the DST in the endogenous depression group was 62.7%, which was significantly higher than that of the schizophrenic group (36.1%), the borderline disorder with depression group (31.6%), and the control group (11.1%) (including dysthymic disorder patients and normal volunteers) (X2 = 24.48, df = 3, p less than 0.001). However, the specificity of the DST was 63.9%, 68.4%, and 88.9% when the endogenous depression group was compared with the other three groups, respectively. To differentiate endogenous depression from other mental disorders (e.g., schizophrenia, borderline disorder), such critical variables as patient history and clinical symptoms may be more valuable. Many factors that were reported to be related with DST were discussed.

Cortisol response to ACTH infusion in depressed patients: comparison with age-, sex-, and weight-matched normal subjects.

Adrenal responsiveness to Cosyntropin (synthetic ACTH) was investigated in five patients with major depression and five individually matched normal subjects. Three hours following suppression of endogenous ACTH secretion with dexamethasone (1 mg orally), the adrenal response to a 10-min infusion of Cosyntropin (0.05 micrograms/kg body weight) was monitored for 2 1/2 hr by plasma cortisol measured at 15-min intervals. The depressed patients had significantly higher baseline plasma cortisol, but not higher baseline ACTH, than the controls. During the 3-hr post-dexamethasone (and prior to Cosyntropin infusion), the depressed patients maintained significantly higher cortisol secretion, but not higher ACTH secretion, than the controls. After Cosyntropin infusion, there were no differences in ACTH and cortisol increases between the two groups. These findings stand in contrast to previous reports of enhanced adrenal responsiveness to the administration of much larger amounts of Cosyntropin in major depression.

An optimal rice-based oral rehydration solution: the effect of different concentrations of amylase on production of short chain polymers of glucose.

As part of a plan to develop a rice-based oral rehydration solution containing short polymers of glucose instead of glucose, we determined the concentration of amylase that would yield the largest amount of short chain polymers. Thai rice (25 g) was boiled with 500 ml of distilled water for 30 min. Of 200 ml supernatant rice water obtained, 100 ml were digested with different amounts of amylase after cooling to 50 degrees C for 60 min, boiled for 5 min, and centrifuged (10,000 g, 25 degrees C) for 60 min. The resulting supernatant (80 ml) was freeze-dried; 1.75 g of the powder obtained were dissolved in 3.5 ml of water, passed through a Bio-Gel P2 column to separate short chain polymers (2-9 molecules of glucose) and long chain polymers (> 9 molecules of glucose), which were identified by spectrophotometry (lambda = 190 nm) or by high performance liquid chromatography. Ten mg of amylase (equivalent to 12,000 modified Wohlgemath units) per 100 ml of rice water was optimal for the production of short polymers of glucose from rice.

Platelet 5-HT and plasma MHPG levels in patients with bipolar I and bipolar II depressions and normal controls.

BACKGROUND: It has been suggested that platelet serotonin (5-HT) content may reflect aspects of the presynaptic reuptake of 5-HT, while plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels may provide an index of central noradrenergic function. METHODS: In order to determine if there is a biological distinction in 5-HT or noradrenergic function within bipolar I and bipolar II depressions, we measured levels of platelet 5-HT and plasma MHPG in 12 patients with bipolar I depression, 12 patients with bipolar II depression, and 20 normal healthy controls. All subjects were medication free for at least 4 weeks prior to the study. RESULTS: There was a trend towards higher platelet 5-HT in bipolar I or II depressions when compared to normal controls, whereas there was no difference in platelet 5-HT levels between bipolar I and II depressed patients. When bipolar I and II patients were pooled, there was a significant increase in platelet 5-HT levels in bipolar depressives compared to normal controls, and there was a trend towards a weak positive correlation between platelet 5-HT and 21-item HAMD scores in the patient group. In contrast, there was no difference in plasma MHPG levels between the three groups. LIMITATIONS: This study was limited to a small sample size, single point sampling and did not match seasons. CONCLUSIONS: Our findings did not provide supportive evidence for a distinctive 5-HT or noradrenergic function within bipolar I and bipolar II depressions. However, the finding of increased platelet 5-HT levels in bipolar depressed patients compared to normal controls is consistent with the results of previous studies, and may suggest an increase in presynaptic 5-HT reuptake, presumably resulting from diminished synaptic 5-HT availability in this condition.

Correlation between plasma cortisol and CSF catecholamines in endogenous depressed dexamethasone nonsuppressors.

Nineteen endogenous depressive in-patients (13 with major depression and 6 with bipolar disorder-depressed) and 10 other patients with dysthymic disorder serving as the control group were given the dexamethasone suppression test (DST, 1 mg/subject). The results showed that the DST sensitivity in endogenous depressives was 73.7% and the specificity was 90%. After the patients were treated daily for 6 weeks with 150-200 mg imipramine, 88.9% of those endogenous depressive patients who previously had a positive DST response exhibited a negative response. Moreover, a significantly negative correlation was found between the CSF norepinephrine level and the pre-dexamethasone 4 p.m. plasma cortisol level in those endogenous depressed patients who had a positive DST response. Pre-treatment data also showed that the 4 p.m. plasma cortisol had a significant negative correlation with CSF dopamine. These findings suggest that endogenous depression with positive DST could be related not only to a lower norepinephrine level, but also to a lower dopamine level.

Prolactin response to single and multiple doses of haloperidol in schizophrenic patients.

Serum prolactin and blood levels of haloperidol were assessed in schizophrenic patients after single acute oral doses of haloperidol and during fixed dose treatment with this medication. Although significant intrapatient correlations between prolactin responses to different doses of haloperidol were found, no statistically significant interpatient relationship between haloperidol dose and prolactin response emerged. There were statistically significant relationships between steady-state plasma and red cell haloperidol levels (measured by radioreceptor or gas liquid chromatographic techniques) and serum prolactin response, but not between blood levels after the acute haloperidol dose and prolactin response.