The use of a mobile app to motivate evidence-based oral hygiene behaviour.
Mobile apps are software programmes that run on smartphones and other mobile devices. Mobile health apps can help people manage their own health and wellness, promote healthy living and gain access to useful information when and where they need it. The Brush DJ oral health app was developed to use the opportunity mobile apps offer to motivate an evidence-based oral hygiene routine. A literature review has found no research investigating the use of a mobile app to motivate evidence-based oral hygiene behaviour. The objective of this preliminary investigation was to assess user perception of an oral health app to give a basis for future research and development of app technology in relation to oral health. A cross-sectional qualitative user perception questionnaire.RESULTS :One hundred and eighty-nine people responded to the questionnaire. Seventy percent (n = 113) of respondents reported that their teeth felt cleaner since using the app. Eighty-eight percent (n = 133) reported the app motivated them to brush their teeth for longer and 92.3% (n = 144) would recommend the app to their friends and family. Four broad themes relating to how the app helped toothbrushing were reported. These themes were motivation, education, compliance and perceived benefits. A mobile app is a promising tool to motivate an evidence-based oral hygiene routine.


Dynamics of water in concentrated solutions of amphiphiles: key roles of local structure and aggregation.
Water translational and reorientational dynamics in concentrated solutions of amphiphiles are investigated through molecular dynamics simulations and analytic modeling. We evidence the critical importance of the solute concentration in determining the magnitude of the slowdown in water dynamics compared to the bulk situation. The comparison of concentrated aqueous solutions of tetramethylurea, which tends to aggregate, and of trimethylamine N-oxide, which does not, shows the dramatic impact of solute clustering on the water dynamics. No significant decoupling of the reorientation and translation dynamics of water is observed, even at very high solute concentrations. The respective roles of energetic and topological disorders in determining the translational subdiffusive water dynamics in these confining environments are discussed. The water reorientational dynamics is shown to be quantitatively described by an extended jump model which combines two factors determined by the local structure: the transition-state excluded volume and the transition-state hydrogen-bond strength.


Effects of Altering Trunk Position during Landings on Patellar Tendon Force and Pain.
This study aimed to verify the immediate effects of altering sagittal plane trunk position during jump landings on lower limb biomechanics, patellar tendon force, and pain of athletes with and without patellar tendinopathy. Twenty-one elite male athletes were categorized into three groups: athletes with patellar tendinopathy (TG; n = 7), asymptomatic athletes with patellar tendon abnormalities (n = 7), and asymptomatic athletes without tendon abnormalities (CG; n = 7). A biomechanical evaluation was conducted while the athletes performed drop landings from a bench in a self-selected trunk position (SS). Afterward, the athletes were randomly assigned to land with either a flexed trunk position (FLX) or an extended trunk position (EXT). Variables of interest for this study included sagittal plane peak kinematics, kinetics, patellar tendon force, and pain during the landing tasks. Peak patellar tendon force, knee extensor moment, and knee pain decreased in the FLX landing compared with the SS landing, regardless of group. In addition, peak patellar tendon force, knee extensor moment, and vertical ground reaction force were smaller in the FLX landing compared with the EXT landing. The TG had smaller peak ankle dorsiflexion compared with the CG during jump landings, regardless of trunk position. Landing with greater trunk flexion decreased patellar tendon force in elite jumping athletes. An immediate decrease in knee pain was also observed in symptomatic athletes with a more flexed trunk position during landing. Increasing trunk flexion during landing might be an important strategy to reduce tendon overload in jumping athletes.


Validation of an immunohistochemical signature predictive of 8-year outcome for patients with breast carcinoma.
We recently reported that standardized quantitative immunohistochemical (IHC) assays allowed prediction of an adverse outcome among 572 node negative (N-) patients with breast carcinoma (BrCa). To further validate our prior findings, we repeated the IHC stains including a second series of BrCa diagnosed at Yale University. Tissue microarrays (TMAs) of two cohorts of patients with BrCa (418 Marseille University and 303 Yale University) were respectively investigated for IHC expression of 15 markers (HIF-1α, PI3K, pAKT, pmTOR, moesin, P21, 4(E) BP-1, P27, Ker5-6, pMAPKAPK-2, SHARP2, claudin-1, ALDH, AF6 and CD24). Quantitative measurements of immunoprecipitates densitometry assessed with an image analyzer were correlated with 8-year patients' outcome and compared in the two cohorts. The best predictive signature consisted of a combination of five markers that included HIF-1α, PI3K, claudin-1, AF6 and pAKT in N- BrCa. This combination permitted an accurate prediction of outcome in 92.34% (386/418) of N- patients in the first set (Marseille) and 89.8% (158/176) in the second set (Yale). The close results in both cohorts confirmed the validity of this original IHC signature predictive of prognosis in node negative BrCa. This validation suggests that in clinical practice, it would be possible with standardized kits (i) to identify patients with poor prognosis at diagnosis time, particularly in the N- BrCa subset, who would require more aggressive adjuvant therapy and (ii) to avoid useless expensive therapies and their side effects in N- patients with favorable prognosis.


Fabrication of flexible UV nanoimprint mold with fluorinated polymer-coated PET film.
UV curing nanoimprint lithography is one of the most promising techniques for the fabrication of micro- to nano-sized patterns on various substrates with high throughput and a low production cost. The UV nanoimprint process requires a transparent template with micro- to nano-sized surface protrusions, having a low surface energy and good flexibility. Therefore, the development of low-cost, transparent, and flexible templates is essential. In this study, a flexible polyethylene terephthalate (PET) film coated with a fluorinated polymer material was used as an imprinting mold. Micro- and nano-sized surface protrusion patterns were formed on the fluorinated polymer layer by the hot embossing process from a Si master template. Then, the replicated pattern of the fluorinated polymer, coated on the flexible PET film, was used as a template for the UV nanoimprint process without any anti-stiction coating process. In this way, the micro- to nano-sized patterns of the original master Si template were replicated on various substrates, including a flat Si substrate and curved acryl substrate, with high fidelity using UV nanoimprint lithography.


Evodiamine Exerts an Anti-Hepatocellular Carcinoma Activity through a WWOX-Dependent Pathway.
Evodiamine is one of the main components isolated from Evodia rutaecarpa, and it has been reported to exert inhibitory effects on cancers by anti-proliferative and apoptosis-inducing activities. Although the anti-cancer activity of evodiamine has been identified, the precise mechanisms of this action remain obscure. While previous studies indicated that evodiamine exerts anti-tumor effects through inhibiting β-catenin activity, and WW domain-containing oxidoreductase (WWOX) regulates β-catenin accumulation in cytoplasm, the effects of evodiamine on the expression of WWOX are still unknown. In this study, we provide evidence that evodiamine dose- and time-dependently inhibits both Mus musculus and Homo sapiens hepatocellular carcinoma (HCC) cells, as well as Hepa1-6 and HepG2 cell proliferation. We further tested the therapeutic effects of evodiamine in Hepa1-6 hepatoma-bearing mice, and we found that treatment of evodiamine by oral gavage significantly decreased the tumor size of the mice. Moreover, the expressions of WWOX were dose-dependently increased in HCC cell lines as well as in Hepa1-6 hepatoma-bearing mice after the treatment with evodiamine. Knockdown of WWOX in HepG2 and Hepa1-6 cells diminished the effects of evodiamine on the inhibitory effect of cancer cell growth, indicating that evodiamine induced anti-cancer activity through a WWOX-dependent pathway. As such, evodiamine activated WWOX to exert an anti-HCC activity, and might be a potential therapeutic or preventive candidate for HCC treatment.


Deposition error compensation for optical multilayer coatings. I. Theoretical description.
The manufacture of complicated optical coatings consisting of many layers of different thicknesses can be a challenge, especially if the deposition technique does not produce dense layers. Deposition errors in a layer can affect not only the desired performance of a multilayer, but can also lead to a complete breakdown of the monitoring and control of subsequent layers. The best chance to achieve the desired optical performance of a multilayer involves deposition error compensation. In this process, the construction parameters of a completed layer are evaluated to determine if any deposition errors have occurred and then the remaining layers of the multilayer system are reoptimized to compensate for any errors made. This paper describes a versatile deposition error compensation program developed at the National Research Council of Canada for the simulation and real-time control of the manufacture of multilayers composed of dielectric or absorbing films. To model porous layers, an effective medium theory approach is used to relate the optical constants of the layer in vacuum and air to the microstructure of the layer. In the simulation mode, random errors are applied to the thickness and porosity of the layers and measurement errors are also included. The best monitoring strategy for the manufacture of a given multilayer is established on the basis of statistical information obtained from a number of these simulations. In this paper the results of calculations on the effectiveness of various monitoring strategies are presented for a sharp edge filter produced by three different physical vapor deposition methods. An extensive list of references to previous papers dealing with sources of errors during deposition is also provided.


'The software should be a joy to use'.
Since its founding in 1979, Epic Systems Corp. of Verona, Wis., has grown to become the nation's No. 1 healthcare software firm, with $2.5 billion in annual sales and 9,700 employees. Founder Judith Faulkner, one of Modern Healthcare's Top 25 Women In Healthcare, still plays a major role in setting strategy at the firm. At last month's Healthcare Information and Management Systems Society's annual conference in Orlando, Fla., Modern Healthcare Editor Merrill Goozner sat down with Faulkner for an interview. The following is an edited transcript.


Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y.
We hypothesised that hypothalamic feeding-related neuropeptides are differentially expressed in obese-prone and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, in the present study, we measured energy balance and hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA expressions in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10 d old), weaning (21-25 d old) and early adulthood (8-12 weeks). A group of Obese-pair-feeding (PF) rats pair-fed to the Lean-FF rats was included in the adult cohort. The body weights of 10-d-old Obese-FF and Lean-FF pups were not significantly different. However, when the pups were shifted from dams' milk to solid food (weaning), the obese-prone rats exhibited more energy intake over the days than the lean-prone rats and higher body and fat pad weights and fasting plasma glucose, leptin, insulin and lipid levels. These differences were consistent with higher energy consumption and lower energy expenditure. In the young adult cohort, the differences between the Obese-FF and Lean-FF rats became more pronounced, yielding significant age effects on most of the parameters of the metabolic syndrome, which were reduced in the Obese-PF rats. The obese-prone rats displayed higher NPY expression than the lean-prone rats at pre-weaning and weaning, and the expression levels did not differ by age. In contrast, POMC expression exhibited significant age-by-genotype differences. At pre-weaning, there was no genotype difference in POMC expression, but in the weanling cohort, obese-prone pups exhibited lower POMC expression than the lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC expression down-regulation in the presence of established NPY overexpression.


Equity of access to health care: outlining the foundations for action.
The Ministers of Health from Chile, Germany, Greece, New Zealand, Slovenia, Sweden, and the United Kingdom recently established The International Forum on Common Access to Health Care Services, based on a common belief that their citizens should enjoy universal and equitable access to good quality health care. The ministers intend to form a network to share thinking and evidence on health care improvements, with the specific aim of sustaining and promoting equitable access to health care. Despite a vast literature on the notion of equity of access, little agreement has been reached in the literature on exactly what this notion ought to mean. This article provides a brief description of the relevance of the access principle of equity, and summarises the research programme that is necessary for turning the principle into a useful, operational policy objective.


Improved outcomes for out-of-hospital cardiac arrest patients treated by emergency life-saving technicians compared with basic emergency medical technicians: A JCS-ReSS study report.
Emergency life-saving technicians (ELSTs) are specially trained prehospital medical providers believed to provide better care than basic emergency medical technicians (BEMTs). ELSTs are certified to perform techniques such as administration of advanced airways or adrenaline and are considered to have more knowledge; nevertheless, ELSTs' effectiveness over BEMTs regarding out-of-hospital cardiac arrest (OHCA) remains unclear. We investigated whether the presence of an ELST improves OHCA patient outcomes. In a retrospective study of adult OHCA patients treated in Japan from 2011 to 2015, we compared two OHCA patient groups: patients transported with at least one ELST and patients transported by only BEMTs. The primary outcome measure was one-month favorable neurological outcomes, defined as Cerebral Performance Category ≤ 2. A multivariable logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs) to evaluate the effect of ELSTs. Included were 552,337 OHCA patients, with 538,222 patients in the ELST group and 14,115 in the BEMT group. The ELST group had a significantly higher odds of favorable neurological outcomes (2.5% vs. 2.1%, adjusted OR 1.39, 95% CI 1.17-1.66), one-month survival (4.9% vs. 4.1%, adjusted OR 1.37, 95% CI 1.22-1.54), and return of spontaneous circulation (8.1% vs. 5.1%, adjusted OR 1.90, 95% CI 1.72-2.11) compared with the BEMT group. However, ELSTs' limited procedure range (adrenaline administration or advanced airway management) did not promote favorable neurological outcomes. Compared with the BEMT group, transport by the ELST group was associated with better neurological outcomes in OHCA.


Efficient and regioselective one-step synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivatives.
Two facile and efficient one-step procedures for the regioselective synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines have been developed, via reactions of 3,5-diamino-1,2,4-triazole with variously substituted 1-aryl-1,3-butanediones and 1-aryl-2-buten-1-ones, respectively. The excellent yield and/or regioselectivity shown by the reactions decreased when ethyl 5-amino-1,2,4-triazole-3-carboxylate was used. [1,2,4]Triazolo[1,5-a]pyrimidine being a privileged scaffold, the procedures herein reported may be useful for the preparation of biologically active compounds. In this study, the preparation of a set of compounds based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold led to the identification of compound 20 endowed with a very promising ability to inhibit influenza virus RNA polymerase PA-PB1 subunit heterodimerization.


Electronic structure of the Mn-cofactor of modified bacterial reaction centers measured by electron paramagnetic resonance and electron spin echo envelope modulation spectroscopies.
The electronic structure of a Mn(II) ion bound to highly oxidizing reaction centers of Rhodobacter sphaeroides was studied in a mutant modified to possess a metal binding site at a location comparable to the Mn4Ca cluster of photosystem II. The Mn-binding site of the previously described mutant, M2, contains three carboxylates and one His at the binding site (Thielges et al., Biochemistry 44:389-7394, 2005). The redox-active Mn-cofactor was characterized using electron paramagnetic resonance (EPR) and electron spin echo envelope modulation (ESEEM) spectroscopies. In the light without bound metal, the Mn-binding mutants showed an EPR spectrum characteristic of the oxidized bacteriochlorophyll dimer and reduced quinone whose intensity was significantly reduced due to the diminished quantum yield of charge separation in the mutant compared to wild type. In the presence of the metal and in the dark, the EPR spectrum measured at the X-band frequency of 9.4 GHz showed a distinctive spin 5/2 Mn(II) signal consisting of 16 lines associated with both allowed and forbidden transitions. Upon illumination, the amplitude of the spectrum is decreased by over 80 % due to oxidation of the metal upon electron transfer to the oxidized bacteriochlorophyll dimer. The EPR spectrum of the Mn-cofactor was also measured at the Q-band frequency of 34 GHz and was better resolved as the signal was composed of the six allowed electronic transitions with only minor contributions from other transitions. A fit of the Q-band EPR spectrum shows that the Mn-cofactor is a high spin Mn(II) species (S = 5/2) that is six-coordinated with an isotropic g-value of 2.0006, a weak zero-field splitting and E/D ratio of approximately 1/3. The ESEEM experiments showed the presence of one (14)N coordinating the Mn-cofactor. The nitrogen atom is assigned to a His by comparing our ESEEM results to those previously reported for Mn(II) ions bound to other proteins and on the basis of the X-ray structure of the M2 mutant that shows the presence of only one His, residue M193, that can coordinate the Mn-cofactor. Together, the data allow the electronic structure and coordination environment of the designed Mn-cofactor in the modified reaction centers to be characterized in detail and compared to those observed in other proteins with Mn-cofactors.


Ensemble asteroseismology of solar-type stars with the NASA Kepler mission.
In addition to its search for extrasolar planets, the NASA Kepler mission provides exquisite data on stellar oscillations. We report the detections of oscillations in 500 solar-type stars in the Kepler field of view, an ensemble that is large enough to allow statistical studies of intrinsic stellar properties (such as mass, radius, and age) and to test theories of stellar evolution. We find that the distribution of observed masses of these stars shows intriguing differences to predictions from models of synthetic stellar populations in the Galaxy.


Prevalence and risk determinants of human immunodeficiency virus type 2 (HIV-2) and human immunodeficiency virus type 1 (HIV-1) in west African female prostitutes.
The authors studied the prevalence and risk determinants for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in female prostitutes from Dakar (1985-1990), Ziguinchor (1987-1990), and Kaolack (1987-1990), Senegal, West Africa. Each cohort showed a distinct distribution of HIVs: 10.0% HIV-2 and 4.1% HIV-1 in Dakar, 38.1% HIV-2 and 0.4% HIV-1 in Ziguinchor, and 27.4% HIV-2 and 1.3% HIV-1 in Kaolack. In 1,275 female prostitutes from Dakar, increase years of sexual activity and a history of scarification were associated with HIV-2 seropositivity. In contrast, HIV-1 seroprevalence was associated with a shorter duration of prostitution and a history of hospitalization. In 278 female prostitutes from Ziguinchor, HIV-2 seroprevalence was associated with women of Guinea-Bissau nationality and increased years of sexual activity. In 157 female prostitutes from Kaolack, HIV-2 seroprevalence was associated with increased years of sexual activity and a history of never using condoms. The authors also studied the risk determinants for HIV-2 in the 1,280 Senegalese prostitutes pooled from all three sites. Controlling for ethnic group, women from Ziguinchor and Kaolack were more likely to be HIV-2 seropositive as compared with women from the Dakar site. Increased years of sexual activity were associated with HIV-2 seropositivity, while a history of excision and BCG vaccinations decreased the risk of HIV-2 infection.


Community IntraVenous Antibiotic Study (CIVAS): protocol for an evaluation of patient preferences for and cost-effectiveness of community intravenous antibiotic services.
Outpatient parenteral antimicrobial therapy (OPAT) is used to treat a wide range of infections, and is common practice in countries such as the USA and Australia. In the UK, national guidelines (standards of care) for OPAT services have been developed to act as a benchmark for clinical monitoring and quality. However, the availability of OPAT services in the UK is still patchy and until quite recently was available only in specialist centres. Over time, National Health Service (NHS) Trusts have developed OPAT services in response to local needs, which has resulted in different service configurations and models of care. However, there has been no robust examination comparing the cost-effectiveness of each service type, or any systematic examination of patient preferences for services on which to base any business case decision. The study will use a mixed methods approach, to evaluate patient preferences for and the cost-effectiveness of OPAT service models. The study includes seven NHS Trusts located in four counties. There are five inter-related work packages: a systematic review of the published research on the safety, efficacy and cost-effectiveness of intravenous antibiotic delivery services; a qualitative study to explore existing OPAT services and perceived barriers to future development; an economic model to estimate the comparative value of four different community intravenous antibiotic services; a discrete choice experiment to assess patient preferences for services, and an expert panel to agree which service models may constitute the optimal service model(s) of community intravenous antibiotics delivery. The study has been approved by the NRES Committee, South West-Frenchay using the Proportionate Review Service (ref 13/SW/0060). The results of the study will be disseminated at national and international conferences, and in international journals.


[Obesity and endothelial dysfunction].
The endothelium plays a crucial role in modulating vascular function and structure. In healthy conditions, nitric oxide produced by endothelial cells exerts not only vasodilating properties, but also several other protective actions toward the vessel wall against the development of atherosclerosis and thrombosis. Traditional cardiovascular risk factors are characterized by endothelial dysfunction caused by an enhanced production of oxidative stress leading to destroy nitric oxide, thus reducing its availability. Abdominal obesity is associated with endothelial dysfunction, through direct mechanisms, such as insulin resistance and the association with risk factors (including diabetes mellitus, hypertension and dyslipidemia), and direct, by the production of adipokines and pro-inflammatory cytokines, which in turn induce oxidative stress leading to a reduced nitric oxide availability. A reduced endothelium-dependent relaxation is a predictor of cardiovascular events in high-risk patients and represents a putative clinical parameter to stratify the cardiovascular risk and a useful marker for therapy efficacy. Weight loss and a modification of lifestyle ameliorate endothelial function in obese patients, an effect due not only to a better glycemic profile, but also secondary to reduced plasma levels of inflammatory markers and adipokines. At present, whether an improvement of endothelial dysfunction secondary to weight loss is significantly associated with a better cardiovascular prognosis is still unknown. (G Ital Cardiol 2006; 7 (11): 715-723)


The impact of diabetes on the labour force participation, savings and retirement income of workers aged 45-64 years in Australia.
Diabetes is a debilitating and costly condition. The costs of reduced labour force participation due to diabetes can have severe economic impacts on individuals by reducing their living standards during working and retirement years. A purpose-built microsimulation model of Australians aged 45-64 years in 2010, Health&WealthMOD2030, was used to estimate the lost savings at age 65 due to premature exit from the labour force because of diabetes. Regression models were used to examine the differences between the projected savings and retirement incomes of people at age 65 for those currently working full or part time with no chronic health condition, full or part time with diabetes, and people not in the labour force due to diabetes. All Australians aged 45-65 years who are employed full time in 2010 will have accumulated some savings at age 65; whereas only 90.5% of those who are out of the labour force due to diabetes will have done so. By the time they reach age 65, those who retire from the labour force early due to diabetes have a median projected savings of less than $35,000. This is far lower than the median value of total savings for those who remained in the labour force full time with no chronic condition, projected to have $638,000 at age 65. Not only does premature retirement due to diabetes limit the immediate income available to individuals with this condition, but it also reduces their long-term financial capacity by reducing their accumulated savings and the income these savings could generate in retirement. Policies designed to support the labour force participation of those with diabetes, or interventions to prevent the onset of the disease itself, should be a priority to preserve living standards comparable with others who do not suffer from this condition.


Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.
Mutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts. Whole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease-causing variants. We generated patient-derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity. Biochemical analysis of patient-derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality. Our results establish the identified WARS2 variants as disease-causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system.


[Mothers know best].
Nutrition has a critical effect on the infant's brain development during pregnancy and the first 18 months of life. Inappropriate diet can cause infant mortality. Research has shown that medical professionals lack the required knowledge regarding nutrition and that there are no suitable instructional programs on this subject for them. To examine the knowledge and attitudes of gynecologists, pediatricians and nurses who work in mother and child health clinics of "Maccabi" Healthcare Services in Israel concerning infants' and pregnant women's nutrition and to compare these findings to the public's general knowledge. The study population consisted of gynecologists and pediatricians who work in "Maccabi" Healthcare Services throughout the country and all the nurses at the family healthy clinics. In addition, a sample of mothers attending six different family health clinics was recruited. Four structured questionnaires were created for each group in the study population (gynecologist, pediatricians, nurses and mothers). The questionnaires included questions that evaluated the knowledge and attitudes toward infants' nutrition. The mothers showed high level of knowledge (67% correctly answered 3 or more of the 4 questions, compared to 51% of nurses, 27% or pediatricians, 38% of gynecologists, p < 0.01). The physicians showed a higher level of knowledge in the questions related to their specialty. When asked about the effect of nutritional instruction on the infants' health, the pediatricians answered correctly at a higher rate than the other study groups (74% of pediatricians answered correctly 3 out of 3 questions, compared to 60% of gynecologists, 47% nurses, p < 0.01). Professionals believe that they can train mothers on nutritional issues. Appointing a nutritionist to the mother and child clinics should be considered, as the professional caregivers of pregnant women and infants were found to be lacking in sufficient knowledge in certain aspects of nutrition for these populations.


Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring.
Immunohistochemical (IHC) assays performed on formalin-fixed paraffin-embedded (FFPE) tissue sections traditionally have been semi-quantified by pathologist visual scoring of staining. IHC is useful for validating biomarkers discovered through genomics methods as large clinical repositories of FFPE specimens support the construction of tissue microarrays (TMAs) for high throughput studies. Due to the ubiquitous availability of IHC techniques in clinical laboratories, validated IHC biomarkers may be translated readily into clinical use. However, the method of pathologist semi-quantification is costly, inherently subjective, and produces ordinal rather than continuous variable data. Computer-aided analysis of digitized whole slide images may overcome these limitations. Using TMAs representing 215 ovarian serous carcinoma specimens stained for S100A1, we assessed the degree to which data obtained using computer-aided methods correlated with data obtained by pathologist visual scoring. To evaluate computer-aided image classification, IHC staining within pathologist annotated and software-classified areas of carcinoma were compared for each case. Two metrics for IHC staining were used: the percentage of carcinoma with S100A1 staining (%Pos), and the product of the staining intensity (optical density [OD] of staining) multiplied by the percentage of carcinoma with S100A1 staining (OD*%Pos). A comparison of the IHC staining data obtained from manual annotations and software-derived annotations showed strong agreement, indicating that software efficiently classifies carcinomatous areas within IHC slide images. Comparisons of IHC intensity data derived using pixel analysis software versus pathologist visual scoring demonstrated high Spearman correlations of 0.88 for %Pos (p < 0.0001) and 0.90 for OD*%Pos (p < 0.0001). This study demonstrated that computer-aided methods to classify image areas of interest (e.g., carcinomatous areas of tissue specimens) and quantify IHC staining intensity within those areas can produce highly similar data to visual evaluation by a pathologist. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1649068103671302.


Facile synthesis, biofilm disruption properties and biocompatibility study of a poly-cationic peptide functionalized graphene-silver nanocomposite.
Bacterial colonization and biofilm formation is a growing challenge in the biomedical field. Although nanotechnology has emerged as an alternative strategy to combat biofilm formation, the toxicity of nanomaterials is a major concern. In this study, we report a safe-by-design strategy for the synthesis of a poly-cationic peptide functionalized graphene-silver nanocomposite (designated as GAPP) and its enhanced biofilm inhibition and disruption properties to eliminate the biofilm development of Gram-negative bacteria. The graphene-silver (rGOAg) nanocomposite was synthesized by microwave reduction, and subsequently functionalized with an antimicrobial poly-cationic peptide through covalent bonding. The results demonstrated that GAPP effectively killed the planktonic cells and biofilms of Escherichia coli and Pseudomonas aeruginosa depending upon the concentration and duration of the interaction. The complete eradication of preformed biofilm was achieved when treated with 10 μg mL-1 of GAPP for 5 h. The GAPP exerted bactericidal and biofilm inhibition activity through a "contact-kill-release" mode of action, wherein the electrostatic interaction of GAPP with the bacterial cells induced physical disruption accompanied by ROS-mediated biochemical changes. The internalization of GAPP into the cytoplasm through the damaged membrane led to metabolic imbalance in the cells. The peptide functionalization further prevented the dissolution of Ag+ ions, thus minimizing the cytotoxicity of GAPP to adult zebrafish. More importantly, the poly-cationic peptide functionalization enhanced the bioavailability, biofilm inhibition and disruption activities of GAPP, while minimizing its toxicological impact. The results obtained thereby provide an effective strategy in the design of alternative antibacterial agents for fighting biofilms of Gram-negative bacteria.


Sorption and Desorption Mechanisms of Cationic and Zwitterionic Per- and Polyfluoroalkyl Substances in Natural Soils: Thermodynamics and Hysteresis.
Sorption linearity and reversibility are implicit in models for the fate and transport of per- and polyfluoroalkyl substances (PFAS). In this study, however, we found that the sorption of cationic and zwitterionic PFAS in natural soils was highly nonlinear. The nonlinearity was so severe that it led to a variation in the coefficient of sorption by several orders of magnitude over the experimental concentration range. This implies a considerable increase in sorption as concentration falls in the natural environment. Sorption of cationic PFAS correlated strongly with the soil organic matter (SOM) content and was reversible in all soils. Sorption of zwitterionic PFAS, on the other hand, displayed concentration-dependent hysteresis in soils with a low SOM content. The irreversibility, which was associated with neither SOM, pore deformation, nor surface complexation, was likely caused by the entrapment of molecules in porous structures within inorganic components of soil aggregates. Furthermore, electrostatic interactions with negatively charged soil constituents and the hydrophobic effect were found to be major sorption driving forces for cationic/zwitterionic PFAS at low and high concentrations, respectively. The maximum electrostatic potential of PFAS ions, computed using density functional theory, was found to be a useful predictor of the sorption of ionic PFAS species.


Quality assurance for screening mammography: an international comparison.
In 1998, the International Breast Cancer Screening Network (IBSN) sponsored an assessment of quality assurance policies and practices to define their scope for population-based screening mammography programmes across IBSN countries. Analysis of data from a survey designed to assess multiple elements of screening programme quality assurance, including organisation of quality assurance activities, mechanisms for site visits and accreditation, requirements for quality control and data systems, and inclusion of treatment, follow up, and programme evaluation in screening mammography quality assurance activities. IBSN representatives in 23 countries completed a comprehensive questionnaire between May and December 1998. Completed questionnaires were obtained from all 23 countries. Responses indicated that countries vary in their approaches to implementing quality assurance, although all monitor components of structure, process, and outcome. Nearly all have in place laws, surveillance mechanisms, or standards for quality assurance. In all countries, quality assurance activities extend beyond the screening mammography examination. The assessment has enhanced understanding of the organisation of screening mammography programmes across countries, as well as the comparability of screening mammography data. All countries have established mechanisms for assuring the quality of screening mammography in population-based programmes, although these mechanisms vary across countries.


Learning the generative principles of a symbol system from limited examples.
The processes and mechanisms of human learning are central to inquiries in a number of fields including psychology, cognitive science, development, education, and artificial intelligence. Arguments, debates, and controversies linger over the questions of human learning with one of the most contentious being whether simple associative processes could explain human children's prodigious learning, and in doing so, could lead to artificial intelligence that parallels human learning. One phenomenon at the center of these debates concerns a form of far generalization, sometimes referred to as "generative learning", because the learner's behavior seems to reflect more than co-occurrences among specifically experienced instances and to be based on principles through which new instances may be generated. In two experimental studies (N = 148) of preschool children's learning of how multi-digit number names map to their written forms and in a computational modeling experiment using a deep learning neural network, we show that data sets with a suite of inter-correlated imperfect predictive components yield far and systematic generalizations that accord with generative principles and do so despite limited examples and exceptions in the training data. Implications for human cognition, cognitive development, education, and machine learning are discussed.


Network-selectivity and stimulus-discrimination in the primary visual cortex: cell-assembly dynamics.
Visual neurons coordinate their responses in relation to the stimulus; however, the complex interplay between a stimulus and the functional dynamics of an assembly still eludes neuroscientists. To this aim, we recorded cell assemblies from multi-electrodes in the primary visual cortex of anaesthetized cats in response to randomly presented sine-wave drifting gratings whose orientation tilted in 22.5° steps. Cross-correlograms revealed the functional connections at all the tested orientations. We show that a cell-assembly discriminates between orientations by recruiting a 'salient' functional network at every presented orientation, wherein the connections and their strengths (peak-probabilities in the cross-correlogram) change from one orientation to another. Within these assemblies, closely tuned neurons exhibited increased connectivity and connection-strengths compared with differently tuned neurons. Minimal connectivity between untuned neurons suggests the significance of neuronal selectivity in assemblies. This study reflects upon the dynamics of functional connectivity, and brings to the fore the importance of a 'signature' functional network in an assembly that is strictly related to a specific stimulus. It appears that an assembly is the major 'functional unit' of information processing in cortical circuits, rather than the individual neurons.


Molecular evidence on the occurrence of co-infection with Pichia guilliermondii and Wuchereria bancrofti in two filarial endemic districts of India.
Lymphatic filariasis (LF), a vector-borne parasitic disease, is endemic in several parts of India and mostly affects the poor or those with a low-income. The disease results in huge numbers of morbidities, disabilities, and deaths every year. Association of co-infection with other pathogens makes the condition more severe. Although co-infection is becoming a growing area of research, it is yet to emerge as a frontier research topic in filarial research specifically. This study reports the occurrence of a fungal infection in a large number of patients suffering from bancroftian filariasis in two districts of West Bengal, India. Nocturnal blood samples from filarial patients containing parasites and fungus were initially co-cultured, and further the fungus was isolated and characterized. Molecular identification of the isolate was carried out by PCR-based selective amplification and sequencing of highly-conserved D1/D2 region of 26S rDNA, whereas pathogenicity was determined by amplification of the RPS0 gene. A phylogenetic tree was constructed to study the relationship between the isolate and common pathogenic yeasts. The isolate was studied for antibiotic sensitivity, whereas morphological characterization was performed by microscopic techniques. The isolate was identified as Pichia guilliermondii and this fungus was found to exist in co-infection with Wuchereria bancrofti in filarial patients. The fungus showed resistance to azole antifungals, griseofulvin, and, amphotericin B, whereas significant susceptibility was evident in cases of nystatin and cycloheximide. A total of 197 out of 222 patients showed this co-infection. This study revealed, for the first time, that P. guilliermondii exists as a co-infection in microfilaraemic individuals living in a filarial endemic zone. The findings are important and have relevance to human health, especially for filarial patients.


Mueller-matrix characterization of beetle cuticle: polarized and unpolarized reflections from representative architectures.
We discuss the use of Mueller matrices for characterizing the reflecting properties of beetles, including matching patterns of significant elements to specific cuticular architectures. In the case of illumination by natural light, the parameters of the reflected light are related to the elements of the first column of the matrix. The green and red beetle Stephanorrhina guttata is shown to be a narrowband polarization-preserving reflector apart from depolarizing white patches, the green Calloodes grayanus a narrowband left-circular reflector, and the gold Anoplognathus parvulus behaves as a broadband left-circular reflector. Comparison of experimental and simulated matrices confirms that the beetle reflectors are natural analogs of all-dielectric thin-film reflectors. However, the gold Chrysina resplendens, which was formerly known as Plusiotis resplendens and reflects both right-handed and left-handed light, is represented by an ensemble of laterally incoherent chiral thin-film reflectors.


Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a reanalysis using drug-placebo and drug-drug response curve methodology.
Because methylphenidate (MPH) is currently the most widely prescribed medication for attention deficit hyperactivity disorder (ADHD), several studies have used this as the touch-stone for evaluating the efficacy of a newer stimulant, Adderall. In a parallel-groups study of MPH (n = 20), Adderall (n = 20), and placebo (n = 18), Pliszka et al. (2000) reported that both medications were superior to placebo in improving parent, teacher, and clinician ratings of ADHD and associated behaviors. Compared with MPH, Adderall led to significantly more improvements in teacher and clinician ratings. The present study extends these results by addressing the issue of clinical significance using drug-placebo and drug-drug response curve analyses of the same data. The goal of this method is to answer the following questions about drug-placebo or drug-drug differences: Is the effect clinically meaningful? What does the effect tell us about individual responses? Is the effect due to symptom improvement, the prevention of worsening, or both? Our results show that the efficacy of Adderall to improve functioning is seen throughout the full range of improvement scores. In contrast, MPH showed a substantial effect for "mildly" and "much improved" but not for "very much improved." Our analyses also show that both Adderall and MPH prevent worsening of symptoms. They further suggest that, compared with the Conners Teacher Rating Scale, the Clinical Global Impressions scale may be more sensitive to improvements at the "well end" of the spectrum of functioning.


Using support vector machines on photoplethysmographic signals to discriminate between hypovolemia and euvolemia.
Identifying trauma patients at risk of imminent hemorrhagic shock is a challenging task in intraoperative and battlefield settings given the variability of traditional vital signs, such as heart rate and blood pressure, and their inability to detect blood loss at an early stage. To this end, we acquired N = 58 photoplethysmographic (PPG) recordings from both trauma patients with suspected hemorrhage admitted to the hospital, and healthy volunteers subjected to blood withdrawal of 0.9 L. We propose four features to characterize each recording: goodness of fit (r2), the slope of the trend line, percentage change, and the absolute change between amplitude estimates in the heart rate frequency range at the first and last time points. Also, we propose a machine learning algorithm to distinguish between blood loss and no blood loss. The optimal overall accuracy of discriminating between hypovolemia and euvolemia was 88.38%, while sensitivity and specificity were 88.86% and 87.90%, respectively. In addition, the proposed features and algorithm performed well even when moderate blood volume was withdrawn. The results suggest that the proposed features and algorithm are suitable for the automatic discrimination between hypovolemia and euvolemia, and can be beneficial and applicable in both intraoperative/emergency and combat casualty care.


Consistency of Brief Psychiatric Rating Scale factor structure across a broad spectrum of schizophrenia patients.
The Brief Psychiatric Rating Scale (BPRS) has been the workhorse of psychopathology assessment in studies of schizophrenia and related psychotic disorders for over 40 years. Our goal was to evaluate the discriminant validity of the BPRS across the broad spectrum of persons with schizophrenia. The total sample of 565 subjects with schizophrenia (84%) or schizoaffective disorder (16%) came from eight separate studies conducted under the aegis of the UCLA Clinical Research Center for Schizophrenia and Psychiatric Rehabilitation over a period of 15 years. The total sample could be divided into three subsamples based on illness chronicity and degree of refractoriness to treatment: Recent-onset patients had been ill for less than 2 years (n = 178), stable chronic patients between 2 and 19 years (n = 243) and treatment-refractory patients for more than 19 years (n = 144). Exploratory principal components analysis and varimax rotation were performed on the total sample. The results of each of the three subsamples were compared to the total sample using a correlation matrix and by calculating a coefficient of congruence. A 4-factor solution was considered the most interpretable for each subsample, reflecting the same 4 components identified in the total sample: positive symptoms, negative symptoms, agitation-mania and depression-anxiety. Correlation coefficients and coefficient of congruence were very high, ranging from 0.91 to 0.98. The consistency of the 4-factor solution of the 24-item BPRS across the range of subjects, from first psychotic episode to long-stay, institutionalized patients, supports the use of these factors and this instrument as a whole to track changes over time and with treatment in research and clinical samples.


The association between perioperative allogeneic transfusion volume and postoperative infection in patients following lumbar spine surgery.
Perioperative allogeneic red blood cell transfusion is a risk factor for surgical site infection. The purpose of this study was to determine if the volume of perioperative allogeneic red blood cell transfusion influences the risk of surgical site infection following lumbar spine procedures. A retrospective matched case control study was performed by reviewing all patients who had undergone lumbar spine surgery at our institution from 2005 to 2009. Surgical site infections (spinal or iliac crest) were identified, all within thirty days of the procedure. Controls were matched to the infection cohort according to age, sex, body mass index, diabetic status, smoking status, Charlson Comorbidity Index, length of surgery, and procedure. A conditional logistic regression was performed to examine the association between transfusion volume and surgical site infection. The results were summarized by an odds ratio. A total of 1799 lumbar procedures were identified with an infection rate of 3.1% (fifty-six cases). On the basis of the numbers, there was no significant difference in the matched variables between the infection cohort and the matched controls. The volume of transfusion was significantly associated with surgical site infection (odds ratio, 4.00 [95% confidence interval, 1.96 to 8.15]) after adjusting for both unmatched variables of preoperative hemoglobin level and volume of intraoperative blood loss. In this retrospective matched case control study, the association between surgical site infection following lumbar spine surgery and volume of perioperative allogeneic red blood cell transfusion was supported.


Emergence of virulent methicillin-resistant Staphylococcus aureus strains carrying Panton-Valentine leucocidin genes in The Netherlands.
Methicillin-resistant Staphylococcus aureus (MRSA) strains carrying the Panton-Valentine leucocidin (PVL) genes have been reported worldwide and are a serious threat to public health. The PVL genes encode a highly potent toxin which is involved in severe skin infections and necrotizing pneumonia, even in previously healthy individuals. We assessed the prevalence of PVL-positive MRSA in The Netherlands for two periods of time: (i) 1987 through 1995 and (ii) 2000 and 2002, and determined their characteristics by using multilocus sequence typing and staphylococcal chromosome cassette (SCCmec) typing. It was found that up to 15% of all MRSA isolates detected in The Netherlands harbored the PVL genes. Most PVL-positive MRSA isolates were obtained from severe soft tissue infections in relatively young individuals. The first PVL-positive MRSA described in The Netherlands, isolated in 1988, was a single-locus variant of the "Berlin" epidemic MRSA clone. The 20 PVL-positive MRSA isolates studied in 2000 and 2002 consisted of five different sequence types (STs) that belonged to four clonal complexes. One of the STs, ST80, is considered to be a widespread European clone and was the most predominant ST (60%) in this study, while ST37 had never been found to be associated with PVL-positive MRSA. Most isolates harbored SCCmec type IV, a supposed marker for community-acquired MRSA. The number and type of virulence-associated genes varied among the different STs.


RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks.
The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 5' end resection in vivo. RECQL4 physically interacts with MRE11-RAD50-NBS1 (MRN), which senses DSBs and initiates DNA end resection with CtIP. The MRE11 exonuclease regulates the retention of RECQL4 at laser-induced DSBs. RECQL4 also directly interacts with CtIP via its N-terminal domain and promotes CtIP recruitment to the MRN complex at DSBs. Moreover, inactivation of RECQL4's helicase activity impairs DNA end processing and HR-dependent DSBR without affecting its interaction with MRE11 and CtIP, suggesting an important role for RECQL4's unwinding activity in the process. Thus, we report that RECQL4 is an important participant in HR-dependent DSBR.


Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C.
The majority of familial Alzheimer disease mutations are linked to the recently cloned presenilin (PS) genes, which encode two highly homologous proteins (PS-1 and PS-2). It was shown that the full-length PS-2 protein is phosphorylated constitutively within its N-terminal domain by casein kinases, whereas the PS-1 protein is not. Full-length PS proteins undergo endoproteolytic cleavage within their hydrophilic loop domain resulting in the formation of approximately 20-kDa C-terminal fragments (CTF) and approximately 30-kDa N-terminal fragments [Thinakaran, G., et al. (1996) Neuron 17, 181-190]. Here we describe the surprising finding that the CTF of PS-1 is phosphorylated by protein kinase C (PKC). Stimulation of PKC causes a 4- to 5-fold increase of the phosphorylation of the approximately 20-kDa CTF of PS-1 resulting in reduced mobility in SDS gels. PKC-stimulated phosphorylation occurs predominantly on serine residues and can be induced either by direct stimulation of PKC with phorbol-12,13-dibutyrate or by activation of the m1 acetylcholine receptor-signaling pathway with the muscarinic agonist carbachol. However, phosphorylation of full-length PS-1 and PS-2 is not altered upon PKC stimulation. In addition, a mutant form of PS-1 lacking exon 10, which does not undergo endoproteolytic cleavage [Thinakaran, G., et al. (1996) Neuron 17, 181-190] is not phosphorylated by PKC, although it still contains all PKC phosphorylation sites conserved between different species. These results show that PKC phosphorylates the PS-1 CTF. Therefore, endoproteolytic cleavage of full-length PS-1 results in the generation of an in vivo substrate for PKC. The selective phosphorylation of the PS-1 CTF indicates that the physiological and/or pathological properties of the CTF are regulated by PKC activity.


Impact of surveillance stool culture guided selection of antibiotics in the management of pediatric small bowel transplant recipients.
Surveillance stool cultures (SSC) have been used in immunocompromised populations to predict the organisms associated with invasive infections and aid in the selection of empiric antibiotic regimens. To evaluate the utility of this approach in pediatric small bowel transplant (SBT) recipients, we conducted a retrospective review of 33 patients who underwent SBT, 16 of whom had SSC done. In no case was the same organism isolated from SSC and subsequent blood, peritoneal fluid or wound cultures. In the first month post-transplantation, blood cultures were positive in 44% and 35% of patients that had and did not have SSC done, respectively (p = 0.73); peritoneal fluid cultures in 44% and 65% (p = 0.30); and wound cultures in 44% and 24% (p = 0.28). There were no significant differences among both groups in time to first infection, duration of ICU stay following SBT, graft survival or long-term patient survival. We conclude that SSC-guided antibiotic selection does not have a significant impact on the incidence of invasive infections in the first month following SBT or on specific indicators of patient outcome. This suggests that empiric antibiotic regimens should be selected based on clinical presentation and hospital flora and susceptibility patterns.


Maintenance of "stem cell" features of cartilage cell sub-populations during in vitro propagation.
The discovery of mesenchymal stem cells (MSCs) or MSC-like cells in cartilage tissue does not tie in well with the established view that MSCs derive from a perivascular niche. The presence of MSCs may raise concerns about specificity and application safety, particularly in terms of the regulatory site. The aim of the present study was to investigate the benefits or possible risks of the MSC-like properties of cells isolated from cartilage in the context of autologous chondrocyte implantation. Chondrocytic cells were isolated from cartilage or intervertebral disc tissue. Flow cytometry was used to analyze the expression of cell surface antigens. MSC-like cells were either enriched or depleted by means of magnetic cell sorting (MACS) involving the monoclonal antibodies W5C5/SUSD2 and W8B2/MSCA-1. We addressed the issues of prolonged expansion of such cells as well as the influence of culture medium as a trigger for selecting a single cell type. Established protocols were used to study in vitro differentiation. In addition to histological and biochemical assessment, the acquired phenotypes were also evaluated on the mRNA transcript level. In the studied cells, we found strongly analogous expression of antigens typically expressed on MSCs, including CD49e, CD73, CD90, CD105, CD140b and CD166. The expression of W5C5 and W8B2 antigens in cartilage cell sub-populations did not correlate with multi-potency. We demonstrated that a chondroid precursor, but not a bona fide multipotent mesenchymal, cell type can be obtained under established in vitro culture conditions. The culture media used for expansion influenced the cell phenotype. The risk of adverse adipose or osseous differentiation is not posed by expanded chondrocyte cultures, even after enrichment of putative MSC-like cell populations by MACS. It is possible that this limited "stemness" in chondrocytes, expanded for use in ACI, may instead be beneficial as it allows re-differentiation under appropriate conditions despite prolonged times in culture.


Correlates of cooperation in a one-shot high-stakes televised prisoners' dilemma.
Explaining cooperation between non-relatives is a puzzle for both evolutionary biology and the social sciences. In humans, cooperation is often studied in a laboratory setting using economic games such as the prisoners' dilemma. However, such experiments are sometimes criticized for being played for low stakes and by misrepresentative student samples. Golden balls is a televised game show that uses the prisoners' dilemma, with a diverse range of participants, often playing for very large stakes. We use this non-experimental dataset to investigate the factors that influence cooperation when "playing" for considerably larger stakes than found in economic experiments. The game show has earlier stages that allow for an analysis of lying and voting decisions. We found that contestants were sensitive to the stakes involved, cooperating less when the stakes were larger in both absolute and relative terms. We also found that older contestants were more likely to cooperate, that liars received less cooperative behavior, but only if they told a certain type of lie, and that physical contact was associated with reduced cooperation, whereas laughter and promises were reliable signals or cues of cooperation, but were not necessarily detected.


Individual risk factors for Plasmodium vivax infection in the residual malaria transmission focus of Oaxaca, Mexico.
To identify individual risk factors for malaria infection of inhabitants in the residual transmission focus on the Pacific coast of Oaxaca, Mexico. A population-based, matched case-control study was conducted from January 2002 to July 2003 comparing the frequency of exposure to individual risk factors in subjects presenting clinical malaria and uninfected controls. A malaria case was defined as an individual living in the study area presenting malaria symptoms and a Plasmodium vivax-positive thick blood smear; controls were individuals negative to P. vivax parasites and antibodies of the same gender and with +/- five years as the case. A standardized questionnaire was used to record information about the individual risk factors associated with malaria episodes in cases and two controls for each case. In a multiple conditional logistic regression model analysis of data from 119 cases and 238 controls, 18 out of 99 variables were significantly associated (p< 0.05) with increased risk of malaria, including: being born in another locality (RM 3.16, 95% IC 1.16-6.13); speaking only an autochthonous language (RM= 2.48, 95% IC 1.19-3.77); having poor knowledge about malaria (RM= 2.26 95% IC 1.10-4.66 P< 0.02); the amount of vegetation around the house (RM= 20.43, 95% IC 5.98-70.87, P< 0.000; RM= 3.78, 95% IC 1.21-11.80, for 60-100% and 30-59%, respectively); living in houses constructed with perishable materials (RM= 2.85, 95% IC 1.62-5.01); living on the periphery of the town (RM= 6.23, 95% IC 3.50-11.0); sleeping on a dirt floor (RM= 2.98, 95% IC 1.78-5.01) or with two or more people in the same bed (RM= 1.85, 95% CI 1.09-3.14); not using bed nets (RM= 2.39, 95% IC 1.18-4.83, P< 0.003) or using bed nets with holes (RM= 13.93, 95 IC 2.48-78.01); traveling outside of the village (RM= 9.16, 95% IC 1.98-42.2); and previous malaria cases in the house (RM= 5.84, 95% IC 3.33-10.22). Risk of malaria infection was associated with socio-cultural and environmental factors exposing individuals to mosquito bites. A higher risk of malaria infection occurred outside the locality and by intradomiciliar transmission probably as a result of relapsing asymptomatic relatives.


The integrated acute systemic toxicity project (ACuteTox) for the optimisation and validation of alternative in vitro tests.
The ACuteTox project is designed to replace animal testing for acute systemic toxicity, as is widely used today for regulatory purposes, by using in vitro and in silico alternatives. In spite of the fact that earlier studies on acute systemic toxicity demonstrated a good correlation between in vitro basal cytotoxicity data (the 50% inhibitory concentration [IC50]) in human cell lines and rodent LD50 values, and an even better correlation between IC50 values and human lethal blood concentrations, very few non-animal tests have been accepted for general use. Therefore, the aim of the ACuteTox project is to adapt new testing strategies, for example, the implementation of new endpoints and new cell systems for toxicity screening, organ-specific models, metabolism-dependent toxicity, tissue absorption, distribution and excretion, and computer-based prediction models. A new database, AcuBase, containing descriptions and results of in vitro tests of the 97 reference chemicals, as well as the results of animal experimentation, and human acute toxicity data, will be generated within the framework of ACuteTox. Scientists from 13 European countries are working together and making efforts to find the most appropriate testing strategies for the prediction of human acute systemic toxicity, and also to select a robust in vitro test battery for cytotoxicity testing of chemicals.


Implant survival rates after osteotome-mediated maxillary sinus augmentation: a systematic review.
The aim of the present study was to systematically evaluate the implant survival rate after osteotome-mediated maxillary sinus augmentation with or without using grafting materials. MEDLINE database was searched using a combination of specific search terms. Furthermore, a hand searching of the relevant journals and of the bibliographies of reviews was performed. Prospective and retrospective clinical studies with at least 20 patients treated by osteotome-mediated sinus floor elevation were included. Nineteen studies were selected for data analysis. A total of 1,822 patients, accounting for 3,131 implants were considered. Mean weighted cumulative implant survival at 1, 2, 3, and 5 years was estimated as 98.12%, 97.40%, 96.75%, and 95.81%, respectively. No significant difference was found in relation to the use of grafting material nor in relation to implant length. Overall implant survival was 92.7% for 331 implants placed in <5 mm ridge height and 96.9% for 2,525 implants inserted in ≥ 5 mm ridge height. The difference was significant (p = .0003). The transalveolar sinus augmentation technique could be a viable treatment in case of localized atrophy in the posterior maxilla even in case of minimal residual bone height. The prognosis can be more favorable when the residual ridge is at least 5 mm high.


Comprehensive analysis of circulating adipokines and hsCRP association with cardiovascular disease risk factors and metabolic syndrome in Arabs.
Cardiovascular diseases (CVD) are a leading cause of death worldwide including the Middle East. This is caused in part by the dysregulation of adipose tissue leading to increased production of pro-inflammatory adipokines and reduction in cardio-protective adipokines such as adiponectin. Ethnicity has been recognized as a major factor in the association between CVD risk factors and the different circulating adipokines. In this study, for the first time, the relationship between traditional cardiovascular risk factors, Metabolic Syndrome (MetS) and circulating level of adipokines in Arab ethnicity was investigated. We conducted a population-based cross-sectional survey on 379 adult Arab participants living in Kuwait. Traditional cardiovascular risk factors such as blood pressure (BP), low density lipoprotein (LDL) and triglyceride (TG) were measured. Plasma levels of circulating Leptin, Plasminogen Activator Inhibitor (PAI-1) visfatin, adiponectin, resistin and adipsin were assessed using the multiplexing immunobead-based assay. Circulating levels of High sensitivity C-Reactive Protein (hsCRP), Leptin, PAI-1 and adiponectin were significantly higher in Arab women than men (p < 0.0001). In multi-variate analysis, the homeostasis model assessment-insulin resistance (HOMA-IR) and body mass index (BMI) showed strong association with most of the biomarkers (p < 0.05). HsCRP showed significant association with all risk factors (p < 0.05). Leptin, PAI-1 and adipsin showed significant positive correlation with BMI, unlike adiponectin which showed inverse correlation (p < 0.05). Subjects in the highest tertile of leptin, PAI-1 and hsCRP had higher odds of having Metabolic Syndrome (MetS) (odd ratio [OR] = 3.02, 95% confidence interval [CI] = 1.47-6.19) and (OR = 2.52, 95% CI = 1.45-4.35), (OR = 4.26, 95% CI = 2.39-7.59) respectively. On the other hand subjects with highest tertile of adiponectin had lower odds of having MetS (OR = 0.22, 95% CI = 0.12-0.40). Leptin, PAI-1 and hsCRP showed significant positive association with increased MetS components (P-trend <0.05), while adiponectin was negatively associated with increased MetS components (P-trend <0.0001). Our results show positive association between hsCRP, leptin, PAI-1 with increased MetS components and increase the odds of having MetS. Adiponectin on the other hand showed inverse correlation with MetS components and associated with reduction in MetS. Overall, our data highlights the significant clinical value these markers have in MetS especially hsCRP which can be used as good marker of low grade inflammation in Arabs.


Contemporary rates and outcomes of single- vs. dual-coil implantable cardioverter defibrillator lead implantation: data from the Israeli ICD Registry.
Dual-coil leads were traditionally considered standard of care due to lower defibrillation thresholds (DFT). Higher complication rates during extraction with parallel progression in implantable cardioverter defibrillator (ICD) technology raised questions on dual coil necessity. Prior substudies found no significant outcome difference between dual and single coils, although using higher rates of DFT testing then currently practiced. We evaluated the temporal trends in implantation rates of single- vs. dual-coil leads and determined the associated adverse clinical outcomes, using a contemporary nation-wide ICD registry. Between July 2010 and March 2015, 6343 consecutive ICD (n = 3998) or CRT-D (n = 2345) implantation patients were prospectively enrolled in the Israeli ICD Registry. A follow-up of at least 1 year of 2285 patients was available for outcome analysis. The primary endpoint was all-cause mortality. Single-coil leads were implanted in 32% of our cohort, 36% among ICD recipients, and 26% among CRT-D recipients. Secondary prevention indication was associated with an increased rate of dual-coil implantation. A significant decline in dual-coil leads with reciprocal incline of single coils was observed, despite low rates of DFT testing (11.6%) during implantation, which also declined from 31 to 2%. In the multivariate Cox model analysis, dual- vs. single-coil lead implantation was not associated with an increased risk of mortality [hazard ratio (HR) = 1.23; P= 0.33], heart failure hospitalization (HR = 1.34; P=0.13), appropriate (HR = 1.25; P= 0.33), or inappropriate ICD therapy (HR = 2.07; P= 0.12). Real-life rates of single-coil lead implantation are rising while adding no additional risk. These results of single-coil safety are reassuring and obtained, despite low and contemporary rates of DFT testing.


Callipyge mutation affects gene expression in cis: a potential role for chromatin structure.
Muscular hypertrophy in callipyge sheep results from a single nucleotide substitution located in the genomic interval between the imprinted Delta, Drosophila, Homolog-like 1 (DLK1) and Maternally Expressed Gene 3 (MEG3). The mechanism linking the mutation to muscle hypertrophy is unclear but involves DLK1 overexpression. The mutation is contained within CLPG1 transcripts produced from this region. Herein we show that CLPG1 is expressed prenatally in the hypertrophy-responsive longissimus dorsi muscle by all four possible genotypes, but postnatal expression is restricted to sheep carrying the mutation. Surprisingly, the mutation results in nonimprinted monoallelic transcription of CLPG1 from only the mutated allele in adult sheep, whereas it is expressed biallelically during prenatal development. We further demonstrate that local CpG methylation is altered by the presence of the mutation in longissimus dorsi of postnatal sheep. For 10 CpG sites flanking the mutation, methylation is similar prenatally across genotypes, but doubles postnatally in normal sheep. This normal postnatal increase in methylation is significantly repressed in sheep carrying one copy of the mutation, and repressed even further in sheep with two mutant alleles. The attenuation in methylation status in the callipyge sheep correlates with the onset of the phenotype, continued CLPG1 transcription, and high-level expression of DLK1. In contrast, normal sheep exhibit hypermethylation of this locus after birth and CLPG1 silencing, which coincides with DLK1 transcriptional repression. These data are consistent with the notion that the callipyge mutation inhibits perinatal nucleation of regional chromatin condensation resulting in continued elevated transcription of prenatal DLK1 levels in adult callipyge sheep. We propose a model incorporating these results that can also account for the enigmatic normal phenotype of homozygous mutant sheep.


Pyruvate dehydrogenase complex-enzyme 2, a new target for Listeria spp. detection identified using combined phage display technologies.
The genus Listeria comprises ubiquitous bacteria, commonly present in foods and food production facilities. In this study, three different phage display technologies were employed to discover targets, and to generate and characterize novel antibodies against Listeria: antibody display for biomarker discovery and antibody generation; ORFeome display for target identification; and single-gene display for epitope characterization. With this approach, pyruvate dehydrogenase complex-enzyme 2 (PDC-E2) was defined as a new detection target for Listeria, as confirmed by immunomagnetic separation-mass spectrometry (IMS-MS). Immunoblot and fluorescence microscopy showed that this protein is accessible on the bacterial cell surface of living cells. Recombinant PDC-E2 was produced in E. coli and used to generate 16 additional antibodies. The resulting set of 20 monoclonal scFv-Fc was tested in indirect ELISA against 17 Listeria and 16 non-Listeria species. Two of them provided 100% sensitivity (CI 82.35-100.0%) and specificity (CI 78.20-100.0%), confirming PDC-E2 as a suitable target for the detection of Listeria. The binding region of 18 of these antibodies was analyzed, revealing that ≈ 90% (16/18) bind to the lipoyl domains (LD) of the target. The novel target PDC-E2 and highly specific antibodies against it offer new opportunities to improve the detection of Listeria.


Serum magnesium, phosphate and calcium in Nigerian children with sickle cell disease.
Biochemical abnormalities have been associated with sickle cell disease. Studies on phosphorus and magnesium in sickle cell disease have been conflicting. There is paucity of information on the role of these ions in the pathogenesis and management of sickle cell disease. This study was set out to determine the serum levels of magnesium, phosphorus and calcium in Nigerian children with sickle cell disease. A case-control study carried out on children with HbSS genotype (cases) and age-matched controls with HbAA. Serum magnesium, calcium, phosphorus and albumin were measured using colorimetric methods. Eighty-six subjects and forty-five controls were studied. The mean serum magnesium was 0.99mmol/L (0.02) and 0.98mmol/L (0.02) in the cases and controls respectively. The difference was not significant. Mean serum calcium was significantly lower in the cases [2.1mmol/L (0.3)] compared with the controls [2.3mmol/ L (0.15)]; p<0.01. Serum phosphorus was significantly higher in the cases than in the controls [2.2mmol/L (0.7) versus (1.5mmol/L (0.6); p<0.001]. There was no statistical difference in the albumin binding of calcium in both groups. A positive correlation existed between serum phosphorus and magnesium and also between serum calcium and magnesium in the cases group but no correlation between these parameters and age was found. Children with sickle cell anaemia in this study had normo-magnesaemia, hyperphosphataemia and hypocalcaemia. Further studies on changes in intracellular concentrations of these ions in children with sickle cell disease are required. Such findings could be useful in designing better management in individuals with this abnormality.


Random mutagenesis screening indicates the absence of a separate H(+)-sensor in the pH-sensitive Kir channels.
Several inwardly-rectifying (Kir) potassium channels (Kir1.1, Kir4.1 and Kir4.2) are characterised by their sensitivity to inhibition by intracellular H(+) within the physiological range. The mechanism by which these channels are regulated by intracellular pH has been the subject of intense scrutiny for over a decade, yet the molecular identity of the titratable pH-sensor remains elusive. In this study we have taken advantage of the acidic intracellular environment of S. cerevisiae and used a K(+) -auxotrophic strain to screen for mutants of Kir1.1 with impaired pH-sensitivity. In addition to the previously identified K80M mutation, this unbiased screening approach identified a novel mutation (S172T) in the second transmembrane domain (TM2) that also produces a marked reduction in pH-sensitivity through destabilization of the closed-state. However, despite this extensive mutagenic approach, no mutations could be identified which removed channel pH-sensitivity or which were likely to act as a separate H(+) -sensor unique to the pH-sensitive Kir channels. In order to explain these results we propose a model in which the pH-sensing mechanism is part of an intrinsic gating mechanism common to all Kir channels, not just the pH-sensitive Kir channels. In this model, mutations which disrupt this pH-sensor would result in an increase, not reduction, in pH-sensitivity. This has major implications for any future studies of Kir channel pH-sensitivity and explains why formal identification of these pH-sensing residues still represents a major challenge.


Structural and biochemical characterization of a family 7 highly thermostable endoglucanase from the fungus Rasamsonia emersonii.
Thermostable cellulases from glycoside hydrolase family 7 (GH7) are the main components of enzymatic mixtures for industrial saccharification of lignocellulose. Activity improvement of these enzymes via rational design is a promising strategy to alleviate the industrial costs, but it requires detailed structural knowledge. While substantial biochemical and structural data are available for GH7 cellobiohydrolases, endoglucanases are more elusive and only few structures have been solved so far. Here, we report a new crystal structure and biochemical characterization of a thermostable endoglucanase from the thermophilic ascomycete Rasamsonia emersonii, ReCel7B. The enzyme was compared with the homologous endoglucanase from the mesophilic model ascomycete Trichoderma reesei (TrCel7B), which unlike ReCel7B possesses an additional carbohydrate-binding module (CBM). With a temperature optimum of 80 °C, ReCel7B displayed a number of differences in activity and ability to synergize with cellobiohydrolases compared to TrCel7B. We improved both binding and kinetics in a chimeric variant of ReCel7B and a CBM, while we observe the opposite effect when the CBM was removed in TrCel7B. The crystal structure of ReCel7B was determined at 2.48 Å resolution, with Rwork and Rfree factors of 0.182 and 0.206, respectively. Structural analyses revealed that ReCel7B has increased rigidity in a number of peripheral loops compared to TrCel7B and fewer aromatics in the substrate-binding cleft. An increased number of glycosylations were identified in ReCel7B, and we propose a stabilizing mechanism for one of the glycans. Global structure-function interpretations of ReCel7B highlight the differences in temperature stability, turnover, binding, and cellulose accessibility in GH7 endoglucanases. DATABASE: Structural data are available in RCSB Protein Data Bank database under the accession number 6SU8. ENZYMES: ReCel7B, endoglucanase (EC126.96.36.199) from Rasamsonia emersonii; ReCel7A, cellobiohydrolase (EC220.127.116.11) from Rasamsonia emersonii; TrCel7B, endoglucanase (EC188.8.131.52) from Trichoderma reesei; TrCel7A, cellobiohydrolase (EC220.127.116.11) from Trichoderma reesei.


The role of growth factors in nerve regeneration.
Nerve injuries result in functional loss in the innervated organ or body parts, and recovery is difficult unless surgical treatment has been done. Different surgical treatments have been suggested for nerve repair. Tissue engineering related to growth factors has arisen as an alternative approach for triggering and improving nerve regeneration. Therefore, the aim of this review is to provide a comprehensive analysis related to growth factors as tools for optimizing the regeneration process. Studies and reviews on the use of growth factors for nerve regeneration were compiled over the course of the review. According to literature review, it may be concluded that growth factors from different sources present promising treatment related to nerve regeneration involved in neuronal differentiation, greater myelination and axonal growth and proliferation of specific cells for nerve repair.


Left ventricular global strains by linear measurements in three dimensions: interrelations and relations to age, gender and body size in the HUNT Study.
Strain is a relative deformation and has three dimensions, in the left ventricle (LV) usually longitudinal (εL), transmural (εT) and circumferential (εC) strain. All three components can be measured generically by the basic systolic and diastolic dimension measures of LV wall length, wall thickness and diameter. In this observational study we aimed to study the relations of normal generic strains to age, body size and gender, as well as the interrelations between the three strain components. Generic strains derived from dimension measures by longitudinal and cross-sectional M-mode in all three dimensions were measured in 1266 individuals without heart disease from the Nord-Trøndelag Health Study. The mean εL was -16.3%, εC was -22.7% and εT was 56.5%. Normal values by age and gender are provided. There was a gradient of εC from the endocardial, via the midwall to the external level, lowest at the external. All strains decreased in absolute values by increasing body surface area (BSA) and age, relations were strongest for εL. Gender differences were mainly a function of BSA differences. The three strain components were strongly interrelated through myocardial incompressibility. Global systolic strain is the total deformation of the myocardium; the three strain components are the spatial coordinates of this deformation, irrespective of the technology used for measurement. Normal values are method-dependent and not normative across methods. Interrelation of strains indicates a high degree of myocardial incompressibility and that longitudinal strain carries most of the total information.


The role of technology and engineering models in transforming healthcare.
The healthcare system is in crisis due to challenges including escalating costs, the inconsistent provision of care, an aging population, and high burden of chronic disease related to health behaviors. Mitigating this crisis will require a major transformation of healthcare to be proactive, preventive, patient-centered, and evidence-based with a focus on improving quality-of-life. Information technology, networking, and biomedical engineering are likely to be essential in making this transformation possible with the help of advances, such as sensor technology, mobile computing, machine learning, etc. This paper has three themes: 1) motivation for a transformation of healthcare; 2) description of how information technology and engineering can support this transformation with the help of computational models; and 3) a technical overview of several research areas that illustrate the need for mathematical modeling approaches, ranging from sparse sampling to behavioral phenotyping and early detection. A key tenet of this paper concerns complementing prior work on patient-specific modeling and simulation by modeling neuropsychological, behavioral, and social phenomena. The resulting models, in combination with frequent or continuous measurements, are likely to be key components of health interventions to enhance health and wellbeing and the provision of healthcare.


Non-communicable diseases in Mozambique: risk factors, burden, response and outcomes to date.
Mozambique is located on the East Coast of Africa bordering South Africa, Zimbabwe, Zambia, Malawi and Tanzania and is one of the poorest countries in the world. Currently NCDs account for 28% of deaths in Mozambique. Risk factors such as tobacco and alcohol use and poor diet are present in both urban and rural settings. Diseases such as hypertension and diabetes affect large proportions of the population, but people are often unaware of their condition or poorly managed. Data from studies on diabetes highlight the financial burden for NCD management in Mozambique for both the individual and health system. The National Strategic Plan for the prevention and control of NCDs in Mozambique has as its aim to create a positive environment to minimise or eliminate the exposure to risk factors and guarantee access to care. The plan has as its overall objective to reduce exposure to risk factors and morbidity and mortality due to NCDs and has 4 areas of intervention: 1) Prevention and health education with regards to NCDs; 2) Access to quality care, treatment and follow-up; 3) Prevention of disability and premature mortality and 4) Surveillance, research, monitoring and evaluation and advocacy for NCDs. The Ministry of Health developed projects for diabetes and hypertension and used these as key lessons that could then be applied to other NCDs. Mozambique, through political commitment from the Ministry of Health and the dedication of local champions, has been able to garner international support to improve care for people with diabetes and then use this to develop its National Plan for NCDs. Despite this increase in attention resources available do not match the challenge of NCDs in Mozambique. Mozambique's experience provides a practical example of actions that can be undertaken in a resource poor country to tackle the emerging burden of NCDs.


Kinetic analysis of the chronology of patulin- and gossypol-induced cytotoxicity in vitro.
Kinetic analyses of the mechanisms of patulin- and gossypol-induced cellular toxicity in an immortalized rat hepatocyte cell line were examined using a battery of vital fluorescence bioassays. Intracellular glutathione (GSH) content and intracellular Ca2+ ([Ca2+])i were monitored simultaneously using fluorescent probes requiring uv excitation (351-363 nm); reactive oxygen species (ROS) production, mitochondrial and plasma membrane potential, and intracellular pH were monitored simultaneously with visible wavelength probes (488 nm). Changes in gap junction-mediated intercellular communication (GJIC) were monitored using the gap FRAP technique. Cells were exposed to different concentrations of patulin (0, 1.0, 10, 100, and 1000 microM) or gossypol (0, 1.0, 3.0, and 10 microM). All parameters were monitored directly after addition of toxin for 20 min. The analyses provided the following chronology of cellular injury caused by patulin: simultaneous suppression of GJIC and GSH depletion --> ROS generation --> mitochondrial membrane depolarization --> simultaneous increase in [Ca2+]i and cytoplasmic acidification --> depolarization of plasma membrane. A distinct chronology of gossypol-induced cellular injury was also identified: simultaneous suppression of GJIC and generation of ROS --> cytoplasmic acidification --> simultaneous elevation of [Ca2+]i and partial depletion of GSH --> mitochondrial membrane depolarization --> depolarization of plasma membrane. This report indicates the utility of these vital assays as improved mechanistically based methods for toxicity testing in vitro.


Prognostic analysis of carcinoma of the ampulla of Vater: pancreaticoduodenectomy versus local resection.
Pancreaticoduodenectomy (PD) is considered to be the optimal treatment for carcinoma of the ampulla of Vater, but the trauma caused by PD is often severe and extensive. Local resection (LR) for ampullary tumors has been performed for a century but remains controversial. The use of this procedure for benign conditions is clear, but its place, if any, in the management of ampullary carcinoma is debated. The aim of this study was to investigate the outcomes and analyse the prognostic factors of LR of carcinoma of the ampulla of Vater by comparison with PD. A retrospective analysis of 71 patients of carcinoma of the ampulla of Vater was conducted at Zhejiang Cancer Hospital from January 1995 to December 2005. We investigated the differences of the baseline characteristics and the intra- and postoperative data of patients who underwent PD and LR. Prognostic factors for recurrence and survival of carcinoma of the ampulla of Vater between PD and LR was also analysed. Among the 71 patients of ampullary carcinoma who underwent surgical resection, a PD was performed in 46 (64.8%) patients while a LR was performed in 25 (35.2%) patients. The 30-day mortality rate associated with PD (6.5%) was not different from that with LR (0%; p=0.547) while the morbidity following PD (30.4%) and LR (8.0%) was statistically different (p=0.031). The complications were also significantly higher in the PD group than the LR group (34.8% vs 6.5%; p=0.013). In a univariate Cox regression analysis of survival, there were significant differences in tumor size (p=0.031), TNM (Tumor Node Metastasis) stage (p=0.000), pT (pathologic Tumor) stage (p=0.010), pN (pathologic Node) stage (p=0.000), differentiation (p=0.026), and surgical margin (p=0.031). Multivariate Cox regression analysis showed that TNM stage (HR=3.640, 95% CI 1.428~9.282; p=0.007), pT stage (HR=3.090, 95% CI 1.230~7.762; p=0.016), and pN stage (HR=4.479, 95% CI 1.524~013.161; p=0.005) remained as independent predictors of survival rates. According to the method of Kaplan-Meier, the five-year survival rate in the PD group was 53.5% and that in the LR group was 48.0%, no significant differences were found between the two groups in overall survival rates (p=0.540). Compared with the PD, the 5-year survival of patients with the TNM stage-III/IV who undergoing LR was statistically lower (11.1% vs 38.1%; p=0.040). As expected, the overall survival were signicant differences between the two groups in pT stage-T3/T4 (47.4% vs 18.2%, p=0.018) and pN stage-N1 (36.8% vs 11.1%, p=0.004), respectively. Tumor recurrence was diagnosed in 10/43 (23.3%) patients after PD and 12/25 (48.0%) patients after LR (p=0.035). Logistic regression analysis of recurrence showed that TNM stage-III/IV (p=0.004), pT stage-T3/T4 (p=0.034), and pN stage-N1 (p=0.007) were associated with a 2.444, 1.943, and 2.111-fold increased risk of recurrence, respectively. PD is the preferred operation for carcinoma of the ampulla of Vater. LR is less mortal and morbid than PD, which is a suitable treatment in patients with a low-risk cancer in stages I/II or pT1/T2 N0 with a maximum diameter of 2 cm or less. TNM stage, pT stage, and pN stage remained as independent predictors of survival rates.


Effect of Pap smear collection and carrageenan on cervicovaginal human papillomavirus-16 infection in a rhesus macaque model.
Human papillomavirus (HPV) infection of the genital mucosa is thought to require trauma to the cervicovaginal epithelium. Therefore, we determined whether a cytology specimen collection procedure (Pap smear), which disrupts the epithelium by design, renders the cervix more susceptible to HPV infection in a primate model. In a series of female rhesus macaques, a speculum examination was performed with (n = 8) or without (n = 4) a cytology specimen collection procedure as it is commonly practiced in a gynecology clinic. An internal digital examination was performed after specimen collection using Surgilube (n = 4) or 1% iota-carrageenan, a previously indentified HPV inhibitor (n = 4) as the lubricant. The cervix was then inoculated with HPV16 pseudovirions expressing red fluorescent protein. After 3 days, the reproductive tracts were excised and the cervix was cryosectioned. Sections were analyzed by fluorescent confocal microscopy for the number of red fluorescent protein-positive keratinocytes. Substantial infection of the ectocervix, the transformation zone, and the endocervix was detected, but only in conjunction with the cytology specimen collection procedure (cytology using Surgilube vs without cytology using Surgilube, mean = 84 infectious events per section vs mean = 0.05 infectious events per section, difference = 84 infectious events per section, 95% confidence interval = 19 to 384 infectious events per section). When the carrageenan gel was substituted for Surgilube for an internal digital examination, the mean number of infectious events decreased (carrageenan gel vs Surgilube, mean = 3.5 events per section vs mean = 84 infectious events per section difference = 81 events per section, 95% confidence interval = 33 to 213 events per section). These findings indicate that cytology screening in women might lead to a transient enhancement of susceptibility to HPV infection and that use of a carrageenan-based gel during the examination might mitigate this enhancement.


Triplet state dissolved organic matter in aquatic photochemistry: reaction mechanisms, substrate scope, and photophysical properties.
Excited triplet states of chromophoric dissolved organic matter (3CDOM*) play a major role among the reactive intermediates produced upon absorption of sunlight by surface waters. After more than two decades of research on the aquatic photochemistry of 3CDOM*, the need for improving the knowledge about the photophysical and photochemical properties of these elusive reactive species remains considerable. This critical review examines the efforts to date to characterize 3CDOM*. Information on 3CDOM* relies mainly on the use of probe compounds because of the difficulties associated with directly observing 3CDOM* using transient spectroscopic methods. Singlet molecular oxygen (1O2), which is a product of the reaction between 3CDOM* and dissolved oxygen, is probably the simplest indicator that can be used to estimate steady-state concentrations of 3CDOM*. There are two major modes of reaction of 3CDOM* with substrates, namely triplet energy transfer or oxidation (via electron transfer, proton-coupled electron transfer or related mechanisms). Organic molecules, including several environmental contaminants, that are susceptible to degradation by these two different reaction modes are reviewed. It is proposed that through the use of appropriate sets of probe compounds and model photosensitizers an improved estimation of the distribution of triplet energies and one-electron reduction potentials of 3CDOM* can be achieved.


Computational Studies of Carboxylate-Assisted C-H Activation and Functionalization at Group 8-10 Transition Metal Centers.
Computational studies on carboxylate-assisted C-H activation and functionalization at group 8-10 transition metal centers are reviewed. This Review is organized by metal and will cover work published from late 2009 until mid-2016. A brief overview of computational work prior to 2010 is also provided, and this outlines the understanding of carboxylate-assisted C-H activation in terms of the "ambiphilic metal-ligand assistance" (AMLA) and "concerted metalation deprotonation" (CMD) concepts. Computational studies are then surveyed in terms of the nature of the C-H bond being activated (C(sp2)-H or C(sp3)-H), the nature of the process involved (intramolecular with a directing group or intermolecular), and the context (stoichiometric C-H activation or within a variety of catalytic processes). This Review aims to emphasize the connection between computation and experiment and to highlight the contribution of computational chemistry to our understanding of catalytic C-H functionalization based on carboxylate-assisted C-H activation. Some opportunities where the interplay between computation and experiment may contribute further to the areas of catalytic C-H functionalization and applied computational chemistry are identified.


The Drosophila fusome, a germline-specific organelle, contains membrane skeletal proteins and functions in cyst formation.
Oogenesis in Drosophila takes place within germline cysts that support polarized transport through ring canals interconnecting their 15 nurse cells and single oocyte. Developing cystocytes are spanned by a large cytoplasmic structure known as the fusome that has been postulated to help form ring canals and determine the pattern of nurse cell-oocyte interconnections. We identified the adducin-like hts product and alpha-spectrin as molecular components of fusomes, discovered a related structure in germline stem cells and documented regular associations between fusomes and cystocyte centrosomes. hts mutations completely eliminated fusomes, causing abnormal cysts containing a reduced number of cells to form. Our results imply that Drosophila fusomes are required for ovarian cyst formation and suggest that membrane skeletal proteins regulate cystocyte divisions.


Epstein Barr virus binding induces internalization of the C3d receptor: a novel immunotoxin delivery system.
Epstein Barr virus (EBV) infection of human B lymphocytes is initiated by selective binding of the virus to the C3d receptor (EBV/C3d receptor) on the cell surface and results in polyclonal proliferation of infected cells. In these studies we examined the fate of the EBV/C3d receptor during viral infection by using an immunotoxin made from a monoclonal antibody (HB5) reactive with the receptor and the potent toxin, gelonin. Binding of the HB5-gelonin conjugate to the EBV/C3d receptor before EBV infection (at concentrations as low as 10(-11) M) significantly inhibited the subsequent polyclonal proliferation of virus-infected B lymphocytes. HB5 antibody and gelonin alone did not inhibit proliferation. Because internalization of gelonin-antibody conjugates is required to cause cytotoxicity, these results indicate that infection of B lymphocytes with EBV selectively induced endocytosis of the EBV/C3d receptor with concomitant internalization of the immunotoxin. Proliferation of B lymphocytes that were activated by prior infection with EBV, or activated by cross-linking of their surface immunoglobulin molecules, was not inhibited by the antibody-toxin conjugate even at concentrations as high as 10(-7) M. Also, the growth of B lymphoblastoid cell lines cultured in the presence or absence of infectious EBV was not inhibited by HB5-gelonin. Thus, our results suggest that the EBV/C3d receptor is internalized only during the infection of normal B lymphocytes by EBV, with co-internalization of immunotoxin, and indicate that internalization of the EBV/C3d receptor-immunotoxin complex does not occur simply as a consequence of activation and proliferation of B lymphocytes. The use of a ligand to induce endocytosis of its receptor offers a new strategy for the selective delivery of immunotoxins to cells and may be more generally applicable.