Characterization of Diffusion Bonds Using an Acoustic Microscope

Solid state bonding is now being used in aircraft fabrication. As a result of this, various groups have considered the destructive examination of such bonds and categorized them in terms of characteristics seen in the examination of micrographic sections [1,2]. A range of studies which employ ultrasonic non-destructive techniques for bond-line characterization have also been undertaken [1,3,4]

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

Severe vitamin D deficiency in 6 Canadian First Nation formula-fed infants

Background. Rickets was first described in the 17th century and vitamin D deficiency was recognized as the underlying cause in the early 1900s. Despite this long history, vitamin D deficiency remains a significant health concern. Currently, vitamin D supplementation is recommended in Canada for breast fed infants. There are no recommendations for supplementation in formula-fed infants. Objective. The objective of this report is to bring attention to the risk of severe vitamin D deficiency in high risk, formula fed infants. Design. A retrospective chart review was used to create this clinical case series. Results. Severe vitamin D deficiency was diagnosed in six formula-fed infants over a two-and-a-half year period. All six infants presented with seizures and they resided in First Nation communities located at latitude 54 in the province of Manitoba. While these infants had several risk factors for vitamin D deficiency, they were all receiving cow's milk based formula supplemented with 400 IU/L of vitamin D. Conclusion. This report suggests that current practice with regards to vitamin D supplementation may be inadequate, especially for high-risk infants. Health care professionals providing service to infants in a similar situation should be aware of this preventable condition. Hopefully this would contribute to its prevention, diagnosis and management

Improving the coverage of the PMTCT programme through a participatory quality improvement intervention in South Africa

<p>Abstract</p> <p>Background</p> <p>Despite several years of implementation, prevention of mother-to-child transmission (PMTCT) programmes in many resource poor settings are failing to reach the majority of HIV positive women. We report on a data driven participatory quality improvement intervention implemented in a high HIV prevalence district in South Africa.</p> <p>Methods</p> <p>A participatory quality improvement intervention was implemented consisting of an initial assessment undertaken by a team of district supervisors, workshops to assess results, identify weaknesses and set improvement targets and continuous monitoring to support changes.</p> <p>Results</p> <p>The assessment highlighted weaknesses in training and supervision. Routine data revealed poor coverage of all programme indicators except HIV testing. Monthly support to all facilities took place including an orientation to the PMTCT protocol, review of local data and identification of bottlenecks to optimal coverage using a continuous quality improvement approach. One year following the intervention large improvements in programme indicators were observed. Coverage of CD4 testing increased from 40 to 97%, uptake of maternal nevirapine from 57 to 96%, uptake of infant nevirapine from 15 to 68% and six week PCR testing from 24 to 68%.</p> <p>Conclusion</p> <p>It is estimated that these improvements in coverage could avert 580 new infant infections per year in this district. This relatively simple participatory assessment and intervention process has enabled programme managers to use a data driven approach to improve the coverage of this important programme.</p

Epidemiology of severe pediatric adenovirus lower respiratory tract infections in Manitoba, Canada, 1991-2005

<p>Abstract</p> <p>Background</p> <p>Most pediatric adenovirus respiratory infections are mild and indistinguishable from other viral causes. However, in a few children, the disease can be severe and result in substantial morbidity. We describe the epidemiologic, clinical, radiologic features and outcome of adenovirus lower respiratory tract infections (LRTI) in Aboriginal and Non-Aboriginal children in Manitoba, Canada during the years 1991 and 2005.</p> <p>Methods</p> <p>This was a retrospective study of 193 children who presented to the department of pediatrics at Winnipeg Children's Hospital, Manitoba, Canada with LRTI and had a positive respiratory culture for adenovirus. Patients' demographics, clinical and radiologic features and outcomes were collected. Adenovirus serotype distributions and temporal associations were described. Approximate incidence comparisons (detection rates) of adenovirus LRTI among Aboriginal and Non-Aboriginal children were estimated with 95% confidence intervals.</p> <p>Results</p> <p>Adenovirus infections occurred throughout the year with clusters in the fall and winter. Serotypes 1 to 3 were the predominant isolates (two thirds of the cases). The infection was more frequent among Canadian Aboriginals, as illustrated in 2004, where its incidence in children 0-4 years old was 5.6 fold higher in Aboriginals (13.51 vs. 2.39 per 10,000, <it>p </it>< 0.000). There were no significant differences in length of hospitalization and use of ventilator assistance between the two groups (<it>p </it>> 0.185 and <it>p </it>> 0.624, respectively) nor across serotypes (<it>p </it>> 0.10 and <it>p </it>> 0.05, respectively). The disease primarily affected infants (median age, 9.5 months). Most children presented with bronchiolitis or pneumonia, with multi-lobar consolidations on the chest x-ray. Chronic (residual) changes were documented in 16 patients, with eight patients showing bronchiectasis on the chest computerized tomography scan.</p> <p>Conclusions</p> <p>Adenovirus infection is associated with significant respiratory morbidities, especially in young infants. The infection appears to be more frequent in Aboriginal children. These results justify a careful follow-up for children with adenovirus LRTI.</p

High Throughput Functional Assays of the Variant Antigen PfEMP1 Reveal a Single Domain in the 3D7 Plasmodium falciparum Genome that Binds ICAM1 with High Affinity and Is Targeted by Naturally Acquired Neutralizing Antibodies

Plasmodium falciparum–infected erythrocytes bind endothelial receptors to sequester in vascular beds, and binding to ICAM1 has been implicated in cerebral malaria. Binding to ICAM1 may be mediated by the variant surface antigen family PfEMP1: for example, 6 of 21 DBLβC2 domains from the IT4 strain PfEMP1 repertoire were shown to bind ICAM1, and the PfEMP1 containing these 6 domains are all classified as Group B or C type. In this study, we surveyed binding of ICAM1 to 16 DBLβC2 domains of the 3D7 strain PfEMP1 repertoire, using a high throughput Bioplex assay format. Only one DBL2βC2 domain from the Group A PfEMP1 PF11_0521 showed strong specific binding. Among these 16 domains, DBL2βC2PF11_0521 best preserved the residues previously identified as conserved in ICAM1-binding versus non-binding domains. Our analyses further highlighted the potential role of conserved residues within predominantly non-conserved flexible loops in adhesion, and, therefore, as targets for intervention. Our studies also suggest that the structural/functional DBLβC2 domain involved in ICAM1 binding includes about 80 amino acid residues upstream of the previously suggested DBLβC2 domain. DBL2βC2PF11_0521 binding to ICAM1 was inhibited by immune sera from east Africa but not by control US sera. Neutralizing antibodies were uncommon in children but common in immune adults from east Africa. Inhibition of binding was much more efficient than reversal of binding, indicating a strong interaction between DBL2βC2PF11_0521 and ICAM1. Our high throughput approach will significantly accelerate studies of PfEMP1 binding domains and protective antibody responses

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Serologic Cross-Reactivity of Human IgM and IgG Antibodies to Five Species of Ebola Virus

Five species of Ebola virus (EBOV) have been identified, with nucleotide differences of 30–45% between species. Four of these species have been shown to cause Ebola hemorrhagic fever (EHF) in humans and a fifth species (Reston ebolavirus) is capable of causing a similar disease in non-human primates. While examining potential serologic cross-reactivity between EBOV species is important for diagnostic assays as well as putative vaccines, the nature of cross-reactive antibodies following EBOV infection has not been thoroughly characterized. In order to examine cross-reactivity of human serologic responses to EBOV, we developed antigen preparations for all five EBOV species, and compared serologic responses by IgM capture and IgG enzyme-linked immunosorbent assay (ELISA) in groups of convalescent diagnostic sera from outbreaks in Kikwit, Democratic Republic of Congo (n = 24), Gulu, Uganda (n = 20), Bundibugyo, Uganda (n = 33), and the Philippines (n = 18), which represent outbreaks due to four different EBOV species. For groups of samples from Kikwit, Gulu, and Bundibugyo, some limited IgM cross-reactivity was noted between heterologous sera-antigen pairs, however, IgM responses were largely stronger against autologous antigen. In some instances IgG responses were higher to autologous antigen than heterologous antigen, however, in contrast to IgM responses, we observed strong cross-reactive IgG antibody responses to heterologous antigens among all sets of samples. Finally, we examined autologous IgM and IgG antibody levels, relative to time following EHF onset, and observed early peaking and declining IgM antibody levels (by 80 days) and early development and persistence of IgG antibodies among all samples, implying a consistent pattern of antibody kinetics, regardless of EBOV species. Our findings demonstrate limited cross-reactivity of IgM antibodies to EBOV, however, the stronger tendency for cross-reactive IgG antibody responses can largely circumvent limitations in the utility of heterologous antigen for diagnostic assays and may assist in the development of antibody-mediated vaccines to EBOV

Successful Cognitive Aging in Rats: A Role for mGluR5 Glutamate Receptors, Homer 1 Proteins and Downstream Signaling Pathways

Normal aging is associated with impairments in cognition, especially learning and memory. However, major individual differences are known to exist. Using the classical Morris Water Maze (MWM) task, we discriminated a population of 24-months old Long Evans aged rats in two groups - memory-impaired (AI) and memory-unimpaired (AU) in comparison with 6-months old adult animals. AI rats presented deficits in learning, reverse memory and retention. At the molecular level, an increase in metabotropic glutamate receptors 5 (mGluR5) was observed in post-synaptic densities (PSD) in the hippocampus of AU rats after training. Scaffolding Homer 1b/c proteins binding to group 1 mGluR facilitate coupling with its signaling effectors while Homer 1a reduces it. Both Homer 1a and 1b/c levels were up-regulated in the hippocampus PSD of AU animals following MWM task. Using immunohistochemistry we further demonstrated that mGluR5 as well as Homer 1b/c stainings were enhanced in the CA1 hippocampus sub-field of AU animals. In fact mGluR5 and Homer 1 isoforms were more abundant and co-localized in the hippocampal dendrites in AU rats. However, the ratio of Homer 1a/Homer 1b/c bound to mGluR5 in the PSD was four times lower for AU animals compared to AI rats. Consequently, AU animals presented higher PKCγ, ERK, p70S6K, mTOR and CREB activation. Finally the expression of immediate early gene Arc/Arg3.1 was shown to be higher in AU rats in accordance with its role in spatial memory consolidation. On the basis of these results, a model of successful cognitive aging with a critical role for mGluR5, Homer 1 proteins and downstream signalling pathways is proposed here