Histone deacetylase co-repressor complex control of Runx2 and bone formation.
A decade has passed since the transcription factor, Runx2, was found to be essential for osteoblast development and chondrocyte hypertrophy. During the last 10 years, our understanding of Runx2's physiological roles and the molecular mechanisms whereby it regulates gene expression to control cell-cycle progression and cellular differentiation has increased exponentially. Runx2 is expressed in osteoblasts, prehypertrophic chondrocytes, mesenchymal cells of the perichondrium, T lymphocytes, endothelial cells, and breast and prostate epithelial cells, with increased expression observed in breast and prostate carcinomas. Although Runx2 and other mammalian Runt domain proteins were originally described as transcriptional activators, they are also transcriptional repressors and thus maintain functional similarities with their Drosophila homolog, Runt. Runx2 binds a consensus DNA sequence but does not possess any enzymatic activities that directly affect chromatin structure. It alters gene expression by recruiting cofactors to gene regulatory elements. Histone deacetylases (HDACs) are among the co-repressors that interact with Runx2. In this review, we summarize data demonstrating that several HDACs and their associated proteins interact with Runx2, regulate its activity, and affect bone formation. HDACs are components of multiprotein complexes that interact with many transcription factors and are subject to regulation by extracellular signals. The elucidation of HDAC complex components that influence Runx2 activity in specific cell types and in response to various extracellular stimuli will increase our understanding of how this crucial transcription factor functions, and how we might be able to control its activity to influence bone formation or reduce bone disease associated with cancer metastasis.


Women's reproductive health and depression: a community survey in the Gambia, West Africa.
Depression is the commonest mental illness in developing countries and impoverished women are most at risk. Formal mental health services in these situations are rare. Depression commonly co-presents with physical symptoms or else is unspectacular, so the condition often goes unrecognised. To strengthen the prevention and management of depression, information is required on easily recognisable correlates of depression. This study explored associations between depression and reproductive health conditions in rural African women of reproductive age. A community-based reproductive health survey among rural women aged 15-54 years in The Gambia, West Africa, included screening with a modified Edinburgh Depression Scale (EDS), a reproductive health questionnaire and a gynaecological examination. Depression was then assessed clinically and data for 565 women were used to estimate the prevalence of depression and examine associations with reproductive health conditions and demographic factors. The weighted prevalence of depression was 10.3% (95% CI 8.3-12.7). Being depressed was most significantly associated with widowhood or divorce (adjusted Odds Ratio (aOR) 8.42, 2.77-25.57), infertility (3.69, 1.42-9.65) and severe menstrual pain (3.94, 1.52-10.27). There were significant differences between ethnic groups. Being in the postpartum period was not associated with an increased likelihood of depression. This study points to the importance of reproductive potential and reproductive health in maintaining women's mental well-being across different strata of a rural and resource-poor society. It could provide an initial focus for the management of women with depression as well as directing future research in reproductive health and psychiatry.


Induction of anagen in telogen mouse skin by topical application of FK506, a potent immunosuppressant.
The effect of topical application of FK506 on the normal hair cycle of C57BL/6J mice was investigated. When telogen mice (7 weeks of age) were treated topically with 1 mumol FK506 on days 0 and 3, 50% of the tested mice entered anagen by day 9 and 100% by day 16. With 0.1 mumol of FK506, 50% of the tested mice entered anagen by day 13 and 80% by day 19, indicating that the effect of FK506 is dose dependent. In control mice, a spontaneous shift from telogen to anagen started on day 14, and 30% of the control animals were in anagen at day 19. Histologic studies revealed that FK506 markedly stimulated the skin and thickened it. The depth and size of hair follicles were also markedly increased in FK506-treated skin compared to control skin. The data on hair growth also support the contention that FK506 induces early onset of anagen and stimulates hair growth. The hair growth stimulated by FK506 looked normal and the hairs were of normal length. The hair growth was restricted to the site of application. These results clearly demonstrate that topical application of FK506 induces anagen hair growth in telogen mouse skin and indicate that the hair-growth-stimulating effect of FK506 is due at least in part to its promoting effect on the hair cycle.


The Critical Periphery in the Growth of Social Protests.
Social media have provided instrumental means of communication in many recent political protests. The efficiency of online networks in disseminating timely information has been praised by many commentators; at the same time, users are often derided as "slacktivists" because of the shallow commitment involved in clicking a forwarding button. Here we consider the role of these peripheral online participants, the immense majority of users who surround the small epicenter of protests, representing layers of diminishing online activity around the committed minority. We analyze three datasets tracking protest communication in different languages and political contexts through the social media platform Twitter and employ a network decomposition technique to examine their hierarchical structure. We provide consistent evidence that peripheral participants are critical in increasing the reach of protest messages and generating online content at levels that are comparable to core participants. Although committed minorities may constitute the heart of protest movements, our results suggest that their success in maximizing the number of online citizens exposed to protest messages depends, at least in part, on activating the critical periphery. Peripheral users are less active on a per capita basis, but their power lies in their numbers: their aggregate contribution to the spread of protest messages is comparable in magnitude to that of core participants. An analysis of two other datasets unrelated to mass protests strengthens our interpretation that core-periphery dynamics are characteristically important in the context of collective action events. Theoretical models of diffusion in social networks would benefit from increased attention to the role of peripheral nodes in the propagation of information and behavior.


Rotation recovery from spherical images without correspondences.
This paper addresses the problem of rotation estimation directly from images defined on the sphere and without correspondence. The method is particularly useful for the alignment of large rotations and has potential impact on 3D shape alignment. The foundation of the method lies in the fact that the spherical harmonic coefficients undergo a unitary mapping when the original image is rotated. The correlation between two images is a function of rotations and we show that it has an SO(3)-Fourier transform equal to the pointwise product of spherical harmonic coefficients of the original images. The resolution of the rotation space depends on the bandwidth we choose for the harmonic expansion and the rotation estimate is found through a direct search in this 3D discretized space. A refinement of the rotation estimate can be obtained from the conservation of harmonic coefficients in the rotational shift theorem. A novel decoupling of the shift theorem with respect to the Euler angles is presented and exploited in an iterative scheme to refine the initial rotation estimates. Experiments show the suitability of the method for large rotations and the dependence of the method on bandwidth and the choice of the spherical harmonic coefficients.


Evolutionary swarm neural network game engine for Capture Go.
Evaluation of the current board position is critical in computer game engines. In sufficiently complex games, such a task is too difficult for a traditional brute force search to accomplish, even when combined with expert knowledge bases. This motivates the investigation of alternatives. This paper investigates the combination of neural networks, particle swarm optimization (PSO), and evolutionary algorithms (EAs) to train a board evaluator from zero knowledge. By enhancing the survivors of an EA with PSO, the hybrid algorithm successfully trains the high-dimensional neural networks to provide an evaluation of the game board through self-play. Experimental results, on the benchmark game of Capture Go, demonstrate that the hybrid algorithm can be more powerful than its individual parts, with the system playing against EA and PSO trained game engines. Also, the winning results of tournaments against a Hill-Climbing trained game engine confirm that the improvement comes from the hybrid algorithm itself. The hybrid game engine is also demonstrated against a hand-coded defensive player and a web player.


Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency.
Interferon-gamma receptor-1 (IFNgammaR1) deficiency is a rare inherited immunodeficiency. We performed a nonmyeloablative allogeneic stem cell transplantation on a boy with complete IFNgammaR1 deficiency and refractory disseminated Myco- bacterium avium infection. Despite the patient's profound immune defect, early donor stem cell engraftment was low. Full donor engraftment was accomplished only following multiple donor lymphocyte infusions. Detection of IFNgammaR1 expression on peripheral blood monocytes and neutrophils corresponded with establishment of stable, complete donor hematopoietic chimerism. However, expression of, and signaling through IFNgammaR1 disappeared shortly thereafter. Disseminated Mycobacterium avium infection persisted and the patient died. Coculture of Myco- bacterium avium with normal myeloid cells resulted in an IFNgamma signaling defect similar to that observed in vivo. Active disseminated Mycobacterium avium infection may significantly compromise normal immune reconstitution following allogeneic stem cell transplantation. Patients with IFNgammaR1 deficiency should receive transplants before developing refractory mycobacterial infections.


Long- versus Short-Range Scattering in Doped Epitaxial Graphene.
Tuning the electronic properties of graphene by adatom deposition unavoidably introduces disorder into the system, which directly affects the single-particle excitations and electrodynamics. Using angle-resolved photoemission spectroscopy (ARPES) we trace the evolution of disorder in graphene by thallium adatom deposition and probe its effect on the electronic structure. We show that the signatures of quasiparticle scattering in the photoemission spectral function can be used to identify thallium adatoms, although charged, as efficient short-range scattering centers. Employing a self-energy model for short-range scattering, we are able to extract a δ-like scattering potential δ = -3.2 ± 1 eV. Therefore, isolated charged scattering centers do not necessarily act just as good long-range (Coulomb) scatterers but can also act as efficient short-range (δ-like) scatterers; in the case of thallium, this happens with almost equal contributions from both mechanisms.


Interpenetrating fibrin-alginate matrices for in vitro ovarian follicle development.
In this report, we investigate the fibrin-alginate interpenetrating network (FA-IPN) to provide dynamic cell-responsive mechanical properties, which we apply to the in vitro growth of ovarian follicles. The mechanical properties and polymerization rate of the gels were investigated by rheology, and the fiber structure was imaged by electron microscopy. Using a mouse model, two-layered secondary follicles were encapsulated in FA-IPNs, and growth, morphology, hormone production, fibrin degradation rate and the numbers of competent eggs were assessed. The initial mechanics of the FA-IPN are determined by the composite material, and subsequent degradation of fibrin by the encapsulated cells would produce a material with mechanical properties due to the alginate alone. The rate of meiotically competent oocytes produced by culture in FA-IPN was 82%, which was significantly greater than in alginate alone. This increase in oocyte quality is an important step in identifying 3D culture systems that can provide a fundamental tool to investigate follicle maturation, and may be applied to promote the growth of human follicles, which can be used to provide reproductive options for women facing a cancer diagnosis.


Current perspectives on pediatric inflammatory bowel disease focusing on transitional care management. What should we consider?
The prevalence of inflammatory bowel disease (IBD) continues to rise around the globe. Although the percentage of pediatric IBD patients seems to be increasing, rates are surprisingly heterogeneous among different populations. Although the pathogenesis of IBD is believed to be multifactorial, a genetic predisposition may be especially relevant in pediatric-onset IBD. Phenotypic characteristics can also be significantly different when comparing pediatric and adult-onset IBD. Patients that develop the disease at a younger age usually present with more extensive and more aggressive disease and develop complications faster when compared to those that develop it during adulthood. Children with IBD are found to have frequent mood disorders and have a higher risk of developing socio-economic hardship, failing to meet development milestones. Therefore, IBD management should always involve a multidisciplinary team that is not limited to medical providers. Most institutions do not have an established transition protocol and lack the resources and training for transition care. Although there is no consensus on an optimal timing to transition the patient's care to an adult team, it is usually accepted they should be eligible for adult care when most of the key transition points have been met. Management strategies should be tailored to each patient's developmental level and environment. A successful transition can improve the long-term outcomes such as sustained remission, medication adherence, mental health and social and academic performance, while decreasing healthcare utilization. Every institution that manages pediatric IBD patients should have a well-established transition protocol in order to make sure to maintain continuity of care.


The Search for Causative Environmental Factors in Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) has become a 'prototype disease' for chronic auto-inflammatory disorders with a polygenic background and important multifaceted environmental trigger components. The environmental factors contribute both to pathogenesis and disease flares. Thus, IBD is a disease par excellence to study the interactions between host genetics, environmental factors (such as infections or smoking) and 'in-vironmental' factors - for example, our intestinal microbiota. Longitudinal intercurrent events, including the impact of long-term medication on disease progression or stabilization, can exemplarily be studied in this disease group. Whilst alterations in the human genome coding relevant variant protein products have most likely not emerged significantly over the last 50 years, the incidence of Crohn's disease and ulcerative colitis has dramatically increased in Western countries and more recently in the Asia Pacific area. An interesting concept indicates that 'Western lifestyle factors' trigger chronic intestinal inflammation or disease flares in a genetically susceptible host. To understand the disease pathogenesis as well as triggers for flares or determinants of disease courses, we must further investigate potential en(in)vironmental factors. As environmental conditions, in contrast to genetic risk factors, can be influenced, knowledge on those risk factors becomes crucial to modulate disease incidence, disease course or clinical presentation. It is obvious that prevention of environmentally triggered disease flares would be a goal most relevant for IBD patients. An increased prevalence of IBD in urban environment has been documented in Switzerland by the Swiss IBD cohort study. Several studies have attempted to identify such factors; however, only a few have been validated. The best investigated environmental factor identified in IBD cohort analyses is smoking. Other environmental factors that have been associated with clinical presentation or risk of inflammatory flares as well as increased incidence are diet and food additives. The so-called 'hygiene hypothesis' suggests that increased hygiene in childhood associated with reduced exposure to pathogens may leave the mucosal immune system insufficiently trained and thus prone to uncontrolled inflammation. Oral contraceptives and non-steroidal anti-inflammatory drugs are the 2 main classes of frequently taken drugs that have been attributed to have the potential to cause flares of the disease. What is likely to be the connection between the genetic susceptibility and the environmental triggers? There is broad evidence for a critical role of the commensal enteric microbiota as a modulator of immunologic responses relevant during onset and chronification of IBD.


Hydrogen sulfide in the pathogenesis of atherosclerosis and its therapeutic potential.
Hydrogen sulfide (H(2)S) was the third gaseous transmitter to be discovered, along with nitric oxide and carbon monoxide, and has been proposed to be involved in numerous physiological processes and pathology of various diseases. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, including atherosclerosis. Atherosclerosis is characterized by multiple key events including endothelial dysfunction, monocyte infiltration and their differentiation into macrophages, conversion of lesion-resident macrophages into foam cells, and smooth muscle cell proliferation. Increasing evidence has indicated that H(2)S plays a potentially significant role in all of these biological processes and that malfunction of H(2)S homeostasis may contribute to the pathogenesis of atherosclerosis. Experiments have demonstrated that H(2)S supplementation ameliorated many of these atherogenic processes and hence, such supplementation potentially may prove to be of therapeutic benefit in the prevention or treatment of atherosclerosis. H(2)S levels may be induced by the administration of H(2)S or H(2)S donors, or alternatively be reduced by the administration of specific cystathionine β-synthase or cystathionine γ-lyase inhibitors. However, issues remain with the potential use of currently available H(2)S-modulating agents in a clinical setting. This review will provide a description of the current literature on the involvement of H(2)S in these key aspects of vascular biology that contribute to the development of atherosclerosis, as well as the therapeutic potential of currently available H(2)S-modulating agents.


Patient Portal Adoption Rates: A Systematic Literature Review and Meta-Analysis.
Despite the increasing availability of online patient portals that provide access to electronic health records, little is known about their adoption by patients. We systematically reviewed the literature to investigate adoption of patient portals across studies. We searched MEDLINE and Scopus to identify relevant papers. We included 40 studies: 24 were controlled experiments, with prospective data collection in an actively recruited population; 16 were real-world experiments, with adoption being evaluated retrospectively after system deployment in clinical practice. Our meta-analysis showed an overall mean adoption rate of 52% (95% Confidence Interval [CI], 42 to 62%). Rates differed markedly between study types: controlled experiments yielded a mean adoption rate of 71% (95% CI 64 to 79%), compared to 23% (95% CI, 13 to 33%) in real-world experiments. This difference was confirmed in a meta-regression analysis of the influence of study characteristics on adoption rates. Our findings suggest that adoption rates reported in controlled studies do not reflect those in everyday clinical practice. Until we understand how to effectively increase adoption, patient portals are unlikely to consistently lead to improvements in care processes and health outcomes.


Fluorescence lifetime system for microscopy and multiwell plate imaging with a blue picosecond diode laser.
We report a wide-field fluorescence lifetime imaging (FLIM) system that uses a blue picosecond pulsed diode laser as the excitation source. This represents a significant miniaturization and simplification compared with other time-domain FLIM instruments that should accelerate the development of clinical and real-world applications of FLIM. We have demonstrated this instrument in two configurations: a macroimaging setup applied to multiwell plate assays of chemically and biologically interesting fluorophores and a microscope system that has been applied to imaging of tissue sections. The importance of the adjustable repetition rate of this laser source is discussed with respect to noise reduction and precision in the lifetime determination, illustrating a further significant advantage over conventional mode-locked solid-state lasers.


Immunocytochemical and morphological evidence for the origin of N-nitrosomethylurea-induced and naturally occurring primary lung tumors in F344/NCr rats.
Naturally occurring and N-nitrosomethylurea-induced lung tumors were studied in male F344/NCr rats by sequential histological, electron microscopic, and immunohistochemical methods. Rats were given one injection at 6 weeks of age of N-nitrosomethylurea at a dosage level of 41.2 mg/kg body weight i.v. Groups of rats were sacrificed at 20, 33, and 52 weeks, while some were sacrificed while moribund. Nine lung tumors from aged F344/NCr male rats were also studied. For determining localization of pulmonary antigens, sections of lungs were stained by the avidin-biotin-peroxidase complex immunocytochemical technique using antibodies to rat surfactant apoprotein or rat Clara cell antigen. At 20 weeks, in rats receiving N-nitrosomethylurea, focal alveolar type II cell hyperplasia, adenoma in focal alveolar type II cell hyperplasia, and adenoma were found in 15 (100%), 1 (7%), and 2 (13%) of 15 rats, respectively. At 33 weeks, there were 19 rats (95%) with focal alveolar type II cell hyperplasias, 10 rats (50%) with adenoma in focal alveolar type II cell hyperplasia, and 2 rats (10%) with adenomas in 20 rats. In 53 rats allowed to live up to 52 weeks, there were 10 (19%) adenomas and 3 (6%) carcinomas, as well as 49 (92%) rats with focal hyperplasia and 31 (58%) with adenomas in focal type II cell hyperplasia. Rat surfactant apoprotein was found in the cytoplasm of normal alveolar type II cells and the majority of cells in focal alveolar type II cell hyperplasias, adenomas in hyperplastic lesions, adenomas, and carcinomas. The ultrastructure of these lesions supported immunocytochemical findings with evidence of lamellar bodies. All nine naturally occurring lung tumors studied contained rat surfactant apoprotein. Rat Clara cell antigen was found, however, only focally within one adenoma induced by N-nitrosomethylurea and one adenoma in a hyperplastic lesion, and also focally in three neoplasms which occurred naturally. This study provided morphological, immunohistochemical, and ultrastructural evidence that the vast majority of N-nitrosomethylurea-induced and naturally occurring pulmonary neoplasms of F344 rats are alveolar type II cell adenomas and carcinomas and that a portion of these tumors arise within focal alveolar type II cell hyperplasias.


[Race and the use of dental health services by the elderly].
We analyze if race can be considered a limiting factor in the use of dental services by the elderly. This study is of an analytical nature, with the use of secondary data collected by the National Survey of Oral Health in 2003. Those examined who declared themselves as being white, brown or black in the 65 to 74-year-old age bracket were included. The sample was composed of 5,108 elderly people: 2,575 whites and 2,533 blacks. Of the whites, 3.8% stated that they had never been to the dentist, while this figure was 7.8% for the blacks. Even after the adjustment for interception for prosthetics and dental pain, the chance of elderly blacks not having used dental services at least once in their life is 0.62 OR less than for elderly whites. Of those who used the services, 21.2% of the elderly whites visited the dentist in the last year, while for elderly blacks the figure was 14.2%, in the adjusted model for interception for prosthetics and dental pain the OR was 0.60. All the relations were statistically significant (p<0,001). Race is a limiting factor in the use of dental services by the elderly and even after the adjustments the elderly blacks continue to manifest greater resistance to the use of oral health services.


Subtelomeric assembly of a multi-gene pathway for antimicrobial defense compounds in cereals.
Non-random gene organization in eukaryotes plays a significant role in genome evolution. Here, we investigate the origin of a biosynthetic gene cluster for production of defence compounds in oat-the avenacin cluster. We elucidate the structure and organisation of this 12-gene cluster, characterise the last two missing pathway steps, and reconstitute the entire pathway in tobacco by transient expression. We show that the cluster has formed de novo since the divergence of oats in a subtelomeric region of the genome that lacks homology with other grasses, and that gene order is approximately colinear with the biosynthetic pathway. We speculate that the positioning of the late pathway genes furthest away from the telomere may mitigate against a 'self-poisoning' scenario in which toxic intermediates accumulate as a result of telomeric gene deletions. Our investigations reveal a striking example of adaptive evolution underpinned by remarkable genome plasticity.


Risk of dementia in older breast cancer survivors: a population-based cohort study of the association with adjuvant chemotherapy.
To assess whether there is an association between delivery of adjuvant chemotherapy to older women with breast cancer and development of dementia over time. Retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) data linked to Medicare claims data. Women residing in geographic areas included in the SEER registry. Women aged 66 to 80 diagnosed with non-metastatic invasive breast cancer from 1992 to 1999 were included. It was determined whether patients had undergone chemotherapy within 6 months of diagnosis. Whether women developed dementia over time was determined using diagnostic codes. The effect of adjuvant chemotherapy on development of dementia was evaluated, adjusting for confounders using a proportional hazards model stratified for age. Twenty-one thousand three hundred sixty-two women met selection criteria; 2,913 received chemotherapy, and 18,449 did not. Women who received chemotherapy were younger than those who did not (median aged 70 vs 73; P<.001). Median follow-up time was 59 months. After controlling for other factors, it was found that chemotherapy was not associated with a greater risk of development of dementia over time for any age group (hazard ratio for dementia in women receiving chemotherapy: aged 66-70=0.83, 95% confidence interval (CI)=0.48-1.45, P=.5; aged 71-75=0.74, 95% CI=0.46-1.18, P=.2; aged 76-80=0.49, 95% CI=0.28-0.88, P=.02). Receipt of chemotherapy in older women with breast cancer was not associated with a greater risk of dementia diagnosis over time; very elderly women who undergo chemotherapy may be at lower baseline risk. The use of a claims-based definition of dementia limited the study.


Analysis of prescriptions dispensed at community pharmacies in Nablus, Palestine.
We investigated the prescription quality and prescribing trends of private clinicians in Nablus governorate, Palestine. A total of 363 prescriptions were collected from a random sample of 36 community pharmacies over a study period of 288 working hours. Data regarding elements in the prescription and the types of drugs prescribed were analysed. Physician-related variables were mostly noted, however, patient's address and weight were absent in all prescriptions and less than half included age and sex. Information regarding strength of the medications prescribed was missing in over 70% of prescriptions. Other drug-related variables like frequency and instruction of use were present in over 80% of prescriptions. Antimicrobial agents were the most commonly prescribed followed by NSAIDs/analgesics. Amoxicillin alone or in combination was the most commonly prescribed antimicrobial agents followed by cefuroxime. Prescription writing quality in Nablus is deficient in certain aspects and improvement is required.


Discrete roles of the Spc1 kinase and the Atf1 transcription factor in the UV response of Schizosaccharomyces pombe.
Exposure of mammalian cells to UV irradiation or alkylating agents leads to the activation of the c-Jun N-terminal kinase and p38 stress-activated protein kinase cascades, phosphorylation of c-Jun and ATF-2 bZIP transcription factors, and finally to selective induction of gene expression. This UV response is believed to be crucially important for cell survival, although conclusive evidence is lacking. Here, we address this issue by investigating a homologous UV response pathway in the fission yeast Schizosaccharomyces pombe. In fission yeast cells, UV irradiation induces activation of Spc1 stress-activated protein kinase, which in turn phosphorylates the Atf1 bZIP transcription factor. spc1 mutants are hypersensitive to killing by UV at a level equivalent to some checkpoint rad mutants. Whereas checkpoint rad mutants fail to arrest division in response to DNA damage, spc1 mutants are defective at resuming cell division after UV exposure. Levels of basal and UV-induced transcription of ctt1+, which encodes a catalase believed important for combating oxidative stress caused by UV, are extremely low in spc1 mutants. Atf1 is required for UV-induced transcription of ctt1+, but atf1 mutants are not hypersensitive to killing by UV. This surprising finding is explained by the observation that ctt1+ basal expression is unaffected in atf1 single mutant and spc1 atf1 double mutant cells, suggesting that unphosphorylated Atf1 represses ctt1+ expression in spc1 cells. In fact, the level of UV sensitivity of spc1 atf1 double mutant cells is intermediate between those of the wild type and spc1 mutants. These findings suggest the following. (i) Key properties of UV response mechanisms are remarkably similar in mammals and S. pombe. (ii) Activation of Spc1 kinase greatly enhances survival of UV-irradiated cells. (iii) Induction of gene expression by activation of Atf1 may not be the most important mechanism by which stress-activated kinases function in the UV response.


Graphene oxide-based micropatterns via high-throughput multiphoton-induced reduction and ablation.
In this study, a developed temporal focusing-based femtosecond laser system provides high-throughput multiphoton-induced reduction and ablation of graphene oxide (GO) films. Integrated with a digital micromirror device to locally control the laser pulse numbers, GO-based micropatterns can be quickly achieved instantly. Furthermore, the degree of reduction and ablation can be precisely adjusted via controlling the laser wavelength, power, and pulse number. Compared to point-by-point scanning laser direct writing, this approach offers a high-throughput and multiple-function approach to accomplish a large area of micro-scale patterns on GO films. The high-throughput micropatterning of GO via the temporal focusing-based femtosecond laser system fulfills the requirement of mass production for GO-based applications in microelectronic devices.


Knowledge Structures, Social Information Processing, and Children's Aggressive Behavior.
Although a multitude of factors may be involved in the development of children's violent behavior, the actual aggressive act is preceded by a decision-making process that serves as the proximal control mechanism. The primary goal of this longitudinal study was to understand the nature of this proximal control mechanism involved in children's aggressive acts by focusing on two aspects of social cognitions: social information processing and stored knowledge (i.e., internal knowledge structures that are the latent memories of past events). It was hypothesized that: (1) children with hostile knowledge structures will display more biased patterns of aggressive social information processing than children whose knowledge structures are less hostile and negative; (2) children who display hostile knowledge structures will behave in chronically aggressive ways; and (3) the development of hostile knowledge structures and hostile patterns of social information processing contribute to the stability of aggressive behavior and thus partially mediate the relation between early and later aggressive behavior. 585 boys and girls (19% African-American) were followed from kindergarten through eighth grade. Results from this investigation support the hypotheses and are discussed in terms of the significance of the inclusion of knowledge structures in our theories of the mental processes involved in children's violent behaviour.


Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder.
Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. We sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. This report analyzed 1180 children enrolled at birth and followed prospectively as part of the Boston Birth Cohort, including 188 with ADHD diagnosis based on electronic medical record review. Maternal biomarkers of acetaminophen intake were measured in plasma samples obtained within 1⁻3 days postpartum. Odds ratios for having ADHD diagnosis or other developmental disorders were estimated using multinomial logistic regression models, adjusting for pertinent covariables. Compared to neurotypical children, we observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose⁻responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. In the stratified analyses, differential point estimates of the associations were observed across some strata of covariates. However, these differences were not statistically significant. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring. Additional clinical and mechanistic investigations are warranted.


Thermal comfort properties of cotton and nonwoven surgical gowns with dual functional finish.
The purpose of this study was to evaluate thermal comfort properties of surgical gowns made of dual functional finish cotton and nonwoven fabrics which have barrier properties of blood and micro-organism. Four types of surgical gowns, which were made of nonwoven fabrics with finish or without and were made of cotton with finish or without, were tested. The thermal insulations of four surgical gowns were measured with thermal manikin. Subjective experiments on thermal comfort, skin temperature and clothing microclimate were conducted. Six male subjects, between 26 and 28 years age old, participated in the wear trials tests. Typical activities for surgeons in the operation theater were simulated during the experimental sessions. Air temperature in a climate chamber was kept at 22 degrees C and its humidity was 60% RH. Air velocity was controlled at less than 0.15 m/s. Inner radiant temperature was almost equal to the air temperature. Basic thermal insulation of the dual functional finished nonwoven surgical gown was 0.87 clo, which was slightly higher than that of untreated (0.84 clo). However, the skin temperature of the subject wearing a dual functional finished surgical gown was significantly lower at P < .05. When the subject wears the dual functional finished gown, the amount of sweating was less than that when wearing untreated. Microclimate temperature and humidity of dual functional finished surgical gown were lower than untreated and it was statistically significant. There was no significant difference in subjective humid and overall comfort sensation between finished and untreated ones. Thermal sensation of dual functional finished one was significantly different from untreated one only during the first exercise. The results of this study indicate that the dual functional finish surgical gown allowed heat to be transferred from the skin of subject to the atmosphere better than untreated. The nonwoven surgical gown showed no difference in comfort properties from cotton one.


CRISPR/Cas9-Mediated Insertion of loxP Sites in the Mouse Dock7 Gene Provides an Effective Alternative to Use of Targeted Embryonic Stem Cells.
Targeted gene mutation in the mouse is a primary strategy to understand gene function and relation to phenotype. The Knockout Mouse Project (KOMP) had an initial goal to develop a public resource of mouse embryonic stem (ES) cell clones that carry null mutations in all genes. Indeed, many useful novel mouse models have been generated from publically accessible targeted mouse ES cell lines. However, there are limitations, including incorrect targeting or cassette structure, and difficulties with germline transmission of the allele from chimeric mice. In our experience, using a small sample of targeted ES cell clones, we were successful ∼50% of the time in generating germline transmission of a correctly targeted allele. With the advent of CRISPR/Cas9 as a mouse genome modification tool, we assessed the efficiency of creating a conditional targeted allele in one gene, dedicator of cytokinesis 7 (Dock7), for which we were unsuccessful in generating a null allele using a KOMP targeted ES cell clone. The strategy was to insert loxP sites to flank either exons 3 and 4, or exons 3 through 7. By coinjecting Cas9 mRNA, validated sgRNAs, and oligonucleotide donors into fertilized eggs from C57BL/6J mice, we obtained a variety of alleles, including mice homozygous for the null alleles mediated by nonhomologous end joining, alleles with one of the two desired loxP sites, and correctly targeted alleles with both loxP sites. We also found frequent mutations in the inserted loxP sequence, which is partly attributable to the heterogeneity in the original oligonucleotide preparation.


A Screening Approach to Identify Clinically Actionable Variants Causing Congenital Heart Disease in Exome Data.
Congenital heart disease (CHD)-structural abnormalities of the heart that arise during embryonic development-is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD. Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. In 3 families (10%), we found pathogenic variants in known CHD genes TBX5, TFAP2B, and PTPN11, explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in PBX1, CNOT1, ZFP36L2, TEK, USP34, UPF2, KDM5A, KMT2C, TIE1, TEAD2, and FLT4. The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.


Characterization of bonds formed between platelet factor 4 and negatively charged drugs using single molecule force spectroscopy.
Immunogenicity (i.e., the ability to initiate immune reactions) is one of the major challenges for the development of new drugs, as it may turn the developed drug therapeutically ineffective or cause severe immune-related effects. Using single molecule force spectroscopy, we study rupture forces between the positively charged, endogenous protein platelet factor 4 (PF4; also known as CXC chemokine ligand 4, CXCL4) and the antithrombotic drug heparin and other negatively charged glycosaminoglycans (GAGs), which are known to form immunogenic PF4/GAG-complexes (e.g., heparin and dextran sulfate) as well as non-immunogenic complexes (e.g., chondroitin sulfate A). Our measurements suggest that the average number of sulfate groups per monosaccharide unit (i.e., the degree of sulfation DS) does not affect the unbinding characteristics of single PF4/GAG-bonds (reaction coordinate x0 = 2.2 ± 0.2 Å, energy barrier ΔG ≈ -1 kBT). However, the average number of GAG bonds formed to a single PF4 molecule increases with increasing DS as indicated by a rising frequency of unbinding events, suggesting a multivalent binding scheme between PF4 and GAGs. Our studies show that at least three GAG bonds have to be formed to each PF4 molecule to induce epitope formation on the PF4/GAG-complex to which PF4/GAG-complex specific antibodies bind. Hence, GAG-based drugs that form less than three bonds per PF4 molecule are unlikely to constitute PF4/drug-complexes that are of immunologic relevance.


Celiac disease and autoimmune pancreatitis: an uncommon association. A case report.
We present the clinical scenario of acute abdominal pain in a 27-year-old man with recent-onset type 1 diabetes mellitus. Evaluation of the patient revealed elevated levels of serum amylase, lipase, and transaminase without any biliary obstruction. He had elevated serum IgG4 levels, and his computed tomography scan showed features consistent with autoimmune pancreatitis. Further evaluation revealed celiac disease. He was treated as a patient with autoimmune pancreatitis and was started on steroids in addition to a gluten-free diet. His liver function improved in 6 weeks. He gained weight and his glycemic control also improved. Magnetic resonance cholangiopancreatography after 3 months revealed complete resolution of pancreatic enlargement. The patient is being followed up in our clinic since the past 3 years. To the best of our knowledge and according to the Medline search, this is the first case report of celiac disease as an association of autoimmune pancreatitis.


Ramadan Fasting and Patients with Cancer: State-of-the-Art and Future Prospects.
Ramadan fasting represents one of the five pillars of the Islam creed. Even though some subjects (among which patients) are exempted from observing this religious duty, they may be eager to share this particular moment of the year with their family and peers. However, there are no guidelines or standardized protocols that can help physicians to properly address the issue of patients with cancer fasting in Ramadan and correctly advising them. Moreover, in a more interconnected and globalized society, in which more and more Muslim patients live in the Western countries, this topic is of high interest also for the general practitioner. For this purpose, we carried out a systematic review on the subject. Our main findings are that (1) very few studies have been carried out, addressing this issue, (2) evidence concerning quality of life and compliance to treatment is contrasting and scarce, and (3) generally speaking, few patients ask their physicians whether they can safely fast or not. For these reasons, further research should be performed, given the relevance and importance of this topic.


Cytosine arabinoside kills postmitotic neurons in a fashion resembling trophic factor deprivation: evidence that a deoxycytidine-dependent process may be required for nerve growth factor signal transduction.
Cytosine arabinoside (AraC) is a pyrimidine antimetabolite that kills proliferating cells by inhibiting DNA synthesis. In this paper we report that AraC kills postmitotic rat sympathetic neurons in a fashion similar to the neuronal death that follows nerve growth factor (NGF) deprivation. Postmitotic rat sympathetic neurons were cultured for 1 week in the presence of NGF and then treated with AraC, still in the presence of NGF. AraC killed neurons after 4 d with an EC50 of 50 microns. The morphological and temporal characteristics of neuronal death that began around 3 d after addition of AraC were indistinguishable from those observed beginning 24 hr after NGF deprivation. Death caused by AraC was prevented by the same agents that prevent the death of NGF-deprived neurons, which included inhibitors of RNA and protein synthesis, a cAMP analog, and depolarizing concentrations of KCl. In contrast, neuronal death caused by ultraviolet irradiation, ricin toxin, and a variety of other toxic insults did not share these morphological, biochemical, or temporal characteristics. Other antimitotic drugs, including adenine arabinoside, thymine arabinoside, fluorodeoxyuridine, hydroxyurea, and aphidicolin, did not kill neurons. AraC caused neurons to behave as if deprived of NGF by interfering with deoxycytidine (dC) metabolism distinct from DNA biosynthesis. dC entirely prevented the neurotoxicity of AraC, even when present at a concentration 1000-fold less than that of AraC. Other deoxynucleosides, and cytidine, did not prevent AraC neurotoxicity. dC could not, however, substitute for NGF and thus is unlikely to be a direct mediator of NGF action. It is hypothesized that dC may participate in a pathway, distinct from DNA synthesis, that is necessary for neurons to respond to exogenous trophic factors.


Binding a heparin derived disaccharide to defensin inspired peptides: insights to antimicrobial inhibition from gas-phase measurements.
Due to the ubiquitous presence of polysaccharide moieties on bacterial surfaces, it is hypothesised that a peptide-saccharide interaction plays a key role during the recognition of invading microorganisms by beta-defensins. We have employed different gas-phase methods to investigate these interactions. This manuscript describes: an MS-based titration assay measuring the gas-phase binding of ten beta-defensin related peptides to a sulfated disaccharide derived from heparin (HDD); ion mobility-mass spectrometry-determined collision cross sections of 3 peptides (both free and binding HDD); and results from molecular modelling with the aim of reconciling some of our experimental observations. We observe a clear qualitative correlation between the antimicrobial activity of several beta-defensins and related peptides and their gas-phase binding to a heparin-derived disaccharide (HDD). Four of the ten peptides show >100 micromolar K(d) values with HDD, and no bacteriocidal activity, illustrating that HDD binding correlates with peptide antimicrobial activity. For five of the remaining six peptides, bacteriocidal activity was re-measured with HDD present. For the peptides containing intramolecular disulfide bonds in two out of five, bacteriocidal activity was reduced approximately 10-fold; for the remaining three peptides, which lack intramolecular disulfide bonds, HDD addition had little effect on bacteriocidal activity. The latter results are suggested to arise from the greater degree of flexibility imparted by the removal of disulfide bonds giving the peptides the ability to envelope HDD and assume a "defensin-like" fold. Thus gas-phase analysis is put forward as a powerful tool for assessing the properties of antimicrobial peptides providing valuable insights in the mechanism of antimicrobial inhibition.


Pitch discrimination learning: specificity for pitch and harmonic resolvability, and electrophysiological correlates.
Multiple-hour training on a pitch discrimination task dramatically decreases the threshold for detecting a pitch difference between two harmonic complexes. Here, we investigated the specificity of this perceptual learning with respect to the pitch and the resolvability of the trained harmonic complex, as well as its cortical electrophysiological correlates. We trained 24 participants for 12 h on a pitch discrimination task using one of four different harmonic complexes. The complexes differed in pitch and/or spectral resolvability of their components by the cochlea, but were filtered into the same spectral region. Cortical-evoked potentials and a behavioral measure of pitch discrimination were assessed before and after training for all the four complexes. The change in these measures was compared to that of two control groups: one trained on a level discrimination task and one without any training. The behavioral results showed that learning was partly specific to both pitch and resolvability. Training with a resolved-harmonic complex improved pitch discrimination for resolved complexes more than training with an unresolved complex. However, we did not find evidence that training with an unresolved complex leads to specific learning for unresolved complexes. Training affected the P2 component of the cortical-evoked potentials, as well as a later component (250-400 ms). No significant changes were found on the mismatch negativity (MMN) component, although a separate experiment showed that this measure was sensitive to pitch changes equivalent to the pitch discriminability changes induced by training. This result suggests that pitch discrimination training affects processes not measured by the MMN, for example, processes higher in level or parallel to those involved in MMN generation.


Quality of life in schizophrenia: a multicenter, randomized, naturalistic, controlled trial comparing olanzapine to first-generation antipsychotics.
To assess the effectiveness of olanzapine for treating schizophrenia and to assess if olanzapine promotes a better quality of life than first-generation antipsychotics (FGAs). Multicenter, naturalistic, randomized controlled study, comparing olanzapine with FGAs, at hospitalization and during a 9-month follow-up. Outcome assessors were blind to the allocated drug. The dose of antipsychotic was determined by doctors according to their clinical practice routines. Data collection was performed from April 1999 to August 2001. 197 patients with DSM-IV-diagnosed schizophrenia were allocated to olanzapine (N = 104) and FGA (N = 93). Patients taking olanzapine showed greater improvements in Positive and Negative Syndrome Scale (PANSS) negative symptoms (mean difference = 2.3, 95% CI = 0.6 to 4.1) and general psychopathology (mean difference = 4.0, 95% CI = 0.8 to 7.2) sub-scales and fewer incidences of tardive dyskinesia (RR = 2.4, 95% CI = 1.4 to 4.2, p < .0001). Olanzapine was also associated with greater improvement in a number of health-related quality-of-life outcomes on the Medical Outcomes Study 36-item Short-Form Health Survey, including physical functioning (mean difference = 6.6, 95% CI = 1.2 to 11.9), physical role limitations (mean difference = 13.7, 95% CI = 3.0 to 24.3), and emotional role limitations (mean difference = 12.1, 95% CI = 0.7 to 23.5). Patients taking olanzapine gained significantly more weight during the trial than patients taking FGAs, with a correspondent endpoint increase in the body mass index (BMI) of 28.7 versus 25.3 (p < .001). Compared with FGAs, olanzapine has advantages in terms of improvements of negative symptoms and quality of life. It is also associated with fewer incidences of tardive dyskinesia and greater increases in weight and BMI. These findings are highlighted by the naturalistic approach adopted in this trial.


Dietary Patterns and Cognitive Decline: key features for prevention.
The decline in cognitive function is generally the result of the complex interaction of several factors. First of all, age, but also demographic, educational, genetic, socio-economic, and environmental determinants, including nutrition. Cognitive decline and dementia prevalence are increasing, and they are projected to continue increasing in the next decades due to the aging of the world population. Currently, there are no effective pharmacological treatments for these devastating and disabling conditions, which emphasize the key role of preventive strategies. There is compelling evidence of the role of diet and lifestyle on cognitive function. Therefore, dietary/ nutritional approaches that contribute to prevent, or slow cognitive decline may have a remarkable public health impact. Numerous studies have explored the role of dietary components and patterns on age-associated cognitive decline, with accruing evidence that combinations of foods and nutrients can have synergistic effects beyond those attributable to individual foods or nutrients. Dietary patterns show the strongest evidence for slowing the development of cognitive decline, Alzheimer's disease and other dementias including the Mediterranean diet, the Dietary Approaches to Stop Hypertension diet, and their combination (the MedDiet-DASH Intervention for Neurodegenerative Delay - MIND), among others with few positive results. There are also dietary patterns with no evidence of such effects. This review examines the evidence for the effects of some dietary patterns as neuroprotective with a potential to delay cognitive decline and the onset of dementia.


Investigating the impact of age-depended hair colour darkening during childhood on DNA-based hair colour prediction with the HIrisPlex system.
Predictive DNA analysis of externally visible characteristics exerts an increasing influence on contemporary forensic and anthropological investigations, with pigmentation traits currently being the most advanced for predictive modelling. Since pigmentation prediction error in some cases may be due to the result of age-related hair colour darkening, and sex influence in eye colour, this study aims to investigate these less explored phenomena on a group of juvenile individuals. Pigmentation phenotypes of children between the age of 6-13 years old were evaluated, in addition to data about their hair colour during early childhood from a select number of these individuals. The HIrisPlex models for DNA-based eye and hair colour prediction were used with input from SNP genotyping using massive parallel sequencing. Analysis of the total group of 476 children showed high accuracy in blue (AUC = 0.89) and brown (AUC = 0.91) eye colour prediction, while hair colour was predicted with AUC = 0.64 for blond, AUC = 0.64 for brown and AUC = 0.97 for red. 70.8% (n = 143) of the total number of children phenotypically blond for hair colour during early childhood progressed to brown during advanced childhood. In 70.6% (n = 101) of those cases, an incorrect blond hair prediction was made during the time of analysis. A noticeable decline in AUC values for blond (from 0.76 to 0.65) and brown (from 0.72 to 0.64) were observed when comparing hair colour prediction outcomes for the phenotypes recorded for the two different time points (at the age of 2-3 and 6-13). The number of incorrect blond hair colour predictions was significantly higher in children with brown hair at age 6-13 who were blond at early childhood (n = 47, 32.9%), relative to children who had brown hair at both time points (n = 6, 9.4%). However, in 28.0% (n = 40) of children who did experience hair colour darkening, HIrisPlex provided the correct prediction for the darkened hair colour phenotype, despite them being blond in early childhood. Our study implies that HIrisPlex can correctly predict adult hair colour in some individuals who experience age-related hair colour darkening during adolescence. However, in most instances prediction seems to default to the pre-adolescent hair colour for individuals with this phenomenon. In the future, the full adolescent age range in which hair colour darkening can occur should be considered in the study samples used for training hair colour prediction models to obtain a more complete picture of the phenomenon and its impact on DNA-based hair colour prediction in adults.


Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes.
To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults.


Cultural variation in early feeding pattern and maternal perceptions of infant growth.
The perception of healthy growth and weight may differ between cultures, which could influence feeding practises and consequently affect the development of overweight. The present study examined ethnic variation in maternal perceptions of growth and their influence on feeding practises among Turkish and Dutch infants aged 0-6 months. Data were obtained from the mothers of 143 Turkish and 143 Dutch healthy, singleton, term infants with birth weights appropriate for gestational age, using structured interviews at 1, 4 and 6 months after birth. Compared with Dutch mothers, mothers of Turkish descent perceived a chubby infant more often as pretty (43 v. 22%), and were more often worried about their infant's growth (13 v. 4%). Turkish mothers were more likely to give full breast-feeding (BF) until at least 6 months (adjusted OR (aOR) 2.1, 95% CI 1.0, 4.3) and to start introducing complementary feeding, including rice flour porridge, at the age of 6 months (aOR 2.4, 95% CI 1.1, 4.9). Infants of Turkish descent were fed on average one milk feeding more during the day and, if introduced to complementary foods before 6 months, were more often given uncommon types of foods (e.g., yogurt and cookies) (aOR 2.1, 95% CI 1.1, 4.3). The differences in perceptions affected differences in feeding practises only to a small extent. Preventive advice offered to Turkish mothers in Child Health Care should include discussing choices of complementary foods and frequency of feeding from an early age onwards. In Dutch mothers, support for the continuation of BF remains an important issue.


Detecting ultraviolet damage in single DNA molecules by atomic force microscopy.
We report detection and quantification of ultraviolet (UV) damage in DNA at a single molecule level by atomic force microscopy (AFM). By combining the supercoiled plasmid relaxation assay with AFM imaging, we find that high doses of medium wave ultraviolet (UVB) and short wave ultraviolet (UVC) light not only produce cyclobutane pyrimidine dimers (CPDs) as reported but also cause significant DNA degradation. Specifically, 12.5 kJ/m(2) of UVC and 165 kJ/m(2) of UVB directly relax 95% and 78% of pUC18 supercoiled plasmids, respectively. We also use a novel combination of the supercoiled plasmid assay with T4 Endonuclease V treatment of irradiated plasmids and AFM imaging of their relaxation to detect damage caused by low UVB doses, which on average produced approximately 0.5 CPD per single plasmid. We find that at very low UVB doses, the relationship between the number of CPDs and UVB dose is almost linear, with 4.4 CPDs produced per Mbp per J/m(2) of UVB radiation. We verified these AFM results by agarose gel electrophoresis separation of UV-irradiated and T4 Endonuclease V treated plasmids. Our AFM and gel electrophoresis results are consistent with the previous result obtained using other traditional DNA damage detection methods. We also show that damage detection assay sensitivity increases with plasmid size. In addition, we used photolyase to mark the sites of UV lesions in supercoiled plasmids for detection and quantification by AFM, and these results were found to be consistent with the results obtained by the plasmid relaxation assay. Our results suggest that AFM can supplement traditional methods for high resolution measurements of UV damage to DNA.


Visualizing the Nonhomogeneous Structure of RAD51 Filaments Using Nanofluidic Channels.
RAD51 is the key component of the homologous recombination pathway in eukaryotic cells and performs its task by forming filaments on DNA. In this study we investigate the physical properties of RAD51 filaments formed on DNA using nanofluidic channels and fluorescence microscopy. Contrary to the bacterial ortholog RecA, RAD51 forms inhomogeneous filaments on long DNA in vitro, consisting of several protein patches. We demonstrate that a permanent "kink" in the filament is formed where two patches meet if the stretch of naked DNA between the patches is short. The kinks are readily seen in the present microscopy approach but would be hard to identify using conventional single DNA molecule techniques where the DNA is more stretched. We also demonstrate that protein patches separated by longer stretches of bare DNA roll up on each other and this is visualized as transiently overlapping filaments. RAD51 filaments can be formed at several different conditions, varying the cation (Mg(2+) or Ca(2+)), the DNA substrate (single-stranded or double-stranded), and the RAD51 concentration during filament nucleation, and we compare the properties of the different filaments formed. The results provide important information regarding the physical properties of RAD51 filaments but also demonstrate that nanofluidic channels are perfectly suited to study protein-DNA complexes.


Gene therapy of fibroproliferative vasculopathies: current ideas in molecular mechanisms and biomedical technology.
Intimal hyperplasia occurs primarily as a part of the pathogenesis of coronary artery disease or secondary to therapeutic intervention in relieving vascular occlusion. Intimal hyperplasia involving vascular smooth muscle cells is found in atherosclerosis, post-balloon angioplasty restenosis, in-stent restenosis and vein graft disease, predominantly involving the use of saphenous vein conduits in coronary artery bypass grafting procedures. One potentially exciting area is that of gene therapy. Gene and protein expression patterns at the site of vasculoproliferative lesions have been widely studied and several target areas have been identified on the basis of whether the gene has an antiproliferative, proapoptotic, matrix degrading or endothelial protective action. Blood vessels are easily accessible for the delivery of the gene product, and experimental studies using animal models have used catheter-delivered gene products at the site of vascular injury. Currently, the application of antisense technology and adenoviral vector-mediated delivery has shown significant promise, albeit in in vitro or animal model settings. In this review, we discuss the current knowledge in the application of gene therapy in fibroproliferative vasculopathies. We examine some of the cellular mechanisms and intermediaries which could be potential candidates for gene targeting. We also present some of the advances in biomedical technology that might provide useful vehicles for pinpoint delivery of the gene product. Could the future of restenosis treatment be in gene therapy or is it misplaced enthusiasm?


Development and delivery of an exercise intervention for rheumatoid arthritis: strengthening and stretching for rheumatoid arthritis of the hand (SARAH) trial.
This paper describes the development and implementation of a hand exercise intervention for rheumatoid arthritis (RA) as part of a large multi-centred randomised controlled trial in a U.K. National Health Service (NHS) setting. Participants are eligible if diagnosed with RA according to American College of Rheumatology criteria, have a history of disease activity, functional deficit or impairment in the hand and/or wrist, and have been on a stable medication regime for at least 3 months. The intervention development was informed by the current evidence base, published guidelines, clinician and expert opinion, and a pilot study. The exercise programme targets known, potentially modifiable physical impairments of the hand with 5 exercise sessions and a home exercise component over a 12 week period. The intervention will be provided to 240 participants along with usual care. A further 240 will receive usual care only as part of the control arm. Specific details of the treatments delivered are described. [ISRCTN no: 89936343].


Noncovalent polymerization and assembly in water promoted by thermodynamic incompatibility.
This work studies the phase separations between polymers and a small molecule in a common aqueous solution that do not have well-defined hydrophobic-hydrophilic separation. In addition to poly(acrylamide) (PAAm) and poly(vinyl alcohol) (PVA), poly(vinyl pyrrolidone) (PVP) also promotes liquid crystal (LC) droplet formation by disodium cromoglycate (5'DSCG) solvated in water. In the presence of these polymers, the concentration of 5'DSCG needed for forming LC droplets is substantially lower than that needed for forming an LC phase by 5'DSCG alone. To define the concentration ranges that 5'DSCG molecules form liquid crystals (either as droplets or as an isotropic-LC mixture), we constructed ternary phase diagrams for 5'DSCG, water, and a polymer - PVA, PVP, or PAAm. We discovered that PAAm with high molecular weight promotes LC droplet formation by 5'DSCG more effectively than PAAm with low molecular weight. At the same weight percentage, long-chain PAAm can cause 5'DSCG to form LC droplets in water, whereas short-chain PAAm does not. Poly(vinyl pyrrolidone) (PVP), which has functional groups that are more dissimilar to 5'DSCG than PVA and PAAm, promotes LC droplet formation by 5'DSCG more effectively than either of the other two polymers. Additionally, small angle neutron scattering data revealed that the assembly structure of 5'DSCG promoted by the presence of PVA is similar to the thread structure formed by 5'DSCG alone. Together, these results reveal how noncovalent polymerization can be promoted by mixing thermodynamically incompatible molecules and elucidate the basic knowledge of nonamphiphilic colloidal science.


Features distinguishing amoebic from pyogenic liver abscess: a review of 577 adult cases.
Distinguishing amoebic from pyogenic liver abscesses is crucial because their treatments and prognoses differ. We retrospectively reviewed the medical records of 577 adults with liver abscess in order to identify clinical, laboratory, and radiographic factors useful in differentiating these microbial aetiologies. Presumptive diagnoses of amoebic (n = 471; 82%) vs. pyogenic (n = 106; 18%) abscess were based upon amoebic serology, microbiological culture results, and response to therapy. Patients with amoebic abscess were more likely to be young males with a tender, solitary, right lobe abscess (P = 0.012). Univariate analysis found patients with pyogenic abscess more likely to be over 50 years old, with a history of diabetes and jaundice, with pulmonary findings, multiple abscesses, amoebic serology titres <1:256 IU, and lower levels of serum albumin (P < 0.04). Multivariate logistic regression analysis confirmed that age >50 years, pulmonary findings on examination, multiple abscesses, and amebic serology titres <1:256 IU were predictive of pyogenic infection. Several clinical and laboratory parameters can aid in the differentiation of amebic and pyogenic liver abscess. In our setting, amebic abscess is more prevalent and, in most circumstances, can be identified and managed without percutaneous aspiration.


The nucleotide-binding domain, leucine-rich repeat protein 3 inflammasome/IL-1 receptor I axis mediates innate, but not adaptive, immune responses after exposure to particulate matter under 10 μm.
Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. Inhaled PM induces innate immune responses by airway epithelial cells that may lead to the exacerbation or de novo development of airway disease. We have previously shown that 10-μm PM (PM10) activates the nucleotide-binding domain, leucine-rich repeat protein (NLRP) 3 inflammasome in human airway epithelial cells. Our objective was to determine the innate and adaptive immune responses mediated by the airway epithelium NLRP3 inflammasome in response to PM10 exposure. Using in vitro cultures of human airway epithelial cells and in vivo studies with wild-type and Nlrp3(-/-) mice, we investigated the downstream consequences of PM10-induced NLPR3 inflammasome activation on cytokine production, cellular inflammation, dendritic cell activation, and PM10-facilitated allergic sensitization. PM10 activates an NLRP3 inflammasome/IL-1 receptor I (IL-1RI) axis in airway epithelial cells, resulting in IL-1β, CC chemokine ligand-20, and granulocyte/macrophage colony-stimulating factor production, which is associated with dendritic cell activation and lung neutrophilia. Despite these profound innate immune responses in the airway epithelium, the NLRP3 inflammasome/IL-1RI axis is dispensable for PM10-facilitated allergic sensitization. We demonstrate the importance of the lung NLRP3 inflammasome in mediating PM10 exposure-associated innate, but not adaptive, immune responses. Our study highlights a mechanism by which PM10 exposure can contribute to the exacerbation of airway disease, but not PM10-facilitated allergic sensitization.


Assembling activity/setting participation with disabled young people.
Rehabilitation research investigating activity participation has been largely conducted in a realist tradition that under-theorises the relationship between persons, technologies, and socio-material places. In this Canadian study we used a post-critical approach to explore activity/setting participation with 19 young people aged 14 to 23 years with complex communication and/or mobility impairments. Methods included integrated photo-elicitation, interviews, and participant observations of community-based activities. We present our results using the conceptual lens of assemblages to surface how different combinations of bodies, social meanings, and technologies enabled or constrained particular activities. Assemblages were analysed in terms of how they organised what was possible and practical for participants and their families in different contexts. The results illuminate how young people negotiated activity needs and desires in particular 'spacings' each with its own material, temporal, and social constraints and affordances. The focus on assemblages provides a dynamic analysis of how dis/abilities are enacted in and across geotemporal spaces, and avoids a reductive focus on evaluating the accessibility of static environmental features. In doing so the study reveals possible 'lines of flight' for healthcare, rehabilitation, and social care practices.


Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer.
Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.


Bulbar microcircuit model predicts connectivity and roles of interneurons in odor coding.
Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells) linearize the input-output transformation of the principal neurons (mitral cells), unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells). Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb.


Bipolar disorder and cell membrane dysfunction. Progress toward integrative management.
Bipolar disorder (BD) is characterized by periods of abnormally elevated mood (mania) that cycle with abnormally lowered mood (depression). Multiple structural, metabolic, and biochemical abnormalities are evident in the brain's cortex, subcortex, and deeper regions. This disorder is highly genetically conditioned but also highly susceptible to environmental stressors: prenatal or perinatal insults, childhood sexual or physical abuse, challenging life events, substance abuse, and other toxic chemical exposures. Its high morbidity, lost productivity, and suicide risk place a great toll on society. Since World War II, BD has been steadily worsening with earlier age of onset, greater intensity of symptoms, and development of drug resistance. Incidence in children is rising and misdiagnosis is common. Disciplined management of the many risk factors is essential, including cognitive psychotherapy and support from family and community. Lithium has been the foundational treatment, followed by valproate and other mood stabilizers, antidepressants, and anticonvulsants. Several single-nutrient and multinutrient supplements have also proven beneficial. Controlled, double-blind trials show multinutrient combinations of vitamins, minerals, orthomolecules, herbals, and the omega-3 fatty acids EPA and DHA to be effective monotherapy. The molecular action of lithium and valproate converge with nutrients on the level of the cell membrane and its molecular signal transduction systems. This emergent, unified rationale presages effective integrative management of bipolar disorder.


'All illness is personal to that individual': a qualitative study of patients' perspectives on treatment adherence in bronchiectasis.
Adherence to treatment is low in bronchiectasis and is associated with poorer health outcomes. Factors affecting adherence decisions have not been explored in patients with bronchiectasis. We aimed to explore patients' perspectives on adherence, factors affecting adherence decision making and to develop a conceptual model explaining this decision-making process in adults with bronchiectasis. Adults with bronchiectasis participated in one-to-one semi-structured interviews. Interviews were audio-recorded, transcribed verbatim and analysed independently by two researchers using thematic analysis. Data from core themes were extracted, categorized into factors affecting adherence decision making and used to develop the conceptual model. Participants' beliefs about treatment, the practical aspects of managing treatment, their trust in health-care professionals and acceptance of disease and treatment were important aspects of treatment adherence. The conceptual model demonstrated that adherence decisions were influenced by participants' individual balance of barriers and motivating factors (treatment-related, disease-related, health-care-related, personal and social factors). Adherence decision-making in bronchiectasis is complex, but there is the potential to enhance adherence by understanding patients' specific barriers and motivators to adherence and using this to tailor adherence strategies to individual patients and treatments.


Success and survival of autotransplanted premolars and molars during short-term clinical follow-up.
Autotransplantation is an elegant therapy for single tooth replacement that is too often overlooked in patients with missing teeth. Especially, autotransplantation of third molars to replace heavily damaged or missing molars is often not considered. This study investigated the success and survival of autotransplanted premolars and molars during clinical follow-up. The medical files and radiographs of 97 consecutive patients were retrospectively investigated. Seventy-nine patients could be included in this study. Autotransplantation of 97 premolars and 14 molars (111 procedures) was performed. The median follow-up time was equal to 13.4 months. In this study group, 82.0% of transplanted teeth were classified as successful and 98.2% were present at the end of follow-up. No transplants were extracted during standard follow-up of 1 year. The 5-year tooth survival probability was 87.5% (95%CI 64.5-100). One premolar and one molar were extracted, respectively, 4 and 9 years after autotransplantation. These results show that autotransplantation is associated with high success and survival rates and can provide a reliable treatment option for tooth replacement in young patients. Further research regarding long-term outcome is necessary to assess if the transplanted teeth function as normal teeth after clinical follow-up.


Causal evidence for frontal cortex organization for perceptual decision making.
Although recent research has shown that the frontal cortex has a critical role in perceptual decision making, an overarching theory of frontal functional organization for perception has yet to emerge. Perceptual decision making is temporally organized such that it requires the processes of selection, criterion setting, and evaluation. We hypothesized that exploring this temporal structure would reveal a large-scale frontal organization for perception. A causal intervention with transcranial magnetic stimulation revealed clear specialization along the rostrocaudal axis such that the control of successive stages of perceptual decision making was selectively affected by perturbation of successively rostral areas. Simulations with a dynamic model of decision making suggested distinct computational contributions of each region. Finally, the emergent frontal gradient was further corroborated by functional MRI. These causal results provide an organizational principle for the role of frontal cortex in the control of perceptual decision making and suggest specific mechanistic contributions for its different subregions.


Frontline worker responses to domestic violence disclosure in public welfare offices.
Although substantial numbers of women seeking Temporary Assistance for Needy Families (TANF) report domestic violence, few receive mandated services through the Family Violence Option (FVO). This study used transcripts ofinterviews between welfare caseworkers and their clients to identify and classify the responses made by workers to client disclosures of abuse and to assess the match or mismatch of these responses with FVO policy requirements. Only 22 of 782 client interviews involved the disclosure of abuse to the welfare caseworker. A typology of worker responses was created, from least to most engaged. This typology shows that only half of those who disclosed abuse received assistance from the welfare worker, despite policy mandates that clients receive information on TANF waivers and community resources. This study suggests that problems with implementation of the FVO reflect a systemic reluctance to address issues of violence with women rather than problems of individual workers.


Risk of post-fire metal mobilization into surface water resources: A review.
One of the significant economic benefits to communities around the world of having pristine forest catchments is the supply of substantial quantities of high quality potable water. This supports a saving of around US$ 4.1 trillion per year globally by limiting the cost of expensive drinking water treatments and provision of unnecessary infrastructure. Even low levels of contaminants specifically organics and metals in catchments when in a mobile state can reduce these economic benefits by seriously affecting the water quality. Contamination and contaminant mobility can occur through natural and anthropogenic activities including forest fires. Moderate to high intensity forest fires are able to alter soil properties and release sequestered metals from sediments, soil organic matter and fragments of vegetation. In addition, the increase in post-fire erosion rate by rainfall runoff and strong winds facilitates the rapid transport of these metals downslope and downstream. The subsequent metal deposition in distal soil and water bodies can influence surface water quality with potential impacts to the larger ecosystems inclusive of negative effects on humans. This is of substantial concern as 4 billion hectares of forest catchments provide high quality water to global communities. Redressing this problem requires quantification of the potential effects on water resources and instituting rigorous fire and environmental management plans to mitigate deleterious effects on catchment areas. This paper is a review of the current state of the art literature dealing with the risk of post-fire mobilization of the metals into surface water resources. It is intended to inform discussion on the preparation of suitable management plans and policies during and after fire events in order to maintain potable water quality in a cost-effective manner. In these times of climate fluctuation and increased incidence of fires, the need for development of new policies and management frameworks are of heighted significance.


Sequential effects of punishment.
Punishment is found to produce a large reduction in reinforced responses when it is initially introduced. Continued exposure to punishment, however, results in substantial recovery within each hour of exposure as well as from day to day. A compensatory increase in responding occurs after the removal of punishment, even after the punishment has ceased to be effective.


Measuring the efficiency of health systems in Asia: a data envelopment analysis.
This study aims to estimate the technical efficiency of health systems in Asia. The study was conducted in Asian countries. We applied an output-oriented data envelopment analysis (DEA) approach to estimate the technical efficiency of the health systems in Asian countries. The DEA model used per-capita health expenditure (all healthcare resources as a proxy) as input variable and cross-country comparable health outcome indicators (eg, healthy life expectancy at birth and infant mortality per 1000 live births) as output variables. Censored Tobit regression and smoothed bootstrap models were used to observe the associated factors with the efficiency scores. A sensitivity analysis was performed to assess the consistency of these efficiency scores. The main findings of this paper demonstrate that about 91.3% (42 of 46 countries) of the studied Asian countries were inefficient with respect to using healthcare system resources. Most of the efficient countries belonged to the high-income group (Cyprus, Japan, and Singapore) and only one country belonged to the lower middle-income group (Bangladesh). Through improving health system efficiency, the studied high-income, upper middle-income, low-income and lower middle-income countries can improve health system outcomes by 6.6%, 8.6% and 8.7%, respectively, using the existing level of resources. Population density, bed density, and primary education completion rate significantly influenced the efficiency score. The results of this analysis showed inefficiency of the health systems in most of the Asian countries and imply that many countries may improve their health system efficiency using the current level of resources. The identified inefficient countries could pay attention to benchmarking their health systems within their income group or other within similar types of health systems.


Obstructive micro diffracting structures as an alternative to plasmonics nano slits for making efficient microlenses.
Miniature optical components at the wavelength scale remain today a theoretically opened challenging problem of great technological interest. Appart from refractive micro-optics, plasmonics have been proposed to realize micro lenses with properly designed planar metallic nano-patterns. We show in this paper that efficient light focusing at the diffraction limit with higher transmission can be obtained with micro-structures much easier to fabricate than nano ones, such as a simple micro-slit studied here as an example. Optical properties are attributed to diffraction and a quantitative excellent agreement between experiment and theory is obtained.


Preoperative detection of malignancy in fine-needle aspiration cytology (FNAC) smears with indeterminate cytology (Bethesda III, IV) by a combined molecular classifier.
Analysis of molecular markers in addition to cytological analysis of fine-needle aspiration (FNA) samples is a promising way to improve the preoperative diagnosis of thyroid nodules. Previously, we have developed an algorithm for the differential diagnosis of thyroid nodules by means of a small set of molecular markers. Here, we aimed to validate this approach using FNA cytology samples of Bethesda categories III and IV, in which preoperative detection of malignancy by cytological analysis is impossible. A total of 122 FNA smears from patients with indeterminate cytology (Bethesda III: 13 patients, Bethesda IV: 109 patients) were analysed by real-time PCR regarding the preselected set of molecular markers (the BRAF V600E mutation, normalised concentrations of HMGA2 mRNA, 3 microRNAs, and the mitochondrial/nuclear DNA ratio). The decision tree-based classifier was used to discriminate between benign and malignant tumours. The molecular testing detected malignancy in FNA smears of indeterminate cytology with 89.2% sensitivity, 84.6% positive predictive value, 92.9% specificity and 95.2% negative predictive value; these characteristics are comparable with those of more complicated commercial tests. Residual risk of malignancy for the thyroid nodules that were shown to be benign by this molecular method did not exceed the reported risk of malignancy for Bethesda II histological diagnosis. Analytical-accuracy assessment revealed required nucleic-acid input of ≥5 ng. The study shows feasibility of preoperative differential diagnosis of thyroid nodules of indeterminate cytology using a small panel of molecular markers of different types by a simple PCR-based method using stained FNA smears.


The cardiac hypoxic niche: emerging role of hypoxic microenvironment in cardiac progenitors.
Resident stem cells persist throughout the entire lifetime of an organism where they replenishing damaged cells. Numerous types of resident stem cells are housed in a low-oxygen tension (hypoxic) microenvironment, or niches, which seem to be critical for survival and maintenance of stem cells. Recently our group has identified the adult mammalian epicardium and subepicardium as a hypoxic niche for cardiac progenitor cells. Similar to hematopoietic stem cells (LT-HSCs), progenitor cells in the hypoxic epicardial niche utilize cytoplasmic glycolysis instead of mitochondrial oxidative phosphorylation, where hypoxia inducible factor 1α (Hif-1α) maintains them in glycolytic undifferentiated state. In this review we summarize the relationship between hypoxic signaling and stem cell function, and discuss potential roles of several cardiac stem/progenitor cells in cardiac homeostasis and regeneration.


Design aspects of a case-control clinical investigation of the effect of HIV on oral and gastrointestinal soluble innate factors and microbes.
The impaired host defense system in HIV infection impacts the oral and gastrointestinal microbiota and associated opportunistic infections. Antiretroviral treatment is predicted to partially restore host defenses and decrease the oral manifestation of HIV/AIDS. Well-designed longitudinal studies are needed to better understand the interactions of soluble host defense proteins with bacteria and virus in HIV/AIDS. "Crosstalk" was designed as a longitudinal study of host responses along the gastrointestinal (GI) tract and interactions between defense molecules and bacteria in HIV infection and subsequent therapy. The clinical core formed the infrastructure for the study of the interactions between the proteome, microbiome and innate immune system. The core recruited and retained study subjects, scheduled visits, obtained demographic and medical data, assessed oral health status, collected samples, and guided analysis of the hypotheses. This manuscript presents a well-designed clinical core that may serve as a model for studies that combine clinical and laboratory data. Crosstalk was a case-control longitudinal clinical study an initial planned enrollment of 170 subjects. HIV+ antiretroviral naïve subjects were followed for 9 visits over 96 weeks and HIV uninfected subjects for 3 visits over 24 weeks. Clinical prevalence of oral mucosal lesions, dental caries and periodontal disease were assessed. During the study, 116 subjects (47 HIV+, 69 HIV-) were enrolled. Cohorts of HIV+ and HIV- were demographically similar except for a larger proportion of women in the HIV- group. The most prevalent oral mucosal lesions were oral candidiasis and hairy leukoplakia in the HIV+ group. The clinical core was essential to enable the links between clinical and laboratory data. The study aims to determine specific differences between oral and GI tissues that account for unique patterns of opportunistic infections and to delineate the differences in their susceptibility to infection by HIV and their responses post-HAART.


Validation of CFD predictions of flow in a 3D alveolated bend with experimental data.
Verifying numerical predictions with experimental data is an important aspect of any modeling studies. In the case of the lung, the absence of direct in vivo flow measurements makes such verification almost impossible. We performed computational fluid dynamics (CFD) simulations in a 3D scaled-up model of an alveolated bend with rigid walls that incorporated essential geometrical characteristics of human alveolar structures and compared numerical predictions with experimental flow measurements made in the same model by particle image velocimetry (PIV). Flow in both models was representative of acinar flow during normal breathing (0.82ml/s). The experimental model was built in silicone and silicone oil was used as the carrier fluid. Flow measurements were obtained by an ensemble averaging procedure. CFD simulation was performed with STAR-CCM+ (CD-Adapco) using a polyhedral unstructured mesh. Velocity profiles in the central duct were parabolic and no bulk convection existed between the central duct and the alveoli. Velocities inside the alveoli were approximately 2 orders of magnitude smaller than the mean velocity in the central duct. CFD data agreed well with those obtained by PIV. In the central duct, data agreed within 1%. The maximum simulated velocity along the centerline of the model was 0.5% larger than measured experimentally. In the alveolar cavities, data agreed within 15% on average. This suggests that CFD techniques can satisfactorily predict acinar-type flow. Such a validation ensure a great degree of confidence in the accuracy of predictions made in more complex models of the alveolar region of the lung using similar CFD techniques.


Functional Ability in the Changing Demographic Landscape: Evidence and Opportunities for Occupational Therapy.
The growing number of older adults is changing the demographic landscape. Occupational therapy can better serve the older adult population by helping them maintain their functional ability, which is the ability to engage in occupations. This special issue includes both studies of interventions to evaluate and support functional ability in community-dwelling older adults and systematic reviews of such studies. This editorial highlights the six systematic reviews, which were completed in collaboration with the American Occupational Therapy Association's Evidence-Based Practice Project. These reviews compile evidence for the effectiveness of interventions within the scope of occupational therapy practice to promote occupational performance in community-dwelling older adults. The distinct value of occupational therapy in supporting the functional ability of community-dwelling older adults with stable or declining health is discussed using the World Health Organization's framework for healthy aging.


Does primary closure increase surgical site infection after intestinal stoma reversal? A retrospective cohort study.
This study was undertaken to test the veracity of the hypothesis that primary incision closure after intestinal stoma reversal in adult patients is associated with a greater risk of surgical site infection (SSI) than are open incisions. A retrospective cohort study was conducted at the Surgical Department of the Aga Khan University Hospital, Karachi, Pakistan. The study included adult patients who underwent elective loop and double-barreled intestinal stoma (ileostomy or colostomy) reversal through peristomal incisions between January 2005 and May 2011. Files were reviewed independently by two surgeons to establish main exposure (closed or open surgical sites) and outcome; i.e., SSI based on U.S. Centers for Disease Control and Prevention criteria. Sample size calculation prior to the study required 71 patients to be included in each exposure arm. Patients with closed surgical sites were relatively younger (mean 36±15 [standard deviation] years) than those with open surgical sites (41±15 years), with a male preponderance in both groups. Fifteen patients were found to have SSI: 3/71 (4.2%) in open and 12/71 (16.9%) in closed incisions. The risk of SSI in closed surgical sites was 5.8 times greater than in open sites (95% confidence interval for relative risk 1.5-22.5) after adjusting for gender, body mass index (BMI), site of stoma, malignant disease, and preoperative chemo-radiotherapy. The risk of SSI in closed incisions is greater than that in open incisions. It is suggested that incisions not be closed primarily in patients undergoing stoma reversal.