controlling the disease

Surveillance and outbreak reports Surveillance of extensively drug-resistant tuberculosis in Europe, 2003-2007 15 by I Devaux, D Manissero, K Fernandez de la Hoz, K Kremer, D van Soolingen, on behalf of the EuroTB network Analysis of tuberculosis treatment outcomes in the European Union and European Economic Area: efforts needed towards optimal case management and control 21 by D Manissero, V Hollo, E Huitric, C Ködmön, A Amato-Gauci Risk of developing tuberculosis from a school contact: retrospective cohort study

Recessive TMOD1 mutation causes childhood cardiomyopathy.

Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy

Effects of Acute Cytomegalovirus Infection on Rat Islet Allograft Survival

Transplantation of pancreatic islets is a promising therapy for the treatment of type 1 diabetes mellitus. However, long-term islet graft survival rates are still unsatisfactory low. In this study we investigated the role of cytomegalovirus (CMV) in islet allograft failure. STZ-diabetic rats received an allogenic islet graft in combination with either an acute CMV infection or control infection. A third group received ganciclovir treatment in addition to the CMV infection. Graft function was assessed by measuring basal blood glucose levels. After sacrifice, the islet grafts were retrieved for analysis of infection and leukocyte infiltration. CMV-infected recipients demonstrated accelerated islet graft failure compared to noninfected controls. CMV infection of the graft was only observed prior to complete graft failure. Quantification of the leukocyte infiltration demonstrated increased CD8(+) T-cell and NK cell infiltration in the CMV-infected grafts compared to the controls. This suggests that CMV infection accelerates immune-mediated graft destruction. Antiviral ganciclovir treatment did not prevent accelerated graft failure, despite effectively decreasing the grade of infection. Our data confirm the recently published CITR data, which state that CMV is an independent risk factor for failure of islet grafts. Also, our data demonstrate that new approaches for preventing virus-induced islet allograft failure may be required

Sleep-related breathing disorder in non-infectious pulmonary complications after pediatric allogeneic stem cell transplantation

Abstract Background: Chronic lung problems are a rare but serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). We studied clinical phenotypes and polysomnography appearance of breathing abnormality in late onset non-infectious pulmonary complications (NIPS). Methods: We reviewed Finnish national reference database between the years 1999 and 2016. We identified 12 children with most severely decreased pulmonary function and performed polysomnography and 24 aged-matched controls out of 325 performed pediatric allogeneic HSCTs. Results: All patients with NIPS had severely decreased pulmonary function already at 6 months post HSCT with median FEV1 value 42% (interquartile range (IQR) 30–52%) of predicted normal values. Seven children had obstructive and five children more restrictive lung function. Children with obstructive lung function showed laborious breathing (7/7), decreased oxygenation and ventilation-to-perfusion mismatch (6/7), or REM-sleep-related hypoventilation (4/7) on polysomnography. Children with restrictive lung function (5/12) did not show sleep-related breathing disorder. Conclusions: Children going through allogeneic HSCT who develop severe chronic obstructive lung function are more likely to present with sleep-related hypoxia and hypoventilation than children with restrictive lung function. Impact: Children with severe obstructive lung function and chronic lung graft-versus-host disease following hematopoietic stem cell transplantation are more likely to present with sleep-related mild hypoxia and hypoventilation than children with restrictive lung disease. To our knowledge there are no reports on sleep-related breathing disorders and ventilatory function measured by polysomnography in children with pulmonary complications after allogeneic HSCT. Polysomnography may add to the differential diagnostics between patients with BOS and other non-infectious pulmonary complications

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes

Background: The nuclear factor kappa light-chain enhancer of activated B cells (NF-kappa B) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-kappa B pathway genes cause immunodeficiency. Objective: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation. Methods: We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles. Results: In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behc, et disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions. Conclusion: Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behcet disease, can be caused by rare monogenic variants in genes of the NF-kappa B pathway.Peer reviewe