B cells play an important role in the development and maintenance of rheumatoid arthritis (RA). Although IL-10-producing B cells represent a major subset of regulatory B cells (Bregs) able to ...suppress autoimmune and inflammatory responses, recent reports showed that B cell-mediated immune suppression may also occur independent of IL-10. For instance, B cells can modulate T cell immune responses through the expression of regulatory molecules such as PD-L1. So far, PD-L1-expressing B cells have not been analyzed in RA patients.
To analyze the frequency of PD-L1-expressing B cells in the peripheral blood of RA patients compared to healthy controls (HC) matched for sex and age, their function on T cell response and their changes in response to therapy.
Fresh peripheral blood B cells from RA patients and HC were characterized by flow cytometry and their functionality assessed in a co-culture system with autologous T cells.
The frequencies of CD19
PD-L1
B cells, CD24
CD38
PD-L1
and CD24
CD38
PD-L1
B cells were significantly lower in untreated RA patients than in HC. In a follow-up study, the frequencies of PD-L1
B cells (CD19
PD-L1
B cells, CD24
CD38
PD-L1
and CD24
CD38
PD-L1
B cells) increased significantly after treatment in good responder patients, although the frequency of total CD24
CD38
B cells decreased. CD19
B cells from untreated RA patients and HC upregulated PD-L1 expression similarly upon stimulation with CpG plus IL-2 and were able to suppress,
, CD8
T cell proliferation and cytokine production in a PD-L1-dependent manner.
Our results show that PD-L1
B cells exhibiting T cell suppressive capacity are significantly decreased in untreated RA patients but increase in response to successful treatment. PD-L1 expression on B cells from RA patients can be modulated
and PD-L1
B cells could thus provide new perspectives for future treatment strategies.
Snoring is extremely common in the general population and may indicate OSA. However, snoring is not objectively measured during polysomnography, and no standard treatment is available for primary ...snoring or when snoring is associated with mild forms of OSA. This study determined the effects of oropharyngeal exercises on snoring in minimally symptomatic patients with a primary complaint of snoring and diagnosis of primary snoring or mild to moderate OSA.
Patients were randomized for 3 months of treatment with nasal dilator strips plus respiratory exercises (control) or daily oropharyngeal exercises (therapy). Patients were evaluated at study entry and end by sleep questionnaires (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index) and full polysomnography with objective measurements of snoring.
We studied 39 patients (age, 46 ± 13 years; BMI, 28.2 ± 3.1 kg/m2; apnea-hypopnea index (AHI), 15.3 ± 9.3 events/h; Epworth Sleepiness Scale, 9.2 ± 4.9; Pittsburgh Sleep Quality Index, 6.4 ± 3.3). Control (n = 20) and therapy (n = 19) groups were similar at study entry. One patient from each group dropped out. Intention-to-treat analysis was used. No significant changes occurred in the control group. In contrast, patients randomized to therapy experienced a significant decrease in the snore index (snores > 36 dB/h), 99.5 (49.6-221.3) vs 48.2 (25.5-219.2); P = .017 and total snore index (total power of snore/h), 60.4 (21.8-220.6) vs 31.0 (10.1-146.5); P = .033.
Oropharyngeal exercises are effective in reducing objectively measured snoring and are a possible treatment of a large population suffering from snoring.
ClinicalTrials.gov; No.: NCT01636856; URL: www.clinicaltrials.gov.
Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations.
To evaluate clinical, laboratory features and outcome in ...HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network.
A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity.
From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%).
HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.
Increasing evidence supports a close relationship between Ras-ERK1/2 activation in the striatum and L-DOPA-induced dyskinesia (LID). ERK1/2 activation by L-DOPA takes place through the crosstalk ...between D1R/AC/PKA/DARPP-32 pathway and NMDA/Ras pathway. Compelling genetic and pharmacological evidence indicates that Ras-ERK1/2 inhibition prevents LID onset and may even revert already established dyskinetic symptoms. However, it is currently unclear whether exacerbation of Ras-ERK1/2 activity in the striatum may further aggravate dyskinesia in experimental animal models. Here we took advantage of two genetic models in which Ras-ERK1/2 signaling is hyperactivated, the Nf1
mice, in which the Ras inhibitor neurofibromin is reduced, and the Ras-GRF1 overexpressing (Ras-GRF1 OE) transgenic mice in which a specific neuronal activator of Ras is enhanced. Nf1
and Ras-GRF1 OE mice were unilaterally lesioned with 6-OHDA and treated with an escalating L-DOPA dosing regimen. In addition, a subset of Nf1
hemi-parkinsonian animals was also co-treated with the Ras inhibitor lovastatin. Our results revealed that Nf1
and Ras-GRF1 OE mice displayed similar dyskinetic symptoms to their wild-type counterparts. This observation was confirmed by the lack of differences between mutant and wild-type mice in striatal molecular changes associated to LID (i.e., FosB, and pERK1/2 expression). Interestingly, attenuation of Ras activity with lovastatin does not weaken dyskinetic symptoms in Nf1
mice. Altogether, these data suggest that ERK1/2-signaling activation in dyskinetic animals is maximal and does not require further genetic enhancement in the upstream Ras pathway. However, our data also demonstrate that such a genetic enhancement may reduce the efficacy of anti-dyskinetic drugs like lovastatin.
BACKGROUND Snoring is extremely common in the general population and may indicate OSA. However, snoring is not objectively measured during polysomnography, and no standard treatment is available for ...primary snoring or when snoring is associated with mild forms of OSA. This study determined the effects of oropharyngeal exercises on snoring in minimally symptomatic patients with a primary complaint of snoring and diagnosis of primary snoring or mild to moderate OSA. METHODS Patients were randomized for 3 months of treatment with nasal dilator strips plus respiratory exercises (control) or daily oropharyngeal exercises (therapy). Patients were evaluated at study entry and end by sleep questionnaires (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index) and full polysomnography with objective measurements of snoring. RESULTS We studied 39 patients (age, 46 ± 13 years; BMI, 28.2 ± 3.1 kg/m2 ; apnea-hypopnea index (AHI), 15.3 ± 9.3 events/h; Epworth Sleepiness Scale, 9.2 ± 4.9; Pittsburgh Sleep Quality Index, 6.4 ± 3.3). Control (n = 20) and therapy (n = 19) groups were similar at study entry. One patient from each group dropped out. Intention-to-treat analysis was used. No significant changes occurred in the control group. In contrast, patients randomized to therapy experienced a significant decrease in the snore index (snores > 36 dB/h), 99.5 (49.6-221.3) vs 48.2 (25.5-219.2); P = .017 and total snore index (total power of snore/h), 60.4 (21.8-220.6) vs 31.0 (10.1-146.5); P = .033. CONCLUSIONS Oropharyngeal exercises are effective in reducing objectively measured snoring and are a possible treatment of a large population suffering from snoring. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT01636856; URL: www.clinicaltrials.gov
ZnO thin films were processed by radio frequency magnetron sputtering at room temperature on p-Si/SiO2 substrates under pure argon (Ar:O2=100:0vol.%) and argon–oxygen mixture (Ar:O2=99:1vol.%) gas ...environment. Morphological, optical and electrical characteristics of the ZnO films are reported, and they show a clear relationship with the gas mixture employed for the sputtering process. Scanning Electron Microscopy revealed the formation of grains of 15.3 and 19.9nm average sizes and thicknesses of 59nm and 82nm for films growth in pure argon and argon–oxygen, respectively. Photoluminescence measurements at room temperature showed the violet emission band (centered at 3eV) which was only detected in the ZnO film grown under pure argon. From thermally stimulated conductivity measurements two traps with 0.27 and 0.14eV activation energies were identified for films grown in pure argon and argon–oxygen mixture, respectively. The trap at 0.27eV is associated with a level located below the conduction band edge and it is supported by the PL band centered at 3eV. Both types of ZnO films were used as the active channel layer in thin film transistors with thermal SiO2 as gate dielectric. Field effect mobility, threshold voltage and current ratio were improved in the devices with ZnO channel deposited with the argon–oxygen mixture (99% Ar/1% O2 vol.). Threshold voltage decreased from 25V to 15V, field effect mobility and current ratio increased from 0.8 to 2.4cm2/Vs and from 102 to 106, in that order.
In 2011, the Latin-American DILI-Network (LATINDILIN) set up under the guidance of the Spanish DILI Registry a network of hepatologists to prospectively identify and characterize DILI patients.
To ...evaluate the drugs more frequently associated with DILI in LA, clinical phenotype and outcome.
Demographics, clinical and biochemical parameters of all cases included in the LATINDILI Network were analysed according to the type of liver injury (hepatocellular, Hep; cholestatic, Chol and mixed, Mix).
404 DILI cases were included. Anti-infectives (31%), musculoskeletal system drugs (13%) and herbal products (9.2%) were the main causative therapeutic drug classes. Mean age was 49 years (female sex, 61%). Hep injury predominated (62%) whereas Chol and Mix patterns were 24% and 15% of cases, respectively. Chol patients (mean age 56y) were older than Hep and Mix cases (47 and 50, p<0.05). Jaundice was more prevalent in Chol and Mix injury than in Hep cases (65% vs 75% vs 58%, respectively, p=0.062), though no differences in hospitalization rates were observed (Hep 43%, Chol and Mix 46%, p=0.867). Of note, 12 cases, mostly Hep, had a positive rechallenge. Positive autoantibodies were more common in Hep cases (25% vs Chol 9.1% vs Mix 19%, p=0.010), with nitrofurantoin/herbal products as the most common causative agents. Hep cases showed a higher risk of severe/fatal injury (18% vs 6.0% and 1.8% in Chol and Mix cases, respectively, p<0.001). The new Hy's law performed as expected, with 14% of ALF/Tx cases. Hep cases more frequently died from liver-related death (3.5%) compared with Chol (1.1%) and Mix (0) cases.
In Latin-American DILI cases with Hep pattern predominated, showing a higher severity and most frequent inadvertent re-exposition. The LATINDILI Network is proving as an important tool for the characterization of DILI singularities in this world region, and improvement of Public Health.
AEMPS, FEDER (PI18/01804). COST Action CA-17112.
Complete and accurate data on smoking prevalence at a local level would enable health authorities to plan context-dependent smoking interventions. However, national health surveys do not generally ...provide direct estimates of smoking prevalence by sex and age groups at the subnational level. This study uses a small-area model-based methodology to obtain precise estimations of smoking prevalence by sex, age group and region, from a population-based survey.
The areas targeted for analysis consisted of 180 groups based on a combination of sex, age group (15-34, 35-54, 55-64, 65-74, and ≥75 years), and Autonomous Region. Data on tobacco use came from the 2017 Spanish National Health Survey (2017 SNHS). In each of the 180 groups, we estimated the prevalence of smokers (S), ex-smokers (ExS) and never smokers (NS), as well as their coefficients of variation (CV), using a weighted ratio estimator (direct estimator) and a multinomial logistic model with random area effects.
When smoking prevalence was estimated using the small-area model, the precision of direct estimates improved; the CV of S and ExS decreased on average by 26%, and those of NS by 25%. The range of S prevalence was 11-46% in men and 4-37% in women, excluding the group aged ≥75 years.
This study proposes a methodology for obtaining reliable estimates of smoking prevalence in groups or areas not covered in the survey design. The model applied is a good alternative for enhancing the precision of estimates at a detailed level, at a much lower cost than that involved in conducting large-scale surveys. This method could be easily integrated into routine data processing of population health surveys. Having such estimates directly after completing a health survey would help characterize the tobacco epidemic and/or any other risk factor more precisely.
Biocorrosion refers to the influence of microorganisms adhered to surfaces, in the corrosion process of metals. At Embalse Nuclear Power Plant (ENPP), this phenomenon has been detected in several ...water cooling systems. In order to mitigate this process, it was proposed to modify the current chlorination water treatment by adding a commercial bromide-based biocide. This study evaluated in situ the effect of the addition of the biocide on biofilm formation and also on the corrosion rate of carbon steel components. The results of the corrosion rate measurements, as well as the evaluation of the kinetics of biofilm growth, showed no significant difference between the former and the modified water treatments. It was concluded that, under the current conditions of operation, the addition of a bromide-based biocide (BBB) does not improve the effectiveness against biofouling and biocorrosion of the water treatment.
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