Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication.

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.

Emerging Treatment Strategies for Impetigo in Endemic and Nonendemic Settings: A Systematic Review.

PURPOSE: Impetigo affects approximately 162 million children worldwide at any given time. Lack of consensus on the most effective treatment strategy for impetigo and increasing antibiotic resistance continue to drive research into newer and alternative treatment options. We conducted a systematic review to assess the effectiveness of new treatments for impetigo in endemic and nonendemic settings. METHODS: We searched PubMed, MEDLINE, CINAHL, Web of Science, and Embase via Scopus for studies that explored treatments for bullous, nonbullous, primary, and secondary impetigo published between August 1, 2011, and February 29, 2020. We also searched online trial registries and hand-searched the reference lists of the included studies. We used the revised Cochrane risk of bias (version 2.0) tool for randomized trials and the National Heart, Lung, and Blood Institute for nonrandomized uncontrolled studies to assess the risk of bias. FINDINGS: We included 10 studies that involved 6651 participants and reported on 9 treatments in the final analysis. Most clinical trials targeted nonbullous impetigo or did not specify this. The risk of bias varied among the studies. In nonendemic settings, ozenoxacin 1% cream appeared to have the strongest evidence base compared with retapamulin and a new minocycline formulation. In endemic settings, oral co-trimoxazole and benzathine benzylpenicillin G injection were equally effective in the treatment of severe impetigo. Mass drug administration intervention emerged as a promising public health strategy to reduce the prevalence of impetigo in endemic settings. IMPLICATIONS: This review highlights the limited research into new drugs used for the treatment of impetigo in endemic and nonendemic settings. Limited recent evidence supports the use of topical ozenoxacin or retapamulin for impetigo treatment in nonendemic settings, whereas systemic antibiotics and the mass drug administration strategy have evidence for use in endemic settings. Given the troubling increase in resistance to existing treatments, there is a clear need to ensure the judicious use of antibiotics and to develop new treatments and alternative strategies; this is particularly important in endemic settings. PROSPERO identifier: CRD42020173042.

Comparative efficacy and safety of interventions for treating head lice: a protocol for systematic review and network meta-analysis.

Background: Head lice infestation is a major public health problem around the globe. Its treatment is challenging due to product failures resulting from rapidly emerging resistance to existing treatments, incorrect treatment applications and misdiagnosis. Various head lice treatments with different mechanism of action have been developed and explored over the years, with limited report on systematic assessments of their efficacy and safety. This work aims to present a robust evidence summarising the interventions used in head lice. Method: This is a systematic review and network meta-analysis which will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for network meta-analyses. Selected databases, including PubMed, Embase, MEDLINE, Web of Science, CINAHL and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials exploring head lice treatments. Searches will be limited to trials published in English from database inception till 2021. Grey literature will be identified through Open Grey, AHRQ, Grey Literature Report, Grey Matters, ClinicalTrials.gov, WHO International Clinical Trials Registry and International Standard Randomised Controlled Trials Number registry. Additional studies will be sought from reference lists of included studies. Study screening, selection, data extraction and assessment of methodological quality will be undertaken by two independent reviewers, with disagreements resolved via a third reviewer. The primary outcome measure is the relative risk of cure at 7 and 14 days postinitial treatment. Secondary outcome measures may include adverse drug events, ovicidal activity, treatment compliance and acceptability, and reinfestation. Information from direct and indirect evidence will be used to generate the effect sizes (relative risk) to compare the efficacy and safety of individual head lice treatments against a common comparator (placebo and/or permethrin). Risk of bias assessment will be undertaken by two independent reviewers using the Cochrane Risk of Bias tool and the certainty of evidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations guideline for network meta-analysis. All quantitative analyses will be conducted using STATA V.16. Discussion: The evidence generated from this systematic review and meta-analysis is intended for use in evidence-driven treatment of head lice infestations and will be instrumental in informing health professionals, public health practitioners and policy-makers. PROSPERO registration number: CRD42017073375.

Rhinovirus and Cell Death.

Rhinoviruses (RVs) are the etiological agents of upper respiratory tract infections, particularly the common cold. Infections in the lower respiratory tract is shown to cause severe disease and exacerbations in asthma and COPD patients. Viruses being obligate parasites, hijack host cell pathways such as programmed cell death to suppress host antiviral responses and prolong viral replication and propagation. RVs are non-enveloped positive sense RNA viruses with a lifecycle fully contained within the cytoplasm. Despite decades of study, the details of how RVs exit the infected cell are still unclear. There are some diverse studies that suggest a possible role for programmed cell death. In this review, we aimed to consolidate current literature on the impact of RVs on cell death to inform future research on the topic. We searched peer reviewed English language literature in the past 21 years for studies on the interaction with and modulation of cell death pathways by RVs, placing it in the context of the broader knowledge of these interconnected pathways from other systems. Our review strongly suggests a role for necroptosis and/or autophagy in RV release, with the caveat that all the literature is based on RV-A and RV-B strains, with no studies to date examining the interaction of RV-C strains with cell death pathways.

Manuka Oil-A Review of Antimicrobial and Other Medicinal Properties.

Manuka oil is an essential oil derived from Leptospermum scoparium, a plant that has been used by the indigenous populations of New Zealand and Australia for centuries. Both the extracted oil and its individual components have been associated with various medicinal properties. Given the rise in resistance to conventional antibiotics, natural products have been targeted for the development of antimicrobials with novel mechanism of action. This review aimed to collate available evidence on the antimicrobial, anti-parasitic and anti-inflammatory activities of manuka oil and its components. A comprehensive literature search of was conducted using PubMed and Embase (via Scopus) targeting articles from database inception until June 2020. Chemical structures and IUPAC names were sourced from PubChem. Unpublished information from grey literature databases, Google search, targeted websites and Google Patents were also included. The present review found extensive in vitro data supporting the antimicrobial effects of manuka oil warrants further clinical studies to establish its therapeutic potential. Clinical evidence on its efficacy, safety and dosing guidelines are necessary for its implementation for medical purposes. Further work on regulation, standardization and characterization of the medicinal properties of manuka oil is required for establishing consistent efficacy of the product.

Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro.

Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants and young children, causing considerable respiratory disease and repeat infections that may lead to chronic respiratory conditions such as asthma, wheezing, and bronchitis. RSV causes ∼34 million new episodes of lower respiratory tract illness (LRTI) in children younger than 5 years of age, with >3 million hospitalizations due to severe RSV-associated LRTI. The standard of care is limited to symptomatic relief as there are no approved vaccines and few effective antiviral drugs; thus, a safe and efficacious RSV therapeutic is needed. Therapeutic targeting of host proteins hijacked by RSV to facilitate replication is a promising antiviral strategy as targeting the host reduces the likelihood of developing drug resistance. The nuclear export of the RSV M protein, mediated by the nuclear export protein exportin 1 (XPO1), is crucial for RSV assembly and budding. Inhibition of RSV M protein export by leptomycin B correlated with reduced RSV replication in vitro In this study, we evaluated the anti-RSV efficacy of Verdinexor (KPT-335), a small molecule designed to reversibly inhibit XPO1-mediated nuclear export. KPT-335 inhibited XPO1-mediated transport and reduced RSV replication in vitro KPT-335 was effective against RSV A and B strains and reduced viral replication following prophylactic or therapeutic administration. Inhibition of RSV replication by KPT-335 was due to a combined effect of reduced XPO1 expression, disruption of the nuclear export of RSV M protein, and inactivation of the NF-κB signaling pathway.IMPORTANCE RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy of KPT-335 as an anti-RSV drug and show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and reduction in RSV levels. KPT-335 treatment also resulted in inhibition of proinflammatory pathways, which has important implications for its effectiveness in vivo.

CRM1 Inhibitors for Antiviral Therapy.

Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review.

Prevalence of depression in consecutive patients with type 2 diabetes mellitus of 5-year duration and its impact on glycemic control.

CONTEXT: Type 2 diabetes mellitus doubles the odds of suffering from depressive illness. Co-morbid depression is associated with poorer outcomes in diabetes mellitus in terms of glycemic control, medication adherence, quality of life, physical activity, and blood pressure control. AIM: The present study aims to estimate the prevalence of depression among a consecutive group of patients with type 2 diabetes and assess its impact on glycemic and blood pressure control. SETTING: Outpatient department of the endocrinology department of a university affiliated teaching hospital in north India. SUBJECTS: Consecutive adult patients (18-65 years) with type 2 diabetes mellitus of over 5-year duration with no prior history of psychiatric illnesses or intake of anti-depressants. MATERIALS AND METHODS: A semi-structured questionnaire was used for demographic data, HbA1c was obtained to assess glycemic control, and blood pressure was recorded twice during patient interview to assess blood pressure control. Depression was assessed with the Major Depression Inventory and scores obtained were classified as consistent with mild, moderate and severe depression. Data was analyzed with SPSS v16, and multiple logistical regression test was done to compare the effect of depression on glycemic control after adjusting for age and sex. RESULTS: Of the 80 patients interviewed, 31 (38.8%) had depressive symptoms. Among them 20 (25%) had mild depression, 10 (12.5%) had moderate depression, and 1 (1.3%) had severe depression. CONCLUSIONS: Over one third of patients with type 2 diabetes mellitus of over 5-year duration had depressive symptoms. The presence of depressive symptoms was associated with a significant worsening of glycemic control.