Panoscopically optimized thermoelectric performance of a half-Heusler/full-Heusler based in situ bulk composite Zr(0.7)Hf(0.3)Ni(1+x)Sn: an energy and time efficient way.

All scale hierarchical architecturing, matrix/inclusion band alignment and intra-matrix electronic structure engineering, the so called panoscopic approach for thermoelectric materials has been demonstrated to be an effective paradigm for optimizing high ZT. To achieve such hierarchically organized microstructures, composition engineering has been considered to be an efficient strategy. In this work, such a panoscopic concept has been extended to demonstrate for the first time in the case of half-Heusler based thermoelectric materials via a composition engineering route. A series of new off-stoichiometric n-type Zr0.7Hf0.3Ni1+xSn (0 ≤x≤ 0.10) HH compositions have been modified to derive HH(1 -x)/full-Heusler (FH)(x) composite with an all scale hierarchically modified microstructure with FH inclusions within the matrix to study the temperature dependent thermoelectric properties. The structural analysis employing XRD, FE-SEM and HR-TEM of these materials reveal a composite of HH and FH, with hierarchically organized microstructures. In such a submicron/nano-composite, the electronic properties are observed to be well optimized yielding a large power factor; α(2)σ (∼30.7 × 10(-4) W m(-1) K(-2) for Zr0.7Hf0.3Ni1.03Sn) and reduced thermal conductivity (∼2.4 W m(-1) K(-1) for Zr0.7Hf0.3Ni1.03Sn) yielding a high ZT∼ 0.96 at 773 K for composition Zr0.7Hf0.3Ni1.03Sn which is ∼250% larger than the normal HH Zr0.7Hf0.3NiSn (ZT∼ 0.27 at 773 K). The enhancement in ZT of these composites has been discussed in terms of primary electron filtering, electron injection and several phonon scattering mechanisms such as alloy scattering, point defect scattering, and grain boundary scattering. The Bergman and Fel model is used to calculate effective thermoelectric parameters of these composites for comparing the experimental results.

Lithium transport across red cell membrane: a cell membrane abnormality in manic-depressive illness.

In the families of manic-depressive patients, relatives with a history of affective disorders had a significantly higher ratio of mean red cell lithium to plasma lithium in vitro than relatives with no such history. A genetically controlled abnormality in lithium-sodium transport, the mechanism that determines the lithium ratio, may play a role in the etiology of some forms of affective disorders.

Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone.

Earlier studies have implicated brain-derived neurotrophic factor in stress and in the mechanism of action of antidepressants. It has been shown that antidepressants upregulate, whereas corticosterone downregulates, brain-derived neurotrophic factor expression in rat brain. Whether various classes of antidepressants reverse corticosterone-mediated downregulation of brain-derived neurotrophic factor is unclear. Also not known is how antidepressants or corticosterone regulates brain-derived neurotrophic factor expression. To clarify this, we examined the effects of various classes of antidepressants and corticosterone, alone and in combination, on the mRNA expression of total brain-derived neurotrophic factor and of individual brain-derived neurotrophic factor exons, in rat brain. Normal or corticosterone pellet-implanted (100 mg, 21 days) rats were injected with different classes of antidepressants, fluoxetine, desipramine, or phenelzine, intraperitoneally for 21 days and killed 2 h after the last injection. mRNA expression of total brain-derived neurotrophic factor and of exons I-IV was measured in frontal cortex and hippocampus. Given to normal rats, fluoxetine increased total brain-derived neurotrophic factor mRNA only in hippocampus, whereas desipramine or phenelzine increased brain-derived neurotrophic factor mRNA in both frontal cortex and hippocampus. When specific exons were examined, desipramine increased expression of exons I and III in both brain areas, whereas phenelzine increased exon I in both frontal cortex and hippocampus but exon IV only in hippocampus. On the other hand, fluoxetine increased only exon II in hippocampus. Corticosterone treatment of normal rats decreased expression of total brain-derived neurotrophic factor mRNA in both brain areas, specifically decreasing exons II and IV. Treatment with desipramine or phenelzine of corticosterone pellet-implanted rats reversed the corticosterone-induced decrease in total brain-derived neurotrophic factor expression in both brain areas; however, fluoxetine reversed the decrease only partially in hippocampus. Interestingly, antidepressant treatment of corticosterone pellet-implanted rats increased only those specific exons that are increased during treatment of normal rats with each particular antidepressant. We found that although corticosterone and antidepressants both modulate brain-derived neurotrophic factor expression, and antidepressants reverse the corticosterone-induced brain-derived neurotrophic factor decrease, antidepressants and corticosterone differ in how they regulate the expression of brain-derived neurotrophic factor exon(s).

Lithium transport pathways in human red blood cells.

In human red cells, Li is extruded against its own concentration gradient if the external medium contains Na as a dominant cation. This uphill net Li extrusion occurs in the presence of external Na but not K, Rb, Cs, choline, Mg, or Ca, is ouabain-insensitive, inhibited by phloretin, and does not require the presence of cellular ATP. Li influx into human red cells has a ouabain-sensitive and a ouabain-insensitive but phloretin-sensitive component. Ouabain-sensitive Li influx is competitively inhibited by external K and Na and probably involves the site on which the Na-K pump normally transports K into red cells. Ouabain does not inhibit Li efflux from red cells containing Li concentrations below 10 mM in the presence of high internal Na or K, whereas a ouabain-sensitive Li efflux can be measured in cells loaded to contain 140 mM Li in the presence of little or no internal Na or K. Ouabain-insensitive Li efflux is stimulated by external Na and not by K, Rb, Cs, choline, Mg, or Ca ions. Na-dependent Li efflux does not require the presence of cellular ATP and is inhibited by phloretin, furosemide, quinine, and quinidine. Experiments carried out in cells loaded in the presence of nystatin to contain either only K or only Na show that the ouabain-insensitive, phloretin-inhibited Li movements into or out of human red cells are stimulated by Na on the trans side and inhibited by Na on the cis side of the red cell membrane. The characteristics of the Na-dependent unidirectional Li fluxes and uphill Li extrusion are similar, suggesting that they are mediated by the same Na-Li countertransport system.

Genetic determinant of lithium ion distribution. An in vitro and in vivo monozygotic-dizygotic twin study.

In previous research, evidence was provided of genetic control of in vitro red blood cell (RBC) uptake of lithium ion following a 24-hour incubation using a monozygotic (MZ)-dizygotic (DZ) twin study method. To extend these data, in vitro RBC lithium ion concentrations were assessed for five MZ and five DZ twin pairs. To extend this line of research on genetic control of lithium ion distribution to in vivo conditions, these twin pairs were administered lithium carbonate for seven days during which time RBC and plasma lithium ion concentrations were assessed. In this limited sample, the data provide evidence of genetic control of distribution of lithium ion across the RBC membrane in vivo as well as of in vitro RBC uptake of lithium ion.

Lithium transport across the RBC membrane. A study of genetic factors.

The measurement of the ratio of RBC to plasma lithium ion levels in vitro in 291 members of 120 families indicated that genetic factors contribute substantially to interindividual variability in the lithium ion distribution across the RBC membrane. These factors affect the lithium-sodium ion exchange system that determines the lithium ion distribution.

Lithium ion transport and affective disorders within families of bipolar patients. Identification of a major gene locus.

We have identified a genetic polymorphism in which one allele results in elevated RBC lithium ion ratios and also contributes to vulnerability to some forms of affective disorders. Interindividual variability in the lithium ion ratio (the ratio of the RBC to the plasma lithium ion concentration) is determined by variability in a lithium ion ratio (the ratio of the RBC to the plasma lithium ion concentration) is determined by variability in a lithium-sodium ion counterflow mechanism. Segregation analyses were conducted on lithium ion ratios in vitro in members of 120 normal families and on both the lithium ion ratio and the history of affective disorder in first-degree relatives of 31 bipolar patients. These analyses provided evidence for an autosomal major gene locus that influences the lithium ion ratio both in members of normal families and in relatives of bipolar patients. The allele at the major locus resulting in elevated lithium ion ratios was associated with an increased likelihood of psychiatric hospitalization among relatives of bipolar patients.

Genetic determinant of lithium ion metabolism. II. An in vivo study of lithium ion distribution across erythrocyte membranes.

A study was conducted to determine if membrane factors, known to influence the distribution of sodium ion (Na) and potassium ion (K), also influence lithium ion distribution. Two groups of sheep with genetically determined differences in their cation concentrations were administered lithium chloride for ten days. The low red blood cell (RBC) potassium ion sheep (LK) had a greater RBC lithium ion concentration than the high RBC potassium ion sheep (HK). In vitro incubation of erythrocytes with lithium chloride also produced substantially different RBC lithium ion: plasma lithium ion ratios similar to those seen in the vivo study. Distribution of lithium ion was generally similar to that of Na ion. It seems that lithium ion distribution may be controlled by the same genetic factors that regulate Na ion distribution.

Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia and polydipsia.

BACKGROUND: For unclear reasons, life-threatening water intoxication often coincides with acute psychosis in polydipsic schizophrenic patients with chronic hyponatremia. In contrast, most polydipsic schizophrenic patients are normonatremic and never manifest hyponatremia. To explore whether the effect of acute psychosis on water balance differs in these 2 schizophrenic subgroups, we compared their responses to drug-induced psychotic exacerbations. METHODS: Matched polydipsic schizophrenic patients with (n = 6) and without (n = 8) hyponatremia were identified based on past and current indexes of fluid intake and hydration. A transient psychotic exacerbation was induced with an infusion of the psychotomimetic methylphenidate hydrochloride (0.5 mg/kg of body weight over a 60-second period). Antidiuretic hormone levels, subjective desire for water, and factors known to influence water balance were measured at 15-minute intervals for 2 hours. RESULTS: Except for the expected differences in plasma osmolality and sodium, basal measures were similar in the 2 groups. Following methylphenidate administration, antidiuretic hormone levels increased more in the hyponatremic patients (P < .02), despite their consistently lower plasma osmolality (P < .007). No known or putative antidiuretic hormone stimulus could account for this finding. Only basal positive psychotic symptoms (P < .09) and plasma sodium (P < .18) were even marginally associated with the peak antidiuretic hormone responses, but neither factor could explain the difference in the response by the 2 groups. CONCLUSION: Psychotic exacerbations are associated with enhanced antidiuretic hormone secretion, for unknown reasons, in schizophrenic patients with hyponatremia and polydipsia, thereby placing them at increased risk of life-threatening water intoxication.

Pharmacologic evidence for specificity of pursuit dysfunction to schizophrenia. Lithium carbonate associated with abnormal pursuit.

Conflicting findings regarding the prevalence of abnormal smooth-pursuit eye movements in patients with major affective disorders call into question the specificity of impaired smooth-pursuit eye movements to schizophrenia. We report that pursuit is impaired in 88% of lithium carbonate-treated affective disorder patients whose pursuit was normal prior to receiving this drug. Over half of lithium carbonate-treated affective disorder patients in remission also showed impairment of smooth-pursuit eye movements. In conjunction with recent prevalence data on family members of psychiatric patients, the findings support the specificity of abnormal pursuit as a biological trait associated with schizophrenia, but not with the major affective disorders. The mechanisms by which lithium carbonate impairs pursuit are discussed.

Altered expression of neuroplasticity-related genes in the brain of depressed suicides.

BACKGROUND: Expression of the neuronal membrane glycoprotein M6a (GPM6A), the proteolipid protein (PLP/DM20) family member, is downregulated in the hippocampus of chronically stressed animals. Its neuroplastic function involves a role in neurite formation, filopodium outgrowth and synaptogenesis through an unknown mechanism. Disruptions in neuroplasticity mechanisms have been shown to play a significant part in the etiology of depression. Thus, the current investigation examined whether GPM6A expression is also altered in human depressed brain. METHODS: Expression levels and coexpression patterns of GPM6A, GPM6B, and PLP1 (two other members of PLP/DM20 family) as well as of the neuroplasticity-related genes identified to associate with GPM6A were determined using quantitative polymerase chain reaction (qPCR) in postmortem samples from the hippocampus (n = 18) and the prefrontal cortex (PFC) (n = 25) of depressed suicide victims and compared with control subjects (hippocampus n = 18; PFC n = 25). Neuroplasticity-related proteins that form complexes with GPM6A were identified by coimmunoprecipitation technique followed by mass spectrometry. RESULTS: Results indicated transcriptional downregulation of GPM6A and GPM6B in the hippocampus of depressed suicides. The expression level of calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) and coronin1A (CORO1A) was also significantly decreased. Subsequent analysis of coexpression patterns demonstrated coordinated gene expression in the hippocampus and in the PFC indicating that the function of these genes might be coregulated in the human brain. However, in the brain of depressed suicides this coordinated response was disrupted. CONCLUSIONS: Disruption of coordinated gene expression as well as abnormalities in GPM6A and GPM6B expression and expression of the components of GPM6A complexes were detected in the brain of depressed suicides.

Protein kinase C in platelets of depressed patients.

BACKGROUND: We studied the role of protein kinase C (PKC), a major regulatory enzyme and an important component of the phosphoinositide signaling system, in depression. METHODS: PKC was determined using [3H]phorbol dibutyrate (PDBu) as the radioligand in the membranal and cytosolic fractions of platelets obtained from hospitalized drug-free depressed patients during a baseline period and from drug-free normal control subjects. RESULTS: We observed that the [3H]PDBu binding was significantly higher in the cytosolic fraction obtained from platelets of depressed patients compared to normal control subjects. CONCLUSIONS: Our studies indicate increased formation of PKC in platelets of depressed patients. The significance and mechanisms involved in increased PKC in the cytosolic fraction of platelets are unclear, but they suggest that increased PKC may be associated with the pathophysiology of depressive illness.

Platelet monoamine oxidase in alcoholism.

We studied platelet monamine oxidase (MAO) activity using 14C-tyramine as substrate in hospitalized alcoholic patients in the early phases of abstinence and in nonhospitalized normal control volunteers. Platelet MAO was determined in 75 patients (67 men, 8 women) with alcoholism and 123 normal control volunteers (52 men, 71 women). The platelet MAO activity in alcoholic patients was significantly lower than in normal control volunteers. We also observed that the mean platelet MAO activity in male alcoholics was significantly lower than in normal males. The analysis of platelet MAO in alcoholics revealed a mixture of two normal distributions. Alcoholic patients falling into the low MAO component were younger in age, with a lower age of onset of alcoholism, and had higher frequencies of family history of alcoholism. They thus resembled type II alcoholics described by other investigators. Platelet MAO may thus serve as a useful biological marker for subtyping alcoholism and identifying high-risk groups at an early stage. The findings of this study are consistent with previous reports of low platelet MAO activity in alcoholic patients.

Behavioral and biochemical effects of methylphenidate in schizophrenic and nonschizophrenic patients.

The authors examined the specific behavioral and biochemical effects of intravenous methylphenidate in a sample of schizophrenic and nonschizophrenic patients. Twenty drug-free patients participated in a double-blind, placebo randomized study of methylphenidate, with multiple samples of plasma homovanillic acid (HVA) and serum growth hormone (GH) obtained during the infusion procedure. Methylphenidate caused a significant increase in positive symptoms that was relatively specific to the schizophrenic patients and was evident even in those with otherwise dormant symptomatology. When behavioral response was correlated with the biochemical responses (i.e., changes in plasma HVA and GH), there was a significant positive relationship between the increase in the BPRS-positive symptoms as well as the hostility/suspiciousness factor, and the increase in GH. These results suggest that the expression of psychotic symptoms may be associated with increased dopaminergic postsynaptic sensitivity, although the nonspecific nature of methylphenidate's actions discourages a stronger interpretation of the results.

Platelet 3H-imipramine binding sites in obsessive-compulsive behavior.

Several studies indicate a serotonergic dysfunction in patients with obsessive-compulsive disorder (OCD). We examined serotonergic function in OCD by determining platelet 3H-impiramine binding sites in patients with OCD during a drug-free baseline period as well as normal control volunteers. The maximum number of binding sites (Bmax) and apparent dissociation constant (Kd) was determined using 3H-imipramine (IMI) as the binding ligand. We observed that the mean 3H-IMI binding Bmax (fmol/mg protein) determined in 24 patients with OCD was not significantly different from that in 23 normal control subjects. There were no significant differences in the Kd between patients with OCD and normal control subjects. Our results are thus similar to those reported by Insel et al (1985) and Black et al (1990), who observed no significant differences in platelet 3H-IMI binding between OCD patients and controls; but different from those reported by Weizmann et al (1986), who observed decreased 3H-IMI Bmax in OCD patients. The discrepancy in the results is not clear, but may be related to several factors. Our results thus indicate that any abnormality in serotonergic function present in patients with OCD is not related to imipramine binding sites in the platelets. However, the possibility that there may be an abnormal platelet serotonin uptake or other serotonergic function in OCD cannot be ruled out.

Platelet serotonin-2 receptor binding sites in depression and suicide.

In order to examine the role of serotonin-2 (5HT2) receptors in depression and suicide, we determined 5HT2 receptors using 125I-lysergic acid diethylamide (LSD) as the binding ligand in platelets obtained from 20 normal control and 23 drug-free depressed patients. Our results indicate significantly increased 125I-LSD binding sites (Bmax) in the platelets of depressed patients compared with normal control subjects. We also observed that a subgroup of depressed patients with a recent history of suicide attempts or suicidal ideation had significantly higher 5HT2 binding sites as compared with nonsuicidal depressed patients and normal controls. There were no significant differences in the apparent dissociation constant (Kd) values in the platelets of depressed patients compared with normal control subjects. To examine if the baseline 5HT2 receptors are related to either the severity of illness or treatment response, we determined the relationships of the baseline Bmax and Kd with baseline Hamilton Depression Rating Scale (HDRS) and Brief Psychiatric Rating Scale (BPRS) scores and change in scores after treatment. We found no significant correlation between baseline Bmax and Kd with the baseline HDRS or BPRS scores or change in these scores after psychoactive drug treatment. These results thus indicate increased platelet 5HT2 receptors in depression, but much more so in depressed patients with suicidal ideation or attempts.

Platelet serotonin-2 receptors in obsessive-compulsive disorder.

To examine the role of serotonin-2 (5-HT2) receptors in obsessive-compulsive disorder (OCD), we studied 5-HT2 receptors in platelets obtained from patients with OCD (n = 20) during a drug free baseline period, as well as in normal control subjects (n = 25). The maximum number of binding sites (Bmax) and the apparent dissociation constant (Kd) of 5-HT2 receptors were determined by receptor binding techniques using 125I-lysergic acid diethylamide (LSD) as radioligand. We observed that the mean Bmax of 125I-LSD binding in platelets of patients with OCD was not significantly different when compared with normal control subjects. There was also no significant difference in Kd values between patients with OCD and normal control subjects. To examine whether the baseline 5-HT2 receptors are related to the severity of illness, we determined the relationships of the baseline Bmax and Kd with baseline scores of the Hamilton Depression Rating Scale (HDRS), the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and the National Institute of Mental Health (NIMH) Obsessive-Compulsive scale (GOCS). We found no significant correlation between baseline Bmax and Kd with the baseline HDRS, Y-BOCS, or NIMH-GOCS scores. Our results do not indicate abnormal 5-HT2 receptors in platelets of patients with OCD.

Mixture distributions in psychiatric research.

This paper describes the application of Gaussian mixture distributions to biological marker research in psychiatry. Mixtures of univariate and multivariate normal distributions can be used to determine if diagnostically similar psychiatric patients belong to biologically distinct subpopulations. The resulting biological subtypes may be important in understanding the etiology of psychiatric disorders. The general model and estimation procedure are described (EM algorithm; Dempster, Laird and Rubin 1977). The method is illustrated using two examples of biological data: (1) red cell membranes and monoamine oxidase activity data in normal individuals having no family history of psychiatric illness, the first-degree relatives of bipolar depressed patients and a heterogeneous patient population; and (2) smooth pursuit eye movements that classify relatives of schizophrenics, nonschizophrenics and normal controls into biologically distinct populations.

Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans.

In the present study, homovanillic acid in plasma (pHVA) and benzodiazepine receptors (3H-PK11195 binding) in neutrophil membranes were determined in blood obtained from cocaine-dependent (DSM-III-R) adult male inpatients at baseline-(within 72 hr of last cocaine use) and after 3 weeks of cocaine abstinence, and normal controls. The mean (+/- SEM) pHVA at baseline (10.3 ng/ml +/- 1.1) was similar to normals and did not change after 3 weeks of cocaine abstinence. Similarly, the binding indices of benzodiazepine receptors in cocaine-dependent subjects as a group were not significantly different than in normal controls. In 10 cocaine-dependent subjects, however, where both blood samples were available, the number of 3H-PK11195 binding sites was significantly (p < 0.05) decreased after 3 weeks of cocaine abstinence (mean +/- sem: Bmax = 6371 +/- 657 fmol/mg protein) compared with baseline (Bmax = 7553 +/- 925 fmol/mg protein), although there were no differences in the binding affinity (mean +/- sem: KD = 8.6 +/- 1.2 nmol/L after 3 weeks of abstinence compared with 8.1 +/- 1.0 nmol/L at baseline). These preliminary results suggest that peripheral benzodiazepine receptors may play an important role in the pathophysiology of cocaine withdrawal in cocaine-dependent human subjects.

The effect of diagnosis and age on the DST: a metaanalytic approach.

The authors present new data on the results of the pretreatment Dexamethasone Suppression Test (DST) in 164 drug-free inpatients, as well as on the effects of age on postdexamethasone cortisol values. Nonsuppression rates were 18% in schizophrenic patients (n = 44), versus 46% in patients with a major depression (n = 56). In addition, a significant correlation was found between age and the 4:00 PM postdexamethasone cortisol value among the depressed patients (r = 0.33). The authors then applied a metaanalysis to summarize 25 other studies that have addressed the schizophrenia/major depression dichotomy as it relates to the DST outcome. Nonsuppression rates were consistently different in schizophrenic patients (19%) when compared to patients with a major depression (51%) or normal controls (7%). These differences were highly significant as measured by the Mantel-Haenszel chi-square statistic. A metaanalysis applied to a series of correlations obtained from 14 other studies reporting an age/postdexamethasone cortisol relationship in affective patients indicated a modest, but significant correlation (r = 0.24) in a total of 1284 patients (p less than 1 x 10(-8)).