Aim
To determine the validity of the proposed clinical diagnostic criteria for anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis in paediatric patients.
Method
The diagnostic criteria for ...anti‐NMDAR encephalitis proposed by Graus et al. (2016) use clinical features and conventional investigations to facilitate early immunotherapy before antibody status is available. The criteria are satisfied if patients develop four out of six symptom groups within 3 months, together with at least one abnormal investigation (electroencephalography/cerebrospinal fluid) and reasonable exclusion of other disorders. We evaluated the validity of the criteria using a retrospective cohort of paediatric patients with encephalitis. Twenty‐nine patients with anti‐NMDAR encephalitis and 74 comparison children with encephalitis were included.
Results
As expected, the percentage of patients with anti‐NMDAR encephalitis who fulfilled the clinical criteria increased over time. During the hospital inpatient admission, most patients (26/29, 90%) with anti‐NMDAR encephalitis fulfilled the criteria, significantly more than the comparison group (3/74, 4%) (p<0.001). The median time of fulfilling the criteria in patients with anti‐NMDAR encephalitis was 2 weeks from first symptom onset (range 1–6). The sensitivity of the criteria was 90% (95% confidence interval 73–98) and the specificity was 96% (95% confidence interval 89–99).
Interpretation
The proposed diagnostic criteria for anti‐NMDAR encephalitis have good sensitivity and specificity. Incomplete criteria do not exclude the diagnosis.
What this paper adds
The proposed clinical diagnostic criteria for anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients.
The median time of fulfilling the criteria in patients with anti‐NMDAR was 2 weeks from first symptom onset.
Resumen
Alta sensibilidad y especificidad en los criterios diagnósticos clínicos propuestos para la encefalitis anti receptores de N‐metil‐D‐aspartato
Objetivo
Determinar la validez de los criterios diagnósticos clínicos propuestos para la encefalitis anti receptores de N‐metil‐D‐aspartato (NMDAR) en pacientes pediátricos.
Métodos
Los criterios diagnósticos para la encefalitis anti NMDAR propuestos por Graus et. al. (2016) utiliza características clínicas y estudios convencionales para facilitar la utilización temprana de inmunoterapia, antes de que los niveles de anticuerpos estén disponibles. Los criterios son cumplidos si el paciente desarrolla cuatro de los seis síntomas de los criterios diagnósticos propuestos, junto con al menos un estudio auxiliar anormal (electroencefalograma/líquido cefalorraquídeo) y una exclusión racional de otras enfermedades. En este estudio, hemos evaluado la validez de los criterios usando una cohorte retrospectiva de pacientes pediátricos con encefalitis. Veinte y nueve pacientes con encefalitis anti receptores de NDMAR fueron comparados con 74 niños con encefalitis de otras causas (grupo control).
Resultados
Como se esperaba, el porcentaje de pacientes con encefalitis anti‐NMDAR que cumplían los criterios diagnósticos aumentaron con el tiempo. Durante la hospitalización, la mayoría de los pacientes (26 de 29, 90%) cumplieron los criterios de encefalitis anti‐NMDAR, significativamente mayor que el grupo control (3 de 74, 4%) (p<0.001). El promedio de tiempo en el cual los pacientes cumplieron con los criterios fue de 2 semanas a partir de la aparición del primer síntoma (rango 1–6). La sensibilidad de los criterios fue de 90% (95% intervalo de confianza 73–98) y la especificidad fue de 96% (95% intervalo de confianza de 89–99).
Interpretación
Los criterios diagnósticos clínicos propuestos para la encefalitis anti‐NMDAR tienen buena sensibilidad y especificidad. Es importante tener en cuenta, que no reunir todos los criterios no excluye el diagnóstico.
Resumo
Alta sensibilidade e especificidade em critérios de diagnóstico clínico propostos para encefalite anti‐receptor N‐metil‐D‐aspartato
Objetivo
Determinar a validade dos critérios de diagnóstico clínico para a encefalite anti‐receptor N‐metil‐D‐aspartato (NMDAR) em pacientes pediátricos.
Método
Os critérios para diagnóstico da encefalite anti‐NMDAR propostos por Graus et al. (2016) usam aspectos clínicos e investigação convencional para facilitar a imunoterapia precoce antes que o status dos anticorpos esteja disponível. Os critérios são satisfeitos se o paciente desenvolver quatro em seis grupos de sintomas dentro de 3 meses, juntamente com pelo menos uma investigação anormal (eletroencefalografia/fluido cérebro‐espinahal) e exclusão razoável de outras desordens. Nós avaliamos a validade dos critérios usando uma coorte retrospectiva de pacientes pediátricos com encefalite. Vinte e nove pacientes com encefalite anti‐NMDAR e 74 crianças de um grupo comparação com encefalite foram incluídos.
Resultados
Como esperado, a porcentagem de pacientes com encefalite anti‐NMDAR que preencheram os critérios clínicos aumentou com o tempo. Durante a admissão para internação hospitalar, a maioria dos pacientes (26 de 29, 90%) com encefalite anti‐NMDAR preencheu os critérios, significantemente mais do que no grupo comparação (3 de 74, 4%) (p<0.001). O tempo mediano para atingir os critérios nos pacientes com encefalite anti‐NMDAR foi 2 semanas após o início dos primeiros sintomas (interval 1‐6). A sensibilidade dos critérios foi de 90% (intervalo de confiança a 95% 73–98) e a especificidade 96% (intervalo de confiança a 95% 89–99).
Interpretação
Os critérios propostos para diagnóstico da encefalite anti‐NMDAR têm boa sensibilidade e especificidade. Critérios incompletos não excluem o diagnóstico.
What this paper adds
The proposed clinical diagnostic criteria for anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients.
The median time of fulfilling the criteria in patients with anti‐NMDAR was 2 weeks from first symptom onset.
This article is commented on by Day and Reynolds on pages 1211–1212 of this issue.
This article's has been translated into Spanish and Portuguese.
Follow the links from the to view the translations.
Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory ...FLT3-ITD+ AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.
•This study investigates the effects of psychosocial factors on four types of purchase intentions of financial products.•Retirement goal clarity partially mediates the effects of psychosocial factors ...on the purchase intention of annuity products.•The mediation of retirement goal clarity in the social norms-purchase intention relation is stronger among younger workers.
Previous research on retirement planning largely focuses on the general tendency to save for retirement. By integrating two theoretical models, namely, interdisciplinary psycho-motivation model and the theory of reasoned action, the present study aims to advance the previous work to examine the effects of social (social norms and social support) and psychological (future time perspective and financial literacy) factors on behavioral intentions for purchasing specific financial products for retirement. Cross-sectional data were obtained from 598 Hong Kong Chinese working adults of a wide age range. Mediation analysis showed that retirement goal clarity could partly account for the effects of financial literacy, social norms, and social support on the purchase intentions of both annuity and other saving products in the commercial market. Additional moderated mediation analyses revealed a stronger mediating effect of retirement goal clarity on the relationship between social norms and annuity products in younger workers than that in older workers. Findings of this study provide valuable insights into the roles of retirement goal clarity and age in the purchase intentions of financial products for retirement. The examination of the newly launched tax-deductible products in younger and older workers further discloses these products are relatively more attractive to younger individuals as a means of financial retirement planning.
Epidemiological studies, animal models, and case–control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), ...Tourette syndrome, and obsessive–compulsive disorder (OCD). We report eight children (mean age 6y 6mo range 4–15y; six males and two females) referred over a 2‐year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD n=6, tics n=5, and/or psychosis n=1), associated with an autistic or global regression. Four children had a pre‐existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing‐remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli.
What this paper adds
Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring.
Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.
Resumen
Autoinmunidad materna tiroidea asociada con trastornos neuropsiquiátricos de inicio agudo y regresión global en la descendencia
Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses rango 4‐15 años; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC n = 6, tics n = 5 y / o psicosis n = 1), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes.
Resumo
Autoimunidade tireóide materna associada com desordens neuropsiquiátricas de início agudo e regressão global na prole
Estudos epidemiológicos, modelos animais, e estudos de caso‐controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m variação 4–15a; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto‐imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC n=6, tiques n=5, e/ou psicose n=1), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré‐existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência‐remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse.
What this paper adds
Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring.
Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.
This article is commented on by Scola on page 866 of this issue.
This article's has been translated into Spanish and Portuguese.
Follow the links from the to view the translations.
The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and ...cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.
IMPORTANCE: Unrecognized obstructive sleep apnea increases cardiovascular risks in the general population, but whether obstructive sleep apnea poses a similar risk in the perioperative period remains ...uncertain. OBJECTIVES: To determine the association between obstructive sleep apnea and 30-day risk of cardiovascular complications after major noncardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study involving adult at-risk patients without prior diagnosis of sleep apnea and undergoing major noncardiac surgery from 8 hospitals in 5 countries between January 2012 and July 2017, with follow-up until August 2017. Postoperative monitoring included nocturnal pulse oximetry and measurement of cardiac troponin concentrations. EXPOSURES: Obstructive sleep apnea was classified as mild (respiratory event index REI 5-14.9 events/h), moderate (REI 15-30), and severe (REI >30), based on preoperative portable sleep monitoring. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, and stroke within 30 days of surgery. Proportional-hazards analysis was used to determine the association between obstructive sleep apnea and postoperative cardiovascular complications. RESULTS: Among a total of 1364 patients recruited for the study, 1218 patients (mean age, 67 SD, 9 years; 40.2% women) were included in the analyses. At 30 days after surgery, rates of the primary outcome were 30.1% (41/136) for patients with severe OSA, 22.1% (52/235) for patients with moderate OSA, 19.0% (86/452) for patients with mild OSA, and 14.2% (56/395) for patients with no OSA. OSA was associated with higher risk for the primary outcome (adjusted hazard ratio HR, 1.49 95% CI, 1.19-2.01; P = .01); however, the association was significant only among patients with severe OSA (adjusted HR, 2.23 95% CI, 1.49-3.34; P = .001) and not among those with moderate OSA (adjusted HR, 1.47 95% CI, 0.98-2.09; P = .07) or mild OSA (adjusted HR, 1.36 95% CI, 0.97-1.91; P = .08) (P = .01 for interaction). The mean cumulative duration of oxyhemoglobin desaturation less than 80% during the first 3 postoperative nights in patients with cardiovascular complications (23.1 95% CI, 15.5-27.7 minutes) was longer than in those without (10.2 95% CI, 7.8-10.9 minutes) (P < .001). No significant interaction effects on perioperative outcomes were observed with type of anesthesia, use of postoperative opioids, and supplemental oxygen therapy. CONCLUSIONS AND RELEVANCE: Among at-risk adults undergoing major noncardiac surgery, unrecognized severe obstructive sleep apnea was significantly associated with increased risk of 30-day postoperative cardiovascular complications. Further research would be needed to assess whether interventions can modify this risk.
Abstract
To evaluate the impact of elevator travel on intraocular pressure after vitreoretinal surgery with gas tamponade. Patients undergoing pars plana vitreoretinal surgery with and without gas ...insertion were recruited on post-operative day 1. All intraocular pressures were measured three times by Tono-Pen AVIA (Reichert, USA) on the fourth floor and, after rapid ascent in an elevator, on the 12th floor of the hospital. All patients were observed and asked for any symptoms of pain or nausea for at least 15 min. In this study, 54 patients were recruited. Twenty-seven patients underwent vitreoretinal procedures with gas insertion, while 27 patients without gas insertion acted as controls. The mean age of patients was 60.9 years. The mean changes in intraocular pressure of the patients with gas insertion (+ 1.39 mmHg) were greater than those without gas insertion (− 0.43 mmHg) and statistically significantly different (95% CI 1.17–2.48,
P
< 0.0001). Patients undergoing vitreoretinal surgery with gas insertion had statistically significant intraocular pressure rise even with 8-floor ascent in the immediate post-operative period. Further studies are needed to evaluate the change in intraocular pressure with a larger range of altitudes and different gases.
Intrathecal baclofen pump associated central nervous system (CNS) infection and meningitis is a rare but serious complication and may have dire consequences. Due to bacterial biofilm formation, the ...optimal treatment strategy is usually for removal of the pump, followed by systemic antibiotics for treatment of local and CNS infection. We describe this case of a patient with recurrent Staphylococcus aureus pump site empyema and meningitis leading to status dystonicus, who was successfully managed with radical debridement and intrareservoir baclofen-vancomycin co-infusion.
We retrospectively report a case of infected intrathecal baclofen pump with meningitis and provide a full review of literature.
To the best of our knowledge, this is the first reported case of intrathecal baclofen (ITB)-associated pump site empyema and meningitis successfully treated with this technique. In selected cases where surgical explantation is deemed not feasible, this method can provide clinicians with an additional option for pump salvage and retention, while eradicating CNS infection and maintaining optimal control of spasticity and dystonia.
A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell ...proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell-specific
knockout (
βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult
βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of
in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.
Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with ...intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.
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