Different modes of transport for 3H-thymidine, 3H-FLT, and 3H-FMAU in proliferating and nonproliferating human tumor cells.
The basis for the use of nucleoside tracers in PET is that activity of the cell-growth-dependent enzyme thymidine kinase 1 is the rate-limiting factor driving tracer retention in tumors. Recent publications suggest that nucleoside transporters might influence uptake and thereby affect the tracer signal in vivo. Understanding transport mechanisms for different nucleoside PET tracers is important for evaluating clinical results. This study examined the relative role of different nucleoside transport mechanisms in uptake and retention of [methyl-(3)H]-3'-deoxy-3'-fluorothymidine ((3)H-FLT), [methyl-(3)H]-thymidine ((3)H-thymidine), and (3)H-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil ((3)H-FMAU). Transport of (3)H-FLT, (3)H-thymidine, and (3)H-FMAU was examined in a single human adenocarcinoma cell line, A549, under both nongrowth and exponential-growth conditions. (3)H-Thymidine transport was dominated by human equilibrative nucleoside transporter 1 (hENT1) under both growth conditions. (3)H-FLT was also transported by hENT1, but passive diffusion dominated its transport. (3)H-FMAU transport was dominated by human equilibrative nucleoside transporter 2. Cell membrane levels of hENT1 increased in cells under exponential growth, and this increase was associated with a more rapid rate of uptake for both (3)H-thymidine and (3)H-FLT. (3)H-FMAU transport was not affected by changes in growth conditions. All 3 tracers concentrated in the plateau phase, nonproliferating cells at levels many-fold greater than their concentration in buffer, in part because of low levels of nucleoside metabolism, which inhibited tracer efflux. Transport mechanisms are not the same for (3)H-thymidine, (3)H-FLT, and (3)H-FMAU. Levels of hENT1, an important transporter of (3)H-FLT and (3)H-thymidine, increase as proliferating cells enter the cell cycle.


Restricting tobacco sales to only pharmacies combined with cessation advice: a modelling study of the future smoking prevalence, health and cost impacts.
Restricting tobacco sales to pharmacies only, including the provision of cessation advice, has been suggested as a potential measure to hasten progress towards the tobacco endgame. We aimed to quantify the impacts of this hypothetical intervention package on future smoking prevalence, population health and health system costs for a country with an endgame goal: New Zealand (NZ). We used two peer-reviewed simulation models: 1) a dynamic population forecasting model for smoking prevalence and 2) a closed cohort multi-state life-table model for future health gains and costs by sex, age and ethnicity. Greater costs due to increased travel distances to purchase tobacco were treated as an increase in the price of tobacco. Annual cessation rates were multiplied with the effect size for brief opportunistic cessation advice on sustained smoking abstinence. The intervention package was associated with a reduction in future smoking prevalence, such that by 2025 prevalence was 17.3%/6.8% for Māori (Indigenous)/non-Māori compared to 20.5%/8.1% projected under no intervention. The measure was furthermore estimated to accrue 41 700 discounted quality-adjusted life-years (QALYs) (95% uncertainty interval (UI): 33 500 to 51 600) over the remainder of the 2011 NZ population's lives. Of these QALYs gained, 74% were due to the provision of cessation advice over and above the limiting of sales to pharmacies. This work provides modelling-level evidence that the package of restricting tobacco sales to only pharmacies combined with cessation advice in these settings can accelerate progress towards the tobacco endgame, and achieve large population health benefits and cost-savings. :.


Incidence of retinopathy of prematurity in the United States: 1997 through 2005.
To determine the incidence of retinopathy of prematurity (ROP) based on a national database and to identify baseline characteristics, demographic information, comorbidities, and surgical interventions. Retrospective study based on the National Inpatient Sample from 1997 through 2005. The National Inpatient Sample was queried for all newborn infants with and without ROP. Multivariate logistic regression was used to predict risk factors for ROP. Thirty-four million live births were recorded during the study period. The total ROP incidence was 0.17% overall and 15.58% for premature infants with length of stay of more than 28 days. Our results conclusively demonstrated the importance of low birth weight as a risk for ROP development in infants with length of stay of more than 28 days, as well as association with respiratory conditions, fetal hemorrhage, intraventricular hemorrhage, and blood transfer. An interesting finding was the protective effect conferred by hypoxia, necrotizing enterocolitis, and hemolytic disease of the newborn. Infants with ROP had a higher incidence of undergoing laser photocoagulation therapy, pars plana vitrectomy, and scleral buckle surgery. The current study represents a large, retrospective analysis of newborns with ROP. The multivariate analysis emphasizes the role of birth weight in extended-stay infants, as well as respiratory conditions, fetal hemorrhage, intraventricular hemorrhage, and blood transfer.


[Anemia in pregnant women from the community of Puente Alto, Chile].
Micronutrient deficiencies, specially iron, render pregnant women as one of the most vulnerable groups to have anemia. To report the prevalence of anemia during pregnancy and its associated features in women attending public clinics in the Puente Alto County. We studied 1683 pregnant women aged 18 years old or more. Hemoglobin concentration was determined using the cianmetahemoglobin method. Anemia was defined using the 5th percentile cut-off for each week of gestational age as proposed by R Yip from the Centers of Disease Control, 1989. The influence of maternal age, parity, nutritional status classified using weight/height, diseases and smoking habits on hemoglobin concentration were analyzed using logistic regression with a stepwise procedure. Thirteen percent of the study population was anemic. The single factor significantly associated with anemia was nutritional status. Twenty one percent of women with a low weight for height were anemic. These results support the concept that pregnant women with a low weight for height have the greatest risk for anemia and should be specially benefited with preventive or treatment programs to avoid this problem.


A low glycaemic diet improves oral glucose tolerance but has no effect on β-cell function in C57BL/6J mice.
Clinical studies have suggested a role for dietary glycaemic index (GI) in body weight regulation and diabetes risk. Here, we investigated the long-term metabolic effects of low and high glycaemic diets using the C57BL/6J mouse model. Female C57BL/6J mice were fed low or high glycaemic starch in either low-fat or medium-fat diets for 22 weeks. Oral and intravenous glucose tolerance tests were performed to investigate the effect of the experimental diets on glucose tolerance and insulin resistance. In this study, a high glycaemic diet resulted in impaired oral glucose tolerance compared to a low glycaemic diet. This effect was more pronounced in the group fed a medium-fat diet, suggesting that a lower dietary fat content ameliorates the negative effect of a high glycaemic diet. No effect on body weight or body fat content was observed in either a low-fat diet or a medium-fat diet. Static incubation of isolated islets did not show any differences in basal (3.3 mM glucose) or glucose-stimulated (8.6 and 16.7 mM glucose) insulin secretion between mice fed a low or high glycaemic diet. Together, our data suggest that the impaired glucose tolerance seen after a high glycaemic diet is not explained by altered β-cell function.


Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer.
Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs). In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa) and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1) and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3' UTR of several target genes (such as RAC1, EGFR and EP300) that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa.


p66ShcA potentiates the cytotoxic response of triple-negative breast cancers to PARP inhibitors.
Triple-negative breast cancers (TNBCs) lack effective targeted therapies, and cytotoxic chemotherapies remain the standard of care for this subtype. Owing to their increased genomic instability, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are being tested against TNBCs. In particular, clinical trials are now interrogating the efficacy of PARPi combined with chemotherapies. Intriguingly, while response rates are low, cohort of patients do respond to PARPi in combination with chemotherapies. Moreover, recent studies suggest that an increase in levels of ROS may sensitize cells to PARPi. This represents a therapeutic opportunity, as several chemotherapies, including doxorubicin, function in part by producing ROS. We previously demonstrated that the p66ShcA adaptor protein is variably expressed in TNBCs. We now show that, in response to therapy-induced stress, p66ShcA stimulated ROS production, which, in turn, potentiated the synergy of PARPi in combination with doxorubicin in TNBCs. This p66ShcA-induced sensitivity relied on the accumulation of oxidative damage in TNBCs, rather than genomic instability, to potentiate cell death. These findings suggest that increasing the expression of p66ShcA protein levels in TNBCs represents a rational approach to bolster the synergy between PARPi and doxorubicin.


[Therapeutic efficacy of buparvaquone (buparvon) in cattle with theileriosis].
The aim of this study was to examine the efficacy of buparvaquone (Buparvon, ALKE, Istanbul) in the treatment of theileriosis in cattle. The causative agent T. annulata causes direct and indirect gross economical loss in Turkey. Theileriosis was microscopically diagnosed by determining the presence of piroplasms in erythrocytes in thin blood smears stained with Giemsa stain. Buparvaquone was administered intramuscularly to the cattle with theileriosis using a single dose of 2.5 mg/kg. Clinical and laboratory examinations in cattle with theileriosis were carried out before and on the first, third and seventh days after treatment. As a result, it was concluded that a single deep intramuscular dose of 2.5 mg/kg buparvaquone was effective in the treatment of cattle which are naturally infected with T. annulata. However, further studies are needed using control groups of the same breed and age including suitable numbers of naturally infected and experimentally infected cattle.


Tips and tricks of the propensity score methods in the thoracic surgery research.
Without randomization, the differences in the distribution of baseline covariates can confound the evaluation of outcomes between the groups. To estimate the causal effects of treatment on the results randomized clinical trials (RCT) are routinely used. When RCT are not feasible for cost, time, and ethical issues, the effect of treatment on an inevitable outcome could be investigated by using a non-experimental study design. The propensity score (PS) refers to the individual probability, for a subject involved in a study, of receiving a new treatment rather than the control treatment. PS matching is a valuable and increasingly popular tool for dealing with observational data and non-random treatment assignment. Nevertheless, surgeons need to proceed with caution and apply PS methods appropriately.


Anastomosis Grouping of Rhizoctonia solani Associated with Black Scurf and Stem Canker of Potato in South Africa.
Rhizoctonia disease (black scurf of tubers and stem canker) of potato (Solanum tuberosum L.) caused by Rhizoctonia solani Kühn was first recorded in South Africa in 1918 (3). Although the sclerotial form on tubers is one of the most common potato diseases in the country, it is not known which anastomosis groups (AGs) of R. solani are involved. Between 1999 and 2001, R. solani was isolated from 28 plant and 56 soil samples collected in 7 (Eastern Free State, Gauteng, KwaZulu-Natal, Limpopo, Mpumalanga, Northern Cape, and Sandveld) of the 14 potato-production regions of South Africa and screened for hyphal anastomosis with tester strains of R. solani AG-1 to AG-10 according to Carling et al. (1). Of the 411 isolates from tubers with black scurf symptoms, 408 were AG-3 and three were AG-5. Symptomless tubers yielded two AG-3 isolates and three AG-5 isolates. Of 39 isolates from symptomatic stems and roots, 32 were AG-3, five were AG-4, and two were AG-5. Of the 127 isolates obtained from soil, 86, 28, 7, 3, and 3 were AG-3, AG-4, AG-5, AG-7, and AG-8, respectively. More than one AG was isolated from five of the seven regions. Virulence of 40 isolates representative of the above AGs was determined in triplicate on sprouts growing from seed tubers of potato cultivar Up-to-Date in a sand/soil mixture as described by Carling and Leiner (2) but using cultures grown in cornmeal/sand instead of colonized agar disks as inoculum. Damage to sprouts (lesions, girdling, and death) was assessed after 28 days at 16 to 28°C according to the 0 to 4 rating scale (2). Chi-square analysis of the data indicated that AG-3 was the most virulent, with isolates from sclerotia on tubers and lesions on stems more aggressive than those from symptomless tubers or soil. AG-4 and AG-5 caused significantly less disease than AG-3, but none of the AG-7 and AG-8 isolates showed any virulence to potato sprouts. References: (1) D. E. Carling et al. Phytopathology 77:1609, 1987. (2) D. E. Carling and R. H. Leiner. Phytopathology 80:930, 1990. (3) E. M. Doidge. S. Afr. Fruit Growers 5:6, 1918.


MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice.
Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF.


Higher Education Is Associated with a Lower Risk of Dementia after a Stroke or TIA. The Rotterdam Study.
Higher education is associated with a lower risk of dementia, possibly because of a higher tolerance to subclinical neurodegenerative pathology. Whether higher education also protects against dementia after clinical stroke or transient ischemic attack (TIA) remains unknown. Within the population-based Rotterdam Study, 12,561 participants free of stroke, TIA and dementia were followed for occurrence of stroke, TIA and dementia. Across the levels of education, associations of incident stroke or TIA with subsequent development of dementia and differences in cognitive decline following stroke or TIA were investigated. During 124,862 person-years, 1,463 persons suffered a stroke or TIA, 1,158 persons developed dementia, of whom 186 developed dementia after stroke or TIA. Risk of dementia after a stroke or TIA, compared to no stroke or TIA, was highest in the low education category (hazards ratio [HR] 1.46, 95% CI 1.18-1.81) followed by intermediate education category (HR 1.36, 95% CI 1.03-1.81). No significant association was observed in the high education category (HR 0.62, 95% CI 0.25-1.54). In gender stratified analyses, decrease in risk of dementia with increasing education was significant only in men. Higher education is associated with a lower risk of dementia after stroke or TIA, particularly in men, which might be explained by a higher cognitive reserve.


Umbilical necrosis rates after abdominal-based microsurgical breast reconstruction.
Umbilical stalk necrosis represents a rare, yet important complication after abdominal-based microsurgical breast reconstruction, which is both underrecognized and understudied in the literature. Once identified, umbilical reconstruction can be an extremely challenging problem. All consecutive breast free flaps at a single institution from February 2004 to February 2016 were reviewed, excluding non-abdominal-based flaps. Patients were divided based on the development of umbilical necrosis postoperatively. Demographics, surgical characteristics, and other complications were compared between the groups. A total of 918 patients met the inclusion criteria, with 29 developing umbilical necrosis identified (3.2%). Patients developing necrosis tended to be older (49.4 yrs versus 52.9 yrs; P < 0.01); have higher BMI (31.3 versus 27.8; P < 0.01); and were more likely to be smokers (27.5% versus 11.6%; P = 0.01). Umbilical necrosis was also associated with increased flap weight (830 g versus 656 g; P < 0.01), decreased time of perforator dissection (151 min versus 169 min; P = 0.02); bilateral cases (68.9% versus 44.7%; P < 0.01), and increased number of perforators per flap (2.5 versus 2.2; P = 0.03). There was no association with flap type (deep inferior epigastric perforator, superficial inferior epigastric artery, or free TRAM), diabetes, previous abdominal surgery, or use of preoperative imaging. Umbilical necrosis was not associated with any concomitant complications. Umbilical stalk necrosis was found to occur in 3.2% of patients and was associated with several preoperative comorbidities and intraoperative characteristics. This information should help influence intraoperative decision-making to prevent the development of this undesirable complication.


Reports to the Membership.
The following are edited/abbreviated versions of the annual reports of the APA Secretary, Treasurer, CEO and Medical Director, Speaker, and Speaker-Elect and the chairpersons of the APA Committee on Bylaws, Membership Committee, Committee of Tellers, and Elections Committee. The full reports were presented at the APA Annual Business Meeting in Atlanta, May 15th, 2016.


Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study.
Normal aging is associated with progressive functional losses in perception, cognition, and memory. Although the root causes of age-related cognitive decline are incompletely understood, psychophysical and neuropsychological evidence suggests that a significant contribution stems from poorer signal-to-noise conditions and down-regulated neuromodulatory system function in older brains. Because the brain retains a lifelong capacity for plasticity and adaptive reorganization, dimensions of negative reorganization should be at least partially reversible through the use of an appropriately designed training program. We report here results from such a training program targeting age-related cognitive decline. Data from a randomized, controlled trial using standardized measures of neuropsychological function as outcomes are presented. Significant improvements in assessments directly related to the training tasks and significant generalization of improvements to nonrelated standardized neuropsychological measures of memory (effect size of 0.25) were documented in the group using the training program. Memory enhancement appeared to be sustained after a 3-month no-contact follow-up period. Matched active control and no-contact control groups showed no significant change in memory function after training or at the 3-month follow-up. This study demonstrates that intensive, plasticity-engaging training can result in an enhancement of cognitive function in normal mature adults.


The clock drawing test: A systematic review and meta-analysis of diagnostic accuracy.
The aim of this study was to evaluate the accuracy of the clock drawing test and to compare its scoring methods. Dementia refers to a symptom where an adult demonstrates memory disorder and cognitive impairment. Early diagnosis of dementia is very important for medication management and prognosis. The clock drawing test is one of the most used cognitive screening tools for dementia. However, due to its scoring system, the accuracy of the clock drawing test remains a topic of debate. A systematic review with meta-analysis following Cochrane's methods and the guidelines of the Agency for Healthcare Research and Quality. A literature search was carried out in the OVID-MEDLINE, OVID-EMBASE and OVID-PsycINFO databases (27 October 2015). The quality assessment of diagnostic accuracy studies (QUADAS-2) tool was employed for this review. We used hierarchical regression models to pool the values of diagnostic accuracy in a random effects model. A total of 18 studies with 5,531 participants were identified for this review. Fifteen of these studies were included for meta-analysis according to each scoring system. The pooled sensitivity and specificity of the clock drawing test using the Shulman system were 82% and 75.7% respectively. In the Sunderland system, these were 72.6% and 87.9% respectively. The findings indicate that the accuracy of the clock drawing test using the Shulman system was the most studied and highly sensitive. After gaining a better understanding of the clock drawing test through this study, we recommend it for widespread use in the diagnosis of dementia.


Early sequence of events triggered by the interaction of Neisseria meningitidis with endothelial cells.
Neisseria meningitidis is a bacterium responsible for severe sepsis and meningitis. Following type IV pilus-mediated adhesion to endothelial cells, bacteria proliferating on the cellular surface trigger a potent cellular response that enhances the ability of adhering bacteria to resist the mechanical forces generated by the blood flow. This response is characterized by the formation of numerous 100 nm wide membrane protrusions morphologically related to filopodia. Here, a high-resolution quantitative live-cell fluorescence microscopy procedure was designed and used to study this process. A farnesylated plasma membrane marker was first detected only a few seconds after bacterial contact, rapidly followed by actin cytoskeleton reorganization and bulk cytoplasm accumulation. The bacterial type IV pili-associated minor pilin PilV is necessary for the initiation of this cascade. Plasma membrane composition is a key factor as cholesterol depletion with methyl-β-cyclodextrin completely blocks the initiation of the cellular response. In contrast membrane deformation does not require the actin cytoskeleton. Strikingly, plasma membrane remodelling undermicrocolonies is also independent of common intracellular signalling pathways as cellular ATP depletion is not inhibitory. This study shows that bacteria-induced plasma membrane reorganization is a rapid event driven by a direct cross-talk between type IV pili and the plasma membrane rather than by the activation of an intracellular signalling pathway that would lead to actin remodelling.


Protective effects of curcumin against liver fibrosis through modulating DNA methylation.
Recent research has demonstrated that advanced liver fibrosis in patients could be reversed, but no approved agents are available for the treatment and prevention of liver fibrosis in humans. Curcumin (CUR) is the principal curcuminoid of turmeric. Inhibitory effects of CUR and its underlying mechanisms in liver fibrogenesis have been explored. In the present study, we hypothesized that epigenetic mechanisms contribute to the protective effects of CUR against liver fibrosis. We used CCl4-induced liver injury in BALB/c mice and the rat hepatic stellate cell line HSC-T6 as experimental models. Genomic DNA methylation was analyzed by MeDIP-chip and verified by real-time PCR on MeDIP-enriched DNA. The mRNA and protein expressions of DNMT1, α-SMA, and Col1α1 were determined by real-time PCR and Western blotting, respectively. The methylation statuses of FGFR3, FZD10, Gpx4, and Hoxd3 were further confirmed by quantitative methylation-specific PCR (qMSP). Our results showed that CUR treatment reversed liver injury in vivo and in vitro, possibly through down regulation of DNMT1, α-SMA, and Col1α1 and by demethylation of the key genes. In conclusion, aberrant methylation is closely associated with liver fibrosis and CUR treatment may reverse liver fibrosis by epigenetic mechanisms.


Synthesis of Highly Functionalized Decalins via Metallacycle-Mediated Cross-Coupling.
Bridged bicyclic metallacyclopentenes generated from the [4 + 2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2 + 2 + 2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2 + 2 + 2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting intermediates en route to cyclohexadiene products formed by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins--structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of such species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.


Piezoelectric-transducer-based miniature catheter for ultrahigh-speed endoscopic optical coherence tomography.
We developed a piezoelectric-transducer- (PZT) based miniature catheter with an outer diameter of 3.5 mm for ultrahigh-speed endoscopic optical coherence tomography (OCT). A miniaturized PZT bender actuates a fiber and the beam is scanned through a GRIN lens and micro-prism to provide high-speed, side-viewing capability. The probe optics can be pulled back over a long distance to acquire three-dimensional (3D) data sets covering a large area. Imaging is performed with 11 μm axial resolution in air (8 μm in tissue) and 20 μm transverse resolution, at 960 frames per second with a Fourier domain mode-locked laser operating at 480 kHz axial scan rate. Using a high-speed data acquisition system, endoscopic OCT imaging of the rabbit esophagus and colon in vivo and human colon specimens ex vivo is demonstrated.


Global Cancer Incidence and Mortality Rates and Trends--An Update.
There are limited published data on recent cancer incidence and mortality trends worldwide. We used the International Agency for Research on Cancer's CANCERMondial clearinghouse to present age-standardized cancer incidence and death rates for 2003-2007. We also present trends in incidence through 2007 and mortality through 2012 for select countries from five continents. High-income countries (HIC) continue to have the highest incidence rates for all sites, as well as for lung, colorectal, breast, and prostate cancer, although some low- and middle-income countries (LMIC) now count among those with the highest rates. Mortality rates from these cancers are declining in many HICs while they are increasing in LMICs. LMICs have the highest rates of stomach, liver, esophageal, and cervical cancer. Although rates remain high in HICs, they are plateauing or decreasing for the most common cancers due to decreases in known risk factors, screening and early detection, and improved treatment (mortality only). In contrast, rates in several LMICs are increasing for these cancers due to increases in smoking, excess body weight, and physical inactivity. LMICs also have a disproportionate burden of infection-related cancers. Applied cancer control measures are needed to reduce rates in HICs and arrest the growing burden in LMICs.


Positive or Negative? Consistency and Inconsistency in Claims of Conscience.
The debate about positive and negative claims of conscience is, in large part, about ethical consistency. In this commentary I argue that there can be differences between conscientious provision of treatment and conscientious nonprovision of treatment that are ethically relevant. However, in many cases, including those described in this commentary, there is not sufficient ethical reason to treat them differently. This means that asymmetrical conscientious objection policies are potentially unjustified.


Impact of patient language proficiency and interpreter service use on the quality of psychiatric care: a systematic review.
This literature review examined the effects of patients' limited English proficiency and use of professional and ad hoc interpreters on the quality of psychiatric care. PubMed, PsycINFO, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) were systematically searched for English-language publications from inception of each database to April 2009. Reference lists were reviewed, and expert sources were consulted. Among the 321 articles identified, 26 met inclusion criteria: peer-reviewed articles reporting primary data on clinical care for psychiatric disorders among patients with limited proficiency in English or in the provider's language. Evaluation in a patient's nonprimary language can lead to incomplete or distorted mental status assessment. Although both untrained and trained interpreters may make errors, untrained interpreters' errors may have greater clinical impact, compromising diagnostic accuracy and clinicians' detection of disordered thought or delusional content. Use of professional interpreters may improve disclosure in patient-provider communications, referral to specialty care, and patient satisfaction. Little systematic research has addressed the impact of language proficiency or interpreter use on the quality of psychiatric care in contemporary U.S. settings. Findings are insufficient to inform evidence-based guidelines for improving quality of care among patients with limited English proficiency. Clinicians should be aware of the ways in which quality of care can be compromised when they evaluate patients in a nonprimary language or use an interpreter. Given U.S. demographic trends, future research should help guide practice and policy by addressing deficits in the evidence base.


Effects of a 12% carbohydrate beverage on tackling technique and running performance during rugby league activity: A randomised, placebo-controlled trial.
The purpose of this study was to investigate the effects of a 12% carbohydrate (CHO) beverage on tackling technique and running performance during rugby league activity. Using a double-blind, placebo-controlled, randomised, crossover design, 15 academy rugby league players ingested a 250 ml bolus of a 12% CHO solution (30 g maltodextrin and 30 g sucrose in 500 ml) 15 minutes before two bouts of rugby activity. The rugby league match simulation for interchange players was used to standardise the movement patterns of activity and provide reliable outcome measures, whilst also reflecting the duration of a typical field-based conditioning session. Measures of tackling technique, external responses (e.g., fatigue index from sprint data) and rating of perceived exertion (RPE) were recorded throughout. Gut discomfort was measured before each bout. The interaction effect was largely compatible with the hypothesis for relative distance (P<0.001, η2 = 0.217) and fairly compatible for tackling technique (P = 0.068, η2 = 0.0640). The time effect for tackling technique, relative and high-intensity distance, sprint, and sprint to contact velocity, time at high metabolic power, PlayerLoad™, and RPE (all P<0.05; η2 = 0.131-0.701) was compatible with the hypothesis. Data for tackling technique, relative and high-intensity distance, sprint, and sprint to contact velocity, sprint, and sprint to contact fatigue index (all P<0.05; η2 = 0.189-0.612) was compatible with a supplement effect overall despite few differences in the pattern of change (interaction). Minimal gut discomfort was reported for the CHO (bout 1 = 27 ± 17; bout 2 = 23 ± 17 AU) and placebo (bout 1 = 23 ± 18 AU; bout 2 = 24 ± 13) trials. This study shows that a 12% CHO beverage before two bouts of standardised rugby activity is a practical and effective strategy for retaining tackling technique, increasing external responses, and reducing RPE without compromising gut comfort.


Saccadic eye movements as indicators of cognitive function in older adults.
Older adults appear to have greater difficulty ignoring distractions during day-to-day activities than younger adults. To assess these effects of age, the ability of adults aged between 50 and 80 years to ignore distracting stimuli was measured using the antisaccade and oculomotor capture tasks. In the antisaccade task, observers are instructed to look away from a visual cue, whereas in the oculomotor capture task, observers are instructed to look toward a colored singleton in the presence of a concurrent onset distractor. Index scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were compared with capture errors, and with prosaccade errors on the antisaccade task. A higher percentage of capture errors were made on the oculomotor capture tasks by the older members of the cohort compared to the younger members. There was a weak relationship between the attention index and capture errors, but the visuospatial/constructional index was the strongest predictor of prosaccade error rate in the antisaccade task. The saccade reaction times (SRTs) of correct initial saccades in the oculomotor capture task were poorly correlated with age, and with the neurospsychological tests, but prosaccade SRTs in both tasks moderately correlated with antisaccade error rate. These results were interpreted in terms of a competitive integration (or race) model. Any variable that reduces the strength of the top-down neural signal to produce a voluntary saccade, or that increases saccade speed, will enhance the likelihood that a reflexive saccade to a stimulus with an abrupt onset will occur.


Inducing properties of rifampicin and rifabutin for selected enzyme activities of the cytochrome P-450 and UDP-glucuronosyltransferase superfamilies in female rat liver.
Important species differences have been reported concerning the induction properties of rifampicin towards enzymes of the P-450 superfamily. Mice, rabbits and humans are far more responsive than rats and guinea pigs. In the present study a strong induction of cytochrome P-450 3A-dependent enzyme activities was observed in female rat liver microsomes after high dose treatment (> or = 250 mg/kg/day for 9 days) with rifampicin, resulting in an up to 30-fold enhanced hydroxylation rate of testosterone in the 2 beta-, 6 beta- and 15 beta-position in vitro. Other cytochrome P-450 isozyme-selective reactions were not, or only marginally, affected. A steep increase in cytochrome P-450 3A activity on a moderate elevation of the dose administered, together with the previously observed lack of efficient induction with doses below 200 mg/kg/day demonstrated that there is a threshold in enzyme induction by rifampicin. For rifabutin such a threshold was not apparent. Induction by rifabutin showed an isoenzyme-selectivity profile similar to that produced by rifampicin, but the maximally achievable induction of cytochrome P-450 3A by rifabutin was about two-fold lower compared with rifampicin. Rifampicin and rifabutin enhanced the glucuronidation of 1-naphthol, 4-hydroxybiphenyl and beta-estradiol by a factor of two to three. The potential implications of the enzyme induction by rifampicin derivatives in terms of possible drug-drug interactions are discussed.


The evolution of crystalline structures during gel spinning of ultra-high molecular weight polyethylene fibers.
Most studies are focused on the final mechanical properties of the fiber and the processing window required to achieve high moduli and tensile strength. Several studies have alluded to the fact that the crystalline morphologies developed during gel spinning and post-drawing are very important in determining the final mechanical properties. However, it is surprising to know that no clear correlation exists between the crystalline structure and initial, evolving, and final mechanical properties. In an attempt to define structure-property relationships, we have developed novel tools to quantify the effect of processing on crystalline structure evolution. We examine through controlled gel-spinning and SAXS analysis the effect of flow kinematics on the development of crystalline structures. Direct correlations are made between polymer solution relaxation time, extension rates, crystallization time and gel-spun crystalline morphologies. We report direct evidence of flow induced crystallization, which approaches an asymptotic crystallization rate at high Weissenberg numbers. For Wi < 1, the crystalline structure is only slightly affected by equilibrium. For Wi > 1, the crystalline structure is highly anisotropic due to chain orientation/stretch during spinning. Fibers spun at different Weissenberg numbers are drawn to low draw ratios at constant temperature to measure the initial structure evolution. A qualitative SAXS analysis clearly shows similar evolution of different starting structures with the formation of more straight chain crystals upon drawing. However, there remain quantitative differences between the length of straight chain crystals and the size and distribution of lamellar domains depending on the starting structure.


PACE EH post project assessment of quality of life changes in a Florida community related to infrastructure improvements.
The Indian River county health department, environmental health division (IRCHD EH) in Florida implemented the Protocol for Assessing Community Excellence in Environmental Health (PACE EH) in the low-income community of West Wabasso, Florida. Over two and a half years, IRCHD EH worked with the community and various governmental agencies to bring much-needed improvements to the area. At the end of the two and a half years, a survey was conducted to discover if the residents' quality of life had increased due to the community's improvements. The survey results yielded high satisfaction rates among residents. The general response was that their feelings of safety and overall well-being attributed to infrastructure improvements in their community had increased significantly. An unforeseen benefit realized by all parties involved was a renewed trust in government. The majority of surveyed residents (91%) felt that governmental agencies were better able to respond to their issues.


Central topography of cranial motor nuclei controlled by differential cadherin expression.
Neuronal nuclei are prominent, evolutionarily conserved features of vertebrate central nervous system (CNS) organization. Nuclei are clusters of soma of functionally related neurons and are located in highly stereotyped positions. Establishment of this CNS topography is critical to neural circuit assembly. However, little is known of either the cellular or molecular mechanisms that drive nucleus formation during development, a process termed nucleogenesis. Brainstem motor neurons, which contribute axons to distinct cranial nerves and whose functions are essential to vertebrate survival, are organized exclusively as nuclei. Cranial motor nuclei are composed of two main classes, termed branchiomotor/visceromotor and somatomotor. Each of these classes innervates evolutionarily distinct structures, for example, the branchial arches and eyes, respectively. Additionally, each class is generated by distinct progenitor cell populations and is defined by differential transcription factor expression; for example, Hb9 distinguishes somatomotor from branchiomotor neurons. We characterized the time course of cranial motornucleogenesis, finding that despite differences in cellular origin, segregation of branchiomotor and somatomotor nuclei occurs actively, passing through a phase of each being intermingled. We also found that differential expression of cadherin cell adhesion family members uniquely defines each motor nucleus. We show that cadherin expression is critical to nucleogenesis as its perturbation degrades nucleus topography predictably.


The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells.
The consumption of drinking water rich in fluoride has toxic effects on the central nervous system. In cell biology research, fluoride is currently used as a phosphatase inhibitor. The aim of the present study was to evaluate the effect of fluoride on different physiological processes in GH4C1 pituitary tumour cells. We used a range of different fluoride concentrations, from levels below normal human serum concentrations (0.23 and 1.2 micromol/L) to those observed in chronically exposed persons (10.7 micromol/L) and above (107 and 1072 micromol/L). Treatment of 10.7 micromol/L fluoride resulted in a discrete induction of DNA synthesis, without a change in cell number. Cell migration, a behaviour stimulated by growth factors, was increased in cells treated with 2.4 micromol/L. At this fluoride concentration, changes in phosphorylation status of both cytoskeletal and cytosolic protein fractions, as well as in actin cytoskeletal arrangements were observed. The GH4C1 fluoride treated cells had significantly less cellular protein than control cells, suggesting an effect of fluoride on hormone secretion and protein synthesis in this endocrine cell. The bioreduction of MTT was significantly increased with a wide range of fluoride concentrations. With the highest fluoride concentration, 1072 micromol/L, all of the analysed parameters were significantly reduced, suggesting that this dose is highly toxic in GH4C1 cells. Our results show that biologically relevant concentrations of fluoride are capable of increasing cell migration in tumour cells, suggesting that exposure to fluoride could stimulate tumour invasion.


A moiré deflectometer for antimatter.
The precise measurement of forces is one way to obtain deep insight into the fundamental interactions present in nature. In the context of neutral antimatter, the gravitational interaction is of high interest, potentially revealing new forces that violate the weak equivalence principle. Here we report on a successful extension of a tool from atom optics--the moiré deflectometer--for a measurement of the acceleration of slow antiprotons. The setup consists of two identical transmission gratings and a spatially resolving emulsion detector for antiproton annihilations. Absolute referencing of the observed antimatter pattern with a photon pattern experiencing no deflection allows the direct inference of forces present. The concept is also straightforwardly applicable to antihydrogen measurements as pursued by the AEgIS collaboration. The combination of these very different techniques from high energy and atomic physics opens a very promising route to the direct detection of the gravitational acceleration of neutral antimatter.


Surgeon cost feedback through a surgical receipt program reduces cost in sinonasal surgery.
Operating room (OR) costs are a large portion of healthcare expenses. This study evaluates the impact of a surgeon-targeted surgical receipt cost feedback system on OR supply costs in sinonasal surgery and individual components contributing to procedural cost. Itemized weekly surgical receipts detailing individual case supply costs were analyzed before and after the implementation of a non-incentivized surgeon cost feedback system between January 2017 and June 2019. Supply cost data collected 15 months prior to intervention was compared to cost data 15 months after implementation of the weekly automated receipt dissemination to surgeons. Chi square test was used for categorical data and the Wilcoxon test was used to compare change in cost. Univariate and mediation analyses were performed to assess variables impacting cost. Of 502 sinonasal procedures analyzed, 239 were before and 264 after cost feedback implementation. There were no significant differences in age/gender, or indication for surgery. The median OR supply cost decreased from $1229.64 to $1097.22 (p = 0.02) after receipt implementation. There were effects of procedure type (p = 0.02), circulating nurse specialization (p < 0.001), steroid eluting stent (p = 0.002), and sinus drill (p < 0.001) on cost. Mediation analysis confirmed full mediation by decreasing use of steroid-eluting stents. Surgeon cost feedback in the form of individualized OR surgical receipts is an effective model to reduce supply cost per case in sinonasal surgery.


Characterization of the axon initial segment (AIS) of motor neurons and identification of a para-AIS and a juxtapara-AIS, organized by protein 4.1B.
The axon initial segment (AIS) plays a crucial role: it is the site where neurons initiate their electrical outputs. Its composition in terms of voltage-gated sodium (Nav) and voltage-gated potassium (Kv) channels, as well as its length and localization determine the neuron's spiking properties. Some neurons are able to modulate their AIS length or distance from the soma in order to adapt their excitability properties to their activity level. It is therefore crucial to characterize all these parameters and determine where the myelin sheath begins in order to assess a neuron's excitability properties and ability to display such plasticity mechanisms. If the myelin sheath starts immediately after the AIS, another question then arises as to how would the axon be organized at its first myelin attachment site; since AISs are different from nodes of Ranvier, would this particular axonal region resemble a hemi-node of Ranvier? We have characterized the AIS of mouse somatic motor neurons. In addition to constant determinants of excitability properties, we found heterogeneities, in terms of AIS localization and Nav composition. We also identified in all α motor neurons a hemi-node-type organization, with a contactin-associated protein (Caspr)+ paranode-type, as well as a Caspr2+ and Kv1+ juxtaparanode-type compartment, referred to as a para-AIS and a juxtapara (JXP)-AIS, adjacent to the AIS, where the myelin sheath begins. We found that Kv1 channels appear in the AIS, para-AIS and JXP-AIS concomitantly with myelination and are progressively excluded from the para-AIS. Their expression in the AIS and JXP-AIS is independent from transient axonal glycoprotein-1 (TAG-1)/Caspr2, in contrast to juxtaparanodes, and independent from PSD-93. Data from mice lacking the cytoskeletal linker protein 4.1B show that this protein is necessary to form the Caspr+ para-AIS barrier, ensuring the compartmentalization of Kv1 channels and the segregation of the AIS, para-AIS and JXP-AIS. α Motor neurons have heterogeneous AISs, which underlie different spiking properties. However, they all have a para-AIS and a JXP-AIS contiguous to their AIS, where the myelin sheath begins, which might limit some AIS plasticity. Protein 4.1B plays a key role in ensuring the proper molecular compartmentalization of this hemi-node-type region.


Guava fruit extract and its triterpene constituents have osteoanabolic effect: Stimulation of osteoblast differentiation by activation of mitochondrial respiration via the Wnt/β-catenin signaling.
The aim of this study was to evaluate the skeletal effect of guava triterpene-enriched extract (GE) in rats and identify osteogenic compounds thereof, and determine their modes of action. In growing female rats, GE at 250 mg/kg dose increased parameters of peak bone mass including femur length, bone mineral density (BMD) and biomechanical strength, suggesting that GE promoted modeling-directed bone growth. GE also stimulated bone regeneration at the site of bone injury. In adult osteopenic rats (osteopenia induced by ovariectomy, OVX) GE completely restored the lost bones at both axial and appendicular sites, suggesting a strong osteoanabolic effect. Serum metabolomics studies showed changes in several metabolites (some of which are related to bone metabolism) in OVX compared with ovary-intact control and GE treatment to OVX rats reversed those. Out of six abundantly present triterpenes in GE, ursolic acid (UA) and 2α-hydroxy ursolic acid (2α-UA) induced osteogenic differentiation in vitro as did GE by activating Wnt/β-catenin pathway assessed by phosphorylation of GSK-3β. Over-expressing of constitutively active GSK-3β (caGSK-3β) in osteoblasts abolished the differentiation-promoting effect of GE, UA and 2α-UA. All three increased both glycolysis and mitochondrial respiration but only rotenone (inhibitor of mitochondrial electron transfer) and not 2-deoxyglucose (to block glycolysis) inhibited osteoblast differentiation. In addition, caGSK-3β over-expression attenuated the enhanced mitochondrial respiration caused by GE, UA and 2α-UA. We conclude that GE has osteoanabolic effect which is contributed by UA and 2α-UA, and involve activation of canonical Wnt signaling which in turn modulates cellular energy metabolism leading to osteoblast differentiation.


Low level of knowledge of heart attack symptoms and inappropriate anticipated treatment-seeking behaviour among older Chinese: a cross-sectional survey.
Prehospital delay of acute myocardial infarction (AMI) is common globally, and Hong Kong-home of a rapidly ageing Chinese population-is not an exception. Seeking emergency medical care promptly is important for patients. Treatment-seeking behaviours have been shown to be associated with knowledge of AMI symptoms and specific cultural beliefs. This study aimed to assess the level of knowledge of AMI symptoms and expected treatment-seeking behaviour among older Chinese in Hong Kong. A cross-sectional population-based survey was conducted at the Elderly Health Centres in Hong Kong from March to September 2016. Face-to-face interviews were conducted with a structured questionnaire based on previous studies and local adaptations. Among 1804 people aged 65 years and above who completed the questionnaire, chest pain (80.2%), palpitations (75.8%) and fainting (71.9%) were the major symptoms recognised as AMI related. Meanwhile, stomach ache (46.9%), coughing (45.4%) and neck pain (40.8%) were recognised as not AMI related. The mean expected discomfort intensity during AMI onset was 7.7 out of 10 (SD=2.1). Regarding the expected treatment-seeking behaviour, seeking non-emergent medical care was the most popular action when AMI symptoms emerged during the day, without chest pain or with lower discomfort intensity, whereas calling an ambulance was the most common option when AMI symptoms emerged at night or with high discomfort intensity. To minimise delays in seeking treatment, future health education should focus on increasing the public knowledge of AMI symptoms and the need to call an ambulance during an emergency.


Effects of sphingomyelin degradation on cell cholesterol oxidizability and steady-state distribution between the cell surface and the cell interior.
This study addresses questions related to (i) the distribution of cholesterol between the cell surface and intracellular membranes in cultured fibroblasts and (ii) the effects of plasma membrane sphingomyelin on this distribution. Cholesterol oxidase (Streptomyces sp.) converts cell cholesterol to cholestenone and was used in this study to probe the cellular distribution of cholesterol. The availability of cell cholesterol for oxidation by cholesterol oxidase was markedly influenced by the presence of sphingomyelin. In native, glutaraldehyde-fixed fibroblasts only about 20% of the cell cholesterol was oxidized under our experimental conditions. However, degradation of cell sphingomyelin with sphingomyelinase (Staphylococcus aureus) markedly enhanced the oxidation of cell surface cholesterol in glutaraldehyde-fixed fibroblasts. About 90% of the total unesterified cholesterol could be oxidized to cholestenone in confluent, sphingomyelin-depleted fibroblasts. These results suggest that about 90% of the unesterified cholesterol was at the cell surface in these cells. It was also observed that degradation of cell sphingomyelin exerted a dramatic effect on the distribution of cell cholesterol between the cell surface and intracellular membranes. Within 90 min after hydrolysis of cell sphingomyelin, about 30% of the total cell-associated unesterified cholesterol was transported from a cholesterol oxidase-susceptible pool to an oxidase-resistant pool. Together with the redistribution of cell cholesterol after sphingomyelin degradation, a marked enhancement of the endogenous cholesterol esterification reaction was observed. We conclude that the degradation of plasma membrane sphingomyelin resulted in a new apparent steady-state distribution of cellular cholesterol, with less cholesterol in the plasma membrane and more in intracellular membranes. It therefore appears that sphingomyelin is a major determinant of the distribution of cholesterol in intact cells.


Familial cutaneous melanoma.
Approximately 5-10 % of all cutaneous melanomas occur in families with hereditary melanoma predisposition. Worldwide, approximately 20-40% of kindreds with familial elanoma harbor germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence. In different populations several recurring CDKN2A founder mutations have been described. The risk of melanoma in CDKN2A mutations carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population. Some CDKN2A mutations have been associated not only with melanoma but also with increased risk of other malignancies--most notably pancreatic carcinoma. A much smaller number of families have germline mutations in the CDK4 gene on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A. The management of families with hereditary melanoma is discussed.


Malaria rapid diagnostic test transport and storage conditions in Burkina Faso, Senegal, Ethiopia and the Philippines.
As more point of care diagnostics become available, the need to transport and store perishable medical commodities to remote locations increases. As with other diagnostics, malaria rapid diagnostic tests (RDTs) must be highly reliable at point of use, but exposure to adverse environmental conditions during distribution has the potential to degrade tests and accuracy. In remote locations, poor quality diagnostics and drugs may have significant negative health impact that is not readily detectable by routine monitoring. This study assessed temperature and humidity throughout supply chains used to transport and store health commodities, such as RDTs. Monitoring devices capable of recording temperature and humidity were deployed to Burkina Faso (8), Senegal (10), Ethiopia (13) and the Philippines (6) over a 13-month period. The devices travelled through government supply chains, usually alongside RDTs, to health facilities where RDTs are stored, distributed and used. The recording period spanned just over a year, in order to avoid any biases related to seasonal temperature variations. In the four countries, storage and transport temperatures regularly exceeded 30.0°C; maximum humidity level recorded was above 94% for the four countries. In three of the four countries, temperatures recorded at central storage facilities exceeded pharmaceutical storage standards for over 20% of the time, in another case for a majority of the time; and sometimes exceeded storage temperatures at peripheral sites. Malaria RDTs were regularly exposed to temperatures above recommended limits for many commercially-available RDTs and other medical commodities such as drugs, but rarely exceeded the recommended storage limits for particular products in use in these countries. The results underline the need to select RDTs, and other commodities, according to expected field conditions, actively manage the environmental conditions in supply chains in tropical and sub-tropical climates. This would benefit from a re-visit of current global standards on stability of medical commodities based in tropical and sub-tropical climatic zones.


Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators.
Herniated intervertebral disc tissue has been shown to produce a number of proinflammatory mediators and cytokines, but there have been no similar studies using discs from patients with discogenic low back pain. We have compared the levels of production of interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E2 (PGE2) in disc tissue from patients undergoing discectomy for sciatica (63) with that from patients undergoing fusion for discogenic low back pain (20) using an enzyme-linked immunoabsorbent assay. There was a statistically significant difference between levels of production of IL-6 and IL-8 in the sciatica and low back pain groups (p < 0.006 and p < 0.003, respectively). The high levels of proinflammatory mediator found in disc tissue from patients undergoing fusion suggest that production of proinflammatory mediators within the nucleus pulposus may be a major factor in the genesis of a painful lumbar disc.


A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.
Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually causes CDGs. While both in vivo models ostensibly cause cellular stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.


Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer.
It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial. In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate. A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival. In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.


Running performance and thermal sensation in the heat are improved with menthol mouth rinse but not ice slurry ingestion.
The purpose of this study was to compare the effects of a cooling strategy designed to predominately lower thermal state with a strategy designed to lower thermal sensation on endurance running performance and physiology in the heat. Eleven moderately trained male runners completed familiarization and three randomized, crossover 5-km running time trials on a non-motorized treadmill in hot conditions (33 °C). The trials included ice slurry ingestion before exercise (ICE), menthol mouth rinse during exercise (MEN), and no intervention (CON). Running performance was significantly improved with MEN (25.3 ± 3.5 min; P = 0.01), but not ICE (26.3 ± 3.2 min; P = 0.45) when compared with CON (26.0 ± 3.4 min). Rectal temperature was significantly decreased with ICE (by 0.3 ± 0.2 °C; P < 0.01), which persisted for 2 km of the run and MEN significantly decreased perceived thermal sensation (between 4 and 5 km) and ventilation (between 1 and 2 km) during the time trial. End-exercise blood prolactin concentration was elevated with MEN compared with CON (by 25.1 ± 24.4 ng/mL; P = 0.02). The data demonstrate that a change in the perception of thermal sensation during exercise from menthol mouth rinse was associated with improved endurance running performance in the heat. Ice slurry ingestion reduced core temperature but did not decrease thermal sensation during exercise or improve running performance.


Mortality risk by body weight and weight change in people with NIDDM. The WHO Multinational Study of Vascular Disease in Diabetes.
Care guidelines for people with non-insulin-dependent diabetes mellitus (NIDDM) emphasize the importance of weight loss in reducing mortality risk. However, existing evidence regarding the relationship between weight and mortality and the effects of weight change is conflicting. We examined these relationships in the World Health Organization Multinational Study of Vascular Disease in Diabetes. This was a cohort study of 1,416 men and 1,544 women. Baseline examinations were performed in 1975 through 1977, a morbidity follow-up was performed in 1983, and a mortality follow-up continued until 1988. Data were analyzed according to geographical groups: Europeans, East Asians, and Native Americans. The relationship between weight change and mortality was analyzed for Europeans only. Generally, body mass index (BMI) was positively associated with age, blood pressure, and cholesterol but was negatively associated with duration of diabetes, prevalence of retinopathy, and use of insulin. There was no clear relationship between BMI and mortality across the geographical groups. In Europeans, weight loss in the leanest subjects at baseline (BMI < 26 kg/m2) was associated with a threefold increase in mortality risk compared with those who had maintained a steady weight (relative risk [RR] 3.05, 95% confidence interval [CI] 1.26-7.36). Only in the most obese group was weight loss associated with a reduction in mortality risk (BMI > 29 kg/m2, RR 0.84, 95% CI 0.40-1.74). The positive association of BMI with age, blood pressure, and cholesterol and the negative association with duration of diabetes, retinopathy, and use of insulin may explain why there is no strong relationship between BMI and mortality in NIDDM. Weight loss, particularly in the relatively lean diabetic person, may be associated with an increased mortality risk.


Apoptosis and expression of Bax, Bcl-x, and Bcl-2 apoptotic regulatory proteins in colorectal carcinomas, and association with p53 genotype/phenotype.
Spontaneous apoptosis and expression of the apoptotic regulatory proteins Bax, Bcl-x, and Bcl-2 were investigated in 50 colorectal carcinomas. The p53 genotypes/phenotypes and BAX genotypes were also determined, and possible associations of these with apoptosis and/or with expression of the different apoptotic regulatory proteins were studied. Terminal deoxynucleotidyl transferase (TdT) mediated dUTP labelling of DNA fragments was used to detect apoptotic tumour cells in sections and peroxidase immunohistochemistry was used to assess protein expression. p53 genotype/phenotype was determined using constant denaturant gel electrophoresis/immunoblotting and bax genotype was determined using polymerase chain reaction based methods. The distribution of tumour apoptotic indices was bimodal with a natural cut off at 1.0% (range, 0.0-5.4%); the median fraction of apoptotic tumour cells was 0.8%. Tumour apoptosis was not associated significantly with tumour DNA ploidy status. Normal mucosal tissue had less than 0.1% apoptotic cells. Staining intensities for Bax, Bcl-x, and Bcl-2 were strong; that is, equivalent to or greater than positive normal mucosal cells, in 11 of 50, 20 of 49, and 20 of 48 carcinomas. Frameshift mutations in the bax gene were detected in three of 42 tumours analysed, all of which were DNA diploid, and Bax protein expression in these tumours was absent or very low. Bax, Bcl-x, and Bcl-2 protein expression were not correlated with tumour apoptosis or tumour DNA ploidy status. p53 was expressed in 34 of 50 tumours and p53 gene mutations were detected in 22 of 29 p53 positive tumours analysed. Apoptosis was significantly lower in a greater number of p53 positive tumours than p53 negative tumours. In addition, Bcl-2 protein expression was significantly higher in a greater number of p53 positive tumours compared with p53 negative tumours. Bax and Bcl-x protein expression were not significantly associated with p53 phenotype/genotype. The results indicate that acquisition of a p53 phenotype is associated with lower spontaneous apoptosis and higher expression of Bcl-2. The results also suggest that p53 is not a major determinant for Bax expression in colorectal carcinomas in vivo.


Adapting agriculture to climate change.
The strong trends in climate change already evident, the likelihood of further changes occurring, and the increasing scale of potential climate impacts give urgency to addressing agricultural adaptation more coherently. There are many potential adaptation options available for marginal change of existing agricultural systems, often variations of existing climate risk management. We show that implementation of these options is likely to have substantial benefits under moderate climate change for some cropping systems. However, there are limits to their effectiveness under more severe climate changes. Hence, more systemic changes in resource allocation need to be considered, such as targeted diversification of production systems and livelihoods. We argue that achieving increased adaptation action will necessitate integration of climate change-related issues with other risk factors, such as climate variability and market risk, and with other policy domains, such as sustainable development. Dealing with the many barriers to effective adaptation will require a comprehensive and dynamic policy approach covering a range of scales and issues, for example, from the understanding by farmers of change in risk profiles to the establishment of efficient markets that facilitate response strategies. Science, too, has to adapt. Multidisciplinary problems require multidisciplinary solutions, i.e., a focus on integrated rather than disciplinary science and a strengthening of the interface with decision makers. A crucial component of this approach is the implementation of adaptation assessment frameworks that are relevant, robust, and easily operated by all stakeholders, practitioners, policymakers, and scientists.


Errors and Action Monitoring: Errare Humanum Est Sed Corrigere Possibile.
It was recognized long ago by Seneca through his famous "errare humanum est." that the human information processing system is intrinsically fallible. What is newer is the fact that, at least in sensorimotor information processing realized under time pressure, errors are largely dealt with by several (psycho)physiological-specific mechanisms: prevention, detection, inhibition, correction, and, if these mechanisms finally fail, strategic behavioral adjustments following errors. In this article, we review several datasets from laboratory experiments, showing that the human information processing system is well equipped not only to detect and correct errors when they occur but also to detect, inhibit, and correct them even before they fully develop. We argue that these (psycho)physiological mechanisms are important to consider when the brain works in everyday settings in order to render work systems more resilient to human errors and, thus, safer.


Methods for establishing a surveillance system for cardiovascular diseases in Indian industrial populations.
To establish a surveillance network for cardiovascular diseases (CVD) risk factors in industrial settings and estimate the risk factor burden using standardized tools. We conducted a baseline cross-sectional survey (as part of a CVD surveillance programme) of industrial populations from 10 companies across India, situated in close proximity to medical colleges that served as study centres. The study subjects were employees (selected by age and sex stratified random sampling) and their family members. Information on behavioural, clinical and biochemical determinants was obtained through standardized methods (questionnaires, clinical measurements and biochemical analysis). Data collation and analyses were done at the national coordinating centre. We report the prevalence of CVD risk factors among individuals aged 20-69 years (n = 19 973 for the questionnaire survey, n = 10 442 for biochemical investigations); mean age was 40 years. The overall prevalence of most risk factors was high, with 50.9% of men and 51.9% of women being overweight, central obesity was observed among 30.9% of men and 32.8% of women, and 40.2% of men and 14.9% of women reported current tobacco use. Self-reported prevalence of diabetes (5.3%) and hypertension (10.9%) was lower than when measured clinically and biochemically (10.1% and 27.7%, respectively). There was marked heterogeneity in the prevalence of risk factors among the study centres. There is a high burden of CVD risk factors among industrial populations across India. The surveillance system can be used as a model for replication in India as well as other developing countries.


Dynamical properties of liquid water from ab initio molecular dynamics performed in the complete basis set limit.
Dynamical properties of liquid water were studied using Car-Parrinello [Phys. Rev. Lett. 55, 2471 (1985)] ab initio molecular dynamics (AIMD) simulations within the Kohn-Sham (KS) density functional theory employing the Becke-Lee-Yang-Parr exchange-correlation functional for the electronic structure. The KS orbitals were expanded in a discrete variable representation basis set, wherein the complete basis set limit can be easily reached and which, therefore, provides complete convergence of ionic forces. In order to minimize possible nonergodic behavior of the simulated water system in a constant energy (NVE) ensemble, a long equilibration run (30 ps) preceded a 60 ps long production run. The temperature drift during the entire 60 ps trajectory was found to be minimal. The diffusion coefficient [0.055 A2/ps] obtained from the present work for 32 D2O molecules is a factor of 4 smaller than the most up to date experimental value, but significantly larger than those of other recent AIMD studies. Adjusting the experimental result so as to match the finite-sized system used in the present study brings the comparison between theory and experiment to within a factor of 3. More importantly, the system is not observed to become "glassy" as has been reported in previous AIMD studies. The computed infrared spectrum is in good agreement with experimental data, especially in the low frequency regime where the translational and librational motions of water are manifested. The long simulation length also made it possible to perform detailed studies of hydrogen bond dynamics. The relaxation dynamics of hydrogen bonds observed in the present AIMD simulation is slower than those of popular force fields, such as the TIP4P potential, but comparable to that of the TIP5P potential.


Cost-effectiveness of a nurse-led intervention to optimise implementation of guideline-concordant continence care: Study protocol of the COCON study.
Guidelines on urinary incontinence recommend that absorbent products are only used as a coping strategy pending definitive treatment, as an adjunct to ongoing therapy, or for long-term management after all treatment options have been explored. However, these criteria are rarely met and a significant share of long-term product users could still benefit from therapeutic interventions recommended in guidelines for urinary incontinence. Better implementation of these guidelines can potentially result in both health benefits for women and long-term cost savings for society. The aim of the COCON study is to evaluate the (cost-)effectiveness of a nurse-led intervention to optimise implementation of guideline-concordant continence care in comparison with usual care for urinary incontinent women aged 55 years and over who use absorbent products. This randomised clinical trial compares usual care with a nurse-led intervention to optimise implementation of guideline-concordant continence care. Women (anticipated N = 160) are recruited in 12 community pharmacies in three Dutch regions, and are eligible for trial entry when they are 55 years and over, community-dwelling and long-term users of absorbent products (≥4 months) reimbursed by health insurance. Measurements are administered at baseline, 3, 6 and 12 months. Primary outcome is severity of urinary incontinence (ICIQ-UI SF); other outcomes include health related quality of life (EQ-5D-5 L), use of absorbent products (in accordance with the recommended criteria in guidelines) (yes/no), and societal costs. Mixed model analysis will be performed to compare (the course) of outcomes between groups. The economic evaluation will be performed from a societal perspective. The implementation process is investigated using the Tailored Implementation for Chronic Diseases (TICD) framework. Results will add to current knowledge of the (cost-)effectiveness of nurse-led primary healthcare to improve guideline-concordant care for older women with urinary incontinence. In addition, the results will provide more insight into care needs and health service utilization of this group of women, as well as into use of absorbent products in accordance with the recommended criteria in guidelines. Finally, results will increase our understanding of the intervention's uptake and could provide useful insights for future dissemination and sustenance. Dutch Trial Register NTR4396, registered 13-January-2014.


Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis.
Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients with KRAS and NRAS mutations, such as K-Ras(G12D). Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras(G12D) that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras(G12D) promoted T-ALL through distinct mechanisms. In K-Ras(G12D) T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor-activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.


Antibiotic Class and Outcome in Post-stroke Infections: An Individual Participant Data Pooled Analysis of VISTA-Acute.
Introduction: Antibiotics used to treat post-stroke infections have differing antimicrobial and anti-inflammatory effects. Our aim was to investigate whether antibiotic class was associated with outcome after post-stroke infection. Methods: We analyzed pooled individual participant data from the Virtual International Stroke Trials Archive (VISTA)-Acute. Patients with ischemic stroke and with an infection treated with systemic antibiotic therapy during the first 2 weeks after stroke onset were eligible. Antibiotics were grouped into eight classes, according to antimicrobial mechanism and prevalence. The primary analysis investigated whether antibiotic class for any infection, or for pneumonia, was independently associated with a shift in 90 day modified Rankin Scale (mRS) using ordinal logistic regression. Results: 2,708 patients were eligible (median age [IQR] = 74 [65 to 80] y; 51% female; median [IQR] NIHSS score = 15 [11 to 19]). Pneumonia occurred in 35%. Treatment with macrolides (5% of any infections; 9% of pneumonias) was independently associated with more favorable mRS distribution for any infection [OR (95% CI) = 0.59 (0.42 to 0.83), p = 0.004] and for pneumonia [OR (95% CI) = 0.46 (0.29 to 0.73), p = 0.001]. Unfavorable mRS distribution was independently associated with treatment of any infection either with carbapenems, cephalosporins or monobactams [OR (95% CI) = 1.62 (1.33 to 1.97), p < 0.001], penicillin plus β-lactamase inhibitors [OR (95% CI) = 1.26 (1.03 to 1.54), p = 0.025] or with aminoglycosides [OR (95% CI) = 1.73 (1.22 to 2.46), p = 0.002]. Conclusion: This retrospective study has several limitations including effect modification and confounding by indication. Macrolides may have favorable immune-modulatory effects in stroke-associated infections. Prospective evaluation of the impact of antibiotic class on treatment of post-stroke infections is warranted.


Associations of circulating fatty acids with incident coronary heart disease: a prospective study of 89,242 individuals in UK Biobank.
The role of fatty acids in coronary heart disease (CHD) remains uncertain. There is little evidence from large-scale epidemiological studies on the relevance of circulating fatty acids levels to CHD risk. This study aims to examine the independent associations of the major circulating types of fatty acids with CHD risk. UK Biobank is a prospective study of adults aged 40-69 in 2006-2010; in 2012-2013, a subset of the participants were resurveyed. Analyses were restricted to 89,242 participants with baseline plasma fatty acids (measured using nuclear magnetic resonance spectroscopy) and without prior CHD. Cox proportional hazards models were used to estimate hazard ratios (HRs) for the associations with incidence CHD, defined as the first-ever myocardial infarction, unstable angina pectoris, coronary-related death, or relevant procedure. And the major types of fatty acids were mutually adjusted to examine the independent associations. Hazard ratios were corrected for regression dilution using the correlation of baseline and resurvey fatty acids measures. During a median follow-up of 11.8 years, 3,815 incident cases of CHD occurred. Independently of other fatty acids, CHD risk was positively associated with saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA), inversely associated with omega-3 polyunsaturated fatty acids (PUFA), but there was no strong evidence of an association with omega-6 PUFA: HR per standard deviation higher were 1.14 (95% CI, 1.09-1.20), 1.15 (1.10-1.21), 0.91 (0.87-0.94), and 1.04 (0.99-1.09) respectively. Independently of triglycerides and cholesterol, the inverse association with omega-3 PUFA was not materially changed, but the positive associations with SFA and MUFA attenuated to null after adjusting for triglycerides levels. This large-scale study has quantitated the independent associations of circulating fatty acids with CHD risk. Omega-3 PUFA was inversely related to CHD risk, independently of other fatty acids and major lipid fractions. By contrast, independently of other fatty acids, the positive associations of circulating SFA and MUFA with CHD risk were mostly attributed to their relationship with triglycerides.


Carbon storage by urban soils in the United States.
We used data available from the literature and measurements from Baltimore, Maryland, to (i) assess inter-city variability of soil organic carbon (SOC) pools (1-m depth) of six cities (Atlanta, Baltimore, Boston, Chicago, Oakland, and Syracuse); (ii) calculate the net effect of urban land-use conversion on SOC pools for the same cities; (iii) use the National Land Cover Database to extrapolate total SOC pools for each of the lower 48 U.S. states; and (iv) compare these totals with aboveground totals of carbon storage by trees. Residential soils in Baltimore had SOC densities that were approximately 20 to 34% less than Moscow or Chicago. By contrast, park soils in Baltimore had more than double the SOC density of Hong Kong. Of the six cities, Atlanta and Chicago had the highest and lowest SOC densities per total area, respectively (7.83 and 5.49 kg m(-2)). On a pervious area basis, the SOC densities increased between 8.32 (Oakland) and 10.82 (Atlanta) kg m(-2). In the northeastern United States, Boston and Syracuse had 1.6-fold less SOC post- than in pre-urban development stage. By contrast, cities located in warmer and/or drier climates had slightly higher SOC pools post- than in pre-urban development stage (4 and 6% for Oakland and Chicago, respectively). For the state analysis, aboveground estimates of C density varied from a low of 0.3 (WY) to a high of 5.1 (GA) kg m(-2), while belowground estimates varied from 4.6 (NV) to 12.7 (NH) kg m(-2). The ratio of aboveground to belowground estimates of C storage varied widely with an overall ratio of 2.8. Our results suggest that urban soils have the potential to sequester large amounts of SOC, especially in residential areas where management inputs and the lack of annual soil disturbances create conditions for net increases in SOC. In addition, our analysis suggests the importance of regional variations of land-use and land-cover distributions, especially wetlands, in estimating urban SOC pools.


Illness and injury as contributors to bankruptcy.
In 2001, 1.458 million American families filed for bankruptcy. To investigate medical contributors to bankruptcy, we surveyed 1,771 personal bankruptcy filers in five federal courts and subsequently completed in-depth interviews with 931 of them. About half cited medical causes, which indicates that 1.9-2.2 million Americans (filers plus dependents) experienced medical bankruptcy. Among those whose illnesses led to bankruptcy, out-of-pocket costs averaged dollar 11,854 since the start of illness; 75.7 percent had insurance at the onset of illness. Medical debtors were 42 percent more likely than other debtors to experience lapses in coverage. Even middle-class insured families often fall prey to financial catastrophe when sick.


Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study.
Some risk factors for coronary heart disease (CHD) incidence in the general population are not associated with CHD incidence among patients with ESRD but have not been well characterized in chronic kidney disease (CKD). The association of several risk factors with CHD incidence was studied among participants with CKD in the population-based Atherosclerosis Risk in Communities (ARIC) Study. CHD risk factors and estimated GFR using serum creatinine were measured among 807 ARIC participants with CKD (estimated GFR between 15 and 59 ml/min per 1.73 m(2)). The incidence of CHD during 10.5 yr of follow-up was 6.3, 8.5, and 14.4 per 1000 person-years among ARIC participants with an estimated GFR of >/=90, 60 to 89, and 15 to 59 ml/min per 1.73 m(2), respectively. After adjustment for age, race, gender, and ARIC field center, among those with CKD, the relative risk (95% confidence interval) of CHD was 1.65 (1.01 to 2.67) for current smoking, 2.02 (1.27 to 3.22) for hypertension, 3.06 (2.01 to 4.67) for diabetes, and 1.96 (1.14 to 3.36) for anemia. The comparably adjusted relative risks of CHD for each standard deviation higher total and HDL cholesterol were 1.50 (1.25 to 1.71) and 0.79 (0.62 to 1.01), respectively, and 1.38 (1.13 to 1.69), 1.24 (1.06 to 1.46), 0.65 (0.54 to 0.79), and 1.38 (1.19 to 1.59) for waist circumference, leukocyte count, serum albumin, and fibrinogen, respectively. CHD risk factors in the general population remain predictive among patients with CKD. Given the high risk for CHD among patients with CKD, control of these risk factors may have a substantial impact on their excess burden of CHD.


Closure of rural hospital obstetric units in Missouri.
We studied 65 rural hospitals in Missouri that provided obstetric services in 1986. The hospitals were divided into three groups on the basis of their physician obstetric staff: family or general practitioners only (38 hospitals), family practitioners and obstetricians (22 hospitals), and obstetricians only (five hospitals). From birth certificate data, we detected a decline in the mean number of births in all groups of rural hospitals comparing 1980-1983 with 1984-1987. Births in family practice only hospitals declined most over the past four years (35%), whereas there was only a 4 percent decline in the number of births to rural Missouri women. In 1987, 10 of the 38 family practice only hospital obstetric units closed due to loss of physician services, whereas none of the other hospitals stopped providing obstetric care (X2 = 8.40, p less than 0.005). These findings suggest that rural hospitals with family and general practitioners exclusively on their obstetric staffs are at significant risk of closing their obstetric units.


A strategic and systematic approach for the determination of biosensor regeneration conditions.
Determining the optimal conditions for surface regeneration is fundamental for performance of efficient and robust protein-protein interaction kinetic studies. We devised a systematic methodology comprised of an automated seven-cycle analyte and buffer injection Biacore scheme and data interpretation algorithm. The efficiency and utility is illustrated using an antigen/monoclonal antibody interaction that required ultimately six pulses of acid for regeneration. This technique has broad applicability to any biosensor assay that requires regeneration of a surface.


Sterol isomerase HYDRA1 interacts with RNA silencing suppressor P1b and restricts potyviral infection.
Plants use RNA silencing as a strong defensive barrier against virus challenges, and viruses counteract this defence by using RNA silencing suppressors (RSSs). With the objective of identifying host factors helping either the plant or the virus in this interaction, we have performed a yeast two-hybrid screen using P1b, the RSS protein of the ipomovirus Cucumber vein yellowing virus (CVYV, family Potyviridae), as a bait. The C-8 sterol isomerase HYDRA1 (HYD1), an enzyme involved in isoprenoid biosynthesis and cell membrane biology, and required for RNA silencing, was isolated in this screen. The interaction between CVYV P1b and HYD1 was confirmed in planta by Bimolecular Fluorescence Complementation assays. We demonstrated that HYD1 negatively impacts the accumulation of CVYV P1b in an agroinfiltration assay. Moreover, expression of HYD1 inhibited the infection of the potyvirus Plum pox virus, especially when antiviral RNA silencing was boosted by high temperature or by coexpression of homologous sequences. Our results reinforce previous evidence highlighting the relevance of particular composition and structure of cellular membranes for RNA silencing and viral infection. We report a new interaction of an RSS protein from the Potyviridae family with a member of the isoprenoid biosynthetic pathway.


Rituximab dissociates the tight link between disease activity and joint damage in rheumatoid arthritis patients.
Progression of joint damage is linked to disease activity. This link is dissociated upon treatment with tumour necrosis factor (TNF)- or IL-6-inhibitors plus methotrexate (MTX). It is hitherto unknown if this may also be true for therapies targeting B-cells. We thus evaluated if rituximab (RTX) therapy inhibits joint damage irrespective of its effects on disease activity. We used a random 90% sample of data from two arms of the IMAGE trial comprising patients with active early rheumatoid arthritis (RA) receiving MTX (n=188) or MTX+RTX 1000 mg (n=204). Patients were divided into low, moderate and high disease activity at one year of treatment by simplified disease activity index (low disease activity (LDA), moderate disease activity (MDA), high disease activity (HDA)), or by swollen joint count (SJC) or C reactive protein (CRP) tertiles. Progression of damage by the Genant modified total Sharp score (TGSS) was compared between therapies (Kruskal-Wallis, Wilcoxon tests) for each of these subgroups. In patients treated with MTX, 1-year progression of TGSS In LDA, MDA and HDA was 0.40±0.88, 1.04±1.73, and 1.31±3.02, respectively. In contrast, on RTX+MTX, TGSS progression was 0.38±1.07, 0.39±1.28, and -0.05±0.44, respectively (for MDA and HDA the progression of TGSS was significantly lower in the combined group than in the MTX group: p=0.003 and p=0.05, respectively). Additional analyses (tertiles of SJC, CRP, and matching for disease activity) confirmed the primary analysis. In early RA, progression of joint damage increases with increasing disease activity on MTX. RTX plus MTX retards damage independently of its effects on disease activity, since even in HDA destruction is halted, contrasting MTX monotherapy. This indicates that beyond cytokine blockade (TNF- and IL-6 inhibitors), also cell-directed therapy (anti-CD20 antibody) conveys profound anti-destructive effects and dissociates the link between disease activity and joint damage.


Efficacy of telemedicine for stroke: pooled analysis of the Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) and STRokE DOC Arizona telestroke trials.
Telemedicine can disseminate vascular neurology expertise and optimize recombinant tissue plasminogen activator (rt-PA) use for acute ischemic stroke in rural underserved communities. The purpose of this study was to prospectively assess whether telemedicine or telephone was superior for decision-making. The study design is a pooled analysis of two identically designed randomized controlled trials conducted in a multistate hub and spoke telestroke network setting with acute stroke syndrome patients, comparing telemedicine versus telephone-only consultations. From each trial, common data elements were pooled to assess, principally, for correctness of thrombolysis decision-making. Secondary outcomes included rt-PA use rate, 90-day functional outcome, post-thrombolysis intracranial hemorrhage, and data completeness. Two hundred seventy-six pooled patients were evaluated. Correct thrombolysis eligibility decisions were made more often with telemedicine (96% telemedicine, 83% telephone; odds ratio [OR] 4.2; 95% confidence interval [CI] 1.69-10.46; p=0.002). Intravenous rt-PA usage was 26% (29% telemedicine, 24% telephone; OR 1.27; 95% CI 0.71-2.25; p=0.41). Ninety-day outcomes were not different for Barthel Index, modified Rankin Scale, or mortality. There was no difference in post-thrombolysis intracranial hemorrhage (8% telemedicine, 6% telephone; p>0.999). This pooled analysis supports the hypothesis that stroke telemedicine consultations, compared with telephone-only, result in more accurate decision-making. Together with high rt-PA utilization rate, low post-rt-PA intracranial hemorrhage rate, and acceptable patient outcome, the results confirm that telemedicine is a viable consultative tool for acute stroke. The replication of the hub and spoke network infrastructure supports the generalizability of telemedicine when used in broader settings.


Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial.
Chronic kidney disease (CKD) is a public health problem worldwide, and proteinuria is a well-established marker of disease progression in CKD patients. Propolis, a natural resin produced by bees from plant materials, has anti-inflammatory, immunomodulatory, and anti-oxidant properties, as well as having been shown to have an antiproteinuric effect in experimental CKD. The aim of this study was to evaluate the impact of Brazilian green propolis extract on proteinuria reduction and the changes in the estimated glomerular filtration rate (eGFR). This was a randomized, double-blind, placebo-controlled study including patients with CKD caused by diabetes or of another etiology, 18-90 years of age, with an eGFR of 25-70 ml/min per 1.73 m2 and proteinuria (urinary protein excretion > 300 mg/day) or micro- or macro-albuminuria (urinary albumin-to-creatinine ratio > 30 mg/g or > 300 mg/g, respectively). We screened 148 patients and selected 32, randomly assigning them to receive 12 months of Brazilian green propolis extract at a dose of 500 mg/day (n = 18) or 12 months of a placebo (n = 14). At the end of treatment, proteinuria was significantly lower in the propolis group than in the placebo group-695 mg/24 h (95% CI, 483 to 999) vs. 1403 mg/24 h (95% CI, 1031 to 1909); P = 0.004-independent of variations in eGFR and blood pressure, which did not differ between the groups during follow-up. Urinary monocyte chemoattractant protein-1 was also significantly lower in the propolis group than in the placebo group-58 pg/mg creatinine (95% CI, 36 to 95) vs. 98 pg/mg creatinine (95% CI, 62 to 155); P = 0.038. Brazilian green propolis extract was found to be safe and well tolerated, as well as to reduce proteinuria significantly in patients with diabetic and non-diabetic CKD. ( ClinicalTrials.gov number NCT02766036. Registered: May 9, 2016).