The dual anti-inflammatory and antioxidant activities of natural honey promote cell proliferation and neural regeneration in a rat model of colitis.
A decreased antioxidant capacity and excessive inflammation are well-known features in the pathogenesis of ulcerative colitis (UC). Recent evidence has suggested a role of honey in reducing colitis-induced inflammatory and oxidative stress markers. In this study, we examined whether the anti-inflammatory and anti-oxidative properties of honey have a beneficial effect on the enteric innervation and cellular proliferation of UC in rat. The colitis was induced in rats by dextran sodium sulphate (DSS). The effect of natural honey on induced colitis was assessed by the following parameters in colonic samples: tissue injury, inflammatory infiltration, interleukin-1β and -6, superoxide dismutase and reduced glutathione. In addition, the expression of tumour necrosis factor-α, inducible NO synthase, caspase-3, CD34, Ki67, S100, c-kit, and neuron-specific enolase were examined by immunohistochemistry. Compared to the DSS-induced colitis group, the honey-treated group had significantly improved macroscopic and microscopic scores and exhibited the down-regulation of oxidative, inflammatory, and apoptotic markers. In addition, up-regulation of intrinsic muscular innervation and epithelial cellular proliferation markers was detected. These results provide new insight into the beneficial role of natural honey in the treatment of DSS-induced colitis via the inhibition of colonic motor dysfunction and the inflammatory-oxidative-apoptotic cascade. In addition, the role of honey in epithelial regeneration was clarified.


A vaccine against the salmonid pathogen Piscirickettsia salmonis based on recombinant proteins.
We report here the protective effect against piscirickettsiosis elicited in fish by a mixture of recombinant proteins. A comparative genomics strategy was used on a genomic library of Piscirickettsia salmonis in order to select optimal candidates for a recombinant subunit vaccine to protect fish from rickettsial septicaemia (SRS). Based on this information, 15 P. salmonis ORFs encoding heat shock proteins, virulence factors, membrane bound and other surface exposed antigens, were isolated and expressed. Seven of the most promising antigens were formulated in three mixtures (V1-V3) containing two or three recombinant proteins each and injected into salmon to test their protective efficacy. Two of the three formulations (V1, V2) elicited a strong protective response in a challenge against the pathogen, which was coincident with the humoral response against the corresponding recombinant proteins present in each formulation. V1, formulated with recombinant chaperonines Hsp60, Hsp70 and flagellar protein FlgG of P. salmonis achieved the highest level of protection with a relative percent survival (RPS) of 95%.


Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomised trials.
The objective of this study was to determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B12 or B6. Meta-analysis of individual data on 1114 people in 12 randomised controlled trials assessed the effects of folic acid-based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentration of different doses of folic acid and of the addition of vitamin B12 or B6. The results showed that the proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pre-treatment blood homocysteine concentrations (p<0.001) and at lower pre-treatment blood folate concentrations (p<0.001). After standardisation to pre-treatment blood concentrations of homocysteine of 12 micromol/L and of folate of 12 nmol/L (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25 percent (95% confidence interval 23%-28%; p<0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B12 (mean 0.5 mg daily) produced an additional 7 percent (3%-10%) reduction in blood homocysteine. Vitamin B6 (mean 16.5 mg daily) did not have a significant additional effect. In conclusion, typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 micromol/L to 8-9 micromol/L). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentration reduces the risk of vascular disease.


Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells.
Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF) elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1) and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF-induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells.


"There is such a thing as too many daughters, but not too many sons": A qualitative study of son preference and fetal sex selection among Indian immigrants in the United States.
In response to concerns from feminists, demographers, bioethicists, journalists, and health care professionals, the Indian government passed legislation in 1994 and 2003 prohibiting the use of sex selection technology and sex-selective abortion. In contrast, South Asian families immigrating to the United States find themselves in an environment where reproductive choice is protected by law and technologies enabling sex selection are readily available. Yet there has been little research exploring immigrant Indian women's narratives about the pressure they face to have sons, the process of deciding to utilize sex selection technologies, and the physical and emotional health implications of both son preference and sex selection. We undertook semi-structured, in-depth interviews with 65 immigrant Indian women in the United States who had pursued fetal sex selection on the East and West coasts of the United States between September 2004 and December 2009. Women spoke of son preference and sex selection as separate though intimately related phenomena, and the major themes that arose during interviews included the sociocultural roots of son preference; women's early socialization around the importance of sons; the different forms of pressure to have sons that women experienced from female in-laws and husbands; the spectrum of verbal and physical abuse that women faced when they did not have male children and/or when they found out they were carrying a female fetus; and the ambivalence with which women regarded their own experience of reproductive "choice." We found that 40% of the women interviewed had terminated prior pregnancies with female fetuses and that 89% of women carrying female fetuses in their current pregnancy pursued an abortion. These narratives highlight the interaction between medical technology and the perpetuation of this specific form of violence against women in an immigrant context where women are both the assumed beneficiaries of reproductive choice while remaining highly vulnerable to family violence and reproductive coercion.


Immunoscore®: A Diagnostic Assay for Clinical Management of Colon Cancer.
Immunoscore® is an in vitro diagnostic assay that is designed to predict the risk of relapse in patients with early-stage colon cancer, thus helping to guide treatment strategies. Immunoscore has CE-IVD status in the EU, is CLIA certified in the USA, and is commercially available in many other countries worldwide. It is designed to be used in conjunction with TNM staging. Immunoscore uses digital images of tumour samples and advanced software to quantify the densities of CD3+ and CD8+ lymphocytes in defined regions of the tumour (i.e. core tumour and the invasive margin). A risk score is calculated, with a lower Immunoscore (i.e. lower densities) corresponding to a higher risk of recurrence. In an international, retrospective, validation study led by the Society for Immunotherapy of Cancer (SITC), Immunoscore was found to be robust, reproducible, quantitative and standardized, providing a reliable estimate of the risk of recurrence. The clinical utility of Immunoscore has been validated in the SITC-led study and in several supportive studies in which Immunoscore predicted survival, optimal treatment duration and relapse in patients with colon cancer.


Novel patterns of genome rearrangement and their association with survival in breast cancer.
Representational Oligonucleotide Microarray Analysis (ROMA) detects genomic amplifications and deletions with boundaries defined at a resolution of approximately 50 kb. We have used this technique to examine 243 breast tumors from two separate studies for which detailed clinical data were available. The very high resolution of this technology has enabled us to identify three characteristic patterns of genomic copy number variation in diploid tumors and to measure correlations with patient survival. One of these patterns is characterized by multiple closely spaced amplicons, or "firestorms," limited to single chromosome arms. These multiple amplifications are highly correlated with aggressive disease and poor survival even when the rest of the genome is relatively quiet. Analysis of a selected subset of clinical material suggests that a simple genomic calculation, based on the number and proximity of genomic alterations, correlates with life-table estimates of the probability of overall survival in patients with primary breast cancer. Based on this sample, we generate the working hypothesis that copy number profiling might provide information useful in making clinical decisions, especially regarding the use or not of systemic therapies (hormonal therapy, chemotherapy), in the management of operable primary breast cancer with ostensibly good prognosis, for example, small, node-negative, hormone-receptor-positive diploid cases.


Effect of electrolyte and adsorbates on charging rates in mesoporous gold electrodes.
The classical model for porous electrodes reported by De Levie several decades ago (and expanded upon since then) was developed mainly to describe pores with micrometer-scale diameters. Presumably it will break down as pore diameters approach atomic dimensions. Mesoporous gold formed by dealloying is a valuable test platform for this because its 10 nm pores are on the boundary of this expected breakdown and because the electrochemical and surface properties of gold are relatively well understood. The De Levie model works for these electrodes at high salt concentrations, but under dilute conditions, there is not enough salt locally to charge the interface, increasing real impedance on intermediate time scales. Specific adsorption on pore walls can cause a similar increase and also cause an effective mobility decrease, tunable through electrolyte choice and the use of alkanethiol monolayers. These effects are not expected in micrometer-scale pores and are important considerations when designing devices with nanoporous electrodes.


Utilization of protein expression profiles as indicators of environmental impairment of smallmouth bass (Micropterus dolomieu) from the Shenandoah River, Virginia, USA.
The Shenandoah River (VA, USA), the largest tributary of the Potomac River (MD, USA) and an important source of drinking water, has been the site of extensive fish kills since 2004. Previous investigations indicate environmental stressors may be adversely modulating the immune system of smallmouth bass (Micropterus dolomieu) and other species. Anterior kidney (AK) tissue, the major site of blood cell production in fish, was collected from smallmouth bass at three sites along the Shenandoah River. The tissue was divided for immune function and proteomics analyses. Bactericidal activity and respiratory burst were significantly different between North Fork and mainstem Shenandoah River smallmouth bass, whereas South Fork AK tissue did not significantly differ in either of these measures compared with the other sites. Cytotoxic cell activity was highest among South Fork and lowest among North Fork AK leukocytes. The composite two-dimension gels of the North Fork and mainstem smallmouth bass AK tissues contained 584 and 591 spots, respectively. South Fork smallmouth bass AK expressed only 335 proteins. Nineteen of 50 proteins analyzed by matrix-assisted laser desorption ionization-time of flight were successfully identified. Three of the four identified proteins with increased expression in South Fork AK tissue were involved in metabolism. Seven proteins exclusive to mainstem and North Fork smallmouth bass AK and expressed at comparable abundances serve immune and stress response functions. The proteomics data indicate these fish differ in metabolic capacity of AK tissue and in the ability to produce functional leukocytes. The variable responses of the immune function assays further indicate disruption to the immune system. Our results allow us to hypothesize underlying physiological changes that may relate to fish kills and suggest relevant contaminants known to produce similar physiological disruption.


Proteasome-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) is essential for autophagy suppression and muscle remodeling following denervation.
Drastic protein degradation occurs during muscle atrophy induced by denervation, fasting, immobility, and various systemic diseases. Although the ubiquitin-proteasome system is highly up-regulated in denervated muscles, the involvement of autophagy and protein synthesis has been controversial. Here, we report that autophagy is rather suppressed in denervated muscles even under autophagy-inducible starvation conditions. This is due to a constitutive activation of mammalian target of rapamycin complex 1 (mTORC1). We further reveal that denervation-induced mTORC1 activation is dependent on the proteasome, which is likely mediated by amino acids generated from proteasomal degradation. Protein synthesis and ribosome biogenesis are paradoxically increased in denervated muscles in an mTORC1-dependent manner, and mTORC1 activation plays an anabolic role against denervation-induced muscle atrophy. These results suggest that denervation induces not only muscle degradation but also adaptive muscle response in a proteasome- and mTORC1-dependent manner.


Assessment of inter- and intra-operator cephalometric tracings on cone beam CT radiographs: comparison of the precision of the cone beam CT versus the latero-lateral radiograph tracing.
In this study we aimed at quantifying the possible errors which may occur when assessing specific reference planes and linear derivants on cephalometric radiographs traced manually and digitally. Furthermore, we have compared the precision of the tracings according to both the two- and three-dimensional (2D and 3D respectively) techniques and between clinicians. We have obtained via cone beam computed tomography (CBCT) archive of the orthodontics department of the University of Milan 20 cone beam CT radiographs from which we have obtained 20 latero-lateral radiographs. Five independent clinicians referred to as A, B, C, D, E have been randomly selected to trace both radiographs maintaining the same working and lighting conditions to minimize the possibility of operator- and environment-dependent errors from occurring. The results have been statistically assessed by Student's t test. The comparison of the data gathered from the tracings in 2D and 3D shows that certain measurements have statistically significant differences. Particularly, the difference in the measurements of the sagittal dimension of the mandible and the anterior and posterior nasal spines has resulted to be statistically significant. The results of the intra-operator comparison proved that the 3D technique is extremely precise. Our study determines that the 3D technique allows to obtain more precise results and with several advantages when compared to the conventional technique such as a true representation of the anatomical structures, less risk of errors occurring due to clinician skills and absence of overlapping anatomical structures.


Clinical features and practical diagnosis of bullous pemphigoid.
Bullous pemphigoid (BP) represents the most common autoimmune subepidermal blistering disease. BP typically affects the elderly and is associated with significant morbidity. It has usually a chronic course with spontaneous exacerbations. The cutaneous manifestations of BP can be extremely protean. While diagnosis of BP in the bullous stage is straightforward, in the non-bullous stage or in atypical variants of BP signs and symptoms are frequently non-specific with eg, only itchy excoriated, eczematous, papular and/or urticarial lesions that may persist for several weeks or months. Diagnosis of BP critically relies on immunopathologic examinations including direct immunofluorescence microscopy and detection of serum autoantibodies by indirect immunofluorescence microscopy or BP180-ELISA.


Maternal-offspring conflict leads to the evolution of dominant zygotic sex determination.
Sex determination in many species involves interactions among maternally expressed genes (eg, mRNA's and proteins placed into the egg) and zygotically expressed genes. Recent studies have proposed that conflicting selective pressures can occur between maternally and zygotically expressed sex determining loci and that these may play a role in shaping the evolution of sex determining systems. Here we show that such genetic conflict occurs under very general circumstances. Whenever sex ratio among progeny in a family affects the fitness of either progeny in that family or maternal fitness, then maternal-zygotic genetic conflict occurs. Furthermore, we show that this conflict typically results in a "positive feedback loop" that leads to the evolution of a dominant zygotic sex determining locus. When males more negatively effect fitness within the family, a male heterogametic (XY male) sex determining system evolves, whereas when females more negatively effect fitness in the family, a female heterogametic (ZW female) system evolves. Individuals with the dominant sex allele are one sex, and the opposite sex is determined by maternally-expressed genes in individuals without the dominant sex allele. Results therefore suggest that maternal-zygotic conflict could play a role in the early evolution of chromosomal sex determining systems. Predictions are made concerning the patterns of expression of maternal and zygotic sex determining genes expected to result from conflict over sex determination.


Cortical Spiking Network Interfaced with Virtual Musculoskeletal Arm and Robotic Arm.
Embedding computational models in the physical world is a critical step towards constraining their behavior and building practical applications. Here we aim to drive a realistic musculoskeletal arm model using a biomimetic cortical spiking model, and make a robot arm reproduce the same trajectories in real time. Our cortical model consisted of a 3-layered cortex, composed of several hundred spiking model-neurons, which display physiologically realistic dynamics. We interconnected the cortical model to a two-joint musculoskeletal model of a human arm, with realistic anatomical and biomechanical properties. The virtual arm received muscle excitations from the neuronal model, and fed back proprioceptive information, forming a closed-loop system. The cortical model was trained using spike timing-dependent reinforcement learning to drive the virtual arm in a 2D reaching task. Limb position was used to simultaneously control a robot arm using an improved network interface. Virtual arm muscle activations responded to motoneuron firing rates, with virtual arm muscles lengths encoded via population coding in the proprioceptive population. After training, the virtual arm performed reaching movements which were smoother and more realistic than those obtained using a simplistic arm model. This system provided access to both spiking network properties and to arm biophysical properties, including muscle forces. The use of a musculoskeletal virtual arm and the improved control system allowed the robot arm to perform movements which were smoother than those reported in our previous paper using a simplistic arm. This work provides a novel approach consisting of bidirectionally connecting a cortical model to a realistic virtual arm, and using the system output to drive a robotic arm in real time. Our techniques are applicable to the future development of brain neuroprosthetic control systems, and may enable enhanced brain-machine interfaces with the possibility for finer control of limb prosthetics.


Health IT-Enabled Care Coordination: A National Survey of Patient-Centered Medical Home Clinicians.
Health information technology (IT) offers promising tools for improving care coordination. We assessed the feasibility and acceptability of 6 proposed care coordination objectives for stage 3 of the Centers for Medicare and Medicaid Services electronic health record incentive program (Meaningful Use) related to referrals, notification of care from other facilities, patient clinical summaries, and patient dashboards. We surveyed physician-owned and hospital/health system-affiliated primary care practices that achieved patient-centered medical home recognition and participated in the Meaningful Use program, and community health clinics with patient-centered medical home recognition (most with certified electronic health record systems). The response rate was 35.1%. We ascertained whether practices had implemented proposed objectives and perceptions of their importance. We analyzed the association of organizational and contextual factors with self-reported use of health IT to support care coordination activities. Although 78% of the 350 respondents viewed timely notification of hospital discharges as very important, only 48.7% used health IT systems to accomplish this task. The activity most frequently supported by health IT was providing clinical summaries to patients, in 76.6% of practices; however, merely 47.7% considered this activity very important. Greater use of health IT to support care coordination activities was positively associated with the presence of a nonclinician responsible for care coordination and the practice's capacity for systematic change. Even among practices having a strong commitment to the medical home model, the use of health IT to support care coordination objectives is not consistent. Health IT capabilities are not currently aligned with clinicians' priorities. Many practices will need financial and technical assistance for health IT to enhance care coordination.


Verbal learning in the context of background music: no influence of vocals and instrumentals on verbal learning.
Whether listening to background music enhances verbal learning performance is still a matter of dispute. In this study we investigated the influence of vocal and instrumental background music on verbal learning. 226 subjects were randomly assigned to one of five groups (one control group and 4 experimental groups). All participants were exposed to a verbal learning task. One group served as control group while the 4 further groups served as experimental groups. The control group learned without background music while the 4 experimental groups were exposed to vocal or instrumental musical pieces during learning with different subjective intensity and valence. Thus, we employed 4 music listening conditions (vocal music with high intensity: VOC_HIGH, vocal music with low intensity: VOC_LOW, instrumental music with high intensity: INST_HIGH, instrumental music with low intensity: INST_LOW) and one control condition (CONT) during which the subjects learned the word lists. Since it turned out that the high and low intensity groups did not differ in terms of the rated intensity during the main experiment these groups were lumped together. Thus, we worked with 3 groups: one control group and two groups, which were exposed to background music (vocal and instrumental) during verbal learning. As dependent variable, the number of learned words was used. Here we measured immediate recall during five learning sessions (recall 1 - recall 5) and delayed recall for 15 minutes (recall 6) and 14 days (recall 7) after the last learning session. Verbal learning improved during the first 5 recall sessions without any strong difference between the control and experimental groups. Also the delayed recalls were similar for the three groups. There was only a trend for attenuated verbal learning for the group passively listened to vocals. This learning attenuation diminished during the following learning sessions. The exposure to vocal or instrumental background music during encoding did not influence verbal learning. We suggest that the participants are easily able to cope with this background stimulation by ignoring this information channel in order to focus on the verbal learning task.


Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.
Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. clinicaltrials.gov Identifier: ISRCTN 20769191.


Retirees' motivational orientations and bridge employment: Testing the moderating role of gender.
Bridge employment refers to the labor force participation after people retire from career jobs. It is becoming a prevalent phenomenon for retirees transitioning from employment to complete work withdrawal. Building on existing literature on retirement transition and older adults' work motivation, the present study examined the effects of 3 motivational orientations (i.e., status striving, communion striving, and generativity striving) in relating to retirees' bridge employment participation (i.e., bridge employment status and bridge employment work hours). This study also applied the social gender role theory to examine the effect of gender in moderating the effects of motivational orientations. Data from 507 Chinese retirees in Beijing revealed that communion striving and generativity striving were positively related to bridge employment participation. Further, gender moderated the effect of status striving such that status striving was positively related to bridge employment participation for male retirees but not for female retirees. In addition, exploratory analysis was conducted to examine the effects of the same set of motivational orientations on postretirement volunteering activities. Results showed that status striving was negatively related to volunteering after retirement. The findings are discussed in terms of their theoretical implications for the bridge employment literature and practical implications for recruiting and retaining older workers.


Immigration and contract problems experienced by foreign-educated nurses.
More than 8% of employed RNs licensed since 2004 in the United States were educated overseas, yet little is known about the conditions of their recruitment or the impact of that experience on health care practice. This study assessed whether the labor rights of foreign-educated nurses were at risk during the latest period of high international recruitment: 2003 to 2007. Using consensus-based standards contained in the Voluntary Code of Ethical Conduct for the Recruitment of Foreign-Educated Health Professionals to the United States, this study found 50% of actively recruited foreign-educated nurses experienced a negative recruitment practice. The study also found that nurses educated in low-income countries and nurses with high contract breach fees, were significantly more likely to report such problems. If, as experts believe may occur, the nursing shortage in the United States returns around 2014, oversight of international recruitment will become critically important to delivering high-quality health care to Americans.


Potential for Development of Tolerance by Penicillium digitatum and Penicillium italicum after Repeated Exposure to Potassium Sorbate.
Two strains of Penicillium digitatum and one strain of Penicillium italicum were exposed to various levels of sorbic acid and potassium sorbate, and the MICs were determined. Selected strains of the molds were then repeatedly exposed to subinhibitory levels of the compounds to determine whether increased tolerance might develop. The MIC of sorbic acid (pH 4.75) to P. digitatum was between 0.02 and 0.025%. The MIC of sorbate (pH 5.5) to two strains of P. digitatum and P. italicum was found to be between 0.06 and 0.08%. Increasing levels of sorbate resulted in increasing growth suppression of the molds. Populations of P. digitatum were tested for increased tolerance to sorbic acid, and none was found. Individual molds that started from the same parent colony were examined for increased tolerance to potassium sorbate. Two P. digitatum strains developed no observable increased tolerance, but P. italicum developed a slight increase in tolerance to sorbate. When spores of P. italicum and P. digitatum were exposed to higher levels of sorbate for prolonged times, the fungicidal or fungistatic activity of the inhibitor was dependent upon pH, length of exposure time, level of sorbate, and the mold strain.


Effects of profound anemia on brain tissue oxygen tension, carbon dioxide tension, and pH in rabbits.
This study sought to determine the maximum tolerable limit of anemia for the brain during halothane anesthesia. Using a multiparameter sensor, we continuously monitored brain tissue oxygen tension (PO2), carbon dioxide tension (PCO2), and pH during profound hemodilution and subsequent transfusion. Twelve New Zealand White rabbits were anesthetized, intubated, and mechanically ventilated at a fraction of inspired oxygen (FiO2) of 21% to produce an arterial carbon dioxide tension (PaCO2) of 35 to 40 mm Hg. The femoral artery was cannulated to continuously monitor arterial blood pressure and to intermittently measure arterial blood gases. The electroencephalogram (EEG) was recorded throughout the course of the study. A fiberoptic sensor was inserted into the brain for the continuous measurement of brain PO2, PCO2, pH, and temperature. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Severe anemia was induced by repeatedly withdrawing 50-mL aliquots of blood and infusing an equal volume of 6% hetastarch. This procedure was performed four times for each rabbit. After the forth blood draw and fluid infusion, a total of 60 mL of packed red blood cells were transfused. Upon completion of the hemodilution, the hemoglobin concentration was 2.4 +/- 0.3 g/dL (mean +/- SEM). Brain tissue PO2 decreased from 27 +/- 3 mm Hg to a minimum of 12 +/- 2 mm Hg. Brain tissue pH also decreased from 7.22 +/- 0.03 to 7.12 +/- 0.05 and returned to the baseline value with transfusion. Brain PCO2 did not change significantly during the experiment. Cerebral blood flow increased from 37 +/- 3 to 66 +/- 15 mL x 100 g(-1) x min(-1) during hemodilution and returned to baseline after infusion of red blood cells. There was some loss of EEG amplitude and the calculated cerebral metabolic rate (CMRO2) decreased from 4.3 +/- 0.6 to 1.9 +/- 0.3 mL x 100 g(-1) x min(-1) at the most profound level of anemia. This is the first report of which the authors are aware of continuous monitoring of brain tissue pH, PCO2, and PO2 during profound hemodilution and transfusion. Hemodilution results in a decrease in brain tissue PO2. Increases in CBF and oxygen extraction can only partially compensate for the decreased oxygen carrying capacity of the blood. Decreases in brain tissue PO2, pH, CMRO2, and a loss of EEG amplitude suggest that the maximum tolerable limit of hemodilution was achieved in this study.


Blood lipid levels in relation to glucose status in European men and women without a prior history of diabetes: the DECODE Study.
Dyslipidaemia is present not only in diabetic but also in prediabetic subjects. The purpose of this study is to investigate the relationship between lipid and glucose levels in a large European population without a prior history of diabetes. Data from the population-based studies of 8960 men and 10,516 women aged 35-74 years representing 15 cohorts in 8 European countries were jointly analyzed. Multivariate adjusted linear regression analyses with standardized coefficients (beta) were performed to estimate the relationship between lipid and plasma glucose. In subjects without a prior history of diabetes, positive relationships were shown between fasting plasma glucose (FPG) and total cholesterol (TC) (beta=0.06 and 0.03, respectively for men and women, p<0.01), triglycerides (TG) (beta=0.14 and 0.12, p<0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (beta=0.06 and 0.03, p<0.01) and TC to HDL ratio (beta=0.06 and 0.05, p<0.001) but a negative trend between FPG and HDL-C (beta=-0.02, p>0.05 in men and beta=-0.03, p<0.05 in women). The relationship between lipid and 2-h plasma glucose (2hPG) followed a similar pattern as that for FPG, except that TC was not increased and HDL-C was reduced in both sexes in subjects with impaired glucose tolerance (IGT). For cardiovascular prevention, the different lipid patterns between impaired fasting glucose (IFG) and IGT may deserve further attention to evaluate the combined risks of dyslipidaemia and elevated glucose levels below the diagnostic threshold of diabetes.


Physical and physiological consequences of passive intra-oral shimming.
Imaging the human orbitofrontal cortex (OFC) with fMRI is problematic due to the proximity of this region to the air-filled sinuses, which causes susceptibility artifacts. Placing a strongly diamagnetic material into the mouth ('mouthshim') of a human volunteer can significantly reduce the artifacts in this region. Using the same combined olfactory and visual fMRI paradigm, we compared brain activation and static B0 field maps of participants being scanned both with and without the 'mouthshim'. Results demonstrate that the device improves the B0 field homogeneity within OFC, resulting in significantly stronger BOLD activation in this region. However, the device also caused both increased head motion and reduced activation in insular cortices due to more frequent swallowing and tactile stimulation of the tongue. The 'mouthshim' should only, therefore, be used where sensitivity in OFC regions is paramount.


Genome, functional gene annotation, and nuclear transformation of the heterokont oleaginous alga Nannochloropsis oceanica CCMP1779.
Unicellular marine algae have promise for providing sustainable and scalable biofuel feedstocks, although no single species has emerged as a preferred organism. Moreover, adequate molecular and genetic resources prerequisite for the rational engineering of marine algal feedstocks are lacking for most candidate species. Heterokonts of the genus Nannochloropsis naturally have high cellular oil content and are already in use for industrial production of high-value lipid products. First success in applying reverse genetics by targeted gene replacement makes Nannochloropsis oceanica an attractive model to investigate the cell and molecular biology and biochemistry of this fascinating organism group. Here we present the assembly of the 28.7 Mb genome of N. oceanica CCMP1779. RNA sequencing data from nitrogen-replete and nitrogen-depleted growth conditions support a total of 11,973 genes, of which in addition to automatic annotation some were manually inspected to predict the biochemical repertoire for this organism. Among others, more than 100 genes putatively related to lipid metabolism, 114 predicted transcription factors, and 109 transcriptional regulators were annotated. Comparison of the N. oceanica CCMP1779 gene repertoire with the recently published N. gaditana genome identified 2,649 genes likely specific to N. oceanica CCMP1779. Many of these N. oceanica-specific genes have putative orthologs in other species or are supported by transcriptional evidence. However, because similarity-based annotations are limited, functions of most of these species-specific genes remain unknown. Aside from the genome sequence and its analysis, protocols for the transformation of N. oceanica CCMP1779 are provided. The availability of genomic and transcriptomic data for Nannochloropsis oceanica CCMP1779, along with efficient transformation protocols, provides a blueprint for future detailed gene functional analysis and genetic engineering of Nannochloropsis species by a growing academic community focused on this genus.


Ardipithecus ramidus postcrania from the Gona Project area, Afar Regional State, Ethiopia.
Functional analyses of the 4.4 Ma hominin Ardipithecus ramidus postcrania revealed a previously unknown and unpredicted locomotor pattern combining arboreal clambering and a form of terrestrial bipedality. To date, all of the fossil evidence of Ar. ramidus locomotion has been collected from the Aramis area of the Middle Awash Research Project in Ethiopia. Here, we present the results of an analysis of additional early Pliocene Ar. ramidus fossils from the Gona Project study area, Ethiopia, that includes a fragmentary but informative partial skeleton (GWM67/P2) and additional isolated manual remains. While we reinforce the original functional interpretations of Ar. ramidus of having a mixed locomotor adaptation of terrestrial bipedality and arboreal clambering, we broaden our understanding of the nature of its locomotor pattern by documenting better the function of the hip, ankle, and foot. The newly recovered fossils document a greater adaptation to bipedality in the Ar. ramidus ankle and hallux than previously recognized. In addition, a newly discovered scaphoid bone with a fusing os centrale provides further evidence about the nature of hominin hand evolution.


Objective and subjective sleep measures are associated with HbA1c and insulin sensitivity in the general population: Findings from the ORISCAV-LUX-2 study.
To analyze the association of objective and subjective sleep measures with HbA1c and insulin sensitivity in the general population. Using a cross-sectional design, data from 1028 participants in the ORISCAV-LUX-2 study from the general population in Luxembourg were analyzed. Objective sleep measures were assessed using accelerometers whereas subjective measures were assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Sleep measures were defined as predictors, while HbA1c and quantitative insulin sensitivity check index (QUICKI) scores were considered outcomes. Linear and spline regression models were fitted by progressively adjusting for demographic and lifestyle variables in the total sample population as well as by stratified analyses using gender, obesity status, depressive symptoms and diabetes status. In fully adjusted models, total and deep sleep durations were associated with lower HbA1c (mmol/mol) levels, whereas sleep coefficients of variation (%) and poor sleep efficiency, as measured by PSQI scores (units), were associated with higher HbA1c levels. In stratified models, such associations were observed mainly in men, and in subjects who had depressive symptoms, were overweight and no diabetes. In addition, total sleep, deep sleep, coefficients of variation and poor sleep efficiency as measured by PSQI revealed non-linear associations. Similarly, greater insulin sensitivity was associated with longer total sleep time and with PSQI-6 (use of sleep medication). Associations were more frequently observed between sleep characteristics and glycaemic control with the use of objective sleep measures. Also, such associations varied within subgroups of the population. Our results highlight the relevance of measuring sleep patterns as key factors in the prevention of diabetes.


Gender differences in chronic disease risk behaviors through the transition out of high school.
Major life transitions (e.g., graduation from high school) are times when many changes occur in a person's social and physical environment. Men and women likely experience aspects of these changes differently. As a result, health-related behaviors likely change at these times with possible differences in these changes by gender. Gender differences in the performance of chronic disease risk-related behaviors (fruit, juice, and vegetable intake; physical activity; tobacco and alcohol use; and sexual practices) through the transition out of high school (HS) were assessed in a secondary analysis of a nationally representative sample from the 1992 National Health Interview Survey-Youth Risk Behavior Survey. The survey was completed by 5881 young people aged 14 to 21 years. Regression discontinuity analysis with piecewise regression was performed. Statistically significant gender by transition effects were obtained for exercise/physical activity (decreases at the transition point for males), snuff use (decrease for females in HS), binge drinking and number of days drinking alcohol (increases for males at the transition point), and use of alcohol or drugs before sexual intercourse (decrease for females post HS). Fruit intake decreased for males and females and daily and heavy cigarette smoking increased during the HS years. Effect sizes were small but promising, given that the data set was not designed to test this hypothesis. These data offer evidence of differences by gender in chronic disease risk behaviors through the HS transition. Longitudinal studies are needed to assess the true nature of these differences, the tracking of these risk behaviors and their personal, social, and environmental determinants, including gender-specific determinants, that may explain these changes and inform future intervention development.


Sonar Probing in Narragansett Bay.
A 12-kilocycle pulsed transducer, with a 0.1 millisecond duration, is used for tracing a sub-bottom rock profile in Narragansett Bay. The short sonar pulse of high energy is produced by a capacitor discharge. Over-the-side installation of the transducer permits the use of any boat or ship for the survey work. Coherent presentation of the data on a wet paper recorder gives an instantaneous visual record. A cross a north-south rock formation, a recurring rise and fall of the rock is shown throughout the sedimentary deposit.


Narrative possibilities: using mindfulness in clinical practice.
Narrative is ever present in medicine and is an integral aspect of the doctor and patient relationship. Although theoretical discussions of narrative medicine and narrative ethics are important, they may serve to reify the patient's story, to make it a specific entity. In practice, the patient's story unfolds in the moment of communication depending on the individuals and the circumstances; the story is not an "object." Patients' narratives heard in clinical settings are often limited by physician behaviors, especially the tendency of physicians to control the interaction with the patient. To develop individual narratives effectively and competently, physicians must be able to help the patient tell the story that is most important, meaningful, and descriptive of the situation. If the patient's narrative is not heard fully, the possibility of diagnostic and therapeutic error increases, the likelihood of personal connections resulting from a shared experience diminishes, empathic opportunities are missed, and patients may not feel understood or cared for. The practice of mindfulness--moment-to-moment, nonjudgmental awareness--opens a doorway into the patient's story as it unfolds. Such mindful practice develops the physician's focus of attention and offers the possibility for a meaningful and important narrative to arise between patient and physician.


Protective effects of green tea polyphenol extracts against ethanol-induced gastric mucosal damages in rats: stress-responsive transcription factors and MAP kinases as potential targets.
There are multiple lines of compelling evidence from epidemiologic and laboratory studies supporting that frequent consumption of green tea is inversely associated with the risk of chronic human diseases including cancer. The chemopreventive and chemoprotective effects of green tea have been largely attributed to antioxidative and anti-inflammatory activities of its polyphenolic constituents, such as epigallocatechin gallate. The present study was designed to evaluate the efficacy of green tea polyphenols in protecting against alcohol-induced gastric damage and to elucidate the underlying mechanisms. Intragastric administration of ethanol to male Sprague-Dawley rats caused significant gastric mucosal damage, which was accompanied by elevated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as transient activation of redox-sensitive transcription factors, such as NF-kappaB and AP-1, and mitogen-activated protein kinases (MAPKs). Oral administration of the green tea polyphenolic extract (GTE) significantly ameliorated mucosal damages induced by ethanol and also attenuated the ethanol-induced expression of COX-2 and iNOS. Inactivation of MAPKs, especially p38 and ERKl/2, by GTE might be responsible for inhibition of ethanol-induced expression of COX-2 and iNOS.


Self-reporting of symptom development from exposure to radiofrequency fields of wireless smart meters in victoria, australia: a case series.
In 2006, the government in the state of Victoria, Australia, mandated the rollout of smart meters in Victoria, which effectively removed a whole population's ability to avoid exposure to human-made high-frequency nonionizing radiation. This issue appears to constitute an unprecedented public health challenge for Victoria. By August 2013, 142 people had reported adverse health effects from wireless smart meters by submitting information on an Australian public Web site using its health and legal registers. The study evaluated the information in the registers to determine the types of symptoms that Victorian residents were developing from exposure to wireless smart meters. In this case series, the registers' managers eliminated those cases that did not clearly identify the people providing information by name, surname, postal address, and/or e-mail to make sure that they were genuine registrants. Then they obtained consent from participants to have their deidentified data used to compile the data for the case series. The author later removed any individual from outside of Victoria. The study included 92 residents of Victoria, Australia. The author used her medical experience and judgment to group symptoms into clinically relevant clusters (eg, pain in the head was grouped with headache, tinnitus was grouped with ringing in the ears). The author stayed quite close to the wording used in the original entries. She then calculated total numbers and percentages for each symptom cluster. Percentages were rounded to the nearest whole number. The most frequently reported symptoms from exposure to smart meters were (1) insomnia, (2) headaches, (3) tinnitus, (4) fatigue, (5) cognitive disturbances, (6) dysesthesias (abnormal sensation), and (7) dizziness. The effects of these symptoms on people's lives were significant. Review of some key studies, both recent and old (1971), reveals that the participants' symptoms were the same as those reported by people exposed to radiofrequency fields emitted by devices other than smart meters. Interestingly, the vast majority of Victorian cases did not state that they had been sufferers of electromagnetic hypersensitivity syndrome (EHS) prior to exposure to the wireless meters, which points to the possibility that smart meters may have unique characteristics that lower people's threshold for symptom development.


Regional differences in the spatial and temporal heterogeneity of oceanographic habitat used by Steller sea lions.
Over the past three decades, the decline and altered spatial distribution of the western stock of Steller sea lions (Eumetopias jubatus) in Alaska have been attributed to changes in the distribution or abundance of their prey due to the cumulative effects of fisheries and environmental perturbations. During this period, dietary prey occurrence and diet diversity were related to population decline within metapopulation regions of the western stock of Steller sea lions, suggesting that environmental conditions may be variable among regions. The objective of this study, therefore, was to examine regional differences in the spatial and temporal heterogeneity of oceanographic habitat used by Steller sea lions within the context of recent measures of diet diversity and population trajectories. Habitat use was assessed by deploying satellite-depth recorders and satellite relay data loggers on juvenile Steller sea lions (n = 45) over a five-year period (2000-2004) within four regions of the western stock, including the western, central, and eastern Aleutian Islands, and central Gulf of Alaska. Areas used by sea lions during summer months (June, July, and August) were demarcated using satellite telemetry data and characterized by environmental variables (sea surface temperature [SST] and chlorophyll a [chl a]), which possibly serve as proxies for environmental processes or prey. Spatial patterns of SST diversity and Steller sea lion population trends among regions were fairly consistent with trends reported for diet studies, possibly indicating a link between environmental diversity, prey diversity, and distribution or abundance of Steller sea lions. Overall, maximum spatial heterogeneity coupled with minimal temporal variability of SST appeared to be beneficial for Steller sea lions. In contrast, these patterns were not consistent for chl a, and there appeared to be an ecological threshold. Understanding how Steller sea lions respond to measures of environmental heterogeneity will ultimately be useful for implementing ecosystem management approaches and developing additional conservation strategies.


Diagnosis and initial management of dysmenorrhea.
Dysmenorrhea is one of the most common causes of pelvic pain. It negatively affects patients' quality of life and sometimes results in activity restriction. A history and physical examination, including a pelvic examination in patients who have had vaginal intercourse, may reveal the cause. Primary dysmenorrhea is menstrual pain in the absence of pelvic pathology. Abnormal uterine bleeding, dyspareunia, noncyclic pain, changes in intensity and duration of pain, and abnormal pelvic examination findings suggest underlying pathology (secondary dysmenorrhea) and require further investigation. Transvaginal ultrasonography should be performed if secondary dysmenorrhea is suspected. Endometriosis is the most common cause of secondary dysmenorrhea. Symptoms and signs of adenomyosis include dysmenorrhea, menorrhagia, and a uniformly enlarged uterus. Management options for primary dysmenorrhea include nonsteroidal anti-inflammatory drugs and hormonal contraceptives. Hormonal contraceptives are the first-line treatment for dysmenorrhea caused by endometriosis. Topical heat, exercise, and nutritional supplementation may be beneficial in patients who have dysmenorrhea; however, there is not enough evidence to support the use of yoga, acupuncture, or massage.


Mild cognitive impairment in Parkinson's disease.
Prospective studies conducted during the last decade have shown that the majority of patients with Parkinson's disease (PD) develop dementia. In addition, using a variety of definitions and methods, more recent research suggests that approximately a quarter of PD patients without dementia have mild cognitive impairment (PD-MCI). Furthermore, several studies have shown that approximately 20% have MCI even at time of diagnosis of PD. The typical cognitive deficits include visuospatial, attentional, and executive deficits, but memory deficits have also been shown. The etiology of PD-MCI is not known, but it is likely that mechanisms known to contribute to dementia in PD (ie, limbic and cortical Lewy bodies, amyloid plaques, and cholinergic deficits) play a role, in addition to dysfunction of dopaminergic frontostriatal circuits. PD-MCI predicts a shorter time to dementia, and preliminary evidence suggests that this is particularly true for posterior cognitive deficits. There are currently no systematic clinical trials in PD-MCI.


Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial.
Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support. In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (>0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827. 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%. We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK. UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.


Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance.
Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQ(r)) malaria parasite and with parasites derived by in vitro selection with Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We screened a chemical library against CQ(s) and CQ(r) lines and discovered a drug-like compound (IDI-3783) that was potent only in the CQ(r) line. Surprisingly, in vitro selection of Plasmodium falciparum resistant to IDI-3783 restored CQ sensitivity, thereby indicating that CQ might once again be useful as a malaria therapy. In parallel experiments, we selected P. falciparum lines resistant to structurally unrelated PfDHODH inhibitors (Genz-666136 and DSM74). Both selections yielded resistant lines with the same point mutation in PfDHODH:E182D. We discovered a compound (IDI-6273) more potent against E182D than wild-type parasites. Selection of the E182D mutant with IDI-6273 yielded a reversion to the wild-type protein sequence and phenotype although the nucleotide sequence was different. Importantly, selection with a combination of Genz-669178, a wild-type PfDHODH inhibitor, and IDI-6273, a mutant-selective PfDHODH inhibitor, did not yield resistant parasites. These two examples demonstrate that the compromise between resistance and evolutionary fitness can be exploited to design therapies that prevent the emergence and spread of resistant organisms.


Interplay of Entorhinal Input and Local Inhibitory Network in the Hippocampus at the Origin of Slow Inhibition in Granule Cells.
Neuronal activity from the entorhinal cortex propagates through the perforant path (PP) to the molecular layer of the dentate gyrus (DG) where information is filtered and converted into sparse hippocampal code. Nearly simultaneous signaling to both granule cells (GC) and local interneurons (INs) engages network interactions that will modulate input integration and output generation. When triggered, GABA release from interneurons counteracts the glutamatergic signals of PP terminals, scaling down the overall DG activation. Inhibition occurs at fast or slow timescales depending on the activation of ionotropic GABAA-R or metabotropic GABAB-R. Although postsynaptic GABAA and GABAB-R differ in their location at the synapse, mixed GABAA/B-R IPSPs can also occur. Here we describe a slow inhibition mechanism in mouse GCs recorded from either sex, mediated by GABAA/B-R in combination with metabotropic glutamate receptors. Short burst PP stimulation in the gamma frequency range lead to a long-lasting hyperpolarization (LLH) of the GCs with a duration that exceeds GABAB-R IPSPs. As a result, LLH alters GC firing patterns and the responses to concomitant excitatory signals are also affected. Synaptic recruitment of feedforward inhibition and subsequent GABA release from interneurons, also successfully trigger mixed GABA responses in GCs. Together these results suggest that slow inhibition through LLH leads to reduced excitability of GCs during entorhinal input integration. The implication of LLH in regulation of neuronal excitability suggests it also contributes to the sparse population coding in DG.SIGNIFICANCE STATEMENT Our study describes a long-lasting hyperpolarization (LLH) in hippocampal granule cells. We used whole-cell patch-clamp recordings and an optogenetic approach to characterize this event. LLH is a slow inhibitory mechanism that occurs following the stimulation of the perforant pathway in the molecular layer of the dentate gyrus. We found that it is mediated via postsynaptic ionotropic and metabotropic GABA and metabotropic glutamate receptors. The duration of LLH exceeds previously described IPSPs mediated by any of these receptors. The activation of LLH requires presynaptic gamma frequency bursts and recruitment of the local feedforward inhibition. LLH defines prolonged periods of low excitability of GCs and a restrained neuronal discharge. Our results suggest that LLH can contribute to sparse activation of GCs.


Drug Addiction: From Neuroscience to Ethics.
In the present paper, we suggest a potential new ethical analysis of addiction focusing on the relationship between aware and unaware processing in the brain. We take the case of the opioids epidemics to argue that a consideration of both aware and unaware processing provides a more comprehensive ethical framework to discuss the ethical issues raised by addiction. Finally, our hypothesis is that in addition to identified Central Nervous System's neuronal/neurochemical factors contributing to addictive dynamics, the socio-economic status plays a causal role through epigenetic processes, originating the need for additional reward in the brain. This provides a strong base for a socio-political form of responsibility for preventing and managing addiction crisis.


Vestibular neuritis: etiopathogenesis.
Vestibular neuritis presents as sudden unilateral vertigo in the absence of hearing loss or neurologic involvement and is thought to be due to neurotropic viruses. Its morbidity is unknown and it affects both sexes equally, with the highest incidence at 40-50 years of age. The etiology of this condition has been ascribed to viral, bacterial and protozoan infections, as well as allergic and auto-immune causes. Inflammation of the vestibular nerve is followed by demyelination and loss of function, which is not always reversible. Higher plasma fibrinogen and CRP levels in the acute phase, longer BERA latency and I-III interval and increased gadolinium uptake in the vestibular nerve and Scarpa's ganglion on enhanced MRI confirm the inflammatory nature of the process. An animal model of vestibular neuritis using retroauricular inoculation of herpes simplex virus in mice, histologic findings in the temporal bone of individuals who had vestibular neuritis, and influenza A virus infection in cultured Schwann's cells suggest viral infection as the main aetiologic cause.


Image segmentation with a unified graphical model.
We propose a unified graphical model that can represent both the causal and noncausal relationships among random variables and apply it to the image segmentation problem. Specifically, we first propose to employ Conditional Random Field (CRF) to model the spatial relationships among image superpixel regions and their measurements. We then introduce a multilayer Bayesian Network (BN) to model the causal dependencies that naturally exist among different image entities, including image regions, edges, and vertices. The CRF model and the BN model are then systematically and seamlessly combined through the theories of Factor Graph to form a unified probabilistic graphical model that captures the complex relationships among different image entities. Using the unified graphical model, image segmentation can be performed through a principled probabilistic inference. Experimental results on the Weizmann horse data set, on the VOC2006 cow data set, and on the MSRC2 multiclass data set demonstrate that our approach achieves favorable results compared to state-of-the-art approaches as well as those that use either the BN model or CRF model alone.


Evidence for a relationship between the duration of untreated psychosis and the proportion of psychotic homicides prior to treatment.
Recent studies of homicide during psychotic illness have shown that the risk of homicide is greatest during the first episode of psychosis. It is also possible that the proportion of patients who commit homicide before they receive effective treatment may be associated with the length of time they were unwell. We aimed to establish whether there was an association between the average duration of untreated psychosis and the proportion of homicides committed during the first episode of psychosis in the same countries. Systematic searches of published studies of homicide in psychosis and the duration of untreated psychosis were conducted. The results were combined to examine the relationship between the reported delay in receiving treatment and the proportion of homicides committed before initial treatment. We found 16 studies that reported the proportion of psychotic patients who committed homicide prior to treatment. The proportion of first episode patients ranged from 13% to 76%. We were able to match 13 of those studies with DUP studies from the same country. Longer average DUP was associated with a higher proportion of patients who committed homicide prior to receiving treatment. The possibility that the proportion of patients who commit homicide before receiving treatment may be related to the average treatment delay in the region that the homicide occurs needs to be examined using a case controlled design. If this finding were confirmed, then any measure that reduced the delay in treating emerging psychosis would save lives.


Effects of high heeled shoes wearing experience and heel height on human standing balance and functional mobility.
This study aimed to examine the effects of high heeled shoes (HHS) wearing experience and heel height on human standing balance and functional mobility. Thirty young and healthy females (ten experienced and twenty inexperienced HHS wearers) participated in a series of balance tests when they wore shoes of four different heel heights: 1 cm (flat), 4 cm (low), 7 cm (medium) and 10 cm (high). Experimental results show that regardless of the wearing experience, the heel elevation induces more effort from lower limb muscles (particularly calf muscles) and results in worse functional mobility starting at 7 cm heel height. While the heel height increased to 10 cm, the standing balance also becomes worse. Experienced HHS wearers do not show significantly better overall performance on standing balance and functional mobility than inexperienced controls, even though they have better directional control (76.8% vs. 74.4%) and larger maximum excursion (93.3% vs. 89.7%). To maintain standing balance, experienced wearers exert less effort on tibialis anterior, vastus lateralis and erector spinae muscles at the cost of more intensive effort from gastrocnemius medialis muscle. Many women wear high heeled shoes (HHS) to increase female attractiveness. This study shows that HHS induce more muscular effort and worse human standing balance and functional mobility, especially when heel height reaches 10 cm. HHS wearing experience only provides certain advantages to wearers on limits of stability in terms of larger maximum excursion and better directional control.


Uncoupled viral and bacterial distributions in coral reef waters of Tuamotu Archipelago (French Polynesia).
This study examined the distribution of virioplankton and bacterioplankton in two coral reef systems (Ahe and Takaroa atolls) in the Tuamotu Archipelago, in comparison with the surrounding oligotrophic ocean. Mean concentrations of 4.8×10(5) and 6.2×10(5) cells ml(-1) for bacteria and 8.1×10(6) and 4.3×10(6) VLP(virus-like particle) ml(-1) were recorded in Ahe and Takaroa lagoons, respectively. Chlorophyll-a concentrations and dissolved organic matter were higher in Ahe whereas (3)H thymidine incorporation rates were higher in Takaroa. First data on lytic and lysogenic strategies of phages in coral reef environments were discussed in this paper. The fraction of visibly infected cells by viruses was negligible regardless of the lagoon station (mean=0.15%). However, the fraction of lysogenic cells ranged between 2.5% and 88.9%. Our results suggest that the distribution patterns of virioplankton are apparently not coupled to the spatial dynamics of the bacterioplankton communities.


Delta 9-tetrahydrocannabinol suppression of prolactin secretion in the rat: lack of direct pituitary effect.
The effects of (--)trans-delta 9-tetrahydrocannabinol (THC) on tonic PRL secretion were investigated in long term ovariectomized or hypophysectomized/pituitary-autografted female rats and in flask incubations of anterior pituitary tissue. Intravenous injection of 0.25-8.0 mg THC/kg BW into ovariectomized rats markedly suppressed serum PRL 60 min later relative to control PRL levels. In a second experiment, ovariectomized rats bearing intraatrial cannulae were injected with 0.5 mg THC/kg BW, iv, and serial blood samples were drawn. PRL was significantly suppressed at 10 min, with persistence of the suppression for the duration of the 70-min sampling period in this time-course study. In contrast, the administration of 1.0 mg THC/kg BW, iv, to hypophysectomized/pituitary-autografted female rats failed to influence PRL secretion throughout a 120-min posttreatment sampling period. The apparent inability of THC to directly suppress PRL release from pituitary tissue was further studied by in vitro flask incubations of anterior pituitary tissue. Although a 1-h exposure of rat anterior pituitary tissue to bromocryptine (CB-154; 2.2 X 10(-4) M) suppressed subsequent PRL release, similar exposure to 10(-6) or 10(-4) M THC had no influence. The failure of THC to alter tonic PRL secretion in hypophysectomized/pituitary-autografted rts or PRL release from pituitary tissue in vitro strongly suggests that the central nervous system rather than the pituitary is the site of THC action in the acute suppression of tonic PRL secretion.


The effect of color intensity and appropriateness on color-induced odor enhancement.
Coloring solutions has been shown to increase perceived odor intensity. In Experiment 1, subjects rated the odor intensity of red strawberry and green mint solutions that had four levels of color intensity. Ratings of strawberry odor peaked at the medium color intensity and ratings of mint odor increased monotonically with color intensity. Thus, color-induced odor enhancement can increase with increasing color intensity but need not. Experiment 2 found that the color intensities producing maximum odor enhancement in Experiment 1 are not always the ones perceived as most appropriate for the odorants. Using different odors, Experiment 3 found that color intensity has some influence on the strength of the color-induced odor enhancement and color appropriateness has little. The presence or absence of color in the solution seems to be the most important variable.


Early calcium increase triggers the formation of olfactory long-term memory in honeybees.
Synaptic plasticity associated with an important wave of gene transcription and protein synthesis underlies long-term memory processes. Calcium (Ca2+) plays an important role in a variety of neuronal functions and indirect evidence suggests that it may be involved in synaptic plasticity and in the regulation of gene expression correlated to long-term memory formation. The aim of this study was to determine whether Ca2+ is necessary and sufficient for inducing long-term memory formation. A suitable model to address this question is the Pavlovian appetitive conditioning of the proboscis extension reflex in the honeybee Apis mellifera, in which animals learn to associate an odor with a sucrose reward. By modulating the intracellular Ca2+ concentration ([Ca2+]i) in the brain, we show that: (i) blocking [Ca2+]i increase during multiple-trial conditioning selectively impairs long-term memory performance; (ii) conversely, increasing [Ca2+]i during single-trial conditioning triggers long-term memory formation; and finally, (iii) as was the case for long-term memory produced by multiple-trial conditioning, enhancement of long-term memory performance induced by a [Ca2+]i increase depends on de novo protein synthesis. Altogether our data suggest that during olfactory conditioning Ca2+ is both a necessary and a sufficient signal for the formation of protein-dependent long-term memory. Ca2+ therefore appears to act as a switch between short- and long-term storage of learned information.


Endoscopic mucosal resection of early stage colon neuroendocrine carcinoma.
Early stage colorectal neuroendocrine carcinoma is rare. A small colon tumour was found in a 56-year-old man during diagnostic colonoscopy performed after a positive faecal occult blood test, and he was referred for treatment. A slightly reddish superficial elevated lesion with a shallow depression 10 mm in size was found in the transverse colon. Magnifying narrow-band imaging revealed disrupted irregular microvessels and the absence of a surface pattern in the depressed area. En bloc endoscopic mucosal resection (EMR) of the tumour was undertaken. The tumour was positive for chromogranin A and synaptophysin, and had a mitotic rate of >20/10 high-power fields and a Ki-67 proliferative index of >50%; it was diagnosed as a neuroendocrine carcinoma. The tumour minimally invaded the submucosa (300 μm) without lymphovascular involvement. The patient was followed up carefully, and at 1 year after EMR, no recurrence was found using colonoscopy and CT scans.


Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen.
The treatment of patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin sodium therapy is a common clinical problem. We investigated the efficacy and safety of a standardized periprocedural anticoagulation regimen with low-molecular-weight heparin. We studied 650 consecutive patients with a mechanical heart valve, chronic atrial fibrillation, or embolic stroke who required interruption of warfarin therapy because of an invasive procedure. Warfarin was stopped 5 or 6 days before the procedure, and patients received subcutaneous dalteparin sodium, 100 IU/kg twice daily, starting 3 days before the procedure. The risk of postprocedural bleeding determined postprocedural anticoagulant management. In patients undergoing a non-high-bleeding-risk procedure who had adequate postprocedural hemostasis, warfarin was resumed on the evening of the procedure, and dalteparin sodium, 100 IU/kg twice daily, was resumed on the next day and continued until the international normalized ratio was 2.0 or more. If postprocedural hemostasis was not secured, the resumption of dalteparin was delayed. In patients undergoing a high-bleeding-risk procedure, warfarin was resumed on the evening of the procedure, but dalteparin was not given after the procedure. Patients were followed up during the preprocedural and postprocedural period for a mean of 13.8 days (range, 10-18 days). In 542 patients who underwent a non-high-bleeding-risk procedure, there were 2 thromboembolic events (0.4%), 4 major bleeding episodes (0.7%), and 32 episodes of increased wound-related blood loss that precluded postprocedural dalteparin administration (5.9%). In 108 patients who underwent a high-bleeding-risk procedure, there were 2 deaths (1.8%) possibly due to thromboembolism and 2 major bleeding episodes (1.8%). In patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin therapy, a standardized periprocedural anticoagulant regimen with low-molecular-weight heparin is associated with a low risk of thromboembolic and major bleeding complications.


[Radiological manifestations of Baastrup's disease in children].
Baastrup's disease is not usually considered among the possible causes of low back pain in children. Classically, Baastrup's disease is characterized by degenerative phenomena secondary to friction between adjacent spinous processes, with sclerosis of the margins and decrease in the interspinous space. Baastrup's disease becomes more prevalent with age and is usually accompanied by degenerative changes in the vertebral column, such as lumbar facet hypertrophy or disc disease. Certain activities like dance or gymnastics can make Baastrup's disease more likely to appear at an earlier age. In children, Baastrup's disease can manifest in a different way, with increased interspinous spaces and bone remodeling. In this article, we present the cases of two patients with low back pain who were diagnosed with Baastrup's disease.


Re-recurrent Dermatofibrosarcomaprotuberans of the chest wall.
Dermatofibrosarcomaprotuberans is a rare, soft tissue tumour with high rate of recurrence. It is locally aggressive, with a low rate of metastasis. We describe the case of a 42 year old man who presented with a re-recurrent, large tumour situated on the anterior chest wall in the sternal region. We did a wide local excision and covered the resulting defect by using bilateral, pectoralis major myocutaneous flaps. Histopathology and immunohistochemical staining findings were consistent with the diagnosis of Dermatofibrosarcoma Protuberance. Post operatively the patient was treated with chemotherapy and radiotherapy.


Effect of sodium chloride on a lipid bilayer.
Electrostatic interactions govern structural and dynamical properties of membranes and can vary considerably with the composition of the aqueous buffer. We studied the influence of sodium chloride on a pure POPC lipid bilayer by fluorescence correlation spectroscopy experiments and molecular dynamics simulations. Increasing sodium chloride concentration was found to decrease the self-diffusion of POPC lipids within the bilayer. Self-diffusion coefficients calculated from the 100 ns simulations agree with those measured on a millisecond timescale, suggesting that most of the relaxation processes relevant for lipid diffusion are faster than the simulation timescale. As the dominant effect, the molecular dynamics simulations revealed a tight binding of sodium ions to the carbonyl oxygens of on average three lipids leading to larger complexes with reduced mobility. Additionally, the bilayer thickens by approximately 2 A, which increases the order parameter of the fatty acyl chains. Sodium binding alters the electrostatic potential, which is largely compensated by a changed polarization of the aqueous medium and a lipid dipole reorientation.


Promises and trust in human-robot interaction.
Understanding human trust in machine partners has become imperative due to the widespread use of intelligent machines in a variety of applications and contexts. The aim of this paper is to investigate whether human-beings trust a social robot-i.e. a human-like robot that embodies emotional states, empathy, and non-verbal communication-differently than other types of agents. To do so, we adapt the well-known economic trust-game proposed by Charness and Dufwenberg (2006) to assess whether receiving a promise from a robot increases human-trust in it. We find that receiving a promise from the robot increases the trust of the human in it, but only for individuals who perceive the robot very similar to a human-being. Importantly, we observe a similar pattern in choices when we replace the humanoid counterpart with a real human but not when it is replaced by a computer-box. Additionally, we investigate participants' psychophysiological reaction in terms of cardiovascular and electrodermal activity. Our results highlight an increased psychophysiological arousal when the game is played with the social robot compared to the computer-box. Taken all together, these results strongly support the development of technologies enhancing the humanity of robots.


Confirmed archaeological evidence of water deer in Vietnam: relics of the Pleistocene or a shifting baseline?
Studies of archaeological and palaeontological bone assemblages increasingly show that the historical distributions of many mammal species are unrepresentative of their longer-term geographical ranges in the Quaternary. Consequently, the geographical and ecological scope of potential conservation efforts may be inappropriately narrow. Here, we consider a case-in-point, the water deer Hydropotes inermis, which has historical native distributions in eastern China and the Korean peninsula. We present morphological and metric criteria for the taxonomic diagnosis of mandibles and maxillary canine fragments from Hang Thung Binh 1 cave in Tràng An World Heritage Site, which confirm the prehistoric presence of water deer in Vietnam. Dated to between 13 000 and 16 000 years before the present, the specimens are further evidence of a wider Quaternary distribution for these Vulnerable cervids, are valuable additions to a sparse Pleistocene fossil record and confirm water deer as a component of the Upper Pleistocene fauna of northern Vietnam. Palaeoenvironmental proxies suggest that the Tràng An water deer occupied cooler, but not necessarily drier, conditions than today. We consider if the specimens represent extirpated Pleistocene populations or indicate a previously unrecognized, longer-standing southerly distribution with possible implications for the conservation of the species in the future.


Closure or nonclosure of the peritoneum at gynecological operations. Effect on postoperative pain.
To compare the analgesic requirement and pain scores in the postoperative period between closure and nonclosure of the peritoneum in women undergoing gynecological abdominal surgery. We conducted this study as a 2 parallel grouped, double blind, randomized, controlled trial between February 2002 and March 2003. The current study consists of 79 eligible women who were enrolled and completed baseline assessments. We carried out this study at the Cumhuriyet University Hospital, Sivas, Turkey. When the age, gravidity, parity, body mass index, type of surgery, operative time and length of hospital stay were compared, between the 2 groups, no statistically significant difference was found (p>0.05). The postoperative pain was found higher in the closure group than the nonclosure group (p<0.05) when the pain with visual analogue scale (VAS) scores compared. There was no significant difference in analgesic requirements between the 2 groups in the postoperative period. However, less pain and low VAS scores were evident especially after postoperative 2nd and 48th hours in the nonclosure group. We recommend non-closure of peritoneum at abdominal gynecologic procedure as the method of choice.


Simultaneous MEG and EEG source analysis.
A method is described to derive source and conductivity estimates in a simultaneous MEG and EEG source analysis. In addition the covariance matrix of the estimates is derived. Simulation studies with a concentric spheres model and a more realistic boundary element model indicate that this method has several advantages, even if only a few EEG sensors are added to a MEG configuration. First, a simultaneous analysis profits from the 'preferred' location directions of MEG and EEG. Second, deep sources can be estimated quite accurately, which is an advantage compared to MEG. Third, superficial sources profit from accurate MEG location and from accurate EEG moment. Fourth, the radial source component can be estimated, which is an advantage compared to MEG. Fifth, the conductivities can be estimated. It is shown that conductivity estimation gives a substantial increase in precision, even if the conductivities are not identified appropriately. An illustrative analysis of empirical data supports these findings.


Binocular Eye Movements Are Adapted to the Natural Environment.
Humans and many animals make frequent saccades requiring coordinated movements of the eyes. When landing on the new fixation point, the eyes must converge accurately or double images will be perceived. We asked whether the visual system uses statistical regularities in the natural environment to aid eye alignment at the end of saccades. We measured the distribution of naturally occurring disparities in different parts of the visual field. The central tendency of the distributions was crossed (nearer than fixation) in the lower field and uncrossed (farther) in the upper field in male and female participants. It was uncrossed in the left and right fields. We also measured horizontal vergence after completion of vertical, horizontal, and oblique saccades. When the eyes first landed near the eccentric target, vergence was quite consistent with the natural-disparity distribution. For example, when making an upward saccade, the eyes diverged to be aligned with the most probable uncrossed disparity in that part of the visual field. Likewise, when making a downward saccade, the eyes converged to enable alignment with crossed disparity in that part of the field. Our results show that rapid binocular eye movements are adapted to the statistics of the 3D environment, minimizing the need for large corrective vergence movements at the end of saccades. The results are relevant to the debate about whether eye movements are derived from separate saccadic and vergence neural commands that control both eyes or from separate monocular commands that control the eyes independently.SIGNIFICANCE STATEMENT We show that the human visual system incorporates statistical regularities in the visual environment to enable efficient binocular eye movements. We define the oculomotor horopter: the surface of 3D positions to which the eyes initially move when stimulated by eccentric targets. The observed movements maximize the probability of accurate fixation as the eyes move from one position to another. This is the first study to show quantitatively that binocular eye movements conform to 3D scene statistics, thereby enabling efficient processing. The results provide greater insight into the neural mechanisms underlying the planning and execution of saccadic eye movements.


The potential of phototherapy to reduce body fat, insulin resistance and "metabolic inflexibility" related to obesity in women undergoing weight loss treatment.
The metabolic flexibility is often impaired in diseases associated with obesity, and many studies are based on the hypothesis that dysfunction in peripheral tissues such as skeletal muscle, liver and adipose tissue represent the etiology of development of metabolic inflexibility. Experimental evidence shows that the use of phototherapy combined with exercise was effective in controlling the lipid profile, reducing the mass of adipose tissue, suggesting increased metabolic activity and changes in lipid metabolism. However, we found few data in the literature involving the use of phototherapy in association to physical training in the obese population. Thus, our objective was to evaluate the effects of exercise training (aerobic plus resistance exercises) plus phototherapy (laser, 808 nm) on metabolic profile and adiponectinemia in obese women. Sixty-four obese women (BMI 30-40 kg/m2 , age between 20 and 40 years old) were randomly assigned in two groups: Exercise Training plus SHAM group (ET-SHAM, n = 32) and Exercise Training plus Phototherapy group (ET-PHOTO, n = 32). The treatment consisted in physical exercise intervention and the individual application of phototherapy immediately after the end of the training session. However, in the ET-SHAM group the device was turned off simulating the phototherapy application (placebo effect). The study protocol lasted for 20 weeks and comprised of three weekly sessions of aerobic plus resistance training and application of phototherapy (when applicable). The body composition and metabolic parameters were assessed (HOMA, adiponectin, insulin, glucose). Comparing the magnitude of effects between groups (ET-PHOTO vs. ET-SHAM), we observed that physical training plus phototherapy was more effective than physical training in reducing the delta of percentage of fat mass (%; -5.60 ± 1.59 vs. -4.33 ± 1.5; P < 0.04); fat mass (kg; -11.26 ± 2.82 vs. -5.80 ± 2.82; P < 0.0002); HOMA-IR index (-38.08 ± 9.23 vs. -20.91 ± 14.42; P < 0.0001). In addition, we observed an increase in delta (%) of total skeletal muscle mass (kg; 0.60 ± 1.09 vs. -1.38 ± 1.70; P < 0.003), adiponectin concentration (ng/ml; 1.08 (0.04-3.62) vs. -0.42 (-3.15 to 2.26); P < 0.03) in the same comparison. Our results demonstrated for the first time that phototherapy enhances the physical exercise effects in obese women undergoing weight loss treatment promoting significant changes in inflexibility metabolic profile.


Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin.
To study the pharmacodynamic properties of three premixed formulations of the rapid-acting insulin analog insulin lispro and its protamine-retarded preparation, neutral protamine lispro (NPL) insulin. In this open, single-center, euglycemic glucose clamp study, 30 healthy volunteers (12 women, 18 men) aged 27 +/- 2 years (mean +/- SD), whose BMI was 23.0 +/- 2.3 kg/m2, received subcutaneous injections of 0.3 U/kg body wt of insulin mixture (high-mixture 75/25, mid-mixture 50/50, or low-mixture 25/75 insulin lispro/NPL insulin), insulin lispro, or NPL insulin on one of the five study days in randomized order. Glucose infusion rates were determined over a period of 24 h after administration. Maximal metabolic activity decreased after subcutaneous injection of the mixtures with lower insulin lispro content; however, the time point of maximal and of early half-maximal metabolic activity was comparable among the three mixtures. Higher proportions of insulin lispro resulted in higher values for area under the curve within the first 360 min after injection and a more rapid decline to late half-maximal activity. Serum insulin concentrations showed a similar pattern. This study shows that the pharmacodynamic and pharmacokinetic properties of insulin lispro are preserved in stable mixtures with NPL insulin.


The design and application of a 50 K SNP chip for a threatened Aotearoa New Zealand passerine, the hihi.
Next-generation sequencing has transformed the fields of ecological and evolutionary genetics by allowing for cost-effective identification of genome-wide variation. Single nucleotide polymorphism (SNP) arrays, or "SNP chips", enable very large numbers of individuals to be consistently genotyped at a selected set of these identified markers, and also offer the advantage of being able to analyse samples of variable DNA quality. We used reduced representation restriction-aided digest sequencing (RAD-seq) of 31 birds of the threatened hihi (Notiomystis cincta; stitchbird) and low-coverage whole genome sequencing (WGS) of 10 of these birds to develop an Affymetrix 50 K SNP chip. We overcame the limitations of having no hihi reference genome and a low quantity of sequence data by separate and pooled de novo assembly of each of the 10 WGS birds. Reads from all individuals were mapped back to these de novo assemblies to identify SNPs. A subset of RAD-seq and WGS SNPs were selected for inclusion on the chip, prioritising SNPs with the highest quality scores whose flanking sequence uniquely aligned to the zebra finch (Taeniopygia guttata) genome. Of the 58,466 SNPs manufactured on the chip, 72% passed filtering metrics and were polymorphic. By genotyping 1,536 hihi on the array, we found that SNPs detected in multiple assemblies were more likely to successfully genotype, representing a cost-effective approach to identify SNPs for genotyping. Here, we demonstrate the utility of the SNP chip by describing the high rates of linkage disequilibrium in the hihi genome, reflecting the history of population bottlenecks in the species.


Effect of dietary starch level and high rumen-undegradable protein on endocrine-metabolic status, milk yield, and milk composition in dairy cows during early and late lactation.
Diet composition defines the amount and type of nutrients absorbed by dairy cows. Endocrine-metabolic interactions can influence these parameters, and so nutrient availability for the mammary gland can significantly vary and affect milk yield and its composition. Six dairy cows in early and then late lactation received, for 28 d in a changeover design, 2 diets designed to provide, within the same stage of lactation, similar amounts of rumen fermentable material but either high starch plus sugar (HS) content or low starch plus sugar content (LS). All diets had similar dietary crude protein and calculated supply of essential amino acids. Dry matter intake within each stage of lactation was similar between groups. Milk yield was similar between groups in early lactation, whereas a higher milk yield was observed in late lactation when feeding HS. At the metabolic level, the main difference observed between the diets in both stages of lactation was lower blood glucose in cows fed LS. The lower glucose availability during consumption of LS caused substantial modifications in the circulating and postprandial pattern of metabolic hormones. Feeding LS versus HS resulted in an increase in the ratio of bovine somatotropin to insulin. This increased mobilization of lipid reserves resulted in higher blood concentrations of nonesterified fatty acids and β-hydroxybutyrate, which contributed to the higher milk fat content in both stages of lactation in the LS group. This greater recourse to body fat stores was confirmed by the greater loss of body weight during early lactation and the slower recovery of body weight in late lactation in cows fed LS. The lower insulin to glucagon ratio observed in cows fed LS in early and late lactation likely caused an increase in hepatic uptake and catabolism of amino acids, as confirmed by the higher blood urea concentrations. Despite the higher catabolism of amino acids in LS in early lactation, similar milk protein output was observed for both diets, suggesting similar availability of amino acids for peripheral tissue and mammary gland. The latter could be the result of sparing of amino acids at the gut level due to starch that escaped from the rumen, and to the balanced amino acid profile of digestible protein. This last aspect appears worthy of further research, with the aim to enhance the efficiency of protein metabolism of dairy cows, reducing environmental nitrogen pollution without affecting milk yield potential.


Asthma and risk of myelodysplastic syndromes: a population-based cohort study.
Risk factors for the development of myelodysplastic syndromes (MDS) include age, exposure to ionising radiation, and cytotoxic drug treatment. Recently, asthma also has been suggested as a risk factor for MDS. We undertook this nationwide population-based cohort study on patients with a first-time hospital-based asthma diagnosis during 2002-2013 and followed them for the development of MDS/chronic myelomonocytic leukaemia (CMML). We identified 75 995 patients with incident asthma and no previous MDS/CMML diagnosis. Seventy-eight patients subsequently developed MDS and nine patients developed CMML during 402 892 person-years. The cumulative risks of developing MDS/CMML among asthma patients were 0.02% (95% CI: 0.01-0.04%) and 0.07% (95% CI: 0.05-0.09%) during the first year and the first five years of follow-up, respectively. The standardised incidence ratio of MDS/CMML among asthma patients overall was 1.6 (95% CI: 1.3-2.0) with little variation across subgroups. Asthma may be a risk factor for the development of MDS/CMML.