A Mixed-Methods Approach to Humanistic Interprofessional Faculty Development.
This study evaluated the effectiveness of the Mentoring and Professionalism in Training (MAP-IT) program, a longitudinal, interprofessional faculty development curriculum designed to enhance clinicians' humanistic mentoring skills, specifically nurses and physicians. During 2014 to 2016, two consecutive cohorts of nurses and physicians completed the MAP-IT program. Participants included 169 high potential mentors (HPMs) and 61 facilitator leaders. Each 10-month program consisted of small group work, experiential learning, and critical reflection aimed at enhancing humanistic mentoring skills. Throughout the program, facilitator leaders served as mentors for the HPMs. Both quantitative and qualitative data were collected to measure changes in skill levels specific to humanistic teaching practices, as well as overall evaluation of the program's curriculum and logistics. Quantitative data were analyzed using the Wilcoxon signed-rank test, descriptive statistics, and Fisher exact test, as appropriate. Qualitative data assessing the overall impact and applicability of the program to the clinical setting were analyzed using content analysis methodology. Across cohorts, HPMs demonstrated significant increases in perceptions of humanistic teaching skills. During objective structured teaching simulations, significant increases were also found in HPMs' self-reported mentoring skills and their skills as rated by a standardized RN/MD. Qualitative analyses revealed themes of the program to be skill development and application, mentorship, humanism, mindfulness, self-care, and acknowledgment of overlapping interprofessional roles. Utilizing an interprofessional education approach, the MAP-IT program was determined to be a feasible strategy to positively impact the personal and professional development of nurses and physicians.


ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.
The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We found that DX1 penetrated brain endothelial cells and crossed the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies, DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.


Spending on mental and substance use disorders projected to grow more slowly than all health spending through 2020.
Spending on mental and substance use disorders will likely grow more slowly than all health spending through 2020. We project that spending on mental and substance use disorders, as a share of all health spending, will fall from 7.4 percent in 2009 ($172 billion out of $2.3 trillion) to 6.5 percent in 2020 ($281 billion out of $4.3 trillion). This trend is the projected result of reduced spending on mental health drugs because of patent expirations, the low likelihood of innovative drugs entering the market, and a slowdown in spending growth for hospital treatment. By 2020 the expansion of coverage to previously uninsured Americans under the Affordable Care Act (ACA), combined with the projected slowdown in Medicare provider payment rates under the ACA and the Budget Control Act of 2011, are expected to add 2.7 percent to behavioral health spending, compared to spending without these changes.


Tele-Critical Care: An Update From the Society of Critical Care Medicine Tele-ICU Committee.
In 2014, the Tele-ICU Committee of the Society of Critical Care Medicine published an article regarding the state of ICU telemedicine, one better defined today as tele-critical care. Given the rapid evolution in the field, the authors now provide an updated review. We searched PubMed and OVID for peer-reviewed literature published between 2010 and 2018 related to significant developments in tele-critical care, including its prevalence, function, activity, and technologies. Search terms included electronic ICU, tele-ICU, critical care telemedicine, and ICU telemedicine with appropriate descriptors relevant to each sub-section. Additionally, information from surveys done by the Society of Critical Care Medicine was included given the relevance to the discussion and was referenced accordingly. Tele-critical care continues to evolve in multiple domains, including organizational structure, technologies, expanded-use case scenarios, and novel applications. Insights have been gained in economic impact and human and organizational factors affecting tele-critical care delivery. Legislation and credentialing continue to significantly influence the pace of tele-critical care growth and adoption. Tele-critical care is an established mechanism to leverage critical care expertise to ICUs and beyond, but systematic research comparing different models, approaches, and technologies is still needed.


Ultrasound in rural India: a failure of the best intentions.
The Pre-Conception and Pre-Natal Diagnostic Techniques Act was written to prevent societally unacceptable harms including intentional sex selection. The pragmatism required to enforce this law has profound effects on the ability of rural Indians to access diagnostic ultrasonography. In so doing, it may have inadvertently placed a heavier burden on the poorest and worsened health inequity in India, creating serious ethical and justice concerns. It is time to re-examine and update the law such that diagnostic ultrasonography is widely available in even the most peripheral primary health and community health centres. Shorter, more accessible ultrasonography training courses should be offered; collaboration between radiologists and rural practitioners and facilities should be encouraged. Finally, modern ultrasound machines can carefully record all images via a "silent observer" modality. With some modifications to previously used silent observer modalities, this technology allows both greater access and better policing of potential misuse of ultrasound technology.


Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.
Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.


Transsexual patients' psychiatric comorbidity and positive effect of cross-sex hormonal treatment on mental health: results from a longitudinal study.
The aim of the present study was to evaluate the presence of psychiatric diseases/symptoms in transsexual patients and to compare psychiatric distress related to the hormonal intervention in a one year follow-up assessment. We investigated 118 patients before starting the hormonal therapy and after about 12 months. We used the SCID-I to determine major mental disorders and functional impairment. We used the Zung Self-Rating Anxiety Scale (SAS) and the Zung Self-Rating Depression Scale (SDS) for evaluating self-reported anxiety and depression. We used the Symptom Checklist 90-R (SCL-90-R) for assessing self-reported global psychological symptoms. Seventeen patients (14%) had a DSM-IV-TR axis I psychiatric comorbidity. At enrollment the mean SAS score was above the normal range. The mean SDS and SCL-90-R scores were on the normal range except for SCL-90-R anxiety subscale. When treated, patients reported lower SAS, SDS and SCL-90-R scores, with statistically significant differences. Psychiatric distress and functional impairment were present in a significantly higher percentage of patients before starting the hormonal treatment than after 12 months (50% vs. 17% for anxiety; 42% vs. 23% for depression; 24% vs. 11% for psychological symptoms; 23% vs. 10% for functional impairment). The results revealed that the majority of transsexual patients have no psychiatric comorbidity, suggesting that transsexualism is not necessarily associated with severe comorbid psychiatric findings. The condition, however, seemed to be associated with subthreshold anxiety/depression, psychological symptoms and functional impairment. Moreover, treated patients reported less psychiatric distress. Therefore, hormonal treatment seemed to have a positive effect on transsexual patients' mental health.


Fat content, energy value and fatty acid profile of donkey milk during lactation and implications for human nutrition.
Milk contains numerous nutrients. The content of n-3 fatty acids, the n-6/n-3 ratio, and short- and medium-chain fatty acids may promote positive health effects. In Western societies, cow's milk fat is perceived as a risk factor for health because it is a source of a high fraction of saturated fatty acids. Recently, there has been increasing interest in donkey's milk. In this work, the fat and energetic value and acidic composition of donkey's milk, with reference to human nutrition, and their variations during lactation, were investigated. We also discuss the implications of the acidic profile of donkey's milk on human nutrition. Individual milk samples from lactating jennies were collected 15, 30, 45, 60, 90, 120, 150, 180 and 210days after foaling, for the analysis of fat, proteins and lactose, which was achieved using an infrared milk analyser, and fatty acids composition by gas chromatography. The donkey's milk was characterised by low fat and energetic (1719.2kJ·kg-1) values, a high polyunsaturated fatty acids (PUFA) content of mainly α-linolenic acid (ALA) and linoleic acid (LA), a low n-6 to n-3 FA ratio or LA/ALA ratio, and advantageous values of atherogenic and thrombogenic indices. Among the minor PUFA, docosahesaenoic (DHA), eicosapentanoic (EPA), and arachidonic (AA) acids were present in very small amounts (<1%). In addition, the AA/EPA ratio was low (0.18). The fat and energetic values decreased (P < 0.01) during lactation.The fatty acid patterns were affected by the lactation stage and showed a decrease (P < 0.01) in saturated fatty acids content and an increase (P < 0.01) in the unsaturated fatty acids content. The n-6 to n-3 ratio and the LA/ALA ratio were approximately 2:1, with values <1 during the last period of lactation, suggesting the more optimal use of milk during this period. The high level of unsaturated/saturated fatty acids and PUFA-n3 content and the low n-6/n-3 ratio suggest the use of donkey's milk as a functional food for human nutrition and its potential utilisation for infant nutrition as well as adult diets, particular for the elderly.


A novel and high brightness AlN:Mn2+ red phosphor for field emission displays.
Mn(2+) doped-AlN red phosphors were prepared by the solid-state reaction method. X-ray diffraction, SEM-EDS, photoluminescence and cathodoluminescence were utilized to characterize the prepared phosphor. Under UV light or electron beam excitation, the AlN:Mn(2+) phosphors exhibit a strong red emission centered at 600 nm, which is ascribed to the characteristic (4)T1((4)G)-(6)A1((6)S) transition of Mn(2+). Energy level diagrams were constructed to discuss the photoluminescence and cathodoluminescence processes of the AlN:1% Mn(2+) phosphor. The oxygen-related defects in AlN have great influence on the photoluminescence and cathodoluminescence properties of the AlN:1% Mn(2+) phosphor. The dependence of brightness on accelerating voltage or electric current, the decay behavior of CL intensity under the electron bombardment, and the stability of CIE chromaticity coordinates were investigated in detail. The results indicate that the AlN:Mn(2+) phosphor exhibits a higher brightness, higher color purity, and lower saturation compared to the red Y2O3:Eu(3+) phosphor, which gives the AlN:Mn(2+) phosphor great potential as a red phosphor for full color FEDs.


Correlation of neural activity with behavioral kinematics reveals distinct sensory encoding and evidence accumulation processes during active tactile sensing.
Many real-world decisions rely on active sensing, a dynamic process for directing our sensors (e.g. eyes or fingers) across a stimulus to maximize information gain. Though ecologically pervasive, limited work has focused on identifying neural correlates of the active sensing process. In tactile perception, we often make decisions about an object/surface by actively exploring its shape/texture. Here we investigate the neural correlates of active tactile decision-making by simultaneously measuring electroencephalography (EEG) and finger kinematics while subjects interrogated a haptic surface to make perceptual judgments. Since sensorimotor behavior underlies decision formation in active sensing tasks, we hypothesized that the neural correlates of decision-related processes would be detectable by relating active sensing to neural activity. Novel brain-behavior correlation analysis revealed that three distinct EEG components, localizing to right-lateralized occipital cortex (LOC), middle frontal gyrus (MFG), and supplementary motor area (SMA), respectively, were coupled with active sensing as their activity significantly correlated with finger kinematics. To probe the functional role of these components, we fit their single-trial-couplings to decision-making performance using a hierarchical-drift-diffusion-model (HDDM), revealing that the LOC modulated the encoding of the tactile stimulus whereas the MFG predicted the rate of information integration towards a choice. Interestingly, the MFG disappeared from components uncovered from control subjects performing active sensing but not required to make perceptual decisions. By uncovering the neural correlates of distinct stimulus encoding and evidence accumulation processes, this study delineated, for the first time, the functional role of cortical areas in active tactile decision-making.


Seabuckthron (Hippophae rhamnoides L.) leaf extract ameliorates the gamma radiation mediated DNA damage and hepatic alterations.
In vitro assessment showed that H. rhamnoides (HrLE) extract possessed free radical scavenging activities and can protect gamma (gamma) radiation induced supercoiled DNA damage. For in vivo study, Swiss albino mice were administered with HrLE (30 mg/kg body weight) for 15 consecutive days before exposing them to a single dose of 5 Gy of beta radiation. HrLE significantly prevented the radiation induced genomic DNA damage indicated as a significant reduction in the comet parameters. The lipid peroxidation, liver function enzymes, expression of phosphorylated NFkappaB (p65) and IkappaBalpha increased whereas the endogenous antioxidants diminished upon radiation exposure compared to control. Pretreatment of HrLE extract ameliorated these changes. Based on the present results it can be concluded that H. rhamnoides possess a potential preventive element in planned and accidental nuclear exposures.


Ponderomotive shearing for spectral interferometry of extreme-ultraviolet pulses.
We propose a novel method for completely characterizing ultrashort pulses at extreme-ultraviolet (XUV) wavelengths by adapting the technique of spectral phase interferometry for direct electric-field reconstruction to this spectral region. Two-electron wave packets are coherently produced by photoionizing atoms with two time-delayed replicas of the XUV pulse. For one of the XUV pulses, photoionization occurs in the presence of a strong infrared pulse that ponderomotively shifts the binding energy, thereby providing the spectral shear needed for reconstruction of the spectral phase of the XUV pulse.


The implications of a Silurian and other thylacocephalan crustaceans for the functional morphology and systematic affinities of the group.
Thylacocephala is a group of enigmatic extinct arthropods. Here we provide a full description of the oldest unequivocal thylacocephalan, a new genus and species Thylacares brandonensis, which is present in the Silurian Waukesha fauna from Wisconsin, USA. We also present details of younger, Jurassic specimens, from the Solnhofen lithographic limestones, which are crucial to our interpretation of the systematic position of Thylacocephala. In the past, Thylacocephala has been interpreted as a crustacean ingroup and as closely related to various groups such as cirripeds, decapods or remipeds. The Waukesha thylacocephalan, Thylacares brandonensis n. gen. n. sp., bears compound eyes and raptorial appendages that are relatively small compared to those of other representatives of the group. As in other thylacocephalans the large bivalved shield encloses much of the entire body. The shield lacks a marked optical notch. The eyes, which project just beyond the shield margin, appear to be stalked. Head appendages, which may represent antennulae, antennae and mandibles, appear to be present. The trunk is comprised of up to 22 segments. New details observed on thylacocephalans from the Jurassic Solnhofen lithographic limestones include antennulae and antennae of Mayrocaris bucculata, and endites on the raptorial appendages and an elongate last trunk appendage in Clausocaris lithographica. Preserved features of the internal morphology in C. lithographica include the muscles of the raptorial appendage and trunk. Our results indicate that some 'typical' thylacocephalan characters are unique to the group; these autapomorphies contribute to the difficulty of determining thylacocephalan affinities. While the new features reported here are consistent with a eucrustacean affinity, most previous hypotheses for the position of Thylacocephala within Eucrustacea (as Stomatopoda, Thecostraca or Decapoda) are shown to be unlikely. A sister group relationship to Remipedia appears compatible with the observed features of Thylacocephala but more fossil evidence is required to test this assertion. The raptorial appendages of Thylacocephala most likely projected 45 degrees abaxially instead of directly forward as previously reconstructed. The overall morphology of thylacocephalans supports a predatory mode of life.


1,10-Phenanthroline inhibition of lymphoblast cell cycle.
The effects of the metal-chelating agent, 1,10-phenanthroline (OP), on the cell cycle progression of CCRF-CEM lymphoblasts has been studied by flow microfluorometry. Lymphoblasts were incubated with 2,3-dihydro-1H-imidazo[1,2-b]pyrazole in order to block them in G1-early S. The block was then reversed by incubating the cells in fresh media. Within 2 to 4 hr, approximately 90% of the cells were in S phase and, by 6 hr, approximately 80% were in late S. Aliquots of these latter cells then were incubated with podophyllotoxin to block them in G2-M. These cells divided within 4 hr of reversal of the podophyllotoxin block. Lymphoblast populations in G1-early S, mid-S, or G2-M were then incubated with 4 micronM OP. OP blocked entry of G1 cells into S as well as progression through S but had no effect on progression from G2-M to G1. The OP effects were reversed by addition of Zn2+, Cu2+, or Fe2+ or by dilution of the chelating agent in the growth media. Incubation of CCRF-CEM lymphoblasts with 1,7-phenanthroline, a nonchelating analog of OP, did not affect the cell cycle. The data indicate that OP reversibly blocks progression of cells from G1 to S and through S by chelation of metals involved in processes essential for those cell cycle events.


Spinal cord injury combined with felony history: effect on supported employment for Veterans.
In this secondary analysis of data from a randomized controlled trial comparing supported employment with treatment as usual, we sought to evaluate the study incident rate of legal involvement and subsequent effects of legal involvement on employment among 157 job-seeking Veterans with spinal cord injury. The supported employment vocational rehabilitation program, called the Spinal Cord Injury-Vocational Integration Program, adhered as closely as possible to principles of supported employment as developed and described in the individual placement and support model of supported employment for persons with mental illness. Rates of misdemeanor and felony arrests and convictions were analyzed, and their relationship to finding employment was evaluated. Findings indicate that 47% had been arrested and 25% had been convicted of a felony. Overall, those who found employment had fewer average arrests and were significantly less likely to have been convicted of a felony. Future directions and limitations are discussed. ClinicalTrials.gov; NCT00117806.


Yeast seryl tRNA synthetase: two sets of substrate sites involved in aminoacylation.
Seryl tRNA synthetase from Saccharomyces Carlsbergensis C836 contains two sets of sites for tRNASer, L-serine, and Mg2+-ATP, both of which are involved in aminoacylation. This is based on the following experimental results: (a) at low serine concentrations, second order kinetics in tRNASer are observed; (b) biphasic kinetics result when the amino acid is the varied substrate indicating anticooperative binding of two serine molecules to the synthetase; (c) when two molecules of serine are bound the rate of aminoacylation increases strongly and becomes first order in tRNASer; (d) the involvement of more than one site for Mg2+ and ATP is deduced from systematic variations of the concentrations of Mg2+ and ATP. Implications of the anticooperative binding of the substrates for possible reaction mechanisms are discussed. The results indicate that under normal conditions, the activity of seryl tRNA synthetase is regulated mainly by tRNASer while at high serine concentrations regulation by the amino acid itself prevails.


[Taking care of the caregiver in the working setting: an action proposal].
This is an experience report that aimed to stimulate the sensitiveness of a nursing team towards their self care and to develop on the working environment actions to promote it. The theoretical framework adopted followed the assumptions of Watson. The subjects were two nursing teams who work in intensive care unities in which different activities were made such as extreching, dynamics and relaxing activities. It obtained a positive answer from the groups which experienced the feeling of been taken care of and valued and could know themselves better and practice some actions of care towards their self. In this way, the performed actions and interactions could stimulate and propitiate the self care inside and outside of the working environment and could also make them aware to the importance of this kind of care in their working practices.


Dietary flaxseed independently lowers circulating cholesterol and lowers it beyond the effects of cholesterol-lowering medications alone in patients with peripheral artery disease.
Dietary flaxseed lowers cholesterol in healthy subjects with mild biomarkers of cardiovascular disease (CVD). The aim was to investigate the effects of dietary flaxseed on plasma cholesterol in a patient population with clinically significant CVD and in those administered cholesterol-lowering medications (CLMs), primarily statins. This double-blind, randomized, placebo-controlled trial examined the effects of a diet supplemented for 12 mo with foods that contained either 30 g of milled flaxseed [milled flaxseed treatment (FX) group; n = 58] or 30 g of whole wheat [placebo (PL) group; n = 52] in a patient population with peripheral artery disease (PAD). Plasma lipids were measured at 0, 1, 6, and 12 mo. Dietary flaxseed in PAD patients resulted in a 15% reduction in circulating LDL cholesterol as early as 1 mo into the trial (P = 0.05). The concentration in the FX group (2.1 ± 0.10 mmol/L) tended to be less than in the PL group (2.5 ± 0.2 mmol/L) at 6 mo (P = 0.12), but not at 12 mo (P = 0.33). Total cholesterol also tended to be lower in the FX group than in the PL group at 1 mo (11%, P = 0.05) and 6 mo (11%, P = 0.07), but not at 12 mo (P = 0.24). In a subgroup of patients taking flaxseed and CLM (n = 36), LDL-cholesterol concentrations were lowered by 8.5% ± 3.0% compared with baseline after 12 mo. This differed from the PL + CLM subgroup (n = 26), which increased by 3.0% ± 4.4% (P = 0.030) to a final concentration of 2.2 ± 0.1 mmol/L. Milled flaxseed lowers total and LDL cholesterol in patients with PAD and has additional LDL-cholesterol-lowering capabilities when used in conjunction with CLMs. This trial was registered at clinicaltrials.gov as NCT00781950.


Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study.
Although the pathogenic nature of copy number variants (CNVs) on chromosome 22q11.2 has been recognised for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are absent. We aimed to provide the true population prevalence of 22q11.2 CNVs and associated trajectory of disease risk and mortality by use of the unbiased, representative Danish iPSYCH population case cohort. This case-cohort study was done on a population of 86 189 individuals selected from the iPSYCH case cohort of 1 472 762 singletons born in Denmark between May 1, 1981, and Dec 31, 2005, who have a known mother from the Danish Civil Registration System, were residents in Denmark at 1 year of age, and enrolled in the iPSYCH Initiative. We used epidemiological methods in conjunction with nationwide hospital registers to analyse the iPSYCH case cohort of individuals with attention-deficit hyperactivity disorder (ADHD), major depressive disorder, schizophrenia, autism, or bipolar disorder and a random population-based sample. The main outcomes assessed were the population prevalence of 22q11.2 rearrangements, and associated unbiased, population-adjusted estimates and 31-year disease risk trajectories for major neuropsychiatric disorders. Population prevalence in the Danish population was one in 3672 (seven of 25 704 [0·027%; 95% CI 0·012-0·057]) for deletions and one in 1606 (17 of 25 704 [0·066%; 0·040-0·107]) for duplications. Mortality after the age of 1 year among carriers was zero, and hazard ratios for neuropsychiatric disorders ranged from 2·60 to 82·44 for both rearrangements. By the age of 32 years, about 10% of individuals with deletions or duplications had developed ADHD, autism, or intellectual disability, and deletion carriers had higher probability than duplication carriers of co-occurring intellectual disability or epilepsy. The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. Although risk of congenital abnormalities, developmental delay, and intellectual disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.


Redesigning care processes using an electronic health record: a system's experience.
Implementation of health information technology (HIT) has encountered many difficulties and produced mixed outcomes. Yet Trinity Health, a major integrated delivery system, successfully leveraged implementation of a systemwide electronic health record (EHR) to promote process redesign and continuous quality improvement. After several years of planning, two waves of EHR implementation were launched, in 2001 and 2003. One system HIT team collaborated with each hospital team for 18 months before its 24-hour transition to the EHR. During EHR planning, the system HIT team used five principles of redesign of care processes: (1) identify and address safety problems, (2) promote evidence-based practices, (3) reduce practice variations and standardize terminologies and care processes, (4) improve communication and relationships among clinician roles, and (5) augment multiple uses of data in HIT-supported care processes. Patient-centered work flows were developed to design improved patient care processes for different types of patients, such as medical inpatients and emergency outpatients. These admission-to-discharge work flows addressed gaps in quality, safety, and efficiency and helped ensure that the EHR and decision supports reflected crucial interactions among clinicians and with the patient. By the end of 2008, 13 of Trinity Health's 17 major health care organizations ("ministries") made the transformation to using EHRs. EHR-supported care redesign requires development of substantial system capacities in clinical informatics, customization and standardization of vendor's products, collaboration and coordination between system and hospital implementation teams, quality training for clinicians and change agents, and significant clinician participation in local preparations.


Prevalence and Trends in Alcohol Dependence and Alcohol Use Disorders in Japanese Adults; Results from Periodical Nationwide Surveys.
Nationwide surveys to clarify the characteristics and trends of the drinking behavior of Japanese adults were carried out in 2003, 2008, and 2013. These were periodical cross-sectional surveys. Subjects were chosen through a stratified two-stage random sampling method. The surveys included drinking frequency and amount, ICD-10 alcoholism diagnostic standards, questionnaire for the determination of harmful alcohol use ( Alcohol Use Disorders Identification Test). In 2003, the surveys obtained responses from 2547 people (73% response rate); in 2008, 4123 people (55% response rate); and in 2013, 4153 people (59% response rate). The proportion of lifetime experience of alcohol dependence diagnosed by ICD-10 was 1.9% for male and 0.2% for female, and the estimated number of patients was 1.07 million. The declining trends were observed in the percentage of daily drinkers and the amount of alcohol consumed per week for male. The lowering of the age for consuming their first alcoholic drink and their first drunken experience was observed among female. The gender difference of prevalence of problem drinking is getting smaller. The binge drinking and heavy episodic drinking were observed especially younger generation. The only small proportion of patients with alcohol dependence had received specialized medical care, whereas the many of these visited medical institutions and health screening. The survey observed many hidden alcoholic patients, and showed the possibility that the healthcare facilities and health screening became the place of screening and intervention for alcohol dependence.


Roles for transforming growth factor-alpha in the stomach.
The gastric mucosa maintains its integrity despite the harsh environment of an acidic luminal pH and strong mechanical stresses secondary to peristalsis of ingested contents. The mucosa has marshalled a battery of both protective and reparative mechanisms which, in general, prevent the deleterious effects of these factors that, if unchecked, may result in untoward consequences such as gastritis and peptic ulcer disease. An increasing body of evidence suggests that transforming growth factor-alpha (TGF alpha) produced by the gastric mucosa is a critical mediator of gastric mucosal homeostasis. TGF alpha inhibits acid secretion, stimulates mucosal restitution after injury (cell migration and proliferation), and augments gastric mucin levels. We review the data that support a role for this endogenously produced growth factor in both protective and reparative actions in the stomach. In addition, we discuss a possible role for overproduction of TGF alpha in the pathogenesis of Ménétrier's disease, a premalignant disorder of the stomach characterized by fundic gland hyperplasia, hypochlorhydria, increased gastric mucus, and hypoalbuminemia.


Characterization of the interaction between 4-(tetrahydro-2-furanmethoxy)-N-octadecyl-1,8-naphthalimide and human serum albumin by molecular spectroscopy and its analytical application.
A novel 4-(tetrahydro-2-furanmethoxy)-N-octadecyl-1,8-naphthalimide (TNN) was synthesized as a spectrofluorimetric probe for the determination of proteins. The effect of different solvents on the spectral characteristics of TNN was investigated. The results showed that TNN displayed dependent solvent polarity properties due to the effect of internal charge transfer. The interactions between TNN and human serum albumin (HSA) were studied by fluorescence and absorption spectroscopy. Fluorescence data revealed that the fluorescence quenching of HSA by TNN was the result of the formation of TNN-HSA complex. The binding parameters of interactions between TNN and HSA at different temperatures were obtained according to the Stern-Volmer equation. The thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS), for the interactions were calculated to be -7.31 kJ mol(-1) and 72.75 J mol(-1) K(-1) according to the van't Hoff equation, indicating that the hydrogen bonds and hydrophobic interactions were the dominant intermolecular force in stabilizing the complex. The effect of TNN on the conformation of HSA was analyzed by circular dichroism and synchronous fluorescence spectroscopy. Furthermore, the results of displacement experiments using warfarin indicated that TNN could bind to site I of HSA. The fluorescence of TNN could be largely quenched by HSA, based on which a new fluorometric method for detecting HSA in the HCl-Tris buffer solution (pH = 7.4) was developed. The linear ranges of the calibration curves were 0.1~14.2 μM for HSA, 0.1~13.0 μM for bovine serum albumin (BSA), 0.2~9.7 μM for γ-globulin, and 0.3~11.3 μM for hemoglobin (Hb), with detection limits (3σ) of 1.37 × 10(-10) M for HSA, 1.84 × 10(-10) M for BSA, 3.14 × 10(-10) M for γ-globulin, and 6.86 × 10(-10) M for Hb. The effect of metal cations on the fluorescence spectra of TNN in ethanol was also investigated. The method has been applied to the determination of total proteins in human serum samples collected from the hospital and the results were in good agreement with those reported by the hospital.


Oxygen uptake and carbon dioxide elimination during controlled hypotension induced by prostaglandin E1 or nitroglycerin.
To compare the effects of prostaglandin E1 (PGE1) with those of nitroglycerin (NTG) on whole body metabolism (oxygen uptake (VO2) and carbon dioxide elimination (VCO2) during induced hypotension, we have studied 16 patients undergoing elective surgery (radical mastectomy or tympanoplasty). The patients were allocated randomly in a non-blinded manner to two groups. Baseline characteristics were similar in the two groups. Arterial pressure was controlled at about 70% of the baseline value using PGE1 or NTG. VO2, VCO2, gas exchange ratio (RQ) and deadspace ventilation ratio (VD/VT) were measured continuously with mass spectrometry. The values for all variables were measured for 10 min at five times (1 = start of surgery (baseline value); 2 = start of drug infusion; 3 = 60 min after start of drug infusion; 4 = drug infusion stopped; 5 = surgery finished). VO2, VCO2, RQ and VD/VT values were relatively constant in both groups during surgery. The balance between oxygen supply and oxygen demand was maintained during induced hypotension with PGE1 or NTG.


Detection of counterfeit electronic components through ambient mass spectrometry and chemometrics.
In the last several years, illicit electronic components have been discovered in the inventories of several distributors and even installed in commercial and military products. Illicit or counterfeit electronic components include a broad category of devices that can range from the correct unit with a more recent date code to lower-specification or non-working systems with altered names, manufacturers and date codes. Current methodologies for identification of counterfeit electronics rely on visual microscopy by expert users and, while effective, are very time-consuming. Here, a plasma-based ambient desorption/ionization source, the flowing atmospheric pressure afterglow (FAPA) is used to generate a mass-spectral fingerprint from the surface of a variety of discrete electronic integrated circuits (ICs). Chemometric methods, specifically principal component analysis (PCA) and the bootstrapped error-adjusted single-sample technique (BEAST), are used successfully to differentiate between genuine and counterfeit ICs. In addition, chemical and physical surface-removal techniques are explored and suggest which surface-altering techniques were utilized by counterfeiters.


Bound-State Diffusion due to Binding to Flexible Polymers in a Selective Biofilter.
Selective biofilters are used by cells to control the transport of proteins, nucleic acids, and other macromolecules. Biological filters demonstrate both high specificity and rapid motion or high flux of proteins. In contrast, high flux comes at the expense of selectivity in many synthetic filters. Binding can lead to selective transport in systems in which the bound particle can diffuse, but the mechanisms that lead to bound diffusion remain unclear. Previous theory has proposed a molecular mechanism of bound-state mobility based only on transient binding to flexible polymers. However, this mechanism has not been directly tested in experiments. We demonstrate that bound mobility via tethered diffusion can be engineered into a synthetic gel using protein fragments derived from the nuclear pore complex. The resulting bound-state diffusion is quantitatively consistent with theory. Our results suggest that synthetic biological filters can be designed to take advantage of tethered diffusion to give rapid, selective transport.


A Haemophilus ducreyi CpxR deletion mutant is virulent in human volunteers.
Haemophilus ducreyi 35000HP contains a homolog of the CpxRA 2-component signal transduction system, which controls the cell envelope stress response system in other gram-negative bacteria and regulates some important H. ducreyi virulence factors. A H. ducreyi cpxR mutant was compared with its parent for virulence in the human challenge model of experimental chancroid. The pustule formation rate in 5 volunteers was 33% (95% confidence interval [CI], 1.3%-65.3%) at 15 parent sites and 40% (95% CI, 18.1%-61.9%) at 15 mutant sites (P = .35). Thus, the cpxR mutant was not attenuated for virulence. Inactivation of the H. ducreyi cpxR gene did not reduce the ability of this mutant to express certain proven virulence factors, including the DsrA serum resistance protein and the LspA2 protein, which inhibits phagocytosis. These results expand our understanding of the involvement of the CpxRA system in regulating virulence expression in H. ducreyi.


Modulation of endocytosis in nuclear factor IL-6(-/-) macrophages is responsible for a high susceptibility to intracellular bacterial infection.
Activated macrophages kill bacteria, a function known to depend on the expression of NF-IL-6. Here, it is demonstrated that the attenuated Brucella abortus vaccine strain 19 replicates much better in NF-IL-6-/- than in NF-IL-6(+/+) and NF-IL-6(+/+)-activated murine macrophages and at levels comparable to those observed in normal macrophages infected with the pathogenic strain 2308. The role of NF-IL-6 in the inhibition of intracellular bacterial replication is related to its control of endocytosis and membrane fusion between endosomes and Brucella-containing phagosomes. Addition of the granulocyte-CSF (G-CSF), whose induction is impaired in NF-IL-6(-/-) macrophages, restores both endocytosis and the morphology of endosomes, together with bactericidal activity. Regulation of membrane traffic in endocytosis by G-CSF whose expression is controlled by NF-IL-6 may explain how a host cell can control intracellular bacterial replication.


Two new species of Paraboea (Gesneriaceae) in Caryota obtusa forests in Southwest China, with compound and simple dichasia, respectively.
Two new species of Gesneriaceae, Paraboea myriantha sp. nov. and P. brevipedunculata sp. nov. are described and illustrated with photos. They grow in the Caryota obtusa forests from Yunnan Province of China. P. myriantha is closely related to P. glutinosa (Hand.-Mazz.) K.Y.Pan, but differs mainly in corolla outside glandular-puberulent, adaxial corolla lobes semicordate, corolla tube obliquely campanulate, and filaments glandular-puberulent. P. brevipedunculata is closely related to P. crassifolia (Hemsley) B. L. Burtt, but different mainly in simple dichasia with 1 and 2 flowers, peduncles 0.5-2 cm long and capsules slightly twisted. The geographical relationship between the two new species and their similar species has been discussed.


Brassinosteroids: Multidimensional Regulators of Plant Growth, Development, and Stress Responses.
Brassinosteroids (BRs) are a group of polyhydroxylated plant steroid hormones that are crucial for many aspects of a plant's life. BRs were originally characterized for their function in cell elongation, but it is becoming clear that they play major roles in plant growth, development, and responses to several stresses such as extreme temperatures and drought. A BR signaling pathway from cell surface receptors to central transcription factors has been well characterized. Here, we summarize recent progress toward understanding the BR pathway, including BR perception and the molecular mechanisms of BR signaling. Next, we discuss the roles of BRs in development and stress responses. Finally, we show how knowledge of the BR pathway is being applied to manipulate the growth and stress responses of crops. These studies highlight the complex regulation of BR signaling, multiple points of crosstalk between BRs and other hormones or stress responses, and the finely tuned spatiotemporal regulation of BR signaling.


Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees.
The relationship of viral persistence, the immune response to hepatitis C virus (HCV) envelope proteins, and envelope sequence variability was examined in chimpanzees. Antibody reactivity to the HCV envelope proteins E1 or E2 was detected by enzyme-linked immunosorbent assay (ELISA) in more than 90% of a human serum panel. Although the ELISAs appeared to be sensitive indicators of HCV infection in human serum panels, the results of a cross-sectional study revealed that a low percentage of HCV-inoculated chimpanzees had detectable antibody to E1 (22%) and E2 (15%). Viral clearance, which was recognized in 28 (61%) of the chimpanzees, was not associated with an antibody response to E1 or E2. On the contrary, antibody to E2 was observed only in viremic chimpanzees. A longitudinal study of animals that cleared the viral infection or became chronically infected confirmed the low level of antibody to E1, E2, and the HVR-1. In 10 chronically infected animals, the sequence variation in the E2 hypervariable region (HVR-1) was minimal and did not coincide with antibody to E2 or to the HVR-1. In addition, low nucleotide and amino acid sequence variation was observed in the E1 and E2 regions from two chronically infected chimpanzees. These results suggest that mechanisms in addition to the emergence of HVR-1 antibody escape variants are involved in maintaining viral persistence. The significance of antibodies to E1 and E2 in the chimpanzee animal model is discussed.


Trehalose 6-phosphate phosphatase is required for cell wall integrity and fungal virulence but not trehalose biosynthesis in the human fungal pathogen Aspergillus fumigatus.
The trehalose biosynthesis pathway is critical for virulence in human and plant fungal pathogens. In this study, we tested the hypothesis that trehalose 6-phosphate phosphatase (T6PP) is required for Aspergillus fumigatus virulence. A mutant of the A. fumigatus T6PP, OrlA, displayed severe morphological defects related to asexual reproduction when grown on glucose (1%) minimal media. These defects could be rescued by addition of osmotic stabilizers, reduction in incubation temperature or increase in glucose levels (> 4%). Subsequent examination of the mutant with cell wall perturbing agents revealed a link between cell wall biosynthesis and trehalose 6-phosphate (T6P) levels. As expected, high levels of T6P accumulated in the absence of OrlA resulting in depletion of free inorganic phosphate and inhibition of hexokinase activity. Surprisingly, trehalose production persisted in the absence of OrlA. Further analyses revealed that A. fumigatus contains two trehalose phosphorylases that may be responsible for trehalose production in the absence of OrlA. Despite a normal growth rate under in vitro growth conditions, the orlA mutant was virtually avirulent in two distinct murine models of invasive pulmonary aspergillosis. Our results suggest that further study of this pathway will lead to new insights into regulation of fungal cell wall biosynthesis and virulence.


Association of Antithrombotic Drug Use With Subdural Hematoma Risk.
Incidence of subdural hematoma has been reported to be increasing. To what extent this is related to increasing use of antithrombotic drugs is unknown. To estimate the association between use of antithrombotic drugs and subdural hematoma risk and determine trends in subdural hematoma incidence and antithrombotic drug use in the general population. Case-control study of 10 010 patients aged 20 to 89 years with a first-ever subdural hematoma principal discharge diagnosis from 2000 to 2015 matched by age, sex, and calendar year to 400 380 individuals from the general population (controls). Subdural hematoma incidence and antithrombotic drug use was identified using population-based regional data (population: 484 346) and national data (population: 5.2 million) from Denmark. Conditional logistic regression models were used to estimate odds ratios (ORs) that were adjusted for comorbidity, education level, and income level. Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), a direct oral anticoagulant, and combined antithrombotic drug treatment. Association of subdural hematoma with antithrombotic drug use, subdural hematoma incidence rate, and annual prevalence of treatment with antithrombotic drugs. Among 10 010 patients with subdural hematoma (mean age, 69.2 years; 3462 women [34.6%]), 47.3% were taking antithrombotic medications. Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%; adjusted OR, 1.24 [95% CI, 1.15-1.33]), clopidogrel (cases: 5.0%, controls: 2.2%; adjusted OR, 1.87 [95% CI, 1.57-2.24]), a direct oral anticoagulant (cases: 1.0%, controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31-2.28]), and a VKA (cases: 14.3%, controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38-4.03]) were associated with higher risk of subdural hematoma. The risk of subdural hematoma was highest when a VKA was used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40-4.70]; clopidogrel and a VKA: 0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49-14.02]). The prevalence of antithrombotic drug use increased from 31.0 per 1000 individuals from the general population in 2000 to 76.9 per 1000 individuals in 2015 (P < .001 for trend). The overall subdural hematoma incidence rate increased from 10.9 per 100 000 person-years in 2000 to 19.0 per 100 000 person-years in 2015 (P < .001 for trend). The largest increase was among older patients (>75 years; n = 4441) who experienced an increase from 55.1 per 100 000 person-years to 99.7 per 100 000 person-years (P < .001 for trend). In Denmark, antithrombotic drug use was associated with higher risk of subdural hematoma; and the highest odds of subdural hematoma was associated with combined use of a VKA and an antiplatelet drug. The increased incidence of subdural hematoma from 2000 to 2015 appears to be associated with the increased use of antithrombotic drugs, particularly use of a VKA among older patients.


Primary renal synovial sarcoma.
Synovial sarcomas are generally deep-seated tumors that most often occur in the proximity of large joints of adolescents and young adults. We describe two cases of primary renal synovial sarcoma that were treated successfully by radical nephrectomy. Synovial sarcoma originating from the kidney is extremely rare and the histogenesis is uncertain. Surgical resection and ifosfamide based chemotherapy are the mainstay for the management of renal synovial sarcoma. Fewer than 40 patients have been described in the English literature. Physicians should be aware of the possibility of malignancy in cystic renal masses and raise the suspicion of synovial sarcoma, especially when patients with renal masses are a young adult.


Validity and reliability of the Severity of Dependence Scale (SDS) in a Brazilian sample of drug users.
The Severity of Dependence Scale (SDS) is a short, five-item scale which provides a measure of degree of dependence upon different drugs. The present study explores the validity and reliability of a Portuguese version of the instrument with a sample of 374 Brazilian drug users. Concurrent validity of the SDS was assessed in relation to reported quantity of drugs used and to DSM-IV dependence items, and test-retest reliability was assessed with a subsample of 42 subjects. The SDS total scores for powder cocaine, crack cocaine, cannabis and alcohol were significantly and highly positively correlated with severity of dependence as measured by DSM-IV, and with the estimated quantity of drugs used in the last month. Test-retest coefficients were high for all drugs studied. Principal components analysis showed that the SDS scores lie on a single dimension with the exception of crack cocaine where scores lie on a single dimension for treatment attenders and on two dimensions for community samples. The results indicate that the Portuguese version of the SDS is a valid research tool for measuring severity of dependence upon powder cocaine (snorted), crack cocaine (smoked), cannabis and alcohol.


Thrills, spills and pills: Bond, Benzedrine and the pharmacology of peace.
This paper examines the conjunction of pharmacological science and espionage fiction of the post-war era. This paper argues that, during the 1950s, the relatively new science of pharmacology propounded the possibility that illness and human deficiency could be treated in a way that better reflected the post-war zeitgeist. The use of pharmacological medicine, perceived as cleaner and quicker than more 'bodily' forms of treatment, represented progress in contemporary medical science. It is argued that this philosophy extended to more overt means of pharmacological application, directly related to the geopolitical concerns of the 'Cold War'. A growing form of popular literature in this period was the espionage novel. This paper argues that the benefits proffered by pharmacology were incorporated into the fabric of espionage fiction, specifically the James Bond novels of Ian Fleming. Here, it is demonstrated how Fleming used pharmacological knowledge of Benzedrine throughout his novels. His works illustrate a belief that the augmentation of the spy's natural ability with pharmacological science would award decisive advantage in the Cold War conflict played out in spy fiction. However, the relationship between public use of Benzedrine and awareness of its side effects changed during the period of Fleming's publications, moving from a position of casual availability to one of controlled prescription. It is argued that the recognition of the dangers associated with the drug were over-ruled in favour of the benefits its use presented to the state. The continued use of the drug by Bond illustrates how the concerns of the nation are given priority over the health, and life, of the individual.


The future of molecular chaperones and beyond.
Protection of hair cells by HSP70 released by supporting cells is reported by May et al. in this issue of the JCI. Their findings suggest a new way to reduce ototoxicity from therapeutic medications and raise larger questions about the role and integration of heat shock proteins in non–cell-autonomous responses to stress. Increasing evidence suggests an important role for extracellular heat shock proteins in both the nervous system and the immune system. The work also suggests that defective chaperones could cause ear disease and supports the potential use of chaperone therapeutics.


Providing antiretroviral care in conflict settings.
There has been an historic expectation that delivering combination antiretroviral therapy (cART) to populations affected by violent conflict is untenable due to population movement and separation of drug supplies. There is now emerging evidence that cART provision can be successful in these populations. Using examples from Médecins Sans Frontières experience in a variety of African settings and also local nongovernmental organizations' experiences in northern Uganda, we examine novel approaches that have ensured retention in programs and adequate adherence. Emerging guidelines from United Nations bodies now support the expansion of cART in settings of conflict.


Retrograde intramedullary nail fixation compared with fixed-angle plate fixation for fracture of the distal femur: the TrAFFix feasibility RCT.
Fractures of the distal femur are an increasingly common injury; the optimal management of these injuries remains controversial. The two interventions used in UK practice are intramedullary fixation, with a locked retrograde nail, and extramedullary fixation, with a fixed angle plate. This study assessed the feasibility of a definitive trial and included a process evaluation to understand the generalisability and likely success of a future trial. A multicentre, parallel, two-arm, randomised controlled feasibility trial with an embedded process evaluation. Treatment with a plate or nail was allocated in a 1 : 1 ratio, stratified by centre and chronic cognitive impairment. Surgeons were not blinded, but participants were not told their allocation. Seven NHS hospitals. Patients aged ≥ 18 years with a fracture of the distal femur who the attending surgeon believed would benefit from internal fixation were potentially eligible. Patients were excluded if they had a loose arthroplasty requiring revision or a femoral deformity or arthroplasty that precluded nail fixation. The sample was recruited between 29 September 2016 and 31 August 2017. Consent was obtained from the patient or appropriate consultee before enrolment. Patients were randomised to receive fixation of their distal femur fracture with either a proximally and distally locked retrograde nail that spanned the diaphysis of the femur or an anatomical distal femoral locking plate with at least one locked screw distal to the fracture. Reduction and supplemental fixation were at the surgeon's discretion. The primary outcome measures for this study were the recruitment rate and the completion rate of the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), at 6 weeks and 4 months. Additional measurements included baseline characteristics, measures of social support and self-efficacy, disability rating index, dementia quality-of-life measures and a radiographical assessment of any malunion. Participants' and staff views were obtained, at interview, for the process evaluation. The process evaluation showed that surgeon-related factors, principally confidence with both technologies and a lack of individual equipoise, were key barriers to recruitment. A total of 23 participants were randomised and analysed (nail, n = 11; plate, n = 12). The recruitment rate was estimated as 0.42 [95% confidence interval (CI) 0.27 to 0.62] participants per centre per month, lower than the prespecified feasibility threshold of 1.0 participants per centre per month. Data completeness of the EQ-5D-5L was estimated at 65% (95% CI 43% to 83%). This feasibility study has challenged many of the assumptions that underpinned the development of proposed definitive trial protocol. A modified protocol is proposed that would be feasible given the recruitment rate observed here, which is equal to that reported in the similar FixDT trial [Health Technology Assessment (HTA) 11/136/04: Costa ML, Achten J, Hennings S, Boota N, Griffin J, Petrou S, et al. Intramedullary nail fixation versus locking plate fixation for adults with a fracture of the distal tibia: the UK FixDT RCT. Health Technol Assess 2018;22(25)], which delivered to target and budget. A definitive trial with a modified design is recommended, including an internal pilot to confirm initial recruitment rate assumptions. Current Controlled Trials ISRCTN92089567. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 51. See the NIHR Journals Library website for further project information. Funding was also supported by the NIHR Oxford Biomedical Research Centre.


Protein subcellular localization prediction using artificial intelligence technology.
Proteins perform many important tasks in living organisms, such as catalysis of biochemical reactions, transport of nutrients, and recognition and transmission of signals. The plethora of aspects of the role of any particular protein is referred to as its "function." One aspect of protein function that has been the target of intensive research by computational biologists is its subcellular localization. Proteins must be localized in the same subcellular compartment to cooperate toward a common physiological function. Aberrant subcellular localization of proteins can result in several diseases, including kidney stones, cancer, and Alzheimer's disease. To date, sequence homology remains the most widely used method for inferring the function of a protein. However, the application of advanced artificial intelligence (AI)-based techniques in recent years has resulted in significant improvements in our ability to predict the subcellular localization of a protein. The prediction accuracy has risen steadily over the years, in large part due to the application of AI-based methods such as hidden Markov models (HMMs), neural networks (NNs), and support vector machines (SVMs), although the availability of larger experimental datasets has also played a role. Automatic methods that mine textual information from the biological literature and molecular biology databases have considerably sped up the process of annotation for proteins for which some information regarding function is available in the literature. State-of-the-art methods based on NNs and HMMs can predict the presence of N-terminal sorting signals extremely accurately. Ab initio methods that predict subcellular localization for any protein sequence using only the native amino acid sequence and features predicted from the native sequence have shown the most remarkable improvements. The prediction accuracy of these methods has increased by over 30% in the past decade. The accuracy of these methods is now on par with high-throughput methods for predicting localization, and they are beginning to play an important role in directing experimental research. In this chapter, we review some of the most important methods for the prediction of subcellular localization.


A hepatitis B virus mutant with a new hepatocyte nuclear factor 1 binding site emerging in transplant-transmitted fulminant hepatitis B.
Hepatitis B virus (HBV) DNA was cloned from serum of a heart transplant recipient who died from fulminant hepatitis B transmitted by the donor. Restriction enzyme analyses of the clones obtained by conventional cloning yielded six HBV variants: a major species (pF-1) representing 88% and five minor species (pF-2 to pF-6), each representing 2% to 4% of the clones. The complete nucleotide sequence of these six variants revealed that five of the six viral genomes, including pF-1, carried a novel 11 base pair (bp) insertion in the core promoter region as well as an 18 bp and an 108 bp in-frame deletion in the pre-S1 region not present in the donor. One genome was identical to the sequence of the donor. Functional analyses of HBV clones generated by in vitro mutagenesis and cassette exchange showed that the 11 bp insertion is a strong binding site for hepatocyte nuclear factor 1 (HNF-1). In transient transfection experiments, the novel HNF-1 sequence motif was shown to result in enhanced viral replication. Immunohistochemical analyses revealed high levels of cytoplasmic and nuclear hepatitis B core antigen (HBcAg) and only scattered hepatitis B surface antigen (HBsAg) expression in the liver. The data in our immunosuppressed patient showed that HBV variants can rapidly accumulate in severe hepatitis B and suggest that the novel HNF-1 binding site may have contributed to the fulminant clinical course, possibly via enhanced viral replication.


Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase.
To examine the role of the mitochondrial polymerase (Pol gamma) in clinically observed toxicity of nucleoside analogs used to treat AIDS, we examined the kinetics of incorporation catalyzed by Pol gamma for each Food and Drug Administration-approved analog plus 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU), beta-L-(-)-2',3'-dideoxy-3'-thiacytidine (-)3TC, and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). We used recombinant exonuclease-deficient (E200A), reconstituted human Pol gamma holoenzyme in single turnover kinetic studies to measure K(d) (K(m)) and k(pol) (k(cat)) to estimate the specificity constant (k(cat)/K(m)) for each nucleoside analog triphosphate. The specificity constants vary more than 500,000-fold for the series ddC > ddA (ddI) > 2',3'-didehydro-2',3'-dideoxythymidine (d4T) >> (+)3TC >> (-)3TC > PMPA > azidothymidine (AZT) >> Carbovir (CBV). Abacavir (prodrug of CBV) and PMPA are two new drugs that are expected to be least toxic. Notably, the higher toxicities of d4T, ddC, and ddA arose from their 13-36-fold tighter binding relative to the normal dNTP even though their rates of incorporation were comparable with PMPA and AZT. We also examined the rate of exonuclease removal of each analog after incorporation. The rates varied from 0.06 to 0.0004 s(-1) for the series FIAU > (+)3TC approximately equal to (-)3TC > CBV > AZT > PMPA approximately equal to d4T >> ddA (ddI) >> ddC. Removal of ddC was too slow to measure (<0.00002 s(-1)). The high toxicity of dideoxy compounds, ddC and ddI (metabolized to ddA), may be a combination of high rates of incorporation and ineffective exonuclease removal. Conversely, the more effective excision of (-)3TC, CBV, and AZT may contribute to lower toxicity. FIAU is readily extended by the next correct base pair (0.13 s(-1)) faster than it is removed (0.06 s(-1)) and, therefore, is stably incorporated and highly mutagenic. We define a toxicity index for chain terminators to account for relative rates of incorporation versus removal. These results provide a method to rapidly screen new analogs for potential toxicity.


Complete nucleotide sequence and genetic organization of the bacteriocinogenic plasmid, pIP404, from Clostridium perfringens.
The complete nucleotide sequence of the bacteriocinogenic plasmid, pIP404, from Clostridium perfringens has been determined. The plasmid genome comprises 10,207 bp and has a dA + dT content of 75%. Functions have been tentatively assigned to 6 of the 10 open reading frames and an origin-like region of repeated sequence identified. The codon usage of this extremely dA + dT rich plasmid is highly unusual and displays a pronounced preference for codons with the lowest dG + dC content. Only one of the genes from pIP404 was expressed at a significant level in Escherichia coli, suggesting that the atypical codon usage could represent a major obstacle to heterologous gene expression.


[Mechanisms of structural plasticity associated with photic synchronization of the circadian clock within the suprachiasmatic nucleus].
The mammalian circadian clock, whose central component is located in the suprachiasmatic nucleus of the hypothalamus (SCN), orchestrates rhythmic events in metabolism, physiology and behavior. Adaptation of the organism to its environment requires precise adjustment of the clock to the 24 h astronomical time, primarily by the light/dark cycle. Photic synchronization acts on both the molecular loops which trigger circadian oscillations and the phasing of the multiple SCN cellular oscillators whose coordination permits elaboration of the rhythmic message that will be distributed throughout the organism. It is concomitant with structural plastic events characterized by day/night rearrangements of the SCN neuronal-glial network. The two main sources of SCN efferents, namely the VIP (vasoactive intestinal peptide)-synthesizing neurons which are major integrators of photic signals and the AVP (arginine-vasopressin)-synthesizing neurons which are known to importantly contribute to conveying rhythmic messages to brain targets, are involved in these mechanisms. Over the light/dark cycle, they indeed undergo ultrastructural changes in the extent of their membrane coverage by glial, axon terminal and/or somato-dendritic elements. These structural rearrangements appear to be dependent on light entrainment, as the rhythmic expression in SCN of glial fibrillary acidic protein (GFAP), a marker for brain astrocytes whose changing expression has proved to be a reliable index of neuronal-glial plasticity, is disrupted under constant darkness. Glucocorticoid hormones, which are known as important endocrine outputs of the clock, are required to maintain amplitude of the SCN GFAP rhythm to normal values, indicating that they modulate astrocytic plasticity within the SCN and, therefore, nycthemeral changes of the configuration of its neuronal-glial network. The view that such plastic events may subserve synchronization of the clock to the light-dark cycle is reinforced by other data showing that the daily fluctuations of circulating glucocorticoids actually are involved in modulation of light effects, contributing to the resistance of the circadian timing system to variations of the photoperiod. It is thus proposed that the capacity of the clock to integrate cyclic variations of the environment rely on the inherent capacity of the SCN to undergo neuronal-glial plasticity.


Hospital infection society prevalence survey of Healthcare Associated Infection 2006: comparison of results between Northern Ireland and the Republic of Ireland.
As part of the Third Healthcare Associated Infection (HCAI) Prevalence Survey of the United Kingdom and Ireland, HCAI point prevalence surveys were carried out in Northern Ireland (NI) and the Republic of Ireland (RoI). Here we explore the potential benefits of comparing results from two countries with different healthcare systems, which employed similar methodologies and identical HCAI definitions. Forty-four acute adult hospitals in the RoI and 15 in NI participated with a total of 11 185 patients surveyed (NI 3644 patients and RoI 7541). The overall HCAI prevalence was 5.4 and 4.9 in NI and the RoI, respectively. There was no significant difference in prevalence rates of HCAI, device-related HCAI or HCAI associated with bloodstream infection but there was a difference in meticillin-resistant Staphylococcus aureus-related HCAI (P = 0.02) between the two countries. There were significantly more urinary tract infections and Clostridium difficile infections recorded in NI (P = 0.002 and P < 0.001). HCAIs were more prevalent in patients aged >65 years and in the intensive care unit in both countries. HCAIs were also more prevalent if patients were mechanically ventilated, had had recent non-implant surgery (RoI) or had more recorded HCAI risk factors. This is the first time that HCAI prevalence rates have been directly compared between NI and the RoI. By closely examining similarities and differences between HCAI prevalence rates in both countries it is hoped that this will influence healthcare planning and at the same time reassure the public that HCAI is important and that measures are being taken to combat it.


San andreas fault zone head waves near parkfield, california.
Microearthquake seismograms from the borehole seismic network on the San Andreas fault near Parkfield, California, provide three lines of evidence that first P arrivals are "head" waves refracted along the cross-fault material contrast. First, the travel time difference between these arrivals and secondary phases identified as direct P waves scales linearly with the source-receiver distance. Second, these arrivals have the emergent wave character associated in theory and practice with refracted head waves instead of the sharp first breaks associated with direct P arrivals. Third, the first motion polarities of the emergent arrivals are reversed from those of the direct P waves as predicted by the theory of fault zone head waves for slip on the San Andreas fault. The presence of fault zone head waves in local seismic network data may help account for scatter in earthquake locations and source mechanisms. The fault zone head waves indicate that the velocity contrast across the San Andreas fault near Parkfield is approximately 4 percent. Further studies of these waves may provide a way of assessing changes in the physical state of the fault system.


Clinicopathological characteristics and lymph node metastasis pathway of non-small-cell lung cancer located in the left lingular division.
The purpose of this study is to assess the clinicopathological characteristics of non-small-cell lung cancer (NSCLC) occurring in the left lingular division (LLD) in association with a proposal of the LLD-specific regional lymph node stations. Medical records of patients, who underwent complete tumour resection with mediastinal lymph node dissection (MLND) for LLD-NSCLC from 2000 to 2009 in multiple institutions, were retrospectively examined. We analysed patient clinicopathological characteristics and obtained the LLD-specific regional lymph node stations, and then the validity of intraoperative navigation in lymphadenectomy for LLD-NSCLC was investigated. One hundred and eighty-four LLD-NSCLC patients (97 males and 87 females, and 128 adenocarcinomas and 56 non-adenocarcinomas) were studied. The 5-year overall survival (OS) and disease-free survival (DFS) rates for all LLD-NSCLC patients were 72.9 and 58.3%, respectively. We examined the lymph node metastasis patterns in 42 node-positive tumours. The frequent metastatic lymph node stations were #12u lobar node (n = 22), #5 subaortic node (n = 15) and #11 interlobar node (n = 13) in order. These three node stations were also single metastatic sites in some patients. Metastases to sub-carinal (#7) or inferior mediastinal nodes (#8) were rare. Thus, we assigned the three stations (#5, #11, #12u) as the regional lymph node stations for LLD-NSCLC. If these regional lymph node stations had been examined pathologically during surgery for a total of 160 LLD-NSCLC patients with c-T2N1M0 or lower stage disease, 125 p-N0 and 5 p-N1 patients diagnosed with no metastasis would have been subjected to selective MLND, while 14 p-N1 and all 16 p-N2 patients diagnosed with metastasis would have had complete MLND carried out. As a result, these regional lymph node stations could accurately predict the existence of p-N2 metastasis, and appropriately lead to a selective or complete MLND. An intraoperative pathological examination using our proposed LLD-specific regional lymph node stations may accurately diagnose the status of node metastasis, and appropriately lead to selective or complete MLND in LLD-NSCLC patients with c-T2N1M0 or lower stage disease.


Surgery in Traumatic Injury and Perioperative Considerations.
A severely injured patient presents several unique challenges to an admitting trauma team. Not only must the extent of the patient's injuries, particularly those that are life-threatening, be determined within minutes of hospital arrival, but also the trauma team needs to be able to assess whether the patient is bleeding and/or has an attendant coagulopathy. Early management of trauma patients is dictated by the presence (or absence) of significant bleeding. Standard definitive surgical procedures can be conducted in hemodynamically stable patients, but those in hemorrhagic shock should be treated according to damage control resuscitation (DCR) principles. DCR is a practice that has evolved over the last two to three decades, combining limited surgical techniques, which provide early hemorrhage control, and balanced transfusion resuscitation strategies, which mitigate (and ideally) treat trauma-induced coagulopathy (TIC). This review describes the contemporary perioperative management of trauma patients who have significant bleeding and/or TIC and sets out the evidence around the current approach for hemostatic resuscitation in these patients.


Luminescence of apollo 11 lunar samples.
Luminescence measurements were made of four lunar rocks, two terrestrial rocks (granite and gabbro), and one terrestrial mineral (willemite) by comparing the spectral curves with the curve of a barium sulfate standard. Efficiencies with 3000 angstrom excitation were < 6 x 10(-5) for the lunar samples, < 8 x 10(-5) for gabbro of very similar composition to the lunar samples, approximately 10(-4) for granite, and approximately 2 X 10(-2) for willemite. If these are typical values for other ultraviolet excitation wavelengths, the Apollo 11 site appears to contribute little to the observed lunar luminescence.


Active cigarette smoking and the risk of breast cancer: a cohort study.
Tobacco use has been implicated in the etiology of a large number of cancers, and there exists substantial biological plausibility that it could also be involved in breast carcinogenesis. Despite this, epidemiological evidence to date is inconsistent. The aim of this study was to investigate the role of active smoking and the risk of incident, invasive breast cancer using a prospective cohort of women from the Canadian Study of Diet, Lifestyle and Health. Using a case-cohort design, an age-stratified subcohort of 3314 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1096 breast cancer cases were identified in the entire cohort (including 141 cases from the subcohort) by linkage to the Canadian Cancer Registry. Cox regression models were used to estimate hazard ratios for the association between the different smoking exposures and the risk of breast cancer, using a modification for the case-cohort design. After carefully considering early-life exposures and potential confounders, we found no association between any smoking exposure and risk of breast cancer in this study (Hazard ratio=1.00, 95% confidence interval=0.87-1.17 for ever vs never smokers). Although these results cannot rule out an association between smoking and breast cancer, they do agree with the current literature suggesting that, if an association does exist, it is relatively weak.


Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer.
Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.


The multiple roles of salt-inducible kinases in regulating physiology.
Salt-inducible kinases (SIKs), which comprise a family of three homologous serine-threonine kinases, were first described for their role in sodium sensing but have since been shown to regulate multiple aspects of physiology. These kinases are activated or deactivated in response to extracellular signals that are cell surface receptor mediated and go on to phosphorylate multiple targets including the transcription cofactors CRTC1-3 and the class IIa histone deacetylases (HDACs). Thus, the SIK family conveys signals about the cellular environment to reprogram transcriptional and posttranscriptional processes in response. In this manner, SIKs have been shown to regulate metabolic responses to feeding/fasting, cell division and oncogenesis, inflammation, immune responses, and most recently, sleep and circadian rhythms. Sleep and circadian rhythms are master regulators of physiology and are exquisitely sensitive to regulation by environmental light and physiological signals such as the need for sleep. Salt-inducible kinases have been shown to be central to the molecular regulation of both these processes. Here, we summarize the molecular mechanisms by which SIKs control these different domains of physiology and highlight where there is mechanistic overlap with sleep/circadian rhythm control.


Antineoplastic effect and toxicity of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 in athymic mice with Y-79 human retinoblastoma tumors.
To evaluate the in vivo efficacy and toxicity of the 1,25-dihydroxy-16-ene-23-yne-vitamin D3 (16,23-D3) analogue in athymic nude mice injected with Y-79 human retinoblastoma cells and to compare the efficacy and toxicity of this compound with those of 1,25-dihydroxycholecalciferol (D3, calcitriol). Thirty athymic nude mice (4-6 weeks old) were injected subcutaneously with 1 x 10(7) Y-79 human retinoblastoma cells suspended in a 1:1 mixture of Iscove culture medium supplemented with 20% fetal bovine serum and basement membrane matrix suspension. Five days after tumor injection, the mice were randomized to 3 groups of 10 mice each. The first group served as a control group and received intraperitoneal injections of 0.25 mL of mineral oil (vehicle) 5 times a week. The second group received intraperitoneal injections of 0.05 microg of calcitriol in 0.25 mL of mineral oil intraperitoneally 5 times a week. The third group received intraperitoneal injections of 0.5 microg of 16,23-D3 in 0.25 mL of mineral oil 5 times a week. Injections were continued for 5 weeks, during which tumor size and mouse weight were individually measured. Toxicity was assessed by clinical measures such as lethargy, weight loss, and death. The mice were then killed and the size, volume, and weight of each tumor were determined. Also, in representative animals in each group, kidneys were evaluated for calcification and serum calcium concentration was measured. All experimental and control animals developed tumors subcutaneously. The 16,23-D3-treated mice had significantly smaller average tumor size (1.55 cm3) than the control mice (3.45 cm3) (P = .02), less gain in average body weight from the beginning of treatment (2.4 g vs 5.5 g) (P= .06), and a 40% mortality. The calcitriol-treated mice did not have significantly smaller average tumor size (1.26 cm3) than the 16,23-D3-treated mice (P = .35), had significant body weight loss compared with the control animals (calcitriol-treated mice lost 4.03 g) (P =.001), and had a mortality of 90% by the completion of the experiment. Histologically, there was no difference in the degree of tumor necrosis and calcification between control and experimental mice. Serum calcium concentrations were equivalent between the control (2.15 mmol/L [8.6 mg/dL]) and experimental groups (calcitriol, 1.88 mmol/L [7.5 mg/dL] [P = .97]; 16,23-D3, 2.15 mmol/L [8.6 mg/dL] [P = .42]). Mild bilateral renal tubular calcification occurred in 3 of 4 mice in the calcitriol-treated group and in 2 of 4 mice in the 16,23-D3-treated group. The growth of subcutaneous Y-79 human retinoblastoma cells in athymic nude mice is significantly reduced by treatment with intraperitoneal injections of 16,23-D3. The antineoplastic effect of calcitriol is not statistically significantly different but is associated with significantly more toxicity. 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 may be a useful chemotherapeutic adjunct in the treatment of retinoblastoma.


Visible light driven water splitting through an innovative Cu-treated-δ-MnO2 nanostructure: probing enhanced activity and mechanistic insights.
In this study, we have fabricated nanostructured thin films of δ-MnO2 on FTO glass substrates by a facile, room-temperature and low cost chemical bath deposition method. A copper treatment procedure in the synthesis steps results in a film of Cu-δ-MnO2, which displays significant photoactivity when used as a photocathode for hydrogen evolution reaction, with a photocurrent of 3.59 mA cm-2 (at 0 V vs. RHE) in a mild acidic solution. Furthermore, the electrodes also display significant electrocatalytic activity towards water oxidation reaching up to 10 mA cm-2 (at only 1.67 V vs. RHE). The Cu-δ-MnO2 film has been thoroughly characterized via various physicochemical, optical and electrochemical techniques, and an attempt has been made to explain the conductivity mechanism. It is suggested that Cu treatment enhances the photoactivity of δ-MnO2 films through a series of surface dominated processes, which facilitate reduced recombination and enhanced hole consumption at the interface of the electrode and electrolyte. These results establish birnessite-based manganese dioxides as suitable candidates for electrodes in water splitting cells and pave the way for atomic-level engineering of earth abundant materials to reach the ultimate goal of low-cost, sustainable generation of hydrogen.


Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009-2010.
Clinical inference suggests the prevalence of non-celiac gluten sensitivity is substantially higher than that of celiac disease in the USA. Unfortunately, there are currently no data supporting these claims. The authors analyzed nationally representative data to estimate the prevalence of adherence to a gluten-free diet among participants without celiac disease and also to characterize the demographics and general health status of these participants. The Continuous National Health and Nutrition Examination Survey (NHANES) 2009-2010 enrolled 7762 individuals representing the civilian, non-institutionalized, US population free of celiac disease. Participants responded to interviewer administered questionnaires regarding current adherence to a gluten-free diet. Prevalence estimates were computed using SAS survey procedures. There were 49 individuals who reported current adherence to a gluten-free diet reflecting a weighted prevalence of 0.548% (95% CI 0.206-0.889). The prevalence of a gluten-free diet was higher in females (0.58%) than males (0.37%), although this was not statistically significant (p = 0.34). Participants reporting a gluten-free diet were older (46.6 vs. 40.5 years, p = 0.005), had higher high-density lipoprotein, lower iron and lower body mass index. The estimated national prevalence of non-celiac gluten sensitivity is 0.548%, approximately half that of celiac disease. Future studies are merited in order to better understand the population burden of non-celiac gluten sensitivity.


Optimal degree of protonation for ¹H detection of aliphatic sites in randomly deuterated proteins as a function of the MAS frequency.
The (1)H dipolar network, which is the major obstacle for applying proton detection in the solid-state, can be reduced by deuteration, employing the RAP (Reduced Adjoining Protonation) labeling scheme, which yields random protonation at non-exchangeable sites. We present here a systematic study on the optimal degree of random sidechain protonation in RAP samples as a function of the MAS (magic angle spinning) frequency. In particular, we compare (1)H sensitivity and linewidth of a microcrystalline protein, the SH3 domain of chicken α-spectrin, for samples, prepared with 5-25 % H(2)O in the E. coli growth medium, in the MAS frequency range of 20-60 kHz. At an external field of 19.96 T (850 MHz), we find that using a proton concentration between 15 and 25 % in the M9 medium yields the best compromise in terms of sensitivity and resolution, with an achievable average (1)H linewidth on the order of 40-50 Hz. Comparing sensitivities at a MAS frequency of 60 versus 20 kHz, a gain in sensitivity by a factor of 4-4.5 is observed in INEPT-based (1)H detected 1D (1)H,(13)C correlation experiments. In total, we find that spectra recorded with a 1.3 mm rotor at 60 kHz have almost the same sensitivity as spectra recorded with a fully packed 3.2 mm rotor at 20 kHz, even though ~20× less material is employed. The improved sensitivity is attributed to (1)H line narrowing due to fast MAS and to the increased efficiency of the 1.3 mm coil.


The preparation of human intrinsic factor-cobalamin complex from human gastric juice by immunoadsorption.
Immune complexes of human intrinsic factor were prepared by mixing gastric juice saturated with vitamin B12, and sera from patients with pernicious anaemia that had a high proportion of binding (Type II) antibody. The complexes were isolated by sodium sulphate precipitation followed by Sephadex G-150 gel filtration. Acid conditions dissociated the immune complexes and allowed separation of specific antibody and purified antigen bound to vitamin B12 by Sephadex G-200 gel filtration. Specific antibody was covalently attached to Protein A Sepharose CL-4B by coupling with water soluble carbodiimide which allowed intrinsic factor-B12 complex to be purified directly from gastric juice. The intrinsic factor obtained after iodination, ran as a single band on SDS-polyacrylamide gel electrophoresis and was biologically active.


Livestock-associated methicillin and multidrug resistant Staphylococcus aureus is present among industrial, not antibiotic-free livestock operation workers in North Carolina.
Administration of antibiotics to food animals may select for drug-resistant pathogens of clinical significance, such as methicillin-resistant Staphylococcus aureus (MRSA). In the United States, studies have examined prevalence of MRSA carriage among individuals exposed to livestock, but prevalence of multidrug-resistant S. aureus (MDRSA) carriage and the association with livestock raised with versus without antibiotic selective pressure remains unclear. We aimed to examine prevalence, antibiotic susceptibility, and molecular characteristics of S. aureus among industrial livestock operation (ILO) and antibiotic-free livestock operation (AFLO) workers and household members in North Carolina. Participants in this cross-sectional study were interviewed and provided a nasal swab for S. aureus analysis. Resulting S. aureus isolates were assessed for antibiotic susceptibility, multi-locus sequence type, and absence of the scn gene (a marker of livestock association). Among 99 ILO and 105 AFLO participants, S. aureus nasal carriage prevalence was 41% and 40%, respectively. Among ILO and AFLO S. aureus carriers, MRSA was detected in 7% (3/41) and 7% (3/42), respectively. Thirty seven percent of 41 ILO versus 19% of 42 AFLO S. aureus-positive participants carried MDRSA. S. aureus clonal complex (CC) 398 was observed only among workers and predominated among ILO (13/34) compared with AFLO (1/35) S. aureus-positive workers. Only ILO workers carried scn-negative MRSA CC398 (2/34) and scn-negative MDRSA CC398 (6/34), and all of these isolates were tetracycline resistant. Despite similar S. aureus and MRSA prevalence among ILO and AFLO-exposed individuals, livestock-associated MRSA and MDRSA (tetracycline-resistant, CC398, scn-negative) were only present among ILO-exposed individuals. These findings support growing concern about antibiotics use and confinement in livestock production, raising questions about the potential for occupational exposure to an opportunistic and drug-resistant pathogen, which in other settings including hospitals and the community is of broad public health importance.


Countdown to 2015 decade report (2000-10): taking stock of maternal, newborn, and child survival.
The Countdown to 2015 for Maternal, Newborn, and Child Survival monitors coverage of priority interventions to achieve the Millennium Development Goals (MDGs) for child mortality and maternal health. We reviewed progress between 1990 and 2010 in coverage of 26 key interventions in 68 Countdown priority countries accounting for more than 90% of maternal and child deaths worldwide. 19 countries studied were on track to meet MDG 4, in 47 we noted acceleration in the yearly rate of reduction in mortality of children younger than 5 years, and in 12 countries progress had decelerated since 2000. Progress towards reduction of neonatal deaths has been slow, and maternal mortality remains high in most Countdown countries, with little evidence of progress. Wide and persistent disparities exist in the coverage of interventions between and within countries, but some regions have successfully reduced longstanding inequities. Coverage of interventions delivered directly in the community on scheduled occasions was higher than for interventions relying on functional health systems. Although overseas development assistance for maternal, newborn, and child health has increased, funding for this sector accounted for only 31% of all development assistance for health in 2007. We provide evidence from several countries showing that rapid progress is possible and that focused and targeted interventions can reduce inequities related to socioeconomic status and sex. However, much more can and should be done to address maternal and newborn health and improve coverage of interventions related to family planning, care around childbirth, and case management of childhood illnesses.


Patterns of Element Incorporation in Calcium Carbonate Biominerals Recapitulate Phylogeny for a Diverse Range of Marine Calcifiers.
Elemental ratios in biogenic marine calcium carbonates are widely used in geobiology, environmental science, and paleoenvironmental reconstructions. It is generally accepted that the elemental abundance of biogenic marine carbonates reflects a combination of the abundance of that ion in seawater, the physical properties of seawater, the mineralogy of the biomineral, and the pathways and mechanisms of biomineralization. Here we report measurements of a suite of nine elemental ratios (Li/Ca, B/Ca, Na/Ca, Mg/Ca, Zn/Ca, Sr/Ca, Cd/Ca, Ba/Ca, and U/Ca) in 18 species of benthic marine invertebrates spanning a range of biogenic carbonate polymorph mineralogies (low-Mg calcite, high-Mg calcite, aragonite, mixed mineralogy) and of phyla (including Mollusca, Echinodermata, Arthropoda, Annelida, Cnidaria, Chlorophyta, and Rhodophyta) cultured at a single temperature (25°C) and a range of pCO2 treatments (ca. 409, 606, 903, and 2856 ppm). This dataset was used to explore various controls over elemental partitioning in biogenic marine carbonates, including species-level and biomineralization-pathway-level controls, the influence of internal pH regulation compared to external pH changes, and biocalcification responses to changes in seawater carbonate chemistry. The dataset also enables exploration of broad scale phylogenetic patterns of elemental partitioning across calcifying species, exhibiting high phylogenetic signals estimated from both uni- and multivariate analyses of the elemental ratio data (univariate: λ = 0-0.889; multivariate: λ = 0.895-0.99). Comparing partial R 2 values returned from non-phylogenetic and phylogenetic regression analyses echo the importance of and show that phylogeny explains the elemental ratio data 1.4-59 times better than mineralogy in five out of nine of the elements analyzed. Therefore, the strong associations between biomineral elemental chemistry and species relatedness suggests mechanistic controls over element incorporation rooted in the evolution of biomineralization mechanisms.


Reliability of whole crypt mitotic count as a measure of cellular proliferation in rectal biopsies.
We conducted a reliability study of whole crypt mitotic count, a measure of cellular proliferation with potential use as an intermediate marker in studies of colorectal cancer risk and prevention. The study involved biopsies taken from two distinct locations at 8-10 cm from the anal verge for 20 subjects scheduled to undergo routine endoscopy. In addition to the overall count of mitoses per crypt (mitotic count), we investigated two novel measures based on the percentages of heights of mitotic cells within crypts: the mean height, and the maximum minus minimum (max - min) height of mitoses. The max - min height was positively correlated with mitotic count (r = 0.64); however, there was little correlation between mitotic count and the mean height of mitotic cells (r = 0.12). Components of variance were estimated for the three measures; for mitotic count and max - min height, the variability between persons was substantially greater than that between locations within an individual. For mean height, the between-person and between-location variabilities were roughly equal. These results suggest that whole crypt mitotic count has promise as a reliable measure of rectal cellular proliferation, but further studies will be necessary to assess the utility of this assay.


Current advances in lanthanide ion (Ln(3+))-based upconversion nanomaterials for drug delivery.
Lanthanide ion (Ln(3+))-based upconversion nano/micromaterials that emit higher-energy visible light when excited by low-energy NIR light have aroused considerable attention in the forefront of materials science and biomedical fields, which stems from their unique optical and chemical properties including minimum photodamage to living organisms, low autofluorescence, high signal-to-noise ratio and detection sensitivity, and high penetration depth in biological or environmental samples. Thus, Ln(3+)-based upconversion materials are rising new stars and are quickly emerging as potential candidates to revolutionize novel biomedical applications. In this review article, we mainly focus on the recent progress in various chemical syntheses of Ln(3+)-based upconversion nanomaterials, with special emphasis on their application in stimuli-response controlled drug release and subsequent therapy. Functional groups that are introduced into the stimuli-responsive system can respond to external triggers, such as pH, temperature, light, and even magnetic fields, which can regulate the movement of the pharmaceutical cargo and release the drug at a desired time and in a desired area. This is crucial to boost drug efficacy in cancer treatment while minimizing the side effects of cytotoxic drugs. Many multifunctional (magnetic/upconversion luminescence and porous) composite materials based on Ln(3+) have been designed for controlled drug delivery and multimodal bioimaging. Finally, the challenges and future opportunities for Ln(3+)-based upconversion materials are discussed.