The brain exchanges nutrients and small molecules with blood via the blood–brain barrier (BBB). Approximately 20% energy intake for the body is consumed by the brain. Glucose is known for its ...critical roles for energy production and provides substrates for biogenesis in neurons. The brain takes up glucose via glucose transporters GLUT1 and 3, which are expressed in several neural cell types. The brain is also equipped with various transport systems for acquiring amino acids, lactate, ketone bodies, lipids, and cofactors for neuronal functions. Unraveling the mechanisms by which the brain takes up and metabolizes these nutrients will be key in understanding the nutritional requirements in the brain. This could also offer opportunities for therapeutic interventions in several neurological disorders. For instance, emerging evidence suggests a critical role of lactate as an alternative energy source for neurons. Neuronal cells express monocarboxylic transporters to acquire lactate. As such, treatment of GLUT1-deficient patients with ketogenic diets to provide the brain with alternative sources of energy has been shown to improve the health of the patients. Many transporters are present in the brain, but only a small number has been characterized. In this review, we will discuss about the roles of solute carrier (SLC) transporters at the blood brain barrier (BBB) and neural cells, in transport of nutrients and metabolites in the brain.
Tuberculous meningitis remains highly lethal. In this trial, an intensified regimen of levofloxacin and higher-dose rifampin added to standard therapy was compared with standard antituberculosis ...therapy alone. The intensified regimen did not result in a higher survival rate.
Early treatment with antituberculosis chemotherapy and adjunctive treatment with glucocorticoids reduce the rate of death and disability from tuberculous meningitis, but the disease still kills or disables almost half the patients with the condition.
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The current guidelines recommend treatment with four antituberculosis drugs for at least the first 2 months of therapy, followed by treatment with two drugs (rifampin and isoniazid) for an additional 7 to 10 months.
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However, these recommendations are based on data from pulmonary tuberculosis and do not take into account the differential ability of antituberculosis drugs to penetrate the brain.
Rifampin is considered to . . .
This study investigated methyl orange (MO) dye adsorption using three biochars produced from agro-waste and invasive plants; the latter consisted of wattle bark (BA), mimosa (BM), and coffee husks ...(BC). BC had the lowest specific surface area (2.62 m2/g) compared to BA (393.15 m2/g) and BM (285.53 m2/g). The adsorption efficiency of MO was stable at pH 2–7 (95%–96%), whilst it had reduced stability at pH 7–12. Between 0 and 30 min, MO adsorption efficiency was >82%, and at 120 min, representative adsorption equilibrium had occurred. The maximum adsorption capacity of the biochars was 12.3 mg/g. The underlying adsorption mechanisms of the three biochars were governed by electrostatic adsorption and pore diffusion. There was an abundance of active sites for adsorption in BA and BM, while chemical adsorption appeared to be more vital for BC, as it contained more functional groups on its surface. The highest MO adsorption efficiency occurred with BM. BC was not recommended for MO removal, as it was observed to stain the water when a dose exceeding 5.0 g/L was utilized.
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•Biochars were successfully derived from agro-waste and invasive plants.•After only 30 min the methyl orange adsorption efficiency on biochar was more than 82%.•The adsorption equilibrium was established at 120 min.•The highest adsorption occurred with biochar from mimosa.
Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently ...observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis.
Our study suggests that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis. We present evidence that signaling through the S100a8/S100a9‐Emmprin‐Vegfa axis is essential for progression of a lung cancer model established in a microenvironment of Tet2‐deficient immune cells. Furthermore, we provide a novel target for lung cancer patients with accompanying TET2‐mutated clonal hematopoiesis.
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•VSP and its distribution best reflect the impact of driving features on vehicle fuel consumption.•The VSP bin within 0, 1) interval consumes the largest fuel of 3.6 L per 100 km.•The ...average fuel consumption of 3.01 L per 100 km for motorcycles in Hanoi was determined.•The creeping mode was determined to be the most fuel-wasting mode, up to 7.9 L per 100 km.•The highest fuel consumption rate of Hanoi’s motorcycles 159.9 mg/s at acceleration mode was found.
This study aims to identify the impact of real-world driving characteristics on the actual fuel consumption (FC) of motorcycles (MC) so that drivers can have better driving behavior to save fuel and reduce air emissions. A data logger installed directly on MC was utilized to gather real-world operation data of MC which includes instantaneous speed and fuel consumption rate (FRinst), second by second. The collected data were preprocessed, then fed to extract typical driving characteristic parameters that strongly impact the fuel consumption of MC. Among the extracted parameters, vehicle-specific power (VSP) and its distribution best reflect the impact of real-world driving characteristics on the FC rate of MC (R2 = 0.88). The VSP bin in the range 0, 1 has the highest FC, 3.6 L/100 km, while the actual FC corresponding to the full VSP distribution of MC in Hanoi is 3.01 L/100 km only. Among the running modes of MC, creeping mode is the most fuel-wasting one, up to 7.9 L/100 km. In steady running mode, FRinst in the high-speed range is higher than that in the low-speed range. Overall, the larger the average speed and cruising time proportion plus the smaller the proportions of stopping and creeping time, the lower the emissions and the better the fuel economy. Thus, smooth driving technique could save fuel and reduce air pollutant emissions.
The World Health Organization recently revised its recommendations for tuberculosis (TB) diagnosis in people with HIV. Most studies cited to support these policies involved HIV-uninfected patients ...and only evaluated sputum specimens.
To evaluate the performance of acid-fast bacilli smear and mycobacterial culture on sputum and nonsputum specimens for TB diagnosis in a cross-sectional survey of HIV-infected patients.
In Thailand and Vietnam, we enrolled people with HIV regardless of signs or symptoms. Enrolled patients provided three sputum, one urine, one stool, one blood, and, for patients with palpable peripheral adenopathy, one lymph node aspirate specimen for acid-fast bacilli microscopy and mycobacterial culture on solid and broth-based media. We classified any patient with at least one specimen culture positive for Mycobacterium tuberculosis as having TB.
Of 1,060 patients enrolled, 147 (14%) had TB. Of 126 with pulmonary TB, the incremental yield of performing a third sputum smear over two smears was 2% (95% confidence interval, 0-6), 90 (71%) patients were detected on broth-based culture of the first sputum specimen, and an additional 21 (17%) and 12 (10%) patients were diagnosed with the second and third specimens cultured. Of 82 lymph nodes cultured, 34 (42%) grew M. tuberculosis. In patients with two negative sputum smears, broth-based culture of three sputum specimens had the highest yield of any testing strategy.
In people with HIV living in settings where mycobacterial culture is not routinely available to all patients, a third sputum smear adds little to the diagnosis of TB. Broth-based culture of three sputum specimens diagnoses most TB cases, and lymph node aspiration provides the highest incremental yield of any nonpulmonary specimen test for TB.
Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir ...(MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection.
In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662.
Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia.
This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials.
Merck Sharp & Dohme Corp.
•ACH-derived GCB cells with aberrant expression profiles underwent independent clonal evolution in the microenvironment of AITL.•Inhibition of the CD40–CD40LG axis, as revealed by in silico network ...analysis, is a potential novel therapeutic target.
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Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper (TFH)-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development using mouse models and human samples. Among the 2 mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox × G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox × G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of >50 000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells, exhibiting properties of activating light zone (LZ)-like and proliferative dark zone (DZ)-like germinal center B (GCB) cells. The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40–Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40–CD40LG axis.
The second most common peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), arises from T-follicular helper cells in the context of age-related clonal hematopoiesis. Fujisawa and colleagues utilized single cell analyses of primary samples and murine models to reveal that TET methylcytosine dioxygenase 2 (TET2) mutations within clonal B cells in the tumor microenvironment are necessary for facilitating TET2-mutated AITL. Their data also suggest a novel therapeutic possibility.
The lack of country-specific data related to the real-world fuel consumption (FC) of motor vehicles is a significant impediment to the inventory of greenhouse gas (GHG) emissions in the transport ...sector in Vietnam. This study aims to develop a cost-effective solution for estimating the on-road FC of motorcycles (MC) to overcome this lack. An Artificial Neural Network (ANN)-based model (R
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>0.85 and MAPE < 20%) was developed to predict the MC's instant FC rate (FR
inst
) based on the experimental data that were continuously collected using the data logger installed directly on the test MC. The developed ANN-based model was utilized to estimate FR
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according to the real-world driving characteristics that were collected using the Global positioning system (GPS) device. The discrepancy between the estimated and measured FC (in terms of liters per kilometer) was only 6.8%. Consequently, the proposed approach could help improve the consumed fuel-based GHG emission inventory in the transport sector.
Mean duration of recent infection (MDRI) and misclassification of long-term HIV-1 infections, as proportion false recent (PFR), are critical parameters for laboratory-based assays for estimating ...HIV-1 incidence. Recent review of the data by us and others indicated that MDRI of LAg-Avidity EIA estimated previously required recalibration. We present here results of recalibration efforts using >250 seroconversion panels and multiple statistical methods to ensure accuracy and consensus.
A total of 2737 longitudinal specimens collected from 259 seroconverting individuals infected with diverse HIV-1 subtypes were tested with the LAg-Avidity EIA as previously described. Data were analyzed for determination of MDRI at ODn cutoffs of 1.0 to 2.0 using 7 statistical approaches and sub-analyzed by HIV-1 subtypes. In addition, 3740 specimens from individuals with infection >1 year, including 488 from patients with AIDS, were tested for PFR at varying cutoffs.
Using different statistical methods, MDRI values ranged from 88-94 days at cutoff ODn = 1.0 to 177-183 days at ODn = 2.0. The MDRI values were similar by different methods suggesting coherence of different approaches. Testing for misclassification among long-term infections indicated that overall PFRs were 0.6% to 2.5% at increasing cutoffs of 1.0 to 2.0, respectively. Balancing the need for a longer MDRI and smaller PFR (<2.0%) suggests that a cutoff ODn = 1.5, corresponding to an MDRI of 130 days should be used for cross-sectional application. The MDRI varied among subtypes from 109 days (subtype A&D) to 152 days (subtype C).
Based on the new data and revised analysis, we recommend an ODn cutoff = 1.5 to classify recent and long-term infections, corresponding to an MDRI of 130 days (118-142). Determination of revised parameters for estimation of HIV-1 incidence should facilitate application of the LAg-Avidity EIA for worldwide use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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