Doppler vocal fremitus.

A young woman with metastatic breast cancer was found to have a regular spectral Doppler event spanning multiple cardiac cycles and timing to her tachypneic respiratory rate, which suggested an extracardiac source. A chest CT confirmed a large mediastinal mass causing a postobstructive pneumonia. This Doppler signal reflected increased turbulence across the obstructed bronchus due to sound wave conduction through a pulmonary consolidation-a Doppler equivalent of "vocal fremitus" elicited by physical examination of a patient with a lung mass or pneumonia. Careful attention to the timing of Doppler abnormalities is required to avoid misdiagnosis.

Molecular sequelae of topographically guided peripheral nerve repair.

Peripheral nerve injuries cause severe disability with decreased nerve function often followed by neuropathic pain that impacts the quality of life. Even though use of autografts is the current gold standard, nerve conduits fabricated from electrospun nanofibers have shown promise to successfully bridge critical length nerve gaps. However, in depth analysis of the role of topographical cues in the context of spatio-temporal progression of the regenerative sequence has not been elucidated. Here, we explored the influence of topographical cues (aligned, random, and smooth films) on the regenerative sequence and potential to successfully support nerve regeneration in critical size gaps. A number of key findings emerged at the cellular, cytokine and molecular levels from the study. Higher quantities of IL-1α and TNF-α were detected in aligned fiber based scaffolds. Differential gene expression of BDNF, NGFR, ErbB2, and ErbB3 were observed suggesting a role for these genes in influencing Schwann cell migration, myelination, etc. that impact the regeneration in various topographies. Fibrin matrix stabilization and arrest of nerve-innervated muscle atrophy was also evident. Taken together, our data shed light on the cascade of events that favor regeneration in aligned topography and should stimulate research to further refine the strategy of nerve regeneration using topographical cues.

Prevalence of prehypertension and its relationship to cardiovascular disease risk factors in Puducherry.

Prehypertension (PHT) leads to hypertension (HT) and cardiovascular (CVD) disease risk. Identification of CVD risk factors in PHT will reduce the burden of HT and CVD in the population. Three hundred staffs of a medical college were screened for prehypertension (PHT). Sixty five PHT and 91 normotensives (NT) were enrolled. Anthropometric measurements and fasting blood glucose and lipid variables were measured. Prevalence of PHT was 22% (males 71%; females 29%). Hip circumference, waist circumference (WC), body mass index (BMI), fasting blood glucose (FBS) and atherogenic lipid indices triglycerides (TG), VLDL cholesterol, TG/HDL and LDL/HDL were increased in PHT. PHT showed significant positive association with BMI, WC, FBS, TG and TG/HDL. Regression analysis revealed BMI, TG and TG/HDL as the independent CVD risk factors in PHT. PHT is predominant in males and BMI, TG are the independent CVD risk factors in Puducherry.

Unsuspected poor metabolizer phenotypes of fluoxetine in bioavailability/bioequivalence studies from an indian population perspective. Retrospective pharmacokinetic data evaluation.

BACKGROUND: Fluoxetine, belonging to the class of selective serotonin uptake inhibitors, has been extensively used for the treatment of depression and other psychiatry related disorders. Fluoxetine (CAS 59333-67-4) is a substrate of polymorphic cytochrome P450 2D6 isozyme (CYP2D6) leading to the formation of norfluoxetine (CAS 83891-03-06), which is not only active but long lived than the parent in the systemic circulation. Since the parent and metabolite levels are important from a therapeutic perspective, knowledge of phenotypic distribution of the population may be an important consideration. OBJECTIVE: The aim of the work was to retrospectively evaluate the pharmacokinetic data of fluoxetine and norfluoxetine from several bioavailability/bioequivalence (BA/BE) studies to identify the poor metabolizer (PM) phenotypes from the unsuspected healthy subjects across varied protocol designs, dose sizes and differing formulations. METHODS: The pharmacokinetic data of fluoxetine and norfluoxetine were gathered from several BA/BE studies conducted at clinical facilities located at Bangalore and Chennai, India. The BA/BE studies involved open label, two-way randomized crossover designs with two periods and two treatments (reference and test). Blood samples were collected for at least 672 h after fluoxetine dosing and the plasma was analyzed using validated tandem liquid chromatography mass spectrometric assay to determine fluoxetine and norfluoxetine levels. Standard pharmacokinetic parameters were computed using noncompartmental methods. For the purpose of this paper, retrospective evaluation of pharmnacokinetic data from only the reference formulation was considered. The AUC ratio of fluoxetine/norfluoxetine was computed. The individual fluoxetine/norfluoxetine AUC(0-infinity), ratios were plotted in increasing rank order and using outlier test ('T' procedure at 5% level of significance) the subjects were categorized as extensive metabolizer (EM) and PM phenotypes. The unequivocal confirmation of PM phenotypes was obtained by performing linear regression analysis of fluoxetine vs norfluoxetine AUC(0-infinity) values. RESULTS: Each study was evaluated for the distribution of EM and PM phenotypes of fluoxetine. There were 144 subjects evaluable from four studies, 89.6% (129 out of 144) of which could be categorised as EMs and 10.4% (15 out of 144) as PMs of fluoxetine. The pharmacokinetic parameters were quite distinct between the two phenotypes: (1) PM phenotypes showed much higher exposure (approximately 2.3-fold increase in AUC(0-infinity) and much slower elimination (almost 2-fold increase in elimination half-life) for fluoxetine as compared to EM phenotypes; (2) PM phenotypes showed approximately 0.5-fold lower exposure of norfluoxetine as compared to the EM counter parts; (3) There was no change (approximately 1.2-fold) in the elimination half life of norfluoxetine in EM and PM phenotypes. CONCLUSIONS: Retrospective evaluation of fluoxetine and norfluoxetine pharmacokinetic data demonstrated existence of both PM and EM phenotypes in the Indian population. Based on the overall data (n=144 subjects) there appeared to be 10.4% of PM phenotypes for fluoxetine and/or possibly for other polymorphic CYP2D6 substrates commonly used in this region.

Influence of number of calibration standards within a defined range on pharmacokinetic disposition-case studies with omeprazole and clopidogrel carboxylic acid.

While the practice of using a smaller number of non-zero standards (typically seven to eight) has not been entertained in routine bioanalytical work, it is important to innovate and be pragmatic about minimizing the number of calibration standards to promote cost-effective and speedy assessment. In this exercise, two important compounds, omeprazole and clopidogrel carboxylic acid, were considered. Additionally, both analytes offered a 1000-fold calibration curve range with eight non-zero standards to permit a systematic evaluation. Accordingly various scenarios of post-hoc analysis of the calibration data were formulated which included step-wise reduction of the number of calibration standards from a maximum of n = 8 to a minimum of n = 3. In all the scenarios evaluated in this exercise, a calibration curve was reconstructed and both quality control samples and in vivo pharmacokinetics were calculated in each instance. Based on the data generated in this exercise, a minimum of three non-zero calibration standards were adequate to predict the quality control samples with the predefined accuracy and precision estimates for both omeprazole and clopidogrel carboxylic acid. Additionally, the in vivo pharmacokinetic characterization of the chosen compounds was not hampered by the reduction of calibration standards (from n = 8 to n = 3). Hence, consideration for reducing number of calibration standards in bioanalytical work may provide a viable alternative in several situations such as formulation screening strategies, routine therapeutic drug monitoring and sparse sample analyses.

Antiviral activities and cellular toxicities of modified 2',3'-dideoxy-2',3'-didehydrocytidine analogues.

The antiviral efficacies and cytotoxicities of 2',3'- and 4'-substituted 2',3'-didehydro-2',3'-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (iii) for their abilities to inhibit bovine viral diarrhea virus (BVDV) production in acutely infected Madin-Darby bovine kidney cells. Some compounds demonstrated potent antiviral activities against the wild-type HIV-1 strain (range of 90% effective concentrations [EC(90)s], 0.14 to 5.2 micro M), but marked increases in EC(90)s were noted when the compounds were tested against the lamivudine-resistant HIV-1 strain (range of EC(90)s, 53 to >100 micro M). The beta-L-enantiomers of both classes of compounds were more potent than the corresponding beta-D-enantiomers. None of the compounds showed antiviral activity in the assay that determined their abilities to inhibit BVDV, while two compounds inhibited HBV production in HepAD38 cells (EC(90), 0.25 micro M). The compounds were essentially noncytotoxic in human peripheral blood mononuclear cells and HepG2 cells. No effect on mitochondrial DNA levels was observed after a 7-day incubation with the nucleoside analogs at 10 micro M. These studies demonstrate that (i) modification of the sugar ring of cytosine nucleoside analogs with a 4'-thia instead of an oxygen results in compounds with the ability to potently inhibit wild-type HIV-1 but with reduced potency against lamivudine-resistant virus and (ii) the antiviral activity of beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine against wild-type HIV-1 (EC(90), 0.08 micro M) and lamivudine-resistant HIV-1 (EC(90) = 0.15 micro M) is markedly reduced by introduction of a 3'-fluorine in the sugar (EC(90)s of compound 2a, 37.5 and 494 micro M, respectively).