Uterine botulinum toxin injections in severe dysmenorrhea, dyspareunia and chronic pelvic pain: Results on quality of life, pain level and medical consumption.

OBJECTIVE: To evaluate quality of life (Qol), pain level and medical consumption before and after uterine botulinum toxin (BT) injections in severe dysmenorrhea, dyspareunia and chronic pelvic pain. METHODS: This was a before and after study using the database of a pilot study (Open-label non comparative study, on 30 patients, with severe dysmenorrhoea in therapeutic failure) assessing efficacy and cost of uterine injection of BT in women with chronic pelvic pain after failure of conventional treatment (hormonal and analgesics) (CT). Main clinical outcome: Patient Global Impression of Improvement (PGI-I), EuroQol health-related QoL (EQ-5D-5L), EuroQol-visual analogue scale (EQ-VAS), Female Sexual Function Index (FSFI), utility measure of health-related quality of life (also called health state preference values), cost and of health care consumption were collected prospectively and analysed in the two phases (before and after). The two timepoints were 12 months before uterine BT injection, when the patient had been receiving CT, and 12 months after uterine BT injection. RESULTS: Median visual analogue scale scores were significantly improved by BT regarding the patients' main source of pain (31.6 vs 80.55; p < 0.00001). We also noted a significant reduction in the proportion of patients who reported dyspareunia [15 (75%) vs 3 (15%) patients, p = 0.001] and pain during menstruation (p < 0.0001). The PGI-I scale showed a significant increase in the proportion of patients who were satisfied with their treatment after receiving the BT injection. The injection of BT was frequently associated with increase in QoL and a reduction in health care consumption, and cost: 714.82 €+/- €336.43 (BT) versus 1104.16 €+/- €227.37 (CT), which could result in substantial savings approximately (389,34€) per patient. CONCLUSION: This study revealed the clinical effectiveness of BT injections on dysmenorrhea, chronic pelvic pain as well as reduction of cost and health care consumption, in our population, which is innovative since no standard of treatment exists in this domain.

Symptom severity is a major determinant of cannabis-based products use among people with multiple sclerosis.

AIMS AND OBJECTIVES: We aimed to identify correlates of cannabinoid-based products (CBP) use in patients with multiple sclerosis (MS) in France and Spain. BACKGROUND: MS is responsible for a wide range of symptoms, including pain. Access to CBP differs according to local legislation. The French context is more restrictive than the Spanish one, and no data regarding cannabis use among MS patients has yet been published. Characterizing MS patients who use CBP constitutes a first step toward identifying persons most likely to benefit from them. DESIGN: An online cross-sectional survey was submitted to MS patients who were members of a social network for people living with chronic diseases and were living in France or Spain. METHODS: Two study outcomes measured therapeutic CBP use and daily therapeutic CBP use. Seemingly unrelated bivariate probit regression models were used to test for associations between the outcomes and patients' characteristics while accounting for country-related differences. STROBE guidelines were followed in reporting this study. RESULTS: Among 641 study participants (70% from France), the prevalence of CBP use was similar in both countries (23.3% in France vs. 20.1% in Spain). MS-related disability was associated with both outcomes, with a gradient observed between different degrees of disability. MS-related pain level was associated with CBP use only. CONCLUSIONS: CBP use is common in MS patients from both countries. The more severe the MS, the more participants turned to CBP to alleviate their symptoms. Easier access to CBP should be ensured for MS patients in need of relief, especially from pain. RELEVANCE TO CLINICAL PRACTICE: This study highlights the characteristics of MS patients using CBP. Such practices should be discussed by healthcare professional with MS patients.

Circulating extracellular vesicles as a predictive biomarker for acute graft-versus-host disease.

The diagnosis and management of graft-versus-host disease (GVHD) have remained important challenges in allogeneic stem cell transplantation (allo-SCT). Novel diagnostic methods and therapeutic interventions are needed to further improve on patient outcomes. Extracellular vesicles (EV) are microvesicles formed by the inversion of the phospholipid bilayer of different cellular subtypes and have been described as biomarkers of cellular damage, activation, and intercellular signaling in numerous clinical scenarios. We studied the association between the levels of EV and the incidence of acute GVHD (aGVHD). Forty patients undergoing allo-SCT for hematological malignancies had their plasma collected at neutrophil engraftment. Using flow cytometry combined with fluorescent beads, the total circulating EV count (TEV) was established with annexin V positivity; CD61 positivity was used for platelet-derived EV (PEV), and CD235 positivity, for erythrocyte-derived EV (EryEV). TEV counts greater than 516/µL were associated with a higher cumulative incidence (CI) of grade II to IV aGVHD (54% vs. 21%; p = 0.02), as were EryEV counts above 357 /µL (CI of aGVHD: 59% vs. 26%; p = 0.04). In patients who are exposed to reduced intensity conditioning (RIC), stronger associations of both high TEV and EryEV counts with aGVHD were observed (77% vs. 22%; p = 0.003 and 89% vs. 27%; p = 0.002, respectively). PEV levels were not associated with the risk of aGVHD. Our data suggest that the measurement of cell-derived EV at engraftment can be used as a preemptive biomarker for acute GVHD.

Adenanthin Is an Efficient Inhibitor of Peroxiredoxins from Pathogens, Inhibits Bacterial Growth, and Potentiates Antibiotic Activities.

The emergence and re-emergence of bacterial strains resistant to multiple drugs represent a global health threat, and the search for novel biological targets is a worldwide concern. AhpC are enzymes involved in bacterial redox homeostasis by metabolizing diverse kinds of hydroperoxides. In pathogenic bacteria, AhpC are related to several functions, as some isoforms are characterized as virulence factors. However, no inhibitor has been systematically evaluated to date. Here we show that the natural ent-kaurane Adenanthin (Adn) efficiently inhibits AhpC and molecular interactions were explored by computer assisted simulations. Additionally, Adn interferes with growth and potentializes the effect of antibiotics (kanamycin and PMBN), positioning Adn as a promising compound to treat infections caused by multiresistant bacterial strains.

Cost-utility analysis of four WHO-recommended sofosbuvir-based regimens for the treatment of chronic hepatitis C in sub-Saharan Africa.

BACKGROUND: Although direct-acting antivirals (DAA) have become standard care for patients with chronic hepatitis C worldwide, there is no evidence for their value for money in sub-Saharan Africa. We assessed the cost-effectiveness of four sofosbuvir-based regimens recommended by the World Health Organization (WHO) in Cameroon, Côte d'Ivoire and Senegal. METHODS: Using modelling, we simulated chronic hepatitis C progression with and without treatment in hypothetical cohorts of patients infected with the country's predominant genotypes (1, 2 and 4) and without other viral coinfections, history of liver complication or hepatocellular carcinoma. Using the status-quo 'no DAA treatment' as a comparator, we assessed four regimens: sofosbuvir-ribavirin, sofosbuvir-ledipasvir (both recommended in WHO 2016 guidelines and assessed in the TAC pilot trial conducted in Cameroon, Côte d'Ivoire and Senegal), sofosbuvir-daclatasvir and sofosbuvir-ledipasvir (two pangenotypic regimens recommended in WHO 2018 guidelines). DAA effectiveness, costs and utilities were mainly estimated using data from the TAC pilot trial. Secondary data from the literature was used to estimate disease progression probabilities with and without treatment. We considered two DAA pricing scenarios: S1) originator prices; S2) generic prices. Uncertainty was addressed using probabilistic and deterministic sensitivity analyses and cost-effectiveness acceptability curves. RESULTS: With slightly higher effectiveness and significantly lower costs, sofosbuvir/velpatasvir was the preferred DAA regimen in S1 with incremental cost-effectiveness ratios (ICERs) ranging from US$526 to US$632/QALY. At the cost-effectiveness threshold (CET) of 0.5 times the 2017 country's per-capita gross domestic product (GDP), sofosbuvir/velpatasvir was only cost-effective in Senegal (probability > 95%). In S2 at generic prices, sofosbuvir/daclatasvir was the preferred regimen due to significantly lower costs. ICERs ranged from US$139 to US$216/QALY according to country i.e. a 95% probability of being cost-effective. Furthermore, this regimen was cost-effective (probability> 95%) for all CET higher than US$281/QALY, US$223/QALY and US$195/QALY in Cameroon, Côte d'Ivoire and Senegal, respectively, corresponding to 0.14 (Côte d'Ivoire and Senegal) and 0.2 (Cameroon) times the country's per-capita GDP. CONCLUSIONS: Generic sofosbuvir/daclatasvir is very cost-effective for treating chronic hepatitis C in sub-Saharan Africa. Large-scale use of generics and an increase in national and international funding for hepatitis C treatment must be priorities for the HCV elimination agenda.

Late presentation for HCV care: Time to target people with diabetes and/or hazardous alcohol use (ANRS CO22 HEPATHER cohort).

BACKGROUND AND AIMS: Late presentation for care of hepatitis C virus (HCV) infection - defined as having severe liver fibrosis when first consulting a specialist for HCV care - increases morbidity and mortality. Identifying the socio-behavioural correlates of late presentation is essential to improve HCV strategies to optimize HCV cascade of care. We investigated clinical and socio-behavioural correlates of late presentation for care in HCV mono-infected individuals. METHODS: This study included chronic HCV mono-infected patients participating in the French national cohort ANRS CO22 HEPATHER, starting in 2012. The correlates of late presentation were estimated using a Heckman probit selection model, which takes into account the possible selection bias because of missing data in the outcome. RESULTS: Among the 9174 study patients, 1236 had available data on liver fibrosis stage at first presentation for HCV care. Of these, 591 (47.8%) were late presenters. In a multivariable analysis adjusted for age, sex and HCV genotype, having diabetes (adjusted coefficient [95% confidence interval]: 0.55 [0.30; 0.80]), current hazardous alcohol use (0.36 [0.03; 0.69]) and current abstinence but past hazardous alcohol use (0.42 [0.19; 0.64]) (vs. current abstinence and no past hazardous use) were all independently associated with late presentation for HCV care. CONCLUSIONS: As late presentation severely affects HCV cascade of care, our findings bring important new evidence about the need to promptly identify and target people with diabetes and/or past or current hazardous alcohol use for HCV screening and treatment within the wider context of the WHO goal to eliminate HCV by 2030.

Effects of Serine or Threonine in the Active Site of Typical 2-Cys Prx on Hyperoxidation Susceptibility and on Chaperone Activity.

Typical 2-Cys peroxiredoxins (2-Cys Prx) are ubiquitous Cys-based peroxidases, which are stable as decamers in the reduced state, and may dissociate into dimers upon disulfide bond formation. A peroxidatic Cys (CP) takes part of a catalytic triad, together with a Thr/Ser and an Arg. Previously, we described that the presence of Ser (instead of Thr) in the active site stabilizes yeast 2-Cys Prx as decamers. Here, we compared the hyperoxidation susceptibilities of yeast 2-Cys Prx. Notably, 2-Cys Prx containing Ser (named here Ser-Prx) were more resistant to hyperoxidation than enzymes containing Thr (Thr-Prx). In silico analysis revealed that Thr-Prx are more frequent in all domains of life, while Ser-Prx are more abundant in bacteria. As yeast 2-Cys Prx, bacterial Ser-Prx are more stable as decamers than Thr-Prx. However, bacterial Ser-Prx were only slightly more resistant to hyperoxidation than Thr-Prx. Furthermore, in all cases, organic hydroperoxide inhibited more the peroxidase activities of 2-Cys Prx than hydrogen peroxide. Moreover, bacterial Ser-Prx displayed increased thermal resistance and chaperone activity, which may be related with its enhanced stability as decamers compared to Thr-Prx. Therefore, the single substitution of Thr by Ser in the catalytic triad results in profound biochemical and structural differences in 2-Cys Prx.

Relevance of peroxiredoxins in pathogenic microorganisms.

The oxidative and nitrosative responses generated by animals and plants are important defenses against infection and establishment of pathogenic microorganisms such as bacteria, fungi, and protozoa. Among distinct oxidant species, hydroperoxides are a group of chemically diverse compounds that comprise small hydrophilic molecules, such as hydrogen peroxide and peroxynitrite, and bulky hydrophobic species, such as organic hydroperoxides. Peroxiredoxins (Prx) are ubiquitous enzymes that use a highly reactive cysteine residue to decompose hydroperoxides and can also perform other functions, like molecular chaperone and phospholipase activities, contributing to microbial protection against the host defenses. Prx are present in distinct cell compartments and, in some cases, they can be secreted to the extracellular environment. Despite their high abundance, Prx expression can be further increased in response to oxidative stress promoted by host defense systems, by treatment with hydroperoxides or by antibiotics. In consequence, some isoforms have been described as virulence factors, highlighting their importance in pathogenesis. Prx are very diverse and are classified into six different classes (Prx1-AhpC, BCP-PrxQ, Tpx, Prx5, Prx6, and AhpE) based on structural and biochemical features. Some groups are absent in hosts, while others present structural peculiarities that differentiate them from the host's isoforms. In this context, the intrinsic characteristics of these enzymes may aid the development of new drugs to combat pathogenic microorganisms. Additionally, since some isoforms are also found in the extracellular environment, Prx emerge as attractive targets for the production of diagnostic tests and vaccines. KEY POINTS: • Peroxiredoxins are front-line defenses against host oxidative and nitrosative stress. • Functional and structural peculiarities differ pathogen and host enzymes. • Peroxiredoxins are potential targets to microbicidal drugs.

Population attributable fractions of mortality in people living with HIV: roles of delayed antiretroviral therapy, hepatitis coinfections and social factors.

OBJECTIVES: Despite free access to antiretroviral therapy (ART) from 1996 onward, and treatment for all people living with HIV (PLWHIV) from 2013, mortality in Brazil has not homogeneously decreased. We investigated to what extent delayed ART, hepatitis coinfections and sociodemographic factors predict all-cause mortality in Brazilian PLWHIV. DESIGN: We included PLWHIV at least 18 years, with complete CD4 cell count data, followed up between 2007 and 2015 in Brazil. METHODS: After multiple imputation, an extended Cox model helped estimate the effects of fixed and time-varying covariates on mortality. RESULTS: The study population (n = 411 028) were mainly male (61%), white (55%), 40 years or less (61%), heterosexually HIV infected (71%), living in the Southeast region (48%) and had basic education (79%). Hepatitis C virus and hepatitis B virus coinfection prevalences were 2.5 and 1.4%, respectively. During a 4-year median follow-up, 61 630 deaths occurred and the mortality rate was 3.45 (95% confidence interval: 3.42-3.47) per 100 person-years. Older age, male sex, non-white ethnicity, illiteracy/basic education and living outside the Southeast and Central-West regions were independently associated with increased mortality. The main modifiable predictors of mortality were delayed ART (i.e. CD4 cell count <200 cells/µl at ART initiation) (adjusted population attributable fraction: 14.20% [95% confidence interval: 13.81-14.59]), being ART-untreated (14.06% [13.54-14.59]) and ART-treated with unrecorded CD4 at ART initiation (5.74% [5.26-6.21]). Hepatitis C virus and hepatitis B virus coinfections accounted for 2.44 [2.26-2.62] and 0.42% [0.31-0.53] of mortality, respectively. CONCLUSION: The current study demonstrates that besides early ART and coinfection control, actions targeting males, non-whites and illiterate people and those with basic education are important to reduce avoidable deaths among Brazilian PLWHIV.

Glutaredoxin-like protein (GLP)-a novel bacteria sulfurtransferase that protects cells against cyanide and oxidative stresses.

The pathogen Xylella fastidiosa belongs to the Xanthomonadaceae family, a large group of Gram-negative bacteria that cause diseases in many economically important crops. A predicted gene, annotated as glutaredoxin-like protein (glp), was found to be highly conserved among the genomes of different genera within this family and highly expressed in X. fastidiosa. Analysis of the GLP protein sequences revealed three protein domains: one similar to monothiol glutaredoxins (Grx), an Fe-S cluster and a thiosulfate sulfurtransferase/rhodanese domain (Tst/Rho), which is generally involved in sulfur metabolism and cyanide detoxification. To characterize the biochemical properties of GLP, we expressed and purified the X. fastidiosa recombinant GLP enzyme. Grx activity and Fe-S cluster formation were not observed, while an evaluation of Tst/Rho enzymatic activity revealed that GLP can detoxify cyanide and transfer inorganic sulfur to acceptor molecules in vitro. The biological activity of GLP relies on the cysteine residues in the Grx and Tst/Rho domains (Cys33 and Cys266, respectively), and structural analysis showed that GLP and GLPC266S were able to form high molecular weight oligomers (> 600 kDa), while replacement of Cys33 with Ser destabilized the quaternary structure. In vivo heterologous enzyme expression experiments in Escherichia coli revealed that GLP can protect bacteria against high concentrations of cyanide and hydrogen peroxide. Finally, phylogenetic analysis showed that homologous glp genes are distributed across Gram-negative bacterial families with conservation of the N- to C-domain order. However, no eukaryotic organism contains this enzyme. Altogether, these results suggest that GLP is an important enzyme with cyanide-decomposing and sulfurtransferase functions in bacteria, whose presence in eukaryotes we could not observe, representing a promising biological target for new pharmaceuticals.

HCV-Related Mortality Among HIV/HCV Co-infected Patients: The Importance of Behaviors in the HCV Cure Era (ANRS CO13 HEPAVIH Cohort).

Mortality among individuals co-infected with HIV and hepatitis C virus (HCV) is relatively high. We evaluated the association between psychoactive substance use and both HCV and non-HCV mortality in HIV/HCV co-infected patients in France, using Fine and Gray's competing-risk model adjusted for socio-demographic, clinical predictors and confounding factors, while accounting for competing causes of death. Over a 5-year median follow-up period, 77 deaths occurred among 1028 patients. Regular/daily cannabis use, elevated coffee intake, and not currently smoking were independently associated with reduced HCV-mortality (adjusted sub-hazard ratio [95% CI] 0.28 [0.10-0.83], 0.38 [0.15-0.95], and 0.28 [0.10-0.79], respectively). Obesity and severe thinness were associated with increased HCV-mortality (2.44 [1.00-5.93] and 7.25 [2.22-23.6] versus normal weight, respectively). Regular binge drinking was associated with increased non-HCV-mortality (2.19 [1.10-4.37]). Further research is needed to understand the causal mechanisms involved. People living with HIV/HCV co-infection should be referred for tobacco, alcohol and weight control interventions and potential benefits of cannabis-based therapies investigated.

Impact of Alcohol and Coffee Intake on the Risk of Advanced Liver Fibrosis: A Longitudinal Analysis in HIV-HCV Coinfected Patients (ANRS HEPAVIH CO-13 Cohort).

BACKGROUND: Coffee intake has been shown to modulate both the effect of ethanol on serum GGT activities in some alcohol consumers and the risk of alcoholic cirrhosis in some patients with chronic diseases. This study aimed to analyze the impact of coffee intake and alcohol consumption on advanced liver fibrosis (ALF) in HIV-HCV co-infected patients. METHODS: ANRS CO13-HEPAVIH is a French, nationwide, multicenter cohort of HIV-HCV-co-infected patients. Sociodemographic, behavioral, and clinical data including alcohol and coffee consumption were prospectively collected using annual self-administered questionnaires during five years of follow-up. Mixed logistic regression models were performed, relating coffee intake and alcohol consumption to ALF. RESULTS: 1019 patients were included. At the last available visit, 5.8% reported high-risk alcohol consumption, 27.4% reported high coffee intake and 14.5% had ALF. Compared with patients with low coffee intake and high-risk alcohol consumption, patients with low coffee intake and low-risk alcohol consumption had a lower risk of ALF (aOR (95% CI) 0.24 (0.12­0.50)). In addition, patients with high coffee intake had a lower risk of ALF than the reference group (0.14 (0.03­0.64) in high-risk alcohol drinkers and 0.11 (0.05­0.25) in low-risk alcohol drinkers). CONCLUSIONS: High coffee intake was associated with a low risk of liver fibrosis even in HIV-HCV co-infected patients with high-risk alcohol consumption.

Estudos estruturais e funcionais de Tsa1 de Saccharomyces cerevisiae: um modelo biológico para o estudo de inibidores de crescimento celular para leucemia linfoide aguda / Functional and structural evaluation of Tsa1 from Saccharomyces cerevisiae: a biological model for study of cellular growth inhibitors for acute lymphocytic leukemia

As peroxirredoxinas (Prx) são enzimas antioxidantes que se destacam pela capacidade de decompor uma grande variedade de hidroperóxidos com elevada eficiência (106-108M-1s-1), mantendo essas moléculas em níveis adequados à homeostase celular. Entretanto, já foi demonstrado que em diversos tipos tumorais os níveis de Prx são extremamente aumentados e experimentos envolvendo sua inativação resultam na diferenciação ou apoptose de células tumorais. Recentemente, foi descoberto um diterpenóide denominado adenantina que seria o primeiro inibidor para as Prx1 e Prx2 de humanos e foi demonstrada que sua aplicação em células de leucemia mieloide aguda promoveu diferenciação ou apoptose dessas células. Nesse contexto, o presente trabalho apresenta duas vertentes: 1) A caracterização das alterações estruturais e funcionais promovidas pela ligação da adenantina ao sítio ativo das Prx utilizando Tsa1 de Saccharomyces cerevisiae como modelo biológico, em função da sua alta similaridade com Prx2 de humanos; 2) Avaliação da atividade antitumoral dose dependente de adenantina sobre as linhagens celulares REH e MOLT-4 de leucemia linfoide aguda. No que concerne à primeira linha de investigação, nossos resultados revelam que Tsa1 é suscetível à inibição por adenantina, uma vez que o tratamento reduziu em ~66 % a velocidade de decomposição de peróxido de hidrogênio. Adicionalmente, a mutação da Thr44 de Tsa1, pertencente à chamada tríade catalítica, por uma Ser resultou em uma proteína mais suscetível a alterações na estrutura secundária e à inibição da atividade peroxidásica em função da ligação com adenantina, apresentando uma diminuição de ~85% na velocidade de reação. Características semelhantes foram observadas para a proteoforma Tsa2 de S. cerevisiae, que carreia naturalmente a substituição da Thr44 pela Ser. Análises de sequências de Prx em bancos de dados revelaram que majoritariamente proteínas contendo Ser são encontradas em organismos procariotos, muitos deles patogênicos. Finalmente, demonstramos por meio de ensaios citotoxicidade que as bactérias Staphylococcus aureus e Staphylococcus epidermidis, que possuem uma Ser na tríade catalítica, têm seu crescimento inibido pelo tratamento com adenantina (IC50 de 460µM e 77µM, respectivamente), enquanto que para Escherichia coli, que possui Thr nessa posição, a toxicidade da adenantina foi bastante baixa (não foi possível determinar o IC50 nas condições utilizadas). Dessa forma, os dados apresentados neste trabalho demonstram o potencial da utilização da adenantina tanto como antibiótico quanto como antileucêmico

Peroxiredoxins (Prx) are antioxidant enzymes which stand out due the ability to decompose a wide variety of hydroperoxides with high efficiency (106-108M-1s-1) maintaining these molecules at suitable levels to cellular homeostasis and participating in several signaling events. However, it has been shown that, in many tumor types, Prx levels are extremely increased and experiments involving its inactivation have resulted in differentiation or apoptosis of tumor cells. It was recently found a diterpenoid, called adenanthin, that would be the first human Prx1 and Prx2 inhibitor and it was demonstrated that its application in acute myeloid leukemia cells was able to promote differentiation or apoptosis. In this context, this work presents two lines of research: 1) Characterization of structural and functional changes promoted by adenanthin binding to Prx active site using Tsa1 from Saccharomyces cerevisiae as biological model, due to its high similarity to human Prx2. 2) Evaluation of adenanthin dose-dependent antitumor activity over the acute lymphoid leukemia cell lines REH and MOLT-4. As regards the first line of research, our result reveal that Tsa1 is susceptible to inhibition by adenanthin, since the treatment with this binder reduced the hydrogen peroxide decomposition velocity in ~ 66%. In addition, the replacement of Thr44 from Tsa1, aminoacid belonging to the so-called catalytic triad, by a Ser resulted in a protein more susceptible to alterations in secondary structure and to peroxidase activity inhibition in function of adenanthin binding, presenting ~85% of decrease in reaction velocity. Similar characteristics were observed for Tsa2 proteoform from S. cerevisiae, which naturally carries the substitution of Thr44 by Ser. Prx sequences analyzes in databases revealed that mostly Ser-containing proteins are found in prokaryotic organisms, many of them pathogenic ones. Finally, we demonstrate through cytotoxicity assays that the bacteria Staphylococcus aureus and Staphylococcus epidermidis, which have a Ser in catalytic triad, have their growth inhibited by adenanthin treatment (IC50 of 460µM and 77µM, respectively), whereas for Escherichia Coli, which has Thr at that position, the tocyxicity of adenanthin was quite low (it was not possible to determine the IC50 under the used conditions). Regarding the second line of investigation, we found that adenanthin is able to induce the death of leukemic cell lines REH and MOLT-4, and for the last one, there was an unexpected proliferation of cells treated by the longest incubation period (72 hours), characterizing a possible indication of differentiation process. In this sense, the data presented here demonstrate the potential of adenanthin use in both antibiotic and antileukemic treatment

The Brazilian comprehensive response to hepatitis C: from strategic thinking to access to interferon-free therapy.

BACKGROUND: Hepatitis C affects over 185 million people around the world. This silent disease is responsible for up to 700,000 deaths per year. Despite the scientific revolution in diagnosis and treatment, hepatitis C control remains a huge challenge due to the cost of effective medications. In response to the global outcry of hepatitis epidemic and the need to improve the nation's public health response, the Ministry of Health of Brazil revolutionized hepatitis C treatment by incorporating highly effective drugs that can be accessed through sustainable and universal means. DISCUSSION: This paper describes the unique process of implementing evidence-informed policy to respond to hepatitis C epidemic through the update of hepatitis C treatment in Brazil based on the estimate of disease prevalence, current international guidelines, and the cost-effectiveness impact in the Brazilian Unified Health System. Through a debate of an experience report, the authors underlie the strategic plan implemented according to the situation analysis that emphasized the need to improve its current response over a relatively short-term period. The comprehensive response is detailed comprising three main objectives: improve treatment outcomes by evaluating and incorporating new and effective medications at a sustainable price; elaborate on clinical guidelines to treat hepatitis C patients; and develop awareness and diagnosis campaigns targeted at the population of interest. In this scenario, Brazil was able to obtain an unprecedented discount for a high-medium income country; provided treatment to more than 7000 individuals in the last 2 months of 2015; and expects to treat 38,000 new patients in 2016. The remarkable process applied in Brazil was developed according to epidemiological data and scientific evidence, and it was motivated by the engagement of the country in the Sustainable Development Goals, which may inspire other developing countries to identify ways to achieve these goals by 2030.

Catalytic Thr or Ser Residue Modulates Structural Switches in 2-Cys Peroxiredoxin by Distinct Mechanisms.

Typical 2-Cys Peroxiredoxins (2-Cys Prxs) reduce hydroperoxides with extraordinary rates due to an active site composed of a catalytic triad, containing a peroxidatic cysteine (CP), an Arg, and a Thr (or Ser). 2-Cys Prx are involved in processes such as cancer; neurodegeneration and host-pathogen interactions. During catalysis, 2-Cys Prxs switch between decamers and dimers. Analysis of 2-Cys Prx structures in the fully folded (but not locally unfolded) form revealed a highly conserved, non-conventional hydrogen bond (CH-π) between the catalytic triad Thr of a dimer with an aromatic residue of an adjacent dimer. In contrast, structures of 2-Cys Prxs with a Ser in place of the Thr do not display this CH-π bond. Chromatographic and structural data indicate that the Thr (but not Ser) destabilizes the decamer structure in the oxidized state probably through steric hindrance. As a general trend, mutations in a yeast 2-Cys Prx (Tsa1) favoring the dimeric state also displayed a decreased catalytic activity. Remarkably, yeast naturally contains Thr-Ser variants (Tsa1 and Tsa2, respectively) with distinct oligomeric stabilities in their disulfide states.

Estimating the Size of the HCV Infection Prevalence: A Modeling Approach Using the Incidence of Cases Reported to an Official Notification System.

In this paper we propose two methods to give a first rough estimate of the actual number of hepatitis C virus (HCV)-infected individuals (prevalence) taking into account the notification rate of newly diagnosed infections (incidence of notification) and the size of the liver transplantation waiting list (LTWL) of patients with liver failure due to chronic HCV infection. Both approaches, when applied to the Brazilian HCV situation converge to the same results, that is, the methods proposed reproduce both the prevalence of reported cases and the LTWL with reasonable accuracy. We use two methods to calculate the prevalence of HCV that, as a first, and very crude approximation, assumes that the actual prevalence of HCV in Brazil is proportional to the reported incidence to the official notification system with a constant denoted [Formula: see text]. In the paper we discuss the limitations and advantages of this assumption. With the two methods we calculated [Formula: see text], which reproduces both the reported incidence and the size of the LTWL. With the value of [Formula: see text] we calculated the prevalence I(a) (the integral of which resulted in 1.6 million people living with the infection in Brazil, most of whom unidentified). Other variables related to HCV infection (e.g., the distribution of the proportion of people aged a who got infected n years ago) can be easily calculated from this model. These new variables can then be measured and the model can be recursively updated, improving its accuracy.

Tramadol wound infiltration is not different from intravenous tramadol in children: a randomized controlled trial.

STUDY OBJECTIVE: The purpose of this trial was to assess if tramadol wound infiltration is superior to intravenous (IV) tramadol after minor surgical procedures in children because tramadol seems to have local anesthetic-like effect. DESIGN: Randomized double-blind controlled trial. SETTING: Postanesthesia care unit. PATIENTS: Forty children, American Society of Anesthesiologists physical status I or II, scheduled to elective inguinal hernia repair. INTERVENTIONS: Children were randomly distributed in 1 of 2 groups: IV tramadol (group 1) or subcutaneous infiltration with tramadol (group 2). At the end of the surgery, group 1 received 2 mg/kg tramadol (3 mL) by IV route and 3-mL saline into the surgical wound; group 2 received 2 mg/kg tramadol (3 mL) into the surgical wound and 3-mL saline by IV route. MEASUREMENTS: In the postanesthesia care unit, patients were evaluated for pain intensity, nausea and vomiting, time to first rescue medication, and total rescue morphine and dipyrone consumption. MAIN RESULTS: Pain scores measured during the postanesthesia recovery time were similar between groups. Time to first rescue medication was shorter, but not statistically significant in the IV group. The total dose of rescue morphine and dipyrone was also similar between groups. CONCLUSIONS: We concluded that tramadol was effective in reducing postoperative pain in children, and there was no difference in pain intensity, nausea and vomiting, or somnolence regarding IV route or wound infiltration.