Effectiveness of non-pharmacological interventions in reducing pain in preterm infants: A systematic review and network meta-analysis.

OBJECTIVE: To identify the most effective non-pharmacological measures for pain control in preterm infants in the Neonatal Intensive Care Unit (NICU). METHODS: A Systematic review and network meta-analysis of randomized clinical trials published in English, Portuguese, and Spanish from April 2020 to December 2023. The data sources used were MedLine via PubMed, LILACS, EMBASE, The Cochrane Central Register of Controlled Trials, and Pedro. We performed the risk of bias analysis with Rob 2 and the certainty of the evidence and strength of the recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system. We assessed heterogeneity using the Higgins and Thompson I2 test, the classification of interventions using the P-score, and inconsistencies using the Direct Evidence Plot. RESULTS: From 210 publications identified, we utilized 12 studies in analysis with 961 preterm infants, and we combined ten studies in network meta-analysis with 716 preterm infants, and 12 combinations of non-pharmacological measures. With moderate confidence, sensory saturation, sugars, non-nutritive sucking, maternal heart sound, lullaby, breast milk odor/taste, magnetic acupuncture, skin-to-skin contact, and facilitated tucking have been shown to reduce pain in preterm infants when compared to no intervention, placebo, proparacaine or standard NICU routine: sensory saturation [SMD 5,25 IC 95%: -8,98; -1,53], sugars [SMD 2,32 IC 95%: -3,86; -0,79], pacifier [SMD 3,74 IC 95%: -7,30; 0,19], and sugars and pacifier SMD [3,88 IC 95% -7,72; -0,04]. CONCLUSION: Non-pharmacological measures are strongly recommended for pain management in preterm infants in the NICU. IMPLICATIONS FOR CLINICAL PRACTICE: The findings of this study have important implications for policy and practice. This is the only systematic review that compared the effectiveness of non-pharmacological measures, thus making it possible to identify which measure presents the best results and could be the first choice in clinical decision making.

Weight loss and mortality in people living with HIV: a systematic review and meta-analysis.

BACKGROUND: In the first reported cases of human immunodeficiency virus (HIV) infection, people living with HIV (PLHIV) suffered weight loss, which was an independent predictor of mortality. Highly active antiretroviral therapy (HAART) has changed this scenario for ideal weight, overweight, and even obesity. However, some PLHIV, even on HAART, continue to lose weight. Thus, the guiding question of the study was: do PLHIV hospitalized using HAART with weight loss have higher mortality than hospitalized PLHIV using HAART without weight loss? METHOD: A systematic review and meta-analysis of prospective cohort studies published in English, Spanish, or Portuguese, searched in the MedLine, Embase, and LILACS databases from March 2020, until October 2023, reported by MOOSE. We analyzed the methodological quality and risk of bias using the Joanna Briggs Institute Critical Appraisal Tool for Cohort Studies; used the risk ratio (RR) to calculate the probability of hospitalized PLWH who lost weight dying, applied the random effect model and created the funnel plot. We used the inverse variance test estimated by the Mantel-Haenszel method, considering a 95% confidence interval (CI), heterogeneity (I2), total effect size (Z), and significance value of p < 0.05. We performed a sensitivity analysis with meta-regression and meta-analyses on subgroups to diagnose influence and outliers. The quality of evidence and strength of recommendation were analyzed using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE). RESULTS: We included 10 of the 711 studies identified, totaling 1,637 PLHIV. The studies were from South Africa (1), Canada (1), China (1), Brazil (1), Cameroon (1), Ethiopia (1), Thailand (1), Colombia (1), and Tanzania (2), from 1996 to 2017. The average age of the participants was 33.1 years old, and the male was predominant. The leading causes of hospital admission were related to co-infections, and the average hospitalization time was 20.5 days. The prevalence of death in hospitalized PLHIV using HAART who lost weight was 57.5%, with a 1.5 higher risk of dying (RR: 1.50, 95% CI: 1.03, 2.19, p = 0.04) than hospitalized PLHIV who did not lose weight. CONCLUSION: We concluded, with a very low confidence level, that that weight loss significantly increased the risk of death in hospitalized PLWH using HAART. TRIAL REGISTRATION AND FUNDING: PROSPERO International Prospective Register of Systematic Reviews CRD42020191246 https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191246 .

The Anti-Arthritic Activity of Diclofenac Lipid-Core Nanocapsules: Stereological Analysis Showing More Protection of Deep Joint Components.

Diclofenac is the most prescribed nonsteroidal anti-inflammatory drug worldwide and is used to relieve pain and inflammation in inflammatory arthritis. Diclofenac is associated with serious adverse effects, even in regular-dose regimens. Drug delivery systems can overcome this issue by reducing adverse effects and optimizing their efficacy. This study evaluated the activity of lipid-core nanocapsules loaded with diclofenac (DIC-LNCs) in an experimental model of adjuvant-induced arthritis. The diclofenac nanoformulation was obtained via self-assembly. A stereological analysis approach was applied for the morphological quantification of the volume, density, and cellular profile count of the metatarsophalangeal joints of rats. Proinflammatory cytokines and biochemical profiles were also obtained. Our results showed that the diclofenac nanocapsule DIC-LNCs were able to reduce arthritis compared with the control group and the DIC group. DIC-LNCs efficiently reduced proinflammatory cytokines, C-reactive protein, and xanthine oxidase levels. Additionally, DIC-LNCs reduced the loss of synoviocytes and chondrocytes compared with the DIC (p < 0.05) and control groups (p < 0.05). These data suggest that DIC-LNCs have anti-arthritic activity and preserve joint components, making them promising for clinical use.

Cytotoxic and immunomodulatory potential of a novel [2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-3-yl)pyridine] in myeloid leukemia.

Cancer ranks among the leading causes of mortality worldwide. However, the efficacy of commercially available anticancer drugs is compromised by the emerging challenge of drug resistance. This study aimed to investigate the anticancer and immunomodulatory potential of a recently developed a novel [2-(4-(2,5-dimethyl-1 H-pyrrol-1-yl)- 1 H-pyrazol-3-yl) pyridine]. The cytotoxic potential of the compound was assessed using the MTT assay on both cancerous HL60 (acute myeloid leukemia) and K562 (chronic myeloid leukemia) cell lines, as well as non-cancerous Vero cells and human peripheral blood mononuclear cells (PBMCs). A clonogenic assay was employed to evaluate the anticancer efficacy of the compound, while flow cytometry was utilized to investigate its effect on cell cycle arrest. Furthermore, the immunomodulatory potential of the compound was assessed by quantifying inflammatory and anti-inflammatory biomarkers in the supernatant of PBMCs previously treated with the compound. Our study revealed that the novel pyridine ensemble exhibits selective cytotoxicity against HL60 (IC50 = 25.93 µg/mL) and K562 (IC50 = 10.42 µg/mL) cell lines, while displaying no significant cytotoxic effect on non-cancerous cells. In addition, the compound induced a decrease of 18% and 19% in the overall activity of COX-1 and COX-2, respectively. Concurrently, it upregulated the expression of cytokines including IL4, IL6, IL10, and IL12/23p40, while downregulating INFγ expression. These findings suggest that the compound has the potential to serve as a promising candidate for the treatment of acute and chronic myeloid leukemias due to its effective antiproliferative and immunomodulatory activities, without causing cytotoxicity in non-cancerous cells.

Torque Teno virus DNA is found in the intracranial aneurysm wall-Is there a causative role?

Objective: Torque Teno virus (TTV) is a recently discovered virus with high prevalence worldwide, that has been associated with vascular diseases. The aim of this study is to investigate the prevalence of TTV molecular DNA in the intracranial aneurysm (IA) artery walls. Method: Samples of IA walls were collected after microsurgical clipping from 35 patients with IA (22 ruptured/13 unruptured cases). The samples were submitted to molecular DNA extraction using the EasyMag automatized extractor and performed with Qiagen DNA extraction Minikit 250. The samples underwent PCR examination with primers for ß-globin as internal control using the Nanodrop ® 2000 spectrophotometer. A quantitative (real-time) PCR with TTV-specific primers was performed. Clinical and radiological data of patients included was collected. Results: TTV was detected in 15 (42.85%) cases, being 10 (45.4%) ruptured and 5 (38.4%) unruptured (p = 0.732) lesions. Multiple IAs accounted for 14 (40%) cases. Five cases (17.2%) had TTV+ and multiple aneurysms (p = 0.73). Association between presence of virus and aneurysm rupture was not statistically significant (p = 0.96). Conclusion: This study demonstrated a relatively high prevalence of viral DNA in the walls of IAs. This is the first study to identify the presence of TTV DNA in IA's samples, which was found more often in ruptured lesions. This is an exploratory study, therefore, larger studies are required to clarify the relationships between inflammation, viral infection, IA formation and rupture.

Transcranial direct-current stimulation over the motor cortex in patients suffering from anxiety and depression related to rheumatoid arthritis: Study protocol for a randomized, double-blind, placebo-controlled trial.

Rheumatoid arthritis is up to three times more prevalent in women. It is often associated with anxiety and depression, comorbidities causing psychic suffering and potentiating pain perception. It is also related to a higher risk of suicide among diagnosed patients. The high rates of discontinuation of conventional pharmacological treatments are the predominant factor in the search for new therapeutic approaches for the treatment of anxiety and depression. Transcranial direct-current stimulation (tDCS) is a promising, safe and low-cost technique that is very associative with other therapies. When applied to the primary motor cortex (M1) it can induce long-term changes in the synaptic level leading to the improvement of neuroplasticity. The primary aim of this study is to evaluate the effect of tDCS on the symptoms of anxiety and depression. The secondary aim is to evaluate the interference of tDCS on the inflammatory profile, cardiac autonomic behavior and quality of life of patients with rheumatoid arthritis. This is a randomized, double-blind, placebo-controlled clinical trial. The intervention consists of 10 consecutive sessions (once a day) applying tDCS with a 2mA current for 20 minutes. The electrode assembly on the scalp is in accordance with the International Electroencephalogram System 10-20 (EEG) and the anodal electrode is placed over the area of the primary motor cortex (M1 - C3 or C4) and the cathodal electrode on the supraorbital contralateral area (SO - Fp1 or Fp2). The analysis of continuous variables will be described by mean and standard deviation for parametric data and median and interquartile interval for nonparametric data. The evaluation of the effect of tDCS on the inflammatory profile, heart rate variability and quality of life will be obtained by the ANOVA two-way test. tDCS is expected to have a greater effect on reducing anxiety and depression symptoms compared to the placebo, being able to decrease inflammation and improve the quality of life of volunteers.

Therapeutic Potential of Leaves from Fridericia chica (Bonpl.) L. G. Lohmann: Botanical Aspects, Phytochemical and Biological, Anti-Inflammatory, Antioxidant and Healing Action.

Plants of the species Fridericia chica (Bonpl.) L. G. Lohmann (Bignoniaceae), which are widely distributed in Brazil and named crajiru in the state of Amazonas, are known in folk medicine as a traditional medicine in the form of a tea for the treatment of intestinal colic, diarrhea, and anemia, among other diseases. The chemical analysis of extracts of the leaves has identified phenolic compounds, a class of secondary metabolites that provide defense for plants and benefits to the health of humans. Several studies have shown the therapeutic efficacy of F. chica extracts, with antitumor, antiviral, wound healing, anti-inflammatory, and antioxidant activities being among the therapeutic applications already proven. The healing action of F. chica leaf extract has been demonstrated in several experimental models, and shows the ability to favor the proliferation of fibroblasts, which is essential for tissue repair. The anti-inflammatory activity of F. chica has been clearly demonstrated by several authors, who suggest that it is related to the presence of 3-deoxyanthocyanidins, which is capable of inhibiting pro-inflammatory pathways such as the kappa B (NF-kB) nuclear transcription factor pathway. Another important effect attributed to this species is the antioxidant effect, attributed to phenolic compounds interrupting chain reactions caused by free radicals and donating hydrogen atoms or electrons. In conclusion, the species Fridericia chica has great therapeutic potential, which is detailed in this paper with the objective of encouraging new research and promoting the sum of efforts for the inclusion of herbal medicines in health systems around the world.

Anti-inflammatory effects and acute oral toxicity of Copaifera spp. essential oil-loaded nanoemulsion / Efectos antiinflamatorios y toxicidad oral aguda de nanoemulsión cargada de aceite esencial de Copaifera spp

Copaifera spp. essential oil (EOC) was extracted by hydrodistillation of Copaifera oleoresin (COR). The EOC was characterized by GC/MS and a novel EOC-loaded nanoemulsion was developed to enhance the EOC solubility and to evaluate its utility as antinflammatory. EOC contain 14 volatile compounds (including ß-caryophyllene: 51.52%) having a required HLB of 11. The Surfactant: EOC: Water ratio of 13:15:75 (%, w:w:w) produced the optimal formulation (particle size: 94.47 nm). The EOC-loaded nanoemulsion presented a pseudoplastic/thixotropic behavior with excellent shelf stability for 6 months. The anti-inflammatory effect of the nanoemulsion was more potent than that of the EOC, and statistically equal to diclofenac (50 mg/kg). The EOC-loaded nanoemulsion showed no oral acute toxicity (in mice) at 2000 mg/kg; hence, it is considered a nontoxic product. The development of the EOC-loaded nanoemulsion added value to both the COR and the EOC by providinga suitable formulation that could be used as an anti-inflammatory product.

El aceite esencial (EOC) fue extraído por hidrodestilación de oleoresina de Copaifera spp. El EOC fue caracterizado químicamente por GC/MS. Se formuló una nanoemulsión con EOC para mejorar la solubilidad del EOC y evaluar su utilidad como antiinflamatorio. El EOC contiene 14 compuestos volátiles (incluido el ß-cariofileno: 51,52%) con un HLB requerido de 11. La relación Tensioactivo: EOC: Agua de 13:15:75 (%, p:p:p) produjo la formulación óptima (tamaño de partícula: 94,47 nm).. La nanoemulsión cargada con EOC presentó un comportamiento pseudoplástico/tixotrópico con una excelente estabilidad en almacenamiento durante 6 meses. El efecto antiinflamatorio de la nanoemulsión fue más potente que el del EOC y estadísticamente igual al diclofenaco (50 mg/kg). La nanoemulsión cargada con COE no mostró toxicidad aguda oral (en ratones) a 2000 mg/kg; por lo tanto, se considera un producto no tóxico. El desarrollo de la nanoemulsión cargada con EOC agregó valor tanto al COR como al EOC al proporcionar una formulación adecuada que podría usarse como un producto antiinflamatorio.

A genetic variant in the TRAF1/C5 gene lead susceptibility to active pulmonary tuberculosis by decreased TNF-α levels.

Host genetics are important to consider in the role of resistance or susceptibility for developing active pulmonary tuberculosis (TB). Several association studies have reported the role of variants in STAT4 and TRAF1/C5 as risk factors to autoimmune diseases. Nevertheless, more data is needed to elucidate the role of these gene variants in infectious disease. Our data reports for the first time, variant rs10818488 in the TRAF1/C5 gene (found 47% of the population worldwide), is associated with susceptibility (OR = 1.51) to development TB. Multivariate analysis evidenced association between rs10818488 TRAF1/C5 and risk to multibacillary TB (OR = 4.18), confers increased bacteria load in the lung, indicates a decreased ability to control pathogen levels in the lung, and spread of the pathogen to new hosts. We showed that the "loss-of-function" variant in TRAF1/C5 led to susceptibility for TB by decreased production of TNF-α. Our results suggest the role of variant TRAF1/C5 in susceptibility to TB as well as in clinical presentation of multibacillary TB.

Single-Nucleotide Variants in the AIM2 - Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis.

Tuberculosis (TB) remains a serious public health burden worldwide. TB is an infectious disease caused by the Mycobacterium tuberculosis Complex. Innate immune response is critical for controlling mycobacterial infection. NOD-like receptor pyrin domain containing 3/ absent in melanoma 2 (NLRP3/AIM2) inflammasomes are suggested to play an important role in TB. NLRP3/AIM2 mediate the release of pro-inflammatory cytokines IL-1ß and IL-18 to control M. tuberculosis infection. Variants of genes involved in inflammasomes may contribute to elucidation of host immune responses to TB infection. The present study evaluated single-nucleotide variants (SNVs) in inflammasome genes AIM2 (rs1103577), CARD8 (rs2009373), and CTSB (rs1692816) in 401 patients with pulmonary TB (PTB), 133 patients with extrapulmonary TB (EPTB), and 366 healthy control (HC) subjects with no history of TB residing in the Amazonas state. Quantitative Real Time PCR was performed for allelic discrimination. The SNV of AIM2 (rs1103577) is associated with protection for PTB (padj: 0.033, ORadj: 0.69, 95% CI: 0.49-0.97). CTSB (rs1692816) is associated with reduced risk for EPTB when compared with PTB (padj: 0.034, ORadj: 0.50, 95% CI: 0.27-0.94). Serum IL-1ß concentrations were higher in patients with PTB than those in HCs (p = 0,0003). The SNV rs1103577 of AIM2 appeared to influence IL-1ß release. In a dominant model, individuals with the CC genotype (mean 3.78 ± SD 0.81) appeared to have a higher level of IL-1ß compared to carriers of the T allele (mean 3.45 ± SD 0.84) among the patients with PTB (p = 0,0040). We found that SNVs of AIM2 and CTSB were associated with TB, and the mechanisms involved in this process require further study.

Epidemiological, clinical and immune factors that influence the persistence of antiphospholipid antibodies in leprosy.

INTRODUCTION: Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. OBJECTIVES: To determine whether epidemiological, clinical and immunological factors played a role in the long-term persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. METHODS: The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-ß2 glycoprotein I (anti-ß2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. RESULTS: Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-ß2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82-0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0-0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03-7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. CONCLUSION: Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.

Cavernous carotid artery aneurysms on a single institution: An epidemiological study with 201 patients.

OBJECTIVES: Cavernous carotid aneurysms (CCA) represent 2-9% of all intracranial aneurysms. For long considered benign lesions, these entities are unique when it comes to clinical presentation and management. Usually asymptomatic, CCAs can grow and rupture causing different manifestations. The lack of a long-term assessment of both treated and untreated CCAs' natural history justifies why there is no consensus regarding what are the recommended therapeutic measures. While some advocate that an intervention is always necessary, others consider that patients deserve an individualized evaluation. PATIENTS AND METHODS: We describe our single-institution experience in diagnosis, follow-up, and management of 201 CCAs. In addition, we evaluate the association of giant CCAs with aneurysms in other locations using a Chi-square test. RESULTS: 201 patients had 245 CCAs. 92% of the patients were women. The mean age at diagnosis was 61 years. Concomitant aneurysms were observed in 53.2% of the patients, and the middle cerebral artery was the most affected artery. 66 (30.6%) CCAs were considered "giant", and the follow-up period ranged from 1 to 23 years.The presence of a giant CCA seemed to hinder other aneurysms' formation - RR 0.47 (IC 95% 0.31-0.67), p < 0.0001. CONCLUSIONS: CCAs should be individually assessed. A conservative approach ought to be adopted for asymptomatic and oligosymptomatic lesions. Finally, a multidisciplinary team must evaluate the other situations, in order to define whether the microsurgical or the endovascular treatment is better option. Presence of a giant lesion within the cavernous sinus is associated with less occurrence of other aneurysms.

Epidemiological, clinical and immune factors that influence the persistence of antiphospholipid antibodies in leprosy

Abstract Introduction: Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. Objectives: To determine whether epidemiological, clinical and immunological factors played a role in the longterm persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. Methods: The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. Results: Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-β2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82-0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0-0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03-7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. Conclusion: Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.

Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis.

Tuberculosis (TB), caused by mycobacterial species of the Mycobacterium tuberculosis complex, is a serious global health issue. Brazil is among the 22 countries with the highest number of TB cases, and the state of Amazonas has the highest incidence of TB cases in the country. Toll-like receptors (TLRs) are important pattern recognition receptors of the innate immunity and play a key role in orchestrating an effective immune response. We investigated whether the single-nucleotide polymorphisms (SNPs) 1805T/G TLR1, 2258G/A TLR2, 896A/G and 1196C/T of TLR4, 745T/C TLR6, and -1237A/G and -1486A/G of TLR9 are associated with the predisposition to TB and/or bacillary load. The SNPs genotyping was performed by nucleotide sequencing in 263 TB patients and 232 healthy controls residing in the state of Amazonas. Alleles and genotypes frequencies were similar between patients and healthy individuals for most of the investigated SNPs. Stratification of the TB patients according to their bacillary load showed that the genotype 1805TT TLR1 (rs5743618) was prevalent among paucibacillary patients [odds ratio (OR) = 0.38; 95% confidence interval (CI) = 0.19-0.76; p = 0.009] while the genotype 1805TG was common among multibacillary patients (OR = 3.72; CI = 1.65-8.4; p = 0.004). Comparison of demographic characteristics of patients to controls showed that TB is strongly associated with smoking (OR = 6.55; 95% CI = 3.2-13.6; p < 0.0001); alcohol use disorder (OR = 7.14; 95% CI = 3.7-13.9; p < 0.0001); and male gender (OR = 3.66; 95% CI = 2.52-5.3; p < 0.0001). Multivariate logistic regression demonstrated that alcoholism (OR = 2.93; 95% CI = 1.05-8.16; p = 0.03) and the 1805G allele (OR = 2.75; 95% CI = 1.33-5.7; p = 0.006) are predictive variables for multibacillary TB. Altogether, we suggest that the TLR1 1805G allele may be a relevant immunogenetic factor for the epidemiology of TB together with environmental, sociodemographic, and behavioral factors.

Alleles of HLA-DRB1*04 Associated with Pulmonary Tuberculosis in Amazon Brazilian Population.

Immunogenetic host factors are associated with susceptibility or protection to tuberculosis (TB). Strong associations of HLA class II genes with TB are reported. We analyzed the HLA-DRB1*04 alleles to identify subtypes associated with pulmonary TB and their interaction with risk factors such as alcohol, smoking, and gender in 316 pulmonary TB patients and 306 healthy individuals from the Brazilian Amazon. The HLA-DRB1*04 was prevalent in patients with pulmonary TB (p<0.0001; OR = 2.94; 95% CI = 2.12 to 4.08). Direct nucleotide sequencing of DRB1 exon 2 identified nine subtypes of HLA-DRB1*04. The subtype HLA-DRB1*04:11:01 (p = 0.0019; OR = 2.23; 95% CI = 1.34 to 3.70) was associated with susceptibility to pulmonary TB while DRB1*04:07:01 (p<0.0001; OR = 0.02; 95% CI = 0.001 to 0.33) to protection. Notably, the interaction between alcohol and HLA-DRB1*04:11:01 increased the risk for developing pulmonary TB (p = 0.0001; OR = 51.3; 95% CI = 6.81 to 386). Multibacillary pulmonary TB, the clinical presentation of disease transmission, was strongly associated with interaction to alcohol (p = 0.0026; OR = 11.1; 95% CI = 3.99 to 30.9), HLA-DRB1*04:11:01 (p = 0.0442; OR = 2.01; 95% CI = 1.03 to 3.93) and DRB1*04:92 (p = 0.0112; OR = 8.62; 95% CI = 1.63 to 45.5). These results show that HLA-DRB1*04 are associated with pulmonary TB. Interestingly, three subtypes, DRB1*04:07:01, DRB1*04:11:01 and DRB1*04:92 of the HLA-DRB1*04 could be potential immunogenetic markers that may help to explain mechanisms involved in disease development.

Headache-related disability among medical students in Amazon: a cross-sectional study.

OBJECTIVE: To evaluate the prevalence of headache in medical students, and quantify the degree of disability through HIT-6 and MIDAS SCALE. METHOD: The criteria established by International Headache Society were used and the HIT-6 and MIDAS, to asses disability. RESULTS: 140 medical students from UFAM were evaluated. 16.43% cases of migraine headache, 6.43% of probable migraine, and 23.57% of tension headaches were detected. 6.42% reported an absence of headache; and another 11.42% had secondary headache. According to the HIT-6 questionnaire, in 7.14% and 18.57% of the students, headaches were classified as having substantial to severe impact, respectively. CONCLUSION: Migraine and probable migraine had higher scores than the other types of headache and, therefore, led to higher levels of disability. The present study did not find a significant correlation between student semester, age or extracurricular activities on the impact generated by headache.

Headache-related disability among medical students in Amazon: a cross-sectional study / Incapacidade relacionada à cefaleia em estudantes de medicina no Amazonas: um estudo transversal

ABSTRACT Objective To evaluate the prevalence of headache in medical students, and quantify the degree of disability through HIT-6 and MIDAS scale. Method The criteria established by International Headache Society were used and the HIT-6 and MIDAS, to asses disability. Results 140 medical students from UFAM were evaluated. 16.43% cases of migraine headache, 6.43% of probable migraine, and 23.57% of tension headaches were detected. 6.42% reported an absence of headache; and another 11.42% had secondary headache. According to the HIT-6 questionnaire, in 7.14% and 18.57% of the students, headaches were classified as having substantial to severe impact, respectively. Conclusion Migraine and probable migraine had higher scores than the other types of headache and, therefore, led to higher levels of disability. The present study did not find a significant correlation between student semester, age or extracurricular activities on the impact generated by headache.

RESUMO Objetivo Avaliar a prevalência de cefaleia em estudantes médicos e quantificar o grau de incapacidade através das escalas HIT-6 e MIDAS. Método Os critérios da Sociedade Internacional de Cefaleia foram usados e as escalas Hit-6 e MIDAS foram usadas para medir a incapacidade. Resultados 140 estudantes de medicina da UFAM foram avaliados. 16.43% eram migrânea, 6.43% de provável migrânea e 23.57% de cefaleia tipo tensional. 6,42% relataram ausência de cefaleia e 11.42% possuíam cefaleia secundária. De acordo com o questionário HIT-6 em 7,14% e 18,57% dos estudantes, a cefaleia foram classificadas como impacto substancial e grave respectivamente. Conclusão Migrânea e provável migrânea tiveram escores mais elevados do que os outros tipos de cefaleia e maiores níveis de incapacidade. O estudo não encontrou uma associação significante entre o período de graduação, idade ou das atividades extracurriculares com o impacto gerado pela cefaleia.

Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model.

BACKGROUND: Rheumatoid arthritis (RA) is the most common autoimmune disease in the word, affecting 1% of the population. Long-term prognosis in RA was greatly improved following the introduction of highly effective medications such as methotrexate (MTX). Despite the importance of this drug in RA, 8%-16% of patients must discontinue the treatment because of adverse effects. Last decade, we developed a promising new nanocarrier as a drug-delivery system, lipid-core nanocapsules. OBJECTIVE: The aim of the investigation reported here was to evaluate if methotrexate-loaded lipid-core nanocapsules (MTX-LNC) reduce proinflammatory and T-cell-derived cytokines in activated mononuclear cells derived from RA patients and even in functional MTX-resistant conditions. We also aimed to find out if MTX-LNC would reduce inflammation in experimentally inflammatory arthritis at lower doses than MTX solution. METHODS: Formulations were prepared by self-assembling methodology. The adjuvant arthritis was induced in Lewis rats (AIA) and the effect on edema formation, TNF-α levels, and interleukin-1 beta levels after treatment was evaluated. Mononuclear cells obtained from the synovial fluid of RA patients during articular infiltration procedures were treated with MTX solution and MTX-LNC. For in vitro experiments, the same dose of MTX was used in comparing MTX and MTX-LNC, while the dose of MTX in the MTX-LNC was 75% lower than the drug in solution in in vivo experiments. RESULTS: Formulations presented nanometric and unimodal size distribution profiles, with D[4.3] of 175±17 nm and span of 1.6±0.2. Experimental results showed that MTX-LNC had the same effect as MTX on arthritis inhibition on day 28 of the experiment (P<0.0001); however, this effect was achieved earlier, on day 21 (P<0.0001), by MTX-LNC, and this formulation had reduced both TNF-α (P=0.001) and IL-1α (P=0.0002) serum levels by the last day of the experiment. Further, the MTX-LNC were more effective at reducing the cytokine production from mononuclear synovial cells than MTX. CONCLUSION: The MTX-LNC were better than the MTX solution at reducing proinflammatory cytokines and T-cell-derived cytokines such as interferon-gamma and interleukin-17A. This result, combined with the reduction in the dose required for therapy, shows that MTX-LNC are a very promising system for the treatment of RA.

Serum thiols as a biomarker of disease activity in lupus nephritis.

Lupus Nephritis (LN) develops in more than half of the Systemic Lupus Erythematous (SLE) patients. However, lack of reliable, specific biomarkers for LN hampers clinical management of patients and impedes development of new therapeutics. The goal of this study was to investigate whether oxidative stress biomarkers in patients with SLE is predictive of renal pathology. Serum biochemical and oxidative stress markers were measured in patients with inactive lupus, active lupus with and without nephritis and compared to healthy control group. To assess the predictive performance of biomarkers, Receiver Operating Characteristic (ROC) curves were constructed and cut-offs were used to identify SLE patients with nephritis. We observed an increased oxidative stress response in all SLE patients compared to healthy controls. Among the several biomarkers tested, serum thiols had a significant inverse association with SLE Disease Activity Index (SLEDAI). Interestingly, thiols were able too aptly differentiate between SLE patients with and without renal pathology, and serum thiol levels were not affected by immunosuppressive drug therapy. The decreased thiols in SLE correlated significantly with serum creatinine and serum C3 levels. Further retrospective evaluation using serum creatinine or C3 levels in combination with thiol's cutoff values from ROC analysis, we could positively predict chronicity of renal pathology in SLE patients. In summary, serum thiols emerge as an inexpensive and reliable indicator of LN, which may not only help in early identification of renal pathology but also aid in the therapeutic management of the disease, in developing countries with resource poor settings.

A comparison of the ability of Bellucia dichotoma Cogn. (Melastomataceae) extract to inhibit the local effects of Bothrops atrox venom when pre-incubated and when used according to traditional methods.

Bellucia dichotoma Cogn. (Melastomataceae) is one of various plant species used in folk medicine in the west of the state of Pará, Brazil, to treat snake bites. Many studies have been carried out to evaluate the effectiveness of anti-snake bite plants, but few of these use the same preparation methods and doses as those traditionally used by the local populations. This study therefore compared inhibition of the main local effects of B. atrox venom (BaV) by aqueous extract of B. dichotoma (AEBd) administered according to traditional methods and pre-incubated with BaV). The concentrations of phenolic compounds (tannins and flavonoids) in AEBd were determined by colorimetric assays. The effectiveness of AEBd in inhibiting the hemorrhagic and edematogenic activities of BaV was evaluated in mice in four different experimental in vivo protocols: (1) pre-incubation (venom:extract, w/w); (2) pre-treatment (p.o.); (3) post-treatment (p.o.); and (4) AEBd (p.o.) in combination with Bothrops antivenom (BA) (i.v.). To assess in vitro inhibition of BaV phospholipase A2 activity, the pre-incubation method or incorporation of AEBd or BA in agarose gels were used. The effect of AEBd on BaV was determined by SDS-PAGE, zymography and Western blot. Colorimetric assays revealed higher concentrations of (condensed and hydrolyzable) tannins than flavonoids in AEBd. Hemorrhagic activity was completely inhibited using the pre-incubation protocol. However, with pre-treatment there was no significant inhibition for the concentrations tested, and with the post-treatment only the 725 mg/kg dose of AEBd was able to inhibit 40.5% (p = 0.001) of the hemorrhagic activity of BaV. Phospholipase A2 activity was only inhibited when AEBd was pre-incubated with BaV. BaV-induced edema was completely inhibited with pre-incubation (p < 0.05) and significantly reduced (p < 0.05) with pre- and post-treatment (p.o.) for the concentrations tested. The reduction in local edema was even greater when AEBd was administered in combination with BA. The SDS-PAGE profiles showed that several of the BaV protein (SDS-PAGE) and enzyme (zymography) bands were not detected when the venom was pre-incubated, and Western blot revealed that this was not caused by the AEBd enzymes observed in the zymogram. The "pseudo inhibition" observed after pre-incubation in this study may be due to the presence of tannins in the extract, which could act as chelating agents, removing metalloproteins and Ca²âº ions and thus inhibiting hemorrhagin and PLA2 activity. However, when administered according to traditional methods, B. dichotoma extract was effective in blocking BaV-induced edematogenic activity and had an additional effect on inhibition of this activity by BA.