Mental health problems in children of somatically ill parents, e.g. multiple sclerosis

Objectives: Based on the investigation of 144 families (144 patients affected by Multiple Sclerosis (MS), 109 partners, and 192 children) examined in three different European child and adolescent psychiatric University centres by means of questionnaires, we evaluated the prevalence of psychological symptoms in the offspring and associated risk factors such as duration and severity of the disease as well as depression of the ill and the healthy parent. Results: Indicate that the severe disease of MS is associated with depression of the ill and healthy parent. Ill parents, especially ill mothers, as well as depressed ill, or depressed healthy parents evaluate their children's mental health problems with a higher prevalence within the internalizing spectrum. Healthy parents report normal psychological adjustment of their children. If two parents present a depressive state, the prevalence of relevant psychological internalizing symptoms is twice or three times as high as the age norms. Conclusion: Children in families with a parent affected by MS and associated depression of the parental couple are at high risk of mental health problems, especially internalizing disorders. In focusing on the mental health of children one must also be aware of the potential opportunities to address the parents' own psychological need

Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR)

Abstract Introduction A common feature of neoplastic cells is that mutations in SMADs can contribute to the loss of sensitivity to the anti-tumor effects of transforming growth factor-β (TGF-β). However, germline mutation analysis of SMAD3 and SMAD4, the principle substrates of the TGF-β signaling pathway, has not yet been conducted in breast cancer. Thus, it is currently unknown whether germline SMAD3 and SMAD4 mutations are involved in breast cancer predisposition. Methods We performed mutation analysis of the highly conserved mad-homology 2 (MH2) domains for both genes in genomic DNA from 408 non-BRCA1/BRCA2 breast cancer cases and 710 population controls recruited by the Ontario site of the breast cancer family registry (CFR) using denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing. The results were interpreted in several ways. First, we adapted nucleotide diversity analysis to quantitatively assess whether the frequency of alterations differ between the two genes. Next, in silico tools were used to predict variants' effect on domain function and mRNA splicing. Finally, 37 cases or controls harboring alterations were tested for aberrant splicing using reverse-transcription polymerase chain reaction (PCR) and real-time PCR statistical comparison of germline expressions by non-parametric Mann-Whitney test of independent samples. Results We identified 27 variants including 2 novel SMAD4 coding variants c.1350G > A (p.Gln450Gln), and c.1701A > G (p.Ile525Val). There were no inactivating mutations even though c.1350G > A was predicted to affect exonic splicing enhancers. However, several additional findings were of note: 1) nucleotide diversity estimate for SMAD3 but not SMAD4 indicated that coding variants of the MH2 domain were more infrequent than expected; 2) in breast cancer cases SMAD3 was significantly over-expressed relative to controls (P A was associated with elevated germline expression (> 5-fold); 3) separate analysis using tissue expression data showed statistically significant over-expression of SMAD3 and SMAD4 in breast carcinomas. Conclusions This study shows that inactivating germline alterations in SMAD3 and SMAD4 are rare, suggesting a limited role in driving tumorigenesis. Nevertheless, aberrant germline expressions of SMAD3 and SMAD4 may be more common in breast cancer than previously suspected and offer novel insight into their roles in predisposition and/or progression of breast cancer

Functional Characterization of FLT3 Receptor Signaling Deregulation in Acute Myeloid Leukemia by Single Cell Network Profiling (SCNP)

Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in cellular responsiveness to signaling modulation may be more informative.Using single cell network profiling (SCNP), cells were treated with extracellular modulators and their functional responses were quantified by multiparametric flow cytometry. Intracellular signaling responses were compared between healthy bone marrow myeloblasts (BMMb) and AML leukemic blasts characterized as FLT3 wild type (FLT3-WT) or FLT3-ITD. Compared to healthy BMMb, FLT3-WT leukemic blasts demonstrated a wide range of signaling responses to FLT3 ligand (FLT3L), including elevated and sustained PI3K and Ras/Raf/Erk signaling. Distinct signaling and apoptosis profiles were observed in FLT3-WT and FLT3-ITD AML samples, with more uniform signaling observed in FLT3-ITD AML samples. Specifically, increased basal p-Stat5 levels, decreased FLT3L induced activation of the PI3K and Ras/Raf/Erk pathways, decreased IL-27 induced activation of the Jak/Stat pathway, and heightened apoptotic responses to agents inducing DNA damage were observed in FLT3-ITD AML samples. Preliminary analysis correlating these findings with clinical outcomes suggests that classification of patient samples based on signaling profiles may more accurately reflect FLT3 signaling deregulation and provide additional information for disease characterization and management.These studies show the feasibility of SCNP to assess modulated intracellular signaling pathways and characterize the biology of individual AML samples in the context of genetic alterations

An Abundant Dysfunctional Apolipoprotein A1 in Human Atheroma

Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl− system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall

Pembuatan Dan Karakterisasi Filter Particulate Matter 0,1 (Pm0,1 ) Menggunakan Komposit Berbahan Filler Serat Limbah Kokon Dengan Penambahan Bubuk Kulit Pisang Kepok (Musa Paradisiaca L) Dan Matriks Putih Telur

Particulate matter 0,1 (PM0,1) adalah padatan atau cairan yang tersuspensi di udara dengan ukuran 0,1 μm. PM0,1 berdampak pada negatif pada kesehatan manusia. Oleh sebab itu, dalam penelitian ini dikembangkan filter berbasis komposit untuk mengurangi konsentrasi PM0,1 yang dihasilkan dari emisi sepeda motor. Filter dibuat dengan metode hand lay-up. Bahan filler pada filter komposit terdiri atas 3 lapis lembaran kokon dengan penambahan bubuk kulit pisang kepok, sedangkan untuk matriks digunakan 4 ml putih telur. Perbandingan massa antara kokon dan bubuk kulit pisang kepok, yaitu Filter A (1 : 0,6), Filter B (1 : 0,8), Filter C (1 : 1), Filter D (1 : 1,2), Filter E (1 : 1,4), sedangkan Filter F adalah tanpa penambahan bubuk. Efisiensi filter diperoleh melalui pengukuran konsentrasi PM0,1 sebelum dan sesudah menggunakan filter di knalpot motor dengan alat P-Track Model 8528, sedangkan karakteristik fisis filter diperoleh melalui uji densitas, morfologi, porositas, flowrate, dan ketahanan. Hasil penelitian menunjukkan bahwa filter memiliki ukuran pori yang beragam dan tersebar secara acak dengan densitas filter A, B, C, D, E, dan F adalah sebesar 0,70 gr/cm3, 0,76 gr/cm3, 0,77 gr/cm3, 0,86 gr/cm3, 1,12 gr/cm3 dan 0,66 gr/cm3, serta nilai efisiensi filter sebesar 4% hingga 53% yang bergantung dari komposisi penambahan bubuk kulit pisang kepok. Filter juga memiliki blocking sebesar 21% hingga 68% dengan batas ketahanan filter yang ditinjau dari uji flowrate sebesar 23 m/s, dimana filter dengan kompoisi sedikit lebih mudah rusak

Bottleneck Analysis on the DoD Pre-Milestone B Acquisition Processes

Tenth Annual Acquisition Research Symposium Acquisition ManagementExcerpt from the Proceedings of the Tenth Annual Acquisition Research Symposium Acquisition ManagementDisclaimer: The views represented in this report are those of the authors and do not reflect the official policy position of the Navy, the Department of Defense, or the federal government.Naval Postgraduate School Acquisition Research ProgramPrepared for the Naval Postgraduate School, Monterey, CANaval Postgraduate School Acquisition Research ProgramApproved for public release; distribution is unlimited