Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice.

Platelet factors regulate wound healing and can signal from the blood to the brain1,2. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein3-7, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.

Longevity factor klotho enhances cognition in aged nonhuman primates.

Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.

KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.

Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.

The Global COVID-19 Observatory and Resource Center for Childhood Cancer: A response for the pediatric oncology community by SIOP and St. Jude Global.

The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community.

Preoperative calculation of angles of vision and working area in laparoscopic surgery to treat a giant hiatal hernia.

BACKGROUND: Giant hiatal hernias still pose a major challenge to digestive surgeons, and their repair is sometimes a highly complex task. This is usually performed by laparoscopy, while the role of the thoracoscopic approach has yet to be clearly defined. AIM: To preoperatively detect patients with a giant hiatal hernia in whom it would not be safe to perform laparoscopic surgery and who, therefore, would be candidates for a thoracoscopic approach. METHODS: In the present study, using imaging test we preoperatively simulate the field of vision of the camera and the working area (instrumental access) that can be obtained in each patient when the laparoscopic approach is used. RESULTS: From data obtained, we can calculate the access angles that will be obtained in a preoperative computerised axial tomography coronal section, according to the location of the trocar. We also provide the formula for performing the angle calculations If the trocars are placed in loss common situations, thus enabling us to determine the visibility and manoeuvrability for any position of the trocars. CONCLUSION: The working area determines the cases in which we can operate safely and those in which certain areas of the hernia cannot be accessed, which is when the thoracoscopic approach would be safer.

A second X chromosome contributes to resilience in a mouse model of Alzheimer's disease.

A major sex difference in Alzheimer's disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male mice, we varied sex chromosome dosage. With or without a Y chromosome, hAPP mice with one X chromosome showed worse mortality and deficits than did those with two X chromosomes. Thus, adding a second X chromosome conferred resilience to XY males and XO females. In addition, the Y chromosome, its sex-determining region Y gene (Sry), or testicular development modified mortality in hAPP mice with one X chromosome such that XY males with testicles survived longer than did XY or XO females with ovaries. Furthermore, a second X chromosome conferred resilience potentially through the candidate gene Kdm6a, which does not undergo X-linked inactivation. In humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting its relevance to human brain health. Our study suggests a potential role for sex chromosomes in modulating disease vulnerability related to AD.

The Evolution of Antimicrobial Resistance in Mexico During the Last Decade: Results from the INVIFAR Group.

Background: Surveillance of antimicrobial resistance (AMR) requires an international approach with national and local strategies. Our aim was to summarize a retrospective 10-year report of antibiotic resistance of gram-positive and gram-negative bacteria in Mexico. Methods: A total of 46 centers from 22 states of Mexico participated. Databases of AMR from January 2009 to December 2018 were included for most species. The 10-year period was divided into five 2-year periods. Results: For Staphylococcus aureus, a decrease in resistance in all specimens was observed for erythromycin and oxacillin (p < 0.0001 for each). For Enterobacter spp., resistance to meropenem increased for urine specimens (p = 0.0042). For Klebsiella spp., increased drug resistance in specimens collected from blood was observed for trimethoprim/sulfamethoxazole, gentamicin, tobramycin (p < 0.0001 for each), meropenem (p = 0.0014), and aztreonam (p = 0.0030). For Acinetobacter baumannii complex, high drug resistance was detected for almost all antibiotics, including carbapenems, except for tobramycin, which showed decreased resistance for urine, respiratory, and blood isolates (p < 0.0001 for each), and for amikacin, which showed a decrease in resistance in urine specimens (p = 0.0002). An increase in resistance to cefepime was found for urine, respiratory, and blood specimens (p < 0.0001 for each). For Pseudomonas aeruginosa, aztreonam resistance increased for isolates recovered from blood (p = 0.0001). Conclusion: This laboratory-based surveillance of antibiotic resistance shows that resistance is increasing for some antibiotics in different bacterial species in Mexico and highlights the need for continuous monitoring of antibiotic resistance.

Estudios sobre el virus del papiloma humano (VPH) en el Ecuador: parte I / Studies on human papillomavirus (HPV) in Ecuador: part I

Aprovechando la realización de las XL Jornadas Nacionales de Biología Espol en la ciudad de Guayaquil, se realizó una sesión dedicada a la epidemiología del virus de papiloma humano (VPH) y del cáncer cervical. Esta sesión tuvo la participación de varios investigadores provenientes de diferentes zonas del Ecuador. El presente artículo tiene como objeto presentar un resumen de estas charlas, junto a un análisis de la información mostrada además de una reflexión sobre las preguntas que quedan aún por responder en cuanto al perfil epidemiológico de esta patología en el país.

Taking advantage of the realization of theXL National Conference on Espol Biology in the city of Guayaquil, a session was held dedicated to the epidemiology of Human Papilloma Virus (HPV) and cervical cancer. This session was attended by several researchers from different areas of Ecuador. The object of this article is to present a summary of these talks, together with an analysis of the information shown in addition to a reflection on the questions still to be answered regarding the epidemiological profile of this pathology in the country.

Ovarian Cycle Stages Modulate Alzheimer-Related Cognitive and Brain Network Alterations in Female Mice.

Alzheimer's disease (AD) begins several decades before the onset of clinical symptoms, at a time when women may still undergo reproductive cycling. Whether ovarian functions alter substrates of AD pathogenesis is unknown. Here we show that ovarian cycle stages significantly modulate AD-related alterations in neural network patterns, cognitive impairments, and pathogenic protein production in the hAPP-J20 mouse model of AD. Female hAPP mice spent more time in estrogen-dominant cycle stages and these ovarian stages worsened AD-related network dysfunction and cognitive impairments. In contrast, progesterone-dominant stages and gonadectomy attenuated these AD-related deficits. Further studies revealed a direct role for estradiol in stimulating neural network excitability and susceptibility to seizures in hAPP mice and increasing amyloid beta levels. Understanding dynamic effects of the ovarian cycle on the female nervous system in disease, including AD, is of critical importance and may differ from effects on a healthy brain. The pattern of ovarian cycle effects on disease-related networks, cognition, and pathogenic protein expression may be relevant to young women at risk for AD.

Tigeciclina en infecciones de piel y tejidos blandos complicadas / Tigecycline in complicated skin and soft-tissue infection

Objetivo: evaluar la mejor evidencia actual disponible para generar recomendaciones con respecto a la efectividad y seguridad del uso de tigeciclina en adultos con infección de piel y tejidos blandos (IPTB). Materiales y métodos: se realizó una revisión sistemática de la literatura, seleccionando los metaanálisis y experimentos clínicos controlados (ECCs), los cuales se valoraron utilizando la herramienta SIGN (Scottish Intercollegiate Guidelines Network.), con el fin de generar tablas de evidencia según GRADE de los estudios de tigeciclina en la indicación de IPTB, para posteriormente utilizar un proceso Delphi modificado para calificar las diferentes recomendaciones. Resultados: la revisión sistemática se incluyeron 9 metaanálisis que incluyeron 5 estudios clínicos aleatorizados con 1873 pacientes, y de ellos 952 asignados al brazo de tigeciclina, no mostró inferioridad frente a los comparadores en curación clínica (RR= 0.76 IC95% 0,57 - 1.03), curación microbiológica (RR= 0.92 IC95% 0,61 - 1.38), eventos adversos serios RR 1,41 (IC95%0,97 a 2,35), ni mortalidad RR 1,9 (IC95%0,84 a 4,3). La tigeciclina puede relacionarse con mayor frecuencia de eventos adversos leves de origen gastrointestinal. Conclusión: en pacientes adultos con IPTB, se considera que el uso de tigeciclina en monoterapia en pacientes no críticamente enfermos es equivalente en eficacia a otras opciones terapéuticas antimicrobianas. Se debe considerar especialmente como terapia de ajuste en pacientes con infecciones polimicrobianas.

Objective: To assess current best evidence available to generate recommendations regarding the effectiveness and safety of tigecycline use in adults with skin and soft-tissue infections (SSTIs). Materials and methods: A systematic review of the literature was conducted by selecting meta-analyzes and controlled clinical trials (CCTs), which were assessed using the SIGN tool (Scottish Intercollegiate Guidelines Network) in order to generate evidence tables according to GRADE of studies of tigecycline in the SSTIs indication, and then using a modified Delphi Method to score the different recommendations. Results: Nine meta-analyzes were included compounded by five randomized clinical trials with a sample size of 1873 patients, where 952 patients were assigned to tigecycline. The group of patients with tigecycline showed no inferiority to the comparator in clinical cure (RR = 0.76 95% CI 0.57 - 1.03), microbiologic cure (RR = 0.92 95% CI 0.61 - 1.38), serious adverse events RR 1, 41 (95% CI 0.97 to 2.35) or mortality RR 1.9 (95% CI 0.84 to 4.3). Tigecycline may be related to increased frequency of minor adverse events of gastrointestinal origin. Conclusion: In adult patients with SSTIs, it is considered that the use of tigecycline in monotherapy in non-critically ill patients is equivalent in effectiveness to other antimicrobial treatment options. It should be especially considered as an adjustment therapy in patients with polymicrobial infections.

Human Brain-Derived Aß Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP.

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid ß-protein (Aß), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aß, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aß depend on expression of APP and that the Aß-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aß localizing to synapses and binding of soluble Aß aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aß and suggest modulation of APP expression as a therapy for AD.SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid ß-protein (Aß) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aß-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aß localizing to synapses and genetic ablation of APP prevents both Aß binding and Aß-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation.

Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice.

Cognitive dysfunction and decreased mobility from aging and neurodegenerative conditions, such as Parkinson and Alzheimer diseases, are major biomedical challenges in need of more effective therapies. Increasing brain resilience may represent a new treatment strategy. Klotho, a longevity factor, enhances cognition when genetically and broadly overexpressed in its full, wild-type form over the mouse lifespan. Whether acute klotho treatment can rapidly enhance cognitive and motor functions or induce resilience is a gap in our knowledge of its therapeutic potential. Here, we show that an α-klotho protein fragment (αKL-F), administered peripherally, surprisingly induced cognitive enhancement and neural resilience despite impermeability to the blood-brain barrier in young, aging, and transgenic α-synuclein mice. αKL-F treatment induced cleavage of the NMDAR subunit GluN2B and also enhanced NMDAR-dependent synaptic plasticity. GluN2B blockade abolished αKL-F-mediated effects. Peripheral αKL-F treatment is sufficient to induce neural enhancement and resilience in mice and may prove therapeutic in humans.

Synergistic antinociceptive actions and tolerance development produced by morphine-fentanyl coadministration: correlation with µ-opioid receptor internalization.

It has been described that coadministration of opioids with low doses of other analgesics can reduce adverse effects and increase antinociception, but combinations of two µ-opioid receptor agonists have been poorly explored. The objective of this work was threefold: 1) to evaluate the antinociceptive combination of i.c.v. morphine and fentanyl at different doses; 2) to compare the antinociception produced by acute or repeated administration of an effective morphine dose (1 µg) alone, or combined with a low fentanyl dose (1 ng); and 3) to correlate these effects with µ-opioid receptor internalization in periaqueductal gray matter and locus coeruleus. Antinociception was evaluated by the tail-flick test and receptor internalization was analyzed by confocal microscopy in Wistar rats. Drug interactions were examined by administering combinations of opioids in 1:3, 1:1 and 3:1 ratios of their respective ED(50) fractions. For tolerance and internalization studies, animals were i.c.v. injected only once (acute treatment) or twice a day until five administrations were completed. Our results show that morphine and fentanyl have synergistic effects. The combination of 1 ng fentanyl with 1 µg morphine increases the magnitude and duration of antinociception not only after a single injection, but also after five administrations when tolerance develops to morphine alone. Increased and long-lasting antinociception correlates positively with increased ß-arrestin 2 activity and µ-opioid receptor internalization in periaqueductal gray matter and locus coeruleus. These results suggest that combined administration of morphine and fentanyl increases long-lasting antinociception and ß-arrestin 2 signaling contributes to the combination effects.

D-propoxyphene and dipyrone co-administration produces greater antinociception and fewer adverse effects than single treatments in rats.

D-propoxyphene is a commonly prescribed opiate analgesic. Its use is limited by unwanted side effects at high doses and tolerance development after chronic administration. Dipyrone (also known as metamizol) is a non-steroidal anti-inflammatory drug extensively used in Latin America and Europe. The objective of this work was to evaluate the antinociceptive efficacy of a dipyrone/D-propoxyphene combination and the development of tolerance to its repeated administration in the tail flick test in rats. Male Wistar rats (200+/-20 g) were i.v. injected twice daily (8 h apart) with 0.31 mg/kg D-propoxyphene, 400 mg/kg dipyrone, or the combination of these drugs, at the same doses, until complete tolerance was observed. A time course of the effects for each administration was determined. At the doses tested, D-propoxyphene and dipyrone produced mild antinociception per se. Repeated administration resulted in complete tolerance to their antinociceptive effects by the sixth dose. The D-propoxyphene/dipyrone combination produced more antinociception than expected by the sum of individual drug effects. With this treatment, tolerance developed at the 15th administration. In animals already tolerant to D-propoxyphene or dipyrone alone, subsequent administration of the combination partially restored the antinociceptive effect. These results suggest that the use of this combination provides advantages over single drug therapies.