Major scholars in the field, on the basis of a 3-day consensus, created an in-depth review of current knowledge on the role of diet in cardiovascular disease (CVD), the changing global food system ...and global dietary patterns, and potential policy solutions. Evidence from different countries and age/race/ethnicity/socioeconomic groups suggesting the health effects studies of foods, macronutrients, and dietary patterns on CVD appear to be far more consistent though regional knowledge gaps is highlighted. Large gaps in knowledge about the association of macronutrients to CVD in low- and middle-income countries particularly linked with dietary patterns are reviewed. Our understanding of foods and macronutrients in relationship to CVD is broadly clear; however, major gaps exist both in dietary pattern research and ways to change diets and food systems. On the basis of the current evidence, the traditional Mediterranean-type diet, including plant foods and emphasis on plant protein sources provides a well-tested healthy dietary pattern to reduce CVD.
H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that ...knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.
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•A CRISPR screen for HDAC inhibitor sensitizers in DIPG identifies KDM1A (LSD1)•Corin, a dual inhibitor of LSD1 and HDACs, inhibits DIPG growth in vitro and in vivo•Corin alters histone modifications to promote differentiation and block cell cycle•A Corin-induced gene expression signature correlates with prolonged survival in DIPG
Anastas et al. show that inhibition of LSD1 sensitizes diffuse intrinsic pontine glioma (DIPG) cells to HDAC inhibition and that Corin, which inhibits both LSD1 and HDACs, potently suppresses DIPG cell growth. A Corin-induced gene expression profile correlates with improved survival of DIPG patients.
Background & Aims Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the ...effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. Methods HCV-negative subjects with normal hepatic function (n = 7) or mild (Child-Pugh A, n = 6), moderate (Child-Pugh B, n = 6), or severe (Child-Pugh C, n = 5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments. Results Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, Cmax , and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. Conclusions The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.
Decreased bone mineral density (BMD) has been described in HIV-infected patients initiating antiretroviral therapy (ART), but the contributions of ART and immunologic and/or virologic factors remain ...unclear.
We compared total BMD changes over 96 weeks in 106 ART-naive HIV-infected subjects who were randomized to receive efavirenz (EFV) + zidovudine/lamivudine (n = 32) or lopinavir/ritonavir (LPV/r) + zidovudine/lamivudine induction (n = 74) for 24-48 weeks followed by LPV/r monotherapy. We also sought to identify factors associated with BMD loss, including markers of systemic inflammation soluble tumor necrosis factor-alpha receptors (sTNFR I and II).
After 96 weeks, the mean percent change from baseline in total BMD was -2.5% (LPV/r) and -2.3% (EFV) (P < 0.01 for within-group changes in either arm; P = 0.86 for between-group differences). No alteration in the rate of BMD change was observed upon simplification to LPV/r monotherapy. Although soluble tumor necrosis factor-alpha receptor II concentrations at baseline and 24 weeks were at least marginally associated with subsequent changes in BMD (P = 0.06 and P = 0.028, respectively), these associations were no longer significant after adjustment for CD4 T cell count. Subjects with lower baseline CD4 T cell count, non-black race, and higher baseline glucose demonstrated a higher risk for >5% decrease in BMD.
Similar decreases in BMD over 96 weeks occurred in ART-naive subjects receiving either EFV-based regimen or LPV/r-based regimen, which was not altered by simplification to LPV/r monotherapy and was unrelated to markers of tumor necrosis factor-alpha activity.
Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n = 104) or efavirenz (n = 51). Lopinavir/ritonavir-treated subjects demonstrating 3 ...consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P = .17; 95% confidence interval CI for the difference, −29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P = .73; 95% CI for the difference, −19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy. Trial registration. ClinicalTrials.gov identifier: NCT00075231.
Background. Limited data exist on the risk of Chlamydia trachomatis and Neisseria gonorrhoeae transmission from oropharynx to urethra. We examined urethral C. trachomatis and N. gonorrhoeae ...positivity among men who have sex with men (MSM) seen at San Francisco City Clinic (San Francisco, CA) during 2007. Methods. All patients who sought care at the San Francisco City Clinic (the only municipal sexually transmitted disease clinic in San Francisco) received a standardized interview conducted by clinicians. We estimated urethral C. trachomatis and N. gonorrhoeae positivity for 2 groups of visits by MSM who visited during 2007: (1) men who reported their only urethral exposure was receiving fellatio in the previous 3 months and (2) men who reported unprotected insertive anal sex in the previous 3 months. Additionally, urethral C. trachomatis and N. gonorrhoeae positivity was estimated, stratified by human immunodeficiency virus infection status, urogenital symptom history, and whether the patient had been a contact to a sex partner with either chlamydia or gonorrhea. Results. Among MSM who reported only receiving fellatio, urethral C. trachomatis and N. gonorrhoeae positivity were 4.8% and 4.1%, respectively. These positivity estimates were similar to positivity found among MSM who reported unprotected insertive anal sex. Conclusions. A more complete understanding of the risks of transmission of C. trachomatis and N. gonorrhoeae from oropharynx to urethra will help inform prevention and screening programs.
In a sexually transmitted disease clinic-based sample of men who have sex with women, positivity for urethral Chlamydia trachomatis and Neisseria gonorrhoeae was 3.5% and 3.1%, respectively, among ...patients whose only urethral exposure in the previous 3 months was receiving fellatio from a woman. Urethral infections acquired by fellatio might contribute to ongoing disease spread.
Abstract Major scholars in the field, on the basis of a 3-day consensus, created an in-depth review of current knowledge on the role of diet in cardiovascular disease (CVD), the changing global food ...system and global dietary patterns, and potential policy solutions. Evidence from different countries and age/race/ethnicity/socioeconomic groups suggesting the health effects studies of foods, macronutrients, and dietary patterns on CVD appear to be far more consistent though regional knowledge gaps are highlighted. Large gaps in knowledge about the association of macronutrients to CVD in low- and middle-income countries particularly linked with dietary patterns are reviewed. Our understanding of foods and macronutrients in relationship to CVD is broadly clear; however, major gaps exist both in dietary pattern research and ways to change diets and food systems. On the basis of the current evidence, the traditional Mediterranean-type diet, including plant foods and emphasis on plant protein sources provides a well-tested healthy dietary pattern to reduce CVD.
We analyzed 265 urethral Neisseria gonorrhoeae specimens collected from symptomatic males at San Francisco's municipal sexually transmitted disease clinic, a participant in the Gonococcal Isolate ...Surveillance Project, during 2009. We used N. gonorrhoeae multiantigen sequence typing to describe characteristics of patients infected with common sequence type families. Specimens were classified into 6 homology-based families and 1 additional family of all other identified strains. Strain family results were combined with results of culture-based antibiotic sensitivity minimum inhibitory concentration, sociodemographic and behavioral risk data collected at the clinic, and presence or absence of the mosaic penicillin-binding protein 2 (penA) allele. Characteristics of patients were compared across strain families through the use of χ(2) statistics. Among men who have sex with men, strain distribution differed by those reporting receptive oral sex as their only urethral exposure (P = 0.04), by number of sex partners (P = 0.03), and by race/ethnicity (P < 0.001); there were no differences by age or human immunodeficiency virus status. Also, among men who have sex with men, strain family distributions differed for culture specimens with reduced susceptibility to a range of antibiotics, as well as with presence of the mosaic penA allele (all P < 0.001). The combination of molecular, phenotypic, and epidemiologic data on N. gonorrhoeae infection could help develop a more complete epidemiology of gonorrhea in the United States.
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