The link between cutaneous inflammation and cognitive impairment.

Cognitive impairment is a symptom of neurological disorders, including dementia and Alzheimer's disease; and mild cognitive impairment can be a precursor of both disorders. Aged humans and animal models with other systemic disorders, such as cardiovascular diseases and diabetes, display a higher incidence of cognitive decline. Epidemiological studies have shown that the incidence of cognitive impairment also is higher in subjects with certain inflammatory skin disorders, including psoriasis and chronic eczematous dermatitis. Chronologically aged individuals exhibit increased cutaneous inflammation and elevated circulating cytokine levels, linked to alterations in epidermal function, which itself can induce cutaneous inflammation. Conversely, strategies that improve epidermal function can lower cytokine levels in both the skin and circulation. Thus, it seems likely that epidermal dysfunction could contribute, at least in part, to the development of chronic low-grade inflammation, also termed 'inflammaging', in the elderly. The evidence of cognitive impairment in patients with inflammatory dermatoses suggests a link between cutaneous inflammation and cognitive impairment. Because of the pathogenic role of epidermal dysfunction in ageing-associated cutaneous inflammation, improvements in epidermal function could be an alternative approach for mitigation of the ageing-associated decline in cognitive function.

Validation of physician certified verbal autopsy using conventional autopsy: a large study of adult non-external causes of death in a metropolitan area in Brazil.

BACKGROUND: Reliable mortality data are essential for the development of public health policies. In Brazil, although there is a well-consolidated universal system for mortality data, the quality of information on causes of death (CoD) is not even among Brazilian regions, with a high proportion of ill-defined CoD. Verbal autopsy (VA) is an alternative to improve mortality data. This study aimed to evaluate the performance of an adapted and reduced version of VA in identifying the underlying causes of non-forensic deaths, in São Paulo, Brazil. This is the first time that a version of the questionnaire has been validated considering the autopsy as the gold standard. METHODS: The performance of a physician-certified verbal autopsy (PCVA) was evaluated considering conventional autopsy (macroscopy plus microscopy) as gold standard, based on a sample of 2060 decedents that were sent to the Post-Mortem Verification Service (SVOC-USP). All CoD, from the underlying to the immediate, were listed by both parties, and ICD-10 attributed by a senior coder. For each cause, sensitivity and chance corrected concordance (CCC) were computed considering first the underlying causes attributed by the pathologist and PCVA, and then any CoD listed in the death certificate given by PCVA. Cause specific mortality fraction accuracy (CSMF-accuracy) and chance corrected CSMF-accuracy were computed to evaluate the PCVA performance at the populational level. RESULTS: There was substantial variability of the sensitivities and CCC across the causes. Well-known chronic diseases with accurate diagnoses that had been informed by physicians to family members, such as various cancers, had sensitivities above 40% or 50%. However, PCVA was not effective in attributing Pneumonia, Cardiomyopathy and Leukemia/Lymphoma as underlying CoD. At populational level, the PCVA estimated cause specific mortality fractions (CSMF) may be considered close to the fractions pointed by the gold standard. The CSMF-accuracy was 0.81 and the chance corrected CSMF-accuracy was 0.49. CONCLUSIONS: The PCVA was efficient in attributing some causes individually and proved effective in estimating the CSMF, which indicates that the method is useful to establish public health priorities.

Heavy metal contamination in Peru: implications on children's health.

Cerro de Pasco, Peru, has been excessively contaminated with heavy metals due to high mining activities in the region. We investigated the presence of chronic exposure to heavy metals in children living in Cerro de Pasco and its effect on health. Heavy metal concentrations were determined in hair samples collected from 78 children living in a region exposed to an open-pit mine (Paragsha region) and from other 16 children unexposed to mine activities (Carhuamayo region). Children exposed to the mine showed statistically significant higher concentration of aluminum, antimony, arsenic, cadmium, chromium, iron, lead, tin and thallium (p < 0.05) than control children. Hair samples collected from the same children in two occasions (2016 and 2018) showed that the exposure is chronic with higher levels of heavy metals observed in 2018. The concentration of heavy metals was higher in hair tip than in hair root samples. Heavy metals are associated with substantial higher risk of nosebleed (odds ratio, OR = 15.40), chronic colic (OR = 7.30), dermatologic alterations (OR = 6.16), mood alterations (OR = 7.07), presence of white lines on nails (OR = 12.10), reduced visual camp (OR = 3.97) and other symptoms (OR = 5.12). Chronic heavy metal exposure implies various negative consequences on children's health. Preventive measures are crucial to protect children's health.

Estimation of the post-mortem interval: Effect of storage conditions on the determination of vitreous humour [K+].

Obtaining a reliable estimate of the post-mortem interval (PMI) has been a long-running challenge in forensic medicine. Several more or less successful techniques for making such estimates have been developed, but in recent years important advances have been made thanks to the detailed study of the relationship between the PMI and the analytes - in particular K+ - of the vitreous humour (VH). The extraction and pre-treatment of VH samples has been standardized, the influence of certain environmental factors on analytical results has been quantified, and some of the circumstances under which techniques become unreliable have been identified. The present work examines how the conditions to which VH samples are subject in routine practice may alter the results of their analysis. Exposure to light and ambient temperature was found to alter the values returned in determinations of VH [K+], [Na+] and [Cl-], while exposure to several freezing/thawing cycles (even with final heating) led to no significant modifications in determinations of VH [K+] and [Na+]. It is recommended that if analysis has to be delayed, VH should be frozen for storage in a refrigerator before bringing to room temperature for processing. It is also recommended that samples not be exposed to ambient light and temperature.

Reemergence of Yellow Fever in Brazil: The Role of Distinct Landscape Fragmentation Thresholds.

Yellow Fever Virus (YFV) reemergence in Brazil was followed by human suffering and the loss of biodiversity of neotropical simians on the Atlantic coast. The underlying mechanisms were investigated with special focus on distinct landscape fragmentation thresholds in the affected municipalities. An ecological study in epidemiology is employed to assess the statistical relationship between events of YFV and forest fragmentation in municipal landscapes. Negative binomial regression model showed that highly fragmented forest cover was associated with an 85% increase of events of YFV in humans and simians (RR = 1.85, CI 95% = 1.24-2.75, p=0.003) adjusted by vaccine coverage, population size, and municipality area. Intermediate levels of forest cover combined with higher levels of forest edge densities contribute to the YFV dispersion and the exponential growth of YF cases. Strategies for forest conservation are necessary for the control and prevention of YF and other zoonotic diseases that can spillover from the fragmented forest remains to populated cities of the Brazilian Atlantic coast.

CERKL is upregulated in cutaneous squamous cell carcinoma and maintains cellular sphingolipids and resistance to oxidative stress.

BACKGROUND: Ceramide kinase-like protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism. OBJECTIVES: To determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress. METHODS: CERKL expression was determined by RNA-Seq, quantitative polymerase chain reaction and immunohistochemistry. CERKL was knocked down in cSCC cells using small interfering RNA. Sphingolipid content was analysed by liquid chromatography-mass spectrometry. Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin V binding. RESULTS: CERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL is also expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress. CONCLUSIONS: These findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

CERKL is Upregulated in Cutaneous Squamous Cell Carcinoma and Maintains Cellular Sphingolipids and Resistance to Oxidative Stress.

BACKGROUND: Ceramide Kinase-Like Protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease, retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism. OBJECTIVES: To determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress. METHODS: CERKL expression was determined by RNA-Seq, qPCR and immunohistochemistry. CERKL was knocked down in cSCC cells using siRNA. Sphingolipid content was analyzed by liquid chromatography-mass spectrometry (LC-MS). Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin v binding. RESULTS: CERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL also is expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress. CONCLUSIONS: These findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

Comparison of Fundus Biomicroscopy Examination of the Optic Nerve Head with and without Mydriasis.

BACKGROUND: Notwithstanding the significant advances in automated imaging techniques in the past 2 decades, subjective evaluation of the optic disc still remains an important part of glaucoma propaedeutic. In places with limited resources and a high demand for ophthalmic care, anatomical evaluation of glaucoma cases often relies solely on slit-lamp-based fundus biomicroscopic examination, which is frequently performed without mydriasis. OBJECTIVE: The aim of this study was to compare metrics related to fundus biomicroscopy examination of the optic nerve head and peripapillary retinal nerve fiber layer (pRNFL) with and without mydriasis. MATERIAL AND METHODS: Healthy individuals, patients with early glaucoma, and glaucoma suspects were prospectively enrolled. Patients were examined before and after mydriasis by three glaucoma specialists, who estimated patients' vertical cup-to-disc ratio (CDR) and evaluated the presence of glaucomatous signs: laminar dot sign, disc hemorrhage, disc saucering, disc notching, peripapillary atrophy, localized pRNFL defect, and loss of the ISNT pattern. Main outcome measures were the intra-observer comparison, the inter-observer agreement, and the abilities to identify glaucomatous signs before and after mydriasis. RESULTS: Thirty patients (60 eyes) were enrolled (mean age, 62.3 ± 11.6 years). Considering the evaluation of the three examiners, the mean vertical CDR increased from 0.41 to 0.44 (p = 0.02), and the median of the coefficient of variation of the measures was reduced from 0.24 to 0.11 (p = 0.01) after mydriasis. Regarding the inter-observer agreement evaluation, the kappa coefficient values ranged from 0.64 to 0.72 before mydriasis and from 0.71 to 0.77 after mydriasis. Dot sign and disc notching were better identified through fundoscopic examination with mydriasis compared to the nonmydriatic examination (p < 0.01). CONCLUSION: Our results suggest that fundus biomicroscopy should be performed with mydriasis whenever possible, as it yells a better intra- and inter-observer agreement and improves the detection of glaucomatous signs. Moreover, examiners seem to underestimate CDR values without mydriasis. Further investigation is warranted to validate these findings by general ophthalmologists and in different populations.

Increasing Complexity Threatens the Elimination of Extra-Amazonian Malaria in Brazil.

Extra-Amazonian malaria has been reported to be endemic in Brazil since the end of the 19th century. Currently, only a few cases are reported annually. However, recent findings of unexpected Plasmodium infections with uncertain transmission cycles in the Extra-Amazonian region could pose a threat to the malaria elimination agenda in Brazil.

Topical applications of an emollient reduce circulating pro-inflammatory cytokine levels in chronically aged humans: a pilot clinical study.

BACKGROUND: While increased levels of circulating inflammatory cytokines in chronologically aged humans have been linked to the development of ageing-associated chronic disorders (e.g., cardiovascular disease, type II diabetes, osteoporosis and Alzheimer's disease), approaches that reduce circulating cytokines are not yet available. In chronologically aged mice, we recently demonstrated that epidermal dysfunction largely accounts for age-associated elevations in circulating cytokine levels, and that improving epidermal function reduced circulating cytokine levels. OBJECTIVE: We performed a pilot study to determine whether improving epidermal function reduces circulating pro-inflammatory cytokine levels in aged humans. METHODS: Thirty-three aged humans were topically treated twice-daily for 30 days, with ≈ 3 mL of an emollient, previously shown to improve epidermal function, while untreated, aged humans and a cohort of young volunteers served as controls. Changes in epidermal function and levels of three key, age-related, plasma cytokines (IL-1ß, IL-6 and TNFα) were measured at baseline and after treatment, using Luminex 200™ system. RESULTS: We also found significantly higher baseline levels of IL-1ß, IL-6 and TNFα in aged vs. young humans (P < 0.001), as previously reported. Topical applications of the barrier repair emollient significantly enhanced epidermal permeability barrier function (P < 0.01) and stratum corneum hydration (P < 0.05). In parallel, circulating levels of IL-1ß and IL-6 normalized, while TNFα levels declined substantially. CONCLUSION: The results of this preliminary study suggest that a larger clinical trial should be performed to confirm whether improving epidermal function also can reduce circulating pro-inflammatory cytokine levels in aged humans, while also possibly attenuating the downstream development of chronic inflammatory disorders in the aged humans.

Macroevolutionary diversification rates show time dependency.

For centuries, biologists have been captivated by the vast disparity in species richness between different groups of organisms. Variation in diversity is widely attributed to differences between groups in how fast they speciate or go extinct. Such macroevolutionary rates have been estimated for thousands of groups and have been correlated with an incredible variety of organismal traits. Here we analyze a large collection of phylogenetic trees and fossil time series and describe a hidden generality among these seemingly idiosyncratic results: speciation and extinction rates follow a scaling law in which both depend on the age of the group in which they are measured, with the fastest rates in the youngest clades. Using a series of simulations and sensitivity analyses, we demonstrate that the time dependency is unlikely to be a result of simple statistical artifacts. As such, this time scaling is likely a genuine feature of the tree of life, hinting that the dynamics of biodiversity over deep time may be driven in part by surprisingly simple and general principles.

Circulating zearalenone and its metabolites differ in women due to body mass index and food intake.

The environmental estrogen, zearalenone (ZEA), is found in the food supply from Fusarium fungal contamination in grains and sometimes used as a growth promoter for beef cattle. Long-term exposure to ZEA and its metabolites may present health risk due to higher estrogenic activity. Serum ZEA metabolites were measured to determine the exposure and the association with food intake in 48 overweight/obese women (52 ±â€¯9 years). The free and conjugated ZEA indicated the highest detection rate of all the metabolites. Conjugated ZEA and total ZEA metabolites were lower (p = 0.02) in overweight/obese than normal weight women, and free metabolites were either the same or showed a trend to be higher. In addition, those with highest (280-480 g/d) compared those with lowest (<115 g/d) meat consumption had higher conjugated serum ZEA metabolite concentrations (p < 0.05). Intakes of other food groups (i.e., dairy, cereal, etc.) were not associated with ZEA metabolites. These findings indicate that ZEA and its metabolites are detectable in nearly all women and concentrations are associated with greater meat intake, and influenced by body mass index. Determining how the food supply influences human concentrations of ZEA metabolites is warranted, as well as determining vulnerable populations.

Entomological Survey of the Mosquitoes in an Area of Ecological TOurism in the Brazilian Amazon Basin.

Mosquitoes have a great epidemiological importance, since females of several species transmit etiological agents of human diseases, such as malaria and arboviruses. In Brazil, the state of Acre has been highlighted in recent years for its high incidence of diseases of relevance to public health, such as malaria, dengue, and leishmaniases, whose etiological agents are transmitted by insect vectors, including mosquitoes. Nevertheless, few studies have been carried out on the mosquito fauna in Acre State; this study aims to identify the culicid fauna of an ecological tourism area of the municipality of Xapuri, Acre State, Brazilian Amazon. Mosquito collections were carried out monthly at the Seringal Cachoeira settlement, between April 2014 and March 2015 using 6 automatic Centers for Disease Control and Prevention light traps, one in each ecotope. During the study period, 1,021 specimens belonging to the genera Aedeomyia, Aedes, Anopheles, Coquillettidia, Culex, Mansonia, Orthopodomyia, Psorophora, Trichoprosopon, and Uranotaenia were collected. The genus Culex was predominant, Culex (Culex) quinquefasciatus being the most frequent species, followed by Cx. (Melanoconion) gnomatos. The importance of these findings is discussed.

Validation of clinical risk score for colorectal liver metastases resected in a contemporary multicenter cohort.

BACKGROUND: Recent advances in care for colorectal liver metastases (CRLM) have lengthened 5-year survival. In this new era, prognostic tools such as the clinical risk score (CRS) for colorectal liver metastases require reevaluation. METHODS: Patients undergoing resection for CRLM between 2008 and 2012 at 4 specialty hepatobiliary centers in Canada (N = 740) were stratified by CRS and analyzed in Kaplan-Meier survival curves. Primary outcome of overall survival (OS) and secondary outcome of recurrence-free survival (RFS). Multivariate Cox regression compared CRS to patient factors. RESULTS: Median OS not reached (>60 months), median RFS 16 months. Original CRS strata was a significant (p < 0.001) predictor of both OS (5-year OS: 0; 75%, 1; 71%, 2; 57%, 3; 57%, 4; 46%) and RFS (5-year RFS: 0; 39%, 1; 33%, 2; 21%, 3; 21%, 4; 8%). The presence of extrahepatic colorectal metastatic disease increased recurrence risk (RFS hazard ratio of 1.32 (1.06-1.65)), and the use of intraoperative portal pedicle clamping reduced recurrence risk (RFS hazard ratio of 0.78 (0.61-0.99)). CONCLUSIONS: The CRS remains a relevant tool for predicting long-term outcomes for patients undergoing resection of CRLM. Additional factors such as the presence of extrahepatic colorectal metastatic disease and the use of intraoperative portal pedicle clamping may improve the prognostic power of the CRS.

High prevalence of neuropathic pain in the hand of patients with traumatic brachial plexus injury: a cross-sectional study.

OBJECTIVE: To describe the pain profile of patients with traumatic brachial plexus injury. METHODS: We enrolled 65 patients with traumatic brachial plexus injury. The Douleur Neuropathique 4 questionnaire was used to classify pain and the SF-36 was used to evaluate quality of life. RESULTS: The patients with traumatic brachial plexus injury were predominantly young male victims of motorcycle accidents. Pain was present in 75.4% of the individuals and 79% presented with neuropathic pain, mostly located in the hands (30.41%). The use of auxiliary devices (p = 0.05) and marital status (p = 0.03) were both independent predictors of pain. Pain also impacted negatively on the quality of life (p = 0.001). CONCLUSIONS: Pain is frequent in patients with traumatic brachial plexus injury. Despite the peripheral nervous system injury, nociceptive pain is not unusual. Pain evaluation, including validated instruments, is essential to guide optimal clinical management of patients with the condition.

High prevalence of neuropathic pain in the hand of patients with traumatic brachial plexus injury: a cross-sectional study / Alta prevalência de dor neuropática em sujeitos com lesão traumática do plexo braquial: um estudo de corte transversal

ABSTRACT Objective To describe the pain profile of patients with traumatic brachial plexus injury. Methods We enrolled 65 patients with traumatic brachial plexus injury. The Douleur Neuropathique 4 questionnaire was used to classify pain and the SF-36 was used to evaluate quality of life. Results The patients with traumatic brachial plexus injury were predominantly young male victims of motorcycle accidents. Pain was present in 75.4% of the individuals and 79% presented with neuropathic pain, mostly located in the hands (30.41%). The use of auxiliary devices (p = 0.05) and marital status (p = 0.03) were both independent predictors of pain. Pain also impacted negatively on the quality of life (p = 0.001). Conclusions Pain is frequent in patients with traumatic brachial plexus injury. Despite the peripheral nervous system injury, nociceptive pain is not unusual. Pain evaluation, including validated instruments, is essential to guide optimal clinical management of patients with the condition.

RESUMO Objetivo Descrever o perfil de dor de sujeitos com lesão traumática do plexo braquial. Métodos Nós incluímos 65 indivíduos com lesão traumática do plexo braquial. O Douleur Neuropathique 4 foi usado para classificar a dor e o SF-36 foi usado para avaliar a qualidade de vida. Resultados Sujeitos com lesão traumática do plexo braquial eram em sua maioria homens jovens, vítimas de acidentes motociclísticos. A dor esteve presete em 75.4% dos indivíduos e 79% deles apresentaram dor neuropática, mais frequentemente localizada nas mãos (30.41%). O uso de dispositivos auxiliares (p = 0.05) e o estado civil foram, ambos, preditores independentes de dor. A dor ainda impactou negativamente da qualidade de vida (p = 0.001). Conclusões A dor é frequente em sujeitos com lesão traumática do plexo braquial. Apesar de envolver uma lesão do sistema nervoso a dor nociceptiva não é infrequente. A avaliação da dor, incluindo instrumentos validados, é essencial para direcionar as condutas clínicas de sujeitos com esta condição.

Eyes with Suspicious Appearance of the Optic Disc and Normal Intraocular Pressure: Using Clinical and Epidemiological Characteristics to Differentiate Those with and without Glaucoma.

Among all glaucoma suspects, eyes with optic nerve head features suspicious or suggestive of early glaucoma are probably those that offer the greatest challenge for clinicians. In contrast with the robust longitudinal data published on ocular hypertension, there is no specific management guideline for these patients. Therefore, evaluating eyes with suspicious optic disc appearance and normal intraocular pressure (IOP), we sought to investigate potential differences in clinical and epidemiological characteristics to differentiate those with normal-tension glaucoma (NTG) from those with presumed large physiological optic disc cups (pLPC). In this observational case-control study, we consecutively enrolled individuals with pLPC and NTG. All eyes had vertical cup-to-disc ratio (VCDR)≥0.6 and untreated IOP<21 mmHg. Glaucomatous eyes had reproducible visual field defects. Eyes with pLPC required normal visual fields and ≥30 months of follow-up with no evidence of glaucomatous neuropathy. Clinical and epidemiological parameters were compared between groups. Eighty-four individuals with pLPC and 40 NTG patients were included. Regarding our main results, NTG patients were significantly older and with a higher prevalence of Japanese descendants (p<0.01). Not only did pLPC eyes have smaller mean VCDR, but also larger optic discs (p≤0.04). There were no significant differences for gender, central corneal thickness, and spherical equivalent (p≥0.38). Significant odds ratios (OR) were found for race (OR = 2.42; for Japanese ancestry), age (OR = 1.05), VCDR (OR = 5.03), and disc size (OR = 0.04; p≤0.04). In conclusion, in patients with suspicious optic disc and normal IOP, those with older age, Japanese ancestry, smaller optic discs, and larger VCDR are more likely to have NTG, and therefore, deserve deeper investigation and closer monitoring.