Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB: HIV study

Objectives: Mortality among HIV patients with tuberculosis (TB) remains high in Eastern Europe (EE), but details of TB and HIV management remain scarce. Methods: In this prospective study, we describe the TB treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART). Results: A total of 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95%CI 41.5-74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. Conclusions: Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care

Lack of PPARγ in Myeloid Cells Confers Resistance to Listeria monocytogenes Infection

The peroxisomal proliferator-activated receptor γ (PPARγ) is a nuclear receptor that controls inflammation and immunity. Innate immune defense against bacterial infection appears to be compromised by PPARγ. The relevance of PPARγ in myeloid cells, that organize anti-bacterial immunity, for the outcome of immune responses against intracellular bacteria such as Listeria monocytogenes in vivo is unknown. We found that Listeria monocytogenes infection of macrophages rapidly led to increased expression of PPARγ. This prompted us to investigate whether PPARγ in myeloid cells influences innate immunity against Listeria monocytogenes infection by using transgenic mice with myeloid-cell specific ablation of PPARγ (LysMCre×PPARγflox/flox). Loss of PPARγ in myeloid cells results in enhanced innate immune defense against Listeria monocytogenes infection both, in vitro and in vivo. This increased resistance against infection was characterized by augmented levels of bactericidal factors and inflammatory cytokines: ROS, NO, IFNγ TNF IL-6 and IL-12. Moreover, myeloid cell-specific loss of PPARγ enhanced chemokine and adhesion molecule expression leading to improved recruitment of inflammatory Ly6Chi monocytes to sites of infection. Importantly, increased resistance against Listeria infection in the absence of PPARγ was not accompanied by enhanced immunopathology. Our results elucidate a yet unknown regulatory network in myeloid cells that is governed by PPARγ and restrains both listeriocidal activity and recruitment of inflammatory monocytes during Listeria infection, which may contribute to bacterial immune escape. Pharmacological interference with PPARγ activity in myeloid cells might represent a novel strategy to overcome intracellular bacterial infection

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)

Differential proteome and phosphoproteome signatures in human T-lymphoblast cells induced by sirolimus

Ziele: Die vorliegende Studie wurde unternommen, um die frühen Veränderungen des Proteoms und Phosphoproteoms während einer durch Sirolimus (SRL) induzierten Inhibition der Lymphozytenproliferation zu untersuchen. Materialien und Methoden: Die Proliferationstests wurden mit humanen CCRF-CEM T-Lymphoblasten unter verschiedenen SRL-Konzentrationen durchgeführt. Das Gesamtprotein der Zelllysate nach einer SRL-Behandlung wurde verwendet, um signifikant veränderte Proteine und phosphorylierte Proteine in 2DE-Gelen unterscheiden und mittels einem Q-TOF Ultima Global Massenspektrometer identifizieren zu können. Ergebnisse und Diskussion: Die Inkubation mit 2,5 µmol/l SRL führte zu einer annähernd 70%igen Inhibition der Zellproliferation. Die für 30 Minuten mit 2,5 µmol/l SRL inkubierten Zellen zeigten ein differentielles Phosphorylierungsmuster mit einem vermehrt (TCPQ) und sechs vermindert phosphorylierten Proteinen (TBA1B, VIME, HNRPD, ENPL, SEPT9, PLSL). Die Untersuch! ung der differentiellen Proteinexpression zeigte fünf vermehrt (ECHB, PSB3, MTDC, LDHB, NDKA) und vier vermindert (EHD1, AATC, LMNB1, MDHC) exprimierte Proteine. Neun dieser unterschiedlich regulierten Proteine/Phosphoproteine (TCPQ, TBA1B, VIME, HNRPD, ENPL, ECHB, PSB3, LDHB, LMNB1) stellten sich über das Bindeprotein YWHAZ als potentielle Interaktionspartner bei der Auswertung mittels der Software MINT dar. Schlussfolgerungen: In dieser Arbeit wird erstmals der simultane Einfluss von SRL auf den Phosphorylierungsstatus und die Proteinexpression im Gesamtproteom von CCRF-CEM-Zellen beschrieben. Von den sechzehn identifizierten signifikant veränderten Proteinen konnte zwischen neun dieser Proteine und dem mTOR-Komplex eine Beziehung über das Bindungsprotein YWHAZ aus der Gruppe der 14-3-3-Proteine gezeigt werden

Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.

Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and insulin resistance-accompanied liver damage

Assessment of intrahepatic TG (A) and cholesterol (B) contents.

<p><i>^a</i>, <i>^aa</i>, <i>^aaa</i>indicates significant difference of the corresponding group <i>vs</i>. the Co (<i>P</i><0.05, <i>P</i><0.01, <i>P</i><0.001; respectively), <i>^bP</i><0.05, <i>^bbP</i><0.01 <i>vs</i>. the LDC group, while <i>^dd</i>denotes <i>P</i><0.01 <i>vs</i>. the L-Fr group. The animals (n = 6) were fed for 28 d.</p