Static pressure-flow relation in the total systemic vascular bed of the dog and its modification by the baroreceptor reflex.
To evaluate arterial baroreceptor reflex control of total systemic vascular resistance, we studied the relation between mean arterial blood pressure (P) and mean aortic flow (Q) before and after the reflex was abrogated. In 12 dogs with a perfusion pump interposed at the vena-caval-right atrial junction, Q was kept at 60, 80, 100, 120, and 140 ml/min kg-1 for up to 20 minutes. There was little time-dependent change in P at any of these flows. When the reflex was intact, the mean P-Q curve was only slightly convex to the pressure axis; its linearized slope was 0.55 mm Hg-min-kg/ml and its pressure axis intercept was 44 mm Hg. After section of the sinovagal nerves, administration of hexamethonium (30 mg/kg, iv) and norepinephrine (3-5 mug/kg min-1, iv), or both, the slope became 0.96 mm Hg-min-kg/ml and the pressure axis intercept was about 3 mm Hg. Similar findings were obtained in 3 closed-chest dogs in which P was servocontrolled and Q was measured. Therefore, we think that the conventional practice of calculating total peripheral resistance as P/Q and evaluating reflex control of it in terms of the changes in that value involves only a small error in the moderately sub -and supranormal flow range.


Prevalence of AIDS-related risk factors and condom use in the United States.
A national probability survey of human immunodeficiency virus (HIV)-related risk factors among the general heterosexual population, the National AIDS (acquired immunodeficiency syndrome) Behavioral Surveys, has obtained data from 10,630 respondents. Data are presented on the prevalence of HIV-related risks in the general heterosexual population, on the distribution of the three largest risk groups across social strata, and on the prevalence and distribution of condom use among heterosexuals reporting a risk factor. Between 15 and 31 percent of heterosexuals nationally and 20 and 41 percent in cities with a high prevalence of AIDS reported an HIV risk factor. Condom use was relatively low. Only 17 percent of those with multiple sexual partners, 12.6 percent of those with risky sexual partners, and 10.8 percent of untested transfusion recipients used condoms all the time. Overall, the results suggest that current HIV prevention programs have, to a very limited extent, reached those heterosexuals with multiple sexual partners but have failed to reach many other groups of the heterosexual population at risk for HIV. New public health strategies may be needed for these specific risk groups.


Efficiency-enhanced optical parametric down conversion for mid-infrared generation on a tandem periodically poled MgO-doped stoichiometric lithium tantalate chip.
We report an efficiency-enhanced mid-infrared generation via optical parametric down conversion. A tandem periodically-poled MgO-doped stoichiometric lithium tantalate crystal is used to realize on-chip generation and amplification of mid-infrared radiation inside an optical parametric oscillator cavity. We achieved 21.2% conversion efficiency (24% slope efficiency), which is among the highest efficiencies for the pump-to-mid-infrared conversion, with 1064 nm Nd class laser pump. The maximum average output power at 3.87 μm reached 635 mW with a 3.0 W pump.


Volatile Compounds with Characteristic Odor of Essential Oil from Magnolia obovata Leaves by Hydrodistillation and Solvent-assisted Flavor Evaporation.
The present study focuses on the volatile compounds with characteristic odor of essential oil from the leaves of Magnolia obovata by hydrodistillation (HD) and solvent-assisted flavor evaporation (SAFE) method. Eighty-seven compounds, representing 98.0% of the total oil, were identified using HD. The major compounds of HD oil were (E)-β-caryophyllene (23.7%), α-humulene (11.6%), geraniol (9.1%), and borneol (7.0%). In SAFE oil, fifty-eight compounds, representing 99.7% of the total oil, were identified. The main compounds of SAFE oil were (E)-β-caryophyllene (48.9%), α-humulene (15.7%), and bicyclogermacrene (4.2%). In this study, we newly identified eighty-five compounds of the oils from M. obovata leaves. These oils were also subjected to aroma evaluation by gas chromatography-olfactometry (GC-O) and aroma extract dilution analysis (AEDA). As a result, twenty-four (HD) and twenty-five (SAFE) aroma-active compounds were detected. (E)-β-Caryophyllene, α-humulene, linalool, geraniol, 1,8-cineole, and bicyclogermacrene were found to impart the characteristic odor of M. obovata leaves. These results imply that the oils of M. obovata leaves must be investigated further to clarify their potential application in the food and pharmaceutical industries.


Neural effects of the social environment.
Epidemiological studies have suggested that the association between city upbringing and minority status with risk for schizophrenia can be explained by social mechanisms. Neuroimaging approaches hold promise for investigating this claim. Recent studies have shown that in healthy individuals, city upbringing and minority status are associated with increased activity in brain circuits involved in emotion regulation during social evaluative processing. These findings support the hypothesis that changes in the ability to regulate social stress contribute to the mechanism of risk. This is in accordance with a body of evidence demonstrating the sensitivity of the human brain to social stress, based on observational studies investigating the neurological sequelae of interpersonal trauma and experimental studies manipulating exposure to interpersonal distress. In this report, we summarize these initial findings, discuss methodological and conceptual challenges of pursuing this line of inquiry in schizophrenia, and suggest an outline for future research.


Assessing cognitive function and capacity in older adults with cancer.
The number of older individuals with cancer is increasing exponentially, mandating that oncologists contemplate more comprehensive and multidisciplinary approaches to treatment of this cohort. Recruitment of assessment instruments validated in older patients can be invaluable for guiding treatment and decision-making by both patients and providers, and can arguably contribute to improving outcomes and health-related quality of life. The Comprehensive Geriatric Assessment is one such validated instrument that can be used by oncologists to assess patient readiness and appropriateness for prescribed cancer therapy. As a multidisciplinary diagnostic and treatment process, it comprises functional status, cognitive status, social support, and advance care preferences, and is an ideal instrument for evaluating complex older individuals. It is well established that many older individuals with cancer travel with multiple comorbid illnesses, including cognitive impairment, and when presented with a cancer diagnosis struggle to choose from multiple treatment options. In addition to the complete medical history, the ability of patients to decide on a course of therapy in concert with their oncologist is critically important. Alternatively, many oncologists are conflicted as to whether true informed consent for treatment can be obtained from many older patients. Having a roadmap to decision-making capacity is therefore an inescapable imperative in geriatric oncology, because careful attention must be directed at identifying older patients with cancer who might benefit from these assessments and the individualized treatment plans that emerge.


Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial.
Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer. We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9-14·3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths. Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. Ono Pharmaceutical, Bristol-Myers Squibb.


Characterization of a porcine model for associating liver partition and portal vein ligation for a staged hepatectomy.
Publications using the ALPPS (associating liver partition and portal vein ligation for a staged hepatectomy) procedure have demonstrated a future liver remnant growth of 40-160% in only 6-9 days. The present study aimed to develop and describe the first large animal model of ALPPS that can be used for future studies. A total of 13 female domestic pigs underwent ALPPS stage 1 (portal vein division and parenchymal transection) followed by ALPPS stage 2 (completion left-extended hepatectomy) 7 days later. An abdominal computed tomography (CT) scan was performed immediately prior to ALPPS stage 1 surgery and again 7 days later to assess hypertrophy immediately prior to ALPPS stage 2 surgery. Blood samples, as well as tissue analysis for Ki-67, were performed. On CT volumetric analysis, the mean size of the future liver remnant (FLR) prior to ALPPS stage 1 was 21 ± 2% and 40 ± 6% prior to ALPPS stage 2. The median degree of growth was 75% with a mean kinetic growth rate of 11% per day. Liver weights at autopsy correlated well with CT volumetric analysis (r = 0.87). There was no significant difference in mean lab values [asparate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, International Normalized Ratio (INR) or bilirubin] from baseline until immediately prior to ALPPS stage 2. Post ALPPS stage 2 there was a significant increase in INR from baseline 1.1 to 1.6 (P = 0.012). No post-operative deaths secondary to liver failure were observed. The present study describes the first reproducible large animal model of the ALPPS procedure. The degree of liver growth and the kinetic rate of growth were similar to that which has been demonstrated in human publications. This model will be valuable as future laboratory studies are performed.


Specific binding at the cellulose binding module-cellulose interface observed by force spectroscopy.
The need for effective enzymatic depolymerization of cellulose has stimulated an interest in interactions between protein and cellulose. Techniques utilized for quantitative measurements of protein-cellulose noncovalent association include microgravimetry, calorimetry, and atomic force microscopy (AFM), none of which differentiate between specific protein-cellulose binding and nonspecific adhesion. Here, we describe an AFM approach that differentiates nonspecific from specific interactions between cellulose-binding modules (CBMs) and cellulose. We demonstrate that the "mismatched" interaction between murine galectin-3, a lectin with no known affinity for cellulose, and cellulose shows molecular recognition force microscopy profiles similar to those observed during the interaction of a "matched" clostridial CBM3a with the same substrate. We also examine differences in binding probabilities and rupture profiles during CBM-cellulose binding experiments in the presence and absence of a blocking agent-a substrate specific for CBM that presumably blocks binding sites. By comparison of the behavior of the two proteins, we separate specific (i.e., blockable) and nonspecific adhesion events and show that both classes of interaction exhibit nearly identical rupture forces (45 pN at ∼0.4 nN/s). Our work provides an important caveat for the interpretation of protein-carbohydrate binding by force spectroscopy; delineation of the importance of such interactions to other classes of binding warrants further study.


Remembering the forgotten non-communicable diseases.
The forthcoming post-Millennium Development Goals era will bring about new challenges in global health. Low- and middle-income countries will have to contend with a dual burden of infectious and non-communicable diseases (NCDs). Some of these NCDs, such as neoplasms, COPD, cardiovascular diseases and diabetes, cause much health loss worldwide and are already widely recognised as doing so. However, 55% of the global NCD burden arises from other NCDs, which tend to be ignored in terms of premature mortality and quality of life reduction. Here, experts in some of these 'forgotten NCDs' review the clinical impact of these diseases along with the consequences of their ignoring their medical importance, and discuss ways in which they can be given higher global health priority in order to decrease the growing burden of disease and disability.


Formation of carbonates in the Tatahouine meteorite.
The Tatahouine meteorite, in southern Tunisia, shows terrestrial contamination that developed during 63 years of exposure on Earth's surface. Samples collected on the day of the fall in 1931 contained fractures, with no secondary minerals, whereas samples collected in 1994 contain calcite aggregates (70 to 150 micrometers) and rod-shaped forms (100 to 600 nanometers in length and 70 to 80 nanometers in diameter) on the fractures. Carbon isotope analysis of the carbonates within the Tatahouine meteorite [delta13C = -2.0 per mil Pee Dee belemnite standard (PDB)] and the underlying ground (delta13C = -3.2 per mil PDB) confirm their terrestrial origin.


Community contextual predictors of endoscopic colorectal cancer screening in the USA: spatial multilevel regression analysis.
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, and endoscopic screening can both detect and prevent cancer, but utilization is suboptimal and varies across geographic regions. We use multilevel regression to examine the various predictors of individuals' decisions to utilize endoscopic CRC screening. Study subjects are a 100% population cohort of Medicare beneficiaries identified in 2001 and followed through 2005. The outcome variable is a binary indicator of any sigmoidoscopy or colonoscopy use over this period. We analyze each state separately and map the findings for all states together to reveal patterns in the observed heterogeneity across states. We estimate a fully adjusted model for each state, based on a comprehensive socio-ecological model. We focus the discussion on the independent contributions of each of three community contextual variables that are amenable to policy intervention. Prevalence of Medicare managed care in one's neighborhood was associated with lower probability of screening in 12 states and higher probability in 19 states. Prevalence of poor English language ability among elders in one's neighborhood was associated with lower probability of screening in 15 states and higher probability in 6 states. Prevalence of poverty in one's neighborhood was associated with lower probability of screening in 36 states and higher probability in 5 states. There are considerable differences across states in the socio-ecological context of CRC screening by endoscopy, suggesting that the current decentralized configuration of state-specific comprehensive cancer control programs is well suited to respond to the observed heterogeneity. We find that interventions to mediate language barriers are more critically needed in some states than in others. Medicare managed care penetration, hypothesized to affect information about and diffusion of new endoscopic technologies, has a positive association in only a minority of states. This suggests that managed care plans' promotion of this cost-increasing technology has been rather limited. Area poverty has a negative impact in the vast majority of states, but is positive in five states, suggesting there are some effective cancer control policies in place targeting the poor with supplemental resources promoting CRC screening.


Scanning Probe Microwave Reflectivity of Aligned Single-Walled Carbon Nanotubes: Imaging of Electronic Structure and Quantum Behavior at the Nanoscale.
Single-walled carbon nanotubes (SWNTs) are 1-dimensional nanomaterials with unique electronic properties that make them excellent candidates for next-generation device technologies. While nanotube growth and processing methods have progressed steadily, significant opportunities remain in advanced methods for their characterization, inspection, and metrology. Microwave near-field imaging offers an extremely versatile "nondestructive" tool for nanomaterials characterization. Herein, we report the application of nanoscale microwave reflectivity to study SWNT electronic properties. Using microwave impedance microscopy (MIM) combined with microwave impedance modulation microscopy (MIM(2)), we imaged horizontal SWNT arrays, showing the microwave reflectivity from individual nanotubes is extremely sensitive to their electronic properties and dependent on the nanotube quantum capacitance under proper experimental conditions. It is shown experimentally that MIM can be a direct probe of the nanotube-free carrier density and the details of their electronic band structure. We demonstrate spatial mapping of local SWNT impedance (MIM), the density of states (MIM(2)), and the nanotube structural morphology (AFM) simultaneously and with lateral resolution down to <50 nm. Nanoscale microwave reflectivity could have tremendous impact, enabling optimization of enriched growth processes and postgrowth purification of SWNT arrays while aiding in the analysis of the quantum physics of these important 1D materials.


Invasive airway techniques in resuscitation.
Although endotracheal intubation is still the most definitive technique for airway management in patients with cardiac or respiratory arrest, in some emergency care systems, use of endotracheal intubation by prehospital care personnel has been restricted by policy or statute. Therefore, alternative airway devices have been developed. These alternative airway devices include the Esophageal Obturator Airway (EOA) and Esophageal Gastric Tube Airway (EGTA), the Pharyngeotracheal Lumen Airway (PTL), and the Esophageal-Tracheal Combitube (ETC). By examining the available literature concerning these alternative airway devices, we sought to determine 1) if these devices are superior to basic, noninvasive airway techniques (eg, bag-valve-mask ventilation); 2) if they are comparable to endotracheal intubation in terms of ventilation, oxygenation, and potential complications; 3) what the role of these devices should be in prehospital care; and 4) what the best recommendations should be regarding these devices in terms of resuscitation training and future areas for research. The review involved a total of 837 EOA/EGTA, 304 PTL, and 159 ETC study patients. Although ventilation and oxygenation can, in some circumstances, be as good with the EOA/EGTA devices as it is with the endotracheal intubation, in some cases they can be inadequate, and the complication rate is relatively high. Preliminarily, the PTL and the ETC seem to provide adequate ventilation and oxygenation with few complications. However, for both devices, published clinical experience, especially in the prehospital setting, is still limited. Therefore, their use should be left to the discretion of accountable physician directors of applicable resuscitation teams. Regardless of the device used, recognition of proper placement remains the most important aspect of using any invasive airway device. Therefore, proper training and expert medical supervision probably have more influence on the successful use and impact of these devices than any other factors related to the devices themselves. Future training efforts would be most useful if directed at proper endotracheal intubation training and development of improved basic ventilatory skills. Nevertheless, additional controlled, direct-comparison studies of the PTL and ETC devices are recommended and should be conducted in properly supervised emergency medical services systems.


The effects of subcurative praziquantel treatment on life-history traits and trade-offs in drug-resistant Schistosoma mansoni.
Natural selection acts on all organisms, including parasites, to maximize reproductive fitness. Drug resistance traits are often associated with life-history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian state-space models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma mansoni may be limited by life-history costs not present in susceptible counterparts. S. mansoni parasites from a praziquantel-susceptible (S), a praziquantel-resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life-history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade-offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade-offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life-history traits within the molluscan host were complex, but trade-offs were demonstrated between parasite establishment and cercarial output. The observed trade-offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life-history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life-history parameters, aiding our understanding of costs and trade-offs of resistant parasites within this system and beyond.


Local geomagnetic events associated with displacements on the san andreas fault.
The piezomagnetic properties of rock suggest that a change in subsurface stress will manifest itself as a change in the magnetic susceptibility and remanent magnetization and hence the local geomagnetic field. A differential array of magnetometers has been operating since late 1965 on the San Andreas fault in the search for piezomagnetic signals under conditions involving active fault stress. Local changes in the geomagnetic field have been observed near Hollister, California, some tens of hours preceding the onset of abrupt creep displacement on the San Andreas fault.


Value-Based Assessment of Radiology Reporting Using Radiologist-Referring Physician Two-Way Feedback System-a Design Thinking-Based Approach.
In the era of value-based healthcare, many aspects of medical care are being measured and assessed to improve quality and reduce costs. Radiology adds enormously to health care costs and is under pressure to adopt a more efficient system that incorporates essential metrics to assess its value and impact on outcomes. Most current systems tie radiologists' incentives and evaluations to RVU-based productivity metrics and peer-review-based quality metrics. In a new potential model, a radiologist's performance will have to increasingly depend on a number of parameters that define "value," beginning with peer review metrics that include referrer satisfaction and feedback from radiologists to the referring physician that evaluates the potency and validity of clinical information provided for a given study. These new dimensions of value measurement will directly impact the cascade of further medical management. We share our continued experience with this project that had two components: RESP (Referrer Evaluation System Pilot) and FRACI (Feedback from Radiologist Addressing Confounding Issues), which were introduced to the clinical radiology workflow in order to capture referrer-based and radiologist-based feedback on radiology reporting. We also share our insight into the principles of design thinking as applied in its planning and execution.


Quality of collaboration and information handovers in palliative care: a survey study on the perspectives of nurses in the Southwest Region of the Netherlands.
When patients receiving palliative care are transferred between care settings, adequate collaboration and information exchange between health care professionals is necessary to ensure continuity, efficiency and safety of care. Several studies identified deficits in communication and information exchange between care settings. Aim of this study was to get insight in the quality of collaboration and information exchange in palliative care from the perspectives of nurses. We performed a cross-sectional regional survey study among nurses working in different care settings. Nurses were approached via professional networks and media. Respondents were asked questions about collaboration in palliative care in general and about their last deceased patient. Potential associations between quality scores for collaboration and information handovers and characteristics of respondents or patients were tested with Pearson's chi-square test. A total of 933 nurses filled in the questionnaire. Nurses working in nursing homes were least positive about inter-organizational collaboration. Forty-six per cent of all nurses had actively searched for such collaboration in the last year. For their last deceased patient, 10% of all nurses had not received the information handover in time, 33% missed information they needed. An adequate information handover was positively associated with timeliness and completeness of the information and the patient being well-informed, not with procedural characteristics. Nurses report that collaboration between care settings and information exchange in palliative care is suboptimal. This study suggests that health care organizations should give more attention to shared professionalization towards inter-organizational collaboration among nurses in order to facilitate high-quality palliative care.


The Rhizobium etli argC gene is essential for Arginine biosynthesis and nodulation of Phaseolus vulgaris.
A Tn5-induced mutant strain (CTNUX5) of Rhizobium etli unable to grow with ammonium as the sole nitrogen source was isolated and characterized. Sequence analysis showed that Tn5 is inserted into an argC-homologous gene. Unlike its wild-type parent (strain CE3), the mutant strain CTNUX5 had an absolute dependency on arginine to grow. The argC gene was cloned from the wild-type strain CE3, and the resulting plasmid, pAR207, after transformation was shown to relieve the arginine auxotrophy of strain CTNUX5. Unlike strain CE3 or CTNUX5-pAR207, strain CTNUX5 showed undetectable levels of N-acetyl-gamma-glutamylphosphate reductase activity. Unless arginine was added to the growth medium, strain CTNUX5 was unable to produce flavonoid-inducible lipo-chitin oligosaccharides (nodulation factors) and to induce nodules or nodulelike structures on the roots of Phaseolus vulgaris.


Uneventful disappearance of a large left atrial ball thrombus with enoxaparin in a patient with mitral stenosis associated with pregnancy.
An atrial thrombus is a relatively common echocardiographic finding in patients with mitral valve stenosis (MVS) and atrial fibrillation (AF). However, a "ball thrombus" or floating thrombus in the left atrium is a rare and specific entity associated with MVS. A 24-year-old woman with rheumatic MVS presented with complaints of progressive dyspnea and inferior limbs edema that began 23 days earlier after a caesarean operation for stillbirth carried out at 8 months of pregnancy. At the time of hospitalization, she was in New York Heart Association functional class III and the ECG showed sinus rhythm. Transthoracic color-flow Doppler echocardiography revealed a thick, stenotic mitral valve with a valvular area of 0.9 cm(2), and an echogenic large left-atrial mass diagnosed as a free-floating left-atrial thrombus that was corroborated by transesophageal echocardiography. She refused surgery and was treated medically, and low molecular weight heparin (LMWH) (enoxaparin 80 mg/12 h) was given for 14 days and was discharged uneventfully on coumarin. Two days before discharge, a transthoracic and transesophageal ecocardiography showed disappearance of the ball thrombus uneventfully leaving spontaneous echo contrast inside the left atrium. To the best of our knowledge, this is the first case showing disappearance of a giant left atrial ball thrombus with LMWH treatment in a patient with severe MVS during sinus rhythm associated with pregnancy.


Tracking the neurodegenerative gradient after spinal cord injury.
To quantify neurodegenerative changes along the cervical spinal cord rostral to a spinal cord injury (SCI) by means of quantitative MRI (qMRI) and to determine its relationship with clinical impairment. Thirty chronic SCI patients (15 tetraplegics and 15 paraplegics) and 23 healthy controls underwent a high-resolution T1-weighted and myelin-sensitive magnetization transfer (MT) MRI. We assessed macro- and microstructural changes along the cervical cord from levels C1 to C4, calculating cross-sectional spinal cord area, its anterior-posterior and left-right width and myelin content (i.e. MT). Regression analysis determined associations between qMRI parameters and clinical impairment. In SCI patients, cord area decreased by 2.67 mm2 (p = 0.004) and left-right width decreased by 0.35 mm (p = 0.002) per cervical cord level in the caudal direction when compared to the healthy controls. This gradient of neurodegeneration was greater in tetraplegic than paraplegics in the cross-sectional cervical cord area (by 3.28 mm2, p = 0.011), left-right width (by 0.36 mm, p = 0.03), and mean cord MT (by 0.13%, p = 0.04), but independant of lesion severity (p > 0.05). Higher lesion level was associated with greater magnitudes of neurodegeneration. Greater loss in myelin content in the dorsal columns and spinothalamic tract was associated with worse light touch (p = 0.016) and pin prick score (p = 0.024), respectively. A gradient of neurodegeneration is evident in the cervical cord remote from a SCI. Tract-specific associations with appropriate clinical outcomes highlight that remote neurodegenerative changes are clinically eloquent. Monitoring the neurodegenerative gradient could be used to track treatment effects of regenerative and neuroprotective agents, both in trials targeting cervical and thoracic SCI patients.


Systematic Review of the Prevalence of Medication Errors Resulting in Hospitalization and Death of Nursing Home Residents.
Medication errors (MEs) result in preventable harm to nursing home (NH) residents and pose a significant financial burden. Institutionalized older people are particularly vulnerable because of various organizational and individual factors. This systematic review reports the prevalence of MEs leading to hospitalization and death in NH residents and the factors associated with risk of death and hospitalization. A systematic search was conducted of the relevant peer-reviewed research published between January 1, 2000, and October 1, 2015, in English, French, German, or Spanish examining serious outcomes of MEs in NHs residents. Eleven studies met the inclusion criteria and examined three types of MEs: all MEs (n = 5), transfer-related MEs (n = 5), and potentially inappropriate medications (PIMs) (n = 1). MEs were common, involving 16-27% of residents in studies examining all types of MEs and 13-31% of residents in studies examining transfer-related MEs, and 75% of residents were prescribed at least one PIM. That said, serious effects of MEs were surprisingly low and were reported in only a small proportion of errors (0-1% of MEs), with death being rare. Whether MEs resulting in serious outcomes are truly infrequent, or are underreported because of the difficulty in ascertaining them, remains to be elucidated to assist in designing safer systems.


Nanoscale changes in collagen are reflected in physical and mechanical properties of bone at the microscale in diabetic rats.
Diabetes detrimentally affects the musculoskeletal system by stiffening the collagen matrix due to increased advanced glycation end products (AGEs). In this study, tibiae and tendon from Zucker diabetic Sprague-Dawley (ZDSD) rats were compared to Sprague-Dawley derived controls (CD) using Atomic Force Microscopy. ZDSD and CD tibiae were compared using Raman Spectroscopy and Reference Point Indentation (RPI). ZDSD bone had a significantly different distribution of collagen D-spacing than CD (p=0.015; ZDSD n=294 fibrils; CD n=274 fibrils) which was more variable and shifted to higher values. This shift between ZDSD and CD D-spacing distribution was more pronounced in tendon (p<0.001; ZDSD n=350; CD n=371). Raman revealed significant increases in measures of bone matrix mineralization in ZDSD (PO4(3-) ν1/Amide I p=0.008; PO4(3-) ν1/CH2 wag p=0.047; n=5 per group) despite lower bone mineral density (aBMD) and ash fraction indicating diabetes may preferentially reduce the Raman signature of collagen. Decreased indentation distance increase (p=0.010) and creep indentation distance (p=0.040) measured by RPI (n=9 per group) in ZDSD rats suggest a matrix more resistant to indentation under the high stresses associated with RPI at this length scale. There were significant correlations between Raman and RPI measurements in the ZDSD population (n=18 locations) but not the CD population (n=16 locations) indicating that while RPI is relatively unaffected by biological noise, it is sensitive to disease-induced compositional changes. In conclusion, diabetes in the ZDSD rat causes changes to the nanoscale morphology of collagen that result in compositional and mechanical effects in bone at the microscale.


Development of Technical Skills: Education, Simulation, and Maintenance of Certification.
The goal of this article is to provide a focused overview of technical skills education inside the operating room (OR), opportunities for learning outside of the OR (with a focus on simulation), and methods for measuring technical skills. In addition, the authors review the role of maintenance of certification in continuing education and quality improvement and consider the role that simulation plays in this process. The perspectives on teaching in the OR of both residents and faculty going into the case affect the learning environment, and preoperative interactions between attendings and residents to establish learning needs and goals are important. Furthermore, in regards to attending surgeons improving their skills, interaction with more experienced peers and feedback during and after a procedure can be beneficial. Simulation is increasingly being utilized as an education tool outside of the OR. Training in plastic surgery is poised to exploit simulation in multiple technical areas. There is potential to utilize these simulation environments to collect real-time data, such as motion, visual focus, and pressure. How to incorporate technical skill evaluation results in ways that are most beneficial for learning should be the focus of future research and curriculum development. Finally, simulation could be better utilized as a mechanism for both self and peer evaluation and assessment for continuing education and quality improvement. Professional development for faculty and surgery trainees on how to engage with simulation for teaching and learning and how to translate these experiences into improving patient care will be required.


[Lymphatic disorders and prevention of their complications].
The prevalence of lymphedema is clearly underestimated. Too few patients receive treatment. It requires several specifically trained participants and must be conceived in the long term given the chronic nature and the incurability of this pathology. Prevention is therefore of major importance. Successfully applied to operated women for breast cancer, other models of coverage deserve to be developed to reduce the incidence of lymphedema and its complications, particularly after oncologic, orthopedic and vascular surgery and for patients affected by venous insufficiency.


The impact of aerators on water contamination by emerging gram-negative opportunists in at-risk hospital departments.
Our aim was to evaluate the impact of aerators on water microbiological contamination in at-risk hospital departments, with a view to quantifying the possible risk of patient exposure to waterborne microorganisms. We analyzed the microbiological and chemical-physical characteristics of hot and cold water in some critical hospital departments. Two hospitals in northern Italy. We took 304 water samples over a 1-year period, at 3-month intervals, from taps used by healthcare personnel for handwashing, surgical washing, and the washing of medical equipment. We analyzed heterotrophic plate counts (HPCs) at 36°C and 22°C, nonfastidious gram-negative bacteria (GNB-NE), and Legionella pneumophila. The percentages of positivity and mean values of HPCs at 22°C, HPCs at 36°C, and GNB-NE loads were significantly higher at outlet points than in the plumbing system. In particular, GNB-NE positivity was higher at outlet points than in the plumbing system in both the cold water (31.58% vs 6.58% of samples were positive) and hot water (21.05% vs 3.95%) supplies. Our results also revealed contamination by L. pneumophila both in the plumbing system and at outlet points, with percentages of positive samples varying according to the serogroup examined (serogroups 1 and 2-14). The mean concentrations displayed statistically significant (P < .001) differences between the outlet points (27,382.89 ± 42,245.33 colony-forming units [cfu]/L) and the plumbing system (19,461.84 ± 29,982.11 cfu/L). These results reveal a high level of contamination of aerators by various species of gram-negative opportunists that are potentially very dangerous for immunocompromised patients and, therefore, the need to improve the management of these devices.


Mapping the Burkholderia cenocepacia niche response via high-throughput sequencing.
Determining how an organism responds to its environment by altering gene expression is key to understanding its ecology. Here, we used RNA-seq to comprehensively and quantitatively assess the transcriptional response of the bacterial opportunistic cystic fibrosis (CF) pathogen and endemic soil dweller, Burkholderia cenocepacia, in conditions mimicking these 2 environments. By sequencing 762 million bases of cDNA from 2 closely related B. cenocepacia strains (one isolated from a CF patient and one from soil), we identified a number of potential virulence factors expressed under CF-like conditions, whereas genes whose protein products are involved in nitrogen scavenging and 2-component sensing were among those induced under soil-like conditions. Interestingly, 13 new putative noncoding RNAs were discovered using this technique, 12 of which are preferentially induced in the soil environment, suggesting that ncRNAs play an important role in survival in the soil. In addition, we detected a surprisingly large number of regulatory differences between the 2 strains, which may represent specific adaptations to the niches from which each strain was isolated, despite their high degree of DNA sequence similarity. Compared with the CF strain, the soil strain shows a stronger global gene expression response to its environment, which is consistent with the need for a more dynamic reaction to the heterogeneous conditions of soil.


Natural soil microbes alter flowering phenology and the intensity of selection on flowering time in a wild Arabidopsis relative.
Plant phenology is known to depend on many different environmental variables, but soil microbial communities have rarely been acknowledged as possible drivers of flowering time. Here, we tested separately the effects of four naturally occurring soil microbiomes and their constituent soil chemistries on flowering phenology and reproductive fitness of Boechera stricta, a wild relative of Arabidopsis. Flowering time was sensitive to both microbes and the abiotic properties of different soils; varying soil microbiota also altered patterns of selection on flowering time. Thus, soil microbes potentially contribute to phenotypic plasticity of flowering time and to differential selection observed between habitats. We also describe a method to dissect the microbiome into single axes of variation that can help identify candidate organisms whose abundance in soil correlates with flowering time. This approach is broadly applicable to search for microbial community members that alter biological characteristics of interest.


A high performance thin layer chromatographic method for the estimation of colchicine in different formulations.
Colchicine is a main alkaloid present in bitter and sweet variety of colchicum (Colchicum luteum Baker), which have been reported to possess anti-rheumatic, anti-gout, and anticancer potential. Colchicum is an important ingredient of several Unani and Herbal formulations. Quantification of colchicine will play a great role in quality control of these formulations. Hence, a high-performance thin layer chromatographic (TLC) method has been developed for the analysis of colchicine in Unani formulations of various dosage forms such as hubb (tablet) and capsules. The samples were applied on aluminum TLC plates precoated with silica gel 60-F254 and developed using mobile phase toluene-dichloromethane-methanol in equal proportions. Quantification was done by densitometric scanning at 350 nm, which showed a linear response in the range of 50-500 ng/spot. The developed method was validated as per the International Conference on Harmonization guidelines for linearity, precision, accuracy, specificity, robustness, limit of detection, and limit of quantification. The developed method was applied for quantitative estimation of colchicine in different Unani and Herbal formulations. The method was found simple, selective, accurate with a wide range of linearity, hence suitable for the quality control of different formulations and varieties of colchicum with respect to colchicine content.


Cerebral microbleeds and risk of incident dementia: the Framingham Heart Study.
Cerebral microbleeds (CMBs) are MRI markers attributed to the most common cerebral angiopathies in the elderly and in patients with dementia: hypertensive and cerebral amyloid angiopathy. CMB detection in asymptomatic persons may help identify those at risk for dementia and may influence preventive strategies and design of clinical trials testing treatments for dementia. We studied the association of CMB with risk of incident dementia in community dwelling individuals. A total of 1296 dementia-free Framingham Heart Study participants (mean age 72 years; 54% women) with available brain MRI and incident dementia data during a mean follow-up period of 6.7 years were included. Using Cox proportional hazards models, we related CMB presence to incident dementia. Multivariable models were adjusted for age, sex, APOE status, and education, with additional models adjusting for vascular risk factors and MRI markers of ischemic brain injury. CMBs were observed in 10.8% and incident dementia in 85 participants (6.6% over study period). Participants with any CMB had 1.74 times higher risk of dementia (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.00-3.01), whereas those with deep and mixed CMB had a three-fold increased risk (HR 2.99, 95% CI 1.52-5.90). The associations were independent of vascular risk factors, and for deep and mixed CMB also independent of MRI markers of ischemia (HR 2.44, 95% CI 1.22-4.88). Purely lobar CMBs were not associated with incident dementia. Our findings support a role for hypertensive vasculopathy and the interplay of hypertensive and cerebral amyloid angiopathy in risk of dementia and suggest that CMB presence can identify individuals at risk of dementia.


Effect of Hydrocolloids on Rheological Properties and Printability of Vegetable Inks for 3D Food Printing.
In food ink systems in which the particles are dispersed in a hydrocolloid matrix, the source of the particles and the particle content are the main factors affecting the printability and rheological properties of the system. In this study, different contents (10% and 30% w/w) of vegetable (broccoli, spinach, or carrot) powders were added to hydrocolloid matrices with different hydration properties, and their influence on the printability and rheological properties was investigated. At low powder contents (10%), slight differences in the printability and rheological values were observed between the different vegetable sources in all hydrocolloids. When the powder content was increased to 30%, the hydrocolloid with the lowest water hydration capacity, hydroxypropyl methylcellulose, showed the greatest differences in rheology and printability when different vegetable sources were used. Xanthan gum, with its higher water hydration capacity, inhibited the swelling of the particles, thus minimizing the increase in the rheological values at high volume fractions of powder and reducing the differences in printability between different vegetable sources. Confocal laser scanning microscopy analysis of the vegetable inks showed that xanthan gum inhibited swelling of the particles regardless of the vegetable powder source. The mixtures using xanthan gum could be smoothly extruded from the nozzle due to their low extruded hardness (2.96 ± 0.23 to 3.46 ± 0.16 kg), and the resulting objects showed high resolution without collapse over time. PRACTICAL APPLICATION: The powder-based texturization technology introduced in this study provides a standardized method of preparing food ink that can be universally applied to all food materials that can be powdered. In addition, the present invention can be applied to a 3D printing technique in which a powder and a hydrocolloid matrix are independently stored and mixed immediately before printing. This technique can minimize the inherent rheological differences between formulations with different food sources and compositions.


Angiopoietin-4 inhibits angiogenesis and reduces interstitial fluid pressure.
Angiopoietins (Ang) are involved in the remodeling, maturation, and stabilization of the vascular network. Ang-4 was discovered more recently; thus, its effect on angiogenesis and its interplay with other angiogenic factors have not been equivocally established. The role of Ang-4 in angiogenesis was tested in Matrigel chambers implanted into the subcutaneous space of nude mice. Ang-4 inhibited the angiogenic response of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and GLC19 tumor cells. In Matrigel chambers with Ang-4-transfected cells, the mean response was significantly lower than that of mock cells. Subcutaneous tumor interstitial fluid pressure (IFP) was significantly lower in Ang-4-transfected GLC19 tumors than in mock-transfected tumors. IFP reduction in Ang-4-transfected tumors was comparable to the reduction seen after bevacizumab treatment. In vitro, we examined the effect of recombinant Ang-4 on endothelial cell migration in Boyden chambers. Human umbilical vein endothelial cell (HUVEC) migration induced by bFGF and VEGF was inhibited by Ang-4 to control levels. In conclusion, we show that rhAng-4, as well as transfection with Ang-4, inhibits angiogenesis induced by GLC19 tumor cells and that Ang-4 expression reduces elevated tumor IFP. In addition, we demonstrate that rhAng-4 inhibits HUVEC migration and growth factor-induced angiogenesis.


IKKalpha enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas.
Squamous cell carcinomas (SCCs) of the skin display different clinical features according to their epithelial differentiation grade and histological variant. Understanding the causes of these divergences might increase the curability of SCCs. Therefore, it is important to study the mechanisms of differentiation in keratinocytes. IKK (IkappaB kinase) alpha is an important protein for epidermal morphogenesis, although the pathways through which it exerts its function are unknown and controversy exists about its role in cancer development. We show that enhanced IKKalpha expression increases both early and terminal differentiation of human keratinocytes through an E-cadherin-dependent mechanism. Increased expression of IKKalpha in mouse tumorigenic epidermal cells leads to changes in the differentiation pattern of the resulting SCCs, originating a distinct histological variant that resembles the human acantholytic SCC (ASCC) variant. Although human ASCCs have an aggressive clinical course and high risk of metastasis, nothing is known about their etiology. We show that human ASCCs, as observed in the counterpart IKKalpha murine tumors, express high levels of both IKKalpha and E-cadherin, with absence of keratins K1 and K10, usually co-expressed with IKKalpha and E-cadherin. The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKKalpha is responsible for the development of this human SCC variant.


Type II to type I transformation of chronically stimulated goat latissimus dorsi muscle: a histoenzymological, biochemical, bioenergetic, and functional study.
Five goat latissimus dorsi muscles (LDM) were submitted to a progressive chronic electrostimulation program to reach an integrated understanding of the fast-to-slow transformation process in large mammals. LDM were regularly sampled and followed during a period of 8 months. Each sample was simultaneously assessed for histoenzymological study, myosin and LDH isoforms and bioenergetic capacities [NADH dehydrogenase cytochrome c oxidoreductase (NADH Cyt c OR), succinate dehydrogenase cytochrome c oxidoreductase (Succ Cyt c OR), cytochrome c oxidase (Cyt c Ox) and LDH]. Such muscles were also tested with and without completion of II to I transformation for their mechanical properties in isometric and isotonic strain gauge testing. The conversion of fast-to-slow myosin monitored by heavy chain (HC I) and light chain slow component (LC2s) began a few days after stimulation and was almost 100% after 100 days. The H-LDH isoforms evolved similarly but did not reach 100% conversion after 200 days. The activity of respiratory chain oxidases increased within 36 h but to a variable extent and peaked after 32 days, corresponding to a 75% transformation of myosin compared to initial levels. NADH Cyt c OR, Succ Cyt c OR, and Cyt c Ox, respectively increased 10-, 5- and 5-fold. These activities then significantly decreased before the completion of the myofibrillar transformation and reached a plateau with stable activities that remained 2- to 3-fold higher than the unstimulated LDM. LDH activity sharply decreased until day 62 (5-fold) and then plateaued. Functionally, muscle showed a reduced speed of contraction and moderate reduction in power output but had become fatigue-resistant. This study documents the transformation process in large mammals and suggests the dynamic relation between workload, aerobic-anaerobic metabolism and the contractile myofibrillar system.


Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels.
Sudden cardiac death attributable to ventricular tachycardia/fibrillation (VF) remains a catastrophic outcome of myocardial ischemia and infarction. At the same time, conventional antagonist drugs targeting ion channels have yielded poor survival benefits. Although pharmacological and genetic models suggest an association between sodium (Na+) channel loss-of-function and sudden cardiac death, molecular mechanisms have not been identified that convincingly link ischemia to Na+ channel dysfunction and ventricular arrhythmias. Because ischemia can evoke the generation of reactive oxygen species, we explored the effect of oxidative stress on Na+ channel function. We show here that oxidative stress reduces Na+ channel availability. Both the general oxidant tert-butyl-hydroperoxide and a specific, highly reactive product of the isoprostane pathway of lipid peroxidation, E2-isoketal, potentiate inactivation of cardiac Na+ channels in human embryonic kidney (HEK)-293 cells and cultured atrial (HL-1) myocytes. Furthermore, E2-isoketals were generated in the epicardial border zone of the canine healing infarct, an arrhythmogenic focus where Na+ channels exhibit similar inactivation defects. In addition, we show synergistic functional effects of flecainide, a proarrhythmic Na+ channel blocker, and oxidative stress. These data suggest Na+ channel dysfunction evoked by lipid peroxidation is a candidate mechanism for ischemia-related conduction abnormalities and arrhythmias.


Recent mafic volcanism on Mars.
The evidence for volcanism on Mars is commonly accepted, but none has been documented in the Valles Marineris equatorial rift system. A recent survey of the troughs in this valley revealed dark patches that are interpreted to be volcanic vents. The configuration and association of these patches with tectonic structures suggest that they are of internal origin; their albedo and color ratios indicate a mafic composition; and their stratigraphic position, crispness of morphologic detail, and low albedo imply that they are young, perhaps even recent.


"I will survive": A tale of bacteriophage-bacteria coevolution in the gut.
Viruses that infect bacteria, or bacteriophages, are among the most abundant entities in the gut microbiome. However, their role and the mechanisms by which they infect bacteria in the intestinal tract remain poorly understood. We recently reported that intestinal bacteria are an evolutionary force, driving the expansion of the bacteriophage host range by boosting the genetic variability of these viruses. Here, we expand these observations by studying antagonistic bacteriophage-bacteria coevolution dynamics and revealing that bacterial genetic variability is also increased under the pressure of bacteriophage predation. We propose a model showing how the expansion of bacteriophage-bacteria infection networks is relative to the opportunities for coevolution encountered in the intestinal tract. Our data suggest that predator-prey dynamics are perpetuated and differentiated in parallel, to generate and maintain intestinal microbial diversity and equilibrium.


The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens.
The caspase-recruitment domain-containing adaptor protein CARD9 regulates the innate signaling responses to fungal infection. Here we show that CARD9 is required for innate immune responses against intracellular pathogens. We generated Card9(-/-) mice and found that CARD9-deficient macrophages had defects in activation of the kinases p38 and Jnk but not of transcription factor NF-kappaB after bacterial and viral infection. CARD9-deficient mice failed to clear infection and showed altered cytokine production after challenge with Listeria monocytogenes. In wild-type cells, we found CARD9 inducibly associated with both the intracellular 'biosensor' Nod2 and the serine-threonine kinase RICK. Our data demonstrate that CARD9 has a critical function in Nod2-mediated activation of p38 and Jnk in innate immune responses to intracellular pathogens.


Risk of adverse outcomes following urinary tract infection in older people with renal impairment: Retrospective cohort study using linked health record data.
Few studies have investigated the risk of adverse outcomes in older people with renal impairment presenting to primary care with a urinary tract infection (UTI). The aim of this study was to determine the risk of adverse outcomes in patients aged ≥65 years presenting to primary care with a UTI, by estimated glomerular filtration rate (eGFR) and empirical prescription of nitrofurantoin versus trimethoprim. This was a retrospective cohort study using linked health record data from 795,484 patients from 393 general practices in England, who were aged ≥65 years between 2010 and 2016. Patients were entered into the cohort if they presented with a UTI and had a creatinine measurement in the 24 months prior to presentation. We calculated an eGFR to estimate risk of adverse outcomes by renal function, and propensity-score matched patients with eGFRs <60 mL/minute/1.73 m2 to estimate risk of adverse outcomes between those prescribed trimethoprim and nitrofurantoin. Outcomes were 14-day risk of reconsultation for urinary symptoms and same-day antibiotic prescription (proxy for treatment nonresponse), hospitalisation for UTI, sepsis, or acute kidney injury (AKI), and 28-day risk of death. Of 123,607 eligible patients with a UTI, we calculated an eGFR for 116,945 (95%). Median age was 76 (IQR, 70-83) years and 32,428 (28%) were male. Compared to an eGFR of >60 mL/minute/1.73 m2, patients with an eGFR of <60 mL/minute/1.73 m2 had greater odds of hospitalisation for UTI (adjusted odds ratios [ORs] ranged from 1.14 [95% confidence interval (CI) 1.01-1.28, p = 0.028], for eGFRs of 45-59, to 1.68 [95% CI 1.01-2.82, p < 0.001] for eGFRs <15) and AKI (adjusted ORs ranged from 1.57 [95% CI 1.29-1.91, p < 0.001], for eGFRs of 45-59, to 4.53 [95% CI 2.52-8.17, p < 0.001] for eGFRs <15). Compared to an eGFR of >60 mL/minute/1.73 m2, patients with an eGFR <45 had significantly greater odds of hospitalisation for sepsis, and those with an eGFR <30 had significantly greater odds of death. Compared to trimethoprim, nitrofurantoin prescribing was associated with lower odds of hospitalisation for AKI (ORs ranged from 0.62 [95% CI 0.40-0.94, p = 0.025], for eGFRs of 45-59, to 0.45 [95% CI 0.25-0.81, p = 0.008] for eGFRs <30). Nitrofurantoin was not associated with greater odds of any adverse outcome. Our study lacked data on urine microbiology and antibiotic-related adverse events. Despite our design, residual confounding may still have affected some of our findings. Older patients with renal impairment presenting to primary care with a UTI had an increased risk of UTI-related hospitalisation and death, suggesting a need for interventions that reduce the risk of these adverse outcomes. Nitrofurantoin prescribing was not associated with an increased risk of adverse outcomes in patients with an eGFR <60 mL/minute/1.73 m2 and could be used more widely in this population.


The spokane flood controversy and the martian outflow channels.
In a series of papers published between 1923 and 1932, J Harlen Bretz described an enormous plexus of proglacial stream channels eroded into the loess and basalt of the Columbia Plateau, eastern Washington. He argued that this region which he called the Channeled Scabland, was the product of a cataclysmic flood, which he called the Spokane flood. Considering the nature and vehemence of the opposition to his hypothesis, which was considered outrageous, its eventual scientific verification constitutes one of the most fascinating episodes in the history of modern science. The discovery of probable catastrophic flood channels on Mars has given new relevance to Bretz's insights.


The Effects of Radiofrequency or Cryothermal Ablation on Biomechanical Properties of Isolated Human or Swine Cardiac Tissues.
Changes in cardiac tissue properties following the application of various ablation modalities may lead to the development of an array of associated complications. The application of either radio frequency (RF) or cryothermal ablations will alter the biomechanical properties of various cardiac tissues in a differential manner; in some cases, this may be attributable to increased incidences of cardiac tamponade, pulmonary vein stenosis, and/or atrial-esophageal fistula. Thus, a greater understanding of the underlying changes in tissue properties induced by ablative therapies will ultimately promote safer and more efficacious procedures. The effects of applied RF or cryothermal energies on the biomechanical properties of the pulmonary vein, left atrial, or right atrial samples ([Formula: see text]) were examined from fresh excised porcine ([Formula: see text]) and donated human tissue ([Formula: see text]). RF ablations were found to reduce the tensile strength of the porcine cardiac specimens ([Formula: see text]), and a similar trend was noted for human samples. Cryoablations did not have a significant impact on the tissue properties compared with the untreated tissue specimens. Locational and species differences were also observed in this experimental paradigm ([Formula: see text]. Incorporating these findings into cardiac device design and computational modeling should aid to reduce the risks of complications associated with tissue property changes resulting from cardiac ablative procedures.


Quantifying Habitual Levels of Physical Activity According to Impact in Older People: Accelerometry Protocol for the VIBE Study.
Physical activity (PA) may need to produce high impacts to be osteogenic. The aim of this study was to identify threshold(s) for defining high impact PA for future analyses in the VIBE (Vertical Impact and Bone in the Elderly) study, based on home recordings with triaxial accelerometers. Recordings were obtained from 19 Master Athlete Cohort (MAC; mean 67.6 years) and 15 Hertfordshire Cohort Study (HCS; mean 77.7 years) participants. Data cleaning protocols were developed to exclude artifacts. Accelerations expressed in g units were categorized into three bands selected from the distribution of positive Y-axis peak accelerations. Data were available for 6.6 and 4.4 days from MAC and HCS participants respectively, with approximately 14 hr recording daily. Three-fold more 0.5-1.0g impacts were observed in MAC versus HCS, 20-fold more 1.0-1.5g impacts, and 140-fold more impacts ≥ 1.5g. Our analysis protocol successfully distinguishes PA levels in active and sedentary older individuals.


Export of north american ozone pollution to the north atlantic ocean.
Measurement of the levels of ozone and carbon monoxide (a tracer of anthropogenic pollution) at three surface sites on the Atlantic coast of Canada allow the estimation of the amount of ozone photochemically produced from anthropogenic precursors over North America and transported to the lower troposphere over the temperate North Atlantic Ocean. This amount is greater than that injected from the stratosphere, the primary natural source of ozone. This conclusion supports the contention that ozone derived from anthropogenic pollution has a hemisphere-wide effect at northern temperate latitudes.


Reliability of the 123I-mIBG heart/mediastinum ratio: Results of a multicenter test-retest reproducibility study.
A quantitative measurement, the Heart-to-Mediastinum (H/M) ratio of counts derived from a planar acquisition approximately 4 hours after injection of 123I-mIBG, is a strong predictor of outcomes in patients with stable class II-III heart failure and LVEF ≤ 35%. This study assessed the test-retest reproducibility of the H/M ratio in such patients. 47 subjects with class II-III systolic heart failure and LVEF ≤ 35% were tested at two time intervals separated by 5 to 14 days. Subjects were imaged twice on the same camera using the same radionuclide dose. Images were sent to a core analysis lab, where three nuclear technologists independently determined the H/M ratios. The primary endpoint was test-retest H/M ratio reproducibility calculated as the absolute difference in mean value determined by the three readers. Mean subject age was 65 ± 12 years, 85% were male, and mean BMI was 29 ± 6 kg/m2. Mean injected activity was 10.18 ± 0.43 mCi for first dose and 10.09 ± 0.52 mCi for the second dose. The mean and SD values for first and repeat studies were almost identical: the 95% confidence interval of the mean test-retest difference was 0.055 to 0.076. Bland-Altman plots showed no systematic effect of the H/M ratio on the magnitude of the difference between replicate measurements. Inter-reader measurements were nearly identical. There were no serious adverse events despite exposure to 123I-mIBG on 2 occasions in a short time period. The Heart-to-Mediastinum ratio of 123I-mIBG is a consistent and highly reproducible measurement in stable Class II to III heart failure patients.


Physiologic control of the functional status of Foxp3+ regulatory T cells.
Foxp3-lineage CD4 regulatory T cells (Tregs) were named for their ability to maintain self tolerance and suppress T cell immunity. However, resting Tregs from noninflamed tissues exhibit little suppressor activity, and must be stimulated to acquire such function. Conversely, under certain inflammatory conditions, Tregs may undergo rapid reprogramming to acquire helper/effector functions. In this Brief Review, we describe recent progress in elucidating physiologic processes that control the functional status of Foxp3-lineage Tregs. Emerging evidence suggests the surprising possibility that reprogrammed Tregs can be an indispensable source of helper activity in some physiologic settings, such as priming CD8(+) T cell responses. This suggests a novel paradigm in which Foxp3(+) Tregs intrinsically possess bifunctional potential, acting as a preformed pool of first-responder cells at sites of local inflammation that can either provide classical regulatory/suppressor activity, or rapidly reprogram to supply helper/effector activity, contingent on signals that manifest in local physiologic settings.


Developing Methods That Facilitate Coding and Analysis of Synchronous Conversations via Virtual Environments.
Programs via the Internet are uniquely positioned to capture qualitative data. One reason is because the Internet facilitates the creation of a community of similar individuals who can exchange information and support related to living with a chronic illness. Synchronous conversations via the Internet can provide insight into real-time social interaction and the exchange of social support. One way to analyze interactions among individuals is by using qualitative methods such as content, conversation, or discourse analysis. This manuscript describes how we used content analysis with aspects from conversation and discourse analysis to analyze synchronous conversations via the Internet to describe what individuals talk about and how individuals talk in an Internet-mediated interaction. With the increase in Internet interventions that facilitate collection of real-time conversational data, this article provides insight into how combining qualitative methods can facilitate the coding and analysis of these complex data.


Immunologic consequences of signal transducers and activators of transcription 3 activation in human squamous cell carcinoma.
Paracrine cross-talk between tumor cells and immune cells within the tumor microenvironment underlies local mechanisms of immune evasion. Signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in diverse cancer types, is a key regulator of cytokine and chemokine expression in murine tumors, resulting in suppression of both innate and adaptive antitumor immunity. However, the immunologic effects of STAT3 activation in human cancers have not been studied in detail. To investigate how STAT3 activity in human head and neck squamous cell carcinoma (HNSCC) might alter the tumor microenvironment to enable immune escape, we used small interfering RNA and small-molecule inhibitors to suppress STAT3 activity. STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Although conditioned medium containing supernatants from human HNSCC inhibited lipopolysaccharide-induced dendritic cell activation in vitro, supernatants from STAT3-silenced tumor cells reversed this immune evasion mechanism. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention.


Individual variation in macronutrient regulation measured by proton magnetic resonance spectroscopy of human plasma.
Proton nuclear magnetic resonance ((1)H-NMR) spectroscopy of plasma provides a global metabolic profiling method that shows promise for clinical diagnostics. However, cross-sectional studies are complicated by a lack of understanding of intraindividual variation, and this limits experimental design and interpretation of data. The present study determined the diurnal variation detected by (1)H NMR spectroscopy of human plasma. Data reduction methods revealed three time-of-day metabolic patterns, which were associated with morning, afternoon, and night. Major discriminatory regions for these time-of-day patterns included the various kinds of lipid signals (-CH(2)- and -CH(2)OCOR), and the region between 3 and 4 ppm heavily overlapped with amino acids that had alpha-CH and alpha-CH(2). The phasing and duration of time-of-day patterns were variable among individuals, apparently because of individual difference in food processing/digestion and absorption and clearance of macronutrient energy sources (fat, protein, carbohydrate). The times of day that were most consistent among individuals, and therefore most useful for cross-sectional studies, were fasting morning (0830-0930), postprandial afternoon (1430-1630), and nighttime samples (0430-0530). Importantly, the integrated picture of metabolism provided by (1)H-NMR spectroscopy of plasma suggests that this approach is suitable to study complex regulatory processes, including eating patterns/eating disorders, upper gastrointestinal functions (gastric emptying, pancreatic, biliary functions), and absorption/clearance of macronutrients. Hence, (1)H-NMR spectroscopy of plasma could provide a global metabolic tolerance test to assess complex processes involved in disease, including eating disorders and the range of physiological processes causing dysregulation of energy homeostasis.


Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays: Results from a Blinded CiPA Pilot Study.
Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC-CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies). Drugs were selected to define assay sensitivity of prominent repolarizing currents (E-4031 for IKr, JNJ303 for IKs) and depolarizing currents (nifedipine for ICaL, mexiletine for INa) as well as drugs affecting multichannel block (flecainide, moxifloxacin, quinidine, and ranolazine). Inclusion criteria for final analysis was based on demonstrated sensitivity to IKr block (20% prolongation with E-4031) and L-type calcium current block (20% shortening with nifedipine). Despite differences in baseline characteristics across cardiomyocyte lines, multiple sites, and instrument platforms, 10 of 18 studies demonstrated adequate sensitivity to IKr block with E-4031 and ICaL block with nifedipine for inclusion in the final analysis. Concentration-dependent effects on repolarization were observed with this qualified data set consistent with known ionic mechanisms of single and multichannel blocking drugs. hiPSC-CMs can detect repolarization effects elicited by single and multichannel blocking drugs after defining pharmacologic sensitivity to IKr and ICaL block, supporting further validation efforts using hiPSC-CMs for cardiac safety studies.


Assessing local determinants of neural tube defects in the Heshun Region, Shanxi Province, China.
Neural tube defect (NTD) prevalence in northern China is among the highest worldwide. Dealing with the NTD situation is ranked as the number one task in China's scientific development plan in population and health field for the next decade. Physical and social environments account for much of the disease's occurrence. The environmental determinants and their effects on NTD vary across geographical regions, whereas factors that play a significant role in NTD occurrence may be buried by global statistics analysis to a pooled dataset over the entire study area. This study aims at identification of the local determinants of NTD across the study area and exploration of the epidemiological implications of the findings. NTD prevalence rate is represented in terms of the random field theory, and Rushton's circle method is used to stabilize NTD rate estimation across the geographical area of interest; NTD determinants are represented by their measurable proxy variables and the geographical weighted regression (GWR) technique is used to represent the spatial heterogeneity of the NTD determinants. Informative maps of the NTD rates and the statistically significant proxy variables are generated and rigorously assessed in quantitative terms. The NTD determinants in the study area are investigated and interpreted on the basis of the maps of the proxy variables and the relationships between the proxy variables and the NTD determinants. No single determinant was found to dominate the NTD occurrence in the study area. Villages where NTD rates are significantly linked to environmental determinants are identified (some places are more closely linked to certain environmental factors than others). The results improve current understanding of NTD spread in China and provide valuable information for adequate disease intervention planning.


Nutritional Intake in Elite Cross-Country Skiers During Two Days of Training and Competition.
This study investigated the energy, macronutrient, and fluid intakes, as well as hydration status (urine specific gravity), in elite cross-country skiers during a typical day of training (Day 1) and a sprint skiing competition the following day (Day 2). A total of 31 (18 males and 13 females) national team skiers recorded their food and fluid intakes and urine specific gravity was measured on Days 1 and 2. In addition, the females completed the Low Energy Availability in Females Questionnaire to assess their risk of long-term energy deficiency. Energy intake for males was 65 ± 9 kcal/kg on Day 1 versus 58 ± 9 kcal/kg on Day 2 (p = .002) and for females was 57 ± 10 on Day 1 versus 55 ± 5 kcal/kg on Day 2 (p = .445). Carbohydrate intake recommendations of 10-12 g·kg-1·day-1 were not met by 89% of males and 92% of females. All males and females had a protein intake above the recommended 1.2-2.0 g/kg on both days and a postexercise protein intake above the recommended 0.3 g/kg. Of the females, 31% were classified as being at risk of long-term energy deficiency. In the morning of Day 1, 50% of males and 46% of females were dehydrated; on Day 2, this was the case for 56% of males and 38% of females. In conclusion, these data suggest that elite cross-country skiers ingested more protein and less carbohydrate than recommended and one third of the females were considered at risk of long-term energy deficiency. Furthermore, many of the athletes were dehydrated prior to training and competition.


Affinity purification of human factor H on polypeptides derived from streptococcal m protein: enrichment of the Y402 variant.
Recent studies indicate that defective activity of complement factor H (FH) is associated with several human diseases, suggesting that pure FH may be used for therapy. Here, we describe a simple method to isolate human FH, based on the specific interaction between FH and the hypervariable region (HVR) of certain Streptococcus pyogenes M proteins. Special interest was focused on the FH polymorphism Y402H, which is associated with the common eye disease age-related macular degeneration (AMD) and has also been implicated in the binding to M protein. Using a fusion protein containing two copies of the M5-HVR, we found that the Y402 and H402 variants of FH could be efficiently purified by single-step affinity chromatography from human serum containing the corresponding protein. Different M proteins vary in their binding properties, and the M6 and M5 proteins, but not the M18 protein, showed selective binding of the FH Y402 variant. Accordingly, chromatography on a fusion protein derived from the M6-HVR allowed enrichment of the Y402 protein from serum containing both variants. Thus, the exquisite binding specificity of a bacterial protein can be exploited to develop a simple and robust procedure to purify FH and to enrich for the FH variant that protects against AMD.


Healthy Home Offerings via the Mealtime Environment (HOME): feasibility, acceptability, and outcomes of a pilot study.
The primary objective was to develop and test the feasibility and acceptability of the Healthy Home Offerings via the Mealtime Environment (HOME) program, a pilot childhood obesity prevention intervention aimed at increasing the quality of foods in the home and at family meals. Forty-four child/parent dyads participated in a randomized controlled trial (n = 22 in intervention and n = 22 in control conditions). The intervention program, held at neighborhood facilities, included five, 90-min sessions consisting of interactive nutrition education, taste testing, cooking skill building, parent discussion groups, and hands-on meal preparation. Children (8-10-year olds) and parents (89% mothers) completed assessments at their home at baseline, postintervention, and 6-month follow-up, including psychosocial surveys, anthropometry, 24-h dietary recalls, and home food availability and meal offering inventories. Feasibility/acceptability was assessed with participant surveys and process data. All families completed all three home-based assessments. Most intervention families (86%) attended at least four of five sessions. Nearly all parents (95%) and 71% of children rated all sessions very positively. General linear models indicated that at postintervention, compared to control children, intervention children were significantly more likely to report greater food preparation skill development (P < 0.001). There were trends suggesting that intervention children had higher consumption of fruits and vegetables (P < 0.08), and higher intakes of key nutrients (all P values <0.05) than control children. Obesity changes did not differ by condition. Not all findings were sustained at 6-month follow-up. Obesity prevention programming with families in community settings is feasible and well accepted. Results demonstrate the potential of the HOME program.


DNA binding strength increases the processivity and activity of a Y-Family DNA polymerase.
DNA polymerase (pol) processivity, i.e., the bases a polymerase extends before falling off the DNA, and activity are important for copying difficult DNA sequences, including simple repeats. Y-family pols would be appealing for copying difficult DNA and incorporating non-natural dNTPs, due to their low fidelity and loose active site, but are limited by poor processivity and activity. In this study, the binding between Dbh and DNA was investigated to better understand how to rationally design enhanced processivity in a Y-family pol. Guided by structural simulation, a fused pol Sdbh with non-specific dsDNA binding protein Sso7d in the N-terminus was designed. This modification increased in vitro processivity 4-fold as compared to the wild-type Dbh. Additionally, bioinformatics was used to identify amino acid mutations that would increase stabilization of Dbh bound to DNA. The variant SdbhM76I further improved the processivity of Dbh by 10 fold. The variant SdbhKSKIP241-245RVRKS showed higher activity than Dbh on the incorporation of dCTP (correct) and dATP (incorrect) opposite the G (normal) or 8-oxoG(damaged) template base. These results demonstrate the capability to rationally design increases in pol processivity and catalytic efficiency through computational DNA binding predictions and the addition of non-specific DNA binding domains.


Transcutaneous drug delivery by liposomes using fractional laser technology.
Transdermal delivery of hydrophilic peptides remains a challenge due to their poor cellular uptake and transdermal penetration. We hypothesize that combination of a CO2 fractional laser to enhance percutaneous absorption and liposomes as transdermal carriers would improve skin penetration of hydrophilic drugs. NA. Liposomes were prepared using membrane fusion lipid dioleoylphosphatidylethanolamine, and used to deliver 5-carboxyfluorescein (CF) and fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC) as model hydrophilic peptide drugs. Liposome size was estimated by dynamic light scattering. Liposome uptake into murine macrophage cells and penetration or permeation into Yucatan micropig skin after irradiation by CO2 fractional laser at varying energy levels (laser power and exposure duration) were investigated using Franz cell and fluorescence microscopy. Oxidative damage to the irradiated mouse skin was assessed by electron spin resonance. Size of CF and OVA-FITC encapsulated liposomes was 324 ± 75 nm. Cellular uptake of OVA-FITC delivered by liposomes was 10-fold higher (1,370 relative fluorescence units, RFU) than delivered in solution form (130 RFU). Fractional laser irradiation increased skin permeation rate of CF liposomes (0-10%) and OVA-FITC liposomes (4-40%) in a dose-dependent manner. Although peeling off the stratum corneum facilitated CF liposome penetration at low energy levels (2.69-3.29 J/cm2 ; 10-20 W for 500 μs), drug permeation was similar (7-8%) in peeled or untreated skin at higher laser energy levels (6.06 J/cm2 ; 20 W for 1,500 μs). FITC penetrated deeper in the skin after laser irradiation. However, OH, O2-, and VC reactive oxygen species were generated upon irradiation of the skin with a fractional CO2 laser. Increasing laser power and irradiation, time increased liposome uptake by cells and penetration of peptide drugs across the skin in a dose-dependent manner. High-energy CO2 fractional laser overcomes the rate-limiting barrier function of the stratum corneum. Further investigations are required to establish the safety and efficacy of fractional laser-irradiation assisted delivery of liposome-encapsulated drugs as a transcutaneous drug delivery system. Lasers Surg. Med. 49:525-532, 2017. © 2016 Wiley Periodicals, Inc.


Integrating genetic maps in bambara groundnut [Vigna subterranea (L) Verdc.] and their syntenic relationships among closely related legumes.
Bambara groundnut [Vigna subterranea (L) Verdc.] is an indigenous legume crop grown mainly in subsistence and small-scale agriculture in sub-Saharan Africa for its nutritious seeds and its tolerance to drought and poor soils. Given that the lack of ex ante sequence is often a bottleneck in marker-assisted crop breeding for minor and underutilised crops, we demonstrate the use of limited genetic information and resources developed within species, but linked to the well characterised common bean (Phaseolus vulgaris) genome sequence and the partially annotated closely related species; adzuki bean (Vigna angularis) and mung bean (Vigna radiata). From these comparisons we identify conserved synteny blocks corresponding to the Linkage Groups (LGs) in bambara groundnut genetic maps and evaluate the potential to identify genes in conserved syntenic locations in a sequenced genome that underlie a QTL position in the underutilised crop genome. Two individual intraspecific linkage maps consisting of DArTseq markers were constructed in two bambara groundnut (2n = 2x = 22) segregating populations: 1) The genetic map of Population IA was derived from F2 lines (n = 263; IITA686 x Ankpa4) and covered 1,395.2 cM across 11 linkage groups; 2) The genetic map of Population TD was derived from F3 lines (n = 71; Tiga Nicuru x DipC) and covered 1,376.7 cM across 11 linkage groups. A total of 96 DArTseq markers from an initial pool of 142 pre-selected common markers were used. These were not only polymorphic in both populations but also each marker could be located using the unique sequence tag (at selected stringency) onto the common bean, adzuki bean and mung bean genomes, thus allowing the sequenced genomes to be used as an initial 'pseudo' physical map for bambara groundnut. A good correspondence was observed at the macro synteny level, particularly to the common bean genome. A test using the QTL location of an agronomic trait in one of the bambara groundnut maps allowed the corresponding flanking positions to be identified in common bean, mung bean and adzuki bean, demonstrating the possibility of identifying potential candidate genes underlying traits of interest through the conserved syntenic physical location of QTL in the well annotated genomes of closely related species. The approach of adding pre-selected common markers in both populations before genetic map construction has provided a translational framework for potential identification of candidate genes underlying a QTL of trait of interest in bambara groundnut by linking the positions of known genetic effects within the underutilised species to the physical maps of other well-annotated legume species, without the need for an existing whole genome sequence of the study species. Identifying the conserved synteny between underutilised species without complete genome sequences and the genomes of major crops and model species with genetic and trait data is an important step in the translation of resources and information from major crop and model species into the minor crop species. Such minor crops will be required to play an important role in future agriculture under the effects of climate change.


Gastrointestinal effects of the extracts of Rhigiocarya racemifera (Menispermaceae).
The gastrointestinal effects of the aqueous extract of Rhigiocarya racemifera was studied in rats and was compared with that of cimetidine. Ulcers were induced in rats by means of drugs: indomethacin, reserpine and serotonin and by shay rats. The extract was found to have significant (P less than 0.05) antiulcer activity against all the models studied. The LD50 was found to be 141.25 mg/kg body weight and ED50 16.5 mg/kg. Phytochemical studies revealed the presence of glycosides, saponins, and tanins. The extract does not show antimicrobial effects.


Anti-MoS2 Nanostructures: Tl2S and Its Electrochemical and Electronic Properties.
Layered transition metal dichalcogenides are catalytically important compounds. Unlike the mounting interest in transition metal dichalcogenides such as MoS2 and WS2 for electrochemical applications, other metal chalcogenides with layered structure but different chemical composition have received little attention among the scientific community. One such example is represented by thallium(I) sulfide (Tl2S), a Group 13 chalcogenide, which adopts the peculiar anti-CdCl2 type structure where the chalcogen is sandwiched between the metal layers. This is the exact opposite of a number of transition metal dichalcogenides like 1T-MoS2 adopting the regular CdCl2 structure type. The electronic structure of Tl2S thus differs from MoS2. Such structure may provide a useful insight and understanding toward its electrochemical behavior in relation to the electrochemical properties of MoS2. We thus investigated the intrinsic electroactivity of Tl2S and its implications for sensing and energy generation, specifically the electrocatalytic properties toward the hydrogen evolution reaction (HER). We show that Tl2S exhibits four distinct redox signals at ca. 0.4 V, -0.5 V, -1.0 V and -1.5 V vs Ag/AgCl as a result of its inherent cathodic and anodic processes. We also demonstrate that Tl2S possesses slow electron transfer abilities with a rate (k(0)obs) as low as 6.3 × 10(-5) cm s(-1). Tl2S displays a competent performance as a HER electrocatalyst compared to a conventional glassy carbon electrode. However, the poor conductivity of Tl2S renders the HER electrocatalytic behavior second-rate compared to MoS2. Furthermore, we investigated the electronic properties of Tl2S and found that Tl2S exhibits an unusually narrow band dispersion around the Fermi level. We show here that anti-MoS2 structure of Tl2S is accompanied by highly unusual features.


BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are synthetically lethal when combined with 2-deoxy-D-glucose.
Cancer cells display differences regarding their engagement of glycolytic vs. mitochondrial oxidative phosphorylation (OXPHOS) pathway. Triple negative breast cancer, an aggressive form of breast cancer, is characterized by elevated glycolysis, while estrogen receptor positive breast cancer cells rely predominantly on OXPHOS. BCL2 proteins control the process of mitochondrial outer membrane permeabilization during apoptosis, but also regulate cellular bioenergetics. Because BCL2 proteins are overexpressed in breast cancer and targetable by selective antagonists, we here analysed the effect of BCL2 and BCL(X)L selective inhibitors, Venetoclax and WEHI-539, on mitochondrial bioenergetics and cell death. Employing single cell imaging using a FRET-based mitochondrial ATP sensor, we found that MCF7 breast cancer cells supplied with mitochondrial substrates reduced their mitochondrial ATP production when treated with Venetoclax or WEHI-539 at concentrations that per se did not induce cell death. Treatments with lower concentrations of both inhibitors also reduced the length of the mitochondrial network and the dynamics, as evaluated by quantitative confocal microscopy. We next tested the hypothesis that mitochondrial ATP production inhibition with BCL2 or BCL(X)L antagonists was synthetically lethal when combined with glycolysis inhibition. Treatment with 2-deoxy-D-glucose in combination with Venetoclax or WEHI-539 synergistically reduced the cellular bioenergetics of ER+ and TNBC breast cancer cells and abolished their clonogenic potential. Synthetic lethality was also observed when cultures were grown in 3D spheres. Our findings demonstrate that BCL2 antagonists exert potent effects on cancer metabolism independent of cell death-inducing effects, and demonstrate a synthetic lethality when these are applied in combination with glycolysis inhibitors.


Duration of anti-tuberculosis therapy and timing of antiretroviral therapy initiation: association with mortality in HIV-related tuberculosis.
Antiretroviral therapy (ART) decreases mortality risk in HIV-infected tuberculosis patients, but the effect of the duration of anti-tuberculosis therapy and timing of anti-tuberculosis therapy initiation in relation to ART initiation on mortality, is unclear. We conducted a retrospective observational multi-center cohort study among HIV-infected persons concomitantly treated with Rifamycin-based anti-tuberculosis therapy and ART in Latin America. The study population included persons for whom 6 months of anti-tuberculosis therapy is recommended. Of 253 patients who met inclusion criteria, median CD4+ lymphocyte count at ART initiation was 64 cells/mm(3), 171 (68%) received >180 days of anti-tuberculosis therapy, 168 (66%) initiated anti-tuberculosis therapy before ART, and 43 (17%) died. In a multivariate Cox proportional hazards model that adjusted for CD4+ lymphocytes and HIV-1 RNA, tuberculosis diagnosed after ART initiation was associated with an increased risk of death compared to tuberculosis diagnosis before ART initiation (HR 2.40; 95% CI 1.15, 5.02; P = 0.02). In a separate model among patients surviving >6 months after tuberculosis diagnosis, after adjusting for CD4+ lymphocytes, HIV-1 RNA, and timing of ART initiation relative to tuberculosis diagnosis, receipt of >6 months of anti-tuberculosis therapy was associated with a decreased risk of death (HR 0.23; 95% CI 0.08, 0.66; P=0.007). The increased risk of death among persons diagnosed with tuberculosis after ART initiation highlights the importance of screening for tuberculosis before ART initiation. The decreased risk of death among persons receiving > 6 months of anti-tuberculosis therapy suggests that current anti-tuberculosis treatment duration guidelines should be re-evaluated.


Sodium and potassium channel dysfunctions in rare and common idiopathic epilepsy syndromes.
Mutations in the SCN1A gene are found in up to 80% of individuals with severe myoclonic epilepsy of infancy (SMEI), and mutations in KCNQ2 and KCNQ3 were identified in benign familial neonatal convulsions (BFNC) as well as in single families with Rolandic epilepsy (RE) and idiopathic generalized epilepsies (IGE). This paper summarizes recent findings concerning sodium (SCN1A) and potassium channel (KCNQ2 and KCNQ3) dysfunctions in the pathogenesis of rare and common idiopathic epilepsies (IE). SMEI, severe idiopathic generalized epilepsy of infancy (SIGEI), and myoclonic-astatic epilepsy (MAE) are rare IE. Because of some semeiologic overlap, a comparative analysis of the SCN1A gene performed in 20 patients with MAE and in 18 with SIGEI. This revealed mutations in three subjects with SIGEI only. Since BFNC are over-represented in families with RE, a mutational analysis was performed in 58 families with RE with and without BNFC. This revealed functionally relevant mutations in two index cases with BNFC, and three missense mutations (one resulting in a significantly reduced potassium current amplitude) in three patients with RE, but without BNFC. One KCNQ3 missense variant was also detected in eight out of 455 IGE patients but not in 454 controls, and a silent KCNQ2-SNP was found over-represented in both epilepsy samples. These findings confirm that mutations in the SCN1A gene are mainly involved in the pathogenesis of SMEI, rarely in that of SIGEI, and are commonly not found in patients with MAE. They also demonstrate that sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common IE syndromes.


A high affinity kidney targeting by chitobionic acid-conjugated polysorbitol gene transporter alleviates unilateral ureteral obstruction in rats.
Aside from kidney transplantation - a procedure which is exceedingly dependent on donor-match and availability leading to excessive costs - there are currently no permanent treatments available which reverse kidney injury and failure. However, kidney-specific targeted gene therapy has outstanding potential to treat kidney-related dysfunction. Herein we report a novel kidney-specific targeted gene delivery system developed through the conjugation of chitobionic acid (CBA) to a polysorbitol gene transporter (PSGT) synthesized from sorbitol diacrylate and low molecular weight polyethylenimine (PEI) carrying hepatocyte growth factor (HGF) gene to alleviate unilateral ureteral obstruction (UUO) in rats. CBA-PSGT performed exceptionally well for targeted delivery of HGF to kidney tissues compared to its non-targeted counterparts (P < 0.001) after systemic tail-vein injection and significantly reduced the UUO symptoms, returning the UUO rats to a normal health status. The kidney-targeted CBA-PSGT-delivered HGF also strikingly reduced various pathologic and molecular markers in vivo such as the level of collagens (type I and II), blood urea nitrogen (BUN), creatinine, and the expressions of ICAM-1, TIMP-1 and α-SMA which play a critical role in obstructive kidney functions. Therefore, CBA-PSGT should be further investigated because of its potential to alleviate UUO and kidney-related diseases using high affinity kidney targeting.