The influence of simultaneous pancreas-kidney transplantation on the evolution of diabetic foot lesions and peripheral arterial disease.

PURPOSE: Simultaneous pancreas-kidney transplantation (SPKT) remains the best treatment option in patients with type 1 diabetes and chronic kidney failure. There are only a few studies addressing the potential ischemic deterioration of peripheral arterial disease (PAD) due to blood diverting from the iliac artery to the kidney graft. We aimed to evaluate diabetic foot lesions and PAD evolution in SPKT recipients and investigate if they are more frequent in ipsilateral lower limb of kidney graft. METHODS: We developed a retrospective cohort, including patients submitted to SPKT in our tertiary center, between 2000 and 2017. Diabetic foot lesions and PAD frequencies were compared in the period before and after transplantation. RESULTS: Two hundred and eleven patients were included, 50.2% (n = 106) female, with a median age at transplantation of 35 years (IQR 9). After a median follow-up period of 10 years (IQR 7), patient, kidney, and pancreatic graft survival were 90.5% (n = 191), 83.4% (n = 176), and 74.9% (n = 158), respectively. Before transplant, 2.8% (n = 6) had PAD and 5.3% (n = 11) had history of foot lesions. In post-transplant period, 17.1% (n = 36) patients presented PAD and 25.6% (n = 54) developed diabetic foot ulcers, 47.6% (n = 35) of which in the ipsilateral and 53.3% (n = 40) in the contralateral lower limb of the kidney graft (p = 0.48). Nine patients (4.3%) underwent major lower limb amputation, 3 (30%) ipsilateral and 7 (70%) contralateral to the kidney graft (p = 0.29). CONCLUSIONS: Diabetic foot lesions were not more frequent in the ipsilateral lower limb of the kidney graft, therefore downgrading the 'steal syndrome' role in these patients.

Anti-Melanogenic Potential of Natural and Synthetic Substances: Application in Zebrafish Model.

Melanogenesis is a biosynthetic pathway for the formation of the pigment melanin in human skin. A key enzyme in the process of pigmentation through melanin is tyrosinase, which catalyzes the first and only limiting step in melanogenesis. Since the discovery of its methanogenic properties, tyrosinase has been the focus of research related to the anti-melanogenesis. In addition to developing more effective and commercially safe inhibitors, more studies are required to better understand the mechanisms involved in the skin depigmentation process. However, in vivo assays are necessary to develop and validate new drugs or molecules for this purpose, and to accomplish this, zebrafish has been identified as a model organism for in vivo application. In addition, such model would allow tracking and studying the depigmenting activity of many bioactive compounds, important to genetics, medicinal chemistry and even the cosmetic industry. Studies have shown the similarity between human and zebrafish genomes, encouraging their use as a model to understand the mechanism of action of a tested compound. Interestingly, zebrafish skin shares many similarities with human skin, suggesting that this model organism is suitable for studying melanogenesis inhibitors. Accordingly, several bioactive compounds reported herein for this model are compared in terms of their molecular structure and possible mode of action in zebrafish embryos. In particular, this article described the main metabolites of Trichoderma fungi, in addition to substances from natural and synthetic sources.

Impact of breast cancer cells´ secretome on the brain metastatic niche remodeling.

Brain metastases occur in approximately 10-20% of patients with metastatic breast cancer showing a very poor overall survival. Curiously, different molecular subtypes (that show specific gene expression signatures and differential prognostic significance) are associated with different risks for brain metastases development, suggesting that cancer cells harbor specific molecular programs that award them intrinsic advantages to survive in this specific foreign tissue. Emerging data has been revealing that biophysical and/or mechanical properties of the brain extracellular matrix (ECM), along with those of the brain resident cells, play a crucial role in creating the best conditions for survival, colonization and outgrowth of breast cancer cells in this distinct microenvironment. Although several reports show that cancer cells modulate metastatic niches way before they reach the target organ, few data exist for the brain metastatic niche. Indeed, little is known concerning how factors secreted by cancer cells activate brain resident cells and/or modify brain ECM biomechanical properties and how these modifications impact cells´ ability to metastasize the brain. The brain is a particular organ, protected by the blood brain barrier (BBB), and containing exclusive functional units and very special cell types. Additionally, it is the organ with the most singular ECM and biomechanical properties. Thus, this cancer cell-brain metastatic niche interaction must present distinct properties. Consequently, the search for putative molecular markers that modulate the brain pre-metastatic niche, thus promoting the successful metastatic homing of cancer cells, is urgently needed. In this review, we will discuss key aspects regarding breast cancer cells and the brain pre-metastatic niche paracrine communication that is crucial to initiate the metastatic cascade. We will focus on cancer cell`s secretome influence into the brain microenvironment, specifically on its impact on tissue mechanics and on brain resident cells as regulators of the pre-metastatic niche formation, ultimately promoting metastatic colonization.

Risk and protective behaviors for chronic non-communicable diseases among Brazilian adults.

OBJECTIVES: This study aimed to analyze behavioral patterns of protective and risk factors for chronic non-communicable diseases (NCDs) among adults and to explore the association between these patterns and sociodemographic characteristics using data from the National Health Survey 2013. STUDY DESIGN: This was a cross-sectional study. METHODS: This is a population-based study, nationwide, of individuals aged ≥18 years (n = 60,202). The sampling process used was grouping with three selection stages: census sector, households, and individuals. The factor analysis by principal component was used to identify behavioral patterns of protective and risk factors for NCDs. Linear regression was used to explore the association between patterns and sociodemographic characteristics. RESULTS: Two behavioral patterns were identified: a 'protective pattern' featured by consumption of vegetable, fruits/natural fruit juice, and low-fat milk and recommended physical activity practice during leisure time; and a 'risk pattern' characterized by consumption of high-fat meat and soft drinks, alcohol abuse, and smoking habit. Adherence to the protective pattern was associated with older White women who had higher levels of education, were economically active, and lived in the urban areas of the country. Younger, economically active men living in the urban areas were associated with the risk patterns. CONCLUSIONS: Two behavioral patterns for NCDs have been identified and are distributed non-randomly in the adult Brazilian population. These findings are expected to contribute to better targeting health promotion and prevention of NCDs.

Caffeine exposure ameliorates acute ischemic cell death in avian developing retina.

In infants, the main cause of blindness is retinopathy of prematurity that stems in a hypoxic-ischemic condition. Caffeine is a psychoactive compound that at low to moderate concentrations, selectively inhibits adenosine A1 and A2A receptors. Caffeine exerts beneficial effects in central nervous system of adult animal models and humans, whereas it seems to have malefic effect on the developing tissue. We observed that 48-h exposure (during synaptogenesis) to a moderate dose of caffeine (30 mg/kg of egg) activated pro-survival signaling pathways, including ERK, CREB, and Akt phosphorylation, alongside BDNF production, and reduced retinal cell death promoted by oxygen glucose deprivation in the chick retina. Blockade of TrkB receptors and inhibition of CREB prevented caffeine protection effect. Similar signaling pathways were described in previously reported data concerning chemical preconditioning mechanism triggered by NMDA receptors activation, with low concentrations of agonist. In agreement to these data, caffeine increased NMDA receptor activity. Caffeine decreased the levels of the chloride co-transporter KCC2 and delayed the developmental shift on GABAA receptor response from depolarizing to hyperpolarizing. These results suggest that the caffeine-induced delaying in depolarizing effect of GABA could be facilitating NMDA receptor activity. DPCPX, an A1 adenosine receptor antagonist, but not A2A receptor inhibitor, mimicked the effect of caffeine, suggesting that the effect of caffeine occurs through A1 receptor blockade. In summary, an in vivo caffeine exposure could increase the resistance of the retina to ischemia-induced cell death, by triggering survival pathways involving CREB phosphorylation and BDNF production/TrkB activation.

BIO-NAIL: a bacterial cellulose dressing as a new alternative to preserve the nail bed after avulsion.

Avulsion of the nail plate is the most accomplished surgical procedure among the nail apparatus surgeries. Since it is not possible to use the removed nail to cover the nail bed, some materials have been suggested, however, they are generally not available for use and often at a high cost. To evaluate the use of Bacterial Cellulose (BC) dressing as a biological nail (Bio-Nail) after partial or total avulsion of the nail plate. Twenty-six candidates for nail avulsion, were randomized into two groups: Control, using Vaseline with gauze (11 patients) and Experimental group, BC group, using the Bio-Nail (15 patients). The patients were followed up during the 180-day period. The distribution of the patients in the groups was homogeneous for both sociodemographic and clinical data. The occurrence of infection (1 case in the control group) was not statistically relevant. The BC group had lower pain intensity (p = 0.011) with earlier temporal resolution when compared to the control group (p = 0.003). The BC group presented earlier reepithelization (p = 0.022) and better quantitative (p = 0.021) and qualitative conditions (p = 0.011) for the exudate. Regarding satisfaction, all the patients were satisfied. Good preservation of the nail plate area was observed in the BC group at the end of the 180-day period (p = 0.024). Average time of BC dressing permanence was 16.4 ± 7.1 days. BC showed to be appropriate as a dressing after partial or total avulsion of the nail plate. BC is a Bio-Nail promising for nail bed healing.

Short communication: Heat stress does not affect induced luteolysis in Holstein cows.

Heat stress (HS) has deleterious effects on bovine reproduction, including prolongation of the luteal phase in Holstein cows, perhaps due to compromised luteolysis. The objective was to characterize effects of HS on luteolytic responses of nonlactating Holstein cows given 25 or 12.5 mg of PGF2α on d 7 of the estrous cycle. Cows were randomly distributed into 2 environments: thermoneutral (n = 12; 25°C) or HS (n = 12; 36°C). In each environment, cows were treated with 2 mL of saline, 25 or 12.5 mg of PGF2α (n = 4 cows per group). The HS environment induced a significant increase in rectal temperature and respiratory rate compared with the thermoneutral environment. Heat stress did not have significant effects on luteolytic responses or circulating progesterone concentrations. Rapid and complete luteolysis occurred in all cows given 25 mg of PGF2α and in 4 of 8 cows given 12.5 mg; the other 4 cows given 12.5 mg had partial luteolysis, with circulating progesterone concentrations initially suppressed, but subsequently rebounding. Therefore, we conclude that HS does not change corpus luteum sensitivity to PGF2α.

Safety attributes in primary care: understanding the needs of patients, health professionals, and managers.

OBJECTIVES: The aims of this study were (1) to identify attributes for patient safety at a primary healthcare level and (2) to analyze conceptions of patients, professionals, and managers about how these attributes are being addressed. STUDY DESIGN: This was a qualitative study. METHODS: Participants were recruited from three primary care settings in Brazil. A total of 37 subjects (four physicians, three nurses, three dentists, three managers, five community assistants, and 19 patients) participated on interviews about their perceptions of safety attributes at the primary care settings involved in the study. Some of these participants attended a focus group meeting. A thematic categorical analysis was carried out to interpret the interviews. RESULTS: The main attributes for patient safety were valued by the participants. However, barriers such as discontinuity of care, interruptions during consultations, breakdowns in the communication, and ineffective teamwork were reported as frequent sources of patient safety issues. Reports of patients left unattended for excessive time because of the lack of accurate information and disruptions that took up to 35 min show that there is still a long way to go for primary care to be safe and effective in the study settings. CONCLUSIONS: It is necessary that the strategies meet the patient safety needs more effectively and efficiently. Further research is needed to understand the complex nature of the problems that affect patient safety in these settings so that appropriate decisions can be made.

Different outcomes of a cardiac rehabilitation programme in functional parameters among myocardial infarction survivors according to ejection fraction.

INTRODUCTION: Exercise-based cardiac rehabilitation (EBCR) is part of the management of patients who have suffered an acute myocardial infarction (AMI). Patients with a reduced ejection fraction (EF) comprise a higher-risk subgroup and are referred less often for these programmes. This study aimed at assessing the impact of the baseline EF on the functional benefits, as assessed by peak oxygen uptake (pVO2) and exercise duration, of an EBCR programme in AMI survivors. METHODS: Observational, retrospective cohort study including all patients admitted to a tertiary centre due to an AMI who completed a phase II EBCR programme after discharge, between November 2012 and April 2017. Functional parameters were assessed by a symptom-limited cardiopulmonary exercise test. RESULTS: A total of 379 patients were included [40.9% with reduced EF (<50%) at discharge]. After the programme, pVO2 and exercise duration increased significantly (p < 0.001). Patients with a reduced EF had a lower pVO2 and completed a shorter duration of exercise at the beginning and end of the programme. This group presented a higher increase in pVO2 (p = 0.001) and exercise duration (p = 0.007). This was maintained after adjusting for age, gender, history of coronary artery disease, number of sessions, Killip classification, arterial hypertension, dyslipidaemia, diabetes mellitus, smoking status and baseline pVO2. CONCLUSION: A phase II EBCR programme was associated with significant improvements in pVO2 and exercise duration among AMI survivors, irrespective of baseline EF classification. Those with a reduced baseline EF derived an even greater improvement, highlighting the importance of EBCR in this subgroup of patients.

Instruments for evaluation of safety culture in primary health care: integrative review of the literature.

OBJECTIVES: This research aimed to conduct an investigation of the tools used to assess safety culture in the primary health care. STUDY DESIGN: Integrative review of the literature. METHODS: We conducted a literature search using an instrument that included quantitative assessments of safety culture, using the following databases: CINAHL, ScienceDirect, PubMed, BIREME, and SciELO. Retrieved material comprised original articles published from 1998 to 2014, with titles and abstracts available in English, Portuguese, Spanish, and French. RESULTS: The search resulted in seven instruments; however, only three were primary healthcare focused. CONCLUSION: Most of the existing instruments for assessing safety culture have acceptable psychometric properties. The study serves as a source for students, workers, and researchers who want to know more about appropriate instruments for evaluating safety culture in primary care.

Molecular Dynamics of Cyclodextrins in Water Solutions from NMR Deuterium Relaxation: Implications for Cyclodextrin Aggregation.

The aggregation of the most common natural cyclodextrins (α-, ß-, and γ-) in aqueous solutions is addressed by studying the CD-CD interactions using deuterium relaxation rates for deuterium labeled CDs. Relaxation times (T1) and their corresponding relaxation rates (R1 = 1/T1) provide information about the rotational correlation times of CDs and serve as a proxy for solute-solute interactions. Measured T1's for α-, ß-, and γ-CD at the lowest CD concentrations were in agreement with predictions of a hydrodynamic model for toroids, in particular with regard to the dependence of T1 on CD size. On the other hand, the dependence of T1's with respect to the increase in CD concentration could not be explained by hydrodynamic or direct interaction between CD molecules, and it is suggested that there is an equilibrium between monomeric and dimeric CD to account for the observed concentration dependence. No evidence in favor of large aggregates of CDs involving a non-negligible fraction was found for the investigated CDs.

Naphthoquinoxaline metabolite of mitoxantrone is less cardiotoxic than the parent compound and it can be a more cardiosafe drug in anticancer therapy.

Mitoxantrone (MTX) is an antineoplastic agent used to treat several types of cancers and on multiple sclerosis, which shows a high incidence of cardiotoxicity. Still, the underlying mechanisms of MTX cardiotoxicity are poorly understood and the potential toxicity of its metabolites scarcely investigated. Therefore, this work aimed to synthesize the MTX-naphthoquinoxaline metabolite (NAPHT) and to compare its cytotoxicity to the parent compound in 7-day differentiated H9c2 cells using pharmacological relevant concentrations (0.01-5 µM). MTX was more toxic in equivalent concentrations in all cytotoxicity tests performed [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, neutral red uptake, and lactate dehydrogenase release assays] and times tested (24 and 48 h). Both MTX and NAPHT significantly decreased mitochondrial membrane potential in 7-day differentiated H9c2 cells after a 12-h incubation. However, energetic pathways were affected in a different manner after MTX or NAPHT incubation. ATP increased and lactate levels decreased after a 24-h incubation with MTX, whereas for the same incubation time and concentrations, NAPHT did not cause any significant effect. The increased activity of ATP synthase seems responsible for MTX-induced increases in ATP levels, as oligomycin (an inhibitor of ATP synthase) abrogated this effect on 5 µM MTX-incubated cells. 3-Methyladenine (an autophagy inhibitor) was the only molecule to give a partial protection against the cytotoxicity produced by MTX or NAPHT. To the best of our knowledge, this was the first broad study on NAPHT cardiotoxicity, and it revealed that the parent drug, MTX, caused a higher disruption in the energetic pathways in a cardiac model in vitro, whereas autophagy is involved in the toxicity of both compounds. In conclusion, NAPHT is claimed to largely contribute to MTX-anticancer properties; therefore, this metabolite should be regarded as a good option for a safer anticancer therapy since it is less cardiotoxic than MTX.

Influence of glass fibre post length and remaining dentine thickness on the fracture resistance of root filled teeth.

AIM: To evaluate, ex vivo, the influence of glass fibre post length and remaining thickness of dentine on the fracture resistance of bovine roots, after thermomechanical ageing. METHODOLOGY: Ninety bovine roots of the same size were root filled and randomly distributed into nine groups (n = 10), according to the root weakening protocol (NW - nonweakened; MW - medium weakened; HW - highly weakened) and post length (7 mm; 9 mm and 12 mm). The weakening of roots was performed using diamond burs, resulting in different thicknesses of remaining dentine. The post spaces were prepared, and in the weakened roots, the glass fibre posts were customized with composite resin, to create posts matching the canal size. Chemically activated resin cement was used to lute the posts. After luting, full crowns made of composite resin were attached to a silicon matrix. To reproduce physiological mobility, the roots were covered with polyether and embedded in polyurethane. The thermomechanical cycling was performed (1 200 000 cycles; 88N; 3,8 Hz; 5 ± 1 °C to 55 ± 1 °C). Then, the specimens were subjected to compressive force in a universal testing machine (1 mm min-1 ; 100 kgf) to analyse the fracture resistance. The specimens were analysed through a stereomicroscope to classify the failure mode (repairable/catastrophic). The values were subjected to statistical analysis (two-way anova and Tukey's test at 5%). The frequencies of failure mode were compared using chi-square test. RESULTS: The association between length and dentine thickness was significant (P > 0.05). The difference was between NW and HW roots for posts of 12 mm in length. There was an association between failure mode and the length and remaining dentine thickness. CONCLUSIONS: Reduced dentine thickness in roots with longer posts had lower fracture resistance values, as catastrophic failure was more predominant.

Neuromyelitis optica spectrum disorders: beyond longitudinally extensive transverse myelitis.

AIM: To describe the neuroradiological features and their prevalence in patients with neuromyelitis optica (NMO). MATERIALS AND METHODS: Two neuroradiologists independently reviewed 35 spinal cord and 37 brain MRI studies from patients with NMO. The examinations were analysed for the presence of lesion, topography, enhancement, and brain lesions suggestive of multiple sclerosis and/or NMO. RESULTS: Seventy percent of the spinal cord lesions involved over three or more vertebral segments. Seventy-eight percent of brain scans were abnormal, and the most prevalent findings were non-specific foci of T2 hyperintensities in the cerebral white matter (55%) and brainstem lesions (52%). One patient had lesions disseminated in space compatible with multiple sclerosis according to 2010 revised McDonald criteria. Brain lesions suggestive of NMO occurred at least once in 17 (59%) patients. CONCLUSION: Spinal cord lesions were often longitudinally extensive and brain lesions were common, with the majority of patients having at least one distinctive NMO lesion.

The Amniotic Membrane: Development and Potential Applications - A Review.

Foetal membranes are essential tissues for embryonic development, playing important roles related to protection, breathing, nutrition and excretion. The amnion is the innermost extraembryonic membrane, which surrounds the foetus, forming an amniotic sac that contains the amniotic fluid (AF). In recent years, the amniotic membrane has emerged as a potential tool for clinical applications and has been primarily used in medicine in order to stimulate the healing of skin and corneal diseases. It has also been used in vaginal reconstructive surgery, repair of abdominal hernia, prevention of surgical adhesions and pericardium closure. More recently, it has been used in regenerative medicine because the amniotic-derived stem cells as well as AF-derived cells exhibit cellular plasticity, angiogenic, cytoprotective, immunosuppressive properties, antitumoural potential and the ability to generate induced pluripotent stem cells. These features make them a promising source of stem cells for cell therapy and tissue engineering. In this review, we discussed the development of the amnion, AF and amniotic cavity in different species, as well as the applicability of stem cells from the amnion and AF in cellular therapy.

Bos taurus papillomavirus activity in peripheral blood mononuclear cells: demonstrating a productive infection.

Bovine papillomavirus (BPV) is an oncogenic virus with mucous and epithelial tropism. Possible productive virus infection in other tissues, such as blood, has been hypothesized. In order to investigate this possibility, three samples of skin papillomas and blood were collected from bovines with BPV infection and five samples of peripheral blood and one sample of normal tissue were collected from a calf without BPV infection. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and examined by reverse transcription-polymerase chain reaction, immunofluorescence, in situ hybridization, and electron microscopy. The tissue samples were examined for histopathological and immunohistochemical features. The skin papillomas showed the presence of DNA sequences of BPV-2, BPV-11, and a putative virus type. The blood samples showed DNA sequences of BPV-1, 2, and 4 simultaneously. Immunohistochemistry showed BPV L1 protein in both epithelium and stroma and BPV E2 protein in koilocytes. In situ hybridization confirmed the presence of BPV DNA in PBMCs and immunofluorescence showed nuclear labeling of E2 and L1 BPV proteins in PBMCs. The transcription analysis revealed transcripts of BPV-1 L1, BPV-2 L2, and BPV-4 E7 in blood and papilloma samples of BPV-infected cattle. The comet assay revealed high levels of host cell DNA damage upon BPV infection. Electron microscopy analysis of PBMCs identified the presence of particles in the cytoplasm that are consistent with papillomavirus in size and shape. The productive infection of PBMCs with BPV has been previously discussed and this study provides evidence indicating that PBMCs are a target of BPV.

Hyperproliferative action of bovine papillomavirus: genetic and histopathological aspects.

The bovine papillomavirus (BPV) causes papillomas that regress spontaneously, but can also progress to malignancy. This study evaluated the role of BPV in oncogenesis. Twenty-four samples from uninfected calves and the papillomas of BPV infected cattle were subjected to molecular diagnosis, as well as histopathological and immunohistochemical analyses. The comet assay (CA) was used to evaluate the clastogenic potential of BPV. The results confirmed the presence of BPV-2, 3, 5, and 9 in infected samples. Histopathological analysis revealed acanthosis, koilocytosis, hypergranulosis, hyperkeratosis, and transformed fibroblasts.E7 and L1 BPV proteins were detected in the epithelium, as well as in the connective tissues, indicating productive infection at different sites. CA results showed that BPV-2, 5, and 9 exhibit the same level of clastogenicity. These findings support the oncogenic action of BPV in establishing a favorable microenvironment for oncogenesis.