Quality and effectiveness of different approaches to primary care delivery in Brazil

BACKGROUND: Since 1994, Brazil has developed a primary care system based on multidisciplinary teams which include not only a physician and a nurse, but also 4–6 lay community health workers. This system now consists of 26,650 teams, covering 46% of the Brazilian population. Yet relatively few investigations have examined its effectiveness, especially in contrast with that of the traditional multi-specialty physician team approach it is replacing, or that of other existing family medicine approaches placing less emphasis on lay community health workers. Primary health care can be defined through its domains of access to first contact, continuity, coordination, comprehensiveness, community orientation and family orientation. These attributes can be ascertained via instruments such as the Primary Care Assessment Tool (PCATool), and correlated with the effectiveness of care. The objectives of our study are to validate the adult version of this instrument in Portuguese, identify the extent (quality) of primary care present in different models of primary care services, and correlate this extent with measures of process and outcomes in patients with diabetes, hypertension and coronary heart disease (CHD). METHODS/DESIGN: We are conducting a population-based cross-sectional study of primary care in the municipality of Porto Alegre. We will interview a random sample totaling 3000 adults residing in geographic areas covered by four distinct models of primary care of the Brazilian national health system or, alternatively, by one nationally prominent complementary health care service, as well as the physicians and nurses of the health teams of these services. Interviews query perceived quality of care (PCATool-Adult Version), patient satisfaction, and process indicators of management of diabetes, hypertension and known CHD. We are measuring blood pressure, anthropometrics and, in adults with known diabetes, glycated hemoglobin. DISCUSSION: We hope to contribute not only by validating the PCATool-Adult Version for use in Brazil, but also by furnishing ample data concerning the appropriate mix of health care professionals in the primary care team, a question of international import. Once validated, future use of this instrument should help direct advances aiming at improving the quality of primary care in Brazil

Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)–CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARβ-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARβ signaling, both neuronal and neuronal–glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs

Purification, characterization and structural determination of UDP-N-acetylglucosamine pyrophosphorylase produced by Moniliophthora perniciosa

The enzyme UDP-N-acetylglucosamine pyrophosphorylase (PyroMp) from Moniliophthora perniciosa (CCMB 0257), a pathogenic fungal strain and the causative agent of the witches' broom disease in Theobroma cacao, was partially purified by precipitation with ammonium sulfate and gel filtration on Sephacryl S-200. The buffer for enzyme extraction was sodium phosphate, 0.050 mol L-1, pH 7.0, containing 1.0 mol L-1 NaCl. Response surface methodology (RSM) was used to determine the optimum pH and temperature conditions. Four different isoenzymes (PyroMp I, PyroMp II, PyroMp III and PyroMp IV) were obtained with optimal pH ranging from 6.9-8.4 and optimum temperature ranging from 28 to 68 °C. The 3D structure of pyrophosphorylase of M. perniciosa was determined by comparative modeling. The model obtained showed a good quality, possessing 78.6% of amino acids in energetically allowed regions. The model was then submitted for DM simulation and showed a good geometric quality (91.1% Ramachandran plot). The active site of the enzyme was found to be extremely well conserved. This model will be useful for developing new inhibitors against witches' broom disease22610151023CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DA BAHIA - FAPESBFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçãoA enzima UDP-N-acetilglicosamina pirofosforilase de Moniliophthora perniciosa (CCMB 0257), o fungo patogênico causador da doença vassoura-de-bruxa do Theobroma cacao, foi parcialmente purificada por precipitação com sulfato de amônio e cromatografia de gel filtração em Sephacryl S-200. O tampão de extração da enzima foi o fosfato de sódio, 0,050 mol L-1, pH 7,0, contendo 1,0 mol L-1 de NaCl. A metodologia de superfície de resposta (MSR) foi usada para a obtenção do pH e temperatura ótima. Os resultados mostraram quatro diferentes isoenzimas (PyroMp I, PyroMp II, PyroMp III e PyroMp IV) que apresentaram pH ótimo na faixa de 6,9-8,4 e temperatura ótima variando entre 28 a 68 °C. A estrutura 3D de pirofosforilase de M. perniciosa foi obtida por modelagem comparativa. O modelo obtido mostrou uma boa qualidade, possuindo 78,6% de aminoácidos nas regiões energeticamente favoráveis. O modelo foi então submetido a simulações de dinâmica molecular (DM). O modelo apresentou uma boa qualidade geométrica após as simulações de DM (91,1% -gráfico de Ramachandran). A procura pelo sítio ativo da enzima mostrou que este é mantido extremamente conservado. Este modelo pode ser útil para desenvolvimento de inibidores contra a doença vassoura de brux

12 item Allodynia Symptom Checklist/Brasil: cross-cultural adaptation, internal consistency and reproducibility

Since there was no Portuguese questionnaire to evaluate cutaneous allodynia, which has been pointed out as a risk factor of migraine, we aimed to perform the cross-cultural adaptation of the 12 item Allodynia Symptom Checklist for the Brazilian population and to test its measurement properties. It consisted in six stages: translation, synthesis, back translation, revision by a specialist committee, pretest and submission the documents to the committee. In the pretest stage, the questionnaire was applied to 30 migraineurs of both sexes, who had some difficulty in understanding it. Thus, a second version was applied to 30 additional subjects, with no difficulties being reported. The mean filling out time was 3'36", and the internal consistency was 0.76. To test reproducibility, 15 other subjects filled out the questionnaire at two different times, it was classified as moderate (weighted kappa=0.58). We made available to Brazilian population an easy, quick and reliable questionnaire.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Apoio ao Ensino, Pesquisa e Assistencia of HCFMRP (FAEPA)Fundacao de Apoio ao Ensino, Pesquisa e Assistencia of HCFMRP (FAEPA

RARb agonist drug (C286) demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms

Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodelling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARb agonist, C286, currently under clinical research, in NP. A four week treatment initiated two days after the injury normalised pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286 mediated pain modulation, suggest that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore

Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL‐286, a novel retinoic acid receptor‐β agonist for treatment of spinal cord injury, in male healthy participants

Aims: KCL‐286 is an orally available agonist taht activates the retinoic acid receptor (RAR) β2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL‐286 in male healthy volunteers to establish dosing to be used in the SCI patient population. Methods: The design was a double blind, randomized, placebo‐controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARβ2 mRNA expression was evaluated in white blood cells. Results: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration–time curve up to 24 h showing a trend to subproportionality with dose. RARβ2 was upregulated by the investigational medicinal product in white blood cells. Conclusion: KCL‐286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL‐286 as a novel oral treatment for SCI

Anisotropy and chemical composition of ultra-high energy cosmic rays using arrival directions measured by the Pierre Auger Observatory

The Pierre Auger Collaboration has reported evidence for anisotropy in the distribution of arrival directions of the cosmic rays with energies $E>E_{th}=5.5\times 10^{19}$ eV. These show a correlation with the distribution of nearby extragalactic objects, including an apparent excess around the direction of Centaurus A. If the particles responsible for these excesses at $E>E_{th}$ are heavy nuclei with charge $Z$, the proton component of the sources should lead to excesses in the same regions at energies $E/Z$. We here report the lack of anisotropies in these directions at energies above $E_{th}/Z$ (for illustrative values of $Z=6,\ 13,\ 26$). If the anisotropies above $E_{th}$ are due to nuclei with charge $Z$, and under reasonable assumptions about the acceleration process, these observations imply stringent constraints on the allowed proton fraction at the lower energies