Localization of synaptotagmin-binding domains on syntaxin.
Synaptotagmin, an abundant calcium- and phospholipid-binding protein of synaptic vesicles, has been proposed to regulate neurotransmitter release at the nerve terminal. To understand better the biochemical mechanism of neurotransmitter release, we have investigated the calcium-dependent and -independent protein-protein interactions between synaptotagmin I and syntaxin 1a, a subunit of the receptor for synaptic vesicles on the presynaptic plasma membrane. Soluble syntaxin 1a binds to synaptotagmin glutathione S-transferase (GST) fusion protein, and the binding was decreased in the presence of calcium. A synaptotagmin fragment containing the second C2 repeat (Syt3-5) had the same binding profile as the whole cytoplasmic domain; however, fragments containing the first C2 repeat (Syt1-3 and Syt2-3) showed calcium-dependent binding to syntaxin. In addition, the soluble full-length cytoplasmic domain of synaptotagmin binds to a syntaxin GST fusion protein in a calcium-dependent manner. Syntaxin domains required for calcium-dependent and -independent synaptotagmin-binding were localized using syntaxin deletion mutants. Amino acids 241-266 of the syntaxin C terminus were required for calcium-independent binding of synaptotagmin. The minimal domain required for calcium-dependent binding of synaptotagmin to syntaxin was localized to amino acids 220-266. The syntaxin domains required for synaptotagmin binding overlap with the domains for vesicle-associated membrane protein (or VAMP) and alpha-soluble N-ethyl-maleimide-sensitive fusion protein attachment protein (or alphaSNAP) interactions. The data suggest both calcium-dependent and -independent roles of synaptotagmin in regulating synaptic vesicle release and/or recycling.


Cannabis as a substitute for alcohol and other drugs.
Substitution can be operationalized as the conscious choice to use one drug (legal or illicit) instead of, or in conjunction with, another due to issues such as: perceived safety; level of addiction potential; effectiveness in relieving symptoms; access and level of acceptance. This practice of substitution has been observed among individuals using cannabis for medical purposes. This study examined drug and alcohol use, and the occurrence of substitution among medical cannabis patients. Anonymous survey data were collected at the Berkeley Patient's Group (BPG), a medical cannabis dispensary in Berkeley, CA. (N = 350) The sample was 68% male, 54% single, 66% White, mean age was 39; 74% have health insurance (including MediCal), 41% work full time, 81% have completed at least some college, 55% make less than $40,000 a year. Seventy one percent report having a chronic medical condition, 52% use cannabis for a pain related condition, 75% use cannabis for a mental health issue. Fifty three percent of the sample currently drinks alcohol, 2.6 was the average number of drinking days per week, 2.9 was the average number of drinks on a drinking occasion. One quarter currently uses tobacco, 9.5 is the average number of cigarettes smoked daily. Eleven percent have used a non-prescribed, non OTC drug in the past 30 days with cocaine, MDMA and Vicodin reported most frequently. Twenty five percent reported growing up in an abusive or addictive household. Sixteen percent reported previous alcohol and/or drug treatment, and 2% are currently in a 12-step or other recovery program. Forty percent have used cannabis as a substitute for alcohol, 26% as a substitute for illicit drugs and 66% as a substitute for prescription drugs. The most common reasons given for substituting were: less adverse side effects (65%), better symptom management (57%), and less withdrawal potential (34%) with cannabis. The substitution of one psychoactive substance for another with the goal of reducing negative outcomes can be included within the framework of harm reduction. Medical cannabis patients have been engaging in substitution by using cannabis as an alternative to alcohol, prescription and illicit drugs.


The VITAL assay: a versatile fluorometric technique for assessing CTL- and NKT-mediated cytotoxicity against multiple targets in vitro and in vivo.
Assessment of cell-mediated toxicity has traditionally been achieved by measuring the specific activity of enriched effector cell populations against antigen-loaded target cells labeled with radioactive isotopes in vitro. Fluorometric techniques are viewed as a promising alternative to the use of radioactive isotopes for these analyses. Direct assessment of cytotoxicity in vivo can be achieved by monitoring survival of injected fluorescent targets relative to a differentially labeled internal control population without specific antigen. We have developed this approach, incorporating the use of multiple target cell populations labeled with different dyes so that cytotoxicity can be assessed against titrated doses of a given antigen, or against a range of different antigens, simultaneously. We show that this assay, referred to as the VITAL assay, can be used to assess cytotoxic activity of CTL and iNKT cells in vivo and in vitro. CTL responses measured in vivo could be correlated with antigen doses used in immunization strategies, and also with the size of specific CTL populations enumerated in the blood with fluorescent MHC/peptide tetramers. The VITAL assay is, therefore, a sensitive technique allowing analysis of complex multi-epitope responses.


Promoting critical consciousness and social mobilization in HIV/AIDS programmes: lessons and curricular tools from a South African intervention.
The development of critical consciousness is seen as a key stage in communities increasing levels of dialogue about priority problems and effecting structural change for health. However, relatively little research identifies concrete methods for programmes to build critical consciousness. We examined how a South African structural intervention used critical consciousness as a tool for prevention of intimate partner violence and HIV infection. We collected qualitative data in the form of in-depth interviews with managers, trainers, and participants of the Intervention with Microfinance for AIDS and Gender Equity intervention (IMAGE) in rural South Africa. The data were analysed through a coding structure developed in QSR NVivo. We draw practical lessons from IMAGE to guide other HIV programmes aiming to promoting critical consciousness and social mobilization. This research suggests that specific curricular tools can work towards critical consciousness and that mobilization efforts in future programmes can be strengthened by including individual and collective efforts by participants.


Childhood cancer and nuclear power plants in Switzerland: a census-based cohort study.
Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland. We computed person-years at risk for children aged 0-15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5-10 km and 10-15 km from the nearest NPP with children born >15 km away, using Poisson regression models. We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0-4 and 0-15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0-4 and 0-15 year olds were 1.20 (0.60-2.41) and 1.05 (0.60-1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61-1.54) and 0.89 (0.63-1.27). There was no evidence of a dose-response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results. This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.


Dietary fiber and blood pressure control.
In the past few years, new strategies to control blood pressure levels are emerging by developing new bioactive components of foods. Fiber has been linked to the prevention of a number of cardiovascular diseases and disorders. β-Glucan, the main soluble fiber component in oat grains, was initially linked to a reduction in plasma cholesterol. Several studies have shown afterward that dietary fiber may also improve glycaemia, insulin resistance and weight loss. The effect of dietary fiber on arterial blood pressure has been the subject of far fewer studies than its effect on the above-mentioned variables, but research has already shown that fiber intake can decrease arterial blood pressure in hypertensive rats. Moreover, certain fibers can improve arterial blood pressure when administered to hypertensive and pre-hypertensive subjects. The present review summarizes all those studies which attempt to establish the antihypertensive effects of dietary fiber, as well as its effect on other cardiovascular risk factors.


Aggregation of vasopressin mRNA in a subset of axonal swellings of the median eminence and posterior pituitary: light and electron microscopic evidence.
The mRNA encoding vasopressin has recently been documented within the magnocellular hypothalamo-neurohypophyseal projections of the rat such as the median eminence (ME) and the posterior pituitary (PP), suggesting the possibility of its axonal transport. To address the origin of this mRNA and to investigate the functional significance of this unexpected axonal transport of mRNA, we have examined its subcellular localization within both magnocellular perikarya and their axonal projections. For this purpose, we have used nonradioactive in situ hybridization techniques in order to localize the vasopressin mRNA with precision at the ultrastructural level in magnocellular perikarya, dendrites, and axons from control, salt-loaded, and lactating rats. This approach permitted us to demonstrate directly the axonal localization of vasopressin mRNA. Moreover, we were able to obtain novel information concerning vasopressin mRNA compartmentation within both perikarya and axons. At both light and electron microscopic levels, we observed vasopressin mRNA-containing cells in the hypothalamic magnocellular cell body groups, but not in the ME or in the PP. When vasopressin mRNA was detected in medium-size dendrites, it was always associated with the rough endoplasmic reticulum (RER). Within the labeled magnocellular perikarya, the abundant vasopressin mRNA was mainly associated with discrete areas of the RER. However, vasopressin mRNA was never detected in the Golgi apparatus or in association with neurosecretory granules, in perikarya or axons. These data suggest that vasopressin mRNA translation is restricted to certain segments within the RER, and that axonal transport of vasopressin mRNA does not involve the classical neurosecretory pathway, via the Golgi apparatus and the neurosecretory granules, as has been proposed. Within the magnocellular neuron axons, vasopressin mRNA could be detected only in a subset of axonal swellings, all of which were confined to the internal layer of the ME and the PP. The mRNA-containing swellings were numerous in 7 d salt-loaded animals, less abundant in lactating animals, and almost undetectable in control animals. In all groups of animals, no vasopressin mRNA was detectable in any other region of the magnocellular neuron axons, including undilated axonal segments or varicose swellings. These results strongly suggest that, under physiological activation such as chronic salt loading, axonal vasopressin mRNA is increased and becomes aggregated in a selected subset of swellings of the ME and the PP. Furthermore, these data indicate that along the magnocellular neuron axons, the swellings may differ in their biochemical and functional features. Further analysis focused on the mRNA-accumulating swellings may illuminate the function of RNA within the axonal compartment.


A 17-My-old whale constrains onset of uplift and climate change in east Africa.
Timing and magnitude of surface uplift are key to understanding the impact of crustal deformation and topographic growth on atmospheric circulation, environmental conditions, and surface processes. Uplift of the East African Plateau is linked to mantle processes, but paleoaltimetry data are too scarce to constrain plateau evolution and subsequent vertical motions associated with rifting. Here, we assess the paleotopographic implications of a beaked whale fossil (Ziphiidae) from the Turkana region of Kenya found 740 km inland from the present-day coastline of the Indian Ocean at an elevation of 620 m. The specimen is ∼ 17 My old and represents the oldest derived beaked whale known, consistent with molecular estimates of the emergence of modern strap-toothed whales (Mesoplodon). The whale traveled from the Indian Ocean inland along an eastward-directed drainage system controlled by the Cretaceous Anza Graben and was stranded slightly above sea level. Surface uplift from near sea level coincides with paleoclimatic change from a humid environment to highly variable and much drier conditions, which altered biotic communities and drove evolution in east Africa, including that of primates.


Novel agents for relapsed and refractory follicular lymphoma.
Follicular lymphoma is one of the most common non-Hodgkin's lymphomas. Although current frontline regimens are associated with high response rates, most patients still relapse. When progression is discovered, re-establishing the diagnosis and ruling out transformation in paramount. The outcomes following relapse have been improving due to the activity and increasing availability of novel agents with various mechanisms of action. Despite these advances, single agent activity is limited and the disease remains incurable in the majority of cases. Examples of drug classes with promising activity in relapsed disease include anti-CD20 monoclonal antibodies, immunomodulatory drugs (IMiDs), small molecule tyrosine kinase inhibitors, bcl2 inhibitors, epigenetic modifiers, conjugated antibodies, and checkpoint inhibitors. Many drugs in each class are associated with unique, variable and often surprising toxicity profiles. Combination studies are currently underway with novel-novel combinations and with traditional chemotherapy regimens. This overview will discuss the results of several recent studies exploring activity of novel drugs in relapsed follicular lymphoma.


Programmed cell death of keratinocytes culminates in apoptotic secretion of a humectant upon secretagogue action of acetylcholine.
The programmed cell death of the stratified squamous epithelial cells comprising human epidermis culminates in abrupt transition of viable granular keratinocytes (KC) into dead corneocytes sloughed by the skin. The granular cell-corneocyte transition is associated with a loss in volume and dry cell weight but the mechanism for and biological significance of this form of keratinocyte apoptosis remain obscure. We show that terminally differentiated KC extrude into the intercellular spaces of living epidermis the cytoplasmic buds containing randomly congregated components of the cytosol as well as filaggrin, a precursor of the natural moisturizing factor. The discharge of secretory product is reminiscent of holocrine secretion, suggesting the term 'apoptotic secretion' for this novel, essential step in the process of cornification. The secretory product may become a part of the glycocalyx (a.k.a. 'intercellular cement substance' of epidermis) and serve as a humectant that counterbalances the osmotic pressure imposed by the natural moisturizing factor located in the stratum corneum comprised by corneocytes. The apoptotic secretion commences upon secretagouge action of acetylcholine which is synthesized and released by KC. A combination of a cholinergic nicotinic agonist and a muscarinic antagonist which increases intracellular calcium levels is required to trigger the apoptotic secretion. Analysis of the relative amounts of cholinergic enzymes and receptors expressed by KC capable of secretion and the pharmacological profiles of secretion regulation revealed an upward concentration gradient of free acetylcholine in epidermis which may provide for its unopposed secretagogue action via the m1 muscarinic and the alpha7, and alpha9 nicotinic receptor types expressed by KC at the latest stage of their development in the epidermis.


Selection-, age-, and exercise-dependence of skeletal muscle gene expression patterns in a rat model of metabolic fitness.
Intrinsic aerobic exercise capacity can influence many complex traits including obesity and aging. To study this connection we established two rat lines by divergent selection of untrained aerobic capacity. After 32 generations the high capacity runners (HCR) and low capacity runners (LCR) differed in endurance running distance and body fat, blood glucose, other health indicators, and natural life span. To understand the interplay among genetic differences, chronological age, and acute exercise we performed microarray-based gene expression analyses in skeletal muscle with a 2×2×2 design to simultaneously compare HCR and LCR, old and young animals, and rest and exhaustion. Transcripts for mitochondrial function are expressed higher in HCRs than LCRs at both rest and exhaustion and for both age groups. Expression of cell adhesion and extracellular matrix genes tend to decrease with age. This and other age effects are more prominent in LCRs than HCRs, suggesting that HCRs have a slower aging process and this may be partly due to their better metabolic health. Strenuous exercise mainly affects transcription regulation and cellular response. The effects of any one factor often depend on the other two. For example, there are ∼140 and ∼110 line-exercise "interacting" genes for old and young animals, respectively. Many genes highlighted in our study are consistent with prior reports, but many others are novel. The gene- and pathway-level statistics for the main effects, either overall or stratified, and for all possible interactions, represent a rich reference dataset for understanding the interdependence among lines, aging, and exercise.


Eccentric exercise-induced delayed-onset muscle soreness and changes in markers of muscle damage and inflammation.
The purpose of this study was to determine the relationships among delayed-onset muscle soreness (DOMS), muscle damage and inflammatory responses to eccentric exercise and investigate the underlying mechanisms. Nine healthy males performed one-leg calf-raise exercise with their right leg on a force plate. They performed 10 sets of 40 repetitions of exercise at 0.5 Hz by the load corresponding to the half of their body weight, with a rest for 3 min between sets. DOMS was evaluated by a visual analogue scale (VAS). Blood and urine samples were collected before and 2, 4, 24, 48, 72 and 96 h post-exercise. Blood samples were analyzed for leucocyte differential counts and neutrophil functions (migratory activity and oxidative burst activity). We also determined a serum marker of muscle damage, myoglobin (Mb), and plasma and urinary prostaglandin E2 as an algesic substance. As for the inflammatory mediators, plasma and urine were analyzed for cytokines (interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, tumour necrosis factor-alpha, interferon-gamma, monocyte chemotactic protein-1, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and granulocyte macrophage colony-stimulating factor), leucocyte activation markers (calprotectin and myeloperoxidase), and neutrophil chemotactic factor complement 5a. All subjects reported muscle soreness on subsequent days and VAS peaked at 72 h after exercise. Serum Mb concentration significantly increased (p < 0.05) at 72 h after exercise as compared with the pre-exercise values which was correlated with the increases in VAS at 72 h (r = 0.73, p < 0.05). Circulating neutrophil count and migratory activity increased significantly (p < 0.01, and p < 0.05, respectively) at 4 h after exercise, whereas there were no significant changes in the other plasma and urinary inflammatory mediators. These results suggest that neutrophils can be mobilized into the circulation and migrate to the muscle tissue several hours after the eccentric exercise. There were also positive correlations between the exercise-induced increases in neutrophil migratory activity at 4 h and the increases in Mb at 48 h (r = 0.67, p < 0.05). These findings suggest that neutrophil mobilization and migration after exercise may be involved in the muscle damage and inflammatory processes.


Variation in blood pressure among adolescent schoolchildren in an urban slum of Kolkata, West Bengal.
High blood pressure in childhood is a potential risk factor for cardiovascular and cerebrovascular diseases. The roots of essential hypertension in adults may be initiated in childhood. This study was conducted to investigate blood pressure profiles of adolescent schoolchildren in the practice field area of the Urban Health Centre, Chetla, Kolkata. This cross-sectional study was carried out to determine the prevalence of hypertension in adolescent schoolchildren, to compare the blood pressure between boys and girls, and to study the association between selected variables and blood pressure. The study was conducted among adolescent schoolchildren aged 10-19 years in two randomly selected secondary schools situated in the practice field area of the Urban Health Centre, Chetla, Kolkata. All students aged 10-19 years present on the day of the visit were included in the study; the sample was 129. A predesigned questionnaire was used to carry out the study. Measurements of height, weight, body mass index (BMI) and blood pressure were made using standardised physical instruments following standard operative guidelines. The data were collected and analysed using appropriate statistical methods. The prevalence of hypertension was found to be 10.1% (11.1% in boys and 8.8% in girls). The prevalence of pre-hypertension was 20.2% (16.7% in boys and 24.6% in girls). Hypertension was found to be significantly associated with physical exercise (p<0.05) and salt intake (p<0.05); BMI was also significantly associated with both systolic blood pressure (p<0.05) and diastolic blood pressure (p<0.05). There was a significant (p<0.05) positive correlation of systolic blood pressure and diastolic blood pressure with BMI (r=0.303, p<0.05; r=0.262, p<0.05), age (r=0.326, p<0.05; r=0.267, p<0.05) and height (r=0.322, p<0.05; r=0.174, p<0.05). There was a negative correlation between hypertension and physical exercise (r=-0.313, p<0.05) and a positive correlation between hypertension and salt intake (r=0.298, p<0.05). The prevalence of pre-hypertension and hypertension together in adolescents was 30.3%. To avoid the consequences and sequelae of hypertension, prevention should start from childhood by encouraging physical exercise, promoting low salt intake, advising on maintaining normal body weight, and checking up on blood pressure at regular intervals.


Effect of dietary acids on growth performance of nursery pigs: a cooperative study.
An experiment involving 854 crossbred pigs (20 replicate pens of 4 to 8 pigs per pen) was conducted at 8 experiment stations to determine the effects of acids in nursery pig diets and their inclusion amounts on growth performance using diets and weaning ages typical of those used in the United States commercial pork industry. Diets were formulated to have constant a ME and contain 1.45, 1.45, and 1.30% standardized ileal digestible Lys for phases 1, 2, and 3, respectively. The basal diets were supplemented with various types and concentrations of acid at the expense of corn (Zea mays). Treatment diets included 0% acid (control), 0.1 or 0.2% phosphoric acid, 1 or 2% organic acids, and 0.1% phosphoric acid plus 1% organic acids with or without an antibiotic. The organic acids consisted of 50% citric acid and 50% fumaric acid by weight. All but the final diet contained the antibiotic carbadox. All diets contained 3,000 mg of Zn/kg diet from zinc oxide during phases 1 and 2 and had limited acid buffering capacity, ranging from 142, 127, and 122 mEq/kg of feed for phases 1, 2, and 3, respectively. At each participating station, pigs were randomly allotted to dietary treatments on the basis of their initial BW. Sex and ancestry were equally distributed across the treatments. Results indicated that treatment effects on pig performance were observed in phases 1 and 2 but not in phase 3. In phase 1, ADG of pigs fed 0.2% phosphoric acid was greater than that of pigs fed the combination of acids with no antibiotic (P = 0.041). In phase 2, pigs fed treatments containing an antibiotic had a greater ADG than those fed the combination of acids without antibiotic (P < 0.05). Addition of acids to diets did not affect growth performance during any phase or the overall period. Over the 4-wk study, growth rate was slowest on the treatment without antibiotic, with specific differences that were often statistically significant (P < 0.05). In summary, under the conditions of this experiment, the acid treatments had no effect but the antibiotic improved growth performance.


Functional differences and interactions among the putative RecA homologs Rad51, Rad55, and Rad57.
The genes of the Saccharomyces cerevisiae RAD52 epistasis group are required for the repair of ionizing radiation-induced DNA damage. Three of these genes, RAD51, RAD55, and RAD57, have been identified as putative RecA homologs. An important feature of RecA is its ability to bind and hydrolyze ATP. RAD55 and RAD57 contain putative nucleotide binding motifs, and the importance of these motifs was determined by constructing site-directed mutations of the conserved lysine residue within the Walker A-box. Changing the lysine residue to arginine or alanine resulted in a mutant phenotype in DNA repair and sporulation for Rad55 but not for Rad57. Protein-protein interactions among Rad51, Rad55, and Rad57 were tested for by the two-hybrid system. Rad55 was shown to interact with Rad51 and Rad57 but not with itself. Additionally, no interaction between Rad57 and Rad51 or between Rad57 and itself was detected. Consistent with the hypothesis that Rad55 and Rad57 may function within, or stabilize, a protein complex, we found that RAD51 expressed from a high-copy-number plasmid suppresses the DNA repair defect of strains carrying rad55 and rad57 mutations. These data, in conjunction with other reports, demonstrate the importance of protein-protein interactions in the process of DNA repair.


Optimal cultivation of simultaneous ammonium and phosphorus removal aerobic granular sludge in A/O/A sequencing batch reactor and the assessment of functional organisms.
In this study, sequencing batch reactor (SBR) with an anaerobic/aerobic/anoxic operating mode was used to culture granular sludge. Optimal adjustment of cycle duration was achieved by the direction ofpH, oxidation reduction potential and dissolved oxygen parameters. The results showed that the treating efficiency was significantly improved as the cycle was shortened from 450 to 360 min and further to 200 min. Nitrogen and phosphorus removal were nearly quantitative after 50 days operation and maintained stable to the end of the study period. The typical cycle tests revealed that simultaneous denitrification and phosphorus removal occurred when aerobic granules were gradually formed. The nitrite effect tests showed that less than 4.8 mg N/L of the nitrite could enhance superficial specific aerobic phosphate uptake rate (SAPUR) under aerobic condition, indicating that the traditional method to evaluate the capability of total phosphate-accumulating organisms (PAOs) was inaccurate. Additionally, a high level of nitrite was detrimental to PAOs. A novel method was developed to determine the activity of each kind of PAOs and other denitrifying organisms. The results showed that (1) nitrate, besides nitrite, could also enhance SAPUR and (2) aerobic granular sludge could perform denitrification even when phosphate was not supplied under anoxic condition, suggesting that other denitrifying organisms besides denitrifying phosphate-accumulating organisms also contributed to denitrification.


Safe glycemic management during closed-loop treatment of type 1 diabetes: the role of glucagon, use of multiple sensors, and compensation for stress hyperglycemia.
Patients with type 1 diabetes mellitus (T1DM) must make frequent decisions and lifestyle adjustments in order to manage their disorder. Automated treatment would reduce the need for these self-management decisions and reduce the risk for long-term complications. Investigators in the field of closed-loop glycemic control systems are now moving from inpatient to outpatient testing of such systems. As outpatient systems are developed, the element of safety increases in importance. One such concern is the risk for hypoglycemia, due in part to the delayed onset and prolonged action duration of currently available subcutaneous insulin preparations. We found that, as compared to an insulin-only closed-loop system, a system that also delivers glucagon when needed led to substantially less hypoglycemia. Though the capability of glucagon delivery would mandate the need for a second hormone chamber, glucagon in small doses is tolerated very well. People with T1DM often develop hyperglycemia from emotional stress or medical stress. Automated closed-loop systems should be able to detect such changes in insulin sensitivity and adapt insulin delivery accordingly. We recently verified the adaptability of a model-based closed-loop system in which the gain factors that govern a proportional-integral-derivative-like system are adjusted according to frequently measured insulin sensitivity. Automated systems can be tested by physical exercise to increase glucose uptake and insulin sensitivity or by administering corticosteroids to reduce insulin sensitivity. Another source of risk in closed-loop systems is suboptimal performance of amperometric glucose sensors. Inaccuracy can result from calibration error, biofouling, and current drift. We found that concurrent use of more than one sensor typically leads to better sensor accuracy than use of a single sensor. For example, using the average of two sensors substantially reduces the proportion of large sensor errors. The use of more than two allows the use of voting algorithms, which can temporarily exclude a sensor whose signal is outlying. Elements such as the use of glucagon to minimize hypoglycemia, adaptation to changes in insulin sensitivity, and sensor redundancy will likely increase safety during outpatient use of closed-loop glycemic control systems.


Preventive role of Pycnogenol® against the hyperglycemia-induced oxidative stress and DNA damage in diabetic rats.
Diabetes mellitus, a complex progressive metabolic disorder, leads to some oxidative stress related complications. Pycnogenol® (PYC), a plant extract obtained from Pinus pinaster, has been suggested to be effective in many diseases including diabetes, cancer, inflammatory and immune system disorders. The mechanisms underlying the effects of PYC in diabetes need to be elucidated. The aim of this study was to determine the effects of PYC treatment (50 mg/kg/day, orally, for 28 days) on the DNA damage and biochemical changes in the blood, liver, and kidney tissues of experimental diabetic rats. Changes in the activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase enzymes, and the levels of 8-hydroxy-2'-deoxyguanosine, total glutathione, malondialdehyde, insulin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, high density lipoprotein, low density lipoprotein, total cholesterol, and triglyceride were evaluated. DNA damage was also determined in the whole blood cells and the liver and renal tissue cells using the alkaline comet assay. PYC treatment significantly ameliorated the oxidative stress, lipid profile, and liver function parameters as well as DNA damage in the hyperglycemic rats. The results show that PYC treatment might improve the hyperglycemia-induced biochemical and physiological changes in diabetes.


Visceral leishmaniasis and Coombs' positive hemolytic anemia: a rare association in an infant treated with liposomal amphotericin B.
Visceral leishmaniasis is a worldwide, disseminated intracellular protozoal infection that usually manifests by fever, hepatosplenomegaly, anemia, thrombocytopenia, leukopenia and hypergammaglobulinemia. Although anemia is a usual finding, Coombs' positive hemolytic anemia has rarely been reported in association with this disease. Pentavalent antimonials have been the preferred treatment for this disease for decades, but increasing numbers of treatment failure with antimony are being reported. Liposomal amphotericin B is a new drug which is highly efficacious in the treatment of visceral leishmaniasis and produces minimal toxicity. Here we report an infant with visceral leishmaniasis associated with Coombs' positive hemolytic anemia who was successfully treated with liposomal amphotericin B.


Canonical source reconstruction for MEG.
We describe a simple and efficient solution to the problem of reconstructing electromagnetic sources into a canonical or standard anatomical space. Its simplicity rests upon incorporating subject-specific anatomy into the forward model in a way that eschews the need for cortical surface extraction. The forward model starts with a canonical cortical mesh, defined in a standard stereotactic space. The mesh is warped, in a nonlinear fashion, to match the subject's anatomy. This warping is the inverse of the transformation derived from spatial normalization of the subject's structural MRI image, using fully automated procedures that have been established for other imaging modalities. Electromagnetic lead fields are computed using the warped mesh, in conjunction with a spherical head model (which does not rely on individual anatomy). The ensuing forward model is inverted using an empirical Bayesian scheme that we have described previously in several publications. Critically, because anatomical information enters the forward model, there is no need to spatially normalize the reconstructed source activity. In other words, each source, comprising the mesh, has a predetermined and unique anatomical attribution within standard stereotactic space. This enables the pooling of data from multiple subjects and the reporting of results in stereotactic coordinates. Furthermore, it allows the graceful fusion of fMRI and MEG data within the same anatomical framework.


Macrophage activation and polarization.
Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.


VEGF-A-Expressing Adipose Tissue Shows Rapid Beiging and Enhanced Survival After Transplantation and Confers IL-4-Independent Metabolic Improvements.
Adipocyte-derived vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and contributes to adipocyte function and systemic metabolism, such as insulin resistance, chronic inflammation, and beiging of subcutaneous adipose tissue. Using a doxycycline-inducible adipocyte-specific VEGF-A-overexpressing mouse model, we investigated the dynamics of local VEGF-A effects on tissue beiging of adipose tissue transplants. VEGF-A overexpression in adipocytes triggers angiogenesis. We also observed a rapid appearance of beige fat cells in subcutaneous white adipose tissue as early as 2 days postinduction of VEGF-A. In contrast to conventional cold-induced beiging, VEGF-A-induced beiging is independent of interleukin-4. We subjected metabolically healthy VEGF-A-overexpressing adipose tissue to autologous transplantation. Transfer of subcutaneous adipose tissues taken from VEGF-A-overexpressing mice into diet-induced obese mice resulted in systemic metabolic benefits, associated with improved survival of adipocytes and a concomitant reduced inflammatory response. These effects of VEGF-A are tissue autonomous, inducing white adipose tissue beiging and angiogenesis within the transplanted tissue. Our findings indicate that manipulation of adipocyte functions with a bona fide angiogenic factor, such as VEGF-A, significantly improves the survival and volume retention of fat grafts and can convey metabolically favorable properties on the recipient on the basis of beiging.


Associations Between Impaired Cerebral Blood Flow Autoregulation, Cerebral Oxygenation, and Biomarkers of Brain Injury and Postoperative Cognitive Dysfunction in Elderly Patients After Major Noncardiac Surgery.
Increasing evidence links postoperative cognitive dysfunction (POCD) to surgery and anesthesia. POCD is recognized as an important neuropsychological adverse outcome in surgical patients, particularly the elderly. This prospective cohort study aimed to investigate whether POCD is associated with impaired intraoperative cerebral autoregulation and oxygenation, and increased levels of biomarkers of brain injury. Study subjects were patients ≥65 years of age scheduled for major noncardiac surgery. Cognitive function was assessed before and 1 week after surgery. POCD was diagnosed if a decline of >1 standard deviation of z-scores was present in ≥2 variables of the test battery. The incidence of POCD 1 week after surgery was modeled as a multivariable function of the index of autoregulation (MxA) and tissue oxygenation index (TOI), adjusting for baseline neuropsychological assessment battery (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery [CERAD-NAB]) total score and the maximum C-reactive protein (CRP) concentration. The biomarkers of brain injury neuron-specific enolase and S100β protein, age, and level of education were included in secondary multivariable logistic regression analyses. Of the 82 patients who completed the study, 38 (46%) presented with POCD 1 week after surgery. In the multivariable regression analysis, higher intraoperative MxA (odds ratio [OR; 95% confidence interval (CI)], 1.39 [1.01-1.90] for an increase of 0.1 units, P = .08 after Bonferroni adjustment), signifying less effective autoregulation, was not associated with higher odds of POCD. The univariable logistic regression model for MxA yielded an association with POCD (OR [95% CI], 1.44 [1.06-1.95], P = .020). Tissue oxygenation index (1.12 [0.41-3.01] for an increase of 10%, P = 1.0 after Bonferroni adjustment) and baseline CERAD-NAB total score (0.80 [0.45-1.42] for an increase of 10 points, P = .45) did not affect the odds of POCD. POCD was associated with elevated CRP on postoperative day 2 (median [interquartile range]; 175 [81-294] vs 112 [62-142] mg/L, P = .033); however, the maximum CRP value (OR [95% CI], 1.35 [0.97-1.87] for a 2-fold increase, P = .07) had no distinct effect on POCD. Impairment of intraoperative cerebral blood flow autoregulation is not predictive of early POCD in elderly patients, although secondary analyses indicate that an association probably exists.


Segmental Rearrangements Relax Stresses in Nonequilibrated Polymer Films.
We probed the relaxation of preparation-induced residual stresses in nonequilibrated polymer films through dewetting experiments. While we observed fast relaxations at temperatures close to or below the glass transition, at elevated temperatures these relaxation times were orders of magnitude longer than the reptation time. Intriguingly, applying appropriate scaling of preparation conditions allowed us to present all relaxation times, including published data, from various complementary experiments on a single master curve exhibiting an Arrhenius-type behavior. The corresponding activation energy (75 ± 10 kJ/mol) is similar to values obtained for the relaxation of segments in polystyrene. The observed long relaxation times suggest that residual stresses, a consequence of nonequilibrium conformations inherited from preparation, relax via concerted rearrangements of many segments.


MRI of hepatocellular carcinoma: an update of current practices.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and liver transplantation is the optimal treatment for selected patients with HCC and chronic liver disease (CLD). Accurate selection of patients for transplantation is essential to maximize patient outcomes and ensure optimized allocation of donor organs. Magnetic resonance imaging (MRI) is a powerful tool for the detection, characterization, and staging of HCC. In patients with CLD, the MRI findings of an arterial-enhancing mass with subsequent washout and enhancing capsule on delayed interstitial phase images are diagnostic for HCC. Major organizations with oversight for organ donor distribution, such as The Organ Procurement and Transplantation Network (OPTN), accept an imaging diagnosis of HCC, no longer requiring tissue biopsy. In patients that are awaiting transplantation, or are not candidates for liver transplantation, localized therapies such as transarterial chemoembolization and radiofrequency ablation may be offered. MRI can be used to monitor treatment response. The purpose of this review article is to describe the role of imaging methods in the diagnosis, staging, and follow-up of HCC, with particular emphasis on established and evolving MRI techniques employing nonspecific gadolinium chelates, hepatobiliary contrast agents, and diffusion weighted imaging. We also briefly review the recently developed Liver Imaging Reporting and Data System (LI-RADS) formulating a standardized terminology and reporting structure for evaluation of lesions detected in patients with CLD.


Stimulatory effects of advanced glycation endproducts (AGEs) on fibronectin matrix assembly.
Advanced glycation endproducts (AGEs) are a heterogeneous group of compounds that form via non-enzymatic glycation of proteins throughout our lifespan and at a higher rate in certain chronic diseases such as diabetes. AGEs contribute to the progression of fibrosis, in part by stimulating cellular pathways that affect gene expression. Long-lived ECM proteins are targets for non-enzymatic glycation but the question of whether the AGE-modified ECM leads to excess ECM accumulation and fibrosis remains unanswered. In this study, cellular changes due to AGE accretion in the ECM were investigated. Non-enzymatic glycation of proteins in a decellularized fibroblast ECM was achieved by incubating the ECM in a solution of methylglyoxal (MGO). Mass spectrometry of fibronectin (FN) isolated from the glycated matrix identified twenty-eight previously unidentified MGO-derived AGE modification sites including functional sites such as the RGD integrin-binding sequence. Mesangial cells grown on the glycated, decellularized matrix assembled increased amounts of FN matrix. Soluble AGE-modified bovine serum albumin (BSA) also stimulated FN matrix assembly and this effect was reduced by function-blocking antibodies against the receptor for AGE (RAGE). These results indicate that cells respond to AGEs by increasing matrix assembly and that RAGE is involved in this response. This raises the possibility that the accumulation of ECM during the progression of fibrosis may be enhanced by cell interactions with AGEs on a glycated ECM.


The chromatin-associated protein H-NS alters DNA topology in vitro.
H-NS is one of the two most abundant proteins in the bacterial nucleoid and influences the expression of a number of genes. We have studied the interaction of H-NS with DNA; purified H-NS was demonstrated to constrain negative DNA supercoils in vitro. This provides support for the hypothesis that H-NS influences transcription via changes in DNA topology, and is evidence of a structural role for H-NS in bacterial chromatin. The effects of H-NS on topology were only observed at sub-saturating concentrations of the protein. In addition, a preferred binding site on DNA was identified by DNase I footprinting at sub-saturating H-NS concentrations. This site corresponded to a curved sequence element which we previously showed, by in vivo studies, to be a site at which H-NS influences transcription of the proU operon. When present in saturating concentrations, H-NS did not constrain supercoils and bound to DNA in a sequence-independent fashion, covering all DNA molecules from end to end, suggesting that H-NS may form distinct complexes with DNA at different H-NS:DNA ratios. The data presented here provide direct support for the hypothesis that H-NS acts at specific sites to influence DNA topology and, hence, transcription.


Use of stress testing early after coronary artery bypass graft surgery.
The American College of Cardiology/American Heart Association guidelines for exercise testing do not take a position regarding the utility of routine stress testing after coronary artery bypass grafting (CABG). Our purposes were (1) to document the patterns of use of stress testing after CABG and (2) to establish whether the choice of stress testing strategy is associated with clinical characteristics of patients. The Routine versus Selective Exercise Treadmill Testing after Coronary Artery Bypass Graft Surgery (ROSETTA-CABG) Registry is a prospective multicenter study that examined the use of stress testing after CABG among 395 patients at 16 clinical centers in 6 countries. During the 12 months after CABG, 37% of patients underwent stress testing (range across centers 0% to 100%). Among patients who underwent stress testing, 24% had a clinical indication and 76% had it as a routine follow-up. A total of 65% of stress tests involved exercise treadmill testing alone, 17% involved stress nuclear perfusion imaging, 13% involved stress echocardiographic imaging, and 5% involved other types of stress tests, such as positron emission tomographic scans. The first stress test was performed at a median of 13 weeks after CABG, with 20% of patients having second tests at a median of 28 weeks and 6% having additional tests at a median of 34 weeks. Univariate and multivariate analyses demonstrated that the chief determinant of using routine stress testing was the clinical center. In conclusion, these results suggest that there is little consensus on the appropriate use of stress testing soon after CABG. Practice patterns vary widely; poorly diagnostic tests are used routinely; and the clinical center at which the procedure is performed, rather than the clinical characteristics of the patient, determines the use of stress testing after CABG.


Trial of early, goal-directed resuscitation for septic shock.
Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).


Elucidation of the monoclonal antibody 5G8-reactive, virulence-associated lipopolysaccharide epitope of Haemophilus influenzae and its role in bacterial resistance to complement-mediated killing.
The phase-variable locus lex2 is required for expression of a Haemophilus influenzae lipopolysaccharide (LPS) epitope of previously unknown structure. This epitope, which is reactive with monoclonal antibody (MAb) 5G8, has been associated with virulence of type b strains. When strain RM118 (from the same source as strain Rd), in which the lex2 locus and MAb 5G8 reactivity are absent, was transformed with lex2 DNA, transformants that were reactive with MAb 5G8 were obtained. Surprisingly, the 5G8 reactivity of these transformants was phase variable, although the lex2 locus lacked tetrameric repeats and was constitutively expressed. This phase variation was shown to be the result of phase-variable expression of phosphorylcholine (PCho) such that MAb 5G8 reacted only in the absence of PCho. Structural analysis showed that, compared to RM118, the lex2 transformant had acquired a tetrasaccharide, Gal-alpha1,4-Gal-beta1,4-Glc-beta1,4-Glc-beta1,4, linked to the proximal heptose (HepI). A terminal GalNAc was detected in a minority of glycoforms. LPS derived from a mutant of RM7004, a virulent type b strain which naturally expresses lex2 and has LPS containing the same tetrasaccharide linked to HepI as the sole oligosaccharide extension from the inner core, confirmed that GalNAc is not a part of the MAb 5G8-reactive epitope. Thus, MAb 5G8 specifically binds to the structure Gal-alpha1,4-Gal-beta1,4-Glc-beta1,4-Glc-beta attached via a 1,4 linkage to HepI of H. influenzae LPS, and we show that the ability to synthesize this novel tetrasaccharide was associated with enhanced bacterial resistance to complement-mediated killing.


Structural basis for arginine glycosylation of host substrates by bacterial effector proteins.
The bacterial effector proteins SseK and NleB glycosylate host proteins on arginine residues, leading to reduced NF-κB-dependent responses to infection. Salmonella SseK1 and SseK2 are E. coli NleB1 orthologs that behave as NleB1-like GTs, although they differ in protein substrate specificity. Here we report that these enzymes are retaining glycosyltransferases composed of a helix-loop-helix (HLH) domain, a lid domain, and a catalytic domain. A conserved HEN motif (His-Glu-Asn) in the active site is important for enzyme catalysis and bacterial virulence. We observe differences between SseK1 and SseK2 in interactions with substrates and identify substrate residues that are critical for enzyme recognition. Long Molecular Dynamics simulations suggest that the HLH domain determines substrate specificity and the lid-domain regulates the opening of the active site. Overall, our data suggest a front-face SNi mechanism, explain differences in activities among these effectors, and have implications for future drug development against enteric pathogens.


Interaction of PIMT with transcriptional coactivators CBP, p300, and PBP differential role in transcriptional regulation.
PIMT (PRIP-interacting protein with methyltransferase domain), an RNA-binding protein with a methyltransferase domain capable of binding S-adenosylmethionine, has been shown previously to interact with nuclear receptor coactivator PRIP (peroxisome proliferator-activated receptor (PPAR)-interacting protein) and enhance its coactivator function. We now report that PIMT strongly interacts with transcriptional coactivators, CBP, p300, and PBP but not with SRC-1 and PGC-1alpha under in vitro and in vivo conditions. The PIMT binding sites on CBP and p300 are located in the cysteine-histidine-rich C/H1 and C/H3 domains, and the PIMT binding site on PBP is in the region encompassing amino acids 1101-1560. The N-terminal of PIMT (residues 1-369) containing the RNA binding domain interacts with both C/H1 and C/H3 domains of CBP and p300 and with the C-terminal portion of PBP that encompasses amino acids 1371-1560. The C-terminal of PIMT (residues 611-852), which binds S-adenosyl-l-methionine, interacts respectively with the C/H3 domain of CBP/p300 and with a region encompassing amino acids 1101-1370 of PBP. Immunoprecipitation data showed that PIMT forms a complex in vivo with CBP, p300, PBP, and PRIP. PIMT appeared to be co-localized in the nucleus with CBP, p300, and PBP. PIMT enhanced PBP-mediated transcriptional activity of the PPARgamma, as it did for PRIP, indicating synergism between PIMT and PBP. In contrast, PIMT functioned as a repressor of CBP/p300-mediated transactivation of PPARgamma. Based on these observations, we suggest that PIMT bridges the CBP/p300-anchored coactivator complex with the PBP-anchored coactivator complex but differentially modulates coactivator function such that inhibition of the CBP/p300 effect may be designed to enhance the activity of PBP and PRIP.


New perspectives on chinese herbal medicine (zhong-yao) research and development.
Synthetic chemical drugs, while being efficacious in the clinical management of many diseases, are often associated with undesirable side effects in patients. It is now clear that the need of therapeutic intervention in many clinical conditions cannot be satisfactorily met by synthetic chemical drugs. Since the research and development of new chemical drugs remain time-consuming, capital-intensive and risky, much effort has been put in the search for alternative routes for drug discovery in China. This narrative review illustrates various approaches to the research and drug discovery in Chinese herbal medicine. Although this article focuses on Chinese traditional drugs, it is also conducive to the development of other traditional remedies and innovative drug discovery.


'A systematic overview--a decade of research'. The information and counselling needs of people with epilepsy.
This paper explores the background to epilepsy in terms of medical impact and psychosocial effects. The argument that information and counselling may be central to the person with epilepsy is explored. The evidence from primary research published between 1990 and 2000 investigating the information and counselling needs of people with epilepsy is appraised and synthesized. This paper seeks to answer the following questions: What are the information and counselling needs of people with epilepsy? What are the preferred formats, timing and delivery of information and counselling? What are the outcomes of information giving and counselling for people with epilepsy? The review suggests that there are unmet needs for personal and general information about epilepsy which may include individual or group education and counselling. Information related to gaining control for people with epilepsy and targeted public education may contribute to improved quality of life for people with epilepsy. Information is required which is individually relevant and could be delivered in small groups or as part of an individual counselling service. Specialist epilepsy clinics and specialist nurses can improve patient knowledge and communication and provide an effective and high quality service for people with epilepsy.


Interaction studies of carbon nanomaterials and plasma activated carbon nanomaterials solution with telomere binding protein.
Most cancer cells have telomerase activity because they can express the human telomerase reverse transcriptase (hTERT) gene. Therefore, the inhibition of the hTERT expression can play an important role in controlling cancer cell proliferation. Our current study aims to inhibit hTERT expression. For this, we synthesized graphene oxide (GO) and a functionalized multiwall carbon nanotube (f-MWCNT), latter treated them with cold atmospheric pressure plasma for further analysis of the hTERT expression. The inhibition of hTERT expression by GO, f-MWCNT, plasma activated GO solution (PGOS), and plasma activated f-MWCNT solution (PCNTS), was studied using two lung cancer cell lines, A549 and H460. The hTERT experimental results revealed that GO and PGOS sufficiently decreased the hTERT concentration, while f-MWCNT and PCNTS were unable to inhibit the hTERT concentration. Therefore, to understand the inhibition mechanism of hTERT, we studied the binding properties of GO and PGOS with telomere binding protein (AtTRB2). The interaction studies were carried out using circular dichroism, fluorescence, 1H-15N NMR spectroscopy, and size-exclusion chromatography (SEC) binding assay. We also used docking simulation to have an better understanding of the interactions between GO nanosheets and AtTRB2 protein. Our results may provide new insights that can benefit in biomedical treatments.


Bereaved Family Cancer Caregivers' Unmet Needs: Measure Development and Validation.
Accumulating evidence shows that bereaved family caregivers report elevated distress for an extended period, which compromises their quality of life. A first step in the development of programs to enhance bereaved caregivers' quality of life should be determining the needs they experience to manage the loss, and the needs that are not being satisfied. Thus, this study aimed to develop a new measure to assess unmet needs among bereaved family caregivers. The 20-item Needs Assessment of Family Caregivers-Bereaved to Cancer measure was developed and validated with bereaved cancer caregivers 5 (n = 159) and 8 (n = 194) years after the initial cancer diagnosis of the index patient, when stress in providing care to the patient was assessed. Exploratory factor analysis yielded two primary factors: unmet needs for reintegration and unmet needs for managing the loss. Bereaved caregivers who were younger and ethnic minority, and who had greater earlier perceived stress of caregiving, reported their needs were more poorly met (t > 2.33, p < .05). The extent to which bereaved caregivers' needs to manage the loss were not perceived as being met was a consistent and strong predictor of poor adjustment to bereavement at both 5- and 8-year marks (t > 1.96, p < .05), beyond the effects of a host of demographic and earlier caregiving characteristics. Findings support the validity of the Needs Assessment of Family Caregivers-Bereaved to Cancer and suggest that interventions to help bereaved caregivers manage the loss by assisting their transition to re-engagement in daily and social activities will benefit caregivers by mitigating bereavement-related distress years after the loss.


Cartilage-sparing surgery for melanoma of the external ear.
The excision of melanoma of the external ear poses a challenge to surgeons, who must achieve adequate oncological control while minimising impact on form and function. Cartilage-preserving surgery is an attractive option, as it leaves behind a scaffold for immediate reconstruction with a variety of techniques including full-thickness skin grafts (FTSGs) and local flaps. This manuscript will review the literature comparing cartilage-sparing surgery with composite excision of the skin and the cartilage for the treatment of auricular melanoma. We report the results of a 17 year experience of using both techniques, together with sentinel node biopsy at our centre. A structured review of MEDLINE and EMBASE was conducted to evaluate all studies reporting local recurrence or survival rates for melanoma of the external ear treated with cartilage-preserving surgery. A retrospective review of all patients undergoing wide local excision (WLE) and sentinel lymph node biopsy (SLNB) for auricular melanoma at our centre between 2000 and 2017 was performed. Of 40 patients identified, 29 underwent cartilage-preserving surgery with no local recurrences or evidence of perichondral involvement. There was one local recurrence out of 11 patients who had their cartilage excised. There were no significant differences in recurrence rates or melanoma-specific survival rates when comparing cartilage-preserving and cartilage-sparing surgery. Our results are supported by the literature review, which suggests that cartilage-sparing surgery is gaining acceptance as a safe practice.


Exposure to sodium fluoride produces signs of apoptosis in rat leukocytes.
Fluoride is naturally present in the earth's crust and can be found in rocks, coal, and clay; thus, it can be found in small quantities in water, air, plants, and animals. Therefore, humans are exposed to fluoride through food, drinking water, and in the air they breathe. Flouride is essential to maintain bone strength and to protect against dental decay, but if it is absorbed too frequently, it can cause tooth decay, osteoporosis, and damage to kidneys, bones, nerves, and muscles. Therefore, the present work was aimed at determining the effect of intake of sodium fluoride (NaF) as an apoptosis inducer in leukocytes of rats treated for eight weeks with 1 or 50 parts per million (ppm) NaF. Expression of p53, bcl-2, and caspade-3 were used as apoptotic and general metabolism indicators of leukocyte-like indicators of the (INT) oxidation system. Male rats were exposed to NaF (1 and 500 ppm) for eight weeks, and then sacrificed weekly to obtain blood samples. Expression of p53, bcl-2, and caspase-3 were determined in leukocytes by Western blot, and general metabolism of leukocytes was analyzed with a commercial kit. We found changes in the expression of the proteins described, especially when the animals received 50 ppm of NaF. These results indicate that NaF intoxication can be an apoptosis inducer in rat leukocytes treated with the compound for eight weeks.


Earliest directly-dated human skull-cups.
The use of human braincases as drinking cups and containers has extensive historic and ethnographic documentation, but archaeological examples are extremely rare. In the Upper Palaeolithic of western Europe, cut-marked and broken human bones are widespread in the Magdalenian (∼15 to 12,000 years BP) and skull-cup preparation is an element of this tradition. Here we describe the post-mortem processing of human heads at the Upper Palaeolithic site of Gough's Cave (Somerset, England) and identify a range of modifications associated with the production of skull-cups. New analyses of human remains from Gough's Cave demonstrate the skilled post-mortem manipulation of human bodies. Results of the research suggest the processing of cadavers for the consumption of body tissues (bone marrow), accompanied by meticulous shaping of cranial vaults. The distribution of cut-marks and percussion features indicates that the skulls were scrupulously 'cleaned' of any soft tissues, and subsequently modified by controlled removal of the facial region and breakage of the cranial base along a sub-horizontal plane. The vaults were also 'retouched', possibly to make the broken edges more regular. This manipulation suggests the shaping of skulls to produce skull-cups. Three skull-cups have been identified amongst the human bones from Gough's Cave. New ultrafiltered radiocarbon determinations provide direct dates of about 14,700 cal BP, making these the oldest directly dated skull-cups and the only examples known from the British Isles.


Proposal to improve vertebrate cell cultures to establish them as substitutes for the regulatory testing of chemicals and effluents using fish.
Cultures of vertebrate cells are widely applied in mechanistic studies in human toxicology as well as in toxicity identification in ecotoxicology. As in vitro models, they display many advantages over whole animal experimentation, pertaining to such characteristics as availability, reproducibility and costs. As well, they satisfy the societal desire to reduce the number of animals in toxicology. For these reasons vertebrate cell models also appear to be a desirable replacement for animals in regulatory tests. Several vertebrate cell models are now accepted for regulatory purposes in human health sciences, with the test for photocytotoxicity using the 3T3 mouse cell line being one example. However, an in vitro alternative to whole animal tests has not yet been established for regulatory risk assessment in ecotoxicology. This review sets out to outline why such a replacement has not yet been possible and explores avenues to improve vertebrate cell cultures so that a replacement of whole animal tests could more likely be achieved. Inasmuch as fish is the most widely used non-mammalian vertebrate in risk assessment and regulation, focus will be on the replacement, by in vitro vertebrate models, of fish.


Minor Elevation in C-Reactive Protein Levels Predicts Incidence of Erythropoiesis-Stimulating Agent Hyporesponsiveness among Hemodialysis Patients.
Hemodialysis (HD) patients occasionally experience minor asymptomatic elevation in C-reactive protein (CRP) levels, which may be associated with difficulty in managing renal anemia using erythropoiesis-stimulating agents (ESAs). Here, we assessed whether elevation of CRP predicts future incidences of ESA hyporesponsiveness. A total of 2,956 HD patients lacking ESA hyporesponsiveness and infectious diseases were enrolled, and the association between CRP levels and incidence of ESA hyporesponsiveness was assessed. CRP levels were divided into 4 categories (normal [<1.0 mg/l], mild [1.0 ≤ CRP <3.0 mg/l], moderate [3.0 ≤ CRP <10.0 mg/l] and high [≥ 10.0 mg/l]). The primary outcome was the cumulative incidence of ESA hyporesponsiveness, defined as a failure to achieve hemoglobin level ≥ 10 g/dl despite receiving high doses of ESAs (≥ 9,000 U/week recombinant human epoetin [rHuEPO]-α or rHuEPO-β and ≥ 60 μg/week darbepoetin-α) during 12 months of follow-up. The cumulative incidence of ESA hyporesponsiveness was 134 (4.8%) occurrences over 4 months and 300 (12.4%) over 12 months. The elevated CRP groups had significantly higher incidence of ESA hyporesponsiveness over 4 months of follow-up than the normal reference group (adjusted relative risk [RR] 1.6, 95% CI 1.0-2.6 for moderate; adjusted RR 2.5, 95% CI 1.5-4.1 for high). Furthermore, the association remained consistent even over 12 months (adjusted RR 1.4, 95% CI 1.0-1.8 for moderate; adjusted RR 1.6, 95% CI 1.1-2.4 for high). Elevated CRP levels were associated with future incidence of ESA hyporesponsiveness from low-grade inflammation (3.0 ≤ CRP <10.0 mg/l).


Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.
Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838. Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39-0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. AbbVie.


Habitual Coffee and Tea Consumption and Cardiometabolic Biomarkers in the UK Biobank: The Role of Beverage Types and Genetic Variation.
Mechanisms linking habitual consumption of coffee and tea to the development of type 2 diabetes and cardiovascular diseases remain unclear. We leveraged dietary, genetic, and biomarker data collected from the UK Biobank to investigate the role of different varieties of coffee and tea in cardiometabolic health. We included data from ≤447,794 participants aged 37-73 y in 2006-2010 who provided a blood sample and completed questionnaires regarding sociodemographic factors, medical history, diet, and lifestyle. Multivariable linear regression was used to examine the association between coffee or tea consumption and blood concentrations of glycated hemoglobin, fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, fasting triglycerides (TGs), apoA-1, apoB, lipoprotein-a, and C-reactive protein (CRP). Lifestyle and genetic factors affecting caffeine metabolism, responses, or intake were tested for interactions with beverage intake in relation to biomarker concentrations. Compared with coffee nonconsumers, each additional cup of coffee was significantly associated with higher total cholesterol, HDL-cholesterol, and LDL-cholesterol concentrations and lower TG and CRP concentrations in both men and women (P-trend < 0.002). Higher consumption of espresso coffee (≥2 compared with 0 cups/d) was associated with higher LDL cholesterol in men (β: 0.110 mmol/L; 95% CI: 0.058, 0.163 mmol/L) and women (β: 0.161 mmol/L; 95% CI: 0.088, 0.234 mmol/L), whereas no substantial association was observed for instant coffee. Compared with tea nonconsumers, higher tea consumption was associated with lower total and LDL cholesterol and apoB and higher HDL cholesterol (P-trend < 0.002); these associations were similar for black and green tea. Associations were not modified by genetics. In the UK Biobank, consumption of certain coffee brews such as espresso had unfavorable associations with blood lipids, whereas consumption of tea had favorable associations. Findings were not modified by genetic variants affecting caffeine metabolism, suggesting a role of noncaffeine constituents of these beverages in cardiometabolic health.


First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis.
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib have proven efficacy in terms of progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, an overall view for comparing efficacy and toxicity on a meta-level is lacking. This study compared efficacy and toxicity of first-line treatment with five different EGFR-TKIs by conducting a network meta-analysis (NMA). A systematic review was performed, aiming to find eligible literature. Data of PFS, overall survival (OS), objective response rate (ORR), and adverse events were extracted. An NMA based on Bayesian statistics was established to synthesize the efficacy and toxicity of all treatments. Thirteen randomized controlled trials, including data from 3,539 patients with EGFR-mutated NSCLC, were analyzed. Rank probabilities showed that osimertinib had a potentially better efficacy in terms of PFS and OS compared to all other TKIs. For ORR, afatinib and osimertinib showed a trend of superiority compared to the other four TKIs. Furthermore, there was a high risk of diarrhea and rash for patients treated with afatinib or dacomitinib as well as a moderate risk for treatment with erlotinib, gefitinib, and osimertinib. Our study showed a favorable efficacy of osimertinib in terms of PFS and OS compared to all other EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations. Furthermore, gefitinib, erlotinib, and osimertinib were associated with fewer toxicities compared to the other TKIs. Therefore, osimertinib is indicated as a preferable first-line TKI in patients with activating EGFR-mutated NSCLC.


Sexual dysfunction in Assyrian/Syrian immigrants and Swedish-born persons with type 2 diabetes.
Few studies have investigated sexual dysfunction in immigrant patients with type 2 diabetes in Sweden. The aim of this study was to examine the association between ethnicity and sexual dysfunction and to analyze if this association remains after adjusting for explanatory variables including age, marital status, HbA1c, triglycerides, and hypertension. This cross-sectional study was conducted at four primary health care centers in the Swedish town of Södertälje. A total of 354 persons with type 2 diabetes (173 Assyrians/Syrians and 181 Swedish-born patients) participated in the survey. The main outcome measure was the self-reported presence of sexual dysfunction based on two questions, one regarding loss of ability to have sexual intercourse and the other loss of sexual desire. Response rates were 78% and 86%, respectively. The total prevalence of loss of ability to have intercourse was 29.5%. In the multivariate models, the odds of loss of ability to have intercourse was significantly higher in the oldest age group (OR = 5.80; 95% CI, 2.33-14.40), in men (OR = 3.33; 95% CI, 1.33-8.30), and in unmarried individuals (OR = 2.40; 95% CI, 1.02-5.70). The odds of reporting loss of sexual desire was higher in Assyrians/Syrians than in Swedish-born patients and increased from 2.00 in the age- and gender-adjusted model to 2.70 in the fully adjusted model when all confounders were taken into account. Sexual dysfunction appears to be more common in Assyrians/Syrians than in Swedish-born patients. Health care workers should actively ask about sexual function in their patients with type 2 diabetes.


Back problems. Neuroanatomy and neurological examination.
Components of the equine nervous system are described including classical anatomy and newer sensory innervation maps that are useful for localizing lesions to and within the nervous system. The key components in a neurological examination that help differentiate primary neurologic disease from musculoskeletal disorders are explained. Gait deficits associated with neurologic dysfunction are listed as well as diagnostic aids and an overview of differential diagnoses.


Computational prediction of type III and IV secreted effectors in gram-negative bacteria.
In this review, we provide an overview of the methods employed in four recent studies that described novel methods for computational prediction of secreted effectors from type III and IV secretion systems in Gram-negative bacteria. We present the results of these studies in terms of performance at accurately predicting secreted effectors and similarities found between secretion signals that may reflect biologically relevant features for recognition. We discuss the Web-based tools for secreted effector prediction described in these studies and announce the availability of our tool, the SIEVE server (http://www.sysbep.org/sieve). Finally, we assess the accuracies of the three type III effector prediction methods on a small set of proteins not known prior to the development of these tools that we recently discovered and validated using both experimental and computational approaches. Our comparison shows that all methods use similar approaches and, in general, arrive at similar conclusions. We discuss the possibility of an order-dependent motif in the secretion signal, which was a point of disagreement in the studies. Our results show that there may be classes of effectors in which the signal has a loosely defined motif and others in which secretion is dependent only on compositional biases. Computational prediction of secreted effectors from protein sequences represents an important step toward better understanding the interaction between pathogens and hosts.


Lower limit of cerebral blood flow autoregulation in experimental renovascular hypertension in the baboon.
The effect of chronic renovascular hypertension on the autoregulation of cerebral blood flow was studied in anesthetized baboons. Cerebral blood flow was measured by the intracarotid 133Xe clearance method. Six baboons with renal hypertension of 8-12 weeks' duration were compared with six normotensive controls. The lower limit of autoregulation was determined following controlled hemorrhage. In the initially normotensive baboons, cerebral blood flow remained constant until mean arterial pressure had decreased to the range of 45-59 mm Hg. Thereafter, cerebral blood flow decreased with each further decrease in mean arterial pressure. In the chronically hypertensive baboons cerebral blood flow autoregulated until the mean arterial pressure had decreased to the range of 75-89 mm Hg. Therefore, the lower limit of autoregulation of cerebral blood flow was shifted to higher absolute levels of mean arterial pressure in baboons with chronic renovascular hypertension presumably due to adaptive changes in the cerebral circulation.


The safety of combined triple drug therapy with ivermectin, diethylcarbamazine and albendazole in the neglected tropical diseases co-endemic setting of Fiji: A cluster randomised trial.
Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases.


Effect of Morphological Changes due to Increasing Carbon Nanoparticles Content on the Quasi-Static Mechanical Response of Epoxy Resin.
Mechanical failure in epoxy polymer and composites leads them to commonly be referred to as inherently brittle due to the presence of polymerization-induced microcrack and microvoids, which are barriers to high-performance applications, e.g., in aerospace structures. Numerous studies have been carried out on epoxy's strengthening and toughening via nanomaterial reinforcement, e.g., using rubber nanoparticles in the epoxy matrix of new composite aircraft. However, extremely cautious process and functionalization steps must be taken in order to achieve high-quality dispersion and bonding, the development of which is not keeping pace with large structures applications. In this article, we report our studies on the mechanical performance of an epoxy polymer reinforced with graphite carbon nanoparticles (CNPs), and the possible effects arising from a straightforward, rapid stir-mixing technique. The CNPs were embedded in a low viscosity epoxy resin, with the CNP weight percentage (wt %) being varied between 1% and 5%. Simplified stirring embedment was selected in the interests of industrial process facilitation, and functionalization was avoided to reduce the number of parameters involved in the study. Embedment conditions and timing were held constant for all wt %. The CNP filled epoxy resin was then injected into an aluminum mold and cured under vacuum conditions at 80 °C for 12 h. A series of test specimens were then extracted from the mold, and tested under uniaxial quasi-static tension, compression, and nanoindentation. Elementary mechanical properties including failure strain, hardness, strength, and modulus were measured. The mechanical performance was improved by the incorporation of 1 and 2 wt % of CNP but was degraded by 5 wt % CNP, mainly attributed to the morphological change, including re-agglomeration, with the increasing CNP wt %. This change strongly correlated with the mechanical response in the presence of CNP, and was the major governing mechanism leading to both mechanical improvement and degradation.


The phylogenetic placement of Ostropales within Lecanoromycetes (Ascomycota) revisited.
Results of molecular studies regarding the phylogenetic placement of the order Ostropales and related taxa within Lecanoromycetes were thus far inconclusive. Some analyses placed the order as sister to the rest of Lecanoromycetes, while others inferred a position nested within Lecanoromycetes. We assembled a data set of 101 species including sequences from nuLSU rDNA, mtSSU rDNA, and the nuclear protein-coding RPB1 for each species to examine the cause of incongruencies in previously published phylogenies. MP, minimum evolution, and Bayesian analyses were performed using the combined three-region data set and the single-gene data sets. The position of Ostropales nested in Lecanoromycetes is confirmed in all single-gene and concatenated analyses, and a placement as sister to the rest of Lecanoromycetes is significantly rejected using two independent methods of alternative topology testing. Acarosporales and related taxa (Acarosporaceae group) are basal in Lecanoromycetes. However, if the these basal taxa are excluded from the analyses, Ostropales appear to be sister to the rest of Lecanoromycetes, suggesting different ingroup rooting as the cause for deviating topologies in previously published phylogenies.


Creatine supplementation as an ergogenic aid for sports performance in highly trained athletes: a critical review.
Creatine supplementation has become a common practice among competition athletes participating in different sports over the last few years. The mechanism by which supplementary creatine could have potential ergogenic effects would be an increased muscle creatine and phosphocreatine concentration, leading to a higher rate of ATP resynthesis, a delay in the onset of muscular fatigue and a facilitated recovery during repeated bouts of high-intensity exercise. A critical review of the literature reveals that these ergogenic effects, when found, have been generally shown in untrained subjects performing several exercise bouts under laboratory conditions. The limited body of scientific data available concerning highly trained athletes performing single competition-like exercise tasks indicates that this type of population does not benefit from creatine supplementation. Therefore, the widespread use of creatine ingestion to improve competition performance does not seem to be justified. The potential interest of creatine supplementation for elite athletes could be related to an increased ability to perform repeated high-intensity exercise bouts, either during training or during competition in sports in which repeated efforts are required (e.g. soccer, basketball), but this possibility needs scientific confirmation.


Herbal medicines, other than St. John's Wort, in the treatment of depression: a systematic review.
To evaluate herbal medicines, other than St. John's wort, in the treatment of depression. DATA SOURCES/SEARCH METHODS: A computer-based search of Medline, Cinahl, AMED, ALT Health Watch, Psych Articles, Psych Info, Current Contents databases, Cochrane Controlled Trials Register, and Cochrane Database of Systematic Reviews, was performed. Researchers were contacted, and bibliographies of relevant papers and previous meta-analysis were hand searched for additional references. Trials were included in the review if they were prospective human trials assessing herbal medicines, other than St. John's wort, in the treatment of mild-to-moderate depression and utilized validated instruments to assess participant eligibility and clinical endpoints. Nine trials were identified that met all eligibility requirements. Three studies investigated saffron stigma, two investigated saffron petal, and one compared saffron stigma to the petal. Individual trials investigating lavender, Echium, and Rhodiola were also located. Results of the trials are discussed. Saffron stigma was found to be significantly more effective than placebo and equally as efficacious as fluoxetine and imipramine. Saffron petal was significantly more effective than placebo and was found to be equally efficacious compared to fluoxetine and saffron stigma. Lavender was found to be less effective than imipramine, but the combination of lavender and imipramine was significantly more effective than imipramine alone. When compared to placebo, Echium was found to significantly decrease depression scores at week 4, but not week 6. Rhodiola was also found to significantly improve depressive symptoms when compared to placebo. A number of herbal medicines show promise in the management of mild-to-moderate depression.


The relationship between obsessive compulsive beliefs and symptoms, anxiety and disgust sensitivity, and Swine Flu fears.
Using the 2009 Swine Flu outbreak as a contemporary example of pandemic fears, this study examined the relationship between various symptoms related to anxiety sensitivity and Swine Flu fears. It was hypothesized that both obsessive-compulsive (OC) beliefs and OC symptoms would significantly predict Swine Flu fears. It was also hypothesized that symptoms of anxiety, including measures of anxiety sensitivity and disgust sensitivity would significantly mediate the relationship between both OC beliefs and OC symptoms and Swine Flu fears. A total of 393 undergraduate students completed measures of Swine Flu fears, anxiety sensitivity, OC beliefs and symptoms, and disgust sensitivity. It was found that both OC beliefs and OC symptoms significantly predicted Swine Flu fears. While disgust sensitivity significantly mediated the relationship between both OC beliefs and OC symptoms and Swine Flu fears using the Sobel test, anxiety sensitivity was a significant mediator only for OC symptoms. Additionally, path modeling showed that anxiety sensitivity mediated the relationship between OC symptoms and Swine Flu fears best. The results of this study may be useful for treating individuals suffering from anxiety in light of future pandemics, as well as continuing to research the role of anxiety symptoms in predicting pandemic fears.


Bacteriological survey of ready-to-eat lettuce, fresh-cut fruit, and sprouts collected from the Swiss market.
The consumption of ready-to-eat fresh vegetables has increased significantly in the recent decades. So far, no data are available on the bacteriological burden and the prevalence of foodborne pathogens in ready-to-eat lettuce, fresh-cut fruit, and sprouts on the Swiss market. This study was based on investigations carried out during 2 months of the summer season in 2011. Samples of 142 salads, 64 fresh-cut fruit, and 27 sprouts were included in this study. Escherichia coli, an indicator microorganism for fecal contamination, was only found in 5 lettuce samples, with amounts ranging between 2 and 3 log CFU/g. No Salmonella spp. were detected from any of the 233 samples analyzed in this study, and a low occurrence was found for contamination with L. monocytogenes, Shiga toxin-producing E. coli, enteropathogenic E. coli, and Cronobacter. From the results of the present study, we conclude that even in a country where the use of chlorine solutions to sanitize fruits and vegetables in the fresh-cut industry is not allowed, it is possible to produce ready-to-eat lettuce, fresh-cut fruit, and sprouts with high microbiological standards. Strict maintenance of good practices of hygiene at preharvest, harvest, and postharvest levels is of central importance to ensure both public health protection and product quality.


Efficient production of L-lactic acid from xylose by Pichia stipitis.
Microbial conversion of renewable raw materials to useful products is an important objective in industrial biotechnology. Pichia stipitis, a yeast that naturally ferments xylose, was genetically engineered for l-(+)-lactate production. We constructed a P. stipitis strain that expressed the l-lactate dehydrogenase (LDH) from Lactobacillus helveticus under the control of the P. stipitis fermentative ADH1 promoter. Xylose, glucose, or a mixture of the two sugars was used as the carbon source for lactate production. The constructed P. stipitis strain produced a higher level of lactate and a higher yield on xylose than on glucose. Lactate accumulated as the main product in xylose-containing medium, with 58 g/liter lactate produced from 100 g/liter xylose. Relatively efficient lactate production also occurred on glucose medium, with 41 g/liter lactate produced from 94 g/liter glucose. In the presence of both sugars, xylose and glucose were consumed simultaneously and converted predominantly to lactate. Lactate was produced at the expense of ethanol, whose production decreased to approximately 15 to 30% of the wild-type level on xylose-containing medium and to 70 to 80% of the wild-type level on glucose-containing medium. Thus, LDH competed efficiently with the ethanol pathway for pyruvate, even though the pathway from pyruvate to ethanol was intact. Our results show, for the first time, that lactate production from xylose by a yeast species is feasible and efficient. This is encouraging for further development of yeast-based bioprocesses to produce lactate from lignocellulosic raw material.


Early introduction of complementary foods in preterm infants.
The aim of the present study was to determine the odds of early introduction of solid foods in a nationally representative sample of preterm infants when compared with term infants and to examine whether factors associated with early introduction are the same for preterm and term infants. Our sample of 7650 came from the first wave of the Early Childhood Longitudinal Study, Birth Cohort (2001-2002). We performed multivariable logistic regression to determine whether preterm infants were introduced to solid foods more frequently before 4 months than term infants using adjusted age for preterm infants and chronological age for term infants. In a separate analysis in preterm infants, we used multivariable logistic regression to determine whether the factors associated with early introduction in term infants were the same in the preterm sample. Infants born 22 to 32 weeks' gestation had a 9.90 (95% confidence interval 5.54-18.0) odds of being fed solid food before 4 months compared with term infants, and infants born 33 to 36 weeks' gestation had a 6.19 (95% confidence interval 4.58-8.36) odds. Race/ethnicity and maternal smoking were the only factors that predicted early solid feeding in both preterm and term infants; the remaining predictors differed. Preterm infants are significantly more likely to be introduced to complementary foods early compared with term infants. The predictors of early solid feeding differ for preterm infants. Given the health implications, specific guidelines for preterm infants should be developed and future research should examine predictors of early introduction in preterm infants.


Antegrade perfusion with bacillus Calmette-Guérin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: who may benefit?
There is paucity of data on bacillus Calmette-Guérin (BCG) perfusion in patients with non-muscle-invasive urothelial carcinoma (NMIUC) of the upper urinary tract (UUT). To assess the long-term results of BCG perfusion in patients with UUT NMIUC in terms of efficacy and tolerability. Retrospective analysis of 55 consecutive patients (64 renal units [RUs]) with UUT NMIUC prospectively followed according to a standardised protocol for a median of 42 mo (range: 2-237 mo). Our series includes negatively selected patients, most of whom were not eligible for radical surgery, with additional invasive urothelial carcinoma of the urinary tract in roughly one-third of the cases. Antegrade BCG perfusion of the UUT was performed either with curative intent for carcinoma in situ (Tis; 42 RUs) or with adjuvant intent after ablation of Ta/T1 tumours (22 RUs). Primary outcome measures were recurrence-free, progression-free, and nephroureterectomy-free survival. The secondary outcome measure was treatment tolerability. Recurrence occurred in 30 of 64 RUs (47%), 17 of 42 (40%) with Tis and 13 of 22 (59%) with Ta/T1 tumours. Progression occurred in 11 of 64 RUs (17%), 2 of 42 (5%) with Tis and 9 of 22 (41%) with Ta/T1 tumours. Nephroureterectomy was eventually performed in 7 of 64 RUs (11%), 2 of 42 (5%) with Tis and 5 of 22 (23%) with Ta/T1 tumours. Patients treated with curative intent for Tis tended to have better recurrence-free survival (p=0.42) and significantly better progression-free survival (p<0.01) and nephroureterectomy-free survival (p=0.05) compared with those treated with adjuvant intent after ablation of Ta/T1 tumours. Adverse events, mostly minor, occurred in a total of 11 patients (20%), with one case of fatal Escherichia coli septicaemia. In our patients with UUT NMIUC, antegrade BCG perfusion resulted in a high kidney-preservation rate. Patients treated with curative intent for Tis apparently benefited in terms of local disease control more than those treated with adjuvant intent after ablation of Ta/T1 tumours. Treatment tolerability was good.