John E. Poulos

Congestive heart failure: increased cardiac and extracardiac atrial natriuretic peptide gene expression

OBJECTIVES The present investigation was designed to determine if atrial natriuretic peptide (ANP) gene expression increases in extracardiac as well as within the heart in congestive heart failure. METHODS Congestive heart failure (CHF) was induced by producing cardiac hypertrophy secondary to an aortocaval fistula in Sprague-Dawley rats. To characterize this model, control and CHF rats had cardiac catheterizations and transthoracic echocardiography. ANP messenger RNA was measured by RNAase protection analysis in atria, ventricles, liver, colon, and stomach of CHF and sham rats and quantitated by 2-D scanning. The product of ANP gene expression was determined in each of these tissues with high performance-gel permeation chromatography. To help determine if increased degradation of atrial natriuretic peptides occur in congestive heart failure, the circulating concentrations and the excretion of the atrial natriuretic peptides into urine were measured by specific radioimmunoassays. RESULTS ANP steady-state mRNA increased 4.2 +/- 0.05 and 4.3 +/- 0.06-fold, respectively, in the antrum of the stomach and within the heart ventricle of CHF rats compared with age-matched sham rats. ANP gene expression was present but not increased in atria, liver, and gastrointestinal tract of the CHF rats. High-performance gel permeation chromatography revealed that the product of this ANP gene expression within the stomach and heart ventricle in CHF animals was the ANP prohormone. There was not any decrease in the metabolism of these peptides by the kidney in CHF. CONCLUSIONS ANP steady-state mRNA increases in extracardiac (i.e., stomach antrum) tissue as well as in the ventricle of the heart in CHF. The product of the ANP gene expression, i.e., the ANP prohormone is the same in the extracardiac tissues as within the heart. Whether the increased extracardiac ANP steady-state mRNA and its resultant increased atrial natriuretic peptides helps prevent bowel wall edema in CHF needs to be elucidated.

Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion: A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (Hepatology 2016;63:437–444)

Cirrhosis with ascites: Increased atrial natriuretic peptide messenger RNA expression in rat ventricle

BACKGROUND/AIMS Atrial natriuretic peptides (ANPs) are increased in the circulation of cirrhotics with ascites; however, it is unknown whether this increase is caused by increased synthesis or a decrease in the metabolic processing of these peptides. ANP gene expression in the liver, atria, ventricles, and gastrointestinal tract of cirrhotic vs. control rats was studied as was their metabolism. METHODS Sprague-Dawley rats developed cirrhosis with ascites approximately 20 weeks after weekly intragastric instillation of carbon tetrachloride. Their circulating, ascitic, and urinary levels of ANPs were measured by radioimmunoassays. ANP gene expression was measured by a ribonuclease protection assay. RESULTS ANP gene expression was increased 2.8- to 4.1-fold in the ventricles of cirrhotic rats compared with age-matched healthy rats. ANP gene expression was present but not increased in the liver, atria, and gastrointestinal tract of cirrhotic rats. No increase of metabolic processing of these peptides was found in the circulation. Cardiac ultrasonography and catheterization revealed no ventricular dilation or increased ventricular pressure. CONCLUSIONS Elevation of circulating ANPs with cirrhosis was associated with increased ventricular steady-state ANP messenger RNA concentrations. The increased ANP gene expression in cirrhosis seems to involve a novel mechanism not related to stretch because neither increased ventricular pressure nor dilation was present.

Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data: HEPATOLOGY, Vol. XX, No. X, 2015

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion: A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (Hepatology 2016;63:437–444)

Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion: A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (Hepatology 2016;63:437–444)

Pain and chronic diarrhea in an elderly cancer patient.

›DISCUSSION The abdominal radiograph revealed a nonspecific bowel gas pattern with nongas distention of the small bowel and no definite air fluid levels. CT findings were markedly abnormal compared with findings from a few months earlier with diffuse collections of air in the portal-venous system of the liver. Gas was also seen in the superior mesenteric vein (Figure 2). Pneumatosis was present in loops of bowel with mesenteric venous gas (Figure 3). The imaging study results were consistent with pneumatosis intestinalis (PI) of the large and small bowels and hepatic portal venous gas (HPVG). The patient was admitted to the intensive care unit and was seen by gastroenterology, general surgery, and critical care providers, who determined that the patient was not a candidate for surgery and that her prognosis was grim. She stated that she did not wish to be intubated or resuscitated and was provided supportive care. Her condition gradually worsened, and she died later that day. Etiology Pneumatosis intestinalis, although a rare radiographic finding, is not a diagnosis.1 It is distinguished by the occurrence of subserosal or submucosal gas-filled cysts throughout the GI tract.2 PI morphology is classified as primary or secondary, with primary being cystic or bubblelike and secondary being more linear or bandlike in appearance.3 Secondary PI is much more common than primary PI (85% versus 15% of cases, respectively).4 While the exact pathophysiology is unknown, pneumatosis intestinalis is thought to be caused by production of hydrogen gas by coliform bacteria that diffuses across the mucosa or by gas dissection through the bowel wall caused by increased intraluminal pressure.1 Presentation and diagnosis The average age of presentation for PI is 45 to 60 years,5 and it often occurs secondary to a host of illnesses such as COPD, collagen vascular diseases, HIV infection, mesenteric ischemia, or necrotizing enterocolitis2. PI may also occur as a result of immunosuppressive and cytotoxic therapies.6 In patients with the condition, CT usually reveals collections of gas with low attenuation within the bowel wall.2 A review of patients with known PI showed that most occurrences were in Pain and chronic diarrhea in an elderly cancer patient Diagnostic Imaging Review

Endoscopy Unit Efficiency and Patient Satisfaction Utilizing Propofol in Comparison to Combination Propofol and Conscious Sedation

patients, 31(32.29%) had proximal colonic lesion (26 adenomas, 12 significant CRN and 1 CRC) and 20(20.8%) (13 adenomas and 7 significant CRN) had lesion in the distal colon. CONCLUSION: Asymptomatic patients aged 75 years and above have a significantly higher prevalence of CRN that might necessitate the need to consider screening in this age group. Our study also showed significantly more number of CRN in the proximal colon than the distal colon, signifies the importance of complete colonoscopy rather than sigmoidoscopy especially in patients aged 75 and above.

Fibroblast chemotaxis in response to dexamethasone

Dear Editor: The anti-inflammatory and wound modifying properties of glucocorticoids are felt to be elicited through the induction of lipocortin (1). Lipocortin inhibits the action of phospholipase Aa by interacting with substrate phospholipids and preventing cyclooxygenase generation of eicosanoids (2). Glucocorticoids have been shown to inhibit neutrophil chemotaxis (6), fibroblast proliferation, and the deposition of collagen (4). The use of glucocorticoids as disease-modifying agents in the treatment of collagen vascular diseases prompted us to examine the effect of dexamethasone on fibroblast chemotaxis. Human fetal foreskin fibroblasts were harvested and a 500-#1 aliquot cell suspensions at a concentration of 3.5 X l 0 s cells/ml was added to the upper half of the Boyden chambers. Conditioned medium (CM), a chemoattraetant for fibroblasts (7,9) was added to the bottom well of modified Boyden chambers and chemotaxis assays were performed as previously described (10). Fibroblasts were treated with dexamethasone at concentrations ranging from 1 × 10 -a M to 1 X 10 -~° M for 25 min at 37.5 ° C before the addition of the cell suspension to the upper well of Boyden chambers. Data represent the mean + SEM of 10 independent experiments performed in duplicate. Dexamethasone at a concentration of 10 -4 M inhibited fibroblast chemotaxis (Fig. 1) by 14% (21.42 _+ 0,76 SEM) vs. controls (24.3 _+ 0.6) (P < 0.05). Cell migration in response to 10 -6 M dexamethasone was not statistically different from positive controls. Enhancement of fibroblast chemotaxis by dexamethasone was observed at 10 ~ M (29%) (32.33 _+ 0.82) and 10 ~ M (33%)