Expanding the clinical and molecular spectrum of FOXG1- and ZBTB18-associated neurodevelopmental disorders.

Introduction The zinc finger BTB domain-containing protein ZBTB18 binds to FOXG1 to form a transcriptional repressive complex involved in neuronal differentiation. Disruption of the components of this complex results in chromosome 1q43-q44 deletion syndrome/intellectual developmental disorder 22 or in FOXG1 syndrome. Case presentation This study reports on five patients with cognitive and behavioral impairment, seizures, microcephaly, and/or congenital brain abnormalities. Whole exome sequencing identified deleterious ZBTB18 variants in three patients and deleterious FOXG1 variants in the remaining patients. We have detected a missense variant within the BTB domain of ZBTB18 in two affected monozygotic twins. In addition, we observed agenesis of the septum pellucidum in a missense FOXG1 carrier with a severe FOXG1 syndrome. Conclusion Although the ZBTB18 zinc finger domains harbor the majority of known deleterious variants, we report a novel de novo rare missense variant within the BTB domain. The agenesis of the septum pellucidum observed in a missense FOXG1 carrier could be considered as a novel clinical feature associated with FOXG1 syndrome. The severe FOXG1 syndrome in this patient contrasts with the milder phenotype expected for a missense. Genetic or environmental factors may explain this phenotypic variability in FOXG1 syndrome.

Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis.

In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. Current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects accompanied by increased neuroblast death and high loss of newly formed neurons in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. We also show that NSCs with Kidins220 can survive with lower concentrations of EGF than the ones lacking this molecule. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs growth and expansion. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair.

How do Lay Health Worker Engage Caregivers? A Qualitative Study to Enhance Equity in Evidence-Based Parenting Programs.

Engaging caregivers in their children's mental health treatment is critical for delivering high quality, evidence-based care, particularly for young children with externalizing behaviors. Lay health workers (LHWs), including peer providers and promotoras de salud, have been identified as important workforces in addressing structural and stigma-related barriers to engagement in mental health services. Importantly, research has suggested that LHWs may be integral in efforts to address engagement disparities in evidence-based behavioral parent training programs (BPTs) for Latinx caregivers. The purpose of the study was to understand how different LHW workforces engage caregivers within their usual services, in order to inform strategies that improve access to and engagement in BPTs. Qualitative interviews were conducted with two different LHW workforces: volunteer LHWs (i.e., promotoras de salud) (n = 14), who were part of a community-embedded network, and paid LHWs (i.e., parent support partners, home visitors) (n = 9) embedded within children's mental health agencies. Participants were predominately Latinx (79%) and female (96%). Qualitative analyses revealed three primary themes related to engagement strategies used by LHWs to address barriers to care: 1.) Building Trust, 2.) Empowerment, 3.) Increasing Access. Although the majority of themes and sub-themes were consistent across the two LHW workforces, agency-embedded LHWs often discussed having the means to provide resources through their organizations, whereas community-embedded LHWs discussed acting as a bridge to services by providing information and conducting outreach. Findings have implications for partnering with different workforces of LHWs to increase equity in access to BPTs.

Higher plasma levels of thymosin-α1 are associated with a lower waning of humoral response after COVID-19 vaccination: an eight months follow-up study in a nursing home.

BACKGROUND: Older people achieve lower levels of antibody titers than younger populations after Covid-19 vaccination and show a marked waning humoral immunity over time, likely due to the senescence of the immune system. Nevertheless, age-related predictive factors of the waning humoral immune response to the vaccine have been scarcely explored. In a cohort of residents and healthcare workers from a nursing home that had received two doses of the BNT162b2 vaccine, we measured specific anti-S antibodies one (T1), four (T4), and eight (T8) months after receiving the second dose. Thymic-related functional markers, including thymic output, relative telomere length, and plasma thymosin-α1 levels, as well as immune cellular subsets, and biochemical and inflammatory biomarkers, were determined at T1, and tested for their associations with the magnitude of the vaccine response (T1) and the durability of such response both, at the short- (T1-T4) and the long-term (T1-T8). We aimed to identify age-related factors potentially associated with the magnitude and persistence of specific anti-S immunoglobulin G (IgG)-antibodies after COVID-19 vaccination in older people. RESULTS: Participants (100% men, n = 98), were subdivided into three groups: young (< 50 years-old), middle-age (50-65 years-old), and older (≥65 years-old). Older participants achieved lower antibody titers at T1 and experienced higher decreases in both the short- and long-term. In the entire cohort, while the magnitude of the initial response was mainly associated with the levels of homocysteine [ß (95% CI); - 0.155 (- 0.241 to - 0.068); p = 0.001], the durability of such response at both, the short-term and the long-term were predicted by the levels of thymosin-α1 [- 0.168 (- 0.305 to - 0.031); p = 0.017, and - 0.123 (- 0.212 to - 0.034); p = 0.008, respectively]. CONCLUSIONS: Higher plasma levels of thymosin-α1 were associated with a lower waning of anti-S IgG antibodies along the time. Our results suggest that plasma levels of thymosin-α1 could be used as a biomarker for predicting the durability of the responses after COVID-19 vaccination, possibly allowing to personalize the administration of vaccine boosters.

Factors associated with the humoral response after three doses of COVID-19 vaccination in kidney transplant recipients.

Introduction: Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients. Methods: To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response. Results: Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses. Discussion: In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.

R-Ras1 and R-Ras2 Expression in Anatomical Regions and Cell Types of the Central Nervous System.

Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), many myelin diseases affect the visual system. In this sense, our laboratory has recently reported that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival and maturation. Hypomyelination produced by the absence of one or both proteins triggers axonal degeneration and loss of visual and motor function. However, little is known about R-Ras specificity and other possible roles that they could play in the CNS. In this work, we describe how a lack of R-Ras1 and/or R-Ras2 could not be compensated by increased expression of the closely related R-Ras3 or classical Ras. We further studied R-Ras1 and R-Ras2 expression within different CNS anatomical regions, finding that both were more abundant in less-myelinated regions, suggesting their expression in non-oligodendroglial cells. Finally, using confocal immunostaining colocalization, we report for the first time that R-Ras2 is specifically expressed in neurons. Neither microglia nor astrocytes expressed R-Ras1 or R-Ras2. These results open a new avenue for the study of neuronal R-Ras2's contribution to the process of myelination.

Pathways Involved in Remyelination after Cerebral Ischemia.

Brain ischemia, also known as ischemic stroke, occurs when there is a lack of blood supply into the brain. When an ischemic insult appears, both neurons and glial cells can react in several ways that will determine the severity and prognosis. This high heterogeneity of responses has been a major obstacle in developing effective treatments or preventive methods for stroke. Although white matter pathophysiology has not been deeply assessed in stroke, its remodelling can greatly influence the clinical outcome and the disability degree. Oligodendrocytes, the unique cell type implied in CNS myelination, are sensible to ischemic damage. Loss of myelin sheaths can compromise axon survival, so new Oligodendrocyte Precursor Cells are required to restore brain function. Stroke can, therefore, enhance oligodendrogenesis to regenerate those new oligodendrocytes that will ensheath the damaged axons. Given that myelination is a highly complex process that requires coordination of multiple pathways such as Sonic Hedgehog, RTKs or Wnt/ß-catenin, we will analyse new research highlighting their importance after brain ischemia. In addition, oligodendrocytes are not isolated cells inside the brain, but rather form part of a dynamic environment of interactions between neurons and glial cells. For this reason, we will put some context into how microglia and astrocytes react against stroke and influence oligodendrogenesis to highlight the relevance of remyelination in the ischemic brain. This will help to guide future studies to develop treatments focused on potentiating the ability of the brain to repair the damage.

Absence of R-Ras1 and R-Ras2 causes mitochondrial alterations that trigger axonal degeneration in a hypomyelinating disease model.

Fast synaptic transmission in vertebrates is critically dependent on myelin for insulation and metabolic support. Myelin is produced by oligodendrocytes (OLs) that maintain multilayered membrane compartments that wrap around axonal fibers. Alterations in myelination can therefore lead to severe pathologies such as multiple sclerosis. Given that hypomyelination disorders have complex etiologies, reproducing clinical symptoms of myelin diseases from a neurological perspective in animal models has been difficult. We recently reported that R-Ras1-/- and/or R-Ras2-/- mice, which lack GTPases essential for OL survival and differentiation processes, present different degrees of hypomyelination in the central nervous system with a compounded hypomyelination in double knockout (DKO) mice. Here, we discovered that the loss of R-Ras1 and/or R-Ras2 function is associated with aberrant myelinated axons with increased numbers of mitochondria, and a disrupted mitochondrial respiration that leads to increased reactive oxygen species levels. Consequently, aberrant myelinated axons are thinner with cytoskeletal phosphorylation patterns typical of axonal degeneration processes, characteristic of myelin diseases. Although we observed different levels of hypomyelination in a single mutant mouse, the combined loss of function in DKO mice lead to a compromised axonal integrity, triggering the loss of visual function. Our findings demonstrate that the loss of R-Ras function reproduces several characteristics of hypomyelinating diseases, and we therefore propose that R-Ras1-/- and R-Ras2-/- neurological models are valuable approaches for the study of these myelin pathologies.

Direct-to-Consumer Marketing for Parent-Child Interaction Therapy: Impact of Language and Messenger.

OBJECTIVES: Parent-Child Interaction Therapy (PCIT) is an effective therapy to treat early onset disruptive behavior problems and child physical maltreatment. In order to support the successful implementation and sustainment of PCIT, strategies are needed to recruit parents into care, especially for racial and ethnic minority families, who often have lower rates of access and utilization of mental health services. METHODS: This study investigated the impact of direct-to-consumer advertisements on parents' attitudes towards PCIT. Advertisements were delivered in Spanish and English, with either a parent testimony or therapist explaining the treatment. Participants were parents of children between the ages of 2 and 7, who were recruited through Amazon Mechanical Turk. Participants (N = 204) were 38.2% female and 49.5% Spanish speaking. RESULTS: There were no main effects for language or messenger related to PCIT Help-Seeking Intentions, Attitudes, or Stigmatization. However, there was an interaction effect for language and messenger for PCIT Help-Seeking Intentions. Specifically, Spanish-speaking participants had higher intentions when the messenger was a therapist rather than a parent, and had lower intentions than English-speaking parents when the messenger was a parent. CONCLUSIONS: These findings are promising for direct-to-consumer advertising strategies that may help recruit more Spanish-speaking families into PCIT, which could help address disparities in access to mental health services.

R-Ras GTPases Signaling Role in Myelin Neurodegenerative Diseases.

Myelination is required for fast and efficient synaptic transmission in vertebrates. In the central nervous system, oligodendrocytes are responsible for creating myelin sheaths that isolate and protect axons, even throughout adulthood. However, when myelin is lost, the failure of remyelination mechanisms can cause neurodegenerative myelin-associated pathologies. From oligodendrocyte progenitor cells to mature myelinating oligodendrocytes, myelination is a highly complex process that involves many elements of cellular signaling, yet many of the mechanisms that coordinate it, remain unknown. In this review, we will focus on the three major pathways involved in myelination (PI3K/Akt/mTOR, ERK1/2-MAPK, and Wnt/ß-catenin) and recent advances describing the crosstalk elements which help to regulate them. In addition, we will review the tight relation between Ras GTPases and myelination processes and discuss its potential as novel elements of crosstalk between the pathways. A better understanding of the crosstalk elements orchestrating myelination mechanisms is essential to identify new potential targets to mitigate neurodegeneration.

Valoración de movimientos generales como herramienta pronóstica de parálisis cerebral infantil en prematuros: revisión sistemática / General movement assessment as a tool for determining the prognosis in infantile cerebral palsy in preterm infants: a systematic review

INTRODUCCIÓN: La parálisis cerebral infantil se considera la principal causa de discapacidad física en la infancia. La valoración de los movimientos generales es una herramienta de evaluación con el fin de pronosticar la afectación neurológica y el desenlace a largo plazo del recién nacido. OBJETIVO: Analizar la evidencia científica sobre la valoración de los movimientos generales en recién nacidos prematuros como medida pronóstica de parálisis cerebral infantil. SUJETOS Y MÉTODOS: Revisión sistemática siguiendo la normativa PRISMA. Se consultaron las bases de datos PubMed/Medline, Lilacs, IBECS, Cochrane, PEDro, Cinhal, Sport Discuss, Phyinfo, Academic Search Complete, Web of Science y SciELO. Se incluyeron estudios donde se valoraban movimientos generales en las primeras 20 semanas de recién nacidos prematuros y se excluyeron aquellos donde la muestra presentaba otras patologías o administraba medicación. Se utilizó la Newcastle-Ottawa Scale para valorar el riesgo de sesgo. RESULTADOS: Se seleccionaron 10 estudios de cohortes para esta revisión y se analizaron un total de 2.243 prematuros, con una media de 30,9 semanas de gestación. Se llevó a cabo la grabación de movimientos generales entre 5 y 30 minutos. Cuando se observan movimientos generales anormales, aumentan las posibilidades de afectación neurológica durante el desarrollo, mientras que cuando se valoran movimientos generales normales, raramente habrá un posterior diagnóstico de parálisis cerebral. CONCLUSIONES: Se confirma la validez predictiva de la valoración de los movimientos generales en prematuros para pronosticar parálisis cerebral de forma precoz. Como los recién nacidos prematuros tienen mayor posibilidad de desencadenar movimientos generales anormales, es interesante promover este tipo de valoración

INTRODUCTION: Cerebral palsy is considered to be the main cause of physical disability in childhood. General movements are an assessment tool in order to predict the neurological and long-term outcome of the newborn. AIM: To analyze the current evidence on the general movements assessment in preterm infants as cerebral palsy prognostic tool. SUBJECTS AND METHODS: Systematic review following PRISMA statements. Databases consulted were: PubMed/Medline, Lilacs, IBECS, Cochrane, PEDro, Cinhal, Sport Discuss, Phyinfo, Academic Search Complete, Web of Science, and SciELO. We included studies that evaluated general movements in the first 20 weeks premature newborns. We excluded studies where the sample submit other pathologies or medication was administered. Newcastle-Ottawa Scale was used to assessment the risk of bias. RESULTS: Ten cohort studies form this review. 2243 premature, with an average of 30.9 weeks of gestation, were analyzed. General movements recording was carried out between 5 and 30 minutes. When there are abnormal general movements, the chances of neurological involvement increase during development, whereas when normal general movements are evaluated, there will rarely be a subsequent cerebral palsy diagnosis. CONCLUSIONS: The predictive validity of the preterm general movements assessment is confirmed as a tool to predict cerebral palsy early. Since preterm infants are more likely to trigger abnormal general movements, it is interesting to promote this type of assessment

Climate-induced changes in the suitable habitat of cold-water corals and commercially important deep-sea fishes in the North Atlantic.

The deep sea plays a critical role in global climate regulation through uptake and storage of heat and carbon dioxide. However, this regulating service causes warming, acidification and deoxygenation of deep waters, leading to decreased food availability at the seafloor. These changes and their projections are likely to affect productivity, biodiversity and distributions of deep-sea fauna, thereby compromising key ecosystem services. Understanding how climate change can lead to shifts in deep-sea species distributions is critically important in developing management measures. We used environmental niche modelling along with the best available species occurrence data and environmental parameters to model habitat suitability for key cold-water coral and commercially important deep-sea fish species under present-day (1951-2000) environmental conditions and to project changes under severe, high emissions future (2081-2100) climate projections (RCP8.5 scenario) for the North Atlantic Ocean. Our models projected a decrease of 28%-100% in suitable habitat for cold-water corals and a shift in suitable habitat for deep-sea fishes of 2.0°-9.9° towards higher latitudes. The largest reductions in suitable habitat were projected for the scleractinian coral Lophelia pertusa and the octocoral Paragorgia arborea, with declines of at least 79% and 99% respectively. We projected the expansion of suitable habitat by 2100 only for the fishes Helicolenus dactylopterus and Sebastes mentella (20%-30%), mostly through northern latitudinal range expansion. Our results projected limited climate refugia locations in the North Atlantic by 2100 for scleractinian corals (30%-42% of present-day suitable habitat), even smaller refugia locations for the octocorals Acanella arbuscula and Acanthogorgia armata (6%-14%), and almost no refugia for P. arborea. Our results emphasize the need to understand how anticipated climate change will affect the distribution of deep-sea species including commercially important fishes and foundation species, and highlight the importance of identifying and preserving climate refugia for a range of area-based planning and management tools.

X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world.

BACKGROUND: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. METHODS: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. RESULTS: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. CONCLUSIONS: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

Study of an extended family with CTLA-4 deficiency suggests a CD28/CTLA-4 independent mechanism responsible for differences in disease manifestations and severity.

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

De novo recipient-specific Glutathione S-transferase T1 antibody development after HLA-identical hematopoietic cell transplantation.

Donor-specific antibodies against Glutathione S-transferase T1 (GSTT1) have been associated with de novo immune hepatitis after liver transplantation. These antibodies have also been found very early in allo-HCT associated with acute hepatic GvHD but in all the cases the donor cells had experienced previous priming through pregnancies. It remained to be explored whether or not primary recognition of the antigen occurs after HCT and what could be the consequences in the long term outcome. We genotyped a cohort of 68 HCT patients and found 11 with the GSTT1 null donor/positive recipient mismatch. After testing 114 serum samples, we found a unique case of a 33-year-old patient transplanted from his HLA-identical sibling donor in which IgG GSTT1 antibodies were detected for the first time on day +178. After stimulation of peripheral blood mononuclear cells with GSTT1 peptides we could demonstrate that this patient also had GSTT1-specific T lymphocytes that became activated upon exposure to the GSTT1 antigen. In this report, we describe the first case in which simultaneous T and B cell response against GSTT1 is developed in HCT although the clinical consequences in GvHD are still unclear.

T-cell allorecognition of donor glutathione S-transferase T1 in plasma cell-rich rejection.

AIM: To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts. METHODS: The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1 (GSTT1) alleles (don+/rec-), and 4 were matched (don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection (former de novo immune hepatitis). For the detection of specific T lymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ. RESULTS: Activation of CD8+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection (3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides (1.45%-5.18%). Highly unexpected was the finding of a double positive CD4+CD8low T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4+CD8low cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION: Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.

Establecimiento de la situación de enfermedad terminal en enfermedades oncológicas y no oncológicas: estudio retrospectivo con historias clínicas / Indentifying terminal illness situation in cancer and non cancer diseases: A retrospective study using clinical records

OBJETIVO: Conocer cómo y en qué momento del proceso de enfermedad se identifica la situación terminal en las historias clínicas de pacientes con enfermedades avanzadas oncológicas y no oncológicas; las expresiones y argumentos registrados para definirla y la presencia de factores pronósticos. MÉTODO: Estudio observacional y retrospectivo de las historias clínicas de los pacientes que fallecieron en 4 hospitales de Granada (España) en el año 2010, por enfermedad oncológica, enfermedad pulmonar crónica/EPOC, insuficiencia cardiaca crónica, enfermedad hepática avanzada e insuficiencia renal crónica. Se revisaron los informes clínicos de ingreso, el informe de alta y la evolución médica y enfermera correspondientes a los últimos 3 meses de vida del paciente. Se registraron los datos sociodemográficos, clínicos y específicos relacionadas con el pronóstico de enfermedad terminal. RESULTADOS: Se revisaron 202 historias clínicas. En un 51,5% de los casos consta el establecimiento de la situación de enfermedad terminal. Un 33,6% han sido registrados como paciente en situación terminal entre los 7 días y las últimas 48h antes del fallecimiento. Se produce una mayor identificación de situación terminal en pacientes oncológicos (p = 0,004). Las expresiones que más se emplean en las historias son «enfermedad terminal» (32,7%) en el caso de pacientes de cáncer y «mal pronóstico» (41,3%) en pacientes no oncológicos. Los argumentos que más se emplean son cuestiones relativas a un mal pronóstico (42,2%) y al estadio de la enfermedad (39,8%), especialmente en los pacientes de cáncer. No existen diferencias entre los pacientes identificados como en situación terminal y aquellos que no, en relación con la edad, el sexo, la comorbilidad y el tiempo de evolución de la enfermedad. CONCLUSIONES: Este trabajo muestra la dificultad de los clínicos en identificar la fase terminal de forma temprana y una actitud poco favorable a registrarla en las historias clínicas. Esta conducta puede constatarse por la frecuente utilización de expresiones ambiguas y por la falta de criterios y argumentos para señalar la situación terminal

AIM: To know how and when terminal illness situation is identified in advanced cancer and non-cancer patients in medical records, and which expressions and arguments are used when this situation is established, as well as the presence of prognosis factors. METHOD: Observational, retrospective study of medical records of patients who died of oncological disease, COPD disease, chronic heart failure, advanced liver disease, and chronic renal failure in 4 hospitals in Granada (Spain). Medical records including hospitalisation reports, discharge documents, and medical and nurse evaluations of the last 3 months of life were reviewed. Sociodemographic, clinical, and specific data related to the prognosis of terminal illness were recorded. RESULTS: From the 202 medical records reviewed, 51.5% patients were identified as in terminal illness situation. One third (33.6%) of them were identified between 7 days and the last 48h before death. Doctors tend to identify more cancer-patients than non-cancer patients as in terminal illness situation (P=.004). The most used expressions in medical records are 'terminal disease' in cancer patients (32.7%) and 'poor prognosis' in non-cancer patients (41.3%). The arguments most used are related to poor prognosis (42.2%), and related to the stage of the disease (39.8%), especially in cancer PATIENTS: There are no statistical differences between patients identified as terminally ill, and patients not identified, related to age, gender, comorbidity and time of evolution. CONCLUSIONS: This paper shows how difficult it is for clinicians to identify terminal illness at an early stage, and an unfavourable attitude towards reporting it in medical records. This attitude could be confirmed by the frequent use of ambiguous expressions regarding terminally ill, the lack of criteria and arguments to identify this situation

Defining adaptation measures collaboratively: A participatory approach in the Doñana socio-ecological system, Spain.

The uncertainty associated with the definition of strategies for climate change adaptation poses a challenge that cannot be faced by science alone. We present a participatory experience where, instead of having science defining solutions and eliciting stakeholders' feedback, local actors actually drove the process. While principles and methods of the approach are easily adaptable to different local contexts, this paper shows the contribution of participatory dynamics to the design of adaptation measures in the biodiversity-rich socio-ecological region surrounding the Doñana wetlands (Southern Spain). During the process, stakeholders and scientists collaboratively designed a common scenario for the future in which to define and assess a portfolio of potential adaptation measures, and found a safe, informal space for open dialogue and information exchange. Through this dialogue, points of connection among local actors emerged around the need for more integrated, transparent design of adaptation measures; for strengthening local capacity; and for strategies to diversify economic activities in order to increase the resilience of the region.

Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature.

BACKGROUND: Autosomal dominant gain-of-function mutations in PIK3R1 encoding for the regulatory subunit (p85α, p55α, and p50α) of Class IA phosphoinositide 3-kinase (PI3K) result in the activated PI3Kδ syndrome (APDS) type 2 characterized by childhood-onset combined immunodeficiency, lymphoproliferation, and immune dysregulation. To improve clinical awareness and understanding of these rare diseases, we reviewed all hitherto published cases with APDS type 1 and type 2 for their clinical and immunologic symptoms and added novel clinical, immunologic, and genetic findings of two patients with APDS type 2. METHODS: Clinical, immunologic, and genetic evaluation of two new patients with APDS2 was performed followed by the systematic collection of all available previously published data of patients with APDS1 and APDS2. RESULTS: Patients with APDS type 1 (n = 49) and type 2 (n = 15) showed an indistinguishable immunologic phenotype. Overlapping clinical features shared by APDS type 1 and type 2 were observed, but our review also revealed previously unnoticed clinical differences such as remarkably high incidence of microcephaly, poor growth/short stature in patients with APDS2. Clinical management and outcome were variable and included prophylactic antibiotics, immunosuppression, immunoglobulin substitution, and hematopoietic stem cell transplantation. CONCLUSIONS: A disease-specific registry collecting prospective and long-term follow-up data of patients with APDS, as currently set up by the European Society for Immunodeficiencies, are needed to better understand the natural history and to optimize treatment concepts and thereby improving the outcome of this heterogenous patient group.

Diagnostic and therapeutic challenges in a child with complete interferon-γ receptor 1 deficiency.

Autosomal recessive (AR) complete Interferon-γ Receptor1 (IFN-γR1) deficiency is a rare variant of Mendelian susceptibility to mycobacterial disease (MSMD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, outcomes are heterogeneous; delayed engraftment and/or graft rejection being commonly observed. This case report and literature review expands the knowledge about this rare but potentially fatal pathology, providing details regarding diagnosis, antimicrobial treatment, transplant performance, and outcome that may help to guide physicians caring for patients with AR complete IFN-γR1 or IFN-γR2 deficiency.