Striatal D(2) receptor occupancy in bipolar patients treated with olanzapine.

We explored the relationship between striatal dopamine-2 (D(2)) receptor occupancy and extra-pyramidal symptoms (EPS) in bipolar patients receiving olanzapine. Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5-45 mg/day olanzapine for at least 14 days. After that period, D(2) receptor occupancy was determined using Iodobenzamide (IBZM) and SPECT. EPS were assessed by the Simpson-Angus Scale (SAS) and Barnes-Akathisia Scale (BAS). We found a dose-dependent increase in occupancy: 5 mg led to 28-50%, 10 mg to 40-68%, 15 mg to 69%, 20 mg to 57-66%, 30 mg to 66% and 45 mg to 80% D(2) receptor occupancy; and a significant correlation between plasma levels and occupancy (R(2)=.55, P=.001). Similar to schizophrenic patients, bipolar patients did not exhibit EPS at D(2) occupancy levels of 28 to 80%. Although we did not find an increased vulnerability for acute EPS in bipolar patients receiving olanzapine at clinical relevant doses, this needs to be replicated with larger sample sizes.     

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND: Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS: Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS: We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS: The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.     

Cerebrospinal fluidCHOLINESTERASES—MARKERS for loss ofcholinergic basal forebrain neurons?

The present study was conducted to test the hypothesis that cholinergic basalforebrain neurons are a major source of cerebrospinal fluid (CSF) cholinesterases. To address thisquestion enzyme activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inboth CSF and parietal cortex were assayed following selective lesion of basal forebrain cholinergicneurons by a single intracerebroventricular application of the cholinergic immunotoxin192IgG-saporin. Cholinergic immunolesions led to a dramatic decrease in total AChE activity inparietal cortex, which was due to the specific loss of the G4 molecular form while the activity ofthe G1 form was increased as compared to nonlesioned animals. In contrast, the total enzymeactivity of BChE and its molecular forms were not affected by cholinergic lesion in both parietalcortex and CSF. The data suggest, that cholinergic basal forebrain neurons are seemingly not amajor source of cholinesterases in the CSF, and do not provide any evidence for using CSFcholinesterases as a diagnostic marker of basal forebrain cholinergic cell loss in humans.     

Principal neuron spiking: neither necessary nor sufficient for cerebral blood flow in rat cerebellum

Neuronal activity, cerebral blood flow, and metabolic responses are all strongly coupled, although the mechanisms behind the coupling remain unclear. One of the key questions is whether or not increases in spiking activity in the stimulated neurons are sufficient to drive the activity-dependent rises in cerebral blood flow (CBF) that form the basis of the signals used in functional neuroimaging such as the blood oxygen level-dependent (BOLD) signal. To this end the present study examined the effect of enhanced spike activity per se on CBF in rat cerebellar cortex under conditions of disinhibition, achieved by blocking GABA_A receptors using either bicuculline or picrotoxin. Purkinje cell spiking activity and local field potentials were recorded by glass microelectrodes, and laser Doppler flowmetry was used to monitor CBF. Disinhibition increased Purkinje cell spiking rate to 200–300% of control without incurring any increase in basal CBF. This demonstrates that increased spike activity per se is not sufficient to affect basal CBF. The neurovascular coupling between excitatory synaptic activity and CBF responses evoked by inferior olive (climbing fibre) stimulation was preserved during disinhibition. Thus, the unchanged basal CBF in the presence of the dramatic rise in Purkinje cell spiking rate was not explained by impaired synaptic activity–CBF coupling. On the basis of our previous and the present studies, we conclude that increased spiking activity of principal neurons is neither sufficient nor necessary to elicit CBF responses and in turn BOLD signals, and that activation-dependent vascular signals reflect excitatory synaptic activity.     

Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion

During the process of malignant transformation, nascent melanoma cells escape keratinocyte control through down-regulation of E-cadherin and instead communicate among themselves and with fibroblasts via N-cadherin-based cell-cell contacts. The zonula occludens (ZO) protein-1 is a membrane-associated component of both the tight and adherens junctions found at sites of cell-cell contact. In most cancers, levels of ZO-1 are typically down-regulated, leading to increased motility. Here we report the novel observation that ZO-1 expression is up-regulated in melanoma cells and is located at adherens junctions between melanoma cells and fibroblasts. Immunofluorescence and co-immunoprecipitation studies showed co-localization of ZO-1 with N-cadherin. Down-regulation of ZO-1 in melanoma cells through RNA interference produced marked changes in cell morphology--leading to a less-dendritic, more rounded phenotype. Consistent with a role in N-cadherin-based adhesion, RNAi-treated melanoma cells were less adherent and invasive when grown in a collagen gel. These data provide the first evidence that increased ZO-1 expression in melanoma contributes to the oncogenic behavior of this tumor and further illustrate that protein products of genes, such as ZO-1, can function in either a pro- or anti-oncogenic manner when expressed in different cellular contexts.     

Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction

Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis of locally advanced adenocarcinomas of the gastroesophageal junction. This study aimed to asses if serum microRNA profiles are useable as response indicators in this therapeutic setting. Fifty patients with locally advanced adenocarcinomas of the gastroesophageal junction were included in the study. All patients received neoadjuvant therapy and subsequently underwent surgical resection. Histomorphologic regression was defined as major histopathological response when resected specimens contained less than 10% vital residual tumor cells. Circulating RNA was isolated from pretherapeutic/post‐neoadjuvant blood serum samples. RNA from nine patients was applied to PCR microarray analyses Based on these findings possible predictive miRNA markers were validated by quantitative RT‐PCR analyses. Depending on the histomorphologic regression, a differential serum microRNA profile was identified by microarray analyses. Based on the divergent miRNA pattern, miR‐21, miR‐192, miR‐222, miR‐302c, miR‐381 and miR‐549 were selected for further validation. During neoadjuvant therapy, there was a significant increase of miR 222 and miR‐549. Although on an expanded patient cohort, the six microRNAs could not be validated as markers for therapy response, there was a significant correlation between a high miR‐192 and miR‐222 expression with a high T‐category as well as miR‐302c and miR‐222 expression significantly correlated with overall survival. Comprehensive miRNA profiling showed a differential microRNA expression pattern depending on the histomorphologic regression in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Moreover, using single RT‐PCR analyses a prognostic impact of miR‐222 and miR‐302c was detected.     

Corifollitropin alfa compared with follitropin beta in GnRH-antagonist ovarian stimulation protocols in an unselected population undergoing IVF/ICSI

Recombinant DNA technologies have produced Corifollitropin alfa (CFa) used during IVF/ICSI in order to keep the circulating FSH levels above the threshold necessary to support multi-follicular growth for a week. In this prospective case-control study, we compared 70 participants treated with 150?μg CFa combined with 150?IU of follitropin beta (study group) with 70 subfertile participants with matching baseline characteristics, conforming with the same inclusion criteria and treated with an antagonist protocol using follitropin beta (control group). Live birth was the primary outcome, while secondary outcome measures were IVF/ICSI cycles characteristics, including adverse events and complications. Live birth was determined in reduced rates in the study compared to the control group, reaching statistical significance [6/70 versus 20/70, p?=?0.002], as also in the respective number of clinical pregnancies [9/70 versus 23/70, p?=?0.005], although the incidence of miscarriage was similar for both groups [6/70 versus 5/70, p?>?0.99]. Most of the secondary parameters examined were similar between groups. Logistic regression revealed that protocol and AFC had a direct impact on live birth. Ovarian stimulation with CFa does not seem to constitute an equally effective method as compared with follitropin beta to be offered in a general subfertile population seeking IVF/ICSI treatments.     

Post-synthetically modified metal–porphyrin framework GaTCPP for carbon dioxide adsorption and energy storage in Li–S batteries

Lithium–sulphur batteries attract increasing interest due to their high theoretical specific capacity, advantageous economy, and “eco-friendliness”. In this study, a metal–organic framework (MOF) GaTCPP containing a porphyrinic base ligand was used as a conductive additive for sulphur. GaTCPP was synthesized, characterized, and post-synthetically modified by the transition metal ions (Co²⁺/Ni²⁺). The doping of GaTCPP ensured an increase in the carbon dioxide adsorption capacities, which were measured under different conditions. Post-synthetic modification of GaTCPP with Co²⁺/Ni²⁺ ions has been shown to increase carbon dioxide storage capacity from 22.8 wt% for unmodified material to 23.1 wt% and 26.5 wt% at 0 °C and 1 bar for Co²⁺ and Ni²⁺-doped analogues, respectively. As a conductive part of cathode material, MOFs displayed successful sulphur capture and encapsulation proven by stable charge/discharge cycle performances, high-capacity retention, and coulombic efficiency. The electrodes with pristine GaTCPP showed a discharge capacity of 699 mA h g⁻¹ at 0.2C in the fiftieth cycle. However, the doping of GaTCPP by Ni²⁺ has a positive impact on the electrochemical properties, the capacity increased to 778 mA h g⁻¹ in the fiftieth cycle at 0.2C.

Metal–porphyrin framework GaTCPP was used for carbon dioxide adsorption and as a host for preparation of a Li–S battery cathode material.