MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization.

Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics, by coactivating serum response factor. Recently, the first human with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with 2 siblings with a homozygous frameshift mutation in MKL1. The index case died as an infant from progressive and severe pneumonia caused by Pseudomonas aeruginosa and poor wound healing. The younger sibling was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. In addition to the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as a transcriptional coregulator. Degranulation was enhanced upon suboptimal neutrophil activation, whereas production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis or bacterial killing was found. Also, monocyte-derived macrophages showed intact phagocytosis, and lymphocyte counts and proliferative capacity were normal. Nonhematopoietic primary fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and F-actin content, most likely as a result of compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as the most prominent features.

A failed attempt to conduct an individual patient data meta-analysis.

A study-level meta-analysis has shown that proton magnetic resonance spectroscopy is a promising prognostic marker in neonatal hypoxic-ischemic encephalopathy. An individual patient data meta-analysis could yield a prognostic tool with improved accuracy enabling well-founded clinical decisions. Our request to share patient data remained unanswered by five out of 18 research groups. Another four declined collaboration for various reasons, including own reanalysis of the data, and lack of parental consent. With less than 40% of the individual patient data available, we refrained from pursuing the proposed study. As future patients may benefit from it, policies mandating data sharing should be introduced.

Magnetic resonance spectroscopy as a prognostic marker in neonatal hypoxic-ischemic encephalopathy: a study protocol for an individual patient data meta-analysis.

BACKGROUND: The prognostic accuracy of 1H (proton) magnetic resonance spectroscopy (MRS) in neonatal hypoxic-ischemic encephalopathy has been assessed by a criticized study-based meta-analysis. An individual patient data meta-analysis may overcome some of the drawbacks encountered in the aggregate data meta-analysis. Moreover, the prognostic marker can be assessed quantitatively and the effect of covariates can be estimated. METHODS: Diagnostic accuracy studies relevant to the study topic were retrieved. The primary authors will be invited to share the raw de-identified study data. These individual patient data will be analyzed using logistic regression analysis. A prediction tool calculating the individualized risk of very adverse outcome will be devised. DISCUSSION: The proposed individual patient data meta-analysis provides several advantages. Inclusion and exclusion criteria can be applied more uniformly. Furthermore, adjustment is possible for confounding factors and subgroup analyses can be conducted. Our goal is to develop a prediction model for outcome in newborns with hypoxic-ischemic encephalopathy.

Severe kerion celsi due to Trichophyton mentagrophytes: a case report.

UNLABELLED: We report on a 5-year-old girl with a severe kerion celsi, caused by Trichophyton mentagrophytes, probably acquired from a pet guinea pig. The lesions had started as small irritating squamous lesions that had been accurately diagnosed as skin infection, but had only been treated with local antifungal agents. The lesions progressed and developed into a kerion celsi that had to be treated with long-term systemic griseofulvin. Nevertheless, reinfection occurred and treatment had to be restarted. The girl is left with areas of alopecia, as a result of which she is required to wear a wig. CONCLUSION: Tinea capitis is a common skin infection that should be considered in any type of scalp lesion. It requires systemic treatment, and inappropriate and delayed treatment can result in the development of kerion celsi, with sometimes devastating consequences.

[A boy with an abnormal right part of his body]. / Een jongen met een afwijkende rechter lichaamshelft.

We were consulted with pictures of a 10-year-old Ukrainian boy with red maculae over a large part of his body and hypertrophy and varicose veins of the right arm and leg due to Klippel-Trenaunay syndrome.

Azathioprine maintains first remission in newly diagnosed pediatric Crohn's disease.

6-Mercaptopurine (6-MP) maintains remission in pediatric Crohn's disease (CD). Azathioprine, a prodrug of 6-MP, is used for maintenance of remission of CD in Europe. We evaluated to what extent azathioprine is used in newly diagnosed pediatric CD patients and whether maintenance of remission differed between patients using azathioprine or not. Charts of children (diagnosed 1998-2003, follow-up > or = 18 mo) were reviewed. Active disease was defined as Pediatric Crohn's Disease Activity Index (PCDAI) greater than 10 or systemic corticosteroid use. Remission was defined as PCDAI 10 or less without use of corticosteroids. Eighty-eight children (55M/33F, age 12 +/- 3 yr) were included. Seventy-two (82%) patients received azathioprine during the follow-up period (38 +/- 17 mo). Patients diagnosed after 2000 received azathioprine significantly earlier during the course of disease compared with those diagnosed earlier (median, at 233 vs. 686 days; P < 0.05). At initial presentation, moderate-severe disease activity and prescription of corticosteroids were more prevalent in patients using azathioprine compared with nonazathioprine patients (75% vs. 52%; P < 0.05; and 89% vs. 58%; P < 0.005, respectively). Duration of corticosteroid use was longer in patients receiving azathioprine (232 vs. 168 days; P < 0.005). Median maintenance of first remission in patients who initially used corticosteroids, however, was longer in patients receiving azathioprine compared with nonazathioprine patients (PCDAI, 544 vs. 254 days, P = 0.08; corticosteroid free, 575 vs. 259 days, P < 0.05, respectively). We conclude that, since 2000, azathioprine is being introduced earlier in the treatment of newly diagnosed pediatric CD patients. The use of azathioprine is associated with prolonged maintenance of the first remission.