Ethnic differences in the association between depression and chronic pain: cross sectional results from UK Biobank.
Comorbid chronic pain and depression is a challenging dyad of conditions to manage in primary care and reporting has shown to vary by ethnic group. Whether the relationship between depression and chronic pain varies by ethnicity is unclear. This study aims to explore chronic pain and depression reporting across ethnic groups and examine whether this association differs, independently of potential confounding factors. Cross-sectional study of UK Biobank participants with complete data on chronic pain and probable lifetime history of depression, who reported their ethnic group as White, Asian/Asian British or Black/Black British. Chronic pain classification: present if participants had ≥ 1 site of body pain (up to seven sites or "pain all over the body" could be selected) that lasted ≥ 3 months; extent of chronic pain categories: 0, 1, 2-3, 4-7 sites or pain all over the body. Probable depression classification: an algorithm of low mood, anhedonia and help-seeking behaviour. Relationship between depression and presence/extent of chronic pain assessed using logistic/multinomial regression models (odds ratio (OR); relative risk ratio (RRR), 95 % confidence intervals), adjusted for sociodemographic, lifestyle, and morbidity factors; and a final adjustment for current depressive symptoms. The number of participants eligible for inclusion was 144,139: 35,703 (94 %) White, 4539 (3 %) Asian, and 3897 (3 %) Black. Chronic pain was less (40.5 %, 45.8 %, 45.0 %, respectively) and depression more (22.1 %, 12.9 %, 13.8 %, respectively) commonly reported in White participants than Asian and Black participants. Statistically significant associations between depression and presence/extent of chronic pain persisted following adjustment for potential confounding variables; this relationship was strongest for Black participants (presence of chronic pain: OR 1.86 (1.52, 2.27); RRR 1 site 1.49 (1.16, 1.91), 2-3 sites 1.98 (1.53, 2.56), 4-7 sites 3.23 (2.09, 4.99), pain all over the body 3.31 (2.05, 5.33). When current depressive symptoms were considered these relationships were attenuated. Chronic pain and depression reporting varies across ethnic groups. Differences in health seeking behaviour between ethnic groups may impact on the results reported. Clinicians, particularly in primary care, need to be aware of the cultural barriers within certain ethic groups to expressing concern over mood and to consider their approach accordingly.


Trampoline Park and Home Trampoline Injuries.
Trampoline parks, indoor recreational facilities with wall-to-wall trampolines, are increasing in number and popularity. The objective was to identify trends in emergency department visits for trampoline park injuries (TPIs) and compare TPI characteristics with home trampoline injuries (HTIs). Data on trampoline injuries from the National Electronic Injury Surveillance System from 2010 to 2014 were analyzed. Sample weights were applied to estimate yearly national injury trends; unweighted cases were used for comparison of injury patterns. Estimated US emergency department visits for TPI increased significantly, from 581 in 2010 to 6932 in 2014 (P = .045), whereas HTIs did not increase (P = .13). Patients with TPI (n = 330) were older than patients with HTI (n = 7933) (mean 13.3 vs 9.5 years, respectively, P < .001) and predominantly male. Sprains and fractures were the most common injuries at trampoline parks and homes. Compared with HTIs, TPIs were less likely to involve head injury (odds ratio [OR] 0.64; 95% confidence interval [CI], 0.46-0.89), more likely to involve lower extremity injury (OR 2.39; 95% CI, 1.91-2.98), more likely to be a dislocation (OR 2.12; 95% CI, 1.10-4.09), and more likely to warrant admission (OR 1.76; 95% CI, 1.19-2.61). TPIs necessitating hospital admission included open fractures and spinal cord injuries. TPI mechanisms included falls, contact with other jumpers, and flips. TPI patterns differed significantly from HTIs. TPIs are an emerging concern; additional investigation and strategies are needed to prevent injury at trampoline parks.


Membrane steroid receptor-mediated action of soy isoflavones: tip of the iceberg.
Soy isoflavone's (genistein and daidzein in particular) biological significance has been thoroughly studied for decades, so we started from the premise that refreshed investigation approach in this field should consider identification of their new molecular targets. In addition to recently described epigenetic aspects of polyphenole action, the cell membrane constituents-mediated effects of soy isoflavones are worthy of special attention. Accordingly, the expanding concept of membrane steroid receptors and rapid signaling from the cell surface may include the prominent role of these steroid-like compounds. It was observed that daidzein strongly interacts with membrane estrogen receptors in adrenal medullary cells. At low doses, daidzein was found to stimulate catecholamine synthesis through extracellular signal-regulated kinase 1/2 or protein kinase A pathways, but at high doses, it inhibited catecholamine synthesis and secretion induced by acetylcholine. Keeping in mind that catecholamine excess can contribute to the cardiovascular pathologies and that catecholamine lack may lead to depression, daidzein application promises to have a wide range of therapeutic effects. On the other hand, it was shown in vitro that genistein inhibits LNCaP prostate cancer cells invasiveness by decreasing the membrane fluidity along with immobilization of the androgen receptor containing membrane lipid rafts, with down regulation of the androgen receptors and Akt signaling. These data are promising in development of the molecular pharmacotherapy pertinent to balanced soy isoflavone treatment of cardiovascular, psychiatric, and steroid-related malignant diseases.


[Pseudodominant inheritance of pseudoxanthoma elasticum].
Pseudoxanthoma elasticum (PXE) is a system disease due to mutations in the ABCC6 gene with characteristic alterations in the eyes, the skin and the cardiovascular system. Herein, we report on two families with PXE in two subsequent generations due to genetically confirmed pseudodominance. A literature review revealed that PXE due to mutations in ABCC6 follows an autosomal recessive inheritance and that disease manifestation in two subsequent generations is due to pseudodominance.


Imaging properties of digital magnification radiography.
Flat panel detectors exhibit improved signal-to-noise ratio (SNR) and display capabilities compared to film. This improvement necessitates a new evaluation of optimal geometry for conventional projection imaging applications such as digital projection mammography as well as for advanced x-ray imaging applications including cone-beam computed tomography (CT), tomosynthesis, and mammotomography. Such an evaluation was undertaken in this study to examine the effects of x-ray source distribution, inherent detector resolution, magnification, scatter rejection, and noise characteristics including noise aliasing. A model for x-ray image acquisition was used to develop generic results applicable to flat panel detectors with similar x-ray absorption characteristics. The model assumed a Gaussian distribution for the focal spot and a rectangular distribution for a pixel. A generic model for the modulated transfer function (MTF) of indirect flat panel detectors was derived by a nonlinear fit of empirical receptor data to the Burgess model for phosphor MTFs. Noise characteristics were investigated using a generic noise power spectrum (NPS) model for indirect phosphor-based detectors. The detective quantum efficiency (DQE) was then calculated from the MTF and NPS models. The results were examined as a function of focal spot size (0.1, 0.3, and 0.6 mm) and pixel size (50, 100, 150, and 200 microm) for magnification ranges 1 to 3. Mammography, general radiography (also applicable to mammotomography), and chest radiography applications were explored using x-ray energies of 28, 74, and 120 kVp, respectively. Nodule detection was examined using the effective point source scatter model, effective DQE, and the Hotelling SNR2 efficiency. Results indicate that magnification can potentially improve the signal and noise performance of digital images. Results also show that a cross over point occurs in the spatial frequency above and below which the effects of magnification differ indicating that there are task dependent tradeoffs associated with magnification. The cross over point varies depending upon focal spot size, pixel size, x-ray energy, and source-to-image-distance (SID). For mammography, the cross over point occurs for a 0.3 mm focal spot while a 0.6 mm focal spot indicates that magnification does not improve image quality due to focal spot blurring. Thus, the benefit of magnification may be limited. For general radiography (as well as mammotomography), and chest radiography, the cross over point changes with SID. For a system with a 0.3 mm focal spot, 100 microm pixel size, a 2 m SID, and the applicable tissue thickness and scatter components, optimal magnification improved SNR2 by approximately 1.2 times for mammography and 1.5 times for general radiography (and mammotomography). These results indicate that the optimal geometry can improve image quality without changing patient dose or otherwise reduce dose without compromising image quality.


GEP- NETS UPDATE: Genetics of neuroendocrine tumors.
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.


Country and Gender-Specific Achievement of Healthy Nutrition and Physical Activity Guidelines: Latent Class Analysis of 6266 University Students in Egypt, Libya, and Palestine.
Research on healthy behaviour such as physical activity and healthy nutrition and their combination is lacking among university students in Arab countries. The current survey assessed healthy nutrition, and moderate/vigorous physical activity (PA) of 6266 students in Egypt, Libya, and Palestine. We computed a nutrition guideline achievement index using WHO recommendation, as well as the achievement of PA recommendations using guidelines for adults of the American Heart Association guidelines. Latent class regression analysis identified homogenous groups of male and female students, based on their achievements of both guidelines. We examined associations between group membership and achievement of guidelines. A three-class solution model best fitted the data, generating three student Groups: "Healthy Eaters" (7.7% of females, 10.8% of males), "Physically Active" (21.7% of females, 25.8% of males), and "Low Healthy Behaviour" (70.6% of females, 63.4% of males). We did not observe a latent class that exhibited combined healthy behaviours (physically active and healthy eaters), and there were no major differences between countries. We observed a very low rate of healthy nutrition (≈10% of students achieved greater than four of the eight nutrition guidelines), with little gender differences across the countries. About 18-47% of students achieved the PA guidelines, depending on country and gender, more often among males. Few females achieved the PA guidelines, particularly in Libya and Palestine. Culturally adapted multi-behavioural interventions need to encourage healthy lifestyles, nutrition and PA behaviours. National policies need to promote active living while addressing cultural, geographic, and other barriers to young adults' engagement in PA.


The cytological characteristics of small cell change of dysplasia in small hepatic nodules.
Small cell change of dysplasia (SCD) is characterized as an initial step in hepatocarcinogenesis. Histopathological diagnosis is an important diagnostic procedure for nodular lesions in the liver. However, the biopsied specimen is so small that it is sometimes difficult to differentiate between regenerative nodules, dysplastic nodules, and hepatocellular carcinoma even histologically. To examine the usefulness of cytology in the differential diagnosis of hepatic nodular lesions, the cellular characteristics of SCD were evaluated using Papanicolaou staining and a micrometer. Sixty-four histologically diagnosed small nodular lesions in the liver were analyzed retrospectively. All cases were histologically classified according to the Terminology of Nodular Hepatocellular Lesions by the International Working party: hepatocellular carcinoma (HCC) (n=17); low-grade dysplastic nodule (LGDN) (n=26); high-grade dysplastic nodule (HGDN) (n=6); large regenerative nodule: (n=15). SCD was noted in all of the histological categories, and the proportion of SCD tended to be higher in W-HCC than in dysplastic nodules. Although the cellular size was the smallest in HGDN, the nuclear size was the largest in well-differentiated HCC (W-HCC). The nuclear/cytoplasmic ratio was higher in HGDN and W-HCC than in other nodular lesions. Hyperchromasia in W-HCC was obviously stronger than that in other nodules. SCD was frequently found in HGDN and W-HCC. The present study showed that detailed cytological findings of SCD are useful for differentiating HGDN from LGDN, and HGDN from W-HCC.


One-pot synthesis of ultra-small cerium oxide nanodots exhibiting multi-colored fluorescence.
CeO(2) nanodots of diameter 2nm have been synthesized by the thermolysis of cerium acetate in diphenylether in the presence of an oleic acid surfactant. The surfactant coating enabled them to be easily dispersible in nonpolar solvents. The CeO(2) dots exhibited size dependant optical properties such as a red shift in absorption and band gap. As a result, the surfactant coated CeO(2) nanocrystals emit photons in the visible region with broad photoluminescence spectra resulting in multi-colored fluorescence, which originates from defects associated with CeO(2) nanocrystals approaching molecular dimensions.


Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial.
Creatine synthesis from guanidinoacetate consumes ~50% of s-adenosylmethionine (SAM)-derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats. We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys. Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 μg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 μg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA. Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: -0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (β = 0.30; 95% CI: 0.17, 0.43; P < 0.0001). Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while receiving creatine plus folic acid supplementation. This trial was registered at clinicaltrials.gov as NCT01050556.


Reduced glomerular function and prevalence of gout: NHANES 2009-10.
The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population. Cross-sectional, survey-weighted analyses of data on adults (age>20 years) in the 2009-10 cycle of the US National Health and Nutrition Examination Surveys (n = 5,589). Associations between self-reported physician diagnosis of gout and degrees of renal impairment were the primary focus of the present analyses. In the 2009-2010 period, there was an estimated 7.5 million people with gout in the US. There were 1.25 million men and 0.78 million women with moderate or severe renal impairment and gout. The age standardized prevalence of gout was 2.9% among those with normal GFR compared to 24% among those with GFR<60 ml/min/1.73 m(2).In multivariable logistic regression analyses that adjusted for age, gender, body mass index, hypertension, diabetes, hypertension medications, including diuretics, blood lead levels, and hyperlipidemia, the odds ratios of gout and hyperuricemia were 5.9 (2.2, 15.7) and 9.58 (4.3, 22.0) respectively among those with severe renal impairment compared to those with no renal impairment. Approximately 2-3 fold increase in prevalence of gout was observed for each 30 ml/min/1.73 m(2) decrease in GFR, after accounting for the above factors. Renal glomerular function is an important risk factor for gout. The prevalence of hyperuricemia and gout increases with decreasing glomerular function independent of other factors. This association is non-linear and an eGFR of 60 ml/min/1.73 m(2) appears to be a threshold for the dramatic increase in the prevalence of gout.


Trait structure and redundancy determine sensitivity to disturbance in marine fish communities.
Trait diversity is believed to influence ecosystem dynamics through links between organismal traits and ecosystem processes. Theory predicts that key traits and high trait redundancy-large species richness and abundance supporting the same traits-can buffer communities against environmental disturbances. While experiments and data from simple ecological systems lend support, large-scale evidence from diverse, natural systems under major disturbance is lacking. Here, using long-term data from both temperate (English Channel) and tropical (Seychelles Islands) fishes, we show that sensitivity to disturbance depends on communities' initial trait structure and initial trait redundancy. In both ecosystems, we found that increasing dominance by climatically vulnerable traits (e.g., small, fast-growing pelagics/corallivores) rendered fish communities more sensitive to environmental change, while communities with higher trait redundancy were more resistant. To our knowledge, this is the first study demonstrating the influence of trait structure and redundancy on community sensitivity over large temporal and spatial scales in natural systems. Our results exemplify a consistent link between biological structure and community sensitivity that may be transferable across ecosystems and taxa and could help anticipate future disturbance impacts on biodiversity and ecosystem functioning.


Cognitive consequences of overweight and obesity in the ninth decade of life?
the association between late-life obesity and late-life cognitive abilities is poorly understood. We studied the association between body mass index (BMI) and cognitive change in longitudinal population-based study spanning over the ninth decade of life. in total, 475 participants free of dementia at baseline from the Lothian Birth Cohort 1921 (mean age: 79.1 years, SD: 0.6) were included. Height and weight were assessed at baseline. BMI was calculated as kg/m(2). Cognitive abilities were assessed at age ∼11 years and at age ∼79, ∼83, ∼87 and ∼90 years. latent growth models showed that men being overweight and obese had a 0.65 (SD: 0.3) and 1.10 (SD: 0.5) points less steep decline in general cognitive ability (as measured by the Moray House Test) for each year than people of normal weight. These associations were to some extent confounded by childhood intelligence. No other association between BMI and cognition was significant, either for men or women. People who were obese in old age had significantly lower childhood intelligence (m = 43.6, SD: 1.3) than people who were normal in weight (m = 47.0, SD: 0.8) and persons being overweight (m = 47.5, SD: 0.8), F (472, 3) = 3.2, P = 0.043. the current study shows weak or no evidence for an association between BMI in old age and cognitive function, especially not when childhood intelligence is controlled for. Lower intelligence at the age of 11 years predicted obesity at the age of 79 years.


Contribution of pannexin 1 and connexin 43 hemichannels to extracellular calcium-dependent transport dynamics in human blood-brain barrier endothelial cells.
Dysregulation of blood-brain barrier (BBB) transport function is thought to exacerbate neuronal damage in acute ischemic stroke. The purpose of this study was to clarify the characteristics of pannexin (Px) and/or connexin (Cx) hemichannel(s)-mediated transport of organic anions and cations in human BBB endothelial cell line hCMEC/D3 and to identify inhibitors of hemichannel opening in hCMEC/D3 cells in the absence of extracellular Ca(2+), a condition mimicking acute ischemic stroke. In the absence of extracellular Ca(2+), the cells showed increased uptake and efflux transport of organic ionic fluorescent dyes. Classic hemichannel inhibitors markedly inhibited the enhanced uptake and efflux. Quantitative targeted absolute proteomics confirmed Px1 and Cx43 protein expression in plasma membrane of hCMEC/D3 cells. Knockdown of Px1 and Cx43 with the small interfering RNAs significantly inhibited the enhanced uptake and efflux of organic anionic and cationic fluorescent dyes. Clinically used cilnidipine and progesterone, which have neuroprotective effects in animal ischemia models, were identified as inhibitors of hemichannel opening. These findings suggest that altered transport dynamics at the human BBB in the absence of extracellular Ca(2+) is at least partly attributable to opening of Px1 and Cx43 hemichannels. Therefore, we speculate that Px1 and Cx43 may be potential drug targets to ameliorate BBB transport dysregulation during acute ischemia.


Variation in oral susceptibility to dengue type 2 virus of populations of Aedes aegypti from the islands of Tahiti and Moorea, French Polynesia.
Twenty three samples of Aedes aegypti populations from the islands of Tahiti and Moorea (French Polynesia) were tested for their oral susceptibility to dengue type 2 virus. The high infection rates obtained suggest that the artificial feeding protocol used was more efficient than those previously described. Statistical analysis of the results allowed us to define two distinct geographic areas on Tahiti with respect to the susceptibility of Ae. aegypti: the east coast, with homogeneous infection rates, and the west coast, with heterogeneous infection rates. No geographic differences could be demonstrated on Moorea. The possible mechanisms of this phenomenon are discussed in connection with recent findings on the variability of susceptibility of Ae. aegypti to insecticides.


Analysis of human immunodeficiency virus type 1 Gag dimerization-induced assembly.
The nucleocapsid (NC) domains of retrovirus precursor Gag (PrGag) proteins play an essential role in virus assembly. Evidence suggests that NC binding to viral RNA promotes dimerization of PrGag capsid (CA) domains, which triggers assembly of CA N-terminal domains (NTDs) into hexamer rings that are interconnected by CA C-terminal domains. To examine the influence of dimerization on human immunodeficiency virus type 1 (HIV-1) Gag protein assembly in vitro, we analyzed the assembly properties of Gag proteins in which NC domains were replaced with cysteine residues that could be linked via chemical treatment. In accordance with the model that Gag protein pairing triggers assembly, we found that cysteine cross-linking or oxidation reagents induced the assembly of virus-like particles. However, efficient assembly also was observed to be temperature dependent or required the tethering of NTDs. Our results suggest a multistep pathway for HIV-1 Gag protein assembly. In the first step, Gag protein pairing through NC-RNA interactions or C-terminal cysteine linkage fosters dimerization. Next, a conformational change converts assembly-restricted dimers or small oligomers into assembly-competent ones. At the final stage, final particle assembly occurs, possibly through a set of larger intermediates.


Health behaviors and quality of life predictors for risk of hospitalization in an electronic health record-linked biobank.
Hospital risk stratification models using electronic health records (EHRs) often use age and comorbid health burden. Our primary aim was to determine if quality of life or health behaviors captured in an EHR-linked biobank can predict future risk of hospitalization. Participants in the Mayo Clinic Biobank completed self-administered questionnaires at enrollment that included quality of life and health behaviors. Participants enrolled as of December 31, 2010 were followed for one year to ascertain hospitalization. Data on comorbidities and hospitalization were derived from the Mayo Clinic EHR. Hazard ratios (HR) and 95% confidence interval (CI) were used, adjusted for age and sex. We used gradient boosting machines models to integrate multiple factors. Different models were compared using C-statistic. Of the 8,927 eligible Mayo Clinic Biobank participants, 834 (9.3%) were hospitalized. Self-perceived health status and alcohol use had the strongest associations with risk of hospitalization. Compared to participants with excellent self-perceived health, those reporting poor/fair health had higher risk of hospitalization (HR =3.66, 95% CI 2.74-4.88). Alcohol use was inversely associated with hospitalization (HR =0.57 95% CI 0.45-0.72). The gradient boosting machines model estimated self-perceived health as the most influential factor (relative influence =16%). The predictive ability of the model based on comorbidities was slightly higher than the one based on the self-perceived health (C-statistic =0.67 vs 0.65). This study demonstrates that self-perceived health may be an important piece of information to add to the EHR. It may be another method to determine hospitalization risk.


Food Advertising on Television Before and After a National Unhealthy Food Marketing Regulation in Chile, 2016-2017.
Objectives. To study changes in food advertising on television after Chile's food marketing restriction was implemented in June 2016.Methods. Food advertisements shown between 6 am and 12 am on the 4 primary broadcast and 4 cable channels with the largest Chilean youth audiences during 2 random weeks in April and May 2016 and 2017 were analyzed for product nutrition and child-directed marketing.Results. The percentage of ads for foods high in energy, saturated fats, sugars, or sodium (HEFSS) decreased from 41.9% before the regulation to 14.8% after the regulation (P < .001). This decrease occurred in programs intended for children (from 49.7% to 12.7%; P < .001) as well as general audiences (from 38.5% to 15.7%; P < .001). The largest declines were seen for sodas, desserts, breakfast cereals and industrialized fruit- and vegetable-flavored drinks. Fewer HEFSS ads featured child-directed content (a decrease from 44.0% to 12.0%; P < .001), and the remaining child-directed HEFSS ads primarily aired on internationally owned cable channels.Conclusions. The significant postregulation decrease in the prevalence of HEFSS television ads suggests that children in Chile are now less exposed to unhealthy food advertising. However, television originating from national and international outlets should still be monitored for compliance.


Detection of species diversity in oral candida colonization and anti-fungal susceptibility among non-oral habit adult diabetic patients.
Patients with diabetes mellitus are prone to secondary infections. In this study we aim to determine the prevalence of one such secondary infection (oral Candida colonization) and evaluate the influence of local and systemic factors on the oral candidal colonization in patients with diabetes mellitus. Forty non-insulin-dependent diabetic patients and 40 healthy individuals were included in this study. Samples were collected by using the oral rinse method. The candidal species were isolated and identified through phenotypic methods. An in vitro antifungal susceptibility profile was evaluated. Glycemic control, as determined by the glycosylated hemoglobin concentrations (HbA1c) of the study subjects, was correlated with the candidal colonization. Patients with diabetes showed a significantly higher prevalence of candidal colonization. The rate of carriage and density (P = 0.001) was higher. Candida albicans was the most predominantly isolated species, however, C. dubliniensis, C. tropicalis, and C. parapsilosis were also observed. Variable resistance toward the antifungal drugs (amphotericin B and fluconazole) was observed in the Candida isolated from diabetics, but not from healthy patients. Interestingly, a positive correlation was observed between glycemic control and candidal colonization. Diabetic patients had a higher candidal carriage rate, with a variety of candidal strains, which significantly varied in their resistance to routinely used anti-fungal agents. Interestingly the higher oral candidal colonization in diabetic patients is related to local and systemic factors, independent of their oral habits.


New Imaging Technology for Simultaneous Multiwavelength-UWF Fundus Fluorescein Angiography and Indocyanine Green Angiography With Navigated Central and Peripheral SS-OCT.
Our aim was to assess central and peripheral retinal and choroidal diseases using novel simultaneous multiwavelength-ultra-widefield (MW-UWF) fundus fluorescein angiography (FFA)/indocyanine green angiography (ICGA) with navigated central and peripheral swept-source optical coherence tomography (SS-OCT) technology. Retrospective evaluation was carried out of 30 consecutive patients (60 eyes) who underwent UWF red/green (RG), infrared (IR), FFA and ICGA with simultaneous navigated SS-OCT using Optos Silverstone (Optos PLC). Angiographic retinal and choroidal findings in vascular pathologies and their relationship with the vitreoretinal interface (VRI) were assessed. Simultaneous FFA with navigated SSOCT was performed in all patients and simultaneous FFA-ICGA with SS-OCT in 18 eyes (30%). Cross-sectional central and peripheral changes in the retina, choroid, and VRI corresponding with angiographic findings in several diseases were imaged. First-in-human study of a new technology providing UWF RG/FFA/ICGA with simultaneous navigated central and peripheral SS-OCT can guide clinical management and provide new insights and understanding of central and peripheral retinal and choroidal disease. [Ophthalmic Surg Lasers Imaging Retina 2023;54:401-410.].


Why do nominal characteristics acquire status value? A minimal explanation for status construction.
Why do beliefs that attach different amounts of status to different categories of people become consensually held by the members of a society? We show that two microlevel mechanisms, in combination, imply a system-level tendency toward consensual status beliefs about a nominal characteristic. (1) Status belief diffusion: a person who has no status belief about a characteristic can acquire a status belief about that characteristic from interacting with one or more people who have that status belief. (2) Status belief loss: a person who has a status belief about a characteristic can lose that belief from interacting with one or more people who have the opposite status belief. These mechanisms imply that opposite status beliefs will tend to be lost at equal rates and will tend to be acquired at rates proportional to their prevalence. Therefore, if a status belief ever becomes more prevalent than its opposite, it will increase in prevalence until every person holds it.


Alternative uses of dermoscopy in daily clinical practice: An update.
Dermoscopy is a noninvasive diagnostic tool that is currently being used for neoplastic skin lesions, several inflammatory and infectious diseases, and skin appendage disorders. As the clinical applications of dermoscopy beyond pigmented lesions are constantly increasing, the aim of this article is to provide an update on this topic. This comprehensive review substantiates how several diseases may show peculiar dermoscopy features so as to enhance the diagnosis and avoid (in selected cases) unnecessary histologic confirmation. In other cases, dermoscopy features may be shared with other conditions, with the advantage of narrowing down the differential diagnosis by ruling out those dermatoses with similar clinical aspect but different dermoscopic presentation.


What lies behind the low rates of vaccinations among nurses who treat infants?
In most countries rates of immunizations of health care workers with recommended vaccines are not satisfactory. To identify reasons behind the low rates of compliance of Israeli nurses in Mother and Child Healthcare Centers (MCHC) with an official request for pertussis vaccination. Three focus groups were conducted. Qualitative analysis identified themes that could explain the nurses' non-compliance. Trust in health authorities was low, mainly following the A/H1N1 purported influenza pandemic. In addition, nurses did not see the importance of being role models for the public and demanded the autonomy to decide whether to receive vaccinations. The nurses differentiated between their role as nurses and their personal life, expressed fear of new vaccines and exhibited low levels of risk perception. Misconceptions regarding vaccinations were expressed by the nurses. Antivaccinationist ideas were expressed by MCHC nurses and these attitudes may have led to non-compliance with vaccination guidelines.


Genome information of Methylobacterium oryzae, a plant-probiotic methylotroph in the phyllosphere.
Pink-pigmented facultative methylotrophs in the Rhizobiales are widespread in the environment, and many Methylobacterium species associated with plants produce plant growth-promoting substances. To gain insights into the life style at the phyllosphere and the genetic bases of plant growth promotion, we determined and analyzed the complete genome sequence of Methylobacterium oryzae CBMB20T, a strain isolated from rice stem. The genome consists of a 6.29-Mb chromosome and four plasmids, designated as pMOC1 to pMOC4. Among the 6,274 coding sequences in the chromosome, the bacterium has, besides most of the genes for the central metabolism, all of the essential genes for the assimilation and dissimilation of methanol that are either located in methylotrophy islands or dispersed. M. oryzae is equipped with several kinds of genes for adaptation to plant surfaces such as defense against UV radiation, oxidative stress, desiccation, or nutrient deficiency, as well as high proportion of genes related to motility and signaling. Moreover, it has an array of genes involved in metabolic pathways that may contribute to promotion of plant growth; they include auxin biosynthesis, cytokine biosynthesis, vitamin B12 biosynthesis, urea metabolism, biosorption of heavy metals or decrease of metal toxicity, pyrroloquinoline quinone biosynthesis, 1-aminocyclopropane-1-carboxylate deamination, phosphate solubilization, and thiosulfate oxidation. Through the genome analysis of M. oryzae, we provide information on the full gene complement of M. oryzae that resides in the aerial parts of plants and enhances plant growth. The plant-associated lifestyle of M. oryzae pertaining to methylotrophy and plant growth promotion, and its potential as a candidate for a bioinoculant targeted to the phyllosphere and focused on phytostimulation are illuminated.


Unchanging visions: the effects and limitations of ocular stillness.
Scientists have pondered the perceptual effects of ocular motion, and those of its counterpart, ocular stillness, for over 200 years. The unremitting 'trembling of the eye' that occurs even during gaze fixation was first noted by Jurin in 1738. In 1794, Erasmus Darwin documented that gaze fixation produces perceptual fading, a phenomenon rediscovered in 1804 by Ignaz Paul Vital Troxler. Studies in the twentieth century established that Jurin's 'eye trembling' consisted of three main types of 'fixational' eye movements, now called microsaccades (or fixational saccades), drifts and tremor. Yet, owing to the constant and minute nature of these motions, the study of their perceptual and physiological consequences has met significant technological challenges. Studies starting in the 1950s and continuing in the present have attempted to study vision during retinal stabilization-a technique that consists on shifting any and all visual stimuli presented to the eye in such a way as to nullify all concurrent eye movements-providing a tantalizing glimpse of vision in the absence of change. No research to date has achieved perfect retinal stabilization, however, and so other work has devised substitute ways to counteract eye motion, such as by studying the perception of afterimages or of the entoptic images formed by retinal vessels, which are completely stable with respect to the eye. Yet other research has taken the alternative tack to control eye motion by behavioural instruction to fix one's gaze or to keep one's gaze still, during concurrent physiological and/or psychophysical measurements. Here, we review the existing data-from historical and contemporary studies that have aimed to nullify or minimize eye motion-on the perceptual and physiological consequences of perfect versus imperfect fixation. We also discuss the accuracy, quality and stability of ocular fixation, and the bottom-up and top-down influences that affect fixation behaviour.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.


Beyond copy and paste: clinician approaches to meeting information needs during note writing.
Clinicians need historical information that does not change over time, as well as other information from the notes of others to inform their documentation--to save time, they cut and paste since that is a feature in many conventional EHRs. Copy and paste is a solution to clinicians' needs that has associated downsides including errors. As part of a study of clinicians using an innovative system which gives them complete control over information selection and arrangement, two used the process of note splitting to meet needs that are sometimes solved through cut and paste; four others used text insertion (partial note sections) to address related needs. The purpose of this study is to enhance understanding of the note splitting and text insertion phenomena by describing the processes, the resulting creations, and the associated clinician rationales. Mixed methods included a thinkaloud protocol and analysis of user interface creations and time sequences.


A prospective observational study of tracheal intubation in an emergency department in a 2300-bed hospital of a developing country in a one-year period.
To assess the competency of physicians in the non-traumatic emergency department (ED) in intubating critically ill patients, to describe the methods, success rates and immediate complications after intubation in Siriraj Hospital. A one-year prospective observational study of endotracheal intubation in the ED of Siriraj Hospital, which has an annual census of 150 518 patients. Data were collected by each intubator at the time of each intubation for indications, success rates, use of drugs to facilitate intubation and immediate complications of tracheal intubation and the outcomes of patients. A total of 757 patients underwent endotracheal attempts in the ED, including 176 (23.2%) patients in cardiopulmonary arrest; 754 (99.6%) of these were successfully intubated and 602 (79.5%) patients were successfully intubated at the first attempt. Three patients could not be intubated and underwent surgical airway management. In non-cardiac arrest patients, intubation by neuromuscular blocking agent was performed in 16 (2.75%) patients only, and all the intubators were anaesthesiologists. 396 (68.1%) patients were successfully intubated without using any drug. 285 (37.6%) patients were found to have a total of 341 complications. At this institution, the majority of ED intubations were performed by residents and no drug was used. In this ED patients were intubated with a high success rate and a low rate of serious complications.


Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome.
Dietary polyphenols protect against metabolic syndrome, despite limited absorption and digestion, raising questions about their mechanism of action. We hypothesized that one mechanism may involve the gut microbiota. To test this hypothesis, C57BL/6J mice were fed a high-fat diet (HFD) containing 1% Concord grape polyphenols (GP). Relative to vehicle controls, GP attenuated several effects of HFD feeding, including weight gain, adiposity, serum inflammatory markers (tumor necrosis factor [TNF]α, interleukin [IL]-6, and lipopolysaccharide), and glucose intolerance. GP lowered intestinal expression of inflammatory markers (TNFα, IL-6, inducible nitric oxide synthase) and a gene for glucose absorption (Glut2). GP increased intestinal expression of genes involved in barrier function (occludin) and limiting triglyceride storage (fasting-induced adipocyte factor). GP also increased intestinal gene expression of proglucagon, a precursor of proteins that promote insulin production and gut barrier integrity. 16S rRNA gene sequencing and quantitative PCR of cecal and fecal samples demonstrated that GP dramatically increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes, consistent with prior reports that similar changes in microbial community structure can protect from diet-induced obesity and metabolic disease. These data suggest that GP act in the intestine to modify gut microbial community structure, resulting in lower intestinal and systemic inflammation and improved metabolic outcomes. The gut microbiota may thus provide the missing link in the mechanism of action of poorly absorbed dietary polyphenols.


Mitochondria as target of endocrine-disrupting chemicals: implications for type 2 diabetes.
Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin resistance and pancreatic β-cell dysfunction or death. Among several environmental factors contributing to type 2 diabetes development, endocrine-disrupting chemicals (EDCs) have been receiving special attention. These chemicals include a wide variety of pollutants, from components of plastic to pesticides, with the ability to modulate endocrine system function. EDCs can affect multiple cellular processes, including some related to energy production and utilization, leading to alterations in energy homeostasis. Mitochondria are primarily implicated in cellular energy conversion, although they also participate in other processes, such as hormone secretion and apoptosis. In fact, mitochondrial dysfunction due to reduced oxidative capacity, impaired lipid oxidation and increased oxidative stress has been linked to insulin resistance and type 2 diabetes. Herein, we review the main mechanisms whereby metabolism-disrupting chemical (MDC), a subclass of EDCs that disturbs energy homeostasis, cause mitochondrial dysfunction, thus contributing to the establishment of insulin resistance and type 2 diabetes. We conclude that MDC-induced mitochondrial dysfunction, which is mainly characterized by perturbations in mitochondrial bioenergetics, biogenesis and dynamics, excessive reactive oxygen species production and activation of the mitochondrial pathway of apoptosis, seems to be a relevant mechanism linking MDCs to type 2 diabetes development.


Transient gain and cross talk in erbium-doped fiber amplifiers.
Transient gain saturation and recovery with 110-340-microsec time constants were observed in erbium-doped fiber amplifiers. This slow response reduces the effects of saturation-induced cross talk and intermodulation distortion associated with multichannel signal amplification. In a two-channel amplification experiment, negligible saturation-induced cross talk was measured at signal modulation frequencies >5 kHz. Increased suppression of saturation-induced cross talk was achieved through feed-forward compensation to reduce low-frequency gain fluctuations.


Agro-ecological zone and farm diversity are factors associated with haemoglobin and anaemia among rural school-aged children and adolescents in Ghana.
Understanding contextual risk factors for haemoglobin (Hb) status and anaemia of rural school-aged children (SAC) and adolescents is critical in developing appropriate interventions to prevent anaemia. We analysed secondary data from the baseline of an impact evaluation of the Ghana School Feeding Programme to determine the severity of anaemia and contextual factors associated with anaemia and Hb status among rural SAC (6-9 years; n = 323) and adolescents (10-17 years; n = 319) in Ghana. We used regression models with variable selection based on backward elimination in our analyses. The mean Hb was 113.8 ± 13.1 g/L, and the overall prevalence of anaemia was 52.3%, being 55.1% and 49.5% among SAC and adolescents, respectively. We identified child's age (β = 2.21, P < 0.001); farm diversity score (β = 0.59, P = 0.036); and agro-ecological zone (P trend <0.001) as the main predictors of Hb of SAC. Household asset index (P trend = 0.042) and agro-ecological zone (P trend <0.001) were predictors of Hb in adolescents. Agro-ecological zone and age were predictors of anaemia, but the effect of age was only significant for girls and not boys (prevalence odds ratio [POR] = 1.35, 95% CI [1.04, 1.76] vs. POR = 1.14, 95% CI [0.88, 1.46]). SAC in households with maize stock were less likely to be anaemic (POR = 0.55, 95% CI [0.32, 0.97]). Household dietary diversity score (β = 0.59, P = 0.033) was associated with Hb status for the full sample only. Anaemia is a severe public health problem among SAC and adolescents in rural Ghana irrespective of sex. Farm diversity score, availability of maize stock in the household, household asset index, and agro-ecological zone were the main predictors of Hb and anaemia among the rural SAC and adolescents.


Comparative whole-body kinematics of closely related insect species with different body morphology.
Legged locomotion through natural environments is very complex and variable. For example, leg kinematics may differ strongly between species, but even within the same species it is adaptive and context-dependent. Inter-species differences in locomotion are often difficult to interpret, because both morphological and ecological differences among species may be strong and, as a consequence, confound each other's effects. In order to understand better how body morphology affects legged locomotion, we compare unrestrained whole-body kinematics of three stick insect species with different body proportions, but similar feeding ecology: Carausius morosus, Aretaon asperrimus and Medauroidea extradentata (=Cuniculina impigra). In order to co-vary locomotory context, we introduced a gradually increasing demand for climbing by varying the height of stairs in the setup. The species were similar in many aspects, for example in using distinct classes of steps, with minor differences concerning the spread of corrective short steps. Major differences were related to antenna length, segment lengths of thorax and head, and the ratio of leg length to body length. Whereas all species continuously moved their antennae, only Medauroidea executed high swing movements with its front legs to search for obstacles in the near-range environment. Although all species adjusted their body inclination, the range in which body segments moved differed considerably, with longer thorax segments tending to be moved more. Finally, leg posture, time courses of leg joint angles and intra-leg coordination differed most strongly in long-legged Medauroidea.


Solar geoengineering to reduce climate change: a review of governance proposals.
Although solar geoengineering (alternatively 'solar radiation management' or 'solar radiation modification') appears to offer a potentially effective, inexpensive and technologically feasible additional response to climate change, it would pose serious physical risks and social challenges. Governance of its research, development and deployment is thus salient. This article reviews proposals for governing solar geoengineering. Its research may warrant dedicated governance to facilitate effectiveness and to reduce direct and socially mediated risks. Because states are not substantially engaging with solar geoengineering, non-state actors can play important governance roles. Although the concern that solar geoengineering would harmfully lessen abatement of greenhouse gas emissions is widespread, what can be done to reduce such displacement remains unclear. A moratorium on outdoor activities that would surpass certain scales is often endorsed, but an effective one would require resolving some critical, difficult details. In the long term, how to legitimately make decisions regarding whether, when and how solar geoengineering would be used is central, and suggestions how to do so diverge. Most proposals to govern commercial actors, who could provide goods and services for solar geoengineering, focus on intellectual property policy. Compensation for possible harm from outdoor activities could be through liability or a compensation fund. The review closes with suggested lines of future inquiry.


Possible amelioration of atherogenic diet induced dyslipidemia, hypothyroidism and hyperglycemia by the peel extracts of Mangifera indica, Cucumis melo and Citrullus vulgaris fruits in rats.
Hitherto unknown efficacy of the peel extracts of Mangifera indica (MI), Cucumis melo (CM) and Citrullus vulgaris (CV) fruits in ameliorating the diet-induced alterations in dyslipidemia, thyroid dysfunction and diabetes mellitus have been investigated in rats. In one study, out of 4 different doses (50-300 mg/kg), 200 mg/kg of MI and 100 mg/kg for other two peel extracts could inhibit lipidperoxidation (LPO) maximally in liver. In the second experiment rats were maintained on pre-standardized atherogenic diet CCT (supplemented with 4% cholesterol, 1% cholic acid and 0.5% 2-thiouracil) to induce dyslipidemia, hypothyroidism and diabetes mellitus and the effects of the test peel extracts (200 mg/kg of MI and 100 mg/kg for CM and CV for 10 consecutive days) were studied by examining the changes in tissue LPO (in heart, liver and kidney), concentrations of serum lipids, thyroid hormones, insulin and glucose. Rats, treated simultaneously with either of the peel extracts reversed the CCT-diet induced increase in the levels of tissue LPO, serum lipids, glucose, creatinine kinase-MB and decrease in the levels of thyroid hormones and insulin indicating their potential to ameliorate the diet induced alterations in serum lipids, thyroid dysfunctions and hyperglycemia/diabetes mellitus. A phytochemical analysis indicated the presence of a high amount of polyphenols and ascorbic acid in the test peel extracts suggesting that the beneficial effects could be the result of the rich content of polyphenols and ascorbic acid in the studied peels.


The therapeutic potential of bacteriophages targeting gram-negative bacteria using Galleria mellonella infection model.
Phage therapy is the therapeutic use of bacteriophages to treat highly drug resistant bacterial infections. The current surge in bacteriophage therapy is motivated mainly because of the emergence of antibiotic-resistant bacteria in clinics. This study evaluated the therapeutic potential of three bacteriophages isolated against Escherichia coli ec311, Klebsiella pneumoniae kp235 and Enterobacter cloacae el140 strains using Galleria mellonella. The in vitro activity of three different phages belonging to Podoviridae and Myoviridae families was studied by the double agar overlay method against multi-drug resistant strains. Larval survivability studies were performed to evaluate the potential of phages against infection using G. mellonella. All the three phages were found to have potential to infect the host bacterial strains. For in vivo studies it was observed that E. coli and E. cloacae infected larvae, should be treated with three phage doses (20 μL, 104 PFU/mL) at 6 h interval to achieve 100% survival rate. But in the case of K. pneumoniae, a single phage dose treatment showed promising outcome. When mixed bacterial infections (all three bacterial cultures at 108 CFU/mL) were tested, minimum of four doses of phage cocktail (three phages) at 6 h interval was necessary to recover the larvae. All the results were confirmed by enumerating bacteria from the larvae. Our data shows that although in vitro studies showed high infectivity of phages, for in vivo models multiple phage doses were required for effective treatment.


Depression influences intellectual impairment in stroke patients.
Patients with ischaemic lesions of the left cerebral hemisphere were examined for depression and intellectual impairment: in non-depressed patients, the severity of impairment was related to both lesion volume and location, as assessed by CT scan analysis. Cognitive impairment in patients with major depression was greater than predicted by lesion volume alone, and when patients were matched for severity of impairment, depressed patients had smaller lesion volumes than the non-depressed. After six months, non-depressed patients had significantly less cognitive impairment than depressed patients who showed no improvement. Both depression and lesion volume were significantly and independently related to cognitive impairment. These findings suggest that post-stroke depression can produce a true dementia in its own right, and that treatment of post-stroke depression might benefit cognitive function.


Application of Liquid Chromatography-Tandem Mass Spectrometry To Determine Urinary Concentrations of Five Commonly Used Low-Calorie Sweeteners: A Novel Biomarker Approach for Assessing Recent Intakes?
Although the use of low-calorie sweeteners (LCSs) is widespread, methods of assessing consumption within free-living populations have inherent limitations. Five commonly consumed LCSs, namely, acesulfame-K, saccharin, sucralose, cyclamate, and steviol glycosides, are excreted via the urine, and therefore a urinary biomarker approach may provide more objective LCS intake data. A LC-ESI-MS/MS method of simultaneously determining acesulfame-K, saccharin, sucralose, cyclamate, and the excretory metabolite of steviol glycosides, steviol glucuronide, in human urine was developed and validated. Linearity was observed over a concentration range of 10-1000 ng/mL with coefficients of determination ranging from 0.9969 to 0.9997. Accuracy ranged from 92 to 104%, and intrabatch and interday precisions were within acceptable limits with %CV below 8% for all compounds. A double-blind, randomized crossover dose-response study was conducted to assess the usefulness of urinary LCS excretions (from both fasting spot and a full 24-h urine collection) for investigating recent intakes. Both modes of sampling were useful for distinguishing between the three short-term intakes of acesulfame-K, saccharin, cyclamates, and steviol glycosides (p < 0.001), whereas for sucralose, urinary concentrations were useful for distinguishing between low (0.1% ADI) and high doses (10% ADI) only (p < 0.001). In summary, this biomarker approach may be useful for assessing intakes of five commonly consumed LCSs.


DNA shuffling of adeno-associated virus yields functionally diverse viral progeny.
Adeno-associated virus (AAV) vectors are extremely effective gene-delivery vehicles for a broad range of applications. However, the therapeutic efficacy of these and other vectors is currently limited by barriers to safe, efficient gene delivery, including pre-existing antiviral immunity, and infection of off-target cells. Recently, we have implemented directed evolution of AAV, involving the generation of randomly mutagenized viral libraries based on serotype 2 and high-throughput selection, to engineer enhanced viral vectors. Here, we significantly extend this capability by performing high-efficiency in vitro recombination to create a large (10(7)), diverse library of random chimeras of numerous parent AAV serotypes (AAV1, 2, 4-6, 8, and 9). In order to analyze the extent to which such highly chimeric viruses can be viable, we selected the library for efficient viral packaging and infection, and successfully recovered numerous novel chimeras. These new viruses exhibited a broad range of cell tropism both in vitro and in vivo and enhanced resistance to human intravenous immunoglobulin (IVIG), highlighting numerous functional differences between these chimeras and their parent serotypes. Thus, directed evolution can potentially yield unlimited numbers of new AAV variants with novel gene-delivery properties, and subsequent analysis of these variants can further extend basic knowledge of AAV biology.


Hyperpolarized (13) C-labelled anhydrides as DNP precursors of metabolic MRI agents.
The extraordinary enhancement of the nuclear magnetic resonance (NMR) signal that can be obtained by dynamic nuclear polarization (DNP) techniques is prompting new avenues of research based on the in vivo detection of metabolic abnormalities associated with the onset and progression of human diseases. (13) C-labelled short-chain fatty acids appear to be interesting candidates for this novel class of metabolic-active contrast agents (MCAs), as they have been shown to report on metabolic differences between healthy and ischaemic tissues in mice. In spite of their promising biological efficacy, the formulations of short-chain fatty acids that fulfil the many technical constraints of the DNP procedure, as it is today, may limit their clinical potential. New solutions have been sought to circumvent technology-related challenges and facilitate clinical translation of these molecules. In particular, it has been shown that, by using symmetric anhydrides as chemical precursors for short-chain fatty acids, no glass-forming additives are needed in the DNP formulations. Furthermore, novel esterified trityl radicals and lipophilic gadolinium complexes allow easy removal of the polarization-promoting additives at the end of the DNP process. By applying the three concepts reported, we have succeeded in preparing aqueous formulations of short-chain fatty acids for pharmaceutical use that have favourable properties compared with those obtained from current procedures. The use of organic derivatives as chemical precursors of the MCA of interest appears to be a generally valid concept, not restricted to symmetric anhydrides of fatty acids, which can markedly improve the clinical potential of other (13) C-labelled compounds.


A new understanding of how temperature affects the catalytic activity of enzymes.
The two established thermal properties of enzymes are their activation energy and their thermal stability, but experimental data do not match the expectations of these two properties. The recently proposed Equilibrium Model (EM) provides a quantitative explanation of enzyme thermal behaviour under reaction conditions by introducing an inactive (but not denatured) intermediate in rapid equilibrium with the active form. It was formulated as a mathematical model, and fits the known experimental data. Importantly, the EM gives rise to a number of new insights into the molecular basis of the temperature control of enzymes and their environmental adaptation and evolution, it is consistent with active site properties, and it has fundamental implications for enzyme engineering and other areas of biotechnology.


Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD.
Twenty children with attention deficit/hyperactivity disorder (AD/HD) were treated with either Ritalin (10 children) or dietary supplements (10 children), and outcomes were compared using the Intermediate Visual and Auditory/Continuous Performance Test (IVA/CPT) and the WINKS two-way analysis of variance with repeated measures and with Tukey multiple comparisons. Subjects in both groups showed significant gains (p less than 0.01) on the IVA/CPT's Full Scale Response Control Quotient and Full Scale Attention Control Quotient (p less than 0.001). Improvements in the four sub-quotients of the IVA/CPT were also found to be significant and essentially identical in both groups: Auditory Response Control Quotient (p less than 0.001), Visual Response Control Quotient (p less than 0.05), Auditory Attention Quotient (p less than 0.001), and Visual Attention Quotient (p less than 0.001). Numerous studies suggest that biochemical heterogeneous etiologies for AD/HD cluster around at least eight risk factors: food and additive allergies, heavy metal toxicity and other environmental toxins, low-protein/high-carbohydrate diets, mineral imbalances, essential fatty acid and phospholipid deficiencies, amino acid deficiencies, thyroid disorders, and B-vitamin deficiencies. The dietary supplements used were a mix of vitamins, minerals, phytonutrients, amino acids, essential fatty acids, phospholipids, and probiotics that attempted to address the AD/HD biochemical risk factors. These findings support the effectiveness of food supplement treatment in improving attention and self-control in children with AD/HD and suggest food supplement treatment of AD/HD may be of equal efficacy to Ritalin treatment.


MEG delta mapping along the healthy aging-Alzheimer's disease continuum: diagnostic implications.
New diagnostic criteria for Alzheimer's disease (AD) stress the role of in vivo biomarkers. Neurophysiological markers are usually not considered as such criteria, although theoretical and practical reasons would justify them. In order to assess the value of neurophysiology as an AD biomarker, whole-head magnetoencephalographic (MEG) resting state recordings were obtained from 35 AD patients, 23 mild cognitive impairment (MCI) patients, and 24 healthy controls. The AD group was further split into two groups differing in severity according to the GDS/FAST criteria. A Minimum Norm Estimation procedure was utilized to estimate the cortical origin of slow brain oscillatory activity in the delta band (2-4 Hz). Eight regions of interest (ROIs) discriminated between AD patients and controls. Delta current density (DCD) in all ROIs showed a significant negative correlation with cognitive status (p < 0.001). DCD values in posterior parietal, occipital, prerolandic, and precuneus cortices distinguished reliably between MCI patients, AD patients with different severity scores, and controls. Importantly, an increase of DCD in right parietal cortex and precuneus indexed the transition from MCI to mild dementia and from mild to more severe dementia. MEG delta mapping might be a serious candidate for a "neural degeneration" marker of AD reflecting dysfunctional synaptic transmission. More importantly, the localization of DCD values is in line with functional imaging markers of AD. However, MEG delta mapping is a totally non-invasive technique that directly measures neural activity. We propose that individuals with enhanced DCD in posterior parietal and precuneus cortices are at risk of progression to full dementia.


The costs of non-insurance in Maryland.
This study calculates expenditures and costs related to a lack of health insurance coverage in the State of Maryland. The study is based on detailed primary and secondary data collection on the following sources of payment and care related to non-insurance: (1) uncompensated hospital care; (2) other public subsidies; (3) ambulatory services; (4) philanthropic spending; and (5) uninsured individuals' costs. Expenditures by and for the uninsured in Maryland total $1.47 billion dollars. On a per-capita basis, this is equivalent to $2,371 per full-year uninsured person in the state. Twenty-seven percent of this total, or $633 per uninsured person, is paid directly by the uninsured themselves in out-of-pocket medical expenditures. The state and local governments spent $497 per uninsured person (21% of the total), and the federal government spent an additional $401 (17%). Private payers (including insurance, physicians, and philanthropy) accounted for $460 (19%). The sources and flows of spending on the uninsured are complex, and these expenditure levels should not be interpreted as savings that would directly result from an expansion of insurance coverage. Our results are consistent with earlier studies completed at the national level, and add considerable detail.


Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90.
Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1⁻68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9⁻99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.


Childhood leukaemia: long-term excess mortality and the proportion 'cured'.
Survival from childhood leukaemia has increased, but the proportion of children cured is unknown. The proportion 'cured' is defined as the proportion of survivors for whom, as a group, there is no longer excess mortality compared to the general population. Average time to cure is defined as the time since diagnosis at which the excess mortality rate has declined to or below a predetermined small value. Data on children diagnosed with leukaemia during 1971-2000 in Great Britain were used to estimate trends in survival, the proportion cured and the average time to cure. Five-year survival for all types of leukaemia combined rose from 33 to 79% by 2000. The percentage cured rose from 25 to 68% by 1995; it is predicted to increase to 73% for those diagnosed more recently. Average time to cure increased from 12 years (95% confidence interval (CI): 11-14) to 19 years (95% CI: 14-26) for lymphoid leukaemia (average annual increase of 0.3 years; P<0.001), but remained at about 5 years for acute nonlymphoblastic leukaemia. The proportion of children cured of leukaemia has risen dramatically, but the period of excess mortality associated with lymphoid leukaemia has also increased, possibly because of late relapse, secondary malignancy and toxicity from treatment.


Spinal dural closure with nonpenetrating titanium clips in pediatric neurosurgery.
The authors report a retrospective review of their experience using nonpenetrating titanium anastomotic clips for dural closure in 27 pediatric cases (26 patients) of spinal surgery for a variety of diagnoses. The goal of this review was to define the utility of these clips in pediatric neurosurgical spinal procedures, identify complications of their use, and assess the effects on postoperative imaging because of their use. Institutional review board approval was obtained for a retrospective chart review of all patients in whom titanium dural clips had been utilized. Patients were identified over a 2-year period using hospital and clinic records, and data were collected on the patient demographics, surgical diagnosis and procedure, durotomy location and length, and adjunctive closure methods. Postoperative complications were assessed. When available, postoperative imaging data were reviewed. Twenty-six patients underwent 27 operations over a 20-month period. They ranged in age from 2.5 months to 18.5 years, with a median age of 3.2 years and an average age of 5.8 years. The operative diagnosis was some form of spinal dysraphism in 19 patients, with a syrinx or dural tear in 2 patients each, and an arachnoid cyst in 3 cases; 1 patient had a tumor resected. Operative levels included lumbosacral (19), thoracic (7), and cervical (1). Dural exposure was limited to 1 laminar level in 16 cases, 2 levels in 8, and 3 levels in 1; 2 cases involved focal dural tears. A combination of additional hemostatic and tissue sealant materials was applied over the clips in 16 cases. One patient required reoperation 13 months after clip placement. Prior clip use did not make subsequent exposure and opening more complicated. No significant complications were identified in the follow-up period ranging from 1 to 24 months. There were no documented CSF leaks. The clips are not easily seen on plain radiographs and did not cause artifacts or distortion on either CT or MR imaging. Nonpenetrating titanium anastomotic clips afford an effective means of closure while limiting the exposure needed, and thus allowing more minimally invasive approaches. In tight spaces, dural closure is accomplished more easily and faster with the clips as compared with conventional suturing. No significant complications were seen from clip use, and the clips did not interfere with postoperative imaging.


Books average previous decade of economic misery.
For the 20(th) century since the Depression, we find a strong correlation between a 'literary misery index' derived from English language books and a moving average of the previous decade of the annual U.S. economic misery index, which is the sum of inflation and unemployment rates. We find a peak in the goodness of fit at 11 years for the moving average. The fit between the two misery indices holds when using different techniques to measure the literary misery index, and this fit is significantly better than other possible correlations with different emotion indices. To check the robustness of the results, we also analysed books written in German language and obtained very similar correlations with the German economic misery index. The results suggest that millions of books published every year average the authors' shared economic experiences over the past decade.


Bose-Einstein condensation of molecules.
We report on the Bose-Einstein condensation of more than 10(5) Li2 molecules in an optical trap starting from a spin mixture of fermionic lithium atoms. During forced evaporative cooling, the molecules are formed by three-body recombination near a Feshbach resonance and finally condense in a long-lived thermal equilibrium state. We measured the characteristic frequency of a collective excitation mode and demonstrated the magnetic field-dependent mean field by controlled condensate spilling.


Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trial.
Limited pharmacological options are available for the management of Alzheimer's disease (AD) in severe stages. Cognitive-enhancing properties of saffron, the dried stigma of Crocus sativus L., have been evidenced in different studies. We aimed to compare the efficacy and safety of saffron extract versus memantine in reducing cognitive deterioration of patients with moderate to severe AD. In this randomized double-blind parallel-group study, 68 patients with moderate to severe AD (Mini-Mental State Examination score of 8-14) received memantine (20 mg/day) or saffron extract (30 mg/day) capsules for 12 months. Participants were evaluated every month by Severe Cognitive Impairment Rating Scale (SCIRS) and Functional Assessment Staging (FAST) in addition to recording the probable adverse events. Both treatment groups showed similar outcomes as demonstrated by insignificant effect for time × treatment interaction on SCIRS scores [F(2.95, 194.78) = 2.25, p = 0.08]. There was no significant difference between the two groups in the scores changes from baseline to the endpoint on SCIRS (p = 0.38) and FAST (p = 0.87). The frequency of adverse events was not significantly different between the two groups as well. In addition to its favorable safety profile, 1-year administration of saffron extract capsules showed to be comparable with memantine in reducing cognitive decline in patients with moderate to severe AD. Confirmatory studies with larger sample sizes and longer follow-up periods are warranted.


Estrogen replacement therapy in breast cancer survivors: a matched-controlled series.
We prospectively administered estrogen replacement therapy (ERT) to control estrogen deficiency symptoms in breast cancer survivors as part of our clinical practice. We report the consequences of ERT compared with a historical matched-control group. Two hundred seventy-seven disease-free survivors received ERT. Controls were matched for exact stage, a recurrence-free period similar to the period to ERT initiation in the ERT group, approximate age, and duration of follow-up. The mean time from breast cancer diagnosis to initiation of ERT was 3.61 (+/- 0.25) years, with a median of 1.88 years. The mean duration of ERT was 3.7 (+/- 3.01) years, with a median of 3.05 years. Hot flashes were relieved in 206 of 223 women (92%), dyspareunia/vaginal dryness in 149 of 167 women (89%), and reactive depression/anxiety/mood change in 111 of 126 women (88%). Univariate analysis demonstrated no statistical differences between the groups for age, stage, pathology at diagnosis, progesterone receptor status, local therapy, breast at risk, prior chemotherapy, and duration of follow-up. The ERT group was more likely to be estrogen receptor negative (P = 0.01), to have received prior ERT (P < 0.001), and to have received no adjuvant tamoxifen (P < 0.001). There was no significant difference between the ERT and control groups in ipsilateral primary/recurrence (5/155 v 5/143; P = 0.85), contralateral breast cancers (10/258 v 9/260; P = 0.99), or systemic metastasis (8/277 v 15/277; P = 0.13). Noncause-specific deaths in the control group numbered 15 (of 277), and in the ERT group, 7 (of 277) (P = 0.03). Overall survival favored the ERT group (P = 0.02). In these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases.


The MLC1v gene provides a transgenic marker of myocardium formation within developing chambers of the Xenopus heart.
Many details of cardiac chamber morphogenesis could be revealed if muscle fiber development could be visualized directly within the hearts of living vertebrate embryos. To achieve this end, we have used the active promoter of the MLC1v gene to drive expression of green fluorescent protein (GFP) in the developing tadpole heart. By using a line of Xenopus laevis frogs transgenic for the MLC1v-EGFP reporter, we have observed regionalized patterns of muscle formation within the ventricular chamber and maturation of the atrial chambers, from the onset of chamber formation through to the adult frog. In f1 generation MLC1v-EGFP animals, promoter activity is first detected within the looping heart tube and delineates the forming ventricular chamber and proximal outflow tract throughout their development. The 8-kb MLC1v promoter faithfully reproduces the embryonic expression of the endogenous MLC1v mRNA. At later larval stages, weak patches of EGFP fluorescence are found on the atrial side of the atrioventricular boundary. Subsequently, an extensive lattice of MLC1v-expressing fibers extend across the mature atrial chambers of adult frog hearts and the transgene reveals the differing arrangement of muscle fibers in chamber versus outflow myocardium. The complete activity of the promoter resides within the proximal 4.5 kb of the MLC1v DNA fragment, whereas key elements regulating chamber-specific expression are present in the proximal-most 1.5 kb. Finally, we demonstrate how cardiac and craniofacial muscle expression of the MLC1v promoter can be used to diagnose mutant phenotypes in living embryos, using the injection of RNA encoding a Tbx1-engrailed repressor-fusion protein as an example.


Disruption of Mycobacterium avium subsp. paratuberculosis-specific genes impairs in vivo fitness.
Mycobacterium avium subsp. paratuberculosis (MAP) is an obligate intracellular pathogen that infects many ruminant species. The acquisition of foreign genes via horizontal gene transfer has been postulated to contribute to its pathogenesis, as these genetic elements are absent from its putative ancestor, M. avium subsp. hominissuis (MAH), an environmental organism with lesser pathogenicity. In this study, high-throughput sequencing of MAP transposon libraries were analyzed to qualitatively and quantitatively determine the contribution of individual genes to bacterial survival during infection. Out of 52384 TA dinucleotides present in the MAP K-10 genome, 12607 had a MycoMarT7 transposon in the input pool, interrupting 2443 of the 4350 genes in the MAP genome (56%). Of 96 genes situated in MAP-specific genomic islands, 82 were disrupted in the input pool, indicating that MAP-specific genomic regions are dispensable for in vitro growth (odds ratio = 0.21). Following 5 independent in vivo infections with this pool of mutants, the correlation between output pools was high for 4 of 5 (R = 0.49 to 0.61) enabling us to define genes whose disruption reproducibly reduced bacterial fitness in vivo. At three different thresholds for reduced fitness in vivo, MAP-specific genes were over-represented in the list of predicted essential genes. We also identified additional genes that were severely depleted after infection, and several of them have orthologues that are essential genes in M. tuberculosis. This work indicates that the genetic elements required for the in vivo survival of MAP represent a combination of conserved mycobacterial virulence genes and MAP-specific genes acquired via horizontal gene transfer. In addition, the in vitro and in vivo essential genes identified in this study may be further characterized to offer a better understanding of MAP pathogenesis, and potentially contribute to the discovery of novel therapeutic and vaccine targets.


Derived neutrophil lymphocyte ratio is predictive of survival from intermittent therapy in advanced colorectal cancer: a post hoc analysis of the MRC COIN study.
The phase III COntinuous or INtermittent (COIN) trial failed to show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in overall survival (OS). The present analysis evaluated whether the derived neutrophil to lymphocyte ratio (dNLR) could predict the effect of intermittent vs continuous chemotherapy on OS in patients with advanced colorectal cancer. A post hoc exploratory analysis of COIN arms A and C was performed. Landmark analysis was conducted on all patients with available WBC and neutrophils data. The dNLR was calculated using a formula which has previously demonstrated predictive power in cancer patients: dNLR = ANC/(WBC-ANC). A high dNLR was defined using a cut-off value of ⩾ 2.22. Derived neutrophil to lymphocyte ratio was then correlated with clinical outcomes. Survival curves were generated based on dNLR using the Kaplan-Meier method. Comparison between groups was performed using Cox regression. A total of 1630 patients were assigned to the continuous (N = 815) or intermittent (N = 815) arms. There was a strong association between dNLR level and OS. The median survival times in the ITT population were 18.6 months and 12.5 months for patients with low and high dNLR, respectively (HR = 1.70; 95% CI = 1.52-1.90; P < 0.001). The estimate of the hazard ratio did not alter substantially (HR = 1.54) after adjusting for treatment, tumour status, number of metastatic sites, alkaline phosphate and platelet count. Derived neutrophil to lymphocyte ratio is strongly prognostic for survival in the COIN intermittent vs continuous treatment arms. Derived neutrophil to lymphocyte ratio does not predict for detrimental survival in patients treated with intermittent therapy.


Thromboxane antagonism in experimental canine carotid artery thrombosis.
The two objectives of this study were to assess the potential of BAY U 3405 to prevent arterial thrombosis in response to vessel wall injury and to determine the ability of BAY U 3405 to prevent thrombotic reocclusion after thrombolysis with anisoylated plasminogen streptokinase activator complex. Dogs were instrumented with a carotid flow probe, stimulating electrode, and a stenosis. Current (150 microA) was applied to the intimal surface of the right carotid artery, and time to occlusive thrombus formation was noted. BAY U 3405 was administered, and the procedure for thrombus formation was repeated for the left carotid artery. BAY U 3405 administration prevented occlusive arterial thrombosis formation. Ex vivo platelet aggregation was inhibited, bleeding time increased, and thrombus weight reduced after BAY U 3405 treatment. In a second group, thrombi were formed initially in both carotid arteries, BAY U 3405 was administered as before, and anisoylated plasminogen streptokinase activator complex was infused in the right carotid artery proximal to the occlusive thrombus. BAY U 3405 did not alter the incidence of rethrombosis compared with the lytic agent alone. BAY U 3405 prevented primary arterial thrombosis, corresponding to inhibition of platelet aggregation, and increased bleeding times. BAY U 3405, however, did not prevent rethrombosis after successful thrombolysis with anisoylated plasminogen streptokinase activator complex, despite the fact that platelet reactivity was inhibited. The data are consistent with the concept that the residual thrombus represents a more effective thrombogenic stimulus as compared with arterial wall injury alone and that the mechanisms associated with primary versus secondary thrombus formation may require separate therapeutic approaches.


Safety education and control: A tool to measure the safety locus of control.
Effective safety education can prevent many occupational accidents. To -educate the public about safety effectively, determinants of safe behavior must be addressed. Personality constructs are among the most important determinants of safe behavior. One of the personality constructs that has been studied recently in relation to accidents is locus of control. The main aim of this study was designing, validating, and determining the reliability of safety locus of control scale. This study was a descriptive, cross-sectional study. The "forward-backward" procedure was applied to translate safety locus of control scale (Jones and Becker 1985) from English to Persian. To determine the scientific validity of the scale, face validity and content validity by expert judgments were used. Internal consistency was determined using Cronbach's α-coefficient. Questionnaires were distributed to a group of 400 workers from different parts of Isfahan Steel Company. Finally, 317 workers completed the questionnaires. Exploratory factor analysis was performed with software SPSS13, and confirmatory factor analysis was performed with software LISREL8.8. The exploratory factor analysis results revealed that the three components of the items can be extracted from the scale including internal control (4 questions), environmental and equipment control (4 questions), and chance and fate (4 questions). Confirmatory factor analysis using maximum likelihood estimation results indicated that the data had good fit with three-component scale and fit indices were acceptable: χ(2)/df=3.96, df=41, χ(2) =120.59, RMSIA=0.080, 95% Confidence Interval=0.64-0.097, CFI=0.96, GFI=0.94, AGFI=0.89. The internal control components and equipment and environmental control were negatively correlated with each other (P≤0.05, r=-0.41). Also, a weak correlation between chance and fate and environmental and equipment control was seen (P≤0.05, r=0.31). In most studies, designing a scale and determining its validity and reliability is costly and time consuming. The available reliable and valid scale leads to reduced costs and accelerated research. In other words, duplication will be avoided. The scale obtained in this study can be used in safety and industrial psychology research.


Willingness to pay for improved respiratory and cardiovascular health: a multiple-format, stated-preference approach.
This study uses stated-preference (SP) analysis to measure willingness to pay (WTP) to reduce acute episodes of respiratory and cardiovascular ill health. The SP survey employs a modified version of the health state descriptions used in the Quality of Well Being (QWB) Index. The four health state attributes are symptom, episode duration, activity restrictions and cost. Preferences are elicited using two different SP formats: graded-pair and discrete-choice. The different formats cause subjects to focus on different evaluation strategies. Combining two elicitation formats yields more valid and robust estimates than using only one approach. Estimates of indirect utility function parameters are obtained using advanced panel econometrics for each format separately and jointly. Socio-economic differences in health preferences are modelled by allowing the marginal utility of money relative to health attributes to vary across respondents. Because the joint model captures the combined preference information provided by both elicitation formats, these model estimates are used to calculate WTP. The results demonstrate the feasibility of estimating meaningful WTP values for policy-relevant respiratory and cardiac symptoms, even from subjects who never have personally experienced these conditions. Furthermore, because WTP estimates are for individual components of health improvements, estimates can be aggregated in various ways depending upon policy needs. Thus, using generic health attributes facilitates transferring WTP estimates for benefit-cost analysis of a variety of potential health interventions.


Local temperatures inferred from plant communities suggest strong spatial buffering of climate warming across Northern Europe.
Recent studies from mountainous areas of small spatial extent (<2500 km(2) ) suggest that fine-grained thermal variability over tens or hundreds of metres exceeds much of the climate warming expected for the coming decades. Such variability in temperature provides buffering to mitigate climate-change impacts. Is this local spatial buffering restricted to topographically complex terrains? To answer this, we here study fine-grained thermal variability across a 2500-km wide latitudinal gradient in Northern Europe encompassing a large array of topographic complexities. We first combined plant community data, Ellenberg temperature indicator values, locally measured temperatures (LmT) and globally interpolated temperatures (GiT) in a modelling framework to infer biologically relevant temperature conditions from plant assemblages within <1000-m(2) units (community-inferred temperatures: CiT). We then assessed: (1) CiT range (thermal variability) within 1-km(2) units; (2) the relationship between CiT range and topographically and geographically derived predictors at 1-km resolution; and (3) whether spatial turnover in CiT is greater than spatial turnover in GiT within 100-km(2) units. Ellenberg temperature indicator values in combination with plant assemblages explained 46-72% of variation in LmT and 92-96% of variation in GiT during the growing season (June, July, August). Growing-season CiT range within 1-km(2) units peaked at 60-65°N and increased with terrain roughness, averaging 1.97 °C (SD = 0.84 °C) and 2.68 °C (SD = 1.26 °C) within the flattest and roughest units respectively. Complex interactions between topography-related variables and latitude explained 35% of variation in growing-season CiT range when accounting for sampling effort and residual spatial autocorrelation. Spatial turnover in growing-season CiT within 100-km(2) units was, on average, 1.8 times greater (0.32 °C km(-1) ) than spatial turnover in growing-season GiT (0.18 °C km(-1) ). We conclude that thermal variability within 1-km(2) units strongly increases local spatial buffering of future climate warming across Northern Europe, even in the flattest terrains.


Biological Processes and Biomarkers Related to Frailty in Older Adults: A State-of-the-Science Literature Review.
The objectives of this literature review were to (1) synthesize biological processes linked to frailty and their corresponding biomarkers and (2) identify potential associations among these processes and biomarkers. In September 2016, PubMed, Cumulative Index to Nursing and Allied Health, Cochrane Library, and Embase were searched. Studies examining biological processes related to frailty in older adults (≥60 years) were included. Studies were excluded if they did not employ specific measures of frailty, did not report the association between biomarkers and frailty, or focused on nonelderly samples (average age < 60). Review articles, commentaries, editorials, and non-English articles were also excluded. Fifty-two articles were reviewed, reporting six biological processes related to frailty and multiple associated biomarkers. The processes (biomarkers) include brain changes (neurotrophic factor, gray matter volume), endocrine dysregulation (growth hormones [insulin-like growth factor-1 and binding proteins], hormones related to glucose and insulin, the vitamin D axis, thyroid function, reproductive axis, and hypothalamic-pituitary-adrenal axis), enhanced inflammation (C-reactive protein, interleukin-6), immune dysfunction (neutrophils, monocytes, neopterin, CD8+CD28-T cells, albumin), metabolic imbalance (micronutrients, metabolites, enzyme-activity indices, metabolic end products), and oxidative stress (antioxidants, telomere length, glutathione/oxidized glutathione ratio). Bidirectional interrelationships exist within and between these processes. Biomarkers were associated with frailty in varied strengths, and the causality remains unclear. In conclusion, frailty is related to multisystem physiological changes. Future research should examine the dynamic interactions among these processes to inform causality of frailty. Given the multifactorial nature of frailty, a composite index of multisystem biomarkers would likely be more informative than single biomarkers in early detection of frailty.


Msx1 role in craniofacial bone morphogenesis.
The homeobox gene Msx1 encodes a transcription factor that is highly expressed during embryogenesis and postnatal development in bone. Mutations of the MSX1 gene in humans are associated with cleft palate and (or) tooth agenesis. A similar phenotype is observed in newborn mice invalidated for the Msx1 gene. However, little is known about Msx1 function in osteoblast differentiation and bone mineralization in vivo. In the present study, we aimed to explore the variations of individualized bone shape in a subtle way avoiding the often severe consequences associated with gene mutations. We established transgenic mice that specifically express Msx1 in mineral-matrix-secreting cells under the control of the mouse 2.3kb collagen 1 alpha 1 (Col1α1) promoter, which enabled us to investigate Msx1 function in bone in vivo. Adult transgenic mice (Msx1-Tg) presented altered skull shape and mineralization resulting from increased Msx1 expression during bone development. Serial section analysis of the mandibles showed a high amount of bone matrix in these mice. In addition, osteoblast number, cell proliferation and apoptosis were higher in Msx1-Tg mice than in controls with regional differences that could account for alterations of bone shape. However, Von Kossa staining and μCT analysis showed that bone mineralization was lower in Msx1-Tg mice than in controls due to alteration of osteoblastic differentiation. Msx1 appears to act as a modeling factor for membranous bone; it stimulates trabecular bone metabolism but limits cortical bone growth by promoting apoptosis, and concomitantly controls the collagen-based mineralization process.


[The survey for anti-emetic guideline by using questioner].
Japan Society of Clinical Oncology published a guideline for anti-emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire. Questionnaire analysis; From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff for the anti-emetic guideline published by (JSCO). Questionnaire; 1,529 medical stuff responded to our questionnaire. 1,308 (85.5%) stuffs recognized JSCO guidelines, 586 (51%) had regard for guideline and 489 (42.6%) referred to the guideline. 899 (78.3%) changed their practice in clinic to recommended practice by the guideline. But 385 (33.5%) complained high medical cost of recommended anti-emetic therapy. Degree of recognition and penetration of our guideline for anti-emetic therapy were very high in Japan.


Attention and performance in miniature golf across the life span.
Highly skilled adolescent (15-19 years), young (25-35 years), middle-aged (50-57 years), and older (58-73 years) miniature golf players were examined in training and competitive conditions. Number of shots, heart rate, ratings of anxiety, and concentration time were registered. IN addition, two attentional subscales from the Test of Attentional and Interpersonal Style (TAIS) inventory (Nideffer, 1976) were administered. Results indicated (a) parallel increases of heart rate and rated anxiety in competition for all age groups, (b) improvement of motor performance in competition for adolescent and young-adult players, and deterioration of motor performance in competition for middle-aged and older players, and (c) increased concentration time for the two younger samples, and decreased concentration time for the two older samples in competition. As well, the TAIS data indicated greater self-perceived external and internal distractability in the two older, compared to the two younger samples. This age-related vulnerability to distractions was shown to partly mediate age differences in competitive motor performance. The overall pattern of outcome is discussed relative to the view that the adult aging process is associated with a deficit in the ability to handle situations of high arousal due to age-related deficits in a variety of basic cognitive capacities.