Circunferência do Pescoço e Risco Cardiovascular em 10 Anos na Linha de Base do ELSA-Brasil: Diferenciais por Sexo

Background:Neck circumference (NC), an indirect measure of upper-body subcutaneous adipose tissue, has been pointed out as an independent predictor of cardiometabolic diseases.Objectives:To assess the association between NC and 10-year cardiovascular risk in men and in women.Methods:Cross-sectional analysis of 13,920 participants of the (baseline) Longitudinal Study of Adult Health (ELSA-Brasil). The association between NC (used as continuous variable and grouped into quartiles) and the 10-year cardiovascular risk was estimated by the Framingham Global Risk Score and analyzed by generalized linear models after adjustments for sociodemographic characteristics, health behaviors, body mass index and waist circumference. The significance level adopted was 5%.Results:Mean NC was 39.5 cm (SD± 3.6) in men and 34.0 cm (SD±2.9) in women. After adjustments, a one-centimeter increase in NC was associated with an increment of 3% (95%CI1.02-1.03) and 5% (95% 1.04-1.05) in the arithmetic mean of the 10-year CVD risk in men and women, respectively. Men and women in the last quartile showed an increment of 18% (95%CI 1.13-1.24) and 35% (95%CI 1.28-1.43), respectively in the arithmetic mean of the 10-year CVD risk, after adjustments.Conclusions:We found a positive, independent association between NC and the 10-year cardiovascular disease risk. NC may contribute to the prediction of cardiovascular risk, over and above traditional anthropometric measures.     

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the “minor pocket,” previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR^−/− mice compared with WT mice. Furthermore, treatment of C5aR^−/− mice with DF2593A did not produce any further antinociceptive effect compared with C5aR^−/− mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain.Inflammatory and neuropathic pain are the most prevalent types of pathological pain and represent important health problems. Whereas inflammatory pain is one of the classic symptoms of the inflammatory process, neuropathic pain arises from any of multiple nerve lesions or diseases, with symptoms including hyperalgesia or allodynia (1, 2). Some of the most powerful painkillers, including opioids and nonsteroidal anti-inflammatory drugs, are only partially effective and prolonged exposure can cause unwanted effects (3, 4). As a result, there is continuous effort to identify novel therapeutics for pain control with alternative biological mechanisms and that elicit fewer side effects.Inflammatory mediators, including cytokines/chemokines, play a critical role in the pathogenesis of inflammatory and neuropathic pain (5, 6). Emerging evidences suggest that C5a, the anaphylatoxin produced by complement activation, has potent nociceptive activity in several models of inflammatory and neuropathic pain by interacting with its selective receptor C5aR (7, 8). C5aR belongs to the class A subfamily of the seven-transmembrane (TM) G protein-coupled receptors (GPCR) (9) and is widely expressed in immune cells, including neutrophils (polymorphonuclear cells, PMN), monocytes, microglia, and in nonimmune cells, including neurons in the CNS and dorsal root ganglia (10, 11).Evidence for a role of C5a in nociception sensitization has been obtained in several models of inflammatory pain. For example, C5a was produced at the inflammatory sites and elicited mechanical hyperalgesia by activating the C5aR on infiltrated PMN (7). Direct intraplantar injection of C5a in mice elicited both heat and mechanical hyperalgesia by sensitizing primary afferent C-nociceptors (12, 13). Local activation of C5aR has been also implicated in the pathogenesis of postsurgical pain, a model of postoperative pain (13). Finally, local administration of PMX-53, a C5aR antagonist, attenuated mechanical hyperalgesia induced by carrageenan, zymosan, or lipopolysaccharide (7). In addition to the peripheral role of C5a/C5aR in inflammatory pain, up-regulated levels of C5 and C5aR have been found in spinal cord microglia in animals subjected to spared nerve injury (SNI), a model of neuropathic pain (8). Indeed, C5-null mice or the infusion of PMX-53 into the intrathecal space reduced neuropathic pain hypersensitivity in the SNI model (8). Collectively, these data suggest that a neuroimmune interaction in the periphery and spinal cord through activation of the complement cascade and the production of C5a contributes to the genesis of both inflammatory and neuropathic pain.As for other peptidergic GPCRs, the efforts to identify small molecular weight C5aR antagonists have led to a limited number of molecules, mostly lacking adequate potency and selectivity (14). The most promising candidate so far described, PMX-53, is a cyclic peptidomimetic antagonist designed to mimic the C-terminal portion of C5a (15). Despite the encouraging results obtained in preclinical studies, as for many peptide drugs, the development of PMX-53 has been limited by its short half-life and unfavorable bioavailability (16). In the present study, we report the successful design of a nonpeptidic C5a allosteric small molecular weight inhibitor driven by the structural information on a minor pocket spanning between TM1, -2, -3, -6, and -7 that is highly conserved across the GPCR family and that has been recently proposed as a key motif for the intracellular activation process. Reparixin was previously reported as a neutral allosteric inhibitor of CXCR1 and CXCR2 that binds the TM in a region that overlaps the minor pocket (17, 18). Combining the information from independent sources on structural and functional features of allosteric sites in homologous chemokine receptors, this paper intends to provide what is, to our knowledge, the first example of de novo design of a new class of allosteric small molecular weight inhibitors of a GPCR not belonging to the chemokine receptor family, C5aR. The preclinical candidate, DF2593A, is a potent and orally active C5a noncompetitive allosteric inhibitor with significant antinociceptive effects in a wide range of inflammatory and neuropathic pain models.     

Identifying maternal risk factors associated with Fetal Alcohol Spectrum Disorders: a systematic review

To identify the demographic, psychological, and social maternal risk factors associated with the development of Fetal Alcohol Spectrum Disorders (FASD). A bibliographic search was conducted in PubMed, SciELO, Lilacs, Web of Knowledge, and PsycINFO. The Newcastle–Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the studies with case–control design. Articles were selected based on their relevance and presentation of data related to statistical comparisons of at least one or more demographic, psychological, or social maternal risk factors for FASD. 738 references were identified, of which 15 met the criteria to be included in the present review. Mothers of FASD children tend to: be older at the time of birth of the affected child, present lower educational level, have other family relatives with alcohol abuse, have other children with FASD, present a pattern of little prenatal care and a distinguishing pattern of alcohol consumption (alcohol use before and during pregnancy, failure to reduce alcohol use during pregnancy, and frequent episodes of binge drinking). Application of the NOS scale of methodological quality indicated that 8 studies (53 %) met the criterion for selection, 4 (27 %) were suitable for the criterion for comparability and only 4 studies were suitable for the exposition criterion. Mothers of FASD children have a distinctive pattern of drinking and accumulate several social risk factors. Maternal age at birth of the child seems to accentuate the risk. There are, however, few controlled studies that are adequate according to the NOS requirements for methodological quality. Fewer are based on the verification of a theoretical model. Clinicians should be aware of the relevance of preventive assessment of FASD risk mothers.     

A random set approach to confidence regions with applications to the effective dose with combinations of agents

The effective dose (ED) is the pharmaceutical dosage required to produce a therapeutic response in a fixed proportion of the patients. When only one drug is considered, the problem is a univariate one and has been well‐studied. However, in the multidimensional setting, that is, in the presence of combinations of agents, estimation of the ED becomes more difficult. This study is focused on the plug‐in logistic regression estimator of the multidimensional ED. We discuss consistency of such estimators and focus on the problem of simultaneous confidence regions. We develop a bootstrap algorithm to estimate confidence regions for the multidimensional ED. Through simulation, we show that the proposed method gives 95% confidence regions, which have better empirical coverage than the previous method for moderate to large sample sizes. The novel approach is illustrated on a cytotoxicity study on the effect of two toxins in the leukemia cell line HL‐60 and a decompression sickness study of the effects of the duration and depth of the dive. Copyright © 2014 John Wiley & Sons, Ltd.     

Time Course Analysis of the Effects of Botulinum Neurotoxin Type A on Pain and Vasomotor Responses Evoked by Glutamate Injection into Human Temporalis Muscles

The effect of botulinum neurotoxin type A (BoNTA) on glutamate-evoked temporalis muscle pain and vasomotor responses was investigated in healthy men and women over a 60 day time course. Subjects participated in a pre-BoNTA session where their responses to injection of glutamate (1 M, 0.2 mL) and saline (0.2 mL) into the temporalis muscles were assessed. On Day 1, BoNTA (5 U) was injected into one temporalis muscle and saline into the contralateral temporalis muscle, in a randomized order. Subjects then received intramuscular injections of glutamate (1 M, 0.2 mL) into the left and right temporalis muscles at 3 h and subsequently 7, 30 and 60 days post-injection of BoNTA. Pain intensity, pain area, and neurogenic inflammation (skin temperature and skin blood perfusion) were recorded. Prior to BoNTA treatment, glutamate evoked significantly greater pain and vasomotor reactions (P < 0.001) than saline. BoNTA significantly reduced glutamate-evoked pain intensity (P < 0.05), pain area (P < 0.01), skin blood perfusion (P < 0.05), and skin temperature (P < 0.001). The inhibitory effect of BoNTA was present at 3 h after injection, peaked after 7 days and returned to baseline by 60 days. Findings from the present study demonstrated a rapid action of BoNTA on glutamate-evoked pain and neurogenic inflammation, which is in line with animal studies.     

Conventional type 1 dendritic cells induce TH1, TH1-like follicular helper T cells and regulatory T cells after antigen boost via DEC205 receptor

Conventional dendritic cells (cDCs) are specialized in antigen presentation. In the mouse spleen, cDCs are classified in cDC1s and cDC2s, and express DEC205 and DCIR2 endocytic receptors, respectively. Monoclonal antibodies (mAbs) αDEC205 (αDEC) and αDCIR2 have been fused to different antigens to deliver them to cDC1s or cDC2s. We immunized mice with αDEC and αDCIR2 fused to an antigen using Poly(I:C) as adjuvant. The initial immune response was analyzed from days 3 to 6 after the immunization. We also studied the influence of a booster dose. Our results showed that antigen targeting to cDC1s promoted a pro-inflammatory T_H1 cell response. Antigen targeting to cDC2s induced T_FH cells, GCs, and plasma cell differentiation. After boost, antigen targeting to cDC1s improved the T_H1 cell response and induced T_H1-like T_FH cells that led to an increase in specific antibody titers and IgG class switch. Additionally, a population of regulatory T cells was also observed. Antigen targeting to cDC2s did not improve the specific antibody response after boost. Our results add new information on the immune response induced after the administration of a booster dose with αDEC and αDCIR2 fusion mAbs. These results may be useful for vaccine design using recombinant mAbs.     

Analysis of HLA-G gene polymorphism and protein expression in invasive breast ductal carcinoma

The human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule predominantly expressed in trophoblastic placental cells to protect the fetus during pregnancy. However, evidence has shown that this molecule may be implicated in the immune escape mechanism of tumor cells. Thus, the aim of this study was to evaluate the frequency of 14-bp insertion/deletion HLA-G polymorphism, as well as the expression of this molecule in patients with invasive breast ductal carcinoma (IDC). A significant association between the expression of HLA-G and the presence of metastasis in lymph nodes (p = 0.01) was observed and the expression of HLA-G was significantly higher in patients with shorter survival time (p = 0.03). The analysis suggests that the polymorphism observed in patients with IDC may be inducing a higher expression of the HLA-G molecule, which may possibly contribute to shorter survival time and a worse clinical prognosis for such patients.