Programming of neural progenitors of the adult subependymal zone towards a glutamatergic neuron lineage by neurogenin 2.

Although adult subependymal zone (SEZ) neural stem cells mostly generate GABAergic interneurons, a small progenitor population expresses the proneural gene Neurog2 and produces glutamatergic neurons. Here, we determined whether Neurog2 could respecify SEZ neural stem cells and their progeny toward a glutamatergic fate. Retrovirus-mediated expression of Neurog2 induced the glutamatergic lineage markers TBR2 and TBR1 in cultured SEZ progenitors, which differentiated into functional glutamatergic neurons. Likewise, Neurog2-transduced SEZ progenitors acquired glutamatergic neuron hallmarks in vivo. Intriguingly, they failed to migrate toward the olfactory bulb and instead differentiated within the SEZ or the adjacent striatum, where they received connections from local neurons, as indicated by rabies virus-mediated monosynaptic tracing. In contrast, lentivirus-mediated expression of Neurog2 failed to reprogram early SEZ neurons, which maintained GABAergic identity and migrated to the olfactory bulb. Our data show that NEUROG2 can program SEZ progenitors toward a glutamatergic identity but fails to reprogram their neuronal progeny.

A new approach to 'on-demand' treatment of lifelong premature ejaculation by treatment with a combination of a 5-HT1A receptor antagonist and SSRI in rats.

Lifelong premature ejaculation (PE) in men lacks an adequate on-demand pharmacological treatment. Although selective serotonin reuptake inhibitors (SSRIs) are used for PE they only work after chronic treatment, or if used on-demand, less adequately than chronic SSRI treatment. It has been shown that the addition of a behaviorally silent 5-HT1A-receptor antagonist to an SSRI can generate acute inhibitory effects on male rat sexual behavior. Atlas987 is a selective 5-HT1A-receptor antagonist with equal potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. To investigate whether Atlas987 together with the SSRI paroxetine, a combination called Enduro, induces acute inhibitory effects on male rat sexual behavior, we tested Enduro in Wistar rats in a dose-dependent manner. We first tested the 5-HT1A receptor antagonist Atlas987 in 8-OH-DPAT induced serotonergic behavior in rats. Second, we tested Enduro in a dose-dependent manner in male sexual behavior. Third, we tested the effective time window of Enduro's action, and lastly, we measured the plasma levels of Atlas987 and paroxetine over an 8-h period. Results showed that Enduro acutely and dose-dependently reduced the number of ejaculations and increased the ejaculation latencies. The behavioral pattern induced reflected a specific effect on sexual behavior excluding non-specific effects like sedation or sensoric-motoric disturbances. The time-window of activity of Enduro showed that this sexual inhibitory activity was at least found in a 1-4 h' time window after administration. Plasma levels showed that in this time frame both Atlas987 and paroxetine are present. In conclusion, in rats, Enduro is successful in acutely inhibiting sexual behavior. These results may be therapeutically attractive as "on demand" treatment for life-long premature ejaculation in men.

The Influence of Extracerebral Tissue on Continuous Wave Near-Infrared Spectroscopy in Adults: A Systematic Review of In Vivo Studies.

Near-infrared spectroscopy (NIRS) is a non-invasive technique for measuring regional tissue haemoglobin (Hb) concentrations and oxygen saturation (rSO2). It may be used to monitor cerebral perfusion and oxygenation in patients at risk of cerebral ischemia or hypoxia, for example, during cardiothoracic or carotid surgery. However, extracerebral tissue (mainly scalp and skull tissue) influences NIRS measurements, and the extent of this influence is not clear. Thus, before more widespread use of NIRS as an intraoperative monitoring modality is warranted, this issue needs to be better understood. We therefore conducted a systematic review of published in vivo studies of the influence of extracerebral tissue on NIRS measurements in the adult population. Studies that used reference techniques for the perfusion of the intra- and extracerebral tissues or that selectively altered the intra- or extracerebral perfusion were included. Thirty-four articles met the inclusion criteria and were of sufficient quality. In 14 articles, Hb concentrations were compared directly with measurements from reference techniques, using correlation coefficients. When the intracerebral perfusion was altered, the correlations between Hb concentrations and intracerebral reference technique measurements ranged between |r| = 0.45-0.88. When the extracerebral perfusion was altered, correlations between Hb concentrations and extracerebral reference technique measurements ranged between |r| = 0.22-0.93. In studies without selective perfusion modification, correlations of Hb with intra- and extracerebral reference technique measurements were generally lower (|r| < 0.52). Five articles studied rSO2. There were varying correlations of rSO2 with both intra- and extracerebral reference technique measurements (intracerebral: |r| = 0.18-0.77, extracerebral: |r| = 0.13-0.81). Regarding study quality, details on the domains, participant selection and flow and timing were often unclear. We conclude that extracerebral tissue indeed influences NIRS measurements, although the evidence (i.e., correlation) for this influence varies considerably across the assessed studies. These results are strongly affected by the study protocols and analysis techniques used. Studies employing multiple protocols and reference techniques for both intra- and extracerebral tissues are therefore needed. To quantitatively compare NIRS with intra- and extracerebral reference techniques, we recommend applying a complete regression analysis. The current uncertainty regarding the influence of extracerebral tissue remains a hurdle in the clinical implementation of NIRS for intraoperative monitoring. The protocol was pre-registered in PROSPERO (CRD42020199053).

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders-Denial is not an option.

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aß1 - 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

Abandono de la lactancia materna en Galicia: ¿cuándo se produce y por qué? / Cessation of breastfeeding in Galicia: when is it happening and why?

Introduction: International organizations recommend maintaining breastfeeding at least until 6 months after the birth of the child. However, the prevalence of breastfeeding at 6 moths in Europe is below the recommendations. The aims of this study are to estimate the prevalence of breastfeeding cessation month by month and to ascertain the reasons associated with the cessation during the first 12 months of life in galician women. Methods: The information analysed comes from the Health Risk Behaviour Information System conducted in 2016, which included women who had given birth in the previous 12 months (n = 6436) in Galicia (Spain). The prevalence of breastfeeding cessation was estimated and the age of the child at the time of cessation was collected. The causes of abandonment were classified into 5 global categories and the frequencies were estimated. Results: A total of 5,177 mothers of 3- to 16-month-old babies were included. At the age of 12 months, 33.8% of the children were still breastfed. The main reason for cessation of breastfeeding was hypogalactia (46.5%), followed by being back to work (24.1%). After birth to 4 months, hypogalactia and health problems were the principal reasons of cessation; between 4 and 7 months after birth, hypogalactia and returning to work or studies were the most important reasons; and after 7 months, rejection by the baby became important. Conclusion: The cessation of breastfeeding during the first year of life is due mainly to preventable causes. It is necessary to improve maternal health education, both during and after the pregnancy, as well as to develop effective work-life balance measures. (AU)

Introducción: Las organizaciones internacionales recomiendan mantener la lactancia materna (LM) durante los primeros 6 meses de vida. En Europa, la prevalencia de LM a los 6 meses está por debajo de las recomendaciones. Los objetivos son estimar la prevalencia de cese de LM mes a mes y conocer los motivos asociados al abandono de la LM durante el primer año de vida en Galicia. Metodología: Los datos proceden de la encuesta del Sistema de Información sobre Conductas de Riesgo para la Salud 2016 que incluyó a mujeres que habían dado a luz en los 12 meses previos (n = 6.436) en Galicia (España). Se estimaron las prevalencias de cese de LM en función de la edad del niño. Se clasificaron las causas de abandono en cinco categorías y se estimaron las frecuencias. Resultados: Se incluyeron a 5.177 madres con niños de 3-16 meses. Al año de vida, el 33,8% de los niños mantenían LM. La razón principal del abandono fue la hipogalactia (46,5%), seguida de la vuelta al trabajo (24,1%). Hasta los 4 meses, la hipogalactia y los problemas de salud fueron los motivos principales; entre los 4-7 meses, la vuelta al trabajo y la hipogalactia; y después de los 7 meses, el rechazo del bebé y la vuelta al trabajo. Conclusión: El abandono de la LM durante el primer año de vida es principalmente debido a causas prevenibles. Es imprescindible mejorar la educación en salud de las madres, tanto durante como después del embarazo, así como desarrollar medidas de conciliación eficaces. (AU)

Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic stem cell transplant (HSCT) is indicated in pediatric patients with acute lymphoblastic leukemia (ALL) who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning are employed before allogeneic HSCT: total body irradiation (TBI)-based regimens and chemotherapy (CHT) alone. This study compares the efficacy and safety of TBI-based regimens and CHT-based conditioning in pediatric, adolescent, and young adult patients with ALL (0-24 years old). TBI-based and CHT-conditioning regimens were evaluated in 4262 and 1367 patients, respectively, from 15 studies. Compared to CHT alone, TBI-based regimens were associated with better overall survival (OS), relative risk (RR) 1.21, better event-free survival (RR 1.34), and a reduced risk of relapse (RR 0.69). Both approaches had comparable risk of acute graft-versus-host disease (GVHD), grades 3 to 4 acute GVHD, chronic GVHD, and nonrelapse mortality (NRM). In the subgroup analysis for patients in first complete remission, TBI-based regimens and CHT alone had comparable OS and NRM. Our results demonstrate the superiority of TBI-based regimens compared to CHT alone in pediatric patients with ALL.

Validation of Tokyo guidelines 2018 for safety and mortality benefit from urgent ERCP in acute cholangitis across different age groups.

BACKGROUND: The 2018 Tokyo Guidelines (TG18) recommend urgent endoscopic biliary drainage based on acute cholangitis (AC) severity. Therefore, we evaluated the safety and mortality benefits of urgent endoscopic retrograde cholangiopancreatography (ERCP) in different age groups. METHODS: Using International Classification of Diseases-10 (ICD-10) codes, we sampled adult AC patients from National Inpatient Sample. TG18 definition of cholangitis severity was used to identify patients with severe and nonsevere (mild or moderate) AC. Age categories were 18-64, 65-79, and 80 and above. Multivariate linear or logistic regression was used as appropriate. We used Stata, version 14.2, to perform analyses considering two-sided p < .05 as statistically significant. RESULTS: Among 137 100 patients, there were 93 365 (68.09%) patients with nonsevere cholangitis and 43 735 (31.91%) patients with severe cholangitis. Urgent ERCP (within 24 h) resulted in decreased mortality in all age groups for both severe and nonsevere AC. Post-sphincterotomy bleeding was more common in patients ≥80 years of age, whereas post-ERCP acute cholecystitis was more common in patients 65-79 years. The rates of post-ERCP pancreatitis, bile duct perforation, and duodenal perforation did not differ among the age groups. In addition, there were no differences in the rate of sedation-related complications between different age groups who underwent urgent ERCP. CONCLUSION: This study demonstrates the mortality benefit from urgent ERCP for AC in different age groups and describes the safety of performing urgent ERCP in patients of various ages. Therefore, we recommend that urgent ERCP be performed according to the TG18 guidelines regardless of age.

Mating disrupts morning anticipation in Drosophila melanogaster females.

After mating, the physiology of Drosophila females undergo several important changes, some of which are reflected in their rest-activity cycles. To explore the hypothesis that mating modifies the temporal organization of locomotor activity patterns, we recorded fly activity by a video tracking method. Monitoring rest-activity patterns under light/dark (LD) cycles indicated that mated females lose their ability to anticipate the night-day transition, in stark contrast to males and virgins. This postmating response is mediated by the activation of the sex peptide receptor (SPR) mainly on pickpocket (ppk) expressing neurons, since reducing expression of this receptor in these neurons restores the ability to anticipate the LD transition in mated females. Furthermore, we provide evidence of connectivity between ppk+ neurons and the pigment-dispersing factor (PDF)-positive ventral lateral neurons (sLNv), which play a central role in the temporal organization of daily activity. Since PDF has been associated to the generation of the morning activity peak, we hypothesized that the mating signal could modulate PDF levels. Indeed, we confirm that mated females have reduced PDF levels at the dorsal protocerebrum; moreover, SPR downregulation in ppk+ neurons mimics PDF levels observed in males. In sum, our results are consistent with a model whereby mating-triggered signals reach clock neurons in the fly central nervous system to modulate the temporal organization of circadian behavior according to the needs of the new status.

Comparison of outcomes between variceal and non-variceal gastrointestinal bleeding in patients with cirrhosis: Insights from a Nationwide Inpatient Sample.

Background: Variceal upper gastrointestinal bleeding (VUGIB) occurs in patients with decompensated cirrhosis, but non-VUGIB (NVUGIB) is not uncommon. We compared the outcomes of VUGIB and NVUGIB in cirrhotic patients. Methods: This retrospective study used Nationwide Inpatient Sample employing International Classification of Diseases codes for adult NVUGIB and VUGIB patients. Mortality, morbidity, and resource utilization were compared. Analyses were performed using STATA; proportions and continuous variables were compared using Fisher's exact and Student's t-test, respectively. Confounding variables were adjusted using propensity matching, multivariate logistic and linear regression analyses. Results: Of 2,166,194 cirrhotics, 92,439 had a diagnosis of NVUGIB and 17,620 VUGIB. VUGIB patients had higher rates of mortality [adjusted odds ratio (aOR) 1.42, 95% confidence interval (CI) 1.19-1.69], hemorrhagic shock (aOR 1.84, 95%CI 1.54-2.17) and intensive care unit admission (aOR 2.47, 95%CI 2.18-2.81), greater hospitalization costs ($16,251 vs. $12,295, P<0.001), more need for packed red blood cell transfusion (aOR 1.12, 95%CI 1.03-1.22) or endoscopic therapy (aOR 2.71, 95%CI 2.47-2.93), and a longer hospital stay compared to NVUGIB. However, NVUGIB had higher aOR of undergoing diagnostic endoscopy and radiography-guided vessel embolization. There were no differences in the rates of acute kidney injury between the 2 groups. Ascites and spontaneous bacterial peritonitis were independently associated with increased VUGIB mortality. Conclusions: VUGIB in patients with cirrhosis is associated with greater hospital costs, mortality, and morbidity burden than NVUGIB. This study provides updated and current knowledge of patient characteristics and differences in outcomes between VUGIB and NVUGIB, required to successfully address the healthcare delivery gaps.

Racial differences in hospitalizations for acute cholangitis: a nationwide time trend analysis, 2008-2018.

Background: The data on racial epidemiologic trends for acute cholangitis (AC) are scarce. Therefore, we conducted a longitudinal assessment of the racial breakdown of AC-related hospitalizations in the United States (US) over 11 years (2008-2018). Methods: Using the National Inpatient Sample, we retrieved adult (>18 years) patients with AC. The adjusted yearly hospitalization rate per 100,000 for each race category was calculated based on the US population estimate for July 1 of the corresponding year obtained from the US Census Bureau. We followed Healthcare Cost and Utilization Project recommendations to: (1) derive a time-interrupted trend (before and after 2015), after determining that the International Classification of Diseases coding change affected AC hospitalizations because of more specific coding in the tenth revision; and (2) generate proportionate estimates using revised trend weights. Results: A total of 321,849 patients with AC were included in the analysis. Before 2015, the overall hospitalizations (per 100,000 persons) increased from 16.03 in 2008 to 20.76 in 2014 (P<0.001). Following 2015, the overall hospitalizations increased from 14.34 in 2016 to 14.70 in 2018 (P=0.04). After Whites, Asians represented the ethnic group with the highest race-specific AC hospitalizations per 100,000 persons. Conclusions: This cohort study demonstrated an overall rising and disproportionate rate among different races for AC-related hospitalizations. Even though Asians constitute only 6.5% of the US population, they represent the ethnic minority with most hospitalizations for AC.

Apendicitis aguda en una gestante lúpica / Acute appendicitis in pregnant lupus

El lupus eritematoso sistémico es una enfermedad autoinmune que se caracteriza por un proceso inflamatorio crónico y el aumento de la producción de autoanticuerpos como mecanismos patogénicos. Se presenta con mayor frecuencia en pacientes femeninas y en edad fértil. La gestación en pacientes con esta enfermedad se considera como una condición de extrema precaución, ya que existe influencia de la gestación en la actividad clínica del lupus y del lupus en la evolución de la gestación. Las complicaciones quirúrgicas, como es el caso de una apendicitis aguda, aportan mayor riesgo al binomio madre-feto. El objetivo del presente trabajo es comunicar la experiencia de tratamiento de una paciente de 31 años de edad, con diagnóstico de lupus eritematoso sistémico y a quien a las 35,6 semanas de gestación se le presentó un cuadro de apendicitis aguda que no solo provocó la actividad de la enfermedad, sino que causó la interrupción de la gestación. La paciente y el recién nacido presentaron una evolución favorable sin complicaciones posteriores.

Systemic lupus erythematosus is an autoimmune disease that includes the presence of a chronic inflammatory process and increased production of autoantibodies as etiopathogenic mechanisms. As a disease, it occurs more frequently in female patients and those of childbearing age. Pregnancy in patients with this disease is considered an element of extreme caution since there is an influence of pregnancy on the clinical activity of lupus and lupus on the evolution of pregnancy. The presence of surgical complications, as is the case of acute appendicitis, brings greater risk to the mother-fetus binomial. The objective of this report is to communicate the treatment experience of a 31-year-old patient, diagnosed with systemic lupus erythematosus and who at 35.6 weeks of gestation presented acute appendicitis that not only causes disease activity, but it generates the need to interrupt the pregnancy. The patient and the newborn had a favorable evolution, with no subsequent complications.

EASI Transformation Protocol: An Agrobacterium-Mediated Transient Transformation Protocol for Catharanthus roseus Seedlings.

Catharanthus roseus produces medicinal terpenoid indole alkaloids, including the critical anti-cancer compounds vinblastine and vincristine in its leaves. Recently, we developed a highly efficient transient expression method relying on Agrobacterium-mediated transformation of seedlings to facilitate rapid and high-throughput studies on the regulation of terpenoid indole alkaloid biosynthesis in C. roseus . We detail our optimized protocol known as efficient Agrobacterium-mediated seedling infiltration method (EASI), including the development of constructs used in EASI and an example experimental design that includes appropriate controls. We applied our EASI method to rapidly screen and evaluate transcriptional activators and repressors and promoter activity. Our EASI method can be used for promoter transactivation studies or transgene overexpression paired with downstream analyses like quantitative PCR or metabolite analysis. Our protocol takes about 16 days from sowing seeds to obtaining the results of the experiment.

Emerging Role of Antibody-Drug Conjugates and Bispecific Antibodies for the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is characterized by malignant proliferation of malignant plasma cells; it is the second most common hematological malignancy associated with significant morbidity. Genetic intricacy, instability, and diverse clinical presentations remain a barrier to cure. The treatment of MM is modernized with the introduction of newer therapeutics agents, i.e., target-specific monoclonal antibodies. The currently available literature lacks the benefits of newer targeted therapy being developed with an aim to reduce side effects and increase effectiveness, compared to conventional chemotherapy regimens. This article aims to review literature about the current available monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies for the treatment of MM.

Hemispheric Cortical, Cerebellar and Caudate Atrophy Associated to Cognitive Impairment in Metropolitan Mexico City Young Adults Exposed to Fine Particulate Matter Air Pollution.

Exposures to fine particulate matter PM2.5 are associated with Alzheimer's, Parkinson's (AD, PD) and TDP-43 pathology in young Metropolitan Mexico City (MMC) residents. High-resolution structural T1-weighted brain MRI and/or Montreal Cognitive Assessment (MoCA) data were examined in 302 volunteers age 32.7 ± 6.0 years old. We used multivariate linear regressions to examine cortical surface area and thickness, subcortical and cerebellar volumes and MoCA in ≤30 vs. ≥31 years old. MMC residents were exposed to PM2.5 ~ 30.9 µg/m3. Robust hemispheric differences in frontal and temporal lobes, caudate and cerebellar gray and white matter and strong associations between MoCA total and index scores and caudate bilateral volumes, frontotemporal and cerebellar volumetric changes were documented. MoCA LIS scores are affected early and low pollution controls ≥ 31 years old have higher MoCA vs. MMC counterparts (p ≤ 0.0001). Residency in MMC is associated with cognitive impairment and overlapping targeted patterns of brain atrophy described for AD, PD and Fronto-Temporal Dementia (FTD). MMC children and young adult longitudinal studies are urgently needed to define brain development impact, cognitive impairment and brain atrophy related to air pollution. Identification of early AD, PD and FTD biomarkers and reductions on PM2.5 emissions, including poorly regulated heavy-duty diesel vehicles, should be prioritized to protect 21.8 million highly exposed MMC urbanites.

Effects of Folinic Acid Administration on Lower Limb Ischemia/Reperfusion Injury in Rats.

Surgery under ischemic conditions, lasting up to 3 h, is routinely performed in orthopedic surgery, causing undesirable injury due to ischemia-reperfusion syndrome, with short and medium-term functional repercussions. To date, there is no established prophylactic treatment. In this work we evaluated folinic acid (FA) in a rodent model of lower limb ischemia-reperfusion (IRI-LL). 36 male WAG rats underwent 3 h of lower limb ischemia. In the saline group, rats received intraperitoneal administration of saline (used as vehicle for treatment). In the experimental group, rats were pretreated with FA (2.5 mg/kg) before the end of ischemia. After ischemia, animals were sacrificed at 3 h, 24 h or 14 days (for biochemical determination (Na+, K+, Cl-, urea, creatinine, CK, LDH, ALP, ALT, and AST), pathological assessment, or functional study using the rotarod test; respectively). Another six animals were used to establish the reference values. The prophylactic administration of FA significantly reduced the elevation of biochemical markers, especially those that most directly indicate muscle damage (CK and LDH). In addition, it also improved direct tissue damage, both in terms of edema, weight, PMN infiltrate and percentage of damaged fibers. Finally, the administration of FA allowed the animals to equal baseline values in the rotarod test; what did not occur in the saline group, where pre-ischemia levels were not recovered. Following 3 h of lower limb ischemia, FA minimizes the increase of CK and LDH, as well as local edema and leukocyte infiltration, allowing a faster recovery of limb functionality. Therefore, it could be considered as a prophylactic treatment when tourniquet is used in clinics.

A reproducible method for biochemical, histological and functional assessment of the effects of ischaemia-reperfusion syndrome in the lower limbs.

Current methodology described to mimic lower limb ischaemia-reperfusion injury (LL-IRI) does not accurately define the procedures and pressures exerted to induce and maintain ischaemia. In this piece of work, we propose a well-defined and detailed rat model that simulates the conditions established in clinical practice guidelines for tourniquet application and allows us to test treatments that aim to prevent/reduce LL-IRI. Eighty-six male WAG/RijHsd rats were subjected to hind limb IRI (LL-IRI), using a mechanical system applying a 1 kg tension to induce and maintain ischemia for 2 or 3 h, and assessed the damage caused by reperfusion at biochemical and muscular levels at different time points. At the biochemical level, both 2 and 3 h of ischemia induced changes (except for electrolyte levels); 3 h of ischemia induced greater changes in specific markers of muscular damage: creatine kinase (CK) and lactate dehydrogenase (LDH). At the histopathological level, 3 h of ischemia and 24 h of reperfusion was associated with an increase in hind limb girth, cross-sectional area, and weight and presence of neutrophils, as well as histological damage in more than 60% of muscle fibres. Our model allows to reliably reproduce the damage associated with the use of a pneumatic tourniquet. CK and LDH, as well as measures of tissue damage, allow to define and characterize the response to LL-IRI-related damage. A period of 3 h of ischemia followed by 3 h of reperfusion caused only local damage but showed greater sensitivity to detect differences in future studies on prophylactic treatments against LL-IRI.

Brainstem Quadruple Aberrant Hyperphosphorylated Tau, Beta-Amyloid, Alpha-Synuclein and TDP-43 Pathology, Stress and Sleep Behavior Disorders.

Quadruple aberrant hyperphosphorylated tau (p-τ), amyloid-ß peptide, alpha-synuclein and TDP-43 brainstem and supratentorial pathology are documented in forensic ≤40y autopsies in Metropolitan Mexico City (MMC), and p-τ is the major aberrant protein. Post-traumatic stress disorder (PTSD) is associated with an elevated risk of subsequent dementia, and rapid eye movement sleep behavior disorder (RBD) is documented in PD, AD, Lewy body dementia and ALS. This study aimed to identify an association between PTSD and potential pRBD in Mexico. An anonymous online survey of 4502 urban college-educated adults, 29.3 ± 10.3 years; MMC, n = 1865; non-MMC, n = 2637, measured PTSD symptoms using the Impact of Event Scale-Revised (IES-R) and pRBD symptoms using the RBD Single-Question. Over 50% of the participants had IES-R scores ≥33 indicating probable PTSD. pRBD was identified in 22.6% of the participants across Mexico and 32.7% in MMC residents with PTSD. MMC subjects with PTSD had an OR 2.6218 [2.5348, 2.7117] of answering yes to the pRBD. PTSD and pRBD were more common in women. This study showed an association between PTSD and pRBD, strengthening the possibility of a connection with misfolded proteinopathies in young urbanites. We need to confirm the RBD diagnosis using an overnight polysomnogram. Mexican women are at high risk for stress and sleep disorders.

Metals, Nanoparticles, Particulate Matter, and Cognitive Decline.

Exposure to metals is ubiquitous and emission sources include gasoline, diesel, smoke from wildfires, contaminated soil, water and food, medical implants, waste recycling facilities, subway exposures, and occupational environments. PM2.5 exposure is associated with impaired cognitive performance, neurobehavioral alterations, incidence of dementia, and Alzheimer's disease (AD) risk. Heavy-duty diesel vehicles are major emitters of metal-rich PM2.5 and nanoparticles in Metropolitan Mexico City (MMC). Cognitive impairment was investigated in 336 clinically healthy, middle-class, Mexican volunteers, age 29.2 ± 13.3 years with 13.7 ± 2.4 years of education using the Montreal Cognitive Assessment (MoCA). MoCA scores varied with age and residency in three Mexican cities with cognition deficits impacting ~74% of the young middle-class population (MoCA ≤ 25). MMC residents ≥31 years ( x ¯ 46.2 ± 11.8 y) had MoCA x ¯ 20.4 ± 3.4 vs. low pollution controls 25.2 ± 2.4 (p < 0.0001). Formal education years positively impacted MoCA total scores across all participants (p < 0.0001). Residency in PM2.5 polluted cities impacts multi-domain cognitive performance. Identifying and making every effort to lower key pollutants impacting neural risk trajectories and monitoring cognitive longitudinal performance are urgent. PM2.5 emission control should be prioritized, metal emissions targeted, and neuroprevention interventions implemented early.

Gait and balance disturbances are common in young urbanites and associated with cognitive impairment. Air pollution and the historical development of Alzheimer's disease in the young.

To determine whether gait and balance dysfunction are present in young urbanites exposed to fine particular matter PM2.5 ≥ annual USEPA standard, we tested gait and balance with Tinetti and Berg tests in 575 clinically healthy subjects, age 21.0 ±â€¯5.7 y who were residents in Metropolitan Mexico City, Villahermosa and Reynosa. The Montreal Cognitive Assessment was also applied to an independent cohort n:76, age 23.3 ±â€¯9.1 y. In the 575 cohort, 75.4% and 34.4% had abnormal total Tinetti and Berg scores and high risk of falls in 17.2% and 5.7% respectively. BMI impacted negatively Tinetti and Berg performance. Gait dysfunction worsen with age and males performed worse than females. Gait and balance dysfunction were associated with mild cognitive impairment MCI (19.73%) and dementia (55.26%) in 57/76 and 19 cognitively intact subjects had gait and balance dysfunction. Seventy-five percent of urbanites exposed to PM2.5 had gait and balance dysfunction. For MMC residents-with historical documented Alzheimer disease (AD) and CSF abnormalities, these findings suggest Alzheimer Continuum is in progress. Early development of a Motoric Cognitive Risk Syndrome ought to be considered in city dwellers with normal cognition and gait dysfunction. The AD research frame in PM2.5 exposed young urbanites should include gait and balance measurements. Multicity teens and young adult cohorts are warranted for quantitative gait and balance measurements and neuropsychological and brain imaging studies in high vs low PM2.5 exposures. Early identification of gait and balance impairment in young air pollution-exposed urbanites would facilitate multidisciplinary prevention efforts for modifying the course of AD.