Development and validation of a Sensitive bioanalytical method for the quantitative estimation of Pantoprazole in human plasma samples by LC–MS/MS: Application to bioequivalence study

The present study aims at developing a simple, sensitive and specific liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the quantification of pantoprazole sodium (PS) in human plasma using pantoprazole D3 (PSD3) as internal standard (IS). Chromatographic separation was performed on Zorbax SB-C18, 4.6 mm × 75 mm, 3.5 μm, 80 Å column with an isocratic mobile phase composed of 10 mM ammonium acetate (pH 7.10): acetonitrile (30:70, v/v), pumped at 0.6 mL/min. PS and PSD3 were detected with proton adducts at m/z 384.2 → 200.1 and 387.1 → 203.1 in multiple reaction monitoring (MRM) positive mode, respectively. Precipitation method was employed in the extraction of PS and PSD3 from the biological matrix. This method was validated over a linear concentration range of 10.00–3000.00 ng/mL with correlation coefficient (r) ≥ 0.9997. Intra- and inter-day precision of PS were found to be within the range of 1.13–1.54 and 1.76–2.86, respectively. Both analytes were stable throughout freeze/thaw cycles, bench top and postoperative stability studies. This method was successfully utilized in the analysis of blood samples following oral administration of PS (40 mg) in healthy human volunteers.     

Improved liquid chromatography–tandem mass spectrometry method for the analysis of eptifibatide in human plasma

A rapid, selective and highly sensitive high performance liquid chromatography–tandem mass spectrometry method (LC–MS/MS) was developed and validated for the determination and pharmacokinetic investigation of eptifibatide in human plasma. Eptifibatide and the internal standard (IS), EPM-05, were extracted from plasma samples using solid phase extraction. Chromatographic separation was performed on a C₁₈ column at a flow rate of 0.5 mL/min. Detection of eptifibatide and the IS was achieved by tandem mass spectrometry with an electrospray ionization (ESI) interface in positive ion mode. Traditional multiple reaction monitoring (MRM) using the transition of m/z 832.6 → m/z 646.4 and m/z 931.6 → m/z 159.4 was performed to quantify eptifibatide and the IS, respectively. The calibration curves were linear over the range of 1–1000 ng/mL with the lower limit of quantitation validated at 1 ng/mL. The intra- and inter-day precisions were within 13.3%, while the accuracy was within ±7.6% of nominal values. The validated LC–MS/MS method was successfully applied for the evaluation of pharmacokinetic parameters of eptifibatide after intravenous (i.v.) administration of a 45 μg/kg bolus of eptifibatide to 8 healthy volunteers.     

以反复多发脓肿为表现的播散型隐球菌病1例

报道以反复多发脓肿为表现的播散型隐球菌病患者1例。患者男,68岁,因＂全身反复多发性脓肿1a,伴低热2个月余＂入院,该患者以背部脓肿起病,反复发作累及肺部、骨骼、皮肤等多部位,多次组织及血标本病原学检查、隐球菌乳胶凝集试验均阴性,给予多种抗菌药物治疗无效,后在右髂部脓肿切开组织物中培养到新生隐球菌。经脓肿切开引流及静脉滴注两性霉素B脂质体联合伊曲康唑治疗后,脓肿消退,症状消失,改用氟康唑联合氟胞嘧啶治疗4个月后停药,并已随访至今7个月,患者未有发热及新的脓肿出现。     

Resilience under conditions of extreme stress: a multilevel perspective

Resilience has been conceptualized as a dynamic developmental process encompassing the attainment of positive adaptation within the context of significant threat, severe adversity, or trauma. Until the past decade, the empirical study of resilience predominantly focused on behavioral and psychosocial correlates of, and contributors to, the phenomenon and did not examine neurobiological or genetic correlates of and contributors to resilience. Technological advances in molecular genetics and neuroimaging, and in measuring other biological aspects of behavior, have made it more feasible to begin to conduct research on pathways to resilient functioning from a multilevel perspective. Child maltreatment constitutes a profound immersion in severe stress that challenges and frequently impairs development across diverse domains of biological and psychological functioning. Research on the determinants of resilience in maltreated children is presented as an illustration of empirical work that is moving from single-level to multilevel investigations of competent functioning in the face of adversity and trauma. These include studies of personality, neural, neuroendocrine, and molecular genetic contributors to resilient adaptation. Analogous to neural plasticity that takes place in response to brain injury, it is conjectured that it may be possible to conceptualize resilience as the ability of individuals to recover functioning after exposure to extreme stress. Multilevel randomized control prevention and intervention trials have substantial potential for facilitating the promotion of resilient functioning in diverse high-risk populations that have experienced significant adversity. Determining the multiple levels at which change is engendered through randomized control trials will provide insight into the mechanisms of change, the extent to which neural plasticity may be promoted, and the interrelations between biological and psychological processes in the development of maladaptation, psychopathology, and resilience.     

Two-dimensional predictive equation to classify visceral obesity in clinical practice

Objective: Visceral obesity assessment is not easy, and although computed tomography (CT) is an accurate tool, this technique is expensive and sometimes not suitable in clinical practice. We developed a new two‐dimensional elliptical anthropometric equation to classify visceral obesity and evaluated the validity and the reliability of the new equation compared with CT. Research Methods and Procedures: We collected anthropometric and CT data from overweight/obese subjects (n = 61, BMI = 32.4 ± 3.7 kg/m²). A validation group of 32 subjects was also selected. An equation for the assessment of visceral obesity was developed using multiple regression analysis. Once validated, the equation was compared with previous models. Tests for accuracy included mean differences, analysis of diagnostic, R², Snedecor's F‐test, and Bland‐Altman plot. Results: Multiple regression analysis revealed that the sagittal and coronal diameters and the triceps skinfold were significant contributors to the model. The final equation was: visceral area (VA)/subcutaneous area (SA)_predicted = 0.868 + 0.064 × sagittal diameter ?0.036 × coronal diameter ?0.022 × triceps skinfold. Patients with visceral‐subcutaneous area ratio (VA/SA) >0.42 were classified as having visceral obesity. The predictive equation was valid, showing a significant association with VA/SA assessed by CT (VA/SA_CT; r = 0.68; p < 0.0001). Paired Student's t test showed no significant differences with VA/SA_CT (p = 0.541). The reliability was high [F(24/60) = 2.12; p = 0.01]. Discussion: The new two‐dimensional and elliptical predictive equation is valid to assess visceral obesity and is more precise than previous models.     

New modes of data partitioning based on PARS peak alignment for improved multivariate biomarker/biopattern detection in 1H-NMR spectroscopic metabolic profiling of urine

This paper addresses the possibility of mathematically partition and process urine ¹H-NMR spectra to enhance the efficiency of the subsequent multivariate data analysis in the context of metabolic profiling of a toxicity study. We show that by processing the NMR data with the peak alignment using reduced set mapping (PARS) algorithm and the use of sparse representation of the data results in the information contained in the original NMR data being preserved with retained resolution but free of the problem of peak shifts. We can now describe a method for differential expression analysis of NMR spectra by using prior knowledge, i.e., the onset of dosing, a partitioning not possible to achieve using raw or bucketed data. In addition we also outline a scheme for soft removal of “biological noise” from the aligned data: exhaustive bio-noise subtraction (EBS). The result is a straightforward protocol for detection of peaks that appear as a consequence of the drug response. In other words, it is possible to elucidate peak origin, either from endogenous substances or from the administered drug/biomarkers. The partition of data originating from the normally regulating metabolome can, furthermore, be analyzed free of the superimposed biological noise. The proposed protocol results in enhanced interpretability of the processed data, i.e., a more refined metabolic trace, simplification of detection of consistent biomarkers, and a simplified search for metabolic end products of the administered drug.     

Maternal panic disorder and congenital abnormalities: a population-based case-control study

BACKGROUND: Maternal panic disorder in pregnancy is the most common manifestation of anxiety disorders in Hungary. The association between panic disorder during pregnancy and structural birth defects, i.e., congenital abnormalities, was studied. METHODS: The prevalence of maternal panic disorder in cases with different congenital abnormalities was compared to that of matched controls in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS: Of 22,843 cases with congenital abnormalities, 210 (0.9%) had mothers with panic disorder during pregnancy compared to 187 (0.5%) of 38,151 controls (adjusted prevalence odds ratio [POR] 1.6; 95% CI, 1.3-2.0). Specific groups of congenital abnormalities were also assessed versus controls. Cases with isolated cleft lip with or without cleft palate (CL/P) (adjusted POR, 3.4; 95% CI, 1.3-9.0) and multiple congenital abnormalities (adjusted POR, 3.0; 95% CI, 1.2-7.2) were more likely to have had mothers with panic disorder during the study pregnancy. Notably, among mothers with panic disorders, the associations were found only in offspring of untreated mothers. CONCLUSIONS: A higher rate of isolated CL/P and multiple congenital abnormalities may be caused by the direct biological effect of panic disorder or by the interaction of maternal panic disorder and lifestyle factors. Antipanic drug treatment seems to have a protective effect for isolated CL/P and multiple congenital abnormalities. Birth Defects Research (Part A), 2006.     

Time ordering of gene coexpression

Temporal microarray gene expression profiles allow characterization of gene function through time dynamics of gene coexpression within the same genetic pathway. In this paper, we define and estimate a global time shift characteristic for each gene via least squares, inferred from pairwise curve alignments. These time shift characteristics of individual genes reflect a time ordering that is derived from ob- served temporal gene expression profiles. Once these time shift characteristics are obtained for each gene, they can be entered into further analyses, such as clustering. We illustrate the proposed methodology using Drosophila embryonic development and yeast cell-cycle gene expression profiles, as well as simulations. Feasibility is demonstrated through the successful recovery of time ordering. Estimated time shifts for Drosophila maternal and zygotic genes provide excellent discrimination between these two categories and confirm known genetic pathways through the time order of gene expression. The application to yeast cell-cycle data establishes a natural time order of genes that is in line with cell-cycle phases. The method does not require periodicity of gene expression profiles. Asymptotic justifications are also provided.     

干扰素-τ治疗多发性硬化症的临床应用前景

作为从反刍动物体内发现的一种新型干扰素,干扰素-τ(IFN-τ)具有免疫调节、低细胞毒性等特点。实验性变应性脑脊髓炎(EAE)是多发性硬化症(MS)的动物模型。IFN-τ能够抑制实验性脑脊髓炎的发生、发展。本文简要综述了IFN-τ的结构、生物活性、低细胞毒性,以及它对EAE的治疗作用和机制。     

Male courtship signals and female signal assessment in Photinus greeni fireflies

The evolutionary dynamic of courtship signaling systems is drivenby the interaction between male trait distributions and femalepreferences. This interaction is complex because females maychoose mates based on multiple components of male signals, andfemale preference functions may vary depending on mate availability,female reproductive state, and environmental conditions. InPhotinus fireflies (Coleoptera: Lampyridae), flying males emitbioluminescent flash signals to locate sedentary females, whichreply selectively to attractive male flash signals with theirown response flash. In this study, we first examined temporalvariation in the paired-pulse flash patterns produced by Photinusgreeni males in the field and found significant among-male variation(70% of total variation) in interpulse intervals (IPIs). Therewas no significant relationship between male IPI and spermatophoresize, suggesting that P. greeni male courtship signals do notprovide females with reliable indicators of male material resources.In laboratory playback experiments, we presented P. greeni femaleswith simulated flash signals to assess how IPI and pulse durationindependently affected the likelihood of female flash response.We also examined the effects of female body mass and time duringthe mating season on female preference functions, hypothesizingthat females would be less discriminating when they were heavier(more fecund) and when mate availability declined. We foundthat P. greeni females discriminated among signals within theirspecies' range based primarily on flash pattern IPI. Neitherthe time during the mating season nor female weight alteredfemale preference functions for IPI, although season did influencefemale response to pulse duration. These results reveal thatP. greeni females discriminate among conspecific males basedprimarily on male IPIs, the same signal character previouslyshown to be important for firefly species recognition. Fieldplayback experiments indicated that female responsiveness peakednear the average IPI given by males at different ambient temperatures,suggesting that fireflies exhibit temperature coupling similarto that seen in many acoustically signaling animals.