Symptomatic hypogammaglobulinemia in infancy and childhood – clinical outcome and in vitro immune responses

BACKGROUND: Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution. METHODS: Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed. RESULTS: 32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. Clinical presentation: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients. CONCLUSIONS: The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign

Feasibility study of a clinically-integrated randomized trial of modifications to radical prostatectomy

<p>Abstract</p> <p>Background</p> <p>Numerous technical modifications to radical prostatectomy have been proposed. Such modifications are likely to lead to only slight improvements in outcomes. Although small differences would be worthwhile, an appropriately powered randomized trial would need to be very large, and thus of doubtful feasibility given the expense, complexity and regulatory burden of contemporary clinical trials. We have proposed a novel methodology, the clinically-integrated randomized trial, which dramatically streamlines trial procedures in order to reduce the marginal cost of an additional patient towards zero. We aimed to determine the feasibility of implementing such a trial for radical prostatectomy.</p> <p>Methods</p> <p>Patients undergoing radical prostatectomy as initial treatment for prostate cancer were randomized in a factorial design to involvement of the fascia during placement of the anastomotic sutures, urethral irrigation, both or neither. Endpoint data were obtained from routine clinical documentation. Accrual and compliance rates were monitored to determine the feasibility of the trial.</p> <p>Results</p> <p>From a total of 260 eligible patients, 154 (59%) consented; 56 patients declined to participate, 20 were not approached on recommendation of the treating surgeon, and 30 were not approached for logistical reasons. Although recording by surgeons of the procedure used was incomplete (~80%), compliance with randomization was excellent when it was recorded, with only 6% of procedures inconsistent with allocation. Outcomes data was received from 71% of patients at one year. This improved to 83% as the trial progressed.</p> <p>Conclusions</p> <p>A clinically-integrated randomized trial was conducted at low cost, with excellent accrual, and acceptable compliance with treatment allocation and outcomes reporting. This demonstrates the feasibility of the methodology. Improved methods to ensure documentation of surgical procedures would be required before wider implementation.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00928850">NCT00928850</a></p

γ-Catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of β-catenin

Canonical Wnt signaling regulates the transcription of T-cell factor (TCF)-responsive genes through the stabilization and nuclear translocation of the transcriptional co-activator, β-catenin. Overexpression of β-catenin features prominently in acute myeloid leukemia (AML) and has previously been associated with poor clinical outcome. Overexpression of γ-catenin mRNA (a close homologue of β-catenin) has also been reported in AML and has been linked to the pathogenesis of this disease, however, the relative roles of these catenins in leukemia remains unclear. Here we report that overexpression and aberrant nuclear localization of γ-catenin is frequent in AML. Significantly, γ-catenin expression was associated with β-catenin stabilization and nuclear localization. Consistent with this, we found that ectopic γ-catenin expression promoted the stabilization and nuclear translocation of β-catenin in leukemia cells. β-Catenin knockdown demonstrated that both γ- and β-catenin contribute to TCF-dependent transcription in leukemia cells. These data indicate that γ-catenin expression is a significant factor in the stabilization of β-catenin in AML. We also show that although normal cells exclude nuclear translocation of both γ- and β-catenin, this level of regulation is lost in the majority of AML patients and cell lines, which allow nuclear accumulation of these catenins and inappropriate TCF-dependent transcription

Meta-analysis of gene expression microarrays with missing replicates

<p>Abstract</p> <p>Background</p> <p>Many different microarray experiments are publicly available today. It is natural to ask whether different experiments for the same phenotypic conditions can be combined using meta-analysis, in order to increase the overall sample size. However, some genes are not measured in all experiments, hence they cannot be included or their statistical significance cannot be appropriately estimated in traditional meta-analysis. Nonetheless, these genes, which we refer to as <it>incomplete genes</it>, may also be informative and useful.</p> <p>Results</p> <p>We propose a meta-analysis framework, called "Incomplete Gene Meta-analysis", which can include incomplete genes by imputing the significance of missing replicates, and computing a meta-score for every gene across all datasets. We demonstrate that the incomplete genes are worthy of being included and our method is able to appropriately estimate their significance in two groups of experiments. We first apply the <it>Incomplete Gene Meta-analysis </it>and several comparable methods to five breast cancer datasets with an identical set of probes. We simulate incomplete genes by randomly removing a subset of probes from each dataset and demonstrate that our method consistently outperforms two other methods in terms of their false discovery rate. We also apply the methods to three gastric cancer datasets for the purpose of discriminating diffuse and intestinal subtypes.</p> <p>Conclusions</p> <p>Meta-analysis is an effective approach that identifies more robust sets of differentially expressed genes from multiple studies. The incomplete genes that mainly arise from the use of different platforms may also have statistical and biological importance but are ignored or are not appropriately involved by previous studies. Our Incomplete Gene Meta-analysis is able to incorporate the incomplete genes by estimating their significance. The results on both breast and gastric cancer datasets suggest that the highly ranked genes and associated GO terms produced by our method are more significant and biologically meaningful according to the previous literature.</p

Informatics Technology Mimics Ecology: Dense, Mutualistic Collaboration Networks Are Associated with Higher Publication Rates

Information technology (IT) adoption enables biomedical research. Publications are an accepted measure of research output, and network models can describe the collaborative nature of publication. In particular, ecological networks can serve as analogies for publication and technology adoption. We constructed network models of adoption of bioinformatics programming languages and health IT (HIT) from the literature

Diode-pumped ultrafast Yb:KGW laser with 56 fs pulses and multi-100 kW peak power based on SESAM and Kerr-lens mode locking

A high-power sub-60 fs mode-locked diode-pumped Yb:KGW laser based on hybrid action of an InGaAs quantum-dot saturable absorber mirror and Kerr-lens mode locking was demonstrated. The laser delivered 56 fs pulses with 1.95 W of average power corresponding to 450 kW of peak power. The width of the generated laser spectrum was 20.5 nm, which was near the gain bandwidth limit of the Yb:KGW crystal. To the best of our knowledge, these are the shortest pulses generated from the monoclinic double tungstate crystals (and Yb:KGW laser crystal in particular) and the most powerful in the sub-60 fs regime. At the same time, they are also the shortest pulses produced to date with the help of a quantum-dot-based saturable absorber. High-power operation with a pulse duration of 90 fs and 2.85 W of average output power was also demonstrated

The desmosome and pemphigus

Desmosomes are patch-like intercellular adhering junctions (“maculae adherentes”), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to significant mechanical stress such as stratified epithelia and myocardium. Desmosomal adhesion is based on the Ca2+-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate filament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases affect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suffering from severe blistering skin diseases such as pemphigus. To develop disease-specific therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required