다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

正しい方法がわかる臨床基本手技 : from the New England journal of medicine

Despite advances in combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to experience gastrointestinal dysfunction. Infusions of anti-α4β7 monoclonal antibodies (mAbs) have been proposed to increase virologic control during simian immunodeficiency virus (SIV) infection in macaques with mixed results. Recent evidences suggested that therapeutic efficacy of vedolizumab (a humanized anti-α4β7 mAb), during inflammatory bowel diseases depends on microbiome composition, myeloid cell differentiation, and macrophage phenotype. We tested this hypothesis in SIV-infected, anti-α4β7 mAb-treated macaques and provide flow cytometric and microscopic evidence that anti-α4β7 administered to SIV-infected macaques increases the maturity of macrophage phenotypes typically lost in the small intestines during SIV disease progression. Further, this increase in mature macrophage phenotype was associated with tissue viral loads. These phenotypes were also associated with dysbiosis markers in the gut previously identified as predictors of HIV replication and immune activation in PLWH. These findings provide a novel model of anti-α4β7 efficacy offering new avenues for targeting pathogenic mucosal immune response during HIV/SIV infection.

/pdf/early-treatment-with-anti-a4b7-antibody-facilitates-3vjo8ont.pdf

Early treatment with anti-α4β7 antibody facilitates increased gut macrophage maturity in SIV-infected rhesus macaques

The microbiomes of people living with HIV (PLWH) are significantly dysregulated with a loss of bacteria diversity and shifts in composition, including increases in pathogenic and decreases in beneficial species. Because of the microbiome's role in modulating health, the effect of this dysbiosis on immune response in PLWH has been a significant concern, mainly because these shifts can persist even after viral suppression during combination antiretroviral therapy (cART). However, due to limitations on sample availability, few studies have been able to provide insights into these microbiome-immune interactions. Recently, Olivas-Martínez, et al. characterized ileum and caecum mucosa-associated microbiomes of PLWH based on their level of peripheral CD4+ T-cell reconstitution following long-term cART. Their analysis revealed distinct microbiome signatures predictive of recovery. Additionally, differences in markers of gut inflammation and damage between response groups were described, further implicating mucosal disruptions with immune reconstitution. These new data demonstrate an interdependence of microbiome and therapy response, and additional studies were urgently required to fully elucidate this crosstalk and microbiome dynamics from before/after infection and finally, long-term viral suppression with cART.

HIV-associated dysbiosis and immune recovery during antiretroviral therapy.

With the advent of antiretroviral therapy, improved survival of people with HIV (PWH) is accompanied with increased prevalence of HIV-associated comorbidities. Chronic lung anomalies are recognized as one of the most devastating sequelae in PWH. The limited available data describing the lung complications in PWH with a history of opioid abuse warrants more research to better define the course of disease pathogenesis. The current study was conducted to investigate the progression of lung tissue remodeling in a morphine (Mor)–exposed rhesus macaque model of SIV infection. Pathologic features of lung remodeling, including histopathologic changes, oxidative stress, inflammation, and proliferation of fibroblasts, were investigated in archival lung tissues of SIVmac-251/macaque model with or without Mor dependence. Lungs of Mor-exposed, SIV-infected macaques exhibited significant fibrotic changes and collagen deposition in the alveolar and the bronchiolar region. There was increased oxidative stress, profibrotic transforming growth factor-β, fibroblast proliferation and trans-differentiation, epithelial-mesenchymal transition, and matrix degradation in SIV-infected macaques, which was further exacerbated in the lungs of Mor-exposed macaques. Interestingly, there was decreased inflammation-associated remodeling in Mor-dependent SIV-infected macaques compared with SIV-infected macaques that did not receive Mor. Thus, the current findings suggest that SIV independently induces fibrotic changes in macaque lungs, which is further aggravated by Mor. With the advent of antiretroviral therapy, improved survival of people with HIV (PWH) is accompanied with increased prevalence of HIV-associated comorbidities. Chronic lung anomalies are recognized as one of the most devastating sequelae in PWH. The limited available data describing the lung complications in PWH with a history of opioid abuse warrants more research to better define the course of disease pathogenesis. The current study was conducted to investigate the progression of lung tissue remodeling in a morphine (Mor)–exposed rhesus macaque model of SIV infection. Pathologic features of lung remodeling, including histopathologic changes, oxidative stress, inflammation, and proliferation of fibroblasts, were investigated in archival lung tissues of SIVmac-251/macaque model with or without Mor dependence. Lungs of Mor-exposed, SIV-infected macaques exhibited significant fibrotic changes and collagen deposition in the alveolar and the bronchiolar region. There was increased oxidative stress, profibrotic transforming growth factor-β, fibroblast proliferation and trans-differentiation, epithelial-mesenchymal transition, and matrix degradation in SIV-infected macaques, which was further exacerbated in the lungs of Mor-exposed macaques. Interestingly, there was decreased inflammation-associated remodeling in Mor-dependent SIV-infected macaques compared with SIV-infected macaques that did not receive Mor. Thus, the current findings suggest that SIV independently induces fibrotic changes in macaque lungs, which is further aggravated by Mor. 

Inflammation-Associated Lung Tissue Remodeling and Fibrosis in Morphine-Dependent SIV-Infected Macaques.


 An “ultra” long-acting (LA) integrase strand transfer inhibitor was created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led, to the best of our knowledge, a “first in class” 18-carbon chain modified prodrug nanocrystal (coined as NM2DTG). Ideal physiochemical and pharmacokinetic (PK) properties facilitated slow drug release from tissue macrophage prodrug depot stores for up to one year after a single intramuscular injection. Both the muscle injection site and secondary lymphoid tissues were depots of prodrug hydrolysis; dependent on nanocrystal dissolution and prodrug release rates, drug-depot volume, perfusion, and cell-tissue pH. Each affected an extended NM2DTG apparent half-life by recorded PK parameters. The NM2DTG LA product can impact therapeutic adherence, tolerability, and access to a widely used integrase inhibitor in resource-limited and rich settings to reduce HIV-1 transmission and achieve optimal treatment outcomes.

/pdf/pathways-for-dolutegravir-transformation-from-a-daily-oral-3ihgtrri.pdf

Pathways for Dolutegravir Transformation 
from a Daily Oral to a Once-a-Year Parenteral Medicine

/pdf/combined-effects-of-drugs-of-abuse-and-hiv-infection-5516k1w8li.pdf

Siddappa N. Byrareddy

Papers

Early treatment with anti-α4β7 antibody facilitates increased gut macrophage maturity in SIV-infected rhesus macaques

HIV-associated dysbiosis and immune recovery during antiretroviral therapy.

Inflammation-Associated Lung Tissue Remodeling and Fibrosis in Morphine-Dependent SIV-Infected Macaques.

Pathways for Dolutegravir Transformation from a Daily Oral to a Once-a-Year Parenteral Medicine

Combined Effects of Drugs of Abuse and HIV Infection Comorbidity on Primary Pericytes