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Open-pollinated onion cultivars predominate in the southern region of Brazil, due to their higher adaptability to local climatic conditions, unlike commercial hybrids, which have shown a lower adaptability. Cytoplasmic male sterility (CMS) systems are employed to develop hybrid onion cultivars. Two molecular markers, 5’cob and orfA501, were used to differentiate the cytoplasm type, and the AcSKP1 marker to identify the nuclear male fertility-restoring locus (Ms). A total of 1,126 plants from the most common onion cultivars grown in southern Brazil, including Bola Precoce®, Crioula®, Valessul®, Mega®, Joia® and Princesa do Sul®, were analyzed using all the three markers. An extremely rare occurrence of the S cytoplasm was observed among the cultivars, being detected in only 1.8 % of the samples, while the T cytoplasm was the most prevalent, accounting for 56.3 % of the samples. Among the 1,126 plants analyzed, only three exhibited the S cytoplasm and were recessive for the Ms-locus (Smsms). Additionally, 49 plants with the N-cytoplasm (as per the Engelke’s classification) and recessive for the nuclear genotype (Nmsms) were identified, 45 of which were pollen producers. The male-fertility restoration occurred in 22.2 % of the crosses between Tmsms male-sterile plants and male-fertile N cytoplasmic-msms plants (as per the Engelke’s classification).

Abstract Background Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model. Methods Data for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2− advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1. Results A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed. Conclusions A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes. Registration: ClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017).

Topic: To review clinical evidence on systemic factors that might be relevant to update diabetic retinal disease (DRD) staging systems, including prediction of DRD onset, progression, and response to treatment. Clinical relevance: Systemic factors may improve new staging systems for DRD to better assess risk of disease worsening and predict response to therapy. Methods: The Systemic Health Working Group of the Mary Tyler Moore Vision Initiative reviewed systemic factors individually and in multivariate models for prediction of DRD onset or progression (i.e., prognosis) or response to treatments (prediction). Results: There was consistent evidence for associations of longer diabetes duration, higher glycosylated hemoglobin (HbA1c), and male sex with DRD onset and progression. There is strong trial evidence for the effect of reducing HbA1c and reducing DRD progression. There is strong evidence that higher blood pressure (BP) is a risk factor for DRD incidence and for progression. Pregnancy has been consistently reported to be associated with worsening of DRD but recent studies reflecting modern care standards are lacking. In studies examining multivariate prognostic models of DRD onset, HbA1c and diabetes duration were consistently retained as significant predictors of DRD onset. There was evidence of associations of BP and sex with DRD onset. In multivariate prognostic models examining DRD progression, retinal measures were consistently found to be a significant predictor of DRD with little evidence of any useful marginal increment in prognostic information with the inclusion of systemic risk factor data apart from retinal image data in multivariate models. For predicting the impact of treatment, although there are small studies that quantify prognostic information based on imaging data alone or systemic factors alone, there are currently no large studies that quantify marginal prognostic information within a multivariate model, including both imaging and systemic factors. Conclusion: With standard imaging techniques and ways of processing images rapidly evolving, an international network of centers is needed to routinely capture systemic health factors simultaneously to retinal images so that gains in prediction increment may be precisely quantified to determine the usefulness of various health factors in the prognosis of DRD and prediction of response to treatment. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Hyponatremia on admission has been related to worse outcomes in patients with COVID-19 infection. However, little is known about the frequency and the associated risk factors of hyponatremia after COVID-19 discharge. We performed an observational 24-month follow-up study of patients admitted during the first COVID-19 wave. Kaplan–Meier curves and Cox proportional hazard models were used to assess the main variables in predicting hyponatremia on follow-up (HYPO-FU). A total of 161 out of 683 (24.4%) developed HYPO-FU. The group with HYPO-FU comprised of more men [(62.3%) vs. (49.2%); p

Topic: The goal of this review was to summarize the current level of evidence on biomarkers to quantify diabetic retinal neurodegeneration (DRN) and diabetic macular edema (DME). Clinical relevance: With advances in retinal diagnostics, we have more data on patients with diabetes than ever before. However, the staging system for diabetic retinal disease is still based only on color fundus photographs and we do not have clear guidelines on how to incorporate data from the relatively newer modalities into clinical practice. Methods: In this review, we use a Delphi process with experts to identify the most promising modalities to identify DRN and DME. These included microperimetry, full-field flash electroretinogram, spectral-domain OCT, adaptive optics, and OCT angiography. We then used a previously published method of determining the evidence level to complete detailed evidence grids for each modality. Results: Our results showed that among the modalities evaluated, the level of evidence to quantify DRN and DME was highest for OCT (level 1) and lowest for adaptive optics (level 4). Conclusion: For most of the modalities evaluated, prospective studies are needed to elucidate their role in the management and outcomes of diabetic retinal diseases. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

ABSTRACT Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics and less frequently with atypical or second-generation antipsychotics. The diagnosis relies on both clinical and laboratory criteria, with other organic and psychiatric conditions being ruled out. CASE REPORT: A 39-year-old female patient, who is institutionalized and completely dependent, has a medical history of recurrent urinary infections and colonization by carbapenem-resistant Klebsiella pneumoniae. Her regular medication regimen included sertraline, valproic acid, quetiapine, risperidone, lorazepam, diazepam, haloperidol, baclofen, and fentanyl. The patient began experiencing dyspnea. Upon physical examination, she exhibited hypotension and a diminished vesicular murmur at the right base during pulmonary auscultation. Initially, after hospitalization, she developed high febrile peaks associated with hemodynamic instability, prompting the initiation of antibiotic treatment. Despite this, her fever persisted without an increase in blood inflammatory parameters, and she developed purulent sputum, necessitating antibiotherapy escalation. The seventh day of hospitalization showed no improvement in symptoms, suggesting NNMS as a differential diagnosis. All antipsychotic and sedative drugs, as well as antibiotherapy, were discontinued, after which the patient showed significant clinical improvement. CONCLUSION: Antipsychotic agents are commonly employed to manage behavioral changes linked to various disorders. However, their severe side effects necessitate a high degree of vigilance, the cessation of all medications, and the implementation of supportive care measures. A prompt and accurate diagnosis of NMS is crucial to alleviating the severe, prolonged morbidity and potential mortality associated with this syndrome.

ABSTRACTLong-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.

Abstract Background While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. Results We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.

IntroductionIndividuals with type 2 diabetes (T2D) should be considered a susceptible group for pulmonary dysfunction. So, we aimed to evaluate the sensation of breathlessness in this population by administering two well-validated questionnaires.MethodsThis is a crosssectional study with 592 people without known respiratory disease (353 with T2D) who answered the modified Medical Research Council (mMRC) questionnaire. In addition, 47% also responded to the St George Respiratory Questionnaire, a specific instrument designed to be applied to patients with obstructive airway disease.ResultsPatients with T2D showed a higher mMRC score in comparison to the control group [1.0 (0.0 – 4.0) vs. 0.0 (0.0 – 4.0), p

Objectivea) To evaluate the accuracy of the pre-existing equations (based on cm2 provided by CT images), to estimate in kilograms (Kg) the body composition (BC) in patients with obesity (PwO), by comparison with Dual-energy X-ray absorptiometry (DXA). b) To evaluate the accuracy of a new approach (based on both cm2 and Hounsfield Unit parameters provided by CT images), using an automatic software and artificial intelligence to estimate the BC in PwO, by comparison with DXA.MethodsSingle-centre cross-sectional study including consecutive PwO, matched by gender with subjects with normal BMI. All the subjects underwent BC assessment by Dual-energy X-ray absorptiometry (DXA) and skeletal-CT at L3 vertebrae. CT images were processed using FocusedON-BC software. Three different models were tested. Model 1 and 2, based on the already existing equations, estimate the BC in Kg based on the tissue area (cm2) in the CT images. Model 3, developed in this study, includes as additional variables, the tissue percentage and its average Hounsfield unit.Results70 subjects (46 PwO and 24 with normal BMI) were recruited. Significant correlations for BC were obtained between the three models and DXA. Model 3 showed the strongest correlation with DXA (r= 0.926, CI95% [0.835-0.968], p

Un globo super presurizado es una estructura sellada hecha de una membrana delgada de polietileno lineal de baja densidad (LLDPE) reforzada con cuerdas, cuya tensión se calcula para contrarrestar intensos esfuerzos esperados sobre la película que se muestran en este trabajo. Proponemos un diseño de globo doble superpresurizado (DSP), con una membrana interna dentro de otra un poco mayor. Ambas membranas están conectadas por películas LLDPE que unen los cordones de cada globo formando paneles externos que rodean la membrana interna. El globo interior está lleno de Hidrógeno, que es un gas barato pero inflamable, mientras que los paneles se llenan con Helio no inflamable pero muy costoso, dado que el volumen interno es mucho mayor que el volumen de los paneles externos, se reduce drásticamente el costo del llenado, que en globos tradicionales se realiza solamente con Helio. En el globo DSP el Hidrógeno debe pasar primero por los paneles exteriores para escapar, lo cual reduce la tasa de pérdida de forma significativa, incrementado la seguridad del uso de globos de Hidrógeno. Además, el globo DSP puede tolerar la ruptura de la membrana exterior y la ruptura de la membrana interior si no se rompen en la misma sección.

Pesticides offer stakeholders cost-effective solutions to control weeds. Nevertheless, such active compounds can manifest as severe environmental pollutants when escaping from agroecosystems into surrounding natural ecosystems, driving the need to remediate them. We, hence, analyzed whether Mucuna pruriens can develop a potential phytoremediator for treating tebuthiuron (TBT) in soil with vinasse. We exposed M. pruriens to microenvironments containing tebuthiuron at 0.5, 1, 1.5, and 2 (standard dose) L ha−1 and vinasse at 75, 150 (industrial recommendation), and 300 m3·ha−1. Experimental units without organic compounds represented controls. We assessed M. pruriens for morphometrical features, such as plant height and stem diameter and shoot/root dry mass, over approximately 60 days. We obtained evidence for M. pruriens not effectively removing tebuthiuron from the terrestrial medium. Such a pesticide developed phytotoxicity, significantly limiting its germination and growth. The higher the dose, the more negatively the tebuthiuron impacted the plant. In addition, introducing vinasse into the system, irrespective of volume, intensified the damage to photosynthetic and non-photosynthetic structures. Equally important, its antagonist action further decreased the production and accumulation of biomass. As M. pruriens could not effectively extract tebuthiuron from the soil, it could allow neither Crotalaria juncea nor Lactuca sativa to grow on synthetic media containing residual pesticide. An atypical performance of such testing (tebuthiuron-sensitive) organisms over independent ecotoxicological bioassays validated inefficient phytoremediation. Hence, M. pruriens could not offer a functional remediative option to treat environmental pollution by tebuthiuron in agroecosystems where vinasse occurs, such as sugarcane-producing areas. Although M. pruriens considered a tebuthiuron phytoremediator as cited in the literature, satisfactory results did not occur in our research due to high concentrations of vinasse in the soil. Therefore, this information requires more specific studies about the influence of high concentrations of organic matter on M. pruriens productivity and phytoremediation performance.

The presence of type 2 diabetes acts as an accelerator of cognitive impairment (mild cognitive impairment and later dementia), with a significant impact on the management of the disease and its complications. Therefore, it is recommended to perform an annual evaluation of cognitive function in patients with diabetes older than 65 years. Current guidelines still recommend the use of the Minimental State Evaluation Test (MMSE) as screening test, but it has a modest sensitivity and specificity for identifying mild cognitive impairment. This represents an important gap because patients with mild cognitive impairment are at risk of progressing to dementia. The neurocognitive diagnosis is based on complex neuropsychological tests, which require specifically trained personnel and are time consuming, making its routine incorporation into daily clinical practice unfeasible. Therefore, at present there are no reliable biomarkers to identify patients with type 2 diabetes at increased risk of developing cognitive impairment. Since the brain and the retina have a common embryological origin, our Research Group, has worked over the last 10 years evaluating the usefulness of the retina as a “window” to the brain. We provided evidence that retinal microperimetry is a simple, feasible and useful tool for screening and monitoring cognitive function in patients with type 2 diabetes. We propose a review of actual tests recommended for screening of cognitive impairment as well as an update of new emerging methods, such as retinal microperimetry.

Introduction: In the context of obesity pandemic, the health care providers involved in the primary care should have a significant role. Several guidelines for the management of obesity in primary care were proposed recently. In general lines, these guidelines include recommendation on the baseline assessment, therapy and algorithm for referral to specialized obesity clinic and follow-up. Nevertheless, at present there is no guideline or protocol that continuously and bidirectionally links the two settings: primary care and specialized obesity clinic. Methods: We present a model of continuous, bilateral and integrative interaction between primary care units and reference tertiary care setting in the chronic management of obesity that is already implemented in a public health system. Results: The novelty of our algorithm is that incorporates the support and continuous communication with the specialized obesity clinic of the tertiary care setting from the beginning in the management of a patient with obesity, in a bidirectional manner. Conclusion: This kind of bidirectional and continuous collaboration will help engage health care providers in the management of obesity, optimize efforts, shorten the time until proper intervention, personalize the approach and, finally, save costs for the health system.

ContextSome reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients.ObjectiveThis study aimed at identifying predictors of response to SRL in elderly patients.DesignMulticentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years.ResultsOne-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4–91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01–0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71–0.94).ConclusionsThe most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se, were associated with a greater chance of response to SRL.

Genetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (−3.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill–Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives.

Thyroid hormone, as a modifiable risk factor for dementia, promo tes neurocognitive function and regulates metabolic processes. Various studies have defined different thyroid-stimulating hormone cutoffs, but the safest thyroid-stimulating hormone concentration was absent. A dose–response meta-analysis describing the overall functional relation and identifying exposure intervals associated with a higher or lower disease risk is thus desirable. Therefore, our current analysis was conducted to und erstand the influence of thyroid dysfunction on dementia risk. We searched PubMed, Embase, and Web of Science before May 1, 2020 for human studies published in English. Studies were considered for inclusion if they used a cohort study design to measure the ris k of dementia in different thyroid function status groups, diagnosed thyroid functional status and all-cause dementia, included participants aged >18 years, and provided quantitative measures of data. The analysis contained 17 articles with 344,248 individuals with a 7.8-year mean follow-up. Ten studies with 329,287 participants indicated that only subclinical hyperthyroidism was associated with an increased risk of dementia. In contrast, subclinical hypothyroidism, clinical hyperthyroidism, and clinical hypothyroidism did not a ffect dementia. In the dose– response meta-analysis with 46,417 samples from 11 studies, the association of thyroid-stimulating hormone with the risk of dementia exhibited a U-shaped curve. Our study indicated that subclinical hyperthyroidism was associated with the risk of dementia and the thyroid-stimulating hormone concentration at around 1.55–1.60 mU/L as the optimum range for the risk of dementia.

This study aimed to evaluate the predictive value of diabetic retinopathy (DR) and its stages with the incidence of major cardiovascular events and all-cause mortality in type 2 diabetes mellitus (T2DM) persons in our large primary healthcare database from Catalonia (Spain). A retrospective cohort study with pseudo-anonymized routinely collected health data from SIDIAP was conducted from 2008 to 2016. We calculated incidence rates of major cardiovascular events [coronary heart disease (CHD), stroke, or both—macrovascular events] and all-cause mortality for subjects with and without DR and for different stages of DR. The proportional hazards regression analysis was done to assess the probability of occurrence between DR and the study events. About 22,402 T2DM subjects with DR were identified in the database and 196,983 subjects without DR. During the follow-up period among the subjects with DR, we observed the highest incidence of all-cause mortally. In the second place were the macrovascular events among the subjects with DR. In the multivariable analysis, fully adjusted for DR, sex, age, body mass index (BMI), tobacco, duration of T2DM, an antiplatelet or antihypertensive drug, and HbA1c, we observed that subjects with any stage of DR had higher risks for all of the study events, except for stroke. We observed the highest probability of all-cause death events (adjusted hazard ratios, AHRs: 1.34, 95% CI: 1.28; 1.41). In conclusion, our results show that DR is related to CHD, macrovascular events, and all-cause mortality among persons with T2DM.

A concepção de sistema nacional de arquivos como uma entidade é recorrente no pensamento e nas práticas arquivísticas em Moçambique. O respectivo projeto, assim como o processo de sua implementação neste País, tendem a não se referir a essa noção como um mecanismo para a implementação de uma política nacional de arquivos, para entendê-la como uma política em si. Esse processo adquire matizes específicos, considerando a falta de estrutura de arquivos, em nível nacional, que compreenda serviços e instituições arquivísticos. Nessa direção, a pesquisa, de caráter qualitativa, adotou como recurso metodológico a contextualização histórica da noção de sistema nacional de arquivos e sua relação com a concepção de políticas arquivísticas, para posterior análise não apenas das três leis instituidoras de igual número de versões do projeto de Sistema Nacional de Arquivos em Moçambique, mas também das várias representações empíricas. Baseado na pesquisa bibliográfica e documental, e visando estimular um debate sobre a necessidade de uma estrutura organizacional de arquivos em Moçambique sustentada por políticas arquivísticas, o artigo aponta possíveis desafios, atores, estratégias e ações inerentes à eventual estruturação dessa área no País.

Abstract Background Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer’s disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake. Aims We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD. Methods One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/−) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2. Results Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02–1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02–1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months. Conclusions Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake.

Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of Adra2a and Pcsk9, but decreased Prox1. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of ADRA2A with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.

Abstract Background Prediabetes has recently been associated with subclinical atheromatous disease in the middle-aged population. Our aim was to characterize atheromatous plaque burden by the number of affected territories and the total plaque area in the prediabetes stage. Methods Atheromatous plaque burden (quantity of plaques and total plaque area) was assessed in 12 territories from the carotid and femoral regions using ultrasonography in 6688 non-diabetic middle-aged subjects without cardiovascular disease. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association guidelines. Results Prediabetes was diagnosed in 33.9% (n = 2269) of the ILERVAS participants. Subjects with prediabetes presented a higher prevalence of subclinical atheromatous disease than participants with HbA1c

Sulfur deficiency in soils has become a worldwide concern for agricultural production. This study aimed to evaluate the concequence of variable sulfur source and dosing on the nutritional status and production of Piatã forage in a dystrophic Ultisol. The experiment was arranged in a completely randomized block design with four replications. The 4 x 5 factorial treatments consisted of four sulfur sources (elemental sulfur pastilles [ESPA], gypsum [GY], gypsite [GI], and elemental sulfur powder [ESPO]) and five sulfur doses (0, 50, 100, 150. and 200 mg kg-1). The sulfur applications resulted in similar maximum shoot dry mass (SDM) production (16.66 to 17.69 g pot-1) with all sources. However, Piatã grass achieved maximum production in the treatments with 112 mg kg-1 of GI, 118 mg kg-1 of GY and ESPA, and 146 mg kg-1 of ESPO. The number of tillers, the leaf:stem ratio, and SPAD increased with increasing sulfur dose. The greatest increments of root dry mass (RDM) and of the tiller number were obtained with the ESPO source. Macronutrient concentrations in shoot dry mass tissue were in the order K > N > Ca > P > S > Mg. Low sulfur supply resulted in decreased Piatã grass growth with all sulfur sources tested. Differential responses were found with applications of different sulfur sources for SDM, RDM, and tillers number. The sources did not alter the leaf:stem ratio or SPAD index.

Hyperglycemia-induced oxidative stress plays a key role in the impairment of the retinal neurovascular unit, an early event in the pathogenesis of DR. The aim of this study was to assess the antioxidant properties of topical administration (eye drops) of sitagliptin in the diabetic retina. For this purpose, db/db mice received sitagliptin or vehicle eye drops twice per day for two weeks. Age-matched db/+ mice were used as the control group. We evaluated retinal mRNA (RT-PCR) and protein levels (Western blotting and immunohistochemistry) of different components from both the antioxidant system (NRF2, CAT, GPX, GR, CuZnSOD, and MnSOD) and the prooxidant machinery (PKC and TXNIP). We also studied superoxide levels (dihydroethidium staining) and oxidative damage to DNA/RNA (8-hydroxyguanosine immunostaining) and proteins (nitrotyrosine immunostaining). Finally, NF-кB translocation and IL-1β production were assessed through Western blotting and/or immunohistochemistry. We found that sitagliptin protected against diabetes-induced oxidative stress by reducing superoxide, TXNIP, PKC, and DNA/RNA/protein oxidative damage, and it prevented the downregulation of NRF2 and antioxidant enzymes, with the exception of catalase. Sitagliptin also exerted anti-inflammatory effects, avoiding both NF-кB translocation and IL-1β production. Sitagliptin prevents the diabetes-induced imbalance between ROS production and antioxidant defenses that occurs in diabetic retinas.

Tebuthiuron is often used to control weed growth in sugarcane cultures. This herbicide is highly toxic and can persist in soil for up to 2 years according to its degradation half-life. Hence, its residual effect is highly hazardous for the environment and local habitants via leaching, surface runoff. Screening out of species of green manure as potential phytoremediators for tebuthiuron in soil, with and with no vinasse, accordingly is the scientific point of this study. Green manure species selected for the trial in greenhouse were jack bean [Canavalia ensiformis (L.) DC.], pigeon pea [Cajanus cajan (L. Millsp.)], velvet bean [Mucuna pruriens (L.) DC.)], and millet [Pennisetum glaucum (L.) R.Br.], and Crotalaria juncea L. as bioindicator of this herbicide. The determination/quantification of height, stem diameter, and number of leaves in all plants were monitored, as well as other morphological traits for drafting any inference on biomass production. Moreover, ecotoxicity bioassays were performed from soil samples at the beginning and at the end of the experiment. Results showed preliminary evidence of effective phytoremediation capacity by M. pruriens and P. glaucum in soils with tebuthiuron, as the growth of C. juncea was sustained. Both Gompertz approach and principal component analysis predicted that these green manure species could grow healthier and for longer periods in soils containing tebuthiuron and vinasse and, thus, reduce physiological anomalies due to ecotoxicity. The implications of this study may aid in the implementation of cost-effective strategies targeting decontamination of tebuthiuron in sugarcane crops with vinasse application in fertigation.

Background/Aims: Obesity is characterized by the immune activation that eventually dampens insulin sensitivity and changes metabolism. This study explores the impact of different inflammatory/ anti-inflammatory paradigms on the expression of toll-like receptors (TLR) found in adipocyte cultures, adipose tissue, and blood. Methods: We evaluated by real time PCR the impact of acute surgery stress in vivo (adipose tissue) and macrophages (MCM) in vitro (adipocytes). Weight loss was chosen as an anti-inflammatory model, so TLR were analyzed in fat samples collected before and after bariatric surgery-induced weight loss. Associations with inflammatory and metabolic parameters were analyzed in non-obese and obese subjects, in parallel with gene expression measures taken in blood and isolated adipocytes/ stromal-vascular cells (SVC). Treatments with an agonist of TLR3 were conducted in human adipocyte cultures under normal conditions and upon conditions that simulated the chronic low-grade inflammatory state of obesity. Results: Surgery stress raised TLR1 and TLR8 in subcutaneous (SAT), and TLR2 in SAT and visceral (VAT) adipose tissue, while decreasing VAT TLR3 and TLR4. MCM led to increased TLR2 and diminished TLR3, TLR4, and TLR5 expressions in human adipocytes. The anti-inflammatory impact of weight loss was concomitant with decreased TLR1, TLR3, and TLR8 in SAT. Cross-sectional associations confirmed increased V/ SAT TLR1 and TLR8, and decreased TLR3 in obese patients, as compared with non-obese subjects. As expected, TLR were predominant in SVC and adipocyte precursor cells, even though expression of all of them but TLR8 (very low levels) was also found in ex vivo isolated and in vitro differentiated adipocytes. Among SVC, CD14+ macrophages showed increased TLR1, TLR2, and TLR7, but decreased TLR3 mRNA. The opposite patterns shown for TLR2 and TLR3 in V/ SAT, SVC, and inflamed adipocytes were observed in blood as well, being TLR3 more likely linked to lymphocyte instead of neutrophil counts. On the other hand, decreased TLR3 in adipocytes challenged with MCM dampened lipogenesis and the inflammatory response to Poly(I:C). Conclusion: Functional variations in the expression of TLR found in blood and hypertrophied fat depots, namely decreased TLR3 in lymphocytes and inflamed adipocytes, are linked to metabolic inflammation.

The neurovascular unit (NVU) plays an essential role in the development of diabetic retinopathy (DR). We previously reported that the topical administration (eye drops) of sitagliptin and saxagliptin, two dipeptidyl peptidase-4 inhibitors (DPP-4i), prevents retinal neurodegeneration and vascular leakage in db/db mice. The aim of the present study is to evaluate the minimum effective dose of the topical administration of these DPP-4i. For this purpose, sitagliptin and saxagliptin were tested at different concentrations (sitagliptin: 1 mg/mL, 5 and 10 mg/mL, twice per day; saxagliptin: 1 and 10 mg/mL, once or twice per day) in db/db mice. As end points of efficacy, the hallmarks of NVU impairment were evaluated: reactive gliosis, neural apoptosis, and vascular leakage. These parameters were assessed by immunohistochemistry, cell counting, and the Evans blue method, respectively. Our results demonstrated that the minimum effective dose is 5 mg/mL twice per day for sitagliptin, and 10 mg/mL twice per day for saxagliptin. In conclusion, this study provides useful results for the design of future preclinical regulatory studies and for planning clinical trials.

Cardiovascular diseases (CVD) are one of the leading causes of death in the developed countries. Previous studies suggest that retina blood vessels provide relevant information on cardiovascular risk. Retina fundus imaging (RFI) is a cheap medical imaging test that is already regularly performed in diabetic population as screening of diabetic retinopathy (DR). Since diabetes is a major cause of CVD, we wanted to explore the use Deep Learning architectures on RFI as a tool for predicting CV risk in this population. Particularly, we use the coronary artery calcium (CAC) score as a marker, and train a convolutional neural network (CNN) to predict whether it surpasses a certain threshold defined by experts. The preliminary experiments on a reduced set of clinically verified patients show promising accuracies. In addition, we observed that elementary clinical data is positively correlated with the risk of suffering from a CV disease. We found that the results from both informational cues are complementary, and we propose two applications that can benefit from the combination of image analysis and clinical data.

Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role.

The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.

Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL; 5 μL once/daily) or vehicle (PBS; 5 μL once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-κB), proinflammatory cytokines (IL-1β, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglutide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes.

Background: Hyperglycemia-induced oxidative stress plays a key role in diabetic complications, including diabetic retinopathy. The main goal of this study was to assess whether the topical administration (eye drops) of glucagon-like peptide-1 (GLP-1) has any effect on oxidative stress in the retina. Methods: db/db mice were treated with eye drops of GLP-1 or vehicle for three weeks, with db/+ mice being used as control. Studies included the assessment by western blot of the antioxidant defense markers CuZnSOD, MnSOD, glutathione peroxidase and reductase; immunofluorescence measurements of DNA/RNA damage, nitro tyrosine and Ki67 and Babam2 proteins. Results: GLP-1 eye drops protected from oxidative stress by increasing the protein levels of glutathione reductase, glutathione peroxidase and CuZnSOD and MnSOD in diabetic retinas. This was associated with a significant reduction of DNA/RNA damage and the activation of proteins involved in DNA repair in the retina (Babam2) and Ki67 (a biomarker of cell proliferation). Conclusions: GLP-1 modulates the antioxidant defense system in the diabetic retina and has a neuroprotective action favoring DNA repair and neuron cells proliferation.

Ceria nanoparticles are cell compatible antioxidants whose activity can be enhanced by gold deposition and by surface functionalization with positive triphenylphosphonium units to selectively target the mitochondria. The antioxidant properties of these nanoparticles can serve as the basis of a new strategy for the treatment of several disorders exhibiting oxidative stress, such as cancer, diabetes or Alzheimer’s disease. However, all of these pathologies require a specific antioxidant according with their mechanism to remove oxidant species excess in cells and diminish their effect on mitochondrial function. The mechanism through which ceria nanoparticles neutralize oxidative stress and their effect on mitochondrial function have not been characterized yet. In the present study, the mitochondria antioxidant effect of ceria and ceria-supported gold nanoparticles, with or without triphenylphosphonium functionalization, was assessed in HeLa cells. The effect caused by ceria nanoparticles on mitochondria function in terms of mitochondrial membrane potential (∆Ψm), adenosine triphosphate (ATP) production, nuclear respiratory factor 1 (NRF1) and nuclear factor erythroid–2–like 1 (NFE2L1) was reversed by the presence of gold. Furthermore, this effect was enhanced when nanoparticles were functionalized with triphenylphosphonium. Our study illustrates how the mitochondrial antioxidant effect induced by ceria nanoparticles can be modulated by the presence of gold.

Abstract Objective The objective of this study was to evaluate dental sensitivity using visual analogue scale, a Computerized Visual Analogue Scale (CoVAS) and a neurosensory analyzer (TSA II) during at-home bleaching with 10% carbamide peroxide, with and without potassium oxalate. Materials and Methods Power Bleaching 10% containing potassium oxalate was used on one maxillary hemi-arch of the 25 volunteers, and Opalescence 10% was used on the opposite hemi-arch. Bleaching agents were used daily for 3 weeks. Analysis was performed before treatment, 24 hours later, 7, 14, and 21 days after the start of the treatment, and 7 days after its conclusion. The spontaneous tooth sensitivity was evaluated using the visual analogue scale and the sensitivity caused by a continuous 0°C stimulus was analyzed using CoVAS. The cold sensation threshold was also analyzed using the TSA II. The temperatures obtained were statistically analyzed using ANOVA and Tukey's test (α=5%). Results The data obtained with the other methods were also analyzed. 24 hours, 7 and 14 days before the beginning of the treatment, over 20% of the teeth presented spontaneous sensitivity, the normal condition was restored after the end of the treatment. Regarding the cold sensation temperatures, both products sensitized the teeth (p0.05). In addition, when they were compared using CoVAS, Power Bleaching caused the highest levels of sensitivity in all study periods, with the exception of the 14th day of treatment. Conclusion We concluded that the bleaching treatment sensitized the teeth and the product with potassium oxalate was not able to modulate tooth sensitivity.

Dental caries is considered a disease of high prevalence and a constant problem in public health. Proanthocyanidins (PAs) are substances that have been the target of recent studies aiming to control or treat caries. Objective The aim of this in vitro study was to evaluate the efficacy of a treatment with grape seed extract, under cariogenic challenge, to minimize or even prevent the onset of caries in the enamel and dentin. Material and Methods Blocks of enamel and dentin (6.0x6.0 mm) were obtained from bovine central incisors, polished, and selected by analysis of surface microhardness (SH). The blocks were randomly divided into 3 groups (n=15), according to the following treatments: GC (control), GSE (grape seed extract), GF (fluoride – 1,000 ppm). The blocks were subjected to 6 daily pH cycles for 8 days. Within the daily cycling, the specimens were stored in buffered solution. The blocks were then analyzed for perpendicular and surface hardness and polarized light microscopy. Results The means were subjected to statistical analysis using the ANOVA and Fisher's PLSD tests (p

The aim of the study was to develop a novel risk estimation model for predicting silent myocardial ischemia (SMI) in patients with type 1 diabetes (T1DM) and no clinical cardiovascular disease, evaluating the potential role of insulin resistance in such a model. Additionally, the accuracy of this model was compared with currently available models for predicting clinical coronary artery disease (CAD) in general and diabetic populations.Patients with T1DM (35-65years, >10-year duration) and no clinical cardiovascular disease were consecutively evaluated for: 1) clinical and anthropometric data (including classical cardiovascular risk factors), 2) insulin sensitivity (estimate of glucose disposal rate (eGDR)), and 3) SMI diagnosed by stress myocardial perfusion gated SPECTs.Eighty-four T1DM patients were evaluated [50.1±9.3 years, 50% men, 36.9% active smokers, T1DM duration: 19.0(15.9-27.5) years and eGDR 7.8(5.5-9.4)mg·kg-1·min-1]. Of these, ten were diagnosed with SMI (11.9%). Multivariate logistic regression models showed that only eGDR (OR = -0.593, p = 0.005) and active smoking (OR = 7.964, p = 0.018) were independently associated with SMI. The AUC of the ROC curve of this risk estimation model for predicting SMI was 0.833 (95%CI:0.692-0.974), higher than those obtained with the use of currently available models for predicting clinical CAD (Framingham Risk Equation: 0.833 vs. 0.688, p = 0.122; UKPDS Risk Engine (0.833 vs. 0.559; p = 0.001) and EDC equation: 0.833 vs. 0.558, p = 0.027).This study provides the first ever reported risk-estimation model for predicting SMI in T1DM. The model only includes insulin resistance and active smoking as main predictors of SMI.

A group of members of the Spanish Retina and Vitreous Society (SERV) and of the Working Group of Ocular Health of the Spanish Society of Diabetes (SED) updated knowledge regarding the diagnosis and treatment of diabetic retinopathy (DR) based on recent evidence reported in the literature. A synthesis of this consensus forms the basis of the present review, which is intended to inform clinicians on current advances in the field of DR and their clinical applicability to patients with this disease. Aspects presented in this article include screening procedures of DR, new technologies in the early diagnosis of DR, control of risk factors in the different stages of the disease, indications of panretinal laser photocoagulation, efficacy of intravitreal antiangiogenic agents and steroids, and surgical options for treating DR-related complications. Practical information regarding periodicity of screening procedures in patients with type 1 and type 2 diabetes, ophthalmological controls according to the stage of retinopathy and complications, and criteria and degree of urgency for referral of a DR patient to the ophthalmologist are also presented.

Características oligogênicas de distribuição discreta e expressão governada por poucos genes de maior efeito têm se mostrado importantes na condução dos programas de melhoramento, com destaque para a resposta de resistência das plantas às doenças. Métodos tradicionais de detecção de QTL's, que pressupõem normalidade e herança governada por múltiplos fatores, não deveriam ser utilizados para mapeamento dessas características de distribuição discreta e interação epistática predominante. O objetivo deste trabalho é avaliar os resultados de um método para mapeamento e detecção de locos controladores da expressão de características oligogênicas, OTL's (Oligogenic Trait Loci). Esse método, definido como MMCO (Método de Mapeamento de Características Oligogênicas), utiliza funções de verossimilhança para obtenção de estimativas de ligação fatorial entre locos marcadores e locos controladores de características oligogênicas. Os resultados indicam que o método foi adequado para detecção de OTL's em populações F2 relativamente pequenas, compostas por 200 indivíduos, e que a determinação a priori do padrão de herança é condição necessária para a utilização dessa estratégia, que se diferencia por atender as pressuposições de análise, não necessitar de informação prévia de ordenamento entre as marcas e por permitir a obtenção de estimativas a partir da informação contida em todas as classes genotípicas.Oligogenic traits are distinguished by their heritage ruled by higher effect genes and by their importance for cultivated plants, with emphasis to the plant disease resistance inheritance. The qualitative nature and epistatic interaction of these traits results in a heritage pattern that should not be interpreted through traditional QTL detection strategies. The objective of this work was to propose a method for Oligogenic Traits Loci (OTL) detection. This method, defined as Oligogenic Trait Mapping Method (OTMM) uses maximum likehood probability functions to obtain adjusted "r" estimates that express the distance among the molecular markers and the OTL loci. The results show that the method was adequate for OTL detection even in relatively small F2 populations. The prior definition of the oligogenic heritage pattern is one the main requirements of this method that focus in the attainment of the analysis presumptions without previous markers order information.

The efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily (OD) compared with insulin glargine U100 (IGlar) OD over 52 weeks in insulin-naïve adults with type 2 diabetes mellitus (T2DM) was investigated.In this open-label, parallel-group treat-to-target trial, participants were randomized (1:1) to receive IDegAsp OD (breakfast, n = 266) or IGlar OD (as per label, n = 264). Participants then entered a 26-week extension phase (IDegAsp OD, n = 192; IGlar OD, n = 221). The primary endpoint was change from baseline to Week 26 in HbA1c.After 26 and 52 weeks, mean HbA1c decreased to similar levels in both groups. After 52 weeks, the mean estimated treatment difference was -0.08% (-0.26, 0.09 95%CI), confirming the non-inferiority of IDegAsp OD versus IGlar OD evaluated at Week 26. After 52 weeks, there was a similar reduction in mean fasting plasma glucose in both treatment groups. The rate of confirmed hypoglycemic episodes was 86% higher (p < 0.0001) whereas the rate of nocturnal hypoglycemia was 75% lower (p < 0.0001) for IDegAsp versus IGlar.Nocturnal-confirmed hypoglycemia was higher with IGlar whereas overall and diurnal hypoglycemia were higher with IDegAsp dosed at breakfast. These results highlight the importance of administration of IDegAsp with the main meal of the day, tailored to the individual patient's needs.ClinicalTrials.gov: NCT01045707 [core]) and NCT01169766 [ext].

Diabetic retinopathy (DR) is the main cause of working-age adult-onset blindness. The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR. Therefore, new pharmacological treatments for these early stages of the disease are required. In order to develop therapeutic strategies for early stages of DR new diagnostic tools are urgently needed. In this regard, circulating biomarkers could be useful to detect early disease, to identify those diabetic patients most prone to progressive worsening who ought to be followed up more often and who could obtain the most benefit from these therapies, and to monitor the effectiveness of new drugs for DR before more advanced DR stages have been reached. Research of biomarkers for DR has been mainly based on the pathogenic mechanism involved in the development of DR (i.e., AGEs, oxidative stress, endothelial dysfunction, inflammation, and proangiogenic factors). This review focuses on circulating biomarkers at both early and advanced stages that could be relevant for the prediction or detection of DR.

Diabetic retinopathy (DR) is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although neuronal death and visual impairment appear before vascular lesions, suggesting an important role played by neurodegeneration in DR and the appropriateness of neuroprotective strategies. Upregulation of vascular endothelial growth factor (VEGF), the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting, and spectral domain optical coherence tomography seems the most indicated technique. Many substances have been tested in animal studies for their neuroprotective properties and for possible use in humans. Perhaps, the most intriguing perspective is the use of endogenous neuroprotective substances or nutraceuticals. Together, the data point to the central role of neurodegeneration in the pathogenesis of DR and indicate neuroprotection as an effective strategy for treating this disease. However, clinical trials to determine not only the effectiveness and safety but also the compliance of a noninvasive route of drug administration are needed.

Although sleep apnea-hypopnea syndrome (SAHS) is highly prevalent in patients with type 2 diabetes (T2D), it is unknown whether or not subjects with and without T2D share the same sleep breathing pattern.A cross-sectional study in patients with SAHS according to the presence (n = 132) or not (n = 264) of T2D. Both groups were matched by age, gender, BMI, and waist and neck circumferences. A subgroup of 125 subjects was also matched by AHI. The exclusion criteria included chronic respiratory disease, alcohol abuse, use of sedatives, and heart failure. A higher apnea hypopnea index (AHI) was observed in T2D patients [32.2 (10.2-114.0) vs. 25.6 (10.2-123.4) events/hours; p = 0.002). When sleep events were evaluated separately, patients with T2D showed a significant increase in apnea events [8.4 (0.1-87.7) vs. 6.3 (0.0-105.6) e/h; p = 0.044), as well as a two-fold increase in the percentage of time spent with oxygen saturation

Se investigó si el VIMANG, un extracto de la corteza del tallo de la Mangifera indica L, protege a las lipoproteínas de baja densidad de la oxidación in vitro mediada por iones de Cu++. Para esto las lipoproteínas de baja densidad obtenidas por ultracentrifugación a partir de muestras de sangre de voluntarios sanos, fueron oxidadas por incubación con CuSO4, a 37 °C durante 3 h, en presencia de diferentes dosis de VIMANG (0,0001-0,1 % w/v), como un modelo para investigar las propiedades antioxidantes de este producto. La peroxidación lipídica fue medida como sustancias reactivas al ácido tiobarbitúrico. Las dosis de VIMANG ensayadas mostraron una acción antioxidante potente. Solo la dosis menor permitió una discreta formación de peróxidos lipídicos en las lipoproteínas de baja densidad al cabo de las 3 h de incubación, al compararse con las lipoproteínas de baja densidad controles. El resultado obtenido constituye una evidencia del posible uso del VIMANG como antioxidante en la prevención o retardo de la aterosclerosis.An investigation was carried out to know if Vimang, an extract from the cortex of the stem of Mangifera indica L, protects low density lipoproteins from the in vitro oxidation mediated by ions of Cu++ . To this end, low density lipoproteins obtained by ultracentrifugation from blood samples of sound volunteers, were oxidized by incubation with CuS04 at 37 °C during 3 hours in the presence of different doses of Vimang (0.0001-0.1 % w/v), as a model to investigate the antioxidant properties of this product. The lipid peroxidation was measured as reactive substances to tiobarbituric acid, The assayed doses of Vimang showed a potent antioxidant action. Only the lowest dose allowed a discrete formation of lipid peroxides in low density lipoproteins after 3 hours of incubation on comparing them with the low density lipoproteins controls. The final result is an evidence of the possible use of Vimang as an antioxidant in the prevention or delay of atherosclerosis.

Se evaluó la utilidad de un procedimiento experimental para desarrollar aterosclerosis carotídea en conejos. Se estudiaron 18 animales divididos en 3 grupos, con 6 animales cada uno. Los animales fueron alimentados mediante pienso suplementado con 0,5 y 1 % de colesterol (grupos I y II, respectivamente), en tanto el III (control) solo con pienso. Se hicieron determinaciones bioquímicas antes de comenzar el experimento y en las semanas 4, 8 y 12, posteriores a la dieta. Se observó un aumento significativo en el peso de los animales de los grupos I y II en la semana 8 para p < 0,05, se mantuvieron sin variaciones la hemoglobina y el hematócrito. El colesterol mostró un incremento significativo para los grupos I y II a partir de la semana 4 hasta el final. El estudio morfométrico dio como resultado que en los animales del grupo II en ambas carótidas había presencia de estrías adiposas, lo que demostró la utilidad de este modelo de aterosclerosis carotídeaThe advantages of an experimental procedure to develop carotid atherosclerosis in rabbits were evaluated. Eighteen animals distributed into 3 groups, 6 animals each, were examined. Animals were fed with fodder supplemented with 0.5 and 1% of cholesterol (group I and II respectively) whereas group 3 (control) was given only fodder. Biochemical determinations were performed before the experiments and at weeks 4, 8 and 12 after the dietary treatments. The animals´weight in groups I and II had significantly increased by the 8th week for a p< 0,05;hemoglobin and hematocrit values remained unchanged. Cholesterol substantially increased in groups I and II from the 4th week on. The morphometric study revealed that there were fatty streaks in both carotids of animals included in group 2, which proved the benefits of this experimental model of carotid atherosclerosis

BackgroundThe aim of the present study is to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population.MethodsA nested case-control study was conducted within a defined cohort (275,164 type 2 diabetic patients attending 16 Primary Health Care Centers of Barcelona). Cases (n = 1,040) comprised those subjects with any cancer diagnosed between 2008 and 2010, registered at the Cancer Registry of Hospital Vall d'Hebron (Barcelona). Three control subjects for each case (n = 3,120) were matched by age, sex, diabetes duration, and geographical area. The treatments analyzed (within 3 years prior to cancer diagnosis) were: insulin glargine, insulin detemir, human insulin, fast-acting insulin and analogues, metformin, sulfonylureas, repaglinide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and alpha glucosidase inhibitors. Conditional logistic regressions were used to calculate the risk of cancer associated with the use of each drug adjusted by age, BMI, dose and duration of treatment, alcohol use, smoking habit, and diabetes duration.ResultsNo differences were observed between case and control subjects for the proportion, dose or duration of exposure to each treatment. None of the types of insulin and oral agents analyzed showed a significant increase in the risk of cancer. Moreover, no cancer risk was observed when glargine was used alone or in combination with metformin.ConclusionsOur results suggest that diabetes treatment does not influence the risk of cancer associated with type 2 diabetes. Therefore, an eventual increase of cancer should not be a reason for biasing the selection of any glucose-lowering treatment in type 2 diabetic population.

Diabetic retinopathy (DR) remains as the leading cause of blindness among working age individuals in developed countries. Current treatments for DR (laser photocoagulation, intravitreal corticosteroids, intravitreal anti-VEGF agents, and vitreoretinal surgery) are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Emerging evidence indicates that peroxisome proliferator-activator receptors (PPARs) agonists (in particular PPARα) are useful for the treatment of DR. However, the underlying molecular mechanisms are far from being elucidated. This paper mainly focuses on PPARs expression in the diabetic eye, its molecular implications, and the effect of PPAR agonists as a new approach for the treatment of DR. The availability of this new strategy will not only be beneficial in treating DR but may also result in a shift towards treating earlier stages of diabetic retinopathy, thus easing the burden of this devastating disease (Cheung et al. (2010)).

Diabetic retinopathy (DR) is the major cause of acquired blindness in working-age adults. Current treatments for DR (laser photocoagulation, intravitreal corticosteroids, intravitreal antivascular endothelial growth factor (VEGF) agents, and vitreo-retinal surgery) are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Vitreous fluid obtained from diabetic patients undergoing vitreoretinal surgery is currently used to explore the events that are taking place in the retina for clinical research. However, several confounding factors such as vitreous haemorrhage and concentration of vitreous proteins should be considered in the analysis of the results. In this paper we will focus on the vitreous fluid as a tool for exploring the mediators of DR and in particular the molecules related to inflammatory pathways. In addition, their role in the pathogenesis of DR will be discussed. The usefulness of new technologies such as flow cytometry and proteomics in identifying new candidates involved in the inflammatory process that occurs in DR will be overviewed. Finally, a more personalized treatment based on vitreous fluid analysis aiming to reduce the burden associated with DR is suggested.

OBJECTIVE: 1) To evaluate whether peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients present an impairment of phagocytic activity; 2) To determine whether the eventual impairment in phagocytic activity is related to glycemic control and can be reversed by improving blood glucose levels. METHODS: 21 type 2 diabetic patients and 21 healthy volunteers were prospectively recruited for a case-control study. In addition, those patients in whom HbA1c was higher than 8% (n = 12) were hospitalized in order to complete a 5-day intensification treatment of blood glucose. Phagocytic activity was assessed by using a modified flow cytometry procedure developed in our laboratory based on DNA/RNA viable staining to discriminate erythrocytes and debris. This method is simple, highly sensitive and reproducible and it takes advantage of classic methods that are widely used in flow cytometry. RESULTS: Type 2 diabetic patients showed a lower percentage of activated macrophages in comparison with non-diabetic subjects (54.00±18.93 vs 68.53±12.77%; p = 0.006) Significant negative correlations between phagocytic activity and fasting glucose (r = -0.619, p = 0.004) and HbA1c (r = -0.506, p = 0.019) were detected. In addition, multiple linear regression analyses showed that either fasting plasma glucose or HbA1c were independently associated with phagocytic activity. Furthermore, in the subset of patients who underwent metabolic optimization a significant increase in phagocytic activity was observed (p = 0.029). CONCLUSIONS: Glycemic control is related to phagocytic activity in type 2 diabetes. Our results suggest that improvement in phagocytic activity can be added to the beneficial effects of metabolic optimization.