A note on the optimal measure of allelic association.
Association of pairs of loci due to departure of gamete frequencies from expected frequencies is called allelic association. This measure is useful for fine-scale mapping. There are several measures of allelic association in the literature. With the availability of a SNP map, the use of linkage disequilibrium to map genes is one of the central issues in the human genome project. The size of linkage disequilibrium blocks is of considerable interest. In this note, we investigate the statistical properties of a measure which is known to have the strongest theoretical population basis and be least sensitive to the marker allele frequencies. In particular, we have shown that this measure has intuitive appeal and the estimator for this measure has several statistically optimal properties such as consistency, asymptotic unbiasedness and asymptotic efficiency.


Salmonella: immune responses and vaccines.
Salmonella infections are a serious medical and veterinary problem world-wide and cause concern in the food industry. Vaccination is an effective tool for the prevention of Salmonella infections. Host resistance to Salmonella relies initially on the production of inflammatory cytokines leading to the infiltration of activated inflammatory cells in the tissues. Thereafter T- and B-cell dependent specific immunity develops allowing the clearance of Salmonella microorganisms from the tissues and the establishment of long-lasting acquired immunity to re-infection. The increased resistance that develops after primary infection/ vaccination requires T-cells cytokines such as IFNgamma TNFalpha and IL12 in addition to opsonising antibody. However for reasons that are not fully understood seroconversion and/or the presence of detectable T-cell memory do not always correlate with the development of acquired resistance to infection.Whole-cell killed vaccines and subunit vaccines are used in the prevention of Salmonella infection in animals and in humans with variable results. A number of early live Salmonella vaccines derived empirically by chemical or u.v. mutagenesis proved to be immunogenic and protective and are still in use despite the need for repeated parenteral administration. Recent progress in the knowledge of the genetics of Salmonella virulence and modern recombinant DNA technology offers the possibility to introduce multiple defined attenuating and irreversible mutations into the bacterial genome. This has recently allowed the development of Salmonella strains devoid of significant side effects but still capable of inducing solid immunity after single oral administration. Live attenuated Salmonella vaccines have been used for the expression of heterologous antigens/proteins that can be successfully delivered to the immune system. Furthermore Salmonella can transfer plasmids encoding foreign antigens under the control of eukaryotic promoters (DNA vaccines) to antigen-presenting cells resulting in targeted delivery of DNA vaccines to these cells. Despite the great recent advances in the development of Salmonella vaccines a large proportion of the work has been conducted in laboratory rodents and more research in other animal species is required.


Resurgence of parathyroidectomy: evidence and outcomes.
Parathyroidectomy (PTx) is the definitive therapy for refractory secondary hyperparathyroidism (SHPT). The drastic effects of PTx on biochemical parameters of SHPT increases the possibility that this intervention will lead to a reduction in the adverse outcomes related to uncontrolled SHPT. The effect of PTx on mortality and cardiovascular outcomes among dialysis patients with severe SHPT have been evaluated in many observational studies from different regions of the world, including Asia, Europe, North America, and South America. In all but one small study, there was a significant association of PTx with lower all-cause mortality. In addition, in all studies, there was a trend in favor of PTx for cardiovascular morbidity and mortality. The effect of PTx on fractures has been evaluated in only one epidemiological study from the United States, which demonstrated a significant association of PTx and lower hip and combined fractures. Although randomized evidence is lacking, these highly consistent results may suggest a strong beneficial effect of PTx on long-term clinical outcomes and eliminate the potential concern of low parathyroid hormone after PTx.


Physical map of the 3' region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype.
We have constructed the physical map of the 3' region of the human immunoglobulin heavy chain variable region (VH) genes. DNA segments extending to 200 kb upstream of the JH segment were isolated in two YAC clones. Five VH segments were identified in this region in the 5' to 3' order, V(II-5), V(IV-4), V(I-3), V(I-2), and V(VI-1) segments which were all structurally normal and orientated in the same direction as the JH segments. From DNA of a different cell line we have isolated a cosmid contig containing the same DNA region which has extraordinary polymorphism. The YAC and cosmid DNAs were called haplotypes A and B, respectively. Haplotype B contained an additional VH-I segment (V(I-4.1b)) between the V(II-5) and V(IV-4) segments. V(I-4.1b) segment is almost identical to a previously published VH sequence encoding a rheumatoid factor. Another VH segment in the B haplotype (V(I-3b)) corresponding to the V(I-3) segment also showed 99.7% nucleotide sequence homology with an anti-DNA autoantibody VH sequence. However, none of the VH sequences in haplotype A showed such strong homology with autoantibody VH sequences. The results suggest that VH haplotypes may have linkage with autoantibody production.


Previous Percutaneous Coronary Intervention Does Not Increase Adverse Events After Coronary Artery Bypass Surgery.
Adverse effects of previous percutaneous coronary intervention (PCI) on clinical outcomes after coronary artery bypass grafting (CABG) are unclear. This study aimed to evaluate the effect of previous PCI on early outcomes after subsequent CABG by using data from the Japanese national database. This study analyzed data from 48,051 consecutive patients that were retrieved from the Japan Adult Cardiovascular Surgery Database. These patients underwent primary, isolated, elective CABG between January 2008 and December 2013. Early mortality and morbidity rates in patients with previous PCI (n = 12,457, 25.9%) were compared with those in patients with no PCI (n = 35,594, 74.1%) by using multivariate logistic regression analysis and propensity score analysis. Operative mortality rates (no PCI, 1.2%; previous PCI, 1.2%; P = 0.970) and morbidity rates (no PCI, 7.4%; previous PCI, 7.2%; p = 0.436) were similar between the two groups. In risk-adjusted multivariate logistic-regression analysis, previous PCI (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.82 to 1.22; p = 0.995) and morbidity (OR, 0.97; 95% CI, 0.89 to 1.05; p = 0.391) were not significant risk factors of operative mortality. Inverse probability of treatment weighting using the propensity score confirmed these results. This study shows that a previous PCI procedure does not increase postoperative adverse events after subsequent CABG. In the setting of repeat coronary revascularization, the most appropriate method of revascularization should be selected by the heart team, without being affected by a history of a previous PCI procedure.


Reductions in the prevalence and incidence of geohelminth infections following a city-wide sanitation program in a Brazilian Urban Centre.
In the city of Salvador, a large urban centre in Northeast Brazil, a city-wide sanitation intervention started in 1997, aimed at improving the sewerage coverage of households from 26% to 80%. Our aim was to study the impact of the intervention on the prevalence and incidence of geohelminths in the school-aged population. THE STUDY COMPRISED TWO COMPARABLE COHORTS: the first assembled in 1997, before the intervention, and the second assembled in 2003, after the intervention. Both were sampled from 24 sentinel areas chosen to represent the different environmental conditions throughout the city. Copro-parasitological examinations were carried out on every individual from both cohorts, at baseline and nine months later. Demographic, socio-economic, and environmental data were collected using semi-structured questionnaires and environmental surveys. A hierarchical modelling approach fitting a sequence of Poisson multivariate linear models was undertaken to test the effect of the intervention variables on the prevalence and incidence rate ratios. 729 and 890 children aged 7-14 years (mean = 10.4 y, SD = 0.05 y) were analysed over the first and the second cohorts, respectively. The adjusted reductions of the prevalence and incidence rates at the second in relation to the first cohort were 27% and 34%, 25% and 32%, 33% and 26%, and 82% and 42% for geohelminths overall, Ascaris lumbricoides, Trichuris trichiura, and hookworm, respectively. Hierarchical modelling showed that a major part of each of these reductions was explained by the intervention. Our results show that a city-wide sanitation program may reduce significantly the prevalence and incidence of geohelminths.


Comparison of associations of outcomes after stroke with estimated GFR using Chinese modifications of the MDRD study and CKD-EPI creatinine equations: results from the China National Stroke Registry.
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation estimates glomerular filtration rate (GFR) more precisely than the MDRD (Modification of Diet in Renal Disease) Study equation. The risk implications of this equation have been compared with the MDRD Study equation in different demographic and clinical characteristics. However, whether a Chinese modification of this equation performs better than a Chinese modification of the MDRD Study equation in risk prediction in Chinese patients with stroke is unknown. Prospective cohort study, China National Stroke Registry. 15,791 consecutive patients with stroke enrolled from September 2007 to August 2008; follow-up time, 1 year. Estimated GFR (eGFR) and eGFR categories computed using Chinese modifications of the MDRD Study and CKD-EPI creatinine equations. All-cause mortality, recurrent stroke, stroke disability, combined end point of stroke or death. GFR was estimated by Chinese modifications of the MDRD Study (eGFRMDRD(CN)) and CKD-EPI (eGFRCKD-EPI(CN)) equations. The median value for eGFRCKD-EPI(CN) was higher than that for eGFRMDRD(CN) (87.3 vs 82.5 mL/min/1.73 m(2); P<0.001). 22.8% of patients were reclassified by the CKD-EPI China equation (11.5% [1,818/15,791] to a higher eGFR category, and 11.3% [1,789/15,791], to a lower eGFR category). Of patients with eGFRMDRD(CN) of 60-89 and 30-59 mL/min/1.73 m(2), 18.3% (1,299/7,090) and 18.4% (422/2,296) were reclassified upward to a higher eGFR category, respectively, reducing the CKD prevalence from 16.4% to 14.2%. Net reclassification improvement favored the Chinese modification of the CKD-EPI equation for the prediction of all-cause mortality, stroke recurrence, death, or stroke recurrence and stroke disability (net reclassification improvements of 0.05, 0.03, 0.04, and 0.1, respectively; all P<0.01). Relatively short follow-up time and no measurement of albuminuria. Our findings suggest that a Chinese modification of the CKD-EPI equation may improve risk prediction of all-cause mortality, stroke recurrence, death or stroke recurrence and stroke disability more than a Chinese modification of the MDRD Study equation in Chinese stroke patients.


Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010.
The incidence rate of the myelodysplastic syndromes (MDS) in the United States is approximately 3.4 per 100,000 people, accounting for more than 10,000 new diagnoses annually and an estimated 60,000 people living with the disease. Common risk factors for developing MDS include advanced age, male gender, and antecedent exposure to chemotherapy or radiation as treatment for other cancers, which alone accounts for 10% of MDS cases. Patients with MDS typically are diagnosed when they are in their 70s, have significant cytopenias, and have substantive transfusion needs. Erythropoiesis stimulating agents are used by more than 50% of patients, although the use of disease-modifying agents is increasing, and may ultimately have an impact on the number of patients living with MDS.


Genetic contribution to factor VII levels in families of patients undergoing coronary arteriography.
An elevated plasma level of factor VII is a risk factor for coronary artery disease. We investigated environmental, familial, and genetic influences on factor VII activity in 508 family members of 87 probands who underwent elective coronary arteriography. Maximum likelihood methods were used to fit several genetic and non-genetic models of inheritance to these data to determine whether an unobserved Mendelian major gene could explain the familial distribution of factor VII. Factor VII activities were adjusted for age, gender, body mass index, smoking, alcohol consumption, menopause status, and triglycerides prior to this segregation analysis (this model accounted for 33.5% of the total variation). Adjusted factor VII activities showed strong familial aggregation with an estimated parent-offspring correlation of 0.34, sibling correlation of 0.36 and a smaller spouse correlation of 0.16. Regressive models were used to test genetic and non-genetic models in these 87 families. Mendelian single-locus models with either two or three underlying genotypic distributions of factor VII activities were best supported by these data. Essentially, these Mendelian models suggest most individuals come from a low distribution (mean, 116%), with a few individuals homozygous for a high allele drawn from a distribution with a mean of 166%. Future linkage studies may be worthwhile to further clarify the mechanisms controlling factor VII activity.


Antibody affinity maturation in vitro using unconjugated peptide antigen.
Selection of antibody library in vitro is almost always performed on a certain solid-phase with immobilized antigen. However, for the selection of small molecule binders, conjugation of the antigen to a carrier molecule is indispensable, which often leads to the selection of unwanted binders such as conjugate-binders or those with insufficient specificity. Here we describe a rapid and efficient way to improve the affinity of an anti-small molecule antibody without antigen derivatization. The method is based on the open-sandwich (OS) principle, which utilizes the antigen-dependent stabilization of antibody variable domain Fv. We used an anti-osteocalcin C-terminal peptide Fv that showed a good response but with moderate sensitivity in OS ELISA as a model. By selecting PCR-randomized V(H)-displaying phages for superior binders to the immobilized V(L) fragment in the presence of limited amount of antigen peptide, V(H) mutants that show superior detection sensitivity in OS ELISA were obtained, and were characterized to retain improved antigen-binding affinity. Furthermore, saturation mutagenesis of a mutant resulted in further improvement in sensitivity. This 'OS-selection' will be the first to select anti-small molecule antibodies without using conjugated antigens, and especially useful in the affinity maturation of antibodies whose Fv has limited stability in the absence of antigen.


'They say "I did it", but they don't say "I got an STI from it"': Exploring the experiences of youth with a migration background with sexual health in Amsterdam, the Netherlands.
Youth with a migration background are underserved by sexual healthcare. Insight in their experiences is essential to develop tailored services and counter disparities. We explored how youth with a migration background access sexual health information, experience public sexual healthcare, and navigate sexual health in their particular sociocultural contexts. We carried out nine semi-structured interviews and one group interview with twelve young people (18-24) with a migration background in Amsterdam, the Netherlands. Respondents were heterosexually oriented and of various sociocultural backgrounds. Data were analysed using thematic content analysis. Three themes emerged: 'Access to sexual health information', 'Access to primary sexual health care', and 'Strategies for sexual self-care'. Youth sought out information online or from peers, however, conversations mostly focussed on pleasure while risk was often not discussed. Youth valued anonymity when accessing sexual healthcare, and used several strategies, such as staying silent or adhering to values such as 'self-respect', to navigate sexual health within their everyday gendered environments. While these strategies manifested as sources of empowerment, they also resulted in potential vulnerabilities. To counter sexual health disparities among youth with a migration background, public sexual health services should provide culturally safe care and foster participatory collaborations with local stakeholders.


Effects of allopurinol and preconditioning on apoptosis due to ischemia-reperfusion on a double jejunum-segment canine model.
To investigate the duration of apoptosis caused by ischemia-reperfusion in the intestine in a new double jejunum-segment model, and to analyze the protective effects of allopurinol or ischemic preconditioning (IPC). In Experiment I for harvesting the double jejunum-segment model after laparotomy a 30-cm-long jejunum part was selected on mongrel dogs (n=24). End-to-end anastomoses were performed at both ends and in the middle of the jejunum part, creating two equal segments. In one segment ischemia was induced by occluding the supplying vessels, the other segment served as control. Tissue samples for detecting apoptosis were taken at 30th minutes, 1st, 2nd, 4th, 6th, 8th, 12th and 24th hours of reperfusion. In Experiment II using the same model the 4-hour reperfusion time period, allopurinol (50 mg/kg) pre-treated and IPC (3 cycles of 5x1) groups (n=5 per each) were also investigated. In Experiment I the greatest apoptotic activity was detected at the 4th and 6th hour of reperfusion (14.2 ± 1.31 and 16.3 ± 1.05 per visual field at 40x magnification). In Experiment II Using the 4-hour reperfusion time period allopurinol pre-treatment increased the apoptotic activity (10.72 ± 0.47 per 50 intestinal villi) approximately two-fold than the IPC (6.72 ± 0.46 per 50 intestinal villi) did (p<0.05). Apoptotic activity has a characteristic time curve, reaching the highest values between the 4th and 6th hours after 30-minute intestinal ischemia. Ischemic preconditioning seemed to be protective against the morphological changes caused by intestinal ischemia-reperfusion.


[Population dynamics of Aedes aegypti (L) in an urban area with high incidence of dengue].
Aspects of the population dynamics of Aedes aegypti were investigated from collections over a two-year period in the urban area of Uberlândia, State of Minas Gerais. The population dynamics of this mosquito were influenced by physical factors such as temperature and rainfall. High larval densities also had an influence on mosquito development.


MRA image production and display.
Magnetic resonance angiography (MRA) refers to a collection of imaging techniques which accentuate the signal intensity of flowing blood and suppress the signal intensity of stationary tissues. The resulting images are processed to resemble conventional catheter angiograms but carry fundamentally different information which is derived from flow rather than anatomy. All MRA techniques are subject to a variety of artifacts can stimulate pathology. A knowledge of the techniques used to produce and display MR angiographic images is essential for their accurate interpretation.


Isospecific polymerization of 1-hexene by C1-symmetric half-metallocene dimethyl complexes of group 4 metals with bidentate N-substituted iminomethylpyrrolyl ligands.
Non-bridged half-metallocene dimethyl complexes of group 4 metals 2a-4a with an N-4-methoxyphenyl(iminomethyl)pyrrolyl ligand 1a were synthesized and characterized by NMR spectroscopy and X-ray analysis. Upon activation with [Ph3C][B(C6F5)4], these complexes became active catalysts for the polymerization of 1-hexene. A series of hafnium complexes with various N-substituents on the imine group of ligands 1b-1g were also prepared and applied as catalysts for 1-hexene polymerization. The activation parameters for the exchange process between the two methyl groups bound to the metal for Cp*MMe2(R-pyr) complexes were estimated by NMR shape analysis at various temperatures. The findings indicated that the transition state of the ligand flipping process might be associated with the isoselectivity of the polymerization reaction.


A model for Vision Zero implementation in Iran: a grounded theory study.
Road Traffic injuries (RTIs) are major global health issues, but they have been neglected. RTIs are multi-faceted in nature and, like many injuries, are costly but preventable. Iran has one of the highest rates of deaths due to traffic accidents among middle-income countries. Hence, there is a need for effective and preventive approaches in road safety management. One of the new approaches to road safety is the Vision Zero. The aim of this study was to design a Vision Zero implementation model in Iran. This present study was conducted using the qualitative grounded theory approach. Purposive, snowball and maximum variety sampling were used to select participants. In-depth interviews were used to collect data. Grounded theory method was used to analyze the data using Corbin and Strauss method. In this study, 19 interviews were conducted with 17 participants. Based on data analysis, a total of 4 main categories and 13 subcategories were obtained. According to the participants, the lead agency was recognized as the core category. Other concepts were categorized as causal conditions, intervening conditions, contextual conditions, action/interaction strategies, and consequences. Establishing a lead agency with inter-organizational coordination through political support and legislation and changing the approach of road safety can be effective in implementing a Vision Zero. Also, improving the safety attitude of the stakeholders and changing their approach through training and advocacy from various organizations related to road safety is effective in creating a lead agency and implementing a vision zero. In addition, in order to implementation of the model, it is very important to pay attention to the economic, political and ethical underlying factors towards human beings.


KCNMA1-linked channelopathy.
KCNMA1 encodes the pore-forming α subunit of the "Big K+" (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1-/- ) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as "KCNMA1-linked channelopathy." These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.


Fb'2, a new peptic fragment of human immunoglobulin G.
The digestion of a human IgG1 K myeloma protein with pepsin in the presence of 8M-urea was observed to produce a fragment, designated Fb'2, which differed from the products of aqueous peptic digestion and from other characteristic immunoglobulin digestion products. 2. Fragment Fb's was also found when two other IgG1/K proteins were treated similarly. 3. Sedimentation-equilibrium studies showed the mol.wt. of fragment Fb'2 to be 56800. 4. On reduction, two equivalents of each of three peptides were released from fragment Fb's; these were characterized by N- and C-terminal determinations and by amino acid sequencing. 5. Fragment Fb'2 was shown to consist of the constant regions of both light chains, from residue Ile-117 to the C-terminus, and the CH1 domains and hinge region of the heavy chains, from residue Val-113 to residue Met-252, with a gap of five residues within the intrachain disulphide loop, between residues Leu-174 and Tyr-180.


[The simulator for mastering of tendon suture technique].
The article describes the tendon and simulator model for mastering of tendon suture technique. As a tendon model, the authors suggest to use segments of silicone rods, which remain unclaimed after a two-stage tendon reconstruction. Diameter, shape, elasticity of silicone prostheses satisfies to similar parameters of the fingers hand man tendons. The plastic board with holes is using as a support for fixation of the tendon model. The proposed device is simpler and more available in comparison with the known analogues. The effectiveness of the original model and simulator tested in practice at training young surgeons.


Expression of CYP4F12 in gastrointestinal and urogenital epithelia.
Cytochrome P450 4F12 (CYP4F12) was originally cloned from human liver and small intestine. CYP4F12 can oxidize arachidonic acid, two stable prostaglandin H2 analogues, and an antihistamine, ebastine, but the tissue distribution and catalytic properties of CYP4F12 have not been fully investigated. An antipeptide polyclonal antibody was raised against the C-terminal of CYP4F12 (PLNVGLQ), evaluated by Western blot analysis and used for immunohistological analysis of 50 human tissues. Western blot analysis of recombinant CYP4F12, expressed in yeast, and microsomal proteins from adult and foetal liver, kidney, placenta at term, seminal vesicles, the prostate gland and purified prostasomes showed that the polyclonal antibody detected a protein of the expected size, approximately 60 kDa. CYP4F12 mRNA could be detected in seminal vesicles and prostate gland by reverse transcription-PCR. Prominent CYP4F12 immunoreactivity occurred, inter alia, in the epithelial cells of the gastrointestinal tract (stomach, small intestine, and colon), collecting tubules, transitional epithelium, ovarian follicles, the endothelium of microvessels of placental villi (first trimester), and epidermis. We screened recombinant CYP4F12 for catalytic activity. Arachidonic acid (20:4n-6) was hydroxylated at C18 and laurate at C11, but significant amounts of metabolites of 18:2n-6, 20:3n-9, 20:5n-3, 22:5n-6, and some prostaglandins could not be detected. We conclude that CYP4F12 is widely distributed in gastrointestinal and urogenital epithelia and exhibits a narrow substrate specificity.


Highly diastereoselective 1,3-dipolar cycloaddition reactions of trans-2-methylene-1,3-dithiolane 1,3-dioxide with 3-oxidopyridinium and 3-oxidopyrylium betaines: a route to the tropane skeleton.
The C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide, was found to react with a range of 3-oxidopyridinium betaines (bearing different substituents on nitrogen) in high yield and with total diastereoselectivity. A 2.3:1 mixture of regioisomers was formed with all of the 3-oxidopyridinium betaines but the ratio was found to change over prolonged periods of time due to reversibility of the minor regioisomer. 3-Oxidopyridinium betaines bearing methyl substituents at either the 2- or 6-position were also tested in the cycloaddition process. Improved regioselectivity (8:1) and again high diastereoselectivity were observed with the betaine having an additional substituent at the 2-position, but with betaines having a substituent in the 6-position although high regioselectivity was observed (9.9:1), the major isomer was formed with low diastereoselectivity (5.5:4.4). The origin of the regio- and diastereo-selectivity with all the betaines is discussed. Finally, the C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide was reacted with an oxidopyrylium betaine in moderate yield. Good regioselectivity and moderate diastereoselectivity were observed.


Community Perspectives on Zika Virus Disease Prevention in Guatemala: A Qualitative Study.
Zika virus, which is transmitted by Aedes aegypti mosquitoes and through sexual transmission, disproportionally affects the human fetus. Guatemala experienced a surge of Zika cases beginning in 2016. We conducted a qualitative study of community perceptions of the seriousness of Zika, as well as the effectiveness, feasibility, and collective efficacy of Zika prevention actions. Free listing elicited the preventive actions salient for 68 participants comprising pregnant women, men with a pregnant partner, and women likely to become pregnant; 12 focus group discussions in a highland and a lowland town explored other concepts through rank orderings of prevention practices depicted on cards. Participants' initial concern about Zika, based on recent experience with chikungunya and high media coverage, diminished because of its mild symptoms and reduced media coverage. Participants identified more than 32 salient preventive actions, many of which are considered effective by programs. Participants ranked water storage container cleaning and regular unspecified cleaning of the house and its surroundings as highly effective, feasible, and of high collective efficacy; however, the actions lacked the specificity needed to effectively destroy mosquito eggs. Community-level removal of tires and discarded containers had lower collective efficacy than household-level implementation because of the municipal and community cooperation needed. Condom use, although salient for Zika prevention, was hindered by gender roles. The findings indicate space for increasing self-efficacy for condom use among fathers-to-be, abandoning nonspecific terms such as "cleaning" and "standing water," increasing people's skills in using bleach as an ovicide, and promoting antenatal care and family planning counseling.


Regulation of epithelial sodium transport by promyelocytic leukemia zinc finger protein.
Aldosterone is the principal regulator of Na homeostasis, and thereby blood pressure. One of the main targets of aldosterone is the epithelial Na channel (ENaC) located in the apical membrane of target cells. Previous studies identified several genes involved in the regulation of ENaC such as SGK1; however, SGK1 knockout mice have only a mild salt-losing phenotype, indicating that further genes must be involved in the action of aldosterone. In our search for further aldosterone-regulated genes, we discovered that aldosterone, at physiological concentrations, induces the expression of the promyelocytic leukemia zinc finger protein (PLZF) in renal cortical collecting duct (CCD) cell lines that stably express mineralocorticoid receptors (MRs). This effect is rapid and does not require de novo protein synthesis, suggesting a direct action. Surprisingly, stable overexpression of human or mouse PLZF isoforms significantly decreased transepithelial Na transport in CCD cells while having no effect on the integrity of the monolayers. In parallel with the decline in Na transport, PLZF suppressed the mRNA levels of beta- and gamma-ENaC subunits. These observations suggest that PLZF is a negative regulator of ENaC in renal epithelial cells and might be part of a negative feedback loop that limits aldosterone's stimulatory effects on sodium reabsorption.


Primary Nailing in the Open Fractures of the Tibia-Is it worth?
Context (Background): The tibial shaft is one of the most common sites of open fractures. The specific methods of skeletal stabilization and soft tissue treatment of open fractures continue to be topics of debate in the orthopaedic traumatology. To evaluate the results of the intramedullary nailing in the open fractures of the tibia, especially in the Indian scenario. An observational, descriptive study which was done at a tertiary care hospital from 2006 to 2010. A prospective study was done on thirty cases which had sustained open fractures of t/hable Gustilo and Anderson grades I, II and III, who were operated for primary intramedullary interlocking nail fixation after thorough debridement and closure of their wounds with suturing, lateral skin release, split thickness skin grafting and muscle pedicle flap, where ever necessary. All the patients were followed up for a minimum of two years. Descriptive statistics and Fisher's Exact test were used. Of the total thirty cases, ten were of grade I, seven were of grade II, three were of grade IIIA, seven were of grade IIIB and three were of grade IIIC. Dynamization was done in nine cases. The average time to union was 16.0 weeks in the grade I cases, it was 18.3 weeks in the grade II cases, it was 23.6 weeks in the grade III A cases, it was 28.4 weeks in the grade III B cases and it was 32 weeks in the grade III C cases. The mean time to union was 20.7 weeks. Infection occurred in 3 cases. Delayed unions were observed in 4 cases. A non union occurred in 1 case of type IIIC. A mal union was observed in 1 case of type IIIB. 1 case of grade IIIC had the compartmental syndrome. No case had any implant failure (nail / screw breakage), or deep vein thrombosis. We conclude that the unreamed intramedullary nailing in cases of open fractures of the tibia, with an early soft tissue coverage, results in a faster soft tissue and bony healing, an easier soft tissue coverage, a better biomechanical stability and early rehabilitation and infection rates as comparable to those which are seen with other methods.


Interpersonal Trauma and Sexual Function and Satisfaction: The Mediating Role of Negative Affect Among Survivors of Military Sexual Trauma.
Healthy sexual function among women service members/veterans (SM/Vs) is associated with higher quality of life, lower incidence and severity of mental health diagnoses, higher relationship satisfaction, and less frequent suicidal ideation. Although trauma exposure has been established as a predictor of poor sexual function and satisfaction in women SM/Vs, no study to date has examined whether specific trauma types, such as military sexual trauma (MST), increase risk for sexual issues. Moreover, the possible mechanisms of this association have not been explored. The current study examined whether posttraumatic stress disorder (PTSD) and depression symptom clusters mediated the association of trauma type and sexual function and satisfaction in 426 trauma-exposed women SM/Vs. Two hundred seventy participants (63.4%) identified MST as their index trauma. Path analyses demonstrated that MST was related to poorer sexual function and lower satisfaction relative to the other traumas (χ2[28, N = 426] = 43.3, p = 0.03, CFI = 1.00, TLI = 0.99, and RMSEA = 0.04), and this association was mediated by higher non-somatic depressive symptoms and PTSD symptom clusters of anhedonia and negative alterations in cognition and mood (NACM). Causality cannot be inferred due to the cross-sectional nature of the data. However, our findings suggest that interventions aimed at decreasing sexual issues among female SM/Vs with MST should target depressogenic symptoms, whether the origin is depression or PTSD. Longitudinal research exploring the etiological processes that contribute to sexual dysfunction among those with MST is needed.


Protective effects of transient HO-1 overexpression on susceptibility to oxygen toxicity in lung cells.
Rat fetal lung cells (RFL-6) were transiently transfected with a full-length rat heme oxygenase (HO)-1 cDNA construct and then exposed to hyperoxia (95% O2-5% CO2) for 48 h. Total HO activity and HO-1 protein were measured as well as cell viability, lactate dehydrogenase (LDH) release, protein oxidation, lipid peroxidation, and total glutathione to measure oxidative injury. HO-1 overexpression resulted in increased total HO activity (2-fold), increased HO-1 protein (1.5-fold), and increased cell proliferation. Immunohistochemistry revealed perinuclear HO-1 localization, followed by migration to the nucleus by day 3. Decreased cell death, protein oxidation, and lipid peroxidation but increased LDH release and glutathione depletion were seen with HO-1 overexpression. Reactive iron content could not explain the apparent loss of cell membrane integrity. With the addition of tin mesoporphyrin, total HO activity was decreased and all changes in injury parameters were normalized to control values. We conclude that moderate overexpression of HO-1 is protective against oxidative injury, but we speculate that there is a beneficial threshold of HO-1 expression.


Probable interaction between levothyroxine and ritonavir: Case report and literature review.
A case of probable interaction of levothyroxine and ritonavir is presented along with a review of the relevant literature and recommendations on clinical management. A 37-year-old woman with human immunodeficiency virus infection who had recently undergone thyroidectomy for a benign multinodular goiter presented to a clinic with hypothyroidism (she was also found to be pregnant), and treatment with levothyroxine 75 μg daily was initiated. While receiving antiretroviral therapy (abacavir-lamivudine and lopinavir-ritonavir) during pregnancy, the patient had persistently elevated serum thyroid-stimulating hormone (TSH) concentrations (up to 125.89 μIU/mL) despite gradual escalation of the levothyroxine dosage to 175 μg daily. An interaction between ritonavir and levothyroxine was suspected, and dolutegravir was substituted for lopinavir-ritonavir. Within 4 months, the TSH concentration had normalized. The daily levothyroxine dose was tapered over a 5-month period and stabilized at 125 μg, and TSH concentrations remained within the normal range over an 18-month follow-up period. Scoring of the case using the Drug Interaction Probability Scale yielded a score of 6 out of 11, indicating a probable interaction between levothyroxine and ritonavir. A literature search identified 4 reported cases of interactions involving levothyroxine and ritonavir. A potentially serious and underrecognized drug interaction between ritonavir and levothyroxine was observed in a pregnant woman with postthyroidectomy-related hypothyroidism. This case and a review of other cases reported in the literature indicate that higher-than-usual doses of levothyroxine may be required in patients who are taking ritonavir concurrently.


Clinical study of childhood acute disseminated encephalomyelitis, multiple sclerosis, and acute transverse myelitis in Fukuoka Prefecture, Japan.
Acute disseminated encephalomyelitis (ADEM) has recently been studied in several countries owing to the development and wide spread use of imaging technology, but few epidemiological studies of childhood ADEM have been undertaken in Asian countries. To perform a comprehensive survey of ADEM and related diseases in Japanese children, we conducted a multicenter, population-based study on childhood ADEM, multiple sclerosis, and acute isolated transverse myelitis in Fukuoka Prefecture, Japan. We identified 26 children with ADEM, 8 with multiple sclerosis, and 4 with acute transverse myelitis during 5 years between September 1998 and August 2003. The incidence of childhood ADEM under the age of 15 years was 0.64 per 100,000 person-years, mean age at onset was 5.7 years, and male-female ratio was 2.3:1. The prevalence of childhood multiple sclerosis was 1.3 per 100,000 persons. The mean age at onset of multiple sclerosis, 9.3 years, was significantly higher than that of ADEM. Nineteen (73%) and four (15%) patients with ADEM experienced antecedent infectious illnesses and vaccinations, respectively, within 1 month before the onset. Clinical and radiological findings of ADEM revealed that the frequency of seizures, mean white blood cell counts in cerebrospinal fluid, and the frequency of subcortical lesions in Fukuoka study, seemed to be higher than those in previous non-Asian studies. These findings suggest that there are ethnic or geographical differences in the incidence and clinical features of ADEM, and that there might be potent genetic or environmental risk factors for ADEM distinct from those for multiple sclerosis.


Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency.
Severe combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis. The aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID. From 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study. A total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette-Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 109/L with over 88% patients below 3 × 109/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis. FH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 109/L.


Mechanisms of inhibition of proximal acidification by PTH.
The parathyroid hormone (PTH) effects on luminal Na-H exchange and basolateral Na-HCO3 cotransport were examined in isolated perfused rabbit proximal convoluted tubules. Lumen pH (pHi) and cell pH (pHi) were measured by a fluorescent technique using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). The time course of the PTH effect on proximal acidification was first determined by continuous monitoring of pHi in a stop-flow condition. PTH 10(-8) M added to the bath promptly inhibited the acid pHl generation. Adenosine 3',5'-cyclic monophosphate (cAMP) (10(-4) M) added to the bath mimicked the PTH effect. Luminal Na-H exchange was assayed by monitoring changes in pHi (dpHi/dt) in response to luminal Na+ removal in HCO3- free condition. The addition of PTH or cAMP for 5 min decreased dpHi/dt by 30 and 37%, respectively. Basolateral Na-HCO3 cotransport was assayed by measuring dpHi/dt caused by bath Na+ removal. The addition of PTH or cAMP for 5 min did not change the dpHi/dt. PTH also did not alter the dpHi/dt induced by reducing the bath HCO3- from 25 to 5 mM. The addition of PTH or cAMP to the bath slightly reduced pHi by 0.05. These results suggest that 1) PTH inhibits proximal acidification very rapidly and the effect reached a maximum within 10 min, 2) PTH rapidly inhibits luminal Na-H exchange but not basolateral Na-HCO3 cotransport in a short period, and 3) this effect is at least partly mediated by cAMP-dependent mechanisms.


New horizons in imaging and surgical assessment of breast cancer lymph node metastasis.
Axillary nodal status is one of the most important prognostic factors in breast cancer. While sentinel lymph node biopsy (SLNB) is a safe and validated procedure for clinically node-negative patients, axillary management of clinically node-positive patients has been more controversial. Patients with clinically detected axillary metastases often benefit from neoadjuvant chemotherapy (NAC). Those who convert to node-negative disease following NAC are important to identify, since they can often be spared significant morbidity from axillary dissection. SLNB has shown widely varying false-negative rates (FNR) but with the use of dual mapping and surgical biopsy of 3 or more nodes, it is considered an acceptable method to stage the axilla in clinically node-positive patients who receive NAC. Various methods including targeted axillary dissection (TAD) have been shown to decrease the FNR of SLNB. We will review appropriate methods to identify a metastatic node and subsequent ultrasound-guided biopsy with tissue marking techniques. We underscore key points in monitoring axillary response, techniques to accurately localize the biopsied and clipped known metastatic node for surgical excision and the effect of various methods in reducing the FNR of SLNB, including the emerging concept of TAD on patient care.


MicroRNA-128-1-5p attenuates myocardial ischemia/reperfusion injury by suppressing Gadd45g-mediated apoptotic signaling.
Myocardial ischemia/reperfusion (I/R) injury is a clinically fatal disease, caused by restoring myocardial blood supply after a period of ischemia or hypoxia. However, the underlying mechanism remains unclear. Recently, increasing evidence reveal that microRNAs (miRs) participate in myocardial I/R injury. This study aimed to investigate whether miR-128-1-5p contributed to cardiomyocyte apoptosis induced by myocardial I/R injury. Here, we showed that the expression of miR-128-1-5p was decreased in mice following myocardial I/R injury. Down-regulation of miR-128-1-5p was also showed in H9c2 cardiomyocytes after hypoxia/reoxygenation (H/R), and in neonatal rat cardiomyocytes (NRCMs) with H2O2 treatment. Importantly, we found that overexpression of miR-128-1-5p ameliorates cardiomyocyte apoptosis both in H9c2 cardiomyocytes and NRCMs. Moreover, we also found that growth arrest DNA damage-inducible gene 45 gamma (Gadd45g) is identified as a direct target of miR-128-1-5p, which negatively regulated Gadd45g expression. Additionally, silencing of Gadd45g inhibits cardiomyocyte apoptosis in H9c2 cardiomyocytes and NRCMs. These results reveal a novel mechanism by which miR-128-1-5p regulates Gadd45g-mediated cardiomyocyte apoptosis in myocardial I/R injury.


MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis.
The use of 12-core systematic prostate biopsy is associated with diagnostic inaccuracy that contributes to both overdiagnosis and underdiagnosis of prostate cancer. Biopsies performed with magnetic resonance imaging (MRI) targeting may reduce the misclassification of prostate cancer in men with MRI-visible lesions. Men with MRI-visible prostate lesions underwent both MRI-targeted and systematic biopsy. The primary outcome was cancer detection according to grade group (i.e., a clustering of Gleason grades). Grade group 1 refers to clinically insignificant disease; grade group 2 or higher, cancer with favorable intermediate risk or worse; and grade group 3 or higher, cancer with unfavorable intermediate risk or worse. Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens were recorded. Secondary outcomes were the detection of cancers of grade group 2 or higher and grade group 3 or higher, cancer detection stratified by previous biopsy status, and grade reclassification between biopsy and radical prostatectomy. A total of 2103 men underwent both biopsy methods; cancer was diagnosed in 1312 (62.4%) by a combination of the two methods (combined biopsy), and 404 (19.2%) underwent radical prostatectomy. Cancer detection rates on MRI-targeted biopsy were significantly lower than on systematic biopsy for grade group 1 cancers and significantly higher for grade groups 3 through 5 (P<0.01 for all comparisons). Combined biopsy led to cancer diagnoses in 208 more men (9.9%) than with either method alone and to upgrading to a higher grade group in 458 men (21.8%). However, if only MRI-target biopsies had been performed, 8.8% of clinically significant cancers (grade group ≥3) would have been misclassified. Among the 404 men who underwent subsequent radical prostatectomy, combined biopsy was associated with the fewest upgrades to grade group 3 or higher on histopathological analysis of surgical specimens (3.5%), as compared with MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%). Among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. However, MRI-targeted biopsy alone underestimated the histologic grade of some tumors. After radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy. (Funded by the National Institutes of Health and others; Trio Study ClinicalTrials.gov number, NCT00102544.).


Kissing naevus arising from neural crest cells presenting as upper and the lower lid mass.
A kissing nevus is a type of congenital compound nevus that affects equal portions of the upper and lower eyelid, and it extends to the lid margins. Congenital divided nevi of the eyelids are a rare melanocytic lesion. Only 30 patients are reported in the literature. We report a 40-year-old female of rural background who presented with a large painless enlarging pigmented mass, involving both upper and lower left eyelid since the past 20 years. Complete excision of the lesion was done, and the mass sent for histopathology, which revealed a compound nevus involving both lids. Surgery removed the obstruction, which had caused decreased visual acuity and had altered the cosmetic appearance of the patient. Lesions on the upper lid cause a mechanical ptosis, covers the visual axis, which causes obstruction in vision and is cosmetically unacceptable. There is a definite risk of malignant change in the nevus giving rise to malignant melanoma, and hence they should be removed as early as possible to give better functional and cosmetic results.


Comparison of mortality and morbidity rates among Iranian pilgrims in Hajj 2004 and 2005.
We compared the incidence of common diseases and accidents among Iranian pilgrims during Hajj 2004 and 2005, and determined the factors affecting the prevalence of each disease. We conducted this comparative study on 30037 Iranian pilgrims during Hajj 2004 and 75676 pilgrims during Hajj 2005, in Mecca and Medina in the Kingdom of Saudi Arabia. In this study, 23 types of common illnesses, 8 types of accidents, some important demographic variables, and some probable related factors were investigated. Two-sample tests of proportions in STATA Statistical Software version 8 was used for the data analysis. The most common diseases during the 2 journeys were respiratory diseases and the incidence of these diseases in Hajj 2005 was twice more in the year 2004. The prevalence of cardiovascular diseases among pilgrims in Hajj 2005 was 142 per 10,000 and it was significantly lower than in Hajj 2004 (288 per 10,000). There was no significant difference among gastrointestinal, gynecological, psychological, and other important diseases, in the 2 journeys. Among the 8 types of accidents, the incidence of head and eye injuries during Ramy (one of the components of Hajj rites) in the year 2005, was significantly lower in 2004 (22 per 10,000 against 125 per 10,000). Furthermore, the mortality rate in the year 2005 with 24 deaths per 100000, was significantly lower than the deaths in 2004 (47 per 100000). The findings of this study may guide the Hajj managers to estimate the needs of drugs, equipment, manpower, and educational needs for the pilgrims, also to identify and eliminate casual factors of diseases and accidents.


A class of physical modeling recurrent networks for analysis/synthesis of plucked string instruments.
A new approach is proposed that closely synthesizes tones of plucked string instruments by using a class of physical modeling recurrent networks. The strategies employed consist of a fast training algorithm and a multistage training procedure that are able to obtain the synthesis parameters for a specific instrument automatically. The training vector can be recorded tones of most target plucked instruments with ordinary microphones. The proposed approach delivers encouraging results when it is applied to different types of plucked string instruments such as steel-string guitar, nylon-string guitar, harp, Chin, Yueh-chin, and Pipa. The synthesized tones sound very close to the originals produced by their acoustic counterparts. In addition, the paper presents an embedded technique that can produce special effects such as vibrato and portamento that are vital to the playing of plucked-string instruments. The computation required in the resynthesis processing is also reasonable.


Cell interactions with lipid nanoparticles possessing different internal nanostructures: Liposomes, bicontinuous cubosomes, hexosomes, and discontinuous micellar cubosomes.
Lyotropic liquid crystalline nanoparticles (LLCNPs) with complex internal nanostructures hold promise for drug delivery. Cubosomes, in particular, have garnered interest for their ability to fuse with cell membranes, potentially bypassing endosomal escape challenges and improving cellular uptake. The mesostructure of nanoparticles plays a crucial role in cellular interactions and uptake. Therefore, we hypothesise that the specific internal mesophase of the LLCNPs will affect their cellular interactions and uptake efficiencies, with cubosomes exhibiting superior cellular uptake compared to other LLCNPs. LLCNPs with various mesophases, including liposomes, cubosomes, hexosomes, and micellar cubosomes, were formulated and characterised. Their physicochemical properties and cytotoxicity were assessed. Chinese Hamster Ovarian (CHO) cells were treated with fluorescently labelled LLCNPs, and their interactions were monitored and quantified through confocal microscopy and flow cytometry. The non-lamellar LLCNPs showed significantly higher cellular interactions compared to liposomes, with cubosomes exhibiting the highest level. However, there was no significant difference in relative cell uptake between cubosomes, hexosomes, and micellar cubosomes. Cell uptake experiments at 4 °C revealed the presence of an energy-independent uptake mechanism. This study provides the first comparative analysis of cellular interactions and uptake efficiencies among LLCNPs with varying mesophases, while maintaining similar size, composition, and surface charge.


DNA-flow cytometry (ploidy and s-phase fraction) as prognostic factor in a retrospective series of 515 primary breast-cancer.
Paraffin-embedded tissues are used in retrospective studies to evaluate the prognostic significance of DNA-flow cytometry (DNA-FCM) in human breast cancer. Although paraffin-embedded samples yield information on disease-free survival (DFS) and overall survival (GAS) of homogeneously selected patients, the resulting DNA-histograms have a lower resolution of aneuploid subpopulations and higher debris levels than those of fresh tumor samples. The aim of this study was to evaluate, retrospectively, the prognostic value of ploidy and the S-phase fraction (SPF) using 515 samples of paraffin-embedded consecutive primary breast cancer tissue (median follow-up: 75.4 months). Ploidy was detectable in 89% cases (34% diploid and 66% aneuploid) and SPF in 77%. The optimal cut-off for SPF was 6%. High SPF values were significantly correlated with shorter DFS (p=0.028) and OAS (p=0.018); aneuploidy was significantly correlated only with a shorter OAS (p=0.0058). Using the Cox proportional hazards regression model to evaluate the independence of DNA-FCM derived parameters, only high SPF was able to predict both a shorter DFS (p=0.02) and OAS (p=0.002). Furthermore, high SPF values were found correlated to aneuploidy (p<0.00001), tumor necrosis (p<0.015) and high histopathological grade (p<0.03). The data reported confirm that SPF is a valuable single independent prognostic factor in human breast, cancer and strongly support the use of archival tumor specimens to study the prognostic role of DNA-FCM in human cancer.


Changes to fetal steroidogenesis caused by maternal smoking.
Smoking during pregnancy presents health risks for both the mother and her child. In this study we followed changes in the production of steroid hormones in pregnant smokers. We focused on changes in steroidogenesis in the blood of mothers in their 37(th) week of pregnancy and in mixed cord blood from their newborns. The study included 88 healthy women with physiological pregnancies (17 active smokers and 71 non-smokers). We separately analyzed hormonal changes associated with smoking according to the sex of newborns. In women with male fetuses, we found higher levels of serum cortisone, dehydroepiandrosterone (DHEA), 7alpha-OH-DHEA, 17-OH pregnenolone, testosterone, and androstenedione in smokers at the 37(th) week compared to non-smokers. In women with female fetuses, we found lower serum levels of 7beta-OH-DHEA and higher androstenedione in smokers at the 37(th) week. We found significantly higher levels of testosterone in newborn males of smokers and higher levels of 7alpha-OH-DHEA in female newborns of smokers. Smoking during pregnancy induces changes in the production of steroids in both the mother and her child. These changes are different for different fetal sexes, with more pronounced changes in mothers carrying male newborns as well as in the newborn males themselves.


Characteristics and behaviors in a sample of patients unaware of their infection until AIDS diagnosis in Italy: a cross-sectional study.
The objective of this study was to define the sociodemographic and behavioral characteristics of people unaware of being HIV-positive at AIDS diagnosis. A multi-center cross-sectional study was conducted in 11 Italian centers of infectious diseases, recruited on a voluntary basis. Each center enrolled individuals diagnosed with AIDS aged ≥ 18 years from May 2003 to December 2005. The patients were classified into two groups on the basis of the amount of time that elapsed from diagnosis of HIV infection to AIDS diagnosis. "Late testers" were defined as those with a time period of ≤ 6 months between first HIV positive test and AIDS diagnosis. In order to evaluate the factors independently associated with being a late tester, a multivariate logistic regression model was performed. The McNemar χ(2) test was used to analyze behavioral changes before and after HIV diagnosis. During the study period, 245 patients were enrolled; of these, 51.8% were late testers. The variables independently associated with being a late testers were as follows: being employed; having acquired the infection through sexual contacts; having taken the HIV test because they didn't feel well; having at least one symptom or illness among those indicating infection; and not having had paid sex within the 12 months prior to HIV diagnosis. Before and after HIV diagnosis a significant increase in safe-sex behaviors was observed among individuals with no delay in diagnosis. However, the proportion of people who continue not to use condoms is still high. This study seems to indicate that sexual transmission is often associated with late testing. Individuals enrolled seem to have a low perception of risk, they do not undergo HIV testing, and consequently miss the opportunity of early diagnosis.


Metabolic syndrome in adults with a history of juvenile arthritis.
The objective of this study was to determine the risk of obesity and metabolic syndrome in adults with a history of juvenile arthritis (JA). Using the National Health and Nutrition Examination Survey (NHANES), we compared the characteristics of respondents with arthritis (JA vs rheumatoid arthritis [RA]) to those of the control group without arthritis. We used logistic regression analyses, controlling for age, race, and gender, to determine the ORs for metabolic syndrome. Obesity was increased in the JA group with 67% respondents having body mass index ≥30 kg/m2 vs 55% respondents in the no arthritis cohort (p=0.004). In unadjusted analyses, there was increased odds of metabolic syndrome in JA (OR 6.2, p=0.001) and RA groups compared to those without arthritis (OR 7.7, p=0.001). After adjusting for age, gender, and race, the odds of metabolic syndrome remained increased in JA (OR 5.2, p=0.001) and RA (OR 3.2, p=0.001) groups. Adults with a history of JA have a significantly increased risk of metabolic syndrome compared to those without arthritis. These findings are important because metabolic syndrome has been associated with an increased risk of cardiovascular disease and death in other populations.


Laparoscopic revision of failed fundoplication and hiatal herniorraphy.
The aim of this study was to evaluate the mechanisms of failure after laparoscopic fundoplication and the results of revision laparoscopic fundoplication. Laparoscopic Nissen fundoplication has become the most commonly performed antireflux procedure for the treatment of gastroesophageal reflux disease, with success rates from 90 to 95%. Persistent or new symptoms often warrant endoscopic and radiographic studies to find the cause of surgical failure. In experienced hands, reoperative antireflux surgery can be done laparoscopically. We performed a retrospective analysis of all laparoscopic revision of failed fundoplications done by the principle author and the respective fellow within the laparoscopic fellowship from 1992 to 2006. A review was performed on patients who underwent laparoscopic revision of a failed primary laparoscopic fundoplication. Laparoscopic revision of failed fundoplication was performed on 68 patients between 1992 and 2006. The success rate of the laparoscopic redo Nissen fundoplication was 86%. Symptoms prior to the revision procedure included heartburn (69%), dysphagia (8.8%), or both (11.7%). Preoperative evaluation revealed esophagitis in 41%, hiatal hernia with esophagitis in 36%, hiatal hernia without esophagitis in 7.3%, stenosis in 11.74%, and dysmotility in 2.4%. The main laparoscopic revisions included fundoplication alone (41%) or fundoplication with hiatal hernia repair (50%). Four gastric perforations occurred; these were repaired primarily without further incident. An open conversion was performed in 1 patient. Length of stay was 2.5 +/- 1.0 days. Mean follow-up was 22 months (range, 6-42), during which failure of the redo procedure was noted in 9 patients (13.23%). Laparoscopic redo antireflux surgery, performed in a laparoscopic fellowship program, produces excellent results that approach the success rates of primary operations.


Factors associated with success with hearing aids in older adults.
To examine associations between audiological and non-audiological factors and successful hearing aid use in older adults. In a retrospective study, audiological factors, attitudinal beliefs (as derived from the health belief model), client demographics, psychological factors, and age-related factors were evaluated. Participants included 160 individuals, 60 years or older, with unilateral or bilateral hearing impairment (HI), fitted with hearing aids for the first time in the previous two years. Participants were assigned to either an unsuccessful hearing aid owner group (n=75) or a successful hearing aid owner group (n=85) based on their self-reported hearing aid use and benefit. A multivariate, binomial logistic regression model indicated five factors associated with group membership: participants who had greater support from significant others; more difficulties with hearing and communication in everyday life before getting hearing aids; more positive attitudes to hearing aids; coupled with greater perceived self-efficacy for advanced handling of hearing aids; or who were receiving more gain from their devices; were more likely to be successful hearing aid owners. These findings highlight the importance of addressing non-audiological factors in order to assist older adults achieve success with hearing aids.


Mechanics and tribology of a zwitterionic polymer blend: Impact of molecular weight.
Despite decades of biomimetic materials development, the tribological properties of articular cartilage remain unrivalled. This manuscript presents the design and material properties of a polymer blend composed of poly (vinyl alcohol) (PVA) and a zwitterionic polysulfobetaine (PMEDSAH) prepared into hydrogel form using a cyclic freeze-thaw method. The PVA hydrogel matrix provides mechanical strength while the zwitterionic polymer, PMEDSAH, is intended to act as a boundary lubricant. The formation of PVA-PMEDAH hydrogel blends was found to result in unique biomimetic system where the boundary lubricant elutes from the bulk material to the surface in response to applied pressure. This behavior is attributed to the high-water content of the PVA hydrogel matrix and the solubility of PMEDSAH in aqueous solution. In addition to characterizing the effects of boundary lubricant molecular weight on the diffusive properties of the hydrogel blend, we report the coefficient of friction, μ, versus sliding speed for the hydrogel/glass interface. Consistent with our prior findings, PMEDSAH was found to engender lubricious behavior and the dependence of μ on sliding velocity indicated a repulsive interaction with glass rather than an attractive one. This result agrees with the hydration lubrication hypothesis. Contact mechanics analyzed within the context of Hertzian biphasic theory were also investigated, revealing that the introduction of PMEDSAH enhances the hydrogel's ability to provide interstitial fluid load support.


Chest x-ray survey in breast cancer follow-up--a contrary view.
The authors report on 83 cases of intrathoracic metastases (ITM) observed as isolated first recurrences in a ten-year experience of periodic chest x-ray (CXR) survey of primary breast cancer. In 44 of 83 cases ITM were detected on CXR in absence of subjective symptoms or clinical signs (A) whereas 39 ITM cases were detected as subjectively (S) symptomatic in the interval between two planned CXR controls. Diagnosis was anticipated by CXR survey as the disease-free interval was significantly shorter (30 vs. 43 months, p less than 0.04) for A respect to S cases. Nevertheless such a diagnostic anticipation had no prognostic impact as the ten year survival from primary treatment did not differ (0.12 vs. 0.16, p = 0.6) between A and S cases. Multivariate analysis confirmed that no impact on survival from primary treatment is expected whether ITM are detected in an earlier (asymptomatic, preclinical) or in a more advanced (subjectively symptomatic) phase. CXR survey after primary treatment of breast cancer seems thus a very questionable policy.


Polymerase Epsilon Exonuclease Domain Mutations in Ovarian Endometrioid Carcinoma.
Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsible for the recognition and excision of mispaired bases, thereby allowing high-fidelity DNA replication to occur. The Cancer Genome Atlas research network recently identified an ultramutated group of endometrial carcinomas, characterized by mutations in POLE, and exceptionally high substitution mutation rates. These POLE mutated endometrial tumors were almost exclusively of the endometrioid histotype. The prevalence and patterns of POLE mutated tumors in endometrioid carcinomas of the ovary, however, have not been studied in detail. In this study, we investigate the frequency of POLE exonuclease domain mutations in a series of 89 ovarian endometrioid carcinomas. We found POLE mutations in 4 of 89 (4.5%) cases, occurring in 3 of 23 (13%) International Federation of Gynecology and Obstetrics (FIGO) grade 1, 1 of 43 (2%) FIGO grade 2, and 0 of 23 (0%) FIGO grade 3 tumors. All mutations were somatic missense point mutations, occurring at the commonly reported hotspots, P286R and V411L. All 3 POLE-mutated FIGO grade 1 tumors displayed prototypical histology, and the POLE-mutated FIGO grade 2 tumor displayed morphologic heterogeneity with focally high-grade features. All 4 patients with POLE-mutated tumors followed an uneventful clinical course with no disease recurrence; however, this finding was not statistically significant (P = 0.59). The low rate of POLE mutations in ovarian endometrioid carcinoma and their predominance within the low FIGO grade tumors are in contrast to the findings in the endometrium.


[Cereal products as a source of selenium in Polish food rations].
The aim of the study was to update the data concerning the level of selenium in cereal products and to determine its uptake with daily food rations and percentage of cereal products in the 24-hour pool of selenium ingested. Selenium was determined fluorometrically after the reaction of Se (IV) with 2.3-diaminonaphthalene and extraction of naphtho-[2.3-d]-2-seleno-1.3-diazole to cyclohexane. Compared to the results found several years ago, the selenium levels observed in cereals, flour and bakery products were significantly lower. The mean levels of selenium in the above-mentioned products ranged from 22.9 micrograms/kg to 53.0 micrograms/kg and were markedly lower compared with pasta which reach to level 528 micrograms/kg, especially when pasta was made from semoline or contained eggs. The average daily intake of selenium with reconstructed rations was 37.9 micrograms while with home made rations 60.4 micrograms. The values calculated on the basis of the data collected in the 80-ties were significantly stray to analytical results, and those based on our findings was comparable. The percentage of the most important products in the daily selenium pool changed significantly after taking into account these new results because according to the data from 80-ties, the major sources of selenium in home and reconstructed rations were cereal products which share to 48%. According to the new results the main source of selenium in daily rations were meat one its products about 26% and cereal products somewhat less than 20%.


Photochemotherapy for mycosis fungoides: a clinical and histological study.
Nine patients with stages 2 or 3 mycosis fungoides (MF) and one with Sézary's syndrome were treated with oral methoxsalen and long-wave ultraviolet light. Previous therapy had either failed or achieved only partial control. Satisfactory clinical control was achieved in all but one case. Histological improvement was seen in all cases, but complete clearance of lymphoid infiltrate was noted mainly in epidermal and papillary dermal infiltrates. Lower dermal infiltrate remained largely unchanged. The case of Sézary's syndrome was inadequately controlled with systemic prednisone and cyclophosphamide, but addition of photochemotherapy improved the erythema and pruritus. This shows that photochemotherapy may have a place in MF treatment both alone and perhaps in conjunction with other treatments. An early relapse occurred on stopping photochemotherapy in four cases, but one patient has had three months' full remission.


Risk factors for delirium after spine surgery in elderly patients.
Postoperative delirium is a common complication in the elderly after surgery but few papers have reported after spinal surgery. We analyzed various risk factors for postoperative delirium after spine surgery. Between May 2012 and September 2013, 70 patients over 60 years of age were examined. The patients were divided into two groups : Group A with delirium and Group B without delirium. Cognitive function was examined with the Mini-Mental State Examination-Korea (MMSE-K), Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS). Information was also obtained on the patients' education level, underlying diseases, duration of hospital stay and laboratory findings. Intraoperative assessment included Bispectral index (BIS), type of surgery or anesthesia, blood pressure, fluid balance, estimated blood loss and duration of surgery. Postoperative delirium developed in 17 patients. The preoperative scores for the MMSE, CDR, and GDS in Group A were 19.1±5.4, 0.9±0.6, and 3.3±1.1. These were significantly lower than those of Group B (25.6±3.4, 0.5±0.2, and 2.1±0.7) (p<0.05). BIS was lower in Group A (30.2±6.8 compared to 35.4±5.6 in group B) (p<0.05). The number of BIS <40 were 5.1±3.1 times in Group A, 2.5±2.2 times in Group B (p<0.01). In addition, longer operation time and longer hospital stay were risk factors. Precise analysis of risk factors for postoperative delirium seems to be more important in spinal surgery because the surgery is not usually expected to have an effect on brain function. Although no risk factors specific to spinal surgery were identified, the BIS may represent a valuable new intraoperative predictor of the risk of delirium.


A Novel One-Stage Obstruction-Based Endoscopic Approach to Congenital Nasolacrimal Duct Obstruction.
To report 10-year results of a 1-stage, obstruction-based, endoscopic approach in children with congenital nasolacrimal duct obstruction (CNLDO) with and without prior failed probing/intubation. In a retrospective study, children with primary CNLDO of >6 months old previously failed probing/intubation, acute dacryocystitis or dacryocele at any age, and at least 6 months follow up. Diagnosis was based on history of tearing and dye disappearance test. Excluded were patients with complete puncto-canalicular obstruction and craniofacial anomaly. Type of CNLDO was confirmed using endonasal endoscopic guided probing. An endoscopic probing was performed for membranous, intubation for incomplete complex, and dacryocystorhinostomy for complete complex CNLDO. They were followed at 1 week, 1, 3, and 6 months, and then after. Success was defined as no or occasional tearing related to noxious stimulus at least 6 months after the procedure. There were 226 eyes (200 patients). Mean age was 26.72 months. Previous failed probing/intubation was in 34.1%. Inferior turbinate impaction in 73.5% and septal deviation in 2.7% were noted. Membranous CNLDO was found in 38.9%, incomplete complex in 57.9%, and complete complex in 3.1%. Mean time of tube removal was 11.9 weeks and last follow-up time was 24.3 months. There was no significant effect of any variables on the final success rates (probing: 96.5%, intubation: 95.4%, dacryocystorhinostomy: 100%). One-stage, obstruction-based endoscopic approach to CNLDO resulted in a high success rate for different types of CNLDO (membranous, incomplete complex, and complete complex). No variable significantly affected the success rates.


Comparison of perioperative versus postoperative intratumoral administration of cisplatin for treatment of cutaneous sarcoids and squamous cell carcinomas in horses.
To determine the benefits of reducing the interval between surgical cytoreduction and intratumoral administration of cisplatin. Randomized clinical study. 70 horses with 89 incompletely resected T2- and T3-stage sarcoids (n = 64) and squamous cell carcinomas (25). Horses were given 4 intratumoral treatments of cisplatin at 2-week intervals. The first treatment was given at the time of, or immediately after, surgical resection for horses treated in accordance with the perioperative protocol (group 1). Horses in group 2 were treated with cisplatin after the skin healed following surgical resection in accordance with the postoperative protocol. A difference was not found in duration of overall local tumor control between the 2 groups. Patterns of treatment failures and interval to failure differed between the 2 groups. Length of the surgical scar was the only factor that affected prognosis; an increase in length was associated with a poorer prognosis. A detrimental effect of postoperative treatment was only found in tumors with a high tumor proliferative fraction. Local reactions were similar for the 2 treatment groups, and chronic reactions were not observed. Intratumoral administration of cisplatin is beneficial for treatment of cutaneous tumors in horses. Tumor repopulation during the interval between surgery and intratumoral administration of cisplatin decreases treatment efficacy. These results provide evidence of rapid tumor repopulation following surgical resection without a lag period for tumors with a high proliferation index. When tumor proliferation index is not known, it may be prudent to use the perioperative protocol.


Enhanced electrocatalytic performance of functionalized carbon nanotube electrodes for oxygen reduction in proton exchange membrane fuel cells.
Although nitrogen doped CNTs (N-CNTs) are considered as a promising alternative to platinized carbon for the oxygen reduction reaction (ORR) in polymer electrolyte membrane fuel cells (PEMFCs), the origin of the enhanced ORR activity with N-CNTs is not clear at present. Among several plausible reasons, the exposure of edge plane and creation of impurity band/surface states near the Fermi level are considered as major causes behind the catalytic activity. However, CNTs without nitrogen doping are not known to catalyze the ORR. In this work, we study the ORR activity of functionalized carbon nanotubes with different functional groups, such as sulfonic acid and phosphonic acid, in order to understand the role of surface functionalities in catalyzing the reaction. Functionalized CNTs show significantly enhanced activity towards the ORR, while CNTs without such surface functional groups do not reveal any such special ORR activity. Linear sweep voltammetry experiments with different rotation rates show diffusion controlled limiting current values for functionalized CNTs, and the 'n' values derived from Koutecky-Levich plots are 3.3 and 1.7 for S-MWCNTs and P-MWCNTs, respectively. This work demonstrates the ORR activity of functionalized MWCNTs, which opens up new strategies for electrocatalyst design in PEMFCs.


Improving Prediction of Suicide and Accidental Death After Discharge From General Hospitals With Natural Language Processing.
Suicide represents the 10th leading cause of death across age groups in the United States (12.6 cases per 100 000) and remains challenging to predict. While many individuals who die by suicide are seen by physicians before their attempt, they may not seek psychiatric care. To determine the extent to which incorporating natural language processing of narrative discharge notes improves stratification of risk for death by suicide after medical or surgical hospital discharge. In this retrospective health care use study, clinical data were analyzed from individuals with discharges from 2 large academic medical centers between January 1, 2005, and December 31, 2013. The primary outcome was suicide as a reported cause of death based on Massachusetts Department of Public Health records. Regression models for prediction of death by suicide or accidental death were compared relying solely on coded clinical data and those using natural language processing of hospital discharge notes. There were 845 417 hospital discharges represented in the cohort, including 458 053 unique individuals. Overall, all-cause mortality was 18% during 9 years, and the median follow-up was 5.2 years. The cohort included 235 (0.1%) who died by suicide during 2.4 million patient-years of follow-up. Positive valence reflected in narrative notes was associated with a 30% reduction in risk for suicide in models adjusted for coded sociodemographic and clinical features (hazard ratio, 0.70; 95% CI, 0.58-0.85; P < .001) and improved model fit (χ22 = 14.843, P < .001 by log-likelihood test). The C statistic was 0.741 (95% CI, 0.738-0.744) for models of suicide with or without inclusion of accidental death. Multiple clinical features available at hospital discharge identified a cohort of individuals at substantially increased risk for suicide. Greater positive valence expressed in narrative discharge summaries was associated with substantially diminished risk. Automated tools to aid clinicians in evaluating these risks may assist in identifying high-risk individuals.


First Revision of the German S3 Guideline 'Diagnosis, Therapy, and Follow-Up of Breast Cancer'
The development and implementation of evidence-based, interdisciplinary, consensus-based guidelines is a very important step towards decreasing breast cancer mortality and optimizing the process of early detection, diagnosis, therapy, and follow-up of breast cancer. A revised version of the German S3 guideline was published in February 2008. Different working groups, departments, and organizations participate as coeditors of the new guideline. To fulfill international methodic requirements, a systematic search of the literature with selection of new publications (used as evidence) in the established data bases (Medline, BIOSIS, Previews, CDSR, ACP Journal Club, DARE, CCTR, CINHAL) and the Guidelines International Network (GIN) was performed for the time period of 2003-2006. Varied specialist opinions concerning diagnosis, therapy, and follow-up of breast cancer were considered in formal consensus processes. In different steps, Nominal Group Process techniques, the Delphi technique, and formal consensus processes were used. Besides differently weighted, study-based recommendations, statements resulting from structured consensus finding by the interdisciplinary group - in terms of good clinical practice - were postulated.


Synthesis and antitrichomonal activity of certain pyrazolo (1,5-a) pyrimidines.
Several bridgehead nitrogen heterocycles were synthesized to be screened as antimicrobial agents, modeled after nalidixic acid. The activity of these new compounds, all derivatives of 3-nitro-4,6-disubstituted pyrazolo (1,5-a)pyrimidin-7-ones (3,7,8, and 9), however, was found to be highly specific for Trichomonas foetus and completely lacking in activity against bacteria, fungi, and parasites other than Trichomonas. Of the nine componds synthesized, including the intermediate 4,6-disubstituted pyrazolo (1,5-a) pyrimidin-7-ones (2-6) and the 6-substituted or unsubstituted pyrazolo (1,5-a) pyrimidin-7-ones (1 and 4), only 6-carbethoxy-4-ethyl-3-nitropyrazolo(1,5-a)pyrimidin-7-one (7) was found to be a potent antitrichomal agent, being comparable or perhaps better than metronidazole. From a tentative structure-activity relationship study, it was apparent that the combination of the 3-mitro, 4-ethyl, and 6-carbethoxy groups imparted specific activity, wheras other substitutions imparted little or no antitrichomonal activity.


Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation.
Retinal angiomatous proliferation (RAP) is a distinct form of neovascularization in patients with age-related macular degeneration. Lacking definitive sequential histopathologic evidence of its intraretinal versus choroidal origin, the clinical observations of early stages of RAP lesions may provide clues to help further expand our understanding of this entity. Five eyes of four patients with early Stage 1 RAP were examined. Fundus photography, fluorescein and indocyanine green angiography as well as time-domain and spectral-domain optical coherence tomography were performed. Images were assessed to determine the characteristics of neovascularization in early stage RAP lesions and the response of the lesions to treatment or observation. The analysis of the selected cases suggests a choroidal origin of the neovascular complex with the early formation of a retinal choroidal anastomosis without evidence of underlying occult Type 1 neovascularization. Three eyes responded to a single treatment with intravitreal ranibizumab (0.5 mg) and 2 eyes (1 patient) resolved spontaneously without treatment. The neovascularization in RAP may originate not only from deep retinal capillaries but also from the choroid. We therefore propose the more descriptive term "Type 3 neovascularization" for this entity to emphasize the intraretinal location of the vascular complex and distinguish this type from the two types of neovascularization previously described by J. Donald Gass in his classic text.


An analysis of single amino acid repeats as use case for application specific background models.
Sequence analysis aims to identify biologically relevant signals against a backdrop of functionally meaningless variation. Increasingly, it is recognized that the quality of the background model directly affects the performance of analyses. State-of-the-art approaches rely on classical sequence models that are adapted to the studied dataset. Although performing well in the analysis of globular protein domains, these models break down in regions of stronger compositional bias or low complexity. While these regions are typically filtered, there is increasing anecdotal evidence of functional roles. This motivates an exploration of more complex sequence models and application-specific approaches for the investigation of biased regions. Traditional Markov-chains and application-specific regression models are compared using the example of predicting runs of single amino acids, a particularly simple class of biased regions. Cross-fold validation experiments reveal that the alternative regression models capture the multi-variate trends well, despite their low dimensionality and in contrast even to higher-order Markov-predictors. We show how the significance of unusual observations can be computed for such empirical models. The power of a dedicated model in the detection of biologically interesting signals is then demonstrated in an analysis identifying the unexpected enrichment of contiguous leucine-repeats in signal-peptides. Considering different reference sets, we show how the question examined actually defines what constitutes the 'background'. Results can thus be highly sensitive to the choice of appropriate model training sets. Conversely, the choice of reference data determines the questions that can be investigated in an analysis. Using a specific case of studying biased regions as an example, we have demonstrated that the construction of application-specific background models is both necessary and feasible in a challenging sequence analysis situation.


Further discussion on reliability: the art of reliability estimation.
Sijtsma and van der Ark (2015) focused in their lead article on three frameworks for reliability estimation in nursing research: classical test theory (CTT), factor analysis (FA), and generalizability theory. We extend their presentation with particular attention to CTT and FA methods. We first consider the potential of yielding an overly negative or an overly positive assessment of reliability based on coefficient alpha. Next, we discuss other CTT methods for estimating reliability and how the choice of methods affects the interpretation of the reliability coefficient. Finally, we describe FA methods, which not only permit an understanding of a measure's underlying structure but also yield a variety of reliability coefficients with different interpretations. On a more general note, we discourage reporting reliability as a two-choice outcome--unsatisfactory or satisfactory; rather, we recommend that nursing researchers make a conceptual and empirical argument about when a measure might be more or less reliable, depending on its use.


Flexural properties of eight flowable light-cured restorative materials, in immediate vs 24-hour water storage.
This study evaluated the flexural strength, flexural modulus, modulus of resilience and water sorption of eight flowable light-cured restorative materials compared with two conventional restoratives (as control). Forty specimens of each material were made. Twenty specimens were immediately flexural tested, while the remaining 20 were weight-measured and immersed in distilled water in a 37 degrees C incubator. After 24 hours, the samples were weight-measured again to identify water sorption and they were flexural tested. The findings were statistically analyzed using t-test, one-way ANOVA, Tukey test and Pearson's Product-Moment Correlation. The results of the flexural strength test were also analyzed using Weibull statistic. All flowable light-cured restorative materials except Palfique Estelite Low Flow exhibited immediate flexural strength values between the conventional ones. All flowable light-cured restorative materials showed 24-hour flexural strength values between the conventional ones. The Weibull modulus for immediate flexural strength of the materials varied from 6.37 to 15.23, while for 24-hour flexural strength, the strength varied from 8.10 to 14.30. In both conditions, all flowable light-cured resin composites showed lower flexural moduli but higher modulus of resilience than the conventional ones. The water sorption of all resin composites was lower than the flowable light-cured compomer. There was a distinct relation (r=-0.84, p<0.01) between the increasing ratio in modulus of resilience and the amount of water sorption.


A service evaluation of the Gen-Probe APTIMA nucleic acid amplification test for Trichomonas vaginalis: should it change whom we screen for infection?
A service evaluation of the new Gen-Probe APTIMA nucleic acid amplification test was performed to determine the prevalence of Trichomonas vaginalis (TV) infection in a UK sexual health clinic and identify risk factors to inform an appropriate TV screening strategy. Unselected patients presenting with a new clinical episode were offered TV testing with Gen Probe transcription-mediated amplification (TV TMA) in addition to routine sexually transmitted infection screening. Asymptomatic females provided a self-collected vulvovaginal specimen and asymptomatic men a first-void urine sample. Symptomatic patients were examined and a urethral swab taken from men and two posterior vaginal swabs from females; one for culture and one for TV TMA testing. Demographic and clinical data were collected on all patients positive for TV infection and 100 randomly selected TV-negative controls. 3503 patients underwent TV TMA testing during the evaluation period. The prevalence of TV infection was 21/1483, 1.4% (95% CI 0.9% to 2.2%) in men and 72/2020, 3.6% (95% CI 2.8% to 4.5%) in women. The rate of TV positivity was higher in Black Caribbean patients compared with Caucasian patients (men 5.4% vs 0.1%, p<0.001; women 9.0% vs 1.2%, p<0.001). TV TMA detected an additional 16 infections (38%) in symptomatic women compared with culture. While screening all patients with TV TMA will identify more TV infections, the UK prevalence remains low and this approach is unlikely to be cost effective. In addition to testing symptomatic patients, targeted testing of high-risk asymptomatic groups using TV TMA should be considered.


Analysis of surface-exposed outer membrane proteins in Helicobacter pylori.
More than 50 Helicobacter pylori genes are predicted to encode outer membrane proteins (OMPs), but there has been relatively little experimental investigation of the H. pylori cell surface proteome. In this study, we used selective biotinylation to label proteins localized to the surface of H. pylori, along with differential detergent extraction procedures to isolate proteins localized to the outer membrane. Proteins that met multiple criteria for surface-exposed outer membrane localization included known adhesins, as well as Cag proteins required for activity of the cag type IV secretion system, putative lipoproteins, and other proteins not previously recognized as cell surface components. We identified sites of nontryptic cleavage consistent with signal sequence cleavage, as well as C-terminal motifs that may be important for protein localization. A subset of surface-exposed proteins were highly susceptible to proteolysis when intact bacteria were treated with proteinase K. Most Hop and Hom OMPs were susceptible to proteolysis, whereas Hor and Hof proteins were relatively resistant. Most of the protease-susceptible OMPs contain a large protease-susceptible extracellular domain exported beyond the outer membrane and a protease-resistant domain at the C terminus with a predicted β-barrel structure. These features suggest that, similar to the secretion of the VacA passenger domain, the N-terminal domains of protease-susceptible OMPs are exported through an autotransporter pathway. Collectively, these results provide new insights into the repertoire of surface-exposed H. pylori proteins that may mediate bacterium-host interactions, as well as the cell surface topology of these proteins.


Characterization of the denatured structure of pyrrolidone carboxyl peptidase from a hyperthermophile under nondenaturing conditions: role of the C-terminal alpha-helix of the protein in folding and stability.
The cysteine-free pyrrolidone carboxyl peptidase (PCP-0SH) from a hyperthermophile, Pyrococcus furiosus, can be trapped in the denatured state under nondenaturing conditions, corresponding to the denatured structure that exists in equilibrium with the native state under physiological conditions. The denatured state is the initial state (D1 state) in the refolding process but differs from the completely denatured state (D2 state) in the concentrated denaturant. Also, it has been found that the D1 state corresponds to the heat-denatured state. To elucidate the structural basis of the D1 state, H/D exchange experiments with PCP-0SH were performed at pD 3.4 and 4 degrees C. The results indicated that amide protons in the C-terminal alpha6-helix region hardly exchanged in the D1 state with deuterium even after 7 days, suggesting that the alpha6-helix (from Ser188 to Glu205) of PCP-0SH was stably formed in the D1 state. In order to examine the role of the alpha6-helix in folding and stability, H/D exchange experiments with a mutant, A199P, at position 199 in the alpha6-helix region were performed. The alpha6-helix region of A199P in the D1 state was partially unprotected, while some hydrophobic residues were protected against the H/D exchange, although these hydrophobic residues were unprotected in the wild-type protein. These results suggest that the structure of A199P in the D1 state formed a temporary stable denatured structure with a non-native hydrophobic cluster and the unstructured alpha6-helix. Both the stability and the refolding rate decreased by the substitution of Pro for Ala199. We can conclude that the native-like helix (alpha6-helix) of PCP-0SH is already constructed in the D1 state and is necessary for efficient refolding into the native structure and stabilization of PCP-0SH.


Measures of psychological stress and physical health in family caregivers of stroke survivors: a literature review.
Studies have demonstrated that the stress of family caregiving places caregivers at risk for developing depression, poor quality of life, and health problems. The purpose of this review was to identify the ways in which variables are operationalized in studies addressing psychological stressors and physical health of family caregivers of stroke survivors. The adapted Pittsburgh Mind-Body Center model provides the organizing conceptual framework for this literature review. A literature search for relevant articles was conducted using Ovid Medline, PsycINFO, and Ovid Nursing Database for the period of July 1999 through June 2009 using the following search terms: caregiver (or family caregiver), stroke, stress, and health. Articles were included if they met the following inclusionary criteria: (a) written in English, (b) published in peer-reviewed journal, (c) focused on adults who were caring for an adult who experienced stroke, (d) included measures of stress and physical health or health-related quality of life, and (e) primarily used quantitative research methods. Twenty-four articles were identified that met the inclusion criteria. Findings related to the variables included in the adapted Pittsburgh Mind-Body Center model are discussed. Variables were not well defined, a wide array of measurement instruments were used, and measures were taken at broadly divergent time frames following stroke. Future research guided by a theoretical framework, consistent measures of variables, and standardized measurement time points would allow for better comparison of findings across studies, thus enabling clinicians to better understand the health risks of family caregivers.