Next‐generation sequencing for the diagnosis of MYH9‐RD: Predicting pathogenic variants

The heterogeneous manifestations of MYH9‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE‐BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9‐RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9‐RD in clinical practice.     

Priority actions for the non-communicable disease crisis

The UN High-Level Meeting on Non-Communicable Diseases (NCDs) in September, 2011, is an unprecedented opportunity to create a sustained global movement against premature death and preventable morbidity and disability from NCDs, mainly heart disease, stroke, cancer, diabetes, and chronic respiratory disease. The increasing global crisis in NCDs is a barrier to development goals including poverty reduction, health equity, economic stability, and human security. The Lancet NCD Action Group and the NCD Alliance propose five overarching priority actions for the response to the crisis--leadership, prevention, treatment, international cooperation, and monitoring and accountability--and the delivery of five priority interventions--tobacco control, salt reduction, improved diets and physical activity, reduction in hazardous alcohol intake, and essential drugs and technologies. The priority interventions were chosen for their health effects, cost-effectiveness, low costs of implementation, and political and financial feasibility. The most urgent and immediate priority is tobacco control. We propose as a goal for 2040, a world essentially free from tobacco where less than 5% of people use tobacco. Implementation of the priority interventions, at an estimated global commitment of about US$9 billion per year, will bring enormous benefits to social and economic development and to the health sector. If widely adopted, these interventions will achieve the global goal of reducing NCD death rates by 2% per year, averting tens of millions of premature deaths in this decade.     

Follicular carcinoma of thyroid following successful liver transplantation – A report

Dantuluri S, Urs A, Karthik SV. Follicular carcinoma of thyroid following successful liver transplantation – A report. Abstract: Follicular carcinoma of the thyroid is a relatively rare malignancy in childhood even in paediatric solid organ transplant recipients. The risk of developing de novo malignancies after liver transplantation is higher compared to the general population. We report an 18‐yr‐old girl who had successfully undergone liver transplantation five yr earlier for neonatal sclerosing cholangitis complicated by the development of dysplastic nodules. Baseline immunosuppression was with tacrolimus and prednisolone. Mycophenolate mofetil was later added in view of steroid‐resistant episodes of graft rejection. She subsequently suffered from marked obesity and essential hypertension needing antihypertensive medication. Five yr after liver transplantation, she presented with a right‐sided thyroid swelling that was rapidly progressive with no associated lymphadenopathy and normal systemic examination. Ultrasound of her neck revealed a solid lesion in the right lobe of the thyroid gland with ill‐defined margins, and a diagnostic right thyroid lobectomy confirmed the diagnosis of follicular carcinoma with focal capsular and vascular invasion. She underwent total thyroidectomy and currently remains well on thyroxine supplements. Our report highlights the need for high level of suspicion and prompt investigation into any abnormal lesion in the long‐term follow‐up of solid organ transplant recipients.     

In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens

Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.     

Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al. [1999: Am J Hum Genet 65:1096-1103].