Accesibilidad, disponibilidad y asequibilidad de medicamentos para Niños con Enfermedad Renal Crónica en Guatemala / Access, availability and affordability of medications for children with Advanced Chronic Kidney Disease in Guatemala

El artículo tiene como objetivo analizar la disponibilidad, acceso y asequibilidad de los medicamentos para niños con Enfermedad Renal Crónica (ERC) en tratamiento con hemodiálisis (HD) en un país de bajos a medianos ingresos. Se llevó a cabo un estudio transversal para determinar los medicamentos más utilizados en una unidad de hemodiálisis pediátrica, incluyendo el nombre del medicamento, dosis, frecuencia, forma farmacéutica y vía de administración. Dos farmacias dentro del perímetro del hospital, una pública y una privada, fueron consultadas para determinar el costoy disponibilidad de medicamentos genéricos y de marca. De un total de 30 pacientes de la unidad de hemodiálisis, 22 expedientes fueron revisados. En general 94% de marca se encontraban disponibles en las farmacias consultadas en comparación a un 52% de los medicamentos genéricos. En farmacias públicas, 41% de medicamentos de marca y 29% de medicamentos genéricos se encontraban disponibles. El costo promedio para un mes de tratamiento con medicamentos de marca adquiridos en una farmacia privada era de $495.00 vs $299.00 en una farmacia pública. Para medicamentos genéricos, el costo promedio correspondía a $414.00 y $239.00 en farmacias privadas y públicas respectivamente. En promedio, los medicamentos de marca adquiridos en una farmacia privada requieren 41 días de trabajo en un mes a comparación de 25 días si se adquieren en una farmacia pública. Los medicamentos genéricos adquiridos en farmacias privadas corresponden a 34 días de trabajo vs 20 días en farmacias públicas. En general existió un acceso limitado a medicamentos genéricos y los medicamentos poseen un costo general más elevado a comparación de otros países lo que implica un posible impacto en la adherencia terapéutica y los padecimientos secundarios de la ERC en los pacientes pediátricos en Guatemala. Esta realidad se puede aplicar a otros países de bajos a medianos ingresos.

This article aims to analyze the availability, access, and affordability of medications for children with advanced Chronic Kidney Disease (CKD) treated with hemodialysis (HD) in a low to middle income country (LMIC). A cross- sectional chart review was carried out to determine the most common medications used in an HD pediatric unit, including medication name, dose, frequency, dosage form, and route of administration. Two pharmacies within the hospital perimeter, one public and one private, were consulted to determine medication cost and availability for generic and brand-name equivalents. From 30 patients attending the HD unit, 22 records were reviewed. Overall, 94 % of brand name medications were available at pharmacies consulted, versus and 52% of generic medications. In public pharmacies, 41% of brand name, and 29% of generic medications were available. The average cost for a full month´s treatment for brand name drugs in the private pharmacy was 495.00 USD versus 299.00 USD in the public pharmacy. For generic drugs, the average cost was 414.00 USD, and 239.00 USD in private and public pharmacies respectively. On average, brand-name drugs in the private pharmacy cost 41 days' wages versus 25 in the public pharmacy. Generic drugs in the private pharmacy cost 34 days' wages versus 20 in the public pharmacy. Overall, there was limited access to generic medications, medications had an overall high cost compared to other countries both of which have the potential to impact treatment adherence and overall outcomes of CKD5 pediatric patients in Guatemala. This reality can be translated to other LMIC.

Face-valid phenotypes in a mouse model of the most common mutation in EEF1A2-related neurodevelopmental disorder.

De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K heterozygotes were not observed to have convulsive seizures, they exhibited frequent electrographic seizures and EEG abnormalities, transient early motor deficits and growth defects. Both E122K homozygotes and Eef1a2-null mice developed progressive motor abnormalities, with E122K homozygotes reaching humane endpoints by P31. The null phenotype is driven by progressive spinal neurodegeneration; however, no signs of neurodegeneration were observed in E122K homozygotes. The E122K protein was relatively stable in neurons yet highly unstable in skeletal myocytes, suggesting that the E122K/E122K phenotype is instead driven by loss of function in muscle. Nevertheless, motor abnormalities emerged far earlier in E122K homozygotes than in nulls, suggesting a toxic gain of function and/or a possible dominant-negative effect. This mouse model represents the first animal model of an EEF1A2 missense mutation with face-valid phenotypes and has provided mechanistic insights needed to inform rational treatment design.

Provision of DMPA-SC for self-administration in different practice settings during the COVID-19 pandemic: Data from providers across the United States.

OBJECTIVES: Depot medroxyprogesterone acetate-subcutaneous (DMPA-SC) can be prescribed through telemedicine and self-administered, but data about availability, particularly during the COVID-19 pandemic, are limited. This study assessed changes in the availability of DMPA-SC for self-administration during the pandemic. STUDY DESIGN: This study used survey data from a convenience sample of US providers engaged in contraceptive care and participating in a Continuing Medical Education-accredited contraceptive training (April 2020-April 2022; n = 849). Providers were recruited from across 503 clinics, including primary care and family planning clinics, public health departments, college and school-based health centers, independent abortion care clinics, and outpatient clinics in hospital settings. Measures included the availability of DMPA-SC for self-administration before and during the pandemic and the use of telemedicine. We used Poisson regression models and cluster-robust errors by clinic, adjusting for region, time of survey, and clinic size, to assess clinic availability of DMPA-SC for self-administration by practice setting. RESULTS: Compared to the prepandemic period (4%), the availability of DMPA-SC for self-administration increased significantly during the pandemic (14%) (adjusted prevalence ratios [aPR] 3.43, 95% CI [2.43-4.85]). During the pandemic, independent abortion clinics were more likely to offer DMPA-SC for self-administration compared to primary care clinics (aPR 2.44, 95% CI [1.10-5.41]). Clinics receiving Title X funds were also more likely to provide DMPA-SC for self-administration during the pandemic compared to other clinics (aPR 2.32, 95% CI [1.57-3.43]), and more likely to offer DMPA-SC for self-administration through telemedicine (aPR 2.35, 95% CI [1.52-3.63]). Compared to the early pandemic period (April-September 2022), telemedicine access to DMPA-SC for self-administration was highest during the later pandemic time period (October 2021-April 2022) (aPR 2.10, 95% CI [1.06-4.17]). CONCLUSIONS: The availability of DMPA-SC for self-administration significantly increased during the pandemic with differences by practice setting and Title X funding. However, overall method availability remains persistently low. IMPLICATIONS: Despite increased availability of DMPA-SC for self-administration among US contraceptive providers during the COVID-19 pandemic, there remains a need to train providers, educate patients, and remove barriers to ensure broader availability of this method across different practice settings.

Plica Neuropathica in 2 Hispanic Patients.

Introduction: Plica neuropathica (PN) is a rare, acquired, and irreversible condition characterized by the formation of a compacted mass of tangled hair held together by a hard keratin cement. Case Presentation: In case 1, a 50-year-old woman with history of contact dermatitis of the scalp presented with hair tangling and difficulty combing. Physical examination revealed a matted mass of hair with a dirty appearance and non-scarring alopecia. Case 2 involved a 46-year-old woman who experienced spontaneous hair matting after using various products, resulting in a dreadlock-like appearance. Clinical examination showed a compact and matted mass of hair with irregular twists, dirt, and yellowish exudate. Conclusion: PN's exact pathogenesis is not fully understood, but it is believed to involve physical and chemical insults to the hair shaft. Risk factors include self-neglect, hair felting or rubbing, certain substances, religious practices, chemotherapy, immunosuppressive drugs, infections, and contact dermatitis. Trichoscopy can provide valuable clues for an accurate diagnosis, such as fractured hairs, bent hair shafts, trichorrhexis nodosa, retained telogen hairs, and twisted hairs. Treatment involves cutting the matted hair, and early-stage manual separation may be beneficial.

c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.

The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.

Psychometric Testing of the CEECCA Questionnaire to Assess Ability to Communicate among Individuals with Aphasia.

(1) Background: The CEECCA questionnaire assesses the ability to communicate among individuals with aphasia. It was designed using the NANDA-I and NOC standardised nursing languages (SNLs), reaching high content validity index and representativeness index values. The questionnaire was pilot-tested, demonstrating its feasibility for use by nurses in any healthcare setting. This study aims to identify the psychometric properties of this instrument. (2) Methods: 47 individuals with aphasia were recruited from primary and specialist care facilities. The instrument was tested for construct validity and criterion validity, reliability, internal consistency, and responsiveness. The NANDA-I and NOC SNLs and the Boston test were used for criterion validity testing. (3) Results: five language dimensions explained 78.6% of the total variance. Convergent criterion validity tests showed concordances of up to 94% (Cohen's κ: 0.9; p < 0.001) using the Boston test, concordances of up to 81% using DCs of NANDA-I diagnoses (Cohen's κ: 0.6; p < 0.001), and concordances of up to 96% (Cohen's κ: 0.9; p < 0.001) using NOC indicators. The internal consistency (Cronbach's alpha) was 0.98. Reliability tests revealed test-retest concordances of 76-100% (p < 0.001). (4) Conclusions: the CEECCA is an easy-to-use, valid, and reliable instrument to assess the ability to communicate among individuals with aphasia.

Novel bioengineered collagen with Manuka honey and hydroxyapatite sheet for the treatment of lower extremity chronic wounds in an urban hospital wound care setting.

INTRODUCTION: A novel BCMH sheet has been shown to achieve improved wound closure rates in chronic and acute wounds when compared with SOC. OBJECTIVE: This retrospective evaluation assessed chronic wound closure rates with SOC or treatment with the BCMH sheet in an urban hospital wound clinic. METHODS: Forty-seven chronic wounds were treated with SOC or the BCMH sheet. The primary endpoint was time to closure. For wounds that did not close, investigations were conducted to determine the reason. RESULTS: Twenty wounds were treated with SOC, which varied in usage of multiple products and/or therapies, and 27 wounds were treated with the BCMH sheet. The average initial wound size was not statistically different between the groups. In both groups, most wounds that were treated did not close. For wounds that did close, the average time to closure was 2x faster in the BCMH group compared with the SOC group (7.4 weeks and 14.8 weeks, respectively; P < .05). CONCLUSIONS: This retrospective evaluation showed average time to wound closure to be significantly faster with BCMH compared with SOC in patients who maintained adherence with regular visits.

c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases.

Our ability to learn and remember depends on the active formation, remodeling, and elimination of synapses. Thus, the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring. The structural reorganization of synaptic complexes, changes in actin cytoskeleton and organelle dynamics, as well as modulation of gene expression, determine synaptic plasticity. It has been proposed that dysregulation of these key synaptic homeostatic processes underlies the synaptic dysfunction observed in many neurodegenerative diseases. Much is known about downstream signaling of activated N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoazolepropionate receptors; however, other signaling pathways can also contribute to synaptic plasticity and long-lasting changes in learning and memory. The non-receptor tyrosine kinase c-Abl (ABL1) is a key signal transducer of intra and extracellular signals, and it shuttles between the cytoplasm and the nucleus. This review focuses on c-Abl and its synaptic and neuronal functions. Here, we discuss the evidence showing that the activation of c-Abl can be detrimental to neurons, promoting the development of neurodegenerative diseases. Nevertheless, c-Abl activity seems to be in a pivotal balance between healthy synaptic plasticity, regulating dendritic spines remodeling and gene expression after cognitive training, and synaptic dysfunction and loss in neurodegenerative diseases. Thus, c-Abl genetic ablation not only improves learning and memory and modulates the brain genetic program of trained mice, but its absence provides dendritic spines resiliency against damage. Therefore, the present review has been designed to elucidate the common links between c-Abl regulation of structural changes that involve the actin cytoskeleton and organelles dynamics, and the transcriptional program activated during synaptic plasticity. By summarizing the recent discoveries on c-Abl functions, we aim to provide an overview of how its inhibition could be a potentially fruitful treatment to improve degenerative outcomes and delay memory loss.

Differential Detection of Amyloid Aggregates in Old Animals Using Gold Nanorods by Computerized Tomography: A Pharmacokinetic and Bioaccumulation Study.

Introduction: The development of new materials and tools for radiology is key to the implementation of this diagnostic technique in clinics. In this work, we evaluated the differential accumulation of peptide-functionalized GNRs in a transgenic animal model (APPswe/PSENd1E9) of Alzheimer's disease (AD) by computed tomography (CT) and measured the pharmacokinetic parameters and bioaccumulation of the nanosystem. Methods: The GNRs were functionalized with two peptides, Ang2 and D1, which conferred on them the properties of crossing the blood-brain barrier and binding to amyloid aggregates, respectively, thus making them a diagnostic tool with great potential for AD. The nanosystem was administered intravenously in APPswe/PSEN1dE9 model mice of 4-, 8- and 18-months of age, and the accumulation of gold nanoparticles was observed by computed tomography (CT). The gold accumulation and biodistribution were determined by atomic absorption. Results: Our findings indicated that 18-month-old animals treated with our nanosystem (GNR-D1/Ang2) displayed noticeable differences in CT signals compared to those treated with a control nanosystem (GNR-Ang2). However, no such distinctions were observed in younger animals. This suggests that our nanosystem holds the potential to effectively detect AD pathology. Discussion: These results support the future development of gold nanoparticle-based technology as a more effective and accessible alternative for the diagnosis of AD and represent a significant advance in the development of gold nanoparticle applications in disease diagnosis.

Amyloid ß-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation.

Alzheimer's disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aß) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aß oligomers (oAß) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAß on CaMKIIα. We found that oAß produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAß.

Spores of Trichoderma Strains over P. vulgaris Beans: Direct Effect on Insect Attacks and Indirect Effect on Agronomic Parameters.

Acanthoscelides obtectus is an insect pest that attacks wild and cultivated common beans (Phaseolus vulgaris L). Four Trichoderma strains, the T. arundinaceum IBT 40837 wild-type strain (=Ta37), a producer of trichothecene harzianum A (HA), two transformants of T. arundinaceum strain, Ta37-17.139 (=Δtri17) and Ta37-23.74 (=Δtri23), and the T. brevicompactum IBT 40841 wild-type strain (=Tb41), which produces the trichothecene trichodermin, were assessed to establish their direct effect on insect attacks and their indirect effect on the plants grown from the beans treated with those fungal strains and exposed to insect attacks. Treatments of bean seeds with different Trichoderma strains led to different survival rates in the insects, and the Tb41 strain caused the lowest survival rate of all. An 86.10% of the insect cadavers (in contact with Δtri23) showed growth of this strain. This was the treatment that attracted the greatest number of insects. The daily emergence was reduced in beans treated with the Ta37, Tb41, and Δtri17 strains. The undamaged beans treated with Ta37 and Δtri23 showed a high capacity of germination (80.00% and 75.00%, respectively), whereas the Δtri17 and Tb41 treatments increased the capacity of germination in the damaged beans (66.67%). The undamaged beans treated with Δtri23 had the greatest dry weights for the aerial part (4.22 g) and root system in the plants (0.62 g). More studies on the mechanisms of insect control, plant growth promotion, and trichodermol and trichodermin production by Δtri23 and Tb41, respectively, should be explored in order to commercialize these fungal species on a large scale.

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction.

Gaucher disease (GD) is an inherited disorder caused by recessive mutations in the GBA1 gene that encodes the lysosomal enzyme ß-glucocerebrosidase (ß-GC). ß-GC hydrolyzes glucosylceramide (GluCer) into glucose and ceramide in the lysosome, and the loss of its activity leads to GluCer accumulation in different tissues. In severe cases, enzymatic deficiency triggers inflammation, organomegaly, bone disease, and neurodegeneration. Neuronopathic Gaucher disease (nGD) encompasses two different forms of the disease, characterized by chronic or acute damage to the central nervous system (CNS). The cellular and molecular studies that uncover the pathological mechanisms of nGD mainly focus on lysosomal dysfunction since the lysosome is the key organelle affected in GD. However, new studies show alterations in other organelles that contribute to nGD pathology. For instance, abnormal accumulation of GluCer in lysosomes due to the loss of ß-GC activity leads to excessive calcium release from the endoplasmic reticulum (ER), activating the ER-associated degradation pathway and the unfolded protein response. Recent evidence indicates mitophagy is altered in nGD, resulting in the accumulation of dysfunctional mitochondria, a critical factor in disease progression. Additionally, nGD patients present alterations in mitochondrial morphology, membrane potential, ATP production, and increased reactive oxygen species (ROS) levels. Little is known about potential dysfunction in other organelles of the secretory pathway, such as the Golgi apparatus and exosomes. This review focuses on collecting evidence regarding organelle dysfunction beyond lysosomes in nGD. We briefly describe cellular and animal models and signaling pathways relevant to uncovering the pathological mechanisms and new therapeutic targets in GD.

Organic and Conventional Bean Pesticides in Development of Autochthonous Trichoderma Strains.

Pesticides of chemical synthesis have mainly been used to control pests, diseases and adventitious plants up until now. However, it has been shown that some pesticides can remain in the soil for long periods of time, thus affecting the development of organisms in the rhizosphere as well as human health, which are two of the most noteworthy side effects. The aim of this research was to analyze the compatibility of autochthonous Trichoderma strains with different synthetic fungicides, acaricides, insecticides (including an entomopathogenic fungus) and herbicides. Sulfur encouraged the growth of all autochthonous strains assayed, and the combination Trichoderma-B. bassiana did not disturb their growth. So, the combination of the autochthonous Trichoderma strains with these organic pesticides will be a positive strategy to apply in the field to control pests and some diseases. Conventional pesticides modified the development of all autochthonous Trichoderma strains, demonstrating that not only do they affect weeds, fungus or pests but also rhizosphere microorganisms. In conclusion, conventional pesticides indiscriminately used to control pests, diseases and weeds could reduce the development of autochthonous Trichoderma strains, especially fungicides and herbicides.

Experiencias latinoamericanas en la prevención de la suicidalidad en jóvenes y adolescentes: una revisión teórica / Latin American experiences in the prevention of suicidality in young people and adolescents: a theoretical review

Resumen Introducción: A nivel latinoamericano el suicidio en jóvenes y adolescente representa una problemática grave, por lo que es necesario trabajar en su prevención. En ese sentido, este trabajo presenta una revisión teórica narrativa sobre la temática. Objetivo: Conocer las principales experiencias de prevención de la suicidalidad en jóvenes y adolescentes de Latinoamérica en los últimos 15 años. Método: Se revisaron y analizaron 44 estudios empíricos, realizando búsquedas bibliográficas en revistas científicas indexadas en Scopus, Scielo, WoS, REDALYC y ERIH PLUS y motores de búsqueda como Google Académico y EBSCO. Resultados: Los hallazgos obtenidos en los 44 estudios se organizaron en tres categorías: 1) diagnósticos sobre suicidalidad realizados en población juvenil y adolescente; 2) intervenciones psicoterapéuticas destinadas a tratamiento en suicidalidad; y 3) intervenciones en base a programas, estrategias y técnicas enfocadas en la prevención del suicidio juvenil y adolescente. Discusión: Los principales diagnósticos asociados a la suicidalidad están vinculados a disfuncionalidades emocionales, donde las mujeres son las principales afectadas, la familia y el entorno surgen como principales factores protectores o de riesgo dependiendo de su funcionalidad y cohesión. Además, las intervenciones más valoradas están asociadas a los modelos clásicos de psicoterapia y las estrategias psicoeducativas aparecen como los principales focos de los programas preventivos. Conclusión: Por la multifactoriedad del fenómeno, se debería realizar un cambio paradigmal en el enfrentamiento de la suicidalidad.

Abstract Introduction: At the Latin American level, suicide in young people and adolescents represents a serious problem, so it is necessary to work on its prevention. In this sense, this work presents a narrative theoretical review on the subject. Objective: To know the main experiences of suicide prevention in young people and adolescents in Latin America in the last 15 years. Method: 44 empirical studies were reviewed and analyzed, performing bibliographic searches in scientific journals indexed in Scopus, Scielo, WoS, REDALYC and ERIH PLUS and search engines such as Google Scholar and EBSCO. Results: The findings obtained in the 44 studies were organized into three categories: 1) diagnoses of suicidality made in the youth and adolescent population; 2) psychotherapeutic interventions aimed at treating suicidality; and 3) interventions based on programs, strategies and techniques focused on the prevention of youth and adolescent suicide. Discussion: The main diagnoses associated with suicidality are linked to emotional dysfunctionalities, where women are the main affected, the family and the environment appear as the main protective or risk factors depending on their functionality and cohesion. In addition, the most valued interventions are associated with the classic models of psychotherapy and psychoeducational strategies appear as the main focuses of preventive programs. Conclusion: Due to the multifactorial nature of the phenomenon, a paradigm shift should be made in the confrontation of suicidality.

Surface enhanced fluorescence effect improves the in vivo detection of amyloid aggregates.

The ß-amyloid (Aß) peptide is one of the key etiological agents in Alzheimer's disease (AD). The in vivo detection of Aß species is challenging in all stages of the illness. Currently, the development of fluorescent probes allows the detection of Aß in animal models in the near-infrared region (NIR). However, considering future applications in biomedicine, it is relevant to develop strategies to improve detection of amyloid aggregates using NIR probes. An innovative approach to increase the fluorescence signal of these fluorophores is the use of plasmonic gold nanoparticles (surface-enhanced fluorescence effect). In this work, we improved the detection of Aß aggregates in C. elegans and mouse models of AD by co-administering functionalized gold nanorods (GNRs-PEG-D1) with the fluorescent probes CRANAD-2 or CRANAD-58, which bind selectively to different amyloid species (soluble and insoluble). This work shows that GNRs improve the detection of Aß using NIR probes in vivo.

c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease.

Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.

The c-Abl/p73 pathway induces neurodegeneration in a Parkinson's disease model.

Parkinson's disease is the second most common neurodegenerative disorder. Although it is clear that dopaminergic neurons degenerate, the underlying molecular mechanisms are still unknown, and thus, successful treatment is still elusive. One pro-apoptotic pathway associated with several neurodegenerative diseases is the tyrosine kinase c-Abl and its target p73. Here, we evaluated the contribution of c-Abl and p73 in the degeneration of dopaminergic neurons induced by the neurotoxin 6-hydroxydopamine as a model for Parkinson's disease. First, we found that in SH-SY5Y cells treated with 6-hydroxydopamine, c-Abl and p73 phosphorylation levels were up-regulated. Also, we found that the pro-apoptotic p73 isoform TAp73 was up-regulated. Then, to evaluate whether c-Abl tyrosine kinase activity is necessary for 6-hydroxydopamine-induced apoptosis, we co-treated SH-SY5Y cells with 6-hydroxydopamine and Imatinib, a c-Abl specific inhibitor, observing that Imatinib prevented p73 phosphorylation, TAp73 up-regulation, and protected SH-SY5Y cells treated with 6-hydroxydopamine from apoptosis. Interestingly, this observation was confirmed in the c-Abl conditional null mice, where 6-hydroxydopamine stereotaxic injections induced a lesser reduction of dopaminergic neurons than in the wild-type mice significantly. Finally, we found that the intraperitoneal administration of Imatinib prevented the death of dopaminergic neurons induced by injecting 6-hydroxydopamine stereotaxically in the mice striatum. Thus, our findings support the idea that the c-Abl/p73 pathway is involved in 6-hydroxydopamine degeneration and suggest that inhibition of its kinase activity might be used as a therapeutical drug in Parkinson's disease.

Tendencias sociodemográficas en mortalidad por suicidio en la región de Atacama, Chile, 2010-2017 / Sociodemographic trends in suicide mortality in the Atacama region, Chile, 2010- 2017

La presente investigación buscó caracterizar la población suicida de la Región de Atacama entre los años 2010-2017. Asimismo, pretendió describir los casos en los cuales se constató intentos previos que pasaron por la atención del Sistema de Salud. Se realizó un estudio de tipo epidemiológico descriptivo donde se revisaron estadísticas del Servicio Médico Legal y del Servicio de Salud. El análisis se realizó a partir de los 266 casos registrados y tipificados como suicidios por el Servicio Médico Legal en el periodo estudiado. Se describieron las tasas anuales regionales y comunales, y se compararon los casos por sexo, edad, causa de muerte, estado civil, actividad laboral, nacionalidad, fecha de muerte y presencia de sustancias. Se constató un comportamiento semejante al nacional, evidenciándose una primacía de hombres, solteros, con un promedio de edad de 38,8 años, dedicado a oficios, quienes usaron preferentemente como método el ahorcamiento. Se destaca de manera significativa la ocurrencia de suicidios en el periodo octubre-enero. Se discute respecto a la necesidad de profundizar esta problemática a partir de variables socioambientales, con el fin de explicar las diferencias comunales detectadas, y problematizar los datos a nivel local, en búsqueda de favorecer la prevención.

Suicide is a major global, national, and regional public health problem. The present investigation sought to characterise the suicidal population of the Atacama Region between 2010-2017. It also describes the cases with previous attempts detected by the Health System. The analysis is based on 266 registered cases classified as suicides by the Legal Medical Service in the studied period. The annual regional and city rates are described, and the cases are compared by gender, age, cause of death, marital status, work activity, nationality, date of death and presence of substances. The behaviour observed is similar to the national one, which reflects evidence of a predominance of single men with an average age of 38.8 years, of different trades, who preferably used hanging. The study underscores the occurrence of suicides in the period October-January. The study raises the need to go deep into this problem, considering socio-environmental variables to explain the detected differences between cities and analysing the local data to favour prevention.

Salud Mental y Apoyo Social en habitantes de Copiapó, Chile, en el contexto de la COVID-19 / Mental Health and Social Support in the inhabitants of Copiapó, Chile, in the context of COVID-19

Resumen Introducción: La pandemia de la COVID-19 ha venido a cambiar de forma abrupta las formas de vida de buena parte de la población mundial. Conocer la presencia de psicopatología en este contexto se hace relevante para generar políticas públicas de promoción y prevención en salud mental. Objetivo: Establecer la presencia de psicopatología en habitantes de Copiapó, Chile, y determinar su relación con las variables sexo, edad, ocupación y apoyo social percibido. Método: El estudio, de tipo transversal, se efectuó en una muestra de 523 personas, habitantes de la ciudad de Copiapó, Chile. Se aplicaron la Escala de Salud General, GHQ-12, la Escala de Apoyo Social percibido, MSPSS, y un cuestionario de caracterización sociodemográfica. Las técnicas de análisis de datos fueron estadísticos descriptivos de frecuencia, tendencia central y variabilidad, y estadígrafos de asociación no paramétricos, chi-cuadrado y Eta. También se utilizó t de Student y Anova, para los datos de nivel escalar. Resultados: Se evidencia que un 51,82 % de los evaluados presenta sospecha o presencia de psicopatología, asociada a sintomatología de depresión, ansiedad y/o disfunción social. Se constatan diferencias significativas según sexo, edad y ocupación de los sujetos. Junto a ello, se aprecian niveles estadísticamente significativos de apoyo social entre quienes tienen ausencia y presencia de psicopatología. Conclusiones: El estudio logra describir los niveles de psicopatología en el grupo estudiado en tiempos de la COVID 19, evidenciándose su relación con variables de género, edad y ocupación, lo cual tiene implicancias para la focalización de intervenciones considerando los grupos más afectados: mujeres, jóvenes y estudiantes. Además, se destaca el apoyo social como un factor protector de la salud mental.

Abstract Introduction: The COVID-19 pandemic has come to abruptly change the ways of life of a large part of the world population. Knowing the presence of psychopathology in this context becomes relevant to generate public politics to promote and prevent mental health. Objective: To establish the presence of psychopathology in the inhabitants of Copiapó, Chile, and determine its relationship with the variables sex, age, occupation and perceived social support. Method: The cross-sectional study was carried out on a sample of 523 people, inhabitants of the city of Copiapó, Chile. The General Health Scale, GHQ-12, the Perceived Social Support Scale, MSPSS, and a questionnaire of sociodemographic characterization were applied. Data analysis techniques were descriptive statistics of frequency, central tendency and variability, and non-parametric association statistic, chi-square, and Eta. T Student and Anova were also used for the scalar level data. Results: It is evident that 51,82% of those evaluated show suspicion or presence of psychopathology, associated with symptoms of depression, anxiety and/or social dysfunction. Significant differences were found according to sex, age, and occupation subjects' occupation. Along with this, there are statistically significant levels of social support among those who have absence and presence of psychopathology. Conclusions: The study achieve to describe the levels of psychopathology in the group studied at time of COVID-19, evidencing its relationship with variables of gender, age and occupation, which has implications for targeting interventions considering the most affected groups: women, youth and students. In addition, social support is highlighted as a protective factor of mental health.

Role of whole brain radiotherapy in the management of infratentorial metastases from lung and breast cancer.

BACKGROUND: Brain metastases (BM) occur in almost one third of patients with systemic malignancies. Only a small number of studies focus on infratentorial location and whole brain radiotherapy (WBRT) as the main non-surgical management. The aim of the study was to compare the prognosis of patients treated with WBRT among patients with supra- or infratentorial lesions. MATERIALS AND METHODS: At a single center, 263 patients with either breast (BC) or lung (LC) cancer, that had developed BM and received treatment with WBRT, were analyzed during an 8-year period. RESULTS: A total of 152 patients with BC and 111 with LC were analyzed, median age at the time of BM was 50.7 years, systemic activity other than BM was detected in 91%. Newly diagnosed BM were supratentorial in 40%, infratentorial in 10% and 51% in both locations. Median overall survival was 13 months (95% CI: 11.1-14.8 months), without significant difference between supra- or infratentorial location. WBRT alone was administered in 79% of patients, whereas WBRT with chemtoreapy was provided for 21%. CONCLUSION: In patients with BM from LC or BC that were not candidates for surgical resection, palliative WBRT appears to be equally effective in those with supra- or infratentorial locations.