Short biceps femoris fascicles and eccentric knee flexor weakness increase the risk of hamstring injury in elite football (soccer): a prospective cohort study.
To investigate the role of eccentric knee flexor strength, between-limb imbalance and biceps femoris long head (BFlh) fascicle length on the risk of future hamstring strain injury (HSI). Elite soccer players (n=152) from eight different teams participated. Eccentric knee flexor strength during the Nordic hamstring exercise and BFlh fascicle length were assessed at the beginning of preseason. The occurrences of HSIs following this were recorded by the team medical staff. Relative risk (RR) was determined for univariate data, and logistic regression was employed for multivariate data. Twenty seven new HSIs were reported. Eccentric knee flexor strength below 337 N (RR=4.4; 95% CI 1.1 to 17.5) and possessing BFlh fascicles shorter than 10.56 cm (RR=4.1; 95% CI 1.9 to 8.7) significantly increased the risk of a HSI. Multivariate logistic regression revealed significant effects when combinations of age, history of HSI, eccentric knee flexor strength and BFlh fascicle length were explored. From these analyses the likelihood of a future HSI in older athletes or those with a HSI history was reduced if high levels of eccentric knee flexor strength and longer BFlh fascicles were present. The presence of short BFlh fascicles and low levels of eccentric knee flexor strength in elite soccer players increases the risk of future HSI. The greater risk of a future HSI in older players or those with a previous HSI is reduced when they have longer BFlh fascicles and high levels of eccentric strength.


Space-based optical image encryption.
In this paper, we propose a new method based on a three-dimensional (3D) space-based strategy for the optical image encryption. The two-dimensional (2D) processing of a plaintext in the conventional optical encryption methods is extended to a 3D space-based processing. Each pixel of the plaintext is considered as one particle in the proposed space-based optical image encryption, and the diffraction of all particles forms an object wave in the phase-shifting digital holography. The effectiveness and advantages of the proposed method are demonstrated by numerical results. The proposed method can provide a new optical encryption strategy instead of the conventional 2D processing, and may open up a new research perspective for the optical image encryption.


Endogenous gas gangrene after laparoscopic cholecystectomy.
Clostridial gas gangrene of the abdominal wall is rare, and it is usually associated with organ perforation, immunosuppression or gastrointestinal malignancies. In this paper we present a case of fulminant, endogenous gas gangrene in a 58-year old diabetic female with arterial hypertension and atherosclerosis, following uneventful laparoscopic cholecystectomy. She developed gas gangrene of the abdominal wall 12-hours after cholecystectomy and died 24-hours after the onset of the first symptoms, in spite of treatment.


Comparative hyperthermia effects of silica-gold nanoshells with different surface coverage of gold clusters on epithelial tumor cells.
Silica-gold nanoshell (SGNS), which is a silica core surrounded by a gold layer, was synthesized by seed-mediated coalescence of gold clusters in an electroless plating solution. SGNS variations with different surface coverage of gold clusters were prepared by adjusting the amounts of gold salts in the presence of formaldehyde-reducing agents. Fully covered SGNS (f-SGNS) with connected gold clusters exhibited stronger intensity and more redshift of plasmon bands located around 820 nm than those of partially covered SGNS (p-SGNS) with disconnected gold clusters. Upon irradiation with near-infrared light (30 W/cm(2), 700-800 nm), f-SGNS caused a larger hyperthermia effect, generating a large temperature change (ΔT =42°C), as compared to the relatively small temperature change (ΔT =24°C) caused by p-SGNS. The therapeutic antibody, Erbitux™ (ERB), was further conjugated to SGNS for specific tumor cell targeting. The f-ERB-SGNS showed excellent therapeutic efficacy based on the combined effect of both the therapeutic antibody and the full hyperthermia dose under near-infrared irradiation. Thus, SGNS with well-controlled surface morphology of gold shells may be applicable for near-infrared-induced hyperthermia therapy with tunable optical properties.


Improved Polarizable Dipole-Dipole Interaction Model for Hydrogen Bonding, Stacking, T-Shaped, and X-H···π Interactions.
The polarizable dipole-dipole interaction model was formulated in our laboratory to rapidly simulate hydrogen bonding in biosystems. In this paper, this model is improved and further parametrized for stacking, T-shaped, and X-H···π interactions by adding the orbital overlap term and fitting to 19 CCSD(T)/CBS interaction energy curves of training dimers. The performance of our model is assessed through its application to more than 100 complexes, including hydrogen-bonded, stacked, T-shaped, and X-H···π complexes. For 124 relatively small testing complexes, our model reproduces benchmark equilibrium intermolecular distances with a root-mean-square deviation (RMSD) of 0.08 Å, and it reproduces benchmark interaction energies with a 0.64 kcal/mol RMSD. For 14 large noncovalent complexes, our model reproduces benchmark equilibrium intermolecular distances with a RMSD of 0.05 Å, and it reproduces benchmark interaction energies with a 0.80 kcal/mol RMSD. Extensive comparisons are made to interaction energies calculated via the M06-2X and M06-2X-D3 methods, via the well-known nonpolarizable AMBER99 force field method, via the popular polarizable AMOEBA force field method, and via semiempirical quantum mechanical (SQM) methods. Our statistical evaluations show that our model outperforms the AMBER99, AMOEBA, and SQM methods and is as accurate as the M06-2X and M06-2X-D3 methods. In summary, the model developed in this work is reasonable, and the newly introduced orbital overlap term is effective in the accurate modeling of the noncovalent interactions. Our testing results also indicate that the polarization interaction term is important in the evaluation of hydrogen bonding, whereas the orbital overlap is important in examining short hydrogen bonding, T-shaped, and X-H···π interactions. Our model may serve as a new tool for modeling biological systems where hydrogen bonding, stacking, T-shaped, and X-H···π interactions are of general importance.


Metformin use and the risk of esophageal cancer in Barrett esophagus.
Diabetes mellitus is a significant risk factor for total cancer incidence and mortality. Metformin, a commonly used antidiabetic drug, has been shown to be protective against different types of cancers; however, its role in esophageal cancer is unknown. The goal of this study was to determine whether the use of metformin modifies the risk of development of esophageal adenocarcinoma in patients with Barrett esophagus. Patients with diagnoses of Barrett esophagus and esophageal cancer were identified during a 20-year period. Demographic and clinical data were collected. The outcome variable was esophageal adenocarcinoma. Univariate analysis was performed using two-sample t tests for continuous variables or the Fisher exact test for categorical variables. Multiple logistic regression analysis was then performed using the significant variables. A total of 583 patients were identified with the diagnosis of Barrett esophagus or esophageal adenocarcinoma from 1992 to 2012. Of these, 115 had esophageal adenocarcinoma and 468 had Barrett esophagus. Age, smoking, and diabetes mellitus were found to be significant risk factors for the development of esophageal cancer with the following results: age (P < 0.001), smoking (P = 0.003), diabetes mellitus (P = 0.007). Statin use was protective against the development of cancer with P = 0.001. Metformin use was neither associated with an increased nor a decreased risk of esophageal cancer. The three independent variables that predicted progression of Barrett esophagus to esophageal adenocarcinoma in our study were older age, smoking, and diabetes mellitus. Statin use showed protective effect against development of esophageal adenocarcinoma. Metformin use did not demonstrate any statistically significant protective effect.


Molecular sampling of prostate cancer: a dilemma for predicting disease progression.
Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.


The last frontiers of wilderness: Tracking loss of intact forest landscapes from 2000 to 2013.
An intact forest landscape (IFL) is a seamless mosaic of forest and naturally treeless ecosystems with no remotely detected signs of human activity and a minimum area of 500 km2. IFLs are critical for stabilizing terrestrial carbon storage, harboring biodiversity, regulating hydrological regimes, and providing other ecosystem functions. Although the remaining IFLs comprise only 20% of tropical forest area, they account for 40% of the total aboveground tropical forest carbon. We show that global IFL extent has been reduced by 7.2% since the year 2000. An increasing rate of global IFL area reduction was found, largely driven by the tripling of IFL tropical forest loss in 2011-2013 compared to that in 2001-2003. Industrial logging, agricultural expansion, fire, and mining/resource extraction were the primary causes of IFL area reduction. Protected areas (International Union for Conservation of Nature categories I to III) were found to have a positive effect in slowing the reduction of IFL area from timber harvesting but were less effective in limiting agricultural expansion. The certification of logging concessions under responsible management had a negligible impact on slowing IFL fragmentation in the Congo Basin. Fragmentation of IFLs by logging and establishment of roads and other infrastructure initiates a cascade of changes that lead to landscape transformation and loss of conservation values. Given that only 12% of the global IFL area is protected, our results illustrate the need for planning and investment in carbon sequestration and biodiversity conservation efforts that target the most valuable remaining forests, as identified using the IFL approach.


Analysis of fullerenes in soils samples collected in The Netherlands.
Fullerenes are carbon based nanoparticles that may enter the environment as a consequence of both natural processes and human activities. Although little is known about the presence of these chemicals in the environment, recent studies suggested that soil may act as a sink. The aim of the present work was to investigate the presence of fullerenes in soils collected in The Netherlands. Samples (n = 91) were taken from 6 locations and analyzed using a new developed LC-QTOF-MS method. The locations included highly trafficked and industrialized as well as urban and natural areas. In general, C60 was the most abundant fullerene found in the environment, detected in almost a half of the samples and at concentrations in the range of ng/kg. Other fullerenes such as C70 and an unknown structure containing a C60 cage were detected to a lower extent. The highest concentrations were found in the proximity of combustion sites such as a coal power plant and an incinerator, suggesting that the nanoparticles were unintentionally produced during combustions processes and reached the soil through atmospheric deposition. Consistent with other recent studies, these results show that fullerenes are widely present in the environment and that the main route for their entrance may be due to human activities. These data will be helpful in the understanding of the distribution of fullerenes in the environment and for the study of their behavior and fate in soil.


Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome.
Pathological and clinical data from 56 patients operated on for craniopharyngioma since 1981 were analyzed to determine the utility of dividing patients with this tumor into distinct clinical groups based on recognized pathological type and to determine the prognostic import of brain invasion. Of the tumors in the 30 adult patients, 66% were adamantinomatous, 28% were squamous papillary, and the remainder were mixed. However, of the tumors in the 26 children, 96% were adamantinomatous and none were pure squamous papillary (P < 0.01). Forty-six percent of the children compared with 17% of the adults had brain invasion (P < 0.01). Brain invasion was present in 37% of the adamantinomatous but in only 13% of the squamous papillary tumors. Seventy-seven percent of the children underwent gross total resection (GTR) compared with 27% of the adults (P < 0.01). Sixty-three percent of the squamous papillary tumors underwent GTR compared with 54% of the adamantinomatous and mixed tumors. Follow-up ranged from 7 to 187 months (mean, 49 mo). After subtotal resection, with or without radiation therapy, 58% of the tumors recurred compared with 17% recurrence after GTR (P < 0.01), with a mean time to recurrence of 34 months. In both tumor histological types, subtotal resection was associated with a higher rate of tumor recurrence compared with gross total resection. Among the subtotally resected craniopharyngiomas, 2 of the 3 (67%) squamous papillary and 11 of the 21 (52%) adamantinomatous and mixed tumors recurred. In contrast, among the totally resected tumors, none of the 5 squamous papillary and only 5 of the 25 (20%) adamantinomatous and mixed tumors recurred. There were no significant differences in Karnofsky performance status score, mortality rate, or visual and endocrine outcomes when comparing patients based on histological tumor type. When controlling for age and extent of resection, we found that brain invasion had no significant effect on recurrence rate in totally resected tumors. Based on the limited number of patients in this series, we conclude as follows. 1) Contrary to previous reports, squamous papillary craniopharyngiomas, like adamantinomatous tumors, may recur when subtotally resected. 2) For both tumor variants, the most significant factor associated with craniopharyngioma recurrence is the extent of surgical resection rather than histopathological subtype. 3) Contrary to prior hypotheses, brain invasion in totally resected tumors does not predict higher recurrence. 4) GTR is associated with a significantly lower recurrence rate and can be achieved without sacrificing functional outcome.


The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells.
NF-kappaB/Rel transcription factors regulate many genes involved in control of cellular proliferation, neoplastic transformation, and apoptosis, including the c-myc oncogene. Recently, we have observed that levels of NF-kappaB and aryl hydrocarbon receptor (AhR), which mediates malignant transformation by environmental carcinogens, are highly elevated and appear constitutively active in breast cancer cells. Rel factors have been found to functionally interact with other transcription factors. Here we demonstrate a physical and functional association between the RelA subunit of NF-kappaB and AhR resulting in the activation of c-myc gene transcription in breast cancer cells. RelA and AhR proteins were co-immunoprecipitated from cytoplasmic and nuclear extracts of non-malignant MCF-10F breast epithelial and malignant Hs578T breast cancer cells. In transient co-transfection, RelA and AhR gene products demonstrated cooperation in transactivation of the c-myc promoter, which was dependent on the NF-kappaB elements, and in induction of endogenous c-Myc protein levels. A novel AhR/RelA-containing NF-kappaB element binding complex was identified by electrophoretic mobility shift analysis of nuclear extracts from RelA and AhR co-transfected Hs578T cells. Thus, the RelA and AhR proteins functionally cooperate to bind to NF-kappaB elements and induce c-myc gene expression. These findings suggest a novel signaling mechanism whereby the Ah receptor can stimulate proliferation and tumorigenesis of mammary cells.


Synthesis, antitubulin, and antiproliferative SAR of analogues of 2-methoxyestradiol-3,17-O,O-bis-sulfamate.
The synthesis and antiproliferative activity of analogues of estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent reveal that an H-bond acceptor is essential for high antiproliferative activity. The local environment in which this H-bond acceptor lies can be varied to an extent. The C-17-oxygen linker can be deleted or substituted with an electronically neutral methylene group, and replacement of the terminal NH(2) with a methyl group is also acceptable. Mesylates 10 and 14 prove equipotent to the E2bisMATEs 2 and 3, while sulfones 20 and 35 display enhanced in vitro antiproliferative activity. In addition, the SAR of 2-substituted estradiol-3-O-sulfamate derivatives as inhibitors of tubulin polymerization has been established for the first time. These agents inhibit the binding of radiolabeled colchicine to tubulin.


Which observations from the complete blood cell count predict mortality for hospitalized patients?
Information on the prognostic utility of the admission complete blood count (CBC) and differential count is lacking. To identify independent predictors of mortality from the varied number and morphology of cells in the complete blood count defined as a hemogram, automated five cell differential count and manual differential count. Retrospective cohort study and chart review. Wishard Memorial Hospital, a large urban primary care hospital. A total of 46,522 adult inpatients admitted over 10 years to Wishard Memorial Hospital-from January 1993 through December 2002. None. Thirty-day mortality measured from day of admission as determined by electronic medical records and Indiana State death records. Controlling for age and sex, the multivariable regression model identified 3 strong independent predictors of 30-day mortality-nucleated red blood cells (NRBCs), burr cells, and absolute lymphocytosis-each of which was associated with a 3-fold increase in the risk of death within 30 days. The presence of nucleated RBCs was associated with a 30-day mortality rate of 25.5% across a range of diagnoses, excluding patients with sickle-cell disease and obstetric patients, for whom NRBCs were not associated with increased mortality. Having burr cells was associated with a mortality rate of 27.3% and was found most commonly in patients with renal or liver failure. Absolute lymphocytosis predicted poor outcome in patients with trauma and CNS injury. Among patients admitted to Wishard Memorial Hospital, the presence of nucleated RBCs, burr cells, or absolute lymphocytosis at admission was each independently associated with a 3-fold increase in risk of death within 30 days of admission.


Prenatal exposure to the probiotic Lactococcus lactis decreases anxiety-like behavior and modulates cortical cytoarchitecture in a sex specific manner.
Development of the cerebral cortex may be influenced by the composition of the maternal gut microbiota. To test this possibility, we administered probiotic Lactococcus lactis in drinking water to mouse dams from day 10.5 of gestation until pups reached postnatal day 1 (P1). Pups were assessed in a battery of behavioral tests starting at 10 weeks old. We found that females, but not males, exposed to probiotic during prenatal development spent more time in the center of the open field and displayed decreased freezing time in cue associated learning, compared to controls. Furthermore, we found that probiotic exposure changed the density of cortical neurons and increased the density of blood vessels in the cortical plate of P1 pups. Sex-specific differences were observed in the number of mitotic neural progenitor cells, which were increased in probiotic exposed female pups. In addition, we found that probiotic treatment in the latter half of pregnancy significantly increased plasma oxytocin levels in mouse dams, but not in the offspring. These results suggest that exposure of naïve, unstressed dams to probiotic may exert sex-specific long-term effects on cortical development and anxiety related behavior in the offspring.


The ligand-sensitive gate of a potassium channel lies close to the selectivity filter.
Potassium channels selectively conduct K(+) ions across cell membranes and have key roles in cell excitability. Their opening and closing can be spontaneous or controlled by membrane voltage or ligand binding. We used Ba(2+) as a probe to determine the location of the ligand-sensitive gate in an inwardly rectifying K(+) channel (Kir6.2). To a K(+) channel, Ba(2+) and K(+) are of similar sizes, but Ba(2+) blocks the pore by binding within the selectivity filter. We found that internal Ba(2+) could still access its binding site when the channel was shut, which indicates that the ligand-sensitive gate lies above the Ba(2+)-block site, and thus within or above the selectivity filter. This is in marked contrast to the voltage-dependent gate of K(V) channels, which is located at the intracellular mouth of the pore.


A functionally distinct member of the DP family of E2F subunits.
E2F transcription factors regulate genes involved in cell-cycle progression. In mammalian cells, physiological E2F exists as an E2F/DP heterodimer. Currently, eight E2F and two DP subunits have been characterized. We report here the characterization of a new member of the DP family, DP-4. While DP-4 exhibits certain similarities with members of the DP family, it also possesses a number of significant differences. Thus, DP-4 forms a heterodimer with E2F subunits, binds to the E2F site and associates with pocket proteins including pRb. In contrast to DP-1, however, DP-4/E2F-1 complexes exhibit reduced DNA binding activity. Furthermore, DP-4 interferes with E2F-1-dependent transcription and delays cell-cycle progression. These results highlight an emerging complexity in the DP family of E2F subunits, and suggest that DP-4 may endow E2F heterodimers with distinct transcription properties.


Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes.
Detection of non-self RNA by TLRs within endosomes and by retinoic acid-inducible gene I (RIG-I)-like helicases in the cytosol is central to mammalian antiviral immunity. In this study, we used pathway-specific agonists and targeted delivery to address RNA immunorecognition in primary human immune cells. Within PBMC, plasmacytoid dendritic cells (pDC) and monocytes were found to be responsible for IFN-alpha production upon immunorecognition of RNA. The mechanisms of RNA recognition in pDC and monocytes were distinct. In pDC, recognition of ssRNA and dsRNA oligonucleotides was TLR7-dependent, whereas a 5' triphosphate moiety (RIG-I ligand activity) had no major contribution to IFN-alpha production. In monocytes, the response to RNA oligonucleotides was mediated by either TLR8 or RIG-I. TLR8 was responsible for IL-12 induction upon endosomal delivery of ssRNA oligonucleotides and RIG-I was responsible for IFN-alpha production upon delivery of 5' triphosphate RNA into the cytosol. In conclusion, the dissection of these pathways by selecting the appropriate structure and delivery of RNA reveals pDC as major producer of IFN-alpha upon TLR-mediated stimulation and monocytes as major producer of IFN-alpha upon RIG-I-mediated stimulation. Furthermore, our results uncover the potential of monocytes to function as major producers of IL-12p70, a key Th1 cytokine classically ascribed to myeloid dendritic cells that cannot be induced by CpG oligonucleotides in the human system.


A pragmatic group sequential, placebo-controlled, randomised trial to determine the effectiveness of glyceryl trinitrate for retained placenta (GOT-IT): a study protocol.
A retained placenta is diagnosed when the placenta is not delivered following delivery of the baby. It is a major cause of postpartum haemorrhage and treated by the operative procedure of manual removal of placenta (MROP). The aim of this pragmatic, randomised, placebo-controlled, double-blind UK-wide trial, with an internal pilot and nested qualitative research to adjust strategies to refine delivery of the main trial, is to determine whether sublingual glyceryl trinitrate (GTN) is (or is not) clinically and cost-effective for (medical) management of retained placenta. The primary clinical outcome is need for MROP, defined as the placenta remaining undelivered 15 min poststudy treatment and/or being required within 15 min of treatment due to safety concerns. The primary safety outcome is measured blood loss between administration of treatment and transfer to the postnatal ward or other clinical area. The primary patient-sided outcome is satisfaction with treatment and a side effect profile. The primary economic outcome is net incremental costs (or cost savings) to the National Health Service of using GTN versus standard practice. Secondary outcomes are being measured over a range of clinical and economic domains. The primary outcomes will be analysed using linear models appropriate to the distribution of each outcome. Health service costs will be compared with multiple trial outcomes in a cost-consequence analysis of GTN versus standard practice. Ethical approval has been obtained from the North-East Newcastle & North Tyneside 2 Research Ethics Committee (13/NE/0339). Dissemination plans for the trial include the Health Technology Assessment Monograph, presentation at international scientific meetings and publication in high-impact, peer-reviewed journals. ISCRTN88609453; Pre-results.


Postoperative hemodynamics following aortic cross-clamping during aortocoronary bypass surgery.
Forty-one patients undergoing aortocoronary bypass surgery were divided into two groups: an "unclamped" group (17 patients) in whom the aorta was not cross-clamped during operation and a "clamped" group (24 patients) in whom the ascending aorta was cross-clamped during performance of distal anastomoses. Myocardial protection was provided during aortic clamping by cooling the anoxic heart with cold saline immersion. Immediate postoperative hemodynamic function was assayed in both groups, as was cardiopulmonary bypass time and cardiopulmonary bypass time/graft. Cardiopulmonary bypass time was 107 minutes in the unclamped group and 87 minutes in the clamped group (P less than 0.05). Cardiopulmonary bypass time/graft was 48 minutes in the unclamped group and 40 minutes in the clamped group (P less than 0.01). Results of hemodynamic studies with values for the unclamped group listed first were as follows: cardiac index (L/min/m2) 2.3 and 2.5 (NS), stroke index (ml/beat/m2) 23 and 25 (NS), left ventricular minute work index (kg-m/min/m2) 3.03 and 2.81 (NS), and stroke work index (g-m/min/m2) 31 and 30 (NS). These data indicate that aortic cross-clamping during performance of distal anastomoses expedites the performance of aortocoronary bypass surgery and does not adversely affect postoperative hemodynamics.


'heartfailurematters.org', an educational website for patients and carers from the Heart Failure Association of the European Society of Cardiology: objectives, use and future directions.
In 2007, the Heart Failure Association of the European Society of Cardiology (ESC) launched the information website heartfailurematters.org (HFM site) with the aim of creating a practical tool through which to provide advice and guidelines for living with heart failure to patients, their carers, health care professionals and the general public worldwide. The website is managed by the ESC at the European Heart House and is currently available in nine languages. The aim of this study is to describe the background, objectives, use, lessons learned and future directions of the HFM site. Data on the number of visitor sessions on the site as measured by Google Analytics were used to explore use of the HFM site from 2010 to 2015. Worldwide, the annual number of sessions increased from 416 345 in 2010 to 1 636 368 in 2015. Most users (72-75%) found the site by using a search engine. Desktops and, more recently, smartphones were used to visit the website, accounting for 50% and 38%, respectively, of visits to the site in 2015. Although its use has increased, the HFM site has not yet reached its full potential: fewer than 2 million users have visited the website, whereas the number of people living with heart failure worldwide is estimated to be 23 million. Uptake and use could be further improved by a continuous process of qualitative assessment of users' preferences, and the provision of professional helpdesk facilities, comprehensive information technology, and promotional support.


A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens.
The intestinal microbiome modulates host susceptibility to enteric pathogens, but the specific protective factors and mechanisms of individual bacterial species are not fully characterized. We show that secreted antigen A (SagA) from Enterococcus faecium is sufficient to protect Caenorhabditis elegans against Salmonella pathogenesis by promoting pathogen tolerance. The NlpC/p60 peptidoglycan hydrolase activity of SagA is required and generates muramyl-peptide fragments that are sufficient to protect C. elegans against Salmonella pathogenesis in a tol-1-dependent manner. SagA can also be heterologously expressed and secreted to improve the protective activity of probiotics against Salmonella pathogenesis in C. elegans and mice. Our study highlights how protective intestinal bacteria can modify microbial-associated molecular patterns to enhance pathogen tolerance.


Pointing in visual periphery: is DF's dorsal stream intact?
Observations of the visual form agnosic patient DF have been highly influential in establishing the hypothesis that separate processing streams deal with vision for perception (ventral stream) and vision for action (dorsal stream). In this context, DF's preserved ability to perform visually-guided actions has been contrasted with the selective impairment of visuomotor performance in optic ataxia patients suffering from damage to dorsal stream areas. However, the recent finding that DF shows a thinning of the grey matter in the dorsal stream regions of both hemispheres in combination with the observation that her right-handed movements are impaired when they are performed in visual periphery has opened up the possibility that patient DF may potentially also be suffering from optic ataxia. If lesions to the posterior parietal cortex (dorsal stream) are bilateral, pointing and reaching deficits should be observed in both visual hemifields and for both hands when targets are viewed in visual periphery. Here, we tested DF's visuomotor performance when pointing with her left and her right hand toward targets presented in the left and the right visual field at three different visual eccentricities. Our results indicate that DF shows large and consistent impairments in all conditions. These findings imply that DF's dorsal stream atrophies are functionally relevant and hence challenge the idea that patient DF's seemingly normal visuomotor behaviour can be attributed to her intact dorsal stream. Instead, DF seems to be a patient who suffers from combined ventral and dorsal stream damage meaning that a new account is needed to explain why she shows such remarkably normal visuomotor behaviour in a number of tasks and conditions.


Research productivity in neurosurgery: trends in globalization, scientific focus, and funding.
While research is important for the survival, growth, and expansion of neurosurgery, little work has been done to quantify the status and trends of neurosurgical publications. The purpose of this bibliometric study was to quantitatively analyze trends in neurosurgical publications, including changes in worldwide productivity, study methodology, subspecialty topic, and funding. This was a retrospective bibliometric study using MEDLINE to record all publications between 1996 and 2009 by first authors affiliated with neurosurgical departments. Country of origin, MEDLINE-defined methodology, study topic, and funding sources (for US articles) were recorded. Linear regression was used to derive growth rates. Total articles numbered 53,425 during the study period, with leading global contributors including the US with 16,943 articles (31.7%) and Japan with 10,802 articles (20.2%). Countries demonstrating rapid growth in productivity included China (121.9 ± 9.98%/year, p < 0.001), South Korea (50.5 ± 4.7%/year, p < 0.001), India (19.4 ± 1.8%/year, p < 0.001), and Turkey (25.3 ± 2.8%/year, p < 0.001). While general research articles, case reports, and review articles have shown steady growth since 1996, clinical trials and randomized controlled trials have declined to 2004 levels. The greatest overall subspecialty growth was seen in spine surgery. Regarding funding, relative contribution of National Institutes of Health (NIH)-funded publications decreased from 30.2% (290 of 959) to 22.5% (356 of 1229) between 1996 and 2009. Neurosurgical publications demonstrate continued increases in productivity as well as in global expansion, although US contributions remain dominant. Two challenges that the neurosurgical community is facing include the preponderance of case reports and review articles and the relative decline in NIH funding for US neurosurgical publications, as productivity has outpaced government financial support.


Abnormalities in sex hormones are a risk factor for premature manifestation of coronary artery disease in South African Indian men.
The relation between sex hormone levels and myocardial infarction was studied in a case-control study among 117 Indian men with myocardial infarction aged 30-60 years and in 107 healthy Indian male controls. The patients and controls were further divided into subsets defined by age in decades. In the total patient population, testosterone concentration was significantly lower than in the controls (P less than 0.01), whilst oestradiol (P less than 0.0005) and the oestradiol to testosterone ratio (P less than 0.0005) were significantly higher. Multivariate stepwise logistic regression analyses demonstrated that free testosterone index, the free oestradiol index, and the oestradiol to testosterone ratio were significantly associated with myocardial infarction, and that this association was independent of age, body mass index, smoking and serum lipids. Further analyses according to age subsets revealed that compared to respective control groups, patients in the 4th decade had both significant hypotestosteronaemia and hyperoestrogenaemia, whereas in patients of the 5th decade significant differences in total and in the calculated free oestradiol index were noted, and in the 6th decade a significant difference was detected only in the free oestradiol index. Hence, we conclude that aberrations in endogenous sex hormones are significantly associated with myocardial infarction, and that this association appears to be strongest in young men and diminishes with age, suggesting that these disturbances in sex hormones may be associated with premature manifestation of coronary artery disease.


Anomalous adsorption of biomolecules on a Zn-based metal-organic framework obtained via a facile room-temperature route.
Herein, we report a new method for the crystal growth of two Zn-based MOFs at room temperature (known MOF-5 and a new modification of [{Zn2(TBAPy)(H2O)2}·3.5DEF]n (1)) by employing slow diffusion conditions. Employing both Zn-based MOFs with different pore morphology made it possible to discover an anomalous adsorption of L-histidine in of up to 24.3 × 10(15) molecules cm(-2) at 25 °C. This is one of the first reports aimed not only at describing a new method for the targeted formation of crystalline MOFs and coordination polymers, but also at demonstrating the use of Zn-based MOFs as potential drug delivery materials, with highly effective adsorption of l-histidine given herein as an example.


Ethical Guidelines for Genetic Research on Alcohol Addiction and Its Applications.
Research on the genomic correlates to addiction raises ethical issues in a number of different domains. In this paper, we evaluate the status of genetic research on alcohol dependence as background to addressing the ethical issues raised in conducting research on addiction and the application of that research to the formulation of public policies. We conclude that genetic testing is not yet ready for use in the prediction of alcohol dependence liability. Pharmacogenetic testing for responses to treatments may have more clinical utility, although additional research is required to demonstrate utility and cost-effectiveness. Genetic research on addiction raises potential risks for participants that must be clearly communicated to participants, including limitations on the ability of researchers to protect their privacy. Responsible communication of research findings is essential to prevent common misunderstandings about the role of genetics in addiction liability, to prevent its premature or inappropriate use, and to reduce discrimination and stigmatization experienced by addicted individuals. More research is needed to determine the impact of genetic explanations on addicted individuals, treatment-seeking behavior, and on public attitudes towards addicted persons. Importantly, genetic research on addiction must not be at the expense of investments in social, behavioral, and psychological research on addiction.


Relationships Between Measures of Physical Fitness Change When Age-Dependent Bias is Removed in a Group of Young Male Soccer Players.
James, RS, Thake, CD, and Birch, SL. Relationships between measures of physical fitness change when age-dependent bias is removed in a group of young male soccer players. J Strength Cond Res 31(8): 2100-2109, 2017-Age-dependent bias is a key issue within talent identification of children, particularly when measures of physical fitness are used. Coaches in sport would benefit from a relatively straightforward method to remove age-dependent bias, enabling identification of children who are relatively high performers for their age. This study aimed to determine whether removal of age effects caused changes in the relationships between physical performance and anthropometric measures commonly used in talent identification and development systems. Sixty male soccer players, aged 11-17 years, underwent measures of anthropometry, muscular power, strength, sprint speed, and agility. Most absolute measures of performance were significantly correlated with each other, and all performance measures were significantly correlated with age. Age residuals were calculated, for all variables, to determine which players performed relatively well for their age and to investigate age-independent relationships between variables. In general, players with relatively fast sprint performance for their age were taller and had relatively high performance in jump power output and grip strength for their age (r > 0.25 and p < 0.025 in each case). Absolute sprint performance PC1 was significantly correlated with absolute agility performance PC1 (r = 0.473, p < 0.001). However, there was no significant relationship between age-independent measures of agility and any other measures. Usage of age residuals highlights performers that have relatively high physical fitness for their age. Such analyses may assist the talent identification and development processes as long as differential rates of physical development between players are also considered.


Urogenital complications among girls with genital mutilation: a hospital-based study in Khartoum.
To explore paediatric complications of female genital mutilation (FGM), 255 consecutive girls aged 4-9 years presenting to an emergency ward in Sudan were included in this clinical study. Full examination, including inspection of genitalia, was performed. Dipsticks for nitrite and leucocytes were used to diagnose suspected urinary tract infection (UTI). Girls with a form of FGM narrowing vulva had significantly more UTI than others, and among girls below the age of seven there was a significant association between FGM and UTI. Only 8% of girls diagnosed as having UTI reported urogenital symptoms. In spite of the fact that 73% of the girls subjected to FGM were reported to have been bedridden for one week or more after the operation, only 10% stated immediate complications. We conclude that FGM contributes significantly to morbidity among girls, a large share of which does not come to medical attention.


A single point mutation reveals gating of the human ClC-5 Cl-/H+ antiporter.
ClC-5 is a 2Cl(-)/1H(+) antiporter highly expressed in endosomes of proximal tubule cells. It is essential for endocytosis and mutations in ClC-5 cause Dent's disease, potentially leading to renal failure. However, the physiological role of ClC-5 is still unclear. One of the main issues is whether the strong rectification of ClC-5 currents observed in heterologous systems, with currents elicited only at positive voltages, is preserved in vivo and what is the origin of this rectification. In this work we identified a ClC-5 mutation, D76H, which, besides the typical outward currents of the wild-type (WT), shows inward tail currents at negative potentials that allow the estimation of the reversal of ClC-5 currents for the first time. A detailed analysis of the dependence of these inward tail currents on internal and external pH and [Cl(-)] shows that they are generated by a coupled transport of Cl(-) and H(+) with a 2 : 1 stoichiometry. From this result we conclude that the inward tail currents are caused by a gating mechanism that regulates ClC-5 transport activity and not by a major alteration of the transport mechanism itself. This implies that the strong rectification of the currents of WT ClC-5 is at least in part caused by a gating mechanism that activates the transporter at positive potentials. These results elucidate the biophysical properties of ClC-5 and contribute to the understanding of its physiological role.


Project MATCH secondary a priori hypotheses. Project MATCH Research Group.
(1) To assess the benefits of matching alcohol dependent clients to three treatments, based upon a priori hypotheses involving 11 client attributes; (2) to discuss the implications of these findings and of matching hypotheses previously reported from Project MATCH. (1) Clients receiving outpatient therapy (N = 952; 72% male); (2) clients receiving aftercare therapy following inpatient or day hospital treatment (N = 774; 80% male). Clients were randomly assigned to one of three 12-week, manual-guided, individual treatments: Cognitive Behavioral Coping Skills Therapy (CBT), Motivational Enhancement Therapy (MET) or Twelve-Step Facilitation Therapy (TSF). Two parallel but independent randomized clinical trials were conducted, one with outpatients, one with aftercare clients. Participants were monitored over 15 months including a 1-year post-treatment period. Individual differences in response to treatment were modeled as a latent growth process and evaluated for 17 contrasts specified a priori. Outcome measures were percentage of days abstinent and drinks per drinking day. Two a priori contrasts demonstrated significant post-treatment attribute by treatment interactions: (1) outpatients high in anger and treated in MET had better post-treatment drinking than in CBT; (2) aftercare clients high in alcohol dependence had better post-treatment outcomes in TSF; low dependence clients did better in CBT. Other matching effects varied over time, while still other interactions were opposite that predicted. (1) Anger and dependence should be considered when assigning clients to these three treatments; (2) considered together with the results of the primary hypotheses, matching effects contrasting these psychotherapies are not robust. Possible explanations include: (a) among the client variables and treatments tested, matching may not be an important factor in determining client outcomes; (b) design issues limited the robustness of effects; and (c) a more fully specified theory of matching is necessary to account for the complexity of the results.


Amelioration of the behavioral phenotype in genetically ataxic mice through bilateral intracerebellar grafting of fetal Purkinje cells.
We have previously applied neural grafting to "Purkinje cell degeneration" mutant mice (gene symbol pcd, mouse chromosome 13), a model of recessively inherited cerebello-olivary atrophy, to create appropriate interactions between wild-type and mutant cells in elucidating gene effects on the involved neuron populations and to address issues of the structural integration of donor Purkinje cells into the disrupted cerebellar loop. Behaviorally, pcd homozygotes manifest ataxic signs beginning at 3-4 wk of age. The functional effects of cerebellar transplants on motor performance have long remained an open question. The aim of the present study was to determine the recovery of motor responses in pcd mutants in a battery of behavioral tasks after bilateral transplantation of cerebellar cell suspensions (prepared from wild-type mice) into the parenchyma of the deep cerebellar nuclei of the hosts, according to a protocol that emphasizes the reconstruction of the missing inhibitory cortico-nuclear projection. With this approach, the denervated deep nuclei of the host receive a new Purkinje axonal innervation; further, most transplanted Purkinje cells end up occupying cortical localities anyway and display a correct dendritic tree orientation toward the pia. Motor coordination and fatigue resistance were assessed in a rotarod treadmill apparatus, a behavioral paradigm useful in studying various brain abiotrophies and treatments, including developmental perturbations of the cerebellar cytoarchitecture. Locomotor activity was quantified by the number of squares mice crossed as they moved about in an open-field matrix. Grafted pcd mice performed significantly better than sham-operated mutants in both of these tasks. Moreover, graft-recipient mice were able to sustain their abdomen above the floor on their limbs during movement, contrasting to the typical lowered, widened stance of sham-operated pcd mutants. These findings clearly demonstrate that bilateral transplants of fetal Purkinje cells have functional effects on motor performance in the pcd model of hereditary cerebellar ataxia.


Inflammasomes and the microbiota--partners in the preservation of mucosal homeostasis.
Inflammasomes are multiprotein complexes that serve as signaling platforms initiating innate immune responses. These structures are assembled upon a large array of stimuli, sensing both microbial products and endogenous signals indicating loss of cellular homeostasis. As such, inflammasomes are regarded as sensors of cellular integrity and tissue health, which, upon disruption of homeostasis, provoke an inflammatory response by the release of potent cytokines. Recent evidence suggests that in addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the host and its indigenous microbiota. Here, we summarize the involvement of various inflammasomes in host-microbiota interactions and focus on the role of commensal as well as pathogenic bacteria in inflammasome signaling.


Comment on "A study on tetrahedron-based inhomogeneous Monte-Carlo optical simulation".
The Monte Carlo (MC) method is a popular approach to modeling photon propagation inside general turbid media, such as human tissue. Progress had been made in the past year with the independent proposals of two mesh-based Monte Carlo methods employing ray-tracing techniques. Both methods have shown improvements in accuracy and efficiency in modeling complex domains. A recent paper by Shen and Wang [Biomed. Opt. Express 2, 44 (2011)] reported preliminary results towards the cross-validation of the two mesh-based MC algorithms and software implementations, showing a 3-6 fold speed difference between the two software packages. In this comment, we share our views on unbiased software comparisons and discuss additional issues such as the use of pre-computed data, interpolation strategies, impact of compiler settings, use of Russian roulette, memory cost and potential pitfalls in measuring algorithm performance. Despite key differences between the two algorithms in handling of non-tetrahedral meshes, we found that they share similar structure and performance for tetrahedral meshes. A significant fraction of the observed speed differences in the mentioned article was the result of inconsistent use of compilers and libraries.


Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease.
Hyperkalemia in patients with renal failure is frequently treated with a cation exchange resin (sodium polystyrene sulfonate, hereafter referred to as resin) in combination with a cathartic, but the effect of such therapy on serum potassium concentration has not been established. This study evaluates the effect of four single-dose resin-cathartic regimens and placebo on 5 different test days in six patients with chronic renal failure. Dietary intake was controlled. Fecal potassium output and serum potassium concentration were measured for 12 h. Phenolphthalein alone caused an average fecal potassium output of 54 mEq. The addition of resin caused an increase in insoluble potassium output but a decrease in soluble potassium output; therefore, there was no significant effect of resin on total potassium output. Sorbitol plus resin caused less potassium output than phenolphthalein plus resin. On placebo therapy, the average serum potassium concentration increased slightly (0.4 mEq/L) during the 12-h experiment. This rise was apparently abrogated by some of the regimens that included resin; this may have been due in part to extracellular volume expansion caused by absorption of sodium released from resin. Phenolphthalein regimens were associated with a slight rise in serum potassium concentrations (similar to placebo); this may have been due to extracellular volume contraction produced by high volume and sodium-rich diarrhea and acidosis secondary to bicarbonate losses. None of the regimens reduced serum potassium concentrations, compared with baseline levels. Because single-dose resin-cathartic therapy produces no or only trivial reductions in serum potassium concentration, and because this therapy is unpleasant and occasionally is associated with serious complications, this study questions the wisdom of its use in the management of acute hyperkalemic episodes.


Prevalence of glaucoma in a South brazilian population: Projeto Glaucoma.
To assess the prevalence of glaucoma in a South Brazilian population. Subjects older than 40 years underwent a screening examination that included a medical interview, slit lamp examination, tonometry, and fundoscopy. Those with suspected glaucoma (based on optic disc appearance and/or intraocular pressure) underwent a comprehensive ophthalmic evaluation during the definitive examination. Glaucoma was diagnosed based on the International Society of Geographical and Epidemiologic Ophthalmology classification. A total of 1636 subjects were examined (76.5% participation rate); 71% of the study population self-reported their race as white and 24% as nonwhite (most black and mixed-black/white). Glaucoma was found in 56 subjects (crude prevalence of all glaucoma: 3.4%; 95% CI, 2.5-4.3), primary open-angle glaucoma (POAG) was found in 40 (2.4%; 95% CI, 1.7-3.2), and primary angle-closure glaucoma (PACG) in 12 (0.7%; 95% CI, 0.3-1.1). Six (12%) subjects with primary glaucoma had a previous diagnosis of the disease. Nonwhite persons had a higher prevalence rate of POAG than did white participants, although this difference was not significant (3.8% vs. 2.1%, respectively, P = 0.11). Unilateral blindness due to primary glaucoma was observed in seven subjects (five POAG/2 PACG), and nonwhites had a higher rate of unilateral blindness than did whites (five versus two cases, respectively, P = 0.014). Compared to incidence in Hispanic and European populations, PACG was more common among South Brazilians, whereas the POAG rates were similar. The rate of undiagnosed glaucoma was almost 90%. The higher POAG prevalence in the population self-reported as nonwhite may affect the estimation of glaucoma in Brazil, as more than 40% of the population self-report their race as nonwhite.


DNA-templated nanoparticle complexes for photothermal imaging and labeling of cancer cells.
In situ monitoring of the photothermal (PT) effect at the cellular level is of great importance in the photothermal (PT) treatment of cancer. Herein, we report a class of DNA-templated gold nanoparticle (GNP)-quantum dot (QD) complexes (GQC) for PT sensing in solution and in cancer cells in vitro. Specifically, the QD photoluminescence (PL) could be activated at elevated temperature with a wide thermo-responsive range between 45 °C and 70 °C, which fits the temperature threshold for effective cancer cell ablation. The general applicability of GQC for intracellular PT sensing is explored using three types of PT agents (gold nanorods (GNRs), gold nanostars (GNSs), and Prussian blue nanoparticles (PBNPs)) with various PT performances. We show that the intracellular QD PL is gradually activated with increasing near-infrared (NIR) irradiation time, providing a good correlation with the surrounding medium temperature for PT sensing. Moreover, we demonstrate that the GQC sensor could be used for specific photothermal labeling and imaging of cancer cells. The QD PL signal is retained in the cells post-treatment, thereby potentially enabling persistent photothermal labeling of cancer cells for post-treatment cell tracking and imaging-guided therapy evaluation.


Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs.
We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit(+) CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit(+) CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit(+) CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit(+) CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit(+) CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit(+) CSCs compared with MI hearts engrafted with control siRNA-treated c-kit(+) CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFP-infected c-kit(+) CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit(+) CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit(+) CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit(+) CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.


B cell targeted therapies.
Although the precise pathogenesis of rheumatoid arthritis (RA) remains unclear, many cell populations, including monocytes, macrophages, endothelial cells, fibroblasts and B cells, participate in the inflammatory process. Ongoing research continues to evaluate the critical roles played by B cells in sustaining the chronic inflammatory process of RA. These findings have contributed to the development of targeted therapies that deplete B cells, such as rituximab, as well as inhibitors of B lymphocyte stimulation, such as belimumab. In a phase I trial, belimumab treatment significantly reduced CD20+ levels in patients with systemic lupus erythematosus. Phase I and phase II trials of rituximab found that rituximab plus methotrexate achieved significantly better American College of Rheumatology 50% responses for patients with RA than those patients receiving monotherapy with methotrexate. These clinical trial data present promising evidence for B cell targeted therapies as future therapeutic options for RA.


Pancreatic L-Glutamine Administration Protects Pig Islets From Cold Ischemic Injury and Increases Resistance Toward Inflammatory Mediators.
The isolation and transplantation of porcine islets represent a future option for the treatment of type 1 diabetic patients. Stringent product release criteria and limited availability of transgenic and specific pathogen-free pigs will essentially require processing of explanted pig pancreata in specialized, possibly remote isolation facilities, whereby pancreata are exposed to cold ischemia due to prolonged tissue transit time. In the present study we investigated whether pancreas oxygenation can be efficiently combined with an antioxidant strategy utilizing intraductal L-glutamine administration. Pig pancreata were intraductally perfused after retrieval and after cold storage in oxygen-precharged perfluorohexyloctane utilizing University of Wisconsin solution supplemented with (n = 16) or without (n = 14) 5 mmol/L L-glutamine. After isolation purified islets were subjected to extensive quality assessment. Islet recovery postpurification was significantly higher in glutamine-treated pancreata (77.0 ± 3.3% vs. 60.3 ± 6.0%, p < 0.05). Glutamine administration increased intraislet content of reduced glutathione (117.8 ± 16.5 vs. 15.9 ± 2.8 ng/ng protein, p < 0.001) associated with increased islet recovery after culture (65.8 ± 12.1% vs. 40.3 ± 11.7%, p < 0.05), enhanced glucose stimulation index (1.82 ± 0.16 vs. 1.38 ± 0.10, p < 0.05), and improved posttransplant function in diabetic nude mice (p < 0.05). Furthermore, intraductally administered glutamine increased pig islet resistance toward reactive oxygen species, nitric oxide, and high-dose proinflammatory cytokines. The present study demonstrates that quality and function of pig islets exposed to warm and cold ischemia can significantly be improved using intraductal l-glutamine administration. As the efficiency of the intraductal route may be inferior compared to intravascular administration further studies should aim on assessment of l-glutamine as supplement for pancreas perfusion during organ procurement.


Platelet factor V New York: a defect in factor V distinct from that in factor V Quebec resulting in impaired prothrombinase generation.
Studies were performed on a patient with a longstanding bleeding disorder whose major defects were impaired platelet prothrombinase activity in the absence of added factor Va, and a platelet factor V value that was either decreased or at the lower limit of normal when assayed on multiple occasions. In contrast, plasma factor V values were consistently normal. Unlike Scott Syndrome, in which platelet prothrombinase activity is decreased in both the presence and absence of added factor V, her platelets appeared to utilize added factor Va normally in supporting the generation of prothrombinase activity. These findings suggest an intrinsic defect in platelet factor V as the basis of her platelet prothrombinase defect. This defect appears to be different than that described in the Quebec platelet disorder (factor V Quebec). Immunoblot analyses of washed platelet lysates demonstrated a pattern of variably sized factor V molecules that was entirely similar to that observed in normal platelets, and both the heavy and light chains of her factor V after thrombin cleavage were of the same size as that observed in normal platelets. In addition, her platelet multimerin was normal and immunoblot analysis excluded the type of generalized granular protein defect and pathological proteolysis that has been suggested to explain the factor V defect in the Quebec platelet disorder. The findings in this patient thus suggest a new type of platelet factor V defect as the basis for the impaired capacity of her activated platelets to support prothrombinase generation. The findings further support an important role for platelet factor V in hemostasis.


Prescribing for nausea in palliative care: a cross-sectional national survey of Australian palliative medicine doctors.
Nausea can be a debilitating symptom for patients with a life-limiting illness. While addressing reversible components, nonpharmacological strategies and antiemetics are the main therapeutic option. The choice of medication, dose, and route of administration remain highly variable. The aim of this study was to codify the current clinical approaches and quantify any variation found nationally. A cross-sectional study utilizing a survey of palliative medicine clinicians examined prescribing preferences for nausea using a clinical vignette. Respondent characteristics, the use of nonpharmacological interventions, first- and second-line antiemetic choices, commencing and maximal dose, and time to review were collected. Responding clinicians were predominantly working in palliative medicine across a range of settings with a 49% response rate (105/213). The main nonpharmacological recommendation was "small, frequent snacks." Metoclopramide was the predominant first-line agent (69%), followed by haloperidol (26%), while second-line haloperidol was the predominant agent (47%), with wide variation in other nominated agents. Respondents favoring metoclopramide as first-line tended to use haloperidol second-line (65%), but not vice versa. Maximal doses for an individual antiemetic varied up to tenfold. For nausea, a commonly encountered symptom in palliative care, clinicians' favored metoclopramide and haloperidol; however, after these choices, there was large variation in antiemetic selection. While most clinicians recommended modifying meal size and frequency, use of other nonpharmacological therapies was limited.


Case report: Individualized pulsed electromagnetic field therapy in a Long COVID patient using the Adaptive Force as biomarker.
The increasing prevalence of Long COVID is an imminent public health disaster, and established approaches have not provided adequate diagnostics or treatments. Recently, anesthetic blockade of the stellate ganglion was reported to improve Long COVID symptoms in a small case series, purportedly by "rebooting" the autonomic nervous system. Here, we present a novel diagnostic approach based on the Adaptive Force (AF), and report sustained positive outcome for one severely affected Long COVID patient using individualized pulsed electromagnetic field (PEMF) at the area C7/T1. AF reflects the capacity of the neuromuscular system to adapt adequately to external forces in an isometric holding manner. In case, maximal isometric AF (AFisomax) is exceeded, the muscle merges into eccentric muscle action. Thereby, the force usually increases further until maximal AF (AFmax) is reached. In case adaptation is optimal, AFisomax is ~99-100% of AFmax. This holding capacity (AFisomax) was found to be vulnerable to disruption by unpleasant stimulus and, hence, was regarded as functional parameter. AF was assessed by an objectified manual muscle test using a handheld device. Prior to treatment, AFisomax was considerably lower than AFmax for hip flexors (62 N = ~28% AFmax) and elbow flexors (71 N = ~44% AFmax); i.e., maximal holding capacity was significantly reduced, indicating dysfunctional motor control. We tested PEMF at C7/T1, identified a frequency that improved neuromuscular function, and applied it for ~15 min. Immediately post-treatment, AFisomax increased to ~210 N (~100% AFmax) at hip and 184 N (~100% AFmax) at elbow. Subjective Long COVID symptoms resolved the following day. At 4 weeks post-treatment, maximal holding capacity was still on a similarly high level as for immediately post-treatment (~100% AFmax) and patient was symptom-free. At 6 months the patient's Long COVID symptoms have not returned. This case report suggests (1) AF could be a promising diagnostic for post-infectious illness, (2) AF can be used to test effective treatments for post-infectious illness, and (3) individualized PEMF may resolve post-infectious symptoms.


Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide.
Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This review attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.


Coherent anti-Stokes Raman scattering and spontaneous Raman spectroscopy and microscopy of microalgae with nitrogen depletion.
Microalgae are extensively researched as potential feedstocks for biofuel production. Energy-rich compounds in microalgae, such as lipids, require efficient characterization techniques to investigate the metabolic pathways and the environmental factors influencing their accumulation. The model green alga Coccomyxa accumulates significant amounts of triacylglycerols (TAGs) under nitrogen depletion (N-depletion). To monitor the growth of TAGs (lipid) in microalgal cells, a study of microalgal cells (Coccomyxa sp. C169) using both spontaneous Raman and coherent anti-Stokes Raman scattering (CARS) spectroscopy and microscopy were carried out. Spontaneous Raman spectroscopy was conducted to analyze the components in the algal cells, while CARS was carried out to monitor the distribution of lipid droplets in the cells. Raman signals of carotenoid are greater in control microalgae compared to N-depleted cells. Raman signals of lipid droplets appear after N-depletion and its distribution can be clearly observed in the CARS microscopy. Both spontaneous Raman spectroscopy and CARS microscopy were found to be suitable analysis tools for microalgae.


AMP-activated protein kinase mediates carotid body excitation by hypoxia.
Early detection of an O2 deficit in the bloodstream is essential to initiate corrective changes in the breathing pattern of mammals. Carotid bodies serve an essential role in this respect; their type I cells depolarize when O2 levels fall, causing voltage-gated Ca2+ entry. Subsequent neurosecretion elicits increased afferent chemosensory fiber discharge to induce appropriate changes in respiratory function (1). Although depolarization of type I cells by hypoxia is known to arise from K+ channel inhibition, the identity of the signaling pathway has been contested, and the coupling mechanism is unknown (2). We tested the hypothesis that AMP-activated protein kinase (AMPK) is the effector of hypoxic chemotransduction. AMPK is co-localized at the plasma membrane of type I cells with O2-sensitive K+ channels. In isolated type I cells, activation of AMPK using 5-aminoimidazole-4-carboxamide riboside (AICAR) inhibited O2-sensitive K+ currents (carried by large conductance Ca2+-activated (BKCa) channels and TASK (tandem pore, acid-sensing potassium channel)-like channels, leading to plasma membrane depolarization, Ca2+ influx, and increased chemosensory fiber discharge. Conversely, the AMPK antagonist compound C reversed the effects of hypoxia and AICAR on type I cell and carotid body activation. These results suggest that AMPK activation is both sufficient and necessary for the effects of hypoxia. Furthermore, AMPK activation inhibited currents carried by recombinant BKCa channels, whereas purified AMPK phosphorylated thealpha subunit of the channel in immunoprecipitates, an effect that was stimulated by AMP and inhibited by compound C. Our findings demonstrate a central role for AMPK in stimulus-response coupling by hypoxia and identify for the first time a link between metabolic stress and ion channel regulation in an O2-sensing system.


Optical near field in nanometallic slits.
The propagation and the distribution of the optical near field in nanometallic slits are measured by a near-field scanning optical microscope. The optical near field for the p-polarized wave is confined to the middle of the slit. In contrast, the near field for the s-polarized wave is located at the edges. Asimulation by the finite-difference time-domain method verifies that the near-field distribution for the s-polarized wave is due to the propagation of the surface plasmon wave (SPW) at the air-metal surface. The existence of the SPW also accounts for the extraordinary transmittance of s-polarized light, which is one order of magnitude larger than that of p-polarized light.


A population-based analysis of qualitative features of the neuropsychological test performance of individuals with dementia of the Alzheimer type: implications for individuals with questionable dementia.
Qualitative features of the neuropsychological test performance of individuals with dementia of the Alzheimer type (DAT) were examined in a population-based study. Qualitative error scores were derived from measures of verbal and figural memory, verbal fluency and confrontation naming for 38 patients with clinically diagnosed DAT, 236 normal elderly (NE) individuals, and 72 others who were questionably demented and at risk (AR) for DAT. Persons with DAT made a greater proportion of intrusion and perseverative errors, and more lexical and semantic naming errors, than the NE participants. These measures provided fair specificity but poor sensitivity for the diagnosis of DAT, and a logistic model based on these measures correctly classified 98% of the NE participants, but only 29% of the DAT participants. The AR participants demonstrated a pattern of errors that was highly similar to that of the DAT patients, and when their scores were subjected to the logistic model, 90% were classified as NE and 10% as DAT. These results indicate that specific error types that have been associated with DAT in self-referred or clinic-based samples also occur in the general population to a greater degree in individuals with DAT or questionable dementia than in NE individuals. Furthermore, these qualitative features may have some diagnostic usefulness in that their presence provides reasonable specificity for DAT or questionable dementia.


A component of the Sec61 ER protein transporting pore is required for plant susceptibility to powdery mildew.
Biotrophic pathogens, like the powdery mildew fungi, require living plant cells for their growth and reproduction. During infection, a specialized structure called the haustorium is formed by the fungus. The haustorium is surrounded by a plant cell-derived extrahaustorial membrane (EHM). Over the EHM, the fungus obtains nutrients from and secretes effector proteins into the plant cell. In the plant cell these effectors interfere with cellular processes such as pathogen defense and membrane trafficking. However, the mechanisms behind effector delivery are largely unknown. This paper provides a model for and new insights into a putative transfer mechanism of effectors into the plant cell. We show that silencing of the barley Sec61βa transcript results in decreased susceptibility to the powdery mildew fungus. HvSec61βa is a component of both the endoplasmic reticulum (ER) translocon and retrotranslocon pores, the latter being part of the ER-associated protein degradation machinery. We provide support for a model suggesting that the retrotranslocon function of HvSec61βa is required for successful powdery mildew fungal infection. HvSec61βa-GFP and a luminal ER marker were co-localized to the ER, which was found to be in close proximity to the EHM around the haustorial body, but not the haustorial fingers. This differential EHM proximity suggests that the ER, including HvSec61βa, may be actively recruited by the haustorium, potentially to provide efficient effector transfer to the cytosol. Effector transport across this EHM-ER interface may occur by a vesicle-mediated process, while the Sec61 retrotranslocon pore potentially provides an escape route for these proteins to reach the cytosol.


Imaging by integrating stitched spectrograms.
A new diffractive imaging technique called Imaging By Integrating Stitched Spectrograms (IBISS) is presented. Both the data collection and phase retrieval algorithm used in IBISS are direct extensions of frequency resolved optical gating to higher dimensions. Data collection involves capturing an array of diffraction patterns generated by scanning a sample across a coherent beam of light. Phase retrieval is performed using the Principal Components Generalized Projections Algorithm (PCGPA) by reducing the four dimensional data set of images to two remapped two-dimensional sets. The technique is successfully demonstrated using a Helium Neon laser to image a 350μm wide sample with 12μm resolution.


Patterned gallium surfaces as molecular mirrors.
An entirely new means of printing molecular information on a planar film, involving casting nanoscale impressions of the template protein molecules in molten gallium, is presented here for the first time. The metallic imprints not only replicate the shape and size of the proteins used as template. They also show specific binding for the template species. Such a simple approach to the creation of antibody-like properties in metallic mirrors can lead to applications in separations, microfluidic devices, and the development of new optical and electronic sensors, and will be of interest to chemists, materials scientists, analytical specialists, and electronic engineers.


Polarization decorrelation in optical fibers with randomly varying elliptical birefringence.
Polarization decorrelation in single-mode fibers with randomly varying elliptical birefringence is studied. It is found that the effects of ellipticity on the polarization decorrelation length depend on the relative sizes of the beat length and the autocorrelation length of the birefringence fluctuations in the fiber. However, the evolution of the differential group delay remains unaffected by ellipticity.


Single-cell genomics of a rare environmental alphaproteobacterium provides unique insights into Rickettsiaceae evolution.
The bacterial family Rickettsiaceae includes a group of well-known etiological agents of many human and vertebrate diseases, including epidemic typhus-causing pathogen Rickettsia prowazekii. Owing to their medical relevance, rickettsiae have attracted a great deal of attention and their host-pathogen interactions have been thoroughly investigated. All known members display obligate intracellular lifestyles, and the best-studied genera, Rickettsia and Orientia, include species that are hosted by terrestrial arthropods. Their obligate intracellular lifestyle and host adaptation is reflected in the small size of their genomes, a general feature shared with all other families of the Rickettsiales. Yet, despite that the Rickettsiaceae and other Rickettsiales families have been extensively studied for decades, many details of the origin and evolution of their obligate host-association remain elusive. Here we report the discovery and single-cell sequencing of 'Candidatus Arcanobacter lacustris', a rare environmental alphaproteobacterium that was sampled from Damariscotta Lake that represents a deeply rooting sister lineage of the Rickettsiaceae. Intriguingly, phylogenomic and comparative analysis of the partial 'Candidatus Arcanobacter lacustris' genome revealed the presence chemotaxis genes and vertically inherited flagellar genes, a novelty in sequenced Rickettsiaceae, as well as several host-associated features. This finding suggests that the ancestor of the Rickettsiaceae might have had a facultative intracellular lifestyle. Our study underlines the efficacy of single-cell genomics for studying microbial diversity and evolution in general, and for rare microbial cells in particular.


Complex haplotypic structure of the central MHC region flanking TNF in a West African population.
TNF polymorphisms have been associated with susceptibility to malaria and other infectious and inflammatory conditions. We investigated a sample of 150 West African chromosomes to determine linkage disequilibrium (LD) between 25 SNP markers located in an 80 kb segment of the MHC Class III region encompassing TNF and eight neighbouring genes. We observed 45 haplotypes, and 22 of them comprise 80% of the sample. The pattern of LD is remarkably patchy, such that many markers show no LD with adjacent markers but high LD with markers that are much further away. We introduce a method of examining the implications of LD data for disease association studies based on sample size considerations: this shows that certain TNF polymorphisms would be likely to yield positive associations if the true disease allele resided in LTA or BAT1. We conclude that detailed marker maps are needed to resolve the causal origin of disease associations observed at the TNF locus.


First-Generation Versus Second-Generation Drug-Eluting Stents in Coronary Chronic Total Occlusions: Two-Year Results of a Multicenter Registry.
Limited data are available regarding the long-term clinical outcomes of second-generation drug-eluting stents (DES) versus first-generation DES in patients with coronary chronic total occlusion (CTO) who undergo percutaneous coronary intervention (PCI). The aim of this study was to compare the clinical outcomes of second-generation DES with those of first-generation DES for the treatment of CTO. Between March 2003 and February 2012, 1,006 consecutive patients with CTO who underwent successful PCI using either first-generation DES (n = 557) or second-generation DES (n = 449) were enrolled in a multicenter, observational registry. Propensity-score matching was also performed. The primary outcome was cardiac death over a 2-year follow-up period. No significant differences were observed between the two groups regarding the incidence of cardiac death (first-generation DES versus second-generation DES; 2.5% vs 2.0%; hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.37 to 1.98; p = 0.72) or major adverse cardiac events (MACE, 11.8% vs 11.4%; HR: 1.00; 95% CI: 0.67 to 1.50; p = 0.99). After propensity score matching, the incidences of cardiac death (HR: 0.86; 95% CI: 0.35 to 2.06; p = 0.86) and MACE (HR: 0.93; 95% CI: 0.63 to 1.37; p = 0.71) were still similar in both groups. Furthermore, no significant differences were observed between sirolimus-eluting, paclitaxel-eluting, zotarolimus-eluting, and everolimus-eluting stents regarding the incidence of cardiac death or MACE. This study shows that the efficacy of second-generation DES is comparable to that of first-generation DES for treatment of CTO over 2 years of follow-up.


Hyperthermic intraperitoneal chemotherapy in ovarian cancer: first report of the HYPER-O registry.
An analysis of experience of surgical and gynecologic oncologists in the United States with the use of hyperthermic intraperitoneal chemotherapy for women with invasive epithelial ovarian cancer (EOC). An Internet-based registry (HYPER-O) collected data from collaborating institutions. Eligibility included women with EOC treated with hyperthermic intraperitoneal chemotherapy. Borderline and nonepithelial cancers were excluded. As of July 1, 2008, 141 women were eligible for analysis treated at the following time points: frontline (n = 26), interval debulking (n = 19), consolidation (n = 12), and recurrence (n = 83). The mean perfusion temperatures were 38.5 to 43.6 degrees C (median, 41.9 degrees C) for inflow and 36.9 to 42.9 degrees C (median, 41 degrees C) for outflow for 30 to 120 minutes. Treatment was with a platinum agent (n = 72), mitomycin (n = 53), or a combination (n = 14). Median follow-up was 18 months (range, 0.3-140.5 months) and median overall survival 30.3 months (95% confidence interval, 23.0-37.6) with 2-, 5-, and 10-year overall survival probabilities of 49.1%, 25.4%, and 14.3%, respectively. Of the 141 patients, 110 (78%) experienced recurrence of ovarian cancer and 87 died, 3 (0.5%) dying within 30 days of surgery. In the multivariable analysis, the factors significant for increased survival were sensitivity to platinum response (P = 0.048), completeness of cytoreduction scores of 1 or 0 (P = 0.025), carboplatin alone or a combination of 2 or more chemotherapy agents used (P = 0.011), and duration of hospital stays of 10 days or less (P = 0.021). Hyperthermic intraperitoneal chemotherapy is a viable additional treatment option for patients with invasive EOC and may extend life in selected groups. It warrants further study in randomized controlled trials.


Presentation and management of gastrointestinal stromal tumors of the duodenum.
Duodenal gastrointestinal stromal tumors (GIST) have been described primarily in isolated case reports. In order to learn more about duodenal GIST, a retrospective review of patients with GIST managed at a single institution between 2000 and 2005 was conducted. Thirty-eight GIST of the stomach and small bowel were analyzed. Eight (21%) were duodenal GIST. The median size of duodenal GIST (6.0 cm) and small bowel GIST (6.3 cm) was larger than the median size of gastric GIST (3.0 cm). The most common presentation of duodenal GIST was bleeding (50%) which was similar to other small bowel GIST (49%) but different from gastric GIST which were most commonly an incidental finding (62%). Two patients (25%) with duodenal GIST had a history of neurofibromatosis. The duodenal GIST were located in the 2nd (n = 5, 63%) and 3rd portion of duodenum (n = 3, 37%). Seven of 8 patients underwent complete resection of duodenal GIST. Pancreaticoduodenectomy was the most common operation performed (n = 5); 2 patients were treated with partial duodenal resection. No patients undergoing pancreaticoduodenectomy (n = 5) were found to have lymph node metastases. No patients received neo-adjuvant or adjuvant therapy with Imatinib. Following resection, 2 patients have recurred (12 and 48 mo.), 4 patients are without disease (1, 6, 6, and 24 mo.), 1 patient died postoperatively. Duodenal GIST are relatively rare tumors that present most commonly with gastrointestinal bleeding. Duodenal GIST are associated with neurofibromatosis. Many duodenal GIST require pancreaticoduodenectomy for complete removal.


Subunit-selective N-Methyl-d-aspartate (NMDA) Receptor Signaling through Brefeldin A-resistant Arf Guanine Nucleotide Exchange Factors BRAG1 and BRAG2 during Synapse Maturation.
The maturation of glutamatergic synapses in the CNS is regulated by NMDA receptors (NMDARs) that gradually change from a GluN2B- to a GluN2A-dominated subunit composition during postnatal development. Here we show that NMDARs control the activity of the small GTPase ADP-ribosylation factor 6 (Arf6) by consecutively recruiting two related brefeldin A-resistant Arf guanine nucleotide exchange factors, BRAG1 and BRAG2, in a GluN2 subunit-dependent manner. In young cortical cultures, GluN2B and BRAG1 tonically activated Arf6. In mature cultures, Arf6 was activated through GluN2A and BRAG2 upon NMDA treatment, whereas the tonic Arf6 activation was not detectable any longer. This shift in Arf6 regulation and the associated drop in Arf6 activity were reversed by a knockdown of BRAG2. Given their sequential recruitment during development, we examined whether BRAG1 and BRAG2 influence synaptic currents in hippocampal CA1 pyramidal neurons using patch clamp recordings in acute slices from mice at different ages. The number of AMPA receptor (AMPAR) miniature events was reduced by depletion of BRAG1 but not by depletion of BRAG2 during the first 2 weeks after birth. In contrast, depletion of BRAG2 during postnatal weeks 4 and 5 reduced the number of AMPAR miniature events and compromised the quantal sizes of both AMPAR and NMDAR currents evoked at Schaffer collateral synapses. We conclude that both Arf6 activation through GluN2B-BRAG1 during early development and the transition from BRAG1- to BRAG2-dependent Arf6 signaling induced by the GluN2 subunit switch are critical for the development of mature glutamatergic synapses.


Tropical forest light regimes in a human-modified landscape.
Light is the key energy input for all vegetated systems. Forest light regimes are complex, with the vertical pattern of light within canopies influenced by forest structure. Human disturbances in tropical forests impact forest structure and hence may influence the light environment and thus competitiveness of different trees. In this study, we measured vertical diffuse light profiles along a gradient of anthropogenic disturbance, sampling intact, logged, secondary, and fragmented sites in the biodiversity hot spot of the Atlantic forest, southeast Brazil, using photosynthetically active radiation sensors and a novel approach with estimations of vertical light profiles from hemispherical photographs. Our results show clear differences in vertical light profiles with disturbance: Fragmented forests are characterized by rapid light extinction within their low canopies, while the profiles in logged forests show high heterogeneity and high light in the mid-canopy despite decades of recovery. The secondary forest showed similar light profiles to intact forest, but with a lower canopy height. We also show that in some cases the upper canopy layer and heavy liana infestations can severely limit light penetration. Light extinction with height above the ground and depth below the canopy top was highest in fragmented forest and negatively correlated with canopy height. The novel, inexpensive, and rapid methods described here can be applied to other sites to quantify rarely measured vertical light profiles.


Older patients' understanding of emergency department discharge information and its relationship with adverse outcomes.
To describe older patients' understanding of emergency department (ED) discharge information and to explore the relationship between understanding of ED discharge information and adverse outcomes. Telephone interviews were conducted with patients 65 years or older (or their proxies) within 72 hours of discharge from an academic medical center ED. We assessed 4 areas of discharge information: ED diagnosis, expected course of illness, self-care instructions, and return precautions. Adverse events were defined as repeat ED visits and hospitalizations or deaths within 90 days of ED discharge. Reverse Kaplan-Meier curves were constructed to illustrate cumulative event probabilities according to patient understanding of discharge information (differences examined with log-rank tests). Of 92 respondents (mean patient age, 75.1; SD, 7.4; 59.8% female subjects), patients or proxies reported not understanding discharge information about diagnosis (20.7%), self-care instructions (16.3%), expected course of illness (63%), and return precautions (55.7%). Within 90 days of ED discharge, 42.3% of patients had returned to the ED, 30.4% were hospitalized, and 4.3% had died. There was little difference in cumulative event probabilities according to whether patients understood self-care instructions or return precautions. Adverse event probabilities were higher among patients who did not understand their ED diagnosis (P = 0.33) and those who did not understand expected course of illness (P = 0.12), although these did not achieve statistical significance. A substantial number of older patients, or proxies, may not understand ED discharge information, and this could have an effect on patient outcomes. Strategies are needed to improve communication of ED discharge information to older patients and their families.


Altered structural networks and executive deficits in traumatic brain injury patients.
Recent research on traumatic brain injury (TBI) has shown that impairments in cognitive and executive control functions are accompanied by a disrupted neural connectivity characterized by white matter damage. We constructed binary and weighted brain structural networks in 21 patients with chronic TBI and 17 healthy young adults utilizing diffusion tensor tractography and calculated topological properties of the networks using a graph theoretical method. Executive function was assessed with the local global task and the trail making task, requiring inhibition, updating, and switching. The results revealed that TBI patients were less successful than controls on the executive tasks, as shown by the higher reaction times, higher switch costs, and lower accuracy rates. Moreover, both TBI patients and controls exhibited a small world topology in their white matter networks. More importantly, the TBI patients demonstrated increased shortest path length and decreased global efficiency of the structural network. These findings suggest that TBI patients have a weaker globally integrated structural brain network, resulting in a limited capacity to integrate information across brain regions. Furthermore, we showed that the white matter networks of both groups contained highly connected hub regions that were predominately located in the parietal cortex, frontal cortex, and basal ganglia. Finally, we showed significant correlations between switching performance and network property metrics within the TBI group. Specifically, lower scores on the switching tasks corresponded to a lower global efficiency. We conclude that analyzing the structural brain network connectivity provides new insights into understanding cognitive control changes following brain injury.


Regulating the for-profit private health sector: lessons from East and Southern Africa.
International evidence shows that, if poorly regulated, the private health sector may lead to distortions in the type, quantity, distribution, quality and price of health services, as well as anti-competitive behaviour. This article provides an overview of legislation governing the for-profit private health sector in East and Southern Africa. It identifies major implementation problems and suggests strategies Ministries of Health could adopt to regulate the private sector more effectively and in line with key public health objectives. This qualitative study was based on a document review of existing legislation in the region, and seven semi-structured interviews with individuals selected purposively on the basis of their experience in policymaking and legislation. Legislation was categorized according to its objectives and the level at which it operates. A thematic content analysis was conducted on interview transcripts. Most legislation focuses on controlling the entry of health professionals and organizations into the market. Most countries have not developed adequate legislation around behaviour following entry. Generally the type and quality of services provided by private practitioners and facilities are not well-regulated or monitored. Even where there is specific health insurance regulation, provisions seldom address open enrolment, community rating and comprehensive benefit packages (except in South Africa). There is minimal control of prices. Several countries are updating and improving legislation although, in most cases, this is without the benefit of an overarching policy on the private sector, or reference to wider public health objectives. Policymakers in the East and Southern African region need to embark on a programme of action to strengthen regulatory frameworks and instruments in relation to private health care provision and insurance. They should not underestimate the power of the private health sector to undermine efforts for increased regulation. Consequently they should conduct careful stakeholder analyses and build alliances to help drive through reform.


The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice.
The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway plays a protective role in both acute neuronal damage and chronic neurodegeneration-related oxidative stress. Circular RNAs (circRNAs) are involved with various diseases in the central nervous system (CNS). This study aimed to identify the key circRNAs involved in Nrf2-neuroprotection against oxidative stress. The differentially expressed circRNAs (DEcircRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice were identified by microarray analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was then used to validate the expression of selected DEcircRNAs in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice. Based on our previous microarray analysis of the differentially expressed mRNAs (DEmRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice, the DEcircRNA-miRNA-DEmRNA interaction network was constructed. Functional annotation of DEmRNAs that shared the same binding miRNAs with DEcircRNAs was performed using gene ontology (GO) and pathway analyses. A total of 65 and 150 significant DEcircRNAs were obtained in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, respectively, and seventeen shared DEcircRNAs were found in both these two tissues. The qRT-PCR results were generally consistent with the microarray results. The DEcircRNA-miRNA-DEmRNA interaction network and pathway analysis indicated that mmu_circRNA_34132, mmu_circRNA_017077 and mmu-circRNA-015216 might be involved with Nrf2-mediated neuroprotection against oxidative stress. Mmu_circRNA_015216 and mmu_circRNA_017077 might play roles in the Nrf2-related transcriptional misregulation and Nrf2-mediated processes of rheumatoid arthritis, respectively. In addition to these two processes, mmu_circRNA_34132 may be a potential regulator of Nrf2-mediated protection for diabetes mellitus and Nrf2-mediated defence against ROS in hearts. In conclusion, our study identified the key DEcircRNAs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, which might provide new clues for further exploring the mechanism of Nrf2-mediated neuroprotection against oxidative stress and other Nrf2-mediated processes.


Effects of multiple dimensions of bacterial diversity on functioning, stability and multifunctionality.
Bacteria are essential for many ecosystem services but our understanding of factors controlling their functioning is incomplete. While biodiversity has been identified as an important driver of ecosystem processes in macrobiotic communities, we know much less about bacterial communities. Due to the high diversity of bacterial communities, high functional redundancy is commonly proposed as explanation for a lack of clear effects of diversity. The generality of this claim has, however, been questioned. We present the results of an outdoor dilution-to-extinction experiment with four lake bacterial communities. The consequences of changes in bacterial diversity in terms of effective number of species, phylogenetic diversity, and functional diversity were studied for (1) bacterial abundance, (2) temporal stability of abundance, (3) nitrogen concentration, and (4) multifunctionality. We observed a richness gradient ranging from 15 to 280 operational taxonomic units (OTUs). Individual relationships between diversity and functioning ranged from negative to positive depending on lake, diversity dimension, and aspect of functioning. Only between phylogenetic diversity and abundance did we find a statistically consistent positive relationship across lakes. A literature review of 24 peer-reviewed studies that used dilution-to-extinction to manipulate bacterial diversity corroborated our findings: about 25% found positive relationships. Combined, these results suggest that bacteria-driven community functioning is relatively resistant to reductions in diversity.