Securing sustainable funding for viral hepatitis elimination plans

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct‐acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries’ health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro‐elimination approach in specific populations is less complex and less costly than country‐wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO.     

Mammalian cell invasion by closely related Trypanosoma species T. dionisii and T. cruzi

Protozoan parasites of the genus Trypanosoma can infect virtually all mammalian species. Within this genus, Trypanosoma dionisii from bats and Trypanosoma cruzi that causes Chagas' disease, belonging to the subgenus Schizotrypanum, can invade mammalian cells. The mechanisms of cell invasion by T. dionisii are poorly understood. To address that question, metacyclic trypomastigotes (MT) and human epithelial HeLa cells were used. Similarly to genetically divergent T. cruzi strains G (TcI) and CL (TcVI), associated, respectively with marsupial and human infections, T. dionisii infectivity increased under nutritional stress, a condition that induces host cell lysosome exocytosis required for parasite internalization. For efficient internalization, T. dionisii depended on MT protein tyrosine kinase (PTK) and Ca(2+) mobilization from acidocalcisomes, whereas T. cruzi strains also relied on phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC) and Ca(2+) released from thapsigargin-sensitive compartments. T. dionisii-induced signaling in host cells implicated PKC and Ca(2+) mobilized from thapsigargin-sensitive stores, like T. cruzi, but without PI3K involvement. Unlike T. cruzi, T. dionisii metacyclic forms did not use l-proline as source of energy required for internalization. Molecules related to T. cruzi surface glycoproteins involved in MT-host cell interaction were undetectable in T. dionisii. The difference in the surface profile of the two species was also inferred from the susceptibility of T. dionisii metacyclic forms to complement-mediated lysis, as opposed to complete resistance of T. cruzi. In summary, the two Trypanosoma species display distinct surface profiles but invade host cells through a common mechanism involving lysosome mobilization to the site of parasite entry.     

Intra-aortic balloon pumping recruits graft flow reserve by lowering coronary resistances

Background

The intra-aortic balloon pump (IABP) is used worldwide as an anti-ischemic strategy and to reduce myocardial workload. However, whether IABP augments coronary flow after coronary bypass via a passive increase in diastolic pressure or an active response of the coronary bed remains uncertain.

Methods

We analyzed transit-time flow measurements and the contemporary changes in coronary resistances obtained during 1:1 IABP and during its cessation in 144 consecutive patients receiving prophylactic IABP before isolated coronary artery bypass grafting (n = 340 graft segments).

Results

Normally functioning grafts showed lower coronary resistances, greater percentage decrease in resistance, and greater increases in average maximum diastolic and mean flow during 1:1 IABP compared with IABP cessation (P < .001). Arterial and sequential saphenous vein grafts showed better flowmetry and greater reductions in coronary resistances compared with single venous grafts. Accordingly, graft flow reserve (defined as mean flow during 1:1 IABP/mean flow with IABP off) was recruited (graft flow reserve > 1) during 1:1 IABP in all normally functioning grafts, with higher values in single arterial or sequential saphenous vein grafts than in single venous grafts (both P < .001). Coronary resistances were higher in 7 failed grafts versus normal-functioning grafts at baseline; these did not decrease during 1:1 IABP and showed worse transit-time flow results.

Conclusions

IABP recruits graft flow reserve by lowering coronary resistance in functioning grafts. Arterial and sequential venous grafts showed greater reduction in coronary resistance compared with single saphenous grafts.     

The Val66Met Polymorphism at the BDNF Gene does not Influence Wisconsin Card Sorting Test Results in Children and Adolescents with Bipolar Disorder

ObjectivesTo assess the role of the Val66Met polymorphism at the brain-derived neurotrophic factor (BDNF) gene on the performance of children and adolescents with bipolar disorder [juvenile bipolar disorder (JBD)] on the Wisconsin Card Sorting Test (WCST).MethodsChildren and adolescents were assessed by the K-SADS-PL and a clinical evaluation for BD and comorbid conditions. Manic and depressive symptoms were assessed with the Young Mania Rating Scale and the Children Depression Rating Scale – Reviewed. The Val66Met polymorphism at the BDNF was genotyped from a blood sample. Patients’ IQ and executive functions were assessed by a standard cognitive flexibility test (WCST).ResultsFifty-three subjects were included in the study. No significant difference was observed between the Val/Val and Val/Met+Met/Met groups on any WCST scores in the MANCOVA (F48,5 = .76; p = .59; Perseverative Errors, p = .66; Nonperseverative Errors, p = .58; Categories Completed, p = .34; Attempts to Reach First Category, p=.64; and Percentage of Conceptual Level Responses, p = .99).ConclusionsOur findings from this sample of children and adolescents with BD do not replicate results from studies of adults and suggest the existence of differences in the neurobiology of this disorder across the life cycle. Investigations of larger samples are necessary to confirm these data.     

Retinoic Acid-related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Rationale: The discovery that retinoic acid-related orphan receptor (Rora)-α is highly expressed in lungs of patients with COPD led us to hypothesize that Rora may contribute to the pathogenesis of emphysema. Objectives: To determine the role of Rora in smoke-induced emphysema. Methods: Cigarette smoke extract in vitro and elastase or cigarette smoke exposure in vivo were used to model smoke-related cell stress and airspace enlargement. Lung tissue from patients undergoing lung transplantation was examined for markers of DNA damage and Rora expression. Measurements and Main Results: Rora expression was induced by cigarette smoke in mice and in cell culture. Gene expression profiling of Rora-null mice exposed to cigarette smoke demonstrated enrichment for genes involved in DNA repair. Rora expression increased and Rora translocated to the nucleus after DNA damage. Inhibition of ataxia telangiectasia mutated decreased the induction of Rora. Gene silencing of Rora attenuated apoptotic cell death in response to cigarette smoke extract, whereas overexpression of Rora enhanced apoptosis. Rora-deficient mice were protected from elastase and cigarette smoke induced airspace enlargement. Finally, lungs of patients with COPD showed evidence of increased DNA damage even in the absence of active smoking. Conclusions: Taken together, these findings suggest that DNA damage may contribute to the pathogenesis of emphysema, and that Rora has a previously unrecognized role in cellular responses to genotoxicity. These findings provide a potential link between emphysema and features of premature ageing, including enhanced susceptibility to lung cancer.     

Chagasic patients are able to respond against a viral antigen from influenza virus

ABSTRACT: BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas' disease, is an obligate intracellular parasite which induces a CD8+ T cell immune response with secretion of cytokines and release of cytotoxic granules. Although an immune-suppressive effect of T. cruzi on the acute phase of the disease has been described, little is known about the capacity of CD8+ T cell from chronic chagasic patients to respond to a non-T. cruzi microbial antigen.Methods and resultsIn the present paper, the frequency, phenotype and the functional activity of the CD8+ T cells specific from Flu-MP*, an influenza virus epitope, were determined in 13 chagasic patients and 5 healthy donors. The results show that Flu-MP* peptide specific CD8+ T cells were found with similar frequencies in both groups. In addition, Flu-MP* specific CD8+ T cells were distributed in the early or intermediate/late differentiation stages without showing enrichment of a specific sub-population. The mentioned Flu-MP* specific CD8+ T cells from chagasic patients were predominately TEM (CCR7- CD62L-), producing IL-2, IFNgamma, CD107a/b and perforin, and did not present significant differences when compared with those from healthy donors. CONCLUSIONS: Our results support the hypothesis that there is no CD8+ T cell nonspecific immune-suppression during chronic Chagas disease infection. Nonetheless, other viral antigens must be studied in order to confirm our findings.     

Ferritin above 100 mcg/L could rule out colon cancer, but not gastric or rectal cancer in patients with involuntary weight loss

ABSTRACT: BACKGROUND: A tenth of patients with involuntary weight loss (IWL) have gastrointestinal cancer. Ferritin is the first parameter to be modified during the process leading to iron deficiency anaemia, therefore it should be the most sensitive. The aim of this study was to assess the ability of ferritin to rule out gastrointestinal cancer in patients with involuntary weight loss. METHODS: All consecutive patients with IWL admitted in a secondary care university hospital were prospectively studied. Ferritin, haemoglobin with erythrocyte indices and serum iron were recorded for all patients. The reference standard was bidirectional endoscopy and/or 6 months follow-up. RESULTS: 290 patients were included, a quarter had cancer, of which 22 (7.6%) had gastrointestinal cancer (8 gastric cancer, 1 ileum cancer, 13 colorectal cancer). Ferritin had the best area under the curve (AUC), both for gastrointestinal cancer (0.746, CI: 0.691-0.794), and colorectal cancer (0.765, CI: 0.713-0.813), compared to the other parameters of iron deficiency. In the diagnosis of colorectal cancer, ferritin with a cut-off value of 100 mcg/L had a sensitivity of 93% (CI: 69-100%), and negative likelihood ratio of 0.13, with a negative predictive value of 99% (96-100%), while for gastrointestinal cancer, the sensitivity was lower (89%, CI: 67-95%), with a negative likelihood ratio of 0.24. There were three false negative patients, two with gastric cancer, and one with rectal cancer. CONCLUSION: In patients with involuntary weight loss, a ferritin above 100mcg/L could rule out colon cancer, but not gastric or rectal cancer.