Blocking Zika virus vertical transmission.

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity

Author Correction: Blocking Zika virus vertical transmission.

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A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKRP1(NK1.1) receptors. This murine cytomegalovirus(MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a ‘‘polar claw’’ mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay

Dectin-2 recognises mannosylated O-antigens of human opportunistic pathogens and augments lipopolysaccharide activation of myeloid cells

Lipopolysaccharide (LPS) consists of a relatively conserved region of lipid A and core-oligosaccharide, and a highly variable region of O-antigen polysaccharide. While lipid A is known to bind to the toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex, the role of the O-antigen remains unclear. Here we report a novel molecular interaction between dendritic cell-associated C-type lectin-2 (Dectin-2) and the mannosylated O-antigen found in a human opportunistic pathogen Hafnia alvei PCM 1223, which has a repeating unit of [-Man-α1,3-Man-α1,2-Man-α1,2-Man-α1,2-Man-α1,3-]. H. alvei LPS induced higher levels of TNFα and IL-10 from mouse bone marrow-derived dendritic cells (BM-DCs), when compared to Salmonella enterica O66 LPS which has a repeat of [-Gal-α1,6-Gal-α1,4-[Glc-β1,3]GalNAc-α1,3-GalNAc-β1,3-]. In a cell-based reporter assay, Dectin-2 was shown to recognise H. alvei LPS. This binding was inhibited by mannosidase treatment of H. alvei LPS and by mutations in the carbohydrate-binding domain of Dectin-2, demonstrating that H. alvei LPS is a novel glycan ligand of Dectin-2. The enhanced cytokine production by H. alvei LPS was Dectin-2 dependent, as Dectin-2 knockout BM-DCs failed to do so. This receptor crosstalk between Dectin-2 and TLR4 involved events including spleen tyrosine kinase (Syk) activation and receptor juxtaposition. Furthermore, another mannosylated LPS from Escherichia coli O9a, also bound to Dectin-2 and augmented TLR4 activation of BM-DCs. Taken together, these data indicate that mannosylated O-antigens from several gram-negative bacteria augment TLR4 responses through interaction with Dectin-2

A review of the surgical options for the correction of presbyopia

Presbyopia is an age-related eye condition where one of the signs is the reduction in the amplitude of accommodation, resulting in the loss of ability to change the eye's focus from far to near. It is the most common age-related ailments affecting everyone around their mid-40s. Methods for the correction of presbyopia include contact lens and spectacle options but the surgical correction of presbyopia still remains a significant challenge for refractive surgeons. Surgical strategies for dealing with presbyopia may be extraocular (corneal or scleral) or intraocular (removal and replacement of the crystalline lens or some type of treatment on the crystalline lens itself). There are however a number of limitations and considerations that have limited the widespread acceptance of surgical correction of presbyopia. Each surgical strategy presents its own unique set of advantages and disadvantages. For example, lens removal and replacement with an intraocular lens may not be preferable in a young patient with presbyopia without a refractive error. Similarly treatment on the crystalline lens may not be a suitable choice for a patient with early signs of cataract. This article is a review of the options available and those that are in development stages and are likely to be available in the near future for the surgical correction of presbyopia

Effect of Alprazolam as a Preoperative Adjuvant Analgesic on Postoperative Pain in Laparoscopic Donor Nephrectomy Patients

12th Congress of the Turkish-Transplantation-Centers-Coordination-Association (TTCCA) -- OCT 18-21, 2018 -- Trabzon, TURKEYDogru, Volkan/0000-0002-6468-622XWOS: 000500179300008PubMed: 31101168Objective. The aim of this study was to evaluate the effectiveness of alprazolam, administered at different doses, for the control of adjuvant analgesia in laparoscopic donor nephrectomy patients preoperatively in the Akdeniz University Organ Transplantation Center, using various pain scales. Materials and Methods. Only patients with a body mass index <= 28 kg/m(2), aged between 18 and 65 years old, and with an American Society of Anesthesiologists score of 1 to 2 were included in the study. The patients were studied in 3 groups, which were given 0.5 mg alprazolam (group 1), 1 mg alprazolam (group 2), or no alprazolam (group 3) in the preoperative period. Collected data were evaluated for preoperative, intraoperative, and postoperative periods. Results. There were 75 patients (31 men, 44 women). Mean age was 43.1 years. Twenty-five patients were evaluated in all 3 groups. Mean operation time was 137.8 minutes. There was no statistical difference among the groups in the duration of administered alprazolam before the operation, on the Ramsey sedation score, verbal pain score, or numeric pain score, and duration of administered first analgesic in the postoperative period. Additional dose of analgesics were administered in 7, 7, and 11 of the patients in group 1, group 2, and group 3, respectively. We found a significant difference between groups 1 and 2 in blood pressure (P = .017 and P = .014). We found a significant difference in group 1 in heart rate (P = .002). Conclusion. More effective analgesia protocols need to be identified for pain control in patients of laparoscopic donor nephrectomy. It is thought that the effectiveness of pain control may increase the number of donors and progress in the treatment of patients with renal failure.Turkish Transplantat Ctr Coordinat Asso

Mutation Spectrum of Fumarylacetoacetase Gene and Clinical Aspects of Tyrosinemia Type I Disease

Dursun, Ali/0000-0003-1104-9902; Ozgul, Riza Koksal/0000-0002-0283-635XWOS: 000294929800003PubMed: 23430822Tyrosinemia type I (OMIM 276700) is a rare, autosomal recessive disorder caused by a deficiency in the fumarylacetoacetate hydrolase (FAH) enzyme. This study examined the spectrum of FAH gene mutation in 32 patients with tyrosinemia type I. In addition, clinical and biochemical findings were evaluated to establish a genotype phenotype relationship in the patients. Mutation screening was performed using a 50K custom-designed resequencing microarray chip (TR_06_01r520489, Affymetrix) and sequencing analysis. Of the 12 different mutations found, 6 are categorized as novel. Three of the mutations-IVS6-1G>A, D233V, and IVS3-3C>G-are the most common in Turkish patients, comprising 25%, 17.1%, and 12.5% of mutant alleles, respectively. Clinical evaluations suggest that the spectrum of symptoms observed in the patients with very early and early disease were of the more nonspecific form, whereas the patients with late-presenting disease had more of the distinctive form over the course of the disease. This study adds support to the notion that the D233V mutation is specific to the Turkish population