Association of Secondhand Smoke Exposure with Pediatric Invasive Bacterial Disease and Bacterial Carriage: A Systematic Review and Meta-analysis

Background: A number of epidemiologic studies have observed an association between secondhand smoke (SHS) exposure and pediatric invasive bacterial disease (IBD) but the evidence has not been systematically reviewed. We carried out a systematic review and meta-analysis of SHS exposure and two outcomes, IBD and pharyngeal carriage of bacteria, for Neisseria meningitidis (N. meningitidis), Haemophilus influenzae type B (Hib), and Streptococcus pneumoniae (S. pneumoniae). Methods and Findings: Two independent reviewers searched Medline, EMBASE, and selected other databases, and screened articles for inclusion and exclusion criteria. We identified 30 case-control studies on SHS and IBD, and 12 crosssectional studies on SHS and bacterial carriage. Weighted summary odd ratios (ORs) were calculated for each outcome and for studies with specific design and quality characteristics. Tests for heterogeneity and publication bias were performed. Compared with those unexposed to SHS, summary OR for SHS exposure was 2.02 (95% confidence interval [CI] 1.52–2.69) for invasive meningococcal disease, 1.21 (95% CI 0.69–2.14) for invasive pneumococcal disease, and 1.22 (95% CI 0.93–1.62) for invasive Hib disease. For pharyngeal carriage, summary OR was 1.68 (95% CI, 1.19–2.36) for N. meningitidis, 1.66 (95% CI 1.33–2.07) for S. pneumoniae, and 0.96 (95% CI 0.48–1.95) for Hib. The association between SHS exposure and invasive meningococcal and Hib diseases was consistent regardless of outcome definitions, age groups, study designs, and publication year. The effect estimates were larger in studies among children younger than 6 years of age for all three IBDs, and in studies with the more rigorous laboratory-confirmed diagnosis for invasive meningococcal disease (summary OR 3.24; 95% CI 1.72–6.13). Conclusions: When considered together with evidence from direct smoking and biological mechanisms, our systematic review and meta-analysis indicates that SHS exposure may be associated with invasive meningococcal disease. The epidemiologic evidence is currently insufficient to show an association between SHS and invasive Hib disease or pneumococcal disease. Because the burden of IBD is highest in developing countries where SHS is increasing, there is a need for high-quality studies to confirm these results, and for interventions to reduce exposure of children to SHS

Physical and Psychosocial Health in Older Women with Chronic Pain: Comparing Clusters of Clinical and Nonclinical Samples

This investigation examined why some elderly women with severe pain symptoms and impairment in health status were not seen in a tertiary care pain center.Three groups of older (≥60 years) women were included in the study: women seeking chronic pain treatment at a multidisciplinary pain center (N = 49), and research volunteers from the same institution with (N = 28) and without (N = 27) chronic pain. A clustering classification technique was used to identify clusters of older women with similar physical and mental health status.We found three clusters: 1) a healthy cluster (cluster 1: mostly nonclinical women); 2) a cluster with very poor physical and mental health status (cluster 3); and 3) a cluster with low physical health but average mental health (cluster 2). Although only cluster 1 had significantly higher physical health ( P  < 0.001), all three clusters had different mental health ( P  < 0.001). Within cluster 2, clinical women had more pain than nonclinical women, but within cluster 3, this was not so, indicating that mental health issues may create an obstacle to women having their pain appropriately assessed and treated.Our findings support that while disability and pain severity contribute to specialized pain services usage among older women, there is a subgroup of people not receiving pain care for whom these pain symptoms are similar. Further studies are needed to assess the role of health-seeking behavior, coping preferences, referral patterns, and patient–physician communication on access to tertiary pain care for older women.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79094/1/j.1526-4637.2010.00803.x.pd

Multidimensional Methods for the Formulation of Bipharmaceuticals and Vaccines

Determining and preserving the higher order structural integrity and conformational stability of proteins, plasmid DNA and macromolecular complexes such as viruses, virus-like particles and adjuvanted antigens is often a significant barrier to the successful stabilization and formulation of biopharmaceutical drugs and vaccines. These properties typically must be investigated with multiple lower resolution experimental methods, since each technique monitors only a narrow aspect of the overall conformational state of a macromolecular system. This review describes the use of empirical phase diagrams (EPDs) to combine large amounts of data from multiple high-throughput instruments and construct a map of a target macromolecule's physical state as a function of temperature, solvent conditions, and other stress variables. We present a tutorial on the mathematical methodology, an overview of some of the experimental methods typically used, and examples of some of the previous major formulation applications. We also explore novel applications of EPDs including potential new mathematical approaches as well as possible new biopharmaceutical applications such as analytical comparability, chemical stability, and protein dynamics

An Improved Methodology for Multidimensional High- Throughput Preformulation Characterization of Protein Conformational Stability

The Empirical Phase Diagram (EPD) technique is a vector-based multidimensional analysis method for summarizing large data sets from a variety of biophysical techniques. It can be used to provide comprehensive preformulation characterization of a macromolecule’s higher-order structural integrity and conformational stability. In its most common mode, it represents a type of stimulus-response diagram using environmental variables such as temperature, pH, and ionic strength as the stimulus, with alterations in macromolecular structure being the response. Until now EPD analysis has not been available in a high throughput mode because of the large number of experimental techniques and environmental stressor/stabilizer variables typically employed. A new instrument has been developed that combines circular dichroism, UV-absorbance, fluorescence spectroscopy and light scattering in a single unit with a 6-position temperature controlled cuvette turret. Using this multifunctional instrument and a new software system we have generated EPDs for four model proteins. Results confirm the reproducibility of the apparent phase boundaries and protein behavior within the boundaries. This new approach permits two EPDs to be generated per day using only 0.5 mg of protein per EPD. Thus, the new methodology generates reproducible EPDs in high-throughput mode, and represents the next step in making such determinations more routine

Synthetic Cationic Autoantigen Mimics Glatiramer Acetate Persistence at the Site of Injection and Is Efficacious Against Experimental Autoimmune Encephalomyelitis

A synthetic peptide, K-PLP, consisting of 11-unit poly-lysine (K11) linked via polyethylene glycol (PEG) to proteolipid protein epitope (PLP) was synthesized, characterized, and evaluated for efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE) induced by PLP. K-PLP was designed to mimic the cationic nature of the relapsing-remitting multiple sclerosis treatment, glatiramer acetate (GA). With a pI of ~10, GA is able to form visible aggregates at the site of injection via electrostatic interactions with the anionic extracellular matrix. Aggregation further facilitates the retention of GA at the site of injection and draining lymph nodes, which may contribute to its mechanism of action. K-PLP with a pI of ~11, was found to form visible aggregates in the presence of glycosaminoglycans and persist at the injection site and draining lymph nodes in vivo, similar to GA. Additionally, EAE mice treated with K-PLP showed significant inhibition of clinical symptoms compared to free poly-lysine and to PLP, which are the components of K-PLP. The ability of the poly-lysine motif to retain PLP at the injection site, which increased the local exposure of PLP to immune cells may be an important factor affecting drug efficacy

Structure-Function Analysis of Invasion Plasmid Antigen C (IpaC) from Shigella flexneri

Shigella flexneri causes a self-limiting gastroenteritis in humans, characterized by severe localized inflammation and ulceration of the colonic mucosa. Shigellosis most often targets young children in underdeveloped countries. Invasion plasmid antigen C (IpaC) has been identified as the primary effector protein for Shigella invasion of epithelial cells. Although an initial model of IpaC function has been developed, no detailed structural information is available that could assist in a better understanding of the molecular basis for its interactions with the host cytoskeleton and phospholipid membrane. We have therefore initiated structural studies of IpaC, IpaC I′, (residues 101–363 deleted), and IpaC ΔH (residues 63–170 deleted). The secondary and tertiary structure of the protein was examined as a function of temperature, employing circular dichroism and high resolution derivative absorbance techniques. ANS (8-anilino-1-napthalene sulfonic acid) was used to probe the exposure of the hydrophobic surfaces under different conditions. The interaction of IpaC and these mutants with a liposome model (liposomes with entrapped fluorescein) was also examined. Domain III (residues 261–363) was studied using linker-scanning mutagenesis. It was shown that domain III contains periodic, sequence-dependent activity, suggesting helical structure in this section of the protein. In addition to these structural studies, investigation into the actin nucleation properties of IpaC was conducted, and actin nucleation by IpaC and some of the mutants was exhibited. Structure-function relationships of IpaC are discussed

The role of covalent dimerization on the physical and chemical stability of the EC1 domain of human E-cadherin

The objective of this work was to evaluate the solution stability of the EC1 domain of E-cadherin under various conditions. The EC1 domain was incubated at various temperatures (4, 37, and 70 °C) and pH values (3.0, 7.0, and 9.0). At pH 9.0 and 37 or 70 °C, a significant loss of EC1 was observed due to precipitation and a hydrolysis reaction. The degradation was suppressed upon addition of DTT, suggesting that the formation of EC1 dimer facilitated the EC1 degradation. At 4 °C and various pH values, the EC1 secondary and tertiary showed changes upon incubation up to 28 days, and DTT prevented any structural changes upon 28 days of incubation. Molecular dynamics simulations indicated that the dimer of EC1 has higher mobility than does the monomer; this higher mobility of the EC1 dimer may contribute to instability of the EC1 domain

Executive Functioning: Relationship with High School Student Role Performance

BACKGROUND. Student role performance for academic success in secondary education is under represented in the occupational therapy literature, despite the persistently high dropout rate in the United States (Stillwell & Sable, 2013). Executive dysfunction is one of many possible contributors to difficulties in the classroom (Dirette & Kolak, 2004) and is a better indicator of school performance than IQ (Diamond, 2012). This research examined executive functioning of both alternative and traditional high school students to determine if there is a relationship between executive function and academic success as measured by cumulative grade point average. METHOD. 132 high school students from three different school settings were given the Behavioral Rating Inventory of Executive Function-Self Report (BRIEF-SR). The Global Executive Composite (GEC) and individual subscale scores were compared to GPA. RESULTS. No significant difference in GEC scores was found among settings. Subscale scores for “inhibition” and “task completion” were significantly different in the alternative school setting. A weak negative correlation was seen between the GEC and GPA. However, academically unsuccessful students scored statistically lower on the GEC. CONCLUSION. Global executive dysfunction was not predicted by setting but was seen in academically unsuccessful students