The Endocannabinoid System and Oligodendrocytes in Health and Disease.
Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP)-producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.


Effects of transdermal estrogen on collagen turnover at rest and in response to exercise in postmenopausal women.
Menopause is associated with loss of collagen content in the skin and tendon as well as accumulation of noncontractile tissue in skeletal muscle. The relative role of hormones and physical activity on these changes is not known. Accordingly, in a randomized, controlled, crossover study we investigated effects of transdermal estrogen replacement therapy (ERT) on type I collagen synthesis in tendon and skeletal muscle in 11 postmenopausal women. Patches with estrogen (Evorel) were placed on the skin above the patellar tendons and compared with no patch (control period). On day 2 all subjects performed one-legged exercise, and thereafter the exercised leg (EX leg) was compared with the nonexercised leg (Rest leg). Microdialysis catheters were placed in front of the patellar tendons and in the vastus lateralis muscle of both legs at days 3 and 5. The collected dialysate was analyzed for procollagen type I NH(2)-terminal propeptide (PINP), insulin-like growth factor I (IGF-I), and interleukin-6 (IL-6). Neither loading (Rest leg vs. EX leg) nor treatment (control vs. ERT) influenced peritendinous PINP, whereas combined exercise and ERT enhanced muscle PINP after 72 h (interaction between loading and treatment P = 0.008). In neither skeletal muscle nor peritendinous fluid were IGF-I and IL-6 influenced by treatment or exercise. In conclusion, ERT was associated with enhanced synthesis of type I collagen in the skeletal muscle in response to acute exercise. In perspective, this indicates that the availability of estrogen in postmenopausal women is important for repair of muscle damage or remodeling of the connective tissue within the skeletal muscle after exercise.


Uncommon cause of ventricular tachycardia in a patient with a giant pseudoaneurysm of the ascending aorta.
Ventricular arrhythmias occur predominantly in patients with structural heart disease. The most common substrate is scarring due to ischemic heart disease. We present an uncommon cause of ventricular tachycardia due to excessive right coronary artery stretch in a patient with a giant pseudoaneurysm of the ascending aorta years after aortic root repair.


The effect of cholestyramine on intestinal absorption.
Cholestyramine in a mean dosage of 0-6 g/kg/day has been given to 18 children with familial hypercholesterolaemia for between one and two and a half years. With prolonged treatment folate deficiency occurred, as evidenced by a fall in the mean serum folate concentration from 7-7 ng/ml before treatment to 4-4 ng/ml for patients on treatment for over one year; a corresponding lowering of red cell folate was also seen. Oral folic acid 5 mg daily overcame this depletion, and should be given to all patients on long-term anion exchange resins. Prothrombin time has remained normal in all patients; there has been a significant decrease in the mean serum concentrations of vitamins A and E and of inorganic phosphorus over the first two years of treatment, although values remain within the normal range. The routine administration of fat-soluble vitamins appears unnecessary but it is prudent to measure prothrombin time and serum vitamins A and E at intervals. In children who were having a normal intake of dietary fat five out of seven tested had faecal fat of over 5 g/day while on cholestyramine. No chold has developed diarrhoea, and growth has been normal. The concentrations of serum iron, vitamin B12, plasma calcium, and protein did not change significantly in any patient.


Bigger and Better? Representativeness of the Influenza A Surveillance Using One Consolidated Clinical Microbiology Laboratory Data Set as Compared to the Belgian Sentinel Network of Laboratories.
Infectious diseases remain a serious public health concern globally, while the need for reliable and representative surveillance systems remains as acute as ever. The public health surveillance of infectious diseases uses reported positive results from sentinel clinical laboratories or laboratory networks, to survey the presence of specific microbial agents known to constitute a threat to public health in a given population. This monitoring activity is commonly based on a representative fraction of the microbiology laboratories nationally reporting to a single central reference point. However, in recent years a number of clinical microbiology laboratories (CML) have undergone a process of consolidation involving a shift toward laboratory amalgamation and closer real-time informational linkage. This report aims to investigate whether such merging activities might have a potential impact on infectious diseases surveillance. Influenza data was used from Belgian public health surveillance 2014-2017, to evaluate whether national infection trends could be estimated equally as effectively from only just one centralized CML serving the wider Brussels area (LHUB-ULB). The overall comparison reveals that there is a close correlation and representativeness of the LHUB-ULB data to the national and international data for the same time periods, both on epidemiological and molecular grounds. Notably, the effectiveness of the LHUB-ULB surveillance remains partially subject to local regional variations. A subset of the Influenza samples had their whole genome sequenced so that the observed epidemiological trends could be correlated to molecular observations from the same period, as an added-value proposition. These results illustrate that the real-time integration of high-throughput whole genome sequencing platforms available in consolidated CMLs into the public health surveillance system is not only credible but also advantageous to use for future surveillance and prediction purposes. This can be most effective when implemented for automatic detection systems that might include multiple layers of information and timely implementation of control strategies.


Effects of metallic, semiconducting, and insulating substrates on the coupling involving radiative polaritons in thin oxide films.
Through simulations, this work explores the effects of conducting, semiconducting, and insulating substrates on the absorption of infrared radiation by radiative polaritons in oxide layers with thicknesses that range from 30 nm to 9 μm. Using atomic layer deposition, oxide layers can be formed in the nanometer scale. Our results suggest that the chemistry and conductivity of the substrate determine the amount of absorption by radiative polaritons in oxide layers thinner than the skin depth. The effects of the chemistry and conductivity of the substrate are especially effective for oxide films thinner than about 250 nm, which we label as the substrate sensitive thickness of the oxide film.


Production of monoclonal antibodies against serum immunoglobulins of black rockfish (Sebastes schlegeli Higendorf).
The present study was undertaken to produce monoclonal antibodies (MAbs) against immunoglobulin (Ig) purified from black rockfish (Sebastes schlegeli Higendorf) serum using protein A, mannan binding protein, and goat IgG affinity columns. These three different ligands were found to possess high affinity for black rockfish serum Ig. All of the Igs purified eluted at only 0.46 M NaCl concentration in anion exchange column chromatography and consisted of two bands at 70 kDa and 25 kDa in SDS-PAGE; they also had similar antigenicity for MAbs to Ig heavy chain in immunoblot assays. Therefore, black rockfish Ig is believed to exist as a single isotype within serum. The MAbs produced against Ig heavy chain reacted specifically with spots distributed over the pI range from 4.8 to 5.6 with a molecular weight of 70 kDa on two dimensional gel electrophoresis immunoblot profiles.


Proposal for refining the definition of dysgranulopoiesis in acute myeloid leukemia and myelodysplastic syndromes.
Studies of morphology of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) refer to the definitions produced by the French-American-British (FAB) group and by the World Health Organization expert group. To clarify some points regarding the dysgranulopoiesis that are still unclear we analyzed a series of 98 neutrophils from MDS patients with regard to granularity, nuclear segmentation, the appearance of the chromatin, the presence of giant neutrophils, and the presence of nuclear chromatin extensions. We found that cells with at least 2/3 reduction of the content of granules, Pelger-like neutrophils, dysplastic non-Pelger cells, neutrophils with abnormal clumping of the chromatin, and macropolycytes could be recognized as dysplastic and included in the 10% count recommended by these two classifications. In addition, we suggest that neutrophils with more than 4 nuclear projections could be recognized as a relevant dysplastic feature.


Promotion of Remyelination by Sulfasalazine in a Transgenic Zebrafish Model of Demyelination.
Most of the axons in the vertebrate nervous system are surrounded by a lipid-rich membrane called myelin, which promotes rapid conduction of nerve impulses and protects the axon from being damaged. Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS characterized by infiltration of immune cells and progressive damage to myelin and axons. One potential way to treat MS is to enhance the endogenous remyelination process, but at present there are no available treatments to promote remyelination in patients with demyelinating diseases. Sulfasalazine is an anti-inflammatory and immune-modulating drug that is used in rheumatology and inflammatory bowel disease. Its anti-inflammatory and immunomodulatory properties prompted us to test the ability of sulfasalazine to promote remyelination. In this study, we found that sulfasalazine promotes remyelination in the CNS of a transgenic zebrafish model of NTR/MTZ-induced demyelination. We also found that sulfasalazine treatment reduced the number of macrophages/microglia in the CNS of demyelinated zebrafish larvae, suggesting that the acceleration of remyelination is mediated by the immunomodulatory function of sulfasalazine. Our data suggest that temporal modulation of the immune response by sulfasalazine can be used to overcome MS by enhancing myelin repair and remyelination in the CNS.


Effects of greenspace morphology on mortality at the neighbourhood level: a cross-sectional ecological study.
The association between urban greenspace and mortality risk is well known, but less is known about how the spatial arrangement of greenspace affects population health. We aimed to investigate the relation between urban greenspace distribution and mortality risk. We did a cross-sectional study in Philadelphia, PA, USA, using high-resolution landcover data for 2008 from the Pennsylvania Spatial Data Access database. We calculated landscape metrics to measure the greenness, fragmentation, connectedness, aggregation, and shape of greenspace, including and omitting green areas 83·6 m2 or smaller, using Geographical Information System and spatial pattern analysis programs. We analysed all-cause and cause-specific mortality (related to heart disease, chronic lower respiratory diseases, and neoplasms) recorded in 2006 for 369 census tracts (small geographical areas with a population of 2500-8000 people). We did negative binomial regression and principal component analyses to assess associations between landscape spatial metrics and mortality, controlling for geographical, demographic, and socioeconomic factors. A 1% increase in the percentage of greenspace was predicted to reduce all-cause mortality by 0·419% (95% CI 0·050-0·777), with no effect on cause-specific mortality. All-cause mortality was negatively associated with the area of greenspace. A 1 m2 increase in the mean area of greenspace led to a 0·011% (95% CI 0·004-0·018) fall in all-cause mortality and a 0·019% (0·007-0·032) decrease in cardiac mortality; considering only green areas larger than 83·6 m2 would contribute to a 0·002% (95% CI 0·001-0·003) decrease in all-cause mortality and a 0·003% (0·001-0·006) reduction in cardiac deaths. Census tracts with more connected, aggregated, coherent, and complex shape greenspaces had a lower risk of all-cause and cause-specific mortality. The negative association between articulated landscape parcels and all-cause mortality varied with age and education, such that the relation was stronger for census tracts with a higher percentage of older and less well-educated adults. A significant modest association exists between the spatial distribution of greenspace in cities and mortality risk. The overall amount of greenspace alone is probably failing to capture significant variance in local health outcomes and, thus, environment-based health planning should consider the shape, form, and function of greenspace. None.


Community-wide job loss and teenage fertility: evidence from North Carolina.
Using North Carolina data for the period 1990-2010, we estimate the effects of economic downturns on the birthrates of 15- to 19-year-olds, using county-level business closings and layoffs as a plausibly exogenous source of variation in the strength of the local economy. We find little effect of job losses on the white teen birthrate. For black teens, however, job losses to 1 % of the working-age population decrease the birthrate by around 2 %. Birth declines start five months after the job loss and then last for more than one year. Linking the timing of job losses and conceptions suggests that black teen births decline because of increased terminations and perhaps also because of changes in prepregnancy behaviors. National data on risk behaviors also provide evidence that black teens reduce sexual activity and increase contraception use in response to job losses. Job losses seven to nine months after conception do not affect teen birthrates, indicating that teens do not anticipate job losses and lending confidence that job losses are "shocks" that can be viewed as quasi-experimental variation. We also find evidence that relatively advantaged black teens disproportionately abort after job losses, implying that the average child born to a black teen in the wake of job loss is relatively more disadvantaged.


Lifestyle and sarcopenia-etiology, prevention, and treatment.
The term sarcopenia describes the loss of skeletal muscle mass, strength, and function in old age. As the world population continues to grow older, more attention is given to the phenomena of sarcopenia and the search for strategies of prevention and treatment. The progression of sarcopenia is affected by age-related physiological and systemic changes in the body, including alterations in skeletal muscle tissue, hormonal changes, increased inflammatory activities, and oxidative stress. Sarcopenia progression is also affected by lifestyle factors which are far more controllable. These factors include various aspects of nutrition, physical activity, exercise, alcohol intake, and tobacco use. Raising the public awareness regarding the impact of these factors, as causes of sarcopenia and potential strategies of prevention and treatment, is of great importance. In this review we aim to describe various lifestyle factors that affect the etiology, prevention, and treatment of sarcopenia.


The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation.
Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source, so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences.


The research utilization process: the use of guided imagery to reduce anxiety.
In the rapidly changing health care environment, nurses need to keep current with developments, assess their applicability to practice, and make changes where appropriate. There is evidence that nursing research is underutilized and that a considerable gap exists between nursing research and practice (Bostrum & Suter, 1993; Brett, 1987; Sokop & Coyle, 1990). The objectives of a study carried out on a bone marrow transplant unit in a teaching hospital were to: (1) by introducing a framework for research-based care, enhance research utilization in a selected setting, and (2) evaluate the outcomes of research utilization on a specific clinical nursing problem chosen by nurses and researchers. This paper describes the research utilization process and its outcomes, presents an evaluation of the participatory approach from the perspective of the participating nurses, and discusses facilitators and barriers to research utilization. Guided imagery was the intervention used to decrease patient anxiety.


Evidence that sensitivity to growth hormone (GH) is growth period and tissue type dependent: studies in GH-deficient lit/lit mice.
We previously found that the magnitude of skeletal deficits caused by GH deficiency varied during different growth periods. To test the hypothesis that the sensitivity to GH is growth period dependent, we treated GH-deficient lit/lit mice with GH (4 mg/kg body weight.d) or vehicle during the prepubertal and pubertal (d 7-34), pubertal (d 23-34), postpubertal (d 42-55), and adult (d 204-217) periods and evaluated GH effects on the musculoskeletal system by dual energy x-ray absorptiometry (DEXA) and peripheral quantitative computed tomography. GH treatment during different periods significantly increased total body bone mineral content, bone mineral density (BMD), bone area, and lean body mass and decreased percentage of fat compared with vehicle; however, the magnitude of change varied markedly depending on the treatment period. For example, the increase in total body BMD was significantly (P < 0.01) greater when GH was administered between d 42-55 (15%) compared with pubertal (8%) or adult (7.7%) periods, whereas the net loss in percentage of body fat was greatest (-56%) when GH was administered between d 204 and 216 and least (-27%) when GH was administered between d 7 and 35. To determine whether GH-induced anabolic effects on the musculoskeletal system are maintained after GH withdrawal, we performed DEXA measurements 3-7 wk after stopping GH treatment. The increases in total body bone mineral content, BMD, and lean body mass, but not the decrease in body fat, were sustained after GH withdrawal. Our findings demonstrate that the sensitivity to GH in target tissues is growth period and tissue type dependent and that continuous GH treatment is necessary to maintain body fat loss but not BMD gain during a 3-7 wk follow-up.


Intraspecific trait variation influences physiological performance and fitness in the South Africa shrub genus Protea (Proteaceae).
Global plant trait datasets commonly identify trait relationships that are interpreted to reflect fundamental trade-offs associated with plant strategies, but often these trait relationships are not identified when evaluating them at smaller taxonomic and spatial scales. In this study we evaluate trait relationships measured on individual plants for five widespread Protea species in South Africa to determine whether broad-scale patterns of structural trait (e.g. leaf area) and physiological trait (e.g. photosynthetic rates) relationships can be detected within natural populations, and if these traits are themselves related to plant fitness. We evaluated the variance structure (i.e. the proportional intraspecific trait variation relative to among-species variation) for nine structural traits and six physiological traits measured in wild populations. We used a multivariate path model to evaluate the relationships between structural traits and physiological traits, and the relationship between these traits and plant size and reproductive effort. While intraspecific trait variation is relatively low for structural traits, it accounts for between 50 and 100 % of the variation in physiological traits. Furthermore, we identified few trait associations between any one structural trait and physiological trait, but multivariate regressions revealed clear associations between combinations of structural traits and physiological performance (R2 = 0.37-0.64), and almost all traits had detectable associations with plant fitness. Intraspecific variation in structural traits leads to predictable differences in individual-level physiological performance in a multivariate framework, even though the relationship of any particular structural trait to physiological performance may be weak or undetectable. Furthermore, intraspecific variation in both structural and physiological traits leads to differences in plant size and fitness. These results demonstrate the importance of considering measurements of multivariate phenotypes on individual plants when evaluating trait relationships and how trait variation influences predictions of ecological and evolutionary outcomes.


Human ovarian tissue cortex surrounding benign and malignant lesions.
To quantify the number of follicles in patients with ovarian pathologies, benign and malignant, in pregnant and nonpregnant states and to determine how the presence of ovarian masses and BRCA status affects follicular counts. Slides from 134 reproductive-aged women undergoing oophorectomy were examined using light microscopy by 3 independent counters blinded to the diagnosis. In all, 20 patients had cancer, 69 had benign conditions, and 35 patients were BRCA+ or had a strong family history of breast and/or ovarian cancer. In all, 10 women were either pregnant or immediately postpartum. Patients undergoing risk-reducing surgery had significantly decreased follicle count compared to physiologic control. Patients with cancer had significantly decreased counts compared to all other groups. There were no differences within the benign cohort. When compared to benign masses, the cortex surrounding an ovarian malignancy has decreased follicle density. The stretch impact may minimize any impact on total follicle numbers. Furthermore, there may be a proliferation of ovarian stroma, with the same number of follicles spread over a larger surface area. This information is important when counseling women with ovarian masses regarding the use of ovarian tissue cryopreservation.


Moderate-to-Vigorous Physical Activity in Primary School Children: Inactive Lessons Are Dominated by Maths and English.
A large majority of primary school pupils fail to achieve 30-min of daily, in-school moderate-to-vigorous physical activity (MVPA). The aim of this study was to investigate MVPA accumulation and subject frequency during academic lesson segments and the broader segmented school day. 122 children (42.6% boys; 9.9 ± 0.3 years) from six primary schools in North East England, wore uniaxial accelerometers for eight consecutive days. Subject frequency was assessed by teacher diaries. Multilevel models (children nested within schools) examined significant predictors of MVPA across each school-day segment (lesson one, break, lesson two, lunch, lesson three). Pupils averaged 18.33 ± 8.34 min of in-school MVPA, and 90.2% failed to achieve the in-school 30-min MVPA threshold. Across all school-day segments, MVPA accumulation was typically influenced at the individual level. Lessons one and two-dominated by maths and English-were less active than lesson three. Break and lunch were the most active segments. This study breaks new ground, revealing that MVPA accumulation and subject frequency varies greatly during different academic lessons. Morning lessons were dominated by the inactive delivery of maths and English, whereas afternoon lessons involved a greater array of subject delivery that resulted in marginally higher levels of MVPA.


Functional Exercise Improves Mobility Performance in Older Adults With Type 2 Diabetes: A Randomized Controlled Trial.
Background: Diabetes-related disability occurs in approximately two-thirds of older adults with diabetes and is associated with loss of independence, increased health care resource utilization, and sedentary lifestyle. The objective of this randomized controlled trial was to determine the effect of a center-based functional circuit exercise training intervention followed by a 10-week customized home-based program in improving mobility function in sedentary older adults with diabetes. Methods: Participants (n = 111; mean age 70.5 [7.1] y; mean body mass index 32.7 [5.9] kg/m2) were randomized to either a moderate-intensity functional circuit training (FCT) plus 10-week home program to optimize physical activity (FCT-PA) primary intervention or one of 2 comparison groups (FCT plus health education [FCT-HE] or flexibility and toning plus health education [FT-HE]). Results: Compared with FT-HE, FCT-PA improvements in comfortable gait speed of 0.1 m/s (P < .05) and 6-minute walk of 80 ft were consistent with estimates of clinically meaningful change. At 20 weeks, controlling for 10-week outcomes, improvements were found between groups for comfortable gait speed (FCT-PA vs FT-HE and FCT-HE vs FT-HE) and 6-minute walk (FCT-PA vs FCT-HE). Conclusions: Functional exercise training can improve mobility in overweight/obese older adults with diabetes and related comorbidities. Future studies should evaluate intervention sustainability and adaptations for those with more severe mobility impairments.


[Vascular dysfunction in metabolic disorders: evaluation of some therapeutic interventions].
Cardiovascular diseases continue to be the main cause of death in most industrialized countries. Endothelial dysfunction, a systemic process, is the earliest known marker of atherosclerosis and has become a major focus in acute ischemic disorders. We are investigating the hypothesis that, in these diseases, microvascular and endothelial dysfunctions occur simultaneously and precede the onset of macrovascular disease. We studied, to our knowledge for the first time in the same subjects, microvascular and endothelial functions in 11 patients with type 2 diabetes. 36 metabolic syndrome patients (NCEP-ATPIII criteria) and 25 young obese women matched with healthy controls. Micro vascular morphology and hemodynamics were evaluated non-invasively by means of nailfold videocapillaroscopy. Red blood cell velocity (RBCV, mm/s) was measured at rest and after release from 60 s of arterial occlusion (RBCVmax, mm/s) at the finger base, along with the time to reach RBCVmax (TRBCVmax, s), by video analysis with Cap Image software. Venous occlusion plethysmography was performed after intra-arterial infusions of acetylcholine and sodium nitroprusside to assess endo thelial-dependent and -independent vasodilation, respectively. We found similar results in the three groups of subjects, namely a significant decrease in RBCVmax, an increase in TRBCVmax, and a decrease in endothelial-dependent vasodilation. These findings clearly demonstrate that the two dysfunctions occur simultaneously in these groups of patients. Several mechanisms which could impair micro vascular and endothelial functions are associated with insulin resistance, and drugs that act on insulin resistance might thus be beneficial. Metformin, given to 16 first-degree relatives of patients with type 2 diabetes mellitus, who had the metabolic syndrome and normal glucose tolerance (ADA criteria), improved endothelial-dependent vasodilation and microcirculatory function. Rosiglitazone, given to 18 patients with the metabolic syndrome, enhanced vascular responses by improving endothelial function and increasing adiponectin levels. Increased triglyceride storage is often associated with insulin resistance, contributing to free fatty acid (FFA) overexposure. The two drugs tested here stimulate AMP-activated protein kinase, which promotes FFA oxidation and thus reduces oxidative stress, and might therefore attenuate endothelial lipotoxicity. The results strongly suggest that targeting micro vascular and endothelial dysfunctions in patients with metabolic disorders might help to prevent cardiovascular events, and warrant long-term clinical trials.


Pharmacotherapy of obsessive-compulsive disorder: experience with the selective serotonin reuptake inhibitors.
Since the introduction of the selective serotonin reuptake inhibitors (SSRIs) a decade ago, they have become first-line agents in the treatment of obsessive-compulsive disorder (OCD). Numerous clinical trials have confirmed their efficacy, and established their superior risk-benefit ratio in comparison with clomipramine, a non-selective serotonin reuptake inhibitor. Relatively higher doses and longer duration of treatment may be necessary to effect a response in OCD, with long-term treatment being required to maintain therapeutic gains. Despite the advances represented by the SSRIs, treatment resistance remains a problem. While no one solution exists, various strategies, including pharmacotherapy augmentation, look promising.


Spot-checks to measure general hygiene practice.
A variety of hygiene behaviors are fundamental to the prevention of diarrhea. We used spot-checks in a survey of 761 households in Burundi to examine whether something we could call general hygiene practice is responsible for more specific hygiene behaviors, ranging from handwashing to sweeping the floor. Using structural equation modeling, we showed that clusters of hygiene behavior, such as primary caregivers' cleanliness and household cleanliness, explained the spot-check findings well. Within our model, general hygiene practice as overall concept explained the more specific clusters of hygiene behavior well. Furthermore, the higher general hygiene practice, the more likely children were to be categorized healthy (r = 0.46). General hygiene practice was correlated with commitment to hygiene (r = 0.52), indicating a strong association to psychosocial determinants. The results show that different hygiene behaviors co-occur regularly. Using spot-checks, the general hygiene practice of a household can be rated quickly and easily.


The development and design of an electronic patient record using open source web-based technology.
This paper describes the method used to develop the One Stop Crisis Centre (OSCC) Portal, an open source web-based electronic patient record system (EPR) for the One Stop Crisis Center, Hospital Universiti Sains Malaysia (HUSM) in Kelantan, Malaysia. Features and functionalities of the system are presented to demonstrate the workflow. Use of the OSCC Portal improved data integration and data communication and contributed to improvements in care management. With implementation of the OSCC portal, improved coordination between disciplines and standardisation of data in HUSM were noticed. It is expected that this will in turn result in improved data confidentiality and data integrity. The collected data will also be useful for quality assessment and research. Other low-resource centers with limited computer hardware and access to open-source software could benefit from this endeavour.


Neonatal intramuscular injection of plasmid encoding glucagon-like peptide-1 affects anxiety behaviour and expression of the hippocampal glucocorticoid receptor in adolescent rats.
Early-life endocrine intervention may programme hippocampal glucocorticoid receptor (GR) expression and cause psychiatric disorders in later life. Glucagon-like peptide-1 (GLP-1) has been implicated in the regulation of neuroendocrine and behavioural responses, but it is yet to be determined whether and how neonatal GLP-1 overexpression may modify hippocampal GR expression and thus programme adolescent behaviour in rats. Two-day old pups were injected intramuscularly with vacant plasmid (VP) or plasmid DNA encoding secretory GLP-1 (GP). Anxiety-related behaviour was assessed in the elevated plus maze (EPM) test at 8 weeks of age. Plasma corticosterone levels were measured with enzyme immunoassay (EIA). Protein and mRNA levels were determined by western blot and real-time polymerase chain reaction (PCR), respectively. The DNA methylation status of the GR exon 1(7) promoter was determined by bisulphate sequencing PCR (BSP). GP rats exhibited anxiolytic behaviour compared with their VP counterparts. Hippocampal GLP-1 receptor (GLP-1R) and GR mRNA expression were significantly elevated in GP rats without a significant difference in plasma corticosterone. Significant reduction in DNA methyltransferase 1 (DNMT1) expression was observed in GP rats disconnected with alterations in DNA methylation of the GR exon 1(7) promoter. Nevertheless, mRNA expression of nerve growth factor-inducible protein A (NGFI-A) was significantly elevated in GP rats. These results suggest that neonatal intramuscular injection of plasmid DNA encoding GLP-1 affects anxiety behaviour in adolescent rats, probably through NGFI-A-activated upregulation of hippocampal GR expression.


Enantioselective synthesis of novel pyrano[3,2-c]chromene derivatives as AChE inhibitors via an organocatalytic domino reaction.
A series of optically active pyrano[3,2-c]chromenes have been synthesized through an asymmetric domino reaction of 4-hydroxy-2H-chromen-2-ones with malononitriles. The targeted molecules were obtained in excellent yields and enantioselectivities (up to 94% yield, 99% ee). The AChE inhibitory activity studies revealed that compounds 4n (IC50 = 21.3 μM) and 4p (IC50 = 19.2 μM) displayed potent acetylcholinesterase inhibition. In most cases, the S-enantiomers were superior to the corresponding R-enantiomers. Moreover, molecular modelling provides a practical method for understanding the enantioselective discrimination of AChE with these kinds of compounds.


Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial.
Epimedium brevicornum maxim, a nonleguminous medicinal plant, has been found to be rich in phytoestrogen flavonoids. Results from a 24-month randomized double-blind placebo-controlled clinical trial showed that Epimedium-derived phytoestrogen flavonoids were able to exert beneficial effects on preventing bone loss in late postmenopausal women, without resulting in a detectable hyperplasia effect on the endometrium. We performed a 24-mo randomized double-blind placebo-controlled clinical trial for evaluating the effect of the Epimedium-derived phytoestrogen flavonoids (EPFs) on BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness in postmenopausal women. One hundred healthy late postmenopausal women, with a natural menopausal history within 10 approximately 18 yr and with a BMD T-score at the lumbar spine between -2 and -2.5 SD, were randomized into EPF treatment group (n = 50; a daily dose of 60 mg Icariin, 15 mg Daidzein, and 3 mg Genistein) or placebo control group (n = 50). All participants received 300 mg element calcium daily. BMD, bone turnover biochemical markers, serum estradiol, and endometrial thickness were measured at baseline and 12 and 24 mo after intervention. Eighty-five participants completed the trial. The patterns of BMD changes were significantly different between the EPF treatment group and placebo control group by repeated-measures ANOVA (p = 0.045 for interaction between time and group at femoral neck; p = 0.006 for interaction between time and group at lumbar spine). BMD was found with a decreased tendency in the placebo control group at 12 (femoral neck: -1.4%, p = 0.104; lumbar spine: -1.7%, p = 0.019) and 24 mo (femoral neck: -1.8%, p = 0.048; lumbar spine: -2.4%, p = 0.002), whereas EPF treatment maintained BMD at 12 (femoral neck: 1.1%, p = 0.285; lumbar spine:1.0%, p = 0.158) and 24 mo (femoral neck: 1.6%, p = 0.148; lumbar spine: 1.3%, p = 0.091). The difference in lumbar spine between the two groups was significant at both 12 (p = 0.044) and 24 mo (p = 0.006), whereas the difference in the femoral neck was marginal at 12 mo (p = 0.061) and significant at 24 mo (p = 0.008). Levels of bone biochemical markers did not change in the placebo control group. In contrast, EPF intervention significantly decreased levels of deoxypyrdinoline at 12 (-43%, p = 0.000) and 24 mo (-39%, p = 0.000), except for osteocalcin at 12 (5.6%, p = 0.530) and 24 mo (10.7%, p = 0.267). A significant difference in deoxypyrdinoline between the two groups was found at both 12 (p = 0.000) and 24 mo (p = 0.001). Furthermore, neither serum estradiol nor endometrial thickness was found to be changed in either groups during the clinical trial. EPFs exert a beneficial effect on preventing bone loss in late postmenopausal women without resulting in a detectable hyperplasia effect on the endometrium.


Response inhibition, hyperactivity, and conduct problems among preschool children.
Investigated the relation among response inhibition, hyperactivity, and conduct problems in a nonclinical sample of 115 preschool children, using 2 different types of go/no-go tasks well as a Stroop-like task. In line with the assumption that hyperactivity is related to disinhibition, the results showed that it was the measures of response inhibition, and not other performance measures, that were related to teacher ratings of hyperactivity. There was also a significant relation between response inhibition and conduct problems. Interestingly, the correlation between response inhibition and conduct problems was not significant when partialling out the effect of hyperactivity, whereas the correlation between inhibition and hyperactivity did remain significant when controlling for conduct problems. Although the association between inhibition, hyperactivity, and conduct problems appeared to be partly different for boys and girls, these differences were not statistically significant.


Distribution of fish assemblages in Lajes reservoir, Rio de Janeiro, Brazil.
Spatial distribution of fish assemblages in Lajes Reservoir, a 30 km2 impoundment in Rio de Janeiro State (Lat. 22 degrees 42'-22 degrees 50'S; Long. 43 degrees 53'-44 degrees 05'W) was assessed to detect patterns of available habitat use by the fish. A standardized monthly sampling program was carried out from January to December 1994 at three zones of the reservoir (upper, near tributary mouths; middle; and lower, near the dam). Fishes were caught by gillnets, (50 m long, 3 m height), with mesh ranging having from 25 to 45 mm between knots, submerged during 12 hours. A total of 5,089 fishes were collected comprising 15 species, 14 genera and 9 families. Loricariichthys spixii, Astyanax bimaculatus, Parauchenipterus striatulus. Astyanax fasciatus parahybae, Oligosarchus hepsetus, Rhamdia parahybace, Hypostomus affinis. and Geophagus brasiliensis were the most abundant species, each contributing above 1% of the total number. Loricariichthys spixii was the dominant species, contributing over 80% of total number and biomass. Fish abundance, number of species, and biomass were higher in the upper zone, but differences from this overall pattern were shown by some species. Loricariichthys spixii and Rhamdia parahybae were more abundant in the upper zone, while all other species showed no differences in their abundance among the zones. Seasonal environmental variables of temperature, pH, transparency, and water level did not show a clear association with fish occurrence. Most fish used the different zones of the reservoir with no clear sign of spatial separation. High dominance of L. spixii. reduced abundance of reolific species Leporinus copelandii and Cyphocharax gilberti, and presence of introduced species such as Cichla monoculus and Tilapia rendallalli are indications of antropic effects in the fish community.


Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates.
This study was undertaken to determine whether recently identified proteins could be translated to clinical practice as markers to distinguish pancreatic adenocarcinoma from chronic pancreatitis on fine-needle aspirate (FNA) samples. Resected pancreatic tissue sections (n = 40) and FNA samples (n = 65) were stained for clusterin-beta, MUC4, survivin, and mesothelin. For each biomarker, the staining patterns in adenocarcinoma and in reactive ductal epithelium were evaluated and compared. Clusterin-beta stained reactive ductal epithelium significantly more frequently than pancreatic adenocarcinoma (P < .001). In comparison, MUC4 and mesothelin were expressed more frequently in pancreatic adenocarcinoma on tissue sections. Positive staining for MUC4 (91% vs 0%; P < .001) and mesothelin (62% vs 0%; P = .01) and absence of staining for clusterin-beta (90% vs 7%; P < .001) were noted significantly more frequently in adenocarcinoma cells than in reactive cells in FNA samples. Clusterin-beta and MUC4 can help distinguish reactive ductal epithelial cells from the cells of pancreatic adenocarcinoma in FNA samples.


Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.
A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.


The influence of socioeconomic deprivation on multimorbidity at different ages: a cross-sectional study.
Multimorbidity occurs at a younger age in individuals in areas of high socioeconomic deprivation but little is known about the 'typology' of multimorbidity in different age groups and its association with socioeconomic status. To characterise multimorbidity type and most common conditions in a large nationally representative primary care dataset in terms of age and deprivation. Cross-sectional analysis of 1 272 685 adults in Scotland. Multimorbidity type of participants (physical-only, mental-only, mixed physical, and mental) and most common conditions were analysed according to age and deprivation. Multimorbidity increased with age, ranging from 8.1% in those aged 25-34 to 76.1% for those aged ≥75 years. Physical-only (56% of all multimorbidity) was the most common type of multimorbidity in those aged ≥55 years, and did not vary substantially with deprivation. Mental-only was uncommon (4% of all multimorbidity), whereas mixed physical and mental (40% of all multimorbidity) was the most common type of multimorbidity in those aged <55 years and was two- to threefold more common in the most deprived compared with the least deprived in most age groups. Ten conditions (seven physical and three mental) accounted for the top five most common conditions in people with multimorbidity in all age groups. Depression and pain featured in the top five conditions across all age groups. Deprivation was associated with a higher prevalence of depression, drugs misuse, anxiety, dyspepsia, pain, coronary heart disease, and diabetes in multimorbid patients at different ages. Mixed physical and mental multimorbidity is common across the life-span and is exacerbated by deprivation from early adulthood onwards.


Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries.
Diagnostic X-rays are the largest man-made source of radiation exposure to the general population, contributing about 14% of the total annual exposure worldwide from all sources. Although diagnostic X-rays provide great benefits, that their use involves some small risk of developing cancer is generally accepted. Our aim was to estimate the extent of this risk on the basis of the annual number of diagnostic X-rays undertaken in the UK and in 14 other developed countries. We combined data on the frequency of diagnostic X-ray use, estimated radiation doses from X-rays to individual body organs, and risk models, based mainly on the Japanese atomic bomb survivors, with population-based cancer incidence rates and mortality rates for all causes of death, using life table methods. Our results indicate that in the UK about 0.6% of the cumulative risk of cancer to age 75 years could be attributable to diagnostic X-rays. This percentage is equivalent to about 700 cases of cancer per year. In 13 other developed countries, estimates of the attributable risk ranged from 0.6% to 1.8%, whereas in Japan, which had the highest estimated annual exposure frequency in the world, it was more than 3%. We provide detailed estimates of the cancer risk from diagnostic X-rays. The calculations involved a number of assumptions and so are inevitably subject to considerable uncertainty. The possibility that we have overestimated the risks cannot be ruled out, but that we have underestimated them substantially seems unlikely.


Individual differences in first- and second-order temporal judgment.
The ability of subjects to identify and reproduce brief temporal intervals is influenced by many factors whether they be stimulus-based, task-based or subject-based. The current study examines the role individual differences play in subsecond and suprasecond timing judgments, using the schizoptypy personality scale as a test-case approach for quantifying a broad range of individual differences. In two experiments, 129 (Experiment 1) and 141 (Experiment 2) subjects completed the O-LIFE personality questionnaire prior to performing a modified temporal-bisection task. In the bisection task, subjects responded to two identical instantiations of a luminance grating presented in a 4deg window, 4deg above fixation for 1.5 s (Experiment 1) or 3 s (Experiment 2). Subjects initiated presentation with a button-press, and released the button when they considered the stimulus to be half-way through (750/1500 ms). Subjects were then asked to indicate their 'most accurate estimate' of the two intervals. In this way we measure both performance on the task (a first-order measure) and the subjects' knowledge of their performance (a second-order measure). In Experiment 1 the effect of grating-drift and feedback on performance was also examined. Experiment 2 focused on the static/no-feedback condition. For the group data, Experiment 1 showed a significant effect of presentation order in the baseline condition (no feedback), which disappeared when feedback was provided. Moving the stimulus had no effect on perceived duration. Experiment 2 showed no effect of stimulus presentation order. This elimination of the subsecond order-effect was at the expense of accuracy, as the mid-point of the suprasecond interval was generally underestimated. Response precision increased as a proportion of total duration, reducing the variance below that predicted by Weber's law. This result is consistent with a breakdown of the scalar properties of time perception in the early suprasecond range. All subjects showed good insight into their own performance, though that insight did not necessarily correlate with the veridical bisection point. In terms of personality, we found evidence of significant differences in performance along the Unusual Experiences subscale, of most theoretical interest here, in the subsecond condition only. There was also significant correlation with Impulsive Nonconformity and Cognitive Disorganisation in the sub- and suprasecond conditions, respectively. Overall, these data support a partial dissociation of timing mechanisms at very short and slightly longer intervals. Further, these results suggest that perception is not the only critical mitigator of confidence in temporal experience, since individuals can effectively compensate for differences in perception at the level of metacognition in early suprasecond time. Though there are individual differences in performance, these are perhaps less than expected from previous reports and indicate an effective timing mechanism dealing with brief durations independent of the influence of significant personality trait differences.


Clinical usefulness of the common carotid artery blood flow velocity ratio as measured by an ultrasonic quantitative flow measurement system: evaluation with respect to prevalence of ischemic heart disease.
The present study evaluated the clinical usefulness of the measurement of common carotid artery blood flow velocity by an ultrasonic quantitative flow measurement system (QFM), and its correlation with the prevalence of ischemic heart disease (IHD). The subjects in this study included 287 patients (149 men and 138 women; mean age, 67.6+/-11.0 years) being treated as outpatients. Bilateral common carotid artery blood flow velocity was measured using a QFM-1100 (Hayashi Denki Co., Ltd.). The "high to low velocity ratio" (H/L ratio) was calculated by dividing the higher value by the lower value of the velocity of the common carotid artery. In 43 of 287 patients, we used an SSA-270 ACE (Toshiba Co., Ltd) to determine the presence of plaque and measure intimal-medial thickness (IMT) in the common carotid arteries. The mean H/L ratio was 1.45, with a median value of 1.25. The patients were stratified into subgroups based on H/L ratios from 1.0 and above in 0.1 increments in order to compare the prevalence rates of IHD. The prevalence rates in groups with H/L ratios of 1.3 and greater were significantly higher than those in the group with H/L ratios less than 1.3. In logistic regression analysis, the unadjusted H/L ratio was an independent risk factor for IHD at ratios from greater than 1.1 to greater than 1.6. The age-adjusted H/L ratio was an independent risk factor for IHD at ratios from greater than 1.1 to greater than 1.4. IMT was significantly higher in patients with a H/L ratio of 1.4 or greater versus patients with a ratio less than 1.4 (1.154+/-0.417 mm vs. 0.421+/-0.425 mm; p<0.05). The prevalence of carotid artery plaque was also significantly higher in patients with a H/L ratio of 1.4 or greater versus patients with a ratio of less than 1.4 (76.5% vs. 38.5%; p<0.03). Therefore, determination of the carotid artery H/L ratio by means of QFM may be clinically useful in screening patients for coronary artery lesions.


Amygdalin mediates relieved atherosclerosis in apolipoprotein E deficient mice through the induction of regulatory T cells.
Regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses in atherosclerosis, a chronic autoimmune-like disease. Therefore, in this study, we aimed to investigate the therapeutic effect of amygdalin on atherosclerosis of apolipoprotein E deficient (ApoE(-/-)) mice, and to explore its immune regulatory function by stimulation of Tregs. To evaluate the anti-atherosclerotic effect of amygdalin and for in vivo Treg expansion/activation analysis, ApoE(-/-) mice received intraperitoneal injections of amygdalin, and this therapy resulted in a comparatively 2-fold decrease in triglyceride (TG), 1.5-fold decrease in total cholesterol (TC) and low density lipoprotein (LDL). By comparing the vessel areas, lumen areas, plaque areas, and aortic plaque coverage percentage, the effects of amygdalin on pre-existing lesions were assessed. Studies on IL-10 and TGF-β indicated that mice treated with amygdalin had increased expression of Treg-related cytokines. Meanwhile, flow cytometry and real-time PCR data showed that mice treated with amygdalin had higher percentage of CD4(+)CD25(+)Foxp3(+) T cells than untreated mice and increased expression of forkhead box P3 (FOXP3) gene. Our data showed amygdalin could attenuate the development of atherosclerosis by suppressing inflammatory responses and promoting the immunomodulation function of Tregs. The effects of amygdalin ultimately resulted in the enlarged lumen area and the loss of atherosclerotic plaque. All these data indicated the therapeutic potential of amygdalin in preventing and/or treating of atherosclerosis.


Personality dimensions and their behavioral correlates in wild Virunga mountain gorillas (Gorilla beringei beringei).
Studies of animal personality improve our understanding of individual variation in measures of life history and fitness, such as health and reproductive success. Using a 54 trait personality questionnaire developed for studying great apes and other nonhuman primates, we obtained ratings on 116 wild mountain gorillas (Gorilla beringei beringei) monitored by the Dian Fossey Gorilla Fund's Karisoke Research Center in Rwanda. There were 8 raters who each had more than 1.5 years of working experience with the subjects. Principal component analyses identified 4 personality dimensions with high interrater reliabilities-Dominance, Openness, Sociability, and Proto-Agreeableness-that reflected personality features unique to gorillas and personality features shared with other hominoids. We next examined the associations of these dimensions with independently collected behavioral measures derived from long-term records. Predicted correlations were found between the personality dimensions and corresponding behaviors. For example, Dominance, Openness, Sociability, and Proto-Agreeableness were related to gorilla dominance strength, time spent playing, rates of approaches, and rates of interventions in intragroup conflicts, respectively. These findings enrich the comparative-evolutionary study of personality and provide insights into how species differences in personality are related to ecology, social systems, and life history.


Development and evaluation of a novel (99m)tc-labeled annexin A5 for early detection of response to chemotherapy.
(99m)Tc-HYNIC-annexin A5 can be considered as a benchmark in the field of apoptosis imaging. However, (99m)Tc-HYNIC-annexin A5 has characteristics of high uptake and long retention in non-target tissues such as kidney and liver. To minimize this problem, we developed a novel (99m)Tc-labeled annexin A5 using a bis(hydroxamamide) derivative [C3(BHam)2] as a bifunctional chelating agent, and evaluated its usefulness as an imaging agent for detecting apoptosis. The amino group of C3(BHam)2 was converted to a maleimide group, and was coupled to thiol groups of annexin A5 pretreated with 2-iminothiolane. (99m)Tc labeling was performed by a ligand exchange reaction with (99m)Tc-glucoheptonate. Biodistribution experiments for both (99m)Tc-C3(BHam)2-annexin A5 and (99m)Tc-HYNIC-annexin A5 were performed in normal mice. In addition, in tumor-bearing mice, the relationship between the therapeutic effects of chemotherapy (5-FU) and the tumor accumulation of (99m)Tc-C3(BHam)2-annexin A5 just after the first treatment of 5-FU was evaluated. (99m)Tc-C3(BHam)2-annexin A5 was prepared with a radiochemical purity of over 95%. In biodistribution experiments, (99m)Tc-C3(BHam)2-annexin A5 had a much lower kidney accumulation of radioactivity than (99m)Tc-HYNIC-annexin A5. In the organs for metabolism, such as liver and kidney, radioactivity after the injection of (99m)Tc-HYNIC-annexin A5 was residual for a long time. On the other hand, radioactivity after the injection of (99m)Tc-C3(BHam)2-annexin A5 gradually decreased. In therapeutic experiments, tumor growth in the mice treated with 5-FU was significantly inhibited. Accumulation of (99m)Tc-C3(BHam)2-annexin A5 in tumors significantly increased after 5-FU treatment. The accumulation of radioactivity in tumor correlated positively with the counts of TUNEL-positive cells. These findings suggest that (99m)Tc-C3(BHam)2-annexin A5 may contribute to the efficient detection of apoptotic tumor response after chemotherapy.


Dynamic category structure in spatial memory.
This study examines bias (constant error) in spatial memory in an effort to determine whether this bias is defined by a dynamic egocentric reference frame that moves with the observer or by an environmentally fixed reference frame. Participants learned the locations of six target objects around them in a room, were blindfolded, and then rotated themselves to face particular response headings. From each response heading, participants used a pointer to indicate the remembered azimuthal locations of the objects. Analyses of the angular pointing errors showed a previously observed pattern of bias. More importantly, it appeared that this pattern of bias was defined relative to and moved with the observer--that is, was egocentric and dynamic. These results were interpreted in the framework of a modified category adjustment model as suggesting the existence of dynamic categorical (nonmetric) spatial codes.


Quantifying evolutionary development using non-model organisms: integrating morphology, metrical frameworks, and gene expression.
Keeping pace with the forward progression of evolutionary developmental studies and their trajectory toward ever-more integrative and broad-scale study presents a challenge for researchers from diverse disciplines. Increasing the capacity for discourse and opening opportunity to further interdisciplinary work is highly desirable, and one way that activities can be hindered is through a lack of communication between those developing new methods and those applying methods to new data sets. The goal of this special issue, which brings together contributions from a recent symposium at the 10(th) International Congress for Vertebrate Morphology (ICVM 10, Barcelona, July 2013) along with select additions, was to integrate methodological developments with molecular and morphological data to present a broad spectrum of avenues for investigating ontogeny in land vertebrates. A balance between methods-focused papers and papers presenting novel data and perspectives from molecular and morphological approaches in evo-devo was sought with the hope of promoting greater interchange between each side, and drawing attention to new opportunities for future research on non-model organisms.


Central Obesity and Advanced Liver Stiffness in Hepatitis B: Result from Golestan Hepatitis B Cohort Study.
Chronic infection with the hepatitis B virus and obesity may both contribute synergistically to liver disease, although relatively few studies have investigated this hypothesis. Therefore, in this study, we evaluated the relationship between central obesity and the liver stiffness in the Golestan Hepatitis B cohort study (GHBCS). Our study included 304 chronic hepatitis B (CHB) patients enrolled from GHBCS. Liver stiffness measurement (LSM) and laboratory tests were performed after a follow-up of 4 years (2012). The hepatitis B viral load was measured at the baseline and follow-up using the real-time PCR method. Waist circumference ≥ 102 cm in men and ≥ 89 cm in women (central obesity) was considered to be abnormal. Advanced liver stiffness (ALS) was defined as LSM ≥ 8 KPa. Statistical analysis was performed using SPSS-V17. Logistic regression was used to test predictors of advanced liver stiffness (LSM ≥ 8 KPa). Linear regression was used to test the predictive value of variables in ALT (as a continuous variable). P-value of less than 0.05 was considered statistically significant. Among these CHB patients, 19 (7.4%) cases with a mean (±SD) age of 49.5 (±6.3) developed ALS after 4 years of follow-up. Multivariate analysis showed a significant predictive role of central obesity and viral load in ALS. Central obesity is related to the liver stiffness in chronic hepatitis B patients.


An outcome measure for patients with cervical myelopathy: the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): an average score of healthy volunteers.
An outcome measure to evaluate the neurological function of patients with cervical myelopathy was proposed by the Japanese Orthopaedic Association (JOA score) and has been widely used in Japan. However, the JOA score does not include patients' satisfaction, disability, handicaps, or general health, which can be affected by cervical myelopathy. In 2007, a new outcome measure, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), which is a self-administered questionnaire, was developed. However, the influence of age and gender on the scores has not been fully examined. The purpose of this study was to establish the standard value of the JOACMEQ by age using healthy volunteers. This study was conducted in 23 university hospitals and their affiliated hospitals from September to December 2011. The questionnaire included 24 questions for evaluation of physical function of the cervical spine and spinal cord. A total of 1,629 healthy volunteers were recruited for the study. The ages ranged from 20 to 89 years old. The volunteers comprised 798 men and 831 women. In the elderly healthy volunteers, the JOACMEQ scores decreased with age. In general, the scores for cervical spine function and upper/lower extremity function were retained up to the 60s, then decreased in the 70s and 80s. The scores for quality of life were retained up to the 70s; however, the score for bladder function was retained up to the 40s, then declined with age from the 50s to 80s. The standard values of the JOACMEQ by age were established. Differences in the scores were found among different generations. Patients with cervical myelopathy should be evaluated with this new self-administered questionnaire taking into account the standard values according to different ages.


Vitamin D and macular thickness in the elderly: an optical coherence tomography study.
Vitamin D insufficiency is associated with age-related macular degeneration. Our objective was to determine whether low serum 25-hydroxyvitamin D (25OHD) concentration was associated with macular thickness among older adults with no signs of macular dysfunction. Sixty-two French older community-dwellers with no patent macular dysfunction (mean ± SD, 71.2 ± 5.0 years; 45.2% female) included in the Gait and Alzheimer Interaction Tracking (GAIT) study (ClinicalTrials.gov number, NCT01315717) were separated into two groups according to serum 25OHD level (i.e., insufficient < 50 nmol/L or sufficient ≥ 50 nmol/L). The macular thickness was measured on 1000 μm central macula with optical coherence tomography, and further binarized according to normal values of macular thickness (i.e., 267.74 μm for males, and 255.60 μm for females). Age, sex, number of comorbidities, cognitive disorders, body mass index, mean arterial pressure, visual acuity, intraocular pressure, serum calcium concentration and season of testing were considered as potential confounders. The mean serum 25OHD concentration was 61.2 ± 26.3 nmol/L. Patients with vitamin D insufficiency had a reduced macular thickness compared to those without (232.9 ± 40.4 μm vs. 253.3 ± 32.1 μm, P = 0.042). After adjustment for potential confounders, vitamin D insufficiency was associated with a decreased macular thickness (β = -59.4 μm, P = 0.001). Consistently, the participants with vitamin D insufficiency had a 3.7-fold higher risk of having abnormally low macular thickness compared with those with sufficient 25OHD level (P = 0.042). Vitamin D insufficiency was associated with reduced macular thickness among older patients with no patent macular dysfunction. This implies that vitamin D insufficiency may be involved in macular thinning, and provides a scientific base for vitamin D replacement trials in age-related macular degeneration.


Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role.
The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.


First Report of Alternaria alternata Causing Postharvest Black Spot of Fresh Date Palm Fruit in Spain.
Commercial production of date palm fruit (Phoenix dactylifera L.) for fresh consumption has increased in the grove of Elx (Alacant Province, southeast Spain) after the successful development of tissue culture technologies and induced ripening and cold storage protocols. In a survey of losses after harvest, disease symptoms consisting of superficial, small, and firm black spots irregularly distributed throughout the fruit skin were observed in commercially handled and cold-stored fruit. At room temperature, superficial lesions expanded and produced dark mycelium. The potential causal agent was transferred to potato dextrose agar (PDA), incubated at 25°C in darkness, and subcultured on PDA. The identification was performed at the Spanish Type Culture Collection (CECT, University of Valencia, Spain) using colony morphology on PDA and malt extract agar at 26 or 37°C. At 26°C, the fungus rapidly produced cottony white mycelium that turned olivaceous and dark brown to black. Conidiophores were simple, straight or bent, with plain walls. Conidia were brown, obpyriform to ellipsoid (average 22 to 39 × 8 to 15 μm; n = 50), with both transversal and longitudinal septa, often observed in branched chains with more than 5 conidia. Growth occurred at 37°C. The identification of Alternaria alternata (Fr.:Fr.) Keissler was confirmed by the amplification and subsequent sequencing with the primers NL1 and NL4 of the region D1/D2 in the 5' end of the 28S rRNA gene of the isolate IVIA DAA-4 (GenBank Accession No. JX987100). A BLAST search showed 100% identity with A. alternata strain DAOM 216376 (JN938894). Selected healthy 'Medjool' dates were surface disinfected by dipping them for 2 min in a 0.5% sodium hypochlorite solution and thoroughly rinsed with fresh water. To fulfill Koch's postulates, 20 μl of a spore suspension at 1 × 105 spores per ml prepared from 7-day-old colonies grown on PDA were placed in fresh skin wounds made in disinfected fruit using a sterile stainless steel rod with a probe tip 1 mm wide and 2 mm in length (one wound per fruit; three humid chambers with nine fruits each). Wounded but not inoculated fruit were used as controls (one humid chamber with nine fruit). While disease symptoms were observed on all fruit inoculated with A. alternata (average black spots of 3, 6, and 12 mm after 4, 7, and 10 days of incubation at 20°C), no decay was observed on any of the control fruit. Reisolation of the fungus was performed from 10 infected dates and it was positive in all cases. A. alternata has been reported to cause date palm fruit disease in Israel (1) and Egypt (2), whereas Alternaria spp. have been cited in California (3) and Iran (4). To our knowledge, this is the first report of A. alternata causing date palm fruit rot in Spain. References: (1) R. Barkai-Golan et al. Hassadeh 69:1446, 1989. (2) H. M. El-Deeb et al. Acta Hort. 736:421, 2007. (3) H. S. Fawcett and L. J. Klotz. University of California Bulletin 522, 1932. (4) F. Karampourland and H. Pejman. Acta Hort. 736:431, 2007.


Stereoscopic display using rapid varifocal mirror oscillations.
A dynamic volumetric display technique is described in which a vibrating membrane mirror is used in conjunction with an appropriate two-dimensional pattern generator. The mirror can be driven electrostatically or by a loudspeaker and causes the virtual image of the pattern surface to sweep out a volume of image space. The two-dimensional pattern is a repetitively time-varying one and can be generated by stroboscopic optical projection, by a computer, or other means. The volumetric figures which were generated include a simulated air traffic control situation display and a mathematical surface.


High-energy flexible quasi-solid-state lithium-ion capacitors enabled by a freestanding rGO-encapsulated Fe3O4 nanocube anode and a holey rGO film cathode.
Flexible energy storage devices have become critical components for next-generation portable electronics. In the present work, a flexible quasi-solid-state lithium-ion capacitor (LIC) is developed based on graphene-based bendable freestanding films in a gel polymer electrolyte. A graphene encapsulated Fe3O4 nanocube hybrid film (rGO@Fe3O4) has been fabricated as the anode of LICs through a filtration assisted self-assembly and the subsequent thermal annealing process. In this hybrid architecture, flexible and ultrathin graphene shells uniformly enwrap the Fe3O4 within the whole film, which can effectively suppress the aggregation of Fe3O4 and also accommodate the volume change of Fe3O4 during the cycling process. As a consequence, the electrochemical performance of the rGO@Fe3O4 half-cell versus Li/Li+ shows high specific capacity (731 mA h g-1 at 0.1 A g-1), excellent rate capability (210 mA h g-1 at 10 A g-1) and superior cycling stability (98% retention after 600 cycles). After chemically etching rGO@Fe3O4 with hydrochloric acid, a holey rGO film is successfully obtained as a high-rate cathode of LICs. On the basis of such a flexible anode and cathode, the as-fabricated quasi-solid-state LIC device delivers a high energy density of 148 W h kg-1, a high power density of 25 kW kg-1 (achieved at 70 W h kg-1) and an excellent capacity retention of 82% after 2000 cycles. More importantly, the rGO@Fe3O4//holey rGO LIC shows good mechanical flexibility with stable Li-storage capacities under harsh bending.


Neocortical correlates of vibrotactile detection in humans.
This study examined the cortical representation of vibrotactile detection in humans using event-related fMRI paired with psychophysics. Suprathreshold vibrotactile stimulation activated several areas, including primary (SI) and second somatosensory cortices (SII/PV). For threshold-level stimuli, poststimulus activity in contralateral and ipsilateral SII/PV was the best correlate of detection success. In these areas, evoked signals on hit trials were significantly greater than on missed trials in all participants, and the relative activity level across stimulation amplitudes matched perceptual performance. Activity in the anterior insula and superior temporal gyrus also correlated with hits and misses, suggesting that a "ventral stream" of somatosensory representations may play a crucial role in detection. In contrast, poststimulus activity in Area SI was not well correlated with perception and showed an overall negative response profile for threshold-level stimulation. A different correlate of detection success was, however, observed in SI. Activity in this representation immediately before stimulus onset predicted performance, a finding that was unique to SI. These findings emphasize the potential role of SII/PV in detection, the importance of state dynamics in SI for perception, and the possibility that changes in the temporal and spatial pattern of SI activity may be essential to the optimal representation of threshold-level stimuli for detection.


Cyclic nucleotide dependent dephosphorylation of regulator of G-protein signaling 18 in human platelets.
Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein that turns off Gq signaling in platelets. RGS18 is regulated by binding to the adaptor protein 14-3-3 via phosphorylated serine residues S49 and S218 on RGS18. In this study we confirm that thrombin, thromboxane A2, or ADP stimulate the interaction of RGS18 and 14-3-3 by increasing the phosphorylation of S49. Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216. To understand the effect of S216 phosphorylation we studied the phosphorylation kinetics of S49, S216, and S218 using Phos-tag gels and phosphorylation site-specific antibodies in transfected cells and in platelets. Cyclic nucleotide-induced detachment of 14-3-3 from RGS18 coincides initially with double phosphorylation of S216 and S218. This is followed by dephosphorylation of S49 and S218. Dephosphorylation of S49 and S218 might be mediated by protein phosphatase 1 (PP1) which is linked to RGS18 by the regulatory subunit PPP1R9B (spinophilin). We conclude that PKA and PKG induced S216 phosphorylation triggers the dephosphorylation of the 14-3-3 binding sites of RGS18 in platelets.


Evaluation of phentermine and fenfluramine, alone and in combination, in normal, healthy volunteers.
Recent clinical reports indicate that combined administration of phentermine and fenfluramine may have useful effects in the treatment of drug abuse. The present study was designed to evaluate the subjective and mood-altering effects of these drugs, alone and in combination, in normal healthy volunteers. Seven male and five female volunteers participated in an eight-session, double-blind study in which each subject received each of the following drug conditions: d-amphetamine (10 and 20 mg), phentermine (30 mg), fenfluramine (40 and 80 mg), phentermine (30 mg) with fenfluramine (40 mg), phentermine (30 mg) with fenfluramine (80 mg), and placebo. Sessions were conducted in a laboratory setting two or three days a week. Subjects completed standardized self-report questionnaires and psychomotor tests before and at regular intervals after each drug administration. Phentermine produced effects that were similar to those of d-amphetamine, whereas fenfluramine produced different and apparently aversive effects (e.g., it increased measures of anxiety and confusion). Phentermine reduced the apparently aversive effects of fenfluramine when the two drugs were given together. These results suggest that the combination of phentermine and fenfluramine would have a low potential for abuse.


Consumption of polyphenol-rich peach and plum juice prevents risk factors for obesity-related metabolic disorders and cardiovascular disease in Zucker rats.
Polyphenols from fruits have been implied in the prevention of risk factors for cardiometabolic disorders and cardiovascular disease. The purpose of this study was to investigate if the consumption of peach and plum juice has a protective effect against obesity and metabolic disorders that promote the development of cardiovascular diseases. Obese Zucker and lean rats were fed with peach, plum juice ad libitum or placebo. Body weight gain, biochemical markers and molecular markers for inflammation and cardiovascular disease in heart tissue were quantified. Results show that peach and plum juice consumption protected against a combination of obesity-induced metabolic disorders including hyperglycemia, insulin and leptin resistance, dyslipidemia and low-density lipoprotein oxidation. This was accompanied by a decreased expression of pro-atherogenic and pro-inflammatory biomarkers in plasma and heart tissues including intercellular cell adhesion molecule-1, monocyte chemotactic protein-1, NF-κB and foam cell adherence to aortic arches. In addition, peach and plum juice consumption decreased the levels of angiotensin II in plasma and its receptor Agtr1 in heart tissues, suggesting a role of peach and plum polyphenols as peroxisome proliferator-activated receptor-γ agonists. Furthermore, only plum juice significantly prevented body weight gain and increased the ratio high-density lipoprotein cholesterol/total cholesterol in plasma. This effect is most likely attributed to the plum's higher content of polyphenols (three times that of peach). Altogether, these results imply that cardioprotective effects can be achieved by replacing drinks high in sugar content with fruit juice rich in polyphenols in a diet.


An aryl-phosphonate appended macrocyclic platform for lanthanide based bimodal imaging agents.
Four ligand systems have been prepared whose characteristics are well suited to the design of bimodal MRI and luminescence probes. The lanthanide complexes display high relaxivities and luminescence quantum yields. These properties are retained at higher magnetic fields and in a range of competitive environments including model extracellular medium and cultured cells.


Deacetylation of diltiazem by rat liver.
The enzyme system mediating the hydrolysis of the calcium antagonist diltiazem to give deacetyldiltiazem was characterized in the rat. Tissue distribution studies showed that the highest level of activity was mainly localized in the microsomal fraction of the liver. Some activity was also detected in the red blood cells. The kinetics of the enzymatic reaction demonstrated that the formation of deacetyldiltiazem increased linearly with time up to 60 min and with protein content up to 7.8 mg. Apparent Km and Vmax values calculated from a Lineweaver-Burk plot were 0.17 X 10(-3) M and 0.013 mumol/mg of protein/min. Mercuric chloride, silver nitrate, and cupric chloride at concentrations of 0.6 X 10(-3) M decreased the diltiazem deacetylase activity to 47%, 24%, and 19%, respectively, as compared to control incubations. At a concentration of 6.7 X 10(-8) M, cadmium sulfate decreased the hydrolysis of diltiazem by 40%, whereas cobaltous sulfate at concentrations of 10(-3) M did not affect the deacetylation activity. The hydrolysis reaction was depressed by the organophosphorus compounds, bis-p-nitrophenylphosphate and diisopropyl fluorophosphate to 31% and 0%, respectively, at concentrations of 10(-6) M. Eserine sulfate at a concentration of 2.2 X 10(-4) M, and disulfiram and aspirin at concentrations of 10(-3) M decreased the diltiazem deacetylase activity to 17%, 71%, and 79%, respectively. Rifampicin and phenacetin at concentrations of 10(-3) M did not inhibit the hydrolysis reaction. In vivo pretreatment of the rats with phenobarbital increased the in vitro diltiazem deacetylase activity 3.2-fold, whereas 3-methylcholanthrene did not affect the enzymatic hydrolysis of diltiazem.


"Immuno-flowFISH" for the Assessment of Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia.
Imaging flow cytometry is emerging as a diagnostic tool for the assessment of leukemia. It has the functionality of standard flow cytometry and generates high-resolution digital images of each cell with quantifiable numerical data. We demonstrate the use of an automated high-throughput method for performing fluorescence in situ hybridization (FISH) on immunophenotyped whole cells in suspension and analyzed by imaging flow cytometry, a technique called "Immuno-flowFISH". The aim of this study was to demonstrate the application of immuno-flowFISH for the detection of chromosomal abnormalities in CLL, specifically trisomy 12 and del(17p). Mononuclear cells were isolated and immunophenotyped with fluorescently conjugated CD3, CD5, and CD19 monoclonal antibodies. Following fixation, cells were permeabilized, dsDNA denatured and hybridized with chromosome 12 or 17 enumeration (CEP 12 and CEP17) and 17p12 locus-specific FISH probes. Cells were analyzed on the Amnis ImageStream®X Mark II to assess the number and percent FISH-positive CLL cells and the ratio of FISH spot counts for CD5/CD19-positive CLL cells to CD3/CD5-positive T cells (FISH "mean spot ratio"). Deletion of 17p was detected in about 8% of cases to date, with del(17p) ranged from 3.5-22.8% and the FISH "mean spot ratio" 0.86-0.96. Immuno-flowFISH also detected a minimal residual disease case with +12 with a limit of detection of 0.13% and a rare case that presented with atypical phenotype and cytogenetics. Immuno-flowFISH could detect del(17p) in phenotypically identified CD5/CD19-positive B-cells. The 100-fold increase in analyzed cells, as well as the addition of cell phenotype increased the sensitivity and specificity over current clinical FISH testing. Furthermore, immuno-flowFISH analysis demonstrated specific utility in unique clinical scenarios such as residual disease and atypical biology cases which may be of significant benefit with regards to prognostication and MRD analysis. The method will assist in therapeutic decision making and disease monitoring for many hematological malignancies. © 2019 International Society for Advancement of Cytometry.


PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain.
The dynorphin κ-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.


Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention.
Natural phytochemicals derived from dietary sources or medicinal plants have gained significant recognition in the potential management of several human clinical conditions. Much research has also been geared towards the evaluation of plant extracts as effective prophylactic agents since they can act on specific and/or multiple molecular and cellular targets. Plants have been an abundant source of highly effective phytochemicals which offer great potential in the fight against cancer by inhibiting the process of carcinogenesis through the upregulation of cytoprotective genes that encode for carcinogen detoxifying enzymes and antioxidant enzymes. The mechanistic insight into chemoprevention further includes induction of cell cycle arrest and apoptosis or inhibition of signal transduction pathways mainly the mitogen-activated protein kinases (MAPK), protein kinases C (PKC), phosphoinositide 3-kinase (PI3K), glycogen synthase kinase (GSK) which lead to abnormal cyclooxygenase-2 (COX-2), activator protein-1 (AP-1), nuclear factor-kappaB (NF-κB) and c-myc expression. Effectiveness of chemopreventive agents reflects their ability to counteract certain upstream signals that leads to genotoxic damage, redox imbalances and other forms of cellular stress. Targeting malfunctioning molecules along the disrupted signal transduction pathway in cancer represent a rational strategy in chemoprevention. NF-κB and AP-1 provide mechanistic links between inflammation and cancer, and moreover regulate tumor angiogenesis and invasiveness, indicating that signaling pathways that mediate their activation provide attractive targets for new chemotherapeutic approaches. Thus cell signaling cascades and their interacting factors have become important targets of chemoprevention and phenolic phytochemicals and plant extracts seem to be promising in this endeavor.


Productivity Losses and Their Explanatory Factors Amongst People with Impaired Vision.
Purpose: To estimate productivity losses amongst people with impaired vision in Portugal and to investigate explanatory factors associated with non-participation in the labour market.Methods: A total of 546 visually impaired individuals participated in face-to-face interviews. Participants were asked about their workforce participation to determine productivity (employment status questionnaire), their health-related quality of life - HRQoL (EQ-5D) and their visual acuity and visual ability (Activity Inventory). Productivity losses included absenteeism and reduction in workforce participation. Logistic regression was used to determine independent factors associated with participation in the labour market.Results: From the 546 participants, 50% were retired, 47% were of working age and 3% were students. The employment rate was 28%, and the unemployment rate was 21% for the working age sample. For those of working age, productivity losses were estimated at €1.51 million per year, mean of €5496 per participant. The largest contributor to productivity losses was reduced workforce participation, estimated from 159 early retired or unemployed participants. After controlling for visual acuity and ability, younger individuals, with more years of education, without comorbidities and high HRQoL had a higher probability of being employed.Conclusions: Our findings show a high unemployment rate and high productivity losses amongst people with impaired vision. The probability of being employed was associated with education, HRQoL and comorbidities. We speculate that promoting education and health through effective visual rehabilitation programs may help to increase participation in the labour market. These findings can inform decisions to intervene to reduce the burden of vision loss.


Single-molecule spectroscopy reveals polymer effects of disordered proteins in crowded environments.
Intrinsically disordered proteins (IDPs) are involved in a wide range of regulatory processes in the cell. Owing to their flexibility, their conformations are expected to be particularly sensitive to the crowded cellular environment. Here we use single-molecule Förster resonance energy transfer to quantify the effect of crowding as mimicked by commonly used biocompatible polymers. We observe a compaction of IDPs not only with increasing concentration, but also with increasing size of the crowding agents, at variance with the predictions from scaled-particle theory, the prevalent paradigm in the field. However, the observed behavior can be explained quantitatively if the polymeric nature of both the IDPs and the crowding molecules is taken into account explicitly. Our results suggest that excluded volume interactions between overlapping biopolymers and the resulting criticality of the system can be essential contributions to the physics governing the crowded cellular milieu.


A review of the clinical efficacy of linaclotide in irritable bowel syndrome with constipation.
The aims were: firstly, to review the definition and diagnosis of irritable bowel syndrome with constipation (IBS-C, a subtype of IBS); secondly, to critically assess current therapies for IBS-C with a focus on effectiveness for abdominal pain; and thirdly, to review clinical studies evaluating the efficacy of linaclotide, a therapy recently approved by the US Food and Drug Administration for the treatment of adults with IBS-C and chronic idiopathic constipation and the European Medicines Agency for the symptomatic treatment of moderate to severe IBS-C in adults, and in development for treatment of IBS-C worldwide. A comprehensive literature review was performed to summarize IBS-C and current treatments. MEDLINE and gastrointestinal society congress proceedings were searched to identify data from linaclotide clinical studies in adults with IBS-C published between January 2010 and August 2012. IBS-C patients have chronic, relapsing symptoms. Rome III diagnostic criteria define the presence of chronic abdominal pain that improves with defecation and has onset associated with changes in stool frequency or form as a key element of IBS-C and other IBS subtypes. IBS-C patients generally are not completely satisfied with existing therapies. A therapy that treats bowel and abdominal symptoms effectively and can be taken safely on a chronic basis is a current unmet need for IBS-C patients. The guanylate cyclase-C agonist linaclotide has been shown to reduce visceral hypersensitivity in preclinical studies and to improve abdominal pain and constipation symptoms in phase 2 and 3 clinical trials of IBS-C patients. IBS-C is a functional gastrointestinal disorder with chronic, relapsing abdominal and constipation symptoms. By virtue of its effects in relieving abdominal pain by reducing visceral hypersensitivity and improving constipation symptoms by increasing intestinal secretion and accelerating transit, linaclotide may be uniquely positioned for a role in the management of IBS-C patients.


Testing DSM-III symptom criteria for schizotypal and borderline personality disorders.
Schizotypal and borderline personality disorders (SPD and BPD, respectively) appear to be different at follow-up, yet they are poorly discriminated from each other by current DSM-III symptom criteria. In the Chestnut Lodge Follow-up Study, three axis II study cohorts (pure SPD, n = 10; pure BPD, n = 81; mixed SPD/BPD, n = 18) with distinctive outcomes are defined using current borderline systems. This study compares the relative frequency with which individual symptom criteria from each system discriminate across study cohorts. Findings suggest that for SPD, the most characteristic (core) DSM-III symptoms are odd communication, suspiciousness/paranoid ideation, and social isolation, while the least discriminating symptom is illusions/depersonalization/derealization; the core DSM-III symptoms for BPD are unstable relationships, impulsivity, and self-damaging acts, while the least discriminating symptoms are inappropriate anger and intolerance of aloneness; depression as a symptom does not discriminate between SPD and BPD; and transient psychoses and brief paranoid experiences and/or regression in treatment discriminate for SPD but against BPD and therefore fit better as SPD criteria. Results support the retention of some, but the elimination of other, DSM-III symptom criteria for the diagnosis of SPD and BPD.


Protective Effect of Ginseng on Salivary Dysfunction Following Radioiodine Therapy in a Mouse Model.
Following radioiodine (RI) therapy, oxidative stress is a putative damage mechanism resulting in salivary gland (SG) dysfunction. Since ginseng is a known anti-oxidative herb, we examined the SG radioprotective effects of Korea red ginseng (KRG) in a mouse model, when administered prior to RI. Four-week-old mice (n = 60) were divided into four groups: (1) normal control, (2) RI only treated (0.01 mCi/g, orally), (3) KRG administered (0.2 mg/g, intraperitoneal injection) 0.5 and 24 hours before RI, and (4) amifostine-treated group (0.2 mg/g, intraperitoneally) 0.5 hour before RI. The salivary lag times and flow rates were assessed, and sampled tissues were subjected to histologic examinations including hematoxylin and eosin and immunohistochemical staining. Apoptosis was examined by the terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling (TUNEL) assay, and excretion changes in salivary 99mTc pertechnetate were evaluated by single-photon emission computed tomography. The body weight of the KRG group was similar to the control group. Salivary lag times and flow rates in the RI + KRG group were faster than in the RI only group. There was no significant intergroup difference in the SG weight. The RI + KRG group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Salivary epithelial (aquaporin 5) and myoepithelial (smooth muscle actin) cells of the RI + KRG group were protected from radiation damage. Low 8-OhdG (oxidative stress biomarker) and high superoxide dismutase 2 (reactive oxygen species scavenger) immunostaining reactivity was detected in the RI + KRG group when compared with the RI only group. Fewer apoptotic cells were observed in the RI + KRG or amifostine group compared to the RI only group in the TUNEL assay. The 99mTc pertechnetate excretion level recovered in the KRG group. Pretreatment with KRG before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.


Withdrawal-Emergent Dyskinesia and Supersensitivity Psychosis Due to Olanzapine Use.
Tardive dyskinesia (TD) usually appears after years of antipsychotic drug use and appears to be related to the total lifetime medication dose. In withdrawal-emergent dyskinesia (WE-D), which is considered to be a subtype of TD, dyskinetic symptoms often appear shortly after a rapid reduction in antipsychotic drug dose or sudden discontinuation of the drug. Supersensitivity psychosis, which is frequently observed along with TD and is considered to have a similar etiology as TD, is a psychotic relapse phenomenon that occurs after the withdrawal of an antipsychotic drug or a rapid reduction in the drug dosage. In general, atypical antipsychotics tend to be associated with less propensity to cause TD when compared with typical antipsychotics. Furthermore, olanzapine and clozapine may have a therapeutic potential in improving or totally curing TD. In this study, a case of WE-D because of discontinuing olanzapine use and supersensitivity psychosis is discussed.