Impact of SARS-CoV-2 Pandemic on Antiretroviral Access at a Large Treatment Centre in Lagos, Nigeria.

INTRODUCTION: The SARS-CoV-2 pandemic has ravaged the world with significant implications on the socio-economic and health status of individuals. Several measures were put in place to curtail the pandemic especially movement restrictions. The effect of this pandemic and the restriction measures could further compound the health needs of PLWHA. This study thus described the trend in access to HIV/AIDS care services before and during the COVID-19 induced lockdown and the possible consequences on their treatment outcome. METHODS: A secondary analysis of client data was carried out at the HIV clinic of the Nigerian Institute of Medical Research. The sociodemographic and clinical data [type of ART, duration on ART, clinical services 3-months before and during the COVID-19 induced Lockdown] were extracted from the electronic medical records. Data obtained was analyzed using the SPSS version 22.0. RESULTS: The median age of PLWHA was 45 years (IQR: 39-51), with the predominant age group being 25-49 years (65.4%). The majority were females (68.7%), married (59.5%), had at least secondary education (82.8%), and employed (81.5%). The median duration on ART was 102 months (IQR: 67-138) with the majority on non-Protease Inhibitor based regimen (77.7%). In the 3 months before the lockdown, there was an increase in drug pick-up of approximately 25% over the booked appointment compared to a decline of 40% when the lockdown was enacted. CONCLUSION: The significant decline in drug pick-up during the SARS-CoV-2 pandemic raises the need for measures to ensure continued access to drugs and care among PLWHA.

INTRODUCTION: La pandémie de SRAS-CoV-2 a ravagé le monde avec des implications significatives sur l'état socio- économique et sanitaire. Plusieurs mesures ont été mises en place pour freiner la pandémie, en particulier la restriction des déplacements. L'effet de cette pandémie et les mesures de restriction pourraient encore aggraver les besoins de santé des PVVIH. Cette étude décrit ainsi la tendance des services de soins du VIH / SIDA avant et pendant le verrouillage induit par le COVID-19 et les conséquences possibles sur l'issue de leur traitement. MÉTHODES: Une étude transversale parmi les PVVIH fréquentant la clinique VIH de l'Institut nigérian de recherche médicale. Les données sociodémographiques et cliniques [type de TAR, durée de la TAR, services cliniques 3 mois avant et pendant le verrouillage induit par COVID-19] ont été extraites des dossiers médicaux électroniques. Les données obtenues ont été analysées à l'aide de la version 22.0 de SPSS. RÉSULTATS: L'âge médian des PVVIH était de 45 ans (IQR (39-51), le groupe d'âge prédominant étant 25-49 ans (65,4%). La majorité étaient des femmes (68,7%), mariées (59,5%), avaient au moins secondaire (82,8%) et employé (81,5%). La durée médiane des TAR était de 102 mois (IQR: 67-138), la majorité sous traitement sans inhibiteur de protéase (77,7%). Au cours des 3 mois précédant le verrouillage , il y a eu une augmentation de la cueillette de médicaments d'environ 25% par rapport au rendez-vous réservé, comparativement à une baisse de 40% lorsque le verrouillage a été décrété. CONCLUSION: La baisse significative de la collecte de médicaments pendant la pandémie de SRAS-CoV-2 fait ressortir la nécessité de prendre des mesures pour assurer un accès continu aux médicaments et aux soins parmi les PVVIH. Mots Clés: SRAS-CoV-2, antirétroviral, COVID-19, ramassage de médicaments, VIH, verrouillage.

Migration and season explain tick prevalence in Brazilian birds.

Neotropical birds are mostly parasitized by immature ticks and act as reservoir hosts of tick-borne pathogens of medical and veterinary interest. Hence, determining the factors that enable ticks to encounter these highly mobile hosts and increase the potential for tick dispersal throughout migratory flyways are important for understanding tick-borne disease transmission. We used 9682 individual birds from 572 species surveyed across Brazil and Bayesian models to disentangle possible avian host traits and climatic drivers of infestation probabilities, accounting for avian host phylogenetic relationships and spatiotemporal factors that may influence tick prevalence. Our models revealed that the probability of an individual bird being infested with tick larvae and nymphs was lower in partial migrant hosts and during the wet season. Notably, infestation probability increased in areas with a higher proportion of partial migrant birds. Other avian ecological traits known to influence tick prevalence (foraging habitat and body mass) and environmental condition that might constrain tick abundance (annual precipitation and minimum temperature) did not explain infestation probability. Our findings suggest that migratory flyways harbouring a greater abundance of migrant bird hosts also harbour a higher prevalence of immature ticks with potential to enhance the local transmission of tick-borne pathogens and spread across regions.

Effects of cryolipolysis with adiposity plates located with the Crioplace concept in women.

BACKGROUND: Cryolipolysis with plates is a method of applying cooling without a vacuum system, which can be used in regions with less chance of forming a "crease." OBJECTIVE: To investigate the effects of cryolipolysis using a plate-shaped applicator (Crioplac) in the treatment of fat. MATERIALS AND METHODS: This is an experimental study in which women aged 25 to 45 years with adiposity located in the abdomen participated. Two applications of 75 min were made, using 04 plates in the abdomen regions, with -4 degree C being programmed as a temperature parameter. Anthropometric and ultrasound assessments were performed, and a satisfaction questionnaire on the validated treatment was conducted. The reassessments were performed 30 and 60 days after the first intervention. RESULTS: A reduction in adiposity was observed in the measurements of perimetry, plicometry and abdominal ultrasound (p<0.05). It was found that about 62.5% of the volunteers reported an improvement in water retention, about 62.5% reported the presence of loose clothing, and 31.3% reported satisfaction with the results obtained. It was observed that 18.5% of the volunteers reported that the treatment was excellent. CONCLUSION: The Crioplace method proved to be effective in reducing adiposity, with a high clinical satisfaction with the reduction in body measurements.

Experimental manipulation of beliefs about the importance of thoughts and the effect on an aggressive impulse.

BACKGROUND: Cognitive models of obsessive-compulsive disorder attribute a causal role to maladaptive beliefs. AIMS: To test this hypothesis, we manipulated Overimportance of Thoughts (OT) beliefs and experimentally evaluated their effect on the response to an induced aggressive impulse. METHOD: Eighty-five participants completed a battery of self-report instruments assessing obsession symptoms, thought control, affectivity and obsessive beliefs, and were then randomly assigned to two conditions. In the experimental condition participants read a scientific abstract on the importance of thought control whilst those in the control condition read a neutral abstract. All participants identified a loved person and imagined feeling the impulse to stab this person, then completed again OT beliefs measures (Overimportance of Thought, Moral-Thought Action Fusion and Thought Action Fusion Likelihood). RESULTS: The Moral component of the Thought Action Fusion was reduced by reading a brief text about the possibility and desirability of thought control. However, experimentally induced changes in beliefs did not yield differences in the intrusiveness of the aggressive impulse. CONCLUSIONS: Some beliefs can be modified through a single session in which information similar to what could be obtained in quotidian life is provided.

Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Ectoparasites of small-mammals: determinants of community structure in South American savannah.

This study aimed to assess the contribution of hosts characteristics (rodents and marsupials) in the organization of ectoparasite communities present in woodland patches in western central Brazil. We verified the effect of host species, sex, body mass and vertical strata in addition to the role of seasonality on the ectoparasite composition, richness and abundance. The total sampling effort was 22 032 trap-nights equally distributed in 54 woodland patches. Variance partition and principal coordinate analysis were used to verify the existence of significant relationships between response variables and predictors. As expected, host species was the most important variable in ectoparasite community assembly. The composition, richness and abundance of mites and lice were highly influenced by host species, although higher for mites than for lice. Host body mass had a determining role on the richness and abundance of tick species. Vertical stratification and seasonality had weak influence, while the sex of the host had no influence on the organization of these communities. The results are closely related to the evolutionary characteristics of the species involved, as well as with local environmental characteristics of the study area.

Diallel and prediction (REML/BLUP) for yield components in intervarietal maize hybrids.

Genetic improvement is essential to achieve increments in maize (Zea mays L.) grain yield components. It may be obtained through crosses, which enable to exploit the effects of intervarietal heterosis, allelic complementarity, as well as gene actions and effects. This study estimated the components of variance and genetic parameters (REML/BLUP) of an intervarietal diallel to select and predict the best genotypes for maize yield components. The experimental design was randomized blocks containing 60 intervarietal maize hybrids arranged in three repetitions. They were obtained through intervarietal crosses and evaluated in a diallel scheme, where 14 open-pollinated varieties were designated as parentals. Thus, 10 crosses were performed for each hybrid combination to obtain the number of seeds necessary for the competition test. The measured traits were: grain volume relative index, the mass of one hundred grains, and grain yield. The male parents and the additive genetic fraction were determinants for grain volume relative index. Mass of one hundred grains and grain yield were defined by the specific combining ability, and female parents revealed low narrow sense heritability. The female parent Taquarão and male parent Argentino Amarelo presented the best general combining abilities for the measured traits. The specific combining abilities were expressed for crosses AL 25 x Dente de Ouro Roxo, AL 25 x BRS Pampeano, and Taquarão x Argentino Branco. Genetic estimates and predictions were consistent and applicable to breeding programs and could be applied in future quantitative genetic studies of maize.

Risk factors associated with resistance to HIV testing among transwomen in Brazil.

Transwomen are a high-risk population for HIV/AIDS worldwide. However, many transwomen do not test for HIV. This study aimed to identify factors associated with resistance to HIV testing among transwomen in Fortaleza/CE. A cross-sectional study was conducted between August and December 2008 with a sample of 304 transwomen recruited through respondent-driven sampling. Data analysis utilized Respondent-Driven Sampling Analysis Tool and SPSS 11.0. Univariate, bivariate, and multivariate analyses examined risk factors associated with resistance to HIV testing. Less than 18 years of age (OR = 4.221; CI = 2.419-7.364), sexual debut before 10 years of age (OR = 6.760; CI = 2.996-15.256), using illegal drugs during sex (OR = 2.384; CI = 1.310-4.339), experience of discrimination (OR = 3.962; CI = 1.540-10.195) and a belief that the test results were not confidential (OR = 3.763; CI = 2.118-6.688) are independently associated with resistance to testing. Intersectoral and targeted strategies aimed at encouraging the adoption of safer sexual behaviors and testing for HIV among transwomen are required.

A survey of tick-borne pathogens in dogs and their ticks in the Pantanal biome, Brazil.

Tick and blood samples collected from domestic dogs in the Brazilian Pantanal were tested by molecular methods for the presence of tick-borne protozoa and bacteria. Among 320 sampled dogs, 3.13% were infected by Babesia vogeli (Piroplasmida: Babesiidae), 8.75% by Hepatozoon canis (Eucoccidiorida: Hepatozoidae), 7.19% by Anaplasma platys (Rickettsiales: Anaplasmataceae), and 0.94% by an unclassified Anaplasma sp. In three tick species collected from dogs, the following tick-borne agents were detected: (a) B. vogeli, An. platys and Ehrlichia canis (Rickettsiales: Anaplasmataceae), infecting Rhipicephalus sanguineus sensu lato (Ixodida: Ixodidae) ticks; (b) H. canis, an unclassified Anaplasma sp. and Rickettsia amblyommii (Rickettsiales: Rickettsiaceae), infecting Amblyomma cajennense sensu lato (Ixodida: Ixodidae) ticks, and (c) Rickettsia sp. strain Atlantic rainforest, an emerging human pathogen, infecting Amblyomma ovale ticks. Molecular analysis, based on a mitochondrial gene, revealed that the Am. cajennense s.l. ticks of the present study corresponded to Amblyomma sculptum, a member of the Am. cajennense species complex, and that Rh. sanguineus s.l. belonged to the tropical lineage. Whereas dogs are exposed to a number of tick-borne bacterial and protozoan agents in the Pantanal biome, humans are potentially exposed to infection by spotted fever group rickettsiae (e.g. R. amblyommii and Rickettsia sp. strain Atlantic rainforest) because both Am. sculptum and Am. ovale are among the most important human-biting ticks in Brazil.

Tipping point analysis of atmospheric oxygen concentration.

We apply tipping point analysis to nine observational oxygen concentration records around the globe, analyse their dynamics and perform projections under possible future scenarios, leading to oxygen deficiency in the atmosphere. The analysis is based on statistical physics framework with stochastic modelling, where we represent the observed data as a composition of deterministic and stochastic components estimated from the observed data using Bayesian and wavelet techniques.

In vitro isolation from Amblyomma ovale (Acari: Ixodidae) and ecological aspects of the Atlantic rainforest Rickettsia, the causative agent of a novel spotted fever rickettsiosis in Brazil.

Recently, a novel human rickettsiosis, namely Atlantic rainforest spotted fever, was described in Brazil. We herein report results of a survey led around the index case in an Atlantic rainforest reserve in Peruibe municipality, southeastern Brazil. A Rickettsia parkeri-like agent (Rickettsia sp. Atlantic rainforest genotype) and Ricketsia bellii were isolated from adult Amblyomma ovale ticks collected from dogs. Molecular evidence of infection with strain Atlantic rainforest was obtained for 30 (12.9%) of 232 A. ovale adult ticks collected from dogs. As many as 88.6% of the 35 examined dogs had anti-Rickettsia antibodies, with endpoint titres at their highest to R. parkeri. High correlation among antibody titres in dogs, A. ovale infestations, and access to rainforest was observed. Amblyomma ovale subadults were found predominantly on a rodent species (Euryoryzomys russatus). From 17 E. russatus tested, 6 (35.3%) displayed anti-Rickettsia antibodies, with endpoint titres highest to R. parkeri. It is concluded that Atlantic rainforest genotype circulates in this Atlantic rainforest area at relatively high levels. Dogs get infected when bitten by A. ovale ticks in the forest, and carry infected ticks to households. The role of E. russatus as an amplifier host of Rickettsia to A. ovale ticks deserves investigation.

Protective effect of mannan oligosaccharides against early colonization by Salmonella Enteritidis in chicks is improved by higher dietary threonine levels.

AIMS: To evaluate mannan oligosaccharide (MOS) and threonine effects on performance, small intestine morphology and Salmonella spp. counts in Salmonella Enteritidis-challenged birds. METHODS AND RESULTS: One-day-old chicks (1d) were distributed into five treatments: nonchallenged animals fed basal diet (RB-0), animals fed basal diet and infected with Salmonella Enteritidis (RB-I), animals fed high level of threonine and infected (HT-I), birds fed basal diet with MOS and infected (MOS-I), birds fed high level of threonine and MOS and infected (HT+MOS-I). Birds were inoculated at 2d with Salmonella Enteritidis, except RB-0 birds. Chicks fed higher dietary threonine and MOS showed performance similar to RB-0 and intestinal morphology recovery at 8 dpi. Salmonella counts and the number of Salmonella-positive animals were lower in HT+MOS-I compared with other challenged groups. CONCLUSION: Mannan oligosaccharides and threonine act synergistically, resulting in improved intestinal environment and recovery after Salmonella inoculation. SIGNIFICANCE AND IMPACT OF THE STUDY: Nutritional approaches may be useful to prevent Salmonella infection in the first week and putative carcass contamination at slaughter. This is the first report on the possible synergistic effect of mannan oligosaccharides and threonine, and further studies should be performed including performance, microbiota evaluation, composition of intestinal mucins and immune assessment.

Timed artificial insemination programs during the summer in lactating dairy cows: comparison of the 5-d Cosynch protocol with an estrogen/progesterone-based protocol.

The objective of this study was to compare a GnRH-based to an estrogen/progesterone (E2/P4)-based protocol for estrous cycle synchronization and fixed timed artificial insemination (TAI), both designed for synchronization of ovulation and to reduce the period from follicular emergence until ovulation in cows with a synchronized follicular wave. A total of 1,190 lactating Holstein cows (primiparous: n=685 and multiparous: n=505) yielding 26.5 ± 0.30 kg of milk/d at 177 ± 5.02 d in milk were randomly assigned to receive one of the following programs: 5-d Cosynch protocol [d -8: controlled internal drug release (CIDR) + GnRH; d -3: CIDR removal + PGF2α; d -2: PGF2α; d 0: TAI + GnRH] or E2/P4 protocol (d -10: CIDR + estradiol benzoate; d -3: PGF2α; d -2: CIDR removal + estradiol cypionate; d 0: TAI). Rectal temperature and circulating progesterone (P4) were measured on d -3, -2, 0 (TAI), and 7. The estrous cycle was considered to be synchronized when P4 was ≥ 1.0 ng/mL on d 7 in cows that had luteolysis (P4 ≤ 0.4 ng/mL on d 0). To evaluate the effects of heat stress, cows were classified by number of heat stress events: 0, 1, and 2-or-more measurements of elevated body temperature (≥ 39.1 °C). Pregnancy success (pregnancy per artificial insemination, P/AI) was determined at d 32 and 60 after TAI. The cows in the 5-d Cosynch protocol had increased circulating P4 at the time of PGF2α injection (2.66 ± 0.13 vs. 1.66 ± 0.13 ng/mL). The cows in the E2/P4 protocol were more likely to be detected in estrus (62.8 vs. 43.4%) compared with the cows in the 5-d Cosynch protocol, and expression of estrus improved P/AI in both treatments. The cows in the 5-d Cosynch protocol had greater percentage of synchronized estrous cycle (78.2%), compared with cows in the E2/P4 protocol (70.7%). On d 60, the E2/P4 protocol tended to improve P/AI (20.7 vs. 16.7%) and reduced pregnancy loss from 32 to 60 d (11.0 vs. 19.6%), compared with the 5-d Cosynch protocol. In cows withtheir estrous cycle synchronized, the E2/P4 protocol had greater P/AI (25.6 vs. 17.7%) on d 60 and lower pregnancy loss from 32 to 60 d (6.7 vs. 21.7%) compared with cows in the 5-d Cosynch protocol. Follicle diameter affected pregnancy loss from 32 to 60d only in the cows in the 5-d Cosynch protocol, with smaller follicles resulting in greater pregnancy loss. Pregnancy per AI at d 60 was different between protocols in the cows with 2 or more measurements of heat stress (5-d Cosynch=12.2% vs. E2/P4=22.8%), but not in the cows without or with 1 heat stress measurement. In conclusion, the 5-d Cosynch protocol apparently produced better estrous cycle synchronization than the E2/P4 protocol but did not improve P/AI. The potential explanation for these results is that increased E2 concentrations during the periovulatory period can improve pregnancy success and pregnancy maintenance, and this effect appears to be greatest in heat-stressed cows when circulating E2 may be reduced.

Unravelling the role of 17ß-estradiol on advancing uterine luteolytic cascade in cattle.

In cattle, 17ß-estradiol (E2) stimulates prostaglandin F2α (PGF2α) synthesis, which causes luteolysis. Except for the well-established upregulation of oxytocin receptor gene (OXTR), molecular mechanisms of E2-induced PGF2α release in vivo remain unknown. We hypothesized that E2-induced PGF2α release requires de novo transcription of components of the PGF2α synthesis machinery. Beef cows (n = 52) were assigned to remain untreated (Control; n = 10), to receive 50% ethanol infusion intravenously (Placebo; n = 21), or 3 mg E2 in 50% ethanol infusion intravenously (Estradiol; n = 21) on day 15 (D15) after estrus. We collected a single endometrial biopsy per animal at the time of the treatment (0h; Control B0h group), 4 hours (4h; Placebo B4h group and Estradiol B4h group), or 7 hours (7h; Placebo B7h group and Estradiol B7h group) post-treatment. Compared to the Placebo group, the Estradiol group presented significantly greater 13,14-dihydro-15-keto-PGF2α concentrations between 4h and 7h and underwent earlier luteolysis. At 4h, the qPCR analysis showed a lower abundance of ESR1, ESR2 and aldo-keto reductase family 1 member B1 (AKR1B1) genes in the Estradiol B4h group, and a greater abundance of OXTR compared to the Placebo B4h group. Similarly, the E2 treatment significantly reduced the abundance of AKR1B1, and AKR1C4 in the Estradiol B7h group, compared to the placebo group. Overall, E2-induced PGF2α release and luteolysis involved an unexpected and transient downregulation of components of the PGF2α-synthesis cascade, except for OXTR, which was upregulated. Collectively, our data suggest that E2 connects newly-synthesized OXTR to pre-existing cellular machinery to synthesize PGF2α and cause luteal regression.

Spinal subarachnoid haematoma after neuraxial anaesthesia in a patient with polycythaemia vera.

Polycythaemia vera is a common haematological proliferative disorder. It is characterised by uncontrolled red cell production with ensuing peri-operative vaso-occlusive and haemorrhagic complications. Spinal haematoma after neuraxial anaesthesia is rare; most cases are associated with technical difficulties or bleeding disorders. Current consensus opinion suggests that neuraxial anaesthesia in patients with polycythaemia vera is safe due to a lower risk of thrombotic events and hypoxaemia compared with general anaesthesia. We report a case of a spinal subarachnoid haematoma after uneventful neuraxial anaesthesia in a patient with optimised polycythaemia vera. Despite an emergent laminectomy, the patient developed permanent motor deficits. This report highlights that although neuraxial anaesthesia is recommended by many authors, patients with polycythaemia vera can paradoxically have an increased haemorrhagic risk from platelet dysfunction and acquired von Willebrand disease. Clinicians proceeding with surgery under neuraxial anaesthesia should appreciate these risks even in patients with normal or apparently elevated thrombotic states. This case also demonstrates that traditional coagulation tests may need to be complemented by pre-operative platelet function tests and screening for von Willebrand disease. Finally, the importance of the patient participation in the choice of the anaesthesia technique cannot be understated, with specific attention paid to this frequently unrecognised risk.

Puberty attainment and reproductive performance of yearling Bos indicus-influenced heifers after two sequential treatments with progesterone.

Number of pubertal heifers at time of breeding season initiation is a primary determinant to pregnancy success during the breeding season. It was hypothesized that pre-breeding progesterone (P4) supplementation (induction) would increase the number of heifers pubertal at the time of imposing estrous synchronization treatment regimens and P/AI. Yearling, Bos indicus-influenced (n = 577) or Bos indicus (n = 174) heifers were or were not treated with P4 (CIDR and Non-CIDR, respectively) for 10 d starting on D-23 (D0 = TAI). Presence of a CL on D-33 or D-23 was considered to indicate heifers were pubertal. On D-13, there was a PGF analogue administered. On D-9, there was treatment with GnRH analogue, 6d-CIDR and PGF. There were inseminations based on estrus (D-2 to D0) or TAI on D0 for non-estrous animals. There were 5.2 % and 62.9 % purebred and crossbred heifers pubertal, respectively. Proportion of prepubertal crossbred than purebred heifers with CL on D-3 was greater as a result of imposing the pubertal induction regimen (P < 0.05 and P> 0.10, respectively). Regardless of puberty status, proportion of heifers in estrus prior to AI in the CIDR group was similar to the heifers of the Non-CIDR group for crossbreds and purebreds. Similarly, P/AI of CIDR group was similar to the Non-CIDR group for crossbreds and purebreds. In summary, imposing the pubertal induction regimen hastened attainment of puberty in yearling crossbred, but not purebred heifers. Puberty induction did not affect estrous response, neither fertility after imposing an estrous synchronization treatment regimen.

Pitavastatin ameliorates autoimmune neuroinflammation by regulating the Treg/Th17 cell balance through inhibition of mevalonate metabolism.

While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.

Artificial neural networks for prediction of recurrent venous thromboembolism.

BACKGROUND: Recurrent venous thromboembolism (RVTE) is a multifactorial disease with occurrence rates which vary from 13 % to 25 % in 5 years after the initial event. Once a patient the first thrombotic event, the probability of recurrence should be determined, as well as the most adequate anticoagulant therapy. To our knowledge based on the published literature, three statistical models have been proposed to calculate RVTE probability. However, these models present several limitations, such as: limited input variables, lack of external validation and applicability only for patients with a first unprovoked thrombosis. Additionally, some of the models have been recognized to fail in determining RVTE when patients have a low risk of recurrence. OBJECTIVE: An alternative procedure in which three Artificial Neural Network (ANN) models were developed to classify which patients will present RVTE based solely on clinical data. METHODS: Data of 39 clinical factors from 235 patients were used to train several ANN structures. The difference among the three models was its inputs. In ANN 1, the inputs were all 39 factors. In ANN 2, 18 factors determined previously as the main predictors of RTVE using Principal Component Analysis (PCA). Finally, in ANN 3, 15 factors combining PCA results with practical aspects. Different number of hidden layers and neurons, and three optimization algorithms were considered. 5-fold cross validation was also performed. RESULTS: The results showed that all models were capable of performing this task. Different optimization algorithms lead to different results. The best models presented high accuracy. The best structures were 39-10-10-1, 18-10-5-1, and 15-15-10-1 for ANN 1, ANN 2, and ANN 3 models, respectively. The cross-validation showed that the results are consistent. CONCLUSIONS: This work showed that the association of multivariate techniques and ANNs is a powerful tool that can be used to model a complex phenomenon such as RVTE without the restrictions of existing approaches. APPLICATION: After proper validation, these ANN models can be used to help clinicians with decisions regarding VTE treatment.

Effect of a puberty induction protocol based on injectable long acting progesterone on pregnancy success of beef heifers serviced by TAI.

Induction protocols based on progesterone (P4) are used prior to a synchronization program for timed-AI (TAI) to increase number of pubertal heifers and pregnancy per AI (P/AI). Injectable, long-lasting P4 (iP4) is a novel, practical method to supplement P4 in cattle. Here, we aimed to test the effect of an induction protocol based on a single injection of iP4 on P/AI of heifers. Bos indicus (Nellore) heifers were classified as pubertal (PUB; n = 224) or prepubertal (PRE; n = 414) based on two ovarian ultrasonographyc exams conducted 10 d apart. Heifers with a corpus luteum (CL) in any of the exams were considered PUB. Within each puberty status, heifers were assigned to receive nothing (NoiP4) or an induction protocol (iP4). Induction consisted of a single injection of 150 mg of iP4 on D-31, followed by injections of 1 mg of estradiol benzoate (EB) and 150 µg of prostaglandin analogue (PGF) on D-21. On D-9, all heifers received 2 mg of EB + 75 µg of PGF associated to intravaginal P4-device insertion. On D-3, P4-releasing devices were removed and 150 µg of PGF injected. Heifers were inseminated based on estrus on D-1 or were TAI on D0. On D0, all heifers received a dose of GnRH analogue. On D-21, iP4 treatment stimulated a 50% increase in the uterine score (UTS) and a 19% increase in the diameter of the largest follicle of PRE heifers (P < 0.01). On D-9, PRE|iP4 group had a greater proportion (P < 0.01) of CL (63.3%) than PRE|NoiP4 group (11.6%). On D-3, exposure to 6 d P4-releasing device stimulated UTS of PRE|NoiP4 group in a similar fashion than the induction protocol, but it did not have any additional positive effect for PRE|iP4 heifers. P/AI of PRE|iP4 group was similar to that of the PUB groups (44.7 vs 46.9%), but was more than that of PRE|NoiP4 (34.2%). There was an overall 7.7% increment (P = 0.07) on P/AI of iP4 treated heifers (iP4: 46.0% vs. NoiP4: 38.3%). In conclusion, implementation of an induction protocol based on iP4 was efficacious to hasten puberty. Induction stimulated uterine development and follicular growth of prepubertal heifers, ultimately leading to pregnancy success similar to that of pubertal heifers.