Antiplatelet antibody predicts platelet desialylation and apoptosis in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a bleeding disorder caused by dysregulated B- and T- cell functions, which lead to platelet destruction. A well-recognized mechanism of ITP pathogenesis involves anti-platelet and anti-megakaryocyte antibodies recognizing membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa. In addition to the current view of phagocytosis of the opsonised platelets by splenic and hepatic macrophages via their Fc γ receptors, antibodyinduced platelet desialylation and apoptosis have also been reported to contribute to ITP pathogenesis. Nevertheless, the relationship between the specific thrombocytopenic mechanisms and various types of anti-platelet antibodies has not been established. In order to ascertain such association, we used sera from 61 ITP patients and assessed the capacity of anti-platelet antibodies to induce neuraminidase 1 (NEU1) surface expression, RCA-1 lectin binding and loss of mitochondrial inner membrane potential on donors' platelets. Sera from ITP patients with detectable antibodies caused significant platelet desialylation and apoptosis. Anti-GPIIb/IIIa antibodies appeared more capable of causing NEU1 surface translocation while anti-GPIb/IX complex antibodies resulted in a higher degree of platelet apoptosis. In ITP patients with anti-GPIIb/IIIa antibodies, both desialylation and apoptosis were dependent on FcγRIIa signaling rather than platelet activation. Finally, we confirmed in a murine model of ITP that destruction of human platelets induced by anti-GPIIb/IIIa antibodies can be prevented with the NEU1 inhibitor oseltamivir. A collaborative clinical trial is warranted to investigate the utility of oseltamivir in the treatment of ITP.

Autism spectrum disorder screening in Chinese-language preschools.

LAY ABSTRACT: The 13-item Classroom Observation Scale is an autism spectrum disorder screening tool for teachers and non-clinically trained observers to make real-time observation of children's peer interaction (or the lack thereof) in regular preschool classrooms. The Classroom Observation Scale was originally developed in English and validated with ethnically diverse preschoolers at English-speaking international schools serving families from middle to middle-upper socioeconomic backgrounds in Hong Kong. These private schools can usually afford a higher teacher-student ratio, which is not typical for most preschools. This study, therefore, investigated whether the Classroom Observation Scale is ecologically valid when used by Chinese teachers with teacher-student ratios typically found in less-resourced preschools. We found that the Classroom Observation Scale reliably helped observers with little or no clinical training-research assistants with just a few hours of Classroom Observation Scale training and preschool teachers with an hour of briefing-to identify children in their first year of Chinese-language preschool who were more likely than their peers to have autism spectrum disorder. Reliability estimates of Classroom Observation Scale-Teacher and Classroom Observation Scale-Researcher in this study were comparable to those for the original English Classroom Observation Scale. Our results provided further evidence on the versatility and ecological validity of the Classroom Observation Scale for use by preschool teachers and non-clinically trained observers in the early identification of children with autism spectrum disorder in community settings.

Autism spectrum disorder screening in preschools.

LAY ABSTRACT: With professional training and regular opportunities to observe children interacting with their peers, preschool teachers are in a good position to notice children's autism spectrum disorder symptomatology. Yet even when a preschool teacher suspects that a child may have autism spectrum disorder, fear of false alarm may hold the teacher back from alerting the parents, let alone suggesting them to consider clinical assessment for the child. A valid and convenient screening tool can help preschool teachers make more informed and hence more confident judgment. We set out to develop a screening tool that capitalizes on peer interaction as a naturalistic "stress test" to identify children more likely than their peers to have autism spectrum disorder. A total of 304 3- to 4-year-olds were observed at school with an 84-item preliminary checklist; data-driven item reduction yielded a 13-item Classroom Observation Scale. The Classroom Observation Scale scores correlated significantly with Autism Diagnostic Observation Schedule-2 scores. To validate the scale, another 322 2- to 4-year-olds were screened using the Classroom Observation Scale. The screen-positive children and randomly selected typically developing peers were assessed for autism spectrum disorder 1.5 years later. The Classroom Observation Scale as used by teachers and researchers near preschool onset predicted autism spectrum disorder diagnoses 1.5 years later. This user-friendly 13-item Classroom Observation Scale enables teachers and healthcare workers with little or no clinical training to identify, with reliable and valid results, preschoolers more likely than their peers to have autism spectrum disorder.

The Hong Kong Survey on the Epidemiology of Trauma Exposure and Posttraumatic Stress Disorder.

This study examined the epidemiology of trauma exposure (TE) and posttraumatic stress disorder (PTSD) among community-dwelling Chinese adults in Hong Kong. Multistage stratification sampling design was used, and 5,377 participants were included. In Phase 1, TE, probable PTSD (p-PTSD), and psychiatric comorbid conditions were examined. In Phase 2, the Structured Clinical Interview for the DSM-IV (SCID-I) was used to determine the weighted diagnostic prevalence of lifetime full PTSD. Disability level and health service utilization were studied. The findings showed that the weighted prevalence of TE was 64.8%, and increased to 88.7% when indirect TE types were included, with transportation accidents (50.8%) reported as the most common TE. The prevalence of current p-PTSD among participants with TE was 2.9%. Results of logistic regression suggested that nine specific trauma types were significantly associated with p-PTSD; among this group, severe human suffering, sexual assault, unwanted or uncomfortable sexual experience, captivity, and sudden and violent death carried the greatest risks for developing PTSD, odds ratio (OR) = 2.32-2.69. The occurrence of p-PTSD was associated with more mental health burdens, including (a) sixfold higher rates for any past-week common mental disorder, OR = 28.4, (b) more mental health service utilization, p < .001, (c) poorer mental health indexes in level of symptomatology, suicide ideation and functioning, p < .001, and (d) more disability, ps < .001-p = .014. The associations found among TE, PTSD, and health service utilization suggest that both TE and PTSD should be considered public health concerns.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) La Encuesta Hong Kong sobre la Epidemiología de las Experiencias Traumáticas y el Trastorno de Estrés Postraumático ENCUESTA HONG KONG SOBRE EXPERIENCIA TRAUMÁTICA Y TEPT Este estudio examinó la epidemiología de la experiencia traumática (ET) y el trastorno por estrés postraumático (TEPT) entre adultos chinos que viven en comunidades en Hong Kong. Se utilizó un diseño de muestreo de estratificación multietapa y se incluyeron 5,377 participantes. En la Fase 1, ET, probable TEPT (p-TEPT) y enfermedades psiquiátricas comórbidas fueron examinadas. En la Fase 2, se utilizó la Entrevista Clínica Estructurada para el DSM-IV (SCID-I) para determinar la prevalencia de diagnóstico ponderado de TEPT completo a lo largo de la vida. Se estudiaron el nivel de discapacidad y la utilización de los servicios de salud. Los resultados mostraron que la prevalencia ponderada de ET fue del 64.8% y aumentó al 88.7% cuando se incluyeron tipos indirectos de ET, tales como accidentes de transporte (50.8%), los que fueron reportados como el ET más común. La prevalencia actual de p-TEPT entre los participantes con ET fue del 2.9%. Los resultados de la regresión logística sugirieron que nueve tipos específicos de trauma fueron significativamente asociados con p-PTSD; entre este grupo encontramos: sufrimiento humano severo, agresión sexual, experiencia sexual no deseada o incómoda, cautiverio y la muerte inesperada y violenta acarrearon el mayor riesgo para desarrollar TEPT, odds ratio (OR) = 2.32-2.69. La aparición de p-PTSD fue asociado con más riesgo de problemas de salud mental, que incluyen (a) tasas 6 veces más altas para cualquier trastorno mental común experimentado la última semana, OR = 28.4 (b) más utilización de servicios de salud mental, p <.001, (c) índices de salud mental más pobres a nivel de sintomatología, ideación y funcionamiento suicida, p <.001, y (d) más discapacidad, p <.001 - p = .014. Las asociaciones encontradas entre ET, TEPT, y la utilización de los servicios de salud sugieren que tanto el ET como el TEPT deben considerarse una preocupación de salud pública.

Drug-induced immune thrombocytopenia: Mapping of the drug binding site to the membrane-proximal region of platelet GPIX.

Drug-induced Immune thrombocytopenia (DIT) is a common complication of several medications, including commonly used antibiotics. The most widely studied DIT is caused by quinine. In DIT, antibodies predominantly bind to the platelet membrane glycoprotein (GP) IX in a drug-dependent fashion resulting in increased platelet clearance. Binding of the sensitizing drug, such as quinine, to GPIX has been proposed but is yet to be established. This work demonstrates that quinine is retained specifically by human GPIX. Quinine binding was first analyzed in wild-type mouse platelets and in transgenic mouse platelet expressing human GPIX using high performance liquid chromatography. Binding of quinine to GPIX was then measured in Chinese hamster ovary (CHO) cells expressing a combination of wild type, human or mouse, three human/mouse chimeric constructs and six mutant GPIX proteins. Quinine was retained by human GPIX. No detectable absorption was observed with mouse GPIX or human GPIbα. The quinine binding site was mapped to residues 110-115 of human GPIX suggesting that quinine interacts with specific residues of the GP. These findings provide further insights into the molecular mechanisms of DIT.

Culturally Sensitive Depression Assessment for Chinese American Immigrants: Development of a Comprehensive Measure and a Screening Scale Using an Item Response Approach.

The present mixed methods study developed a comprehensive measure and a screening scale of depression for Chinese American immigrants by combining an emic approach with item response analysis. Clinical participants were immigrants diagnosed by licensed clinicians who worked in the community. Qualitative interviews with clinicians and clinical participants (N = 63) supported the definition of the construct of depression-which guided scale development-and a 47-item pilot scale. Clinical and community participants (N = 227) completed the pilot scale and measures of neurasthenia and acculturative stress, and the Patient Health Questionnaire Depression Module (PHQ-9). A Rasch Partial Credit Model of 42-items-representing psychological, somatic and interpersonal domains of distress-best fit the data. Twenty-three items overlapped with the DSM-IV symptoms of major depression. Twenty-seven items were biased by acculturation-related variables. Nine items appropriate for self-report screening in primary care and community organizations were chosen to form a brief scale. Both measures showed strong reliability and concurrent and convergent validity. The 9-item scale had better content validity than the PHQ-9. Implications regarding the impact of culture for assessment are highlighted.

CXCR4 expression on transplanted peripheral blood CD34+ cells: relationship to engraftment after autologous transplantation in a cohort of multiple myeloma patients.

Expression of the chemokine receptor CXCR4 by haematopoietic stem cells (HSCs) is believed to influence the process of these cells 'homing' back to the bone marrow post-transplantation, in response to the stromal cell-derived factor-1 gradient, followed by engraftment. The primary aim of this retrospective study was to compare reinfused CD34(+) cell dose, assessed from the fresh collection, with the post-thaw viable (v) CD34(+) and vCD34/CXCR4(+) dual positive cell dose as predictors of haematopoietic recovery in multiple myeloma patients undergoing autologous stem cell transplantation. Cryopreserved samples from stem cell collections of 27 myeloma patients were analysed for CD34 and CXCR4 expression and times to haematological engraftment measured. Dosage of transplanted vCD34(+) cells was on average 79% of the original calculation from the fresh collection bag (range 29-98%). The median percentage of vCD34+ cells co-expressing CXCR4 was 37% (3.7-97%). Surface expression of CXCR4 by thawed vCD34(+) cells was closely correlated to complementary DNA levels. The median dose of CD34/CXCR4(+) cells in the autografts was 1.2 × 10(6)/kg (0.2-3.0 × 10(6)/kg) compared with 3.3 × 10(6)/kg for transplanted vCD34(+) cells (1.2-5.5 × 10(6)/kg). Both CD34 and vCD34 doses correlated with neutrophil engraftment (p < 0.005) although vCD34/CXCR4(+) dose did not. However, patients given a higher dose of CD34/CXCR4(+) cells (≥1.75 × 10(6)/kg) showed a faster time to platelet recovery (p < 0.05) than those given a lower dose (≤0.42 × 10(6)/kg). These results warrant further study of CD34/CXCR4 expression by mobilised HSCs and the relationship to platelet recovery post-transplantation on a larger cohort of patients.

Functional maturation of fetal porcine beta-cells by glucagon-like peptide 1 and cholecystokinin.

Fetal beta-cells are immature in their responsiveness to glucose, and maturation occurs after oral feeding commences at birth. The incretin hormones glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are known to be released from the gut in response to oral feeding and enhance insulin secretion from pancreatic beta-cells. We hypothesized that these fetal beta-cells would mature in their glucose responsiveness if they were previously exposed to incretins. We exposed fetal pig islet-like cell clusters (ICCs) to 100 nM GLP-1, 5 micro M CCK, or 10 mM nicotinamide (NIC; a positive control) for 6 h and demonstrated 3- and 1.7-fold increases in glucose-induced insulin secretion for GLP-1 and CCK, respectively. This effect did not reach statistical significance if the ICCs were exposed to the incretins for 3 d. However, exposure for 4 d enhanced formation of beta-cells from undifferentiated cells, from 8 +/- 1% (controls) to 17 +/- 3% for GLP-1, 20 +/- 4% for CCK, and 15 +/- 1 for NIC (P < 0.001). ICCs exposed to GLP-1 for 3 d also showed a 1.9-fold increase in the intensity of PDX-1(+) cells, as assessed by semiquantitative fluorescent immunocytochemistry. Exposure of ICCs to incretins for 3 d did not show any increase in size of the islet clusters. ICCs exposed to either incretin as well as controls were transplanted into severe combined immunodeficient mice and examined at 1 and 2 months. We found a significant increase in the number of beta-cells in the GLP-1- and NIC-treated groups compared with the untreated controls or CCK. Perfusion of these grafts at 2 months showed that ICCs previously exposed to GLP-1, CCK, and NIC (but not controls), were functional and mature. In conclusion, GLP-1 and CCK have a dual effect on fetal pig ICCs, causing maturation of glucose-induced insulin secretion from beta-cells as well as enhancement of differentiation from undifferentiated precursors.