Kolkata, India
Kolkata, India

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Ramkumar N.,University of Utah | Gao Y.,University of Utah | Kohan D.E.,University of Utah | Kohan D.E.,Salt Lake Medical Center
Physiological Reports | Year: 2017

Collecting duct (CD) endothelin-1 (ET-1) is an autocrine inhibitor of Na+ and water reabsorption. Salt or water loading increases CD ET-1 production; this is likely due, at least in part, to increased tubule fluid flow. The mechanisms by which flow stimulates CD ET-1 production are incompletely understood. In particular, flow induction of cortical CD (CCD) and inner medullary CD (IMCD) ET-1 synthesis may occur via different mechanisms. Since flow-mediated ET-1 production in IMCD has been more extensively characterized than in the CCD, this study was undertaken to further examine putative signaling pathways involved in flow-stimulated CCD ET-1 production. The CD cell line, mpkCCDcl4, was exposed to static or flow (2 dyne/cm2 for 2 h) conditions and ET-1/GAPDH mRNA levels were assessed. Intracellular Ca2+, Ca2+-stimulated Ca2+ release, calcineurin, and protein kinase c α/β isoforms were all involved in the ET-1 flow response. TRPC6, but not other CD-expressed TRP channels (TRPC3, 4, and 5, or TRPV4) played a role in the ET-1 flow response. Purinergic signaling pathways and cilia were not involved in the ET-1 flow response. Based on these and previously published findings, we present a comparison of flow-stimulated CD ET-1 production between CCD and IMCD. We suggest that flow-stimulated CCD ET-1 production may be more involved in responding to Na+ delivery, while IMCD ET-1 production may be more responsive to water and solute delivery; the responsible pathways for mediating these effects in the two regions of the CD appear to be substantially distinct from one another. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.


Levesque M.C.,Durham Medical Center | Levesque M.C.,Duke University | Levesque M.C.,University of Pittsburgh | Hobbs M.R.,University of Utah | And 30 more authors.
Human Genetics | Year: 2010

Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described. © 2009 Springer-Verlag.


Bravo L.,University of the Philippines at Manila | Chitkara A.,Max Superspeciality Hospital | Liu A.,Glaxosmithkline | Choudhury J.,Dr Jaydeeps Clinic | And 11 more authors.
Human Vaccines and Immunotherapeutics | Year: 2014

Regulatory bodies in The Philippines, Sri Lanka, and India require post-marketing surveillance to provide additional safety data on Rotarix™ in real-life settings. In such studies conducted in The Philippines (November 2006 to July 2012; NCT00353366), Sri Lanka (November 2008 to August 2009; NCT00779779), and India (August 2009 to April 2010; NCT00938327), 2 doses of Rotarix™ were administered according to the local prescribing information (PI). The occurrence of at least Grade "2"/"3" solicited adverse event (AE) (fever, vomiting, or diarrhea), within 15 days in The Philippines or 8 days in Sri Lanka and India; unsolicited AEs within 31 days and serious adverse events (SAEs) throughout the study were recorded. Of the 1494, 522, and 332 infants enrolled in The Philippines, Sri Lanka, and India, 14.7% 14.9% and 12.7% infants, respectively recorded at least Grade "2"/"3" solicited AEs. The most commonly reported solicited AEs were irritability in The Philippines (32.2% post-Dose-1; 23.5% post-Dose-2) and India (23.0% post-Dose-1; 13.2% post-Dose-2), and fever (18.0% post-Dose-1; 20.2% post-Dose-2) in Sri Lanka. Unsolicited AEs were recorded in 24.5% (The Philippines), 4.8% (Sri Lanka), and 6.9% (India) of infants. Forty-one SAEs were recorded in the Philippines of which 6 (decreased oral intake with increased sleeping time and constipation; pneumonia, urinary tract infection, and intussusception) were considered by the investigators as causally related to vaccination. One vaccine-unrelated SAE occurred in a Sri Lankan infant. All SAEs resolved and the infants recovered. Two doses of Rotarix™, administered to healthy infants according to local PI, were well tolerated in The Philippines, Sri Lanka, and India. © 2014 Landes Bioscience.


Young S.,Pennsylvania State University | Riding D.,Salt Lake Medical Center | Antonio M.,Omega Prime | Al-Mondhiry H.,Pennsylvania State University
Hospital Pharmacy | Year: 2012

Background: Argatroban is a direct thrombin inhibitor used in the treatment of heparin-induced thrombocytopenia (HIT). No study has evaluated the safety and efficacy of a nurse-managed argatroban dosing protocol.Methods: We performed a retrospective analysis of 151 total admissions (129 patients) in which argatroban infusions were administered before and after protocol implementation. The preprotocol and postprotocol groups consisted of 69 and 68 admissions, respectively. Patients were eligible for inclusion if they were ≥18 years old and received an argatroban drip for any reason in the 2 years prior to or following protocol implementation.Results: There were no statistically significant differences in the incidence of clinically overt bleeding (primary study safety endpoint) between groups. There was no difference between groups in the primary efficacy endpoints, the mean number of partial thromboplastin time (aPTT) assessments per day, and dose adjustments. The mean number of sub-and supratherapeutic aPTTs during treatment was higher in the preprotocol group when utilizing the specified range in the preprotocol group and the protocol's aPTT range (45-90 s); the preprotocol and postprotocol groups had an average of 3.4 and 1.04 subtherapeutic aPTTs, respectively (P = .008). Similarly, the preprotocol group had an average of 4.98 supratherapeutic aPTTs, while the postprotocol group had 1.84 (P < .001). There was no difference in duration of argatroban infusion in the preprotocol group compared to the postprotocol group with regard to duration of infusion or final infusion rate.Conclusions: This nurse-managed argatroban adjustment protocol provides similar safety and efficacy outcomes and decreased monitoring when pre and post implementation were compared. © 2012 Thomas Land Publishers, Inc.

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