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The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
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Adenosina Desaminasa/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Proteínas de Unión al ARN/genética , Convulsiones/genética , Alelos , Empalme Alternativo/genética , Niño , Preescolar , Células HEK293 , Humanos , Masculino , Empalme del ARN/genéticaRESUMEN
BACKGROUND: Various mammalian species emit ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interactions. USVs are usually analyzed by manual or semi-automated methodologies that categorize discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders the effective use of USVs as a readout for high-throughput analysis of behavioral changes in animals. RESULTS: Here we present a novel automated open-source tool that utilizes a different approach towards USV analysis, termed TrackUSF. To validate TrackUSF, we analyzed calls from different animal species, namely mice, rats, and bats, recorded in various settings and compared the results with a manual analysis by a trained observer. We found that TrackUSF detected the majority of USVs, with less than 1% of false-positive detections. We then employed TrackUSF to analyze social vocalizations in Shank3-deficient rats, a rat model of autism, and revealed that these vocalizations exhibit a spectrum of deviations from appetitive calls towards aversive calls. CONCLUSIONS: TrackUSF is a simple and easy-to-use system that may be used for a high-throughput comparison of ultrasonic vocalizations between groups of animals of any kind in any setting, with no prior assumptions.
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Trastorno Autístico , Ultrasonido , Animales , Emociones , Mamíferos , Ratones , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso , Ratas , Vocalización AnimalRESUMEN
BACKGROUND: Abdominal pathology in pregnant patients is a frequent challenge for emergency department physicians. Ultrasound is the imaging modality of choice but is inconclusive in approximately one-third of cases. Magnetic resonance imaging (MRI) is becoming increasingly available, even in acute settings. Multiple studies have defined the sensitivity and specificity of MRI in this population. OBJECTIVES: To evaluate the use of MRI findings in pregnant patients presenting with acute abdominal complaints to the emergency department. METHODS: This retrospective cohort study was conducted at a single institution. Data were collected on pregnant patients who underwent an MRI for acute abdominal complaints between 2010 and 2019 at a university center. Patient demographics, diagnosis at admission, ultrasound and MRI findings, and discharge diagnosis were recorded and evaluated. RESULTS: In total, 203 pregnant patients underwent an MRI for acute abdominal complaints during the study period. MRI was found without pathology in 138 cases (68%). In 65 cases (32%), the MRI showed findings that could explain the patient's clinical presentation. Patients presenting with long-standing abdominal pain (> 24 hours), fever, leukocytosis, or elevated C-reactive protein values were at a significantly increased risk of having an acute pathology. In 46 patients (22.6%), MRI findings changed the primary diagnosis and management while in 45 patients (22.1%) MRI findings improved characterization of the suspected pathology. CONCLUSIONS: MRI is helpful when clinical and sonographic findings are inconclusive, leading to changes in patient management in more than one-fifth of patients.
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Dolor Abdominal , Servicio de Urgencia en Hospital , Femenino , Embarazo , Humanos , Estudios Retrospectivos , Dolor Abdominal/etiología , Fiebre , Imagen por Resonancia MagnéticaRESUMEN
PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type ß-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.
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Trastorno del Espectro Autista , Epilepsia , Discapacidad Intelectual , Convulsiones Febriles , Niño , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Trastorno del Espectro Autista/genética , Discapacidades del Desarrollo , Epilepsia/genética , Discapacidad Intelectual/genética , Mutación Missense/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
In this work, we theoretically and experimentally demonstrate the possibility to create an image of an opaque object using a few-photon thermal optical field. We utilize the quadrature-noise shadow imaging (QSI) technique that detects the changes in the quadrature-noise statistics of the probe beam after its interaction with an object. We show that such a thermal QSI scheme has an advantage over the classical differential imaging when the effect of dark counts is considered. At the same time, the easy availability of thermal sources for any wavelength makes the method practical for broad range of applications, not accessible with, e.g., quantum squeezed light. As a proof of principle, we implement this scheme by two different light sources: a pseudo-thermal beam generated by rotating ground glass (RGG) method and a thermal beam generated by four-wave mixing (FWM) method. The RGG method shows simplicity and robustness of QSI scheme while the FWM method validates theoretical signal-to-noise ratio predictions. Finally, we demonstrate low-light imaging abilities with QSI by imaging a biological specimen on a CCD camera, detecting as low as 0.03 photons on average per pixel per 1.7 µs exposure.
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Experimental limitations such as optical loss and noise have prevented entanglement-enhanced measurements from demonstrating a significant quantum advantage in sensitivity. Holland-Burnett entangled states can mitigate these limitations and still present a quantum advantage in sensitivity. Here we model a fiber-based Mach-Zehnder interferometer with internal loss, detector efficiency, and external phase noise and without pure entanglement. This model features a practical fiber source that transforms the two-mode squeezed vacuum (TMSV) into Holland-Burnett entangled states. We predict that a phase sensitivity 28% beyond the shot noise limit is feasible with current technology. Simultaneously, a TMSV source can provide about 25 times more photon flux than other entangled sources. This system will make fiber-based quantum-enhanced sensing accessible and practical for remote sensing and probing photosensitive materials.
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We combine single-pixel imaging and homodyne detection to perform full object recovery (phase and amplitude). Our method does not require any prior information about the object or the illuminating fields. As a demonstration, we reconstruct the optical properties of several semi-transparent objects and find that the reconstructed complex transmission has a phase precision of 0.02 radians and a relative amplitude precision of 0.01.
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The solubility limit of carbon in α-Al2O3 (alumina) equilibrated at 1,600°C under He in a graphite furnace was measured by wavelength-dispersive spectroscopy. Undoped alumina and alumina containing carbon at a concentration resulting in the precipitation of a second phase were prepared and equilibrated at 1,600°C. The undoped alumina was used to quantify the amount of carbon deposited on the surface of samples because of hydrocarbon contamination in the electron microscope, and this background level was removed from the signal measured from carbon-doped samples. The solubility limit of carbon in alumina was found to be 5,300 ± 390 at. ppm, and it is believed that carbon substitutes oxygen as an anion and is charge-compensated by oxygen vacancies. Doping alumina with carbon at concentrations below the solubility limit does not impede densification and reduces grain growth. Doping above the solubility limit hinders densification during sintering.
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OBJECTIVES: We examined patterns in alliance development in cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) compared to attention bias modification (ABM). We focused on the occurrence of sawtooth patterns (increases within- and decreases between-sessions) and sudden gains and their association with outcome. METHODS: Clients received CBT (n = 33) or ABM (n = 17). Client-rated alliance was measured before and after each session. Self-reported and clinician-rated anxiety were measured weekly and monthly, respectively. RESULTS: The alliance increased in CBT in a sawtooth pattern and did not change in ABM. When examining individual clients, sawtooths were more common in CBT (61% clients) than in ABM (6%) and predicted worse outcome in CBT. Sudden gains were equally frequent (CBT, 18%; ABM, 18%) and did not predict outcome. CONCLUSION: The alliance in CBT is dynamic and important for outcome. Sawtooths are common in CBT and may mark worse outcome.
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Sesgo Atencional , Terapia Cognitivo-Conductual , Fobia Social , Ansiedad , Trastornos de Ansiedad/terapia , Humanos , Fobia Social/terapia , Resultado del TratamientoRESUMEN
The problem of simulating complex quantum processes on classical computers gave rise to the field of quantum simulations. Quantum simulators solve problems, such as boson sampling, where classical counterparts fail. In another field of physics, the unification of general relativity and quantum theory is one of the greatest challenges of our time. One leading approach is loop quantum gravity (LQG). Here, we connect these two fields and design a linear-optical simulator such that the evolution of the optical quantum gates simulates the spin-foam amplitudes of LQG. It has been shown that computing transition amplitudes in simple quantum field theories falls into the bounded-error quantum polynomial time class, which strongly suggests that computing transition amplitudes of LQG are classically intractable. Therefore, these amplitudes are efficiently computable with universal quantum computers, which are, alas, possibly decades away. We propose here an alternative special-purpose linear-optical quantum computer that can be implemented using current technologies. This machine is capable of efficiently computing these quantities. This work opens a new way to relate quantum gravity to quantum information and will expand our understanding of the theory.
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Objective: The aim of the current study was to examine changes in the therapeutic alliance and its role as a mediator of treatment outcome in cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) compared to attention bias modification (ABM). Method: Patients were randomized to 16-20 sessions of CBT (n = 33) or 8 sessions of ABM (n = 17). Patient-rated alliance and self-reported social anxiety were measured weekly and evaluator-rated social anxiety was measured monthly. Results: Early alliance predicted greater subsequent anxiety reduction in CBT but not in ABM. The alliance increased and weekly improvements in alliance predicted weekly contemporaneous and subsequent decreases in anxiety only in CBT. Decreases in anxiety did not predict subsequent improvements in alliance. Both treatments were effective in reducing anxiety, but treatment effects were mediated by stronger early alliance and stronger cross-lagged effects of alliance on outcome in CBT compared to ABM. Conclusions: The results highlight the importance of the alliance in CBT for SAD. Further studies should examine the role of alliance alongside additional mediators to better understand differential mechanisms in CBT and ABM.
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Sesgo Atencional , Terapia Cognitivo-Conductual , Fobia Social , Alianza Terapéutica , Trastornos de Ansiedad/terapia , Humanos , Fobia Social/terapia , Resultado del TratamientoRESUMEN
PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Ensamble y Desensamble de Cromatina/genética , Discapacidades del Desarrollo/genética , Femenino , Estudios de Asociación Genética , Genotipo , Pérdida Auditiva/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Megalencefalia/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Anomalías Musculoesqueléticas/genética , Mutación Missense/genética , Fenotipo , Síndrome , Factores de Transcripción/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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We present a technique for squeezed light detection based on direct imaging of the displaced-squeezed-vacuum state using a CCD camera. We show that the squeezing parameter can be accurately estimated using only the first two moments of the recorded pixel-to-pixel photon fluctuation statistics, with accuracy that rivals that of the standard squeezing detection methods such as a balanced homodyne detection. Finally, we numerically simulate the camera operation, reproducing the noisy experimental results with low signal samplings and confirming the theory with high signal samplings.
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Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.
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Discapacidad Intelectual/genética , Megalencefalia/genética , Convulsiones/genética , Quinasas p21 Activadas/genética , Actinas/metabolismo , Adolescente , Trastorno Autístico/genética , Niño , Preescolar , Femenino , GTP Fosfohidrolasas/metabolismo , Humanos , Discapacidad Intelectual/psicología , Masculino , Megalencefalia/psicología , Modelos Moleculares , Mutación Missense/genética , Fosforilación , Convulsiones/psicología , Transducción de Señal/genética , Secuenciación del Exoma , Adulto Joven , Proteína de Unión al GTP cdc42/metabolismo , Quinasas p21 Activadas/química , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2ß, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.
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Adenosina Trifosfato/metabolismo , Autoantígenos/genética , Ensamble y Desensamble de Cromatina/genética , Discapacidad Intelectual/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Mutación Missense/genética , Anomalías Múltiples/genética , Adolescente , Animales , Núcleo Celular/metabolismo , Niño , Preescolar , ADN Helicasas/genética , Discapacidades del Desarrollo/genética , Exoma/genética , Cara/anomalías , Femenino , Deformidades Congénitas de la Mano/genética , Pérdida Auditiva/genética , Histona Desacetilasa 1/metabolismo , Humanos , Masculino , Megalencefalia/genética , Ratones , Micrognatismo/genética , Cuello/anomalías , Proteínas Nucleares/genética , Síndrome , Factores de Transcripción/genéticaRESUMEN
We present a technique that improves the signal-to-noise-ratio (SNR) of range-finding, sensing, and other light-detection applications. The technique filters out low photon numbers using photon-number-resolving detectors. This technique has no classical analog and cannot be done with classical detectors. We investigate the properties of our technique and show under what conditions the scheme surpasses the classical SNR. Finally, we simulate the operation of a rangefinder, showing improvement with a low number of signal samplings and confirming the theory with a high number of signal samplings.
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BACKGROUND: C-reactive protein (CRP) blood level is associated with clinical outcomes of several diseases. However, the independent predictive role of CRP in the heterogeneous population of patients admitted to internal medicine wards is not known. OBJECTIVES: To determine whether single CRP levels at admission independently predicts clinical outcome and flow of patients in general medicine wards. METHODS: This study comprised 275 patients (50.5% female) with a mean age of 68.25 ± 17.0 years, hospitalized with acute disease in a general internal medicine ward. The association between admission CRP levels and clinical outcomes including mortality, the need for mechanical ventilation, duration of hospitalization, and re-admission within 6 months was determined. RESULTS: A significant association was found between CRP increments of 80 mg/L and risk for the major clinical outcomes measured. The mortality odds ratio (OR) was 1.89 (95% confidence interval (95%CI, 1.37-2.61, P < 0.001), mechanical ventilation OR 1.67 (95%CI, 1.10-2.34, P = 0.006), re-admission within 6 months OR 2.29 (95%CI, 1.66-3.15 P < 0.001), and prolonged hospitalization >7 days OR 2.09 (95%CI, 1.59-2.74, P < 0.001). Lower increments of10 mg/L in CRP levels were associated with these outcomes although with lower ORs. Using a stepwise regression model for admission CRP levels resulted in area under the receiver operating characteristics curves between 0.70 and 0.76 for these outcomes. CONCLUSIONS: A single admission CRP blood level is independently associated with major parameters of clinical outcomes in acute care patients hospitalized in internal medicine wards.
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Proteína C-Reactiva/análisis , Hospitalización/estadística & datos numéricos , Medicina Interna/métodos , Evaluación del Resultado de la Atención al Paciente , Enfermedad Aguda , Adulto , Femenino , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Admisión del Paciente/estadística & datos numéricos , Readmisión del Paciente/estadística & datos numéricos , Valor Predictivo de las Pruebas , Pronóstico , Respiración Artificial/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.455_457del) leading to the loss of one amino acid (p.Thr152del). The third individual was heterozygous for a missense mutation (c.460G>A) which introduces an amino acid change from glycine to serine (p.Gly154Ser). In agreement with animal models, the present data suggest that these mutations severely impair the correct functioning of this potassium channel. Overall, these results establish KPLBS as a channelopathy and suggest that KCNJ6 (GIRK2) could also be a candidate gene for other lipodystrophies. We hope that these results will prompt investigations in this unexplored class of inwardly rectifying K(+) channels.
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Anomalías Múltiples/genética , Discapacidades del Desarrollo/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Discapacidad Intelectual/genética , Modelos Moleculares , Anomalías Múltiples/patología , Secuencia de Bases , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Cartilla de ADN/genética , Discapacidades del Desarrollo/patología , Exoma/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/química , Humanos , Discapacidad Intelectual/patología , Masculino , Datos de Secuencia Molecular , Mutación Missense/genética , Linaje , Análisis de Secuencia de ADN , Eliminación de Secuencia/genética , SíndromeRESUMEN
BACKGROUND: High levels of circulating GLP-1 are associated with severity of sepsis in critically ill nondiabetic patients. Whether patients with type 2 diabetes (T2D) display different activation of the endogenous GLP-1 system during sepsis and whether it is affected by diabetes-related metabolic parameters are not known. METHODS: Serum levels of GLP-1 (total and active forms) and its inhibitor enzyme sDPP-4 were determined by ELISA on admission and after 2 to 4 days in 37 sepsis patients with (n = 13) and without T2D (n = 24) and compared to normal healthy controls (n = 25). Correlations between GLP-1 system activation and clinical, inflammatory, and diabetes-related metabolic parameters were performed. RESULTS: A 5-fold (P < .001) and 2-fold (P < .05) increase in active and total GLP-1 levels, respectively, were found on admission as compared to controls. At 2 to 4 days from admission, the level of active GLP-1 forms in surviving patients were decreased significantly (P < .005), and positively correlated with inflammatory marker CRP (r = 0.33, P = .05). T2D survivors displayed a similar but more enhanced pattern of GLP-1 response than nondiabetic survivors. Nonsurvivors demonstrate an early extreme increase of both total and active GLP-1 forms, 9.5-fold and 5-fold, respectively (P < .05). The initial and late levels of circulating GLP-1 inhibitory enzyme sDPP-4 were twice lower in all studied groups (P < .001), compared with healthy controls. CONCLUSIONS: Taken together, these data indicate that endogenous GLP-1 system is activated during sepsis. Patients with T2D display an enhanced and prolonged activation as compared to nondiabetic patients. Extreme early increased GLP-1 levels during sepsis indicate poor prognosis.