Alginate-encapsulated brain-derived neurotrophic factor-overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons.
The cochlear implant outcome is possibly improved by brain-derived neurotrophic factor treatment protecting spiral ganglion neurons. Implantation of genetically modified mesenchymal stem cells may enable the required long-term brain-derived neurotrophic factor administration. Encapsulation of mesenchymal stem cells in ultra-high viscous alginate may protect the mesenchymal stem cells from the recipient's immune system and prevent their uncontrolled migration. Alginate stability and survival of mesenchymal stem cells in alginate were evaluated. Brain-derived neurotrophic factor production was measured and its protective effect was analyzed in dissociated rat spiral ganglion neuron co-culture. Since the cochlear implant is an active electrode, alginate-mesenchymal stem cell samples were electrically stimulated and alginate stability and mesenchymal stem cell survival were investigated. Stability of ultra-high viscous-alginate and alginate-mesenchymal stem cells was proven. Brain-derived neurotrophic factor production was detectable and spiral ganglion neuron survival, bipolar morphology, and neurite outgrowth were increased. Moderate electrical stimulation did not affect the mesenchymal stem cell survival and their viability was good within the investigated time frame. Local drug delivery by ultra-high viscous-alginate-encapsulated brain-derived neurotrophic factor-overexpressing mesenchymal stem cells is a promising strategy to improve the cochlear implant outcome.


Towards quantitative imaging biomarkers of tumor dissemination: A multi-scale parametric modeling of multiple myeloma.
The advent of medical imaging and automatic image analysis is bringing the full quantitative assessment of lesions and tumor burden at every clinical examination within reach. This opens avenues for the development and testing of functional disease models, as well as their use in the clinical practice for personalized medicine. In this paper, we introduce a Bayesian statistical framework, based on mixed-effects models, to quantitatively test and learn functional disease models at different scales, on population longitudinal data. We also derive an effective mathematical model for the crossover between initially detected lesions and tumor dissemination, based on the Iwata-Kawasaki-Shigesada model. We finally propose to leverage this descriptive disease progression model into model-aware biomarkers for personalized risk-assessment, taking all available examinations and relevant covariates into account. As a use case, we study Multiple Myeloma, a disseminated plasma cell cancer, in which proper diagnostics is essential, to differentiate frequent precursor state without end-organ damage from the rapidly developing disease requiring therapy. After learning the best biological models for local lesion growth and global tumor burden evolution on clinical data, and computing corresponding population priors, we use individual model parameters as biomarkers, and can study them systematically for correlation with external covariates, such as sex or location of the lesion. On our cohort of 63 patients with smoldering Multiple Myeloma, we show that they perform substantially better than other radiological criteria, to predict progression into symptomatic Multiple Myeloma. Our study paves the way for modeling disease progression patterns for Multiple Myeloma, but also for other metastatic and disseminated tumor growth processes, and for analyzing large longitudinal image data sets acquired in oncological imaging. It shows the unprecedented potential of model-based biomarkers for better and more personalized treatment decisions and deserves being validated on larger cohorts to establish its role in clinical decision making.


Teamwork in the operating theatre: cohesion or confusion?
The aim of the research that we report here was to empirically assess the cohesiveness of the multidisciplinary operating theatre (OT) team. We used concepts from the team performance and team mental models literature to assess OT professionals' perceptions of their teamwork, the structure of their teams and their respective roles within them and their teams' performance. Team structure: OT professionals would welcome a change from the current structure of the team, although there was no agreement on what that structure is. Nurses perceived the team as unitary, surgeons and anaesthetists perceived it as comprising multiple subteams. Team roles: OT professionals tended to overrate their own understanding of their colleagues' role in the OT relative to the role understanding that the colleagues attributed to them. This tendency was especially marked for the surgeons. Team communication and team performance: OT professionals agreed on the relative importance of the various communicating pairs in the OT. Moreover, they were satisfied with the quality of communication among them, except for the communication between the surgeon and the anaesthetist, which received lower ratings. Finally, the quality of the teamwork in the OT was deemed acceptable, although there is room for improvement. The OT environment need not be as cohesive as previously assumed--a finding that carries implications for the effectiveness of team training interventions. Further research is needed in order to fully comprehend the dynamics of the OT as a working environment and, most importantly, their relation to patient safety.


The origin of RNA precursors on exoplanets.
Given that the macromolecular building blocks of life were likely produced photochemically in the presence of ultraviolet (UV) light, we identify some general constraints on which stars produce sufficient UV for this photochemistry. We estimate how much light is needed for the UV photochemistry by experimentally measuring the rate constant for the UV chemistry ("light chemistry", needed for prebiotic synthesis) versus the rate constants for the bimolecular reactions that happen in the absence of the UV light ("dark chemistry"). We make these measurements for representative photochemical reactions involving SO32- and HS-. By balancing the rates for the light and dark chemistry, we delineate the "abiogenesis zones" around stars of different stellar types based on whether their UV fluxes are sufficient for building up this macromolecular prebiotic inventory. We find that the SO32- light chemistry is rapid enough to build up the prebiotic inventory for stars hotter than K5 (4400 K). We show how the abiogenesis zone overlaps with the liquid water habitable zone. Stars cooler than K5 may also drive the formation of these building blocks if they are very active. The HS- light chemistry is too slow to work even for early Earth.


Transient activation of the acetyltransferase necessary for paf-acether biosynthesis in thrombin-activated platelets.
Thrombin-activated platelets formed paf-acether (1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine), a molecule susceptible to play a role in haemostasis and thrombosis, and its deacetylated analogue, lyso paf-acether, a biologically inactive molecule. We presently show the presence in human and rabbit platelet lysates of an acetyltransferase which transfers the acetyl moiety of acetyl-coenzyme A (acetyl-CoA) onto synthetic lyso paf-acether, yielding the fully active paf-acether molecule. Under our optimal standard conditions, 0.36 +/- 0.23 nmol paf-acether/10 min/mg proteins was formed by the acetyltransferase from resting human platelets. Upon thrombin stimulation, the acetyltransferase activity doubled within 30 s, reaching a maximum at 2 min (1.17 +/- 0.31 nmol paf-acether/10 min/mg proteins) and decreased progressively. Similar results were obtained using rabbit platelets. In addition we demonstrated that the activation and deactivation of the acetyltransferase correlated with the kinetics of paf-acether formation by thrombin-activated rabbit platelets. It is hypothesized that this enzyme may represent one of the regulating mechanism of paf-acether formation by platelets.


Long-term resistance training in the elderly: effects on dynamic strength, exercise capacity, muscle, and bone.
We examined the effects of 42 weeks of progressive weight-lifting training on dynamic muscle strength, peak power output in cycle ergometry, symptom limited endurance during progressive treadmill walking and stair climbing, knee extensor cross-sectional areas, and bone mineral density and content in healthy males and females aged 60-80 years, currently enrolled in a 2-year resistance training program. Subjects were randomized into either exercise (EX) or control (CON) groups (60-70 years: 38 males and 36 females; 70-80 years: 25 males and 43 females). EX trained several muscle groups twice per week for 42 weeks at intensities ranging from 50-80% of the load that they could lift once only (1 RM); CON did usual daily activities. After the 10 months there was no change in 1 RM strength in CON, but significant gains (mean increases up to 65%) in EX (no independent age or gender effects); 30% and 47% of the increase in 1 RM had occurred by 6 and 12 weeks, respectively. In EX, the 7.1% increase in peak cycling power output was significantly greater than in CON (+1.1%). The 17.8% improvement in symptom limited treadmill walking endurance was also greater than in CON (+3.4%), but the difference between groups during stair climbing was not significant (EX + 57%, CON + 33%). The cross-sectional areas of the knee extensors increased significantly by 5.5% in EX but were unchanged in CON. There were no changes in bone mineral density or content in either group. We conclude that long-term resistance training in older people is feasible and results in increases in dynamic muscle strength, muscle size, and functional capacity.


Targeting kinases for the treatment of inflammatory diseases.
Inflammatory diseases are one of the major health issues and have become a major focus in the pharmaceutical and biotech industries. To date, drugs prescribed for treatment of these diseases target enzymes that are not specific to the immune system resulting in adverse effects. The main challenge of this research field is, therefore, identifying targets that act specifically on the diseased tissue. This review summarizes drug discovery efforts on kinases that have been identified as key players mediating inflammation and autoimmune disorders. In particular, we discuss recent developments on well-established targets such as mammalian target of rapamycin, JAK3, spleen tyrosine kinase, p38α and lymphocyte specific kinase but provide also a perspective on emerging targets. The reader will obtain an overview of drug discovery efforts on kinases in inflammation, recent clinical and preclinical data and developed inhibitor scaffolds. In addition, the reader will be updated on issues in target validation of current drug targets and the potential of selected novel kinase targets in this important disease area. Cellular signaling networks that regulate inflammatory response are still poorly understood making rational selection of targets challenging. Recent data suggest that kinase targets that are specific to the immune system and mediate signals immediately downstream of surface receptors are most efficacious in the clinic.


A review of recent experiments on step-to-step "hand-off" of the DNA intermediates in mammalian base excision repair pathways.
The current "working model" for mammalian base excision repair involves two sub-pathways termed single-nucleotide base excision repair and long patch base excision repair that are distinguished by their repair patch sizes and the enzymes/co-factors involved. These base excision repair sub-pathways are designed to sequester the various DNA intermediates, passing them along from one step to the next without allowing these toxic molecules to trigger cell cycle arrest, necrotic cell death, or apoptosis. Although a variety of DNA-protein and protein-protein interactions are known for the base excision repair intermediates and enzymes/co-factors, the molecular mechanisms accounting for step-to-step coordination are not well understood. In this review, we explore the question of whether there is an actual step-to-step "hand-off" of the DNA intermediates during base excision repair in vitro. The results show that when base excision repair enzymes are pre-bound to the initial single-nucleotide base excision repair intermediate, the DNA is channeled from apurinic/apyrimidinic endonuclease 1 to DNA polymerase beta and then to DNA ligase. In the long patch base excision repair sub-pathway, where the 5'-end of the incised strand is blocked, the intermediate after polymerase beta gap filling is not channeled from polymerase beta to the subsequent enzyme, flap endonuclease 1. Instead, flap endonuclease 1 must recognize and bind to the intermediate in competition with other molecules.


Interleukins 4 and 13 increase intestinal epithelial permeability by a phosphatidylinositol 3-kinase pathway. Lack of evidence for STAT 6 involvement.
Interleukins 4 and 13 can affect their target cells by activation of signal transducer and activator of transcription 6 (STAT 6) or phosphatidylinositol 3-kinase (PI3K). We examined the signal transduction events involved in IL-4 and IL-13 regulation of epithelial paracellular permeability using T84 cells, a model human colonic epithelium. T84 cells treated with IL-4 or IL-13 displayed virtually identical dose- and time-dependent STAT 6 activation as assessed by electrophoretic mobility shift assay (EMSA) and decreases in transepithelial resistance (TER). STAT 6 DNA binding activity was maximal in nuclear extracts 30 min after exposure to IL-4 or IL-13, and TER was maximally reduced by 24 h post-treatment. Pretreatment of epithelia with transcription factor decoys (phosphorothioated DNA oligonucleotides containing the STAT 6 binding site) dramatically reduced STAT 6 activation as detected by EMSA, but did not attenuate the TER reduction by IL-4 or IL-13. In contrast, although the PI3K inhibitors wortmannin and LY294002 did not affect IL-4 or IL-13 STAT 6 activation, they significantly inhibited the ability of either cytokine to lower TER. Thus, we provide evidence for PI3K as the major proximal signaling event in IL-4 and IL-13 regulation of TER and speculate that pharmacological targeting of enterocytic PI3K activity may represent a means to manipulate epithelial permeability.


Epidemiology of hepatitis C in the Middle East.
The epidemiology of hepatitis C virus (HCV) infection is not well defined in the Middle East region. A review of the epidemiology and modes of transmission and spread of HCV infection in regions located in the Middle East, including Iran, Bahrain, Iraq, Oman, Qatar, Jordan, Kuwait, Saudi Arabia, United Arab Emirates, Cyprus, Sudan, Egypt, Pakistan, Syria, Turkey, Lebanon, Gaza Strip and West Bank, and Yemen, was undertaken. Public health strategies, well-programmed, population-based and certain HCV infection at-risk surveys, and transmission risk factors' settings detection are insufficient in some countries of this region. Since significant differences in prevalence and epidemiology of HCV exist among the Middle East countries or even inside the countries, control strategies should take these differences into account.


Dietary fat alters pulmonary metastasis of mammary cancers through cancer autonomous and non-autonomous changes in gene expression.
Metastasis virulence, a significant contributor to breast cancer prognosis, is influenced by environmental factors like diet. We previously demonstrated in an F2 mouse population generated from a cross between the M16i polygenic obese and MMTV-PyMT mammary cancer models that high fat diet (HFD) decreases mammary cancer latency and increases pulmonary metastases compared to a matched control diet (MCD). Genetic analysis detected eight modifier loci for pulmonary metastasis, and diet significantly interacted with all eight loci. Here, gene expression microarray analysis was performed on mammary cancers from these mice. Despite the substantial dietary impact on metastasis and its interaction with metastasis modifiers, HFD significantly altered the expression of only five genes in mammary tumors; four of which, including serum amyloid A (Saa), are downstream of the tumor suppressor PTEN. Conversely, HFD altered the expression of 211 hepatic genes in a set of tumor free F2 control mice. Independent of diet, pulmonary metastasis virulence correlates with mammary tumor expression of genes involved in endocrine cancers, inflammation, angiogenesis, and invasion. The most significant virulence-associated network harbored genes also found in human adipose or mammary tissue, and contained upregulated Vegfa as a central node. Additionally, expression of Btn1a1, a gene physically located near a putative cis-acting eQTL on chromosome 13 and one of the metastasis modifiers, correlates with metastasis virulence. These data support the existence of diet-dependent and independent cancer modifier networks underlying differential susceptibility to mammary cancer metastasis and suggest that diet influences cancer metastasis virulence through tumor autonomous and non-autonomous mechanisms.


Activating HER2 mutations in HER2 gene amplification negative breast cancer.
Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.


[Cytogenetic effects of hyperbaric oxygenation].
This paper presents cytogenetic data obtained from peripheral blood of patients who were treated with hyperbaric oxygenation (HBO) at 0.15-0.2 MPa for 40 min daily during 10 days. The patients showed a significant increase of chromosome aberrations mainly caused by chromatid and chromosome breaks. The level of induced aberrations showed individual variations. These results suggest that HBO may have an indirect effect on the genetic apparatus of human somatic cells.


The police-based crisis intervention team (CIT) model: II. Effects on level of force and resolution, referral, and arrest.
The crisis intervention team (CIT) model is a widely implemented police-based program to improve officers' responses to individuals with behavioral disorders. The authors examined levels of force used by officers with or without CIT training and disposition decisions in a large sample of encounters with individuals whom they suspected of having a serious mental illness, a drug or an alcohol problem, or a developmental disability. A total of 180 officers (91 with CIT training and 89 without) in six departments reported on 1,063 encounters, including level of force and disposition (resolution at the scene, referral or transport to services, or arrest). CIT training status was generally not predictive of level of force, although CIT-trained officers were significantly more likely to report verbal engagement or negotiation as the highest level of force used (odds ratio [OR]=2.00, p=.016). For CIT-trained officers, referral or transport was a more likely outcome (OR=1.70, p=.026) and arrest was less likely (OR=.47, p=.007) than for officers without CIT training; these findings were most pronounced when physical force was necessary. Analyses of disposition differences by officers' perceptions of subjects' primary problem (for example, mental illness only versus a drug or an alcohol problem) found some effects of CIT training status. CIT training appears to increase the likelihood of referral or transport to mental health services and decrease the likelihood of arrest during encounters with individuals thought to have a behavioral disorder. Research should address subject- and system-level outcomes that complement this early evidence of successful prebooking jail diversion.


Performance of the Phoenix bacterial identification system compared with disc diffusion methods for identifying extended-spectrum beta-lactamase, AmpC and KPC producers.
Phenotypic identification of AmpC, KPC and extended-spectrum beta-lactamases (ESBLs) among members of the Enterobacteriaceae remains challenging. This study compared the Phoenix Automated Microbiology System (BD Diagnostics) with the Clinical and Laboratory Standards Institute confirmatory method to identify ESBL production among 200 Escherichia coli and Klebsiella pneumoniae clinical isolates. The Phoenix system misclassified nearly half of the isolates as ESBL-positive, requiring manual testing for confirmation. Inclusion of aztreonam +/- clavulanic acid (CA) and cefpodoxime +/- CA in the testing algorithm increased the ESBL detection rate by 6 %. Boronic acid-based screening identified 24 isolates as AmpC(+), but in a subset of genotypically characterized isolates, appeared to have a high false-positivity rate. PCR screening revealed eight KPC(+) isolates, all of which tested as ESBL(+) or ESBL(+) AmpC(+) by phenotypic methods, but half were reported as carbapenem-susceptible by the Phoenix system. Overall, these results indicate that laboratories should use the Phoenix ESBL results only as an initial screen followed by confirmation with an alternative method.


Monolithic beds of artificial gel antibodies.
The introductions of the continuous beds, now often called monoliths [S. Hjertén, J.-L. Liao, R. Zhang, J. Chromatogr. 473 (1989), 273-275] and the artificial, highly selective gel antibodies against antigens as large as proteins, viruses and cells [J.-L. Liao, Y. Wang, S. Hjertén, Chromatographia 42 (1996), 259-262] were breakthroughs in the design of chromatographic beds. This paper deals with a combination of these two methods, i.e., the artificial gel antibodies have been synthesized in the monolithic mode. As antigen we have used human hemoglobin. A comparison of the ion-exchange chromatograms of the eluates from the monolithic columns shows that the monolith prepared in the presence of hemoglobin adsorbed this protein, but not the other proteins in the sample (ribonuclease A and cytochrome c), i.e., this monolith was selective for hemoglobin, whereas the blank column (prepared in the absence of hemoglobin) had no selective properties, since none of the applied proteins were adsorbed. The diameter of the column was 6mm, but the same approach to synthesize a monolithic selective bed can very likely also be used for capillaries and microchips.


Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation.
Plexins are cell surface receptors widely studied in the nervous system, where they mediate migration and morphogenesis though the Rho family of small GTPases. More recently, plexins have been implicated in immune processes including cell-cell interaction, immune activation, migration, and cytokine production. Plexin-B2 facilitates ligand induced cell guidance and migration in the nervous system, and induces cytoskeletal changes in overexpression assays through RhoGTPase. The function of Plexin-B2 in the immune system is unknown. This report shows that Plexin-B2 is highly expressed on cells of the innate immune system in the mouse, including macrophages, conventional dendritic cells, and plasmacytoid dendritic cells. However, Plexin-B2 does not appear to regulate the production of proinflammatory cytokines, phagocytosis of a variety of targets, or directional migration towards chemoattractants or extracellular matrix in mouse macrophages. Instead, Plxnb2(-/-) macrophages have greater cellular motility than wild type in the unstimulated state that is accompanied by more active, GTP-bound Rac and Cdc42. Additionally, Plxnb2(-/-) macrophages demonstrate faster in vitro wound closure activity. Studies have shown that a closely related family member, Plexin-B1, binds to active Rac and sequesters it from downstream signaling. The interaction of Plexin-B2 with Rac has only been previously confirmed in yeast and bacterial overexpression assays. The data presented here show that Plexin-B2 functions in mouse macrophages as a negative regulator of the GTPases Rac and Cdc42 and as a negative regulator of basal cell motility and wound healing.


Out-of-body experience, heautoscopy, and autoscopic hallucination of neurological origin Implications for neurocognitive mechanisms of corporeal awareness and self-consciousness.
Autoscopic phenomena (AP) are rare illusory visual experiences during which the subject has the impression of seeing a second own body in extrapersonal space. AP consist of out-of-body experience (OBE), autoscopic hallucination (AH), and heautoscopy (HAS). The present article reviews and statistically analyzes phenomenological, functional, and anatomical variables in AP of neurological origin (n = 41 patients) that have been described over the last 100 years. This was carried out in order to further our understanding of the underlying mechanisms of AP, much as previous research into the neural bases of body part illusions has demystified these latter phenomena. Several variables could be extracted, which distinguish between or are comparable for the three AP providing testable hypotheses for subsequent research. Importantly, we believe that the scientific demystification of AP may be useful for the investigation of the cognitive functions and brain regions that mediate processing of the corporeal awareness and self consciousness under normal conditions.


Blood pressure variability and prevalence of hypertension using automated readings from multiple visits to a pharmacy-based community-wide programme.
Blood pressure (BP) measurements taken outside the routine office context may be a useful adjunct strategy to monitor BP. Community-based BP data can also provide estimates of the prevalence of elevated BP. We compared multiple readings taken on different days in pharmacies using an automated BpTRU device during a cardiovascular health programme targeting community-dwelling older adults. Mean systolic (S) and diastolic (D) BP values were compared over time using repeated measures analysis of variance for all participants with at least three separate sets of readings (n=317). BP variability was then examined among four subgroups based on report of antihypertensive medication or no treatment, and normal or elevated SBP at the initial visit (< or >or=140, or 130 if diabetes reported). Prevalence of elevated BP was compared across visits. Overall, mean SBP decreased between visits 1 and 2 (140.4 vs 137.1 mm Hg; P<0.001). Among participants with normal SBP at the initial visit, SBP did not vary significantly, whether or not antihypertensive treatment was reported. Those with initially elevated SBP experienced a significant decrease between visits 1 and 2, also regardless of treatment status. Prevalence of elevated BP decreased from visits 1 to 2 (55.8 vs 48.9%; P=0.026) and from visits 1 to 3 (55.8 vs 42.9%; P<0.001). Analyses of BP data from a community-based programme using an accurate device showed that initial readings may inflate the population estimate of elevated BP. Findings suggest that more than one set of BP readings measured on different occasions are needed, particularly if the first set is elevated.


Comparison of mouse and human HOX-4 complexes defines conserved sequences involved in the regulation of Hox-4.4.
We have cloned and sequenced, in both mouse and human, regions of the HOX-4 complex which contain two Abd-B like genes, Hox-4.4 and Hox-4.5 (HOX4C and HOX4D in human, respectively). The high degree of conservation between the homeoprotein sequences extends to non-coding areas, which suggests that the mechanisms of regulation have been conserved. We show that the Hox-4.5/Hox-4.4 intergenic region can be broadly subdivided into three domains based on DNA conservation between rodents and primates. The presence of all these domains in association with sequences located 3' to the transcription termination site are required to mimick the spatial regulation of Hox-4.4 in transgenic mouse embryos. Several highly conserved short sequences located in this region were studied in gel retardation assays for their binding to potential regulatory factors. One such factor is detected in embryonal carcinoma cells but absent from other differentiated cell lines. This specific binding activity is down regulated upon retinoic acid treatment.


Superoxide anion production and degranulation of rat neutrophils in response to acetaldehyde-altered liver cell membranes.
Rat liver membrane vesicles were exposed to acetaldehyde, with or without reduction of the resultant adducts formed. Superoxide anion production and degranulation of rat neutrophils, upon stimulation with the liver membrane vesicles, were measured by cytochrome c reduction before and after the addition of superoxide dismutase, and beta-glucuronidase release respectively. Preincubation with acetaldehyde significantly enhanced superoxide anion production by both the reduced and non-reduced membrane samples (1.7-fold and 4.4-fold, respectively). Preincubation with acetaldehyde significantly enhanced degranulation (1.5-fold) of neutrophils in response to the non-reduced membranes only. The reductive process itself caused a marked increase (2.4-fold) in the ability of the membrane vesicles to stimulate degranulation. Cytochalasin B, an inhibitor of phagocytosis, did not reduce degranulation, implying that it occurred as a consequence of cell surface stimulation. Neutrophil superoxide anion production and lysosomal enzyme release in response to acetaldehyde-altered liver cell membranes could be an important mechanism of hepatocyte injury in alcoholic liver disease.


A Process-Oriented Approach to Teaching Religion and Spirituality in Psychiatry Residency Training.
Although the importance of addressing issues of spirituality and religion is increasingly acknowledged within psychiatry training, many questions remain about how to best teach relevant knowledge, skills, and attitudes. Current literature on curricula highlights the importance of maintaining a clinical focus and the balance between didactic content and process issues. The authors present findings from a program evaluation study of a course on religion, spirituality, and psychiatry that deliberately takes a primarily process-oriented, clinically focused approach. Two six-session courses were offered. The first course targeted fourth-year psychiatry residents and the second targeted third-year psychiatry residents. Teaching sessions consisted of brief didactics combined with extensive process-oriented discussion. A two-person faculty team facilitated the courses. Clinical case discussions were integrated throughout the curriculum. A panel of chaplains was invited to participate in one session of each course to discuss the interface between spiritual counsel and psychiatry. A modified version of the Course Impact Questionnaire, a 20-item Likert scale utilized in previous studies of spirituality curricula in psychiatry, assessed residents' personal spiritual attitudes, competency, change in professional practice, and change in professional attitudes before and after the course (N = 20). Qualitative feedback was also elicited through written comments. The results from this study showed a statistically significant difference between the pre- and post-test scale for residents' self-perceived competency and change in professional practice. The findings suggest improvement in competency and professional practice scores in residents who participated in this course. This points toward the overall usefulness of the course and suggests that a process-oriented approach may be effective for discussing religion and spirituality in psychiatric training.


Solar concentrator constructed with a circular prism array.
We present a novel idea to construct a solar concentrator with a circular prism array. FRED ray tracing software is used to evaluate our proposed structure in which the incident light rays are deflected by total internal reflection and the optical energy is concentrated and collected at the center. The light rays to be collected travel within the disk once they enter the module, saving the space that is reserved for ray propagation in other concentrators. Simulations for both single-wavelength and broadband light are performed. Our device can be used alone or serve as a secondary concentrator when combined with another solar-energy focusing module. For the proposed concentrator, an optical efficiency of 90% (single wavelength, 0.87 microm) is achieved under normal incidence and with antireflection coating, and a high geometric concentration ratio of 93 is reached. When combined with a Fresnel lens, which is used as a primary concentrator, the overall efficiency and concentration ratio can reach 92% (single wavelength, 0.87 microm) and 837, respectively.


Designing display primaries with currently available light sources for UHDTV wide-gamut system colorimetry.
The wide-gamut system colorimetry has been standardized for ultra-high definition television (UHDTV). The chromaticities of the primaries are designed to lie on the spectral locus to cover major standard system colorimetries and real object colors. Although monochromatic light sources are required for a display to perfectly fulfill the system colorimetry, highly saturated emission colors using recent quantum dot technology may effectively achieve the wide gamut. This paper presents simulation results on the chromaticities of highly saturated non-monochromatic light sources and gamut coverage of real object colors to be considered in designing wide-gamut displays with color filters for the UHDTV.


Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses.
We have characterized the progressive stages of chronic intestinal inflammation that develops spontaneously in specific pathogen-free (SPF) mice with a targeted disruption in the IL-10 gene (IL-10-/-). Our longitudinal studies showed that inflammatory changes first appear in the cecum, ascending and transverse colon of 3-wk-old mutants. As the disease progressed, lesions appeared in the remainder of the colon and in the rectum. Some aged IL-10-/- mice also developed inflammation in the small intestine. Prolonged disease with transmural lesions and a high incidence of colorectal adenocarcinomas (60%) was observed in 6-mo-old mutants. Mechanistic studies have associated uncontrolled cytokine production by activated macrophages and CD4+ Th1-like T cells with the enterocolitis exhibited by IL-10-/- mice. A major role for a pathogenic Th1 response was further suggested by showing that anti-IFNgamma antibody (Ab) treatment significantly attenuated intestinal inflammation in young IL-10-/- mice. When weanlings were treated with IL-10, they failed to develop any signs of intestinal inflammation. Interestingly, IL-10 treatment of adults was not curative but did ameliorate disease progression. Our studies have also shown that inheritable factors strongly influence the disease susceptibility of IL-10-/- mice. In 3-mo-old mutants, intestinal lesions were most severe in IL-10-/- 129/SvEv and IL-10-/- BALB/c strains, of intermediate severity in the IL-10-/- 129 x C57BL/6J outbreds, and least severe in the IL-10-/- C57BL/6J strain.


Evidence that POB1, a Saccharomyces cerevisiae protein that binds to DNA polymerase alpha, acts in DNA metabolism in vivo.
Potential DNA replication accessory factors from the yeast Saccharomyces cerevisiae have previously been identified by their ability to bind to DNA polymerase alpha protein affinity matrices (J. Miles and T. Formosa, Proc. Natl. Acad. Sci. USA 89:1276-1280, 1992). We have now used genetic methods to characterize the gene encoding one of these DNA polymerase alpha-binding proteins (POB1) to determine whether it plays a role in DNA replication in vivo. We find that yeast cells lacking POB1 are viable but display a constellation of phenotypes indicating defective DNA metabolism. Populations of cells lacking POB1 accumulate abnormally high numbers of enlarged large-budded cells with a single nucleus at the neck of the bud. The average DNA content in a population of cells lacking POB1 is shifted toward the G2 value. These two phenotypes indicate that while the bulk of DNA replication is completed without POB1, mitosis is delayed. Deleting POB1 also causes elevated levels of both chromosome loss and genetic recombination, enhances the temperature sensitivity of cells with mutant DNA polymerase alpha genes, causes increased sensitivity to UV radiation in cells lacking a functional RAD9 checkpoint gene, and causes an increased probability of death in cells carrying a mutation in the MEC1 checkpoint gene. The sequence of the POB1 gene indicates that it is identical to the CTF4 (CHL15) gene identified previously in screens for mutations that diminish the fidelity of chromosome transmission. These phenotypes are consistent with defective DNA metabolism in cells lacking POB1 and strongly suggest that this DNA polymerase alpha-binding protein plays a role in accurately duplicating the genome in vivo.


Inhibitory processes in the flash evoked potential of the monkey.
Flash visual evoked potentials (VEP) and concurrent multiple unit activity (MUA) were recorded from closely spaced intracortical sites in unanesthetized monkeys before and after intracortical injection of the GABAA antagonist bicuculline. Laminar VEP profiles were subjected to current source density (CSD) analysis to localize the transmembrane current flows contributing to the generation of the field potentials. Before bicuculline, the first large VEP component, N40, was generated principally within the parvocellular thalamorecipient sublamina 4Cb. After bicuculline injection, the current sinks associated with N40 spread throughout lamina 4, consistent with a release of intracortical inhibition mediated by GABA. A subsequent component, P65, believed to represent recurrent inhibitory activity within 4Cb, was greatly diminished in size after bicuculline injection. The laminar pattern of current sources and sinks coincident with this component was more complicated after bicuculline, reflecting the summation of current flows associated with disinhibited lamina 4 activity. Bicuculline also altered the responses of neuronal elements in laminae 3 and 5, evidenced by large increases in MUA in these laminae that began approximately 50 msec after stimulation. Finally, bicuculline diminished the degree of intracortical ocular dominance, implicating GABAergic mechanisms in the maintenance and refinement of ocular input segregation within cortical columns.


Beclin-1 as a neutrophil-specific immune checkpoint.
Neutrophils are early wound healing and inflammation regulators that, due to functional plasticity, can adopt either pro- or antitumor functions. Until recently, beclin-1 was a protein known mainly for its role as a critical regulator of autophagy. In this issue of the JCI, Tan et al. describe the effects of the beclin-1 conditional myeloid cell-specific deletion in mice, in which immunostimulation resulted in hypersensitive neutrophils. The chronic proinflammatory effect of these neutrophils triggered spontaneous B cell malignancies to develop. Such tumorigenic effects were mediated primarily by IL-21 and CD40 signaling, leading to the upregulation of tolerogenic molecules, such as IL-10 and PD-L1. The authors went on to examine samples derived from patient lymphoid malignancies and showed that beclin-1 expression in neutrophils positively correlated with pre-B cell leukemia/lymphoma. Overall, the study provides an elegant model for neutrophil-driven carcinogenesis and identifies potential targets for immunotherapy of B cell malignancies.


Rational approximations to rational models: alternative algorithms for category learning.
Rational models of cognition typically consider the abstract computational problems posed by the environment, assuming that people are capable of optimally solving those problems. This differs from more traditional formal models of cognition, which focus on the psychological processes responsible for behavior. A basic challenge for rational models is thus explaining how optimal solutions can be approximated by psychological processes. We outline a general strategy for answering this question, namely to explore the psychological plausibility of approximation algorithms developed in computer science and statistics. In particular, we argue that Monte Carlo methods provide a source of rational process models that connect optimal solutions to psychological processes. We support this argument through a detailed example, applying this approach to Anderson's (1990, 1991) rational model of categorization (RMC), which involves a particularly challenging computational problem. Drawing on a connection between the RMC and ideas from nonparametric Bayesian statistics, we propose 2 alternative algorithms for approximate inference in this model. The algorithms we consider include Gibbs sampling, a procedure appropriate when all stimuli are presented simultaneously, and particle filters, which sequentially approximate the posterior distribution with a small number of samples that are updated as new data become available. Applying these algorithms to several existing datasets shows that a particle filter with a single particle provides a good description of human inferences.


Mapping the thermal behavior of DNA origami nanostructures.
Understanding the thermodynamic properties of complex DNA nanostructures, including rationally designed two- and three-dimensional (2D and 3D, respectively) DNA origami, facilitates more accurate spatiotemporal control and effective functionalization of the structures by other elements. In this work fluorescein and tetramethylrhodamine (TAMRA), a Förster resonance energy transfer (FRET) dye pair, were incorporated into selected staples within various 2D and 3D DNA origami structures. We monitored the temperature-dependent changes in FRET efficiency that occurred as the dye-labeled structures were annealed and melted and subsequently extracted information about the associative and dissociative behavior of the origami. In particular, we examined the effects of local and long-range structural defects (omitted staple strands) on the thermal stability of common DNA origami structures. The results revealed a significant decrease in thermal stability of the structures in the vicinity of the defects, in contrast to the negligible long-range effects that were observed. Furthermore, we probed the global assembly and disassembly processes by comparing the thermal behavior of the FRET pair at several different positions. We demonstrated that the staple strands located in different areas of the structure all exhibit highly cooperative hybridization but have distinguishable melting temperatures depending on their positions. This work underscores the importance of understanding fundamental aspects of the self-assembly of DNA nanostructures and can be used to guide the design of more complicated DNA nanostructures, to optimize annealing protocol and manipulate functionalized DNA nanostructures.


Correlations of premorbid adjustment in schizophrenia with auditory event-related potential and neuropsychological abnormalities.
The authors examined the relationship between premorbid adjustment in schizophrenia and event-related potential data and neuropsychological data obtained after onset of the illness. They interviewed 13 male veterans with chronic schizophrenia, 12 normal comparison subjects, and their first-degree relatives and also obtained objective data from the patients' school records and charts. They used interview and objective data to score the Cannon-Spoor Premorbid Adjustment Scale. Patients and comparison subjects were also given event-related potential tests, the Wisconsin Card Sorting Test, and the Wechsler Memory Scale-Revised. Worse premorbid adjustment in the schizophrenic patients was significantly associated with a marked reduction of the N2 component amplitude of the auditory event-related potential measured over the left temporal and central regions, but it was not associated with the P3 component amplitude. Worse Premorbid Adjustment Scale scores were significantly associated with more perseverative errors on the Wisconsin Card Sorting Test and worse performance on the visual memory span task of the Wechsler Memory Scale. Premorbid adjustment may predict the severity of specific neurophysiological and neuropsychological abnormalities in schizophrenia.


Characterizing indirect prey-quality mediated effects of a Bt crop on predatory larvae of the green lacewing, Chrysoperla carnea.
There is increasing evidence that insecticidal transgenic crops can indirectly cause detrimental effects on arthropod predators or parasitoids when they prey on or parasitize sublethally affected herbivores. Our studies revealed that Chrysoperla carnea is negatively affected when fed Bt-susceptible but not Cry1Ac-resistant Helicoverpa armigera larvae that had fed Bt-transgenic cotton expressing Cry1Ac. This despite the fact that the predators ingested 3.5 times more Cry1Ac when consuming the resistant caterpillars. In order to detect potential differences in the nutrient composition of prey larvae, we evaluated the glycogen and lipid content plus the sugar and free amino acid content and composition of caterpillars fed non-Bt and Bt cotton. The only change in susceptible H. armigera larvae attributable to Bt cotton feeding were changes in sugar concentration and composition. In case of the Cry1Ac-resistant H. armigera strain, feeding on Bt cotton resulted in a reduced glycogen content in the caterpillars. The predators, however, appeared to compensate for the reduced carbohydrate content of the prey by increasing biomass uptake which caused an excess intake of the other analyzed nutritional compounds. Our study clearly proves that nutritional prey-quality factors other then the Bt protein underlie the observed negative effects when C. carnea larvae are fed with Bt cotton-fed prey. Possible factors were an altered sugar composition or fitness costs associated with the excess intake of other nutrients.


Flow-through free latissimus dorsi flap for reconstruction of injured limbs: Evaluation of hemodynamic effects on extremity circulation.
Management of vascularized injured extremity requires careful reconstruction for continuity of leg circulation. Protection of the remaining intact vessels during free flap transfer provides condition for blood flow maintenance in the distal extremity. Latissimus dorsi muscle has the correct vessel anatomy for applying flow-through flap because it protects recipient vessel integrity during soft tissue reconstruction. Flow-through flap circulation may cause decreasing blood flow in the recipient artery and steal phenomenon in distal circulation although the main vessel remains intact. The purpose of this study was to describe blood flow changes in the recipient artery, flap pedicle, and distal leg circulation at early and long-term follow- up periods. For this purpose, evaluations of blood flows by using Doppler ultrasonography were performed in 2 vascularized injured extremities which were reconstructed with flow-through free latissimus dorsi musculocutaneous flaps. The results demonstrate that flow-through flaps in our vascularized injured extremity did not disturb distal leg circulation in spite of increased blood flow in the recipient and pedicle arteries.


High-energy ultraviolet dispersive-wave emission in compact hollow capillary systems.
We demonstrate high-energy resonant dispersive-wave emission in the deep ultraviolet (218 to 375 nm) from optical solitons in short (15 to 34 cm) hollow capillary fibers. This down-scaling in length compared to previous results in capillaries is achieved by using small core diameters (100 and 150 μm) and pumping with 6.3 fs pulses at 800 nm. We generate pulses with energies of 4 to 6 μJ across the deep ultraviolet in a 100 μm capillary and up to 11 μJ in a 150 μm capillary. From comparisons to simulations we estimate the ultraviolet pulse to be 2 to 2.5 fs in duration. We also numerically study the influence of pump duration on the bandwidth of the dispersive wave.


To research (or not) that is the question: ethical issues in research when medical care is disrupted by political action: a case study from Eldoret, Kenya.
While considerable attention has been focused on understanding the myriad of ethical analysis in international research in low and middle income countries, new issues always arise that have not been anticipated in guidelines or studied extensively. The disruption of medical care arising as a direct result of political actions, including strikes, postelection violence and related activities, is one such issue that leaves physician-researchers struggling to manage often conflicting professional responsibilities. This paper discusses the ethical conflicts that arise for physician-researchers, particularly when disruption threatens the completion of a study or completion is possible but at the expense of not addressing unmet medical needs of patients. We review three pragmatic strategies and the ethical issues arising from each: not starting research, stopping research that has already started, and continuing research already initiated. We argue that during episodes of medical care disruption, research that has been started can be continued only if the ethical standards imposed at the beginning of the study can continue to be met; however, studies that have been approved but not yet started should not begin until the disruption has ended and ethical standards can again be assured.


The effects of the Danish saturated fat tax on food and nutrient intake and modelled health outcomes: an econometric and comparative risk assessment evaluation.
The World Health Organisation recommends governments to consider the use of fiscal policies to promote healthy eating. However, there is very limited evidence of the effect of food taxation in a real-life setting, as most evidence is based on simulation studies. The objective of this study is to evaluate the effect of the Danish tax on saturated fat in terms of changes in nutritional quality of the diet, that is, changes in saturated fat consumption, as well as other non-targeted dietary measures, and to model the associated changes in mortality for different age groups and genders. On the basis of household scanner data, we estimate the impact of the tax on consumption of saturated fat, unsaturated fat, salt, fruit, vegetables and fibre. The resultant changes in dietary quality are then used as inputs into a comparative risk assessment model (PRIME (Preventable Risk Integrated ModEl)) to estimate the effect of these changes on non-communicable diseases (NCDs) and mortality. The tax resulted in a 4.0% reduction in saturated fat intake. Vegetable consumption increased, and salt consumption increased for most individuals, except younger females. We find a modelled reduction in mortality with 123 lives saved annually, 76 of them below 75 years equal to 0.4% of all deaths from NCDs. Modelling the effect of the changes in diet on health outcomes suggests that the saturated fat tax made a positive, but minor, contribution to public health in Denmark.


Regiochemical control of monolignol radical coupling: a new paradigm for lignin and lignan biosynthesis.
Although the lignins and lignans, both monolignol-derived coupling products, account for nearly 30% of the organic carbon circulating in the biosphere, the biosynthetic mechanism of their formation has been poorly understood. The prevailing view has been that lignins and lignans are produced by random free-radical polymerization and coupling, respectively. This view is challenged, mechanistically, by the recent discovery of dirigent proteins that precisely determine both the regiochemical and stereoselective outcome of monolignol radical coupling. To understand further the regulation and control of monolignol coupling, leading to both lignan and lignin formation, we sought to clone the first genes encoding dirigent proteins from several species. The encoding genes, described here, have no sequence homology with any other protein of known function. When expressed in a heterologous system, the recombinant protein was able to confer strict regiochemical and stereochemical control on monolignol free-radical coupling. The expression in plants of dirigent proteins and proposed dirigent protein arrays in developing xylem and in other lignified tissues indicates roles for these proteins in both lignan formation and lignification. The first understanding of regiochemical and stereochemical control of monolignol coupling in lignan biosynthesis has been established via the participation of a new class of dirigent proteins. Immunological studies have also implicated the involvement of potential corresponding arrays of dirigent protein sites in controlling lignin biopolymer assembly.


A differential proteome screening system for post-translational modification-dependent transcription factor interactions.
Post-translational modifications (PTMs) of transcription factors alter interactions with co-regulators and epigenetic modifiers. For example, members of the C/EBP transcription factor family are extensively methylated on arginine and lysine residues in short, conserved, modular domains, implying modification-dependent cofactor docking. Here we describe array peptide screening (APS), a systematic and differential approach to detect PTM-dependent interactions in the human proteome using chemically synthesized, biotinylated peptides coupled to fluorophore-labeled streptavidin. Peptides with and without a modified residue are applied in parallel to bacterial expression libraries in an arrayed format. Interactions are detected and quantified by laser scanning to reveal proteins that differentially bind to nonmodified or modified peptides. We have previously used this method to investigate the effect of arginine methylation of C/EBPβ peptides. The method enables determination of PTM-dependent transcription factor interactions, quantification of relative binding affinities and rapid protein classification, all independently of the transactivation potential of peptides or cellular abundance of interactors. The protocol provides a cost-effective alternative to mass spectrometric approaches and takes 3-4 d to complete.


Saccadic localization in the presence of cues to three-dimensional shape.
Saccades directed to simple two-dimensional (2D) target shapes under instructions to look at the target as a whole land near the center of gravity (COG) of the shape with a high degree of precision (He & Kowler, 1991; Kowler & Blaser, 1995; McGowan, Kowler, Sharma, & Chubb, 1998; Melcher & Kowler, 1999; Vishwanath, Kowler, & Feldman, 2000). This pattern of performance has been attributed to the averaging of visual signals across the shape. Natural objects, however, are three-dimensional (3D), and the shape of the object can differ dramatically from its 2D retinal projection. This study examined saccadic localization of computer-generated perspective images of 3D shapes. Targets were made to appear either 2D or 3D by manipulating shading, context, and contour cues. Average saccadic landing positions (SD approximately 10% eccentricity) fell at either the 2D or 3D COG, and occasionally in between, depending on the nature of the 3D cues and the subject. The results show that saccades directed to objects are not compelled to land at the 2D COG, but can be sensitive to other visual cues, such as cues to 3D structure. One way to account for these results, without abandoning the averaging mechanism that has accounted well for performance with simple 2D shapes, is for saccadic landing position to be computed based on averaging across a weighted representation of the shape in which portions projected to be located at a greater distance receive more weight.


Thermal effects of cold light sources used in otologic surgery.
The objective of this study was to investigate the thermal effects of cold light sources and endoscopes on the inner ear. 25 male guinea pigs were assigned equally to five groups (1: Halogen-1 min, 2: Halogen-5 min, 3: Xenon-1 min, 4: Xenon-5 min, 5: Controls). After both bullae of the guinea pigs were opened, light sources and endoscopes were positioned in the middle ears of the first four groups for specific time periods. DPOAE and ABR tests were conducted on all animals at the beginning of the study, at the end of surgery, and 2 h after surgery. The temperatures of cold light sources were measured by a thermocouple thermometer, and the surface temperatures of the endoscopes were measured by an infrared thermometer. DPOAE and ABR measurements performed right after and 2 h after surgery in group 1, 2, 3, and 5 did not reveal any significant difference. In group 4, DPOAE values were significantly lower and ABR threshold values were significantly higher than those in the other groups, right after and 2 h after surgery. Thermocouple thermometer readings showed that, after the first minute, the Xenon light source generated significantly more temperature rise than the Halogen light source. The surface temperatures of all endoscopes returned to normal approximately 1 min after light sources were turned off. Our study demonstrated that when an endoscope using a Xenon light source was applied to the middle ear for a specific time periods, inner ear functions deteriorated, as reflected by audiologic tests.


Demographic data and hemodialysis population dynamics in Qatar: A five year survey.
Hemodialysis was initiated in Qatar in 1981, since then the hemodialysis population has been expanding rapidly. This report describes the demographics and outcome of our hemodialysis patients during a five years study period. Data of all the patients on regular hemodialysis from January 1 st , 2002 to December 31 st , 2006 were included in this study was collected from the medical records and entered into an especially designed questionnaire. The prevalence of end stage kidney disease in Qatar is 624 patients per million populations with an incidence of 202 patients per million populations per year. Currently, 278 patients are on hemodialysis, 65% of them are Qatari, males represent 51%, whereas 44.6% are between 65-74 years of age. Diabetic nephropathy is the commonest cause of end stage kidney disease (48%), followed by primary glomerulonephritis and hypertensive glomerulopathy. Arteriovenous fistula was the vascular access in 57% of patients. The incidence of Hepatitis B, C and Human immunodeficiency virus had been stable throughhout the study period though our hemodialysis population had increased by 1.5 fold. The first and five years survival rates of our patients were 84 and 53% respectively. Qatar has one of the highest rates of dialysis patients with a good long-term survival report. Peritoneal dialysis remained to be the key solution for the rapidly expanding patients' pool. Maintenance of national registry of dialysis patients and improving our organ transplant program is an essential goal.


The impact and cost of scaling up midwifery and obstetrics in 58 low- and middle-income countries.
To guide achievement of the Millennium Development Goals, we used the Lives Saved Tool to provide a novel simulation of potential maternal, fetal, and newborn lives and costs saved by scaling up midwifery and obstetrics services, including family planning, in 58 low- and middle-income countries. Typical midwifery and obstetrics interventions were scaled to either 60% of the national population (modest coverage) or 99% (universal coverage). Under even a modest scale-up, midwifery services including family planning reduce maternal, fetal, and neonatal deaths by 34%. Increasing midwifery alone or integrated with obstetrics is more cost-effective than scaling up obstetrics alone; when family planning was included, the midwifery model was almost twice as cost-effective as the obstetrics model, at $2,200 versus $4,200 per death averted. The most effective strategy was the most comprehensive: increasing midwives, obstetricians, and family planning could prevent 69% of total deaths under universal scale-up, yielding a cost per death prevented of just $2,100. Within this analysis, the interventions which midwifery and obstetrics are poised to deliver most effectively are different, with midwifery benefits delivered across the continuum of pre-pregnancy, prenatal, labor and delivery, and postpartum-postnatal care, and obstetrics benefits focused mostly on delivery. Including family planning within each scope of practice reduced the number of likely births, and thus deaths, and increased the cost-effectiveness of the entire package (e.g., a 52% reduction in deaths with midwifery and obstetrics increased to 69% when family planning was added; cost decreased from $4,000 to $2,100 per death averted). This analysis suggests that scaling up midwifery and obstetrics could bring many countries closer to achieving mortality reductions. Midwives alone can achieve remarkable mortality reductions, particularly when they also perform family planning services--the greatest return on investment occurs with the scale-up of midwives and obstetricians together.


The cultural construction of mental illness in prison: a perfect storm of pathology.
Large numbers of individuals in U.S. prisons meet DSM criteria for severe psychiatric disorder. These individuals also have co-occurring personality and substance abuse disorders, medical conditions, and histories of exposure to social pathologies. Based on nine months of ethnographic fieldwork in a U.S. prison, focusing on staff narratives, I utilize interpretivist and constructivist perspectives to analyze how mental health clinicians construct psychiatric disorder among inmates. Discrete categorization of disorders may be confounded by the clinical co-morbidities of inmates and the prison context. Incarcerated individuals' responses to the institutional context substantially inform mental health staffs' illness construction and the prison itself is identified as an etiological agent for disordered behaviors. In addition, diagnostic processes are found to be indeterminate, contested, and shaped by interactions with staff. Analysis of illness construction reveals that what is at stake for clinicians is not only provision of appropriate treatment, but also mandates for the safety and security of the institution. Enmeshed in these mandates, prison mental health becomes a particular local form of psychiatric knowledge. This paper contributes to anthropological approaches to mental disorder by demonstrating how local contexts mediate psychiatric knowledge and contribute to the limited ethnographic record of prisons.


New therapeutic options in metastatic castration-resistant prostate cancer: Can cost-effectiveness analysis help in treatment decisions?
To evaluate the cost-effectiveness of abiraterone, cabazitaxel, and enzalutamide compared to placebo for treatment of metastatic castration-resistant prostate cancer. A decision-tree model compared three treatment options for metastatic castration-resistant prostate cancer patients over 18 months from a societal perspective in 2012 USD. Chance nodes included baseline pain as a severity indicator, significant adverse effects (neutropenia, cardiac events, or seizures), and survival. Probabilities, survival rates, and health utilities were from clinical trials (COU-AA, TROPIC, and AFFIRM) and other published studies. Survival of enzalutamide was adjusted to match placebo groups across trials. Probabilistic sensitivity analyses, acceptability curves and net benefit calculations were performed. Abiraterone was the most cost-effective of the treatments ($123.4 K/quality-adjusted life year) compared to placebo, enzalutamide was $437.6 K/quality-adjusted life year compared to abiraterone, and cabazitaxel was $351.9 K/quality-adjusted life year compared to enzalutamide. Enzalutamide and cabazitaxel were not cost-effective compared to placebo at $154.3 K/quality-adjusted life year and $163.2 K/quality-adjusted life year, respectively. Acceptability curves showed abiraterone was cost-effective 29.3% of the time with a willingness to pay threshold of $100 K. The model was sensitive to changes in cost of the drugs, life expectancy, and survival rate. Sensitivity analysis shows that enzalutamide can become the most cost-effective option if the price of the medication decreased by 26% and other drug costs remained the same. Based on the cost-effective analysis, and survival adjustments necessary to match placebo groups, we would recommend abiraterone for treatment of metastatic castration-resistant prostate cancer despite not quite falling under the usually accepted willingness to pay threshold. Further analysis should examine comparative survival across the three drugs.


Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor.
Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) are structurally related peptides. Purified human TGF-alpha produced in Escherichia coli and pure natural mouse EGF were compared for their ability to bind to target cells in vitro and to promote angiogenesis in the hamster cheek pouch bioassay. Both polypeptides were found to bind in vitro to several target cells, including endothelial cells, and to stimulate their DNA synthesis in an equipotent fashion. In vivo, however, TGF-alpha was more potent than EGF in promoting angiogenesis and, because TGF-alpha is known to be secreted by a variety of human tumors, it is suggested that this growth factor may contribute to tumor-induced angiogenesis.


Inadequate functional health literacy in Spanish as a barrier to cervical cancer screening among immigrant Latinas in New York City.
The objective of this study was to examine the association between inadequate functional health literacy in Spanish among low-income Latinas aged 40 and older and cervical cancer screening knowledge and behavior. Spanish-speaking Latinas aged 40-78 of various nationalities (n = 205) participated in a study that included a survey on cervical cancer knowledge and behavior administered in Spanish and the Spanish version of the Test of Functional Health Literacy in Adults. Compared to those with adequate and marginal health literacy, women with inadequate functional health literacy in Spanish were significantly less likely to have ever had a Papanicolaou (Pap) test (odds ratio, 0.12; 95% confidence interval [CI], 0.04-0.37) or in the last three years (odds ratio, 0.35; 95% CI, 0.18-0.68) and were significantly more likely to have had their last Pap test at a local public hospital (odds ratio, 2.43; 95% CI, 1.18-4.97). Even when controlling for other factors, women with inadequate health literacy were 16.7 times less likely (adjusted odds ratio, 0.06; 95% CI, 0.01-0.55) to have ever had a Pap test. Almost half of the population we studied will have difficulty interpreting written medical materials, even in Spanish. When developing efforts to reach women who have not been screened, programs and service providers need to be aware that the women most in need of information about screening may be more likely to be unable to read any written materials provided to them, regardless of the language or level of simplicity of the materials. Programs and strategies need to be implemented to increase screening prevalence and to minimize the identified gaps in regular screening for Latinas who have low health literacy.


Distinct proteolytic processes generate the C and N termini of MHC class I-binding peptides.
Most of the MHC class I peptides presented to the immune system are generated during the course of protein breakdown by the proteasome. However, the precise role of the proteasome, e.g., whether this particle or some other protease generates the carboxyl (C) and amino (N) termini of the presented 8- to 10-residue peptides, is not clear. Here, we show that presentation on Db of ASNENMETM, a peptide from influenza nucleoprotein, and on Kb of FAPGNYPAL, a peptide from Sendai virus nucleoprotein, was blocked by the proteasome inhibitor, lactacystin. Using plasmid minigene constructs encoding oligopeptides of various lengths, we found that presentation of ASNENMETM from C-terminally extended peptides that contain this antigenic peptide plus three or five additional amino acids and presentation of FAPGNYPAL from a peptide containing FAPGNYPAL plus one additional C-terminal residue required the proteasome. In contrast, the proteasome inhibitor did not reduce presentation of cytosolically expressed ASNENMETM or FAPGNYPAL or N-terminally extended versions of these peptides, suggesting involvement of aminopeptidase(s) in trimming these N-extended variants. Accordingly, when the N termini of these 3N-extended peptides were blocked by acetylation, they were resistant to hydrolysis by cellular aminopeptidases and pure leucine aminopeptidase. Moreover, if introduced into the cytosol, Ag presentation of these peptides occurred to a much lesser extent than from their nonacetylated counterparts. Thus, the proteasome is essential for the generation of ASNENMETM and FAPGNYPAL peptides from the full-length nucleoproteins. Although it generates the C termini of these presented peptides, distinct aminopeptidase(s) can trim the N termini of these presented peptides to their proper size.


Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies.
Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology. Clinically annotated LS-EC were collected. Histological slide review was performed centrally by two specialist gynaecological pathologists. Mutational analysis was by a bespoke 75- gene next-generation sequencing panel. Comparisons were made with sporadic MMRd EC. Multiple correspondence analysis was used to explore similarities and differences between the cohorts. After exclusions, 135 LS-EC underwent independent histological review, and 64 underwent mutational analysis. Comparisons were made with 59 sporadic MMRd EC. Most tumours were of endometrioid histological subtype (92% LS-EC and 100% sporadic MMRd EC, respectively, p = NS). Sporadic MMRd tumours had significantly fewer tumour infiltrating lymphocytes (p ≤ 0.0001) and showed more squamous/mucinous differentiation than LS-EC (p = 0.04/p = 0.05). PTEN mutations were found in 88% sporadic MMRd and 61% LS-EC, respectively (p < 0.001). Sporadic MMRd tumours had significantly more mutations in PDGFRA, ALK, IDH1, CARD11, CIC, MED12, CCND1, PTPN11, RB1 and KRAS, while LS-EC showed more mutations affecting SMAD4 and ARAF. LS-EC showed a propensity for TGF-β signalling disruption. Cluster analysis found that wild type PTEN associates predominantly with LS-EC, whilst co-occurring mutations in PTEN, PIK3CA and KRAS predict sporadic MMRd EC. Whilst MMRd EC of hereditary and sporadic aetiology may be difficult to distinguish by histology alone, differences in infiltrating immune cell counts and mutational profile may predict heterogenous responses to novel targeted therapies and warrant further study.


Plasticity of dorsal horn cell receptive fields after peripheral nerve regeneration.
1. The tibial and sural nerves were transected and repaired in nine adult cats. The receptive field (RF) properties of dorsal horn neurons were examined at three different intervals (5-6, 9, or 12 mo) after axotomy. The properties examined included RF location, area, and modality convergence. In some cases, discrete areas of the cell's RF were stimulated electrically while the evoked cord dorsum potentials (CDPs) and any intracellularly recorded responses were simultaneously recorded. 2. At the shortest interval following reinnervation, the somatotopic organization in the affected areas of the dorsal horn was lost. Dorsal horn cells that received input primarily from regenerated fibers had large, low-threshold excitatory RFs that contained much of the reinnervated skin. Those cells with RFs restricted to a fraction of the reinnervated skin had significant components of their RFs on the foot dorsum supplied by intact fibers (i.e., superficial peroneal nerve). 3. At longer intervals the somatotopic organization remained scrambled. Dorsal horn cell low-threshold RFs were significantly reduced in size. Many cells exhibited large areas of excitatory subliminal fringe and concise inhibitory RFs. In addition, those cells that responded to peripheral stimuli across a wide range of stimulus intensities (wide-dynamic-range cells) also exhibited plasticity in the relative sizes of their low- and high-threshold RFs. 4. At the shortest recovery time, focal electrical stimulation of the skin within the RF of an impaled cell and simultaneous recordings of the evoked CDPs and postsynaptic potentials revealed that at numerous locations within the initial large RFs, single fibers or small groups of fibers could be electrically activated that were not connected to the dorsal horn cell. At the longer recovery times there was a much higher incidence of connectivity. 5. These results suggest that mechanisms affecting both synaptic efficacy of afferent fiber connections and/or the establishment of afferent-driven inhibitory inputs may effect the reshaping of dorsal horn cell RFs after reinnervation. These results are discussed in relation to their potential contribution to previously observed cortical plasticity and functional recovery following similar lesions.


Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de-repress VEGF-signalling genes and promote cell survival.
Protein kinase CK2 promotes cell survival and the activity of this kinase is elevated in several cancers including chronic myeloid leukaemia. We have shown previously that phosphorylation of the Proline-Rich Homeodomain protein (PRH/Hhex) by CK2 inhibits the DNA-binding activity of this transcription factor. Furthermore, PRH represses the transcription of multiple genes encoding components of the VEGF-signalling pathway and thereby influences cell survival. Here we show that the inhibitory effects of PRH on cell proliferation are abrogated by CK2 and that CK2 inhibits the binding of PRH at the Vegfr-1 promoter. Phosphorylation of PRH by CK2 also decreases the nuclear association of PRH and induces its cleavage by the proteasome. Moreover, cleavage of phosphorylated PRH produces a stable truncated cleavage product which we have termed PRHΔC (HhexΔC). PRHΔC acts as a transdominant negative regulator of full-length PRH by sequestering TLE proteins that function as PRH co-repressors. We show that this novel regulatory mechanism results in the alleviation of PRH-mediated repression of Vegfr-1. We suggest that the re-establishment of PRH function through inhibition of CK2 could be of value in treatment of myeloid leukaemias, as well as other tumour types in which PRH is inactivated by phosphorylation.


Early complications of revision total knee arthroplasty in morbidly obese patients.
Morbid obesity is a known risk factor for complications and failure following primary total knee arthroplasty. Complications following revision total knee arthroplasty (rTKA) in the morbidly obese (BMI > 40) have not been well described. A retrospective cohort study was designed to investigate the early complications of rTKA in morbidly obese patients. Revision TKA procedures were performed between January 2009 and December 2012 at a single institution. Comparisons were made between patients with a normal BMI (18.5-25) and patients with morbid obesity (BMI > 40). Thirty-three of 141 morbidly obese patients (23.4%) had a complication compared to 10 of 96 patients with a BMI 18.5-25 (10.4%) (p = 0.011). Morbidly obese patients were younger (69.3 vs. 61.4 years, p < 0.0001), and their most frequent complication in comparison with patients with normal BMI was wound healing problems (p = 0.01). Morbidly obese patients are at a significantly increased rate of early complications following rTKA compared to a normal weight cohort, especially with regard to wound complications. The morbidly obese group was significantly younger at the time of rTKA. In addition, this study highlights the importance of risk stratification for morbidly obese patients undergoing rTKA.


Contact Line and Adhesion Force of Droplets on Concentric Ring-Textured Hydrophobic Surfaces.
Advances made in fabrication of patterned surfaces with well-defined dimensions of topographic features and their lateral dissemination drive the progress in interpretation of liquid spreading, adhesion, and retreat on engineered solid surfaces. Despite extensive studies on liquid droplet spreading and adhesion on textured surfaces in recent years, conformation of the three-phase contact line and its effect on macroscopic contact angle and droplet adhesion remain the focus of intensive debate. Here, we investigate the effect of surface topography on the adhesion force of Cassie-Baxter-state droplets on concentric ring-textured hydrophobic surfaces having rings with lateral dimensions of 5, 10, and 45 μm and separated by 5, 6, and 7 μm trenches, respectively, with fixed depth of 15 μm. Unlike mostly tested surfaces textured with straight ridges, pores, and pillars, where the droplet base contact line is anisotropic and its conformation varies along the apparent boundary, concentric rings are symmetrical and reinforce the microscopic contact line to align to a circular one that reflects the shape of the pattern. In this study, adhesion forces were calculated based on surface tension and Laplace pressure forces and were compared with the experimental forces for both water and ethylene glycol droplets having a varying contact diameter on the concentric ring-pattern at the point of maximum adhesion force. Results show that the microscopic contact line of the liquid retains its circular shape controlled by circular rings of the pattern, irrespectively of the droplet base diameter larger than 0.8 mm, and there is a good agreement between the experimental and calculated adhesion forces.


Hoxa-2 expression in normal and transposed rhombomeres: independent regulation in the neural tube and neural crest.
In this study we have cloned the chick Hoxa-2 gene and analysed its expression during early development. We find that Hoxa-2 has a rostral limit of expression in the rhombencephalic neural tube corresponding precisely to the boundary between rhombomeres (r)1 and 2; a limit further rostral than any other Hox gene reported to date. Neural crest migrates from r2 to populate the first branchial arch, yet although Hoxa-2 is expressed down the full dorsoventral extent of r2 during the phase of neural crest emigration, there is no Hoxa-2 expression in either the emergent neural crest or in the first branchial arch. Conversely, at the level of r4, both the neural tube and the neural crest cells, which migrate out of this rhombomere to populate the second branchial arch, express Hoxa-2. Other Hox genes expressed in the rhombencephalic neural tube demonstrate a transfer of expression from neural tube to neural crest at all axial levels of expression. Hoxa-2 is thus unusual in demonstrating separate anterior expression limits in neural tube and neural crest; this allowed us to test whether Hox gene expression patterns in neural crest are determined by migratory pathways or are prespecified by the site of origin in the neuroepithelium. Grafting experiments in which pairs of rhombomeres were transplanted to ectopic sites at the time of rhombomere boundary formation reveal a prepatterning of the neural crest with respect to Hoxa-2 expression. The decision to down-regulate Hoxa-2 expression in r2-derived neural crest, but to maintain Hoxa-2 expression in r4-derived neural crest is intrinsic to the premigratory crest cell population. Thus, following grafting of r4 to the r2 site and vice-versa, Hoxa-2 expression is maintained in r4-derived neural crest, but lost in r2-derived neural crest.


Environmental and occupational exposure to chemicals and telomere length in human studies.
Telomeres are complexes of tandem repeats of DNA (5'-TTAGGG-3') and protein that cap eukaryotic chromosomes and play a critical role in chromosome stability. Telomeres shorten with aging and this process can be accelerated by increased oxidative stress and episodes of inflammation. Evidence is rapidly growing that telomere length (TL) may be affected by environmental chemicals that have frequently been associated with chronic diseases. In this article, we review the published data on TL in relation to environmental and occupational exposure to several chemicals based on our own and others' studies. The environmental and occupational exposures associated with shorter TL include traffic-related air pollution (ie, particulate matter (PM), black carbon (BC), and benzene and toluene), polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, pesticides, lead, exposure in car mechanical workshops, and hazardous waste exposure. Arsenic, persistent organic pollutants (POPs) and short-term exposure to PM are associated with longer TL. We discuss the possible reasons for the differences in results, including time- and dose-related issues, study design, and possible mechanisms involved in telomere regulation. We also discuss the future directions and challenges for TL-related environmental and occupational health research, such as investigation of TL in subpopulations of blood leukocytes, and the study of genetic and epigenetic factors that may regulate telomere integrity using longitudinal designs.


Self-Paced Online vs. Cue-Based Offline Brain-Computer Interfaces for Inducing Neural Plasticity.
: Brain-computer interfaces (BCIs), operated in a cue-based (offline) or self-paced (online) mode, can be used for inducing cortical plasticity for stroke rehabilitation by the pairing of movement-related brain activity with peripheral electrical stimulation. The aim of this study was to compare the difference in cortical plasticity induced by the two BCI modes. Fifteen healthy participants participated in two experimental sessions: cue-based BCI and self-paced BCI. In both sessions, imagined dorsiflexions were extracted from continuous electroencephalogram (EEG) and paired 50 times with the electrical stimulation of the common peroneal nerve. Before, immediately after, and 30 minutes after each intervention, the cortical excitability was measured through the motor-evoked potentials (MEPs) of tibialis anterior elicited through transcranial magnetic stimulation. Linear mixed regression models showed that the MEP amplitudes increased significantly (p < 0.05) from pre- to post- and 30-minutes post-intervention in terms of both the absolute and relative units, regardless of the intervention type. Compared to pre-interventions, the absolute MEP size increased by 79% in post- and 68% in 30-minutes post-intervention in the self-paced mode (with a true positive rate of ~75%), and by 37% in post- and 55% in 30-minutes post-intervention in the cue-based mode. The two modes were significantly different (p = 0.03) at post-intervention (relative units) but were similar at both post timepoints (absolute units). These findings suggest that immediate changes in cortical excitability may have implications for stroke rehabilitation, where it could be used as a priming protocol in conjunction with another intervention; however, the findings need to be validated in studies involving stroke patients.


Cerebral asymmetries in 12-week-old C57Bl/6J mice measured by magnetic resonance imaging.
Asymmetries of multiple components of the rodent cerebrum have been described at various levels of organization. Yet, despite its ubiquitous nature, many confusing and sometimes contradictory reports regarding structural asymmetries in the rodent brain have been published. There is a need, therefore, for a whole-brain imaging analysis technique for asymmetry studies that is both accurate, reproducible and robust. To this end, a comprehensive three-dimensional examination of differences in brain structure in an inbred mouse strain was undertaken. The goal of this study was thus to use high-resolution magnetic resonance imaging to assess structural asymmetries in the adult C57Bl/6J mouse brain. Fixed brain T2-weighted images of 20 male C57Bl/6J mice were acquired on a 7T scanner at 32 microm isotropic resolution. We used voxel-based analyses to examine structural asymmetries throughout the whole mouse brain. The striatum, medial-posterior regions of the thalamus, and motor, sensorimotor, and visual cortex were found to be asymmetrical. The most significant asymmetry was found in the hippocampus and, specifically, the dentate gyrus. In each case, the left region was larger than the right. No other regions of the mouse brain showed structural asymmetry. The results in the dentate gyrus were confirmed using stereology, revealing a correlation of r=0.61 between magnetic resonance and stereological measures. Hippocampal, along with cortical asymmetry, has been discussed repeatedly in the literature, yet a clear pattern of directionality, until this point, has not been described. The findings of asymmetry in the striatum and absence of asymmetry in the rest of the brain are novel and show the advantage of using the whole-brain three-dimensional techniques developed herein for assessing asymmetry.


Hepcidin detects iron deficiency in Sri Lankan adolescents with a high burden of hemoglobinopathy: A diagnostic test accuracy study.
Anemia affects over 800 million women and children globally. Measurement of hepcidin as an index of iron status shows promise, but its diagnostic performance where hemoglobinopathies are prevalent is unclear. We evaluated the performance of hepcidin as a diagnostic test of iron deficiency in adolescents across Sri Lanka. We selected 2273 samples from a nationally representative cross-sectional study of 7526 secondary schoolchildren across Sri Lanka and analyzed associations between hepcidin and participant characteristics, iron indices, inflammatory markers, and hemoglobinopathy states. We evaluated the diagnostic accuracy of hepcidin as a test for iron deficiency with estimation of the AUCROC , sensitivity/specificity at each hepcidin cutoff, and calculation of the Youden Index to find the optimal threshold. Hepcidin was associated with ferritin, sTfR, and hemoglobin. The AUCROC for hepcidin as a test of iron deficiency was 0.78; hepcidin outperformed Hb and sTfR. The Youden index-predicted cutoff to detect iron deficiency (3.2 ng/mL) was similar to thresholds previously identified to predict iron utilization and identify deficiency in African populations. Neither age, sex, nor α- or β-thalassemia trait affected diagnostic properties of hepcidin. Hepcidin pre-screening would prevent most iron-replete thalassemia carriers from receiving iron whilst still ensuring most iron deficient children were supplemented. Our data indicate that the physiological relationship between hepcidin and iron status transcends specific populations. Measurement of hepcidin in individuals or populations could establish the need for iron interventions. Am. J. Hematol. 92:196-203, 2017. © 2016 Wiley Periodicals, Inc.


Delivery by caesarean section and risk of childhood obesity: analysis of a Peruvian prospective cohort.
Objectives. We aimed to assess if Caesarean section is a risk factor for overnutrition in early- and late-childhood, and to assess the magnitude of the effect of child- versus family-related variables in these risk estimates. Methods. Longitudinal data from Peruvian children from the Young Lives Study was used. Outcomes assessed were overweight, obesity, overnutrition (overweight plus obesity), and central obesity (waist circumference) at the age 5 (first follow-up) and 7 (second follow-up) years. The exposure of interests was delivery by Caesarean section. Relative risks (RR) and 95% confidence intervals (95% CI) were calculated using multivariable models adjusted for child-related (e.g., birth weight) and family-related (e.g., maternal nutritional status) variables. Results. At baseline, mean age was 11.7 (± 3.5) months and 50.1% were boys. Children born by Caesarean section were 15.6%. The 10.5% of the children were overweight and 2.4% were obese. For the obesity outcome, data from 6,038 and 9,625 children-years was included from baseline to the first and second follow-up, respectively. Compared to those who did not experience Caesarean delivery, the risk of having obesity was higher in the group born by Caesarean: RRs were higher at early-childhood (first follow-up: 2.25; 95% CI [1.36-3.74]) than later in life (second follow-up: 1.57; 95% CI [1.02-2.41]). Family-related variables had a greater effect in attenuating the risk estimates for obesity at the first, than at the second follow-up. Conclusion. Our results suggest a higher probability of developing obesity, but not overweight, among children born by Caesarean section delivery. The magnitude of risk estimates decreased over time, and family-related variables had a stronger effect on the risk estimates at early-childhood.


Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding.
The binding of the CD4 receptor by the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein is important for virus entry and cytopathic effect. To investigate the CD4-binding region of the gp120 glycoprotein, we altered gp120 amino acids, excluding cysteines, that are conserved among the primate immunodeficiency viruses utilizing the CD4 receptor. Changes in two hydrophobic regions (Thr-257 in conserved region 2 and Trp-427 in conserved region 4) and two hydrophilic regions (Asp-368 and Glu-370 in conserved region 3 and Asp-457 in conserved region 4) resulted in significant reductions in CD4 binding. For most of the mutations affecting these residues, the observed effects on CD4 binding did not apparently result from global conformational disruption of the gp120 molecule, as assessed by measurements of precursor processing, subunit association, and monoclonal antibody recognition. The two hydrophilic regions exhibit a strong propensity for beta-turn formation, are predicted to act as efficient B-cell epitopes, and are located adjacent to hypervariable, glycosylated regions. This study defines a small number of gp120 residues important for CD4 binding, some of which might constitute attractive targets for immunologic intervention.


A taxonomy of behaviour change methods: an Intervention Mapping approach.
In this paper, we introduce the Intervention Mapping (IM) taxonomy of behaviour change methods and its potential to be developed into a coding taxonomy. That is, although IM and its taxonomy of behaviour change methods are not in fact new, because IM was originally developed as a tool for intervention development, this potential was not immediately apparent. Second, in explaining the IM taxonomy and defining the relevant constructs, we call attention to the existence of parameters for effectiveness of methods, and explicate the related distinction between theory-based methods and practical applications and the probability that poor translation of methods may lead to erroneous conclusions as to method-effectiveness. Third, we recommend a minimal set of intervention characteristics that may be reported when intervention descriptions and evaluations are published. Specifying these characteristics can greatly enhance the quality of our meta-analyses and other literature syntheses. In conclusion, the dynamics of behaviour change are such that any taxonomy of methods of behaviour change needs to acknowledge the importance of, and provide instruments for dealing with, three conditions for effectiveness for behaviour change methods. For a behaviour change method to be effective: (1) it must target a determinant that predicts behaviour; (2) it must be able to change that determinant; (3) it must be translated into a practical application in a way that preserves the parameters for effectiveness and fits with the target population, culture, and context. Thus, taxonomies of methods of behaviour change must distinguish the specific determinants that are targeted, practical, specific applications, and the theory-based methods they embody. In addition, taxonomies should acknowledge that the lists of behaviour change methods will be used by, and should be used by, intervention developers. Ideally, the taxonomy should be readily usable for this goal; but alternatively, it should be clear how the information in the taxonomy can be used in practice. The IM taxonomy satisfies these requirements, and it would be beneficial if other taxonomies would be extended to also meet these needs.


A pilot study of an in-vitro bovine trachea model of the effect of continuous positive airway pressure breathing on airway surface liquid.
Continuous positive air pressure (CPAP) users frequently report troublesome symptoms of airway dryness and nasal congestion. Clinical investigations have demonstrated that supplementary humidification reduces these symptoms but the reason for their occurrence remains unexplained. Investigations using human computational air-conditioning models are unable to reproduce or quantify the apparent airway drying experienced during CPAP therapy. The purpose of this study was to determine whether augmented air pressures change overall mucosal airway surface liquid (ASL) water supply and, if so, the extent of this effect. In an original in vitro experimental set up, maximal ASL supply was determined in whole bovine trachea when exposed to simulated tidal breathing stresses over a range of air pressures. At ambient pressure, the maximal supply of ASL was found to compare well to previously published data (31.2 μl/cm2.hr). CPAP pressures from 5 cm H2O above ambient were found to reduce ASL supply by 22%. Statistical analysis (n = 8) showed a significant difference existed between the ambient and CPAP results (p < 0.0001), and that there was no significant variation between all pressurized results (p = 0.716). These findings provide preliminary data that ASL supply is reduced by CPAP therapy which may explain the airway drying symptoms associated with this therapy.


The Factors Associated With the Successful Outcomes of Percutaneous Disc Decompression in Patients With Lumbar Herniated Nucleus Pulposus.
To determine clinical and radiological factors that predict the successful outcome of percutaneous disc decompression (PDD) in patients with lumbar herniated nucleus pulposus (HNP). We retrospectively reviewed the clinical and radiological features of patients who underwent lumbar PDD from April 2009 to March 2013. Sixty-nine patients with lumbar HNP were studied. Clinical outcome was assessed by the visual analogue scale (VAS) and the Oswestry Disability Index (ODI). Multivariate logistic regression analysis was performed to assess relationship among clinical and radiological factors and the successful outcome of the PDD. The VAS and the ODI decreased significantly at 1 year follow-up (p<0.01). One year after PDD, the reduction of the VAS (ΔVAS) was significantly greater in the patients with pain for <6 months (p=0.03) and subarticular HNP (p=0.015). The reduction of the ODI (ΔODI) was significantly greater in the patients with high intensity zone (p=0.04). Multivariate logistic regression analysis revealed the following 5 factors that were associated with the successful outcome after PDD: pain duration for <6 months (odds ratio [OR]=14.036; p=0.006), positive straight leg raising test (OR=8.425, p=0.014), the extruded HNP (OR=0.106, p=0.04), the sequestrated HNP (OR=0.037, p=0.026), and the subarticular HNP (OR=10.876, p=0.012). PDD provided significant improvement of pain and disability of patients. The results of the analysis indicated that the duration of pain <6 months, positive straight leg raising test, the subarticular HNP, and the protruded HNP were predicting factors associated with the successful response of PDD in patients with lumbar HNP.