Cardiovascular and Cerebrovascular Morbidity in Patients with Urolithiasis: An Epidemiological Approach Based on Hospitalization Burden Data from 1997 to 2021.

Background: Patients with kidney stones (KSFs) are known to have a heightened risk of coronary heart disease (CHD) or stroke. The objective of the present study was to describe the natural history of these complications through the longitudinal analysis of the hospitalizations due to kidney stones in Spain from 1997 to 2021. Methods: A retrospective longitudinal observational study was developed based on nationwide hospitalization data (minimum basic data base). Three different analyses were carried out. In the first step, the prevalence of coronary or cerebrovascular events in kidney stone hospitalizations was compared with the hospitalization burden of CHD or strokes related to the general population. In the second step, a survival analysis of the kidney stones-hospitalized patients using the Kaplan-Meier method was conducted. In the third step, a Cox regression was used to assess the influence of the classical comorbidities in the development of the lithiasic patients-cardiovascular disease. Results: Kidney stone-hospitalized patients exhibit a significantly higher risk of CHD (OR = 14.8 CI95%: 14.7-14.9) and stroke (OR = 6.7 CI95%: 6.6-6.8) compared to the general population across in all age groups, although they had less cardiovascular risk factors. A total of 9352 KSFs (1.5%) developed a coronary event within an average time of 78.8 months. A total of 2120 KSFs (0.33%) suffered a stroke in an average time of 71.1 months. Diabetes, hypertension, hyperlipidemia, and being overweight were identified as risk factors for developing CHD and stroke using a univariate and multivariate analysis. Conclusions: Our study confirms previous studies in which kidney stones must be considered as a risk factor for developing CHD or cerebrovascular disease. Preventive strategies should target patients with kidney stones and classical risk cardiovascular factors to mitigate modifiable conditions associated with cardiovascular diseases.

Sensing technologies and machine learning methods for emotion recognition in autism: Systematic review.

BACKGROUND: Human Emotion Recognition (HER) has been a popular field of study in the past years. Despite the great progresses made so far, relatively little attention has been paid to the use of HER in autism. People with autism are known to face problems with daily social communication and the prototypical interpretation of emotional responses, which are most frequently exerted via facial expressions. This poses significant practical challenges to the application of regular HER systems, which are normally developed for and by neurotypical people. OBJECTIVE: This study reviews the literature on the use of HER systems in autism, particularly with respect to sensing technologies and machine learning methods, as to identify existing barriers and possible future directions. METHODS: We conducted a systematic review of articles published between January 2011 and June 2023 according to the 2020 PRISMA guidelines. Manuscripts were identified through searching Web of Science and Scopus databases. Manuscripts were included when related to emotion recognition, used sensors and machine learning techniques, and involved children with autism, young, or adults. RESULTS: The search yielded 346 articles. A total of 65 publications met the eligibility criteria and were included in the review. CONCLUSIONS: Studies predominantly used facial expression techniques as the emotion recognition method. Consequently, video cameras were the most widely used devices across studies, although a growing trend in the use of physiological sensors was observed lately. Happiness, sadness, anger, fear, disgust, and surprise were most frequently addressed. Classical supervised machine learning techniques were primarily used at the expense of unsupervised approaches or more recent deep learning models. Studies focused on autism in a broad sense but limited efforts have been directed towards more specific disorders of the spectrum. Privacy or security issues were seldom addressed, and if so, at a rather insufficient level of detail.

The RNAi Machinery in the Fungus Fusarium fujikuroi Is Not Very Active in Synthetic Medium and Is Related to Transposable Elements.

Small RNAS (sRNAs) participate in regulatory RNA interference (RNAi) mechanisms in a wide range of eukaryotic organisms, including fungi. The fungus Fusarium fujikuroi, a model for the study of secondary metabolism, contains a complete set of genes for RNAi pathways. We have analyzed by high-throughput sequencing the content of sRNAs in total RNA samples of F. fujikuroi grown in synthetic medium in the dark or after 1 h of illumination, using libraries below 150 nt, covering sRNAs and their precursors. For comparison, a parallel analysis with Fusarium oxysporum was carried out. The sRNA reads showed a higher proportion of 5' uracil in the RNA samples of the expected sizes in both species, indicating the occurrence of genuine sRNAs, and putative miRNA-like sRNAs (milRNAS) were identified with prediction software. F. fujikuroi carries at least one transcriptionally expressed Ty1/copia-like retrotransposable element, in which sRNAs were found in both sense and antisense DNA strands, while in F. oxysporum skippy-like elements also show sRNA formation. The finding of sRNA in these mobile elements indicates an active sRNA-based RNAi pathway. Targeted deletion of dcl2, the only F. fujikuroi Dicer gene with significant expression under the conditions tested, did not produce appreciable phenotypic or transcriptomic alterations.

SLESIS-R: an improved score for prediction of serious infection in patients with systemic lupus erythematosus based on the RELESSER prospective cohort.

OBJECTIVE: To develop an improved score for prediction of severe infection in patients with systemic lupus erythematosus (SLE), namely, the SLE Severe Infection Score-Revised (SLESIS-R) and to validate it in a large multicentre lupus cohort. METHODS: We used data from the prospective phase of RELESSER (RELESSER-PROS), the SLE register of the Spanish Society of Rheumatology. A multivariable logistic model was constructed taking into account the variables already forming the SLESIS score, plus all other potential predictors identified in a literature review. Performance was analysed using the C-statistic and the area under the receiver operating characteristic curve (AUROC). Internal validation was carried out using a 100-sample bootstrapping procedure. ORs were transformed into score items, and the AUROC was used to determine performance. RESULTS: A total of 1459 patients who had completed 1 year of follow-up were included in the development cohort (mean age, 49±13 years; 90% women). Twenty-five (1.7%) had experienced ≥1 severe infection. According to the adjusted multivariate model, severe infection could be predicted from four variables: age (years) ≥60, previous SLE-related hospitalisation, previous serious infection and glucocorticoid dose. A score was built from the best model, taking values from 0 to 17. The AUROC was 0.861 (0.777-0.946). The cut-off chosen was ≥6, which exhibited an accuracy of 85.9% and a positive likelihood ratio of 5.48. CONCLUSIONS: SLESIS-R is an accurate and feasible instrument for predicting infections in patients with SLE. SLESIS-R could help to make informed decisions on the use of immunosuppressants and the implementation of preventive measures.

Activation of mitoKATP channels induces penile vasodilation and inhibits mitochondrial respiration and ROS production: Role of NO.

OBJECTIVE: Mitochondrial ATP-sensitive K+ (mitoKATP) channels are involved in neuronal and cardiac protection from ischemia and oxidative stress. Penile erection is a neurovascular event mediated by relaxation of the erectile tissue via nitric oxide (NO) released from nerves and endothelium. In the present study, we investigated whether mitoKATP channels play a role in the control of penile vascular tone and mitochondrial dynamics, and the involvement of NO. METHODS: The effect of the selective mitoKATP activator BMS191095 was examined on vascular tone, on mitochondrial bioenergetics by real-time measurements with Agilent Seahorse and on ROS production by MitoSOX fluorescence in freshly isolated microarteries. RESULTS: BMS191095 and diazoxide relaxed penile arteries, BMS191095 being one order of magnitude more potent. BMS191095-induced relaxations were reduced by mechanical endothelium removal and by inhibitors of the nitric oxide synthase (NOS) and PI3K enzymes. The NO-dependent component of the relaxation to BMS191095 was impaired in penile arteries from insulin resistant obese rats. The blockers of mitoKATP channel 5-HD, sarcolemma KATP (sarcKATP) channel glibenclamide, and large conductance Ca2+-activated K+ (BKCa) channel iberiotoxin, inhibited relaxations to BMS191095 and to the NO donor SNAP. BMS191095 reduced the mitochondrial bioenergetic profile of penile arteries and attenuated mitochondrial ROS production. Blockade of endogenous NO impaired and exogenous NO mimicked, respectively, the inhibitory effects of BMS191095 on basal respiration and oxygen consumed for ATP synthesis. Exogenous NO exhibited dual inhibitory/stimulatory effects on mitochondrial respiration. CONCLUSIONS: These results demonstrate that selective activation of mitoKATP channels causes penile vasodilation, attenuates ROS production and inhibits mitochondrial respiration in part by releasing endothelial NO. These mechanisms couple blood flow and metabolism in penile arterial wall and suggest that activation of vascular mitoKATP channels may protect erectile tissue against ischemic injury.

A deep-learning strategy to identify cell types across species from high-density extracellular recordings.

High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but don't reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals, revealing the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetic activation and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep-learning classifier that predicts cell types with greater than 95% accuracy based on waveform, discharge statistics, and layer of the recorded neuron. The classifier's predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across animal species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously-recorded cell types during behavior.

Quantifying venom production: A study on Micrurus snakes in Mexico.

Our study quantifies venom production in nine Mexican coral snake species (Micrurus), encompassing 76 specimens and 253 extractions. Noteworthy variations were observed, with M. diastema and M. laticollaris displaying diverse yields, ranging from 0.3 mg to 59 mg. For animals for which we have length data, there is a relationship between size and venom quantity. Twenty-eight percent of the observed variability in venom production can be explained by snake size, suggesting that other factors influence the amount of obtained venom. These findings are pivotal for predicting venom effects and guiding antivenom interventions. Our data offer insights into Micrurus venom yields, laying the groundwork for future research and aiding in medical response strategies. This study advances understanding coral snake venom production, facilitating informed medical responses to coral snake bites.

Construction of a Mycoviral Infectious Clone for Reverse Genetics in Botrytis cinerea.

The most important advances in our understanding of the viral life cycle, such as genome replication, packaging, transmission, and host interactions, have been made via the development of viral infectious full-length clones. Here, we describe the detailed protocols for the construction of an infectious clone derived from Botrytis virus F (BVF), a mycoflexivirus infecting the plant pathogenic fungus Botrytis cinerea, the determination of the complete sequence of the cloned mycovirus, the preparation of fungal protoplasts, and the transfection of protoplasts using transcripts derived from the BVF infectious clone.

Actividades de superación profesional de médicos generales integrales sobre el uso racional de medicamentos / Professional training activities of comprehensive general doctors on the rational use of medications i: en

Introducción: El uso irracional de medicamentos se debe, entre otros elementos, a la falta de superación profesional; situación con mayor repercusión en la atención primaria de salud, donde generalmente laboran los médicos generales integrales. Objetivo: Caracterizar las actividades de superación profesional de médicos generales integrales sobre el uso racional de medicamentos. Métodos: Se realizó un estudio descriptivo y transversal de 269 médicos generales integrales que laboraban en los consultorios del médico de la familia o en los servicios de urgencia de las 17 áreas de salud del municipio de Santiago de Cuba en el período comprendido desde enero hasta julio de 2022, quienes fueron seleccionados mediante muestreo probabilístico por conglomerado bietápico. Se consideró como variable las actividades de superación profesional relacionadas con el uso racional de medicamentos, las cuales fueron valoradas a través de 5 indicadores. Resultados: La triangulación metodológica de los resultados evidenció que el nivel alcanzado en cuanto a la frecuencia de realización de dichas actividades fue bajo (índice de 1,18), al igual que lo obtenido en los indicadores analizados, excepto en el referido a la autopreparación que mostró un nivel medio. Conclusiones: Las actividades de superación profesional de los médicos generales integrales relacionadas con el uso racional de medicamentos en el municipio de Santiago de Cuba se caracterizaron por un nivel bajo de frecuencia de realización.

Introduction: Irrational use of medications is, among other elements, due to the lack of professional training; situation with more repercussion in primary health care, where comprehensive general doctors generally work. Objective: To characterize the professional training activities of comprehensive general doctors on the rational use of medications. Methods: A descriptive and cross-sectional study of 269 comprehensive general doctors who worked in the family doctor offices or in the emergency services of the 17 health areas of Santiago de Cuba municipality was carried out from January to July, 2022, who were selected by means of a probabilistic sampling by biphase conglomerate. The activities of professional training related to the rational use of medications were considered as variable, which were valued through 5 indicators. Results: The methodological triangulation of the results evidenced that the level reached as for the frequency of realization of this activities was low (index of 1.18), as well as what was obtained in the analyzed indicators, except the one referred to the self-preparation which showed a mean level. Conclusions: Professional training activities of comprehensive general doctors related to the rational use of medications in Santiago de Cuba municipality were characterized by a low level of realization frequency.

Does Lower-Limb Tendon Structure Influence Walking Gait?

BACKGROUND: Within the exploration of human gait, key focal points include the examination of functional rockers and the influential role of tendon behavior in the intricate stretch-shortening cycle. To date, the possible relationship between these two fundamental factors in the analysis of human gait has not been studied. Therefore, this study aimed to analyze the relationship between the morphology of the patellar and Achilles tendons and plantar fascia with respect to the duration of the rockers. METHODS: Thirty-nine healthy men (age: 28.42 ± 6.97 years; height: 173 ± 7.17 cm; weight: 67.75 ± 9.43 kg) were included. Data of the rockers were recorded using a baropodometric platform while participants walked over a 10 m walkway at a comfortable velocity. Before the trials, the thickness and cross-sectional area were recorded for the patellar tendon, Achilles tendon and plantar fascia using ultrasound examination. The relationship between the morphology of the soft tissue and the duration of the rockers was determined using a pairwise mean comparison (t-test). RESULTS: A significant difference was found for rocker 1 duration, where a longer duration was found in the group of subjects with thicker patellar tendons. Regarding the Achilles tendon and plantar fascia, no significant differences were observed in terms of tendon morphology. However, subjects with thicker Achilles tendons showed a longer duration of rocker 1. CONCLUSIONS: The findings underscore a compelling association, revealing that an increased thickness of the patellar tendon significantly contributes to the extension of rocker 1 duration during walking in healthy adults.

Influence of walking speed on gait spatiotemporal parameters and the functional rockers of the foot in healthy adults.

BACKGROUND: The gait cycle is generally divided into stance phase and swing phase. The stance phase can also be divided into three functional rockers, each with a distinct fulcrum. It has been shown that walking speed (WS) influences both stance and swing phase but its influence on the functional foot rockers duration is unknown. The aim of the study was to analyze the WS influence on functional foot rockers duration. METHODS: a cross-sectional study is completed with 99 healthy volunteers to assess the effect of WS on kinematics and foot rockers duration in treadmill walking at 4, 5, and 6 km·h-1 RESULTS: Friedman test exhibited that all spatiotemporal variables and the length of the foot rockers changed significantly with WS (p < 0.05) except rocker 1 at 4 and 6 km·h-1. CONCLUSION: Every spatiotemporal parameter and the duration of the three functional rockers are affected by walking speed, although not all rockers are affected equally. The findings of this study reveal that Rocker 2 is the primary rocker whose duration is influenced by changes in gait speed.

Hospitalization Burden of Patients with Kidney Stones and Metabolic Comorbidities in Spain during the Period 2017-2020.

Nephrolithiasis has become an increasing worldwide problem during the last decades. Metabolic syndrome, its components, and related dietary factors have been pointed out as responsible for the increasing incidence. The objective of this study was to evaluate the trends in the hospitalization rates of patients with nephrolithiasis, hospitalization features, costs, and how metabolic syndrome traits influence both the prevalence and complications of lithiasic patients. An observational retrospective study was conducted by analyzing hospitalization records from the minimum basic data set, including all patient hospitalizations in Spain in which nephrolithiasis has been coded as a main diagnosis or as a comorbidity during the period 2017-2020. A total of 106,407 patients were hospitalized and coded for kidney or ureteral lithiasis in this period. The mean age of the patients was 58.28 years (CI95%: 58.18-58.38); 56.8% were male, and the median length of stay was 5.23 days (CI95%: 5.06-5.39). In 56,884 (53.5%) patients, kidney or ureteral lithiasis were coded as the main diagnosis; the rest of the patients were coded mostly as direct complications of kidney or ureteral stones, such as "non-pecified renal colic", "acute pyelonephritis", or "tract urinary infection". The hospitalization rate was 56.7 (CI95%: 56.3-57.01) patients per 100,000 inhabitants, showing neither a significant increasing nor decreasing trend, although it was influenced by the COVID-19 pandemic. The mortality rate was 1.6% (CI95%: 1.5-1.7), which was higher, if lithiasis was coded as a comorbidity (3.4% CI95%: 3.2-3.6). Metabolic syndrome diagnosis component codes increased the association with kidney lithiasis when age was higher, reaching the highest in the eighth decade of life. Age, diabetes, and hypertension or lithiasis coded as a comorbidity were the most common causes associated with the mortality of lithiasic patients. In Spain, the hospitalization rate of kidney lithiasis has remained stable during the period of study. The mortality rate in lithiasic patients is higher in elderly patients, being associated with urinary tract infections. Comorbidity conditions such as diabetes mellitus and hypertension are mortality predictors.

Fusarium Photoreceptors.

Light is an important modulating signal in fungi. Fusarium species stand out as research models for their phytopathogenic activity and their complex secondary metabolism. This includes the synthesis of carotenoids, whose induction by light is their best known photoregulated process. In these fungi, light also affects other metabolic pathways and developmental stages, such as the formation of conidia. Photoreceptor proteins are essential elements in signal transduction from light. Fusarium genomes contain genes for at least ten photoreceptors: four flavoproteins, one photolyase, two cryptochromes, two rhodopsins, and one phytochrome. Mutations in five of these genes provide information about their functions in light regulation, in which the flavoprotein WcoA, belonging to the White Collar (WC) family, plays a predominant role. Global transcriptomic techniques have opened new perspectives for the study of photoreceptor functions and have recently been used in Fusarium fujikuroi on a WC protein and a cryptochrome from the DASH family. The data showed that the WC protein participates in the transcriptional control of most of the photoregulated genes, as well as of many genes not regulated by light, while the DASH cryptochrome potentially plays a supporting role in the photoinduction of many genes.

Do PHI and PHI density improve detection of clinically significant prostate cancer only in the PSA gray zone?

OBJECTIVES: Prostate health index (PHI) is a predictive biomarker of positive prostate biopsy. The majority of evidence refers to its use in the PSA gray zone (4-10 ng/mL) and negative digital rectal exam (DRE). We aim to evaluate and compare the predictive accuracy of PHI and PHI density (PHId) with PSA, percentage of free PSA and PSA density, in a wider range of patients for the detection of clinically significant prostate cancer (csPCa). METHODS: Multicenter prospective study that included patients suspicious of harboring prostate cancer. Non-probabilistic convenience sampling, where men who attended the urology consultation were tested for PHI before prostate biopsy. To evaluate and compare diagnostic accuracy AUC and decision curve analysis (DCA) were calculated. All these procedures were performed for the overall sample and the following subsamples: PSA < 4 ng/ml; PSA 4-10 ng/ml; PSA 4-10 ng/ml plus negative DRE and PSA > 10 ng/ml. RESULTS: Among the 559 men included, 194 (34.7%) were diagnosed of csPCa. PHI and PHId outperfomed PSA in all subgroups. PHI best diagnostic performance was found in PSA 4-10 ng/ml with negative DRE (sensitivity 93.33, NPV 96.04). Regarding AUC, significant differences were found between PHId and PSA in the subgroup of PSA 4-10 ng/ml, whatever DRE status. In DCA, PHI density shows the highest net benefit. CONCLUSIONS: PHI and PHId outperfom PSA in csPCa detection, not only in the PSA grey zone with negative DRE, but also in a wider range of PSA values. There is an urgent need of prospective studies to established a validated threshold and its incorporation in risk calculators.

Somatodendritic orientation determines tDCS-induced neuromodulation of Purkinje cell activity in awake mice.

Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits in vivo. In this study, we observe that tDCS induces a heterogeneous polarity-dependent modulation of the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex. Using a combination of juxtacellular labeling and high-density Neuropixels recordings, we demonstrate that the apparently heterogeneous effects of tDCS on PC activity can be explained by taking into account the somatodendritic orientation relative to the electric field. Our findings emphasize the importance of considering neuronal orientation and morphological aspects to increase the predictive power of tDCS computational models, enhance the reliability of current stimulation protocols and optimize desired effects in basic and clinical human applications.

Absolute agreement and consistency of the OptoGait system and Freemed platform for measuring walking gait.

The gait cycle can be divided into four functional rocker units. Although the widespread use of the OptoGait (OG) system and the Freemed (FM) platform, their accuracy has not been tested. An observational study was completed with eighteen healthy volunteers to determine the accuracy of OG and FM for overground walking gait analysis. The pairwise comparison between data obtained from OG, FM and high-speed video analysis revealed significant differences for most of the measurements (p < 0.05). ICCs revealed an excellent absolute agreement between measurements (ICCs > 0.94) for all measures for OG systems compared to video-analysis. When considering FM vs. video-analysis, ICCs showed good absolute agreement for rocker 1 (ICC = 0.86) and 3 (ICC = 0.82), excellent for rocker 2 (ICC = 0.93) and poor (ICC < 0.5) for rocker 4. Bland-Altman plots (95% limits of agreement) revealed heteroscedasticity of error for OG in all variables for foot rockers (r2 > 0.1) while no heteroscedasticity of error was found when using FM (r2 < 0.1). This study indicates that the OG system and the FM platform can provide consistent foot rockers values when walking at a constant velocity. The differences between the systems assessed and their agreement and consistency values advise against their interchangeable use.

Cost-effectiveness and epidemiological impact of gender-neutral HPV vaccination in Spain.

All EU countries have introduced Human papilloma virus (HPV) vaccination for adolescent girls and many countries are expanding the strategy to include adolescent boys. There is uncertainty about the cost-effectiveness and epidemiological impact of a gender-neutral HPV vaccination strategy. Here we present the results of an economic model adapted for Spain. Five vaccination strategies were compared from the Spanish healthcare system perspective, combining two vaccines (4-valent and 9-valent) in a gender-neutral or girls-only programme in a dynamic population-based model with a discrete-time Markov approach. Costs and benefits were discounted at 3%. The benefits of immunization were measured with quality-adjusted life years (QALYs), which are achieved by reducing the incidence of diseases attributable to HPV. Incremental cost-effectiveness ratio (ICER) was compared with the willingness-to-pay threshold in Spain. The two most effective strategies were compared: gender-neutral 9-valent vaccination vs. girls-only 9-valent vaccination, resulting in an ICER of € 34,040/QALY, and an important number of prevented cases of invasive cancers and anogenital warts. The sensitivity analysis revealed that gender-neutral 9-valent vaccination would become cost-effective if protection against oropharyngeal and penile cancers was included or if the price per dose decreased from €45 to €28. The gender-neutral 9-valent HPV vaccination in Spain offers more benefits than any other modeled strategy, although in the conservative base case it is not cost-effective. However, certain plausible assumptions would turn it into an efficient strategy, which should be borne in mind by the decision makers together with equity and justice arguments.

What is the context? Human papillomavirus (HPV) is a group of viruses that causes sexually transmitted diseases, including certain cancers. European countries offer HPV vaccination to adolescent girls.Many countries have also introduced the vaccination in adolescent boys.There are doubts about whether it is worth vaccinating adolescents of both genders.What this study adds? We estimated costs and benefits of the vaccination in Spain, comparing two types of vaccine, only in girls and in both genders. This analysis considered indirect protection of vaccinated people to unvaccinated ones.It seems that the benefits of HPV vaccination in all adolescents do not compensate the costs.However, when we included likely protection against additional cancers or we reduced the price per vaccine dose, it would be worth vaccinating all adolescents in Spain.We also stated ethical arguments in favor of HPV vaccination for both genders.What is the impact? HPV vaccination in adolescent boys and girls in Spain will prevent more HPV-related diseases.For certain scenarios, HPV vaccination in both genders would be worth in Spain.Ethically, vaccinating also boys would be fair, equitable and would not discriminate a part of the population.

Hyperoxaluria Induces Endothelial Dysfunction in Preglomerular Arteries: Involvement of Oxidative Stress.

Urolithiasis is a worldwide problem and a risk factor for kidney injury. Oxidative stress-associated renal endothelial dysfunction secondary to urolithiasis could be a key pathogenic factor, similar to obesity and diabetes-related nephropathy. The aim of the present study was to characterize urolithiasis-related endothelial dysfunction in a hyperoxaluria rat model of renal lithiasis. EXPERIMENTAL APPROACH: Endothelial dysfunction was assessed in preglomerular arteries isolated from control rats and in which 0.75% ethylene glycol was administered in drinking water. Renal interlobar arteries were mounted in microvascular myographs for functional studies; superoxide generation was measured by chemiluminescence and mRNA and protein expression by RT-PCR and immunofluorescence, respectively. Selective inhibitors were used to study the influence of the different ROS sources, xanthine oxidase, COX-2, Nox1, Nox2 and Nox4. Inflammatory vascular response was also studied by measuring the RNAm expression of NF-κB, MCP-1 and TNFα by RT-PCR. RESULTS: Endothelium-dependent vasodilator responses were impaired in the preglomerular arteries of the hyperoxaluric group along with higher superoxide generation in the renal cortex and vascular inflammation developed by MCP-1 and promoted by NF-κB. The xanthine oxidase inhibitor allopurinol restored the endothelial relaxations and returned superoxide generation to basal values. Nox1 and Nox2 mRNA were up-regulated in arteries from the hyperoxaluric group, and Nox1 and Nox2 selective inhibitors also restored the impaired vasodilator responses and normalized NADPH oxidase-dependent higher superoxide values of renal cortex from the hyperoxaluric group. CONCLUSIONS: The current data support that hyperoxaluria induces oxidative stress-mediated endothelial dysfunction and inflammatory response in renal preglomerular arteries which is promoted by the xanthine oxidase, Nox1 and Nox2 pathways.

Safety of combining dabrafenib plus trametinib in elderly BRAF V600 mutation-positive advanced melanoma patients: real-world data analysis of Spanish patients (ELDERLYMEL).

Efficacy and safety of dabrafenib and trametinib in metastatic melanoma have been demonstrated in two-phase III and one-phase I/II clinical trials. However, patients at least 75 years old (y.o.) were largely underrepresented. Additionally, the safety profile of dabrafenib and trametinib based on age is unknown. ELDERLYMEL is a retrospective noninterventional multicenter study, describing the effectiveness and safety of at least 75 y.o. patients compared with less than 75 y.o. patients with advanced BRAF V600-mutated melanoma treated with dabrafenib plus trametinib or dabrafenib monotherapy. A total of 159 patients were included, 130 less than 75 y.o. and 29 at least 75 y.o. Clinical features were similar between the groups, except in the number of comorbidities, number of metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, and BRAF V600-mutation type. Five patients per group received dabrafenib monotherapy. There were no differences in adverse events (AEs) rate or grade between the groups. However, AE profiles were different between the groups, being pyrexia infrequent in patients at least 75 y.o. (13.8% vs. 42.3%; P = 0.005). Dabrafenib and trametinib dose intensities were lower in at least 75 y.o. patients ( P = 0.018 and P = 0.020), but there were no differences in effectiveness between the groups. Finally, in a multivariate analysis, sex (female) was the only variable independently associated with an increased risk of AE grade ≥3. Data from the ELDERLYMEL study demonstrate that dabrafenib plus trametinib is safe and effective in at least 75 y.o. patients with advanced BRAF V600-mutated melanoma without increasing toxicity. Additionally, we describe a different safety profile depending on age and sex.

Dendritic Inhibition by Shh Signaling-Dependent Stellate Cell Pool Is Critical for Motor Learning.

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and nonmotor functions. The molecular layer interneurons (MLIs), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons, which migrate from the prospective white matter to the ML of the cortex. However, little is known about how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well understood. Here, we show that GABAergic progenitors fated to generate both BCs and SCs respond to the Sonic hedgehog (Shh) signal. Conditional abrogation of Shh signaling of either sex inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+ cells settle into their laminar positions in an inside-out sequence. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.SIGNIFICANCE STATEMENT The cerebellar circuit that enables fine motor learning involves MLIs of BCs and SCs, which provide dendritic and somatic inhibitory synapses onto Purkinje cells. Little is known about how their identities and numbers are determined, nor are their specific contributions to motor learning well understood. We show that MLI subtypes are specified independent of Shh signaling and their birth orders but appear to occur in their terminal laminar positions according to the inside-out sequence. This finding challenges the current view that MLI subtypes are specified sequentially at the progenitor level. We also demonstrate that dendritic inhibition by Shh signaling-dependent SC pool is necessary for motor learning.