Modulation of cognitive performance following single doses of 120 mg Ginkgo biloba extract administered to healthy young volunteers.
Previous research from our laboratory demonstrated that administration of single doses (120, 240, 360 mg) of standardised Ginkgo biloba extract (GBE) had linear, dose-dependent, positive effects on the speed of performing attention tasks in comparison to placebo. However, whilst the lowest dose, which is typical of a recommended daily dose, had no effect on the speed of attention task performance it did engender mild improvements in secondary memory performance. The current study presents a reanalysis of data from three methodologically identical studies that each included a treatment of 120 mg GBE and matched placebo. All three studies were of a multiple dose, placebo-controlled, double-blind, balanced-crossover design, employing four or five treatment arms in total. Across the studies 78 healthy young participants received 120 mg GBE and placebo in randomly counterbalanced order, separated by a wash-out period of at least 7 days. On each study day participants' performance on the Cognitive Drug Research (CDR) computerised cognitive assessment battery was measured immediately prior to dosing and at 1, 2.5, 4 and 6 hr following treatment, with scores collapsed into the six measures (speed of attention, accuracy of attention, secondary memory, working memory, speed of memory, quality of memory) which have previously been derived by factor analysis of the data from CDR subtests. The results showed that 120 mg of Ginkgo engendered a significant improvement on the 'quality of memory' factor that was most evident at 1 and 4 hr post-dose, but had a negative effect on performance on the 'speed of attention' factor that was most evident at 1 and 6 hr post-dose. The current study confirmed the previous observation of modestly improved memory performance following 120 mg of GBE, but suggests that acute administration of this typical daily dose may have a detrimental effect on the speed of attention task performance which is opposite to that seen previously following higher doses.


Ambulatory-based standardized therapy for multi-drug resistant tuberculosis: experience from Nepal, 2005-2006.
The aim of this study was to describe treatment outcomes for multi-drug resistant tuberculosis (MDR-TB) outpatients on a standardized regimen in Nepal. Data on pulmonary MDR-TB patients enrolled for treatment in the Green Light Committee-approved National Programme between 15 September 2005 and 15 September 2006 were studied. Standardized regimen was used (8Z-Km-Ofx-Eto-Cs/16Z-Ofx-Eto-Cs) for a maximum of 32 months and follow-up was by smear and culture. Drug susceptibility testing (DST) results were not used to modify the treatment regimen. MDR-TB therapy was delivered in outpatient facilities for the whole course of treatment. Multivariable analysis was used to explain bacteriological cure as a function of sex, age, initial body weight, history of previous treatment and the region of report. In the first 12-months, 175 laboratory-confirmed MDR-TB cases (62% males) had outcomes reported. Most cases had failed a Category 2 first-line regimen (87%) or a Category 1 regimen (6%), 2% were previously untreated contacts of MDR-TB cases and 5% were unspecified. Cure was reported among 70% of patients (range 38%-93% by Region), 8% died, 5% failed treatment, and 17% defaulted. Unfavorable outcomes were not correlated to the number of resistant drugs at baseline DST. Cases who died had a lower mean body weight than those surviving (40.3 kg vs 47.2 kg, p<0.05). Default was significantly higher in two regions [Eastern OR = 6.2; 95%CL2.0-18.9; Far West OR = 5.0; 95%CL1.0-24.3]. At logistic regression, cure was inversely associated with body weight <36 kg [Adj.OR = 0.1; 95%CL0.0-0.3; ref. 55-75 kg] and treatment in the Eastern region [Adj.OR = 0.1; 95%CL0.0-0.4; ref. Central region]. The implementation of an ambulatory-based treatment programme for MDR-TB based on a fully standardized regimen can yield high cure rates even in resource-limited settings. The determinants of unfavorable outcome should be investigated thoroughly to maximize likelihood of successful treatment.


Former palliative caregivers who identify that additional spiritual support would have been helpful in a population survey.
Palliative care encompasses physical, psychosocial and spiritual care for patients and caregivers. No population data are available on bereaved people who subsequently report that additional spiritual support would have been helpful. In a population survey, a respondent-defined question was asked regarding 'additional spiritual support' that would have been helpful if someone 'close to them had died' an expected death in the previous five years. Data (socio-demographic [respondent]); clinical [deceased]) directly standardized to the whole population were analysed. There were 14,902 participants in this study (71.6% participation rate), of whom 31% (4665) experienced such a death and 1084 (23.2%) provided active hands-on (day-to-day or intermittent) care. Fifty-one of the 1084 (4.7%) active caregivers identified that additional spiritual support would have been helpful. The predictors in a regression analysis were: other domains where additional support would have been helpful (OR 1.69; 95% CI 1.46-1.94; p<0.001); and being female (OR 3.23; 95% CI 1.23 to 8.33; p=0.017). 'Additional spiritual support being helpful' was strongly associated with higher rates where additional support in other domains would also have been helpful in: all bereaved people (2.7 vs 0.6; p<0.0001); and in active caregivers (3.7 vs 0.8; p<0.0001). People who identify that additional spiritual support would have been helpful have specific demographic characteristics. There is also a strong association with the likelihood of identifying that a number of other additional supports would have been helpful. Clinically, the need for additional spiritual support should open a conversation about other areas where the need for further support may be identified.


Estimation and inference on correlations between biomarkers with repeated measures and left-censoring due to minimum detection levels.
Statistical approaches for estimating and drawing inference on the correlation between two biomarkers that are repeatedly assessed over time and subject to left-censoring because minimum detection levels are lacking. We propose a linear mixed-effects model and estimate the parameters with the Monte Carlo expectation maximization (MCEM) method. Inferences regarding the model parameters and the correlation between the biomarkers are performed by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCEM method with existing methods including the maximum likelihood estimation method, the multiple imputation method, and two widely used ad hoc approaches: replacing the censored values with the detection limit or with half of the detection limit. The results show that the performance of the MCEM with respect to relative bias and coverage probability for the 95% confidence interval is superior to the detection limit and half of the detection limit approaches and exceeds that of the multiple imputation method at medium to high levels of censoring, and the standard error estimates from the MCEM method are close to ideal. The maximum likelihood estimation method can estimate the parameters accurately; however, a nonpositive definite information matrix can occur so that the variances are not estimable. These five methods are illustrated with data from a longitudinal human immunodeficiency virus study to estimate and draw inference on the correlation between human immunodeficiency virus RNA levels measured in plasma and in cervical secretions at multiple time points.


Properties and molecular basis of the mouse urinary bladder voltage-gated K+ current.
Potassium channels play an important role in controlling the excitability of urinary bladder smooth muscle (UBSM). Here we describe the biophysical, pharmacological and molecular properties of the mouse UBSM voltage-gated K+ current (IK(V)). The IK(V) activated, deactivated and inactivated slowly with time constants of 29.9 ms at +30 mV, 131 ms at -40 mV and 3.4 s at +20 mV. The midpoints of steady-state activation and inactivation curves were 1.1 mV and -61.4 mV, respectively. These properties suggest that IK(V) plays a role in regulating the resting membrane potential and contributes to the repolarization and after-hyperpolarization phases of action potentials. The IK(V) was blocked by tetraethylammonium ions with an IC50 of 5.2 mM and was unaffected by 1 mM 4-aminopyridine. RT-PCR for voltage-gated K+ channel (KV) subunits revealed the expression of Kv2.1, Kv5.1, Kv6.1, Kv6.2 and Kv6.3 in isolated UBSM myocytes. A comparison of the biophysical properties of UBSM IK(V) with those reported for Kv2.1 and Kv5.1 and/or Kv6 heteromultimeric channels demonstrated a marked similarity. We propose that heteromultimeric channel complexes composed of Kv2.1 and Kv5.1 and/or Kv6 subunits form the molecular basis of the mouse UBSM IK(V).


Single-pulse ultraviolet laser recording of periodically poled structures in polymer thin films.
A simple fabrication technique for nonlinear polymeric optical waveguide patterns is introduced based on the two-beam interference method. We determined that the second-order nonlinearity of poled polymer films is erased by single-pulse ultraviolet (UV) laser irradiation. The erasure mechanism for second-order nonlinearity is discussed. To form a periodic structure in an optical polymer waveguide, two types of optical configuration of two-beam interference were arranged, and a single-pulse UV laser was exposed directly onto poled films. We prove that this method provides a simple way to fabricate volume-type and ridge-type periodically poled structures, i.e., chi(2) gratings, from the submicrometer to the millimeter range.


Injectable myocardial matrix as a scaffold for myocardial tissue engineering.
Current injectable materials utilized in myocardial tissue engineering have been borrowed from other tissue engineering applications and have not been specifically designed for the myocardium. We have recently tested the feasibility of using an injectable form of myocardial extracellular matrix that would provide cardiac specific matrix cues as well as be amenable to minimally invasive delivery. We have demonstrated that this material self-assembles in vivo to form a nanofibrous scaffold, which supports the infiltration of neovasculature. We have also demonstrated that this material may be delivered minimally invasively through a catheter.


Anatomic effects of cryoablation of the atrioventricular conduction system.
Because of the value of cryoablation of the atrioventricular (AV) conduction system in treatment of refractory cardiac rhythm disorders, the anatomic effects of cryoablation on the cardiac conduction system must be defined. In this report we summarize studies done on four patients who had intractable recurrent supraventricular tachyarrhythmias or or refractory atrial flutter-fibrillation. They were treated by cryoablation of the AV conduction system and died 8-360 days postoperatively. Serial sections of the AV conduction system were studied. Cryoablation produced lesions that completely destroyed most of the AV node in three cases, the penetrating portion of the His bundle in all four cases, and the branching portion of the His bundle in two cases. The right bundle branch was not involved markedly in any case. The lesions were discrete and sharply delimited; the patient who died 8 days postoperatively had hemorrhage, necrosis and slight inflammatory infiltrate; patients who survived for 49-360 days showed collagen deposition. The AV nodal artery and its branches showed slight to marked intimal thickening in three cases. Small, partly organized thrombi were present just behind the tricuspid valve in two patients. We conclude that cryoablation of the AV conduction system produced discrete cardiac lesions that did not markedly damage the tricuspid valve or aorta.


Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1.
Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC's physiological actions begin with its stimulation of β1- and β2-adrenergic receptor-mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC's psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse trace amine-associated receptor 1 (mTAAR1), which was completely reversed by the trace amine-associated receptor 1 (TAAR1)-selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human β2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug.


High expression of IL-9R promotes the progression of human hepatocellular carcinoma and indicates a poor clinical outcome.
Interleukin-9 receptor (IL-9R) overexpression has a pivotal role in human hematological malignancies. However, the expression of IL-9R and its biological role in human solid tumors remains elusive. In the present study, western blot analysis and RT-qPCR were used to determine the expression of IL-9R in hepatocellular carcinoma (HCC) cell lines and tumor tissues. Proliferation, cell cycle, apoptosis and Transwell assays were used to examine the biological role of IL-9R in HCC cells. The results showed that IL-9R and its ligand IL-9 were constitutively expressed in HCC cells and tissues. Moreover, the expression levels of IL-9R and IL-9 were significantly higher in tumor tissues compared to the peritumor liver tissues. Functional experiments suggested that IL-9R significantly promoted HCC cell proliferation, invasion and inhibited apoptosis, possibly by acting through the IL-9/IL-9R axis. After silencing IL-9R, the expression of VEGF, p-p38, p-STAT3 and MMP9, markedly decreased suggesting the potential involvement of these molecules in IL-9R activity. Immunohistochemistry‑based survival analysis revealed that a differential expression of IL-9R in HCC tissue was a significant and independent prognostic factor for survival [HR, 1.66; 95% confidence interval (CI), 1.17-2.36; P=0.005] and recurrence [HR, 1.50; 95%CI, 1.04‑2.17; P=0.03]. In addition, a high IL-9R expression positively and significantly correlated with larger (P=0.012) and advanced tumor stage (P=0.018). The findings indicated that IL-9R was constitutively expressed and exerted a tumor-promoting effect in HCC, whose expression level may be a useful biomarker of tumor invasiveness and patient clinical outcome.


Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain.
A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1⁺ monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1⁺ monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain.


Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity.
Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy that includes drugs such as doxorubicin and daunorubicin. Studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. Preventing cardiotoxicity might allow for escalation of the anthracycline dose, which would further enhance the anticancer effects. Based on clinical investigation, although limited, a cumulative dose of doxorubicin of up to 900 mg/m2, and possibly higher, can be administered safely during chemotherapy as long as coenzyme Q10 is administered concurrently. The etiology of the dose-limiting cardiomyopathy that is induced by anthracyclines can be explained by irreversible damage to heart cell mitochondria, which differ from mitochondria of other cells in that they possess a unique enzyme on the inner mitochondrial membrane. This enzyme reduces anthracyclines to their semiquinones, resulting in severe oxidative stress, disruption of mitochondrial energetics, and irreversible damage to mitochondrial DNA. Damage to mitochondrial DNA blocks the regenerative capability of the organelle and ultimately leads to apoptosis or necrosis of myocytes. Coenzyme Q10, an essential component of the electron transport system and a potent intracellular antioxidant, appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy.


Estimation of HIV incidence using multiple biomarkers.
The incidence of human immunodeficiency virus (HIV) is the rate at which new HIV infections occur in populations. The development of accurate, practical, and cost-effective approaches to estimation of HIV incidence is a priority among researchers in HIV surveillance because of limitations with existing methods. In this paper, we develop methods for estimating HIV incidence rates using multiple biomarkers in biological samples collected from a cross-sectional survey. An advantage of the method is that it does not require longitudinal follow-up of individuals. We use assays for BED, avidity, viral load, and CD4 cell count data from clade B samples collected in several US epidemiologic cohorts between 1987 and 2010. Considering issues of accuracy, cost, and implementation, we identify optimal multiassay algorithms for estimating incidence. We find that the multiple-biomarker approach to cross-sectional HIV incidence estimation corrects the significant deficiencies of currently available approaches and is a potentially powerful and practical tool for HIV surveillance.


National Health Spending: Faster Growth In 2015 As Coverage Expands And Utilization Increases.
Total nominal US health care spending increased 5.8 percent and reached $3.2 trillion in 2015. On a per person basis, spending on health care increased 5.0 percent, reaching $9,990. The share of gross domestic product devoted to health care spending was 17.8 percent in 2015, up from 17.4 percent in 2014. Coverage expansions that began in 2014 as a result of the Affordable Care Act continued to affect health spending growth in 2015. In that year, the faster growth in total health care spending was primarily due to accelerated growth in spending for private health insurance (growth of 7.2 percent), hospital care (5.6 percent), and physician and clinical services (6.3 percent). Continued strong growth in Medicaid (9.7 percent) and retail prescription drug spending (9.0 percent), albeit at a slower rate than in 2014, contributed to overall health care spending growth in 2015.


Activation of a remote (1-year old) emotional memory interferes with the retrieval of a newly formed hippocampus-dependent memory in rats.
The persistent intrusion of remote traumatic memories in people with post-traumatic stress disorder (PTSD) may contribute to the impairment of their ongoing hippocampal and prefrontal cortical functioning. In the current work, we have developed a rodent analogue of the intrusive memory phenomenon. We studied the influence of the activation of a remote traumatic memory in rats on their ability to retrieve a newly formed hippocampus-dependent memory. Adult male Sprague-Dawley rats were given inhibitory avoidance (IA) training, and then 24 h or 1, 6 or 12 months later, the same rats were trained to learn, and then remember across a 30-min delay period, the location of a hidden escape platform in the radial-arm water maze (RAWM). When IA-trained rats spent the 30-min delay period in the IA apparatus, they exhibited intact remote (1-year old) memory of the shock experience. More importantly, activation of the rats' memory of the shock experience profoundly impaired their ability to retrieve the newly formed spatial memory of the hidden platform location in the RAWM. Our finding that reactivation of a remote emotional memory exerted an intrusive effect on new spatial memory processing in rats provides a novel approach toward understanding how intrusive memories of traumatic experiences interfere with ongoing cognitive processing in people with PTSD.


Brain potential signs of slowed stimulus processing following cholecystokinin in Parkinson's disease.
Cholecystokinin (CCK) is a neuropeptide which is colocalized with dopamine (DA) in neurons of the mesolimbic-frontocortical and nigrostriatal DA system. In animals CCK enhances DA activity in these systems. The present study examined the effects of a single intranasal administration of CCK-8 on auditory brain potential (AEP) signs of cognitive processing and on motor performance in patients with Parkinson's disease (PD), known to originate from degeneration of DA neurons primarily in the nigrostriatal DA system. Thirteen PD patients were examined after medication withdrawal, on two occasions after administration of placebo and 25 microg CCK-8, and compared with healthy controls matched for age and sex. AEPs were recorded while subjects performed an attention task (oddball paradigm). In the placebo condition, AEPs in the PD patients did not show marked alteration but were rather comparable to those in the controls. In healthy controls, CCK-8 enhanced the P3 complex ( P<0.05) and shortened latencies of the N2 and P3 components of the AEP evoked by task relevant target stimuli ( P<0.05). Contrary to expectations, in PD patients these AEP components were distinctly delayed after CCK-8 ( P<0.05). Motor performance was not changed by CCK-8 in PD patients or in controls. Data indicate a deleterious rather than beneficial effect of CCK on cognitive processing in PD patients that might result from a prevailing effect of the neuropeptide on transmitter systems (e.g. GABAergic) other than the DA system.


Graphical approaches to support the analysis of linear-multilevel models of lamb pre-weaning growth in Kolda (Senegal).
Linear-multilevel models (LMM) are mixed-effects models in which several levels of grouping may be specified (village, herd, animal, ellipsis). This study highlighted the usefulness of graphical methods in their analysis through: (1) the choice of the fixed and random effects and their structure, (2) the assessment of goodness-of-fit and (3) distributional assumptions for random effects and residuals. An LMM was developed to study the effect of ewe deworming with morantel on lamb pre-weaning growth in a field experiment involving 182 lambs in 45 herds and 10 villages in Kolda, Senegal. Growth was described as a quadratic polynomial of age. Other covariates were sex, litter-size and treatment. The choice of fixed and random effects relied on three graphs: (1) a trellis display of mean live-weight vs. age, to select main effects and interactions (fixed effects); (2) a trellis display of individual growth curves, to decide which growth-curve terms should be included as random effects and (3) a scatter plot of parameters of lamb-specific regressions (live-weight vs. quadratic polynomial of age) to choose the random-effects covariance structure.Age, litter-size, agexlitter-size, litter-sizextreatment and agexlitter-sizextreatment were selected graphically as fixed effects and were significant (p<0.05) in subsequent statistical models. The selection of random-effect structures was guided by graphical assessment and comparison of the Akaike's information criterion for different models. The final random-effects selected included no random effect at the village level but intercept, age and squared-age at the herd and lamb levels. The structure of the random-effects variance-covariance matrices were blocked-diagonal at the herd level and unstructured at the lamb level. An order-1 autoregressive structure was retained to account for serial correlations of residuals. Smaller residual variance at 90 days than at younger ages was modeled with a dummy variable taking a value of 1 at 90 days and 0 elsewhere.Ewe-deworming with morantel during the rainy season lead to higher lamb live-weights (probably related to a better ewe-nutrition and -health status). A positive correlation was demonstrated between early weight and growth rate at the population level (with important lamb and herd-level random deviations). The persistence of this correlation at older ages should be checked to determine whether early weights are good predictors of mature weights and ewe-reproductive lifetime performance.


Long-term Effects of Gastric Pacing to Reduce Feed Intake in Swine.
BACKGROUND: The purpose of this study was to show the effect of chronic antral gastric electrical stimulation on the feeding behavior of swine. METHODS: Three groups of swine were investigated; first group control-group, second group- 8 months of electrical antral stimulation (10 Volts; 450 micros; Hertz 100; Mode: Cycling; on time 3.25 s; off time 5.15 s), the third group- 3 months of stimulation with modification of the following parameters- amplitude 8 Volts, Hertz 5. All animals were nourished with a commercial balanced dry feed ad libitum. RESULTS: Group one demonstrated continued increased weight gain. After 90 days of stimulation, group two noted a net decrease of food intake from 12% to 16%, followed by a net cyclical weight loss 30 days later (2 weeks of weight gain followed by 1 week of weight loss). The percentage difference between group one and two in increasing weight was- 12 to 29% respectively. The feed output of the stimulated group (group two) was 12.8 less compared with the control. Finally, group three was used to test a lower stimulation rate, resulting in a shorter rest during feeding and a 7% increase in consumption compared with control. CONCLUSIONS: Long-term antral gastric pacing influences the alimentary behavior of swine. We attempt to extrapolate this influence in humans for possible attendant applications in patients with consumption dysfunction (e.g. bulimia and/or anorexia).


Linking life-history theory and metabolic theory explains the offspring size-temperature relationship.
Temperature often affects maternal investment in offspring. Across and within species, mothers in colder environments generally produce larger offspring than mothers in warmer environments, but the underlying drivers of this relationship remain unresolved. We formally evaluated the ubiquity of the temperature-offspring size relationship and found strong support for a negative relationship across a wide variety of ectotherms. We then tested an explanation for this relationship that formally links life-history and metabolic theories. We estimated the costs of development across temperatures using a series of laboratory experiments on model organisms, and a meta-analysis across 72 species of ectotherms spanning five phyla. We found that both metabolic and developmental rates increase with temperature, but developmental rate is more temperature sensitive than metabolic rate, such that the overall costs of development decrease with temperature. Hence, within a species' natural temperature range, development at relatively cooler temperatures requires mothers to produce larger, better provisioned offspring.


Relationship Between Clinical Nurse Specialist Role Implementation, Satisfaction, and Intent to Stay.
There is a lack of research examining the relationship between role satisfaction and intent to remain in one's professional role from the perspective of nurses in advanced practice roles. The purpose of this study is to examine the strength of the relationship between clinical nurse specialist (CNS) role implementation, role satisfaction, and intent to remain in a CNS role. We conducted a secondary analysis of data from a cross-sectional survey. The setting of this study was Canada. We included 423 of 471 (90%) questionnaires of graduate-prepared CNSs. We surveyed all CNSs in Canada from April to August 2011. Cronbach's α (.79-.96) was used to assess the reliability of the portion of the questionnaire that measured CNS role dimensions. Using logistic regression analysis, we examined the relationship between CNS role implementation, role satisfaction, and intent to stay. Clinical, research, scholarly and professional development, and consultation activities were significantly associated with improved CNS role satisfaction, and role satisfaction positively influenced intent to stay. However, CNS roles heavily focused on consultation activities negatively influenced CNS intent to stay. Only scholarly and professional development activities both improved role satisfaction and indirectly influenced intent to stay in the role. There is a small positive association between some CNS role dimensions and role satisfaction, and role satisfaction positively influences intent to stay. However, too many consultation activities decreased CNS intent to remain in the role. Given the multidimensional role of the CNS and unique patient needs, CNSs will want to work closely with their managers to design a role that meets patient needs and optimizes CNS satisfaction and intent to stay in the role. Further research is needed to understand if CNS role implementation influences CNS departures and the relationship between intending to leave and actual departures from a CNS role.


Narrow optical bandpass filter via nearly degenerate four-wave mixing.
It is shown that a nearly degenerate four-wave mixing process is capable of yielding a real-time optical bandpass filter. The filter has a large field of view and is capable of providing an amplified bandpass. Moreover, the conjugate nature of the output field can be utilized to increase the signal-to-noise ratio of the device. For a 1-cm interaction length in a nondispersive medium, the optical bandpass at 5000 A can be varied from ~9 GHz down to the linewidth of the exciting laser.


Random-effects meta-analysis of combined outcomes based on reconstructions of individual patient data.
Meta-analyses of clinical trials typically focus on one outcome at a time. However, treatment decision-making depends on an overall assessment of outcomes balancing benefit in various domains and potential risks. This calls for meta-analysis methods for combined outcomes that encompass information from different domains. When individual patient data (IPD) are available from all studies, combined outcomes can be calculated for each individual and standard meta-analysis methods would apply. However, IPD are usually difficult to obtain. We propose a method to estimate the overall treatment effect for combined outcomes based on first reconstructing pseudo IPD from available summary statistics and then pooling estimates from multiple reconstructed datasets. We focus on combined outcomes constructed from two continuous original outcomes. The reconstruction step requires the specification of the joint distribution of these two original outcomes, including the correlation which is often unknown. For outcomes that are combined in a linear fashion, misspecifications of this correlation affect efficiency, but not consistency, of the resulting treatment effect estimator. For other combined outcomes, an accurate estimate of the correlation is necessary to ensure the consistency of treatment effect estimates. To this end, we propose several ways to estimate this correlation under different data availability scenarios. We evaluate the performance of the proposed methods through simulation studies and apply these to two examples: (a) a meta-analysis of dipeptidyl peptidase-4 inhibitors vs control on treating type 2 diabetes; and (b) a meta-analysis of positive airway pressure therapy vs control on lowering blood pressure among patients with obstructive sleep apnea.


In vitro and in vivo percutaneous absorption of seleno-L-methionine, an antioxidant agent, and other selenium species.
To investigate the in vitro and in vivo percutaneous absorption of seleno-L-methionine (Se-L-M), an ultraviolet (UV)-protecting agent, from aqueous solutions. Aqueous solutions of Se-L-M were prepared in pH 4, 8, and 10.8 buffers. The pH 8 buffer contained 30% glycerol, propylene glycol (PG) and polyethylene glycol (PEG) 400. The in vitro skin permeation of Se-L-M via porcine skin and nude mouse skin was measured and compared using Franz diffusion cells. The in vivo skin tolerance study was performed, which examined transepidermal water loss (TEWL), skin pH and erythema. In the excised porcine skin, the flux was 0.1, 11.4 and 8.2 μg·cm(-2)·h(-1) for the pH 4, 8, and 10.8 buffers, respectively. A linear correlation between the flux and skin deposition was determined. According to permeation across skin with different treatments (stripping, delipidation, and ethanol treatments), it was determined that the intracellular route comprised the predominant pathway for Se-L-M permeation from pH 8 buffer. Aqueous solutions of seleno-DL-methionine (Se-DL-M), selenium sulfide and selenium-containing quantum dot nanoparticles were also used as donor systems. The DL form showed a lower flux (7.0 vs 11.4 μg·cm(-2)·h(-1)) and skin uptake (23.4 vs 47.3 μg/g) as compared to the L form, indicating stereoselective permeation of this compound. There was no or only negligible permeation of selenium sulfide and quantum dots into and across the skin. With in vivo topical application for 4 and 8 h, the skin deposition of Se-L-M was about 7 μg/g, and values were comparable to each other. The topical application of Se-L-M for up to 5 d did not caused apparent skin irritation. However, slight inflammation of the dermis was noted according to the histopathological examination. Se-L-M was readily absorbed by the skin in both the in vitro and in vivo experiments. The established profiles of Se-L-M skin absorption will be helpful in developing topical products of this compound.


Respectful Disposition After Miscarriage: Clinical Practice Recommendations.
Compassionate clinical practice guidelines for healthcare providers for respectful disposition after miscarriage are presented. When woven into the whole of a clinician's practice, these guidelines provide the framework for giving women and their families the care they want and deserve when experiencing miscarriage. Relying on theoretical concepts of personhood, place, and protection, care providers can assess the unique meaning a woman assigns to her early pregnancy loss and offer interventions that embrace the concept of respectful disposition. Respectful methods of disposition involve a continuum of care that shows respect for remains and relies on person-, family-, and culture-centered nursing care. Policies, practices, and perspectives that flow from respectful disposition have women and families at their core and flexibility to cocreate care. This involves courage and competence. Several states have enacted fetal disposition laws, but these mandates are of questionable benefit because the expertise of healthcare leaders, nurses, physicians, chaplains, and other stakeholders must be involved in this sensitive and important area of care. Compassionate care cannot be legislated. We offer a practical approach to respectful disposition, including how to handle and prepare remains and examples of burial and memorial services, which will give clinicians the ability to respond empathetically and respectfully to the heart-rending plea of a woman who asks, "Where is my baby?"


A novel molecular magnetic resonance imaging agent targeting activated leukocyte cell adhesion molecule as demonstrated in mouse brain metastasis models.
Molecular magnetic resonance imaging (MRI) allows visualization of biological processes at the molecular level. Upregulation of endothelial ALCAM (activated leukocyte cell adhesion molecule) is a key element for leukocyte recruitment in neurological disease. The aim of this study, therefore, was to develop a novel molecular MRI contrast agent, by conjugating anti-ALCAM antibodies to microparticles of iron oxide (MPIO), for detection of endothelial ALCAM expression in vivo. Binding specificity of ALCAM-MPIO was demonstrated in vitro under static and flow conditions. Subsequently, in a proof-of-concept study, mouse models of brain metastasis were induced by intracardial injection of brain-tropic human breast carcinoma, lung adenocarcinoma or melanoma cells to upregulate endothelial ALCAM. At selected time-points, mice were injected intravenously with ALCAM-MPIO, and ALCAM-MPIO induced hypointensities were observed on T2*-weighted images in all three models. Post-gadolinium MRI confirmed an intact blood-brain barrier, indicating endoluminal binding. Correlation between endothelial ALCAM expression and ALCAM-MPIO binding was confirmed histologically. Statistical analysis indicated high sensitivity (80-90%) and specificity (79-83%) for detection of endothelial ALCAM in vivo with ALCAM-MPIO. Given reports of endothelial ALCAM upregulation in numerous neurological diseases, this advance in our ability to image ALCAM in vivo may yield substantial improvements for both diagnosis and targeted therapy.


Prediction of function in daily life following multidisciplinary rehabilitation for individuals with chronic musculoskeletal pain; a prospective study.
The prevalence of chronic musculoskeletal pain is high, with widespread negative economic, psychological, and social consequences for the individual. It is therefore important to find ways to predict the outcome of rehabilitation programmes in terms of function in daily life. The aims of this study were to investigate the improvements over time from multidisciplinary rehabilitation in terms of pain and function, and analyse the relative impact of individual and psychosocial factors as predictors of function in daily life in individuals with chronic musculoskeletal pain. A prospective study was conducted among one hundred and forty three (N = 143) musculoskeletal pain patients. Measures of pain, function, and functional health status were obtained at baseline, after 5 weeks of intensive training, at the end of the 57-week rehabilitation programme, and at a 1 year follow-up, using validated self-administrated measures. Linear regression analysis was applied to investigate the relative impact of musculoskeletal pain, individual-, and psychosocial factors in function. The participants studied showed a significant increase in function during the 57 weeks rehabilitation period. There was also a significant increase in function from the end of the rehabilitation period (57th week) to the one year follow-up measures. Pain intensity associated significantly with pain experience over all measurement periods. High levels of pain intensity (beta = .42**) and pain experience (beta = .37*), and poor psychological capacity (beta = -.68*) at baseline, as well as poor physiological capacity (beta = -.44**) and high levels of anxiety (beta = .48**) and depression (beta = .58***) at the end of the rehabilitation program were the most important prognostic factors of variance in functioning over the 4 measurement periods. The data suggest that physical capacity, emotional distress and coping skills should be priority areas in rehabilitation programmes to improve functioning in daily life.


Education, alcohol use and abuse among young adults in Britain.
In this article we explore the relationship between education and alcohol consumption. We examine whether the probability of abusing alcohol differs across educational groups. We use data from the British Cohort Study, a longitudinal study of one week's birth in Britain in 1970. We analysed data collected at age 34 (in 2004) and complement it with information gathered at previous sweeps. Measures of alcohol abuse include alcohol consumption above NHS guidelines, daily alcohol consumption and problem drinking. We found that higher educational attainment is associated with increased odds of daily alcohol consumption and problem drinking. The relationship is stronger for females than males. Individuals who achieved high educational test scores in childhood are at a significantly higher risk of abusing alcohol across all dimensions. Our results also suggest that educational qualifications and academic performance are associated with the probability of belonging to different typologies of alcohol consumers among women while this association is not present in the case of educational qualifications and is very weak in the case of academic performance among males.


Autophagy and airway fibrosis: Is there a link?
In the past decade, an emerging process named "autophagy" has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.


African swine fever virus organelle rearrangements.
Like most viruses African swine fever virus (ASFV) subsumes the host cell apparatus in order to facilitate its replication. ASFV replication is a highly orchestrated process with a least four stages of transcription, immediate-early, early, intermediate and late. As the infective cycle progresses through these stages most if not all of the organelles that comprise a nucleated cell are modified, adapted or in some cases destroyed. The entry of the virus is receptor-mediated, but the precise mechanism of endocytosis is a matter of keen, current debate. Once ASFV has exited from the endosomal-lysosomal complex the virus life-cycle enters into an intimate relationship with the microtubular network. Genome replication is believed to be initiated within the nucleus and ASFV infection completely reorders the structure of this organelle. The majority of replication and assembly occurs in discrete, perinuclear regions of the cell called virus factories and finally progeny virions are transported to the plasma membrane along microtubules where they bud out or are propelled away along actin projections to infect new cells. The generation of ASFV replication sites induces profound reorganisation of the organelles that comprise the secretory pathway and may contribute to the induction of cellular stress responses that ASFV modulates. The level of organisation and complexity of virus factories are not dissimilar to those seen in cellular organelles. Like their cellular counterparts the formation of virus factories, as well as virus entry and exit, are dependent on the various components of the cytoskeleton. This review will summarise these rearrangements, the viral proteins involved and their functional consequences.


Ranking of elimination feasibility between malaria-endemic countries.
Experience gained from the Global Malaria Eradication Program (1955-72) identified a set of shared technical and operational factors that enabled some countries to successfully eliminate malaria. Spatial data for these factors were assembled for all malaria-endemic countries and combined to provide an objective, relative ranking of countries by technical, operational, and combined elimination feasibility. The analysis was done separately for Plasmodium falciparum and Plasmodium vivax, and the limitations of the approach were discussed. The relative rankings suggested that malaria elimination would be most feasible in countries in the Americas and Asia, and least feasible in countries in central and west Africa. The results differed when feasibility was measured by technical or operational factors, highlighting the different types of challenge faced by each country. The results are not intended to be prescriptive, predictive, or to provide absolute assessments of feasibility, but they do show that spatial information is available to facilitate evidence-based assessments of the relative feasibility of malaria elimination by country that can be rapidly updated.


Fibroblasts and Osteoblasts in Inflammation and Bone Damage.
This review discusses the important role fibroblasts play in the process of inflammation and the evidence that these cells may drive the persistence of inflammation. Fibroblasts are key components of the stroma normally involved in maintenance of extracellular matrix and tissue function; however, the term 'fibroblast' is used to describe a heterogeneous population of cells that vary in phenotype both between and within anatomical sites. Fibroblasts possess Toll-like receptors allowing them to respond to pathogen and damage-related signals by producing proinflammatory mediators such as IL-6, PGE2, and GM-CSF and can produce a range of chemokines such as CXCL12, CXCL13, and CXCL8 which attract B and T lymphocytes, monocytes, and neutrophils to sites of inflammation. Interactions between leukocytes and fibroblasts can facilitate increased survival of the leukocytes and modulate phenotypes leading to differential gene expression in the presence of mediators involved in inflammation. Fibroblasts also contribute to collateral tissue damage during inflammation through the production of members of the metalloproteinase family and cathepsins and also through induction of osteoclastogenesis leading to increased bone resorption rates. In persistent diseases, fibroblasts obtain an imprinted, aggressive phenotype leading to the production of higher basal levels of proinflammatory cytokines and the ability to damage tissue in the absence of continual stimuli. This aggressive phenotype offers an attractive new target for therapeutics that could help alleviate the burden of persistent inflammation.


Congenital capillary proliferation of the kidney: a distinctive renal vascular lesion of childhood.
Renal vascular lesions (RVL) are rare, and their morphological spectrum remains largely unknown, particularly in children. In this study, we characterize the clinicopathological features of RVL in a cohort of 12 children. Seven lesions were classified as previously recognized entities: vascular malformations (4), papillary endothelial hyperplasia (2), and pyogenic granuloma (lobular capillary hemangioma; 1). An eighth lesion showed nonspecific findings, which were interpreted as reactive during our review. The remaining 4 cases presented either prenatally, at birth, or shortly after birth and were morphologically similar. These were characterized by a peculiar pattern of capillary proliferation with entrapment of native renal structures, variable amounts of extramedullary hematopoiesis and reactive lymphocytes, foci of infarction and hemorrhage, and the presence of feeding and draining vessels at their periphery. To our knowledge, this represents a previously undescribed congenital vascular lesion involving the kidney, which we have descriptively and provisionally termed congenital capillary proliferation of the kidney (CCPK). While it is unclear whether CCPK represents a malformation or neoplastic proliferation, it shows overlapping features with congenital hemangioma of the liver (solitary congenital hepatic hemangioma) and congenital nonprogressive hemangioma (CNH) of the skin and soft tissue, suggesting a possible common pathogenesis among these 3 entities.


Gastrointestinal absorption of epidermal growth factor in suckling rats.
Epidermal growth factor (EGF) was detected in the milk of adult lactating Sprague-Dawley female rats (38.85 ng/ml) and in the stomach (37.25 ng/g content) and plasma (32.36 ng/ml) of 13-day-old suckling offspring. Sixty-nanogram (0.12 mCi/ml) doses of 125I-EGF were administered orally to sucklings in 200 microliters of buffer for 0, 0.5, 1.0, and 3.0 h. Lung, liver kidney, brain, and blood each contained 1% or less of the administered radioactivity. Stomach wall (8%) and content (63%), intestinal wall (15%) and flushing (38%), and skin (18%) contained larger amounts reaching maxima in these three regions at 0, 0.5, and 3.0 h, respectively. Except for skin, a substantial amount of radioactivity from all tissues represented intact (6-90%) and immunoreactive (3-90%) EGF based on Sephadex G-25 chromatography and anti-EGF antibody binding, respectively. From 30 to 55% of the radioactivity from wall (gastric or small intestinal) or lumina was also capable of binding to A-431 cell surface receptors. Isoelectric points of major species found in stomach (4.2), intestine (4.1), and other tissues differed from that of administered EGF (4.5).


Lean thinking across a hospital: redesigning care at the Flinders Medical Centre.
Lean thinking is a method for organising complex production processes so as to encourage flow and reduce waste. While the principles of lean thinking were developed in the manufacturing sector, there is increasing interest in its application in health care. This case history documents the introduction and development of Redesigning Care, a lean thinking-based program to redesign care processes across a teaching general hospital. Redesigning Care has produced substantial benefits over the first two-and-a-half years of its implementation, making care both safer and more accessible. Redesigning Care has not been aimed at changing the specifics of clinical practice. Rather, it has been concerned with improving the flow of patients through clinical and other systems. Concepts that emerged in the manufacturing sector have been readily translatable into health care. Lean thinking may play an important role in the reform of health care in Australia and elsewhere.


Walnuts Consumed by Healthy Adults Provide Less Available Energy than Predicted by the Atwater Factors.
Previous studies have shown that the metabolizable energy (ME) content (energy available to the body) of certain nuts is less than predicted by the Atwater factors. However, very few nuts have been investigated to date, and no information is available regarding the ME of walnuts. A study was conducted to determine the ME of walnuts when consumed as part of a typical American diet. Healthy adults (n = 18; mean age = 53.1 y; body mass index = 28.8 kg/m(2)) participated in a randomized crossover study with 2 treatment periods (3 wk each). The study was a fully controlled dietary feeding intervention in which the same base diet was consumed during each treatment period; the base diet was unsupplemented during one feeding period and supplemented with 42 g walnuts/d during the other feeding period. Base diet foods were reduced in equal proportions during the walnut period to achieve isocaloric food intake during the 2 periods. After a 9 d diet acclimation period, subjects collected all urine and feces for ∼1 wk (as marked by a Brilliant Blue fecal collection marker) for analysis of energy content. Administered diets, walnuts, and fecal and urine samples were subjected to bomb calorimetry, and the resulting data were used to calculate the ME of the walnuts. One 28-g serving of walnuts contained 146 kcal (5.22 kcal/g), 39 kcal/serving less than the calculated value of 185 kcal/serving (6.61 kcal/g). The ME of the walnuts was 21% less than that predicted by the Atwater factors (P < 0.0001). Consistent with other tree nuts, Atwater factors overestimate the metabolizable energy value of walnuts. These results could help explain the observations that consumers of nuts do not gain excessive weight and could improve the accuracy of food labeling. This trial was registered at clinicaltrials.gov as NCT01832909.


Organizational cynicism: bases and consequences.
Organizational cynicism is the belief that an organization lacks integrity, which, when coupled with a powerful negative emotional reaction, leads to disparaging and critical behavior. In this article, the author attempts to theoretically clarify the process by which five forms of cynicism develop in the workplace and to empirically relate them to affective outcomes. Societal, employee, and organizational change cynicisms may be attributed to psychological contract violations; work cynicism may be related to burnout; and person-role conflict and personality cynicism may be related to innate hostility. Empirically, personality cynicism emerged as the strongest predictor of organizational cynicism, adversely affecting all of the criteria. Other forms of cynicism had more selective effects. Organizational change cynicism induced job dissatisfaction and alienation, and employee cynicism affected organizational commitment. Societal cynicism actually increased both job satisfaction and commitment. Both personality and work cynicisms were related to organizational citizenship indirectly, through alienation. Theoretical and practical implications are discussed.


[In vitro susceptibilites to levofloxacin and various antibacterial agents of 11,475 clinical isolates obtained from 52 centers in 2002].
The susceptibilities of bacteria to fluoroquinolones (FQs), especially levofloxacin, and other antimicrobial agents were investigated using 11,475 clinical isolates collected in Japan during 2002. Methicillin susceptible staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis, the family of Enterobactericeae, Haemophilus influenzae and Acinetobacter spp. exhibited stable and high susceptibilities to FQs. The rate of FQs-resistant MRSA was 80 approximately 90%, being markedly higher than that of FQs-resistant MSSA. The FQs-resistance rate of MRCNS was also higher than that of MSCNS, however, it was lower than that of MRSA. No FQs-resistant clinical isolates of Salmonella spp. were detected in any of the surveys. Thirteen of Escherichai coli 696 isolates, 8 of Klebsiella pneumoniae 630 isolates and 33 of Proteus mirabilis 373 isolates produced extended-spectrum beta-lactamase (ESBL), furthermore 6 of 13 in E. coli, 1 of 8 in K. pneumoniae and 14 of 31 ESBL-producing isolates, and in P. mirabilis were FQs resistant. Attention should be focused in the future on the emergence of ESBL in relation to FQs resistance. The rate of FQs-resistant P. aeruginosa isolated from urinary tract infection (UTI) was 40 approximately 60%, while 15 approximately 25% of isolates from respiratory tract infection (RTI) were resistant. IMP-1 type metallo beta-lactamase producing organisms were found in 49 of P. aeruginosa 1,095 isolates, 7 of S. marcescens 586 isolates and 4 of Acinetobacter spp. 474 isolates, respectively. Glycopeptide-resistant enterococci or S. aureus was not found.


Effects of Nigella sativa oil with a low-calorie diet on cardiometabolic risk factors in obese women: a randomized controlled clinical trial.
Obesity is typically associated with increased risk factors of cardiovascular diseases (CVDs). Therefore, a therapeutic approach that aims to control body weight and metabolic profile might be effective in preventing CVDs. We aimed to determine the effects of Nigella Sativa (NS) oil with a low-calorie diet on cardiometabolic risk factors in obese women. In this double-blind randomized controlled clinical trial, 90 obese women were recruited. Participants were females aged 25-50 years old with body mass index (BMI) between 30 and 35 kg m(-2). They were randomly assigned to receive a low-calorie diet with 3 g per day (1 g before each meal) NS oil or placebo for 8 weeks. Anthropometric indices, dietary intake and biochemical parameters were measured at the baseline and after the intervention. Eighty-four females completed the trial (intervention n = 43, placebo n = 41). Two groups were similar in the baseline characteristics. After the intervention, dietary intake was changed in both groups compared to the baseline, but the differences were not significant between the two groups. In the NS group, weight (-6.0 vs. -3.6%; p < 0.01) and waist circumference (-6.9 vs. -3.4%; p < 0.01) decreased significantly compared with the placebo group at the end of the trial. Comparison of biochemical parameters presented a significant decline in triglyceride (-14.0 vs. 1.4%; p = 0.02) and very low density lipoprotein (-14.0 vs. 7%; p < 0.01) levels in the NS group compared to the placebo group. NS oil concurrent with a low-calorie diet can reduce cardiometabolic risk factors in obese women. However, more clinical trials are needed to elucidate efficacy of NS as a complementary therapy in obese subjects.


Regulation of Trk receptors following contusion of the rat spinal cord.
Neurotrophins function through high-affinity tyrosine kinase (Trk) receptors to promote growth and survival of cells in the injured nervous system. To investigate the role of Trk receptors in the adult nervous system, we examined TrkA, TrkB, and TrkC mRNA expression in spinal cord and brain after spinal contusion. At 1 day postinjury, all Trk receptor transcripts were down regulated at and around the site of injury, a situation that persisted through the first week. By 42 days, Trk expression was absent only within the cavity. In addition, truncated TrkB expression was substantially increased in ependymal cells and astrocytes surrounding the lesion cavity of chronically injured spinal cords. Rostral and caudal to the injury site, TrkA, TrkB, and TrkC mRNA expression did not differ from that of uninjured control spinal cords. Furthermore, no changes were observed in TrkB or TrkC expression in the axotomized corticospinal and rubrospinal neurons. These studies suggest that loss of Trk receptors at the injury site may contribute to the early progressive cellular loss in injured spinal cords, while increased presence of truncated TrkB receptors in the chronic injured spinal cord may sequester and restrict BDNF availability to support axonal regeneration and neuronal survival. The persistence of Trk receptors on supraspinal neurons suggests that neurotrophin application can support growth and survival in the acute and chronic injury states.


Measurement invariance of the Illness Invalidation Inventory (3*I) across language, rheumatic disease and gender.
The Illness Invalidation Inventory (3*I) assesses patients' perception of responses of others that are perceived as denying, lecturing, not supporting and not acknowledging the condition of the patient. It includes two factors: 'discounting' and 'lack of understanding'. In order to use the 3*I to compare and pool scores across groups and countries, the questionnaire must have measurement invariance; that is, it should measure identical concepts with the same factor structure across groups. The aim of this study was to examine measurement invariance of the 3*I across rheumatic diseases, gender and languages. Participants with rheumatic disease from various countries completed an online study using the 3*I, which was presented in Dutch, English, French, German, Portuguese and Spanish; 6057 people with rheumatic diseases participated. Single and multiple group confirmatory factor analyses were used to test the factorial structure and measurement invariance of the 3*I with Mplus. The model with strong measurement invariance, that is, equal factor loadings and thresholds (distribution cut-points) across gender and rheumatic disease (fibromyalgia vs other rheumatic diseases) had the best fit estimates for the Dutch version, and good fit estimates across the six language versions. The 3*I showed measurement invariance across gender, rheumatic disease and language. Therefore, it is appropriate to compare and pool scores of the 3*I across groups. Future research may use the questionnaire to examine antecedents and consequences of invalidation as well as the effect of treatments targeting invalidation.


Intra-symbol frequency-domain averaging based channel estimation for coherent optical OFDM.
We present an efficient channel estimation method for coherent optical OFDM (CO-OFDM) based on intra-symbol frequency-domain averaging (ISFA), and systematically study its robustness against transmission impairments such as optical noise, chromatic dispersion (CD), polarization-mode dispersion (PMD), polarization-dependent loss (PDL), and fiber nonlinearity. Numerical simulations are performed for a 112-Gb/s polarization-division multiplexed (PDM) CO-OFDM signal, and the ISFAbased channel estimation and the subsequent channel compensation are found to be highly robust against these transmission impairments in typical optical transport systems.


Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK.
Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism. We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays. Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor. Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.


Rapid spread of chikungunya virus infection in Orissa: India.
A large number of cases of undiagnosed fever and joint pain were reported from different parts of the State of Orissa since February 2006. Epidemiological and laboratory investigation were carried out to confirm the cause of emerging illness, which was provisionally suspected as Chikungunya (CHIK) fever. Upon getting the reports of suspected CHIK like illness in different parts of the State, epidemic investigations were carried out in the outbreak affected villages. Case history was recorded, clinical examination undertaken and blood samples collected for seroconfirmation for CHIK IgM antibody using ELISA based kit. Simultaneously vector survey was also carried out. With no previous record of CHIK infection in the State, the first outbreak was confirmed during February 2006. Subsequently, the infection spread to 13 of 30 districts in different episodes covering 79 villages till November 2007. Attack rate was 9-43 per cent in the different outbreaks with average seropositivity of 24 per cent to CHIK specific IgM. Morbidity was high though no deaths were recorded. Aedes aegypti and Ae. albopictus were identified as the possible vectors for transmission. The report confirmed emergence of CHIK infection in the State of Orissa, India, and its spread to a larger geographic zone in a short period which warrants public health measures to control further spread.


The Swedish SCOPA-SLEEP for assessment of sleep disorders in Parkinson's disease and healthy controls.
SCOPA-SLEEP is a rating scale for night-time sleep and daytime sleepiness (DS) proposed for use among people with Parkinson's disease (PD) as well as others. We translated it into Swedish and assessed its psychometric properties in PD and age-matched healthy controls. Following translation according to the dual-panel approach, the Swedish SCOPA-SLEEP was field-tested regarding comprehensibility, relevance and respondent burden (n = 20). It was then psychometrically tested according to classical test theory (data completeness, scaling assumptions, targeting, reliability and construct validity) using data from 149 people with PD and 53 age-matched healthy controls from the prospective Swedish BioFINDER study. SCOPA-SLEEP took a mean of 3.5 min to complete and was considered easy to use and relevant. Missing item responses were <8 %, corrected item-total correlations were ≥0.47 (except for one DS item among controls), factor analyses suggested one dimension per scale, floor/ceiling effects were ≤17 %, reliability was ≥0.85 except for the DS scale among controls (0.65) and construct validity was supported. Observations concur with previous evaluations, thus providing initial support for the Swedish SCOPA-SLEEP among people with PD. Further studies are needed to establish its generic properties and to understand its measurement properties in better detail.


Single-grain OSL chronologies for Middle Palaeolithic deposits at El Mnasra and El Harhoura 2, Morocco: implications for Late Pleistocene human-environment interactions along the Atlantic coast of northwest Africa.
Optically stimulated luminescence (OSL) measurements were made on individual, sand-sized grains of quartz from Middle Palaeolithic deposits at two cave sites (El Harhoura 2 and El Mnasra) on the Atlantic coast of Morocco. We were able to calculate OSL ages for 32 of the 33 samples collected from the Middle Palaeolithic deposits, including the earliest and latest Aterian levels at both sites. These ages reveal periods of occupation between about 110 and 95 ka (thousands of years ago), and at ~75 ka. A late Middle Palaeolithic occupation of El Harhoura 2 is also recorded at ~55 ka. Our single-grain OSL chronologies largely support previous age estimates from El Mnasra and other sites along the Atlantic coast of Morocco, but are generally more precise, reproducible and stratigraphically more coherent (i.e., fewer age reversals). We compare the single-grain ages for El Harhoura 2 and El Mnasra with those obtained from single- and multi-grain OSL dating of Middle Palaeolithic deposits in the nearby sites of Contrebandiers and Dar es-Soltan 1 and 2, and with records of past regional environments preserved in sediment cores collected from off the coast of northwest Africa. A conspicuous feature of the new chronologies is the close correspondence between the three identified episodes of human occupation and periods of wetter climate and expanded grassland habitat. Owing to the precision of the single-grain OSL ages, we are able to discern gaps in occupation during Marine Isotope Stages 5 and 4, which may represent drier periods with reduced vegetation cover. We propose that these climatic conditions can be correlated with events in the North Atlantic Ocean that exert a major control on abrupt, millennial-scale fluctuations between wet and dry periods in northwest and central North Africa.


Flagellins of Salmonella Typhi and nonpathogenic Escherichia coli are differentially recognized through the NLRC4 pathway in macrophages.
Flagellin is recognized by both Toll-like receptor (TLR)5 and NAIP5/NLRC4 inflammasome receptors. We hypothesized that the flagellins derived from different bacteria might differentially activate TLR5 and/or NAIP5/NLRC4 signal pathways. To test this, the immune recognition of recombinant flagellins derived from pathogenic Salmonella Typhi (SF) and the nonpathogenic Escherichia coli K12 strain MG1655 (KF) were examined by the activation of TLR5 and NLRC4 pathways in various cell types. While flagellins SF and KF were not distinguishable in activating the TLR5 pathway, KF induced significantly less interleukin-1β production and pyroptotic cell death in peritoneal macrophages than SF, and showed markedly lower efficiency in activating caspase-1 through the NLRC4 pathway than SF. Macrophages may differentially recognize flagellins by intracellular sensors and thereby initiate the immune response to invading pathogenic bacteria. Our findings suggest an active role of flagellin as an important determinant in host differential immune recognition and for the control of bacteria infection.


A retrospective analysis of the change in anti-malarial treatment policy: Peru.
National malaria control programmes must deal with the complex process of changing national malaria treatment guidelines, often without guidance on the process of change. Selecting a replacement drug is only one issue in this process. There is a paucity of literature describing successful malaria treatment policy changes to help guide control programs through this process. To understand the wider context in which national malaria treatment guidelines were formulated in a specific country (Peru). Using qualitative methods (individual and focus group interviews, stakeholder analysis and a review of documents), a retrospective analysis of the process of change in Peru's anti-malarial treatment policy from the early 1990's to 2003 was completed. The decision to change Peru's policies resulted from increasing levels of anti-malarial drug resistance, as well as complaints from providers that the drugs were no longer working. The context of the change occurred in a time in which Peru was changing national governments, which created extreme challenges in moving the change process forward. Peru utilized a number of key strategies successfully to ensure that policy change would occur. This included a) having the process directed by a group who shared a common interest in malaria and who had long-established social and professional networks among themselves, b) engaging in collaborative teamwork among nationals and between nationals and international collaborators, c) respect for and inclusion of district-level staff in all phases of the process, d) reliance on high levels of technical and scientific knowledge, e) use of standardized protocols to collect data, and f) transparency. Although not perfectly or fully implemented by 2003, the change in malaria treatment policy in Peru occurred very quickly, as compared to other countries. They identified a problem, collected the data necessary to justify the change, utilized political will to their favor, approved the policy, and moved to improve malaria control in their country. As such, they offer an excellent example for other countries as they contemplate or embark on policy changes.


Predictive measures of vascular access thrombosis: a prospective study.
Malfunction of permanent vascular accesses remains a cause of frequent and costly morbidity in patients receiving chronic hemodialysis (CHD). Several recommendations for routine monitoring of these permanent vascular accesses for incipient failure have been proposed. In this study, multiple indicators of incipient vascular access dysfunction, including "venous" and "arterial" pressures at serial blood flows (200 ml/min, 300 ml/min, and 400 ml/min), percent urea recirculation, Doppler ultrasound, and access blood flow by ultrasound dilution technique were simultaneously evaluated in a total of 220 vascular accesses in 170 chronic hemodialysis patients in two separate study periods (6 months apart). The rate of thrombosis was determined within the subsequent 12 weeks of each study period to assess the short-term predictive power of access thrombosis. During the period of follow-up, there were 34 thrombotic events in 172 polytetrafluoroethylene (PTFE) grafts and only one thrombotic event in 48 arterio-venous fistulas (AVF). Therefore, the statistical analysis was limited to the PTFE grafts. When grafts with thromboses were compared to those without thrombosis by univariate analysis, access blood flow measured either by ultrasound dilution technique (875 +/- 426 ml/min with thrombosis vs. 1193 +/- 677 ml/min without thrombosis, P = 0.001) or by Doppler ultrasound (762 +/- 420 ml/min with thrombosis vs. 1171 +/- 657 ml/min without thrombosis, P = 0.001) were significantly different in the two groups. There was good correlation (r = 0.79, P = 0.0001) between the blood flows determined by both techniques. The grade of stenosis determined by ultrasound was also a statistically significant predictor (P = 0.02). "Venous" and "arterial" pressures were numerically similar and were not statistically different between the accesses that did and those that did not thrombose. When multivariate analysis was used, there was a significantly increased risk of thrombosis only with decreasing access blood flow determined by ultrasound dilution techniques after adjusting for other confounding variables. When the average blood flow of all grafts (1134 ml/min) is considered as the reference access blood flow (relative risk of 1.0), the relative risk of a PTFE thrombotic event within the subsequent 12 weeks was 1.23 at a blood flow 950 ml/min, 1.67 at a blood flow of 650 ml/min and to 2.39 at a blood flow of 300 ml/min. In summary, access blood flow measured by either Dilution or Doppler is a reliable indicator of subsequent short-term thrombosis risk. Other proposed methods of evaluating access dysfunction were not useful in our patients. If simple to use, cost-effective devices to measure dialysis access blood flow become readily available, the measurement of access blood flow will likely become the method of choice for screening of PTFE vascular access dysfunction in hemodialysis patients.


Thyroid hormone in health and disease.
Thyroid disease is common, affecting around 2% of women and 0.2% of men in the UK. Our understanding of the effects of thyroid hormones under physiological circumstances, as well as in pathological conditions, has increased dramatically during the last two centuries and it has become clear that overt thyroid dysfunction is associated with significant morbidity and mortality. Both hypo-and hyperthyroidism and their treatments have been linked with increased risk from cardiovascular disease and the adverse effects of thyrotoxicosis in terms of osteoporosis risk are well established. Although the evidence suggests that successful treatment of overt thyroid dysfunction significantly improves overall survival, the issue of treating mild or subclinical hyper- and hypothyroidism remains controversial. Furthermore, the now well-established effects of thyroid hormones on neurodevelopment have sparked a whole new debate regarding the need to screen pregnant women for thyroid function abnormalities. This review describes the current evidence of the effects of thyroid hormone on the cardiovascular, skeletal and neurological systems, as well as the influence of thyroid diseases and their treatments on the development of malignancy. Furthermore we will describe some recent developments in our understanding of the relationship between thyroid status and health.


Significance of DNA polymerase I in in vivo processing of clustered DNA damage.
We examined the biological consequences of bi-stranded clustered damage sites, consisting of a combination of DNA lesions, such as a 1-nucleotide gap (GAP), an apurinic/apyrimidinic (AP) site, and an 8-oxo-7,8-dihydroguanine (8-oxoG), using a bacterial plasmid-based assay. Following transformation with the plasmid containing bi-stranded clustered damage sites into the wild type strain of Escherichia coli, transformation frequencies were significantly lower for the bi-stranded clustered GAP/AP lesions (separated by 1bp) than for either a single GAP or a single AP site. When the two lesions were separated by 10-20bp, the transformation efficiencies were comparable with those of the single lesions. This recovery of transformation efficiency for separated lesions requires DNA polymerase I (Pol I) activity. Analogously, the mutation frequency was found to depend on the distance separating lesions in a bi-stranded cluster containing a GAP and an 8-oxoG, and Pol I was found to play an important role in minimising mutations induced as a result of clustered lesions. The mutagenic potential of 8-oxoG within the bi-stranded lesions does not depend on whether it is situated on the leading or lagging strand. These results indicate that the biological consequences of clustered DNA damage strongly depend on the extent of repair of the strand breaks as well as the DNA polymerase in lesion-avoidance pathways during replication.


Reproducible, portable, and efficient ancient genome reconstruction with nf-core/eager.
The broadening utilisation of ancient DNA to address archaeological, palaeontological, and biological questions is resulting in a rising diversity in the size of laboratories and scale of analyses being performed. In the context of this heterogeneous landscape, we present an advanced, and entirely redesigned and extended version of the EAGER pipeline for the analysis of ancient genomic data. This Nextflow pipeline aims to address three main themes: accessibility and adaptability to different computing configurations, reproducibility to ensure robust analytical standards, and updating the pipeline to the latest routine ancient genomic practices. The new version of EAGER has been developed within the nf-core initiative to ensure high-quality software development and maintenance support; contributing to a long-term life-cycle for the pipeline. nf-core/eager will assist in ensuring that a wider range of ancient DNA analyses can be applied by a diverse range of research groups and fields.


OMERACT 6 Economics Working Group report: a proposal for a reference case for economic evaluation in rheumatoid arthritis.
Standardization of methods for economic evaluation is essential for defining the methodological research agenda that will advance the discipline. Standardization also greatly facilitates the interpretation and comparison of the results of economic analyses. For these reasons, several jurisdictions now require economic evaluation, conducted according to standardized methodological guidelines, as a key ingredient in decision making for reimbursement of health treatments and technologies. The application of these general guidelines, however, can be difficult in the absence of disease-specific information. In the case of rheumatoid arthritis (RA), the recent emergence of innovative, highly effective, but also expensive treatments has created an immediate need to more fully understand the economic implications of RA treatments. With this background, the OMERACT Economics Working Group set out in 1994 to develop an RA-specific reference case for economic evaluation. This report summarizes the OMERACT process leading to specific recommendations on the 12 key elements of a proposed "reference case" for economic evaluation in RA. These elements include: study horizon, duration of therapy, extrapolation beyond trial duration, modeling beyond therapy, synthesis of comparisons where head-to-head trials do not exist, clinical outcome measures, mortality, valuation of health states, resource utilization, discontinuation of therapy, therapeutic sequence, and population risk stratification. Through these efforts, the OMERACT Economics Working Group aims to expedite and enhance the conduct and dissemination of methodological research in economic analyses in the rheumatic diseases.


Learning through connections with others: women's cardiac symptoms.
Conducting group sessions in which women can share experiences, develop connections, and learn from each other may potentially be a powerful health educational tool. In a focus group conducted for evaluative feedback, the authors found that women began spontaneously sharing their experiences and feelings, receiving validation, and learning from each other almost from the start of the group session. The participants who were dissimilar in age, ethnicity/race, and socioeconomic status developed a strong connection based on the common experience of having had a heart attack. Although the participants had received patient education after their heart attack, they learned new information about cardiac symptoms and how to respond to them in the group session. This case example is a compelling reminder that women learn through connections. Therefore, a group approach to health education that acknowledges the salience of personal experiences, the experiences of others, the development of connections, and the exchange of information may provide a meaningful learning environment. Further research needs to be conducted to determine if conducting group appointments for women that fosters the development of connections and the exchange of information enriches the learning environment and enhances patient education.


Direct fabrication of silicon photonic devices on a flexible platform and its application for strain sensing.
We demonstrate a process to fabricate silicon photonic devices directly on a plastic film which is both flexible and transparent. This process allows the integration of complex structures on plastic films without the need of transferring from another substrate. Waveguides, grating couplers, and microring resonators are fabricated and optically characterized. An optical strain sensor is shown as an application using 5 µm-radius microring resonators on the flexible substrate. When strain is applied, resonance wavelength shifts of the microring resonators are observed. Contributions of different effects are analyzed and evaluated. Finally, we measure the influence of residual strain and confirm the material undergoes elastic deformation within the applied strain range.


N-acetylcysteine protects induced pluripotent stem cells from in vitro stress: impact on differentiation outcome.
Induced pluripotent stem cells (iPSCs) have the ability to differentiate towards various cell types of the adult organism and are a potential source of transplantable material in regenerative medicine. The entire process of conversion of iPSCs into terminally differentiated cells takes place in vitro and requires long periods of time. During in vitro culture, cells are exposed to environmental factors, which are capable of decreasing cellular performance and viability. Oxidative stress is the major underlying mechanism of such negative impact of in vitro environmental factors. We aimed to study the alteration of cellular properties during in vitro hematopoietic differentiation of human iPSCs and the ability of N-acetylcysteine (NAC), a potent free radical scavenger, to prevent such alterations. IPSCs were differentiated towards hematopoietic cells in the presence of 1 mM NAC. Intracellular reactive oxygen species (ROS), nitric oxide (NO), senescence, apoptosis and mitochondrial membrane potential (MMP) were evaluated at 1 and 3 weeks of differentiation. In the course of hematopoietic differentiation of iPSCs, cells progressively accumulated intracellular ROS and NO, increased the levels of apoptosis and senescence, and showed a decrease in mitochondrial functionality. NAC supplementation reversed all these phenomena. NAC administration also improved hematopoietic differentiation of iPSCs in terms of production of CD34, CD45 and CD43 positive cells. In conclusion, when supplemented during hematopoietic differentiation of iPSCs, NAC decreased oxidative stress, rescued the decline in cellular properties induced by long-term in vitro culture and promoted hematopoietic differentiation of iPSCs.


Depression and ambulatory care sensitive hospitalizations among Medicare beneficiaries with chronic physical conditions.
We examined the association between depression and hospitalizations for Ambulatory Care Sensitive Conditions (H-ACSC) among Medicare beneficiaries with chronic physical conditions. We used a retrospective longitudinal design using multiple years (2002-2009) of linked fee-for-service Medicare claims and survey data from Medicare Current Beneficiary Survey to create six longitudinal panels. We followed individuals in each panel for a period of 3-years; first year served as the baseline and subsequent 2-years served as the follow-up. We measured depression, chronic physical conditions and other characteristics at baseline and examined H-ACSC at follow-up. We identified chronic physical conditions from survey data and H-ACSC and depression from fee-for-service Medicare claims. We analyzed unadjusted and adjusted relationships between depression and the risk of H-ACSC with chi-square tests and logistic regressions. Among all Medicare beneficiaries, 9.3% had diagnosed depression. Medicare beneficiaries with depression had higher rates of any H-ACSC as compared to those without depression (13.6% vs. 7.7%). Multivariable regression indicated that, compared to those without depression, Medicare beneficiaries with depression were more likely to experience any H-ACSC. Depression was associated with greater risk of H-ACSC, suggesting that health care quality measures may need to include depression as a risk-adjustment variable.


Formation of nucleoprotein filaments by mammalian DNA methyltransferase Dnmt3a in complex with regulator Dnmt3L.
The C-terminal domains of Dnmt3a and Dnmt3L form elongated heterotetramers (3L-3a-3a-3L). Analytical ultracentrifugation confirmed the Dnmt3a-C/3L-C complex exists as a 2:2 heterotetramer in solution. The 3a-3a interface is the DNA-binding site, while both interfaces are essential for AdoMet binding and catalytic activity. Hairpin bisulfite analysis shows correlated methylation of two CG sites in a distance of approximately 8-10 bp in the opposite DNA strands, which corresponds to the geometry of the two active sites in one Dnmt3a-C/3L-C tetramer. Correlated methylation was also observed for two CG sites at similar distances in the same DNA strand, which can be attributed to the binding of two tetramers next to each other. DNA-binding experiments show that Dnmt3a-C/3L-C complexes multimerize on the DNA. Scanning force microscopy demonstrates filament formation rather than binding of single tetramers and shows that protein-DNA filament formation leads to a 1.5-fold shortening of the DNA length.


Immunization with synthetic peptides of a Plasmodium falciparum surface antigen induces antimerozoite antibodies.
Polypeptides expressed on the surface of merozoites, the invasive stage of the asexual blood cycle, are good candidates for the development of malaria vaccines. Five synthetic peptides with predetermined specificity deduced from a genomic DNA clone coding for the NH2-terminal portion of the main merozoite surface polypeptide of Plasmodium falciparum were evaluated for their capability to raise antibodies that react with the P. falciparum merozoites. Antibodies induced by two of the peptides (3 and 5) reacted with the membrane surfaces of seven of seven isolates of P. falciparum from different geographic areas. Antibodies against peptide 4, which contains a repeated amino acid sequence (Gly-Gly-Ser and Val-Ala-Ser), reacted with six of seven isolates. Structural analysis of the deduced polypeptides suggests that peptide 3 is exposed at the surface of merozoites. When it was used to immunize monkeys, three of the four animals were partially protected from a challenge infection that induced a fulminant infection in control animals.


Local parasite lineage sharing in temperate grassland birds provides clues about potential origins of Galapagos avian Plasmodium.
Oceanic archipelagos are vulnerable to natural introduction of parasites via migratory birds. Our aim was to characterize the geographic origins of two Plasmodium parasite lineages detected in the Galapagos Islands and in North American breeding bobolinks (Dolichonyx oryzivorus) that regularly stop in Galapagos during migration to their South American overwintering sites. We used samples from a grassland breeding bird assemblage in Nebraska, United States, and parasite DNA sequences from the Galapagos Islands, Ecuador, to compare to global data in a DNA sequence registry. Homologous DNA sequences from parasites detected in bobolinks and more sedentary birds (e.g., brown-headed cowbirds Molothrus ater, and other co-occurring bird species resident on the North American breeding grounds) were compared to those recovered in previous studies from global sites. One parasite lineage that matched between Galapagos birds and the migratory bobolink, Plasmodium lineage B, was the most common lineage detected in the global MalAvi database, matching 49 sequences from unique host/site combinations, 41 of which were of South American origin. We did not detect lineage B in brown-headed cowbirds. The other Galapagos-bobolink match, Plasmodium lineage C, was identical to two other sequences from birds sampled in California. We detected a close variant of lineage C in brown-headed cowbirds. Taken together, this pattern suggests that bobolinks became infected with lineage B on the South American end of their migratory range, and with lineage C on the North American breeding grounds. Overall, we detected more parasite lineages in bobolinks than in cowbirds. Galapagos Plasmodium had similar host breadth compared to the non-Galapagos haemosporidian lineages detected in bobolinks, brown-headed cowbirds, and other grassland species. This study highlights the utility of global haemosporidian data in the context of migratory bird-parasite connectivity. It is possible that migratory bobolinks bring parasites to the Galapagos and that these parasites originate from different biogeographic regions representing both their breeding and overwintering sites.


Exercise when young provides lifelong benefits to bone structure and strength.
Short-term exercise in growing rodents provided lifelong benefits to bone structure, strength, and fatigue resistance. Consequently, exercise when young may reduce the risk for fractures later in life, and the old exercise adage of "use it or lose it" may not be entirely applicable to the skeleton. The growing skeleton is most responsive to exercise, but low-trauma fractures predominantly occur in adults. This disparity has raised the question of whether exercised-induced skeletal changes during growth persist into adulthood where they may have antifracture benefits. This study investigated whether brief exercise during growth results in lifelong changes in bone quantity, structure, quality, and mechanical properties. Right forearms of 5-week-old Sprague-Dawley rats were exercised 3 days/week for 7 weeks using the forearm axial compression loading model. Left forearms were internal controls and not exercised. Bone quantity (mineral content and areal density) and structure (cortical area and minimum second moment of area [I(MIN)]) were assessed before and after exercise and during detraining (restriction to home cage activity). Ulnas were removed after 92 weeks of detraining (at 2 years of age) and assessed for bone quality (mineralization) and mechanical properties (ultimate force and fatigue life). Exercise induced consistent bone quantity and structural adaptation. The largest effect was on I(MIN), which was 25.4% (95% CI, 15.6-35.3%) greater in exercised ulnas compared with nonexercised ulnas. Bone quantity differences did not persist with detraining, whereas all of the absolute difference in bone structure between exercised and nonexercised ulnas was maintained. After detraining, exercised ulnas had 23.7% (95% CI, 13.0-34.3%) greater ultimate force, indicating enhanced bone strength. However, exercised ulnas also had lower postyield displacement (-26.4%; 95% CI, -43.6% to -9.1%), indicating increased brittleness. This resulted from greater mineralization (0.56%; 95% CI, 0.12-1.00%), but did not influence fatigue life, which was 10-fold greater in exercised ulnas. These data indicate that exercise when young can have lifelong benefits on bone structure and strength, and potentially, fracture risk. They suggest that the old exercise adage of "use it or lose it" may not be entirely applicable to the skeleton and that individuals undergoing skeletal growth should be encouraged to perform impact exercise.


Biological Subtypes of Breast Cancer and Sentinel Lymph Node Biopsy.
Breast cancer subtypes are used as prognostic and predictive factors considering the genomic profile of the disease. This study is designed to investigate the Sentinel Lymph Node (SLN) detection rate in breast cancer for different biological characteristics. Patients on whom we performed the methylene blue method alone were named as Group I, radiocolloid substance method alone as Group II and both methylene blue and radiocolloid method as Group III. The results of biological tumor characteristics and characteristics of the patients on different SLN biopsy techniques were investigated. The overall SLN detecting success rate was 83.3%. When considered for each group, success rate was 80% for group I, 84.9% for group II and 90.6% for group III. While a success rate of 94.6% was achieved with radiocolloid only in the patients in Luminal A and B subgroup, 90% success rate was achieved in Her2 (+) and triple negative (TN) patients with combined method. While successful results could be achieved by using radiocolloid substances alone in patients with Luminal A and B subtypes, combined methods should be used in HER2 (+) and TN patients.


Treatment for prevention of HIV transmission in a localised epidemic: the case for South Australia.
Discussion is currently taking place among international HIV/AIDS groups around increasing HIV testing and initiating earlier use of antiretroviral therapy (ART) among people diagnosed with HIV as a method to reduce the spread of HIV. In this study, we explore the expected epidemiological impact of this strategy in a small population in which HIV transmission is predominantly confined to men who have sex with men (MSM). A deterministic mathematical transmission model was constructed to investigate the impacts of strategies that increase testing and treatment rates, and their likely potential to mitigate HIV epidemics among MSM. Our novel model distinguishes men in the population who are more easily accessible to prevention campaigns through engagement with the gay community from men who are not. This model is applied to the population of MSM in South Australia. Our model-based findings suggest that increasing testing rates alone will have minimal impact on reducing the expected number of infections compared to current conditions. However, in combination with increases in treatment coverage, this strategy could lead to a 59-68% reduction in the number of HIV infections over the next 5 years. Targeting men who are socially engaged with the gay community would result in the majority of potential reductions in incidence, with only minor improvements possible by reaching all other MSM. Investing in strategies that will achieve higher coverage and earlier initiation of treatment to reduce infectiousness of HIV-infected individuals could be an effective strategy for reducing incidence in a population of MSM.