Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Depression in type 1 diabetes and risk of dementia

Objective: Depression afflicts 14% of individuals with type 1 diabetes (T1D). Depression is a robust risk factor for dementia but it is unknown if this holds true for individuals with T1D, who recently started living to an age conferring dementia risk. We examined if depression is a dementia risk factor among elderly individuals with T1D.

Methods: 3,742 individuals with T1D age ≥50 were followed for dementia from 1/1/96-9/30/2015. Depression, dementia, and comorbidities were abstracted from electronic medical records. Cox proportional hazard models estimated the association between depression and dementia adjusting for demographics, glycosylated hemoglobin, severe dysglycemic epidsodes, stroke, heart disease, nephropathy, and end stage renal disease. The cumulative incidence of dementia by depression was estimated conditional on survival dementia-free to age 55.

Results: Five percent (N = 182) were diagnosed with dementia and 20% had baseline depression. Depression was associated with a 72% increase in dementia (fully adjusted HR = 1.72; 95% CI:1.12-2.65). The 25-year cumulative incidence of dementia was more than double for those with versus without depression (27% vs. 12%).

Conclusions: For people with T1D, depression significantly increases dementia risk. Given the pervasiveness of depression in T1D, this has major implications for successful aging in this population recently living to old age.     

Effectiveness of various methods of formaldehyde neutralization using monoethanolamine

Formaldehyde is the most commonly used fixative chemical for the preservation of human cadavers used for educational purposes in the United States. Formaldehyde is also a known carcinogenic agent whose exposure level is regulated by guidelines of the Occupational Safety and Health Administration. Various methods for formaldehyde neutralization exist, yet many donations programs do not take any steps to neutralize the formaldehyde in embalmed donor bodies. The effectiveness of monoethanolamine (MEA) in neutralizing formaldehyde is well documented when used as a final injection during embalming. The purpose of this study is to report the effectiveness of several post‐embalming techniques of formaldehyde neutralization. Twenty‐four donor bodies were assigned to four experimental groups of six. For the three experimental groups, the techniques tested involve delivery of a 20:1 dilution of deionized water:MEA via recannulization and gravity flow infusion, compartment injection, and alternate wetting solution containing four percent MEA. Our results indicated that spray bottle delivery was not effective in neutralization of formaldehyde compared to the control group, but that formaldehyde levels decreased when recannulization or compartment injection were used. The most effective method of formaldehyde neutralization was compartment injection of MEA solution (P < 0.01). The results of this study indicate that, in situations where MEA is not used as a final infusion during embalming, compartment injection of MEA solution is an effective method of formaldehyde neutralization. Clin. Anat. 28:449–454, 2015. © 2015 Wiley Periodicals, Inc.     

Pediatric Inpatient Headache Therapy: What is Available

Status migrainosus is defined by the international classification of headache disorders (ICHD) criteria as a debilitating migraine lasting more then 72 hours. The epidemiology of status migrainosus is still unknown in adult and children, and frequently underdiagnosed. Children and adolescents often end up in the emergency room with an intractable headache that failed outpatient therapy. Six to seven percent of these children do not respond to acute infusion therapy and require hospitalization. It is imperative that more aggressive therapy is considered when patients are affected by a severe intractable headache to prevent further disability and returning the child to baseline activity. Multiple therapies are available for adults and children. Studies for acute therapy in the emergency room are available in adults and pediatric groups. Small studies are available for inpatient therapy in children and, along with available therapies for children and adolescents, are described in this review. A review of the literature shows growing evidence regarding the use of dihydroergotamine intravenously once patients are hospitalized. Effectiveness and safety have been proven in the last decades in adults and small studies in the pediatric populations.     

Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma development and growth in vivo

Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for Braf^V600E‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (Tyr^CreERT2/+; Braf^{LSL‐V600E/+}; Pten^flox/flox) to Sirt5^?/? knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5^?/? mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for Braf^V600E‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor.