Multi-receptor binding profile of clozapine and olanzapine: a structural study based on the new beta (2) adrenergic receptor template

Schizophrenia is a devastating mental disorder that has a largeimpact on the quality of life for those who are afflicted and isvery costly for families and society.[1] Although the etiology ofschizophrenia is still unknown and no cure has yet beenfound, it is treatable, and pharmacological therapy often producessatisfactory results. Among the various antipsychoticdrugs in use, clozapine is widely recognized as one ofthemost clinically effective agents, even if it elicits significant sideeffects such as metabolic disorders and agranulocytosis. Clozapineand the closely related compound olanzapine are goodexamples ofdrug s with a complex multi-receptor profile ;[2]they have affinities toward serotonin, dopamine, a adrenergic,muscarinic, and histamine receptors, among others.

Deep thiopental anesthesia alters steady-state glucose homeostasis but not the neurochemical profile of rat cortex.

Barbiturates are regularly used as an anesthetic for animal experimentation and clinical procedures and are frequently provided with solubilizing compounds, such as ethanol and propylene glycol, which have been reported to affect brain function and, in the case of (1)H NMR experiments, originate undesired resonances in spectra affecting the quantification. As an alternative, thiopental can be administrated without any solubilizing agents. The aim of the study was to investigate the effect of deep thiopental anesthesia on the neurochemical profile consisting of 19 metabolites and on glucose transport kinetics in vivo in rat cortex compared with alpha-chloralose using localized (1)H NMR spectroscopy. Thiopental was devoid of effects on the neurochemical profile, except for the elevated glucose at a given plasma glucose level resulting from thiopental-induced depression of glucose consumption at isoelectrical condition. Over the entire range of plasma glucose levels, steady-state glucose concentrations were increased on average by 48% +/- 8%, implying that an effect of deep thiopental anesthesia on the transport rate relative to cerebral glucose consumption ratio was increased by 47% +/- 8% compared with light alpha-chloralose-anesthetized rats. We conclude that the thiopental-induced isoelectrical condition in rat cortex significantly affected glucose contents by depressing brain metabolism, which remained substantial at isoelectricity.

Improving the sensitivity of the sequence profile method.

The sequence profile method (Gribskov M, McLachlan AD, Eisenberg D, 1987, Proc Natl Acad Sci USA 84:4355-4358) is a powerful tool to detect distant relationships between amino acid sequences. A profile is a table of position-specific scores and gap penalties, providing a generalized description of a protein motif, which can be used for sequence alignments and database searches instead of an individual sequence. A sequence profile is derived from a multiple sequence alignment. We have found 2 ways to improve the sensitivity of sequence profiles: (1) Sequence weights: Usage of individual weights for each sequence avoids bias toward closely related sequences. These weights are automatically assigned based on the distance of the sequences using a published procedure (Sibbald PR, Argos P, 1990, J Mol Biol 216:813-818). (2) Amino acid substitution table: In addition to the alignment, the construction of a profile also needs an amino acid substitution table. We have found that in some cases a new table, the BLOSUM45 table (Henikoff S, Henikoff JG, 1992, Proc Natl Acad Sci USA 89:10915-10919), is more sensitive than the original Dayhoff table or the modified Dayhoff table used in the current implementation. Profiles derived by the improved method are more sensitive and selective in a number of cases where previous methods have failed to completely separate true members from false positives.

The clinical profile of idiopathic and cat scratch neuroretinitis: who is at risk for recurrence?

Background: Most cases of neuroretinitis (NR) are idiopathic or due to cat scratch disease and occur as a single episode but a subgroup of patients experience recurrent attacks with cumulative visual loss. We reviewed our cases of NR to better characterize the clinical features of these subgroups in an effort to predict the risk of recurrence. Methods: Retrospective study of NR patients from a single institution. Sixty-seven patients were divided into three groups: 22 cases due to cat scratch disease (CSD-NR), 24 with idiopathic neuroretinitis (I-NR) and 21 (23 eyes) with recurrent neuroretinitis (R-NR). Results: Preceding systemic symptoms, predominantly central visual field (VF) loss and the combination of poor acuity with small relative afferent pupillary defect at presentation were common features of CSD-NR. There were no cases of recurrent CSD-NR. In the first attack of R-NR, the magnitude of VF loss at presentation was greater compared to the other two groups. While 39% of R-NR had a pattern of VF loss other than a central or cecocentral scotoma, only 13.6% of CSD-NR and 17% of I-NR showed this pattern. Visual recovery was least substantial for the R-NR group (average gain of 3.7 lines of Snellen acuity vs. 5 and 6.4 lines for CSD-NR and I-NR, respectively, and an average gain in VF score of 5.1 in the R-NR group compared to 8.2 and 11.5 for the other two groups). Conclusion: The main predictive factors for recurrence are absence of systemic symptoms, significant VF loss at presentation, particularly loss outside the central 30°, and less substantial visual recovery.

Deep thiopental anesthesia alters steady-state glucose homeostasis but not the neurochemical profile of rat cortex.

Barbiturates are regularly used as an anesthetic for animal experimentation and clinical procedures and are frequently provided with solubilizing compounds, such as ethanol and propylene glycol, which have been reported to affect brain function and, in the case of (1)H NMR experiments, originate undesired resonances in spectra affecting the quantification. As an alternative, thiopental can be administrated without any solubilizing agents. The aim of the study was to investigate the effect of deep thiopental anesthesia on the neurochemical profile consisting of 19 metabolites and on glucose transport kinetics in vivo in rat cortex compared with alpha-chloralose using localized (1)H NMR spectroscopy. Thiopental was devoid of effects on the neurochemical profile, except for the elevated glucose at a given plasma glucose level resulting from thiopental-induced depression of glucose consumption at isoelectrical condition. Over the entire range of plasma glucose levels, steady-state glucose concentrations were increased on average by 48% +/- 8%, implying that an effect of deep thiopental anesthesia on the transport rate relative to cerebral glucose consumption ratio was increased by 47% +/- 8% compared with light alpha-chloralose-anesthetized rats. We conclude that the thiopental-induced isoelectrical condition in rat cortex significantly affected glucose contents by depressing brain metabolism, which remained substantial at isoelectricity.

Enhancement of the photoelectrochemical properties of Cl-doped ZnO nanowires by tuning their coaxial doping profile

Arrays of vertically aligned ZnO:Cl/ZnO core-shell nanowires were used to demonstrate that the control of the coaxial doping profile in homojunction nanostructures can improve their surface charge carrier transfer while conserving potentially excellent transport properties. It is experimentally shown that the presence of a ZnO shell enhances the photoelectrochemical properties of ZnO:Cl nanowires up to a factor 5. Likewise, the ZnO shell promotes the visible photoluminescence band in highly conducting ZnO:Cl nanowires. These lines of evidence are associated with the increase of the nanowires" surface depletion layer

The personality profile of borderline personality disordered patients using the five-factor model of personality

The purpose of this ex post facto study is to analyze the personality profile of outpatients who met criteria for borderline personality disorder according to the Five-Factor Model of personality. All patients (N = 52) completed the International Personality Disorder Examination (IPDE) Screening Questionnaire, the Big Five Questionnaire (BFQ), the Beck Depression Inventory (BDI), and the Beck Hopelessness Scale (BHS). The results show a high comorbidity with other DSM-IV-TR Axis II disorders, in particular with those from Cluster C. The BFQ average score indicates that the outpatients who met borderline criteria score lower than controls on all five dimensions, and especially on emotional stability. Correlations were computed between the BFQ and the IPDE scales in our sample. These results suggest that specific personality profile are linked to different comorbidity patterns. More than a half of our sample has clinically significant scores on Beck's scales. Surprisingly, depression and hopelessness are neither correlated with the borderline scale, nor have an effect in the relationship between personality and personality disorders.

Evolution of the neurochemical profile after transient focal cerebral ischemia in the mouse brain.

Evolution of the neurochemical profile consisting of 19 metabolites after 30 mins of middle cerebral artery occlusion was longitudinally assessed at 3, 8 and 24 h in 6 to 8 microL volumes in the striatum using localized 1H-magnetic resonance spectroscopy at 14.1 T. Profound changes were detected as early as 3 h after ischemia, which include elevated lactate levels in the presence of significant glucose concentrations, decreases in glutamate and a transient twofold glutamine increase, likely to be linked to the excitotoxic release of glutamate and conversion into glial glutamine. Interestingly, decreases in N-acetyl-aspartate (NAA), as well as in taurine, exceeded those in neuronal glutamate, suggesting that the putative neuronal marker NAA is rather a sensitive marker of neuronal viability. With further ischemia evolution, additional, more profound concentration decreases were detected, reflecting a disruption of cellular functions. We conclude that early changes in markers of energy metabolism, glutamate excitotoxicity and neuronal viability can be detected with high precision non-invasively in mice after stroke. Such investigations should lead to a better understanding and insight into the sequential early changes in the brain parenchyma after ischemia, which could be used for identifying new targets for neuroprotection.

Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes.

We have previously reported that the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) induce profound modifications of the metabolic profile of astrocytes. The present study was undertaken to further characterize the effects of cytokines in astrocytes and to determine whether similar effects could also be observed in neurons. To do so, selected pro-inflammatory (IL-6 and interferon-γ, in addition to the above-mentioned TNFα and IL-1β) and anti-inflammatory cytokines (IL-4, IL-10, transforming growth factor-β1 and interferon-β) were applied to primary neuronal and astrocytic cultures, and key metabolic parameters were assessed. As a general pattern, we observed that pro-inflammatory cytokines increased glucose utilization in astrocytes while the anti-inflammatory cytokines IL-4 and IL-10 decreased astrocytic glucose utilization. In contrast, no significant change could be observed in neurons. When pairs of pro-inflammatory cytokines were co-applied in astrocytes, several additive or synergistic modifications could be observed. In contrast, IL-10 partially attenuated the effects of pro-inflammatory cytokines. Finally, the modifications of the astrocytic metabolism induced by TNFα + IL-1β and interferon-γ modulated neuronal susceptibility to an excitotoxic insult in neuron-astrocyte co-cultures. Together, these results suggest that pro- and anti-inflammatory cytokines differentially affect the metabolic profile of astrocytes, and that these changes have functional consequences for surrounding neurons.

Predicting the physicochemical profile of diastereoisomeric histidine-containing dipeptides by property space analysis.

OBJECTIVES: This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them. METHODS: A series of 20 dipeptides of general structure NH(2) -L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1) , pK(2) and pK(3) ) and lipophilicity parameters (log P(N) and log D(7.4) ) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log P(MLP) , meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds). RESULTS: Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters. CONCLUSION: This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression. Chirality 24:566-576, 2012. © 2012 Wiley Periodicals, Inc.