Heart failure (HF) continues to be a highly prevalent syndrome, affecting millions of patients and costing billions of dollars in treatment per year in the United States alone. Studies in failing human heart and in transgenic HF models led to the recognition that enhanced neurohormonal signaling plays a causative role in HF progression, and the use of neurohormone receptor antagonists have proven to decrease hospitalization rates. It has also been long recognized that patients with HF have abnormal water retention, hypo-osmolality, and hyponatremia secondary to elevations in the levels of the neurohormone arginine vasopressin (AVP). AVP is released from the hypothalamus in response to changes in plasma osmolality and pressure, acting at three distinct G protein-coupled receptors: V1AR, V1BR and V2R. Persistent AVP release causes hyponatremia via renal V2R activation, a risk factor for death and hospitalization, and there is a correlation between plasma AVP levels and HF severity/survival of chronic HF patients. Because of the adverse clinical consequences associated with the development of hyponatremia, V2R antagonists were developed for the treatment of HF patients with hyponatremia, however in contrast to other neurohormone blockers they do not relay a survival benefit and may exacerbate decompensated HF requiring inotropic support. Renewed interest in the cardiac V1AR system during HF has arisen due to several recent findings: 1) mice with myocyte-selective transgenic overexpression of cardiac V1AR developed cardiomyopathy in the absence of any pathological insult, 2) cardiac V1AR expression was shown to be increased late-stage human HF, and 3) V1AR antagonism prevented cardiomyopathy development in a mouse model of HF. While cardiac V1AR expression is increased in HF, the role of V1AR signaling in various forms of cardiac injury and in distinct cardiac cell types has been controversial. Therefore this review will primarily focus on V1AR signaling as a potential therapeutic target for HF treatment.

Goals: The goal of this study was to determine the effect and safety of domperidone on QTc interval at the commonly prescribed doses of 30 to 80 mg daily. Background: Domperidone is a dopamine receptor antagonist used for the treatment of gastroparesis. However, it has been associated with QT prolongation, ventricular arrhythmias, and sudden cardiac death. Study: This study analyzed patients prescribed domperidone for treatment of gastroparesis between January 2012 and September 2017 at a single center. This study reviewed EKGs, primarily the QTc interval, taken at baseline, 2 to 6 months after initiation of domperidone, 6 to 12 months after initiation, and ≥12 months after initiation. Concurrent QTc prolonging medications were recorded for each patient. The primary endpoint was QTc prolongation >500 ms. Secondary endpoints were QTc >450 ms for males, a QTc>470 ms for females, QTc prolongation ≥20 ms above baseline, and QTc prolongation >60 ms above baseline. Results: In total, 246 patients were included for analysis (age, 46.3±17.4 y; F 209). EKGs were available for all 246 patients before treatment, 170 patients at 2 to 6 months, 135 at 6 to 12 months, and 152 patients at least 1 year after domperidone initiation. Of 246 subjects, 15 patients (6.1%, 9 female) had clinically important QTc prolongation; 11 had QTc >450 ms for males or >470 ms for females; none had QTc prolongation >500 ms; 5 (2.0%) had >60 ms over baseline and 61 (24.7%) patients had QTc increase of ≥20 ms but <60 ms from baseline. Conclusions: Domperidone at the conventionally used doses to treat gastroparesis (30 to 80 mg/d) was associated with QTc prolongation in only 6% of patients with no QT interval reaching the point considered to be clinically significant. These data suggest that domperidone can be safely prescribed at doses of 30 to 80 mg daily for the treatment of gastroparesis.

Connective tissue growth factor (CTGF/CNN2) is a novel APF target gene. A novel mechanism is described by which the APF cellular receptor, cytoskeleton-associated protein 4 (CKAP4), mediates APF-induced CTGF transcription.

It is an extraordinary challenge to offer an undergraduate laboratory course in virology that teaches hands-on, relevant molecular biology techniques using nonpathogenic models of human virus detection. To our knowledge, there exists no inexpensive kits or reagent sets that are appropriate for demonstrating real-time PCR (RT-PCR) in an undergraduate laboratory course in virology. Here we describe simple procedures for student exercises that demonstrate the PCR detection of an HIV target nucleic acid. Our procedures combine a commercially available kit for conventional PCR with a modification for RT-PCR using the same reagents in the kit, making it possible for an instructor with access to a LightCycler 1 instrument to implement a relevant student exercise on RT-PCR detection of HIV nucleic acid targets. This combination of techniques is useful for demonstrating and comparing conventional PCR amplification and detection with agarose gel electrophoresis, with real-time PCR over a series of three laboratory periods. The series of laboratory periods also is used to provide the foundation for teaching the concept of PCR primer design, optimization of PCR detection systems, and introduction to nucleic acid queries using NCBI-BLAST to find and identify primers, amplicons, and other potential amplification targets within the HIV viral genome. The techniques were successfully implemented at the Biology 364 undergraduate virology course at the University of Scranton during the Fall 2008 semester. The techniques are particularly targeted to students who intend to pursue either postgraduate technical employment or graduate studies in the molecular life sciences.

Several studies report associations between the PINCH (particularly interesting new cysteine histidine-rich) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy, or before and after a change in the current regimen. The intervals were approximately 1 (T2), and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4+ T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration-effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold-change in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm3 at T2 compared to those with CD4 counts <200 cells/mm3 at T2. This trend persisted irrespective of plasma or CSF viral burden or anti-retroviral therapy CPE scores. The fold-changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation co-efficient = 0.69, p-value < 0.001, correlation co-efficient = 0.83, p-value <0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, or WBC, or with anti-retroviral regimen CPE.