Characterization of demographics and NS5A genetic diversity for hepatitis C virus genotype 4-infected patients with or without cirrhosis treated with ombitasvir/paritaprevir/ritonavir.

Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse with 17 confirmed and 4 provisional subtypes. In this report, HCV GT4-infected patient samples from Phase 2/3 clinical studies were analysed to characterize global demographics and genetic diversity of GT4 infection among patients treated with ombitasvir (OBV, NS5A inhibitor) plus paritaprevir/r (NS3/4A inhibitor codosed with ritonavir). Among 17 subtypes isolated from GT4-infected patients in the PEARL-I and AGATE-I studies, subtype prevalence by country of enrolment and country of origin suggested that subtypes 4a and 4d were likely circulating in Europe, while heterogeneous GT4 subtypes and a portion of GT4a detected in European and North American countries were likely due to immigration of HCV-infected patients from Africa. The distributions of birth cohort and race were also significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. In addition, phylogenetic analyses of NS5A sequences revealed clustering within subtype 4a which segregated by the patient-reported country of origin and the presence of the L30R/S polymorphism. HCV NS5A sequences derived from GT4a-infected patients who originated from Europe and the United States clustered separately from sequences derived from patients who originated from Egypt, suggesting that genetically distinct strains of subtype 4a may be circulating globally. Finally, NS5A baseline polymorphisms were frequently detected at amino acid positions of interest for the inhibitor-class and OBV retained activity against 37 of 39 NS5A GT4 clinical isolates, with no impact on treatment outcome in the PEARL-I and AGATE-I studies.

Effects of scale and logging on landscape structure in a forest mosaic.

Landscape structure in a forest mosaic changes with spatial scale (i.e. spatial extent) and thresholds may occur where structure changes markedly. Forest management alters landscape structure and may affect the intensity and location of thresholds. Our purpose was to examine landscape structure at different scales to determine thresholds where landscape structure changes markedly in managed forest mosaics of the Appalachian Mountains in the eastern United States. We also investigated how logging influences landscape structure and whether these management activities change threshold values. Using threshold and autocorrelation analyses, we found that thresholds in landscape indices exist at 400, 500, and 800 m intervals from the outer edge of management units in our study region. For landscape indices that consider all landcover categories, such as dominance and contagion, landscape structure and thresholds did not change after logging occurred. Measurements for these overall landscape indices were strongly influenced by midsuccessional deciduous forest, the most common landcover category in the landscape. When restricting analyses for mean patch size and percent cover to individual forest types, thresholds for early-successional forests changed after logging. However, logging changed the landscape structure at small spatial scale, but did not alter the structure of the entire forest mosaic. Previous forest management may already have increased the heterogeneity of the landscape beyond the point where additional small cuts alter the overall structure of the forest. Because measurements for landscape indices yield very different results at different spatial scales, it is important first to identify thresholds in order to determine the appropriate scales for landscape ecological studies. We found that threshold and autocorrelation analyses were simple but powerful tools for the detection of appropriate scales in the managed forest mosaic under study.

Immunoprophylactic strategies against respiratory influenza virus infection.

The objective of this report is to evaluate the prophylactic efficacy of liposome-mediated immunotherapy for prevention of respiratory influenza virus infection in mice. Antiviral antibody, interferon-gamma and poly (ICLC) were encapsulated in liposomes and they were evaluated for their ability to induce protective immunity against lethal influenza infection. Passive immunization using liposome-encapsulated antiviral antibody was found to offer complete protection against the virus challenge. However, this pretreatment must be administered within 24 h prior to virus challenge to be protective. Pretreatment with liposome-encapsulated interferon-gamma was found to stimulate cellular immune responses, but the protection is partial. Immunoprophylaxis using liposome-encapsulated double-stranded (ds) RNA poly (ICLC) provided complete and longer-lasting protection against influenza infection. These results suggest liposome-mediated immunoprophylactic approaches are effective in the prevention of respiratory influenza virus infection.

Effects of liposome-encapsulated ciprofloxacin on phagocytosis, nitric oxide and intracellular killing of Staphylcoccus aureus by murine macrophages.

The effects of liposome-encapsulated ciprofloxacin on phagocytosis, nitric oxide production and intracellular killing of Staphylococcus aureus in murine macrophages were evaluated in this study. Mice were pretreated with three daily doses of liposome-encapsulated ciprofloxacin (45 mg/kg body weight/dose, intraperitoneal injection). At day 3 post drug administration, peritoneal macrophages were harvested by peritoneal lavage, and the phagocytic activity of the macrophages was determined by a chemiluminescence assay using opsonized zymosan particles. The phagocytic activity was found to be 7-fold higher in the liposome-encapsulated ciprofloxacin-treated group when compared to the untreated control group. For S. aureus-infected macrophages incubated with liposomes containing subinhibitory concentrations of ciprofloxacin (0.05 to 0.25 microg/mL), there were significant increases (up to 40 microM) in the levels of nitrite (NO2-, an end product of nitric oxide synthesis), and concommitant decreases (2-3 log) in the intracellular concentrations of S. aureus. Peak nitrite levels (20-40 microM) were produced when concentrations of liposome-encapsulated ciprofloxacin used were 0.1 to 0.25 microg/mL. These results suggest that liposome-encapsulated ciprofloxacin may have profound effects on the immunological functions of macrophages.

Impaired brachial artery endothelial function is not predicted by elevated triglycerides.

OBJECTIVES: The purpose of this study was to determine if patients with modest hyperlipidemia, and no other risk factors for coronary artery disease (CAD), have impaired endothelium-dependent (ED) vasoactivity. BACKGROUND: Hypercholesterolemia impairs ED vasodilation, but the impact of elevated triglycerides on endothelial function is not as well established. METHODS: High-resolution ultrasound was used to determine flow-mediated dilation (FMD) in the brachial artery (BA) after a 5-min arterial occlusion (endothelium-dependent stimulus) and nitroglycerin-induced dilation (endothelium-independent stimulus). We studied 40 healthy controls (Group 1), 38 patients with elevated low-density lipoprotein (LDL) cholesterol (Group 2) and 35 patients with elevated triglycerides (Group 3). Patients were excluded if they had known CAD or other risk factors for CAD, or if they were receiving lipid-lowering or vasoactive medications. RESULTS: Control patients (Group 1) had normal LDL cholesterol (2.6+/-0.8 mmol/liter) and triglyceride levels (1.0+/-0.5 mmol/liter) compared with Group 2 (5.2+/-1.2 mmol/liter, 1.8+/-0.6 mmol/liter) and Group 3 (3.5+/-0.9 mmol/liter, 4.2+/-2.5 mmol/liter) subjects (p < 0.001). Baseline BA diameters were the same across the three groups. There was no significant attenuation of flow-mediated vasodilation (FMD) in either of the hyperlipidemic groups (Group 1: 10.9+/-5.0% vs. Group 2: 8.6+/-6.1% vs. Group 3: 9.4+/-3.9%; p = 0.14). However, nitroglycerin-induced vasodilation was mildly reduced (Group 1: 21.0+/-5.0% vs. 16.9+/-7.6% vs. 17.3+/-7.7%; p = 0.01). By multivariate analysis, after controlling for baseline diameters, only the ratio of LDL/high-density lipoprotein predicted a minor impairment in FMD. CONCLUSIONS: In patients free from other cardiac risk factors, modest elevations of triglycerides or LDL cholesterol do not significantly attenuate BA endothelial-dependent vasodilation. Synergism with other cardiac risk factors may be required to significantly impair endothelial function in these patients.

Liposome-mediated immunotherapy against respiratory influenza virus infection using double-stranded RNA poly ICLC.

The use of liposome delivery technology to enhance the antiviral activity of poly ICLC (an immunomodulating dsRNA) while decreasing its intrinsic toxicity is evaluated in this study. The antiviral efficacies of free and liposome-encapsulated poly ICLC were evaluated and compared using a lethal respiratory influenza A virus infection in mice. The toxicity profiles of free and liposome-encapsulated poly ICLC were compared by determining the extent of hypothermia and loss in body weights in mice pretreated with these drugs. Poly ICLC was encapsulated in cationic liposomes prepared by the freeze drying method. To determine the antiviral efficacies of free and liposome-encapsulated poly ICLC, mice were intranasally pretreated with two doses of poly ICLC (free or liposomal, 1 mg/kg/dose) given 48 h apart. At various times post pretreatment, mice were intranasally challenged with 10 LD50 mouse-adapted influenza A/PR/8 (H1N1) virus. The survival rates of the mice were determined at day 14 post infected and compared to the untreated control mice. Results indicate mice pretreated with liposome-encapsulated poly ICLC within 3 weeks prior to virus challenge were completely protected (100% survival compared to 0% for the untreated control group, p < 0.001), while window of protection provided by free unencapsulated poly ICLC was 12 days. When the toxicity profiles of free and liposome-encapsulated poly ICLC were compared, it was found that hypothermia and body weight loss induced by poly ICLC were either completely mitigated or significantly reduced in mice given equivalent doses of poly ICLC in the liposome-encapsulated form. These results suggest that liposomes are an excellent drug carrier for poly ICLC, that liposome-encapsulated poly ICLC may provide a safe and effective immunotherapeutic approach for the prevention of respiratory influenza virus infections.

Aerosol delivery of liposome-encapsulated ciprofloxacin: aerosol characterization and efficacy against Francisella tularensis infection in mice.

The aerosol delivery of liposome-encapsulated ciprofloxacin by using 12 commercially available jet nebulizers was evaluated in this study. Aerosol particles containing liposome-encapsulated ciprofloxacin generated by the nebulizers were analyzed with a laser aerodynamic particle sizer. Mean mass aerodynamic diameters (MMADs) and geometric standard deviations (GSDs) were determined, and the drug contents of the sampling filters from each run onto which aerosolized liposome-encapsulated ciprofloxacin had been deposited were analyzed spectrophotometrically. The aerosol particles of liposome-encapsulated ciprofloxacin generated by these nebulizers ranged from 1.94 to 3.5 microm, with GSDs ranging from 1.51 to 1.84 microm. The drug contents of the sampling filters exposed for 1 min to aerosolized liposome-encapsulated ciprofloxacin range from 12.7 to 40.5 microg/ml (0.06 to 0.2 mg/filter). By using the nebulizer selected on the basis of most desirable MMADs, particle counts, and drug deposition, aerosolized liposome-encapsulated ciprofloxacin was used for the treatment of mice infected with 10 times the 50% lethal dose of Francisella tularensis. All mice treated with aerosolized liposome-encapsulated ciprofloxacin survived the infection, while all ciprofloxacin-treated or untreated control mice succumbed to the infection (P < 0.001). These results suggest that aerosol delivery of liposome-encapsulated ciprofloxacin to the lower respiratory tract is feasible and that it may provide an effective therapy for the treatment of respiratory tract infections.

Measurement of flow in infusion systems.

The development of three flow sensors for application in infusion systems is presented. One sensor measures the time of flight of an air bubble. A special design allows the bubble to be reused after every measuring cycle. The second flow sensor determines the pressure drop over a hydraulic bridge that is designed in analogy to an electrical Wheatstone bridge. The third sensor works using the phenomenon of heat transmission into the measuring liquid. Owing to their design, the sensors show different characteristics.

[A thermal flow sensor for infusion technique]. / Ein thermischer Durchflusssensor für die Infusionstechnik.

A flow sensor for measuring flow rates in infusions systems, which is thus suitable for infusion monitoring, is described. The sensor employs a combination of thermal heating and thermal tracing to determine the flow rate. Heating and sensing elements are applied to the outside of the infusion tubing, so that measurement does not compromise the integrity of the tubing. Through the use of two sensor units measurement can be made independently of position.

Population change and its components in Pennsylvania, 1980-1990.

The author analyzes patterns of population growth in Pennsylvania by county. "Although Pennsylvania's population increased only slightly from 1980-1990, the pattern of change portrays noteworthy growth in many counties in the eastern half of the Commonwealth and decline throughout much of the west.... Analysis of the components of change--fertility, mortality, and net-migration--reveals significant differences in the role played by reproductive change in the demographic equation among counties which grew in population and, to a lesser extent, among those which declined. Changes in numbers of inhabitants and their components are related to location and selected demographic, social, and economic characteristics of the county populations."

Prevalence of Campylobacter pylori in patients undergoing upper endoscopy.

From August 1987 through July 1988, we evaluated antral biopsy specimens for Campylobacter pylori (CP) in 212 patients undergoing upper endoscopy. For those patients who had multiple endoscopies, the first endoscopy in which a urease test, histology, and culture were done was used to determine CP status. A patient was regarded as CP-positive if the culture was positive or if both a urease test and the histology were positive. Blacks had an increased CP positivity (61.2%) compared to whites (31.5%). Among non-ulcer patients, CP positivity was 52% in black patients and 18% in white patients. Age and gender were unrelated to CP positivity among controls and those without ulcers. There was increased CP positivity in patients with duodenal ulcers (85%), compared with those without ulcers (37%), and a trend toward increased positivity in those with gastric ulcer (53%) and duodenitis (50%). There was no increased CP positivity in patients with gastroesophageal reflux disease (28%), gastritis (29%), non-ulcer dyspepsia (43%), or the control patients with no gastroduodenal mucosal abnormalities (40%). CP-negative DU patients were older (average 71 yr) than CP-positive DU patients (43 yr), and female DU patients had a lower CP positivity (71%) than males (94%).

Surgical therapy of diabetic gastroparesis.

Diabetic gastroparesis is a complication of diabetes mellitus that usually responds to medical management. We report a patient in whom medical management failed, and a gastrostomy, pyloroplasty, and jejunostomy were done to insure nutrition and to decompress the stomach. We also review the surgical management of this condition.

Usefulness of culture, histology, and urease testing in the detection of Campylobacter pylori.

Several tests have been described which detect the presence of Campylobacter pylori (CP) in the human upper gastrointestinal tract. Antral biopsies from 160 endoscopies were evaluated for the presence of CP; four tests readily available to the practicing endoscopist were used: two urease tests [CLOtest and microtiter biopsy urease test (MBUT)], hematoxylin and eosin staining, and culture. Sensitivity and specificity of each was evaluated and found to be near 90%, except for culture, which was less sensitive. The presence of peptic disease on endoscopy, and age greater than 50 yr, did play a small role in the sensitivity and specificity of the tests. With the advantage of lower cost, ease, and rapidity of performance, either the CLOtest or MBUT is recommended for the standard endoscopic evaluation for CP.

Delta hepatitis: first two cases identified in Kansas City.

Hepatitis delta virus (HDV) was identified in 1977 and has since been found to be a worldwide disease. Prevalence in North America is highest among drug abusers. We present two IV drug abusers from the city hospital in Kansas City as the first two cases identified in the city, one with apparent superinfection and the other with a chronic HDV infection. We review the various manifestations and diagnosis of HDV, and advocate prevention of spread of HDV infection by hepatitis B vaccination and use of single donor blood products in high-risk patients.

Aortogastric fistula from hiatal hernia ulcer. A cause of massive upper gastrointestinal bleeding.

An 83-year-old woman with no history of vascular surgery presented with a fatal upper gastrointestinal bleed from an aortogastric fistula secondary to a penetrating gastric ulcer. The fistula was between the thoracic aorta and the gastric ulcer in a hiatus hernia. On autopsy, a discrete 1-cm ulcer had perforated into the otherwise normal thoracic aorta. Aortogastric fistula involving the thoracic aorta and a gastric ulcer is rare in the absence of vascular graft surgery or aneurysm. We review the pertinent literature.