Biomedical subjects

Vibha Bhatnagar

Publications and source records attributed to Vibha Bhatnagar.

11 recordsLinked to original sources

PubMed2010

Common charge-shift mutation Glu65Lys in K+ channel β₁-Subunit KCNMB1: pleiotropic consequences for glomerular filtration rate and progressive renal disease.

BACKGROUND: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory β₁-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. METHODS: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). RESULTS: The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). CONCLUSIONS: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.

Black or African American↗

PubMed2006

Transmission patterns of smallpox: systematic review of natural outbreaks in Europe and North America since World War II.

BACKGROUND: Because smallpox (variola major) may be used as a biological weapon, we reviewed outbreaks in post-World War II Europe and North America in order to understand smallpox transmission patterns. METHODS: A systematic review was used to identify papers from the National Library of Medicine, Embase, Biosis, Cochrane Library, Defense Technical Information Center, WorldCat, and reference lists of included publications. Two authors reviewed selected papers for smallpox outbreaks. RESULTS: 51 relevant outbreaks were identified from 1,389 publications. The median for the effective first generation reproduction rate (initial R) was 2 (range 0-38). The majority outbreaks were small (less than 5 cases) and contained within one generation. Outbreaks with few hospitalized patients had low initial R values (median of 1) and were prolonged if not initially recognized (median of 3 generations); outbreaks with mostly hospitalized patients had higher initial R values (median 12) and were shorter (median of 3 generations). Index cases with an atypical presentation of smallpox were less likely to have been diagnosed with smallpox; outbreaks in which the index case was not correctly diagnosed were larger (median of 27.5 cases) and longer (median of 3 generations) compared to outbreaks in which the index case was correctly diagnosed (median of 3 cases and 1 generation). CONCLUSION: Patterns of spread during Smallpox outbreaks varied with circumstances, but early detection and implementation of control measures is a most important influence on the magnitude of outbreaks. The majority of outbreaks studied in Europe and North America were controlled within a few generations if detected early.

Communicable Disease Control↗

PubMed2006

Analyses of 5' regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3).

Kidney excretion of numerous organic anionic drugs and endogenous metabolites is carried out by a family of multispecific organic anion transporters (OATs). Two closely related transporters, SLC22A6, initially identified by us as NKT and also known as OAT1, and SLC22A8, also known as OAT3 and ROCT, are thought to mediate the initial steps in the transport of organic anionic drugs between the blood and proximal tubule cells of the kidney. Coding region polymorphisms in these genes are infrequent and pairing of these genes in the genome suggests they may be coordinately regulated. Hence, 5' regulatory regions of these genes may be important factors in human variation in organic anionic drug handling. We have analyzed novel single nucleotide polymorphisms in the evolutionarily conserved 5' regulatory regions of the SLC22A6 and SLC22A8 genes (phylogenetic footprints) in an ethnically diverse sample of 96 individuals (192 haploid genomes). Only one polymorphism was found in the SLC22A6 5' regulatory region. In contrast, seven polymorphisms were found in the SLC22A8 5' regulatory region, two of which were common to all ethnic groups studied. Computational analysis permitted phase and haplotype reconstruction. Proximity of these non-coding polymorphisms to transcriptional regulatory elements (including potential sex steroid response elements) suggests a potential influence on the level of transcription of the SLC22A6 and/or SLC22A8 genes and will help define their role in variation in human drug, metabolite and toxin excretion. The clustering of OAT genes in the genome raises the possibility that nucleotide polymorphisms in SLC22A6 could also effect SLC22A8 expression, and vice versa.

Animals↗

PubMed2005

Treatment options for prostate cancer: evaluating the evidence.

Controversy surrounds the management options for localized prostate cancer-conservative management, prostatectomy, and radiation. Choosing among these options is difficult because of long-term side effects that include sexual, urinary, and bowel dysfunction. Some recent studies suggest that patients who have chosen treatment (i.e., radical prostatectomy or radiation) have longer disease-free survival compared with patients who have chosen conservative management (i.e., watchful waiting). However, several biases may artificially enhance the perceived value of treatment and make the interpretation of studies on treatment outcomes difficult. Sources of bias include lead time, length time, and patient selection. Because of the uncertain efficacy of management options and the risk of long-term treatment complications, family physicians need to engage their patients in the decision-making process.

Counseling↗

PubMed2005

Utilities for prostate cancer health states in men aged 60 and older.

PURPOSE: We sought to measure utilities for prostate cancer health states in older men. METHODS: A total of 162 men aged 60 years or older (52% of whom had been diagnosed with prostate cancer) provided standard gamble utilities for 19 health states associated with prostate cancer or its treatment using an interactive, computer-based utility assessment program. Demographics and experience with specific health states were examined as predictors of ratings using ordinary least squares regression analysis. RESULTS: Mean utilities ranged from 0.67 to 0.84 for living with symptom-free cancer under conservative management ("watchful waiting") and from 0.71 to 0.89 for symptoms occurring with treatment (prostatectomy, radiation, and hormone ablation). For long-term treatment complications, bowel problems (0.71) were rated as significantly worse than impotence (0.89), urinary difficulty (0.88), or urinary incontinence (0.83). Combinations of these conditions were rated as significantly worse than individual component states. Men who had experienced impotence or urinary incontinence rated these states as slightly better than men who had not experienced the specific problems. CONCLUSIONS: Both "watchful waiting" and treatment complications from prostate cancer treatments can have large impacts on quality of life. Mean ratings are important for use in policy-making and cost-effectiveness analyses. Variation in ratings across patients suggests that mean scores do not reflect individual preferences and that shared decision-making may be best for clinical decisions.

Age Factors↗

PubMed2005

Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)].

BACKGROUND: Excretion by the kidney of a variety of organic anionic drugs and metabolites is mediated by a family of multispecific organic anion transporters (OAT genes) that are part of the SLC22 family of solute carriers. Different OATs localize to the apical (OAT2, OAT4, and RST/URAT) or basolateral (OAT1/NKT and OAT3) membranes of the renal proximal tubule; the net transport of organic anions from blood to urine is believed to require both apical and basolateral OATs. These genes are also thought to mediate transport of organic anionic drugs and metabolites (e.g., urate) across choroid plexus, retina, placenta, and possibly olfactory mucosa. The extent of functional redundancy among OATs remains uncertain, but closely related OAT genes are tightly linked in the genome. Hence, a better understanding of human variation in organic anionic drug excretion may be obtained by studying OAT genes in combination rather than individually. METHODS: We have analyzed single nucleotide polymorphisms (SNPs) in OAT1 (NKT), OAT2, OAT3, OAT4, and URAT1 (human homologue of RST) in an ethnically diverse sample of 96 individuals (192 haploid genomes). Ka/Ks analysis was also performed as well as haplotype reconstruction using the software program Arelquin. RESULTS: The data indicate that (1) nonsynonymous SNPs in OAT1 and OAT3 may not be frequent so it will be important to consider promoter region SNPs that regulate gene expression; (2) certain ethnic groups may have a high prevalence of nonsynonymous SNPs in particular OATs (e.g., OAT4 in Sub-Saharan Africans); (3) there are individuals who have nonsynonymous SNPs in apical and basolateral OATs; (4) nonsynonymous OAT4 SNPs may be more frequent, raising the possibility of altered maternofetal transport of drugs and metabolites; and (5) combinations of synonymous SNPs in OAT1 and OAT3 also occur in certain individuals. In addition, Ka/Ks analysis of human, chimp and rodent genes suggests that OAT4 is under accelerated selection pressure, perhaps reflecting specific human environmental exposures during evolution. In contrast, Ka/Ks analysis for URAT1 suggests decelerated selection pressure. Haplotype reconstruction also supports this view. CONCLUSION: Together, these data suggest that, in order to understand the effect of SNPs in genes of the SLC22 family on drug handling as well as excretion of metabolites like uric acid, it is important to consider the entire set of organic anion transporters. It will be particularly interesting to determine if individuals with nonsynonymous apical and basolateral SNPs have altered handling (and toxicity) of organic anionic drugs and metabolites. Certain OAT family members appear to be under greater evolutionary selection pressure.

Carrier Proteins↗

PubMed2004

Treatment options for localized prostate cancer: quality-adjusted life years and the effects of lead-time.

OBJECTIVES: The purposes of this study were to estimate the difference in quality-adjusted life-years between conservative management and prostatectomy or radiotherapy (RT) by clinical Gleason score (2 to 4, 5 to 6, 7, and 8 to 10) for patients aged 55 years and older with clinically localized prostate cancer and to adjust for and explore the effects of lead-time. For localized prostate cancer, it is not known whether treatment (prostatectomy or RT) results in longer quality-adjusted survival than conservative management. Observed survival benefits after treatment may be biased by the lead-time resulting from early diagnosis with prostate-specific antigen screening. METHODS: A Markov simulation was developed, and transition probabilities were derived from a review of published studies. Utility weights were measured in male volunteers older than 60 years. Estimates of disease progression during conservative management were adjusted for lead-time. Sensitivity analyses were performed on all parameters (including estimates for lead-time). RESULTS: For Gleason score 2 to 4 cancer, conservative management yielded the greatest number of quality-adjusted life-years. For Gleason score 5 to 6 cancer, any of the options appeared beneficial, depending on the estimates for disease progression. For Gleason score 7 to 10 cancer, prostatectomy and RT resulted in more quality-adjusted life-years than conservative management; with a lead-time adjustment of greater than 10 years, the outcomes with conservative management and prostatectomy were similar. The choice between prostatectomy and RT was sensitive to estimates of disease progression after treatment. CONCLUSIONS: Conservative management is a reasonable option for Gleason score 2 to 4 cancer and for some patients with Gleason score 5 to 6 cancer. Prostatectomy or RT is recommended for Gleason score 7 to 10 cancer. The survival benefits after treatment were not explained by the lead-time alone.

Adenocarcinoma↗

PubMed2004

The molecular pharmacology of organic anion transporters: from DNA to FDA?

Renal organic anion secretion has been implicated in numerous clinically significant drug interactions and adverse reactions, indicating the importance of a detailed understanding of this pathway for the development of optimum therapeutics. With the cloning of multiple genes encoding organic anion transporters (OATs), the study of organic anion secretion has entered the molecular age. In this review, we focus on various aspects of the molecular biology and pharmacology of the OATs, including discussion of their structural biology, genomic organization in pairs, developmental regulation, toxicology, and pharmacogenetics. We propose functional, pathophysiological, and evolutionary hypotheses to help explain recent experimental and genomic data.

Animals↗

PubMed2003

Novel aspects of renal organic anion transporters.

PURPOSE OF REVIEW: Organic anion transporters, transmembrane proteins present in the renal proximal tubule, are a critical component of the human drug excretion machinery. Recent advances have clarified the function of these transporters, with broad clinical implications for pharmacogenetics, drug interactions and adverse reactions. Here, we discuss these issues in the context of the basic biology of the transporters. RECENT FINDINGS: Understanding of organic anion transporter function has proceeded on several fronts. The continued cataloging of organic anion transporter substrates has revealed that the transporters' activity likely underlies many common drug interactions and nephrotoxic adverse reactions. Meanwhile, immunohistochemical and physiological studies suggest their potential involvement in the apical as well as basolateral steps of renal organic anion secretion. In addition, studies of the genomic organization of these transporters reveal that they are found in pairs of similar and similarly expressed genes, suggesting that pair members are coordinately regulated. Finally, we hypothesize here that organic anion transporters might impact renal susceptibility to ischemia and toxic injury, because their uptake of substrates can result in the efflux of Krebs cycle intermediates, an important nutrient source for the proximal tubule. SUMMARY: The study of these transporters will likely have a significant impact on renal pharmacology and pharmacogenetics. In this regard, the generation of organic anion transporter gene knockout mice could provide invaluable models for defects in renal drug-handling. Ultimately, detailed knowledge of organic anion transporter function will assist in the choice of optimum pharmacological therapies.

Animals↗

PubMed2002

A model for a smallpox-vaccination policy.

BACKGROUND: The new reality of biologic terrorism and warfare has ignited a debate about whether to reintroduce smallpox vaccination. METHODS: We developed scenarios of smallpox attacks and built a stochastic model of outcomes under various control policies. We conducted a systematic literature review and estimated model parameters on the basis of European and North American outbreaks since World War II. We assessed the trade-offs between vaccine-related harms and benefits. RESULTS: Nations or terrorists possessing a smallpox weapon could feasibly mount attacks that vary with respect to tactical complexity and target size, and patterns of spread can be expected to vary according to whether index patients are hospitalized early. For acceptable results, vaccination of contacts must be accompanied by effective isolation. Vaccination of contacts plus isolation is expected to result in 7 deaths (from vaccine or smallpox) in a scenario involving the release of variola virus from a laboratory, 19 deaths in a human-vector scenario, 300 deaths in a building-attack scenario, 2735 deaths in a scenario involving a low-impact airport attack, and 54,729 deaths in a scenario involving a high-impact airport attack. Immediate vaccination of the public in an attacked region would provide little additional benefit. Prior vaccination of health care workers, who would be disproportionately affected, would save lives in large local or national attacks but would cause 25 deaths nationally. Prior vaccination of health care workers and the public would save lives in a national attack but would cause 482 deaths nationally. The expected net benefits of vaccination depend on the assessed probability of an attack. Prior vaccination of health care workers would be expected to save lives if the probability of a building attack exceeded 0.22 or if the probability of a high-impact airport attack exceeded 0.002. The probability would have to be much higher to make vaccination of the public life-saving. CONCLUSIONS: The analysis favors prior vaccination of health care workers unless the likelihood of any attack is very low, but it favors vaccination of the public only if the likelihood of a national attack or of multiple attacks is high.

Bioterrorism↗

PubMed2002

Toward an etiological classification of developmental disorders of the kidney and upper urinary tract.

Toward an etiological classification of developmental disorders of the kidney and upper urinary tract. There are a large number of developmental disorders and syndromes that affect the kidney and upper urinary tract. These have generally been classified according to morphological criteria established decades ago. Although these classifications have been useful, they are incomplete, including some developmental disorders while excluding others. Here, basic cellular and molecular biology studies of kidney and upper urinary tract development in both rodents and humans are utilized to suggest the basis of a new etiologic, if still tentative, classification scheme. This classification may help to identify candidate genes for human diseases by correlating morphology with pathogenetic mechanisms.

Animals↗