Chronic hepatitis C: treatments of the future

The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance has, up to now, only been applicable to genotype-1 patients. Second-wave and second-generation PIs appear to achieve higher antiviral potency, with pan-genotype activities, fewer side-effects and potential activity against PI-resistant mutation by second-generation PIs, through more convenient daily administration. Other direct-acting antivirals (DAAs) include NS5B inhibitors such as nucleoside/nucleotide inhibitors (NIs) and non-nucleoside inhibitors (NNIs). NIs have similar efficacy across all genotypes and present with the highest barrier to resistance of all DAAs to date. PSI-7977, a pyrimidine nucleotide analogue, also has highly potent antiviral activity across all HCV genotypes. In combination with ribavirin in an interferon-free regimen, it can achieve a 100% sustained viral response (SVR) rate in genotype 2/3 treatment-na?ve patients. In association with pegylated interferon and ribavirin (PR), it achieves an SVR of 91% in genotype-1 na?ve patients. NNIs in association with PR appear to be less potent, but they may nonetheless play a key role in many of the combination trials including either PIs or NIs. NS5A inhibitors also exhibit highly potent antiviral activity. Evaluation of their activity in combination with PIs demonstrated for the first time that an interferon-free regimen can cure genotype-1b null-responder patients. Furthermore, quadruple therapy with PR can achieve a 100% SVR in genotype-1 null-responder patients. Other players in the field, such as cyclophilin inhibitors and therapeutic vaccines, may have a role in combination with DAAs. The near future of HCV treatment looks promising. However, whether or not DAA combinations will lead to an interferon-free regimen for all patients remains an open question.     

Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice

The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response.     

Lupulone triggers p38 MAPK-controlled activation of p53 and of the TRAIL receptor apoptotic pathway in human colon cancer-derived metastatic cells

We previously reported that the chemopreventive agent lupulone induces apoptosis through activation of the extrinsic pathway via TRAIL DR4/DR5 death receptors overcoming SW620 cell resistance to TRAIL. However, the underlying molecular mechanisms remain unknown. Since the mitogen-activated protein kinases (MAPKs), Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 control fundamental cellular processes such as apoptosis, we determined the role of these MAPKs in lupulone-triggered apoptosis. We analyzed the effects of JNK, ERK and p38 MAPK inhibitors on lupulone-induced apoptosis by flow cytometry using specific antibodies and real-time RT-PCR. Our data showed that among the MAPKs, only p38 played a major role in lupulone-triggered apoptosis. In contrast to JNK and ERK inhibition, the specific inactivation of p38 inhibited the lupulone-triggered up-regulation of p53 and TRAIL-death receptor DR4/DR5 expression, and prevented DNA fragmentation. Lupulone treatment enhanced the expression of the anti-apoptotic Mcl-1 protein by 60% favoring the preservation of mitochondrial integrity. The inactivation of p38 initiated a 50% reduction in Mcl-1, Bcl-2 and Bax expression without changing the Mcl-1/Bax ratio suggesting that p38 was not involved in the protective effect of lupulone on mitochondria. Our data support the view that the lupulone-triggered enhanced expression of p38 plays a major role in the activation of p53 and of the TRAIL-death receptor apoptotic pathway in SW620 human colon cancer-derived metastatic cells.     

Congenital anomalies of inferior vena cava in young patients with iliac deep venous thrombosis

Venous thromboembolism (VTE) in young patients is frequently associated with hereditary biological thrombophilia, autoimmune disorders, or neoplasia. Advances in venous ultrasound and contrast-enhanced computed tomography have allowed for the identification of inferior vena cava (IVC) anomalies as newly considered etiologic factor. We present two cases of VTE in young patients: the first case involves left IVC in a 22-year-old man and the second involves IVC atresia in a 39-year-old man. IVC anomalies should be identified in young patients with spontaneous VTE involving the iliac veins because they are at a high risk for thrombotic recurrence and adaptation to long periods of antithrombotic therapy.     

Respiratory cryptosporidiosis in two patients with HIV infection in a tertiary care hospital in Morocco

Respiratory cryptosporidiosis is recognized as a late-stage complication in persons with AIDS. We report two cases of respiratory cryptosporidiosis in patients with HIV infection. The first patient was a 46-year-old person with chronic diarrhea, a two-month history of low-grade fever, progressive dyspnea and productive cough. The search for acid-fast bacillus, Pneumocystis jirovecii, Toxoplasma gondii and Cryptococcus sp. in sputum was negative on several samples. The modified Ziehl has shown oocysts of Cryptosporidium sp. in induced sputum. The patient's death occurred, due to electrolytes disorders. The second patient was a 45-year-old person hospitalized for chronic fluid diarrhea, complicated with weight loss, dry cough, dyspnea stage II and low-grade fever. The patient was HIV-positive with low CD4 count and pancytopenia. Acid-fast oocysts of Cryptosporidium sp. were observed in stool samples and induced sputum. The patient was treated daily with azithromycin 500 mg resulting of disappearance of gastrointestinal and respiratory disorders.     

Collapse-Related Bone Changes in Osteonecrotic Femoral Heads at Multidetector CT: Comparison between Femoral Heads with Limited and Advanced Collapse

Aim:To assess the frequency of bone changes in resected osteonecrotic femoral head (ONFH) specimens at multidetector computed tomography (MDCT) and compare their frequencies between ONFH with limited or advanced collapse.Method:Fourteen ONFH were imaged using MDCT (n = 14) and microcomputed tomography ([µCT]; n = 8). Preoperative staging was performed using radiographs and MRI. Coronal reformats of MDCT images of the specimens were analyzed using the grid overlay method. There were 2,933 grid boxes containing cortical bone and 10,596 containing trabecular bone. Two MSK radiologists assessed in every grid box the presence of interface-related sclerosis, cortical bone interruption, trabecular bone interruption, and trabecular bone resorption. The frequency of grid boxes with bone changes at MDCT was calculated and compared between ONFH with limited (<1.5 mm) or advanced (≥1.5 mm) collapse.Results:For both readers R1 and R2, there were 1111/10596 (10.5%) and 1362/10596 (12.9%) grid boxes with interface-related bone sclerosis, 557/2933 (19%) and 413/2933 (14.1%) with cortical bone interruption, 796/10596 (7.5%) and 665/10596 (6.3%) with trabecular bone interruption, and 331/10596 (3.1%) and 595/10596 (5.6%) with trabecular bone resorption. The frequency of grid boxes with cortical interruption and trabecular bone resorption was significantly higher in ONFH with advanced than in ONFH with limited collapse. There was no significant difference in frequency of grid boxes with trabecular interruption and interface-related bone sclerosis between ONFH with advanced or limited collapse.Conclusion:Cortical interruption and trabecular resorption, but not trabecular interruption, were more frequent in osteonecrotic femoral heads with advanced than with limited collapse.     

Framework for refugee and migrant health research in the WHO European Region

Migration is a longstanding, growing global phenomenon. As a social determinant of health, migration can lead to health inequities between people on the move and host populations. Thus, it is imperative that there is a coordinated effort to advance migration- and health-related goals. WHO has a specific remit to support evidence-based decision-making in its Member States. As part of that remit, WHO Europe presents this Framework for Refugee and Migrant Health Research in the WHO European Region. It is designed as a starting point for debating and analysing a broad range of options and approaches to help inform a WHO global research agenda on health and migration. This is important because refugee and migrant health research is a complex interdisciplinary field that is expanding in a fast-changing socio-political environment. The Framework is intended for all stakeholders involved: academic, civil society organisations, refugees, migrants, policy-makers, healthcare providers, educators and funders. It is developed by academics in consultation with these stakeholder groups. It reflects on three specific interrelated dynamics in research practice. These are (i) research prioritisation; (ii) study samples and (iii) research design. The Framework offers recommendations to consider for each one of these. It elucidates the value of involving refugees and migrants in research and research agendas and the need to develop an ecosystem that will support and sustain participatory, interdisciplinary, transdisciplinary and inter-sectoral projects.