Hepatitis C: viral and host factors associated with non‐response to pegylated interferon plus ribavirin

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG‐IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1‐infected patients. Several viral and host factors have been associated with non‐response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non‐responders, some interferon‐stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG‐IFN plus ribavirin) to 70% (for patients treated with a combination of PEG‐IFN plus ribavirin plus telaprevir). Different elements are associated with non‐response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non‐response, to overcome it and to identify factors that can help to predict the response to anti‐HCV therapy.     

Characterization of resident and migratory dendritic cells in human lymph nodes

Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN-resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4(+) and CD8(+) T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities.     

Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension

In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.     

Effects of fenbufen and other anti-inflammatory drugs on rat liver lysosomes

Fenbufen, biphenylacetic acid and other non-steroidal anti-inflammatory drugs were found to labilize the lysosomal membrane of liver lysosomes in vitro. The extent of labilization was pH dependent. All the non-steroidal drugs labilized to a much greater extent at pH 5.0 than at pH 7.4. The two steroids tested, cholesterol and cortisone, stabilized the lysosomes at both pH 5.0 and 7.4. Oral administration of fenbufen and indomethacin caused no change in lysosomal membrane stability when assayed in vitro. Hydrocortisone showed a small degree of stabilization under these conditions. It is concluded that lysosomal membrane stabilization cannot account for the anti-inflammatory activity of fenbufen, biphenylacetic acid or other non-steroidal anti-inflammatory drugs.     

Clinical effectiveness of leukocyte filtration during cardiopulmonary bypass in patients with chronic obstructive pulmonary disease

Background

We tested the hypothesis that leukocyte filtration during pulmonary reperfusion preserves pulmonary function and results in improved oxygenation after cardiopulmonary bypass (CPB) in patients with chronic obstructive pulmonary disease (COPD).

Methods

In a prospective, randomized study, the treatment group consisted of 20 patients with COPD from consecutive open-heart procedures. A primed leukocyte filter was connected to the arterial line downstream of the standard arterial filter but was excluded from circulation. Circulated blood was directed through the leukocyte filter approximately 10 minutes before aortic cross-clamp removal and at early reperfusion for up to 30 minutes. These patients were compared to 20 additional COPD patients (controls) on whom systemic leukocyte filtration was not used during open-heart surgery.

Results

There was no significant difference in gender, age, left ventricular ejection fraction, type of procedure, aortic cross-clamp time, perfusion time, preoperative FEV₁ and preoperative respiratory index (Pao₂/FiO₂ ratio) between treatment and control groups. The respiratory index changed in the treatment group by +9.8% of baseline after completion of CPB, by −14.2% upon arrival in the intensive care unit (ICU), and by −19.6% 12 hours later, whereas in the control group, it changed by −14.5% (p < 0.05), −27.7%, and −24%, respectively. Leukocyte-depleted patients required shorter intubation time (20.4 ± 16.1 hours), ICU stay (46.2 ± 40.1 hours) and length of hospitalization (8.3 ± 2.8 days) than controls (29.5 ± 21.9 hours, p < 0.05; 75.5 ± 34.9 hours, p < 0.005; and 10.4 ± 3.5 days, p < 0.05, respectively). Surgical (30-day) mortality was zero in both groups.

Conclusions

In COPD patients having CPB, systemic leukocyte depletion at early reperfusion was associated with better oxygenation, shorter intubation time, and shorter ICU and hospital stays. Leukocyte filtration during CPB most likely preserves pulmonary function by ameliorating pulmonary reperfusion injury.     

Gender and age effects in structural brain asymmetry as measured by MRI texture analysis

Effects of gender and age on structural brain asymmetry were studied by 3D texture analysis in 380 adults. Asymmetry is detected by comparing the complex 3D gray-scale image patterns in the left and right cerebral hemispheres as revealed by anatomical T1-weighted MRI datasets. The Talairach and Tournoux parcellation system was applied to study the asymmetry on five levels: the whole cerebrum, nine coronal sections, 12 axial sections, boxes resulting from both coronal and axial subdivisions, and by a sliding spherical window of 9 mm diameter. The analysis revealed that the brain asymmetry increases in the anterior-posterior direction starting from the central region onward. Male brains were found to be more asymmetric than female. This gender-related effect is noticeable in all brain areas but is most significant in the superior temporal gyrus, Heschl's gyrus, the adjacent white matter regions in the temporal stem and the knee of the optic radiation, the thalamus, and the posterior cingulate. The brain asymmetry increases significantly with age in the inferior frontal gyrus, anterior insula, anterior cingulate, parahippocampal gyrus, retrosplenial cortex, coronal radiata, and knee region of the internal capsule. Asymmetry decreases with age in the optic radiation, precentral gyrus, and angular gyrus. The texture-based method reported here is based on extended multisort cooccurrence matrices that employ intensity, gradient, and anisotropy features in a uniform way. It is sensitive, simple to reproduce, robust, and unbiased in the sense that segmentation of brain compartments and spatial transformations are not necessary. Thus, it should be considered as another tool for digital morphometry in neuroscience.     

Coronary artery spasm in patients with normal or near normal coronary arteries: Long-term follow-up of 277 patients

Most studies on the natural course of coronary artery spasmin patients with normal or nearly normal coronary arteries arebased on medium-term follow-up in small populations. The presentseries includes 277 successive patients with a median follow-upof 89 months (range: 1 to 198 months). There were 206 men and71 women whose mean age was 53·6 ± 9·3years. They were all assessed with coronary arteriography whichrevealed no stenoses greater than 50%. Spasm was confirmed duringthe coronary arteriography in 157 patients (56·7%), bya positive provocation test following the arteriography in 113patients (40·8%), and by an electrocardiogram which showedPrinzmetal's variant angina in seven patients (25%). The majorityof patients, 264 (95·3%) were treated with calcium channelblockers. At the end of this study: 35 patients (12·6%) were lostto follow-up; 20 patients (7·2 died) including 10 (3·6%)from cardiac causes; 18 patients (6·5%) experienced myocardialinfarction in 11 of whom repeat coronary arteriography consistentlydemonstrated one or more significant stenoses (greater than70%); 109 patients (39%) had persistent angina, in 52 of whomthe severity (more than one episode per month) warranted repeatcoronary arteriography which detected significant stenosis in19 cases; 95 patients (34·3%) were asymptomatic. Multivariate statistical analyses showed that only predictorsof major coronary events (death, myocardial infarction or anginarequiring repeat coronary arteriography) were systemic hypertensionor the finding of minor parietal irregularities on the initialcoronary arterlogram. CONCLUSION: Despite treatment with calcium channel blockers, persistentor recurrent episodes of angina are frequently observed whereascomplications such as myocardial infarction or death are rare.     

X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation

Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5′-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5′-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease.     

An Assessment of the Impact of Fortification of Staples and Condiments on Micronutrient Intake in Young Vietnamese Children

Targeted fortification programs for infants and young children are an effective strategy to prevent micronutrient deficiencies in developing countries, but the role of large-scale fortification of staple foods and condiments is less clear. Dietary modeling in children aged 6–60 months was undertaken, based on food consumption patterns described in the 2009 national food consumption survey, using a 24-h recall method. Consumption data showed that the median intake of a child for iron, vitamin A and zinc, as a proportion of the Vietnamese Recommended Dietary Allowance (VRDA), is respectively 16%–48%, 14%–49% and 36%–46%, (depending on the age group). Potential fortification vehicles, such as rice, fish/soy sauces and vegetable oil are consumed daily in significant amounts (median: 170 g/capita/day, 4 g/capita/day and 6 g/capita/day, respectively) by over 40% of the children. Vegetable oil fortification could contribute to an additional vitamin A intake of 21%–24% of VRDA recommended nutrient intake, while fortified rice could support the intakes of all the other micronutrients (14%–61% for iron, 4%–11% for zinc and 33%–49% of folate requirements). Other food vehicles, such as wheat flour, which is consumed by 16% of children, could also contribute to efforts to increase micronutrient intakes, although little impact on the prevalence of micronutrient deficiencies can be expected if used alone. The modeling suggests that fortification of vegetable oil, rice and sauces would be an effective strategy to address micronutrient gaps and deficiencies in young children.     

The analysis of immunophenotype of gastrin-producing tumors of the pancreas and gastrointestinal tract

BACKGROUND: Gastrinomas are located more frequently in the pancreas, which normally has no cells that can produce gastrin. They have a more aggressive course than other pancreatic endocrine tumors and extrapancreatic gastrinomas associated with multiple endocrine neoplasia Type 1 syndrome. The current study analyzed immunophenotypes of gastrinomas and compared them with other pancreatic endocrine tumors. METHODS: Twenty-one formalin-fixed, paraffin-embedded specimens (15-tumors in the pancreas, 1 in the duodenum, 1 in the stomach, 1 in the liver, and 3 of unknown primary location) accompanied by Zollinger-Ellison syndrome and 17 other pancreatic endocrine tumor specimens were investigated. They were stained immunohistochemically for gastrin, chromogranin A, synaptophysin, insulin, glucagon, somatostatin, pancreatic polypeptide, calcitonin, serotonin, chorionic gonadotropin, adrenocorticotropic hormone, carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin 19. RESULTS: Gastrinomas coexpressed neuroendocrine and exocrine markers, including chromogranin A, synaptophysin, carcinoembryonic antigen, cytokeratin 19, and epithelial membrane antigen. Carcinoembryonic antigen was found in all 17 gastrinomas (100%), cytokeratin 19 was found in 15 of 17 (88.2%) gastrinomas, and epithelial membrane antigen was found in 16 of 18 (88.9 %) gastrinomas. Cytokeratin 19, epithelial membrane antigen, and carcinoembryonic antigen were not found to be present in the pancreatic endocrine tumors, but chromogranin A and synaptophysin were. Chorionic gonadotropin was found in 16 gastrinomas (100%), but only in 2 of 17 other pancreatic endocrine tumors (11.8 %). CONCLUSIONS: Pancreatic gastrinomas were characterized by the coexpression of neuroendocrine markers, exocrine markers, and chorionic gonadotropin. Therefore, pancreatic gastrinomas made a special intermediate group of tumors, which phenotypically combined features of neuroendocrine and exocrine neoplasms. These findings suggested that sporadic pancreatic gastrinomas and other pancreatic endocrine tumors are different phenotypically and are possibly of different origin.