Opposing effects of the purinergic P2X7 receptor on seizures in neurons and microglia in male mice.

BACKGROUND: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. METHODS: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. RESULTS: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome. CONCLUSIONS: Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy.

Integration of selective sweeps across the sheep genome: understanding the relationship between production and adaptation traits.

BACKGROUND: Livestock populations are under constant selective pressure for higher productivity levels for different selective purposes. This pressure results in the selection of animals with unique adaptive and production traits. The study of genomic regions associated with these unique characteristics has the potential to improve biological knowledge regarding the adaptive process and how it is connected to production levels and resilience, which is the ability of an animal to adapt to stress or an imbalance in homeostasis. Sheep is a species that has been subjected to several natural and artificial selective pressures during its history, resulting in a highly specialized species for production and adaptation to challenging environments. Here, the data from multiple studies that aim at mapping selective sweeps across the sheep genome associated with production and adaptation traits were integrated to identify confirmed selective sweeps (CSS). RESULTS: In total, 37 studies were used to identify 518 CSS across the sheep genome, which were classified as production (147 prodCSS) and adaptation (219 adapCSS) CSS based on the frequency of each type of associated study. The genes within the CSS were associated with relevant biological processes for adaptation and production. For example, for adapCSS, the associated genes were related to the control of seasonality, circadian rhythm, and thermoregulation. On the other hand, genes associated with prodCSS were related to the control of feeding behaviour, reproduction, and cellular differentiation. In addition, genes harbouring both prodCSS and adapCSS showed an interesting association with lipid metabolism, suggesting a potential role of this process in the regulation of pleiotropic effects between these classes of traits. CONCLUSIONS: The findings of this study contribute to a deeper understanding of the genetic link between productivity and adaptability in sheep breeds. This information may provide insights into the genetic mechanisms that underlie undesirable genetic correlations between these two groups of traits and pave the way for a better understanding of resilience as a positive ability to respond to environmental stressors, where the negative effects on production level are minimized.

Reliability and Validity of the Spanish Version of the Brief-BESTest in Stroke Patients.

Background: Balance disorders and postural control treatments play an important role in fall prevention. The Brief-BESTest is a short-scale employed to evaluate balance and fall risk in different populations. Balance assessment is a fundamental element in patients with Acquired Brain Injury rehabilitation since postural alteration is one of the most frequent sequelae. The objective was to validate the Spanish version of the Brief-BESTest questionnaire in the stroke population. Methods: Subjects of both sexes aged over 18 years with a diagnosis of acute/chronic stroke were included. The BESTest, Mini-BESTest, Brief-BESTest, Berg Balance Scale, and Timed Up & Go Test were used to assess balance. The scales were implemented once. Cronbach's alpha coefficient was used to assess the internal consistency and confirmatory factorial analysis was employed to assess validity. Results: A total of 44 patients with a mean age of 65.35 years (SD = 10.665) participated. Cronbach's alpha coefficient showed a high internal consistency with a value of 0.839. In the criterion validity, there was a high positive correlation between the Brief-BESTest and BESTest (r = 0.879), Mini-BESTest (r = 0.808), and Berg Balance Scale (r = 0.711). Conclusion: The Spanish version of the Brief-BESTest scale is valid and reliable, showing adequate psychometric properties for balance assessment in patients with acute or chronic stroke.

Organ Donation and Transplantation Registries Across the Globe: A Review of the Current State.

BACKGROUND: The current landscape of organ donation and transplantation (ODT) registries is not well established. This narrative review sought to identify and characterize the coverage, structure, and data capture of ODT registries globally. METHODS: We conducted a literature search using Ovid Medline and web searches to identify ODT registries from 2000 to 2023. A list of ODT registries was compiled based on publications of registry design, studies, and reports. Extracted data elements included operational features of registries and the types of donor and recipient data captured. RESULTS: We identified 129 registries encompassing patients from all continents except Antarctica. Most registries were active, received funding from government or professional societies, were national in scope, included both adult and pediatric patients, and reported patient-level data. Registries included kidney (n = 99), pancreas (n = 32), liver (n = 44), heart (n = 35), lung (n = 30), intestine (n = 15), and islet cell (n = 5) transplants. Most registries captured donor data (including living versus deceased) and recipient features (including demographics, cause of organ failure, and posttransplant outcomes) but there was underreporting of other domains (eg, donor comorbidities, deceased donor referral rates, waitlist statistics). CONCLUSIONS: This review highlights existing ODT registries globally and serves as a call for increased visibility and transparency in data management and reporting practices. We propose that standards for ODT registries, a common data model, and technical platforms for collaboration, will enable a high-functioning global ODT system responsive to the needs of transplant candidates, recipients, and donors.

Corrigendum: Quality of life and quality of education among physiotherapy students in Europe.

[This corrects the article DOI: 10.3389/fmed.2024.1344028.].

Assessing Outcomes of Patients Subject to Intensive Care to Facilitate Organ Donation: A Spanish Multicenter Prospective Study.

Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC. Of the 194 patients, 144 (74.2%) patients fulfilled DNC after a median of 25 h (95% IQR: 17-44) from ICOD onset. Two patients (1%) shifted from ICOD to curative treatment, both were alive at discharge. Factors associated with progression to DNC included: age below 70 years, clinical score consistent with severe brain injury, instability, intracranial hemorrhage, midline shift ≥5 mm and certain types of brain herniation. Overall 151 (77.8%) patients progressed to organ donation. Based on these results, we conclude that ICOD is a beneficial and efficient practice that can contribute to the pool of deceased donors.

Upper Limb Electromyographic Responses to Motor Imagery and Action Observation in Acquired Brain Injury.

Acquired Brain Injuries are one of the leading causes of mortality and disability worldwide. One of the most frequent sequelae is motor impairment of the upper limbs, which affects people's functionality and quality of life. Following the discovery of mirror neurons, new techniques were developed based on the mechanisms of neuronal plasticity, such as motor imagery (MI) and action observation (AO). We propose a protocol using electromyographic recordings of forearm muscles in people who have suffered a stroke during an MI task and an AO task. Three different experimental conditions will be studied during the electromyographic recordings: control recording, recording during MI, and recording during AO. Understanding the muscle activation in each technique will allow us to develop future protocols and intervention plans, improving the quality of care for people who have suffered a stroke.

Quality of life and quality of education among physiotherapy students in Europe.

Background: The study of physiotherapy is challenging and can affect the students' well-being and quality of life. The aim of this study was to describe and compare factors that could affect well-being among students across Europe. Methods: In this descriptive cross-sectional study using an online questionnaire survey, students of bachelor's physiotherapy programs from 23 European faculties, from 8 countries, were interviewed on mental health and stress burden, sleep quality, dietary habits, and physical activity. Results: Although 75% of students rated their quality of life positively and 47% were satisfied with their mental health, 65% showed higher levels of stress and 51% described impaired sleep quality. The minimum physical activity of 150 min weekly was described by 79% of students, within which 67% engaged in strengthening twice a week. Students with a higher stress load/worse psychological health also showed worse sleep quality and lower amount of physical activity, women were significantly worse off. In terms of physical activity and sleep quality, students from Finland and Kosovo achieved the best results, while students from Italy, Greece, and Portugal achieved the worst. Students from Italy indicated the greatest dissatisfaction with the organisation of the study system and communication with teachers, while in Kosovo students rated the communication and study organisation the highest. All students had a problem with adhering to nutritional habits. Students from Italy and Spain, with the lowest body mass indexes and weight averages, were closest to the nutrition recommendations. Conclusion: We demonstrated that physiotherapy students are burdened with stress, suffer from sleep disorders, and do not follow the recommendations regarding nutrition nor physical activity. There are significant differences between universities and countries in some aspects.

Immunoproteasome deficiency results in age-dependent development of epilepsy.

The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating the degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly not expressed in the healthy brain. In this study, we show an age-dependent increase in polyubiquitination in the brains of wild-type mice, accompanied by an induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout mice), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged triple-knockout mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, the aged triple-knockout mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during ageing.

Transplantation in the Context of Migration and Refugees: A Summary of the DICG and TTS Ethics Committee Workshop, Buenos Aires, Argentina, September 2022.

Global conflicts and humanitarian crises have resulted in an unprecedented number of refugees and migrants. This challenges the limited resources of health care systems and jeopardizes the availability of transplant care for these deserving migrants and refugees. This was the basis for a workshop held during the Congress of the Transplantation Society (Buenos Aires, 2022). We elaborate on the proceedings of the workshop entitled "Transplantation in the Context of Migration and Refugees," organized by the Ethics Committee of The Transplantation Society and Declaration of Istanbul Custodian Group. Transplant providers from around the world shared strategies of how each region has responded to providing access to care for refugees and migrants in need of transplant services. The potential exploitation of this vulnerable group leading to illicit organ removal was addressed for each region. The Transplantation Society, Declaration of Istanbul Custodian Group, and global transplant community should continue to focus on the status of refugees and migrants and collaborate on strategies to provide access to transplant care for this deserving population. Global cooperation will be essential to provide vigilant oversight to prevent exploitation of this vulnerable population.

Persistence of microbiological hazards in food and feed production and processing environments.

Listeria monocytogenes (in the meat, fish and seafood, dairy and fruit and vegetable sectors), Salmonella enterica (in the feed, meat, egg and low moisture food sectors) and Cronobacter sakazakii (in the low moisture food sector) were identified as the bacterial food safety hazards most relevant to public health that are associated with persistence in the food and feed processing environment (FFPE). There is a wide range of subtypes of these hazards involved in persistence in the FFPE. While some specific subtypes are more commonly reported as persistent, it is currently not possible to identify universal markers (i.e. genetic determinants) for this trait. Common risk factors for persistence in the FFPE are inadequate zoning and hygiene barriers; lack of hygienic design of equipment and machines; and inadequate cleaning and disinfection. A well-designed environmental sampling and testing programme is the most effective strategy to identify contamination sources and detect potentially persistent hazards. The establishment of hygienic barriers and measures within the food safety management system, during implementation of hazard analysis and critical control points, is key to prevent and/or control bacterial persistence in the FFPE. Once persistence is suspected in a plant, a 'seek-and-destroy' approach is frequently recommended, including intensified monitoring, the introduction of control measures and the continuation of the intensified monitoring. Successful actions triggered by persistence of L. monocytogenes are described, as well as interventions with direct bactericidal activity. These interventions could be efficient if properly validated, correctly applied and verified under industrial conditions. Perspectives are provided for performing a risk assessment for relevant combinations of hazard and food sector to assess the relative public health risk that can be associated with persistence, based on bottom-up and top-down approaches. Knowledge gaps related to bacterial food safety hazards associated with persistence in the FFPE and priorities for future research are provided.

Maintaining the permanence principle of death during normothermic regional perfusion in controlled donation after the circulatory determination of death: Results of a prospective clinical study.

One concern about the use of normothermic regional perfusion (NRP) in controlled donation after the circulatory determination of death (cDCD) is that the brain may be perfused. We aimed to demonstrate that certain technical maneuvers preclude such brain perfusion. A nonrandomized trial was performed on cDCD donors. In abdominal normothermic regional perfusion (A-NRP), the thoracic aorta was blocked with an intra-aortic occlusion balloon. In thoracoabdominal normothermic regional perfusion (TA-NRP), the arch vessels were clamped and the cephalad ends vented to the atmosphere. The mean intracranial arterial blood pressure (ICBP) was invasively measured at the circle of Willis. Ten cDCD donors subject to A-NRP or TA-NRP were included. Mean ICBP and mean blood pressure at the thoracic and the abdominal aorta during the circulatory arrest were 17 (standard deviation [SD], 3), 17 (SD, 3), and 18 (SD, 4) mmHg, respectively. When A-NRP started, pressure at the abdominal aorta increased to 50 (SD, 13) mmHg, while the ICBP remained unchanged. When TA-NRP was initiated, thoracic aorta pressure increased to 71 (SD, 18) mmHg, but the ICBP remained unmodified. Recorded values of ICBP during NRP were 10 mmHg. In conclusion, appropriate technical measures applied during NRP preclude perfusion of the brain in cDCD. This study might help to expand NRP and increase the number of organs available for transplantation.

Improving the Access of Highly Sensitized Patients to Kidney Transplantation From Deceased Donors: The Spanish PATHI Program With Allocation Based on the Virtual Crossmatch.

BACKGROUND: In 2015, the Spanish National Transplant Organization developed a prioritization system (Program for Access to Transplantation for Highly Sensitized Patients [PATHI]) to increase transplant options for patients with calculated panel-reactive antibodies (cPRAs) ≥98%, based on virtual crossmatch. We describe the experience with the implementation of PATHI and assess its efficacy. METHODS: PATHI registry was used to collect characteristics of donors and patients between June 15, 2015, and March 1, 2018. One-year graft and patient survival and acute rejection were also measured. A Cox model was used to identify factors related to patient death and graft loss and logistical regression for those associated with rejection. RESULTS: One thousand eighty-nine patients were included, and 272 (25%) were transplanted. Transplant rate by cPRA was 54.9%, 40.5%, and 12.8% in patients with cPRA98%, cPRA99%, and cPRA100%, respectively. One-year patient survival was 92.5%. Recipient age ≥60, time under dialysis >7 y, and delayed graft function were mortality risk factors. One-year graft survival was 88.7%. The factor related to graft loss was delayed graft function. The rejection rate was 22%. Factors related to rejection were sex, older recipients, and posttransplant donor-specific antibodies. CONCLUSIONS: A prioritization approach increases transplant options for highly sensitized patients with appropriate short-term postransplant outcomes. Along with other programs, PATHI may inspire other countries to adopt strategies to meet transplant needs of these patients.

Review of the allocation criteria for heart transplant in Spain in 2023. SEC-Heart Failure Association/ONT/SECCE consensus document.

Heart transplant (HT) remains the best therapeutic option for patients with advanced heart failure (HF). The allocation criteria aim to guarantee equitable access to HT and prioritize patients with a worse clinical status. To review the HT allocation criteria, the Heart Failure Association of the Spanish Society of Cardiology (HFA-SEC), the Spanish Society of Cardiovascular and Endovascular Surgery (SECCE) and the National Transplant Organization (ONT), organized a consensus conference involving adult and pediatric cardiologists, adult and pediatric cardiac surgeons, transplant coordinators from all over Spain, and physicians and nurses from the ONT. The aims of the consensus conference were as follows: a) to analyze the organization and management of patients with advanced HF and cardiogenic shock in Spain; b) to critically review heart allocation and priority criteria in other transplant organizations; c) to analyze the outcomes of patients listed and transplanted before and after the modification of the heart allocation criteria in 2017; and d) to propose new heart allocation criteria in Spain after an analysis of the available evidence and multidisciplinary discussion. In this article, by the HFA-SEC, SECCE and the ONT we present the results of the analysis performed in the consensus conference and the rationale for the new heart allocation criteria in Spain.

The Communication of Bad News in Palliative Care: The View of Professionals in Spain.

BACKGROUND: Communication is one of the central axes around which end-of-life care revolves in the context of palliative care. Communication of bad news is reported as one of the most difficult and stressful tasks by palliative care professionals. Therefore, the aim of this study is to identify aspects related to the communication of bad news in palliative care in Spain. METHODS: Descriptive cross-sectional study. An ad hoc questionnaire was designed and sent by e-mail to all palliative care teams in Spain. RESULTS: Overall, 206 professionals (102 nurses, 88 physicians and 16 psychologists) completed the questionnaire. A total of 60.2% considered their communication of bad news skills to be good or very good. This was related to older age, experience in both the profession and palliative care, and to having received specific postgraduate training (P < .001). Around 42.2% perform communication of bad news with the patient first, which is associated with lower skill (P = .013). About 78.15% of the professionals do not use any specific protocol. CONCLUSION: This study suggests that patients access palliative care with little information about their diagnosis and prognosis. The barriers identified in the communication of bad news are the lack of specific education and training in protocol management, the difficult balance between hope and honesty, the young age of the patient, and the family.

Is There a Place for Brachytherapy in Vulvar Cancer? A Narrative Review.

Vulvar cancer is a relatively rare neoplasm. The essential treatment is surgery for the primary tumour. However, postoperative recurrence rates are high, even in early-stage disease when tumour-free surgical margins are achieved or in the absence of associated risk factors (lymph node metastases, deep stromal invasion or invasion of the lymphatic vascular space). Radiotherapy plays an important role in the treatment of vulvar cancer. Adjuvant treatment after surgery as well as primary treatment of locally advanced vulvar cancer (LAVC) is composed of two key radiotherapy treatment scenarios, external beam radiation therapy (EBRT) either combined or not combined with brachytherapy (BT). In a recurrence setting, where surgery is not an option, BT alone or in combination with EBRT can be used. Compared to EBRT, BT has the radiobiological potential to improve dose to the target volume, minimise the dose to organs at risk, and facilitate hypofractionated-accelerated treatment. This narrative review presents recent data on the role of BT in the treatment of primary and/or recurrent vulvar cancer, including radiobiological, clinical, and therapeutic aspects.

Synergy of Muscle and Cortical Activation through Vojta Reflex Locomotion Therapy in Young Healthy Adults: A Pilot Randomized Controlled Trial.

BACKGROUND: Vojta Therapy is a neurorehabilitation therapy that allows to activate reflex movement patterns. The scientific literature has shown its ability to generate muscle contractions. The activation of brain neural networks has also been proven. However, the relationship between these processes has not yet been demonstrated. For this reason, the aim of this study is to verify brain activation produced by recording with near-infrared spectroscopy and its relationship with muscle activation produced in the abdominal muscles recorded with surface electromyography. METHODS: A total sample of 27 healthy subjects over 18 years of age was recruited. An experimental study on a cohort was conducted. Two experimental conditions were considered: stimuli according to the Vojta protocol, and a control non-stimuli condition. Abdominal muscle activation was measured using surface electromyography, and the activation of the motor cortex was assessed with near-infrared spectroscopy. RESULTS: In relation to the oxygenated hemoglobin concentration (HbO), an interaction between the stimulation phase and group was observed. Specifically, the Vojta stimulation group exhibited an increase in concentration from the baseline phase to the first resting period in the right hemisphere, contralateral to the stimulation area. This rise coincided with an enhanced wavelet coherence between the HbO concentration and the electromyography (EMG) signal within a gamma frequency band (very low frequency) during the first resting period. CONCLUSIONS: The results underscore the neurophysiological effects on the brain following tactile stimulation via Vojta Therapy, highlighting increased activity in pivotal areas essential for sensory processing, motor planning, and control. This activation, particularly evident in the Vojta stimulation group, aligns with previous findings, suggesting that tactile stimuli can not only evoke the intention to move but can also initiate actual muscle contractions, emphasizing the therapy's potential in enhancing innate locomotion and rolling movements in patients with neurological disorders.

Approaching the Families of Potential Deceased Organ Donors: An Overview of Regulations and Practices in Council of Europe Member States.

The primary aim of this study was to describe regulations and practices concerning the family approach to discuss donation, specifically after the neurological determination of death, one of the most challenging steps in the donation pathway. A secondary objective was to assess the impact of legislation on consent rates for organ donation. The Council of Europe surveyed 39 member states about national regulations, practices, and consent rates; 34 replied. Opt-out legislation is present in 19, opt-in in 9 and a mixed system in six countries. An opt-out register is kept by 24 countries and an opt-in register by 18 countries, some keeping both. The mean consent rate was 81.2% of all family approaches. Most countries regulate how death using neurological criteria is confirmed (85.3%), while regulation of other aspects of the deceased donation pathway varies: the timing of informing the family about brain death (47.1%) and organ donation (58.8%), the profile of professional who discusses both topics with the family (52.9% and 64.7%, respectively) and the withdrawal of treatment after brain death (47.1%). We also noted a mismatch between what regulations state and what is done in practice in most countries. We suggest possible reasons for this disparity.