Challenges for the Maintenance and Cryopreservation of Multiple Isolates of Model Microorganisms: An Example Using the Marine Diatom Skeletonema marinoi.
Modern genomic and metabolomic tools have provided the possibility of generating and interrogating large datasets that can provide answers to previously imponderable taxonomic, evolutionary, ecological, and physiological questions. However, the curatorial tools needed to provide and maintain the relevant biological resources on which new knowledge can be built have not kept pace with this meteoric rise in scientific capacity, its associated activity, or the huge increase in published science. The availability of biological material of guaranteed identity and quality in Biological Resource Centers is fundamental for scientific research, but it crucially depends on there being adequate preservation/maintenance methods that are capable of ensuring phenotypic, genotypic, and functional security of the biological material(s). This article highlights the challenges to the long-term maintenance of genetic resources in general, focusing specifically on the issues associated with the maintenance of a large collection of strains of the ecologically significant diatom Skeletonema marinoi. This research collection, held at the Department of Marine Sciences, University of Gothenburg, has been systematically tested for its capacity to survive cryopreservation. A method, involving incubation in the dark for 20-24 hours before cryopreservation, followed by cryoprotection employing 10% dimethysulphoxide (DMSO) and conventional cooling in a passive cooler, before plunging into liquid nitrogen was successfully applied to ∼80% of the strains tested. In addition, the growth characteristics of exemplar strains were confirmed after storage.


Human cells lacking coilin and Cajal bodies are proficient in telomerase assembly, trafficking and telomere maintenance.
The RNA component of human telomerase (hTR) localizes to Cajal bodies, and it has been proposed that Cajal bodies play a role in the assembly of telomerase holoenzyme and telomerase trafficking. Here, the role of Cajal bodies was examined in Human cells deficient of coilin (i.e. coilin-knockout (KO) cells), in which no Cajal bodies are detected. In coilin-KO cells, a normal level of telomerase activity is detected and interactions between core factors of holoenzyme are preserved, indicating that telomerase assembly occurs in the absence of Cajal bodies. Moreover, dispersed hTR aggregates and forms foci specifically during S and G2 phase in coilin-KO cells. Colocalization of these hTR foci with telomeres implies proper telomerase trafficking, independent of Cajal bodies. Therefore, telomerase adds similar numbers of TTAGGG repeats to telomeres in coilin-KO and controls cells. Overexpression of TPP1-OB-fold blocks cell cycle-dependent formation of hTR foci and inhibits telomere extension. These findings suggest that telomerase assembly, trafficking and extension occur with normal efficiency in Cajal bodies deficient human cells. Thus, Cajal bodies, as such, are not essential in these processes, although it remains possible that non-coilin components of Cajal bodies and/or telomere binding proteins (e.g. TPP1) do play roles in telomerase biogenesis and telomere homeostasis.


Physiological responses of horses to 24 hours of transportation using a commercial van during summer conditions.
Fifteen mature horses (mares, n = 6); geldings, n = 9) were used to assess the physiological responses of 24 h of transport in a commercial van under California summer conditions. The study was conducted on four consecutive days, and data were collected on d 1 and d 2 to obtain baseline values and to determine any diurnal variation in the individual measurements. Travel commenced on d 3 at 0800 for 24 h, with a total of 1,622 km traveled. Blood samples were collected at 0800, 1100, 1400, 2000, and 0200 each day. Horses were weighed and rectal temperatures recorded at 0800 each day and at 2000 each day except d 3. Body weight, rectal temperature, serum cortisol, serum lactate, and white blood cell (WBC) counts exhibited diurnal variation (P = .0001) on d 1 and d 2. Body weight immediately after unloading showed a 6% loss. At 24 h following transit, a 3% deficiency in body weight loss remained. The WBC counts showed a progressive increase with duration of travel and peaked at the termination of transport. Dehydration measures of hematocrit and total protein increased during transport and returned to baseline during the posttransport period. Serum concentrations of lactate, creatine kinase and aspartate aminotransferase increased during transport and in the early posttransit period, but returned to baseline values at the conclusion of the 24-h posttransport period. Glucose concentration increased with the initiation of transport and did not decrease to baseline concentration at the end of the 24-h posttransport period. Plasma cortisol and neutrophil:lymphocyte ratio increased with duration of transit and returned to baseline during the posttransport period. These data clearly showed physiological responses of horses undergoing 24 h of transport including changes in muscle metabolism, stress indices, dehydration and immune parameters, and body weight. These responses may increase disease susceptibility and influence energy availability for athletic performance following long-term transport of horses.


Differential kinetics of oxytocin and vasopressin heteronuclear RNA expression in the rat supraoptic nucleus in response to chronic salt loading in vivo.
Previous studies have shown that the secretion of oxytocin and vasopressin from the posterior pituitary always accompanies systemic hyperosmotic stimuli in rats, and that oxytocin and vasopressin mRNAs consistently increase in response to prolonged hyperosmotic stimuli. Hence, it has been widely interpreted that oxytocin and vasopressin secretion and gene expression are closely coupled. In the present study, we used both vasopressin and oxytocin intron- specific probes to measure vasopressin and oxytocin heteronuclear RNA (hnRNA) levels, respectively, by in situ hybridisation in the rat supraoptic nucleus (SON) in conjunction with radioimmunoassays of vasopressin and oxytocin peptide levels in plasma and in the posterior pituitary in normally hydrated rats and after 1-5 days of salt loading. Increased oxytocin secretion in response to hyperosmotic stimuli exceeded vasopressin secretion at every time point studied. Vasopressin hnRNA in the SON increased to near maximal levels within minutes after the hyperosmotic stimulus, and was maintained throughout all 5 days of salt loading. By contrast, oxytocin hnRNA did not significantly change from control levels until approximately 2 days after hyperosmotic stimulation, and was not maximal until 3 days. In summary, increases in oxytocin gene transcription in response to osmotic stimuli are dramatically delayed compared to increases in vasopressin gene transcription under the same conditions. These data indicate that oxytocin gene transcription is not as closely correlated with pituitary peptide secretion as is vasopressin gene transcription, and suggests that there is a fundamental difference in excitation-secretion-transcription coupling mechanisms that regulate these two closely related genes in the rat magnocellular neurones in the SON.


Active Flow Control on Vertical Tail Models.
Active flow control (AFC) subscale experiments were conducted at the Lucas Wind Tunnel of the California Institute of Technology. Tests were performed on a generic vertical tail model at low speeds. Fluidic oscillators were used at the trailing edge of the main element (vertical stabilizer) to redirect the flow over the rudder and delay or prevent flow separation. Side force increases in excess of 50% were achieved with a 2% momentum coefficient (C μ ) input. The results indicated that a collective C μ of about 1% could increase the side force by 30-50%. This result is achieved by reducing the spanwise flow on the swept back wings that contributes to early flow separation near their tips. These experiments provided the technical backdrop to test the full-scale Boeing 757 vertical tail model equipped with a fluidic oscillator system at the National Full-scale Aerodynamics Complex 40-by 80-foot Wind Tunnel, NASA Ames Research Center. The C μ is shown to be an important parameter for scaling a fluidic oscillator AFC system from subscale to full-scale wind tunnel tests. The results of these tests provided the required rationale to use a fluidic oscillator AFC configuration for a follow-on flight test on the Boeing 757 ecoDemonstrator.


Partitioning of interaction-induced nonlinear optical properties of molecular complexes. II. Halogen-bonded systems.
Following our study on hydrogen-bonded (HB) complexes [Phys. Chem. Chem. Phys., 2018, 20, 19841], the physical nature of interaction-induced (non)linear optical properties of another important class of molecular complexes, namely halogen-bonded (XB) systems, was analyzed in this study. The excess electronic and nuclear relaxation (hyper)polarizabilities of nine representative XB complexes covering a wide range of halogen-bond strengths were computed. The partitioning of the excess properties into individual interaction-energy components (electrostatic, exchange, induction, dispersion) was performed by using the variational-perturbational energy decomposition scheme at the MP2/aug-cc-pVTZ level of theory and further supported by calculations with the SCS-MP2 method. In the case of the electronic interaction-induced properties, the physical composition of Δαel and Δγel was found to be very similar for the two types of bonding, despite the different nature of the binding. For Δβel, the XB complexes exhibit a more systematic interplay of interaction-energy contributions compared to the HB systems studied in the previous work. Our analysis revealed that the patterns of interaction-energy contributions to the interaction-induced nuclear-relaxation contributions to the linear polarizability and the first hyperpolarizability are very similar. For both properties the exchange repulsion term is canceled out by the electrostatic and delocalization terms. The physical composition of these contributions is analogous to those observed for the HB complexes.


A two year study of verified spider bites in Switzerland and a review of the European spider bite literature.
During a two-year study, all spider bites recorded by Swiss primary care physicians were reported to the Swiss Toxicological Information Centre and all collected spiders were identified. A total of 14 verified spider bites were recorded, involving five species from four families: Zoropsis spinimana (five cases), Cheiracanthium punctorium (four cases), Tegenaria atrica (three cases) and one case of Malthonica ferruginea (= Tegenaria ferruginea) (both Agelenidae), and one case of Amaurobius ferox (Amaurobiidae). The bites of all spider species produced relatively mild symptoms. Local symptoms such as moderate to severe pain, circumscribed swelling and redness were the only effects in most cases. Systemic symptoms were rare. There was complete recovery in all cases and all lesions healed completely without further damage or secondary disorders. Following a review of the European spider bite literature, the number of spider species capable of biting humans in Europe is considered to be much larger than could be concluded from this study. Most spider bites are restricted to species living synanthropically, thus promoted by climate and habitat change. The annual frequency of spider bites in Switzerland is estimated at 10-100 bites per million inhabitants, but this is predicted to increase due to the continuous arrival of new alien species, many of which have a high potential to establish in urban areas.


Prediabetic changes in gene expression induced by aspartame and monosodium glutamate in Trans fat-fed C57Bl/6 J mice.
The human diet has altered markedly during the past four decades, with the introduction of Trans hydrogenated fat, which extended the shelf-life of dietary oils and promoted a dramatic increase in elaidic acid (Trans-18.1) consumption. Food additives such as monosodium glutamate (MSG) and aspartame (ASP) were introduced to increase food palatability and reduce caloric intake. Nutrigenomics studies in small-animal models are an established platform for analyzing the interactions between various macro- and micronutrients. We therefore investigated the effects of changes in hepatic and adipose tissue gene expression induced by the food additives ASP, MSG or a combination of both additives in C57Bl/6 J mice fed a Trans fat-enriched diet. Hepatic and adipose tissue gene expression profiles, together with body characteristics, glucose parameters, serum hormone and lipid profiles were examined in C57Bl/6 J mice consuming one of the following four dietary regimens, commencing in utero via the mother's diet: [A] Trans fat (TFA) diet; [B] MSG + TFA diet; [C] ASP + TFA diet; [D] ASP + MSG + TFA diet. Whilst dietary MSG significantly increased hepatic triglyceride and serum leptin levels in TFA-fed mice, the combination of ASP + MSG promoted the highest increase in visceral adipose tissue deposition, serum free fatty acids, fasting blood glucose, HOMA-IR, total cholesterol and TNFα levels. Microarray analysis of significant differentially expressed genes (DEGs) showed a reduction in hepatic and adipose tissue PPARGC1a expression concomitant with changes in PPARGC1a-related functional networks including PPARα, δ and γ. We identified 73 DEGs common to both adipose and liver which were upregulated by ASP + MSG in Trans fat-fed mice; and an additional 51 common DEGs which were downregulated. The combination of ASP and MSG may significantly alter adiposity, glucose homeostasis, hepatic and adipose tissue gene expression in TFA-fed C57Bl/6 J mice.


High-quality draft genome sequence of Rhizobium mesoamericanum strain STM6155, a Mimosa pudica microsymbiont from New Caledonia.
Rhizobium mesoamericanum STM6155 (INSCD = ATYY01000000) is an aerobic, motile, Gram-negative, non-spore-forming rod that can exist as a soil saprophyte or as an effective nitrogen fixing microsymbiont of the legume Mimosa pudica L.. STM6155 was isolated in 2009 from a nodule of the trap host M. pudica grown in nickel-rich soil collected near Mont Dore, New Caledonia. R. mesoamericanum STM6155 was selected as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) genome sequencing project. Here we describe the symbiotic properties of R. mesoamericanum STM6155, together with its genome sequence information and annotation. The 6,927,906 bp high-quality draft genome is arranged into 147 scaffolds of 152 contigs containing 6855 protein-coding genes and 71 RNA-only encoding genes. Strain STM6155 forms an ANI clique (ID 2435) with the sequenced R. mesoamericanum strain STM3625, and the nodulation genes are highly conserved in these strains and the type strain of Rhizobium grahamii CCGE501T. Within the STM6155 genome, we have identified a chr chromate efflux gene cluster of six genes arranged into two putative operons and we postulate that this cluster is important for the survival of STM6155 in ultramafic soils containing high concentrations of chromate.


Consistent estimation of Gibbs energy using component contributions.
Standard Gibbs energies of reactions are increasingly being used in metabolic modeling for applying thermodynamic constraints on reaction rates, metabolite concentrations and kinetic parameters. The increasing scope and diversity of metabolic models has led scientists to look for genome-scale solutions that can estimate the standard Gibbs energy of all the reactions in metabolism. Group contribution methods greatly increase coverage, albeit at the price of decreased precision. We present here a way to combine the estimations of group contribution with the more accurate reactant contributions by decomposing each reaction into two parts and applying one of the methods on each of them. This method gives priority to the reactant contributions over group contributions while guaranteeing that all estimations will be consistent, i.e. will not violate the first law of thermodynamics. We show that there is a significant increase in the accuracy of our estimations compared to standard group contribution. Specifically, our cross-validation results show an 80% reduction in the median absolute residual for reactions that can be derived by reactant contributions only. We provide the full framework and source code for deriving estimates of standard reaction Gibbs energy, as well as confidence intervals, and believe this will facilitate the wide use of thermodynamic data for a better understanding of metabolism.


Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction.
Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases.


Baroreflex failure syndrome: a rare complication of bilateral carotid body tumor excision.
Baroreflex failure syndrome is a rare disorder seen after bilateral carotid body tumor resection. Iatrogenic injuries to the baroreceptor reflex arc cause fluctuations in blood pressure with hypertensive attacks or hypotensive episodes. A 43-year-old woman underwent bilateral carotid body tumor resection with one-week interval for a hypervascular tumor, 78 x 50 x 45 mm in size, at the right carotid artery bifurcation and a smaller tumor (50 x 30 x 20 mm) in the contralateral neck. Blood pressure of the patient became significantly unstable after excision of the second tumor, with hypertensive attacks up to 220/140 mmHg, accompanied by episodes of severe frontal headache, nausea, vomiting, skin flushing, and synchronous sinus tachycardia of 130 beats/min. Intermittent episodes of hypotension and bradycardia were also noted. The patient was clinically diagnosed as having baroreflex failure syndrome. The symptoms of the patient improved with medical therapy including clonidine, low dose beta-blocker, metoprolol, and a sedative. During 10 months of follow-up, she was generally well with residual episodes of hypertension about twice a month. In patients with bilateral carotid body tumors, unilateral excision of the greater tumor and a conservative approach for the contralateral tumor seem to be a more convenient approach to prevent baroreflex failure.


Effects of HIV antiretroviral therapy on sexual and injecting risk-taking behavior: a systematic review and meta-analysis.
Increased global access and use of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) has been postulated to undermine HIV prevention efforts by changing individual risk-taking behavior. This review aims to determine whether ART use is associated with changes in sexual or injecting risk-taking behavior or diagnosis of sexually transmitted infections (STIs). A systematic review and meta-analysis was conducted of HIV-seropositive participants receiving ART compared with no ART use in experimental or observational studies. Primary outcomes included (1) any unprotected sexual intercourse, (2) STI diagnoses, and (3) any unsafe injecting behavior. Fifty-eight studies met the selection criteria. Fifty-six studies containing 32 857 participants reported unprotected sex; 11 studies containing 16 138 participants reported STI diagnoses; and 4 studies containing 1600 participants reported unsafe injecting behavior. All included studies were observational. Unprotected sex was lower in participants receiving ART than in those not receiving ART (odds ratio [OR], 0.73; 95% confidence interval [CI], .64-.83; P < .001; heterogeneity I(2) = 79%) in both high-income (n = 38) and low-/middle-income country (n = 18) settings, without any evidence of publication bias. STI diagnoses were also lower among individuals on ART (OR, 0.58; 95% CI, .33-1.01; P = .053; I(2) = 92%); however, there was no difference in injecting risk-taking behavior with antiretroviral use (OR, 0.90; 95% CI, .60-1.35; P = .6; I(2) = 0%). Despite concerns that use of ART might increase sexual or injecting risk-taking, available research suggests that unprotected sex is reduced among HIV-infected individuals on treatment. The reasons for this are not yet clear, although self-selection and mutually reinforcing effects of HIV treatment and prevention messages among people on ART are likely.


Cross-Talk between Adiponectin and IGF-IR in Breast Cancer.
Obesity is a chronic and multifactorial disorder that is reaching epidemic proportions. It is characterized by an enlarged mass of adipose tissue caused by a combination of size increase of preexisting adipocytes (hypertrophy) and de novo adipocyte differentiation (hyperplasia). Obesity is related to many metabolic disorders like hypertension, type 2 diabetes, metabolic syndrome, and cardiovascular disease, and it is associated with an increased risk of cancer development in different tissues including breast. Adipose tissue is now regarded as not just a storage reservoir for excess energy, but rather as an endocrine organ, secreting a large number of bioactive molecules called adipokines. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin sensitizing, anti-inflammatory, and antiatherogenic properties. The serum concentrations of adiponectin are inversely correlated with body mass index. Recently, low levels of plasma adiponectin have been associated with an increased risk for obesity-related cancers and development of more aggressive phenotype, concomitantly with alterations in the bioavailability of insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR) signaling pathways. In this review, we discuss the cross-talk between adiponectin/AdipoR1 and IGF-I/IGF-IR in breast cancer.


Quantitation of cellular dynamics in growing Arabidopsis roots with light sheet microscopy.
To understand dynamic developmental processes, living tissues have to be imaged frequently and for extended periods of time. Root development is extensively studied at cellular resolution to understand basic mechanisms underlying pattern formation and maintenance in plants. Unfortunately, ensuring continuous specimen access, while preserving physiological conditions and preventing photo-damage, poses major barriers to measurements of cellular dynamics in growing organs such as plant roots. We present a system that integrates optical sectioning through light sheet fluorescence microscopy with hydroponic culture that enables us to image, at cellular resolution, a vertically growing Arabidopsis root every few minutes and for several consecutive days. We describe novel automated routines to track the root tip as it grows, to track cellular nuclei and to identify cell divisions. We demonstrate the system's capabilities by collecting data on divisions and nuclear dynamics.


Describing and mapping human-induced vegetation change in the Australian landscape.
Australian reporting requirements for native vegetation require improved spatial and temporal information on the anthropogenic effects on vegetation. This includes better linkage of information on vegetation type (e.g., native vegetation association), extent and change, vegetation condition, or modification. The Vegetation Assets, States and Transitions (VAST) framework is presented as a means for ordering vegetation by degree of anthropogenic modification as a series of condition states, from a residual or base-line condition through to total removal. The VAST framework facilitates mapping and accounting for change and trends in the status and condition of vegetation. The framework makes clear the links between land management and vegetation condition states, provides a mechanism for describing the consequences of land management practices on vegetation condition, and contributes to an understanding of resilience. VAST is a simple communication and reporting tool designed to assist in describing and accounting for anthropogenic modification of vegetation. A benchmark is identified for each vegetation association. Benchmarks are based on structure, composition, and current regenerative capacity. This article describes the application of the VAST framework as a consistent national framework to translate and compile existing mapped information on the modification of native vegetation. We discuss the correspondence between these compiled VAST datasets at national and regional scales and describe their relevance for natural resource policy and planning.


A review of patient-reported outcome labels in the United States: 2006 to 2010.
In 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drugs approved in the United States from 1997 through 2002 to evaluate the use of patient-reported outcome (PRO) endpoints. Of the labels reviewed, 30% included PROs. Our study aimed to build on this work by describing the current state of PRO label claims granted for new molecular entities (and biologic license applications since February 2006 after the release of the US Food and Drug Administration (FDA) draft PRO guidance. All new molecular entities and biologic license applications approved by the FDA from January 2006 through December 2010 were identified by using the Web page of the FDA Drug Approval Reports. For all identified products, drug approval packages and approved product labels were reviewed to identify PRO endpoint status and to determine the number and type of PRO claims. Of the 116 products identified, 28 (24%) were granted PRO claims; 24 (86%) were for symptoms, and, of these, 9 (38%) claims were pain related. Of the 28 products with PRO claims, a PRO was a primary endpoint for 20 (71%), all symptom related. The FDA continues to approve PRO claims, with 24% of new molecular entities and biologic license applications being granted. Successful PRO label claims over the past 5 years have generally supported treatment benefit for symptoms specified as primary endpoints.


Interactions with the pharmaceutical industry: a survey of family medicine residents in Ontario.
To determine the attitudes, knowledge and practices of family medicine residents relating to the pharmaceutical industry and to assess the effectiveness of existing guidelines on appropriate interactions with the pharmaceutical industry. Survey by mailed questionnaire. Ontario. All 262 second-year family medicine residents in Ontario (seven centres); 226 (86.3%) responded. Fifty-two (23.0%) of the residents who responded stated that they had read the CMA policy statement on appropriate interactions between physicians and the pharmaceutical industry. A total of 124 (54.9%) stated that they would attend a private dinner paid for by a pharmaceutical representative; the proportion was not significantly reduced among those who had read the CMA guidelines, which prohibit the acceptance of personal gifts. In all, 186 (82.3%) reported that they would like the opportunity to interact with pharmaceutical representatives in an educational setting, even though several programs now discourage these interactions. Approximately three quarters (172/226 [76.1%]) of the residents indicated that they plan to see pharmaceutical representatives in their future practice. Residents at Centre 2 were significantly more critical of the pharmaceutical industry than those from the other centres. Overall, being aware of, and familiar with, departmental policy or CMA policy on interactions with the pharmaceutical industry did not affect the residents' attitudes or intended future practices. The presence of guidelines concerning physicians' interactions with the pharmaceutical industry does not appear to have a significant impact on family medicine residents in Ontario.


Curcumin reduces oxidative and nitrative DNA damage through balancing of oxidant-antioxidant status in hamsters infected with Opisthorchis viverrini.
Opisthorchis viverrini (OV) infection is endemic in northeastern Thailand. We have previously reported that OV infection induces oxidative and nitrative DNA damage via chronic inflammation, which contributes to the disease and cholangiocarcinogenesis. Here, we examined the effect of curcumin, an antioxidant, on pathogenesis in OV-infected hamsters. DNA lesions were detected by double immunofluorescence and the hepatic expression of oxidant-generating and antioxidant genes was assessed by quantitative RT-PCR analysis. Dietary 1.0% curcumin significantly decreased OV-induced accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidative DNA lesion, and 8-nitroguanine, a nitrative DNA lesion, in the nucleus of bile duct epithelial and inflammatory cells. Expression of oxidant-generating genes (inducible nitric oxide synthase; iNOS, its nuclear transcriptional factor, NF-kappaB, and cyclooxygenase-2), and plasma levels of nitrate, malondialdehyde, and alanine aminotransferase, were also decreased in curcumin-treated group. In contrast, curcumin increased the mRNA expression of antioxidant enzymes (Mn-superoxide dismutase and catalase), and ferric-reducing anti-oxidant power in the plasma. In conclusion, curcumin reduced oxidative and nitrative DNA damage by suppression of oxidant-generating genes and enhancement of antioxidant genes, leading to inhibition of oxidative and nitrative stress. Therefore, curcumin may be used as a chemopreventive agent to reduce the severity of OV-associated diseases and the risk of cholangiocarcinoma (CCA).


Next-generation nanotechnology laboratories with simultaneous reduction of all relevant disturbances.
The tremendous variety of nanotechnology experiments and tools to fabricate and characterize ever-smaller structures down to molecular or even atomic scales leads to stringent demands for appropriate, so-called "silent", premises that allow such susceptible experiments to be conducted. Reducing dimensions means smaller absolute optical and electrical signal levels, and consequently reduced signal-to-noise ratios. Hence, in addition to short-range disturbances inside the laboratory, remote long-range noise sources have to be considered for next-generation laboratories that aim at screening the disturbances and keeping the remaining values at utmost constancy. We present a novel laboratory concept that addresses simultaneously all the disturbances relevant for nanotechnology, namely, vibrations, electro-magnetic fields, temperature, humidity, and sound. Particular attention was paid to tackling the mutual derogation of the various measures to enable unprecedented performance of the novel research platform.


The clinical effectiveness and cost-effectiveness of primary stroke prevention in children with sickle cell disease: a systematic review and economic evaluation.
Sickle cell disease (SCD) is a recessive genetic blood disorder, caused by a mutation in the β-globin gene. For children with SCD, the risk of stroke is estimated to be up to 250 times higher than in the general childhood population. Transcranial Doppler (TCD) ultrasonography is a non-invasive technique which measures local blood velocity in the proximal portions of large intracranial arteries. Screening with TCD ultrasonography identifies individuals with high cerebral blood velocity; these children are at the highest risk of stroke. A number of primary stroke prevention strategies are currently used in clinical practice in the UK including blood transfusion, treatment with hydroxycarbamide and bone marrow transplantation (BMT). No reviews have yet assessed the clinical effectiveness and cost effectiveness of primary stroke prevention strategies in children with SCD identified to be at high risk of stroke using TCD ultrasonography. To assess the clinical effectiveness and cost-effectiveness of primary stroke prevention treatments for children with SCD who are identified (using TCD ultrasonography) to be at high risk of stroke. Electronic databases were searched from inception up to May 2011, including the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), EMBASE, the Health Technology Assessment (HTA) database, ISI Web of Science Proceedings, ISI Web of Science Citation Index, the NHS Economic Evaluation Database (NHS EED) and MEDLINE. The assessment was conducted according to accepted procedures for conducting and reporting systematic reviews and economic evaluations. A de novo Markov model was developed to determine the cost-effectiveness of TCD ultrasonography and blood transfusion, where clinically appropriate, in patients with SCD. Two randomised controlled trials met the inclusion criteria involving a study population of 209 participants. One compared blood transfusion with standard care for children who are identified as being at high risk of stroke using TCD ultrasonography. In this trial, one patient in the transfusion group had a stroke (1/63) compared with 11 children in the standard care group (11/67). The other trial assessed the impact of halting chronic transfusion in patients with SCD. Sixteen patients in the transfusion-halted group had an event (16/41) (two patients experienced stroke and 14 reverted to abnormal TCD velocity); there were no events in the continued-transfusion group (0/38). No meta-analyses of these trials were undertaken. No relevant economic evaluations were identified for inclusion in the review. The de novo modelling suggests that blood transfusions plus TCD scans (compared with just TCD scans) for patients with SCD at high risk of stroke, aged ≥ 2 years, may be good value for money. The intervention has an incremental cost-effectiveness ratio of £24,075 per quality-adjusted life-year gained, and helps avoid 68 strokes over the lifetime of a population of 1000 patients. The intervention costs an additional £13,751 per patient and generates 0.6 extra years of life in full health per patient. The data available for the economic analysis are limited. Sensitivity analyses and validation against existing data and expert opinion provide some reassurance that the conclusion of the model is reliable but further research is required to validate these findings. The main limitations relate to the availability of published clinical data; no completed randomised controlled trials were identified which evaluated the efficacy of either BMT or hydroxycarbamide for primary stroke prevention. Both the clinical and cost data available for use in the economic analysis are limited. Sensitivity analyses and validation against existing data and expert opinion provide some reassurance that the conclusions of the model are reliable, but further research is required to validate these findings. The use of TCD ultrasonography to identify children at high risk of stroke, and treating these children with prophylactic blood transfusions, appears to be both clinically effective and cost-effective compared with TCD ultrasonography only. However, given the limitations in the data available, further research is required to verify this conclusion. Several research recommendations can be proposed from this review. Clinically, more research is needed to assess the effects and optimal duration of long-term blood transfusion and the potential role of hydroxycarbamide in primary stroke prevention. From an economics perspective, further research is required to generate more robust data on which to base estimates of cost-effectiveness or against which model outputs can be calibrated. More data are required to explain how utility weights vary with age, transfusions and strokes. Research is also needed around the cost of paediatric stroke in the UK. PROSPERO CRD42011001496. The National Institute for Health Research Health Technology Assessment programme.


Improving emotion regulation with CBT in young children with high functioning autism spectrum disorders: a pilot study.
This pilot study tested the efficacy of a developmentally modified CBT for young children with Autism Spectrum Disorders (ASD) to teach emotion regulation strategies for reducing anger and anxiety, commonly noted problems in this population. Eleven 5-7 year-old children participated in a CBT-group while parents participated in psychoeducation. Children were randomly assigned to an experimental or delayed-treatment control group. From pre- to post-treatment, all children had less parent reported negativity/lability, better parent reported emotion regulation, and shorter outbursts, and also generated more coping strategies in response to vignettes. Parents also reported increases in their own confidence and their child's ability to deal with anger and anxiety. This study suggests that young children with high functioning ASD may benefit from CBT to improve regulation of anger and anxiety, and parent training may improve parental self-efficacy. Future studies are needed to make conclusions about its efficacy.


Shared and dissociable features of apathy and reward system dysfunction in bipolar I disorder and schizophrenia.
Bipolar disorder I (BD-I) is defined by episodes of mania, depression and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood. We first assessed the severity of NS in 25 euthymic BD-I patients compared with 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral (VS) and dorsal striatal (DS) activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS. In BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant VS and DS activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole-brain analyses revealed reduced extra-striatal activation in BD-I patients compared with HC and an association between reduced activation of the inferior frontal gyrus and apathy. This study found that in BD-I patients apathy is present to an extent comparable to SZ, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.


Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis.
CDC 25 is a dual phosphatase responsible for dephosphorylation and, thus, activation of CDC 2 kinase in G2. Abnormal activation of cyclin B-associated CDC 2 kinase has been implicated in apoptosis induced by cancer chemotherapeutic agents such as paclitaxel (Taxol) and etoposide (VP-16). In this study, we found that the CDC 2 kinase could be transiently activated when nasopharyngeal carcinoma NPC-TW01 cells were treated for 3 h with a new anticancer agent, GL331. GL331 treatment also induced a concomitant increase in CDC 25A phosphatase activity and a reduced level of Tyr-15-phosphorylated CDC 2 in NPC-TW01 cells. Furthermore, subsequent apoptotic DNA fragmentation induced by GL331 could be interrupted by treatment of the cells with the cyclin B1-specific antisense oligonucleotides, suggesting that abnormal activation of cyclin B1-associated CDC 2 kinase and CDC 25A phosphatase was involved in GL331-induced apoptosis. Raf-1 has been shown to associate with CDC 25A and, thus, to stimulate its phosphatase activity. Our results revealed that GL331 could facilitate the association of CDC 25A with Raf-1, resulting in the cascade of CDC 25A phosphatase activation and CDC 2 kinase activation, as well as related signaling pathways, and ultimately causing apoptosis in cancer cells.


Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis.
The inflammatory response to Mycobacterium tuberculosis (M.tb) at the site of disease is Th1 driven. Whether the Th17 cytokines, IL-17 and IL-22, contribute to this response in humans is unknown. We hypothesized that IL-17 and IL-22 contribute to the inflammatory response in pleural and pericardial disease sites of human tuberculosis (TB). We studied pleural and pericardial effusions, established TB disease sites, from HIV-uninfected TB patients. Levels of soluble cytokines were measured by ELISA and MMP-9 by luminex. Bronchoalveolar lavage or pericardial mycobacteria-specific T cell cytokine expression was analyzed by intracellular cytokine staining. IL-17 was not abundant in pleural or pericardial fluid. IL-17 expression by mycobacteria-specific disease site T cells was not detected in healthy, M.tb-infected persons, or patients with TB pericarditis. These data do not support a major role for IL-17 at established TB disease sites in humans. IL-22 was readily detected in fluid from both disease sites. These IL-22 levels exceeded matching peripheral blood levels. Further, IL-22 levels in pericardial fluid correlated positively with MMP-9, an enzyme known to degrade the pulmonary extracellular matrix. We propose that our findings support a role for IL-22 in TB-induced pathology or the resulting repair process.


Electrochemistry and bioactivity relationship of 6-substituted-4H-pyrido[4,3,2-kl]acridin-4-one antitumor drug candidates.
We report here the electrochemical characterization of eight synthetic DNA intercalators based on the 4H-pyrido[4,3,2-kl]acridin-4-one structure. We found that the electrochemical behavior of these redox active drugs is strongly influenced by the nature of the solvent. A single two-electron reduction is observed in an aqueous phosphate buffer (PB) whereas two successive one-electron reductions are observed in aprotic solution (acetonitrile). The influence of the molecular structure on the potential values is addressed along with a comparison between the DNA binding constant (K(DNA)) and the cytotoxic activity against HT29 cells (IC(50)). For typical DNA intercalators, one could expect that toxicity will be roughly proportional to the DNA binding constant. Yet, a structure/activity comparison solely based on the DNA affinity was not conclusive. In contrast, a direct relationship was evidenced for the first time between the decimal logarithm of the in vitro bioactivity and the reduction potential of pyridoacridones recorded in PB at pH 7.0. Moreover, most of the bio/electrochemical relationships previously described for quinone-based drugs were reported with electrochemical characterization in aprotic solvents (typically acetonitrile, dimethylformamide or dimethylsulfoxide). But aqueous solution electrochemistry is definitely the most bio-relevant because the redox mechanism of quinone or iminoquinone reduction directly depends on the protic nature of the solvent.


Freeze desalination of seawater using LNG cold energy.
With the aid of cold energy from regasification of liquefied natural gas (LNG), freeze desalination (FD) is an emerging technology for seawater desalination because of its low energy characteristics and insensitivities to fouling problems. This work aims to investigate the major operating parameters of FD such as coolant temperature, freezing duration, supercooling, seeding, agitation, crystallizer material and subsequent washing procedure on ice production and water quality. It was found that the optimal freezing duration per batch was 1 h for an iron crystallizer and 1.5 h for a glass crystallizer. The optimal coolant temperature should be around -8 °C. The optimal amount of washing water to clean the raw ice was about 50 wt% of the raw ice. Over 50 wt% of the feed could be recovered as raw ice within 1 h, which means an overall ice recovery rate of higher than 25% (of the original seawater), considering the consumption of washing water. Both artificial and real seawater were tested under the optimized conditions. The total dissolved solid in the product ice was around 300 ppm, which met the World Health Organization (WHO) potable water salinity standard of 500 ppm. Therefore, the process parameters optimized in this study can be directly used for the freeze desalination of seawater.


[Two new species of Phrynopus (Anura: Leptodactylidae) from the Bolivian cloud forests].
We describe two new species of Phrynopus from cloud forests in Cochabamba, Bolivia. The new species are assigned to the P. peruanus group and are characterized by the presence of basal webbing, distinctive coloration, and by having the first finger shorter than the second. The first of these new species was collected near Montepunko in Parque Nacional Carrasco and is known from eight males and six females. Among its distinctive characteristics are round cream-colored glands on its flanks. A second species is known from one male and one female collected near "Zona de Aguirre" near the northwest border of the park. V and X-shaped blotches and a dorsum that is smooth except for dorsolateral and scapular folds characterize this species. Musculature has rarely been described for species of Phrynopus. The species from Montepunko has unusual gular and thigh musculature that is quite unlike other species of the genus.


Melatonin receptor genes in vertebrates.
Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.


Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function.
Presynaptic metabotropic glutamate receptors (mGluRs) often act as feedback inhibitors of synaptic transmission and serve important roles in defining the activity of glutamatergic synapses. Recent investigations have begun to identify novel interactions of presynaptic mGluRs, especially mGluR7, with multiple protein kinases and putative regulatory proteins that probably serve to further shape the overall activity of glutamatergic synapses. In the present study, we report that in addition to protein kinase C (PKC), cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) can inhibit calmodulin (CaM) interactions with the carboxyl-terminal tail of mGluR7. These actions are mediated by PKC-, PKA-, or PKG-dependent phosphorylation of mGluR7 at a single serine residue, Ser(862), in the carboxyl terminus of the receptor. Mutation of this residue inhibits kinase-mediated phosphorylation of the mGluR7 carboxyl terminus and reverses kinase-mediated inhibition of CaM binding to mGluR7. However, PKC-mediated inhibition of the functional coupling of mGluR7 to G protein-coupled inward rectifier potassium (GIRK) currents in a heterologous expression system is not affected by mutating Ser(862). Furthermore, mutation of Ser(862) to glutamate to mimic receptor phosphorylation and inhibit CaM interactions with mGluR7 does not affect receptor function. These studies demonstrate that the ability of these second messenger-dependent kinases to inhibit mGluR7-mediated activation of GIRK current is not dependent on the phosphorylation of Ser(862) or the regulation of CaM binding to mGluR7. Furthermore, our studies suggest that CaM binding is not required for mGluR7-mediated activation of GIRK current.


Development and initial validation of the interprofessional team learning profiling questionnaire.
Informal workplace interprofessional learning occurs as health professionals interact with each other as part of everyday work practice. Participation in interprofessional team meetings is a practical way to foster learning. However, a gap exists in the availability of a reliable and valid instrument that adequately captures the nuances of informal workplace interprofessional learning in this setting. The purpose of this study was to develop a questionnaire to measure the different components of interprofessional learning that contribute to the quality of interprofessional learning within the interprofessional team meeting. Questionnaire items were developed from a review of the literature and interviews with health professionals. Exploratory factor analysis was used to determine the underlying factor structure. Two hundred and eighty-five health professionals completed a 98-item questionnaire. After elimination of unreliable items, the remaining items (n = 41) loaded onto four factors named personal and professional capacity; turning words into action-"walk the talk"; the rhetoric of interprofessional learning-"talk the talk"; and inclusiveness. Internal consistency was high for all sub-scales (Cronbach's alpha 0.91, 0.87, 0.83, and 0.83, respectively). Content, construct, and concurrent validity were assessed. The instrument developed in this study indicated consistency and robust psychometric properties. Future studies that further test the psychometric properties of the questionnaire will help to establish the usefulness of this measure in establishing evidence for the perceived effectiveness of interprofessional learning in a healthcare setting.


Alcohol consumption, cigarette smoking, and risk of benign prostatic hyperplasia.
Alcohol consumption and cigarette smoking were evaluated in relation to development of benign prostatic hyperplasia (BPH) among 29,386 members of the Health Professionals Follow-up Study. Men who were 40-75 years old in 1986 and free of prior BPH surgery, diagnosed cancer at baseline, and prostate cancer at baseline and during follow-up were followed for incidence of BPH surgery from 1986 to 1994. Cases were men who reported BPH surgery between 1986 and 1994 (n = 1,813) or who scored > or = 15 points of 35 on seven lower urinary tract symptom questions modified from the American Urological Association symptom index in 1992 and 1994 (n = 1,786); noncases were men who scored < or = 7 points (n = 20,840). After controlling for age, race/ethnicity, body mass index, physical activity, and mutually for alcohol intake and smoking, moderate alcohol consumption was inversely related with total BPH (30.1-50 g/day vs. 0: odds ratio (OR) = 0.59, 95% confidence interval (CI) 0.51-0.70; p trend < 0.0001), although the relation was attenuated at high intake (> or = 50.1 g/day vs. 0: OR = 0.72, 95% CI 0.57-0.90). Current cigarette smoking was positively related to total BPH only among those who smoked 35 or more cigarettes/day (compared with never smokers: OR = 1.45, 95% CI 1.07-1.97). These findings suggest that moderate alcohol consumption and avoidance of smoking may benefit BPH.


Cognitive impairment in cocaine users is drug-induced but partially reversible: evidence from a longitudinal study.
Cocaine users consistently display cognitive impairments. However, it is still unknown whether these impairments are cocaine-induced and if they are reversible. Therefore, we examined the relation between changing intensity of cocaine use and the development of cognitive functioning within 1 year. The present data were collected as part of the longitudinal Zurich Cocaine Cognition Study (ZuCo(2)St). Forty-eight psychostimulant-naive controls and 57 cocaine users (19 with increased, 19 with decreased, and 19 with unchanged cocaine use) were eligible for analysis. At baseline and after a 1-year follow-up, cognitive performance was measured by a global cognitive index and four neuropsychological domains (attention, working memory, declarative memory, and executive functions), calculated from 13 parameters of a broad neuropsychological test battery. Intensity of cocaine use was objectively determined by quantitative 6-month hair toxicology at both test sessions. Substantially increased cocaine use within 1 year (mean +297%) was associated with reduced cognitive performance primarily in working memory. By contrast, decreased cocaine use (-72%) was linked to small cognitive improvements in all four domains. Importantly, users who ceased taking cocaine seemed to recover completely, attaining a cognitive performance level similar to that of the control group. However, recovery of working memory was correlated with age of onset of cocaine use-early-onset users showed hampered recovery. These longitudinal data suggest that cognitive impairment might be partially cocaine-induced but also reversible within 1 year, at least after moderate exposure. The reversibility indicates that neuroplastic adaptations underlie cognitive changes in cocaine users, which are potentially modifiable in psychotherapeutical or pharmacological interventions.


Estrogen receptor-alpha immunoreactivity in the arcuate hypothalamus of young and middle-aged female mice.
Changes in the neuroendocrine regulation of gonadal function, via altered hypothalamic sensitivity to peripheral hormones, are known to schedule reproductive maturation in the young and influence reproductive senescence. Estrogen (E) is a key hormone in this process. While changes in circulating levels of E over the life span are well documented, less is known about the corresponding changes in E sensitivity over the lifespan, especially during middle-age, when the initial signs of reproductive senescence emerge. Taking Estrogen Receptor (ER)-alpha-immunoreactive cells as an index of hypothalamic sensitivity to E, this investigation aims to quantify alterations occurring at middle age in comparison to young age. We counted ER-alpha-immunoreactive (IR) cells in the Arcuate hypothalamus of 6-week-old (young) and 18-month-old (middle-aged) C57BL/6J female mice, sacrificed at vaginal opening and diestrous, respectively. An automated imaging microscopy system (AIMS) was employed to generate counts of ER-alpha-IR cells for each sampled section of the Arcuate nucleus (ARC). This study shows a 21% reduction in the number of ER-alpha-IR cells and an 18% reduction in total ARC cell populations with aging. However, the calculated percentage of ER-alpha IR cells is similar in both young and middle aged mice, 30% and 29%, respectively. Both ER-alpha IR cell populations and total cell populations within the ARC hypothalamus decline by middle age in comparison to young age. Despite such a significant decrease in ER-alpha immunoreactive and total cells, both young and middle age mice maintain a similar ratio of ER-alpha IR cells to total cells in the ARC hypothalamus.


External validation of the Prostate Cancer Prevention Trial risk calculator in a screened population.
To evaluate the recently developed Prostate Cancer Prevention Trial (PCPT) prostate cancer risk calculator in the San Antonio Center of Biomarkers of Risk for Prostate Cancer (SABOR) cohort of the Early Detection Research Network, a younger and more ethnically diverse population than that in the PCPT. From 3488 SABOR participants, we identified 446 who had undergone prostate biopsy and had undergone prostate-specific antigen measurement and digital rectal examination before biopsy. Most biopsies were performed for abnormal digital rectal examination findings, a prostate-specific antigen level of more than 2.5 ng/mL, or elevated risk because of a first-degree relative with prostate cancer. We evaluated the operating characteristics of the PCPT calculator for detecting prostate cancer in this cohort of SABOR participants. Of the 446 men in this cohort, 24% were younger than 55 years of age. Of the 446 men who had undergone biopsy, 148 (33.2%) had prostate cancer. The observed SABOR prostate cancer rates increased with increasing PCPT risk: 15.7%, 39.0%, 48.8%, and 100.0% for a PCPT risk calculator value of less than 25%, 25% to 50%, 50% to 75%, and greater than 75%, respectively. The PCPT risk calculator had an area under the receiver operating characteristic curve of 65.5% (95% confidence interval 60.2% to 70.8%, P < 0.0001), was greater in African-American men (area under curve of 80.0%, 95% confidence interval 67.8% to 92.2%) than in other races (P = 0.02), and was not different in Hispanic men (P > 0.05). The results of our study have shown that the PCPT risk calculator, available from the Internet and incorporating the current best panel of risk factors, is valid in other, more diverse, populations.


99mTc-Tilmanocept Versus 99mTc-Sulfur Colloid in Lymphoscintigraphy: Sentinel Lymph Node Identification and Patient-Reported Pain.
Lymphoscintigraphy plays a vital role in sentinel lymph node (SLN) identification in oncologic breast surgery. The effectiveness of SLN localization and the degree of patient pain were compared between filtered 99mTc-sulfur colloid (99mTc-SC) and 99mTc-tilmanocept. Methods: A retrospective review of patients undergoing lymphoscintigraphy for breast cancer using 99mTc-SC (June 1, 2010, to December 31, 2011) or 99mTc-tilmanocept (June 1, 2013, to January 31, 2014) was performed. SLN appearance time and uptake, SLN pathology, proportion of positive SLNs removed, and pain scores were compared for each radiopharmaceutical using the χ2 test, Fisher exact test, and unequal variance t test, as appropriate. Results: In total, 76 patients, with 86 evaluated axillae, underwent lymphoscintigraphy: 29 with 99mTc-SC and 47 with 99mTc-tilmanocept. The mean SLN appearance time was 11.0 min for 99mTc-SC and 19.3 min for 99mTc-tilmanocept (P = 0.003). There was no difference in the mean transit uptake percentage: 2.2% for 99mTc-SC and 1.9% for 99mTc-tilmanocept (P = 0.55). 99mTc-tilmanocept identified a greater proportion of intraoperative blue nodes than did 99mTc-SC (P = 0.03). There was no significant difference between 99mTc-SC and 99mTc-tilmanocept in the number of SLNs removed, number of patients with positive SLNs, or pain score. Conclusion: 99mTc-SC use in lymphoscintigraphy is an acceptable alternative to 99mTc-tilmanocept for SLN detection in breast cancer, on the basis of the similarity in intraoperative SLN identification and pain scores.


Effects of Smart Position Only (SPOT) tag deployment on white sharks Carcharodon carcharias in South Africa.
We present 15 individual cases of sub-adult white sharks that were SPOT tagged in South Africa from 2003-2004 and have been re-sighted as recently as 2011. Our observations suggest SPOT tags can cause permanent cosmetic and structural damage to white shark dorsal fins depending on the duration of tag attachment. SPOT tags that detached within 12-24 months did not cause long term damage to the dorsal fin other than pigmentation scarring. Within 12 months of deployment, tag fouling can occur. After 24 months of deployment permanent damage to the dorsal fin occurred. A shark survived this prolonged attachment and there seems little compromise on the animal's long term survival and resultant body growth. This is the first investigation detailing the long term effects of SPOT deployment on the dorsal fin of white sharks.


Multiple transcriptional mechanisms control Ptf1a levels during neural development including autoregulation by the PTF1-J complex.
Ptf1a, along with an E protein and Rbpj, forms the transcription factor complex PTF1-J that is essential for proper specification of inhibitory neurons in the spinal cord, retina, and cerebellum. Here we show that two highly conserved noncoding genomic regions, a distal 2.3 kb sequence located 13.4 kb 5' and a 12.4 kb sequence located immediately 3' of the Ptf1a coding region, have distinct activity in controlling Ptf1a expression in all of these domains. The 5' 2.3 kb sequence functions as an autoregulatory element and directs reporter gene expression to all Ptf1a domains in the developing nervous system. The autoregulatory activity of this element was demonstrated by binding of the PTF1-J complex in vitro, Ptf1a localization to this genomic region in vivo, and the in vivo requirement of Ptf1a for the activity of the regulatory element in transgenic mice. In contrast, the 12.4 kb 3' regulatory region does not contain any conserved PTF1 sites, and its expression in transgenic mice is independent of Ptf1a. Thus, regulatory information for initiation of Ptf1a expression in the developing nervous system is located within the 12.4 kb sequence 3' of the Ptf1a gene. Together, these results identify multiple transcriptional mechanisms that control Ptf1a levels, one modulating levels by autoregulation through the PTF1-J complex, and the other a Ptf1a-independent mechanism for initial activation.


Effectiveness of an intermediate care hospital on readmissions, mortality, activities of daily living and use of health care services among hospitalized adults aged 60 years and older--a controlled observational study.
Intermediate care is a health care model developed to optimize the coordination of health care services and functional independence. In Central Norway, an intermediate care hospital (ICH) was established in a municipality to improve hospital discharge and follow-up among elderly patients with chronic conditions and comprehensive care needs. The aim of this study was to investigate the effectiveness of hospital discharges to a municipality with an ICH compared to discharges to a municipality without an ICH. This was a non-randomized controlled observational study of hospitalized patients aged 60 years and older from two municipalities. Patients (n = 328) admitted to a general hospital from February 2010 through September 2011 were included in the study and followed for 12 months. The data were analyzed using descriptive statistics, analysis of covariance (ANCOVA) and Cox proportional hazard regression. Each patient discharged from the general hospital to the municipality with an ICH had a shorter length of stay and used on average 4.2 (p = 0.046) fewer hospital days during 1 year compared to patients from the municipality without an ICH. Otherwise, no statistical significant differences were found between the municipalities in terms of hospital readmissions, admissions, mortality, activities of daily living, primary health care utilization or total care days. A post hoc analysis of patients discharged to the ICH compared to the municipality without an ICH, showed that the ICH patients were older and frailer, but the outcome was similar to the main analysis. Having an ICH in the municipality facilitated shorter length of hospital stay and kept the risk of readmissions, mortality and post-hospitalization care needs at the same level as without an ICH.


Age-related mechanisms in the context of rheumatic disease.
Ageing is characterized by a progressive loss of cellular function that leads to a decline in tissue homeostasis, increased vulnerability and adverse health outcomes. Important advances in ageing research have now identified a set of nine candidate hallmarks that are generally considered to contribute to the ageing process and that together determine the ageing phenotype, which is the clinical manifestation of age-related dysfunction in chronic diseases. Although most rheumatic diseases are not yet considered to be age related, available evidence increasingly emphasizes the prevalence of ageing hallmarks in these chronic diseases. On the basis of the current evidence relating to the molecular and cellular ageing pathways involved in rheumatic diseases, we propose that these diseases share a number of features that are observed in ageing, and that they can therefore be considered to be diseases of premature or accelerated ageing. Although more data are needed to clarify whether accelerated ageing drives the development of rheumatic diseases or whether it results from the chronic inflammatory environment, central components of age-related pathways are currently being targeted in clinical trials and may provide a new avenue of therapeutic intervention for patients with rheumatic diseases.


Cuticle surface coat of plant-parasitic nematodes.
The surface coat (SC) of the plant-parasitic nematode cuticle is an understudied area of current research, even though it likely plays key roles in both nematode-plant and nematode-microbe interactions. Although in several ways Caenorhabditis elegans is a poor model for plant-parasitic nematodes, it is a useful starting point for investigations of the cuticle and its SC, especially in the light of recent work using this species as a model for innate immunity and the generic biology underpinning much host-parasite biology. We review the research focused on the involvement of the SC of plant-parasitic nematodes. Using the insights gained from animal-parasitic nematodes and other sequenced nematodes, we discuss the key roles that the SC may play.


A smart mobile pouch as a biomechanical energy harvester towards self-powered smart wireless power transfer applications.
A Smart Mobile Pouch Triboelectric Nanogenerator (SMP-TENG) is introduced as a promising eco-friendly approach for scavenging biomechanical energy for powering next generation intelligent devices and smart phones. This is a cost-effective and robust method for harvesting energy from human motion, by utilizing worn fabrics as a contact material. The SMP-TENG is capable of harvesting energy in two operational modes: lateral sliding and vertical contact and separation. Moreover, the SMP-TENG can also act as a self-powered emergency flashlight and self-powered pedometer during normal human motion. A wireless power transmission setup integrated with SMP-TENG is demonstrated. This upgrades the traditional energy harvesting device into a self-powered wireless power transfer SMP-TENG. The wirelessly transferred power can be used to charge a Li-ion battery and light LEDs. The SMP-TENG opens a wide range of opportunities in the field of self-powered devices and low maintenance energy harvesting systems for portable and wearable electronic gadgets.


Outcome saliency modulates behavioral decision switching.
Goal-directed decision making often requires evaluating the outcomes of our decisions, assessing any gains or losses, learning from performance-related feedback, and deciding whether to alter our future decisions. However, it is unclear how these processes can be influenced by the saliency of an outcome (e.g., when one aspect of the outcome is accentuated more than another). Here we investigated whether decision strategies changed when certain aspects of the task outcome (win/loss or correct/incorrect) became more salient and how our brain encoded such saliency signals. We employed a simple two-alternative forced choice gambling task and quantified the frequency at which participants switched decisions to an alternative option in the subsequent trial after receiving feedback on their current selection. We conducted three experiments. In Experiment 1, we established the baseline decision switching behavior: participants switched more frequently following incorrect trials than correct trials, but there was no significant difference between win and loss trials. In Experiment 2, we highlighted the utility (win or loss) or performance (correct or incorrect) dimension of the chosen outcome and we found that the difference in switching frequency was enlarged along the highlighted dimension. However, Experiment 3 showed that when using non-specific saliency emphasis of the outcome, the saliency effect was abolished. We further conducted simultaneous EEG recordings using specific saliency emphasis and found that the feedback-related negativity, P300, and late positive potential could collectively encode saliency modulation of behavioral switching. Lastly, both the frontal and parietal theta-band power encoded the outcome when it was made more salient. Together, our findings suggest that specific outcome saliency can modulate behavioral decision switching between choices and our results have further revealed the neural signatures underlying such saliency modulation. Altering the saliency of an outcome may change how information is weighed during outcome evaluation and thus influence future decisions.


Associations between low-income women's relationship characteristics and their contraceptive use.
Women's relationship context likely influences both their ability and their motivation to use contraceptives. No recent studies, however, have examined associations between women's relationship characteristics and use of different methods. Data were collected in a longitudinal study of 839 low-income women at risk of unintended pregnancy who visited public family planning and postpartum clinics and maternity wards in two Southeastern cities. Simulated probabilities calculated from multivariate analyses assessed associations between a wide range of relationship characteristics and the use of no method, condoms, withdrawal, female methods or dual methods. Women who had had a child with their partner had an increased likelihood of contraceptive nonuse and use of withdrawal, and a decreased likelihood of using any female method. Respondents who were in a relationship for a relatively long time had an elevated likelihood of nonuse and use of female methods, but a lowered likelihood of condom use. Furthermore, married or cohabiting women were less likely than others to use dual methods. Respondents who had good communication with their partner had an elevated likelihood of using condoms. In addition, women who expected to receive a lot of emotional support from their partner if they became pregnant were more likely than others to report any condom use or dual method use, and less likely to report contraceptive nonuse. When counseling family planning clients, providers should consider women in the context of their relationships. Future research exploring factors associated with contraceptive method use should examine variables related to the establishment, quality and expectations of their relationships.


Observation of sequence specificity in the seeding of protein amyloid fibrils.
It is well established that the rate of formation of fibrils by amyloidogenic proteins is enhanced by the addition of preformed fibrils, a phenomenon known as seeding. We show that the efficiency of seeding fibril formation from solutions of hen lysozyme by a series of other proteins depends strongly on the similarity of their sequences. This observation is consistent with the importance of long-range interactions in stabilizing the core structure of amyloid fibrils and may be associated with the existence of a species barrier observed in the transmissible spongiform encephalopathies. In addition, it is consistent with the observation of a single dominant type of protein in the deposits associated with each form of amyloid disease.


Forearm vasorelaxation in hypertensive renal transplant patients: the impact of withdrawal of cyclosporine.
To determine whether cyclosporine A-induced hypertension in renal transplant recipients is accompanied by impairment of endothelium-dependent vasodilatation, which has been suggested by in-vitro and in-vivo animal experiments. In-vivo endothelium-dependent and endothelium-independent vasodilatation, and plasma concentrations of vasoactive hormones in 16 renal transplant patients were determined while they were being treated with cyclosporine A, and 16 weeks later, after their treatment had been changed to azathioprine therapy. The vasodilator response of the forearm vascular bed was measured by strain gauge venous occlusion plethysmography during intra-arterial infusion of acetylcholine (endothelium-dependent vasodilatation) and nitroprusside (endothelium-independent vasodilatation). Postischemic reactive flow was measured after 10 min of arterial occlusion. In addition, plasma concentrations of norepinephrine, and the prostanoids prostaglandin E2 and thromboxane B2, and also concentration of cyclosporine A in blood, were measured. Glomerular filtration rate and renal blood flow were estimated 1 day before the plethysmography study during each treatment period. Upon changing from cyclosporine A to azathioprine treatment, mean arterial pressure fell significantly by 12+/-3% (P< 0.05). Glomerular filtration rate and renal blood flow increased by 13+/-5 and 19+/-8%, respectively (both P< 0.05), while renal vascular resistance fell by 48+/-11% (P< 0.01). Both baseline forearm blood flow and baseline forearm resistance did not change after conversion (5.7+/-0.7 versus 4.9+/-0.6 ml/100 ml/min, and 27.3+/-4.2 versus 26.2+/-3.2 arbitrary units). The absolute and relative forearm blood flow responses, and forearm vascular resistance responses to infusions of acetylcholine and nitroprusside were similar during treatments with cyclosporine A and azathioprine. Peak postischaemic forearm blood flow was 42+/-12% higher during cyclosporine A treatment than it was during azathioprine treatment (P< 0.05), but the minimal postischaemic forearm vascular resistance did not differ for these treatments. Plasma prostaglandin E2 and thromboxane B2 levels decreased by 34+/-7 and 45+/-8%, respectively, after changing treatment, but norepinephrine levels did not change. Our data indicate that cyclosporine A-induced hypertension in renal transplant recipients is not accompanied by an increase in forearm vascular resistance. In addition, changing from cyclosporine A to azathioprine treatment did not cause changes in endothelial vasodilator functioning, although mean arterial pressure decreased significantly. Our results do not support the hypothesis that attenuation of endothelial vasodilator functioning contributes to the development of cyclosporine A-induced hypertension.


Epidemiological analyses for preparation of Clinical Practice Guidelines related to acute coronary syndromes in the Czech Republic.
Coronary heart disease, sometimes also referred to as ischemic heart disease, remains the leading condition causing most deaths and disability-adjusted life years worldwide. Acute coronary syndrome (ACS) represents a subset that is defined by sudden reduction of blood supply in the coronary arteries. ACS consists of unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI).The current short communication aims to provide current ACS prevalence and incidence data analysis to inform development of clinical practice guidelines in the Czech Republic.The Institute of Health Information and Statistics of the Czech Republic has provided the data that are collected by the National Health Information System with the National Register of Reimbursed Health Services as a primary source providing data for the period from 2015 to 2017.There has been a slight decrease in the number of hospitalized patients for ACS in the Czech Republic from 2015 to 2017. Sex difference remains large, with majority (two thirds) of those hospitalized for unstable angina, NSTEMI, or STEMI being men. Hospitalization with STEMI is reported in younger age with no sex difference compared with NSTEMI and unstable angina.


A new taxonomy for describing and defining adherence to medications.
Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication-taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines ('Adherence to medications', 'Management of adherence') and the discipline that studies those processes ('Adherence-related sciences'). 'Adherence to medications' is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: 'Initiation', 'Implementation' and 'Discontinuation'. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence.


Structure, regulation and physiological roles of urea transporters.
Urea is the major constituent of the urine and the principal means for disposal of nitrogen derived from amino acid metabolism. Specialized phloretin-inhibitable urea transporters are expressed in kidney medulla and play a central role in urea excretion and water balance. These transporters allow accumulation of urea in the medulla and enable the kidney to concentrate urine to an osmolality greater than systemic plasma. Recently, expression cloning with Xenopus oocytes has led to the isolation of a novel phloretin-inhibitable urea transporter (UT2) from rabbit, and subsequently from rat kidney. UT2 from both species has the characteristics of the phloretin-sensitive urea transporter previously defined in kidney by in vitro perfused tubule studies. Based on these advances, Ripoche and colleagues cloned a homologous urea transporter (HUT11) from erythrocytes. UT2 and HUT11 predict 43 kDa polypeptides and exhibit 64% amino acid sequence identity. Since regulation of urea transport in the kidney plays an important role in the orchestration of the antidiuretic response, we have studied the regulation of urea transporter in rat kidney at the mRNA level. On Northern blots probed at high stringency, rat UT2 hybridized to two transcripts of 2.9 kb and 4.0 kb, which have spatially distinct distributions within the kidney. Northern analysis and in situ hybridization of kidneys from rats maintained at different physiologic states revealed that the 2.9 and 4.0 kb transcripts are regulated by separate mechanisms. The 4 kb transcript was primarily responsive to changes in the dietary protein content, whereas the 2.9 kb transcript was highly responsive to changes in the hydration state of the animal. We propose that the two UT2 transcripts are regulated by distinct mechanisms to allow optimal fluid balance and urea excretion.


How standards will degrade the concepts of the art of medicine.
The paper is dealing with the problematic positioning of the whole health care system towards the concept of standard. There is a constant quest for standards, and a prediction of how everyday language gradually will disappear. It is the assumption and conjecture of this paper that as we outdo everyday language from our communication in the system we lose major part of meaning-construction concerning health and life of the patient/citizen. It is the normative and ethical aim of the discussion to frame how human factors are terminated as standards and bodies as machines replaces everyday language and bodies as carrier of health. Hans Georg Gadamer has led me on the way through inspiring essays on the Enigma of Health.


Mourning in prison: mission impossible?
The author's interest in the issue of mourning in prison is twofold. As an active hospice volunteer, she became involved with bereavement work, which sensitized her to the issues of loss encountered upon joining the staff at the Maine State Prison. More often than not, the inmates with whom she met had unresolved issues of loss. The impetus for a grief support group came from an inmate who had experienced the death of five relatives during his period of incarceration; he commented on how difficult it is to mourn in prison, and he worried about how he would deal with all his losses when confronted with them upon his release. The author raised the possibility of a support group and the inmate offered to help organize it. This article describes the author's experience with such a prison-based support group and what she has learned, through this experience, about mourning in prison.


Proteogenomics of Pristionchus pacificus reveals distinct proteome structure of nematode models.
Pristionchus pacificus is a nematode model organism whose genome has recently been sequenced. To refine the genome annotation we performed transcriptome and proteome analysis and gathered comprehensive experimental information on gene expression. Transcriptome analysis on a 454 Life Sciences (Roche) FLX platform generated >700,000 expressed sequence tags (ESTs) from two normalized EST libraries, whereas proteome analysis on an LTQ-Orbitrap mass spectrometer detected >27,000 nonredundant peptide sequences from more than 4000 proteins at sub-parts-per-million (ppm) mass accuracy and a false discovery rate of <1%. Retraining of the SNAP gene prediction algorithm using the gene expression data led to a decrease in the number of previously predicted protein-coding genes from 29,000 to 24,000 and refinement of numerous gene models. The P. pacificus proteome contains a high proportion of small proteins with no known homologs in other species ("pioneer" proteins). Some of these proteins appear to be products of highly homologous genes, pointing to their common origin. We show that >50% of all pioneer genes are transcribed under standard culture conditions and that pioneer proteins significantly contribute to a unimodal distribution of predicted protein sizes in P. pacificus, which has an unusually low median size of 240 amino acids (26.8 kDa). In contrast, the predicted proteome of Caenorhabditis elegans follows a distinct bimodal protein size distribution, with significant functional differences between small and large protein populations. Combined, these results provide the first catalog of the expressed genome of P. pacificus, refinement of its genome annotation, and the first comparison of related nematode models at the proteome level.


Mechanistic analysis of AKT1 regulation by the CBL-CIPK-PP2CA interactions.
Arabidopsis K+ transporter 1 (AKT1) participates in K+ uptake in roots, especially under low-K conditions. We recently identified a Ca²⁺ signaling pathway consisting of multiple calcineurin B-like calcium sensors (CBLs) and multiple target kinases (CBL-interacting protein kinases or CIPKs) that phosphorylate and activate AKT1, whereas a specific PP2C-type phosphatase inactivates CIPK-dependent AKT1 activity. In this study, we analyzed the interactions between PP2Cs and the CBL-CIPK pathway and found previously unsuspected mechanisms underlying the CBL-CIPK-PP2C signaling processes. The interaction between the CIPKs and PP2Cs involves the kinase domain of the CIPK component, in addition to the protein phosphatase interacting motif (PPI) in the regulatory domain. Furthermore, specific CBLs physically interact with and inactivate PP2C phosphatases to recover the CIPK-dependent AKT1 channel activity. These findings provide further insights into the signaling network consisting of CBL-CIPK-PP2C interactions in the activation of the AKT1 channel.


Evolution of Viral Genomes: Interplay Between Selection, Recombination, and Other Forces.
Natural selection is a fundamental force shaping organismal evolution, as it both maintains function and enables adaptation and innovation. Viruses, with their typically short and largely coding genomes, experience strong and diverse selective forces, sometimes acting on timescales that can be directly measured. These selection pressures emerge from an antagonistic interplay between rapidly changing fitness requirements (immune and antiviral responses from hosts, transmission between hosts, or colonization of new host species) and functional imperatives (the ability to infect hosts or host cells and replicate within hosts). Indeed, computational methods to quantify these evolutionary forces using molecular sequence data were initially, dating back to the 1980s, applied to the study of viral pathogens. This preference largely emerged because the strong selective forces are easiest to detect in viruses, and, of course, viruses have clear biomedical relevance. Recent commoditization of affordable high-throughput sequencing has made it possible to generate truly massive genomic data sets, on which powerful and accurate methods can yield a very detailed depiction of when, where, and (sometimes) how viral pathogens respond to various selective forces.Here, we present recent statistical developments and state-of-the-art methods to identify and characterize these selection pressures from protein-coding sequence alignments and phylogenies. Methods described here can reveal critical information about various evolutionary regimes, including whole-gene selection, lineage-specific selection, and site-specific selection acting upon viral genomes, while accounting for confounding biological processes, such as recombination and variation in mutation rates.


The lennie test for measuring scapular position in healthy young adult females: a reliability and validity study.
Normal scapular rest position is neither adequately described nor agreed upon by authorities. The purpose of this study was to devise and describe a reliable and valid test (the Lennie Test) to measure scapular position, including normal scapular rest position. Fifteen healthy females (age 19-21 years) participated in the study. Horizontal and vertical scapular position in the frontal plane was quantified by three different investigators using a scoliometer and caliper. Same-day radiographs were used to validate scapular position surface measurements. The medial borders of the scapulae were found to be parallel to the thoracic midline. The scapulae were on average 17.19 +/- 1.85 cm apart (at the level of the root of the scapulae) with the dominant arm scapula being on average 0.49 +/- 0.74 cm lower than the nondominant scapula. This difference in height between scapulae was not statistically significant (p > .01). Correlation coefficients between skin surface and radiograph measurements of scapular position ranged from .43 to .82. Intertester intraclass correlation coefficients for surface measurements of scapular position ranged from .64 to .86. The Lennie Test was found to have moderate to high intertester reliability and to provide an accurate measurement of the anatomical location of the scapulae based on X-ray verification. Surface landmark measurements for scapular position were on average within 0.56 cm and within 1.7 degrees of the measurements made from X-rays for linear and angular position, respectively. We propose the use of the Lennie Test in populations, healthy or otherwise, where scapular position needs to be objectively measured.


A novel approach to selecting and weighting nutrients for nutrient profiling of foods and diets.
Nutrient profiling of foods is the science of ranking or classifying foods based on their nutrient composition. Most profiling systems use similar weighting factors across nutrients due to lack of scientific evidence to assign levels of importance to nutrients. Our aim was to use a statistical approach to determine the nutrients that best explain variation in Healthy Eating Index (HEI) scores and to obtain β-coefficients for the nutrients for use as weighting factors for a nutrient-profiling algorithm. We used a cross-sectional analysis of nutrient intakes and HEI scores. Our subjects included 16,587 individuals from the National Health and Nutrition Examination Survey 2005-2008 who were 2 years of age or older and not pregnant. Our main outcome measure was variation (R(2)) in HEI scores. Linear regression analyses were conducted with HEI scores as the dependent variable and all possible combinations of 16 nutrients of interest as independent variables, with covariates age, sex, and ethnicity. The analyses identified the best 1-nutrient variable model (with the highest R(2)), the best 2-nutrient variable model, and up to the best 16-nutrient variable model. The model with 8 nutrients explained 65% of the variance in HEI scores, similar to the models with 9 to 16 nutrients, but substantially higher than previous algorithms reported in the literature. The model contained five nutrients with positive β-coefficients (ie, protein, fiber, calcium, unsaturated fat, and vitamin C) and three nutrients with negative coefficients (ie, saturated fat, sodium, and added sugar). β-coefficients from the model were used as weighting factors to create an algorithm that generated a weighted nutrient density score representing the overall nutritional quality of a food. The weighted nutrient density score can be easily calculated and is useful for describing the overall nutrient quality of both foods and diets.


Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.
Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.


Comparison of dexmedetomidine and ketamine versus propofol and ketamine for procedural sedation in children undergoing minor cardiac procedures in cardiac catheterization laboratory.
The ideal anaesthetic technique for management of paediatric patients scheduled to undergo cardiac catheterisation is still not standardised. To compare the effects of ketamine-propofol and ketamine-dexmedetomidine combinations on hemodynamic parameters and recovery time in paediatric patients undergoing minor procedures and cardiac catheterisation under sedation for various congenital heart diseases. 60 children of either sex undergoing cardiac catheterisation were randomly assigned into two groups Dexmedetomidine-ketamine group (DK) and Propofol-ketamine (PK) of 30 patients each. All patients were premedicated with glycopyrrolate and midazolam (0.05mg/kg) intravenously 5-10 min before anaesthetic induction. Group 'DK'received dexmedetomidineiv infusion 1 μg/kg over 10 min + ketamine1mg/kg bolus, followed by iv infusion of dexmedetomidine 0.5μg/kg/hr and of ketamine1 mg/kg/hr. Group 'PK' received propofol 1mg/kg and ketamine 1mg/kg/hr for induction followed by iv infusion of propofol 100 μg/kg/hr and ketamine 1 mg/kg/hr for maintenance. Haemodynamic parameters and recovery time was recorded postoperatively. Independent sample t test was used to compare the statistical significance of continuous variables of both the groups.Chi square test was used for numerical data like gender.Fischer exact test was applied for non parametric data like ketamine consumption. We observed that heart rate in dexmedetomidine (DK) group was significantly lower during the initial 25 mins after induction compared to the propofol (PK) group. Recovery was prolonged in the DK group compared to the PK group (40.88 vs. 22.28 min). Even ketamine boluses consumption was higher in DK group. Use of dexmedetomidine-ketamine combination is a safe alternative, without any hemodynamic orrespiratory effects during the cardiac catheterization procedure but with some delayed recovery.


Working conditions, psychosocial environmental factors, and depressive symptoms among wage workers in South Korea.
In South Korea, the number of workers suffering from mental illnesses, such as depression, has rapidly increased. There is growing concern about depressive symptoms being associated with both working conditions and psychosocial environmental factors. To investigate potential psychosocial environmental moderators in the relationship between working conditions and occupational depressive symptoms among wage workers. Data were obtained from the wage worker respondents (n = 4,095) of the Korean National Health and Nutrition Examination Survey of 2009. First, chi-square tests confirmed the differences in working conditions and psychosocial characteristics between depressive and non-depressive groups. Second, multivariate logistic regression analysis was performed to examine the moderating effects of the psychosocial environmental factors between working conditions and depressive symptoms. After adjusting for potential covariates, the likelihood of depressive symptomatology was high among respondents who had dangerous jobs and flexible work hours compared to those who had standard jobs and fixed daytime work hours (OR = 1.66 and 1.59, respectively). Regarding psychosocial factors, respondents with high job demands, low job control, and low social support were more likely to have depressive symptoms (OR = 1.26, 1.58 and 1.61, respectively). There is a need to develop non-occupational intervention programs, which provide workers with training about workplace depression and improve social support, and the programs should provide time for employees to have active communication. Additionally, companies should provide employees with support to access mental healthcare thereby decreasing the occurrence of workplace depression.


BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/- mice.
In mice heterozygous for p53 (Trp53(+/-)), the incidence of mammary tumors varies among strains, with C57BL/6 being resistant and BALB/c being susceptible. Mammary tumor phenotypes were examined in female Trp53(+/-) F1 mice (C57BL/6 x BALB/c;n = 19) and N2 backcross mice [(C57BL/6 x BALB/c) x BALB/c] (n = 224). Susceptibility to mammary tumors segregated as a dominant phenotype in F1 females, but a higher frequency and shorter latency in N2 mice indicated a contribution from recessive-acting modifiers. Segregation of the hypomorphic BALB/c alleles for DNA-dependent protein kinase catalytic subunit (Prkdc) and p16(INK4A) (Cdkn2a) was analyzed in the N2 mice. The time to first tumor (considering all tumor types) was significantly different among the four genotype combinations (P = 0.01). Cdkn2a had a strong effect (P = 0.008) but was restricted to Prkdc(B/B) mice (P = 0.001), indicating a strong interaction between the loci. Differences in mammary tumor occurrence among genotypes for Prkdc and Cdkn2a in N2 mice were not statistically significant. This study indicates that BALB/c Prkdc and Cdkn2a alleles do modify tumor incidence in Trp53(+/-) mice and highlights the complexity of gene interaction effects in determining cancer phenotypes but discounts these alleles as major recessive loci contributing to spontaneous mammary tumor susceptibility.