Roles and mechanisms of the kidney sodium-chloride cotransporter (NCC) in salt-sensitive hypertension

Hypertension is both a domestic and international health issue – diagnosed in 1 in 3 U.S. adults and classified by the World Health Organization as the number one risk factor for mortality worldwide. It has been established that salt plays a role in the development of hypertension, and that a salt-sensitive phenotype indicates heightened sensitivity to salt consumption. Here, we studied the roles of the afferent renal nerves, which travel from the kidney to the central nervous system, and the sodium-chloride cotransporter in fluid and electrolyte homeostasis and blood pressure regulation. Our laboratory utilized a novel technique of afferent renal nerve ablation on Sprague-Dawley rats to examine the effects of afferent renal nerve mechanoreceptors and chemoreceptors in response to acute sympathoinhibitory challenges. Additionally, salt-sensitive and salt-resistant rats were randomly subjected to chronic normal salt (0.6% NaCl) or high salt (8% NaCl) diets, and examined for levels of norepinephrine and substance-P release. A different group of salt-resistant and salt-sensitive rats were subcutaneously infused with terazosin, a selective -1 adrenoreceptor antagonist, or propranolol, a selective -adrenoreceptor antagonist, and then randomly subjected to normal salt (0.6% NaCl) or high salt (4% NaCl) diets for 21 days. We subsequently examined these rats, and analyzed the effects of high salt intake on blood pressure, sodium-chloride cotransporter activity, and expression of the sodium-chloride cotransporter and its relevant kinases. In response to an acute mechanoreceptor-specific stimulus, Sprague-Dawley rats that underwent afferent renal nerve ablation were unable to modulate blood pressure or natriuresis after regaining consciousness. Chronic high salt (8% NaCl) consumption in salt-sensitive rats resulted in increased levels of plasma norepinephrine, renal norepinephrine, and norepinephrine-evoked Substance-P release. In addition, salt-sensitive rats subjected to a 21-day high salt (4% NaCl) diet exhibited increased blood pressure, elevated sodium-chloride cotransporter activity, and upregulated levels of the sodium-chloride cotransporter and the kinases that regulate it. However, these observed increases in blood pressure, protein activity, and protein expression were abolished in salt-sensitive rats experiencing -1 adrenoreceptor antagonism due to terazosin administration. In conclusion, our findings indicate that mechanoreceptor-driven afferent renal nerve activation is needed to maintain fluid and electrolyte homeostasis and regulate blood pressure in response to acute sympathoinhibitory challenges and chronic high salt intake. In addition, our data demonstrates that the sodium-chloride cotransporter is aberrantly upregulated in salt-sensitive rats through a norepinephrine-1-adrenoreceptor gated pathway, and this this upregulation results in excessive salt reabsorption. Thus, our experiments have generated new data that reveals selective 1-adrenoreceptor antagonism and renal denervation as potential treatment options for hypertensive individuals

A Systematic Analysis of Epigenetic Genes across Different Stages of Lung Adenocarcinoma

poster abstractIntroduction: Epigenetic refers to the reversible functional modifications of the genome that do not correlate to changes in the DNA sequence. Hence identifying these epigenetic targets contributing to the cancers and modifying them might provide a new approach to successful drug therapies. The aim of our study is to understand DNA methylation patterns across different stages of lung adenocarcinoma (LUAD). Method: An integrative system biology approach was developed to combine gene-expression, DNA methylation and protein-protein interaction data to obtain the targets for LUAD. The expression and methylation data was downloaded from TCGA. Statistical analysis was performed to further obtain the differentially expressed and significant methylated genes. An integrated network of these significant genes was constructed using BioGRID. Seed and expand approach was then used to identify and analyze epigenetically relevant subnetworks. Results: Our study identified 72, 93 and 170 significant methylated genes in Stage I, II and III respectively of LUAD. Variable methylation patterns were found for the significant genes across the different stages. Chromosomal analysis discovered that most of the methylated genes were distributed across chromosomes 7, 8, and 7 for Stage I, II and III respectively. Functionally conserved subnetworks of DNA methylation were obtained and compared across stages. This comparison showed a pattern of seven functionally conserved genes, mostly belonging to the KRAS pathway. Validation of the results was based on literature review which identified NEFM (beta value 0.36), NMUR2 (beta value 0.28), NEUROG1 (beta value -0.26) and IVL (beta value -0.26) as novel methylated LUAD genes. Conclusion: A distinct methylation pattern exists across stages which can help to characterize LUAD. Several tumor oncogenes and transcription factors were identified in the epigenetically relevant subnetworks, indicating that methylation affects the tumor progression. Methylated genes identified in this study can be further evaluated for their use as potential drug targets

Data analysis and creation of epigenetics database

Indiana University-Purdue University Indianapolis (IUPUI)This thesis is aimed at creating a pipeline for analyzing DNA methylation epigenetics data and creating a data model structured well enough to store the analysis results of the pipeline. In addition to storing the results, the model is also designed to hold information which will help researchers to decipher a meaningful epigenetics sense from the results made available. Current major epigenetics resources such as PubMeth, MethyCancer, MethDB and NCBI’s Epigenomics database fail to provide holistic view of epigenetics. They provide datasets produced from different analysis techniques which raises an important issue of data integration. The resources also fail to include numerous factors defining the epigenetic nature of a gene. Some of the resources are also struggling to keep the data stored in their databases up-to-date. This has diminished their validity and coverage of epigenetics data. In this thesis we have tackled a major branch of epigenetics: DNA methylation. As a case study to prove the effectiveness of our pipeline, we have used stage-wise DNA methylation and expression raw data for Lung adenocarcinoma (LUAD) from TCGA data repository. The pipeline helped us to identify progressive methylation patterns across different stages of LUAD. It also identified some key targets which have a potential for being a drug target. Along with the results from methylation data analysis pipeline we combined data from various online data reserves such as KEGG database, GO database, UCSC database and BioGRID database which helped us to overcome the shortcomings of existing data collections and present a resource as complete solution for studying DNA methylation epigenetics data

Study of outcome of displaced calcaneal fractures by closed reduction and percutaneous internal fixation with multiple k wires and screws

Background: Calcaneum is the largest of the tarsal bones and the largest bone of the foot. Calcaneum fracture account for 2% of all fracture of the body and 60% of all tarsal fractures. Many calcaneal fractures are work related as they result from a fall from height, especially in male age 35-45 years. In our study we treated the displaced calcaneal fracture with closed reduction and percutaneous fixation using multiple percutaneous K-wires and screw to evaluate their functional outcome. Methods: The study was conducted as a prospective study at the department of Orthopaedics, Dr. Shankarrao chavan Government Medical College, Nanded, India during the period January 2019 to June 2020. Thirty patients of 20 to 60 years, who underwent surgical fixation for displaced calcaneal fracture using multiple K wires and screws were followed up. Functional outcomes at six month follow up were assessed. Results: In this study we selected 30 patients with displaced calcaneal fracture admitting in our institute. All patients underwent operative procedure in the form of multiple k wire and cc .screws by percutaneous approach Out of all 30 patients treated with this method had shown excellent results with minimal postoperative complications. Conclusions: The study with percutaneous K wires and screws for displaced calcaneal fractures showed very good functional outcome. Although it was not free of complications, our study has shown very good results. Technique involve in our study is less invasive, with minimum blood loss, less operative time without soft tissue stripping

Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in Real-World Clinical Practice

BACKGROUND: In the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association [NYHA] Functional Class III Heart Failure Patients) trial, heart failure hospitalization (HFH) rates were lower in patients managed with guidance from an implantable pulmonary artery pressure sensor compared with usual care. OBJECTIVES: This study examined the effectiveness of ambulatory hemodynamic monitoring in reducing HFH outside of the clinical trial setting. METHODS: We conducted a retrospective cohort study using U.S. Medicare claims data from patients undergoing pulmonary artery pressure sensor implantation between June 1, 2014, and December 31, 2015. Rates of HFH during pre-defined periods before and after implantation were compared using the Andersen-Gill extension to the Cox proportional hazards model while accounting for the competing risk of death, ventricular assist device implantation, or cardiac transplantation. Comprehensive heart failure (HF)-related costs were compared over the same periods. RESULTS: Among 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.49 to 0.61; p \u3c 0.001). This lower rate of HFH was associated with a 6-month comprehensive HF cost reduction of $7,433 per patient (IQR:$7,000 to $7,884), and was robust in analyses restricted to 6-month survivors. Similar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implantation (HR: 0.66; 95% CI: 0.57 to 0.76; p \u3c 0.001). CONCLUSIONS: As in clinical trials, use of ambulatory hemodynamic monitoring in clinical practice is associated with lower HFH and comprehensive HF costs. These benefits are sustained to 1 year and support the real-world effectiveness of this approach to HF management

Window of opportunity in axial spondyloarthritis: A Stitch in Time

Axial spondyloarthritis comprising both non-radiographic axial spondyloarthritis and ankylosingspondylitis has a deleterious impact on the patient’s quality of life with a detrimental outcome ofstructural damage. Although in the current era of diagnostic advancements, axSpA can be diagnosedearly within a short period after the onset of symptoms, but still there is a delay of up to severalyears in many parts of the world. The concept of a window of opportunity is primarily derived fromrheumatoid arthritis, which is relevant in the context of axSpA based upon the early diagnosis and tocommence highly effective treatment with biologics like anti-TNF and anti-IL-17 to modify thedisease process for arresting structural damage or syndesmophytes formation. Still, challenges existfor early diagnosis of SpA in patients with low back pain which ultimately creates a barrier toeffective treatment initiation. More robust researches along with the available evidence on both theaspects of clinical and imaging factors are the way forward for the early identification of susceptibleindividuals for early intervention with a better outcome

Efficacy of sacubitril/valsartan relative to a prior decompensation: the PARADIGM-HF trial

Objectives: This study assessed whether the benefit of sacubtril/valsartan therapy varied with clinical stability. Background: Despite the benefit of sacubitril/valsartan therapy shown in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, it has been suggested that switching from an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker should be delayed until occurrence of clinical decompensation. Methods: Outcomes were compared among patients who had prior hospitalization within 3 months of screening (n = 1,611 [19%]), between 3 and 6 months (n = 1,009 [12%]), between 6 and 12 months (n = 886 [11%]), >12 months (n = 1,746 [21%]), or who had never been hospitalized (n = 3,125 [37%]). Results: Twenty percent of patients without prior HF hospitalization experienced a primary endpoint of cardiovascular death or heart failure (HF) hospitalization during the course of the trial. Despite the increased risk associated with more recent hospitalization, the efficacy of sacubitril/valsartan therapy did not differ from that of enalapril according to the occurrence of or time from hospitalization for HF before screening, with respect to the primary endpoint or with respect to cardiovascular or all-cause mortality. Conclusions: Patients with recent HF decompensation requiring hospitalization were more likely to experience cardiovascular death or HF hospitalization than those who had never been hospitalized. Patients who were clinically stable, as shown by a remote HF hospitalization (>3 months prior to screening) or by lack of any prior HF hospitalization, were as likely to benefit from sacubitril/valsartan therapy as more recently hospitalized patients. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)