Antibodies to Serine Proteases in the Antiphospholipid Syndrome

It is generally accepted that the major autoantigen for antiphospholipid antibodies (aPL) in the antiphospholipid syndrome (APS) is β2-glycoprotein I (β2GPI). However, a recent study has revealed that some aPL bind to certain conformational epitope(s) on β2GPI shared by the homologous enzymatic domains of several serine proteases involved in hemostasis and fibrinolysis. Importantly, some serine protease–reactive aPL correspondingly hinder anticoagulant regulation and resolution of clots. These results extend several early findings of aPL binding to other coagulation factors and provide a new perspective about some aPL in terms of binding specificities and related functional properties in promoting thrombosis. Moreover, a recent immunological and pathological study of a panel of human IgG monoclonal aPL showed that aPL with strong binding to thrombin promote in vivo venous thrombosis and leukocyte adherence, suggesting that aPL reactivity with thrombin may be a good predictor for pathogenic potentials of aPL

Getting more than they realized they needed: a qualitative study of women's experience of group prenatal care

<p>Abstract</p> <p>Background</p> <p>Pregnant women in Canada have traditionally received prenatal care individually from their physicians, with some women attending prenatal education classes. Group prenatal care is a departure from these practices providing a forum for women to experience medical care and child birth education simultaneously and in a group setting. Although other qualitative studies have described the experience of group prenatal care, this is the first which sought to understand the central meaning or core of the experience. The purpose of this study was to understand the central meaning of the experience of group prenatal care for women who participated in CenteringPregnancy through a maternity clinic in Calgary, Canada.</p> <p>Methods</p> <p>The study used a phenomenological approach. Twelve women participated postpartum in a one-on-one interview and/or a group validation session between June 2009 and July 2010.</p> <p>Results</p> <p>Six themes emerged: (1) "getting more in one place at one time"; (2) "feeling supported"; (3) "learning and gaining meaningful information"; (4) "not feeling alone in the experience"; (5) "connecting"; and (6) "actively participating and taking on ownership of care". These themes contributed to the core phenomenon of women "getting more than they realized they needed". The active sharing among those in the group allowed women to have both their known and subconscious needs met.</p> <p>Conclusions</p> <p>Women's experience of group prenatal care reflected strong elements of social support in that women had different types of needs met and felt supported. The findings also broadened the understanding of some aspects of social support beyond current theories. In a contemporary North American society, the results of this study indicate that women gain from group prenatal care in terms of empowerment, efficiency, social support and education in ways not routinely available through individual care. This model of care could play a key role in addressing women's needs and improving health outcomes.</p

The effect of modifiable risk factors on geographic mortality differentials: a modelling study

Background Australian mortality rates are higher in regional and remote areas than in major cities. The degree to which this is driven by variation in modifiable risk factors is unknown. Methods We applied a risk prediction equation incorporating smoking, cholesterol and blood pressure to a national, population based survey to project all-causes mortality risk by geographic region. We then modelled life expectancies at different levels of mortality risk by geographic region using a risk percentiles model. Finally we set high values of each risk factor to a target level and modelled the subsequent shift in the population to lower levels of mortality risk and longer life expectancy. Results Survival is poorer in both Inner Regional and Outer Regional/Remote areas compared to Major Cities for men and women at both high and low levels of predicted mortality risk. For men smoking, high cholesterol and high systolic blood pressure were each associated with the mortality difference between Major Cities and Outer Regional/Remote areas--accounting for 21.4%, 20.3% and 7.7% of the difference respectively. For women smoking and high cholesterol accounted for 29.4% and 24.0% of the difference respectively but high blood pressure did not contribute to the observed mortality differences. The three risk factors taken together accounted for 45.4% (men) and 35.6% (women) of the mortality difference. The contribution of risk factors to the corresponding differences for inner regional areas was smaller, with only high cholesterol and smoking contributing to the difference in men-- accounting for 8.8% and 6.3% respectively-- and only smoking contributing to the difference in women--accounting for 12.3%. Conclusions These results suggest that health intervention programs aimed at smoking, blood pressure and total cholesterol could have a substantial impact on mortality inequities for Outer Regional/Remote areas. Background: Australian mortality rates are higher in regional and remote areas than in major cities. The degree to which this is driven by variation in modifiable risk factors is unknown. Methods. We applied a risk prediction equation incorporating smoking, cholesterol and blood pressure to a national, population based survey to project all-causes mortality risk by geographic region. We then modelled life expectancies at different levels of mortality risk by geographic region using a risk percentiles model. Finally we set high values of each risk factor to a target level and modelled the subsequent shift in the population to lower levels of mortality risk and longer life expectancy. Results: Survival is poorer in both Inner Regional and Outer Regional/Remote areas compared to Major Cities for men and women at both high and low levels of predicted mortality risk. For men smoking, high cholesterol and high systolic blood pressure were each associated with the mortality difference between Major Cities and Outer Regional/Remote areas - accounting for 21.4%, 20.3% and 7.7% of the difference respectively. For women smoking and high cholesterol accounted for 29.4% and 24.0% of the difference respectively but high blood pressure did not contribute to the observed mortality differences. The three risk factors taken together accounted for 45.4% (men) and 35.6% (women) of the mortality difference. The contribution of risk factors to the corresponding differences for inner regional areas was smaller, with only high cholesterol and smoking contributing to the difference in men - accounting for 8.8% and 6.3% respectively - and only smoking contributing to the difference in women - accounting for 12.3%. Conclusions: These results suggest that health intervention programs aimed at smoking, blood pressure and total cholesterol could have a substantial impact on mortality inequities for Outer Regional/Remote areas

Use of 16S ribosomal RNA gene analyses to characterize the bacterial signature associated with poor oral health in West Virginia

<p>Abstract</p> <p>Background</p> <p>West Virginia has the worst oral health in the United States, but the reasons for this are unclear. This pilot study explored the etiology of this disparity using culture-independent analyses to identify bacterial species associated with oral disease.</p> <p>Methods</p> <p>Bacteria in subgingival plaque samples from twelve participants in two independent West Virginia dental-related studies were characterized using 16S rRNA gene sequencing and Human Oral Microbe Identification Microarray (HOMIM) analysis. Unifrac analysis was used to characterize phylogenetic differences between bacterial communities obtained from plaque of participants with low or high oral disease, which was further evaluated using clustering and Principal Coordinate Analysis.</p> <p>Results</p> <p>Statistically different bacterial signatures (<it>P </it>< 0.001) were identified in subgingival plaque of individuals with low or high oral disease in West Virginia based on 16S rRNA gene sequencing. Low disease contained a high frequency of <it>Veillonella </it>and <it>Streptococcus</it>, with a moderate number of <it>Capnocytophaga</it>. High disease exhibited substantially increased bacterial diversity and included a large proportion of Clostridiales cluster bacteria (<it>Selenomonas</it>, <it>Eubacterium, Dialister</it>). Phylogenetic trees constructed using 16S rRNA gene sequencing revealed that Clostridiales were repeated colonizers in plaque associated with high oral disease, providing evidence that the oral environment is somehow influencing the bacterial signature linked to disease.</p> <p>Conclusions</p> <p>Culture-independent analyses identified an atypical bacterial signature associated with high oral disease in West Virginians and provided evidence that the oral environment influenced this signature. Both findings provide insight into the etiology of the oral disparity in West Virginia.</p

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)

Informed consent for HIV cure research in South Africa: issues to consider

Background: South Africa has made great progress in the development of HIV/AIDS testing, treatment and prevention campaigns. Yet, it is clear that prevention and treatment campaigns alone are not enough to bring this epidemic under control. Discussion: News that the “Berlin patient” and the “Mississippi baby” have both been “cured” of HIV brought hope to people living with HIV/AIDS in South Africa that a cure for HIV/AIDS is within reach. Despite the recent setbacks announced in the “Mississippi Baby” case, protocols aimed at curing HIV/AIDS are being developed in South Africa. However with evidence to suggest that participants in clinical trials do not understand the basic concepts in the informed consent process, there is concern that future participants in HIV/AIDS cure research will lack comprehension of the basic elements of future clinical trials that aims to cure HIV/AIDS and confuse research with clinical care. Summary: Research ethics committees have an important role to play in ensuring that participants understand the basic concepts discussed in the informed consent process, that they understand that research is not clinical care and they are unlikely to benefit from any early phase trials seeking to cure HIV/AIDS

Characterization of simple sequence repeats (SSRs) from Phlebotomus papatasi (Diptera: Psychodidae) expressed sequence tags (ESTs)

<p>Abstract</p> <p>Background</p> <p><it>Phlebotomus papatasi </it>is a natural vector of <it>Leishmania major</it>, which causes cutaneous leishmaniasis in many countries. Simple sequence repeats (SSRs), or microsatellites, are common in eukaryotic genomes and are short, repeated nucleotide sequence elements arrayed in tandem and flanked by non-repetitive regions. The enrichment methods used previously for finding new microsatellite loci in sand flies remain laborious and time consuming; <it>in silico </it>mining, which includes retrieval and screening of microsatellites from large amounts of sequence data from sequence data bases using microsatellite search tools can yield many new candidate markers.</p> <p>Results</p> <p>Simple sequence repeats (SSRs) were characterized in <it>P. papatasi </it>expressed sequence tags (ESTs) derived from a public database, National Center for Biotechnology Information (NCBI). A total of 42,784 sequences were mined, and 1,499 SSRs were identified with a frequency of 3.5% and an average density of 15.55 kb per SSR. Dinucleotide motifs were the most common SSRs, accounting for 67% followed by tri-, tetra-, and penta-nucleotide repeats, accounting for 31.1%, 1.5%, and 0.1%, respectively. The length of microsatellites varied from 5 to 16 repeats. Dinucleotide types; AG and CT have the highest frequency. Dinucleotide SSR-ESTs are relatively biased toward an excess of (AX)n repeats and a low GC base content. Forty primer pairs were designed based on motif lengths for further experimental validation.</p> <p>Conclusion</p> <p>The first large-scale survey of SSRs derived from <it>P. papatasi </it>is presented; dinucleotide SSRs identified are more frequent than other types. EST data mining is an effective strategy to identify functional microsatellites in <it>P. papatasi</it>.</p

A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

Background: b2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of b2GPI generated by anti-b2GPI antibodies is pathologically important, in contrast to monomeric b2GPI which is abundant in plasma. Principal Findings: We created a dimeric inhibitor, A1-A1, to selectively target b2GPI in b2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of b2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of b2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of b2GPI present in human serum, b2GPI purified from human plasma and the individual domain V of b2GPI. We demonstrated that when b2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of b2GPI to cardiolipin, regardless of the source of b2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of b2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-b2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric b2GPI to cardiolipin. Conclusions: Our results suggest that the approach of using a dimeric inhibitor to block b2GPI in the pathologica

A Unique Role for Nonmuscle Myosin Heavy Chain IIA in Regulation of Epithelial Apical Junctions

The integrity and function of the epithelial barrier is dependent on the apical junctional complex (AJC) composed of tight and adherens junctions and regulated by the underlying actin filaments. A major F-actin motor, myosin II, was previously implicated in regulation of the AJC, however direct evidence of the involvement of myosin II in AJC dynamics are lacking and the molecular identity of the myosin II motor that regulates formation and disassembly of apical junctions in mammalian epithelia is unknown. We investigated the role of nonmuscle myosin II (NMMII) heavy chain isoforms, A, B, and C in regulation of epithelial AJC dynamics and function. Expression of the three NMMII isoforms was observed in model intestinal epithelial cell lines, where all isoforms accumulated within the perijunctional F-actin belt. siRNA-mediated downregulation of NMMIIA, but not NMMIIB or NMMIIC expression in SK-CO15 colonic epithelial cells resulted in profound changes of cell morphology and cell-cell adhesions. These changes included acquisition of a fibroblast-like cell shape, defective paracellular barrier, and substantial attenuation of the assembly and disassembly of both adherens and tight junctions. Impaired assembly of the AJC observed after NMMIIA knock-down involved dramatic disorganization of perijunctional actin filaments. These findings provide the first direct non-pharmacological evidence of myosin II-dependent regulation of AJC dynamics in mammalian epithelia and highlight a unique role of NMMIIA in junctional biogenesis

CD56 is a pathogen recognition receptor on human natural killer cells

Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response