The Surgical Safety Checklist and Teamwork Coaching Tools: a study of inter-rater reliability.
To assess the inter-rater reliability (IRR) of two novel observation tools for measuring surgical safety checklist performance and teamwork. Data surgical safety checklists can promote adherence to standards of care and improve teamwork in the operating room. Their use has been associated with reductions in mortality and other postoperative complications. However, checklist effectiveness depends on how well they are performed. Authors from the Safe Surgery 2015 initiative developed a pair of novel observation tools through literature review, expert consultation and end-user testing. In one South Carolina hospital participating in the initiative, two observers jointly attended 50 surgical cases and independently rated surgical teams using both tools. We used descriptive statistics to measure checklist performance and teamwork at the hospital. We assessed IRR by measuring percent agreement, Cohen's κ, and weighted κ scores. The overall percent agreement and κ between the two observers was 93% and 0.74 (95% CI 0.66 to 0.79), respectively, for the Checklist Coaching Tool and 86% and 0.84 (95% CI 0.77 to 0.90) for the Surgical Teamwork Tool. Percent agreement for individual sections of both tools was 79% or higher. Additionally, κ scores for six of eight sections on the Checklist Coaching Tool and for two of five domains on the Surgical Teamwork Tool achieved the desired 0.7 threshold. However, teamwork scores were high and variation was limited. There were no significant changes in the percent agreement or κ scores between the first 10 and last 10 cases observed. Both tools demonstrated substantial IRR and required limited training to use. These instruments may be used to observe checklist performance and teamwork in the operating room. However, further refinement and calibration of observer expectations, particularly in rating teamwork, could improve the utility of the tools.


Trends and Patterns of Disparities in Cancer Mortality Among US Counties, 1980-2014.
Cancer is a leading cause of morbidity and mortality in the United States and results in a high economic burden. To estimate age-standardized mortality rates by US county from 29 cancers. Deidentified death records from the National Center for Health Statistics (NCHS) and population counts from the Census Bureau, the NCHS, and the Human Mortality Database from 1980 to 2014 were used. Validated small area estimation models were used to estimate county-level mortality rates from 29 cancers: lip and oral cavity; nasopharynx; other pharynx; esophageal; stomach; colon and rectum; liver; gallbladder and biliary; pancreatic; larynx; tracheal, bronchus, and lung; malignant skin melanoma; nonmelanoma skin cancer; breast; cervical; uterine; ovarian; prostate; testicular; kidney; bladder; brain and nervous system; thyroid; mesothelioma; Hodgkin lymphoma; non-Hodgkin lymphoma; multiple myeloma; leukemia; and all other cancers combined. County of residence. Age-standardized cancer mortality rates by county, year, sex, and cancer type. A total of 19 511 910 cancer deaths were recorded in the United States between 1980 and 2014, including 5 656 423 due to tracheal, bronchus, and lung cancer; 2 484 476 due to colon and rectum cancer; 1 573 593 due to breast cancer; 1 077 030 due to prostate cancer; 1 157 878 due to pancreatic cancer; 209 314 due to uterine cancer; 421 628 due to kidney cancer; 487 518 due to liver cancer; 13 927 due to testicular cancer; and 829 396 due to non-Hodgkin lymphoma. Cancer mortality decreased by 20.1% (95% uncertainty interval [UI], 18.2%-21.4%) between 1980 and 2014, from 240.2 (95% UI, 235.8-244.1) to 192.0 (95% UI, 188.6-197.7) deaths per 100 000 population. There were large differences in the mortality rate among counties throughout the period: in 1980, cancer mortality ranged from 130.6 (95% UI, 114.7-146.0) per 100 000 population in Summit County, Colorado, to 386.9 (95% UI, 330.5-450.7) in North Slope Borough, Alaska, and in 2014 from 70.7 (95% UI, 63.2-79.0) in Summit County, Colorado, to 503.1 (95% UI, 464.9-545.4) in Union County, Florida. For many cancers, there were distinct clusters of counties with especially high mortality. The location of these clusters varied by type of cancer and were spread in different regions of the United States. Clusters of breast cancer were present in the southern belt and along the Mississippi River, while liver cancer was high along the Texas-Mexico border, and clusters of kidney cancer were observed in North and South Dakota and counties in West Virginia, Ohio, Indiana, Louisiana, Oklahoma, Texas, Alaska, and Illinois. Cancer mortality declined overall in the United States between 1980 and 2014. Over this same period, there were important changes in trends, patterns, and differences in cancer mortality among US counties. These patterns may inform further research into improving prevention and treatment.


The three mitochondrial encoded CcmF proteins form a complex that interacts with CCMH and c-type apocytochromes in Arabidopsis.
Three reading frames called ccmF(N1), ccmF(N2), and ccmF(c) are found in the mitochondrial genome of Arabidopsis. These sequences are similar to regions of the bacterial gene ccmF involved in cytochrome c maturation. ccmF genes are always absent from animal and fungi genomes but are found in mitochondrial genomes of land plant and several evolutionary distant eukaryotes. In Arabidopsis, ccmF(N2) despite the absence of a classical initiation codon is not a pseudo gene. The 3 ccmF genes of Arabidopsis are expressed at the protein level. Their products are integral proteins of the mitochondrial inner membrane with in total 11 to 13 predicted transmembrane helices. The conserved WWD domain of CcmF(N2) is localized in the inter membrane space. The 3 CcmF proteins are all detected in a high molecular mass complex of 500 kDa by Blue Native PAGE. Direct interaction between CcmF(N2) and both CcmF(N1) and CcmF(C) is shown with the yeast two-hybrid split ubiquitin system, but no interaction is observed between CcmF(N1) and CcmF(C). Similarly, interaction is detected between CcmF(N2) and apocytochrome c but also with apocytochrome c(1). Finally, CcmF(N1) and CcmF(N2) both interact with CCMH previously shown to interact as well with cytochrome c. This strengthens the hypothesis that CcmF and CCMH make a complex that performs the assembly of heme with c-type apocytochromes in plant mitochondria.


Reduction of renal stone risk by potassium-magnesium citrate during 5 weeks of bed rest.
Exposure to the microgravity environment of space increases the risk of kidney stone formation, particularly for calcium oxalate and uric acid stones. This study was performed to evaluate the efficacy of potassium alkali as potassium-magnesium citrate in reducing renal stone risk and bone turnover. This study was performed as a double-blind, placebo controlled trial. We studied 20 normocalciuric subjects randomized to either placebo or potassium-magnesium citrate (42 mEq potassium, 21 mEq magnesium, 63 mEq citrate per day) before and during 5 weeks of strict bed rest. The study was performed in the General Clinical Research Center and under a controlled dietary regimen composed of 100 mEq of sodium, 800 mg of calcium, 0.8 gm/kg animal protein and 2,200 kcal per day. Two 24-hour urine collections were obtained under oil each week for assessment of stone risk parameters and relative saturation of calcium oxalate, brushite and undissociated uric acid. Blood was also collected for determination of serum immunoreactive parathyroid hormone and vitamin D metabolites. Bed rest promoted a rapid increase in urinary calcium excretion of approximately 50 mg per day in both groups. Despite this increase subjects treated with potassium-magnesium citrate demonstrated significant decreases in the relative saturation of calcium oxalate and in the concentration of undissociated uric acid compared to placebo. Immunoreactive parathyroid hormone, serum 1,25-dihydroxyvitamin D and intestinal calcium absorption all decreased in both groups with no difference in response between the 2 treatment arms. Provision of alkali as potassium-magnesium citrate is an effective countermeasure for the increased risk of renal stone disease associated with immobilization. Despite an increase in urine calcium concentration, the relative saturation of calcium oxalate decreased due to citrate chelation of calcium and the concentration of undissociated uric acid decreased due to the significant increase in urine pH.


Selective impairment of fast anterograde axonal transport in the peripheral nerves of asymptomatic transgenic mice with a G93A mutant SOD1 gene.
Transgenic mice that express a mutant Cu/Zn superoxide dismutase (SOD1) gene have been provided a valuable model for human amyotrophic lateral sclerosis (ALS). We studied a possible impairment of fast axonal transport in transgenic mice carrying a Gly93-->Ala (G93A) mutant SOD1 gene found in human familial ALS (FALS). Left sciatic nerve was ligated for 6 h in transgenic (Tg) and age-matched wild-type (WT) mice. Immunohistochemical analyses were performed for accumulations of kinesin and cytoplasmic dynein on both sides of the ligation site. Clinical function and histology in the spinal cords, sciatic nerves and gastrocnemius muscles were also assessed. The mice were examined at an early asymptomatic stage (aged 19 weeks) and a late stage (30 weeks) just before the development of the symptoms. WT mice showed an apparent increase in immunoreactivities for kinesin and cytoplasmic dynein at proximal and distal of the ligation, respectively. In contrast, the young Tg mice showed a selective decrease of kinesin accumulation in the proximal of the ligation. The mice were asymptomatic with a mild histological change only in muscles. The old Tg mice showed a marked reduction of the immunoreactivity for kinesin and cytoplasmic dynein on both sides of the ligation. They had a significant loss of spinal motor neurons, relatively small myelinated fiber densities of sciatic nerves, and severe muscular changes. These results provide direct evidence that the SOD1 mutation leads to impaired fast axonal transport, particularly in the anterograde direction at an early, asymptomatic stage preceding loss of spinal motor neurons and peripheral axons. This impairment may contribute to subsequent selective motor neuron death in the present model implicated for human FALS.


Development of carboxymethyl cellulose-based hydrogel and nanosilver composite as antimicrobial agents for UTI pathogens.
Silver nanoparticles (AgNPs) containing hydrogel composite were first synthesized by preparing a new hydrogel from carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), and the cross-linker ethylene glycol diglycidyl ether (EGDE), followed by the incorporation of AgNPs by microwave radiation. The resulting neat hydrogels and AgNPs-hydrogel composites were characterized using spectral, thermal, microscopic analysis and X-ray diffraction (XRD) analyses. The SEM and TEM results demonstrated that the synthesized AgNPs were spherical with diameters ranging from 8 to 14nm. In addition, the XRD analysis confirmed the nanocrystalline phase of silver with face-centered cubic (FCC) crystal structure. Energy dispersive spectroscopy (EDS) analysis of the AgNPs confirmed the presence of an elemental silver signal, and no peaks of any other impurities were detected. Additionally, the antibacterial activities of the neat hydrogel and AgNPs-hydrogel composites were measured by Kirby-Bauer method against urinary tract infection (UTI) pathogens. The rheology measurement revealed that the values of storage modulus (G') were higher than that of loss modulus (G″). The AgNPs-hydrogel composites exhibited higher antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris, Staphylococcus aureus and Proteus mirabilis compared to the corresponding neat hydrogel.


Osmoregulation in Drosophila melanogaster selected for urea tolerance.
Animals may adapt to hyperosmolar environments by either osmoregulating or osmoconforming. Osmoconforming animals generally accumulate organic osmolytes including sugars, amino acids or, in a few cases, urea. In the latter case, they also accumulate 'urea-counteracting' solutes to mitigate the toxic effects of urea. We examined the osmoregulatory adaptation of Drosophila melanogaster larvae selected to live in 300 mmol l(-)(1) urea. Larvae are strong osmoregulators in environments with high NaCl or sucrose levels, but have increased hemolymph osmolarity on urea food. The increase in osmolarity on urea food is smaller in the selected larvae relative to unselected control larvae, and their respective hemolymph urea concentrations can account for the observed increases in total osmolarity. No other hemolymph components appear to act as urea-counteractants. Urea is calculated to be in equilibrium across body compartments in both selected and control larvae, indicating that the selected larvae are not sequestering it to lower their hemolymph osmolarity. The major physiological adaptation to urea does not appear to involve increased tolerance or improved osmoregulation per se, but rather mechanisms (e.g. metabolism, decreased uptake or increased excretion) that reduce overall urea levels and the consequent toxicity.


Striatal involvement in human alcoholism and alcohol consumption, and withdrawal in animal models.
Different regions of the striatum may have distinct roles in acute intoxication, alcohol seeking, dependence, and withdrawal. The recent advances are reviewed and discussed in our understanding of the role of the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum in behavioral responses to alcohol, including alcohol craving in abstinent alcoholics, and alcohol consumption and withdrawal in rat, mouse, and nonhuman primate models. Reduced neuronal activity as well as dysfunctional connectivity between the ventral striatum and the dorsolateral prefrontal cortex is associated with alcohol craving and impairment of new learning processes in abstinent alcoholics. Within the DLS of mice and nonhuman primates withdrawn from alcohol after chronic exposure, glutamatergic transmission in striatal projection neurons is increased, while GABAergic transmission is decreased. Glutamatergic transmission in DMS projection neurons is also increased in ethanol withdrawn rats. Ex vivo or in vivo ethanol exposure and withdrawal causes a long-lasting increase in NR2B subunit-containing NMDA receptor activity in the DMS, contributing to ethanol drinking. Analyses of neuronal activation associated with alcohol withdrawal and site-directed lesions in mice implicate the rostroventral caudate putamen, a ventrolateral segment of the DMS, in genetically determined differences in risk for alcohol withdrawal involved in physical association of the multi-PDZ domain protein, MPDZ, with 5-HT(2C) receptors and/or NR2B. Alterations of dopaminergic, glutamatergic, and GABAergic signaling within different regions of the striatum by alcohol is critical for alcohol craving, consumption, dependence, and withdrawal in humans and animal models.


[The influence of single immersion in Dead Sea water on glucose, insulin, cortisol and C-peptide levels in type 2 diabetes mellitus patients].
Bathing in sweet or mineral water can induce significant physiological changes in several body systems including the endocrine system. To date, there have only been a small number of reports that balneology can reduce blood sugar Levels in patients with type 2 diabetes mellitus (DM]. To compare the effects of a single immersion in sweet or mineral water on blood glucose, insulin, cortisol and c-peptide levels in patients with type 2 DM. Fourteen patients with type 2 DM and six healthy volunteers were immersed in water twice, with an interval of two weeks in between immersions. The first immersion was in Dead Sea water and the second in sweet water. In both cases the water was warmed to a temperature of 35 degrees C and the bath continued for 20 minutes. Three blood samples were taken from each of the participants at every immersion. The first sample was taken just prior to the start of immersion, the second sample was taken directly at the end of immersion, and the third sample, one hour later. In each sample the blood was tested for glucose, insulin, cortisol, and c-peptide Levels. A significant reduction was seen in blood glucose levels among DM patients who were immersed in Dead Sea water. The glucose levels dropped from a base Line level of 163 +/- 32.4 mg/dl prior to immersion, to 151 +/- 28.8 at the end of the immersion, and to 141 +/- 34.6 an hour later. All the differences were statistically significant: baseline to end of immersion (P = 0.006), end of immersion to one hour later (P = 0.024), and baseline to one hour after immersion (P=0.005). The difference in blood glucose was much Less following immersion in sweet water and did not reach statistical significance except between the end of immersion and one hour later. No significant differences were found for insulin, cortisol, and c-peptide levels between DM patients and healthy volunteers following immersion. One-time immersion in Dead Sea water reduces blood glucose levels in type 2 DM patients compared to healthy volunteers.


Approach to invasive pulmonary aspergillosis in critically ill patients.
Apparently immunocompetent critically ill patients represent an increasing population at risk for invasive pulmonary aspergillosis (IPA). The current review gives an update on the epidemiology, diagnosis, and management of IPA in the ICU. Patients without apparent severe immunosuppression (e.g. chronic obstructive pulmonary disease, decompensated liver disease, etc.) represent the majority of ICU IPA cases. IPA diagnosis is problematic and the true incidence of IPA is difficult to be estimated because of the nonspecific clinical presentation. A user-friendly clinical diagnostic algorithm for IPA is valuable, particularly through a high negative predictive value. IPA carries a poor prognosis and has an important impact on hospital costs. Timely diagnosis and prompt administration of appropriate treatment may improve the outcomes. Intravenous voriconazole is the recommended primary IPA treatment, but liposomal amphotericin B also has clinical utility. Voriconazole presents bioavailability and toxicity issues, and drug level monitoring is advocated. Caspofungin or antifungal combinations are recommended as salvage therapy. A high level of suspicion in critically ill patients presenting with Aspergillus-positive respiratory tract cultures or nonresolving pulmonary infection may lead to earlier IPA diagnosis. Dosage individualization may decrease treatment discontinuation and improve clinical efficacy.


Maternal exposure to water disinfection by-products during gestation and risk of hypospadias.
The use of chlorine for water disinfection results in the formation of numerous contaminants called disinfection by-products (DBPs), which may be associated with birth defects, including urinary tract defects. We used Arkansas birth records (1998-2002) to conduct a population-based case-control study investigating the relationship between hypospadias and two classes of DBPs, trihalomethanes (THM) and haloacetic acids (HAA). We utilised monitoring data, spline regression and geographical information systems (GIS) to link daily concentrations of these DBPs from 263 water utilities to 320 cases and 614 controls. We calculated ORs for hypospadias and exposure to DBPs between 6 and 16 weeks' gestation, and conducted subset analyses for exposure from ingestion, and metrics incorporating consumption, showering and bathing. We found no increase in risk when women in the highest tertiles of exposure were compared to those in the lowest for any DBP. When ingestion alone was used to assess exposure among a subset of 40 cases and 243 controls, the intermediate tertiles of exposure to total THM and the five most common HAA had ORs of 2.11 (95% CI 0.89 to 5.00) and 2.45 (95% CI 1.06 to 5.67), respectively, compared to women with no exposure. When exposure to total THM from consumption, showering and bathing exposures was evaluated, we found an OR of 1.96 (95% CI 0.65 to 6.42) for the highest tertile of exposure and weak evidence of a dose-response relationship. Our results provide little evidence for a positive relationship between DBP exposure during gestation and an increased risk of hypospadias but emphasise the necessity of including individual-level data when assessing exposure to DBPs.


Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro.
Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (-19% of maximal response and -60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (-19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.


Talking about living and dying with the oldest old: public involvement in a study on end of life care in care homes.
Public involvement in research on sensitive subjects, such as death and dying, can help to ensure that questions are framed to reflect the interests of their peers, develop a shared understanding of issues raised, and moderate the often unequal power relationship between researcher and participant. This paper describes the contribution and impact of older members of a Public Involvement in Research group (PIRg) to a study on living and dying in care homes. A longitudinal study, with a mixed method approach, its aims were to capture key experiences, events and change over one year, of older people resident in participating care homes in the East of England. Residents were interviewed up to three times and their case notes were reviewed four times over the year. Interviews were semi structured, and recorded. Four members of a Public Involvement in Research group (PIRg) contributed to preliminary discussions about the research and three were involved with many of the subsequent stages of the research process including the facilitation of discussion groups with residents. There were three areas where the involvement of the Public Involvement in Research group (PIRg) positively influenced the study process. These were recruitment, governance and safeguarding, and in collaboration with the residents in the care homes, the discussion and interpretation of emergent findings. PIRg members were of similar age to the residents and their involvement provided different and often more reflective insights of the significance of the findings for the participants. There were examples where decision making about the range of PIRg participation was not always negotiable, and this raised issues about power relationships within the team. Nevertheless, PIRg members expressed personal benefit and satisfaction through participating in the research and a commitment to continue to support research with this older age group. The contribution of the PIRg supported a successful recruitment process that exceeded response rates of other studies in care homes. It safeguarded residents during the conduct of research on a sensitive topic and helped in validating the interview data gathered by the researchers through the discussion groups facilitated by the PIRg. There were power differentials that persisted and affected PIRg participation. The study has showed the value of developing job descriptions and a more formal means of setting out respective expectations. Future research may wish to elicit the views of focal participants in such studies about the mediation of research by public involvement in research.


Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA).
Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients. NCT01318941.


Near infrared spectroscopy calibration for wood chemistry: which chemometric technique is best for prediction and interpretation?
This paper addresses the precision in factor loadings during partial least squares (PLS) and principal components regression (PCR) of wood chemistry content from near infrared reflectance (NIR) spectra. The precision of the loadings is considered important because these estimates are often utilized to interpret chemometric models or selection of meaningful wavenumbers. Standard laboratory chemistry methods were employed on a mixed genus/species hardwood sample set. PLS and PCR, before and after 1st derivative pretreatment, was utilized for model building and loadings investigation. As demonstrated by others, PLS was found to provide better predictive diagnostics. However, PCR exhibited a more precise estimate of loading peaks which makes PCR better for interpretation. Application of the 1st derivative appeared to assist in improving both PCR and PLS loading precision, but due to the small sample size, the two chemometric methods could not be compared statistically. This work is important because to date most research works have committed to PLS because it yields better predictive performance. But this research suggests there is a tradeoff between better prediction and model interpretation. Future work is needed to compare PLS and PCR for a suite of spectral pretreatment techniques.


Evaluation of microvessel density (MVD) in canine mammary tumours by quantitative immunohistochemistry of the claudin-5 molecule.
In our recent investigation, angiogenesis was evaluated and quantified by immunohistochemical evaluation of microvessel density (MVD) using claudin-5 (CLDN-5) as a marker for vascular endothelium in 67 canine mammary gland tumours. Computer image analysis was used to measure the intratumoural MVD. Higher intratumoural MVD was detected in malignant simple neoplasms compared with benign tumours. Furthermore, the results of MVD were correlated with histological grade, higher grades being accompanied by higher MVD. In simple adenomas and grade I tubular-tubulopapillary simple carcinomas the intratumoural microvessels were wide and regular in shape with evident erythrocytes in their lumen. In grade III solid carcinomas the microvessels were smaller, less regular and had irregular shape, often without a distinct lumen, and isolated endothelial cells were frequently present. In the complex carcinomas MVD was low and the intratumoural microvessels were mostly irregular in shape without a distinct lumen. The evaluation of MVD by CLDN-5 immunohistochemistry may give useful additional information on the angiogenic potential of breast cancers in dogs.


Calcific uraemic arteriolopathy.
A 37-year-old African-American woman with end-stage renal disease presumed to be secondary to diabetes mellitus type 2, on daily peritoneal dialysis, was admitted for a painful left lower extremity lesion. Examination revealed a large, dusky, tender region over the left lateral thigh. She was on warfarin for mechanical heart valves. Despite discontinuation of warfarin and placement on heparin, the lesion progressed to extend to the medial left thigh and medial and lateral right thigh. CT scan demonstrated arteriolar medial calcification and vascular calcification of the small subcutaneous vessels, without evidence of abscess or haematoma. The patient declined punch biopsy. Given the known risk factors of high calcium-phosphate and radiological findings, a diagnosis of calcific uraemic arteriolopathy was made. Phosphate-binder therapy was optimised. She was transitioned to daily haemodialysis, and sodium thiosulfate was initiated. Skin lesions demonstrated improvement at her 5 weeks posthospitalisation follow-up.


Oral versus single intravenous bolus dose antibiotic prophylaxis against postoperative surgical site infection in external dacryocystorhinostomy for primary acquired nasolacrimal duct obstruction - A randomized study.
To compare the efficacy of a single perioperative bolus dose of intravenous antibiotic versus postoperative oral antibiotic prophylaxis for prevention of surgical site infection (SSI) in external dacryocystorhinostomy (DCR) for primary acquired nasolacrimal duct obstruction (PANDO). This was a prospective randomized controlled study with a noninferiority design. Patients undergoing external DCR surgery were randomized into two groups A and B. Patients in group A received a single bolus dose of intravenous cefazolin 1 g at surgery, whereas those in group B received oral cephalexin 500 mg postoperatively twice a day for 5 days. Allocation concealment was ensured by sequentially numbered opaque sealed envelopes (SNOSEs). Both groups were advised identical postoperative local wound care regimens. Any clinical evidence of SSI at 4 weeks of follow-up in either group was the main outcome measure. In all, 338 patients randomized into two groups of 169 patients each participated in this study. At follow-up of 4 weeks, only one patient in group B developed postoperative SSI. None in group A developed postoperative SSI. Other potential risk factors for postoperative SSI were also analyzed by univariate and multivariate analyses but none achieved statistical significance in either group. Our results demonstrate that a single bolus dose of perioperative intravenous antibiotic offers adequate prophylaxis against postoperative SSI and compares favorably with the more commonly used oral antibiotic prophylaxis in external DCR for PANDO in our population and our practice scenario.


Pigment protection factor as a predictor of skin photosensitivity--a Polish study.
Assessment of individual photosensitivity by determining the minimal erythema dose (MED) is commonly accepted. MED objectively describes a single individual response to the irradiation of skin with a particular wavelength (UVB, UVA). Pigment protection factor (PPF) is an objective value to measure skin type. The aim of the project was to analyze PPF values in the population of Lodz and the relationship between PPF, skin phototype, and individual MED. The study was conducted on the group of 270 volunteers: 130 men and 140 women, mean age 28.5 years (OS + 9.66) with either skin phototype II or III, as defined by Fitzpatrick Skin Phototype Classification. Phototesting of each volunteer was undertaken with an increasing dose series (UVB radiation) on six squares (1×1 cm) on the skin of the back. The MED was defined as a perceptible erythema 24 hours later. Starting dose was determined by history, physical examination, and phototype ranged from 0.03-0.07 J/cm2. PPF was measured by a skin reflectance meter UV Optimize 555. The mean MED value was 0.15 J/cm2 and the PPF value was 6.15. A positive correlation between the MED value and PPF (R=0.38; P<0.001), and a positive correlation between phototype and MED and PPF (P< 0.001) were found. Both determination of MED and PPF are objective methods of photosensitivity assessment, but PPF determination is an easy and non-invasive method.


Fecal Microbiota Transplantation in Gestating Sows and Neonatal Offspring Alters Lifetime Intestinal Microbiota and Growth in Offspring.
Previous studies suggest a link between intestinal microbiota and porcine feed efficiency (FE). Therefore, we investigated whether fecal microbiota transplantation (FMT) in sows and/or neonatal offspring, using inocula derived from highly feed-efficient pigs, could improve offspring FE. Pregnant sows were assigned to control or FMT treatments and the subsequent offspring to control treatment, FMT once (at birth), or FMT four times (between birth and weaning). FMT altered sow fecal and colostrum microbiota compositions and resulted in lighter offspring body weight at 70 and 155 days of age when administered to sows and/or offspring. This was accompanied by FMT-associated changes within the offspring's intestinal microbiota, mostly in the ileum. These included transiently higher fecal bacterial diversity and load and numerous compositional differences at the phylum and genus levels (e.g., Spirochaetes and Bacteroidetes at high relative abundances and mostly members of Clostridia, respectively), as well as differences in the abundances of predicted bacterial pathways. In addition, intestinal morphology was negatively impacted, duodenal gene expression altered, and serum protein and cholesterol concentrations reduced due to FMT in sows and/or offspring. Taken together, the results suggest poorer absorptive capacity and intestinal health, most likely explaining the reduced body weight. An additive effect of FMT in sows and offspring also occurred for some parameters. Although these findings have negative implications for the practical use of the FMT regime used here for improving FE in pigs, they nonetheless demonstrate the enormous impact of early-life intestinal microbiota on the host phenotype. IMPORTANCE Here, for the first time, we investigate FMT as a novel strategy to modulate the porcine intestinal microbiota in an attempt to improve FE in pigs. However, reprogramming the maternal and/or offspring microbiome by using fecal transplants derived from highly feed-efficient pigs did not recapitulate the highly efficient phenotype in the offspring and, in fact, had detrimental effects on lifetime growth. Although these findings may not be wholly attributable to microbiota transplantation, as antibiotic and purgative were also part of the regime in sows, similar effects were also seen in offspring, in which these interventions were not used. Nonetheless, additional work is needed to unravel the effects of each component of the FMT regime and to provide additional mechanistic insights. This may lead to the development of an FMT procedure with practical applications for the improvement of FE in pigs, which could in turn improve the profitability of pig production.


Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.
Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.


Towards Gas Discrimination and Mapping in Emergency Response Scenarios Using a Mobile Robot with an Electronic Nose.
Emergency personnel, such as firefighters, bomb technicians, and urban search and rescue specialists, can be exposed to a variety of extreme hazards during the response to natural and human-made disasters. In many of these scenarios, a risk factor is the presence of hazardous airborne chemicals. The recent and rapid advances in robotics and sensor technologies allow emergency responders to deal with such hazards from relatively safe distances. Mobile robots with gas-sensing capabilities allow to convey useful information such as the possible source positions of different chemicals in the emergency area. However, common gas sampling procedures for laboratory use are not applicable due to the complexity of the environment and the need for fast deployment and analysis. In addition, conventional gas identification approaches, based on supervised learning, cannot handle situations when the number and identities of the present chemicals are unknown. For the purpose of emergency response, all the information concluded from the gas detection events during the robot exploration should be delivered in real time. To address these challenges, we developed an online gas-sensing system using an electronic nose. Our system can automatically perform unsupervised learning and update the discrimination model as the robot is exploring a given environment. The online gas discrimination results are further integrated with geometrical information to derive a multi-compound gas spatial distribution map. The proposed system is deployed on a robot built to operate in harsh environments for supporting fire brigades, and is validated in several different real-world experiments of discriminating and mapping multiple chemical compounds in an indoor open environment. Our results show that the proposed system achieves high accuracy in gas discrimination in an online, unsupervised, and computationally efficient manner. The subsequently created gas distribution maps accurately indicate the presence of different chemicals in the environment, which is of practical significance for emergency response.


A descriptive cohort study of withdrawal from inhaled corticosteroids in COPD patients.
Inhaled corticosteroid (ICS) therapy is widely prescribed without a history of exacerbations and consensus guidelines suggest withdrawal of ICS in these patients would reduce the risk of side effects and promote cost-effective prescribing. The study describes the prescribing behaviour in the United Kingdom (UK) in relation to ICS withdrawal and identifies clinical outcomes following withdrawal using primary and secondary care electronic health records between January 2012 and December 2017. Patients with a history ≥12 months' exposure who withdrew ICS for ≥6 months were identified into two cohorts; those prescribed a long-acting bronchodilator maintenance therapy and those that were not prescribed any maintenance therapy. The duration of withdrawal, predictors of restarting ICS, and clinical outcomes were compared between both patient cohorts. Among 76,808 patients that had ≥1 prescription of ICS in the study period, 11,093 patients (14%) withdrew ICS therapy at least once during the study period. The median time without ICS was 9 months (IQR 7-14), with the majority (71%) receiving subsequent ICS prescriptions after withdrawal. Patients receiving maintenance therapy with a COPD review at withdrawal were 28% less likely to restart ICS (HR: 0.72, 95% CI 0.61, 0.85). Overall, 69% and 89% of patients that withdrew ICS had no recorded exacerbation event or COPD hospitalisation, respectively, during the withdrawal. This study provides evidence that most patients withdrawing from ICS do not experience COPD exacerbations and withdrawal success can be achieved by carefully planning routine COPD reviews whilst optimising the use of available maintenance therapies.


Double-clicking peptides onto phosphorothioate oligonucleotides: combining two proapoptotic agents in one molecule.
Described here is a method for the conjugation of phosphorothioate oligonucleotides (PSOs) with peptides. PSOs are key to antisense technology. Peptide-PSO conjugates may improve target specificity, tissue distribution, and cellular uptake of PSOs. However, the highly nucleophilic phosphorothioate structure poses a challenge to conjugation chemistry. Herein, we introduce a new method which involves a sequence of oxime ligation and strain-promoted [2+3] cycloaddition. The usefulness of the method was demonstrated in the synthesis of peptide-PSO conjugates that targeted two suppressors of both the intrinsic and the extrinsic pathway of apoptosis. It is shown that the activity of a PSO sequence targeted against mRNA from c-Flip can be enhanced by conjugation with a peptide mimetic designed to inhibit the X-linked inhibitor of apoptosis protein (XIAP).


Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis.
Patients with primary sclerosing cholangitis (PSC) were previously shown to display a bacterial gut dysbiosis but fungal microbiota has never been examined in these patients. The aim of this study was to assess the fungal gut microbiota in patients with PSC. We analysed the faecal microbiota of patients with PSC and concomitant IBD (n=27), patients with PSC and no IBD (n=22), patients with IBD and no PSC (n=33) and healthy subjects (n=30). Bacterial and fungal composition of the faecal microbiota was determined using 16S and ITS2 sequencing, respectively. We found that patients with PSC harboured bacterial dysbiosis characterised by a decreased biodiversity, an altered composition and a decreased correlation network density. These alterations of the microbiota were associated with PSC, independently of IBD status. For the first time, we showed that patients with PSC displayed a fungal gut dysbiosis, characterised by a relative increase in biodiversity and an altered composition. Notably, we observed an increased proportion of Exophiala and a decreased proportion of Saccharomyces cerevisiae. Compared with patients with IBD and healthy subjects, the gut microbiota of patients with PSC exhibited a strong disruption in bacteria-fungi correlation network, suggesting an alteration in the interkingdom crosstalk. This study demonstrates that bacteria and fungi contribute to gut dysbiosis in PSC.


The C-terminal LCAR of host ANP32 proteins interacts with the influenza A virus nucleoprotein to promote the replication of the viral RNA genome.
The segmented negative-sense RNA genome of influenza A virus is assembled into ribonucleoprotein complexes (RNP) with viral RNA-dependent RNA polymerase and nucleoprotein (NP). It is in the context of these RNPs that the polymerase transcribes and replicates viral RNA (vRNA). Host acidic nuclear phosphoprotein 32 (ANP32) family proteins play an essential role in vRNA replication by mediating the dimerization of the viral polymerase via their N-terminal leucine-rich repeat (LRR) domain. However, whether the C-terminal low-complexity acidic region (LCAR) plays a role in RNA synthesis remains unknown. Here, we report that the LCAR is required for viral genome replication during infection. Specifically, we show that the LCAR directly interacts with NP and this interaction is mutually exclusive with RNA. Furthermore, we show that the replication of a short vRNA-like template that can be replicated in the absence of NP is less sensitive to LCAR truncations compared with the replication of full-length vRNA segments which is NP-dependent. We propose a model in which the LCAR interacts with NP to promote NP recruitment to nascent RNA during influenza virus replication, ensuring the co-replicative assembly of RNA into RNPs.


Evaluation of the anti-melanoma activities of sarcophine, (+)-7alpha,8beta-dihydroxydeepoxysarcophine and sarcophytolide from the Red Sea soft coral Sarcophyton glaucum.
Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely sarcophine (1), (+)-7alpha,8beta-dihydroxydeepoxysarcophine (2) and sarcophytolide (3) were evaluated for their potential inhibitory effects on growth of mouse melanoma B16F10 cells. Compounds (1) and (2) maximally inhibit viability of melanoma cells during 48 hr and 72 hr treatment at concentrations that show no cytotoxicity on monkey kidney CV-1 cells and also inhibit de novo DNA synthesis and PARP activity. Compound (3) produced cytotoxic effects at the same concentration range it produces its antitumor effects. These data suggest that (1) and (2), but not (3), have potential for further development as antitumor agents against melanoma.


Ocular dominance column development: analysis and simulation.
The visual cortex of many adult mammals has patches of cells that receive inputs driven by the right eye alternating with patches that receive inputs driven by the left eye. These ocular dominance patches (or "columns") form during early life as a consequence of competition between the activity patterns of the two eyes. A mathematical model of several biological mechanisms that can account for this development is presented. Analysis of this model reveals the conditions under which ocular dominance segregation will occur and determines the resulting patch width. Simulations of the model also exhibit other phenomena associated with early visual development, such as topographic refinement of cortical receptive fields, the confinement of input cell connections to patches, monocular deprivation plasticity including a critical period, and the effect of artificially induced strabismus. The model can be used to predict the results of proposed experiments and to discriminate among various mechanisms of plasticity.


Identification of the transcriptional response of human intestinal mucosa to Lactobacillus plantarum WCFS1 in vivo.
There is limited knowledge on the extent and dynamics of the mucosal response to commensal and probiotic species in the human intestinal lumen. This study aimed to identify the acute, time-dependent responses of intestinal mucosa to commensal Lactobacillus plantarum WCFS1 in vivo in two placebo-controlled human intervention studies in healthy volunteers. Transcriptional changes in duodenal mucosa upon continuous intraduodenal infusion of L. plantarum WCFS1 for one- and six h, respectively, were studied using oro- and nasogastric intubations with dedicated orogastric catheters and tissue sampling by standard flexible gastroduodenoscopy. One- and six-h exposure of small intestinal mucosa to L. plantarum WCFS1 induced differential expression of 669 and 424 gene reporters, respectively. While short-term exposure to L. plantarum WCFS1 inhibited fatty acid metabolism and cell cycle progression, cells switched to a more proliferative phase after prolonged exposure with an overall expression profile characterized by upregulation of genes involved in lipid metabolism, cellular growth and development. Cell death and immune responses were triggered, but cell death-executing genes or inflammatory signals were not expressed. Proteome analysis showed differential expression of several proteins. Only the microsomal protein 'microsomal triglyceride transfer protein' was regulated on both the transcriptional and the protein level in all subjects. Overall, this study showed that intestinal exposure to L. plantarum WCFS1 induced consistent, time-dependent transcriptional responses in healthy intestinal mucosa. This extensive exploration of the human response to L. plantarum WCFS1 could eventually provide molecular support for specific or probiotic activity of this strain or species, and exemplifies the strength of the applied technology to identify the potential bio-activity of microbes in the human intestine.


Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.
Beta-blockers and inhibitors of the renin-angiotensin aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction. There is uncertainty whether these treatments are beneficial for people with heart failure with preserved ejection fraction and a comprehensive review of the evidence is required. To assess the effects of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction. We searched CENTRAL, MEDLINE, Embase and two clinical trial registries on 25 July 2017 to identify eligible studies. Reference lists from primary studies and review articles were checked for additional studies. There were no language or date restrictions. We included randomised controlled trials with a parallel group design enrolling adult participants with heart failure with preserved ejection fraction, defined by a left ventricular ejection fraction of greater than 40 percent. Two review authors independently selected studies for inclusion and extracted data. The outcomes assessed included cardiovascular mortality, heart failure hospitalisation, hyperkalaemia, all-cause mortality and quality of life. Risk ratios (RR) and, where possible, hazard ratios (HR) were calculated for dichotomous outcomes. For continuous data, mean difference (MD) or standardised mean difference (SMD) were calculated. We contacted trialists where neccessary to obtain missing data. 37 randomised controlled trials (207 reports) were included across all comparisons with a total of 18,311 participants.Ten studies (3087 participants) investigating beta-blockers (BB) were included. A pooled analysis indicated a reduction in cardiovascular mortality (15% of participants in the intervention arm versus 19% in the control arm; RR 0.78; 95% confidence interval (CI) 0.62 to 0.99; number needed to treat to benefit (NNTB) 25; 1046 participants; 3 studies). However, the quality of evidence was low and no effect on cardiovascular mortality was observed when the analysis was limited to studies with a low risk of bias (RR 0.81; 95% CI 0.50 to 1.29; 643 participants; 1 study). There was no effect on all-cause mortality, heart failure hospitalisation or quality of life measures, however there is uncertainty about these effects given the limited evidence available.12 studies (4408 participants) investigating mineralocorticoid receptor antagonists (MRA) were included with the quality of evidence assessed as moderate. MRA treatment reduced heart failure hospitalisation (11% of participants in the intervention arm versus 14% in the control arm; RR 0.82; 95% CI 0.69 to 0.98; NNTB 41; 3714 participants; 3 studies; moderate-quality evidence) however, little or no effect on all-cause and cardiovascular mortality and quality of life measures was observed. MRA treatment was associated with a greater risk of hyperkalaemia (16% of participants in the intervention group versus 8% in the control group; RR 2.11; 95% CI 1.77 to 2.51; 4291 participants; 6 studies; high-quality evidence).Eight studies (2061 participants) investigating angiotensin converting enzyme inhibitors (ACEI) were included with the overall quality of evidence assessed as moderate. The evidence suggested that ACEI treatment likely has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalisation, or quality of life. Data for the effect of ACEI on hyperkalaemia were only available from one of the included studies.Eight studies (8755 participants) investigating angiotensin receptor blockers (ARB) were included with the overall quality of evidence assessed as high. The evidence suggested that treatment with ARB has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalisation, or quality of life. ARB was associated with an increased risk of hyperkalaemia (0.9% of participants in the intervention group versus 0.5% in the control group; RR 1.88; 95% CI 1.07 to 3.33; 7148 participants; 2 studies; high-quality evidence).We identified a single ongoing placebo-controlled study investigating the effect of angiotensin receptor neprilysin inhibitors (ARNI) in people with heart failure with preserved ejection fraction. There is evidence that MRA treatment reduces heart failure hospitalisation in heart failure with preserverd ejection fraction, however the effects on mortality related outcomes and quality of life remain unclear. The available evidence for beta-blockers, ACEI, ARB and ARNI is limited and it remains uncertain whether these treatments have a role in the treatment of HFpEF in the absence of an alternative indication for their use. This comprehensive review highlights a persistent gap in the evidence that is currently being addressed through several large ongoing clinical trials.


Designing effective HIV/AIDS social and behavioral interventions for the population of those age 50 and older.
Social and behavioral HIV/AIDS prevention interventions designed to test their effects on older cohorts are sorely lacking in the scientific literature even though middle-aged and older people represent a significant minority of both existing and new AIDS cases. This article raises key issues relevant in developing and evaluating HIV/AIDS social and behavioral interventions for older cohorts. These interventions must build on our current understanding of behavior change and HIV prevention successes with younger populations while considering important intervention principles gathered from work with older populations in other health arenas. In addition, the authors expand on recent national panels and published reviews relevant to the topic and provide a set of intervention recommendations for use in tandem with these intervention principles. The article also calls for additional research into the sociocultural contexts that influence risk-taking among older cohorts and for the development of interventions at multiple levels. Pragmatic considerations such as identifying and dismantling ageism in interventions, delineating intervention outcomes, and planning for intervention transferability, dissemination, and sustainability also are raised.


Interactive Publication: The document as a research tool.
The increasing prevalence of multimedia and research data generated by scientific work affords an opportunity to reformulate the idea of a scientific article from the traditional static document, or even one with links to supplemental material in remote databases, to a self-contained, multimedia-rich interactive publication. This paper describes our concept of such a document, and the design of tools for authoring (Forge) and visualization/analysis (Panorama). They are platform-independent applications written in Java, and developed in Eclipse using its Rich Client Platform (RCP) framework. Both applications operate on PDF files with links to XML files that define the media type, location, and action to be performed. We also briefly cite the challenges posed by the potentially large size of interactive publications, the need for evaluating their value to improved comprehension and learning, and the need for their long-term preservation by the National Library of Medicine and other libraries.


Why has transparency evolved in aposematic butterflies? Insights from the largest radiation of aposematic butterflies, the Ithomiini.
Defended species are often conspicuous and this is thought to be an honest signal of defences, i.e. more toxic prey are more conspicuous. Neotropical butterflies of the large Ithomiini tribe numerically dominate communities of chemically defended butterflies and may thus drive the evolution of mimetic warning patterns. Although many species are brightly coloured, most are transparent to some degree. The evolution of transparency from a warning-coloured ancestor is puzzling as it is generally assumed to be involved in concealment. Here, we show that transparent Ithomiini species are indeed less detectable by avian predators (i.e. concealment). Surprisingly, transparent species are not any less unpalatable, and may in fact be more unpalatable than opaque species, the latter spanning a larger range of unpalatability. We put forth various hypotheses to explain the evolution of weak aposematic signals in these butterflies and other cryptic defended prey. Our study is an important step in determining the selective pressures and constraints that regulate the interaction between conspicuousness and unpalatability.


Aerosol from a candidate modified risk tobacco product has reduced effects on chemotaxis and transendothelial migration compared to combustion of conventional cigarettes.
Reduction of harmful constituents by heating rather than combusting tobacco is a promising new approach to reduce harmful effects associated with cigarette smoking. We investigated the effect from a new candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, on the migratory behavior of monocytes in comparison with combustible 3R4F reference cigarettes. The monocytic cell line (THP-1) and human coronary arterial endothelial cells (HCAECs) were used to analyze chemotaxis and transendothelial migration (TEM). To assess the influence of aerosol extract from THS2.2 and smoke extract from 3R4F on toxicity and inflammation, flow cytometry and ELISA assays were performed. The results show that treatment of THP-1 cells with extract from 3R4F or THS2.2 induced concentration-dependent increases in cytotoxicity and inflammation. The inhibitory effects of THS2.2 extract for chemotaxis and TEM were ∼18 times less effective compared to 3R4F extract. Furthermore, extract from 3R4F or THS2.2 induced concentration-dependent decreases in the integrity of HCAEC monolayer. For all examined endpoints, the extract from 3R4F showed more than one order of magnitude stronger effects than that from THS2.2 extract. These data indicate the potential of a heat not burn tobacco product to reduce the risk for cardiovascular disease compared to combustible cigarettes.


Technical Standards for Nursing Education Programs in the 21st Century.
The Institute of Medicine (2000, 2002) exposed serious safety problems in the health system and called for total qualitative system change. The Institute of Medicine (2011, 2015) also calls for improving the education of nurses to provide leadership for a redesigned health system. Intertwined with improving education is the need to recruit and retain diverse highly qualified students. Disability is part of diversity inclusion, but current technical standards (nonacademic requirements) for admission to many nursing programs are a barrier to the entry of persons with disabilities. Rehabilitation nurse leaders are in a unique position to improve disability diversity in nursing. The purpose of this paper is to discuss the importance of disability diversity in nursing. The history of existing technical standards used in many nursing programs is reviewed along with examples. On the basis of the concept that disability inclusion is a part of diversity inclusion, we propose a new model of technical standards for nursing education. Rehabilitation nurse leaders can lead in eliminating barriers to persons with disabilities entering nursing.


Residential radon and brain tumour incidence in a Danish cohort.
Increased brain tumour incidence over recent decades may reflect improved diagnostic methods and clinical practice, but remain unexplained. Although estimated doses are low a relationship between radon and brain tumours may exist. To investigate the long-term effect of exposure to residential radon on the risk of primary brain tumour in a prospective Danish cohort. During 1993-1997 we recruited 57,053 persons. We followed each cohort member for cancer occurrence from enrolment until 31 December 2009, identifying 121 primary brain tumour cases. We traced residential addresses from 1 January 1971 until 31 December 2009 and calculated radon concentrations at each address using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate-ratios (IRR) and 95% confidence intervals (CI) for the risk of primary brain tumours associated with residential radon exposure with adjustment for age, sex, occupation, fruit and vegetable consumption and traffic-related air pollution. Effect modification by air pollution was assessed. Median estimated radon was 40.5 Bq/m(3). The adjusted IRR for primary brain tumour associated with each 100 Bq/m(3) increment in average residential radon levels was 1.96 (95% CI: 1.07; 3.58) and this was exposure-dependently higher over the four radon exposure quartiles. This association was not modified by air pollution. We found significant associations and exposure-response patterns between long-term residential radon exposure radon in a general population and risk of primary brain tumours, adding new knowledge to this field. This finding could be chance and needs to be challenged in future studies.


TGF-beta 1 polymorphisms and risk of myocardial infarction and stroke: the Rotterdam Study.
Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cardiovascular and cerebrovascular complications. Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine with a central role in inflammation. Little is known of the relation of variations within the gene and risk of cardiovascular and cerebrovascular disease. We therefore investigated 5 polymorphisms in the TGF-beta1 gene (-800 G/A, -509 C/T, codon 10 Leu/Pro, codon 25 Arg/Pro, and codon 263 Thr/Ile) in relation to the risk of myocardial infarction and stroke in a population-based study. Participants (N=6456) of the Rotterdam Study were included in the current study. Analyses of the relations of genotypes with the risk of myocardial infarction and stroke were performed according to Cox proportional-hazards methods. All analyses were adjusted for age, sex, conventional cardiovascular risk factors, and medical history. We found no association with the risk of myocardial infarction. A significantly increased risk of stroke was found, associated with the T allele of the -509 C/T polymorphism (relative risk, 1.26; (95% CI, 1.06 to 1.49) and the Pro variant of the codon 10 polymorphism (relative risk, 1.24; 95% CI, 1.04 to 1.48). No association between the TGF-beta1 polymorphisms and myocardial infarction was observed; however, the -509 C/T and codon 10 Leu/Pro polymorphisms were associated with the risk of stroke.


The Role of mRNA Translational Control in Tumor Immune Escape and Immunotherapy Resistance.
Tremendous advances have been made in cancer immunotherapy over the last decade. Among the different steps of gene expression, translation of mRNA is emerging as an essential player in both cancer and immunity. Changes in mRNA translation are both rapid and adaptive, and translational reprogramming is known to be necessary for sustaining cancer cell proliferation. However, the role of mRNA translation in shaping an immune microenvironment permissive to tumors has not been extensively studied. Recent studies on immunotherapy approaches have indicated critical roles of mRNA translation in regulating the expression of immune checkpoint proteins, tuning the secretion of inflammation-associated factors, modulating the differentiation of immune cells in the tumor microenvironment, and promoting cancer resistance to immunotherapies. Careful consideration of the role of mRNA translation in the tumor-immune ecosystem could suggest more effective therapeutic strategies and may eventually change the current paradigm of cancer immunotherapy. In this review, we discuss recent advances in understanding the relationship between mRNA translation and tumor-associated immunity, the potential mechanisms of immunotherapy resistance in cancers linked to translational reprogramming, and therapeutic perspectives and potential challenges of modulating translational regulation in cancer immunotherapy.


[Nutritional support response in critically ill patients; differences between medical and surgical patients].
To assess the nutritional response of a group of critically ill patients, as well as the differences in the response to nutritional support between medical and surgical patients. One-year long retrospective study including critically ill patients on artificial nutrition for 7 days. Throughout the first week, three nutritional biochemical controls were done that included albumin, prealbumin, transferrin, cholesterol, and electrolytes. Other data gathered were: nutritional risk index, age, gender, weight, height, APACHE, delay of onset of nutritional support, access route, predicted and real caloric intake, medical or surgical patient, hospital stay, duration of the central venous catheter, urinary tube, and/or mechanical ventilation, incidence and density of incidence of nosocomial infections. Sixty-three patients were studied, 30 (47%) medical and 33 (53%) surgical/trauma patients, with a usage of EN higher among medical patients (16/30, 53% vs. 5/33, 15%), PN higher among surgical patients (25/33, 76%), and mixed nutrition similar in both groups (5 medical and 3 surgical patients) (p = 0.001). There were no differences between medical and surgical patients regarding: both predicted and real caloric and nitrogenous intake, APACHE, delay of onset of nutrition, phosphorus, magnesium or glucose levels, mortality and incidence of nosocomial infections. There were no differences either in hospital stay or use of mechanical ventilation, although these tended to be lower in surgical patients. The baseline biochemical parameters did not show differences between both groups, although they were worse among surgical patients. These patients presented during the study period steady albumin levels with improvement in the remaining parameters, whereas medical patients showed a decrease in albumin and transferrin levels, steady prealbumin levels, and slightly improvement in cholesterol levels. We have observed higher usage of PN among surgical patients, which showed worse baseline nutritional biochemical parameters and responded better to nutritional support and having a trend towards shorter hospital stay and lower mechanical ventilation use than medical patients. We have not observed differences regarding the mortality or nosocomial infection.


Induction of apoptosis by an ethanol extract of Poria cocos Wolf. in human leukemia U937 cells.
Poria cocos Wolf., which belongs to the Polyporaceae family, has been widely used as an Oriental traditional herbal medicine for centuries. Its sclerotium has been reported to possess a wide spectrum of pharmacological activities, including free-radical scavenging, anti-viral, anti-microbial, anti-inflammatory and anticancer activities. However, the cellular and molecular mechanisms of apoptosis induction by P. cocos in human cancer cells are poorly understood. In the present study, we investigated the pro-apoptotic potential of an ethanol extract of P. cocos sclerotium (EEPC) in human leukemia U937 cells in vitro. We found that EEPC induced anti-proliferative effects in U937 cells in a concentration- and time-dependent manner, which was due to apoptotic induction, as evident from morphological changes and flow cytometric assays. EEPC-induced apoptosis of U937 cells was associated with an increase in the Bax:Bcl-2 ratio, the release of cytochrome c to the cytosol, and a decrease in the expression of an inhibitor of the apoptosis family of proteins. The events were accompanied by activation of caspase-8, -9 and -3, and cleaved poly(ADP-ribose) polymerase, suggesting the involvement of both the intrinsic and extrinsic apoptotic cascades. In addition, the overexpression of Bcl-2 caused a significant attenuation of EEPC-induced caspase activation, degradation of PARP, and the collapse of mitochondrial membrane potential, and thereby reversed EEPC-induced cell apoptosis and growth inhibition. Collectively, these data provide insights into the molecular mechanisms underlying EEPC-induced apoptosis in U937 cells, suggesting that EEPC may be a new therapeutic option for the treatment of leukemia.


Disruption of cortical connectivity during remifentanil administration is associated with cognitive impairment but not with analgesia.
The authors investigated the effect of remifentanil administration on resting electroencephalography functional connectivity and its relationship to cognitive function and analgesia in healthy volunteers. Twenty-one healthy male adult subjects were enrolled in this placebo-controlled double-blind cross-over study. For each subject, 2.5 min of multichannel electroencephalography recording, a cognitive test of sustained attention (continuous reaction time), and experimental pain scores to bone-pressure and heat stimuli were collected before and after infusion of remifentanil or placebo. A coherence matrix was calculated from the electroencephalogram, and three graph-theoretical measures (characteristic path-length, mean clustering coefficient, and relative small-worldness) were extracted to characterize the overall cortical network properties. Compared to placebo, most graph-theoretical measures were significantly altered by remifentanil at the alpha and low beta range (8 to 18 Hz; all P < 0.001). Taken together, these alterations were characterized by an increase in the characteristic path-length (alpha 17% and low beta range 24%) and corresponding decrements in mean clustering coefficient (low beta range -25%) and relative small-worldness (alpha -17% and low beta range -42%). Changes in characteristic path-lengths after remifentanil infusion were correlated to the continuous reaction time index (r = -0.57; P = 0.009), while no significant correlations between graph-theoretical measures and experimental pain tests were seen. Remifentanil disrupts the functional connectivity network properties of the electroencephalogram. The findings give new insight into how opioids interfere with the normal brain functions and have the potential to be biomarkers for the sedative effects of opioids in different clinical settings.


Irish General Practitioner referrals to psychological therapies.
General Medical Practitioners play a crucial role in the detection and referral of mental health problems in primary care. This study describes the referral patterns of Irish General Practitioners (GPs) to psychological therapies and profiles the range of psychological therapies available. A 21-item study-specific questionnaire exploring referral processes to psychological therapies was sent to all GPs listed by the Irish College of General Practitioners in one county in Ireland. A 19-item questionnaire exploring details of psychological therapies offered and referral pathways was sent to members of psychological therapy accrediting bodies in the same county. Of 97 GP respondents (33% response rate), their estimation of the percentage of their patients who have presenting or underlying mental health issues averaged 22%. When asked to indicate which psychological therapies they consider for referrals, psychiatric referrals was the most frequent referral option (94%), followed by Counsellors (69%), Clinical psychologist (60%) and Psychotherapists (30%). GPs indicated they had some or very little knowledge of specific psychological therapies. Of 129 psychological therapists (45% response rate), self-referral and GP referral were their main referral pathways; 80% worked in private practice; highest qualification level was Undergraduate/Higher Diploma (66%), Master Level (39%) and Doctoral Level (5%). GPs refer patients presenting with mental health problems to psychiatrists with significantly lower percentages referring to other types of psychological therapists. Findings demonstrate that there is a need for greater education and information-sharing between GPs and providers of accredited psychological therapies to increase knowledge on specific therapies and their evidence base.


Celebrating Soft Matter's 10th Anniversary: monitoring colloidal growth with holographic microscopy.
Holographic video microscopy offers valuable and previously unavailable insights into the progress of colloidal synthesis by providing measurements of the size and refractive index of individual colloidal particles in the dispersion. These measurements are precise enough to track subtle changes in particles' properties and rapid enough for real-time process control. We demonstrate this technique by applying it to the synthesis of monodisperse samples of crosslinked polydimethysiloxane (PDMS) spheres. The measured time dependence of these spheres' most probable radius is consistent with the LaMer model for colloidal growth. The joint distribution of size and refractive index, however, also reveals a small proportion of undersize, lower-density spheres. Trends in the distribution's time evolution offer insights into their origin. Applied over longer time periods, holographic characterization also tracks how the newly-synthesized spheres age, and illuminates the aging mechanism.


The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer.
Epithelial to Mesenchymal transition (EMT) in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.


Psychometric profile of children with auditory processing disorder and children with dyslexia.
The aim was to address the controversy that exists over the extent to which auditory processing disorder (APD) is a separate diagnostic category with a distinctive psychometric profile, rather than a reflection of a more general learning disability. Children with an APD diagnosis (N=25) were compared with children with dyslexia (N=19) on a battery of standardised auditory processing, language, literacy and non-verbal intelligence quotient measures as well as parental report measures of communicative skill and listening behaviour. A follow-up of a subset of children included a parent report screening questionnaire for Asperger syndrome (Childhood Asperger Syndrome Test). There were similarly high levels of attentional, reading and language problems in both groups. One peculiarity of the APD group was a discrepancy between parental report of poor communication and listening skill disproportionate to expectations based on standardised test performance. Follow-up assessment suggested high levels of previously unrecognised autistic features within the APD group. Children diagnosed by audiological experts as having APD are likely to have broader neurodevelopmental disorders and would benefit from evaluation by a multidisciplinary team.


A meal or a male: the 'whispers' of black widow males do not trigger a predatory response in females.
Female spiders are fine-tuned to detect and quickly respond to prey vibrations, presenting a challenge to courting males who must attract a female's attention but not be mistaken for prey. This is likely particularly important at the onset of courtship when a male enters a female's web. In web-dwelling spiders, little is known about how males solve this conundrum, or about their courtship signals. Here we used laser Doppler vibrometry to study the vibrations produced by males and prey (house flies and crickets) on tangle webs of the western black widow Latrodectus hesperus and on sheet webs of the hobo spider Tegenaria agrestis. We recorded the vibrations at the location typically occupied by a hunting female spider. We compared the vibrations produced by males and prey in terms of their waveform, dominant frequency, frequency bandwidth, amplitude and duration. We also played back recorded male and prey vibrations through the webs of female L. hesperus to determine the vibratory parameters that trigger a predatory response in females. We found overlap in waveform between male and prey vibrations in both L. hesperus and T. agrestis. In both species, male vibrations were continuous, of long duration (on average 6.35 s for T. agrestis and 9.31 s for L. hesperus), and lacked complex temporal patterning such as repeated motifs or syllables. Prey vibrations were shorter (1.38 - 2.59 s), sporadic and often percussive. Based on the parameters measured, courtship signals of male L. hesperus differed more markedly from prey cues than did those of T. agrestis. Courtship vibrations of L. hesperus males differed from prey vibrations in terms of dominant frequency, amplitude and duration. Vibrations of T. agrestis males differed from prey in terms of duration only. During a playback experiment, L. hesperus females did not respond aggressively to low-amplitude vibrations irrespective of whether the playback recording was from a prey or a male. Unlike courtship signals of other spider species, the courtship signals of L. hesperus and T. agrestis males do not have complex temporal patterning. The low-amplitude 'whispers' of L. hesperus males at the onset of courtship are less likely to trigger a predatory response in females than the high-amplitude vibrations of struggling prey.


Oral rehydration therapy for treatment of rotavirus diarrhoea in a rural treatment centre in Bangladesh.
In November 1977, an enzyme-linked immunosorbent assay for detecting rotavirus antigen was introduced in the laboratory of a rural treatment centre in Bangladesh. During the next 40 days rotavirus without other pathogens was found in the stools of 216 (45%) of 480 children under age 5 years who visited the centre with a gastrointestinal illness. 188 (87%) of these children were treated with oral rehydration alone, using the solution currently recommended by the World Health Organisation, while 28 (13%) also required some intravenous rehydration; there were no deaths. Oral rehydration treatment was judged successful in 205 (95%) of the rotavirus patients and was not associated with any serious side effects. Oral rehydration treatment, with this solution, has been used extensively and successfully in the treatment of enterotoxin-mediated diarrhoea and can also safely be used for treating rotavirus diarrhoea in infants and young children.


Summative assessments are more powerful drivers of student learning than resource intensive teaching formats.
Electrocardiogram (ECG) interpretation is a core clinical skill that needs to be acquired during undergraduate medical education. Intensive teaching is generally assumed to produce more favorable learning outcomes, but recent research suggests that examinations are more powerful drivers of student learning than instructional format. This study assessed the differential contribution of teaching format and examination consequences to learning outcome regarding ECG interpretation skills in undergraduate medical students. A total of 534 fourth-year medical students participated in a six-group (two sets of three), partially randomized trial. Students received three levels of teaching intensity: self-directed learning (two groups), lectures (two groups) or small-group peer teaching facilitated by more advanced students (two groups). One of the two groups on each level of teaching intensity was assessed in a formative, the other in a summative written ECG examination, which provided a maximum of 1% credit points of the total curriculum. The formative examination provided individual feedback without credit points. Main outcome was the correct identification of ≥3 out of 5 diagnoses in original ECG tracings. Secondary outcome measures were time spent on independent study and use of additional study material. Compared with formative assessments, summative assessments increased the odds of correctly identifying at least three out of five ECG diagnoses (OR 5.14; 95% CI 3.26 to 8.09), of spending at least 2 h/week extra on ECG self-study (OR 4.02; 95% CI 2.65 to 6.12) and of using additional learning material (OR 2.86; 95% CI 1.92 to 4.24). Lectures and peer teaching were associated with increased learning effort only, but did not augment examination performance. Medical educators need to be aware of the paramount role of summative assessments in promoting student learning. Consequently, examinations within medical schools need to be closely matched to the desired learning outcomes. Shifting resources from implementing innovative and costly teaching formats to designing more high-quality summative examinations warrants further investigation.


European Non-Communicable Respiratory Disease Research, 2002-13: Bibliometric Study of Outputs and Funding.
This study was conducted in order to map European research in chronic respiratory diseases (CRDs). It was intended to assist the European Commission and other research funders to identify gaps and overlaps in their portfolios, and to suggest ways in which they could improve the effectiveness of their support and increase the impact of the research on patient care and on the reduction of the incidence of the CRDs. Articles and reviews were identified in the Web of Science on research in six non-communicable respiratory diseases that were published in 2002-13 from 31 European countries. They represented only 0.8% of biomedical research output but these diseases accounted for 4.7% of the European disease burden, as measured by Disability-Adjusted Life Years (DALYs), so the sub-field is seriously under-researched. Europe is prominent in the sub-field and published 56% of the world total, with the UK the most productive and publishing more than France and Italy, the next two countries, combined. Asthma and Chronic Obstructive Pulmonary Disease (COPD) were the diseases with the most publications and the highest citation rates. They also received the most funding, with around two acknowledgments per paper (in 2009-13), whereas cystic fibrosis and emphysema averaged only one. Just over 37% of papers had no specific funding and depended on institutional support from universities and hospitals.


Contribution of upper trunk rotation to hand forward-backward movement and propulsion in front crawl strokes.
The study aims to test three hypotheses: (a) the rotation of the upper trunk consists of roll, pitch and yaw of frequencies harmonic to the stroke frequency of the front crawl stroke, (b) the rotation of the upper trunk generates back-and-forth movements of the shoulders, which enhances the movements of the stroking arms, and (c) the angular velocities of roll, pitch and yaw are associated with hand propulsion (HP). Front crawl strokes performed by twenty male swimmers were measured with a motion capture system. The roll, pitch and yaw angles about the three orthogonal axes embedded in the upper trunk were determined as three sequential Cardan angles and their angular velocities were determined as the three respective components of the angular velocity. HP and the drag and lift components of HP (HPD and HPL) were estimated by the hand positions and the data from twelve pressure sensors attached on hands. The roll, pitch, and yaw angles were altered in frequencies harmonic to the stroke frequency during the front crawl stroke. Shoulders alternately moved back and forth due to the upper trunk rotation. In the pull phase the angular velocity of roll was correlated with HPL (r = -0.62, p = 0.004). Based on the back-and-forth movements of the shoulders and roll motion relative to a hand movement, the arm-stroke technique of the front crawl swimming was discussed in terms of increasing the hand velocity and HP.


The Disparity Between Public Utilization and Surgeon Awareness of the STS Patient Education Website.
Many online resources currently provide healthcare information to the public. In 2015, the Society of Thoracic Surgeons (STS) created a multimedia web portal (ctsurgerypatients.org) to educate the public regarding cardiothoracic surgery and provide an informative tool to which cardiothoracic surgeons could refer patients. A patient education task force was created, and disease-specific content was created for 25 pathological conditions. After launching the website online, a marketing campaign was initiated to make STS members aware of its availability. Website visits were monitored, and an online survey for public users was created. An email survey was sent to STS members to evaluate awareness and content. Surveys were analyzed for effectiveness and utilization by both public users and STS member surgeons. From 2016 to 2018, the website had more than 1 million visits, with visits increasing yearly. Surveyed user ratings of the website were positive regarding quality and utility of the information provided. STS member response was poor (379 responses of 6347 emails), and 78.3% of responders were unaware of the website. Surgeon responders were positive about the content, though many still refrain from referring patients. Online education for cardiothoracic surgery is seeing increased public use, with high ratings for content and utility. Despite aggressive marketing to STS members, most remain unaware of this website's existence. Those who are aware approve of its content, but adoption of referring patients to it has been slow. Improved strategies are necessary to make surgeons aware of this STS-provided service and increase patient referrals to it.


Modern imaging techniques: applications in the management of acute aortic pathologies.
Acute aortic pathologies include traumatic and non-traumatic life-threatening emergencies of the aorta. Since the clinical manifestation of these entities can be non-specific and may overlap with other conditions presenting with chest pain, non-invasive imaging plays a crucial role in their rapid and accurate evaluation. The early diagnosis and accurate radiological assessment of acute aortic diseases is essential for improved clinical outcomes. Multidetector CT is the imaging modality of choice for evaluation of acute aortic diseases with MRI playing more of a problem-solving role. The management can be medical, endovascular or surgical depending upon pathology, and imaging remains an indispensable management-guiding tool. It is important to understand the pathogenesis, natural history, and imaging principles of acute aortic diseases for appropriate use of advanced imaging modalities. This understanding helps to formulate a more appropriate management and follow-up plan for optimised care of these patients. Imaging reporting pearls for day-to-day radiology as well as treatment options based on latest multidisciplinary guidelines are discussed. With newer techniques of image acquisition and processing, we are hopeful that imaging would further help in predicting aortic disease progression and assessing the haemodynamic parameters based on which decisions on management can be made.


Multispectral photoacoustic microscopy and optical coherence tomography using a single supercontinuum source.
We report on the use of a single supercontinuum (SC) source for multimodal imaging. The 2-octave bandwidth (475-2300 nm) makes the SC source suitable for optical coherence tomography (OCT) as well as for multispectral photoacoustic microscopy (MPAM). The IR band centered at 1310 nm is chosen for OCT to penetrate deeper into tissue with 8 mW average power on the sample. The 500-840 nm band is used for MPAM. The source has the ability to select the central wavelength as well as the spectral bandwidth. An energy of more than 35 nJ within a less than 50 nm bandwidth is achieved on the sample for wavelengths longer than 500 nm. In the present paper, we demonstrate the capabilities of such a multimodality imaging instrument based on a single optical source. In vitro mouse ear B-scan images are presented.


A multi-target caffeine derived rhodium(i) N-heterocyclic carbene complex: evaluation of the mechanism of action.
A rhodium(i) and a ruthenium(ii) complex with a caffeine derived N-heterocyclic carbene (NHC) ligand were biologically investigated as organometallic conjugates consisting of a metal center and a naturally occurring moiety. While the ruthenium(ii) complex was largely inactive, the rhodium(i) NHC complex displayed selective cytotoxicity and significant anti-metastatic and in vivo anti-vascular activities and acted as both a mammalian and an E. coli thioredoxin reductase inhibitor. In HCT-116 cells it increased the reactive oxygen species level, leading to DNA damage, and it induced cell cycle arrest, decreased the mitochondrial membrane potential, and triggered apoptosis. This rhodium(i) NHC derivative thus represents a multi-target compound with promising anti-cancer potential.


Microbial communities in dark oligotrophic volcanic ice cave ecosystems of Mt. Erebus, Antarctica.
The Earth's crust hosts a subsurface, dark, and oligotrophic biosphere that is poorly understood in terms of the energy supporting its biomass production and impact on food webs at the Earth's surface. Dark oligotrophic volcanic ecosystems (DOVEs) are good environments for investigations of life in the absence of sunlight as they are poor in organics, rich in chemical reactants and well known for chemical exchange with Earth's surface systems. Ice caves near the summit of Mt. Erebus (Antarctica) offer DOVEs in a polar alpine environment that is starved in organics and with oxygenated hydrothermal circulation in highly reducing host rock. We surveyed the microbial communities using PCR, cloning, sequencing and analysis of the small subunit (16S) ribosomal and Ribulose-1,5-bisphosphate Carboxylase/Oxygenase (RubisCO) genes in sediment samples from three different caves, two that are completely dark and one that receives snow-filtered sunlight seasonally. The microbial communities in all three caves are composed primarily of Bacteria and fungi; Archaea were not detected. The bacterial communities from these ice caves display low phylogenetic diversity, but with a remarkable diversity of RubisCO genes including new deeply branching Form I clades, implicating the Calvin-Benson-Bassham (CBB) cycle as a pathway of CO2 fixation. The microbial communities in one of the dark caves, Warren Cave, which has a remarkably low phylogenetic diversity, were analyzed in more detail to gain a possible perspective on the energetic basis of the microbial ecosystem in the cave. Atmospheric carbon (CO2 and CO), including from volcanic emissions, likely supplies carbon and/or some of the energy requirements of chemoautotrophic microbial communities in Warren Cave and probably other Mt. Erebus ice caves. Our work casts a first glimpse at Mt. Erebus ice caves as natural laboratories for exploring carbon, energy and nutrient sources in the subsurface biosphere and the nutritional limits on life.


Endogenous RNAi Pathways Are Required in Neurons for Dauer Formation in Caenorhabditis elegans.
Animals can adapt to unfavorable environments through changes in physiology or behavior. In the nematode, Caenorhabditis elegans, environmental conditions perceived early in development determine whether the animal enters either the reproductive cycle, or enters into an alternative diapause stage named dauer. Here, we show that endogenous RNAi pathways play a role in dauer formation in crowding (high pheromone), starvation, and high temperature conditions. Disruption of the Mutator proteins or the nuclear Argonaute CSR-1 result in differential dauer-deficient phenotypes that are dependent upon the experienced environmental stress. We provide evidence that the RNAi pathways function in chemosensory neurons for dauer formation, upstream of the TGF-β and insulin signaling pathways. In addition, we show that Mutator MUT-16 expression in a subset of individual pheromone-sensing neurons is sufficient for dauer formation in high pheromone conditions, but not in starvation or high temperature conditions. Furthermore, we also show that MUT-16 and CSR-1 are required for expression of a subset of G proteins with functions in the detection of pheromone components. Together, our data suggest a model where Mutator-amplified siRNAs that associate with the CSR-1 pathway promote expression of genes required for the detection and signaling of environmental conditions to regulate development and behavior in C. elegans This study highlights a mechanism whereby RNAi pathways mediate the link between environmental stress and adaptive phenotypic plasticity in animals.


The complete chloroplast genome sequences for four Amaranthus species (Amaranthaceae).
The amaranth genus contains many important grain and weedy species. We further our understanding of the genus through the development of a complete reference chloroplast genome. A high-quality Amaranthus hypochondriacus (Amaranthaceae) chloroplast genome assembly was developed using long-read technology. This reference genome was used to reconstruct the chloroplast genomes for two closely related grain species (A. cruentus and A. caudatus) and their putative progenitor (A. hybridus). The reference genome was 150,518 bp and possesses a circular structure of two inverted repeats (24,352 bp) separated by small (17,941 bp) and large (83,873 bp) single-copy regions; it encodes 111 genes, 72 for proteins. Relative to the reference chloroplast genome, an average of 210 single-nucleotide polymorphisms (SNPs) and 122 insertion/deletion polymorphisms (indels) were identified across the analyzed genomes. This reference chloroplast genome, along with the reported simple sequence repeats, SNPs, and indels, is an invaluable genetic resource for studying the phylogeny and genetic diversity within the amaranth genus.


Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa.
Human GCMa is a zinc-containing transcription factor primarily expressed in placenta. GCMa regulates expression of syncytin gene, which encodes for a placenta-specific membrane protein that mediates trophoblastic fusion and the formation of syncytiotrophoblast layer required for efficient fetal-maternal exchange of nutrients and oxygen. The adenylate cyclase activator, forskolin, stimulates syncytin gene expression and cell fusion in cultured placental cells. Here we present evidence that cyclic AMP (cAMP) signaling pathway activates the syncytin gene expression by regulating GCMa activity. We found that forskolin and protein kinase A (PKA) enhances GCMa-mediated transcriptional activation. Furthermore, PKA treatment stimulates the association of GCMa with CBP and increases GCMa acetylation. CBP primarily acetylates GCMa at lysine367, lysine406, and lysine409 in the transactivation domain (TAD). We found that acetylation of these residues is required to protect GCMa from ubiquitination and increases the TAD stability with a concomitant increase in transcriptional activity, supporting the importance of acetylation in PKA-dependent GCMa activation. Our results reveal a novel regulation of GCMa activity by cAMP-dependent protein acetylation and provide a molecular mechanism by which cAMP signaling regulates trophoblastic fusion.