Impact of Mild-to-Moderate Chronic Kidney Disease on One Year Outcomes after Percutaneous Coronary Intervention.
Patients with severe chronic kidney disease (CKD) have a higher risk of adverse events after percutaneous coronary intervention (PCI). There is conflicting evidence regarding the benefit of drug-eluting stents (DES) in patients with CKD. This study is aimed at assessing the effect of mild-to-moderate CKD on PCI outcomes, and determining if DES reduce adverse events amongst these patients. We used our PCI database to determine demographic, procedural and outcome variables for 1960 consecutive patients (October 2009-October 2012). Kidney function was measured by the estimated glomerular filtration rate (eGFR - CKD-Epidemiology Collaboration creatinine based). Multivariate analysis was performed to determine independent variables associated with mortality and major adverse cardiovascular events (MACE). The independent variables, predictive of 12-month mortality in PCI patients, were: age >64 years (hazard ratio [HR] 3.10 [95% CI 1.73-5.55], p < 0.001), 3-vessel disease (HR 1.72 [95% CI 1.10-2.68], p = 0.016) and CKD stage. Compared to stage 1 CKD (eGFR >89), HR of death increased in a progressive pattern below eGFR <75: eGFR 60-74, HR 2.40 (95% CI 1.2-4.78), p = 0.013, eGFR 45-59, HR 3.27 (95% CI 1.55-6.9), p = 0.002, eGFR 30-44, HR 4.10 (95% CI 1.82-9.24), p = 0.001, eGFR <30, HR 7.97 (95% CI 3.65-17.40), p < 0.001. In patients with eGFR <75, multivariate analysis demonstrated that DES use was an independent predictor of lower MACE (HR BMS vs. DES 1.8, p = 0.0044). Age, severity of CKD and 3-vessel disease were independent predictors of mortality following PCI. The mortality risk in CKD patients increased progressively with eGFR <75. The use of DES was associated with a lower rate of MACE in CKD patients with eGFR <75.


The Moderating Role of Recovery Durations in High-Intensity Interval-Training Protocols.
Purpose: Over recent years, multiple studies have tried to optimize the exercise intensity and duration of work intervals in high-intensity-interval training (HIIT) protocols. Although an optimal work interval is of major importance to facilitate training adaptations, an optimal HIIT protocol can only be achieved with an adequate recovery interval separating work bouts. Surprisingly, little research has focused on the acute responses and long-term impact of manipulating recovery intervals in HIIT sessions. This invited commentary therefore aimed to review and discuss the current literature and increase the understanding of the moderating role of recovery durations in HIIT protocols. Conclusion: The acute responses to manipulations in recovery durations in repeated-sprint training (RST), sprint interval training (SIT), and aerobic interval training (AIT) protocols have recently begun to receive scientific interest. However, limited studies have manipulated only the recovery duration in RST, SIT, or AIT protocols to analyze the role of recovery durations on long-term training adaptations. In RST and SIT, longer recovery intervals (≥80 s) facilitate higher workloads in subsequent work intervals (compared with short recovery intervals), while potentially lowering the aerobic stimulus of the training session. In AIT, the total physiological strain endured per training protocol appears not to be moderated by the recovery intervals, unless the recovery duration is too short. This invited commentary highlights that further empirical evidence on a variety of RST, SIT, and AIT protocols and in exercise modalities other than cycling is needed.


Metals and Metal derivatives in Medicine.
Several chemical elements are required by living organisms in addition to the four elements carbon, hydrogen, nitrogen and oxygen usually present in common organic molecules. Many metals (e.g. sodium, potassium, magnesium, calcium, iron, zinc, copper, manganese, chromium, molybdenum and selenium) are known to be required for normal biological functions in humans. Disorders of metal homeostasis and of metal bioavailability, or toxicity caused by metal excess, are responsible for a large number of human diseases. Metals are also extensively used in medicine as therapeutic and/or diagnostic agents. In the past 5000 years, metals such as arsenic, gold and iron have been used to treat a variety of human diseases. Nowadays, an ever-increasing number of metal-based drugs is available. These contain a broad spectrum of metals, many of which are not among those essential for humans, able to target proteins and/or DNA. This mini-review describes metal-containing compounds targeting DNA or proteins currently in use, or designed to be used, as therapeutics against cancer, arthritis, parasitic and other diseases, with a special focus on the available information, often provided by X-ray studies, about their mechanism of action at a molecular level. In addition, an overview of metal complexes used for diagnosing diseases is presented.


Antimalarial compounds: from bench to bedside.
The emergence and spread of drug-resistant malaria parasites is the major threat to effective malaria control. So far, malaria control has relied heavily on a restricted number of chemically related drugs belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin-type compounds been used widely, predominantly in Southeast Asia. Experience has shown that resistance eventually curtails the life span of antimalarial drugs. If measures are not applied to contain resistance, the investment put into the development of new drugs will be squandered. Current efforts focus, on the one hand, on research into novel compounds with mechanisms of action that are different to the traditionally used drugs, and, on the other hand, on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and expensive ventures. Whilst very few new antimalarial drugs were developed in the last quarter of the 20th century (only four of the nearly 1,400 drugs registered worldwide during 1975-1999), various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial pipeline is relatively healthy. Projects are underway at different stages of drug development, from pre-development to registration. However, there is relatively little novelty, as current development projects still rely upon the traditional quinoline, antifolate and, in particular, artemisinin compounds. New structures are expected from the more upstream discovery efforts but it will take time before they become drugs. Therefore, whilst waiting for the drugs of tomorrow, there is a pressing need for immediately available, effective and affordable drugs that will have long life spans. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focussed on the use of artesunate combined with currently used standard drugs, namely mefloquine, amodiaquine, sulfadoxine/pyrimethamine and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and are dependent on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. Malaria control programmes need efficacious drugs that can be used with ease by the populations of endemic countries. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.


Perchlorate contamination in Chile: Legacy, challenges, and potential solutions.
This paper reviews the unique situation of perchlorate contamination in Chile, including its sources, presence in environmental media and in the human population, and possible steps to mitigate its health impacts. Perchlorate is a ubiquitous water contaminant that inhibits thyroid function. Standards for drinking water range from 2 to 18 µg L-1 in United States and Europe. A major natural source of perchlorate contamination is Chile saltpeter, found in the Atacama Desert. High concentrations of perchlorate have presumably existed in this region, in soils, sediments, surface waters and groundwaters, for millions of years. As a result of this presence, and the use of Chile saltpeter as a nitrogen fertilizer, perchlorate in Chile has been found at concentrations as high as 1480 µg L-1 in drinking water, 140 µg/kg-1 in fruits, and 30 µg L-1 in wine. Health studies in Chile have shown concentrations of 100 µg L-1 in breast milk and 20 µg L-1 in neonatal serum. It is important to acknowledge perchlorate as a potential health concern in Chile, and assess mitigation strategies. A more thorough survey of perchlorate in Chilean soils, sediments, surface waters, groundwaters, and food products can help better assess the risks and potentially develop standards. Also, perchlorate treatment technologies should be more closely assessed for relevance to Chile. The Atacama Desert is a unique biogeochemical environment, with millions of years of perchlorate exposure, which can be mined for novel perchlorate-reducing microorganisms, potentially leading to new biological treatment processes for perchlorate-containing waters, brines, and fertilizers.


Ethylene suppression of sugar-induced anthocyanin pigmentation in Arabidopsis.
Anthocyanin accumulation is regulated negatively by ethylene signaling and positively by sugar and light signaling. However, the antagonistic interactions underlying these signalings remain to be elucidated fully. We show that ethylene inhibits anthocyanin accumulation induced by sucrose (Suc) and light by suppressing the expression of transcription factors that positively regulate anthocyanin biosynthesis, including GLABRA3, TRANSPARENT TESTA8, and PRODUCTION OF ANTHOCYANIN PIGMENT1, while stimulating the concomitant expression of the negative R3-MYB regulator MYBL2. Genetic analyses show that the ethylene-mediated suppression of anthocyanin accumulation is dependent upon ethylene signaling components responsible for the triple response. Furthermore, these positive and negative signaling pathways appear to be under photosynthetic control. Suc and light induction of anthocyanin accumulation was almost fully inhibited in wild-type Arabidopsis (Arabidopsis thaliana) ecotype Columbia and ethylene (ethylene response1 [etr1-1]) and light (long hypocotyl1 [hy1], cryptochrome1/2, and hy5) signaling mutants treated with the photosynthetic electron transport inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea. The transcript level of the sugar transporter gene SUC1 was enhanced in ecotype Columbia treated with the ethylene-binding inhibitor silver and in etr1-1, ethylene insensitive2 (ein2-1), and ein3 ein3-like1 mutants. In contrast, 3-(3,4-dichlorophenyl)-1,1-dimethylurea treatment reduced SUC1 expression, which indicates strongly that SUC1 represents an integrator for signals provided by sugar, light, and ethylene. SUC1 mutations lowered accumulations of anthocyanin pigment, soluble sugar content, and ethylene production in response to Suc and light signals. These data demonstrate that the suppression of SUC1 expression by ethylene inhibits Suc-induced anthocyanin accumulation in the presence of light and, hence, fine-tunes anthocyanin homeostasis.


A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy.
To estimate whether the use of ginger to treat nausea or vomiting in pregnancy is equivalent to pyridoxine hydrochloride (vitamin B6). A randomized, controlled equivalence trial involving 291 women less than 16 weeks pregnant was undertaken at a teaching hospital in Australia. Women took 1.05 g of ginger or 75 mg of vitamin B6 daily for 3 weeks. Differences from baseline in nausea and vomiting scores were estimated for both groups at days 7, 14, and 21. Ginger was equivalent to vitamin B6 in reducing nausea (mean difference 0.2, 90% confidence interval [CI] -0.3, 0.8), retching (mean difference 0.3; 90% CI -0.0, 0.6) and vomiting (mean difference 0.5; 90% CI 0.0, 0.9), averaged over time, with no evidence of different effects at the 3 time points. For women looking for relief from their nausea, dry retching, and vomiting, the use of ginger in early pregnancy will reduce their symptoms to an equivalent extent as vitamin B6. I


Pulmonary fibroblasts stimulate the proliferation of cell lines from human lung adenocarcinomas.
Human lung cancer cell lines are widely used to test anticancer drugs. These in-vitro tests, however, preclude the detection of responses to paracrine factors from surrounding stroma. We have cocultured pulmonary fibroblasts CCD-19Lu, from a healthy donor, or HLF-A, from a patient with epidermoid carcinoma of the lung, with two human pulmonary adenocarcinoma cell lines to test the hypothesis that the fibroblasts stimulate the growth of the tumor cells. Both fibroblast cell lines significantly increased the proliferation of the pulmonary adenocarcinoma cell lines in 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assays, with HLF-A fibroblasts yielding the most pronounced responses. The proliferation of the pulmonary adenocarcinoma cell lines in coculture with fibroblasts was blocked by antibodies against the transforming growth factor-alpha and amphiregulin. In addition, reverse transcription-polymerase chain reaction showed expression of mRNA for amphiregulin and transforming growth factor-alpha in all cell lines, whereas mRNA for the epidermal growth factor was detected only in pulmonary adenocarcinoma cell lines. Western blot analysis revealed that medium containing growth factors released by each fibroblast cell line activated extracellular signal-regulated kinase 1/2 in the both tested pulmonary adenocarcinoma cell lines, but activated Akt kinase only in A549 cells. Assessment of protein levels for cyclin D1 and cyclin E by Western blots demonstrated pronounced increases of both proteins in each pulmonary adenocarcinoma cell line, whereas protein levels for cyclin-dependent kinase inhibitor p21 remained unchanged. Immunocytochemical analysis showed positive immunoreactivity for P-extracellular signal-regulated kinase 1/2, cyclin D1 and cyclin E in pulmonary adenocarcinoma cells cocultured with fibroblasts or exposed to fibroblast-conditioned media. Our data suggest that the growth of pulmonary adenocarcinoma is stimulated by amphiregulin and transforming growth factor-alpha released from pulmonary fibroblasts. This may contribute to the disappointing clinical responses to anticancer drugs, which have shown promise in tests with lung cancer cell lines.


Accumulation of and Response to Auxins in Roots and Nodules of the Actinorhizal Plant Datisca glomerata Compared to the Model Legume Medicago truncatula.
Actinorhizal nodules are structurally different from legume nodules and show a greater similarity to lateral roots. Because of the important role of auxins in lateral root and nodule formation, auxin profiles were examined in roots and nodules of the actinorhizal species Datisca glomerata and the model legume Medicago truncatula. The auxin response in roots and nodules of both species was analyzed in transgenic root systems expressing a beta-glucuronidase gene under control of the synthetic auxin-responsive promoter DR5. The effects of two different auxin on root development were compared for both species. The auxin present in nodules at the highest levels was phenylacetic acid (PAA). No differences were found between the concentrations of active auxins of roots vs. nodules, while levels of the auxin conjugate indole-3-acetic acid-alanine were increased in nodules compared to roots of both species. Because auxins typically act in concert with cytokinins, cytokinins were also quantified. Concentrations of cis-zeatin and some glycosylated cytokinins were dramatically increased in nodules compared to roots of D. glomerata, but not of M. truncatula. The ratio of active auxins to cytokinins remained similar in nodules compared to roots in both species. The auxin response, as shown by the activation of the DR5 promoter, seemed significantly reduced in nodules compared to roots of both species, suggesting the accumulation of auxins in cell types that do not express the signal transduction pathway leading to DR5 activation. Effects on root development were analyzed for the synthetic auxin naphthaleneacetic acid (NAA) and PAA, the dominant auxin in nodules. Both auxins had similar effects, except that the sensitivity of roots to PAA was lower than to NAA. However, while the effects of both auxins on primary root growth were similar for both species, effects on root branching were different: both auxins had the classical positive effect on root branching in M. truncatula, but a negative effect in D. glomerata. Such a negative effect of exogenous auxin on root branching has previously been found for a cucurbit that forms lateral root primordia in the meristem of the parental root; however, root branching in D. glomerata does not follow that pattern.


Orthotic management of instability of the knee related to neuromuscular and central nervous system disorders: systematic review, qualitative study, survey and costing analysis.
Patients who have knee instability that is associated with neuromuscular disease (NMD) and central nervous system (CNS) conditions can be treated using orthoses, such as knee-ankle-foot orthoses (KAFOs). To assess existing evidence on the effectiveness of orthoses; patient perspectives; types of orthotic devices prescribed in the UK NHS; and associated costs. Qualitative study of views of orthoses users - a qualitative in-depth interview study was undertaken. Data were analysed for thematic content. A coding scheme was developed and an inductive approach was used to identify themes. Systematic review - 18 databases were searched up to November 2014: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health, EMBASE, PASCAL, Scopus, Science Citation Index, BIOSIS Previews, Physiotherapy Evidence Database, Recal Legacy, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, Cochrane Central Register of Controlled Trials, Conference Proceedings Citation Index: Science, Health Management Consortium, ClinicalTrials.gov, International Clinical Trials Registry Platform and National Technical Information Service. Studies of adults using an orthosis for instability of the knee related to NMD or a CNS disorder were included. Data were extracted and quality was assessed by two researchers. Narrative synthesis was undertaken. Survey and costing analysis - a web survey of orthotists, physiotherapists and rehabilitation medicine physicians was undertaken. Telephone interviews with orthotists informed a costing analysis. Qualitative study - a total of 24 people participated. Potential for engagement in daily activities was of vital importance to patients; the extent to which their device enabled this was the yardstick by which it was measured. Patients' prime desired outcome was a reduction in pain, falls or trips, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses. Many expressed frustration with perceived deficiencies in service provision relating to appointment and administrative systems and referral pathways. Systematic review - a total of 21 studies (478 participants) were included of people who had post-polio syndrome, inclusion body myositis, were post stroke or had spinal cord injury. The studies evaluated KAFOs (mainly carbon fibre), stance control KAFO and hip KAFOs. All of the studies were at risk of bias and, in general, were poorly reported. Survey and costing analysis - in total, 238 health-care professionals responded. A range of orthoses is prescribed for knee instability that is related to NMD or CNS conditions, approximately half being custom-made. At least 50% of respondents thought that comfort and confidence in mobility were extremely important treatment outcomes. The cost of individual KAFOs was highly variable, ranging from £73 to £3553. Various types of orthoses are used in the NHS to manage patients with NMD/CNS conditions and knee instability, both custom-made and prefabricated, of variable cost. Evidence on the effectiveness of the orthoses is limited, especially in relation to the outcomes that are important to orthoses users. The population included was broad, limiting any in-depth consideration of specific conditions. The response rate to the survey was low, and the costing analysis was based on some assumptions that may not reflect the true costs of providing KAFOs. Future work should include high-quality research on the effectiveness and cost-effectiveness of orthoses; development of a core set of outcome measures; further exploration of the views and experiences of patients; and the best models of service delivery. This study is registered as PROSPERO CRD42014010180. The qualitative study is registered as Current Controlled Trials ISRCTN65240228. The National Institute for Health Research Health Technology Assessment programme.


Factors associated with initiation and persistence of urate-lowering therapy.
Gout is the most common inflammatory arthritic disease and is caused by crystal deposition secondary to persistent hyperuricemia. Etiological treatment with urate-lowering therapy (ULT) has been available since the 1950s but previous studies have demonstrated suboptimal degree of treatment. In recent years we have seen recommendations for ULT earlier in the course of the disease, but there are few contemporary reports reflecting the current situation. Therefore we set out to investigate proportion receiving and persisting with ULT after gout diagnosis and predictors thereof. A population-based cohort study using regional and national population-based registers. Cohort of patients (n = 7709) from western Sweden with incident gout aged 18 years and above from 2011 to 2013. An incident case of gout was defined as having been given a diagnosis of gout (ICD-10 M10, M14.0-14.1) not preceded by a gout diagnosis or a dispensation of ULT during the previous 5 years. Main outcome measures were cumulative incidence and predictors for start of, and persistence with, ULT in gout. Within the first year after first gout diagnosis, 32% received ULT. Male sex, presence of diabetes or cardiovascular comorbidity, reduced kidney function but not diagnosed "end-stage kidney failure" increased the likelihood of receiving ULT. Of those starting ULT a majority (75%) did not persist with ULT treatment within the first 2 years. Age <50 years, lack of comorbidities, and "normal kidney function" or "end-stage kidney failure" were associated with non-persistence with ULT. Only a minority of patients received ULT and a majority of these did not persist with treatment over the next 2 years. However, the older patients with renal impairment and comorbidities, possibly suffering from a more severe gout disease, were more likely to receive and persist with treatment. There is thus still room for considerable improvement with regards to management of ULT in gout.


Mechanisms of iron regulation of luminescence in Vibrio fischeri.
Synthesis of luciferase (an autoinducible enzyme) is repressed by iron in the symbiotic bioluminescent bacterium Vibrio fischeri. Possible mechanisms of iron regulation of luciferase synthesis were tested with V. fischeri and with Escherichia coli clones containing plasmids carrying V. fischeri luminescence genes. Experiments were conducted in complete medium with and without the synthetic iron chelator ethylenediamine-di(o-hydroxyphenyl acetic acid). Comparison of the effect of ethylenediamine-di(o-hydroxyphenyl acetic acid) and another growth inhibitor, (2-n-heptyl-4-hydroxyquinoline-N-oxide), showed that iron repression is not due to inhibition of growth. A quantitative bioassay for autoinducer was developed with E. coli HB101 containing pJE411, a plasmid carrying V. fischeri luminescence genes with a transcriptional fusion between luxI and E. coli lacZ. Bioassay experiments showed no effect of iron on either autoinducer activity or production (before induction) or transcription of the lux operon. Ethylenediamine-di(o-hydroxyphenyl acetic acid) did not affect luciferase induction in E. coli strains with wild-type iron assimilation (ED8654) or impaired iron assimilation (RW193) bearing pJE202 (a plasmid with functional V. fischeri lux genes), suggesting that the genes responsible for the iron effect are missing or substituted in these clones. Two models are consistent with the data: (i) iron represses autoinducer transport, and (ii) iron acts through an autoinduction-independent regulatory system (e.g., an iron repressor).


Epidemiology of dementia in Central Africa (EPIDEMCA): protocol for a multicentre population-based study in rural and urban areas of the Central African Republic and the Republic of Congo.
The worldwide population is ageing and the proportion of elderly aged 60 and over is expected to dramatically rise in Low and Middle Income Countries (LMIC). The epidemic of dementia will not spare those countries, where the largest increases in numbers of people affected are estimated. Besides, dementia is still understudied in sub-Saharan Africa (SSA) compared to other regions. This paper describes the protocol for the 'Epidemiology of Dementia in Central Africa' population-based study, which aims at estimating the prevalence of dementia in two countries of Central Africa and investigating possible risk factors. A multicenter population-based study was carried out in Central African Republic and Republic of Congo between 2011 and 2012 including both urban and rural sites in each country. Around 2000 participants aged ≥65 years old were interviewed in total using the Community Screening Interview for Dementia (CSI-D), the GMS-AGECAT and the CERAD's 10-word list. Elderly with low performance to the cognitive part of the CSI-D (COGSCORE ≤ 24.5) were then clinically assessed by neurologists and underwent further psychometrical tests. DSM-IV and NINCDS-ADRDA criteria were required for dementia and Alzheimer's disease (AD) diagnoses respectively. The algorithmic 10/66 dementia diagnosis was also determined. Petersen's criteria were required for the diagnosis of Mild Cognitive Impairment. Sociodemographic, and environmental factors including vascular, nutritional, biological, psychosocial and lifestyle factors were collected in each setting in order to investigate factors associated with dementia. Blood sampling was realized to investigate genetic variations that could modify the risk of dementia. For now, no large epidemiological study has been undertaken to compare the prevalence of dementia in both rural and urban areas within SSA countries. This programme will provide further evidence regarding the prevalence of dementia in SSA, and also the possible rural/urban disparities existing with associated factors. Furthermore, the genetics of AD in those populations will be addressed.


Risk factors for spontaneous dyskinesia in schizophrenia.
We describe the prevalence, clinical correlates, and prognostic significance of spontaneous dyskinesias among 100 patients with schizophrenia from the Chestnut Lodge Follow-up Study who had never received treatment with neuroleptic agents up to and including the baseline assessment. Extensive case records were screened and descriptions of abnormal movements were recorded verbatim for blind rating. Neuroleptic-naive patients with and without abnormal oral-facial movements were compared across sign and symptom, schizophrenia subtype, and illness natural history variables. Excluding three patients with motor symptoms who had a history of neurologic illness or injury and three who had received prochlorperazine maleate therapy (Compazine), 23% of patient records documented some form of movement disorder; 15% documented oral-facial dyskinesias with sufficient detail so that their presence was considered nearly certain. Compared with patients with schizophrenia without oral-facial movements, patients with oral-facial dyskinesias were more likely to demonstrate a lower IQ score, had more negative symptoms at index admission, and were more symptomatic at follow-up an average of 23 years later. Both the classic hebephrenic schizophrenia subtype and Carpenter's Criteria for the Deficit Syndrome defined high-risk groups for spontaneous oral-facial dyskinesia. In previous studies, intellectual impairment and negative symptoms have been described as risk factors for neuroleptic-induced tardive dyskinesia. The present data, however, suggest that in many cases oral-facial dyskinesias in patients with intellectual impairment and negative symptoms may actually represent spontaneous movement disorders associated with hebephrenic or deficit forms of schizophrenia.


Thermodynamics, Charge Transfer and Practical Considerations of Solid Boosters in Redox Flow Batteries.
Solid boosters are an emerging concept for improving the performance and especially the energy storage density of the redox flow batteries, but thermodynamical and practical considerations of these systems are missing, scarce or scattered in the literature. In this paper we will formulate how these systems work from the point of view of thermodynamics. We describe possible pathways for charge transfer, estimate the overpotentials required for these reactions in realistic conditions, and illustrate the range of energy storage densities achievable considering different redox electrolyte concentrations, solid volume fractions and solid charge storage densities. Approximately 80% of charge storage capacity of the solid can be accessed if redox electrolyte and redox solid have matching redox potentials. 100 times higher active areas are required from the solid boosters in the tank to reach overpotentials of <10 mV.


Mapping QTL affecting a systemic sclerosis-like disorder in a cross between UCD-200 and red jungle fowl chickens.
Systemic sclerosis (SSc) or scleroderma is a rare, autoimmune, multi-factorial disease characterized by early microvascular alterations, inflammation, and fibrosis. Chickens from the UCD-200 line develop a hereditary SSc-like disease, showing all the hallmarks of the human disorder, which makes this line a promising model to study genetic factors underlying the disease. A backcross was generated between UCD-200 chickens and its wild ancestor - the red jungle fowl and a genome-scan was performed to identify loci affecting early (21 days of age) and late (175 days of age) ischemic lesions of the comb. A significant difference in frequency of disease was observed between sexes in the BC population, where the homogametic males were more affected than females, and there was evidence for a protective W chromosome effect. Three suggestive disease predisposing loci were mapped to chromosomes 2, 12 and 14. Three orthologues of genes implicated in human SSc are located in the QTL region on chromosome 2, TGFRB1, EXOC2-IRF4 and COL1A2, as well as CCR8, which is more generally related to immune function. IGFBP3 is also located within the QTL on chromosome 2 and earlier studies have showed increased IGFBP3 serum levels in SSc patients. To our knowledge, this study is the first to reveal a potential genetic association between IGFBP3 and SSc. Another gene with an immunological function, SOCS1, is located in the QTL region on chromosome 14. These results illustrate the usefulness of the UCD-200 chicken as a model of human SSc and motivate further in-depth functional studies of the implicated candidate genes.


The fasted/fed mouse metabolic acetylome: N6-acetylation differences suggest acetylation coordinates organ-specific fuel switching.
The elucidation of extra-nuclear lysine acetylation has been of growing interest, as the cosubstrate for acetylation, acetyl CoA, is at a key metabolic intersection. Our hypothesis was that mitochondrial and cytoplasmic protein acetylation may be part of a fasted/re-fed feedback control system for the regulation of the metabolic network in fuel switching, where acetyl CoA would be provided by fatty acid oxidation, or glycolysis, respectively. To test this, we characterized the mitochondrial and cytoplasmic acetylome in various organs that have a high metabolic rate relative to their mass, and/or switch fuels, under fasted and re-fed conditions (brain, kidney, liver, skeletal muscle, heart muscle, white and brown adipose tissues). Using immunoprecipitation, coupled with LC-MS/MS label free quantification, we show there is a dramatic variation in global quantitative profiles of acetylated proteins from different organs. In total, 733 acetylated peptides from 337 proteins were identified and quantified, out of which 31 acetylated peptides from the metabolic proteins that may play organ-specific roles were analyzed in detail. Results suggest that fasted/re-fed acetylation changes coordinated by organ-specific (de)acetylases in insulin-sensitive versus -insensitive organs may underlie fuel use and switching. Characterization of the tissue-specific acetylome should increase understanding of metabolic conditions wherein normal fuel switching is disrupted, such as in Type II diabetes.


Direct Monitoring of γ-Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized (13) C-Labeled Molecular Probe.
The γ-glutamyl transpeptidase (GGT) enzyme plays a central role in glutathione homeostasis. Direct detection of GGT activity could provide critical information for the diagnosis of several pathologies. We propose a new molecular probe, γ-Glu-[1-(13) C]Gly, for monitoring GGT activity in vivo by hyperpolarized (HP) (13) C magnetic resonance (MR). The properties of γ-Glu-[1-(13) C]Gly are suitable for in vivo HP (13) C metabolic analysis since the chemical shift between γ-Glu-[1-(13) C]Gly and its metabolic product, [1-(13) C]Gly, is large (4.3 ppm) and the T1 of both compounds is relatively long (30 s and 45 s, respectively, in H2 O at 9.4 T). We also demonstrate that γ-Glu-[1-(13) C]Gly is highly sensitive to in vivo modulation of GGT activity induced by the inhibitor acivicin.


Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease.
Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu-->Ala familial Alzheimer's disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Abeta42 peptides, our investigation revealed the presence of a complex array of Abeta peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Abeta species retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Abeta as a consequence of gamma-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions.


Vertebroplasty for the treatment of osteoporotic compression spinal fracture: comparison of remedial action at different stages of injury.
Outstanding results have been achieved using vertebroplasty for the treatment of osteoporotic compression spinal fractures, and a number of studies have reported the results from the application of this procedure. This study compared the results of vertebroplasty used at the different stages of injury. A retrospective study reviewing the period between January 2001 and July 2001 investigated 68 patients who underwent single-level vertebroplasty: 22 patients within 2 weeks of the injury, 22 patients 2 weeks to 2 months after the injury, and 24 patients more than 2 months after the injury. Clinical evaluations compared the results of treatment at different injury stages during a mean follow-up period of 13 months. Although all the patients undergoing vertebroplasty in the acute and subacute stages reported satisfaction within 1 week of the operation, only 72.7% of the acute-stage group reported satisfaction with 24 hours of surgery. Moreover, evidence of cement leakage after vertebroplasty was detected for 27.3% of the acute-stage patients. This percentage significantly higher than for the patients in the subacute and chronic stages. Radiographic examination showed that new, adjacent compression fracture had occurred for 10.3% of the patients, with anterior interbody restabilization occurring for 11.8%. The results for vertebroplasty treatment of osteoporotic compression fractures appear to be injury stage dependent, with patients in the acute-injury stage needing longer recovery times, and with cement leakage quite common. These findings lead to the conclusion that the subacute stage is optimal for vertebroplasty. Furthermore, it is suggested that the use of spinal orthoses and postsurgical supplementation for the bone matrix reduces the risk of new, adjacent compression fractures and increases anterior interbody restabilization. Importantly, the findings suggest that a presurgical magnetic resonance imaging evaluation is an absolute necessity.


Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression.
Activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically-approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class smallmolecule inhibitor of non-canonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking non-canonical G-protein signaling in tumor cells, and inhibiting pro-invasive traits of metastatic cancer cells in vitro and in mice. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable non-canonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.


Marine structure derived calcium phosphate-polymer biocomposites for local antibiotic delivery.
Hydrothermally converted coralline hydroxyapatite (HAp) particles loaded with medically active substances were used to develop polylactic acid (PLA) thin film composites for slow drug delivery systems. The effects of HAp particles within PLA matrix on the gentamicin (GM) release and release kinetics were studied. The gentamicin release kinetics seemed to follow Power law Korsmeyer Peppas model with mainly diffusional process with a number of different drug transport mechanisms. Statistical analysis shows very significant difference on the release of gentamicin between GM containing PLA (PLAGM) and GM containing HAp microspheres within PLA matrix (PLAHApGM) devices, which PLAHApGM displays lower release rates. The use of HAp particles improved drug stabilization and higher drug encapsulation efficiency of the carrier. HAp is also the source of Ca2+ for the regeneration and repair of diseased bone tissue. The release profiles, exhibited a steady state release rate with significant antimicrobial activity against Staphylococcus aureus (S. aureus) (SH1000) even at high concentration of bacteria. The devices also indicated significant ability to control the growth of bacterial even after four weeks of drug release. Clinical release profiles can be easily tuned from drug-HAp physicochemical interactions and degradation kinetics of polymer matrix. The developed systems could be applied to prevent microbial adhesion to medical implant surfaces and to treat infections mainly caused by S. aureus in surgery.


Isotope evidence for the intensive use of marine foods by Late Upper Palaeolithic humans.
We report here on direct evidence for the intensive consumption of marine foods by anatomically modern humans at approximately 12,000 years ago. We undertook isotopic analysis of bone collagen from three humans, dating to the late Palaeolithic, from the site of Kendrick's Cave in North Wales, UK. The isotopic measurements of their bone collagen indicated that ca. 30% of their dietary protein was from marine sources, which we interpret as likely being high trophic level marine organisms such as marine mammals. This indicates that towards the end of the Pleistocene modern humans were pursuing a hunting strategy that incorporated both marine and terrestrial mammals. This is the first occurrence of the intensive use of marine resources, specifically marine mammals, that becomes even more pronounced in the subsequent Mesolithic period.


Fluid Dynamics of a Novel Micro-Fistula Implant for the Surgical Treatment of Glaucoma.
The purpose of this study was to describe the fluidics of a novel non-valved glaucoma implant designed to prevent hypotony and compare the fluidics of this device with two commonly used non-valved glaucoma devices. The XEN 45 micro-fistula implant was designed to limit hypotony by virtue of its length and width according to the Hagen-Poiseuille equation. Flow testing was performed using a syringe pump and pressure transducer at multiple flow rates. The pressure differentials across the XEN implant, the Ex-Press implant, and 10 mm of silicone tubing from a Baerveldt implant at a physiologic flow rate (2.5 μL/min) were extrapolated. The XEN 45 achieved a steady-state pressure calculated at 7.56 mm Hg at 2.5 μL/min. At the same flow rate, the Ex-Press device and Baerveldt tubing reached steady-state pressures of 0.09 and 0.01 mm Hg, respectively. Under flow testing, the XEN micro-fistula implant was able to maintain backpressure above numerical hypotony levels without the use of complex valve systems. This is due to the XEN implant's design, derived from the principles that dictate Newtonian fluids.


Birds and viruses at a crossroad--surveillance of influenza A virus in Portuguese waterfowl.
During recent years, extensive amounts of data have become available regarding influenza A virus (IAV) in wild birds in northern Europe, while information from southern Europe is more limited. Here, we present an IAV surveillance study conducted in western Portugal 2008-2009, analyzing 1653 samples from six different species of waterfowl, with the majority of samples taken from Mallards (Anas platyrhynchos). Overall 4.4% of sampled birds were infected. The sampling results revealed a significant temporal variation in the IAV prevalence, including a pronounced peak among predominantly young birds in June, indicating that IAV circulate within breeding populations in the wetlands of western Portugal. The H10N7 and H9N2 subtypes were predominant among isolated viruses. Phylogenetic analyses of the hemagglutinin and neuraminidase sequences of H10N7, H9N2 and H11N3 virus showed that sequences from Portugal were closely related to viral sequences from Central Europe as well as to IAVs isolated in the southern parts of Africa, reflecting Portugal's position on the European-African bird migratory flyway. This study highlights the importance of Portugal as a migratory crossroad for IAV, connecting breeding stationary waterfowl with birds migrating between continents which enable transmission and spread of IAV.


Using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for Predicting Institutionalization of Patients With Dementia in Taiwan.
World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is an assessment tool and it has been applied for disability status assessment of Taiwanese dementia patients since July 2012. The aim of this study was to investigate the predicting accuracy of WHODAS 2.0 for institutionalization of dementia patients.Of these patients, 13,774 resided in a community and 4406 in a long-term care facility. Demographic data and WHODAS 2.0 standardized scores were analyzed using the Chi-square test and independent t test to compare patients with dementia in an institution with those in a community. The receiver operating characteristic (ROC) curve was applied to investigate accuracy in predicting institutionalization, and the optimal cutoff point was determined using the Youden index. Binary logistic regression was used to analyze variables to determine risk factors for the institutionalization of patients with dementia.WHODAS 2.0 scores in all domains were higher in patients with dementia in a long-term care facility than in those in a community (P < 0.01). The ROC curve showed moderate accuracy for all domains of WHODAS 2.0 (area under curve 0.6~0.8). Binary logistic regression revealed that the male gender, severity of disease, and standardized WHODAS 2.0 scores surpassing the cutoff values were risk factors for the institutionalization of patients with dementia.Although the accuracy of WHODAS 2.0 in predicting institutionalization is not considerably high for patients with dementia, our study found that the WHODAS 2.0 scores, the male gender, education status, urbanization level, and severity of disease were risk factors for institutionalization in long-term care facilities.


Potential effects of environmental contaminants on P450 aromatase activity and DNA damage in swallows from the Rio Grande and Somerville, Texas.
Cliff swallows (Petrochelidon pyrrhonota) and cave swallows (P. fulva) were sampled during the breeding season at several locations in the Rio Grande, Texas, to evaluate the potential effects of environmental contaminants on P450 aromatase activity in brain and gonads and DNA damage in blood cells. The tritiated water-release aromatase assay was used to measure aromatase activity and flow cytometry was used to measure DNA damage in nucleated blood cells. There were no significant differences in brain and gonadal aromatase activities or in estimates of DNA damage (HPCV values) among cave swallow colonies from the Lower Rio Grande Valley (LRGV) and Somerville. However, both brain and gonadal aromatase activities were significantly higher (P < 0.05) in male cliff swallows from Laredo than in those from Somerville. Also, DNA damage estimates were significantly higher (P < 0.05) in cliff swallows (males and females combined) from Laredo than in those from Somerville. Contaminants of current high use in the LRGV, such as atrazine, and some of the highly persistent organochlorines, such as toxaphene and DDE, could be potentially associated with modulation of aromatase activity in avian tissues. Previous studies have indicated possible DNA damage in cliff swallows. We did not observe any differences in aromatase activity or DNA damage in cave swallows that could be associated with contaminant exposure. Also, the differences in aromatase activity and DNA damage between male cliff swallows from Laredo and Somerville could not be explained by contaminants measured at each site in previous studies. Our study provides baseline information on brain and gonadal aromatase activity in swallows that could be useful in future studies.


Identification of minor components of coated vesicles by use of permeation chromatography.
Coated vesicles are thought to be vehicles for the intracellular transport of membranes. Clathrin is the major protein component of coated vesicles. Minor components of these organelles can be identified in highly purified preparations if they can be shown to copurify with clathrin. To show copurification we have made use of the relatively uniform diameter of coated vesicles (50-150 nm) to fractionate conventionally purified coated vesicles according to size in glass bead columns of 200-nm pore size. We have found that bovine brain coated vesicles prepared by the standard procedure of Pearse can be contaminated with large membrane fragments that are removed by permeation chromatography on such glass bead columns. Gel electrophoretic analysis of column fractions shows that only three major polypeptide chains, and a family of polypeptides with molecular weights close to 100,000 are always in constant ratio to clathrin, and are unique to fractions containing coated vesicles. Two other major polypeptides that appear to be components of coated vesicles are also present in other membrane fractions. We have also used permeation chromatography to monitor artifactual membrane trapping during vesicle isolation. Pure radiolabeled synaptic vesicle membranes were added to bovine brain tissue before homogenization. Considerable amounts of the added radioactivity could be recovered in the fractions conventionally pooled in the preparation of coated vesicles. After permeation chromatography, the radioactivity in the coated vesicle peak was reduced essentially to background.


A versatile prion replication assay in organotypic brain slices.
Methods enabling prion replication ex vivo are important for advancing prion studies. However, few such technologies exist, and many prion strains are not amenable to them. Here we describe a prion organotypic slice culture assay (POSCA) that allows prion amplification and titration ex vivo under conditions that closely resemble intracerebral infection. Thirty-five days after contact with prions, mouse cerebellar slices had amplified the abnormal isoform of prion protein, PrP(Sc), >10(5)-fold. This is quantitatively similar to amplification in vivo, but fivefold faster. PrP(Sc) accumulated predominantly in the molecular layer, as in infected mice. The POSCA detected replication of prion strains from disparate sources, including bovines and ovines, with variable detection efficiency. Pharmacogenetic ablation of microglia from POSCA slices led to a 15-fold increase in prion titers and PrP(Sc) concentrations over those in microglia-containing slices, as well as an increase in susceptibility to infection. This suggests that the extensive microglial activation accompanying prion diseases represents an efficacious defensive reaction.


Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery.
Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg-1 , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery.


Silencing expression of the defensin, varisin, in male Dermacentor variabilis by RNA interference results in reduced Anaplasma marginale infections.
Antimicrobial peptides, including defensins, are components of the innate immune system in ticks that have been shown to provide protection against both gram-negative and gram-positive bacteria. Varisin, one of the defensins identified in Dermacentor variabilis, was shown to be produced primarily in hemocytes but transcript levels were also expressed in midguts and other tick cells. In this research, we studied the role of varisin in the immunity of ticks to the gram-negative cattle pathogen, Anaplasma marginale. Expression of the varisin gene was silenced by RNA interference (RNAi) in which male ticks were injected with varisin dsRNA and then allowed to feed and acquire A. marginale infection on an experimentally-infected calf. Silencing expression of varisin in hemocytes, midguts and salivary glands was confirmed by real time RT-PCR. We expected that silencing of varisin would increase A. marginale infections in ticks, but the results demonstrated that bacterial numbers, as determined by an A. marginale msp4 quantitative PCR, were significantly reduced in the varisin-silenced ticks. Furthermore, colonies of A. marginale in ticks used for RNAi were morphologically abnormal from those seen in elution buffer injected control ticks. The colony shape was irregular and in some cases the A. marginale appeared to be free in the cytoplasm of midgut cells. Some ticks were found to be systemically infected with a microbe that may have been related to the silencing of varisin. This appears to be the first report of the silencing of expression of a defensin in ticks by RNAi that resulted in reduced A. marginale infections.


Stacking fault energy of face-centered cubic metals: thermodynamic and ab initio approaches.
The formation energy of the interface between face-centered cubic (fcc) and hexagonal close packed (hcp) structures is a key parameter in determining the stacking fault energy (SFE) of fcc metals and alloys using thermodynamic calculations. It is often assumed that the contribution of the planar fault energy to the SFE has the same order of magnitude as the bulk part, and thus the lack of precise information about it can become the limiting factor in thermodynamic predictions. Here, we differentiate between the interfacial energy for the coherent fcc(1 1 1)/hcp(0 0 0 1) interface and the 'pseudo-interfacial energy' that enters the thermodynamic expression for the SFE. Using first-principles calculations, we determine the coherent and pseudo-interfacial energies for six elemental metals (Al, Ni, Cu, Ag, Pt, and Au) and three paramagnetic Fe-Cr-Ni alloys. Our results show that the two interfacial energies significantly differ from each other. We observe a strong chemistry dependence for both interfacial energies. The calculated pseudo-interfacial energies for the Fe-Cr-Ni steels agree well with the available literature data. We discuss the effects of strain on the description of planar faults via thermodynamic and ab initio approaches.


Longer-than-unit-length viroid minus strands are present in RNA from infected plants.
Nucleic acids isolated from uninfected and potato spindle tuber viroid-infected Rutgers tomato plants were fractionated on agarose gels under two different sets of denaturing conditions and hybridized to (125)I-labeled viroid in a series of blot hybridization experiments. Complementary strand nucleic acids detected in extracts of infected plants were heterogeneous in size, with four discrete bands containing molecules approximately 700, 1050, 1500, and 1800 nucleotides long. Enzymatic studies indicated that these viroid minus strands are composed exclusively of RNA and, as extracted, are present in complexes containing extensive double-stranded regions. After treatment with several RNases under conditions favoring digestion of single-stranded regions, the high molecular weight minus strands can no longer be detected and roughly unit-length minus strands appear. A model for the structure of the viroid replication intermediate is proposed.


Somatic symptoms most often associated with depression in an urban hospital medical setting in Japan.
Somatic symptoms are known to be the major manifestation in patients with depression. The aim of the present study was to investigate the major somatic and psychiatric symptoms associated with depression in each sex. Patients with a DSM-IV diagnosis of depressive disorders (n=335) and comparison patients without depression (n=425) among new outpatients in an urban hospital medical setting were eligible for study. The relationship between the three most distressing subjective symptoms at the first visit, confirmed by the patient's description on a health questionnaire and the admitting physician's interview, and depression was investigated in each sex. Most (77.4%) of the complaints in patients with depression were somatic. In a simple logistic regression analysis, diarrhea, excessive sweating and psychomotor retardation in men, and headache, depressed mood and grief in women were associated with depression. In multiple logistic regression analysis, diarrhea, excessive sweating and weight loss in men, and headache, dysesthesia and grief in women, as well as sleep disturbance, loss of appetite, general fatigue, loss of interest and agitation in both sexes, were statistically significantly associated with depression. Fever in men was also associated with depression by Fisher's exact test.


NMD microarray analysis for rapid genome-wide screen of mutated genes in cancer.
Gene mutations play a critical role in cancer development and progression, and their identification offers possibilities for accurate diagnostics and therapeutic targeting. Finding genes undergoing mutations is challenging and slow, even in the post-genomic era. A new approach was recently developed by Noensie and Dietz to prioritize and focus the search, making use of nonsense-mediated mRNA decay (NMD) inhibition and microarray analysis (NMD microarrays) in the identification of transcripts containing nonsense mutations. We combined NMD microarrays with array-based CGH (comparative genomic hybridization) in order to identify inactivation of tumor suppressor genes in cancer. Such a "mutatomics" screening of prostate cancer cell lines led to the identification of inactivating mutations in the EPHB2 gene. Up to 8% of metastatic uncultured prostate cancers also showed mutations of this gene whose loss of function may confer loss of tissue architecture. NMD microarray analysis could turn out to be a powerful research method to identify novel mutated genes in cancer cell lines, providing targets that could then be further investigated for their clinical relevance and therapeutic potential.


An overview of chemotherapeutic targets for antimalarial drug discovery.
The need for new antimalarials comes from the widespread resistance to those in current use. New antimalarial targets are required to allow the discovery of chemically diverse, effective drugs. The search for such new targets and new drug chemotypes will likely be helped by the advent of functional genomics and structure-based drug design. After validation of the putative targets as those capable of providing effective and safe drugs, targets can be used as the basis for screening compounds in order to identify new leads, which, in turn, will qualify for lead optimization work. The combined use of combinatorial chemistry--to generate large numbers of structurally diverse compounds--and of high throughput screening systems--to speed up the testing of compounds--hopefully will help to optimize the process. Potential chemotherapeutic targets in the malaria parasite can be broadly classified into three categories: those involved in processes occurring in the digestive vacuole, enzymes involved in macromolecular and metabolite synthesis, and those responsible for membrane processes and signalling. The processes occurring in the digestive vacuole include haemoglobin digestion, redox processes and free radical formation, and reactions accompanying haem release followed by its polymerization into haemozoin. Many enzymes in macromolecular and metabolite synthesis are promising potential targets, some of which have been established in other microorganisms, although not yet validated for Plasmodium, with very few exceptions (such as dihydrofolate reductase). Proteins responsible for membrane processes, including trafficking and drug transport and signalling, are potentially important also to identify compounds to be used in combination with antimalarial drugs to combat resistance.


Probing the effect of minor groove interactions on the catalytic efficiency of DNAzymes 8-17 and 10-23.
DNAzymes (Dz) 8-17 and 10-23 are two widely studied and well-characterized RNA-cleaving DNA catalysts. In an effort to further improve the understanding of the fragile interactions and dynamics of the enzymatic mechanism, this study examines the catalytic efficiency of minimally modified DNAzymes. Five single mutants of Dz8-17 and Dz10-23 were prepared by replacing the adenine residues in the corresponding catalytic cores with 3-deazaadenine units. Kinetic assays were used to assess the effect on the catalytic activity and thereby identify the importance of hydrogen bonding that arises from the N3 atoms. The results suggest that modifications at A15 and A15.0 of Dz8-17 have a significant influence and show a reduction in catalytic activity. Modification at each location in Dz10-23 results in a decrease of the observed rate constants, with A12 appearing to be the most affected with a reduction of ∼80% of kobs and ∼25% of the maximal cleavage rate compared to the wild-type DNAzyme. On the other hand, modification of A12 in Dz8-17 showed an ∼130% increase in kobs, thus unraveling a new potential site for the introduction of chemical modifications. A pH-profile analysis showed that the chemical cleavage step is rate-determining, regardless of the presence and/or location of the mutation. These findings point towards the importance of the N3-nitrogens of certain adenine nucleotides located within the catalytic cores of the DNAzymes for efficient catalytic activity and further suggest that they might directly partake in maintaining the appropriate tertiary structure. Therefore, it appears that minor groove interactions constitute an important feature of DNAzymes as well as ribozymes.


Management of patients with anterior abdominal stab wounds: a Western Trauma Association multicenter trial.
The optimal management of hemodynamically stable, asymptomatic patients with anterior abdominal stab wounds (AASWs) remains controversial. The goal is to identify and treat injuries in a safe, cost-effective manner. Common evaluation strategies include local wound exploration (LWE)/diagnostic peritoneal lavage (DPL), serial clinical assessments (SCAs), and computed tomography (CT) imaging. The purpose of this multicenter study was to evaluate the clinical course of patients managed by the various strategies, to determine whether there are differences in associated nontherapeutic laparotomy (NONTHER LAP), emergency department (ED) discharge, or complication rates. A multicenter, Institutional Review Board-approved study enrolled patients with AASWs. Management was individualized according to surgeon/institutional protocols. Data on the presentation, evaluation, and clinical course were recorded prospectively. Three hundred fifty-nine patients were studied. Eighty-one had indications for immediate LAP, of which 84% were therapeutic. ED D/C was facilitated by LWE, CT, and DPL in 23%, 21%, and 16% of patients, respectively. On the other hand, LAP based on abnormalities on LWE, CT, and DPL were NONTHER in 57%, 24%, and 31% of patients, respectively. Twelve percent of patients selected for SCA ultimately had LAP (33% were NONTHER); there was no apparent morbidity due to delay in intervention. Shock, evisceration, and peritonitis warrant immediate LAP after AASW. Patients without these findings can be safely observed for signs or symptoms of bleeding or hollow viscus injury. To limit the number of hospital admissions, we propose a uniform strategy using LWE to ascertain the depth of penetration; the patient may be safely discharged in the absence of peritoneal violation. Peritoneal penetration, absent evidence of ongoing hemorrhage or hollow viscus injury, should not be considered an indication for LAP, but rather an indication for admission for SCAs. We suggest that a prospective multicenter trial be performed to document the safety and cost-effectiveness of such an approach.


Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes.
Among individuals without diabetes, elevated hemoglobin A1c (HbA1c) has been associated with increased morbidity and mortality, but the literature is sparse regarding the prognostic importance of low HbA1c. National Health and Nutrition Examination Survey III (NHANES III) participants, 20 years and older, were followed up to 12 years (median follow-up, 8.8 years) for all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between HbA1c levels and all-cause mortality for 14 099 participants without diabetes. There were 1825 deaths during the follow-up period. Participants with a low HbA1c (<4.0%) had the highest levels of mean red blood cell volume, ferritin, and liver enzymes and the lowest levels of mean total cholesterol and diastolic blood pressure compared with their counterparts with HbA1c levels between 4.0% and 6.4%. An HbA1c <4.0% versus 5.0% to 5.4% was associated with an increased risk of all-cause mortality (HR, 3.73; 95% CI, 1.45 to 9.63) after adjustment for age, race-ethnicity, and sex. This association was attenuated but remained statistically significant after further multivariable adjustment for lifestyle, cardiovascular factors, metabolic factors, red blood cell indices, iron storage indices, and liver function indices (HR, 2.90; 95% CI, 1.25 to 6.76). In this nationally representative cohort, low HbA1c was associated with increased all-cause mortality among US adults without diabetes. Additional research is needed to confirm these results and identify potential mechanisms that may be underlying this association.


Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.
Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.


The Drosophila pipsqueak gene encodes a nuclear BTB-domain-containing protein required early in oogenesis.
Mutations at the pipsqueak locus affect early patterning in the Drosophila egg and embryo. We have cloned pipsqueak and found that it is a large and complex gene, encoding multiple transcripts and protein isoforms. One protein, PsqA, is absent in all of the mutants that we have examined. We show that PsqA is a nuclear protein present in the germ cells and somatically derived follicle cells throughout oogenesis and that it is required prior to stage one of oogenesis. PsqA contains a BTB (POZ) domain at its amino terminus; additionally, we have identified an evolutionarily conserved motif of unknown function present four times in tandem at the C terminus of the protein. PZ pipsqueak mutants produce a putative fusion protein containing the pipsqueak BTB domain fused to sequences resident on the PZ element (H. Horowitz and C. Berg, 1995 Genetics 139, 327-335). We demonstrate here that expression of this fusion protein in wild-type flies has a dominant effect, resulting in infertility and eggshell defects. These dominant phenotypes are discussed in light of current theories on the role of the BTB domain in protein-protein interactions.


Pre-labelling versus direct labelling of anthrax proteins for imaging of matrix metalloproteinases activity using DOTA-GA.
Increased activity of matrix metalloproteases (MMPs) is associated with reduced survival in several cancer subtypes. Aiming to produce an MMP tumour cell-selective cytotoxin, we genetically modified both components of the AB-type lethal toxin from Bacillus anthracis. Component A, Protective Antigen (PA-WT), was re-engineered to form an oligomeric pore in cell membranes only when cleaved by MMPs (PA-L1). The pore-translocation domain (LFn - N-terminal, 30 kDa) of the Lethal Factor (LF), component B, was fused to the catalytic domain of Pseudomonas exotoxin-A to increase its cytotoxic effect when delivered to cancerous cells. Here, we develop radiolabelled forms of LFn for MMP activity imaging by SPECT using the LFn/PA-L1 system. DOTA-GA-maleimide was conjugated to LFn to allow radiolabelling with 111In via two different routes: (1) LFn was conjugated with maleimide-DOTA-GA under mild conditions, and then radiolabelled in acidic conditions at 95°C, or (2) 111In was coordinated to maleimide-DOTA-GA first and then conjugated via maleimide chemistry to LFn. Circular Dichroism Spectroscopy of LFn was performed to evaluate changes in its secondary structure. Cell uptake assays using the differently labelled forms of [111In]In-DOTA-GA-LFn in the presence or not of PA-WT or PA-L1 were performed. LFn was successfully radiolabelled by either strategy. Comparison of the secondary structure content of LFn exposed to 37°C or 95°C, showed a loss of alpha helix content at higher temperatures. Cell uptake of both forms of [111In]In-DOTA-GA-LFn, labelled directly or indirectly, was significantly higher in MMP-positive cells, in the presence of PA-L1, compared to controls. Notably, despite being exposed to high temperatures, uptake of directly labelled [111In]In-DOTA-GA-LFndir was higher than indirectly labelled [111In]In-DOTA-GA-LFnindir. 111In-radiolabelling of LFn results in a functional molecule that targets MMP-activity in cells when combined with PA-L1. [111In]In-LFn/PA-L1 is a promising MMP activity imaging agent for SPECT imaging.


Can emotional content reduce the age gap in visual working memory? Evidence from two tasks.
Ageing is associated with declines in several cognitive abilities including working memory (WM). The goal of the present study was to assess whether emotional information could reduce the age gap in the quantity and quality (precision) of representations in visual WM. Young and older adults completed a serial image recognition (SIR) task and a colour-image binding (CIB) task. Results of the SIR task showed worse performance for negative than neutral and positive images within the older group, hence enlarging the age gap in WM. In the CIB task, recall precision was lower in the old than young adults, showing an ageing decline in the quality of WM representations. Positive images tended to improve precision, but this boost was similar for both age groups. In sum, emotional content did not reduce the age gap in visual WM.


Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1.
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that predisposes sufferers to various forms of neoplasia. Among affected individuals, 15%-20% develop astrocytomas, especially pilocytic astrocytomas (PA), which are benign and classified as grade I by the World Health Organization. They are generally well circumscribed, and their progression is slow. NF1-associated PAs (NF1-PAs) occasionally behave as aggressive tumors. To elucidate underlying genetic events in clinically progressive NF1-PAs, we performed molecular genetic analysis on 12 PAs, including 3 NF1-PAs, for pS3, p16, and epidermal growth factor receptor genes, as well as loss of heterozygosity (LOH) on chromosome 1p, 10, 17, and 19q. None of the obvious genetic alterations typically seen in higher grade astrocytomas were found in 9 sporadic PAs. However, in 2 of 3 NF1-PAs, microsatellite analysis showed LOH10, including the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene locus, despite the diagnosis of pilocytic astrocytoma;one of these also manifested homozygous deletion of the p16 gene. The other NF1-PA harbored only LOH of the NF1 gene locus (17q). Our preliminary results support the hypothesis that some NF1-PAs differ genetically from sporadic PAs.


Synthesis of sequence controlled acrylate oligomers via consecutive RAFT monomer additions.
An effective procedure to synthesize sequence controlled oligoacrylates with up to four monomer insertions via the RAFT technique is presented. Two different sets of oligomers with a preferred monomer order were synthesized. Recycling SEC allowed for facile and automated purification of the monodisperse sequence-controlled materials.


A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans.
A variety of mechanisms have been proposed to explain the extension of adult life span (Age) seen in several mutants in Caenorhabditis elegans (age-1: an altered aging rate; daf-2 and daf-23: activation of a dauer-specific longevity program; spe-26: reduced fertility; clk-1: an altered biological clock). Using an assay for ultraviolet (UV) resistance in young adult hermaphrodites (survival after UV irradiation), we observed that all these Age mutants show increased resistance to UV. Moreover, mutations in daf-16 suppressed the UV resistance as well as the increased longevity of all the Age mutants. In contrast to the multiple mechanisms initially proposed, these results suggest that a single, daf-16-dependent pathway, specifies both extended life span and increased UV resistance. The mutations in daf-16 did not alter the reduced fertility of spe-26 and interestingly a daf-16 mutant is more fertile than wild type. We propose that life span and some aspects of stress resistance are jointly negatively regulated by a set of gerontogenes (genes whose alteration causes life extension) in C. elegans.


Clinically Meaningful Change for Physical Performance: Perspectives of the ICFSR Task Force.
For clinical studies of sarcopenia and frailty, clinically meaningful outcome measures are needed to monitor disease progression, evaluate efficacy of interventions, and plan clinical trials. Physical performance measures including measures of gait speed and other aspects of mobility and strength have been used in many studies, although a definition of clinically meaningful change in performance has remained unclear. The International Conference on Frailty and Sarcopenia Research Task Force (ICFSR-TF), a group of academic and industry scientists investigating frailty and sarcopenia, met in Miami Beach, Florida, USA in February 2019 to explore approaches for establishing clinical meaningfulness in a manner aligned with regulatory authorities. They concluded that clinical meaningful change is contextually dependent, and that both anchor- based and distribution-based methods of quantifying physical function are informative and should be evaluated relative to patient-reported outcomes. In addition, they identified additional research needed to enable setting criteria for clinical meaningful change in trials.


Tandem chemo-mobilization followed by high-dose melphalan and carmustine with single autologous hematopoietic cell transplantation for multiple myeloma.
Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemo-mobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m(2) plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR)+CR pre-mobilization to 76% VGPR+CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P=0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P=0.80). The 100-day non-relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates.


In vivo hydrodynamic delivery of cDNA encoding IL-2: rapid, sustained redistribution, activation of mouse NK cells, and therapeutic potential in the absence of NKT cells.
In the present study, we have tested the ability of hydrodynamically delivered IL-2 cDNA to modulate the number and function of murine leukocyte subsets in different organs and in mice of different genetic backgrounds, and we have evaluated effects of this mode of gene delivery on established murine tumor metastases. Hydrodynamic administration of the IL-2 gene resulted in the rapid and transient production of up to 160 ng/ml IL-2 in the serum. The appearance of IL-2 was followed by transient production of IFN-gamma and a dramatic and sustained increase in NK cell numbers and NK-mediated cytolytic activity in liver and spleen leukocytes. In addition, significant increases in other lymphocyte subpopulations (e.g., NKT, T, and B cells) that are known to be responsive to IL-2 were observed following IL-2 cDNA plasmid delivery. Finally, hydrodynamic delivery of only 4 mug of the IL-2 plasmid to mice bearing established lung and liver metastases was as effective in inhibiting progression of metastases as was the administration of large amounts (100,000 IU/twice daily) of IL-2 protein. Studies performed in mice bearing metastatic renal cell tumors demonstrated that the IL-2 cDNA plasmid was an effective treatment against liver metastasis and moderately effective against lung metastasis. Collectively, these results demonstrate that hydrodynamic delivery of relatively small amounts of IL-2 cDNA provides a simple and inexpensive method to increase the numbers of NK and NKT cells, to induce the biological effects of IL-2 in vivo for use in combination with other biological agents, and for studies of its antitumor activity.


The association between imitation recognition and socio-communicative competencies in chimpanzees (Pan troglodytes).
Imitation recognition provides a viable platform from which advanced social cognitive skills may develop. Despite evidence that non-human primates are capable of imitation recognition, how this ability is related to social cognitive skills is unknown. In this study, we compared imitation recognition performance, as indicated by the production of testing behaviors, with performance on a series of tasks that assess social and physical cognition in 49 chimpanzees. In the initial analyses, we found that males were more responsive than females to being imitated and engaged in significantly greater behavior repetitions and testing sequences. We also found that subjects who consistently recognized being imitated performed better on social but not physical cognitive tasks, as measured by the Primate Cognitive Test Battery. These findings suggest that the neural constructs underlying imitation recognition are likely associated with or among those underlying more general socio-communicative abilities in chimpanzees. Implications regarding how imitation recognition may facilitate other social cognitive processes, such as mirror self-recognition, are discussed.


Cost-Effectiveness of Antibody-Based Induction Therapy in Deceased Donor Kidney Transplantation in the United States.
Induction therapy in deceased donor kidney transplantation is costly, with wide discrepancy in utilization and a limited evidence base, particularly regarding cost-effectiveness. We linked the United States Renal Data System data set to Medicare claims to estimate cumulative costs, graft survival, and incremental cost-effectiveness ratio (ICER - cost per additional year of graft survival) within 3 years of transplantation in 19 450 deceased donor kidney transplantation recipients with Medicare as primary payer from 2000 to 2008. We divided the study cohort into high-risk (age > 60 years, panel-reactive antibody > 20%, African American race, Kidney Donor Profile Index > 50%, cold ischemia time > 24 hours) and low-risk (not having any risk factors, comprising approximately 15% of the cohort). After the elimination of dominated options, we estimated expected ICER among induction categories: no-induction, alemtuzumab, rabbit antithymocyte globulin (r-ATG), and interleukin-2 receptor-antagonist. No-induction was the least effective and most costly option in both risk groups. Depletional antibodies (r-ATG and alemtuzumab) were more cost-effective across all willingness-to-pay thresholds in the low-risk group. For the high-risk group and its subcategories, the ICER was very sensitive to the graft survival; overall both depletional antibodies were more cost-effective, mainly for higher willingness to pay threshold (US $100 000 and US $150 000). Rabbit ATG appears to achieve excellent cost-effectiveness acceptability curves (80% of the recipients) in both risk groups at US $50 000 threshold (except age > 60 years). In addition, only r-ATG was associated with graft survival benefit over no-induction category (hazard ratio, 0.91; 95% confidence interval, 0.84-0.99) in a multivariable Cox regression analysis. Antibody-based induction appears to offer substantial advantages in both cost and outcome compared with no-induction. Overall, depletional induction (preferably r-ATG) appears to offer the greatest benefits.


Variation in blame attributions across different cancer types.
Cancer communication has begun to focus on prevention through lifestyle change. One possible consequence of this is that attitudes towards people with certain types of cancer could become increasingly negative. In this study, we assessed attributions of blame for five common cancers. Data were collected as part of a population-based survey of women's attitudes to cancer. A sample of 1,620 women rated how much they would blame someone who had a diagnosis of breast cancer, cervical cancer, bowel cancer, lung cancer, and leukemia, as well as chlamydia and obesity. Few women attributed any blame for someone with leukemia or breast cancer (9% and 15%). The proportions attributing some blame for bowel cancer and cervical cancer were slightly higher (23% and 37%). Patients with lung cancer were considered at least partly to blame by 70% of respondents, approaching chlamydia (87%) and obesity (96%). Attributions of blame for bowel, cervical, and lung cancer were most common among those with more qualifications, and women who knew that cervical cancer was linked to sexual activity were more likely to attribute blame to it (48% versus 32%). Cancers are not generally seen as a matter of personal responsibility, but lung cancer, and to a lesser extent, cervical and bowel cancer do attract blame attributions. Knowledge of the preventability of cancer seems to be associated with perceived responsibility. Increasing awareness of the preventable nature of some cancers might affect blame attributions. Additional research is needed to explore the implications of these findings.


The neural basis of hand gesture comprehension: A meta-analysis of functional magnetic resonance imaging studies.
Gestures play an important role in face-to-face communication and have been increasingly studied via functional magnetic resonance imaging. Although a large amount of data has been provided to describe the neural substrates of gesture comprehension, these findings have never been quantitatively summarized and the conclusion is still unclear. This activation likelihood estimation meta-analysis investigated the brain networks underpinning gesture comprehension while considering the impact of gesture type (co-speech gestures vs. speech-independent gestures) and task demand (implicit vs. explicit) on the brain activation of gesture comprehension. The meta-analysis of 31 papers showed that as hand actions, gestures involve a perceptual-motor network important for action recognition. As meaningful symbols, gestures involve a semantic network for conceptual processing. Finally, during face-to-face interactions, gestures involve a network for social emotive processes. Our finding also indicated that gesture type and task demand influence the involvement of the brain networks during gesture comprehension. The results highlight the complexity of gesture comprehension, and suggest that future research is necessary to clarify the dynamic interactions among these networks.


Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma.
To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had <or= one line of chemotherapy for recurrent and/or metastatic disease, Eastern Cooperative Oncology Group performance status of <or= 2, and adequate organ function. At the end of stage 1, efficacy criteria for further accrual were not met, but the study was amended to enroll an additional five patients for paired tumor biopsies. Twenty-seven and 26 patients were eligible for toxicity and efficacy evaluations, respectively. One patient (3.7%; 95% CI, 0.1% to 19.0%) achieved a partial response. Disease stabilization was maintained in 10 patients (37.0%; 95% CI, 22.4% to 61.2%). The median time to progression was 1.8 months (95% CI, 1.6 to 3.4 months), and median overall survival time was 4.2 months (95% CI, 3.6 to 8.7 months). Sorafenib was well tolerated with few grade 3 and no grade 4 toxicities. Biomarker analysis of paired tumor samples before and after treatment with sorafenib revealed a decrease of pERK in all five patients, with a decrease in Ki67 in four patients, consistent with a disruption of ERK signaling. The antiapoptotic protein Mcl-1 was downregulated in four patients, and there was also evidence of antiangiogenic activity. Sorafenib was well tolerated and had modest anticancer activity comparable to monotherapy with other targeted agents in this group of patients. Further development in combination with radiation or other agents may be warranted.


Sugar-sweetened beverages, urate, gout and genetic interaction.
The clinical manifestations of gout occur as a result of immune responses to monosodium urate crystals. Elevated serum levels of urate (hyperuricemia) are a prerequisite for the development of gout with reduced fractional renal excretion of uric acid (FEUA) an important cause. In New Zealand, Mãori and Pacific Island people have inherently raised urate levels with one consequence a higher prevalence of more severe gout. One characteristic metabolic effect of fructose, present in sugar-sweetened beverages (SSB), is raised urate from hepatic processing of fructose. Here we discuss, and place in a biological context evidence, linking consumption of SSB with hyperuricemia and gout, including the first review of recent ecological and clinical studies of the impact of fructose and SSB exposure in Pacific Island people. Both increased serum urate and increased FEUA are observed in clinical studies examining the effects of an acute fructose load. In contrast, chronic exposure to increased fructose in the diet also leads to increased serum urate concentrations, but reduced FEUA. Epidemiological studies have consistently associated SSB consumption with increased serum urate levels and increased risk of gout. Non-additive interaction of SSB consumption with a genetic variant of a uric acid transporter in serum urate levels and gout risk emphasizes the causality of SSB in gout. Taken together these data demonstrate the hyperuricemic effect of SSB and fructose, with biochemical pathways reasonably well understood. The evidence that dietary fructose increases urate is strong. The evidence summarized here is of sufficient weight to recommend reduction of SSB consumption, particularly in Pacific Island and Mãori people, to reduce the burden of gout.


Antidementia drug prescription sources and patterns after the diagnosis of dementia in Germany: results of a claims data-based 1-year follow-up.
We examined the patterns of prescription for antidementia drugs by German physicians with special reference to source of prescription, appropriateness of drugs and dosages and continuity of prescription patterns. The study is based on claims data of all 1848 incident cases in persons aged 65 years and older from a nationwide operating statutory health insurance company in the years 2004-2006. Inclusion criteria were one International Statistical Classification of Diseases and Related Health Problems 10th Revision code for dementia in at least three of four consecutive quarters and four quarters without such a code beforehand. Defined daily doses were used to quantify the prescription size. Data analysis used univariate and multivariate techniques. The majority of incident dementia cases in general and Alzheimer's disease cases in particular did not receive medication in conformity with the guidelines during the year after incidence. Inappropriate prescription was related to not visiting a specialist, living in urban areas, age and comorbidity. Further research is needed both on reasons for nonprescription among professionals and for discontinuation by the patients. In addition, the problems of practicability and implementation of guidelines deserve more attention.


A new catalog of protein beta-sheets.
Systematic protein folding studies depend on protein three-dimensional structure annotation, the assignment of amino acid structural types from atomic coordinates. Significant stabilizing factors between adjacent beta-sheet peptide chains have recently been characterized and were not considered during the development of previously published annotation methods. To produce an accurate beta-sheet domain catalog and to encompass the full beta-sheet spectacle, we developed a method, beta-Spider, which evaluates a packing energy between adjacent peptide chains in accordance with the newly discovered stabilizing factors. While considering important energetic factors, our approach also minimizes the use of subjective criteria, such as (phi,psi) boundaries and sets of H-bonding motifs that are used in other existing methods. As a result of the application of beta-Spider to a set of available high-resolution X-ray crystal structures, we present here a new beta-sheet catalog that differs considerably from the one produced by the most acclaimed DSSP method. The catalog includes new H-bonding motifs that were never reported.


Transpositionally active episomal hAT elements.
hAT elements and V(D)J recombination may have evolved from a common ancestral transposable element system. Extrachromosomal, circular forms of transposable elements (referred to here as episomal forms) have been reported yet their biological significance remains unknown. V(D)J signal joints, which resemble episomal transposable elements, have been considered non-recombinogenic products of V(D)J recombination and a safe way to dispose of excised chromosomal sequences. V(D)J signal joints can, however, participate in recombination reactions and the purpose of this study was to determine if hobo and Hermes episomal elements are also recombinogenic. Up to 50% of hobo/Hermes episomes contained two intact, inverted-terminal repeats and 86% of these contained from 1-1000 bp of intercalary DNA. Episomal hobo/Hermes elements were recovered from Musca domestica (a natural host of Hermes), Drosophila melanogaster (a natural host of hobo) and transgenic Drosophila melanogaster and Aedes aegypti (with autonomous Hermes elements). Episomal Hermes elements were recovered from unfertilized eggs of M. domestica and D. melanogaster demonstrating their potential for extrachromosomal, maternal transmission. Reintegration of episomal Hermes elements was observed in vitro and in vivo and the presence of Hermes episomes resulted in lower rates of canonical Hermes transposition in vivo. Episomal hobo/Hermes elements are common products of element excision and can be maternally transmitted. Episomal forms of Hermes are capable of integration and also of influencing the transposition of canonical elements suggesting biological roles for these extrachromosomal elements in element transmission and regulation.


Genetic approaches for understanding virulence in Toxoplasma gondii.
Virulence of the protozoan parasite Toxoplasma gondii is highly variable and dependent upon the genotype of the parasite. The application of forward and reverse genetic approaches for understanding the genetic basis of virulence has resulted in the identification of several members of the ROP family as key mediators of virulence. More recently, modern genomic techniques have been used to address strain differences in virulence and have also identified additional members of the ROP family as likely mediators. The development of forward and reverse genetic, as well as modern genomic techniques, and the path to the discovery of the ROP genes as virulence factors is reviewed here.


Low-dose naltrexone: a unique treatment for amyopathic dermatomyositis.
Gottron papules, a heliotrope rash, scalp and extremity erythema, pruritus, and fatigue are the characteristic signs and symptoms of amyopathic dermatomyositis (ADM). Amyopathic dermatomyositis is considered a distinct entity from dermatomyositis (DM) because the characteristic muscle weakness and muscle enzyme elevations of DM are absent in ADM. With respects to treatment, ADM treatments have traditionally included topical corticosteroids and/or systemic immunosuppressants and immunomodulators. Herein we present a patient with refractory ADM that was responsive to low-dose naltrexone therapy.


Chronic Gamma-Irradiation Induces a Dose-Rate-Dependent Pro-inflammatory Response and Associated Loss of Function in Human Umbilical Vein Endothelial Cells.
A central question in radiation protection research is dose and dose-rate relationship for radiation-induced cardiovascular diseases. The response of endothelial cells to different low dose rates may contribute to help estimate risks for cardiovascular diseases by providing mechanistic understanding. In this study we investigated whether chronic low-dose-rate radiation exposure had an effect on the inflammatory response of endothelial cells and their function. Human umbilical vein endothelial cells (HUVECs) were chronically exposed to radiation at a dose of 1.4 mGy/h or 4.1 mGy/h for 1, 3, 6 or 10 weeks. We determined the pro-inflammatory profile of HUVECs before and during radiation exposure, and investigated the functional consequences of this radiation exposure by measuring their capacity to form vascular networks in matrigel. Expression levels of adhesion molecules such as E-selectin, ICAM-1 and VCAM-1, and the release of pro-inflammatory cytokines such as MCP-1, IL-6 and TNF-α were analyzed. When a total dose of 2 Gy was given at a rate of 4.1 mGy/h, we observed an increase in IL-6 and MCP-1 release into the cell culture media, but this was not observed at 1.4 mGy/h. The increase in the inflammatory profile induced at the dose rate of 4.1 mGy/h was also correlated with a decrease in the capacity of the HUVECs to form a vascular network in matrigel. Our results suggest that dose rate is an important parameter in the alteration of HUVEC inflammatory profile and function.