The contribution of long-term research at Gombe National Park to chimpanzee conservation.
Long-term research projects can provide important conservation benefits, not only through research specifically focused on conservation problems, but also from various incidental benefits, such as increased intensity of monitoring and building support for the protection of an area. At Gombe National Park, Tanzania, long-term research has provided at least four distinct benefits to wildlife conservation. (1) Jane Goodall's groundbreaking discoveries of chimpanzee (Pan troglodytes) tool use, hunting, and complex social relationships in what was then a game reserve drew attention to the area and created support for upgrading Gombe to national park status in 1968. (2) The highly publicized findings have earned Gombe and Tanzania the attention of a worldwide public that includes tourists and donors that provide financial support for Gombe, other parks in Tanzania, and chimpanzee conservation in general. (3) Crucial information on social structure and habitat use has been gathered that is essential for effective conservation of chimpanzees at Gombe and elsewhere. (4) A clear picture of Gombe's chimpanzee population over the past 40 years has been determined, and this has helped identify the greatest threats to the viability of this population, namely disease and habitat loss outside the park. These threats are severe and because of the small size of the population it is extremely vulnerable. Research at Gombe has led to the establishment of conservation education and development projects around Gombe, which are needed to build local support for the park and its chimpanzees, but saving these famous chimpanzees will take a larger integrated effort on the part of park managers, researchers, and the local community with financial help from international donors.


Late effects of total body irradiation on hematopoietic recovery and immune function in rhesus macaques.
While exposure to radiation can be lifesaving in certain settings, it can also potentially result in long-lasting adverse effects, particularly to hematopoietic and immune cells. This study investigated hematopoietic recovery and immune function in rhesus macaques Cross-sectionally (at a single time point) 2 to 5 years after exposure to a single large dose (6.5 to 8.4 Gray) of total body radiation (TBI) derived from linear accelerator-derived photons (2 MeV, 80 cGy/minute) or Cobalt 60-derived gamma irradiation (60 cGy/min). Hematopoietic recovery was assessed through measurement of complete blood counts, lymphocyte subpopulation analysis, and thymus function assessment. Capacity to mount specific antibody responses against rabies, Streptococcus pneumoniae, and tetanus antigens was determined 2 years after TBI. Irradiated macaques showed increased white blood cells, decreased platelets, and decreased frequencies of peripheral blood T cells. Effects of prior radiation on production and export of new T cells by the thymus was dependent on age at the time of analysis, with evidence of interaction with radiation dose for CD8+ T cells. Irradiated and control animals mounted similar mean antibody responses to proteins from tetanus and rabies and to 10 of 11 serotype-specific pneumococcal polysaccharides. However, irradiated animals uniformly failed to make antibodies against polysaccharides from serotype 5 pneumococci, in contrast to the robust responses of non-irradiated controls. Trends toward decreased serum levels of anti-tetanus IgM and slower peak antibody responses to rabies were also observed. Taken together, these data show that dose-related changes in peripheral blood cells and immune responses to both novel and recall antigens can be detected 2 to 5 years after exposure to whole body radiation. Longer term follow-up data on this cohort and independent validation will be helpful to determine whether these changes persist or whether additional changes become evident with increasing time since radiation, particularly as animals begin to develop aging-related changes in immune function.


Lower risk of suicide during pregnancy.
The authors determined the risk of suicide during pregnancy. The autopsy reports of all female residents of New York City, 10-44 years old, who committed suicide from 1990 to 1993 were assessed for pregnancy. These data were compared with age-adjusted and race-adjusted standardized mortality ratios for women, which were calculated by using population data from the 1990 U.S. Census as well as data obtained from the New York City Health Department on the number of live births, spontaneous abortions, and induced abortions. The standardized mortality ratio for suicide during pregnancy was 0.33; that is, the number of suicides of pregnant women was only one-third of that expected. Despite the mood swings and stresses associated with pregnancy and impending childbirth, pregnant women have a significantly lower risk of suicide than women of childbearing age who are not pregnant.


The Lothian Birth Cohort 1936: a study to examine influences on cognitive ageing from age 11 to age 70 and beyond.
Cognitive ageing is a major burden for society and a major influence in lowering people's independence and quality of life. It is the most feared aspect of ageing. There are large individual differences in age-related cognitive changes. Seeking the determinants of cognitive ageing is a research priority. A limitation of many studies is the lack of a sufficiently long period between cognitive assessments to examine determinants. Here, the aim is to examine influences on cognitive ageing between childhood and old age. The study is designed as a follow-up cohort study. The participants comprise surviving members of the Scottish Mental Survey of 1947 (SMS1947; N = 70,805) who reside in the Edinburgh area (Lothian) of Scotland. The SMS1947 applied a valid test of general intelligence to all children born in 1936 and attending Scottish schools in June 1947. A total of 1091 participants make up the Lothian Birth Cohort 1936. They undertook: a medical interview and examination; physical fitness testing; extensive cognitive testing (reasoning, memory, speed of information processing, and executive function); personality, quality of life and other psycho-social questionnaires; and a food frequency questionnaire. They have taken the same mental ability test (the Moray House Test No. 12) at age 11 and age 70. They provided blood samples for DNA extraction and testing and other biomarker analyses. Here we describe the background and aims of the study, the recruitment procedures and details of numbers tested, and the details of all examinations. The principal strength of this cohort is the rarely captured phenotype of lifetime cognitive change. There is additional rich information to examine the determinants of individual differences in this lifetime cognitive change. This protocol report is important in alerting other researchers to the data available in the cohort.


Vagal withdrawal during hot flashes occurring in undisturbed sleep.
Little is known about the impact of hot flashes on cardiac autonomic regulation, particularly vagal control. Therefore, we assessed the cardiac autonomic profile associated with physiological hot flashes occurring in undisturbed sleep. Eleven perimenopausal women (45-56 y) had overnight laboratory recordings of polysomnography, electrocardiography, and skin conductance. Eighteen hot flashes that occurred in stable non-rapid eye movement sleep undisturbed by arousals were analyzed. Heart rate variability measures were obtained for three consecutive 2-minute windows starting from 4 minutes before (baseline and preflash periods) to 2 minutes after the onset of hot flashes (hot flash period). Heart rate increased by, on average, 4 beats/minute with the occurrence of a hot flash compared with both baseline (P < 0.001) and preflash (P < 0.001). High-frequency power was reduced, reflecting a decrease in vagal activity, at the onset of a hot flash compared with baseline (P < 0.001) and preflash (P < 0.001). There was no change in sympathovagal balance with the onset of a hot flash. The magnitude of the hot flash (ie, skin conductance amplitude) was associated with increased heart rate (r = 0.78, P < 0.001) and decreased vagal tone (r = -0.56, P = 0.014). Physiological hot flashes per se, recorded during undisturbed sleep periods and independent of any arousals, are associated with increased heart rate and decreased cardiac autonomic vagal activity. These data support the hypothesis that the parasympathetic branch of the autonomic nervous system is involved in the cardiac response to a hot flash.


Response of human trabecular meshwork cells to topographic cues on the nanoscale level.
purpose To determine how primary human trabecular meshwork (HTM) cells are influenced by their interaction with nanopatterned substrates. HTM cells from several individuals were grown on planar or anisotropically ordered nanopatterned surfaces. Microscopy was used to measure cellular elongation and alignment. Cells were also incubated with 10(-7) M dexamethasone for comparison to control cells. Quantitative PCR for myocilin and versican isoforms was performed in addition to Western blots of myocilin and alphaB-crystallin. Cells on anisotropically ordered nanopatterned substrates aligned with the surface nanopatterns and displayed actin filaments that were parallel to the patterned ridges and grooves. The cells became more elongated on the nanogrooved surfaces compared with the planar control cells. Myocilin mRNA and protein levels increased when HTM cells were plated onto 400-nm pitch surfaces. With some HTM cells, myocilin increased to a greater extent when untreated cells were plated on nanosurfaces compared with the cells grown on planar surfaces with dexamethasone. The V0 and V1 isoforms of versican had increased expression on patterned surfaces. Nanopatterned surfaces containing biomimetic length scale features clearly influenced cellular behavior of HTM cells. Increased mRNA and protein levels of myocilin were observed when cells were grown on 400-nm pitch surfaces, suggesting that the reduction of myocilin mRNA when cells are plated onto flat tissue culture plastic is an artifact of a nonphysiologic culture environment that lacks appropriate topographic cues.


Guinea pig T lymphocyte development analyzed by enzyme histocytochemistry, monoclonal antibodies, and flow cytometry.
Studies of T (thymus-derived) lymphocyte ontogeny in the guinea pig have been hampered by the lack of suitable antigenic or other markers for various T cell subpopulations in this species. Monoclonal antibodies that recognize three distinct surface proteins of guinea pig T cells and react with all peripheral T cells have been used in combination with membrane alkaline phosphatase (AP) to characterize stages of guinea pig T cell development and to determine anatomical localization of different T cell subpopulations. Flow cytofluorographic analysis of thymus, spleen, and lymph node lymphocytes was used to characterize monoclonal antibody specificity. Cortical thymocytes in tissue sections expressed membrane AP activity and contained nuclear terminal deoxynucleotidyl transferase; medullary thymocytes reacted strongly with one of the monoclonal antibodies (8BE6), minimally with a second (5CD2), and not at all with a third (11AE3). In contrast, polyclonal rabbit antiguinea pig T cell antiserum reacted with both cortical and medullary thymocytes. Staining of tissue sections of lymph node and spleen revealed AP+ lymphocytes to be present peripheral to the mantle region of lymph node follicles and to be randomly scattered throughout the splenic red pulp. T cells reactive with monoclonal antibodies were located primarily in paracortical regions of lymph node and the central region around the periarteriolar regions of the spleen. Dual staining of frozen sections and cell suspension of guinea pig lymphoid tissues for AP activity and surface proteins unique to T cells showed that AP+ cells lacked T cell markers. Dual staining for AP activity and surface immunoglobulins or esterase activity showed that AP+ cells are not likely to be derived from either B cell or monocyte-macrophage lineages. AP+ cells in guinea pig secondary lymphoid tissue may represent a unique subset of lymphocytes of unknown function.


Effects of microcystin-LR in isolated perfused rat kidney.
Microcystin is a hepatotoxic peptide which inhibits protein phosphatase types 1 and 2A. The objective of the present study was to evaluate the physiopathologic effects of microcystin-LR in isolated perfused rat kidney. Adult Wistar rats (N = 5) of both sexes (240-280 g) were utilized. Microcystin-LR (1 microg/ml) was perfused over a period of 120 min, during which samples of urine and perfusate were collected at 10-min intervals to determine the levels of inulin, sodium, potassium and osmolality. We observed a significant increase in urinary flow with a peak effect at 90 min (control (C) = 0.20 +/- 0.01 and treated (T) = 0.32 +/- 0.01 ml g-1 min-1, P<0.05). At 90 min there was a significant increase in perfusate pressure (C = 129.7 +/- 4.81 and T = 175.0 +/- 1.15 mmHg) and glomerular filtration rate (C = 0.66 +/- 0.07 and T = 1.10 +/- 0. 04 ml g-1 min-1) and there was a significant reduction in fractional sodium tubular transport at 120 min (C = 78.6 +/- 0.98 and T = 73.9 +/- 0.95%). Histopathologic analysis of the perfused kidneys showed protein material in the urinary space, suggestive of renal toxicity. These data demonstrate renal vascular, glomerular and urinary effects of microcystin-LR, indicating that microcystin acts directly on the kidney by probable inhibition of protein phosphatases.


Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.
Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. (Funded by Janssen Research and Development; MARINER ClinicalTrials.gov number, NCT02111564 .).


A remodeled protein arginine methyltransferase 1 (PRMT1) generates symmetric dimethylarginine.
Protein arginine methylation is emerging as a significant post-translational modification involved in various cell processes and human diseases. As the major arginine methylation enzyme, protein arginine methyltransferase 1 (PRMT1) strictly generates monomethylarginine and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA). The two types of dimethylarginines can lead to distinct biological outputs, as highlighted in the PRMT-dependent epigenetic control of transcription. However, it remains unclear how PRMT1 product specificity is regulated. We discovered that a single amino acid mutation (Met-48 to Phe) in the PRMT1 active site enables PRMT1 to generate both ADMA and SDMA. Due to the limited amount of SDMA formed, we carried out quantum mechanical calculations to determine the free energies of activation of ADMA and SDMA synthesis. Our results indicate that the higher energy barrier of SDMA formation (ΔΔG(‡) = 3.2 kcal/mol as compared with ADMA) may explain the small amount of SDMA generated by M48F-PRMT1. Our study reveals unique energetic challenges for SDMA-forming methyltransferases and highlights the exquisite control of product formation by active site residues in the PRMTs.


Retinoic acid and polyriboinosinic:polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations.
Retinoic acid (RA), a bioactive retinoid, and polyriboinosinic:polyribocytidylic acid (PIC) are known to promote immunity in vitamin A-deficient animals. In this study, we hypothesized that RA, PIC, and the combination can provide significant immunoadjuvant activity even in the vitamin A-adequate state. Six-week-old C57BL/6 mice were immunized with tetanus toxoid (TT) and treated with RA and/or PIC at priming in three independent studies of short and long duration. RA and PIC differentially regulated both primary and secondary anti-TT IgG isotypes, whereas the combination of RA + PIC stimulated the highest level of anti-TT IgG production and, concomitantly, a ratio of IgG1 to IgG2a similar to that of the control group. The regulation of Ab response was strongly associated with type 1/type 2 cytokine gene expression. Whereas RA reduced type 1 cytokines (IFN-gamma and IL-12), PIC enhanced both type 1 and type 2 cytokines (IL-4 and IL-12) and cytokine-related transcription factors. Despite the presence of PIC, the IL-4:IFN-gamma ratio was significantly elevated by RA. In addition, RA and/or PIC modulated NK/NKT cell populations and the level of expression of the costimulatory molecules CD80/CD86, evident 3 days after priming. Notably, the NKT:NK and CD80:CD86 ratios were correlated with the IL-4:IFN-gamma ratio, indicative of multiple converging modes of regulation. Overall, RA, PIC, and RA + PIC rapidly and differentially shaped the anti-tetanus Ig response. The robust, durable, and proportionate increase in all anti-TT IgG isotypes induced by RA + PIC suggests that this combination is promising as a means to enhance the Ab response to TT and similar vaccines.


Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility.
Observational evidence suggests a potential benefit with several anti-adhesion therapies in women undergoing operative hysteroscopy (e.g. insertion of an intrauterine device or balloon, hormonal treatment, barrier gels or human amniotic membrane grafting) for decreasing intrauterine adhesions (IUAs). To assess the effectiveness of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy, following operative hysteroscopy for treatment of female subfertility. We searched the following databases from inception to June 2017: the Cochrane Gynaecology and Fertility Group Specialised Register; the Cochrane Central Register of Studies (CRSO); MEDLINE; Embase; CINAHL and other electronic sources of trials, including trial registers, sources of unpublished literature and reference lists. We handsearched the Journal of Minimally Invasive Gynecology, and we contacted experts in the field. We also searched reference lists of appropriate papers. Randomised controlled trials (RCTs) of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy in subfertile women. The primary outcome was live birth. Secondary outcomes were clinical pregnancy, miscarriage and IUAs present at second-look hysteroscopy, along with mean adhesion scores and severity of IUAs. Two review authors independently selected studies, assessed risk of bias, extracted data and evaluated quality of evidence using the GRADE method. The overall quality of the evidence was low to very low. The main limitations were serious risk of bias related to blinding of participants and personnel, indirectness and imprecision. We identified 16 RCTs comparing a device versus no treatment (two studies; 90 women), hormonal treatment versus no treatment or placebo (two studies; 136 women), device combined with hormonal treatment versus no treatment (one study; 20 women), barrier gel versus no treatment (five studies; 464 women), device with graft versus device without graft (three studies; 190 women), one type of device versus another device (one study; 201 women), gel combined with hormonal treatment and antibiotics versus hormonal treatment with antibiotics (one study; 52 women) and device combined with gel versus device (one study; 120 women). The total number of participants was 1273, but data on 1133 women were available for analysis. Only two of 16 studies included 100% infertile women; in all other studies, the proportion was variable or unknown.No study reported live birth, but some (five studies) reported outcomes that were used as surrogate outcomes for live birth (term delivery or ongoing pregnancy). Anti-adhesion therapy versus placebo or no treatment following operative hysteroscopy.There was insufficient evidence to determine whether there was a difference between the use of a device or hormonal treatment compared to no treatment or placebo with respect to term delivery or ongoing pregnancy rates (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.42 to 2.12; 107 women; 2 studies; I² = 0%; very-low-quality evidence).There were fewer IUAs at second-look hysteroscopy using a device with or without hormonal treatment or hormonal treatment or barrier gels compared with no treatment or placebo (OR 0.35, 95% CI 0.21 to 0.60; 560 women; 8 studies; I² = 0%; low-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 5 to 17). Comparisons of different anti-adhesion therapies following operative hysteroscopyIt was unclear whether there was a difference between the use of a device combined with graft versus device only for the outcome of ongoing pregnancy (OR 1.48, 95% CI 0.57 to 3.83; 180 women; 3 studies; I² = 0%; low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without graft/gel or gel combined with hormonal treatment and antibiotics compared with using a device only or hormonal treatment combined with antibiotics, but the findings of this meta-analysis were affected by evidence quality (OR 0.55, 95% CI 0.36 to 0.83; 451 women; 5 studies; I² = 0%; low-quality evidence). Implications for clinical practiceThe quality of the evidence ranged from very low to low. The effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for researchMore research is needed to assess the comparative safety and (cost-)effectiveness of different anti-adhesion treatments compared to no treatment or other interventions for improving key reproductive outcomes in subfertile women.


Prostaglandin transport.
Newly synthesized prostaglandins (PGs) efflux from cells by simple diffusion, driven by pH and the membrane potential. Metabolic clearance requires energy-dependent uptake across the plasma membrane, followed by cytoplasmic oxidation. Several PG carriers have been cloned and characterized. PGT is broadly expressed in cyclooxygenase (COX)-positive cells, appears to be a lactate/PG exchanger, and is coordinately regulated with COX. By analogy with neurotransmitter release and re-uptake, PGT may regulate pericellular PG levels via re-uptake. PGT may also direct PGs towards and/or away from specific sets of PG receptors. Other members of the OATP transporter family also catalyze PG uptake; these are variably expressed and have variable affinities for PGs. The OATs are alpha-ketoglutarate/organic anion exchangers that accept PGs; these probably represent the uptake step in renal and hepatic PG degradation and excretion. Finally, certain glutathione-conjugated leukotrienes and PGs are actively extruded from cells by the MRPs; these may also play a role in metabolic clearance of PGs.


On Inertial Body Tracking in the Presence of Model Calibration Errors.
In inertial body tracking, the human body is commonly represented as a biomechanical model consisting of rigid segments with known lengths and connecting joints. The model state is then estimated via sensor fusion methods based on data from attached inertial measurement units (IMUs). This requires the relative poses of the IMUs w.r.t. the segments-the IMU-to-segment calibrations, subsequently called I2S calibrations-to be known. Since calibration methods based on static poses, movements and manual measurements are still the most widely used, potentially large human-induced calibration errors have to be expected. This work compares three newly developed/adapted extended Kalman filter (EKF) and optimization-based sensor fusion methods with an existing EKF-based method w.r.t. their segment orientation estimation accuracy in the presence of model calibration errors with and without using magnetometer information. While the existing EKF-based method uses a segment-centered kinematic chain biomechanical model and a constant angular acceleration motion model, the newly developed/adapted methods are all based on a free segments model, where each segment is represented with six degrees of freedom in the global frame. Moreover, these methods differ in the assumed motion model (constant angular acceleration, constant angular velocity, inertial data as control input), the state representation (segment-centered, IMU-centered) and the estimation method (EKF, sliding window optimization). In addition to the free segments representation, the optimization-based method also represents each IMU with six degrees of freedom in the global frame. In the evaluation on simulated and real data from a three segment model (an arm), the optimization-based method showed the smallest mean errors, standard deviations and maximum errors throughout all tests. It also showed the lowest dependency on magnetometer information and motion agility. Moreover, it was insensitive w.r.t. I2S position and segment length errors in the tested ranges. Errors in the I2S orientations were, however, linearly propagated into the estimated segment orientations. In the absence of magnetic disturbances, severe model calibration errors and fast motion changes, the newly developed IMU centered EKF-based method yielded comparable results with lower computational complexity.


Health assessment for chronic HCV infection: results of quality of life.
The perception that chronic hepatitis C is an asymptomatic disease contrasts with many studies that show a strong association between chronic hepatitis C, hepatocellular cancer, and fatal liver disease. In order to resolve these issues, it is logical to directly evaluate the quality of life in patients with chronic hepatitis C and to compare this to the normal population as well as cohorts of patients with other chronic diseases. The Sickness Impact Profile was used to evaluate the impact of disease and interferon therapy on health-related quality of life in patients with chronic hepatitis C. Using this tool, patients with chronic hepatitis C had a total Sickness Impact Profile score of 9.0, compared with a score of 3.6 among the general population (P < 0.05). Patients with chronic hepatitis C also had significantly worse scores in almost every category of the Sickness Impact Profile that could be compared. However, statistically significant differences were observed only at the 24-week evaluation for work and at the end-point evaluation for the sleep and rest and recreation and pastimes categories. A more sophisticated instrument, based on the Medical Outcomes Study 36-item short-form health survey, found that patients with chronic hepatitis C scored significantly lower (P < 0.01) than the general population on each of the subscales in this survey. In addition, they scored significantly lower than patients with hypertension in seven of the subscales and two additional generic scales. Patients with chronic hepatitis C were most comparable to those with type II diabetes. A larger, more comprehensive study is underway to further evaluate these relationships.


Measuring Quantum Coherence with Entanglement.
Quantum coherence is an essential ingredient in quantum information processing and plays a central role in emergent fields such as nanoscale thermodynamics and quantum biology. However, our understanding and quantitative characterization of coherence as an operational resource are still very limited. Here we show that any degree of coherence with respect to some reference basis can be converted to entanglement via incoherent operations. This finding allows us to define a novel general class of measures of coherence for a quantum system of arbitrary dimension, in terms of the maximum bipartite entanglement that can be generated via incoherent operations applied to the system and an incoherent ancilla. The resulting measures are proven to be valid coherence monotones satisfying all the requirements dictated by the resource theory of quantum coherence. We demonstrate the usefulness of our approach by proving that the fidelity-based geometric measure of coherence is a full convex coherence monotone, and deriving a closed formula for it on arbitrary single-qubit states. Our work provides a clear quantitative and operational connection between coherence and entanglement, two landmark manifestations of quantum theory and both key enablers for quantum technologies.


Development and validation of the pressure ulcer management self-efficacy scale for nurses.
Pressure ulcers (PUs) represent a current issue for healthcare delivery. Nurse self-efficacy in managing PUs could predict patients' outcome, being a proxy assessment of their overall competency to managing PUs. However, a valid and reliable scale of this task-specific self-efficacy has not yet been developed. To develop a valid and reliable scale to assess nurses' self-efficacy in managing PUs, that is, the pressure ulcer management self-efficacy scale for nurses (PUM-SES). This study had a multi-method and multi-phase design, where study reporting was supported by the STROBE checklist (File S1). Phase 1 referred to the scale development, consisting in the items' generation, mainly based on themes emerged from the literature and discussed within a panel of experts. Phase 2 focused on a three-step validation process: the first step aimed to assess face and content validity of the pool of items previously generated (initial version of the PUM-SES); the second aimed to assess psychometrics properties through exploratory factorial analysis; the third step assessed construct validity through confirmative factorial analysis, while concurrent validity was evaluated describing the relationships between PUM-SES and an established general self-efficacy measurement. Reliability was assessed through the evaluation of stability and internal consistency. PUM-SES showed evidence of face and content validity, adequate construct and concurrent validity, internal consistency and stability. Specifically, PUM-SES had four domains, labelled as follows: assessment, planning, supervision and decision-making. These domains were predicted by the same second-order factor, labelled as PU management self-efficacy. PUM-SES is a 10-item scale to measure nurses' self-efficacy in PU management. A standardised 0-100 scoring is suggested for computing each domain and the overall scale. PUM-SES might be used in clinical and educational research. Optimising nurses' self-efficacy in PU management might enhance clinical assessment, determining better outcomes in patients with PUs.


Antibiotic resistance of uropathogenic Escherichia coli and ESBL prevalence in general practice patients over 10 years.
Bacterial susceptibility to antibiotics changes over time. Knowledge of the susceptibility is important for antibiotic treatment guidelines in general practices. To determine the antibiotic-susceptibility of E. coli from uncomplicated UTI among women in general practices in the Netherlands and to compare the results with those collected in 2004 and 2009. Urine samples were collected from women with symptoms of uncomplicated UTI, in 30 sentinel GP practices of the Nivel Primary Care database. Patient characteristics, E. coli susceptibility and ESBL prevalence were analysed. In total, 689 samples were collected. E. coli was the most isolated uropathogen (83%). Antibiotic susceptibility was stable over time except for ciprofloxacin (96%, 97% and 94% in 2004, 2009 and 2014, respectively; P<0.05). The susceptibility to co-amoxiclav was 88%, 87% and 92% in 2004, 2009 and 2014, respectively. The prevalence of ESBL producing E. coli increased from 0.1% in 2004, to 2.2% in 2014 (P<0.05). Susceptibility for co-trimoxazole was the highest in the West (88%) and the lowest in the North (72%, P = 0.021). Ciprofloxacin susceptibility was related to antibiotic use in the past 3 months (97% no use versus 90% use, P = 0.002) and those aged >70 years (P = 0.005). In 2014, prescription of fosfomycin increased compared to 2009 (14.3% versus 5.6%) at the expense of co-amoxiclav, co-trimoxazole and ciprofloxacin (P<0.05). The antibiotic susceptibility percentages to the agents tested were stable over the 10-year period, except for ciprofloxacin as was the prevalence of ESBL producing E. coli. Surveillance with regular intervals is warranted.


Ring-opening metathesis polymerization-derived monolithic anion exchangers for the fast separation of double-stranded DNA fragments.
Ring-opening metathesis polymerization- (ROMP) derived monoliths were prepared from 5-norborn-2-enemethyl bromide (NBE-CH(2)Br) and tris(5-norborn-2-enemethoxy)methylsilane ((NBE-CH(2)O)(3)SiCH(3)) within the confines of surface-silanized borosilicate columns (100×3 mm I.D.), applying Grubbs' first generation benzylidene-type catalyst [RuCl(2)(PCy(3))(2)(CHPh)]. Monoliths were converted into weak anion exchangers via reaction with diethyl amine. The resulting monolithic anion exchangers demonstrated a very good potential for the anion-exchange separation of nucleic acids applying a phosphate buffer (0.05 mol/L, pH 7) and NaCl (1.0 mol/L) as a gradient former. Fast and efficient separations, indicated by sharp and highly symmetric analyte peaks, were established. Except for the 267 and 298 base pair fragments, the eleven fragments of a ds-pUC18 DNA Hae III digest were baseline separated within ∼8 min. Nineteen fragments of a ds-pBR322 Hae III digest were separated within ∼12 min. There, only the 192 and 213 base pair fragments and the 458, 504 and 540 base pair fragments coeluted. A ds-pUC18 DNA Hae III digest was used as a control analyte in evaluating the influence of organic additives on the mobile phase such as methanol and acetonitrile on nucleic acid separation. Methanol, and even better, acetonitrile improved the separation efficiency and shortened the analysis time.


Mining new crystal protein genes from Bacillus thuringiensis on the basis of mixed plasmid-enriched genome sequencing and a computational pipeline.
We have designed a high-throughput system for the identification of novel crystal protein genes (cry) from Bacillus thuringiensis strains. The system was developed with two goals: (i) to acquire the mixed plasmid-enriched genomic sequence of B. thuringiensis using next-generation sequencing biotechnology, and (ii) to identify cry genes with a computational pipeline (using BtToxin_scanner). In our pipeline method, we employed three different kinds of well-developed prediction methods, BLAST, hidden Markov model (HMM), and support vector machine (SVM), to predict the presence of Cry toxin genes. The pipeline proved to be fast (average speed, 1.02 Mb/min for proteins and open reading frames [ORFs] and 1.80 Mb/min for nucleotide sequences), sensitive (it detected 40% more protein toxin genes than a keyword extraction method using genomic sequences downloaded from GenBank), and highly specific. Twenty-one strains from our laboratory's collection were selected based on their plasmid pattern and/or crystal morphology. The plasmid-enriched genomic DNA was extracted from these strains and mixed for Illumina sequencing. The sequencing data were de novo assembled, and a total of 113 candidate cry sequences were identified using the computational pipeline. Twenty-seven candidate sequences were selected on the basis of their low level of sequence identity to known cry genes, and eight full-length genes were obtained with PCR. Finally, three new cry-type genes (primary ranks) and five cry holotypes, which were designated cry8Ac1, cry7Ha1, cry21Ca1, cry32Fa1, and cry21Da1 by the B. thuringiensis Toxin Nomenclature Committee, were identified. The system described here is both efficient and cost-effective and can greatly accelerate the discovery of novel cry genes.


On-site wastewater technologies in Australia.
Domestic wastewater reuse is currently not permitted anywhere in Australia but is widely supported by the community, promoted by researchers, and improvised by up to 20% of householders. Its widespread implementation will make an enormous contribution to the sustainability of water resources. Integrated with other strategies in the outdoor living environment of settlements in arid lands, great benefit will be derived. This paper describes six options for wastewater reuse under research by the Remote Area Developments Group (RADG) at Murdoch University and case studies are given where productive use is being made for revegetation and food production strategies at household and community scales. Pollution control techniques, public health precautions and maintenance requirements are described. The special case of remote Aboriginal communities is explained where prototype systems have been installed by RADG to generate windbreaks and orchards. New Australian design standards and draft guidelines for domestic greywater reuse produced by the Western Australian State government agencies for mainstream communities are evaluated. It is recommended that dry composting toilets be coupled with domestic greywater reuse and the various types available in Australia are described. For situations where only the flushing toilet will suffice the unique 'wet composting' system can be used and this also is described. A vision for household and community-scale on-site application is presented.


De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia.
We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit α. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.


Evaluation of methods for monitoring drug resistance in chronic hepatitis B patients during lamivudine therapy based on mass spectrometry and reverse hybridization.
A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based genotyping assay, termed restriction fragment mass polymorphism (RFMP) has been recently developed for detecting hepatitis B virus (HBV) mutants. The assay is based on PCR amplification and mass measurement of oligonucleotides containing sites of mutations that confer resistance to lamivudine. We compared the efficacy and usefulness of the RFMP assay with a commercial assay using a reverse hybridization line probe technology, namely INNO-LiPA HBV DR (referred to henceforth as the LiPA assay), for the detection of lamivudine-resistant HBV mutants. A total of 60 patient samples were analysed for the presence of mutations at rtL1 80M and rtM204I/V of HBV polymerase by the LiPA and RFMP assays. The ability to detect mutations at rtM204I/V was compared with defined mixtures of wild-type and mutant HBV cloned in plasmids at relative concentrations ranging from 1-25%. Concordance between methods was found to be 95.0% (57/60) when only the presence of resistance mutations was considered, regardless of quasispecies. In three cases, additional minor populations of resistant viruses were identified by RFMP. Defined mixtures were consistently successfully identified at a 1% relative concentration of mutant versus wild-type viruses by the RFMP assay and 4% by the LiPA assay. The RFMP assay proved to be an accurate and reliable tool for detection of lamivudine-resistant mutations and was more sensitive than the LiPA assay in detecting mixtures of mutant and wild-type viruses. The improved sensitivity of the RPMP assay can help monitor drug resistance as it develops, enabling early intervention and prevention.


Optimization of alignability in integrated planar-optical interconnect packages.
The efficiency of power transfer and the alignability of an integrated planar-optics holographic optical backplane for board-to-board interconnections are analyzed. Both the efficiency and the alignability are functions of lateral and angular offsets in the input, the error in the spatial frequency of the hologram, errors in the source wavelength, the distance between two boards, the thickness of the substrate, the sizes of the hologram and the beam spot, and the angle of propagation of the beam. From the analyses, design guidelines on integrated planar-optic interconnects are developed, and it is shown that the interconnect design can be optimized for maximum alignability. A design with optimum alignability may not have the highest possible peak efficiency, but it can tolerate greater offsets without a substantial efficiency decrease.


[Arterial hypertension in the elderly: prevalence, associated factors, and control practices in Campinas, São Paulo, Brazil].
The objective of this study was to assess the prevalence of reported hypertension among the elderly in Campinas, São Paulo, Brazil, identifying related factors, the use of healthcare services, and knowledge and practices related to treatment options. This was a cross-sectional population-based study, with stratified clustered multiple-stage sampling. Data analysis for the 426 individuals (60 years of age and older) considered the sampling design and outlining effect. Hypertension prevalence was 51.8% (46.4% in men and 55.9% in women) and was higher among the elderly with less education (55.9%), immigrants from other States (60.2%), and the overweight or obese (57.2%). The results indicate that healthcare services are ensuring access to medical care (71.6% have regular physician appointments) and medication (86.7% take their routine medication), without distinction as to socioeconomic status. However, social inequalities persist in knowledge and use of other measures to control blood pressure, like appropriate diet and exercise, which are also underused by more privileged socioeconomic strata.


Band-limited image plane masks for the Terrestrial Planet Finder coronagraph: materials and designs for broadband performance.
Coronagraphs for detection and characterization of exosolar earthlike planets require accurate masks with broadband performance in the visible and near infrared spectrum. Design and fabrication of image plane masks capable of suppressing broadband starlight to 10(-10) level contrast presents technical challenges. We discuss basic approaches, material choices, designs, and fabrication options for image plane masks with particular focus on material properties to obtain adequate spectral performance. Based on theoretical analysis, we show that metals such as Pt and Ni, and alloys such as Inconel, may be employed as promising mask materials that can meet broadband performance requirements.


Unique longitudinal relationships between symptoms of psychopathology in youth: A cross-lagged panel network analysis in the ABCD study.
The network theory suggests that psychopathology may reflect causal relationships between individual symptoms. Several studies have examined cross-sectional relationships between individual symptoms in youth. However, these studies cannot address the directionality of the temporal relationships hypothesized by the network theory. Therefore, we estimated the longitudinal relationships between individual internalizing, externalizing, and attention symptoms in youth. Data from 4,093 youth participants in the Adolescent Brain Cognitive Development (ABCD) study were used. Symptoms were assessed using the Brief Problem Monitor, which was administered at three time points spaced six months apart. Unique longitudinal relationships between symptoms at T1 and T2 were estimated using cross-lagged panel network modeling. Network replicability was assessed by comparing this network to an identically estimated replication network of symptoms at T2 predicting symptoms at T3. After controlling for all other symptoms and demographic covariates, depressed mood, inattention, and worry at T1 were most predictive of other symptoms at T2. In contrast, threats of violence and destructiveness at T2 were most prospectively predicted by other symptoms at T1. The reciprocal associations between depressed mood and worthlessness were among the strongest bivariate relationships in the network. Comparisons between the original network and the replication network (correlation between edge lists = .61; individual edge replicability = 64%-84%) suggested moderate replicability. Although causal inferences are precluded by the observational design and methodological considerations, these findings demonstrate the directionality of relationships between individual symptoms in youth and highlight depressed mood, inattention, and worry as potential influencers of other symptoms.


Safety and timing of nonobstetric abdominal surgery in pregnancy.
Abdominal disorders occurring during pregnancy pose special difficulties in diagnosis and management to the obstetrician and surgeon. The advisability of nonobstetric abdominal surgery during pregnancy is uncertain. Our objective was to evaluate the safety and timing of abdominal surgery during pregnancy. We retrospectively reviewed 77 consecutive gravid patients undergoing nonobstetric abdominal surgery from 1989 to 1996 at an urban academic medical center and a large affiliated community teaching hospital. Medical records were evaluated for clinical presentation, perioperative management, preterm labor, and maternal and fetal morbidity and mortality. The rate of nonobstetric abdominal surgery during pregnancy was 1 in every 527 births. Among the 77 patients, the indications for surgery were adnexal mass (42%), acute appendicitis (21%), gallstone disease (17%) and other (21%). There was no maternal or fetal loss or identifiable neonatal birth defect. Preterm labor occurred in 26% of the second-trimester patients and 82% of the third-trimester patients. Preterm labor was most common in patients with appendicitis and after adnexal surgery. Preterm delivery occurred in 16% of the patients, but appeared to be directly related to the abdominal surgery in only 5%. Surgery during the first or second trimester is not associated with significant preterm labor, fetal loss or risk of teratogenicity. Surgery during the third trimester is associated with preterm labor, but not fetal loss.


Is there a relationship between platelet parameters and patency of ductus arteriosus in preterm infants?
Postnatal closure of the ductus arteriosus is a complicated two-phase process involving functional and structural changes. So far, the precise mechanisms regulating this process are not fully understood. A growing body of evidence from recent studies suggests that platelets play a key role in inflammatory processes including ductal closure via interaction with endothelial cells. The aim of this study is to assess whether a relationship exists between the occurrence and/or closure of hemodynamically significant ductus arteriosus (HSDA) and platelet parameters (platelet count, circulating platelet mass, mean platelet volume, platelet distribution width) in preterm newborns. This single-center, retrospective study included 824 premature infants between 24 and 34 gestational weeks, evaluated by echocardiography at postnatal 72-96 h. Infants with and without HSDA (n = 208 vs. n = 616) were compared in terms of platelet parameters recorded within the first 3 days of life. Oral or intravenous ibuprofen was commenced for medical treatment, and echocardiography was repeated 24 h thereafter to determine ductal closure. No statistically significant difference could be demonstrated between the groups in terms of baseline platelet parameters. HSDA was independently associated with early-onset neonatal sepsis. Thrombocytopenia, low circulating platelet mass, high platelet distribution width, or high mean platelet volume could not be demonstrated as a risk factor for HSDA. None of the platelet parameters had an influence on ductal closure after medical treatment. Unlike most reports in the literature, presence of HSDA was not associated with any platelet parameter in our study. We could not demonstrate an association between any platelet parameter and either persistence or closure after medical treatment.


The ethics of helping transgender men and women have children.
A transgender man legally married to a woman has given birth to two children, raising questions about the ethics of assisted reproductive treatments (ARTs) for people with cross-sex identities. Psychiatry treats cross-sex identities as a disorder, but key medical organizations and the law in some jurisdictions have taken steps to protect people with these identities from discrimination in health care, housing, and employment. In fact, many people with cross-sex identities bypass psychiatric treatment altogether in order to pursue lives that are meaningful to them, lives that sometimes include children. Cross-sex identification does not render people unfit as parents, because transgender identities do not undercut the ability to understand the nature and consequences of pregnancy or necessarily interfere with the ability to raise children. Moreover, no evidence suggests that being born to and raised by transgender parents triggers the kind of harm that would justify exclusion of trans-identified men and women from ARTs as a class. The normalization of transgender identities by the law and professional organizations contributes, moreover, to the need to reassess pathological interpretations of cross-sex identities, and trans-parenthood puts those interpretations into sharp relief.


LINE-1 (L1) lineages in the mouse.
Recently, a rapidly amplifying family of mouse LINE-1 (L1) has been identified and named T(F). The evolutionary context surrounding the derivation of the T(F) family was examined through phylogenetic analysis of sequences in the 3' portion of the repeat. The Mus musculus domesticus T(F) family was found to be the terminal subfamily of the previously identified L1Md4 lineage. The L1Md4 lineage joins the other prototypical mouse LINE-1 lineage (the L1MdA2 lineage) approximately 1 MYA at about the time of the common ancestor of M. m. domesticus, Mus spicilegus, and Mus spretus. However, the T(F) family from M. m. domesticus was found to join to the previously reported M. spretus Ms475 and Ms7024 LINE-1 families at just 0.5 MYA, indicating horizontal transfer. The T(F) family from M. m. domesticus was then found to be even more recently related to LINE-1's from another species, M. spicilegus. A separate spretus A2 lineage was found through a directed search of a PCR library. This lineage, in contrast to the spretus T(F) lineage, does join domesticus at about 1 MYA, as would be expected in the absence of horizontal transfer. A third major family was also found that splits off from the L1Md4 lineage shortly after its departure from the L1MdA2 lineage. The new family, named the Z family, was found to contain the de novo LINE-1 inserts causing the beige and med mutations. Whether the split with the Z family was before or after the recombination that introduced the F-type promoters and defined the inception of T(F) as a lineage is unclear. In enumerating copies of the various LINE-1 families, we found that T(F) 3' ends were not much more numerous than the reported number of 5' ends, suggesting that T(F) may not be subjected to the 90% truncation pattern typical of LINE-1 as a whole.


Luteinizing hormone-induced expression of Ptger4b, a prostaglandin E2 receptor indispensable for ovulation of the medaka Oryzias latipes, is regulated by a genomic mechanism involving nuclear progestin receptor.
We previously reported that the prostaglandin E2 receptor subtype Ptger4b plays a role in ovulation in a teleost species, medaka and that ptger4b mRNA is drastically induced in preovulatory follicles prior to ovulation. The present study focuses on the hormonal regulation of ptger4b mRNA expression using this nonmammalian vertebrate model. Preovulatory follicles that had not been exposed to luteinizing hormone (Lh) in vivo were incubated in vitro with medaka recombinant Lh (rLh), which induced the ptger4b mRNA expression. The addition of trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase, strongly inhibited rLh-induced ptger4b expression, and trilostane-suppressed ptger4b expression was restored to the level observed in rLh-treated follicles when 17alpha, 20beta-dihydroxy-4-pregnen-3-one was included in the culture. We determined that the expression of the progestin-activated transcription factor nuclear progestin receptor (Pgr) was also induced by medaka rLh in the follicle and that its expression preceded ptger4b expression. Forskolin treatment induced both pgr and ptger4b mRNA expression in the follicle. Follicular ptger4b mRNA expression was drastically suppressed by RU486, which was demonstrated to compete with 17alpha, 20beta-dihydroxy-4-pregnen-3-one for medaka Pgr in vitro, suggesting a role for Pgr in the expression of ptger4b mRNA. A chromatin immunoprecipitation assay with preovulatory follicles isolated from spawning medaka ovaries demonstrated direct binding of Pgr to the ptger4b promoter. These results indicate that ptger4b expression is regulated by a genomic mechanism involving Pgr.


Caustic design in periodic lattices.
We study curved trajectory dynamics and design in discrete array settings. We find that beams with power law phases produce curved caustics associated with the fold and cusp type catastrophes. A parabolic phase produces a focus that suffers from spherical aberrations. More important, we find that by designing the initial phase or wavefront of the beam we can construct trajectories with pure power law caustics as well as aberration-free focusing of discrete waves.


Cost analysis of type 2 diabetes mellitus treatment in economically developed countries.
There is a growing need to evaluate the factors contributing to the increase in health expenditures, as well as the cost of medicines used in the treatment of Type 2 diabetes mellitus (T2DM) in the economically developed countries. A systematic searching of studies describing the direct cost of T2DM and medicine cost of treating T2DM. The quality of the studies found eligible for this study were assessed using a methodological quality appraisal tool. Nine studies were included in this review. All the included studies had data on direct cost and antidiabetic medicine cost of health care. Mean annual direct cost per person/year ranged between US$220 and US$7600. The two components with the greatest impact on direct cost were found to be medicines and hospitalization. The mean annual medicines cost per person/year was found to range between US$140 and US$2990. There is an increased expenditure on treatment of T2DM. However, it is still not clear how the increased use of antidiabetic medicines is reflected in the overall expenditures. Further, we suggest a more comprehensive understanding of prescription patterns as older drugs are more expensive than the newer drugs, hence they are still under patent.


How Prepared Are Medical and Nursing Students to Identify Common Hazards in the Intensive Care Unit?
Care in the hospital is hazardous. Harm in the hospital may prolong hospitalization, increase suffering, result in death, and increase costs of care. Although the interprofessional team is critical to eliminating hazards that may result in adverse events to patients, professional students' formal education may not prepare them adequately for this role. To determine if medical and nursing students can identify hazards of hospitalization that could result in harm to patients and to detect differences between professions in the types of hazards identified. Mixed-methods observational study of graduating nursing (n = 51) and medical (n = 93) students who completed two "Room of Horrors" simulations to identify patient safety hazards. Qualitative analysis was used to extract themes from students' written hazard descriptions. Fisher's exact test was used to determine differences in frequency of hazards identified between groups. Identification of hazards by students was low: 66% did not identify missing personal protective equipment for a patient on contact isolation, and 58% did not identify a medication administration error (medication hanging for a patient with similar name). Interprofessional differences existed in how hazards were identified: medical students noted that restraints were not indicated (73 vs. 2%, P < 0.001), whereas nursing students noted that there was no order for the restraints (58.5 vs. 0%, P < 0.0001). Nursing students discovered more issues with malfunctioning or incorrectly used equipment than medical students. Teams performed better than individuals, especially for hazards in the second simulation that were similar to those in the first: need to replace a central line with erythema (73% teams identified) versus need to replace a peripheral intravenous line (10% individuals, P < 0.0001). Nevertheless, teams of students missed many intensive care unit-specific hazards: 54% failed to identify the presence of pressure ulcers; 85% did not notice high tidal volumes on the ventilator; and 90% did not identify the absence of missing spontaneous awakening/breathing trials and absent stress ulcer prophylaxis. Graduating nursing and medical students missed several hazards of hospitalization, especially those related to the intensive care unit. Orientation for residents and new nurses should include education on hospitalization hazards. Ideally, this orientation should be interprofessional to allow appreciation for each other's roles and responsibilities.


Progressive loss of cones in achromatopsia: an imaging study using spectral-domain optical coherence tomography.
Achromatopsia (ACHM) is a congenital autosomal recessive cone disorder with a presumed stationary nature and only a few causative genes. Animal studies suggest that ACHM may be a good candidate for corrective gene therapy. Future implementation of this therapy in humans requires the presence of viable cone cells in the retina. In this study the presence of cone cells in ACHM was determined, as a function of age. The appearance and thickness of all retinal layers were evaluated by spectral-domain optical coherence tomography (SD-OCT) in 40 ACHM patients (age range, 4-70 years) with known mutations in the CNGB3, CNGA3, and PDE6C genes. A comparison was made with 55 healthy age-matched control subjects. The initial feature of cone cell decay was loss of inner and outer segments with disruption of the ciliary layer on OCT, which was observed as early as 8 years of age. Cone cell loss further progressed with age and occurred in 8 (42%) of 19 patients below 30 years and in 20 (95%) of 21 of those aged 30+ years. Retinal thickness was significantly thinner in the fovea of all patients (126 μm in ACHM vs. 225 μm in the control; P < 0.001) and correlated with age (β = 0.065; P = 0.011). Foveal hypoplasia was present in 24 (80%) of 30 patients and in 1 of 55 control subjects. ACHM is not a stationary disease. The first signs of cone cell loss occur in early childhood. If intervention becomes available in the future, the present results imply that it should be applied in the first decade.


Continuous cerebral blood flow autoregulation monitoring in patients undergoing liver transplantation.
Clinical monitoring of cerebral blood flow (CBF) autoregulation in patients undergoing liver transplantation may provide a means for optimizing blood pressure to reduce the risk of brain injury. The purpose of this pilot project is to test the feasibility of autoregulation monitoring with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) in patients undergoing liver transplantation and to assess changes that may occur perioperatively. We performed a prospective observational study in 9 consecutive patients undergoing orthotopic liver transplantation. Patients were monitored with TCD and NIRS. A continuous Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity and between MAP and NIRS data, rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Both Mx and COx were averaged and compared during the dissection phase, anhepatic phase, first 30 min of reperfusion, and remaining reperfusion phase. Impaired autoregulation was defined as Mx ≥ 0.4. Autoregulation was impaired in one patient during all phases of surgery, in two patients during the anhepatic phase, and in one patient during reperfusion. Impaired autoregulation was associated with a MELD score >15 (p = 0.015) and postoperative seizures or stroke (p < 0.0001). Analysis of Mx categorized in 5 mmHg bins revealed that MAP at the lower limit of autoregulation (MAP when Mx increased to ≥ 0.4) ranged between 40 and 85 mmHg. Average Mx and average COx were significantly correlated (p = 0.0029). The relationship between COx and Mx remained when only patients with bilirubin >1.2 mg/dL were evaluated (p = 0.0419). There was no correlation between COx and baseline bilirubin (p = 0.2562) but MELD score and COx were correlated (p = 0.0458). Average COx was higher for patients with a MELD score >15 (p = 0.073) and for patients with a neurologic complication than for patients without neurologic complications (p = 0.0245). These results suggest that autoregulation is impaired in patients undergoing liver transplantation, even in the absence of acute, fulminant liver failure. Identification of patients at risk for neurologic complications after surgery may allow for prompt neuroprotective interventions, including directed pressure management.


Synthesis and Electrocatalytic HER Studies of Carbene-Ligated Cu3-xP Nanocrystals.
N-heterocyclic carbenes (NHCs) are an important class of ligands capable of making strong carbon-metal bonds. Recently, there has been a growing interest in the study of carbene-ligated nanocrystals, primarily coinage metal nanocrystals, which have found application as catalysts for numerous reactions. The general ability of NHC ligands to positively affect the catalytic properties of other types of nanocrystal catalysts remains unknown. Herein, we present the first carbene-stabilized Cu3-xP nanocrystals. Inquiries into the mechanism of formation of NHC-ligated Cu3-xP nanocrystals suggest that crystalline Cu3-xP forms directly as a result of a high-temperature metathesis reaction between a tris(trimethylsilyl)phosphine precursor and an NHC-CuBr precursor, the latter of which behaves as a source of both the carbene ligand and Cu+. To study the effect of the NHC surface ligands on the catalytic performance, we tested the electrocatalytic hydrogen evolving ability of the NHC-ligated Cu3-xP nanocrystals and found that they possess superior activity to analogous oleylamine-ligated Cu3-xP nanocrystals. Density functional theory calculations suggest that the NHC ligands minimize unfavorable electrostatic interactions between the copper phosphide surface and H+ during the first step of the hydrogen evolution reaction, which contributes to the superior performance of NHC-ligated Cu3-xP catalysts as compared to oleylamine-ligated Cu3-xP catalysts.


Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury.
Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.


Protective effects of buckwheat honey on DNA damage induced by hydroxyl radicals.
To understand the antioxidant properties of buckwheat honeys, we investigated their antioxidant effects on hydroxyl radical-induced DNA breaks in the non-site-specific and site-specific systems, the physicochemical properties, antioxidant activities (1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical scavenging activity, chelating, and reducing power assays), total phenolic content and individual phenolic acids were also determined. Total phenolic content of buckwheat honeys ranged from 774 to 1694 mg PA/kg, and p-hydroxybenzoic and p-coumaric acids proved to be the main components in buckwheat honeys. All the buckwheat honey samples possess stronger capability to protect DNA in the non-site-specific systems than in the site-specific systems from being damaged by hydroxyl radicals. In the non-site-specific and site-specific system, buckwheat honeys samples prevented ()OH-induced DNA breaks by 21-78% and 5-31% over control value, respectively.


Crystal structure of human thimet oligopeptidase provides insight into substrate recognition, regulation, and localization.
Thimet oligopeptidase (TOP) is a zinc metallopeptidase that metabolizes a number of bioactive peptides and degrades peptides released by the proteasome, limiting antigenic presentation by MHC class I molecules. We present the crystal structure of human TOP at 2.0-A resolution. The active site is located at the base of a deep channel that runs the length of the elongated molecule, an overall fold first seen in the closely related metallopeptidase neurolysin. Comparison of the two related structures indicates hinge-like flexibility and identifies elements near one end of the channel that adopt different conformations. Relatively few of the sequence differences between TOP and neurolysin map to the proposed substrate-binding site, and four of these variable residues may account for differences in substrate specificity. In addition, a loop segment (residues 599-611) in TOP differs in conformation and degree of order from the corresponding neurolysin loop, suggesting it may also play a role in activity differences. Cysteines thought to mediate covalent oligomerization of rat TOP, which can inactivate the enzyme, are found to be surface-accessible in the human enzyme, and additional cysteines (residues 321,350, and 644) may also mediate multimerization in the human homolog. Disorder in the N terminus of TOP indicates it may be involved in subcellular localization, but a potential nuclear import element is found to be part of a helix and, therefore, unlikely to be involved in transport. A large acidic patch on the surface could potentially mediate a protein-protein interaction, possibly through formation of a covalent linkage.


The role of eukaryotic subtilisin-like endoproteases for the activation of human immunodeficiency virus glycoproteins in natural host cells.
Proteolytic activation of the precursor envelope glycoproteins gp160 of human immunodeficiency virus type 1 (HIV-1) and gp140 of HIV-2, a prerequisite for viral infection, results in the formation of gp120/gp41 and gp125/gp36, respectively. Cleavage is mediated by cellular proteases. Furin, a member of the eukaryotic subtilisin family, has been shown to be an activating protease for HIV. Here, we compared the presence of furin and other mammalian subtilisins in lymphatic cells and tissues. Northern blot analyses revealed that furin and the recently discovered protease LPC/PC7 were the only subtilisin-like enzymes transcribed in such cells. Furin was identified as an enzymatically active endoprotease present in different lymphocytic, as well as monocytic, cell lines. When expressed from vaccinia virus vectors, the proprotein convertases were correctly processed, transported, and secreted into the media and enzymatically active. Coexpression of different subtilisins with the HIV envelope precursors revealed that furin and LPC/PC7 are able to cleave HIV-1 gp160. Moreover, both enzymes proteolytically processed the envelope precursor of HIV-2. gp140 was also cleaved to some extent by PC1, which is not, however, present in lymphatic cells. Furin- and LPC/PC7-catalyzed cleavage of HIV-1 gp160 resulted in biologically active envelope protein. In conclusion, among the known members of the subtilisin family, only furin and LPC/PC7 fulfill the requirements of a protease responsible for in vivo activation of HIV envelope glycoproteins.


Ultrafast papanicolaou stain modified for developing countries: efficacy and pitfalls.
To study the efficacy of the ultrafast Papanicolaou (UFP) staining technique for immediate cytologic diagnosis, to check specimen adequacy during radiologically guided fine needle aspiration cytology (FNAC) procedures and to objectively assess the quality of UFP stain and factors affecting it. Serial and random samples of cytologic material from 347 patients during a 2-year period were divided in 3 groups. Group I included 238 outpatient FNACs, group II included 59 radiologically guided FNACs, and group III included 50 cases of intraoperative cytology. After staining air-dried smears with UFP stain, immediate diagnosis was given. In group II, material adequacy was also conveyed to the radiologist. Overall diagnosis was possible in 297 (85.6%) cases. Only 8 (2.3%) cases could not be diagnosed due to staining difficulties. The overall concordance rate was 98%. Seventy-five percent of cases showed 'excellent' and 'good' morphology, allowing easy diagnosis. In 25% of 'fair' cases diagnosis was still possible, although with some difficulties. Factors affecting the quality of staining are discussed. The UFP staining technique is an accurate and reliable method for rapid cytology reporting. It significantly reduces total turn around time of the test result, thereby having the potential to be cost-effective, both for the patient and the hospital.


Developing medical device software in compliance with regulations.
In the last decade, the use of information technology (IT) in healthcare has taken a growing role. In fact, the adoption of an increasing number of computer tools has led to several benefits related to the process of patient care and allowed easier access to social and health care resources. At the same time this trend gave rise to new challenges related to the implementation of these new technologies. Software used in healthcare can be classified as medical devices depending on the way they are used and on their functional characteristics. If they are classified as medical devices they must satisfy specific regulations. The aim of this work is to present a software development framework that can allow the production of safe and high quality medical device software and to highlight the correspondence between each software development phase and the appropriate standard and/or regulation.


Directional motion asymmetry in infant VEPs--which direction?
Monocular viewing during early infancy reveals asymmetries in optokinetic nystagmus (OKN) and visual evoked potentials (VEPs). This study investigates the VEP asymmetry to see if it is consistent in direction with the OKN asymmetry. Steady-state VEPs were recorded from infants (5-21 weeks) viewing gratings that underwent successive displacements in the same direction, leftward or rightward. In addition, transient VEPs were recorded to the two directions of an oscillating stimulus. Both tests produced larger VEP amplitudes for nasal-to-temporal compared to temporal-to-nasal movement. Horizontal eye movements were monitored by EOG while viewing these stimuli to test whether the asymmetry was a consequence of eye movements. No difference in eye movements as a function of the stimulus was found, excluding differences in retinal slip as an explanation of the asymmetry. The stronger neural response for nasal-to-temporal displacements is opposite to the asymmetry of OKN. Oculomotor and VEP asymmetries may be related; however this relationship is not simply that the stronger neural response, indicated by the VEP, leads to a stronger optokinetic response.


"It's common sense that it's wrong": young people's perceptions and experiences of cyberbullying.
The use of the Internet, mobile phones, and social networking sites by some young people to harass and intimidate each other has led cyberbullying to become a significant concern for parents, educators, and policy makers. The existing literature on this behavior is largely quantitative, with only a small number of qualitative studies addressing this issue. This study examined perceptions and experiences of cyberbullying in a series of 18 focus groups conducted with young people aged 9-19 in the UK. The results suggest that cyberbullying is perceived to be problematic and serious but relatively routine part of young people's online lives and interactions. The results also highlighted the influence of the characteristics of technologically mediated communication on the dynamics of the behavior. The role of anonymity in determining victim-perpetrator relationships and the seriousness of the behavior was discussed by participants, though the influence of disinhibition and inability to view the direct impact of victimization were perceived to be of greater importance. The implications of the results are discussed, and areas for future research suggested.


Breast cancer mortality in black and in white women: a historical perspective by menopausal status.
To examine racial/ethnic differences in breast cancer mortality over time by menopausal status, data from published U.S. Vital Statistics tables (1950-1992) and the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute (1973-1991) were used to calculate age-adjusted breast cancer mortality and incidence rates. Overall, breast cancer mortality rates for white women were relatively stable from 1950 to 1992. In contrast, breast cancer mortality rates for black women increased during this period. Among premenopausal women there was no difference in breast cancer mortality between black and white women from 1950 to about 1975. However, after 1975, mortality rates in black premenopausal women increased, whereas those in white women decreased. Among postmenopausal women, breast cancer mortality was substantially lower in blacks than in whites in 1950. Between 1950 and 1992, rates in blacks increased and eventually exceeded rates in whites, which remained stable during this period. This excess in breast cancer mortality in black women is not explained by changes in breast cancer incidence rates. There is an unexplained epidemic of breast cancer mortality in black women that appears to differ somewhat by menopausal status. Reasons for temporal increases in breast cancer mortality seen only among black women need to be identified, as do reasons for the heterogeneity of trends by menopausal status.


Ethnic differences in sexual dysfunction among diabetic and nondiabetic males: the Oxford Sexual Dysfunction Study.
Erectile dysfunction (ED), premature ejaculation (PE), and reduced libido are common yet poorly investigated complications of diabetes especially among South Asians (SA). To determine possible variations in prevalence and interassociations of ED, PE, and reduced libido among SA and Europids with and without diabetes. Men with diabetes and a randomly selected sample of age-matched nondiabetic men from 25 general practitioners in eight primary care trusts in the United Kingdom were invited to participate in a linguistically validated questionnaire-based study in English, Hindi, Urdu, Panjabi, Tamil, and Sinhala languages. ED, assessed by International Index of Erectile Function (IIEF-5), PE, evaluated using the Premature Ejaculation Diagnostic Tool, and libido, assessed by asking participants to grade their desire for sexual activity. Sample size was 510 (SA: 184, Europid: 326). Mean age was 56.9 ± 9.7 years. There was no difference in erectile function when assessed by IIEF between SA and Europids with diabetes (84.8% and 84.1%, respectively). The overall prevalence of PE was 28.8% (32.6% and 25.8% in those with and without diabetes, respectively, P = NS). Among men with diabetes, the prevalence of PE was 45.8% and 22.4% for SA and Europids, respectively (P < 0.001). In those without diabetes, this figure was 41.9% in SA and 20.2% in Europids (P < 0.001). There was a significant trend of increasing prevalence of PE with increasing severity grade of ED (P < 0.001). Reduced libido was reported by 26.9% men (32.8% and 22.0% in those with and without diabetes, respectively, P < 0.01), with no significant ethnic difference. The association between reduced libido and increasing severity grades of ED was also significant (P < 0.001). No significant difference was observed in the prevalence of ED between SA and Europid men with diabetes. PE was significantly more common in the SA men irrespective of their diabetes status.


Clinical Performance of the AllplexTM Respiratory Panel 1 Test Compared to SimplexaTM Flu A/B and RSV for Detection of Influenza Virus and Respiratory Syncytial Virus Infection Including Their Subtyping.
TheAllplexTM Respiratory Panel 1 (ARP) is a new assay based on a real-time polymerase chain reaction (RT-PCR) for the detection of influenza A (Flu A), influenza B virus (Flu B), and respiratory syncytial virus (RSV), including subtyping by multiple detection temperature (MuDT) technology. We evaluated the performance of the Allplex Respiratory Panel compared to the SimplexaTM Flu A/B & RSV assay (SP) and other diagnostic tools. A total of 372 samples were collected from patients at the Korea University Guro Hospital in Seoul, Korea. All samples were tested for influenza virus and RSV by ARP, SP, and an in-house RT-PCR. The sensitivity of ARP was 95.56, 100, and 95.24% for Flu A, Flu B, and RSV, respectively. The specificity of ARP was 100, 100, and 100% for Flu A, Flu B, and RSV, respectively. SP had sensitivities and specificities of 98.89 and 100% for Flu A, 100 and 100% for Flu B, and 100 and 100% for RSV. The Allplex panelshowed high sensitivity, specificity, positive predictive, and negative predictive values for the detection of Flu A, Flu B, and RSV. This assay is fast and easy to perform because it takes only about 150 min and there is no need for post-PCR electrophoresis. The ARP can be used as a reliable and convenient assay in clinical laboratories.


Proteogenomic definition of biomarkers for the large Roseobacter clade and application for a quick screening of new environmental isolates.
Whole-cell, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has become a routine and reliable method for microbial characterization due to its simplicity, low cost, and high reproducibility. The identification of microbial isolates relies on the spectral resemblance of low-molecular-weight proteins to already-existing isolates within the databases. This is a gold standard for clinicians who have a finite number of well-defined pathogenic strains but represents a problem for environmental microbiologists with an overwhelming number of organisms to be defined. Here we set a milestone for implementing whole-cell MALDI-TOF mass spectrometry to identify isolates from the biosphere. To make this technique accessible for environmental studies, we propose to (i) define biomarkers that will always show up with an intense m/z signal in the MALDI-TOF spectra and (ii) create a database with all the possible m/z values that these biomarkers can generate to screen new isolates. We tested our method with the relevant marine Roseobacter lineage. The use of shotgun nanoLC-MS/MS proteomics on the small proteome fraction of nine Roseobacter strains and the proteogenomic toolbox helped us to identify potential biomarkers in terms of protein abundance and low variability among strains. We show that the DNA binding protein, HU, and the ribosomal proteins, L29 and L30, are the most robust biomarkers within the Roseobacter clade. The molecular weights of these three biomarkers, as for other conserved homologous proteins, vary due to sequence variation above the genus level. Therefore, we calculated the m/z values expected for each one of the known Roseobacter genera and tested our strategy during an extensive screening of natural marine isolates obtained from coastal waters of the Western Mediterranean Sea. The use of this technique versus standard sequencing methods is discussed.


Dental fear among transgender individuals - a cross-sectional survey.
The aims of this study were to: (1) evaluate the level of dental fear among transgender individuals and (2) investigate specific predictors of dental fear in individuals who identify as transgender. An anonymous survey among transgender adults was conducted using both a web-based and paper survey. The survey included the Dental Fear Survey (DFS), history of hormonal interventions, perceived gender roles, and demographic information. The bivariate analyses did not show a significant difference in DFS between sex assigned at birth (p = 0.628) or among gender identities (p = 0.109). A regression model analysis for the level of DFS by using participants' demographic information as independent variables indicated the fear and experience of discrimination/maltreatment were significant predictors of dental fear; standardized beta coefficients (p-value) were 0.35 (p = 0.017) and 0.28 (p = 0.041), respectively. The fear and experiences of discrimination/maltreatment were significantly positively associated with their level of dental fear.


Non-Traumatic Spontaneous Spinal Subdural Hematoma in a Patient with Non-Valvular Atrial Fibrillation During Treatment with Rivaroxaban.
Spontaneous spinal subdural hematoma (SSDH) is a rare but disabling condition, accounting for only 4.1% of all intraspinal hematomas. Risk factors include arteriovenous malformations, coagulopathy, therapeutic anticoagulation, underlying neoplasms, or following spinal puncture. Vitamin K antagonists, antiplatelet agents, and heparinoids have been associated with SSDHs in prior reports. To the best of our knowledge, no cases have reported this association with the factor Xa inhibitor, rivaroxaban, and SSDHs. We report the case of a 69-year-old Honduran man with a 5-year history of symptomatic palpitations due to non-valvular atrial fibrillation. He was initially refractory to pharmacologic therapy. He underwent cardioversion in February 2014. After cardioversion, he remained asymptomatic on flecainide. He was anticoagulated on rivaroxaban 20 mg daily without incident since early 2013 until presentation in August 2014. He presented with sudden onset of excruciating upper and lower back pain after minimal movement. This was immediately followed by bilateral lower extremity paresis rapidly progressing to paraplegia with bowel and bladder dysfunction over 15 minutes. Magnetic resonance imaging demonstrated an acute spinal subdural hematoma extending from T3 inferiorly to the conus medullaris. Six months after undergoing cervical and lumbar drainage procedures, he has not recovered bowel, bladder, or lower extremity neurologic function. Non-traumatic spontaneous spinal subdural hematoma is a rare neurological emergency that may occur during the use of rivaroxaban in patients with non-valvular atrial fibrillation. Physicians should suspect SSDH in patients on rivaroxaban with acute onset of severe back pain and neurologic symptoms to improve the odds of a favorable outcome.


Isolation and analysis of eight exe genes and their involvement in extracellular protein secretion and outer membrane assembly in Aeromonas hydrophila.
The exeE gene of Aeromonas hydrophila has been shown to be required for the secretion of most if not all of the extracellular proteins produced by this bacterium. In addition, an exeE::Tn5-751 insertion mutant of A. hydrophila was found to be deficient in the amounts of a number of its major outer membrane proteins (B. Jiang and S. P. Howard, J. Bacteriol. 173:1241-1249, 1991). The exeE gene and the exeF gene were previously isolated as part of a fragment which complemented this mutant. In this study, we have isolated and sequenced a further eight exe genes, exeG through exeN, which constitute the 3' end of the exe operon. These genes have a high degree of similarity with the extracellular secretion operons of a number of different gram-negative bacteria. Marker exchange mutagenesis was used to insert kanamycin resistance cassettes into three different regions of the exe operon. The phenotypes of these mutants showed that in A. hydrophila this operon is required not only for extracellular protein secretion but also for normal assembly of the outer membrane, in particular with respect to the quantities of the major porins. Five of the Exe proteins contain type IV prepilin signal sequences, although the prepilin peptidase gene does not appear to form part of the exe operon. Limited processing of the ExeG protein was observed when it was expressed in Escherichia coli, and this processing was greatly accelerated in the presence of the prepilin peptidase of Pseudomonas aeruginosa.


Broadband ringdown spectral photography.
A new technique that enables frequency-resolved cavity ringdown absorption spectra to be obtained over a large optical bandwidth by a single laser shot is described. The technique, ringdown spectral photography (RSP), simultaneously employs two key principles to record the time and frequency response of an optical cavity along orthogonal axes of a CCD array detector. Previously, the principles employed in RSP were demonstrated with narrow-band laser light that was scanned in frequency [Chem. Phys. Lett. 292, 143 (1998)]. Here, the RSP method is demonstrated using single pulses of broadband visible laser light. The ability to obtain broad as well as rotationally resolved spectra over a large bandwidth with high sensitivity is demonstrated.


Fungicidal action of geraniol against Candida albicans is potentiated by abrogated CaCdr1p drug efflux and fluconazole synergism.
Among the several mechanisms of multidrug resistance (MDR), overexpression of drug efflux pumps CaCdr1p and CaMdr1p belonging to ATP binding cassette (ABC) and major facilitator superfamily (MFS) respectively remain the predominant mechanisms of candidal infections. Therefore inhibiting or modulating the function of these transporters continues to draw attention as effective strategy to combat MDR. We have previously reported the antifungal potential of Geraniol (Ger), a natural monoterpenoid from Palmarosa oil, against Candida albicans. Herein, we explored the fungicidal nature of Ger. The Rhodamine 6G (R6G) and Nile red accumulation confirms the specific effect on CaCdr1p. Mechanistic insights with Candida cells overexpressing CaCdr1p and CaMdr1p revealed that Ger specifically modulates CaCdr1p activity. Kinetic studies further unraveled the competitive inhibition of Ger for R6G efflux as evident from increased apparent Km without affecting Vmax value. The effect of Ger on CaCdr1p was substantiated by molecular docking analyses, which depicted in-silico binding affinity of Ger with CaCdr1p and explored that Ger binds to the active site of CaCdr1p with higher binding energy. Although RT-PCR and western blot revealed no change in expressions of CDR1 and CaCdr1p, confocal microscopy images however depicted CaCdr1p mislocalization in presence of Ger. Interestingly, Ger was synergistic (FICI<0.5) with fluconazole (FLC) which is a well known antifungal drug. Furthermore, Ger sensitizes the FLC sensitive and resistant clinical matched pair of isolates Gu4/Gu5 and led to abrogated R6G efflux and depleted ergosterol. Furthermore, Rhodamine B labeling demonstrates altered mitochondrial potential with Ger which suggest possible linkage of dysfunctional mitochondria with CaCdr1p activity. We also estimated phenotypic virulence marker extracellular phospholipase activity which was considerably diminished along with inhibited cell adherence and biofilm biomass. Lastly, antifungal efficacy of Ger was demonstrated by enhanced survival of Caenorhabditis elegans model and negligible hemolytic activity (20%). Together, modulation of efflux pump activity by Ger and FLC synergism represent a promising approach for combinatorial treatment of candidiasis.


Carboxysomal carbonic anhydrases: Structure and role in microbial CO2 fixation.
Cyanobacteria and some chemoautotrophic bacteria are able to grow in environments with limiting CO(2) concentrations by employing a CO(2)-concentrating mechanism (CCM) that allows them to accumulate inorganic carbon in their cytoplasm to concentrations several orders of magnitude higher than that on the outside. The final step of this process takes place in polyhedral protein microcompartments known as carboxysomes, which contain the majority of the CO(2)-fixing enzyme, RubisCO. The efficiency of CO(2) fixation by the sequestered RubisCO is enhanced by co-localization with a specialized carbonic anhydrase that catalyzes dehydration of the cytoplasmic bicarbonate and ensures saturation of RubisCO with its substrate, CO(2). There are two genetically distinct carboxysome types that differ in their protein composition and in the carbonic anhydrase(s) they employ. Here we review the existing information concerning the genomics, structure and enzymology of these uniquely adapted carbonic anhydrases, which are of fundamental importance in the global carbon cycle.


Bone and Soft Tissue Turnover in Relation to All-cause Mortality in Postmenopausal Women.
The relationship between levels of extracellular matrix (ECM) turnover and mortality is currently unknown. The study aimed to determine if levels of ECM turnover are predictors of all-cause mortality in a large cohort of postmenopausal women. 5,855 postmenopausal Danish women enrolled in the Prospective Epidemiologic Risk Factor (PERF) study. Baseline demographics and serum were collected at registration. Dates of death were obtained from the Danish Death Registry. ECM turnover was evaluated by serological biomarkers measuring bone (telopeptide of type I collagen [CTX-1] and osteocalcin) and soft tissue (formation of type VI collagen [PRO-C6], MMP-degraded type IV collagen [C4M], formation of type III collagen [PRO-C3], and MMP-degraded type I collagen [C1M]) turnover. Multivariate Cox analyses were performed with 3, 5, and 15 years of follow-up. The association of bone turnover (CTX-1 and osteocalcin) with all-cause mortality was U-shaped for all time periods. After adjustment for possible confounders, the lowest quintile of bone formation and degradation remained significant for all time periods. We observed J-shaped association between all-cause mortality and PRO-C6, C4M, and PRO-C3, and there was a linear association between C1M and all-cause mortality. After adjustment for possible confounders, the highest quintile of the soft tissue turnover biomarkers (PRO-C6, C4M, PRO-C3, and C1M) remained significantly associated with all-cause mortality for all time periods. Both low and high levels of tissue turnover were associated with increased risk of all-cause mortality in postmenopausal women. Overall, these results highlight the importance of bone and soft tissue homeostasis.


Virtual reality: immersive hepatic surgery educational environment.
Understanding the spatial relationships among the liver segments, and intrahepatic portal and hepatic veins is essential for surgical treatment of liver diseases. Teleimmersive virtual reality enables improved visualization over conventional media because it supports stereo vision, viewer-centered perspective, large angles of view, and interactivity with remote locations. We report a successful pilot study teaching hepatic surgical principles using teleimmersion. We developed a teleimmersive environment for teaching with biomedical models including virtual models of the liver segments and portal and hepatic veins. Using the environment, 1 instructor gave a workshop to 6 senior general surgery residents at 2 physical locations. A 24-question (36-point) examination was administered before and after the workshop. The workshop produced significant improvements in the mean test scores between the pretests and posttests (17.67 to 23.67, P <.02). We found no differences between residents who were with the instructor and those at the remote location. Six-month delayed testing demonstrated complete retention of new knowledge. The teleimmersive environment enabled surgeons to overcome some of the barriers to teaching complex surgical anatomic principles. Using teleimmersive environments, surgical educators and trainees can interact from locations worldwide using virtual anatomic information to achieve their educational goals.


Microvascular Decompression for Trigeminal Neuralgia Using a Novel Fenestrated Clip and Tentorial Flap Technique.
Microvascular decompression (MVD) for neurovascular compression syndromes, such as trigeminal neuralgia and hemifacial spasm, has been traditionally described as an interposing technique using Teflon. Some alternative interposing materials have been proposed. In addition, transposing techniques have been increasingly reported as an alternative with a potentially lower recurrence rate and fewer complications. To describe our experience with a technique consisting of transposition of the superior cerebellar artery using a fenestrated clip and a tentorial flap in patients with trigeminal neuralgia. We describe a novel transposing technique using a fenestrated clip and a tentorial flap in patients with neurovascular compression. An illustrative case is provided of an 83-year-old female patient who complained of a 4-year history of left trigeminal neuralgia caused by compression by the superior cerebellar artery who was treated with this technique. Furthermore, a thorough review of the literature is presented. The patient underwent the procedure with the proposed technique without complication. Both the surgery and the postoperative course were uneventful. The patient remains asymptomatic 1 year after the procedure. We propose a novel technique for the treatment of trigeminal neuralgia, eliminating the need for padding the vessel with a foreign body. This technique can be applied successfully in selected cases of neurovascular compression syndromes.


Soft-Sphere Continuum Solvation in Electronic-Structure Calculations.
We present an implicit solvation approach where the interface between the quantum-mechanical solute and the surrounding environment is described by a fully continuous permittivity built up with atomic-centered "soft" spheres. This approach combines many of the advantages of the self-consistent continuum solvation model in handling solutes and surfaces in contact with complex dielectric environments or electrolytes in electronic-structure calculations. In addition it is able to describe accurately both neutral and charged systems. The continuous function, describing the variation of the permittivity, allows to compute analytically the nonelectrostatic contributions to the solvation free energy that are described in terms of the quantum surface. The whole methodology is computationally stable, provides consistent energies and forces, and keeps the computational efforts and runtimes comparable to those of standard vacuum calculations. The capabilitiy to treat arbitrary molecular or slab-like geometries as well as charged molecules is key to tackle electrolytes within mixed explicit/implicit frameworks. We show that, with given, fixed atomic radii, two parameters are sufficient to give a mean absolute error of only 1.12 kcal/mol with respect to the experimental aqueous solvation energies for a set of 274 neutral solutes. For charged systems, the same set of parameters provides solvation energies for a set of 60 anions and 52 cations with an error of 2.96 and 2.13 kcal/mol, respectively, improving upon previous literature values. To tackle elements not present in most solvation databases, a new benchmark scheme on wettability and contact angles is proposed for solid-liquid interfaces and applied to the investigation of the stable terminations of a CdS (112̅0) surface in an electrochemical medium.