Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.
Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide] is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFRL858R/T790M, human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC50=1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butanamide (BI 37781), a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFRL858R, but less or no detectable activity on cells expressing EGFRL858R/T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor "reprogramming."


Induction of differentiation in cultured rat and human podocytes.
Mature podocytes are highly differentiated cells that are unable to divide in vivo. During glomerulogenesis, podocytes develop from simple cuboidal cells into their adult phenotype, which is characterized by a complex pattern of processes. Cultivation of podocytes under standard conditions leads to dedifferentiation, including the loss of processes and of pp44, a marker of differentiated podocytes. In this study, the cell culture conditions for rat and human podocytes were modified by avoiding repeated subcultivation. This led to profound phenotypic changes in podocytes in vitro. The conversion of cobblestones into arborized cells was directly observed, and a series of intermediate phenotypes was documented. The cells converted within 3 wk from typical cobblestone appearance into individual arborized cells more closely resembling in vivo podocytes. Arborized cells were frequently binucleated and reached a size of up to 500 microns. Both cobblestone and arborized cells originated from podocytes, as evidenced by the expression of a podocyte-specific O-acetylated ganglioside and of the WT-1 protein. In contrast to primary cultures and early passages of cobblestones, a cloned rat podocyte cell line did not express WT-1 and could not be induced to differentiate into arborized cells. This finding indicates a role for WT-1 in maintaining differentiation of adult podocytes. The differentiation of arborized cells led to growth arrest and was reflected by the formation of processes and the expression of pp44 and desmin, which were never detected in cobblestones. It was concluded that partial differentiation of cultured podocytes can be achieved simply by avoiding repeated subcultivation, resulting in an arborized phenotype more closely reflecting in vivo podocytes.


[Self-management and health: Gandulfo's legacy in the "Sanitary Page" and worker's polyclinic (1923-1942)].
There are many ways to understand self-management. They vary from Government-dependent technical-administrative meanings (i.e. hospital self-management, in the context of health reform in Chile), to those related to efforts to abolish the State. Thus, the "self-management" concept was developed from the very beginning by the anarchist movement as one of its organizational principies. Henee, there is a need to break myths and prejudices about anarchist philosophy seen as a synonym of chaos, and to review its deeply constructive aspects and its highly moral character, hand in hand with genuine self-management in health. In this context, the work of Juan Gandulfo, a physician and anarchist, in the management of the Worker Polyclinic of the Industrial Workers of the World (IWW) and its diffusion media "The sanitary page" must be emphasized. The aim of this paper is to review the history of particular initiatives in self management, complementing them with some biographical aspects of Dr. Gandulfo's life.


Patient-centered approaches to health care: a systematic review of randomized controlled trials.
There is growing interest in patient-centered care, but there is little guidance about the interventions required for its delivery and whether it leads to better health outcomes. This systematic review evaluates the efficacy of patient-centered care interventions for people with chronic conditions. Thirty randomized controlled trials were identified from health-related databases. The findings indicated that most interventions were based on the notion of empowering care and included attempts to educate consumers or prompt them about how to manage a health consultation. Other common interventions focused on training providers in delivering empowering care. Although it was difficult to draw firm conclusions because of the moderate to high risk of bias of the research designs, this review has shown some promising findings from implementing a patient-centered care approach. There appeared to be benefits associated with this model of care in terms of patient satisfaction and perceived quality of care.


3-Morpholinopropyl isothiocyanate is a novel synthetic isothiocyanate that strongly induces the antioxidant response element-dependent Nrf2-mediated detoxifying/antioxidant enzymes in vitro and in vivo.
The induction of NF-E2-related factor-2 (Nrf2)-mediated detoxifying/antioxidant enzymes is recognized as an effective strategy for cancer chemoprevention. Here, we report that 3-morpholinopropyl isothiocyanate (3MP-ITC) is an exceptionally strong chemical inducer of these enzymes. Exposure of 3MP-ITC in HepG2C8 cells not only induced endogenous Nrf2 protein but also suppressed endogenous Kelch-like ECH-associated protein 1, resulting in an increased nuclear accumulation of Nrf2. Using chemical inhibitors of protein synthesis (cycloheximide) and 26S proteosomal degradation (MG-132), we observed that the induction of Nrf2 protein by 3MP-ITC appeared to be post-translationally regulated. 3MP-ITC activated ERK1/2 and JNK1/2 and the activation of antioxidant response element (ARE) by 3MP-ITC was significantly attenuated by chemical inhibition of PKC and PI3K signaling pathways in HepG2C8 cells. Treatment with 3MP-ITC significantly depleted the intracellular level of glutathione (GSH) in HepG2C8 cells and oral administration of 3MP-ITC increased the protein expression of hepatic NAD[P]H:quinone oxidoreductase-1 and Nrf2 in Nrf2 (+/+) but not in Nrf2 (-/-) mice, whereas UDP-glucuronosyl transferase 1A1 was induced in both genotypes. Our results indicate that 3MP-ITC is a novel ITC that strongly induces Nrf2-dependent ARE-mediated detoxifying/antioxidant enzymes in vitro and in vivo via the Nrf2 signaling pathway coupled with GSH depletion and activation of multiple signaling kinase pathways, which could be potentially useful agent for cancer chemoprevention.


Passively transferred anti-MUC1 antibodies cause neither autoimmune disorders nor immunity against transplanted tumors in MUC1 transgenic mice.
C57BL/6 mice transgenic for human MUC1 (MUC1.Tg) have been developed to investigate the autoimmune consequences of producing MUC1 tumor immunity in an animal that expresses MUC1 as a self-protein on normal ductal epithelia. Previous work showed that MUC1.Tg mice challenged with MUC1-bearing syngeneic tumors (B16.MUC1) developed progressively growing MUC1-expressing tumors and no detectable MUC1-specific antibody (Ab) response. In contrast, wild-type C57BL/6 (wt) mice developed MUC1-negative tumors at a significantly slower rate and produced approximately 50 microg IgG1 Ab reactive with the MUC1 tandem repeat (TR)/ml of sera. One milliliter of these sera was administered passively to MUC1.Tg or wt mice and the concentration of the MUC1 TR-reactive IgG1 Abs was monitored over time. The results indicate that circulating MUC1-reactive Abs were detectable in MUC1.Tg mice and that significant amounts of these Abs were not absorbed by organs that endogenously express MUC1. No evidence of autoimmune disease, either gross or histological, was observed in the MUC1.Tg recipients of sera suggesting that MUC1, an organ-specific protein expressed primarily by secretory epithelia, is inaccessible to circulating MUC1 -reactive Abs. Additional studies showed that polyclonal sera containing IgG1 Abs reactive with MUC1 TR were unable to provide protection against the growth of syngeneic tumors expressing MUC1 in the MUC1.Tg animal model.


Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages.
Molecular hydrogen has been reported to be effective for a variety of disorders and its effects have been ascribed to the reduction of oxidative stress. However, we have recently demonstrated that hydrogen inhibits type I allergy through modulating intracellular signal transduction. In the present study, we examined the hydrogen effects on lipopolysaccharide/interferon γ LPS/IFNγ-induced nitric oxide (NO) production in murine macrophage RAW264 cells. Treatment with hydrogen reduced LPS/IFNγ-induced NO release, which was associated with a diminished induction of inducible isoform of nitric oxide synthase (iNOS). Hydrogen treatment inhibited LPS/IFNγ-induced phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream signaling molecules, p38 MAP kinase and JNK, as well as IκBα, but did not affect activation of NADPH oxidase and production of reactive oxygen species (ROS). As ROS is an upstream activator of ASK1, inhibition of ASK1 by hydrogen without suppressing ROS implies that a potential target molecule of hydrogen should be located at the receptor or immediately downstream of it. These results suggested a role for molecular hydrogen as a signal modulator. Finally, oral intake of hydrogen-rich water alleviated anti-type II collagen antibody-induced arthritis in mice, a model for human rheumatoid arthritis. Taken together, our studies indicate that hydrogen inhibits LPS/IFNγ-induced NO production through modulation of signal transduction in macrophages and ameliorates inflammatory arthritis in mice, providing the molecular basis for hydrogen effects on inflammation and a functional interaction between two gaseous signaling molecules, NO and molecular hydrogen.


Breastfeeding at the workplace: a systematic review of interventions to improve workplace environments to facilitate breastfeeding among working women.
Breastfeeding can be affected by maternal employment. This is important considering that in 2019, 47.1% of women globally participated in the labor force. The aim of this study was to review workplace interventions to promote, protect and support breastfeeding practices among working mothers globally. A systematic review was conducted following the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Observational, experimental and qualitative peer-reviewed studies in English and Spanish, published between 2008 and 2019 were included. The review focused on working women who were pregnant, breastfeeding or who recently had a child, and women's working environments. The outcomes of interest included breastfeeding intentions, initiation, exclusivity and duration, confidence in breastfeeding or breastmilk extraction, and perceived support at workplace. Quality was assessed according to National Institute for Health and Care Excellence (NICE) checklist for systematic reviews. It was registered on PROSPERO (#140624). Data was extracted from 28 quantitative and 9 qualitative studies. The most common interventions were designated spaces for breastfeeding or breastmilk extraction (n = 24), and the support from co-workers (n = 20). The least common interventions were providing breast pumps (n = 4) and giving mothers the flexibility to work from home (n = 3). Studies explored how interventions affected different breastfeeding outcomes including breastfeeding duration, breastfeeding exclusivity, confidence in breastmilk expression, and breastfeeding support. The evidence suggests that workplace interventions help increase the duration of breastfeeding and prevent early introduction of breastmilk substitutes. Having a lactation space, breastmilk extraction breaks, and organizational policies are key strategies. However, to achieve equitable working conditions for breastfeeding mothers, organizational and interpersonal changes need to occur as well. The systematic review revealed that interventions at the workplace are important in protecting, promoting and supporting breastfeeding among working mothers. To achieve equitable work environments and fair nutritional opportunities for infants of working mothers, interventions should focus at the three ecological layers - individual, interpersonal, and organizational. The quality of studies can be improved. There is a need for studies assessing impacts of workplace interventions on infant feeding practices, mothers' self-esteem and outcomes such productivity and abstentionism.


Stochastic differential equations as a tool to regularize the parameter estimation problem for continuous time dynamical systems given discrete time measurements.
In this paper we consider the problem of estimating parameters in ordinary differential equations given discrete time experimental data. The impact of going from an ordinary to a stochastic differential equation setting is investigated as a tool to overcome the problem of local minima in the objective function. Using two different models, it is demonstrated that by allowing noise in the underlying model itself, the objective functions to be minimized in the parameter estimation procedures are regularized in the sense that the number of local minima is reduced and better convergence is achieved. The advantage of using stochastic differential equations is that the actual states in the model are predicted from data and this will allow the prediction to stay close to data even when the parameters in the model is incorrect. The extended Kalman filter is used as a state estimator and sensitivity equations are provided to give an accurate calculation of the gradient of the objective function. The method is illustrated using in silico data from the FitzHugh-Nagumo model for excitable media and the Lotka-Volterra predator-prey system. The proposed method performs well on the models considered, and is able to regularize the objective function in both models. This leads to parameter estimation problems with fewer local minima which can be solved by efficient gradient-based methods.


Susceptibility of Nebraska Western Corn Rootworm (Coleoptera: Chrysomelidae) Populations to Bt Corn Events.
Transgenic plants have been widely adopted by growers to manage the western corn rootworm, Diabrotica virgifera virgifera LeConte, in field corn. Because of reduced efficacy in some Nebraska fields after repeated use of Cry3Bb1-expressing hybrids, single plant bioassays were conducted in 2012 and 2013 to characterize the susceptibility of western corn rootworm populations to the rootworm-active proteins Cry3Bb1, mCry3A, and Cry34/35Ab1. Results demonstrate that there are heritable differences in susceptibility of Nebraska western corn rootworm populations to rootworm-active Bt traits. Proportional survival and corrected survival data coupled with field histories collectively support the conclusion that a level of field resistance to Cry3Bb1 has evolved in some Nebraska populations in response to selection pressure and that cross-resistance exists between Cry3Bb1 and mCry3A. There was no apparent cross-resistance between Cry34/35Ab1 and either Cry3Bb1 or mCry3A. The potential implications of these results on current and future corn rootworm management strategies are discussed.


Multimodal cerebral arteriovenous malformation treatment: a 12-year experience and comparison of key outcomes to ARUBA.
Curative treatment of unruptured brain arteriovenous malformations (AVMs) remains controversial after the only randomized controlled trial, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA), was halted prematurely because interim analysis revealed superiority of the medical management group. In contrast, meta-analyses of retrospective cohorts suggest that intervention is much safer than was found in ARUBA. The authors retrospectively analyzed 318 consecutive adult patients with brain AVMs treated at their institution with embolization, surgery, and/or proton beam radiosurgery. Analysis was performed in 142 ARUBA-eligible patients (baseline modified Rankin Scale [mRS] score 0-1, no history of hemorrhage), and results were compared to primary and secondary outcomes from ARUBA, as well as to natural history cohorts. The annualized stroke rate (hemorrhagic or ischemic) in this cohort was 1.8%, 4.9% in the first 12 months and 0.8% after the first 12 months, which was lower than in natural history studies and the ARUBA medical management arm (p = 0.001). The primary ARUBA endpoint of symptomatic stroke was reached in 13 patients (9.2%), which compares favorably to the ARUBA intervention arm (39.6%, p = 0.0001) and is similar to the ARUBA medical management arm (9.2%, p = 1.0). The secondary ARUBA endpoint (mRS score ≥ 2 at 5 years of follow-up) was reached in 14.3% of patients, compared to 40.5% in the ARUBA intervention arm (p = 0.002) and 16.7% in the ARUBA medical management arm (p = 0.6). This multimodal approach to the selection and treatment of patients with brain AVMs yields good clinical outcomes with key safety endpoints (stroke, death, and mRS score 0-1) better than the ARUBA intervention arm and similar to the ARUBA medical arm at 5 years of follow-up. Results compare favorably to natural history cohorts at longer follow-up times. This suggests that tertiary care centers with integrated programs, expertise in patient selection, and individualized treatment approaches may allow for better clinical outcomes than reported in ARUBA. It supports current registry studies and merits consideration of future randomized controlled trials in patients with brain AVMs.


A new method for the selection of protein interactions in mammalian cells.
In the present study we present a new method that allows for the selection of protein interactions in mammalian cells. We have used this system to verify two interactions previously characterized in vitro. (1) The interaction between human TATA-binding protein 1 and nuclear factor kappaB and (2) the association of Homo sapiens nuclear autoantigen SP100B with human heterochromatin protein 1alpha, a protein implicated in chromatin remodelling. We observe for the first time that these interactions also occur in vivo. One protein was fused to the N-terminal half of ubiquitin, while the interacting partner was fused to the C-terminal half of ubiquitin, that was itself linked to guanine phosphoryltransferase 2 (gpt2) modified to begin with an arginine residue. Upon interaction of both proteins, ubiquitin is reconstituted, and its association with the Rgpt2 reporter is subsequently cleaved off by ubiquitin-processing enzymes. The presence of arginine in the Rgpt2 gene product leads to the degradation of the product by the N-end rule pathway. In the human fibroblast cell line HT1080HPRT(-) (that is deficient in the enzyme for hypoxanthine-guanine phosphoribosyltransferase) cells in which interaction between both proteins of interest occurs can then be selected for by hypoxanthine/aminopterin/thymine medium and counterselected against by 6-thioguanine medium. This method provides a suitable alternative to the yeast two-hybrid system and is generally applicable.


Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa.
Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing > or =120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing > or =20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.


Palmitoylcarnitine reverses 12-O-tetradecanoylphorbol-13-acetate-induced refractory state for the TPA-caused ornithine decarboxylase induction in mouse epidermis.
When a single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was performed 12 h before the second application, ornithine decarboxylase (ODC) induction by the second application of TPA was markedly suppressed (refractory state). However, at intervals of 96 h between the first and the second application, the ODC activity induced by the second application of TPA was higher (enhanced state) than the activity induced by the single application. When various anti-tumor promoting agents, i.e. p-bromophenacyl bromide, nordihydroguaiaretic acid, quercetin, 1-tosylamide-2-phenylethyl chloromethyl ketone, retinoic acid and palmitoylcarnitine, were applied concurrently with the first TPA application, the ODC induction in the refractory state was restored only by palmitoylcarnitine, but not by other antitumor promoting agents. None of these anti-tumor promoting agents affected the ODC induction in the enhanced state. Stearoylcarnitine also had the restorative effect but was less effective than palmitoylcarnitine. Acetylcarnitine and palmitic acid were not effective. Pretreatment of mice with TPA 12 h or 96 h before the second TPA application resulted in the reduction or the increase in the Vmax values of ODC both for ornithine and pyridoxal-5'-phosphate, respectively. Palmitoylcarnitine restored these reduced Vmax values to the control values. Twelve hours after TPA treatment, the epidermal protein kinase C activity of both cytosol and particulate fractions decreased moderately. At 96 h after TPA application, protein kinase C activities of both cytosol and particulate fractions were fully or at least partially restored to the control levels. Protein kinase C activities both in the cytosol and the particulate fractions tended to be restored by palmitoylcarnitine, but the effect was not always reproducible. The TPA-induced refractory state and the enhanced state for ODC induction appear to result from the changes in the protein kinase C activities caused by TPA. However, it is not known whether such changes in the protein kinase C activities are the major causes for the TPA-induced refractory and/or enhanced state for ODC induction and whether or not the restorative effect of palmitoylcarnitine is due to its modulating action on protein kinase C activity.


Predictors of violent behavior in an early adolescent cohort: similarities and differences across genders.
The authors assessed a cohort of 2,335 students from the Minneapolis, Minnesota, area to identify predictors of violent behavior and to determine whether the predictors varied by gender. The sample was 76% White; boys and girls were equally represented. The majority lived with two parents. A measure of violent behavior collected at the end of the eighth-grade year (2000) was entered into Poisson regression against baseline data collected at the beginning of the seventh-grade year (1998). Predictors of violent behavior influencing both boys and girls included depressive symptoms, perceived invulnerability to negative future events, paternal nonauthoritative behavior, and drinking alcohol. Additional predictors of violent behavior specific to girls included both risk and protective factors.


Identification of leucocyte surface protein interactions by high-throughput screening with multivalent reagents.
We describe a high-throughput screening system to detect interactions between leucocyte surface proteins, taking into account that these interactions are usually of very low affinity. The method involves producing the extracellular regions of leucocyte proteins with tags so that they can be bound to nanoparticles to provide an avid reagent to screen over an array of 36 similar proteins immobilized using the Proteon XPR36 with detection by surface plasmon resonance. The system was tested using established interactions that could be detected without spurious binding. The ability to detect new interactions was shown by identifying a new interaction between carcinoembryonic antigen-related cell adhesion molecule 1 and carcinoembryonic antigen-related cell adhesion molecule 8.


The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry.
Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm(3) during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The African-specific -46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4(+) T-cell counts, such that leukopenic but not nonleukopenic HIV(+) AAs with DARC -46C/C had a survival advantage compared with all Duffy-positive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIV-infected AAs, despite immunodeficiency.


Academics' and students' experiences in a chilean dental school during the COVID-19 pandemic: A qualitative study.
The quick spread of COVID-19 has caused part of the world's population to adopt quarantine protocols that have limited professional activities, including dental training programmes. This study aimed to explore the experiences of students and personnel at a Chilean dental school during the COVID-19 pandemic. This phenomenological descriptive qualitative study reported staff and students' experiences during the pandemic through in-depth, semi-structured interviews. These were recorded on audio and video with a digital platform. Three researchers then transcribed and analyzed the recordings and codified the answers into categories to determine the emerging topics until a saturation point was reached. The core emerging themes among the staff group were (1) change in the personal/professional life balance, (2) online learning through digital platforms, (3) staff perceptions of students' learning experiences, and (4) concerns about the future. For students, the themes were (1) changes in the learning process, (2) online learning through digital platforms, (3) interpersonal relationships, and (4) concerns about the future. The COVID-19 pandemic has been a period of learning for our dental school staff and students. Even though online learning has been a useful tool for delivering didactic (theoretical) concepts, it has been unable to replace conventional education, including skills training. Students and teachers reported being overwhelmed at the beginning of the pandemic, but they have shown remarkable adaptability and resilience during this period.


Flavors of desire: Cognitive representations of appetitive stimuli and their motivational implications.
How do people cognitively represent appetitive stimuli? Do interactions with appetitive stimuli shape how we think about them, and do such representations affect motivation to consume? Although much is known about how people respond to appetitive stimuli, little is known about how they are represented. We examine this in the domain of sugar-sweetened drinks, which constitute a significant self-control problem for many people. Given people's rich and diverse learning histories of consuming them, we propose that representations of these stimuli will show high variability, and that they will reflect idiosyncratic simulations, or reenactments, of previous consumption experiences. Representing drinks in terms of consuming and enjoying them may predict the motivation to consume. In three experiments (total N = 457), participants described nonalcoholic drinks in a "feature listing task," a free production task to assess cognitive representations of concepts through natural language. We also measured consumption frequency, desire to drink, and intake (Experiment 3), and we measured (Experiments 1 and 2) or manipulated (Experiment 3) thirst. Illustrating the variability of participants' representations of drinks, participants reported a large number of different features (210-331 unique features per drink). Drinks were described heavily with words related to consumption and reward experiences, especially sugary drinks, and especially when consumed frequently. Consumption and reward features predicted desire and intake, more strongly than thirst. These findings suggest that simulations of previous rewarding interactions play a key role in representations of appetitive stimuli, and that understanding these representations may be useful across domains of appetitive behavior. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Diabetes and periodontal disease.
Diabetes mellitus is a systemic disease characterized by increased blood glucose levels and abnormalities of lipid metabolism due to absence or decreased level of insulin. It affects all the body organs and their functions either directly or indirectly. Every dentist should have a basic understanding of the etiopathogenesis, oral and systemic manifestations of this disease. The periodontal diseases are a consequence of extension of the gingival inflammation into the underlying supporting structures of the periodontium, initiated by the presence of plaque and its products on the surfaces of the teeth and the adjoining structures. The progression of periodontal disease is influenced by variety of factors like microorganisms, host response, systemic background, and genetic makeup of the host. Amongst them, diabetes mellitus tops the list. Diabetes and periodontitis influence the clinical outcome of each other and control of both influences the clinical improvement of each.


Managing ammonia emissions from dairy cows by amending slurry with alum or zeolite or by diet modification.
Animal agriculture is a significant source of atmospheric ammonia. Ammonia (NH3) volatilization represents a loss of plant available N to the farmer and a potential contributor to eutrophication in low-nitrogen input ecosystems. This research evaluated on-farm slurry treatments of alum or zeolite and compared three diets for lactating dairy cows in their effectiveness to reduce NH3 emissions. NH3 emissions were compared using a group of mobile wind tunnels. The addition of 2.5% alum or 6.25% zeolite to barn-stored dairy slurry reduced NH3 volatilization by 60% and 55%, respectively, compared to untreated slurry. The alum conserved NH3 by acidifying the slurry to below pH 5, while the zeolite conserved ammonia by lowering the solution-phase nitrogen through cation exchange. The use of alum or zeolite also reduced soluble phosphorus in the slurry. NH3 loss from fresh manure collected from lactating dairy cows was not affected by three diets containing the same level of crude protein but differing in forage source (orchardgrass silage vs. alfalfa silage) or neutral detergent fiber (NDF) content (30% vs. 35% NDF). NH3 losses from the freshly excreted manures occurred very rapidly and included the urea component plus some unidentified labile organic nitrogen sources. NH3 conservation strategies for fresh manures will have to be active within the first few hours after excretion in order to be most effective. The use of alum or zeolites as an on-farm amendment to dairy slurry offers the potential for significantly reducing NH3 emissions.


Management of patients with early stage lung cancer - why do some patients not receive treatment with curative intent?
This study aims to understand the factors that influence whether patients receive potentially curative treatment for early stage lung cancer. A key question was whether indigenous Māori patients were less likely to receive treatment. Patients included those diagnosed with early stage lung cancer in 2011-2018 and resident in the New Zealand Midland Cancer Network region. Logistic regression model was used to estimate the odds ratios of having curative surgery/ treatment. The Kaplan Meier method was used to examine the all-cause survival and Cox proportional hazard model was used to estimate the hazard ratio of death. In total 419/583 (71.9%) of patients with Stage I and II disease were treated with curative intent - 272 (46.7%) patients had curative surgery. Patients not receiving potentially curative treatment were older, were less likely to have non-small cell lung cancer (NSCLC), had poorer lung function and were more likely to have an ECOG performance status of 2+. Current smokers were less likely to be treated with surgery and more likely to receive treatment with radiotherapy and chemotherapy. Those who were treated with surgery had a 2-year survival of 87.8% (95% CI: 83.8-91.8%) and 5-year survival of 69.6% (95% CI: 63.2-76.0%). Stereotactic ablative body radiotherapy (SABR) has equivalent effect on survival compared to curative surgery (hazard ratio: 0.77, 95% CI: 0.37-1.61). After adjustment we could find no difference in treatment and survival between Māori and non-Māori. The majority of patients with stage I and II lung cancer are managed with potentially curative treatment - mainly surgery and increasingly with SABR. The outcomes of those being diagnosed with stage I and II disease and receiving treatment is positive with 70% surviving 5 years.


The list strength effect: a contextual competition account.
Research on the list strength effect (LSE) has shown that learning some words on a list more strongly than others impairs memory for the weakly learned words when tested with a recall task. Norman (2002) demonstrated that the LSE also occurs within the recollection process of a recognition test. In this study, a mechanistic dual-process account of the LSE was tested that simultaneously makes predictions concerning additional sources of context in interference effects. In two experiments, we attempted to replicate Norman's (2002) findings and provide the basis for our modeling efforts. We found evidence for a recollection LSE in raw measures of responding, with memory performance also benefiting from reinstatement of perceptual characteristics at test. However, large differences in the hits between the lists were accompanied by small differences in false alarms, such that when d' is calculated, differences between the lists are not significant. We propose an account of the LSE whereby the actual effect of competition between items on the list is small, although present, and difficult to distinguish from large effects of bias due to the strength manipulations. We argue that our findings provide support for a mechanistic explanation of LSE that is based on competition of source activation and changes in the thresholds for responses.


Differences among male/female adolescents participating in a School-based Teenage Education Program (STEP) focusing on HIV prevention in India.
With the rising threat of HIV in India, youth are an important group to reach for prevention education. This pilot study tested the efficacy of STEP (School-based Teenage Education Program focusing on HIV Prevention) for school children. This pilot study randomized 25 schools in Mumbai to receive STEP (N = 1846). We trained forty two undergraduates from local colleges to deliver the, (six-session) program over a six-week period to eighth graders (age 13-15 years). Outcome measures collected at six weeks were HIV knowledge, attitudes toward abstinence/condom use, peer pressure, and confidence in dealing with risky social situations. A repeated measures analysis of variance was conducted with pretest and posttest scores with knowledge, beliefs, attitudes, and confidence as the within-group measures and gender as the between-group measure. Both boys and girls significantly improved on knowledge, attitudes, and beliefs regarding HIV/AIDS and in their confidence level in dealing with risky behavior. However girls increased more on knowledge (P < .05), agreement with abstinence (P < .05), and agreement with condom use (P < .001). Girls had significantly less need to follow peers (P < .05), better understanding of precautions against HIV (P < .001), and a higher confidence level in dealing with risky social situations (P < .05). Overall, girls benefited more from the STEP intervention than boys. The literature documents strong gender disparities in HIV/AIDS knowledge, information sources, and consequences of sex for youth in India. However, more work is needed to define and document the reasons for the differences.


Classification for breast cancer diagnosis with Raman spectroscopy.
In order to promote the development of the portable, low-cost and in vivo cancer diagnosis instrument, a miniature laser Raman spectrometer was employed to acquire the conventional Raman spectra for breast cancer detection in this paper. But it is difficult to achieve high discrimination accuracy. Then a novel method of adaptive weight k-local hyperplane (AWKH) is proposed to increase the classification accuracy. AWKH is an extension and improvement of K-local hyperplane distance nearest-neighbor (HKNN). It considers the features weights of the training data in the nearest neighbor selection and local hyperplane construction stage, which resolve the basic shortcoming of HKNN works well only for small values of the nearest-neighbor. Experimental results on Raman spectra of breast tissues in vitro show the proposed method can realize high classification accuracy.


Validation of Pressure Reactivity and Pulse Amplitude Indices against the Lower Limit of Autoregulation, Part I: Experimental Intracranial Hypertension.
The purpose of this study was to provide validation of intracranial pressure (ICP) derived continuous indices of cerebrovascular reactivity against the lower limit of autoregulation (LLA). Utilizing an intracranial hypertension model within white New Zealand rabbits, ICP, transcranial Doppler (TCD), laser Doppler flowmetry (LDF), and arterial blood pressure were recorded. Data were retrospectively analyzed in a cohort of 12 rabbits with adequate signals for interrogating the LLA. We derived continuous indices of cerebrovascular reactivity: PRx (correlation between ICP and mean arterial pressure [MAP]), PAx (correlation between pulse amplitude of ICP [AMP] and MAP), and Lx (correlation between LDF-based cerebral blood flow [CBF] and cerebral perfusion pressure [CPP]). LLA was derived via piecewise linear regression of CPP versus LDF or CPP versus systolic flow velocity (FVs) plots. We then produced error bar plots for PRx, PAx, and Lx against 2.5 mm Hg bins of CPP, to display the relationship between these indices and the LLA. We compared the CPP values at clinically relevant thresholds of PRx and PAx, to the CPP defined at the LLA. Receiver operating curve (ROC) analysis was performed for each index across the LLA using 2.5 mm Hg bins for CPP. The mean LLA was 51.5 ± 8.2 mm Hg. PRx and PAx error bar plots demonstrate that each index correlates with the LLA, becoming progressively more positive below the LLA. Similarly, CPP values at clinically relevant thresholds of PRx and PAx were not statistically different from the CPP derived at the LLA. Finally, ROC analysis indicated that PRx and PAx predicted the LAA, with areas under the curve (AUCs) of 0.795 (95% confidence interval [CI]: 0.731-0.857, p < 0.0001) and 0.703 (95% CI: 0.631-0.775, p < 0.0001), respectively. Both PRx and PAx generally agree with LLA within this experimental model of intracranial hypertension. Further analysis of clinically used indices of autoregulation across the LLA within pure arterial hypotension models is required.


Dissipative particle dynamics simulations of polymer-protected nanoparticle self-assembly.
Dissipative particle dynamics simulations were used to study the effects of mixing time, solute solubility, solute and diblock copolymer concentrations, and copolymer block length on the rapid coprecipitation of polymer-protected nanoparticles. The simulations were aimed at modeling Flash NanoPrecipitation, a process in which hydrophobic solutes and amphiphilic block copolymers are dissolved in a water-miscible organic solvent and then rapidly mixed with water to produce composite nanoparticles. A previously developed model by Spaeth et al. [J. Chem. Phys. 134, 164902 (2011)] was used. The model was parameterized to reproduce equilibrium and transport properties of the solvent, hydrophobic solute, and diblock copolymer. Anti-solvent mixing was modeled using time-dependent solvent-solute and solvent-copolymer interactions. We find that particle size increases with mixing time, due to the difference in solute and polymer solubilities. Increasing the solubility of the solute leads to larger nanoparticles for unfavorable solute-polymer interactions and to smaller nanoparticles for favorable solute-polymer interactions. A decrease in overall solute and polymer concentration produces smaller nanoparticles, because the difference in the diffusion coefficients of a single polymer and of larger clusters becomes more important to their relative rates of collisions under more dilute conditions. An increase in the solute-polymer ratio produces larger nanoparticles, since a collection of large particles has less surface area than a collection of small particles with the same total volume. An increase in the hydrophilic block length of the polymer leads to smaller nanoparticles, due to an enhanced ability of each polymer to shield the nanoparticle core. For unfavorable solute-polymer interactions, the nanoparticle size increases with hydrophobic block length. However, for favorable solute-polymer interactions, nanoparticle size exhibits a local minimum with respect to the hydrophobic block length. Our results provide insights on ways in which experimentally controllable parameters of the Flash NanoPrecipitation process can be used to influence aggregate size and composition during self-assembly.


Protective salivary immunoglobulin A responses against Streptococcus mutans infection after intranasal immunization with S. mutans antigen I/II coupled to the B subunit of cholera toxin.
The B subunit of cholera toxin (CTB) has been shown to augment mucosal responses to microbial virulence antigens, including those of Streptococcus mutans, which is the principal etiologic agent of dental caries. In the present study, the surface fibrillar protein antigen of S. mutans, antigen I/II (Ag I/II), was chemically coupled to CTB (Ag I/II-CTB), and the conjugate was examined for its effectiveness in inducing salivary immune responses protective against S. mutans infection. Weanling Fischer rats were given Ag I/II-CTB (50 micrograms) by the intranasal route and then orally infected with a virulent strain of S. mutans. Gnotobiotic or conventional rats were given two or three additional immunizations, respectively, at about 2-week intervals. One week after each immunization, individual serum, saliva, and fecal samples were collected and stored frozen until assayed for antibody activity to Ag I/II and cholera toxin (CT) by an enzyme-linked immunosorbent assay. The rats were sacrificed 1 week after the last immunization, when mandibles were also collected from individual rats for assessment of S. mutans levels in plaque and caries activity. Rats immunized only or both immunized and infected showed a salivary immunoglobulin A (IgA) anti-Ag I/II response which reached significantly (P < 0.05) higher levels than those seen in nonimmunized, infected controls. A salivary IgA anti-Ag I/II response was also seen in rats infected only with S. mutans. Essentially no salivary antibody activity to CT was detected. Some serum anti-Ag I/II and anti-CT responses were seen in immunized animals. Serum IgG anti-Ag I/II responses were seen in immunized, infected rats and also in infected-only rats, suggesting that the responses were a result of infection with S. mutans. The immunized and infected rats had significantly (P < 0.05) lower levels of S. mutans in plaque and lower caries activity than nonimmunized, infected rats. These results indicated that intranasal immunization of rats with Ag I/II-CTB induced a protective salivary immune response which was associated with a reduction in S. mutans colonization and S. mutans-induced dental caries.


Tiny spies: mosquito antennae are sensitive sensors for eavesdropping on frog calls.
Most mosquito and midge species use hearing during acoustic mating behaviors. For frog-biting species, however, hearing plays an important role beyond mating as females rely on anuran calls to obtain blood meals. Despite the extensive work examining hearing in mosquito species that use sound in mating contexts, our understanding of how mosquitoes hear frog calls is limited. Here, we directly investigated the mechanisms underlying detection of frog calls by a mosquito species specialized on eavesdropping on anuran mating signals: Uranotaenia lowii. Behavioral, biomechanical and neurophysiological analyses revealed that the antenna of this frog-biting species can detect frog calls by relying on neural and mechanical responses comparable to those of non-frog-biting species. Our findings show that in Ur. lowii, contrary to most species, males do not use sound for mating, but females use hearing to locate their anuran host. We also show that the response of the antennae of this frog-biting species resembles that of the antenna of species that use hearing for mating. Finally, we discuss our data considering how mosquitoes may have evolved the ability to tap into the communication system of frogs.


The best laid plans: community-based natural resource management (CBNRM) group capacity and planning success.
As community-based natural resource management (CBNRM) increases in popularity, the question of the capacity of such groups to successfully manage natural resources becomes increasingly relevant. However, few studies have quantifiably analyzed how the amount or type of capacity in a CBNRM organization directly affects the outputs or the environmental outcomes produced. This paucity of research exists in part due to the diversity of indicators for CBNRM group capacity, as well as the ensuing debate over how to best define and measure success in CBNRM initiatives. Although concrete outputs vary widely, many efforts center on creating natural resource management plans (RMPs). The primary objective of our research was to explore the link between capacity and RMP implementation success, as perceived by practitioners among CBNRM groups across Illinois. A short online survey was constructed, utilizing findings from focus groups in combination with an extensive literature review, to measure CBNRM participants' (n = 190) perceptions of 10 key capacity indicators and RMP implementation success. Results show that capacity perceptions varied significantly among respondents in low, moderate, and high RMP implementation success groups, and that group capacity was predictive of the degree of perceived RMP implementation success. Further, our findings suggest that bonding social capital and outreach are crucial in predicting low versus moderate RMP success, while leadership, motivation, and vision best distinguish the moderately successful and highly successful groups.


Dermatofibrosarcoma protuberans: Role of wide local excision.
The main objective of the present study was to study the outcome of surgical treatment of dermatofibrosarcoma protuberans. This study included 45 patients both retrospective and prospective from December 1995 to December 2010. Out of 45 patients, 30 were males and 15 females with the male to female ratio of 2:1. Mean age of presentation was 38.4 + 13.2 years. Commonest mode of presentation was raised firm multinodular lesion with fixity to overlying skin. Site distribution was 42.22% trunk, 57.88% extremities and head and neck. None of the patients had lymph node involvement All patients underwent wide local excision. On histological examination, 8 patients had positive margins. Overall recurrence rate was 22.22%. (please clarify what is the difference between the rate of recurrence following surgery and the overall recurrence rate) Only 2 patients developed metastasis to lungs in the course of their follow-up. Out of 45 patients, 35 remained recurrence free over a varying period of 5 months to 13 years (mean 68 months). Ten patients developed one or more local recurrences. Average time from initial treatment to recurrence was 32 months. All patients with recurrent tumors were subjected to salvage treatment, i.e., re-excision. Average recurrence-free period was 36 + 44 months within a mean follow-up of 68 months. Because of the potential of local recurrence, therapy for DFSP should be directed toward adequate local excision of the primary lesion. Minimal resection should include a surrounding margin, comprising 3-cm margin of normal skin and removal of underlying deep fascia. Compromising on margins invites higher chances of local recurrence.


Malignant pleural mesothelioma treated in Clinic for Pulmonary Diseases and Tuberculosis "Podhrastovi" in ten-year period (from 1998 to 2007).
Malignant pleural mesothelioma (MPM) is the most common primary malign tumour of pleura. The aim of this study was to evaluate cases of MPM diagnosed and treated in Clinic for Pulmonary Diseases and Tuberculosis "Podhrastovi" during ten-year period (1998-2007). Study is retrospective. The patients were analysed according to age, sex, histopathologic type of the tumour, cantonal distribution in Federation of Bosnia and Herzegovina and regimen of treatment. MPM presented 0,72% (0-1,56% per year) of all hospitalised malignant patients, and the greatest number of registered cases was in the year of 2007. The series included 16 male (57,14%) and 12 female (42,86%). Cases over 64 years old were the most frequent (14-50%) than 45-54 years (7- not 25%). Histopathology types of hospitalised cases of MPM: epitheloid form (8- 28,57%); sarcomatoid form (2- 7,14 %); other forms (18-64,29%). The most patients came from Canton Sarajevo (12-42,86%); ZE-DO canton (8-28,57%) and the UNA-SANA canton (5-17,86%). The therapy applied: chemotherapy (11-39,29%); radiotherapy (3-10,71%); chemotherapy + radiotherapy (4-14,29%); symptomatic therapy (10-35,71 %).


First Report of Leaf Spot Disease in Withania coagulans Caused by Alternaria alternata in India.
Withania coagulans (Paneer doddi) is a medicinal plant in the Solanaceae (1) that grows in northwestern India. An unknown disease appeared in the Amritsar district of Punjab, India on W. coagulans starting in 2009, and was noticed annually in the post-monsoon seasons through 2011. The plants were grown in a net house (74.82323 to 74.82332°E, 31.63678 to 31.63688°N, 221 m elevation), Guru Nanak Dev University, Amritsar. Symptoms first appeared as brown to black spots (2 to 10 mm in diameter) that were sometimes surrounded by a yellow halo, starting on the lower leaves and gradually spreading to the upper leaves. Spots were apparent on both the dorsal and ventral sides of the leaves. In the most severe outbreak of the disease, more than 90% of the leaf area was covered with the leaf spot symptoms. The pathogen was isolated by placing pieces of surface-sterilized leaf spots on potato dextrose agar (PDA), and the hyphae that emerged from the leaf pieces were sub-cultured to PDA. Initially, the fungal colony was white, and gradually turned olive-brown as it matured. Conidiophores were mostly simple, usually becoming geniculate by sympodial elongation. Conidiophores were mostly branched and conidia were arranged in acropetal chains of 6 to 10. Conidia were 15 to 25 μm long and 5 to 10 μm wide, with 3 to 4 transverse septa and 2 to 3 longitudinal septa, muriform, ovoid to ellipsoid, with a broadly rounded base and an apical beak. Based on these morphological characters, the pathogen was identified as Alternaria alternata (Fr.) Keissler (4). The identification of the pathogen was also confirmed by MTCC, Chandigarh, India and deposited in their culture collection with Accession No. MTCC-10939 ( http://mtcc.imtech.res.in ). During preliminary studies, the optimum temperature for its growth was 25 ± 2°C. Pathogenicity of the fungus was demonstrated on three potted W. coagulans plants after spray-inoculating leaves with a spore suspension of 3 × 105 spores per ml. A batch of three plants sprayed with sterile distilled water served as controls. Both inoculated and control plants were incubated at 100% relative humidity for 5 days and transferred to a glasshouse at 25 ± 2°C. Initial symptoms developed on a few plants at 5 to 7 days post-inoculation, and the same leaf symptoms described above from field plants became apparent on all inoculated plants by 10 to 14 days. Control plants did not develop symptoms. The pathogen was recovered from leaf spots using the isolation technique described above, and was identified as A. alternata, thus fulfilling Koch's postulates. Although the leaf spot diseases caused by A. alternata and A. dianthicola were reported on W. somnifera (2,3), to the best of our knowledge, there is no report of either pathogen infecting W. coagulans. Thus, the identification of pathogen will facilitate the disease management program and for enhancing the commercial value of this important endangered medicinal plant. References: (1) S. A. Gilani et al. Afr. J. Biotechnol. 8:2948, 2009. (2) C. K. Maiti et al. Plant Dis. 91:467, 2007. (3) P. K. Pati et al. Indian J Microbiol. 48:432, 2008. (4) E. G. Simmons. Alternaria: An identification manual. American Phytopathological Society, St. Paul, MN, 2007.


Cafestol Inhibits High-Glucose-Induced Cardiac Fibrosis in Cardiac Fibroblasts and Type 1-Like Diabetic Rats.
Diabetes is associated with the development of myocardial fibrosis, which is related to various cardiac diseases. Cafestol, one of the active ingredients in coffee, has been reported to exert biological effects. However, whether cafestol can ameliorate diabetes-induced cardiac fibrosis remains unknown. The aim of this study was to evaluate the effects of cafestol on cardiac fibrosis in high-glucose-treated cardiac fibroblasts and streptozocin- (STZ-) induced diabetic rats. Rat cardiac fibroblasts were cultured in high-glucose (25 mM) media in the absence or presence of cafestol, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed on the basis of 3H-proline incorporation, enzyme-linked immunosorbent assay, and western blotting. Cardiac fibroblasts exposed to high-glucose conditions exhibited increased collagen synthesis, TGF-β1 production, and Smad2/3 phosphorylation, and these effects were mitigated by cafestol treatment. Furthermore, cafestol increased the translocation of nuclear factor erythroid 2-related factor 2 and increased the expression of heme oxygenase-1. The results of molecular docking analysis suggested a selective interaction of cafestol with Kelch-like ECH-associated protein 1. The rats with untreated STZ-induced diabetes exhibited considerable collagen accumulation, which was ameliorated by cafestol. Moreover, activities of catalase, superoxide dismutase, general matrix metalloproteinase, and reduced glutathione concentration were upregulated, whereas malondialdehyde level was downregulated by treatment with cafestol in rats with cardiac fibrosis. These findings highlight the effects of cafestol, which may be useful in treating diabetes-related cardiac fibrosis.


Zoledronic acid improves bone histomorphometry in a murine model of Rett syndrome.
Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT experience early onset osteoporosis, decreased bone mass and an increased fracture risk. There is no defined treatment for osteoporosis associated with RTT. The present study evaluated the effects of zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity, in a mouse model of MeCP2 deficiency. Mice received weekly injections of 20μg/kg ZA for six weeks. Due to the shortened lifespan of hemizygous male (Mecp2-null) mice, treatment began at 3weeks of age for this group and corresponding wildtype (WT) male mice. Treatment for heterozygous (HET) and WT female mice began at 8weeks of age. Micro-computed tomography (micro-CT) and dynamic analyses of bone turnover were performed. ZA treatment led to significant increases in bone volume fraction, number, connectivity density and apparent density of trabecular bone in all genotypes of mice. In contrast, cortical bone generally was unaffected by ZA injections. Parameters of bone turnover, including mineral apposition rate, labeled bone surface and bone formation rate decreased after treatment with ZA. Mecp2-null mice had reduced labeled bone surface and bone formation rate compared to WT male mice. The results indicate that ZA treatment significantly improved trabecular bone mass in a murine model of RTT with little effect on cortical bone.


The influence of feature-based information in the age processing of unfamiliar faces.
The influence of the internal features (eyes, nose, and mouth) in the age processing of unfamiliar faces was examined. Younger and older versions of the faces of six individuals (covering three different age ranges, from infancy to maturity) were used as donor stimuli. For each individual in turn, the effects on age estimates of placing older features in the younger face version (or vice versa) were investigated. Age estimates were heavily influenced by the age of the internal facial features. Experiment 2 replicated these effects with a larger number of faces within a narrower age range (after growth is complete and before major skin changes have occurred). Taken together, these two experiments show that the internal facial features may be influential in conveying age information to the perceiver. However, the mechanisms by which features exert their influence remain difficult to determine: although age estimates might be based on local information from the features themselves, an alternative possibility is that featural changes indirectly influence age estimates by altering the global three-dimensional shape of the head.


Efficient passivated phthalocyanine-quantum dot solar cells.
The power conversion efficiency of CdSe and CdS quantum dot sensitized solar cells is enhanced by passivation with asymmetrically substituted phthalocyanines. The introduction of the phthalocyanine dye increases the efficiency up to 45% for CdSe and 104% for CdS. The main mechanism causing this improvement is the quantum dot passivation. This study highlights the possibilities of a new generation of dyes designed to be directly linked to QDs instead of the TiO2 electrodes.


Direct detection of Theileria annulata in bovine blood samples using standard and isothermal DNA amplification approaches.
Tropical theileriosis is a tick-borne disease responsible for important health problems in cattle, caused by the hemoprotozoan Theileria annulata. Traditionally, detection of Theileria pathogens in infected animals requires the microscopic examination of stained-blood smears and serological methods. Molecular diagnostic assays have been developed for the detection of Theileria parasites, including PCR-based and reverse line blotting approaches, but these methods usually demand qualified personnel, complex instrumentation, and expensive materials. Loop-mediated isothermal amplification (LAMP) can facilitate the design of molecular assays independent of the use of sophisticated equipment. In this chapter we describe the application of two molecular assays for the direct detection of T. annulata in bovine blood samples, based in real-time PCR and LAMP, both targeting the Tams1-encoding gene of this parasite.


High resolution in situ hybridization to determine the cellular distribution of lymphocytic choriomeningitis virus RNA in the tissues of persistently infected mice: relevance to arenavirus disease and mechanisms of viral persistence.
By the application of in situ hybridization to thin sections of paraffin-embedded tissues we have been able to determine with high resolution the cell types containing lymphocytic choriomeningitis virus nucleic acid in the tissues of persistently infected mice. We confirm and extend previous observations of virus persistence in the brain, lung, liver, kidney, pancreas, thyroid and reticuloendothelial system. In addition, we demonstrate for the first time persistence of viral nucleic acid in specific cell types in the thymus, lymph nodes, testes and bladder, and the adrenal, parathyroid and salivary glands; the cell types infected were observed in several animals. In lymphoid tissue, viral nucleic acid was predominantly located in the T cell-dependent areas of the spleen and lymph nodes; it was also present in cells of the thymic medulla. This has important implications for the deficiency in T cell function observed in persistently infected mice. In the testes, viral nucleic acid was detected in spermatogonia but not differentiating spermatocytes and therefore, in this tissue at least, persistence is related to the state of differentiation of the cell. Endocrine and exocrine dysfunctions have been described in persistently infected mice and we report that the highest levels of viral nucleic acid were found in the adrenal gland. The infection of endocrine and exocrine tissue was not pantropic, specific cell types expressed viral nucleic acid in each tissue. In the adrenal cortex, cells of the zona reticularis and zona fasciculata but not the zona glomerulosa were positive, whereas in the adrenal medulla viral nucleic acid was predominantly localized to adrenalin-secreting cells. Infection of the renal tubules, transitional epithelium of the bladder and the ducts of the salivary gland indicates the likely sites of virus production for the dissemination of arenavirus infections.


Utilization of gabapentin by people in treatment for substance use disorders in Belgium (2011-2014): a cross-sectional study.
Although gabapentin has been licensed in the European Union only for neuropathic pain and epilepsy for patients who have partial seizures, it has also been prescribed in treatment for substance use disorders. Many studies report the potential risk of abuse of gabapentin by people with substance use disorders. The objective of this paper is to determine if people who have been in treatment for substance use disorders bought gabapentin in a time span that could indicate consumption at a dose that exceeded the maximum approved dose of 3600 mg/day. This analysis is the result of an observational cross-sectional descriptive study with matching. Two datasets were used and linked at individual level. Subjects were selected based on their first registration in the database of the Treatment Demand Indicator (TDI) between 2011 and 2014, without any exclusion criteria concerning nationality or age. Through linkage with the database of the InterMutualistic Agency (IMA) information on health service use and medication use was determined. In addition, each subject was matched on age, sex and place of residence to four comparators from the general population who were not in specialized treatment. The prevalence of gabapentin purchases in the period between 2008 and 2014 for both populations were compared. Quantification of the amount of gabapentin between two consecutive purchases was used as a proxy for potential abuse. Out of 30,905 patients in treatment for substance use disorders 2.7% had bought at least once gabapentin in a public pharmacy or received it from a hospital pharmacy, compared to 0.7% in the comparison group (n = 122,142). In both populations, more than half of the patients bought only once or twice gabapentin and about 10.0% bought at least once gabapentin in a time span that could indicate potential abuse. A limitation of the study is that it is only based on reimbursed medication without clinical information. Through the linkage of the TDI-database and the database of the Belgian health insurance companies, no evidence was found for regular abuse of prescribed gabapentin in Belgium by people in treatment for substance use disorders.


Molecular weight determinations of proteins by californium plasma desorption mass spectrometry.
The plasma desorption mass spectrometry method is used to determine the molecular weights of larger molecules than before, to determine the molecular weights of proteins and peptides in mixtures, and to monitor protein modification reactions. Proteins up to molecular weight 25,000 can now be studied with a mass spectrometric technique. Protein-peptide mixtures that could not be resolved with conventional techniques were successfully analyzed by this technique. The precision of the method is good enough to permit one to follow the different steps in the conversion of porcine insulin to human insulin.


Normative, passionate, or problematic? Identification of adolescent gamer subtypes over time.
For most youngsters, gaming is a fun and innocent leisure activity. However, some adolescents are prone to develop problematic gaming behavior. It is therefore important to have a comprehensive understanding of psychosocial and game-related characteristics that differentiate highly engaged gamers from problematic gamers. To that end, this study evaluated the stability and consistency of Internet gaming criteria (as suggested by the DSM-5) and psychosocial characteristics in a two-wave longitudinal study including 1928 young adolescents (mean age = 13.3 years, SD = 0.91, 57% boys). A confirmatory factor analysis revealed good stability of the Internet gaming disorder (IGD) construct over time. Latent class analyses revealed three classes for boys (recreational, engaged, and problematic) and two classes for girls (recreational and engaged). Significant differences between classes emerged for problem criteria (conflict and problems in social life), gaming duration, impulsivity, social competence, and attention/hyperactivity. The absence of a problematic gaming class for girls suggests that girls are less likely to develop problematic gaming behavior. The IGD criteria as proposed by the DSM-5 are a helpful tool to identify problematic gamers, although the results of this study suggest that using a strict cut-off point might result in false positives, particularly for boys. Problem criteria appeared to be the most sensitive and specific in identifying the problematic gamer, whereas escapism criteria were the least specific and sensitive. Careful consideration of the current proposed criteria to identify problematic gaming behavior could benefit the research and clinical field.


Female-specific pruritus from childhood to postmenopause: clinical features, hormonal factors, and treatment considerations.
There have been considerable advances in our understanding of the pathophysiology of pruritus in recent years. The purpose of this review was to highlight itch entities in women, and in particular pruritic vulvar dermatoses that women experience among different age groups. Unique temporal shifts may contribute to the etiology of many of these conditions. These changes lead to cyclical changes in the skin's basic composition. Specifically, estrogen receptors have been detected on keratinocytes that respond to rising and falling levels of estrogen. These receptors lead to changes in skin hydration, collagen content, and in the concentration of glycosaminoglycans that form the skin barrier. In addition, hormonal pH changes associated with the menstrual cycle may be an important factor in the aggravation of itch as increasing pH is known to activate the proteinase-activated receptor-2, a well-known itch mediator. Common pruritic conditions in women that will be discussed include atopic and irritant dermatitis, psoriasis, lichen sclerosus, infectious vulvovaginitis, vulvovaginal candidiasis, atrophic vulvovaginitis, squamous cell carcinoma, lichen simplex chronicus, and neuropathic itch. We also examine pruritic conditions associated with pregnancy including pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy and atopic eruption of pregnancy. Finally, acceptable and contraindicated antipruritic agents in pregnancy are examined.


Phenotypic spectrum of 20 novel patients with molecularly defined supernumerary marker chromosomes 15 and a review of the literature.
Supernumerary marker chromosomes (SMC) originating from chromosome 15 are the most common SMCs. They encompass clinically irrelevant SMC(15)s containing only heterochromatin and 15p material, and clinically relevant SMC(15)s that consist of both eu- and heterochromatic 15q material. On the basis of size, the clinically relevant SMC(15)s can be subdivided into type A, "large" asymmetric and type B, "small" symmetric SMC(15)s. Type B SMC(15)s contain the triplicated 15pter to BP3 (located at 26.5 Mb) region, while type A SMC(15)s consist of 15pter --> BP4(28.5 Mb)::BP5(30.5 Mb) --> 15pter. In this study, the clinical and molecular features of 18 patients with A and B SMC(15)s and two patients with a partial trisomy 15q were reviewed. Questionnaires (including Child Behavior Check Lists) were used to assess behavior and developmental features in more detail. The marker size and parental origin were determined by multiplex ligation-dependent probe amplification (MLPA). Based on the MLPA results, the majority of patients (14/18) had type A SMC(15)s. The phenotype observed did not show significant differences between types A and B SMC(15)s. A high prevalence of autistic-like behavior, attention problems, aggressive behavior, anxiety, and sleeping problems was reported. Motor and speech development varied extensively among the patients. An association was found between positive seizure history and degree of intellectual disability.


Implantation of silicon chip microphotodiode arrays into the cat subretinal space.
There are currently no therapies to restore vision to patients blinded by photoreceptor degeneration. This project concerns an experimental approach toward a semiconductor-based subretinal prosthetic designed to electrically stimulate the retina. The present study describes surgical techniques for implanting a silicon microphotodiode array in the cat subretinal space and subsequent studies of implant biocompatibility and durability. Using a single-port vitreoretinal approach, implants were placed into the subretinal space of the right eye of normal cats. Implanted retinas were evaluated post-operatively over a 10 to 27 month period using indirect ophthalmoscopy, fundus photography, electroretinography, and histology. Infrared stimulation was used to isolate the electrical response of the implant from that of the normal retina. Although implants continued to generate electrical current in response to light, the amplitude of the implant response decreased gradually due to dissolution of the implant's gold electrode. Electroretinograms recorded from implanted eyes had normal waveforms but were typically 10-15% smaller in amplitude than those in unimplanted left eyes. The nonpermeable silicon disks blocked choroidal nourishment to the retina, producing degeneration of the photoreceptors. The laminar structure of the inner retinal layers was preserved. Retinal areas located away from the implantation site appeared normal in all respects. These results demonstrate that silicon-chip microphotodiode-based implants can be successfully placed into the subretinal space. Gold electrode-based subretinal implants, however, appear to be unsuitable for long-term use due to electrode dissolution and subsequent decreased electrical activity.


Regulatory T cells: hypes and limitations.
In recent years there has been increased interest in understanding the physiology and function of regulatory T cells. In this review we focus on the characterization of regulatory T-cell subsets and their potential therapeutic use in organ transplantation. Regulatory T cells can play an instrumental role in the establishment of operational tolerance to allografts. The level of expression and the extent of posttranslational acetylation of the regulatory T-cell specific transcription factor Foxp3 are important modulators of their suppressive activity. Low expression of CD127 can be used as a novel marker to define pure regulatory T-cell populations and the expression of CD45RA on CD4CD25 regulatory T cells characterizes a population with a more stable phenotype upon expansion in vitro. Interleukin-35 is a recently discovered immunosuppressive cytokine secreted by CD4CD25 regulatory T cells. Although the presence of allospecific memory T cells in the pretransplant period and the use of immunosuppressants might interfere with the effectiveness of regulatory T-cell-based therapies, encouraging results indicate that the immunosuppressive drug rapamycin does not affect the expansion and function of regulatory T cells and could be included in a combined therapy. Important advances have been made towards establishing regulatory T cells as a viable therapy in transplantation and the first clinical trials using human regulatory T cells are currently underway. There are, however, important limitations and safety issues that have to be addressed before this therapy can be fully translated into the clinic.


Altered resting state EEG in chronic pancreatitis patients: toward a marker for chronic pain.
Electroencephalography (EEG) may be a promising source of physiological biomarkers accompanying chronic pain. Several studies in patients with chronic neuropathic pain have reported alterations in central pain processing, manifested as slowed EEG rhythmicity and increased EEG power in the brain's resting state. We aimed to investigate novel potential markers of chronic pain in the resting state EEG of patients with chronic pancreatitis. Resting state EEG data from 16 patients with persistent abdominal pain due to chronic pancreatitis (CP) were compared to data from healthy controls matched for age, sex and education. The peak alpha frequency (PAF) and power amplitude in the alpha band (7.5-13 Hz) were compared between groups in four regions of interest (frontal, central, parietal, and occipital) and were correlated with pain duration. The average PAF was lowered in CP patients compared with that in healthy controls, observed as a statistically significant between-group effect (mean 9.9 versus 9.5 Hz; P=0.049). Exploratory post hoc analysis of average PAF per region of interest revealed a significant difference, particularly in the parietal and occipital regions. In addition, we observed a significant correlation between pain duration and PAF and showed increased shifts in PAF with longer pain durations. No significant group differences were found in peak power amplitudes. CP pain is associated with alterations in spontaneous brain activity, observed as a shift toward lower PAF. This shift correlates with the duration of pain, which demonstrates that PAF has the potential to be a clinically feasible biomarker for chronic pain. These findings could be helpful for assisting diagnosis, establishing optimal treatment, and studying efficacy of new therapeutic agents in chronic pain patients.


Ammonia emissions from broiler litter: response to bedding materials and acidifiers.
1. In a pen study, NH(3) flux estimates were performed when clean wheat straw or wood shavings were used as bedding materials in combination with two NH(3) control amendments: sodium bisulphate and a commercial premix of phosphoric + hydrochloric + citric acids. 2. Ammonia emissions from wood shavings were 19% greater than from wheat straw around waterers, but statistically similar around feeders. These results could be due to the greater caking observed when wheat straw was used. 3. Sodium bisulphate reduced NH(3) emissions significantly only in the first half of the rearing period; the loss of efficacy in the second half resulted in total NH(3) volatilisation not statistically different from the untreated control. The treatment containing phosphoric + hydrochloric + citric acids did not have a significant effect in decreasing NH(3) emissions. 4. Bird mortality was not affected by the treatments, but broiler weight gain when wheat straw was used was significantly lower than with wood shavings, which could have been caused by the greater caking observed with wheat straw.


Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.
The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.


Adalimumab induction and maintenance therapy achieve clinical remission and response in Chinese patients with Crohn's disease.
This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220-450; high-sensitivity [hs]-C-reactive protein [CRP] ≥3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8-26; patients received 40 mg adalimumab every other week. Serum adalimumab concentration and change from baseline in fecal calprotectin (FC) were measured during the double-blind period. Clinical remission (CDAI <150), response (decrease in CDAI ≥70 points from baseline), and change from baseline in hs-CRP were assessed through week 26. Nonresponder imputation was used for missing categorical data and last observation carried forward for missing hs-CRP/FC values. No formal hypothesis was tested. Adverse events were monitored. Mean adalimumab serum concentrations during the induction phase were 13.9-18.1 µg/mL (160/80 mg group) and 7.5-9.5 µg/mL (80/40 mg group). During the double-blind period, higher remission/response rates and greater reductions from baseline in hs-CRP and FC were observed with adalimumab 160/80 mg compared to that with 80/40 mg. Adverse event rates were similar among all treatment groups. Adalimumab serum concentrations in Chinese patients with CD were comparable to those observed previously in Western and Japanese patients. Clinically meaningful remission rates and improvement in inflammatory markers were achieved with both dosing regimens; changes occurred rapidly with adalimumab 160/80 mg induction therapy. No new safety signals were reported.


Superior endurance performance in aging mountain runners.
Oxygen uptake at the anaerobic threshold (VO(2)AT) is considered as the main determinant for endurance performance in humans. Endurance performance steeply decreases with aging but seems to be kept exceedingly high in elite mountain runners. To obtain the age- and gender-related upper limits of endurance performance in this sport, we analyzed the results of the World Masters Athletic Championships in Mountain Running 2007. Additionally, to investigate the relationship between the individual VO(2)AT values and running times, laboratory tests were performed in 10 mountain runners. The World Championships race times of the first 5 finishers of the 5-year age groups did not differ significantly from 35 to 49 years. The corresponding mean (+/- SD) values of the VO(2)AT were 68.0 +/- 1.7 ml/min/kg in males and 58.1 +/- 1.9 ml/min/kg in females. In the following age groups up to 70+ there was a decrease in the VO(2)AT of 29.1% in males and 33.9% in females. Thus, at the beginning of the 3rd millennium, elite mountain runners demonstrate that VO(2)AT and probably also VO(2max) may be held at top levels in humans up to the age of 45-49 years in both sexes. Despite the following decrease, endurance capacity remains about 3.5-fold higher in elite mountain runners up to 70+ years when compared to their untrained peers.


Baculovirus gp64 gene expression: analysis of sequences modulating early transcription and transactivation by IE1.
Expression of the baculovirus major envelope glycoprotein gene (gp64) is regulated by transcription from both early and late promoters. To characterize the early promoter and identify sequences involved in the regulation of gp64 early transcription, promoter-reporter gene fusions were generated from the Orygia pseudotsugata nuclear polyhedrosis virus gp64 promoter and were analyzed by transient expression in uninfected insect cells. For these analyses, 5' deletion mutations were constructed in the gp64 upstream regulatory region. Larger promoter constructs were functional in uninfected Lymantria dispar cells, indicating that transcription from the gp64 early promoter required no additional viral gene products. Deletion analysis of the gp64 upstream region revealed several regulatory regions. These included a putative negative regulatory element between -319 and -166 nucleotides (nt) and multiple positive regulatory elements between -166 and -77 nt. Deletion of the TATA box located between -77 and -62 nt resulted in the loss of transcriptional activity. Cotransfections of reporter constructs and a plasmid containing a baculovirus transcriptional transactivator gene (Autographa californica nuclear polyhedrosis virus IE1) resulted in transcriptional transactivation of all constructs containing an intact TATA box. These data demonstrate that sequences upstream of the gp64 TATA box are not essential for IE1 transactivation and that only 34 nt upstream of the early transcription start site were necessary for basal levels of transcription and for transactivation by IE1. Function of the gp64 early promoter was also examined in cell lines from Spodoptera frugiperda and Drosophila melanogaster.


Hepatocyte nuclear factors 1alpha and 4alpha control expression of proline oxidase in adult liver.
Adult liver functions are regulated by several hepatocyte nuclear factors (HNFs). HNF4alpha and HNF1alpha are involved in metabolic functions in the liver. The expression of proline oxidase (PO) and proline dehydrogenase was downregulated in the HNF4alpha liver-specific null mice. In addition, the expression of PO was also diminished in the liver derived from HNF1alpha-null mice. The -160 bp proximal promoter region of the PO gene has two HNF4alpha- and HNF1alpha-binding consensus sites. Transactivation, electrophoretic mobility shift and chromatin immunoprecipitation studies revealed that these regions are important for PO promoter activity. These results suggested that HNF4alpha and HNF1alpha regulate proline metabolism in adult liver.


Assessment of tobacco control efforts in three Sub-Saharan African countries.
Tobacco industry's undermining of tobacco control goes on unabated in sub-Saharan African countries, especially in Kenya, Nigeria, and Uganda. The Framework Convention on Tobacco Control (FCTC) contains provisions aimed at curbing these activities. However, the level to which FCTC is implemented and the strength of each country's tobacco control law will determine its usefulness in this regard. We determined the implementation status and strength of tobacco control laws in Kenya, Nigeria, and Uganda. The World Health Organization and Campaign for Tobacco-Free Kids websites were queried for secondary data related to tobacco control. Sources and data were disambiguated and reported as tables. Composite scores for implementation were computed based on the number of indicators of the articles of the FCTC reported on by each country. Strength of tobacco control law (SoTCL) was computed based on the total number of domains of the laws meeting a defined acceptable standard. Total obtainable score for implementation and SoTCL were 148 and 38, respectively. On the FCTC, Kenya, Nigeria, and Uganda achieved 75, 61.5, and 46.6% implementation, respectively. SoTCL was weakest in the smoke-free domain for Kenya, tobacco advertisement promotion and sponsorship domain for Nigeria, and packaging and labeling domain for Uganda. SoTCL scores were 18 (47.4%), 20 (52.6%), and 34 (89.5%) for Nigeria, Kenya, and Uganda, respectively. Kenya, Nigeria, and Uganda will need to strengthen their tobacco control laws through appropriate amendment as well as regulatory mechanisms that guarantee alignment with FCTC and the implementation thereof.


Usefulness of total bladder capacity and post-void residual urine volume as a predictor of detrusor overactivity with impaired contractility in stroke patients.
Detrusor overactivity (DO) with impaired contractility (DOIC) is a mixed pattern of involuntary contraction and increased post-void residual urine volume (PVR) which occurs in stroke patients. Urodynamic study results obtained from patients with detrusor abnormalities and stroke were analyzed to identify the associations between various urodynamic parameters and DOIC. Between August 2003 and November 2010, 127 patients were selected from 178 patients undergoing urodynamic study due to urinary symptoms. Stroke patients were divided into three groups: the DO, DOIC and detrusor underactivity (DU) groups. The significance of differences between the three groups was analyzed using the Kruskal-Wallis test and receiver operating characteristic (ROC) curves were used to calculate the accuracy of the urodynamic study result factors to distinguish between the three groups. The average total bladder capacity (TBC) was 219.15±98.30 ml in the DO, 330.25±115.75 ml in the DOIC and 486.00±111.48 ml in the DU (P<0.001) group. The average PVR was 22.64±20.85 ml in the DO, 146.87±95.09 ml in the DOIC and 425.33±136.70 ml in the DU (P<0.001) group. A ROC curve of DO and DOIC revealed that TBC and PVR were significantly different between the DOIC and DO groups. The area under the curve (AUC) of TBC was 0.812 (P<0.001) and that of PVR was 0.987 (P<0.001). A ROC curve of DOIC and DU revealed that TBC and PVR were significantly different between the DOIC and DU groups. The AUC of TBC was 0.813 (P<0.001) and that of PVR was 0.929 (P<0.001). In the urodynamic study of stroke patients with urinary symptoms, TBC and PVR may provide useful information for treating patients who cannot undergo urodynamic study.


Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).


Guiding Principles for Data Architecture to Support the Pathways Community HUB Model.
The Pathways Community HUB Model provides a unique strategy to effectively supplement health care services with social services needed to overcome barriers for those most at risk of poor health outcomes. Pathways are standardized measurement tools used to define and track health and social issues from identification through to a measurable completion point. The HUB use Pathways to coordinate agencies and service providers in the community to eliminate the inefficiencies and duplication that exist among them. Experience with the Model has brought out the need for better information technology solutions to support implementation of the Pathways themselves through decision-support tools for care coordinators and other users to track activities and outcomes, and to facilitate reporting. Here we provide a basis for discussing recommendations for such a data infrastructure by developing a conceptual model that formalizes the Pathway concept underlying current implementations. The main contribution is a set of core recommendations as a framework for developing and implementing a data architecture to support implementation of the Pathways Community HUB Model. The objective is to present a tool for communities interested in adopting the Model to learn from and to adapt in their own development and implementation efforts. Experience with the Community Health Access Project (CHAP) data base system (the core implementation of the Model) has identified several issues and remedies that have been developed to address these issues. Based on analysis of issues and remedies, we present several key features for a data architecture meeting the just mentioned recommendations. Presentation of features is followed by a practical guide to their implementation allowing an organization to consider either tailoring off-the-shelf generic systems to meet the requirements or offerings that are specialized for community-based care coordination. Looking to future extensions, we discuss the utility and prospects for an ontology to include care coordination in the Unified Medical Language System (UMLS) of the National Library of Medicine and other existing medical and nursing taxonomies. Pathways structures are an important principle, not only for organizing the care coordination activities, but also for structuring the data stored in electronic form in the conduct of such care. We showed how the proposed architecture encourages design of effective decision support systems for coordinated care and suggested how interested organizations can set about acquiring such systems. Although the presentation focuses on the Pathways Community HUB Model, the principles for data architecture are stated in generic form and are applicable to any health information system for improving care coordination services and population health.


Augmented sympathetic nerve activity and pressor responsiveness in DOCA hypertensive rats.
Spike potentials in abdominal sympathetic nerves were recorded together with aortic blood pressure before and during electrical stimulation of the posterior hypothalamus in urethane-anesthetized rats. Both the initial rate of sympathetic nerve firing and the subsequent acceleration produced by hypothalamic stimulation were higher in deoxycorticosterone acetate (DOCA) hypertensive than in normotensive rats. Pressor responsiveness was generally augmented, but responses to hypothalamic stimulation, were increased far more than those to injected norepinephrine. Vasodepression produced by blocking autonomic ganglia pharmacologically with pentolinium was also more pronounced in DOCA hypertensive rats than in normotensive controls. These results support the conclusion that a centrally induced sympathetic hyperactivity is important for maintaining the blood pressure elevation in rats with established DOCA hypertension.


Homocysteine Induces Inflammation in Retina and Brain.
Homocysteine (Hcy) is an amino acid that requires vitamins B12 and folic acid for its metabolism. Vitamins B12 and folic acid deficiencies lead to hyperhomocysteinemia (HHcy, elevated Hcy), which is linked to the development of diabetic retinopathy (DR), age-related macular degeneration (AMD), and Alzheimer's disease (AD). The goal of the current study was to explore inflammation as an underlying mechanism of HHcy-induced pathology in age related diseases such as AMD, DR, and AD. Mice with HHcy due to a lack of the enzyme cystathionine-β-synthase (CBS) and wild-type mice were evaluated for microglia activation and inflammatory markers using immuno-fluorescence (IF). Tissue lysates isolated from the brain hippocampal area from mice with HHcy were evaluated for inflammatory cytokines using the multiplex assay. Human retinal endothelial cells, retinal pigment epithelial cells, and monocyte cell lines treated with/without Hcy were evaluated for inflammatory cytokines and NFκB activation using the multiplex assay, western blot analysis, and IF. HHcy induced inflammatory responses in mouse brain, retina, cultured retinal, and microglial cells. NFκB was activated and cytokine array analysis showed marked increase in pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines. Therefore, elimination of excess Hcy or reduction of inflammation is a promising intervention for mitigating damage associated with HHcy in aging diseases such as DR, AMD, and AD.