Síndrome de Alagille, reporte de un caso y revisión de la literatura / Alagille Syndrome, case study and literature review / Sindrome de Alagille, relato de caso e revisão de literatura

El síndrome de Alagille es una patología poco frecuente, de herencia autosómica dominante. Se caracteriza por la presencia de colestasis crónica progresiva ocasionada por hipoplasia de las vías biliares; anomalías vertebrales, oculares y cardíacas, y fenotipo facial particular. Entre sus diagnósticos diferenciales se incluyen las infecciones, enfermedades endocrinometabólicas, atresia biliar y causas idiopáticas. El pronóstico de este síndrome es variable y depende de la entidad de la afectación hepática y los defectos cardiovasculares. El abordaje terapéutico suele ser interdisciplinario e individualizado, enfocado en el control sintomático, prevención de la malnutrición y el déficit de vitaminas liposolubles. Se presenta el caso de un lactante de 2 meses en el que se estudiaron las causas más frecuentes de colestasis y se llegó al diagnóstico de síndrome de Alagille. Se describe su abordaje terapéutico y seguimiento.

Alagille syndrome is an inherited autosomal dominant rare disease. It is characterized by the presence of progressive chronic cholestasis caused by hypoplasia of the bile ducts; vertebral, ocular and cardiac anomalies, and particular facial phenotype. Its differential diagnoses include infections, endocrine-metabolic diseases, biliary atresia and idiopathic causes. The prognosis of this syndrome is variable and depends on the degree of liver involvement and cardiovascular defects. The therapeutic approach is usually interdisciplinary and customized, focused on symptomatic control, prevention of malnutrition and fat-soluble vitamin deficiency. We present the case of a 2-month-old infant in whom the most frequent causes of cholestasis were studied and to whom Alagille Syndrome was diagnosed. We hereby describe its therapeutic approach and follow-up.

A síndrome de Alagille é uma doença rara, hereditária, autossômica e dominante. Caracteriza-se pela presença de colestase crônica progressiva causada por hipoplasia das vias biliares; anomalias vertebrais, oculares e cardíacas e fenótipo facial particular. Seus diagnósticos diferenciais incluem infecções, doenças endócrino-metabólicas, atresia biliar e causas idiopáticas. O prognóstico desta síndrome é variável e depende do grau de envolvimento hepático e defeitos cardiovasculares. A abordagem terapêutica geralmente é interdisciplinar e personalizada, focada no controle sintomático, prevenção da desnutrição e deficiência de vitaminas lipossolúveis. Apresentamos o caso de uma criança de 2 meses de idade em que foram estudadas as causas mais frequentes de colestase e a quem foi diagnosticada Síndrome de Alagille. Descrevemos a sua abordagem terapêutica e seguimento.

Coronavirus disease 2019 in patients with rheumatic immune-mediated diseases in a single University Hospital, matched case-control study and literature review.

Background: COVID-19 may present different degrees of severity. Viral infections in patients with rheumatic inflammatory diseases (R-IMID) trend to present more severe disease. However, data comparing the severity of the disease between R-IMID and the general population are scarce. Objectives: To compare predisposing factors, clinical, serological features, and severity of COVID-19 infection in patients with and without R-IMID. Methods: Case-control study in a single University Hospital. We included all consecutive patients with a diagnosis of an R-IMID and COVID-19 infection up to March 31st, 2021. This cohort was compared to patients without R-IMID and not receiving immunosuppressive therapy, matched for sex and age (±5 years). Confirmed infection was defined if a patient had a positive nasopharyngeal swab for SARS-CoV-2. Severity was divided into mild, moderate, severe and critical according to the United States National Institute of Health (NIH) guidelines. Results: We included 274 R-IMID patients (185 women/89 men), mean age 59.1 ± 18 years. More frequent R-IMID were: Rheumatoid arthritis (28.8%), Psoriatic Arthritis (20.1%), axial Spondyloarthritis (12.4%), Polymyalgia Rheumatica (8%) and Systemic Lupus Erythematosus (8%). Hypertension and dyslipidemia were more frequent in patients with R-IMID. Although most of the cases were mild, critical cases and deaths were more frequent in R-IMID. When adjusted by comorbidities, no statistical differences were observed. Conclusion: R-IMID have a very similar clinical presentation when compared to the general population. There is a trend to an increased severity of the disease in patients with R-IMID.

PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina.

PURPOSE: PALB2 variants have been scarcely described in Argentinian and Latin-American reports. In this study, we describe molecular and clinical characteristics of PALB2 mutations found in multi-gene panels (MP) from breast-ovarian cancer (BOC) families in different institutions from Argentina. METHODS: We retrospectively identified PALB2 pathogenic (PV) and likely pathogenic (LPV) variants from a cohort of 1905 MP results, provided by one local lab (Heritas) and SITHER (Hereditary Tumor Information System) public database. All patients met hereditary BOC clinical criteria for testing, according to current guidelines. RESULTS: The frequency of PALB2 mutations is 2.78% (53/1905). Forty-eight (90.5%) are PV and five (9.5%) are LPV. Most of the 18 different mutations (89%) are nonsense and frameshift types and 2 variants are novel. One high-rate recurrent PV (Y551*) is present in 43% (23/53) of the unrelated index cases. From the 53 affected carriers, 94% have BC diagnosis with 14% of bilateral cases. BC phenotype is mainly invasive ductal (78%) with 62% of hormone-receptor positive and 22% of triple negative tumors. Self-reported ethnic background of the cohort is West European (66%) and native Latin-American (20%) which is representative of Buenos Aires and other big urban areas of the country. CONCLUSION: This is the first report describing molecular and clinical characteristics of PALB2 carriers in Argentina. Frequency of PALB2 PV in Argentinian HBOC families is higher than in other reported populations. Y551* is a recurrent mutation that seems to be responsible for almost 50% of PALB2 cases.

Longitudinal relationship of liver injury with inflammation biomarkers in COVID-19 hospitalized patients using a joint modeling approach.

The mechanisms underlying liver disease in patients with COVID-19 are not entirely known. The aim is to investigate, by means of novel statistical techniques, the changes over time in the relationship between inflammation markers and liver damage markers in relation to survival in COVID-19. The study included 221 consecutive patients admitted to the hospital during the first COVID-19 wave in Spain. Generalized additive mixed models were used to investigate the influence of time and inflammation markers on liver damage markers in relation to survival. Joint modeling regression was used to evaluate the temporal correlations between inflammation markers (serum C-reactive protein [CRP], interleukin-6, plasma D-dimer, and blood lymphocyte count) and liver damage markers, after adjusting for age, sex, and therapy. The patients who died showed a significant elevation in serum aspartate transaminase (AST) and alkaline phosphatase levels over time. Conversely, a decrease in serum AST levels was observed in the survivors, who showed a negative correlation between inflammation markers and liver damage markers (CRP with serum AST, alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]; and D-dimer with AST and ALT) after a week of hospitalization. Conversely, most correlations were positive in the patients who died, except lymphocyte count, which was negatively correlated with AST, GGT, and alkaline phosphatase. These correlations were attenuated with age. The patients who died during COVID-19 infection displayed a significant elevation of liver damage markers, which is correlated with inflammation markers over time. These results are consistent with the role of systemic inflammation in liver damage during COVID-19.

Enabling Remote Responder Bio-Signal Monitoring in a Cooperative Human-Robot Architecture for Search and Rescue.

The roles of emergency responders are challenging and often physically demanding, so it is essential that their duties are performed safely and effectively. In this article, we address real-time bio-signal sensor monitoring for responders in disaster scenarios. In particular, we propose the integration of a set of health monitoring sensors suitable for detecting stress, anxiety and physical fatigue in an Internet of Cooperative Agents architecture for search and rescue (SAR) missions (SAR-IoCA), which allows remote control and communication between human and robotic agents and the mission control center. With this purpose, we performed proof-of-concept experiments with a bio-signal sensor suite worn by firefighters in two high-fidelity SAR exercises. Moreover, we conducted a survey, distributed to end-users through the Fire Brigade consortium of the Provincial Council of Málaga, in order to analyze the firefighters' opinion about biological signals monitoring while on duty. As a result of this methodology, we propose a wearable sensor suite design with the aim of providing some easy-to-wear integrated-sensor garments, which are suitable for emergency worker activity. The article offers discussion of user acceptance, performance results and learned lessons.

Genomic insights into an andean multiresistant soil actinobacterium of biotechnological interest.

Central-Andean Ecosystems (between 2000 and 6000 m above sea level (masl) are typical arid-to-semiarid environments suffering from the highest total solar and ultraviolet-B radiation on the planet but displaying numerous salt flats and shallow lakes. Andean microbial ecosystems isolated from these environments are of exceptional biodiversity enduring multiple severe conditions. Furthermore, the polyextremophilic nature of the microbes in such ecosystems indicates the potential for biotechnological applications. Within this context, the study undertaken used genome mining, physiological and microscopical characterization to reveal the multiresistant profile of Nesterenkonia sp. Act20, an actinobacterium isolated from the soil surrounding Lake Socompa, Salta, Argentina (3570 masl). Ultravioet-B, desiccation, and copper assays revealed the strain's exceptional resistance to all these conditions. Act20's genome presented coding sequences involving resistance to antibiotics, low temperatures, ultraviolet radiation, arsenic, nutrient-limiting conditions, osmotic stress, low atmospheric-oxygen pressure, heavy-metal stress, and toxic fluoride and chlorite. Act20 can also synthesize proteins and natural products such as an insecticide, bacterial cellulose, ectoine, bacterial hemoglobin, and even antibiotics like colicin V and aurachin C. We also found numerous enzymes for animal- and vegetal-biomass degradation and applications in other industrial processes. The resilience of Act20 and its biotechnologic potential were thoroughly demonstrated in this work.

Movimientos oculares anormales en el lactante, la importancia de un adecuado diagnóstico diferencial / The importance of an adequate differential diagnosis: abnormal eye movements amongst infants

Los trastornos paroxísticos no epilépticos se definen como un conjunto de episodios, de aparición brusca, breves y generalmente recurrentes, cuyo mecanismo fisiopatológico consiste en una disfunción cerebral de diverso origen (hipóxico, psicológico…), no epiléptico. Son muy frecuentes en los lactantes debido a la inmadurez del sistema nervioso central, pudiendo confundirse con verdaderas crisis epilépticas. El conocimiento de estos y la realización de un adecuado diagnóstico diferencial es importante en el manejo de estos pacientes (AU)

Non-epileptic paroxysmal events are defined as a group of disorders characterized by sudden movements, in a short period of time, secondary to an abnormal loss of cerebral function (by hypoxia, psychiatric problems…), non-epileptic. They are very common in infants due to the immaturity of the central nervous system; so they can simulate seizures. It is extremely important for their management to know them and to make a correct differential diagnosis. (AU)

La región sudeste del Gran Buenos Aires frente a la pandemia Evaluación de la ampliación del sistema de salud en el marco de la COVID 19 / The Southeastern region of the Buenos Aires Province metropolitan area in the face of the pandemic: evaluation of the expansion of the health system in the framework of COVID-19

INTRODUCCIÓN: La región sudeste del Gran Buenos Aires (GBA) reformuló el sistema público de salud por la pandemia de COVID19. Entre las medidas que se tomaron, está la ampliación del número de camas mediante la construcción y puesta en marcha de tres hospitales. OBJETIVO: Evaluar el impacto de la ampliación del número de camas en los resultados de internación de los pacientes asistidos por los efectores públicos de salud durante el período de estudio (8 de abril de 2020 al 11 de septiembre de 2020). MÉTODOS: Estudio descriptivo a partir de información registrada en el Tablero COVID-19, software de gestión desarrollado por el equipo del Instituto del Cálculo de la Universidad de Buenos Aires, en el que se obtienen datos de cada paciente internado en la red de efectores de salud; se evalúan los resultados del efecto del aumento de la capacidad instalada. RESULTADOS: Se registraron 2 306 pacientes internados, de los cuales 266 (11,54%) requirieron internación en unidad de cuidados intensivos (UCO), 1 786 (77,4%) en cuidados intermedios y 254 (11%) pacientes en sala general. La media de edad fue de 50,63 y los pacientes de sexo masculino representaron el 55,5% del total. Se produjeron 253 muertes (10,97%), de las cuales el 64% fueron hombres. El 58,3% del total tenían enfermedades preexistentes, estos tienen un riesgo 90% más alto que quienes no las tenían. El promedio total de ocupación de camas en UCI fue del 40,7%, mientras que el de ocupación en cuidados intermedios fue de 61,5%. Sin los hospitales nuevos, 169 pacientes (9,46%) no hubieran tenido camas en cuidados intermedios y 31 pacientes (11,6%) no hubieran tenido cama en la UCI. DISCUSIÓN: El sistema de salud de la región sudeste del GBA se preparó de manera adecuada gracias a la ampliación del número de camas de internación.

Development and validation of a clinical score to estimate progression to severe or critical state in COVID-19 pneumonia hospitalized patients.

The prognosis of a patient with COVID-19 pneumonia is uncertain. Our objective was to establish a predictive model of disease progression to facilitate early decision-making. A retrospective study was performed of patients admitted with COVID-19 pneumonia, classified as severe (admission to the intensive care unit, mechanic invasive ventilation, or death) or non-severe. A predictive model based on clinical, laboratory, and radiological parameters was built. The probability of progression to severe disease was estimated by logistic regression analysis. Calibration and discrimination (receiver operating characteristics curves and AUC) were assessed to determine model performance. During the study period 1152 patients presented with SARS-CoV-2 infection, of whom 229 (19.9%) were admitted for pneumonia. During hospitalization, 51 (22.3%) progressed to severe disease, of whom 26 required ICU care (11.4); 17 (7.4%) underwent invasive mechanical ventilation, and 32 (14%) died of any cause. Five predictors determined within 24 h of admission were identified: Diabetes, Age, Lymphocyte count, SaO2, and pH (DALSH score). The prediction model showed a good clinical performance, including discrimination (AUC 0.87 CI 0.81, 0.92) and calibration (Brier score = 0.11). In total, 0%, 12%, and 50% of patients with severity risk scores ≤ 5%, 6-25%, and > 25% exhibited disease progression, respectively. A risk score based on five factors predicts disease progression and facilitates early decision-making according to prognosis.

Distribution of maternal lineages in hunter-gatherer societies of the southern coast of Tierra del Fuego, Argentina.

OBJECTIVES: The aim of this work is to explore the maternal genetic diversity of hunter-gatherers of the southern Tierra del Fuego, specifically the north coast of Beagle Channel, the Península Mitre, and Isla de los Estados through ancient mitochondrial DNA analysis. MATERIALS AND METHODS: The hypervariable regions 1 and 2 of the mitochondrial genome of five individuals from the north coast of Beagle Channel, six individuals from Península Mitre, and one individual from Isla de los Estados were analyzed. Through diversity statistics, Analysis of Molecular Variance (AMOVA), and Median Joining networks analyses, maternal relationships in the region were evaluated and phylogenetic similarities between ancient and contemporary populations of Tierra del Fuego were determined. RESULTS: The mitochondrial DNA lineages from the ancient individuals analyzed reveals the presence of subclades C1b and D1g. Pattern of decreasing genetic diversity toward the South is observed. The AMOVAs performed found no statistically significant differences between individuals of the north coast of Beagle Channel and Península Mitre-Isla de los Estados, and modern Yámana populations. Median joining network of haplotypes of clades C1 and D1g, show the same results. DISCUSSION: Ethnohistoric and ethnographic records of Península Mitre show that this region was occupied during the 19th century by Haush or Manekenk populations, although their biological, cultural, and subsistence characterization is unclear. We explore their maternal lineages and encounter low levels of genetic diversity and the absence of population differentiation with modern Yámana groups. We suggest that Península Mitre-Isla de los Estado was part of the same hunting and gathering populations as those of the Beagle Channel.

Bacterial Infection Disrupts Clock Gene Expression to Attenuate Immune Responses.

The circadian clock modulates immune responses in plants and animals; however, it is unclear how host-pathogen interactions affect the clock. Here we analyzed clock function in Arabidopsis thaliana mutants with defective immune responses and found that enhanced disease susceptibility 4 (eds4) displays alterations in several circadian rhythms. Mapping by sequencing revealed that EDS4 encodes the ortholog of NUCLEOPORIN 205, a core component of the inner ring of the nuclear pore complex (NPC). Consistent with the idea that the NPC specifically modulates clock function, we found a strong enrichment in core clock genes, as well as an increased nuclear to total mRNA accumulation, among genes that were differentially expressed in eds4 mutants. Interestingly, infection with Pseudomonas syringae in wild-type (WT) plants downregulated the expression of several morning core clock genes as early as 1 h post-infection, including all members of the NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED (LNK) gene family, and this effect was attenuated in eds4. Furthermore, lnk mutants were more susceptible than the WT to P. syringae infection. These results indicate that bacterial infection, acting in part through the NPC, alters core clock gene expression and/or mRNA accumulation in a way that favors bacterial growth and disease susceptibility.

Trastorno de conducta en el niño: en ocasiones se esconde algo más / Conduct disorder in child, sometimes something may be hidden

La epilepsia focal del lóbulo temporal se presenta en la edad pediátrica con manifestaciones clínicas heterogéneas, incluyéndose entre ellas las alteraciones sensoperceptivas y los trastornos de la conducta, pudiendo llegar a ser manejados inicialmente como pacientes psiquiátricos, lo que retrasa el diagnóstico y el inicio del tratamiento

Temporal lobe epilepsy in childhood may present with a wide spectrum of symptoms, including behavioral changes and sensory symptoms. This situation can seem like a psychiatric pathology and can delay the diagnosis and initiation of treatment

A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI).

BACKGROUND: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. OBJECTIVE: To characterize the molecular defect in a patient with short stature and partial GHI. PATIENT AND METHODS: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. RESULTS: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. CONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

Improvement of alfalfa forage quality and management through the down-regulation of MsFTa1.

Alfalfa (Medicago sativa L.) is one of the most important forage crops worldwide. As a perennial, alfalfa is cut several times each year. Farmers face a dilemma: if cut earlier, forage nutritive value is much higher but regrowth is affected and the longevity of the stand is severely compromised. On the other hand, if alfalfa is cut later at full flower, stands persist longer and more biomass may be harvested, but the nutritive value diminishes. Alfalfa is a strict long-day plant. We reasoned that by manipulating the response to photoperiod, we could delay flowering to improve forage quality and widen each harvesting window, facilitating management. With this aim, we functionally characterized the FLOWERING LOCUS T family of genes, represented by five members: MsFTa1, MsFTa2, MsFTb1, MsFTb2 and MsFTc. The expression of MsFTa1 correlated with photoperiodic flowering and its down-regulation led to severe delayed flowering. Altogether, with late flowering, low expression of MsFTa1 led to changes in plant architecture resulting in increased leaf to stem biomass ratios and forage digestibility. By manipulating photoperiodic flowering, we were able to improve the quality of alfalfa forage and management, which may allow farmers to cut alfalfa of high nutritive value without compromising stand persistence.

Chitosan-Hydroxyapatite Scaffold for Tissue Engineering in Experimental Lumbar Laminectomy and Posterolateral Spinal Fusion in Wistar Rats.

STUDY DESIGN: Experimental study with an animal model. PURPOSE: To evaluate the role of a chitosan and hydroxyapatite composite for spinal fusion in a lumbar experimental model based on regenerative tissue engineering principles. OVERVIEW OF LITERATURE: Chitosan and hydroxyapatite represent an alternative biodegradable implant material for tissue engineering and regeneration. The combination of chitosan and hydroxyapatite in a 20:80 ratio could potentiate their individual properties as an implantable composite for experimental laminectomy. METHODS: Phase I: design and synthesis of a porous composite scaffold composed of chitosan-hydroxyapatite using a freeze drying technique. Phase II: experimental microsurgical lumbar laminectomy at L5. A total of 35 Wistar rats were categorized into three experimental groups: control (laminectomy alone), experimental (laminectomy with implant), and reference (intact spine) (n=5 per group). Postoperative structural and functional evaluations were performed using computed tomography scans. In addition, radiologic, clinical, histological, and immunohistochemical microstructures were evaluated. RESULTS: At the laminectomy site, the composite implant induced bone regeneration, which was observed in the axial reconstruction of the rat lumbar spine in all cases. Biomechanical changes in the lumbar spine were observed by radiology in both groups after the surgery. The posterolateral space was covered by a bone structure in the treated spine, a condition not seen in the control group. The range of motion was 7.662°±0.81° in the scaffold group versus 20.72°±3.47° in the control group. Histological findings revealed qualitatively more bone tissue formation in the implant group. CONCLUSIONS: A composite of chitosan-hydroxyapatite at a 20:80 ratio induced bone formation after experimental laminectomy in rats and led to spinal fusion, which was assessed by radiology and biomechanical tests. No functional complications in posture or walking were observed at 90 days post-surgery, despite biomechanical changes in the spine.