Asymmetric mechanosensitivity in a eukaryotic ion channel.
Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian two-pore domain (K2P) K+ channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli.


Shadow removal using bilateral filtering.
In this paper, we propose a simple but effective shadow removal method using a single input image. We first derive a 2-D intrinsic image from a single RGB camera image based solely on colors, particularly chromaticity. We next present a method to recover a 3-D intrinsic image based on bilateral filtering and the 2-D intrinsic image. The luminance contrast in regions with similar surface reflectance due to geometry and illumination variances is effectively reduced in the derived 3-D intrinsic image, while the contrast in regions with different surface reflectance is preserved. However, the intrinsic image contains incorrect luminance values. To obtain the correct luminance, we decompose the input RGB image and the intrinsic image. Each image is decomposed into a base layer and a detail layer. We obtain a shadow-free image by combining the base layer from the input RGB image and the detail layer from the intrinsic image such that the details of the intrinsic image are transferred to the input RGB image from which the correct luminance values can be obtained. Unlike previous methods, the presented technique is fully automatic and does not require shadow detection.


Relationship between sulcular sulfide level and oral malodor in subjects with periodontal disease.
The relationship between oral malodor and sulfide levels in periodontal pockets (pS) has not yet been determined. The aims of this study were: 1) to identify the correlation among oral malodor, pS levels, and the BANA (benzoyl-DL-arginine-naphthylamide) test and 2) to recognize the interaction between oral malodor, demographic factors, tongue coating, and periodontal condition. Eighty-one periodontal patients participated in this study. A portable sulfide monitor and organoleptic method were used to evaluate oral malodor. Demographic data included age, gender, race, and smoking habits. The volume of tongue coating and periodontal condition for all teeth were assessed. The pS levels of 3 different radiographic bone loss (RBL) sites: RBL < 2 mm, healthy; RBL > or = 2 to < 4 mm; low to moderate; RBL > or = 4 mm, severe, were measured using an industrial sulcular sulfide-monitoring device. Subgingival plaque samples from the above 3 sites and tongue scraping were examined by the BANA test. The volume of tongue coating (P<0.001), extent of periodontal disease (P<0.05), pS levels of the sites with low to moderate bone loss (P<0.05), and BANA score of tongue scrapings (P<0.05) were significantly associated with oral malodor. Stepwise multiple regression analysis examined the degree of association between oral malodor and potential explanatory variables. The volume of tongue coating and percent of sites BOP (bleeding on probing) were significantly associated with oral malodor. Females and smoking habit were negatively correlated with organoleptic measurements. The pS level of the representative sites with low to moderate bone loss demonstrated a modest association with oral malodor. Oral malodor in periodontal patients was primarily associated with tongue coating and gingival inflammation.


A combined low-frequency electromagnetic and fluidic stimulation for a controlled drug release from superparamagnetic calcium phosphate nanoparticles: potential application for cardiovascular diseases.
Alternative drug delivery approaches to treat cardiovascular diseases are currently under intense investigation. In this domain, the possibility to target the heart and tailor the amount of drug dose by using a combination of magnetic nanoparticles (NPs) and electromagnetic devices is a fascinating approach. Here, an electromagnetic device based on Helmholtz coils was generated for the application of low-frequency magnetic stimulations to manage drug release from biocompatible superparamagnetic Fe-hydroxyapatite NPs (FeHAs). Integrated with a fluidic circuit mimicking the flow of the cardiovascular environment, the device was efficient to trigger the release of a model drug (ibuprofen) from FeHAs as a function of the applied frequencies. Furthermore, the biological effects on the cardiac system of the identified electromagnetic exposure were assessed in vitro and in vivo by acute stimulation of isolated adult cardiomyocytes and in an animal model. The cardio-compatibility of FeHAs was also assessed in vitro and in an animal model. No alterations of cardiac electrophysiological properties were observed in both cases, providing the evidence that the combination of low-frequency magnetic stimulations and FeHAs might represent a promising strategy for controlled drug delivery to the failing heart.


Functional dialkylimidazolium-mediated synthesis of silver nanocrystals with sensitive Hg(2+)-sensing and efficient catalysis.
Thiol-functionalized dialkylimidazolium bromide was synthesized, and used as a stabilizer to prepare monodisperse silver nanocrystals through a facile one-pot aqueous approach. It is shown that the multipurpose ligands play a vital role in improving the performance of nanocrystals. The mechanisms of dialkylimidazolium-mediated promotion were analyzed on the basis of the physicochemical properties of the specifically designed ligand.


Reviewing research priorities in weed ecology, evolution and management: a horizon scan.
Weedy plants pose a major threat to food security, biodiversity, ecosystem services and consequently to human health and wellbeing. However, many currently used weed management approaches are increasingly unsustainable. To address this knowledge and practice gap, in June 2014, 35 weed and invasion ecologists, weed scientists, evolutionary biologists and social scientists convened a workshop to explore current and future perspectives and approaches in weed ecology and management. A horizon scanning exercise ranked a list of 124 pre-submitted questions to identify a priority list of 30 questions. These questions are discussed under seven themed headings that represent areas for renewed and emerging focus for the disciplines of weed research and practice. The themed areas considered the need for transdisciplinarity, increased adoption of integrated weed management and agroecological approaches, better understanding of weed evolution, climate change, weed invasiveness and finally, disciplinary challenges for weed science. Almost all the challenges identified rested on the need for continued efforts to diversify and integrate agroecological, socio-economic and technological approaches in weed management. These challenges are not newly conceived, though their continued prominence as research priorities highlights an ongoing intransigence that must be addressed through a more system-oriented and transdisciplinary research agenda that seeks an embedded integration of public and private research approaches. This horizon scanning exercise thus set out the building blocks needed for future weed management research and practice; however, the challenge ahead is to identify effective ways in which sufficient research and implementation efforts can be directed towards these needs.


Association between Sleep Patterns and Health in Families with Exceptional Longevity.
Sleep patterns such as longer sleep duration or napping are associated with poor health outcomes. Although centenarians and their offspring demonstrate a delayed onset of age-related diseases, it is not known whether they have healthier sleep patterns or are protected against the negative effects of sleep disturbances. Data on sleep patterns and health history were collected from Ashkenazi Jewish subjects of the Longevity Genes Project using standardized questionnaires. Participants included individuals with exceptional longevity (centenarians) with preserved cognition (n = 348, median age 97 years), their offspring (n = 513, median age 69 years), and controls (n = 199) age-matched to the offspring. Centenarians reported on their sleep patterns at age 70, while the offspring and controls on their current sleep patterns. Biochemical parameters were measured at baseline. Models were adjusted for age, sex, BMI, and use of sleep medication. The offspring and controls reported similar sleep patterns, with 33% sleeping ≥8 h and 17% napping in each group. At age 70, centenarians were more likely to have slept ≥8 h (55%) and to have napped (28%) compared with offspring and controls, p < 0.01. Among centenarians, no association was noted between sleep patterns and health outcomes. Sleeping for ≥8 h was associated with lower high-density lipoprotein cholesterol levels in the offspring and controls, and with insulin resistance in the offspring, but not with diabetes. Napping was associated with insulin resistance among the controls (p < 0.01), but not the offspring. Controls, but not offspring, who napped were 2.79 times more likely to have one or more of the following diseases: hypertension, myocardial infarction, stroke, or diabetes (OR 2.79, 95% CI 1.08-7.21, p = 0.04). Despite being more likely to exhibit risky sleep patterns at age 70 compared with the offspring and controls, the centenarians were protected from age-related morbidities. The offspring of centenarians did exhibit metabolic disturbances in association with less healthy sleep patterns; however, unlike the controls, they were much less likely to manifest age-related diseases. This suggests that offspring may have inherited resilience genotypes from their centenarian parents that protect them against the harmful effects of sleep disturbances.


Minocycline in the treatment of non-gonococcal urethritis.
108 male patients with non-gonococcal urethritis have been treated with minocycline given as two 100 mg. tablets initially, followed by one tablet twice a day over a period of 6 days (13 tablets). Of 96 patients followed, re-treatment for non-gonococcal urethritis within 3 months was undertaken in ten (10.4 per cent.). The findings are compared with those previously reported in seven series involving six other tetracyclines and with nine other treatment regimens. All of the tetracyclines proved superior to other agents and the best results combined with simplicity of administration were obtained with minocycline. Two patients complained of soreness of the mouth after 1 week but no other side-effects were reported. Minocycline thus gives excellent results in the treatment of non-gonococcal urethritis. In the dosage used it was also successful against gonorrhoea in seven patients treated. It is therefore particularly useful in cases in which gonorrhoea is suspected but not found in the smears or in which the smears cannot be read immediately.


Diallyl trisulfide and diallyl disulfide ameliorate cardiac dysfunction by suppressing apoptotic and enhancing survival pathways in experimental diabetic rats.
Cardiovascular disease is one of the major causes of mortality in diabetic patients. Mounting studies have shown that garlic exhibits, possibly through its antioxidant potential, diverse biological activities. In this study, we investigated the alleviating effects of garlic oil (GO) and its two major components, diallyl disulfide (DADS) and diallyl trisulfide (DATS), on diabetic cardiomyopathy in rats. Physiological cardiac parameters were obtained using echocardiography. Apoptotic cells were evaluated using TUNEL and DAPI staining. Protein expression levels were determined using Western blotting analysis. Our findings indicated that in diabetic rat hearts significantly decreased fractional shortening percentage, increased levels of nitrotyrosine, an elevated number of TUNEL-positive cells, enhanced levels of caspase 3 expression, and decreased PI3K-Akt signaling pathway activities were observed. Furthermore, all of these alterations were reversed following both GO and DATS (or DADS) administrations through increasing PI3K-Akt signaling pathway activities and inhibiting both the death receptor-dependent and the mitochondria-dependent apoptotic pathways. In conclusion, this study shows that DATS and DADS, with the efficacy order DATS > DADS, have the therapeutic potential for ameliorating diabetic cardiomyopathy. Furthermore, the therapeutic effects of GO on diabetic cardiomyopathy should be mainly from DATS and DADS.


Solid Phase Microextraction On-Fiber Derivatization Using a Stable, Portable, and Reusable Pentafluorophenyl Hydrazine Standard Gas Generating Vial.
Solid phase microextraction (SPME) on-fiber derivatization methods have facilitated the achievement of lower detection limits and targeted analysis of various substances that exhibit poor chromatographic behavior, thermal instability, or high reactivity while limiting the use of organic solvents. However, previously developed on-fiber derivatization methods have been hindered by poor loading reproducibility and standard lifetime due to derivatization reagent reactivity. In addition, this reactivity often results in these reagents demonstrating toxic effects, complicating handling and standard formulation. To address this, a reusable standard gas generating vial containing pentafluorophenyl hydrazine (PFPH) has been developed. With this development, SPME fibers can now be reproducibly loaded with derivatization reagent, from an easy to use and safe platform. Validation of the vial using C4-C9 linear aldehyde standards as target analytes demonstrated intrabatch vial reproducibility (2% relative standard deviation (RSD), n = 4), along with PFPH headspace stability over a period of 11 weeks, facilitating reduced reagent consumption due to standard longevity. In addition, reproducibility of the derivatization reaction was observed over 1 week (RSD < 9%), and the linear concentration range was evaluated using headspace extractions from aqueous aldehyde solutions (R(2) > 0.996, 10-200 ppb v/v). Finally, the PFPH-generating vial was applied to the monitoring of volatile aldehydes generated during meat spoilage, as well as an on-site application where the free and total concentration of formaldehyde was determined in car exhaust using a portable GC/MS. To the best of our knowledge, the standard gas generating vial proposed in this work is the first documented device for the long-term storage of reusable headspace standards for a reactive, toxic, and otherwise unstable derivatization reagent standard.


Eating Disorders and Mentalization: High Reflective Functioning in Patients with Bulimia Nervosa.
The theory of mentalization has recently been applied in the area of eating disorders (Skårderud 2012). This article reports a qualitative study based on interviews with five women suffering from bulimia nervosa. All five scored high on the Reflective Functioning Scale, indicating a highly developed ability to mentalize. The present qualitative study, which focuses on the women's capacity to relate to and regulate affects, supports the finding that they are relatively skilled at reflecting on their own and others' thoughts and emotions. However, this highly developed capacity for mentalization is apparently not helping them regulate their emotions. This suggests that the capacity to mentalize may not be as closely related to the capacity to regulate affects as Fonagy et al. (2002) have proposed. Indeed, the concept of mentalization may be overinclusive and in need of stricter definition. Thus, it might be envisaged that while the ability to mentalize is closely related to the ability to put feelings into words (the opposite of alexithymia), an ability to mentalize may not necessarily entail a capacity to regulate affects. Finally, the study illustrates that far from all eating-disordered patients have problems mentalizing.


Evaluation of the disease modifying activity of Colchicum luteum Baker in experimental arthritis.
Colchicum luteum (CL) has been traditionally used in the Unani system of medicine as a chief ingredient of many polyherbal formulations for the treatment of joint pain and rheumatoid arthritis (RA). To evaluate the antiarthritic activity of CL hydroalcoholic extract (CLHE) in formaldehyde and complete Freund's adjuvant (CFA) induced arthritis. Arthritis was induced by administration of either formaldehyde (2% v/v) or CFA into the subplantar surface of the hind paw of the animal. Joint swelling was measured on days 8, 9 and 10 in formaldehyde induced arthritis and days 3, 7, 14 and 21 in CFA induced arthritis. In order to evaluate the effect of CLHE on disease progression, serum TNF-α level and synovial expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1β) was determined in CFA induced arthritis. CLHE produced a significant and dose dependent inhibition of joint swelling during the entire duration of the study in both, formaldehyde and CFA induced arthritis. Serum TNF-α level was also reduced significantly in a dose dependent manner in all the CLHE treated groups. The expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1β) was also found to be less in the CLHE treated group as compared to control. We believe that the antiarthritic activity of CLHE was due to its modulatory effect on the expression of proinflammatory cytokine in the synovium. Our results contribute towards validation of the traditional use of CL in the treatment of RA and other inflammatory joint disorders.


Liposome-Encapsulated Human Immunodeficiency Virus-1 gp120 Induces Potent V1V2-Specific Antibodies in Humans.
In the RV144 trial, human immunodeficiency virus (HIV)-1 gp120 V1V2 antibodies correlated inversely with risk of HIV-1 infection; however, the titers waned quickly. We hypothesized that a more potent adjuvant might enhance the magnitude and durability of V1V2 antibodies. We examined archived sera from a phase I randomized, double-blind placebo-controlled trial, conducted in HIV-1-uninfected individuals, vaccinated with HIV-1SF-2 rgp120 either adsorbed to aluminum hydroxide (aluminum hydroxide arm) or encapsulated in liposomes containing monophosphoryl lipid A (MPL®) and then adsorbed to aluminum hydroxide (liposomal arm). The median immunoglobulin G antibody titers across weeks 10-112 were higher in the liposomal arm against subtypes B (2- to 16-fold), AE (4- to 8-fold), and C (4- to 16-fold) V1V2 proteins. High titers were maintained even at 10 months after last boost in the liposomal compared with the aluminum hydroxide arm. The antibodies exhibited antibody-dependent cellular cytotoxicity (ADCC) and α4β7-integrin receptor inhibition-binding functions. Inclusion of 2 adjuvants in the vaccine formulation, aluminum hydroxide, and liposomal MPL®, induced robust, durable, and functional antibodies. Based on the magnitude of antibody responses and the percentage of coiled and β-sheet in the predicted V2/V3-peptide structure, we speculate that liposomal gp120 was presented in a conformation that favored the induction of robust antibody responses.


Factors associated with patient satisfaction for PLIF: Patient satisfaction analysis.
Posterior lumbar interbody fusion (PLIF) has produced satisfactory clinical outcomes; however, all previous reports have only included evaluations by surgeon-based methods. The purpose of this study was to investigate patient-based surgical outcomes and the factors associated with patient satisfaction for PLIF. Patients who underwent PLIF for lumbar spondylolisthesis were reviewed (n=443). The average follow-up period was 8 years. Surgical outcomes were assessed using an original questionnaire, a numerical rating scale (NRS), the 36-Item Short Form Health Survey (SF-36), the Japanese Orthopedic Association (JOA) score, and the recovery rate. The original questionnaire consisted of five categories, with patient-evaluated score out of 100 points for surgery, satisfaction, improvement, recommendation to others, and willingness to undergo repeat surgery on a 5-point scale. According to the questionnaire responses, patient-based outcomes were divided into three groups: positive, intermediate, and negative and were compared with the NRS, SF-36, and JOA scores. Furthermore, factors associated with patient satisfaction were examined. A total of 273 patients responded. Response rate was 62%. The average patient-evaluated score for surgery was 82 points. In terms of satisfaction section, positive, intermediate, and negative response rates were 82%, 7%, and 11%, respectively. With respect to other sections, positive, intermediate, and negative response rates were 87%, 7%, and 6% in improvement section; 66%, 23%, and 11% in recommending section; and 72%, 18%, and 10% in repeat section, respectively. The average pre- and postoperative JOA scores were 12 and 24, respectively. Significant correlations were detected between patient-based surgical outcomes and the NRS scores, physical component scores of the SF-36, and the JOA score. Postoperative permanent motor loss and multiple revision surgery were the major factors related to a negative response. High satisfaction rate to PLIF and significant correlation between patient- and surgeon-based surgical outcomes were detected. Postoperative permanent motor loss and multiple revision surgery were the major factors related to a negative response.


How 'special' is the human face? Evidence from an audiovisual temporal order judgment task.
Upright and inverted audiovisual video clips of a monkey producing a 'coo' and a human imitating this vocalization were presented at a range of stimulus onset asynchronies. Participants made temporal order judgments regarding which modality stream appeared to have been presented first. The results showed that inverting the dynamic human visual display led to a significant differences in the point of subjective simultaneity, with the inverted human faces requiring more time to be processed compared with the upright displays. No such inversion effect was found for the monkey visual displays. These results demonstrate that the effect of inversion on the temporal perception of audiovisual speech stimuli are driven by the viewing of a human face rather than by the integration of audiovisual speech.


Gestational age, birth weight, and risk of respiratory hospital admission in childhood.
To investigate the risk of emergency respiratory hospital admission during childhood associated with gestational age at birth and growth restriction in utero. The study included a total population electronic birth cohort with anonymized record-linkage of multiple health and administrative data sets. Participants were 318,613 children born in Wales, United Kingdom, between May 1, 1998, and December 31, 2008. The main outcome measure was emergency respiratory hospital admissions. The rate of admission in the first year of life ranged from 41.5 per 100 child-years for infants born before 33 weeks' gestation to 9.8 per 100 child-years for infants born at 40 to 42 weeks' gestation. The risk of any emergency respiratory admission up to age 5 years increased as gestational age decreased to <40 weeks. Even at 39 weeks' gestation, there was an increased risk of emergency hospital admissions for respiratory conditions compared with infants born at 40 to 42 weeks (adjusted hazard ratio 1.10; 95% confidence interval 1.08-1.13). Small for gestational age (<10th centile for gestation and gender-specific birth weight) was independently associated with an increased risk of any emergency respiratory admission to hospital (adjusted hazard ratio 1.07; 95% confidence interval 1.04-1.10). The risk of emergency respiratory admission up to age 5 years decreased with each successive week in gestation up to 40 to 42 weeks. Although the magnitude of increased risk associated with moderate and late preterm births is small, the number of infants affected is large and therefore presents a significant impact on health care services.


Payer status is associated with the use of prophylactic inferior vena cava filter in high-risk trauma patients.
It is controversial whether patients at high risk for pulmonary embolism (PE) should receive prophylactic inferior vena cava filters (IVC) filters. This lack of clarity creates the potential for variability and disparities in care. We hypothesized there would be differential use of prophylactic IVC filters for patients at high risk for PE on the basis of insurance status. We performed a retrospective analysis using the National Trauma Databank (2002-2007). We included adult patients at high risk for PE (traumatic brain injury or spinal cord injury) and excluded patients with a diagnosis of deep venous thrombosis (DVT) or PE. Logistic regression was performed to control for confounders and a hierarchical mixed effects model was used to control for center. A prophylactic filter was placed in 3,331 (4.3%) patients in the study cohort. Patients without insurance had an IVC filter placed less often compared with those with any form of insurance (2.7% vs 4.9%, respectively). After adjusting for confounders, we found that patients without insurance were less likely to receive a prophylactic IVC filter, even when we controlled for center (OR 5.3, P < .001). When guidelines lack clarity, unconscious bias has the potential to create a system with different levels of care based on socioeconomic disparities.


Telemedicine in Prehospital Stroke Evaluation and Thrombolysis: Taking Stroke Treatment to the Doorstep.
Mobile stroke treatment units (MSTUs) with on-site treatment teams that include a vascular neurologist can provide thrombolysis in the prehospital setting faster than treatment in the hospital. These units can be made more resource efficient if the need for an on-site neurologist can be eliminated by relying solely on telemedicine for physician presence. To test whether telemedicine is reliable and remote physician presence is adequate for acute stroke treatment using an MSTU. Prospective observational study conducted between July 18 and November 1, 2014. The dates of the study analysis were November 1, 2014, to March 30, 2015. The setting was a community-based study assessing telemedicine success of the MSTU in Cleveland, Ohio. Participants were the first 100 residents of Cleveland who had an acute onset of stroke-like symptoms between 8 am and 8 pm and were evaluated by the MSTU after the implementation of the MSTU program at the Cleveland Clinic. A vascular neurologist evaluated the first 100 patients via telemedicine, and a neuroradiologist remotely assessed images obtained by mobile computed tomography (CT). Data were entered into the medical record and a prospective registry. The study compared the evaluation and treatment of patients on the MSTU with a control group of patients brought to the emergency department via ambulance during the same year. Process times were measured from the time the patient entered the door of the MSTU or emergency department, and any problems encountered during his or her evaluation were recorded. Ninety-nine of 100 patients were evaluated successfully. The median duration of telemedicine evaluation was 20 minutes (interquartile range [IQR], 14-27 minutes). One connection failure was due to crew error, and the patient was transported to the nearest emergency department. There were 6 telemedicine disconnections, none of which lasted longer than 60 seconds or affected clinical care. Times from the door to CT completion (13 minutes [IQR, 9-21 minutes]) and from the door to intravenous thrombolysis (32 minutes [IQR, 24-47 minutes]) were significantly shorter in the MSTU group compared with the control group (18 minutes [IQR, 12-26 minutes] and 58 minutes [IQR, 53-68 minutes], respectively). Times to CT interpretation did not differ significantly between the groups. An MSTU using telemedicine is feasible, with a low rate of technical failure, and may provide an avenue for reducing the high cost of such systems.


Gambling involvement and increased risk of gambling problems.
The opportunity to gamble has undergone rapid expansion with technology allowing for access to gambling products 24 h a day. This increased online availability challenges governments' abilities to restrict access to gambling. Indeed, the ready access to multiple forms of gambling may potentially contribute to impaired control over urges for problem gamblers. The present study considered whether problem gamblers manifested a tendency to engage in multiple forms of gambling and identified forms of gambling which were more strongly related to problem gambling. In reanalyses of two surveys (Sample 1, N = 464, Sample 2, N = 1141), significant relationships accounting for between 11.3 and 13.5% of the variance were found between the numbers of forms of gambling accessed and degree of problem. Participation in online poker, playing cards and sports wagering were linked to problem gambling. Access to multiple forms of gambling may pose difficulties for the tracking and control of gambling.


Ultrasonographic evaluation of plantar fasciitis after low-level laser therapy: results of a double-blind, randomized, placebo-controlled trial.
The aim of this study was to investigate the effect of low-level laser therapy (LLLT) on plantar fasciitis documented by the ultrasonographic appearance of the aponeurosis and by patients' pain scores. Thirty individuals with diagnosis of unilateral plantar fasciitis were enrolled in a randomized, double-blind, placebo-controlled trial, but 25 participants completed the therapeutic protocol. The contralateral asymptomatic fascia was used as control. After enrolment, symptomatic individuals were randomly assigned to receive LLLT, or identical placebo, for 6 weeks. Ultrasonography was performed at baseline and after completion of therapy. The subjective subcalcaneal pain was recorded at baseline and after treatment on a visual analogue scale (VAS). After LLLT, plantar fascia thickness in both groups showed significant change over the experimental period and there was a difference (before treatment and after treatment) in plantar fascia thickness between the two groups. However, plantar fascia thickness was insignificant (mean 3.627 +/- 0.977 mm) when compared with that in the placebo group (mean 4.380 +/- 1.0042 mm). Pain estimation on the visual analogue scale had improved significantly in all test situations (after night rest, daily activities) after LLLT when compared with that of the placebo group. (P=0.006 and P=0.01, respectively). Additionally, when the difference in pain scores was compared between the two groups, the change was statistically significant (after night rest P=0.000; daily activities P=0.001). In summary, while ultrasound imaging is able to depict the morphologic changes related to plantar fasciitis, 904 nm gallium-arsenide (GaAs) infrared laser may contribute to healing and pain reduction in plantar fasciitis.


Intergeneric hybridization between Pleurotus ostreatus and Schizophyllum commune by PEG-induced protoplast fusion.
Intergeneric hybridization between Pleurotus ostreatus and Schizophyllum commune was studied using PEG-induced fusion. The fusion of protoplasts from auxotrophic mutant strains resulted in the formation of fusion hybrids in the frequencies of 3.6 to 7.3×10(-5). Most of these fusion hybrids were monokaryotic and sterile and no heterokaryosis occurred. Most fusants showed a significantly higher nuclear DNA content when compared to parental strains and no diploids (parent 1 genome plus parent 2 genome) were found. Some fusion hybrids revealed both parental fragments in nuclear and mitochondrial rDNA PCR profiles. AP-PCR (Arbitrarily-primed Polymerase Chain Reaction) fingerprints also indicated that most of the fusion products were recombinant hybrids.


Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat.
1. Prostaglandins are important regulatory mediators of cardiovascular and pulmonary functions which may become disordered in patients with sepsis. The mechanisms controlling their synthesis and release under these circumstances remain unclear. Cyclo-oxygenase (COX, prostaglandin G/H synthase) is a key enzyme in prostaglandin synthesis and has two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed and is probably responsible for prostaglandin release under physiological conditions, whereas COX-2 is expressed at high levels upon induction. 2. We investigated the effect of lipopolysaccharide treatment in vivo on differential COX-1 and COX-2 mRNA expression in the rat. 3. The 2.8 kb COX-1 message was detected in all lungs and seven hearts of eight control rats. In lipopolysaccharide-treated animals, COX-1 expression was reduced by approximately 5-fold in lungs and 2-fold in hearts as quantified by densitometry. In parallel, a marked upregulation of COX-2 mRNA expression was observed. The 4.4 kb COX-2 transcript was absent or expressed at low level in control lungs and hearts, but was increased by approximately 7- and 12-fold in lipopolysaccharide-treated lungs and hearts respectively. Neither the down-regulation of COX-1 nor the upregulation of COX-2 mRNA induced by lipopolysaccharide was significantly affected by pretreatment with dexamethasone in lung and heart, although expression of inducible nitric oxide synthase, induced by lipopolysaccharide, was markedly inhibited in the same tissues. 4. The down-regulation of COX-1 and upregulation of COX-2 may contribute to the multi-organ failure seen in sepsis.


Development of an aerosol model of Cryptococcus reveals humidity as an important factor affecting the viability of Cryptococcus during aerosolization.
Cryptococcus is an emerging global health threat that is annually responsible for over 1,000,000 infections and one third of all AIDS patient deaths. There is an ongoing outbreak of cryptococcosis in the western United States and Canada. Cryptococcosis is a disease resulting from the inhalation of the infectious propagules from the environment. The current and most frequently used animal infection models initiate infection via liquid suspension through intranasal instillation or intravenous injection. These models do not replicate the typically dry nature of aerosol exposure and may hinder our ability to decipher the initial events that lead to clearance or the establishment of infection. We have established a standardized aerosol model of murine infection for the human fungal pathogen Cryptococcus. Aerosolized cells were generated utilizing a Collison nebulizer in a whole-body Madison Chamber at different humidity conditions. The aerosols inside the chamber were sampled using a BioSampler to determine viable aerosol concentration and spray factor (ratio of viable aerosol concentration to total inoculum concentration). We have effectively delivered yeast and yeast-spore mixtures to the lungs of mice and observed the establishment of disease. We observed that growth conditions prior to exposure and humidity within the Madison Chamber during exposure can alter Cryptococcus survival and dose retained in mice.


PROLONGING EFFECTIVE PENICILLIN ACTION.
(1) Single injections of penicillin in saline administered intramuscularly with ice applications at the site of the injection produced and maintained bacteriostatic levels for six to twelve hours in nine out of ten patients, nine of whom were diagnosed as having gonorrhea and one urethritis with extracellular diplococci. (2) There was one failure, Subject No. 10, who received only 30,000 units. (3) Eight of the patients with gonorrhea and the one patient with urethritis were cured (bacteriologically and clinically) by this single intramuscular injection of penicillin.


Development of the UTAUT2 model to measure the acceptance of medical laboratory portals by patients in Shiraz.
One of the main stages for achieving the success is acceptance of technology by its users. Hence, identifying the effective factors in successful acceptance of information technology is necessary and vital. One such factor is usability. This study aimed to investigate the software usability in the "Unified Theory of Acceptance and Use of Technology 2 (UTAUT2)" model in patients' use of medical diagnosis laboratories' electronic portals in 2015. This cross-sectional study was carried out on 170 patients in 2015. A 27-item questionnaire adopted from previous research and the Usability Evaluation questionnaire were used for data collection. Data were analyzed using Structural Equation Modeling (SEM), with Partial Least Squares approach by SPSS 20.0 and Smart-PLS V3.0. The results showed that the construct of intention to use had significant associations with price value (t-value=2.77), hedonic motivation (t-value=4.46), habit (t-value=1.99) and usability (t-value=5.2), as well as the construct of usage behavior with usability (t-value=3.45) and intention to use (t-value=2.03). Considering the results of this study, the following recommendations can be made in order for the higher use of portals by the patients: informing patients about the advantages of using these portals, designing portals in a simple and understandable form, increasing the portals' attractiveness, etc.


Quantum Fragment Based ab Initio Molecular Dynamics for Proteins.
Developing ab initio molecular dynamics (AIMD) methods for practical application in protein dynamics is of significant interest. Due to the large size of biomolecules, applying standard quantum chemical methods to compute energies for dynamic simulation is computationally prohibitive. In this work, a fragment based ab initio molecular dynamics approach is presented for practical application in protein dynamics study. In this approach, the energy and forces of the protein are calculated by a recently developed electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. For simulation in explicit solvent, mechanical embedding is introduced to treat protein interaction with explicit water molecules. This AIMD approach has been applied to MD simulations of a small benchmark protein Trpcage (with 20 residues and 304 atoms) in both the gas phase and in solution. Comparison to the simulation result using the AMBER force field shows that the AIMD gives a more stable protein structure in the simulation, indicating that quantum chemical energy is more reliable. Importantly, the present fragment-based AIMD simulation captures quantum effects including electrostatic polarization and charge transfer that are missing in standard classical MD simulations. The current approach is linear-scaling, trivially parallel, and applicable to performing the AIMD simulation of proteins with a large size.


Making COD statistics useful for public health at local level in the city of Cape Town: utilidad para la salud pública a nivel local en Ciudad del Cabo.
To review the quality of the coding of the cause of death (COD) statistics and assess the mortality information needs of the City of Cape Town. Using an action research approach, a study was set up to investigate the quality of COD information, the accuracy of COD coding and consistency of coding practices in the larger health subdistricts. Mortality information needs and the best way of presenting the statistics to assist health managers were explored. Useful information was contained in 75% of death certificates, but nearly 60% had only a single cause certified; 55% of forms were coded accurately. Disagreement was mainly because routine coders coded the immediate instead of the underlying COD. An abridged classification of COD, based on causes of public health importance, prevalent causes and selected combinations of diseases was implemented with training on underlying cause. Analysis of the 2001 data identified the leading causes of death and premature mortality and illustrated striking differences in the disease burden and profile between health subdistricts. Action research is particularly useful for improving information systems and revealed the need to standardize the coding practice to identify underlying cause. The specificity of the full ICD classification is beyond the level of detail on the death certificates currently available. An abridged classification for coding provides a practical tool appropriate for local level public health surveillance. Attention to the presentation of COD statistics is important to enable the data to inform decision-makers.


Irreversible inhibition of DNA polymerase beta by an oxidized abasic lesion.
DNA damage is a source of carcinogenicity and is also the source of the cytotoxicity of gamma-radiolysis and antitumor agents, such as the enediynes. The dioxobutane lesion (DOB) is produced by a variety of DNA-damaging agents, including the aforementioned. Repair of DOB is important for maintaining the integrity of the genome as well as counteracting therapeutic agents that target DNA. We demonstrate that the DOB lesion efficiently and irreversibly inhibits repair by DNA polymerase beta (Pol beta), an integral enzyme in base-excision repair. Irreversible inhibition of Pol beta by DOB suggests that this lesion provides a chemical explanation for the cytotoxicity of drugs that produce it and explains previously unexplained observations in the literature concerning abasic lesions that are not repaired efficiently. Finally, these observations provide the impetus for the design of a new family of inhibitors of Pol beta.


Differences in field effectiveness and adoption between a novel automated chlorination system and household manual chlorination of drinking water in Dhaka, Bangladesh: a randomized controlled trial.
The number of people served by networked systems that supply intermittent and contaminated drinking water is increasing. In these settings, centralized water treatment is ineffective, while household-level water treatment technologies have not been brought to scale. This study compares a novel low-cost technology designed to passively (automatically) dispense chlorine at shared handpumps with a household-level intervention providing water disinfection tablets (Aquatab), safe water storage containers, and behavior promotion. Twenty compounds were enrolled in Dhaka, Bangladesh, and randomly assigned to one of three groups: passive chlorinator, Aquatabs, or control. Over a 10-month intervention period, the mean percentage of households whose stored drinking water had detectable total chlorine was 75% in compounds with access to the passive chlorinator, 72% in compounds receiving Aquatabs, and 6% in control compounds. Both interventions also significantly improved microbial water quality. Aquatabs usage fell by 50% after behavioral promotion visits concluded, suggesting intensive promotion is necessary for sustained uptake. The study findings suggest high potential for an automated decentralized water treatment system to increase consistent access to clean water in low-income urban communities.


Two variants of occupational asthma separable by exhaled breath nitric oxide level.
Exhaled nitric oxide (FE(NO)) has been used as a marker of asthmatic inflammation in non-occupational asthma, but some asthmatics have a normal FE(NO). In this study we investigated whether, normal FE(NO) variants have less reactivity in methacholine challenge and smaller peak expiratory flow (PEF) responses than high FE(NO) variants in a group of occupational asthmatics. We measured FE(NO) and PD(20) in methacholine challenge in 60 workers currently exposed to occupational agents, who were referred consecutively to a specialist occupational lung disease clinic and whose serial PEF records confirmed occupational asthma. Bronchial responsiveness (PD(20) in methacholine challenge) and the degree of PEF change to occupational exposures, (measured by calculating diurnal variation and the area between curves score of the serial PEF record in Oasys), were compared between those with normal and raised FE(NO). Potential confounding factors such as smoking, atopy and inhaled corticosteroid use were adjusted for. There was a significant correlation between FE(NO) and bronchial hyper-responsiveness in methacholine challenge (p = 0.011), after controlling for confounders. Reactivity to methacholine was significantly lower in the normal FE(NO) group compared to the raised FE(NO) group (p = 0.035). The two FE(NO) variants did not differ significantly according to the causal agent, the magnitude of the response in PEF to the asthmagen at work, or diurnal variation. Occupational asthma patients present as two different variants based on FE(NO). The group with normal FE(NO) have less reactivity in methacholine challenge, while the PEF changes in relation to work are similar.


The measurement of fatigue in patients with multiple sclerosis. A multidimensional comparison with patients with chronic fatigue syndrome and healthy subjects.
To provide a multidimensional characterization of fatigue in patients with multiple sclerosis (MS). Cross-sectional design. Fifty patients with clinically definite MS were compared on the dimensions of fatigue with 51 patients with chronic fatigue syndrome (CFS) and 53 healthy subjects. Fourty-six percent of the patients with MS reported fatigue to be present at least once a week. Patients with MS and patients with CFS had significantly higher subjective fatigue severity scores than healthy subjects. Patients with MS and patients with CFS had significantly higher scores on measures of psychological well-being than healthy subjects. Patients with MS had scores similar to those of patients with CFS, except that patients with CFS had significantly higher somatization scores. High somatization scores reflect strong focusing on bodily sensations. Both groups of patients were significantly less active than the healthy subjects. The Kurtzke Expanded Disability Status Scale (EDSS) and the Beck Depression Inventory scores were not related to subjective fatigue severity. In patients with MS and in patients with CFS, subjective fatigue severity was related to impairment in daily life, low sense of control over symptoms, and strong focusing on bodily sensations. In CFS, but not in MS, evidence was found for a relationship between low levels of physical activity and attributing symptoms to a physical cause and between subjective fatigue severity and physical activity. Patients with MS experienced significant fatigue, which had a significant impact on daily functioning and was not related to depression on Expanded Disability Status Scale score. Psychological factors, such as focusing on bodily sensations and low sense of control play a role in the experience of fatigue in MS and CFS.


Genetic regulation of a structural polymorphism of human C3b receptor.
Two forms of the human C3b receptor (C3bR), which have relative molecular weights (Mr) of 250,000 and 260,000 and are designated F and S, respectively, have been identified in specific immunoprecipitates from erythrocytes and leukocytes by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Both forms of the receptor were visualized on gels by autoradiography of 125I-labeled antigen and by silver nitrate staining. Individual donors expressed one of three possible patterns of C3bR, either the F or S form alone or both, and these patterns represented stable phenotypic characteristics of their erythrocytes and polymorphonuclear and mononuclear leukocytes. Removal of N-linked oligosaccharides by endoglycosidase-F treatment decreased the Mr of both forms but did not abolish the difference in their electrophoretic mobilities. That both forms of the receptor were functional was indicated by the capacity of all antigenic C3bR sites on erythrocytes from individuals having any of the three phenotypes to bind dimeric C3b with affinities ranging from 3 to 5 X 10(7) M-1. Analyses of the occurrence of the F and S forms of C3bR in 76 individuals from 15 families revealed that this polymorphism was regulated by two alleles transmitted in an autosomal codominant manner. Of 111 normal unrelated individuals, 64.9% were homozygous for the F form (FF), 1.8% were homozygous for the S form (SS), and 33.3% were heterozygotes (FS). This distribution did not differ from that calculated by the Hardy-Weinberg equilibrium based on two codominant alleles that regulate the expression of the F and S forms and that have frequencies of 81.5 and 18.5%, respectively. The locus regulating structural polymorphism of C3bR is designated C3BRM (M for mobility or Mr), and is distinct from the recently described locus regulating the quantitative expression of C3bR on erythrocytes.


Wound repair and regeneration: mechanisms, signaling, and translation.
The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body's natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.


Establishment of the first humpback whale fibroblast cell lines and their application in chemical risk assessment.
This paper reports the first successful derivation and characterization of humpback whale fibroblast cell lines. Primary fibroblasts were isolated from the dermal connective tissue of skin biopsies, cultured at 37 °C and 5% CO2 in the standard mammalian medium DMEM/F12 supplemented with 10% fetal bovine serum (FBS). Of nine initial biopsies, two cell lines were established from two different animals and designated HuWa1 and HuWa2. The cells have a stable karyotype with 2n=44, which has commonly been observed in other baleen whale species. Cells were verified as being fibroblasts based on their spindle-shaped morphology, adherence to plastic and positive immunoreaction to vimentin. Population doubling time was determined to be ∼41 h and cells were successfully cryopreserved and thawed. To date, HuWa1 cells have been propagated 30 times. Cells proliferate at the tested temperatures, 30, 33.5 and 37 °C, but show the highest rate of proliferation at 37 °C. Short-term exposure to para,para'-dichlorodiphenyldichloroethylene (p,p'-DDE), a priority compound accumulating in southern hemisphere humpback whales, resulted in a concentration-dependent loss of cell viability. The effective concentration which caused a 50% reduction in HuWa1 cell viability (EC50 value) was approximately six times greater than the EC50 value for the same chemical measured with human dermal fibroblasts. HuWa1 exposed to a natural, p,p'-DDE-containing, chemical mixture extracted from whale blubber showed distinctively higher sensitivity than to p,p'-DDE alone. Thus, we provide the first cytotoxicological data for humpback whales and with establishment of the HuWa cell lines, a unique in vitro model for the study of the whales' sensitivity and cellular response to chemicals and other environmental stressors.


Insights into the social context of living with a dual diagnosis of HIV and cancer: a qualitative, thematic analysis of popular discourse in London newspapers.
As growing numbers of people living with HIV also develop cancer, a holistic understanding of their experiences is essential to the provision of patient centred care. Both conditions are linked to powerful beliefs in our society that may affect experiences. This study explored how HIV and cancer were represented in UK newspapers to gain insight into the social context of living with a dual diagnosis. We performed an initial content analysis of HIV articles and of cancer articles published in the free London newspapers, The Metro and The Evening Standard between 2012 and 2017, followed by qualitative thematic analysis and in-depth analysis of selected articles of exemplar cases. Both conditions were presented very differently. The underlying subtext was that cancer could happen to any of us. HIV was framed as a potentially dangerous, stigmatising phenomenon affecting "others". Popular discourse about HIV within news media remains largely negative and stigmatising. People living with a dual diagnosis of HIV and cancer may choose to prioritise the sharing of the more socially acceptable condition, cancer, in order to access support. The negotiation of cancer healthcare services is likely to be adversely influenced by the social burden of HIV related stigma.


Nanoscale optical imaging in chemistry.
Single-molecule-level measurements are bringing about a revolution in our understanding of chemical and biochemical processes. Conventional measurements are performed on large ensembles of molecules. Such ensemble-averaged measurements mask molecular-level dynamics and static and dynamic fluctuations in reactivity, which are vital to a holistic understanding of chemical reactions. Watching reactions on the single-molecule level provides access to this otherwise hidden information. Sub-diffraction-limited spatial resolution fluorescence imaging methods, which have been successful in the field of biophysics, have been applied to study chemical processes on single-nanoparticle and single-molecule levels, bringing us new mechanistic insights into physiochemical processes. However, the scope of chemical processes that can be studied using fluorescence imaging is considerably limited; the chemical reaction has to be designed such that it involves fluorophores or fluorogenic probes. In this article, we review optical imaging modalities alternative to fluorescence imaging, which expand greatly the range of chemical processes that can be probed with nanoscale or even single-molecule resolution. First, we show that the luminosity, wavelength, and intermittency of solid-state photoluminescence (PL) can be used to probe chemical transformations on the single-nanoparticle-level. Next, we highlight case studies where localized surface plasmon resonance (LSPR) scattering is used for tracking solid-state, interfacial, and near-field-driven chemical reactions occurring in individual nanoscale locations. Third, we explore the utility of surface- and tip-enhanced Raman scattering to monitor individual bond-dissociation and bond-formation events occurring locally in chemical reactions on surfaces. Each example has yielded some new understanding about molecular mechanisms or location-to-location heterogeneity in chemical activity. The review finishes with new and complementary tools that are expected to further enhance the scope of knowledge attainable through nanometer-scale resolution chemical imaging.


Meals Enhancing Nutrition After Discharge: Findings from a Pilot Randomized Controlled Trial.
After older adults experience episodes of poor health or are hospitalized, they may not return to premorbid or prehospitalization eating behaviors. Furthermore, poor nutrition increases hospital readmission risk, but evidence-based interventions addressing these risks are limited. This pilot study's objective was to evaluate the feasibility of conducting a randomized controlled trial assessing a post-discharge home-delivered meal program's impact on older adults' nutritional intake and hospital readmissions and to assess patient acceptability and satisfaction with the program. The aims of the study were to evaluate successful recruitment, randomization, and retention of at least 80% of the 24 participants sought; to compare the outcomes of hospital readmission and total daily caloric intake between participants in the intervention and control groups; and to assess patient acceptability and satisfaction with the program. This study used a two-arm randomized controlled trial design, and baseline data were collected at enrollment; three 24-hour food recalls were collected during the intervention period; and health services utilization and intervention satisfaction was evaluated 45 days post-discharge. Twenty-four patients from the University of Alabama at Birmingham Hospital's Acute Care for Elders (ACE) Unit were enrolled from May 2014 to June 2015. They were 65 years or older; at risk for malnutrition; cognitively intact; able to communicate; discharged to a place where the patient or family was responsible for preparing meals; and diagnosed with congestive heart failure, chronic obstructive pulmonary disease, acute myocardial infarction, or pneumonia. Final analysis included 21 participants. The intervention group received 10 days of home-delivered meals and nutrition education; the control group received usual care and nutrition education. The main outcome was intervention feasibility, measured by recruitment and retention goals. Hospital readmissions, caloric intake, and satisfaction with the intervention were also evaluated. Univariate and bivariate parametric statistics were used to evaluate differences between groups. Goals for success were identified to assess feasibility of conducting a full-scale study and outcomes were measured against the goals. Of the randomized participants, 87.5% were retained for final data collection, indicating that this intervention study is feasible. There were no significant differences between groups for hospital readmissions; however, caloric intake during the intervention period was greater for intervention vs control participants (1,595 vs 1,235; P=0.03). Participants were overwhelmingly satisfied (82% to 100% satisfied or very satisfied) with staff performance, meal quality, and delivery processes. Conducting a randomized controlled trial to assess outcomes of providing home-delivered meals to older adults after hospital discharge in partnership with a small nonprofit organization is feasible and warrants future research.


K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance.
Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed. Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome. The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P<.005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23). Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.


Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder.
Acute nicotine treatment has been found to reduce symptoms of attention deficit/hyperactivity disorder in adults (E. D. Levin, C. K. Conners, et al., 1996). In this study, chronic nicotine effects were compared with placebo and methylphenidate. Acute and chronic nicotine treatment significantly attenuated the rise in hit reaction time standard error over session blocks on the Conners Continuous Performance Test (C. K. Conners et al., 1996). Acute nicotine significantly reduced severity of clinical symptoms on the Clinical Global Impressions scale (National Institute of Mental Health, 1985). Nicotine caused a significant decrease in self-report of depressive mood as measured by the Profile of Mood States test (D. M. McNair, M. Lorr, & L. F. Droppleman, 1981). This small study (40 participants) provided evidence that nicotine treatment can reduce severity of attentional deficit symptoms and produce improvement on an objective computerized attention task.


Identification of miRNAs in cervical mucus as a novel diagnostic marker for cervical neoplasia.
microRNAs (miRNAs) play important roles in regulation of gene expression during cervical carcinogenesis. We investigated expression profiles of miRNAs in cervical cancer and its precursor lesions by utilizing cervical mucus. Cervical mucus was collected from 230 patients with a normal cervix, cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), or adenocarcinoma (AD). The levels of miRNA in the mucus were quantified by miRNA array and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). The performance for detecting diseases was statistically analysed. The expression of miRNAs was further validated in the surgical tissues of enrolled patients. Four miRNAs (miR-126-3p, -20b-5p, -451a, and -144-3p) were significantly up-regulated in SCC and AD compared with normal, and their expression levels correlated with disease severity and high-risk human papillomavirus infection. Receiver operating characteristic curve analyses revealed that the area under the curve values for miR-126-3p, -20b-5p, -451a, and -144-3p were 0.89, 0.90, 0.94, and 0.93, respectively, for SCC plus AD compared with normal, showing high accuracy of cancer detection. Real-time RT-PCR analyses confirmed the expression of these four miRNAs in frozen tissues from cervical cancer. miR-126-3p, -20b-5p, -451a, and -144-3p in cervical mucus are promising biomarkers for cervical cancer and high-grade CINs.


Associations among smoking, anhedonia, and reward learning in depression.
Depression and cigarette smoking co-occur at high rates. However, the etiological mechanisms that contribute to this relationship remain unclear. Anhedonia and associated impairments in reward learning are key features of depression, which also have been linked to the onset and maintenance of cigarette smoking. However, few studies have investigated differences in anhedonia and reward learning among depressed smokers and depressed nonsmokers. The goal of this study was to examine putative differences in anhedonia and reward learning in depressed smokers (n=36) and depressed nonsmokers (n=44). To this end, participants completed self-report measures of anhedonia and behavioral activation (BAS reward responsiveness scores) and as well as a probabilistic reward task rooted in signal detection theory, which measures reward learning (Pizzagalli, Jahn, & O'Shea, 2005). When considering self-report measures, depressed smokers reported higher trait anhedonia and reduced BAS reward responsiveness scores compared to depressed nonsmokers. In contrast to self-report measures, nicotine-satiated depressed smokers demonstrated greater acquisition of reward-based learning compared to depressed nonsmokers as indexed by the probabilistic reward task. Findings may point to a potential mechanism underlying the frequent co-occurrence of smoking and depression. These results highlight the importance of continued investigation of the role of anhedonia and reward system functioning in the co-occurrence of depression and nicotine abuse. Results also may support the use of treatments targeting reward learning (e.g., behavioral activation) to enhance smoking cessation among individuals with depression.


Cracking the egg: molecular dynamics and evolutionary aspects of the transition from the fully grown oocyte to embryo.
Fully grown oocytes (FGOs) contain all the necessary transcripts to activate molecular pathways underlying the oocyte-to-embryo transition (OET). To elucidate this critical period of development, an extensive survey of the FGO transcriptome was performed by analyzing 19,000 expressed sequence tags of the Mus musculus FGO cDNA library. Expression of 5400 genes and transposable elements is reported. For a majority of genes expressed in mouse FGOs, homologs transcribed in eggs of Xenopus laevis or Ciona intestinalis were found, pinpointing evolutionary conservation of most regulatory cascades underlying the OET in chordates. A large proportion of identified genes belongs to several gene families with oocyte-restricted expression, a likely result of lineage-specific genomic duplications. Gene loss by mutation and expression in female germline of retrotransposed genes specific to M. musculus is documented. These findings indicate rapid diversification of genes involved in female reproduction. Comparison of the FGO and two-cell embryo transcriptomes demarcated the processes important for oogenesis from those involved in OET and identified novel motifs in maternal mRNAs associated with transcript stability. Discovery of oocyte-specific eukaryotic translation initiation factor 4E distinguishes a novel system of translational regulation. These results implicate conserved pathways underlying transition from oogenesis to initiation of development and illustrate how genes acquire and lose reproductive functions during evolution, a potential mechanism for reproductive isolation.


Introduction of H-2Dd determinants into the H-2Ld antigen by site-directed mutagenesis.
We used site-directed mutagenesis to localize serologically defined (s) and CTL (c)-defined alloantigenic determinants to discrete amino acid sequences of a murine MHC class I antigen. Based on the prediction that amino acid position 63-73 of the H-2Dd antigen forms s-allodeterminants, the H-2Ld gene was mutated in a sequential fashion to replace codons for amino acid positions 63, 65, 66, 70, and 73 with those of the H-2Dd amino acids. Epitopes of the mutant antigens expressed in L-cells were examined by the binding of a series of mAbs specific for the H-2Dd antigen. The mutant antigen M66 had substitutions at residues 63, 65, and 66, and resulted in the acquisition of a number of H-2Dd-specific s-epitopes. Mutant M70 had an additional substitution at residue 70, which led to the gain of multiple additional H-2Dd s-epitopes. Together, more than half of all the relevant H-2Dd s-epitopes were mapped into amino acid position 63-70 of the H-2Dd molecule, which was expressed in the mutant H-2Ld gene. The final mutation at residue 73 (M73) caused no new epitope gains, rather, a few Dd s-epitopes acquired by the preceding mutations were lost. All of the H-2Ld-specific s-determinants were retained in the mutant molecules, as were H-2Dd s-determinants specific for the alpha-2 or alpha-3 domains. Changes of these residues affected c-determinants defined by CTL. Anti-H-2Dd CTL cultures and an anti-H-2Dd CTL clone recognized the mutant H-2Ld molecules, M66 and M70. Some CTL clones generated against the Q10d molecule, which has an identical sequence to H-2Dd between residues 61 and 73, failed to recognize native H-2Dd or Ld but did crossreact with mutant Ld. While bulk-cultured anti-H-2Ld CTL cultures reacted strongly against M73, bulk-cultured H-2Ld restricted anti-vesicular stomatitis virus CTL did not. Finally, at the clonal level two of three anti-H-2Ld CTL clones lost reactivity with some or all of these mutant molecules. From these results we conclude that a stretch of amino acids from position 63 to 70 of the alpha-1 domain controls major s- and c-antigenic sites on the H-2Dd antigen and c-sites on H-2Ld antigen.


Prediction of pre-eclampsia: review of reviews.
Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre-eclampsia, to identify high-value avenues for future research and to minimize future research waste in this field. MEDLINE, EMBASE and The Cochrane Library including DARE (Database of Abstracts of Reviews of Effects) databases, from database inception to March 2017, and bibliographies of relevant articles were searched, without language restrictions, for systematic reviews and meta-analyses on the prediction of pre-eclampsia. The quality of the included reviews was assessed using the AMSTAR tool and a modified version of the QUIPS tool. We evaluated the comprehensiveness of search, sample size, tests and outcomes evaluated, data synthesis methods, predictive ability estimates, risk of bias related to the population studied, measurement of predictors and outcomes, study attrition and adjustment for confounding. From 2444 citations identified, 126 reviews were included, reporting on over 90 predictors and 52 prediction models for pre-eclampsia. Around a third (n = 37 (29.4%)) of all reviews investigated solely biochemical markers for predicting pre-eclampsia, 31 (24.6%) investigated genetic associations with pre-eclampsia, 46 (36.5%) reported on clinical characteristics, four (3.2%) evaluated only ultrasound markers and six (4.8%) studied a combination of tests; two (1.6%) additional reviews evaluated primary studies investigating any screening test for pre-eclampsia. Reviews included between two and 265 primary studies, including up to 25 356 688 women in the largest review. Only approximately half (n = 67 (53.2%)) of the reviews assessed the quality of the included studies. There was a high risk of bias in many of the included reviews, particularly in relation to population representativeness and study attrition. Over 80% (n = 106 (84.1%)) summarized the findings using meta-analysis. Thirty-two (25.4%) studies lacked a formal statement on funding. The predictors with the best test performance were body mass index (BMI) > 35 kg/m2 , with a specificity of 92% (95% CI, 89-95%) and a sensitivity of 21% (95% CI, 12-31%); BMI > 25 kg/m2 , with a specificity of 73% (95% CI, 64-83%) and a sensitivity of 47% (95% CI, 33-61%); first-trimester uterine artery pulsatility index or resistance index > 90th centile (specificity 93% (95% CI, 90-96%) and sensitivity 26% (95% CI, 23-31%)); placental growth factor (specificity 89% (95% CI, 89-89%) and sensitivity 65% (95% CI, 63-67%)); and placental protein 13 (specificity 88% (95% CI, 87-89%) and sensitivity 37% (95% CI, 33-41%)). No single marker had a test performance suitable for routine clinical use. Models combining markers showed promise, but none had undergone external validation. This review of reviews calls into question the need for further aggregate meta-analysis in this area given the large number of published reviews subject to the common limitations of primary predictive studies. Prospective, well-designed studies of predictive markers, preferably randomized intervention studies, and combined through individual-patient data meta-analysis are needed to develop and validate new prediction models to facilitate the prediction of pre-eclampsia and minimize further research waste in this field. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.


Bladder cancer: molecular determinants of personalized therapy.
Several molecular and genetic studies have provided new perspectives on the histologic classification of bladder tumors. Recent developments in the field of molecular mutational pathway analyses based on next generation sequencing technology together with classic data derived from the description of mutations in the FGFR3 (fibroblast growth factor receptor 3) gene, mutations on TP53 gene, and cDNA technology profiling data gives support to a differentiated taxonomy of bladder cancer. All these changes are behind the use of non-traditional approach to therapy of bladder cancer patients and are ready to change our daily practice of uro-oncology. The observed correlation of some molecular alterations with tumor behavior and the identification of their targets at cellular level might support the use of molecular changes together with morphological data to develop new clinical and biological strategies to manage patients with urothelial cancer. The current review provides comprehensive data to support personalized therapy for bladder cancer based on an integrated approach including pathologic and clinical features and molecular biology.


ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.


Failure of medullary tubes. A materials analysis.
The objective of this study is to determine the effects of autoclaving on the stress, strain, ultimate tensile strength (UTS), fracture strain, modulus, and yield stress of nylon medullary tubes. There are three reports describing nylon medullary tube failure in the literature. All cases involved the use of nylon medullary tubes during open reduction internal fixation of fractured long bones. We demonstrated increased brittleness and decreased strength with increased exposure of medullary tubes to autoclaving, most dramatically after 100 autoclave cycles. Visual inspection of tubes is a clear indication of material degradation after repeated autoclaving. Furthermore, there is a significant difference in ultimate tensile strength (P < 0.0001) between tubes exposed to less than 100 sterilization cycles compared to tubes exposed to greater than 100 cycles. Likewise, there is a significant decrease in yield stress (P < 0.0004) between the same groups. We recommend disposal and replacement of nylon medullary tubes before they are exposed to 100 autoclaving cycles in order to avoid failure of the device.


1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis.
Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and developmental disorders as well as numerous other applications. However, widespread utilization of a CGH has been limited by the lack of well characterized, high-resolution clone sets optimized for consistent performance in aCGH assays and specifically designed analytic software. We have assembled a set of approximately 4100 publicly available human bacterial artificial chromosome (BAC) clones evenly spaced at approximately 1-Mb resolution across the genome, which includes direct coverage of approximately 400 known cancer genes. This aCGH-optimized clone set was compiled from five existing sets, experimentally refined, and supplemented for higher resolution and enhancing mapping capabilities. This clone set is associated with a public online resource containing detailed clone mapping data, protocols for the construction and use of arrays, and a suite of analytical software tools designed specifically for aCGH analysis. These resources should greatly facilitate the use of aCGH in gene discovery.


Exploration of knowledge of cervical cancer and cervical cancer screening amongst HIV-positive women.
Although preventable, cervical cancer, an AIDS-related disease, is the second most common cancer amongst South African women and the most common cancer amongst black women. The objective of the study was to determine what women being treated for HIV and AIDS at a specific healthcare centre in Johannesburg knew about cervical cancer and cervical screening. A survey design was used, with data gathered by means of a self-administered questionnaire. Convenience sampling selected 315 women to participate (n = 315). Descriptive statistics were used to analyse the data and chi-square testing found associations between categorical variables. The majority of respondents (78.7%; n = 248) indicated that they had heard of cervical cancer and 62.9% (n = 198) knew about the Pap smear, with nurses and doctors being the primary source of information. Of the women who knew about the Pap smear, less than one-third had had a smear done, the main reason being fear of the procedure. The study provided evidence that women attending the specific HIV clinic were more knowledgeable about cervical cancer and screening than those of unknown HIV status involved in previous studies. Knowledge was still at a low level, especially when their exceptionally high risk was taken into account. Once again it was found that having knowledge did not necessarily mean having had a Pap smear, which remains a huge challenge in the prevention of cervical cancer.


Detrimental effects of adenosine signaling in sickle cell disease.
Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A(2B) receptor (A(2B)R)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A(2B)R has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease.


The Effect of Nanofillers on the Functional Properties of Biopolymer-based Films: A Review.
Waste from non-degradable plastics is becoming an increasingly serious problem. Therefore, more and more research focuses on the development of materials with biodegradable properties. Bio-polymers are excellent raw materials for the production of such materials. Bio-based biopolymer films reinforced with nanostructures have become an interesting area of research. Nanocomposite films are a group of materials that mainly consist of bio-based natural (e.g., chitosan, starch) and synthetic (e.g., poly(lactic acid)) polymers and nanofillers (clay, organic, inorganic, or carbon nanostructures), with different properties. The interaction between environmentally friendly biopolymers and nanofillers leads to the improved functionality of nanocomposite materials. Depending on the properties of nanofillers, new or improved properties of nanocomposites can be obtained such as: barrier properties, improved mechanical strength, antimicrobial, and antioxidant properties or thermal stability. This review compiles information about biopolymers used as the matrix for the films with nanofillers as the active agents. Particular emphasis has been placed on the influence of nanofillers on functional properties of biopolymer films and their possible use within the food industry and food packaging systems. The possible applications of those nanocomposite films within other industries (medicine, drug and chemical industry, tissue engineering) is also briefly summarized.


Conserved DNA Motifs, Including the CENP-B Box-like, Are Possible Promoters of Satellite DNA Array Rearrangements in Nematodes.
Tandemly arrayed non-coding sequences or satellite DNAs (satDNAs) are rapidly evolving segments of eukaryotic genomes, including the centromere, and may raise a genetic barrier that leads to speciation. However, determinants and mechanisms of satDNA sequence dynamics are only partially understood. Sequence analyses of a library of five satDNAs common to the root-knot nematodes Meloidogyne chitwoodi and M. fallax together with a satDNA, which is specific for M. chitwoodi only revealed low sequence identity (32-64%) among them. However, despite sequence differences, two conserved motifs were recovered. One of them turned out to be highly similar to the CENP-B box of human alpha satDNA, identical in 10-12 out of 17 nucleotides. In addition, organization of nematode satDNAs was comparable to that found in alpha satDNA of human and primates, characterized by monomers concurrently arranged in simple and higher-order repeat (HOR) arrays. In contrast to alpha satDNA, phylogenetic clustering of nematode satDNA monomers extracted either from simple or from HOR array indicated frequent shuffling between these two organizational forms. Comparison of homogeneous simple arrays and complex HORs composed of different satDNAs, enabled, for the first time, the identification of conserved motifs as obligatory components of monomer junctions. This observation highlights the role of short motifs in rearrangements, even among highly divergent sequences. Two mechanisms are proposed to be involved in this process, i.e., putative transposition-related cut-and-paste insertions and/or illegitimate recombination. Possibility for involvement of the nematode CENP-B box-like sequence in the transposition-related mechanism and together with previously established similarity of the human CENP-B protein and pogo-like transposases implicate a novel role of the CENP-B box and related sequence motifs in addition to the known function in centromere protein binding.


Neurophysiology of Hungarian subject-verb dependencies with varying intervening complexity.
Non-adjacent dependencies are thought to be more costly to process than sentences wherein dependents immediately follow or precede what they depend on. In English locality effects have been revealed, while in languages with rich case marking (German and Hindi) sentence final structures show anti-locality-effects. The motivation of the current study is to test whether locality effects can be directly applied to a typologically different language than those investigated so far. Hungarian is a "topic prominent" language; it permits a variation of possible word sequencing for semantic reasons, including SVO word order. Hungarian also has a rich morphological system (e.g., rich case system) and postpositions to indicate grammatical functions. In the present ERP study, Hungarian subject-verb dependencies were compared by manipulating the mismatch of number agreement between the sentence's initial noun phrase and the sentence's final intransitive verb as well as the complexity of the intervening sentence material, interrupting the dependencies. Possible lexical class and frequency or cloze-probability effects for the first two words of the intervening sentence material were revealed when used separate baseline for each word, while at the third word of the intervening material as well as at the main verb ERPs were not modulated by complexity but at the verb ERPs were enhanced by grammaticality. Ungrammatical sentences enlarged the amplitude of both LAN and P600 components at the main verb. These results are in line with studies suggesting that the retrieval of the first element of a dependency is not influenced by distance from the second element, as the first element is directly accessible when needed for integration (e.g., McElree, 2000).


Comparison of efficacy of an in-office whitening system used with and without a whitening priming agent.
The purpose of this study was to compare the whitening efficacy of an in-office whitening system with and without the whitening primer application and evaluate tooth and soft tissue sensitivity. This was a randomized, split-mouth design, single-blinded, clinical study. Twenty-five patients received a whitening priming agent (Power Swabs, Power Swabs Corporation, Beaverton, OR, USA) on right or left maxillary incisors prior to in-office tooth whitening with Opalescence Boost (38% hydrogen peroxide; Ultradent Products, Inc., South Jordan, UT, USA). Color was evaluated with the Bleachedguide 3D Master (Vita Zahnfabrik, Bad Sackingen, Germany) and Vita Easyshade spectrophotometer (Vident, Brea, CA, USA), after 30 minutes, 1 day, and 15 days postwhitening. After each tooth color measurement, the subjects were asked to rate their tooth and soft tissue sensitivity experience using a visual analog scale (1-10 categories). Results were analyzed by two-way repeated measurements analysis of variance/Tukey's (p<0.05); Mann-Whitney rank sum test and Kruskal-Wallis. The teeth that were treated with the primer prior to tooth whitening did not show significant difference in ΔL*, Δa*, Δb*, ΔE* and delta shade guide from the teeth that were not treated with the primer, at the three time points evaluated (baseline versus 30 minutes after in-office treatment, baseline versus 1 day, and baseline versus 15 days). None of the subjects experienced soft tissue sensitivity, and those who experienced tooth sensitivity said it was not noticeable after 15 days postwhitening. The primer neither enhanced the whitening effect nor decreased tooth sensitivity when used before vital bleaching with Opalescence Boost (Ultradent Products, Inc., South Jordan, UT, USA). None of the subjects experienced soft tissue sensitivity, and some experienced transient tooth sensitivity.


[Carbamazepine: an efficient adjuvant treatment in schizophrenia].
Different studies published in the last years have focused on the psychotropic effects of carbamazepine (CBZ). This study tries to investigate the efficacity of CBZ as an adjunct treatment of schizophrenia. 20 patients with a diagnosis of paranoid schizophrenia, according to the RDC, have been investigated by double-blind method. Subjects are divided in two groups (n = 10). The first one is treated with CBZ (with dose in order to reach a plasma level between 8-12 mg /l) and Haloperidol (oral fixed dose: 30 mg /day). The second group only with Haloperidol (same dose). Clinic and psychopathological disturbances are evaluated with the BPRS, and secondary effects with the UKU scale. A clinical improvement (90%, measured by the BPRS) was observed for both groups, without significant differences. Patients treated with CBZ show an important reduction of neurological secondary effects related to neuroleptics (Haloperidol). Carbamazepine appears to be a useful treatment, combined with neuroleptics, for acute schizophrenic episodes.


Using visual stimuli to enhance gait control.
Gait control challenges commonly coincide with vestibular dysfunction and there is a long history in using balance and gait activities to enhance functional mobility in this population. While much has been learned using traditional rehabilitation exercises, there is a new line of research emerging that is using visual stimuli in a very specific way to enhance gait control. For example, avatars can be created in an individualized manner to incorporate specific gait characteristics. The avatar could then be used as a visual stimulus to which the patient can synchronize their own gait cycle. This line of research builds upon the rich history of sensorimotor control research in which augmented sensory information (visual, haptic, or auditory) is used to probe, and even enhance, human motor control. This review paper focuses on gait control challenges in patients with vestibular dysfunction, provides a brief historical perspective on how various visual displays have been used to probe sensorimotor and gait control, and offers some recommendations for future research.


Early community context, genes, and youth body mass index trajectories: an investigation of gene-community interplay over early life course.
To investigate additive and interactive influences of community adversity and cumulative genetic sensitivity on youth body mass index (BMI) trajectories over adolescence and young adulthood. We used latent growth curve modeling to examine BMI trajectories over three waves (1995, 2001, and 2008) of the National Longitudinal Study of Adolescent Health (n = 14,563). We measured genetic sensitivity by a cumulative index of genes associated with serotonin and dopamine functions. Community adversity was positively associated with the initial level and rate of change in BMI trajectories over time. Adolescents experiencing community adversity had a higher BMI at Wave 1 and gained weight more quickly than those who did not live in adverse communities. Community adversity interacted with cumulative genetic sensitivity to explain variation in the rate of change in BMI trajectories. The influence of community adversity was greater for those with more sensitivity alleles than those with fewer sensitivity alleles. Gender, race/ethnicity, and family contexts were also associated with youth BMI trajectories. Community adversity in early adolescence, and its interaction with genes, has far-reaching consequences, including the rate of change in BMI trajectories extending into adulthood. This work has practical implications for future intervention/prevention programs.


Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.
Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.


Distal retinal ganglion cell axon transport loss and activation of p38 MAPK stress pathway following VEGF-A antagonism.
There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.


Response to repeated frusemide administration on low chloride and low sodium intake in the rat.
In animals on a normal NaCl intake despite the repeated administration of a diuretic Cl and Na excretion return to baseline values after initial Cl and Na loss. In order to delineate whether this apparent resistance is consequent primarily on a decreased effect of the diuretic, or compensatory Cl and Na reabsorption when the diuretic is not acting, rats were injected with frusemide (1.5 mg twice a day intraperitoneally for 4 days) while on diets differing in Cl and Na content. On a normal NaCl diet Cl and Na excretion increased on day 1 and subsequently returned to baseline. On a low NaCl diet Cl and Na excretion remained above baseline on all 4 days, thereby demonstrating that frusemide continues to promote daily Cl and Na loss. On a low Cl-normal Na intake Na excretion returned to baseline after day 1, while Cl excretion remained above baseline on all 4 days. The increase in K and net acid excretion was highest in these studies. On a low Na-normal Cl intake Cl excretion returned to baseline after day 2, while Na excretion exceeded baseline on all 4 days. Daily K excretion increased least and net acid excretion decreased in these studies. Hourly data on all four diets indicate that frusemide always has an acute effect to promote both Cl and Na excretion. In the recovery period Cl or Na reabsorption is enhanced when the respective ion is available. The apparent resistance to daily frusemide administration on a normal NaCl intake is primarily consequent on enhanced reabsorption balancing the chloriuretic and natriuretic effects. Daily changes in K and net acid excretion are also determined, in part, by these opposing effects.