Duration of menopausal vasomotor symptoms over the menopause transition.
The expected duration of menopausal vasomotor symptoms (VMS) is important to women making decisions about possible treatments. To determine total duration of frequent VMS (≥ 6 days in the previous 2 weeks) (hereafter total VMS duration) during the menopausal transition, to quantify how long frequent VMS persist after the final menstrual period (FMP) (hereafter post-FMP persistence), and to identify risk factors for longer total VMS duration and longer post-FMP persistence. The Study of Women's Health Across the Nation (SWAN) is a multiracial/multiethnic observational study of the menopausal transition among 3302 women enrolled at 7 US sites. From February 1996 through April 2013, women completed a median of 13 visits. Analyses included 1449 women with frequent VMS. Total VMS duration (in years) (hot flashes or night sweats) and post-FMP persistence (in years) into postmenopause. The median total VMS duration was 7.4 years. Among 881 women who experienced an observable FMP, the median post-FMP persistence was 4.5 years. Women who were premenopausal or early perimenopausal when they first reported frequent VMS had the longest total VMS duration (median, >11.8 years) and post-FMP persistence (median, 9.4 years). Women who were postmenopausal at the onset of VMS had the shortest total VMS duration (median, 3.4 years). Compared with women of other racial/ethnic groups, African American women reported the longest total VMS duration (median, 10.1 years). Additional factors related to longer duration of VMS (total VMS duration or post-FMP persistence) were younger age, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at first report of VMS. Frequent VMS lasted more than 7 years during the menopausal transition for more than half of the women and persisted for 4.5 years after the FMP. Individual characteristics (eg, being premenopausal and having greater negative affective factors when first experiencing VMS) were related to longer-lasting VMS. Health care professionals should counsel women to expect that frequent VMS could last more than 7 years, and they may last longer for African American women.


LiveSync: deformed viewing spheres for knowledge-based navigation.
Although real-time interactive volume rendering is available even for very large data sets, this visualization method is used quite rarely in the clinical practice. We suspect this is because it is very complicated and time consuming to adjust the parameters to achieve meaningful results. The clinician has to take care of the appropriate viewpoint, zooming, transfer function setup, clipping planes and other parameters. Because of this, most often only 2D slices of the data set are examined. Our work introduces LiveSync, a new concept to synchronize 2D slice views and volumetric views of medical data sets. Through intuitive picking actions on the slice, the users define the anatomical structures they are interested in. The 3D volumetric view is updated automatically with the goal that the users are provided with expressive result images. To achieve this live synchronization we use a minimal set of derived information without the need for segmented data sets or data-specific pre-computations. The components we consider are the picked point, slice view zoom, patient orientation, viewpoint history, local object shape and visibility. We introduce deformed viewing spheres which encode the viewpoint quality for the components. A combination of these deformed viewing spheres is used to estimate a good viewpoint. Our system provides the physician with synchronized views which help to gain deeper insight into the medical data with minimal user interaction.


Automatic classification of athletes with residual functional deficits following concussion by means of EEG signal using support vector machine.
There is a growing body of knowledge indicating long-lasting residual electroencephalography (EEG) abnormalities in concussed athletes that may persist up to 10-year postinjury. Most often, these abnormalities are initially overlooked using traditional concussion assessment tools. Accordingly, premature return to sport participation may lead to recurrent episodes of concussion, increasing the risk of recurrent concussions with more severe consequences. Sixty-one athletes at high risk for concussion (i.e., collegiate rugby and football players) were recruited and underwent EEG baseline assessment. Thirty of these athletes suffered from concussion and were retested at day 30 postinjury. A number of task-related EEG recordings were conducted. A novel classification algorithm, the support vector machine (SVM), was applied as a classifier to identify residual functional abnormalities in athletes suffering from concussion using a multichannel EEG data set. The total accuracy of the classifier using the 10 features was 77.1%. The classifier has a high sensitivity of 96.7% (linear SVM), 80.0% (nonlinear SVM), and a relatively lower but acceptable selectivity of 69.1% (linear SVM) and 75.0% (nonlinear SVM). The major findings of this report are as follows: 1) discriminative features were observed at theta, alpha, and beta frequency bands, 2) the minimal redundancy relevance method was identified as being superior to the univariate t -test method in selecting features for the model calculation, 3) the EEG features selected for the classification model are linked to temporal and occipital areas, and 4) postural parameters influence EEG data set and can be used as discriminative features for the classification model. Overall, this report provides sufficient evidence that 10 EEG features selected for final analysis and SVM may be potentially used in clinical practice for automatic classification of athletes with residual brain functional abnormalities following a concussion episode.


Scaling of echolocation call parameters in bats.
I investigated the scaling of echolocation call parameters (frequency, duration and repetition rate) in bats in a functional context. Low-duty-cycle bats operate with search phase cycles of usually less than 20 %. They process echoes in the time domain and are therefore intolerant of pulse-echo overlap. High-duty-cycle (>30 %) species use Doppler shift compensation, and they separate pulse and echo in the frequency domain. Call frequency scales negatively with body mass in at least five bat families. Pulse duration scales positively with mass in low-duty-cycle quasi-constant-frequency (QCF) species because the large aerial-hawking species that emit these signals fly fast in open habitats. They therefore detect distant targets and experience pulse-echo overlap later than do smaller bats. Pulse duration also scales positively with mass in the Hipposideridae, which show at least partial Doppler shift compensation. Pulse repetition rate corresponds closely with wingbeat frequency in QCF bat species that fly relatively slowly. Larger, fast-flying species often skip pulses when detecting distant targets. There is probably a trade-off between call intensity and repetition rate because 'whispering' bats (and hipposiderids) produce several calls per predicted wingbeat and because batches of calls are emitted per wingbeat during terminal buzzes. Severe atmospheric attenuation at high frequencies limits the range of high-frequency calls. Low-duty-cycle bats that call at high frequencies must therefore use short pulses to avoid pulse-echo overlap. Rhinolophids escape this constraint by Doppler shift compensation and, importantly, can exploit advantages associated with the emission of both high-frequency and long-duration calls. Low frequencies are unsuited for the detection of small prey, and low repetition rates may limit prey detection rates. Echolocation parameters may therefore constrain maximum body size in aerial-hawking bats.


Extreme Lateral Interbody Fusion (XLIF) in the Thoracic and Thoracolumbar Spine: Technical Report and Early Outcomes.
Previous studies have demonstrated the distinct advantages of thoracoscopically assisted spinal fusion compared to traditional open thoracotomy. However, these techniques are limited by a steep learning curve, prolonged operative time, and lack of three-dimensional visualization of the surgical field. The objective of this study was to describe our initial experience with an adaptation of the extreme lateral interbody fusion (XLIF) technique allowing access to the anterior aspect of the thoracic and thoracolumbar spine with specific reference to (1) early pulmonary complications, (2) non-pulmonary complications, and (3) ability of this technique to successfully achieve spinal decompression and fusion at the operative level. Clinical and radiographic data were reviewed for the entire perioperative period. A total of 18 patients (72% females; mean age, 56.8 years) underwent a thoracic XLIF procedure for spinal pathologies including disc herniation, fracture, tumor, pseudoarthrosis, and proximal junctional kyphosis. A total of 32 levels were treated, with the majority located at the thoracolumbar junction. Twelve of the procedures were done as part of a combined anterior/posterior surgery. The mean estimated blood loss was 577 ml and the mean length of stay was 12 days. At a mean follow-up of 14 months, all patients except for one (who died of widely metastatic disease) had achieved radiographic evidence of fusion. Two patients developed pulmonary effusions requiring medical intervention. Six patients had seven non-pulmonary complications: incidental durotomy (two), infection (one), instrumentation pullout (one), cardiac arrhythmia (two), and death from metastatic disease (one). The XLIF technique can be utilized for access to the anterior column of the thoracic and thoracolumbar spine. The advantages of this minimally invasive technique include avoidance of the need for an access surgeon and for lung deflation during surgery as well as excellent visualization of the spinal pathology.


Oncolytic Newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance.
Oncolytic viruses (OVs) selectively replicate in tumor cells and cause cancer cell death. Most OVs in clinical studies are genetically engineered. In contrast, the avian Newcastle disease virus (NDV) is a naturally oncolytic RNA virus. While anti-viral immunity is considered a major problem in achieving maximal tumor cell killing by OVs, this review discusses the importance of NDV immunogenic cell death (ICD) and how anti-viral immune responses can be integrated to induce maximal post-oncolytic T-cell-mediated anti-tumor immunity. Since replication of NDV is independent of host cell DNA replication (which is the target of many cytostatic drugs and radiotherapy) and because of other findings, oncolytic NDV is a candidate agent to break therapy resistance of tumor cells. Properties of this avian paramyxovirus are summarized with special emphasis to its anti-neoplastic and immune-stimulatory properties. The review then discusses prospective anti-cancer therapies, including treatments with NDV alone, and combinations with an autologous NDV-modified tumor cell vaccine or with a viral oncolysate pulsed dendritic cell vaccine. Various combinatorial approaches between these and with other modalities are also reviewed. Post-oncolytic anti-tumor immunity based on ICD is in the expert's opinion of greater importance for long-term therapeutic effects than maximal tumor cell killing. Of the various combinatorial approaches discussed, the most promising and feasible for clinical practice appears to be the combination of systemic NDV pre-treatment with anti-tumor vaccination.


Molecular determinants of the face map development in the trigeminal brainstem.
The perception of external sensory information by the brain requires highly ordered synaptic connectivity between peripheral sensory neurons and their targets in the central nervous system. Since the discovery of the whisker-related barrel patterns in the mouse cortex, the trigeminal system has become a favorite model for study of how its connectivity and somatotopic maps are established during development. The trigeminal brainstem nuclei are the first CNS regions where whisker-specific neural patterns are set up by the trigeminal afferents that innervate the whiskers. In particular, barrelette patterns in the principal sensory nucleus of the trigeminal nerve provide the template for similar patterns in the face representation areas of the thalamus and subsequently in the primary somatosensory cortex. Here, we describe and review studies of neurotrophins, multiple axon guidance molecules, transcription factors, and glutamate receptors during early development of trigeminal connections between the whiskers and the brainstem that lead to emergence of patterned face maps. Studies from our laboratories and others' showed that developing trigeminal ganglion cells and their axons depend on a variety of molecular signals that cooperatively direct them to proper peripheral and central targets and sculpt their synaptic terminal fields into patterns that replicate the organization of the whiskers on the muzzle. Similar mechanisms may also be used by trigeminothalamic and thalamocortical projections in establishing patterned neural modules upstream from the trigeminal brainstem.


Propagation of slow waves in the guinea-pig gastric antrum.
Intracellular recordings were made from the circular layer of the intact muscular wall of the guinea-pig gastric antrum in preparations where much of the corpus remained attached. When two electrodes were positioned parallel to and near to the greater curvature, slow waves were first detected at the oral site and subsequently at the anal site: the oro-anal conduction velocity was found to be 2.5 mm s(-1). When one electrode was positioned near the greater curvature and the other at a circumferential location, slow waves were first detected near the greater curvature and subsequently at the circumferential site: the circumferential conduction velocity was 13.9 mm s(-1). When recordings were made from preparations in which the circular muscle layer had been removed, the oro-anal and the circumferential conduction velocities were both about 3.5 mm s(-1). When slow waves were recorded from preparations in which much of the myenteric network of antral interstitial cells (ICC(MY)) had been dissected away, slow waves were first detected near the region of intact ICC(MY) and subsequently at a circumferential location: the circumferential conduction velocity of slow waves in regions devoid of ICC(MY) was 14.7 mm s(-1). When the electrical properties of isolated single bundles of circular muscle were determined, their length constants were about 3 mm and their time constant about 230 ms, giving an asymptotic electrotonic propagation velocity of 25 mm s(-1). Oro-anal electrical coupling between adjacent bundles of circular muscle was found to vary widely: some bundles were well connected to neighbouring bundles whereas others were not. Together the observations suggest that the slow oro-anal progression of slow waves results from a slow conduction velocity of pacemaker potentials in the myenteric network of interstitial cells. The rapid circumferential conduction of slow waves results from the electrical properties of the circular muscle layer which allow intramuscular ICC (ICC(IM)) to support the radial spread of slow waves: regions of high resistance between bundles prevent the anally directed spread of slow waves within the circular layer.


[Associations between depression, anxiety and telomere length in a large Dutch psychiatric cohort study].
Not only do depressive and anxiety disorders have psychological consequenses, they can also lead to impaired physical health. Persons with depressieve and anxiety disorders have increased risk of developing several ageing-related somatic ilnesses. This raises the question whether persons with depressive or anxiety disorder are subject to accelerated cellular ageing.
 AIM: To test the cross-sectional and longitudinal associations between depressive and anxiety disorders and telomere length, an indicator of cellular ageing.
 METHOD: We measured telomere length in participants of the Netherlands Study of Depression and Anxiety with and without psychopathology at baseline (N=2936) and we also studied a large number of these participants (N=1883) at 6-year follow-up.
 RESULTS: Telomere length of participants with a lifetime depressive or anxiety disorder was, on average, shorter than the telomere length in the control group. This association was attributed to dysregulations in physiological stress systems and an unhealthy lifestyle. Over time, however, telomere length was shown to have a stable, non-dynamic association with depressive and anxiety disorders.
 CONCLUSION: Our results suggest that psychological stress, as experienced by persons with depressive or anxiety disorders, might indeed be associated with increased 'wear and tear' of the human body. The challenge for future research is to determine whether short telomere length is in fact a long-term consequence or an underlying vulnerability factor for depressive or anxiety disorders.


T cell therapy for nasopharyngeal carcinoma.
Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV)-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL) have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.


Comparison of failure patterns between tubular breast carcinoma and invasive ductal carcinoma (KROG 14-25).
Information on tubular carcinoma (TC) of breast is limited due to its rarity. A multi-institutional study was performed to investigate the prognosis and failure patterns of TC compared to invasive ductal carcinoma (IDC). We collected retrospective data on 205 patients with TC from eleven institutions. For each TC case, 3 cases with IDC were matched according to similar size, t-stage, and n-stage from the same institution. Patterns of failure, disease free survival (DFS) and overall survival (OS) were assessed and compared between the groups. DFS at 5 years was 98.8% and 97.3% and OS at 5 years was 99.5% and 99.6% in TC and IDC, respectively. Among the patients with TC, 5 patients (2.4%) developed contralateral breast cancer, while 3 patients (0.5%) presented with contralateral breast cancer in patients with IDC. The TC of breast presents an excellent prognosis, but the contralateral breast cancer tends to be more frequently observed compared to IDC in Korean women.


Risk of parkinsonism induced by flunarizine or cinnarizine: a population-based study.
This retrospective cohort study used a population-based dataset to test the risk for parkinsonism in patients receiving flunarizine and cinnarizine, compared with matched controls. Data were obtained from the National Health Insurance Research Dataset of Taiwan. Patients receiving flunarizine or cinnarizine for more than 1 month between 2000 and 2005 were enrolled. Exclusion criteria included receiving flunarizine, cinnarizine, or antipsychotics for more than 1 month during 1997-1999, a history of neurodegenerative diseases, and an age of less than 30 years. One matched control for each patient was selected. Each participant was followed for diagnosis of parkinsonism within a 3-year observation period. Stroke, diabetes mellitus, total prescription days, and doses of flunarizine or cinnarizine were recorded. The study and control groups consisted of 9830 subjects. In the study group, 280 patients (2.9 %) were diagnosed with parkinsonism with a median observation period of 1.2 years, and 49 participants (0.5 %) were diagnosed in the control group with a median observation period of 1.9 years. The adjusted hazard ratio for parkinsonism among patients receiving flunarizine and cinnarizine was 5.117 (95 % CI = 3.758-6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the study drugs were not. This study demonstrates that flunarizine and cinnarizine significantly increase the risk for parkinsonism. The treatment benefits of these two agents should be balanced with this adverse effect. Physicians must look carefully for early signs of parkinsonism in patients treated with flunarizine and cinnarizine.


Transcriptional landscapes of Axolotl (Ambystoma mexicanum).
The axolotl (Ambystoma mexicanum) is the vertebrate model system with the highest regeneration capacity. Experimental tools established over the past 100 years have been fundamental to start unraveling the cellular and molecular basis of tissue and limb regeneration. In the absence of a reference genome for the Axolotl, transcriptomic analysis become fundamental to understand the genetic basis of regeneration. Here we present one of the most diverse transcriptomic data sets for Axolotl by profiling coding and non-coding RNAs from diverse tissues. We reconstructed a population of 115,906 putative protein coding mRNAs as full ORFs (including isoforms). We also identified 352 conserved miRNAs and 297 novel putative mature miRNAs. Systematic enrichment analysis of gene expression allowed us to identify tissue-specific protein-coding transcripts. We also found putative novel and conserved microRNAs which potentially target mRNAs which are reported as important disease candidates in heart and liver.


Plant-derived compounds inactivate antibiotic-resistant Campylobacter jejuni strains.
Sixty-three Campylobacter jejuni isolates were screened for their resistance to the antibiotics ampicillin, cefaclor, ciprofloxacin, erythromycin, gentamycin, tetracycline, and trimethoprim-sulfamethoxazole. Based on this screen, the resistant strains D28a and H2a and the nonresistant strain A24a were selected for evaluation of their resistance and susceptibility to inactivation by cinnamaldehyde and carvacrol, the main constituents of plant-derived cinnamon and oregano oils, respectively. Different concentrations (0.05, 0.1, and 0.2% [vol/vol] in sterile phosphate-buffered saline) of cinnamaldehyde and carvacrol were added to C. jejuni cultures with initial populations of 10(4) CFU/ml. The samples were then mixed thoroughly and incubated at 37 degrees C. Viable bacterial populations were enumerated at incubation periods of 0, 30, 60, and 120 min. The results indicate that the extent of inhibition of microbial survival was related to both the nature and concentration of antimicrobials and the incubation time. Both cinnamaldehyde and carvacrol exhibited rapid antimicrobial activity against both antibiotic-resistant and non-resistant C. jejuni strains, at concentrations of approximately 0.1% and higher. The antimicrobial efficacy of cinnamaldehyde was greater than that of carvacrol. The possible significance of the results for microbiological food safety is discussed.


Loneliness matters: a theoretical and empirical review of consequences and mechanisms.
As a social species, humans rely on a safe, secure social surround to survive and thrive. Perceptions of social isolation, or loneliness, increase vigilance for threat and heighten feelings of vulnerability while also raising the desire to reconnect. Implicit hypervigilance for social threat alters psychological processes that influence physiological functioning, diminish sleep quality, and increase morbidity and mortality. The purpose of this paper is to review the features and consequences of loneliness within a comprehensive theoretical framework that informs interventions to reduce loneliness. We review physical and mental health consequences of loneliness, mechanisms for its effects, and effectiveness of extant interventions. Features of a loneliness regulatory loop are employed to explain cognitive, behavioral, and physiological consequences of loneliness and to discuss interventions to reduce loneliness. Loneliness is not simply being alone. Interventions to reduce loneliness and its health consequences may need to take into account its attentional, confirmatory, and memorial biases as well as its social and behavioral effects.


Medication in relation to ST-segment elevation myocardial infarction in patients with a first myocardial infarction: Swedish Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA).
The extent and the severity of acute myocardial infarction (MI) is decreasing. Out-of-hospital medical management before the hospital admission could alter clinical presentation in acute MI. We used a large national patient register to investigate the relation between previous medication use (aspirin, beta-blockers, angiotensin-converting enzyme [ACE] inhibitors, and statins) and the risk of presenting with ST-segment elevation MI (STEMI) or non-STEMI. We included 103 459 consecutive patients from the Swedish Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA) admitted between January 1, 1996, and December 31, 2006, with a first acute MI. The patients with STEMI (43.5% of the total) were younger, had less prior cardiovascular disease, and used fewer medications before hospitalization. Of the STEMI patients, 61.4% had used no medication vs 45.9% of the patients with non-STEMI. After multiple adjustments, use of aspirin, beta-blockers, ACE inhibitors, and statins before hospitalization were all associated with substantially lower odds of presenting with STEMI. Furthermore, the risk decreased with the number of previous medications, and the use of 3 or more medications was associated with a multiply adjusted odds ratio of presenting with STEMI of 0.48 (99% confidence interval, 0.44-0.52) compared with no medications at admission. Use of aspirin, beta-blockers, ACE inhibitors, or statins before hospital admission in patients with a first acute MI is associated with substantially less risk of presenting with STEMI. The risk decreases with the increasing number of these medications used before acute MI, underlining the benefit of preventive medication in high-risk patients.


[Impact of methicillin resistance on mortality and surveillance of vancomycin susceptibility in bacteremias caused by Staphylococcus aureus].
Staphylococcus aureus is a major nosocomial pathogen that causes severe morbidity and mortality in many hospitals worldwide. Besides, the incidence of S. aureus bacteremia has significantly increased over the past decades. The aims of this study were to detect the risk factors for methicillin resistance and mortality and to evaluate vancomycin susceptibility in methicillin-resistant isolates. Thus, 39 S. aureus isolates from blood cultures of hospitalized patients with bacteremia were studied in Nueva Clínica Chacabuco Tandil, Buenos Aires, Argentina during 01/2006-12/2008. The overall mortality was 51.3%, which was significantly associated with methicillin resistance (OR: 4.20, IC95%: 1.08-16.32, p: 0.05), even though it was not an independent mortality predictor as it was the mechanical ventilation (OR: 15.99, IC95%: 3.24 - 78.86). Previous surgery (OR: 17.23, IC95%: 1.80-164.60) and hospitalization in intensive care units (OR: 21.12, IC95%: 2.33-191.30) were independent predictors of meticillin-resistance. No isolates were found with reduced vancomycin susceptibility. All the studied isolates were in vitro susceptible to vancomycin with a MIC50 and MIC90 of 0.5 μg/ml.


Mental Summation of Temporal Duration within and across Senses.
Perceiving, memorizing, and estimating temporal durations are key cognitive functions in everyday life. In this study, a duration summation paradigm was used to examine whether summation of temporal durations introduces an underestimation or overestimation bias, and whether this bias is common to visual and auditory modalities. Two within- or across-modality stimuli were presented sequentially for variable durations. Participants were asked to reproduce the sum of the two durations (0.6-1.1 s). We found that the sum of two durations was overestimated regardless of stimulus modalities. A subsequent control experiment indicated that the overestimation bias arose from the summation process, not perceptual or memory processes. Furthermore, we observed strong positive correlations between the overestimation bias for different sensory modalities within participants. These results suggest that the sum of two durations is overestimated, and that supra-modal processes may be responsible for this overestimation bias.


Mothers and infants exposed to intimate partner violence compensate.
Reasons for the developmental variability in children exposed to intimate partner violence (IPV) are unclear and under studied. This article presents exploratory findings on (a) the potential impact of IPV on mother-child relationships and child development and (b) the association between these maternal-child relationship impacts and child development. The fit of findings with compensatory, spillover, and compartmentalization hypotheses was explored. Participants were 49 mothers and 51 children younger than 3 years of age affected by IPV. Data were collected on maternal-child interactions, child development, social support, difficult life circumstances, family functioning, child temperament, and parental depression. The findings suggested developmental impacts on children in the sample, along with children's high sensitivity and responsiveness to their caregivers. Although some spillover effects were observed, the predominant observation was of mothers and infants compensating for exposure to IPV in their interactions.


[Sport injuries in full contact and semi-contact karate].
Karate enjoys great popularity both in professional and recreational sports and can be classified into full, half and low contact styles. The aim of this study was the analysis of sports injuries in Kyokushinkai (full contact) and traditional Karate (semi-contact). In a retrospective study design, 215 active amateur karateka (114 full contact, 101 semi-contact) were interviewed by means of a standardised questionnaire regarding typical sport injuries during the last 36 months. Injuries were categorised into severity grade I (not requiring medical treatment), grade II (single medical treatment), grade III (several outpatient medical treatments) and grade IV (requiring hospitalisation). In total, 217 injuries were reported in detail. 125 injuries (58%) occurred in full contact and 92 (42%) in semi-contact karate. The time related injury rate of full contact karateka was 1.9/1000 h compared to 1.3/1000 h of semi-contact karateka (p < 0.05). The most common types of injuries were musculoskeletal contusions (33% full contact, 20% semi-contact), followed by articular sprains with 19% and 16%. The lower extremity was affected twice as often in full contact (40%) as in semi-contact (20%) karate. Training injuries were reported by 80% of the full contact and 77% of the semi-contact karateka. Most injuries, both in training and competition, occurred in kumite. 75% of the reported injuries of full contact and 70% of semi-contact karateka were classified as low grade (I or II). The high rate of injuries during training and kumite (sparring) points to specific prevention goals. The emphasis should be put on proprioceptive training and consistent warm-up. In the actual competition the referees play a vital role regarding prevention.


Association of obstructive sleep apnea in rapid eye movement sleep with reduced glycemic control in type 2 diabetes: therapeutic implications.
Severity of obstructive sleep apnea (OSA) has been associated with poorer glycemic control in type 2 diabetes. It is not known whether obstructive events during rapid eye movement (REM) sleep have a different metabolic impact compared with those during non-REM (NREM) sleep. Treatment of OSA is often limited to the first half of the night, when NREM rather than REM sleep predominates. We aimed to quantify the impact of OSA in REM versus NREM sleep on hemoglobin A1c (HbA1c) in subjects with type 2 diabetes. All participants underwent polysomnography, and glycemic control was assessed by HbA1c. Our analytic cohort included 115 subjects (65 women; age 55.2 ± 9.8 years; BMI 34.5 ± 7.5 kg/m(2)). In a multivariate linear regression model, REM apnea-hypopnea index (AHI) was independently associated with increasing levels of HbA1c (P = 0.008). In contrast, NREM AHI was not associated with HbA1c (P = 0.762). The mean adjusted HbA1c increased from 6.3% in subjects in the lowest quartile of REM AHI to 7.3% in subjects in the highest quartile of REM AHI (P = 0.044 for linear trend). Our model predicts that 4 h of continuous positive airway pressure (CPAP) use would leave 60% of REM sleep untreated and would be associated with a decrease in HbA1c by approximately 0.25%. In contrast, 7 h of CPAP use would cover more than 85% of REM sleep and would be associated with a decrease in HbA1c by as much as 1%. In type 2 diabetes, OSA during REM sleep may influence long-term glycemic control. The metabolic benefits of CPAP therapy may not be achieved with the typical adherence of 4 h per night.


The lateral and ventromedial prefrontal cortex work as a dynamic integrated system: evidence from FMRI connectivity analysis.
Recent functional magnetic resonance imaging (fMRI) investigations of the interaction between cognition and reward processing have found that the lateral prefrontal cortex (PFC) areas are preferentially activated to both increasing cognitive demand and reward level. Conversely, ventromedial PFC (VMPFC) areas show decreased activation to the same conditions, indicating a possible reciprocal relationship between cognitive and emotional processing regions. We report an fMRI study of a rewarded working memory task, in which we further explore how the relationship between reward and cognitive processing is mediated. We not only assess the integrity of reciprocal neural connections between the lateral PFC and VMPFC brain regions in different experimental contexts but also test whether additional cortical and subcortical regions influence this relationship. Psychophysiological interaction analyses were used as a measure of functional connectivity in order to characterize the influence of both cognitive and motivational variables on connectivity between the lateral PFC and the VMPFC. Psychophysiological interactions revealed negative functional connectivity between the lateral PFC and the VMPFC in the context of high memory load, and high memory load in tandem with a highly motivating context, but not in the context of reward alone. Physiophysiological interactions further indicated that the dorsal anterior cingulate and the caudate nucleus modulate this pathway. These findings provide evidence for a dynamic interplay between lateral PFC and VMPFC regions and are consistent with an emotional gating role for the VMPFC during cognitively demanding tasks. Our findings also support neuropsychological theories of mood disorders, which have long emphasized a dysfunctional relationship between emotion/motivational and cognitive processes in depression.


Transient motion of visual texture delays saccadic eye movements.
Neurophysiological research has established that a transient stimulus, spatially located outside the receptive field of visual cells, can activate some cells and inhibit firing in others. However, the significance of this phenomenon for behavioural responses in man is unclear. This study investigated the effect of a transient peripheral event on the initiation of saccadic eye movements to a luminance increment. In Experiment 1 human saccadic eye movements to targets that varied in luminance were compared on 'shift' trials, in which the saccadic target was timed to coincide with a step displacement of a vertical grating in the background, and on 'no-shift' trials, when the background remained stationary. The results showed a significant delay in mean saccadic latencies on 'shift trials' compared to 'no-shift' trials. Saccadic latencies were reduced in both conditions with increasing target intensity. Measurement of visual sensitivity showed a small non-significant increase in thresholds in the background 'shift' condition. A second experiment manipulated visuo-temporal information by varying both target duration and intensity. This experiment revealed significant effects of target duration and signal intensity on saccadic latency; and a 3-way interaction showing that saccades suffered the greatest delay in the background 'shift' condition at the lowest duration and intensity targets. These results show that the peripheral motion of visual texture delays the programming of saccadic eye movements and there is a particularly marked effect for targets of low signal strength.


A murine model for retinopathy of prematurity identifies endothelial cell proliferation as a potential mechanism for plus disease.
To characterize the features and possible mechanism of plus disease in the mouse oxygen-induced retinopathy (OIR) model for retinopathy of prematurity. Wild-type and Adam (A Disintegrin And Metalloproteinase) knockout mice were exposed to 75% oxygen from postnatal day 7 to 12 (P7 to P12) (hyperoxia), then returned to normal air (relative hypoxia). Live fundus imaging and fluorescein angiography at P17 were compared to immunofluorescence analysis of flat-mounted retinas. Two hallmarks of plus disease, arterial tortuosity and venous dilation, were analyzed on fixed retinas (P12-P17). The length of tortuous vessels was compared to a straight line between two points; the diameter of retinal vessels was determined using ImageJ software, and bromo-deoxyuridine (BrdU) labeling was used to visualize proliferation of retinal vascular cells. Mice developed retinal arterial tortuosity and venous dilation after exposure to OIR, which was visible in live fundus images and fixed whole-mounted retinas. Vein dilation, arterial tortuosity, and BrdU incorporation gradually increased over time. Moreover, Adam8(-/-) and Adam9(-/-) mice and mice lacking Adam10 in endothelial cells were partially protected from plus disease compared to controls. The mouse OIR model can be used to study the pathogenesis of plus disease and identify potential therapeutic targets. The severity of plus disease increases over time following OIR and correlates with increased proliferation of endothelial cells, suggesting that proliferation of vascular cells may be a mechanism underlying the development of plus disease. Moreover, our findings suggest that ADAMs 8, 9, and 10 could be targets for treatment of plus disease.


Quinclorac-habituation of bean (Phaseolus vulgaris) cultured cells is related to an increase in their antioxidant capacity.
The habituation of bean cells to quinclorac did not rely on cell wall modifications, contrary to what it was previously observed for the well-known cellulose biosynthesis inhibitors dichlobenil or isoxaben. The aim of the present study was to investigate whether or not the bean cells habituation to quinclorac is related to an enhancement of antioxidant activities involved in the scavenging capacity of reactive oxygen species. Treating non-habituated bean calluses with 10 μM quinclorac reduced the relative growth rate and induced a two-fold increase in lipid peroxidation. However, the exposition of quinclorac-habituated cells to a concentration of quinclorac up to 30 μM neither affected their growth rate nor increased their lipid peroxidation levels. Quinclorac-habituated calluses had significantly higher constitutive levels of three antioxidant activities (class-III peroxidase, glutathione reductase, and superoxide dismutase) than those observed in non-habituated calluses, and the treatment of habituated calluses with 30 μM quinclorac significantly increased the level of class III-peroxidase and superoxide dismutase. The results reported here indicate that the process of habituation to quinclorac in bean callus-cultured cells is related, at least partially, to the development of a stable antioxidant capacity that enables them to cope with the oxidative stress caused by quinclorac. Class-III peroxidase and superoxide dismutase activities could play a major role in the quinclorac-habituation. Changes in the antioxidant status of bean cells were stable, since the increase in the antioxidant activities were maintained in quinclorac-dehabituated cells.


Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics.
There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.


Glucocorticoid inhibition of human SP-A1 promoter activity in NCI-H441 cells.
Glucocorticoids have complex effects on human surfactant protein (SP) SP-A1 and SP-A2 gene expression that occur at both transcriptional and post-transcriptional levels. In the lung adenocarcinoma cell line NCI-H441, dexamethasone causes a dose-dependent decrease in total SP-A mRNA levels and inhibits SP-A gene transcription. In this study, a deletional analysis of the SP-A1 promoter was performed in order to identify cis-acting elements that mediate dexamethasone responsiveness in NCI-H441 cells. The region -32/+63 relative to the start of SP-A1 transcription mediated both basal promoter activity and dexamethasone repression of transcription. Removal of the region +18/+63 abolished dexamethasone responsiveness, indicating that sequences within this region are necessary for the inhibitory effect. Furthermore, the region -32/+63 formed a sequence-specific DNA-protein complex with NCI-H441 nuclear extract. This DNA-protein complex was induced by dexamethasone exposure and its formation was mediated partially by sequences within the region +26/+63.


Sex differences in cocaine-dependent individuals' response to disulfiram treatment.
The objective of this study is to evaluate differential response to disulfiram treatment of cocaine dependence by sex. Sex by treatment interactions from two pooled randomized clinical trials involving 191 cocaine-dependent subjects (36% female) were evaluated. Primary outcomes were days of abstinence and percentage of drug-free urine specimens. Significant sex by treatment interactions were found, where men treated with disulfiram had better outcomes than those who were not. Women had an intermediate outcome regardless of whether they received disulfiram. Sex differences in response to disulfiram treatment have important clinical and theoretical implications. Reasons for this apparent sex-based response are not clear, but possible mechanisms worthy of greater study include differences in alcohol use by sex as well as differences in dopamine-mediated responses to cocaine and disulfiram.


Control of phosphorylative activity in human liver mitochondria through changes in respiratory enzyme contents.
1. Oxidative phosphorylation and respiratory enzyme activities were measured in the mitochondria from the non-involved lobe of the liver in eighteen patients with massive tumour mainly localized to one lobe and from the regenerating livers of partially hepatectomized rats treated with chloramphenicol. 2. In patients, the concentrations of cytochrome a(t) varied from 40 to 170 pmol/mg of protein. In mitochondria with cytochrome a(t) concentrations more than 70 pmol/mg of protein, the phosphorylative activity per mg of mitochondrial protein was considerably higher than in controls. The mitochondrial oxidative and phosphorylative activities per unit of cytochrome a(t) were negatively correlated with the concentration of cytochrome a(t). These patients with mitochondrial cytochrome a(t) exceeding 70 pmol/mg of protein tolerated partial hepatectomy well. On the other hand, in patients with mitochondrial cytochrome a(t) less than 60 pmol/mg of protein, phosphorylative activity was very low and there was a high surgical mortality. 3. In the regenerating liver of rats treated with chloramphenicol, the oxidative and phosphorylative activities per unit of cytochrome a(t) were negatively correlated with the concentration of cytochrome a(t). 4. It is suggested that an increase in ATP-synthesizing activity per unit of respiratory assemblies is the most basic homeostatic mechanism maintaining energy production in response to an increased metabolic load upon hepatic cells.


A structure-property-performance investigation of perylenediimides as electron accepting materials in organic solar cells.
Solution-processed perylenediimides (PDIs) with varying peri and bay substituents are characterized in order to better understand the relationships between molecular structure, solid state order, charge transport, and photovoltaic performance. It was found that bulky bay substituents interfere with molecular packing, leading to low charge transport and photovoltaic efficiencies compared to PDIs with fewer or less disruptive substituents. We assessed the potential of PDIs as acceptors for organic photovoltaics (OPVs) by utilizing a solution-processed bilayer OPV device architecture with the donor benzoporphyrin. At AM1.5G illumination, power conversion efficiencies (PCEs) up to 2.0% are obtained for solution-processed bilayer OPVs employing PDIs as acceptors. These results demonstrate the potential of PDIs as photovoltaic acceptor materials while elucidating the relationships between molecular structure and material properties.


Malnutrition Matters in Canadian Hospitalized Patients: Malnutrition Risk in Hospitalized Patients in a Tertiary Care Center Using the Malnutrition Universal Screening Tool.
Malnutrition is common in Canadian hospitalized patients, yet system-wide malnutrition screening is not mandatory in Canada. Our goal was to define the point prevalence of malnutrition risk at a major tertiary care center in Hamilton, Ontario, using the Malnutrition Universal Screening Tool (MUST) to determine feasibility of hospital-wide screening in the Canadian context. After research ethics approval was obtained, we arranged for a clinical nutrition support team to conduct the MUST screening on all inpatients at Hamilton Health Sciences, Juravinski site, a large academic acute care hospital. A total of 315 patients were included (female, n = 160 [51%]; male, n = 155 [49%]; average age, 71 years). We identified 31% at high risk for malnutrition and 14% at medium risk, keeping with reported rates of malnutrition in the literature. Survey of dietitians and interns indicated that the MUST was easy to use and perform and that they had support of their unit supervisors. All respondents thought that the screen was useful and they wanted to repeat it. The MUST is an easy and efficient way to define point prevalence of malnutrition risk in Canadian hospitalized patients. Moving to system-wide nutritional screening will bring about the best practices in nutrition care with the involvement of key stakeholders and decision makers. Nutritional screening will allow us to utilize nutrition resources more efficiently, engage administrators in addressing shortfalls in nutrition care, and form a baseline for which to measure the efficacy of future nutritional interventions.


Internal jugular vein valve incompetence in COPD and primary pulmonary hypertension.
Under physiologic conditions, intact internal jugular vein valves (IJVVs) efficiently prevent retrograde venous flow during intrathoracic pressure increase. Chronically elevated central venous pressure found in patients with chronic obstructive pulmonary disease (COPD) and primary pulmonary hypertension (PPH) might lead to IJVV incompetence (IJVVI). The aim of this study was to analyze the prevalence of IJVVI in patients with COPD and PPH using duplex sonography (DUS). We included 30 COPD patients, 5 PPH patients, and 100 healthy controls in the study. IJVVI was diagnosed if retrograde jugular blood flow was seen on DUS during a Valsalva maneuver. Retrograde venous flow intensity was evaluated and graded according to extent and duration of reflux. IJVVI was found in 18 (60%) COPD patients and in all 5 (100%) PPH patients, which was significantly different from the controls (27%; p < 0.005). The intensity of venous retrograde flow correlated with the pulmonary artery pressure. Compared with healthy controls, COPDand PPH patients demonstrated a significantlygreater prevalence of IJVVI, which seems to be caused by the elevated central venous pressure. These patients may be at higher risk to develop central nervous system diseases related to cerebral outflow obstruction.


Undergraduate Research: Importance, Benefits, and Challenges.
Developing and maintaining undergraduate research programs benefits students, faculty mentors, and the university. Incorporating a research component along with a sound academic foundation enables students to develop independent critical thinking skills along with oral and written communication skills. The research process impacts valuable learning objectives that have lasting influence as undergraduates prepare for professional service. Faculty members at teaching intensive institutions can enhance learning experiences for students while benefiting from a productive research agenda. The university in turn benefits from presentations and publications that serve to increase visibility in the scientific community. Whether projects are derived through student-generated or mentor-generated means, students benefit from completion of exposure to the hypothesis-driven scientific method.


Centrosome aberrations in human mammary epithelial cells driven by cooperative interactions between p16INK4a deficiency and telomere-dependent genotoxic stress.
Virtually all human cancers display chromosome instability (CIN), a condition in which chromosomes are gained or lost at a high rate. CIN occurs early in cancer development where it may undermine the advance of the neoplastic disease. With the aim of establishing the mechanisms underlying CIN in cancer, we investigated possible links between telomere-dysfunction and centrosome defects, which were seen to coincide in early in breast carcinogenesis using human mammary epithelial cells (HMECs). In this study, we show that TP53 proficient vHMECs cells develop centrosome aberrations when telomere-dysfunction genotoxic stress is produced in the presence of a defective p16INK4a setting and in parallel with an activation of the DNA damage checkpoint response. These aberrations consist of the accumulation of centrosomes in polyploid vHMECs, plus centriole overduplication in both diploid and polyploid cells, thus reflecting that distinct mechanisms underlie the generation of centrosome aberrations in vHMECs. Transduction of vHMEC with hTERT, which rescued the telomere dysfunction phenotype and consequently reduced DNA damage checkpoint activation, led to a progressive reduction of centrosome aberrations with cell culture, both in diploid and in polyploid vHMECs. Radiation-induced DNA damage also raised centrosome aberrations in vHMEC-hTERT. Collectively, our results, using vHMECs define a model where p16INK4a deficiency along with short dysfunctional telomeres cooperatively engenders centrosome abnormalities before p53 function is compromised.


Pathophysiological basis for antioxidant therapy in chronic liver disease.
Oxidative stress is a common pathogenetic mechanism contributing to initiation and progression of hepatic damage in a variety of liver disorders. Cell damage occurs when there is an excess of reactive species derived from oxygen and nitrogen, or a defect of antioxidant molecules. Experimental research on the delicately regulated molecular strategies whereby cells control the balance between oxidant and antioxidant molecules has progressed in recent years. On the basis of this evidence, antioxidants represent a logical therapeutic strategy for the treatment of chronic liver disease. Clinical studies with large numbers of patients have not yet been performed. However, results from several pilot trials support this concept and indicate that it may be worth performing multicentre studies, particularly combining antioxidants with anti-inflammatory and/or antiviral therapy. Oxidative stress plays a pathogenetic role in liver diseases such as alcoholic liver disease, chronic viral hepatitis, autoimmune liver diseases and non-alcoholic steatohepatitis. The use of antioxidants (e.g. S-adenosylmethionine [SAMe; ademetionine], tocopherol [vitamin E], polyenylphosphatidylcholine or silymarin) has already shown promising results in some of these pathologies.


Medical students' life and virtual social networks a guide for educational managers and parents.
Social networks have revolutionized the world. Students in Iran after entering the university often enter the college far from family, so the effects of such networks become more evident during the students' period. However, considering the role of the university in the training of specialist human resources, the researcher in this study, the status and application of virtual social networks in the life of students of Zahedan University of Medical Sciences were studied. This is a descriptive-analytical study that was conducted cross-sectional in 2018. All students of Zahedan University of Medical Sciences were the statistical population (4,600) that a sample of 900 people was selected as the final sample. The data gathering tool was a researcher-made questionnaire. To determine the content validity of the questionnaire and its confirmation, the opinions of professors and experts were used, and its reliability was measured by a test-retest method and confirmed by Cronbach's alpha (0/75). After data collection, SPSS software version 16 was used to analyze the data. The average daily student use of social networks was 2 h and 40 min, most of them were subscribed to Telegram, and connecting with friends was the main motive for joining social networks. There was no significant relationship between the use of social networks and the average student's lessons and also most of them had a moderate dependence on the Internet and had a high dependence on the social networks. In addition, there was a significant difference between Internet dependence and the gender of students. A large percentage of students have become members of various social networks. There was excessive and unplanned use of the internet and social networks among them. Hence, by creating good opportunities and attractive social activities in universities to provide more participation of students in the real world, this can provide suitable times for them and prevent their dependence on virtual social networks.


Diagnostic evidence cooperatives: bridging the valley of death in diagnostics development.
Diagnostic tests' impact on patient outcomes and health processes is potentially large, and proper evaluations before widespread adoption are warranted. Such evaluations are challenged by the fact that tests can have multiple purposes, in different clinical pathways, with different roles. The National Institute for Health Research (NIHR) established four Diagnostic Evidence Cooperatives (DEC) in 2013, across England. The aim of these DECs was to facilitate the development and evaluation of clinically relevant in vitro diagnostics, by offering methodological expertise and access to real-life settings for evaluations in patients. In this commentary, we discuss our experience over the past 4 years. The interaction of industry, researchers, and clinicians has proven to be very worthwhile.


The effects of individual and context on aggression in repeated social interaction.
In two studies using variations of the Prisoner's Dilemma game, we explore the impact of individual traits and social context on aggressive behavior. In the first study, we compared defection rates in the Iterated Prisoner's Dilemma when participants were presented with a payoff matrix (Description condition) or learned payoffs through experience (Experience condition). Interpersonal trust and maximizing tendency led to relatively less defection in the Description condition than in the Experience condition, demonstrating that individual characteristics manifest differently depending on the information available to decision-makers. In the second study, we employed a new game paradigm, the Intergroup Prisoner's Dilemma with Intragroup Power Dynamics, to examine the way that power motives influence extreme aggressive behavior. We discovered that certain individuals exhibit very high levels of defection, but only when they play with particular combinations of predefined strategies, further suggesting how the confluence of individual factors and context can induce aggression.


TRPM8-Dependent Dynamic Response in a Mathematical Model of Cold Thermoreceptor.
Cold-sensitive nerve terminals (CSNTs) encode steady temperatures with regular, rhythmic temperature-dependent firing patterns that range from irregular tonic firing to regular bursting (static response). During abrupt temperature changes, CSNTs show a dynamic response, transiently increasing their firing frequency as temperature decreases and silencing when the temperature increases (dynamic response). To date, mathematical models that simulate the static response are based on two depolarizing/repolarizing pairs of membrane ionic conductance (slow and fast kinetics). However, these models fail to reproduce the dynamic response of CSNTs to rapid changes in temperature and notoriously they lack a specific cold-activated conductance such as the TRPM8 channel. We developed a model that includes TRPM8 as a temperature-dependent conductance with a calcium-dependent desensitization. We show by computer simulations that it appropriately reproduces the dynamic response of CSNTs from mouse cornea, while preserving their static response behavior. In this model, the TRPM8 conductance is essential to display a dynamic response. In agreement with experimental results, TRPM8 is also needed for the ongoing activity in the absence of stimulus (i.e. neutral skin temperature). Free parameters of the model were adjusted by an evolutionary optimization algorithm, allowing us to find different solutions. We present a family of possible parameters that reproduce the behavior of CSNTs under different temperature protocols. The detection of temperature gradients is associated to a homeostatic mechanism supported by the calcium-dependent desensitization.


Toxoplasma gondii activates hypoxia-inducible factor (HIF) by stabilizing the HIF-1alpha subunit via type I activin-like receptor kinase receptor signaling.
Toxoplasma gondii is an intracellular protozoan parasite that can cause devastating disease in fetuses and immune-compromised individuals. We previously reported that the alpha subunit of the host cell transcription factor, hypoxia-inducible factor-1 (HIF-1), is up-regulated by infection and necessary for Toxoplasma growth. Under basal conditions, HIF-1alpha is constitutively expressed but rapidly targeted for proteasomal degradation after two proline residues are hydroxylated by a family of prolyl hydroxylases (PHDs). The PHDs are alpha-ketoglutarate-dependent dioxygenases that have low K(m) values for oxygen, making them important cellular oxygen sensors. Thus, when oxygen levels decrease, HIF-1alpha is not hydroxylated, and HIF-1 is activated. How Toxoplasma activates HIF-1 under normoxic conditions remains unknown. Here, we report that Toxoplasma infection increases HIF-1alpha stability by preventing HIF-1alpha prolyl hydroxylation. Infection significantly decreases PHD2 abundance, which is the key prolyl hydroxylase for regulating HIF-1alpha. The effects of Toxoplasma on HIF-1alpha abundance and prolyl hydroxylase activity require activin-like receptor kinase signaling. Finally, parasite growth is severely diminished when signaling from this family of receptors is inhibited. Together, these data indicate that PHD2 is a key host cell factor for T. gondii growth and represent a novel mechanism by which a microbial pathogen subverts host cell signaling and transcription to establish its replicative niche.


Sequencing the transcriptome of milk production: milk trumps mammary tissue.
Studies of normal human mammary gland development and function have mostly relied on cell culture, limited surgical specimens, and rodent models. Although RNA extracted from human milk has been used to assay the mammary transcriptome non-invasively, this assay has not been adequately validated in primates. Thus, the objectives of the current study were to assess the suitability of lactating rhesus macaques as a model for lactating humans and to determine whether RNA extracted from milk fractions is representative of RNA extracted from mammary tissue for the purpose of studying the transcriptome of milk-producing cells. We confirmed that macaque milk contains cytoplasmic crescents and that ample high-quality RNA can be obtained for sequencing. Using RNA sequencing, RNA extracted from macaque milk fat and milk cell fractions more accurately represented RNA from mammary epithelial cells (cells that produce milk) than did RNA from whole mammary tissue. Mammary epithelium-specific transcripts were more abundant in macaque milk fat, whereas adipose or stroma-specific transcripts were more abundant in mammary tissue. Functional analyses confirmed the validity of milk as a source of RNA from milk-producing mammary epithelial cells. RNA extracted from the milk fat during lactation accurately portrayed the RNA profile of milk-producing mammary epithelial cells in a non-human primate. However, this sample type clearly requires protocols that minimize RNA degradation. Overall, we validated the use of RNA extracted from human and macaque milk and provided evidence to support the use of lactating macaques as a model for human lactation.


Messenger RNA splicing in yeast: clues to why the spliceosome is a ribonucleoprotein.
The removal of introns from eukaryotic messenger RNA precursors shares mechanistic characteristics with the self-splicing of certain introns, prompting speculation that the catalytic reactions of nuclear pre-messenger RNA splicing are fundamentally RNA-based. The participation of five small nuclear RNAs (snRNAs) in splicing is now well documented. Genetic analysis in yeast has revealed the requirement, in addition, for several dozen proteins. Some of these are tightly bound to snRNAs to form small nuclear ribonucleoproteins (snRNPs); such proteins may promote interactions between snRNAs or between an snRNA and the intron. Other, non-snRNP proteins appear to associate transiently with the spliceosome. Some of these factors, which include RNA-dependent adenosine triphosphatases, may promote the accurate recognition of introns.


Dengue viremia in blood donors in Northern India: Challenges of emerging dengue outbreaks to blood transfusion safety.
Emerging infectious diseases pose threats to the general human population; including recipients of blood transfusions. Dengue is spreading rapidly to new areas and with increasing frequency of major outbreaks. Screening blood for dengue antigens in dengue-endemic countries would be costly and should, therefore, be recommended only after careful assessment of risk for infection and cost. A prospective study was conducted to establish the magnitude of the threat that dengue poses to blood safety where it is sporadic with seasonal variations, to quantify risk and to assess that whether screening is feasible and cost-effective. Nonstructural protein 1 (NS1) antigen test was done on 1709 donations during dengue outbreak in the months August to November 2013 as an additional test using Bio-Rad Platelia Dengue NS1AG test kit which is one step sandwich format microplate enzyme immunoassay using murine monoclonal antibodies for capture and revelation. Chi-square test was used to find statistical significance. Majority cases were whole blood, replacement, male donors with 76.10% donors in <35 years age group. About 17.85% were single donor platelet donations. NS1 antigen in all donors was negative. In the past, dengue affected mainly children who do not donate blood. With the changing trend, mean age of infection increased affecting the population that does donate blood, further reducing blood donation pool. Further studies need to be done in different geographic regions of the country during dengue transmission season to establish maximum incidence of viremic donations, rates of transfusion transmission and clinical consequences in recipients. If risk is found to be substantial, decision will be taken by the policymakers at what threshold screening should be instituted to ensure safe blood transfusion.


Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis.
Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease.


Immunometabolism: an emerging frontier.
Immunometabolism is an emerging field of investigation at the interface between the historically distinct disciplines of immunology and metabolism. Accelerating interest in this area is being fuelled by the obesity epidemic and the relatively recent realization that obesity affects the immune system and promotes inflammation, and that obesity-induced inflammation potentially promotes a variety of chronic conditions and diseases. The multilevel interactions between the metabolic and immune systems suggest pathogenic mechanisms that may underlie many of the downstream complications of obesity and offer substantial therapeutic promise.


Preventing lead poisoning in children.
Lead poisoning is the most significant and prevalent disease of environmental origin among US children. Despite over 100 years' knowledge of the special hazards of lead exposure for young children, it has taken over a century for effective primary prevention to be adopted. Obstacles to primary prevention have included deliberate campaigns by industry to prevent restrictions upon such uses on lead as plumbing, paints, and gasoline additives; influence of industrial support of biomedical research at major US medical schools: lack of appropriate policy mechanisms to identify and control lead exposures; and opposition to investing resources in lead poisoning prevention. The removal of lead from gasoline, which began in the United States in 1972 and was completed in 1995, has resulted in almost fourfold reductions in median blood lead levels in US children from 1976 to 1991. Increased screening and interventions to identify and abate lead sources, such as lead in housing, also contributed to this major public health success. Nevertheless, lead exposures remain prevalent, although increasingly less generally distributed. Perhaps because of the renewed "ghettoization" of lead, support for lead poisoning prevention has waned. Objections to investing public and private resources in screening and source abatement have challenged the continuing commitment of public health officials to prevention. The demonstrable success and social benefits of preventing lead toxicity are cited in support of continued preventive health policies.


Elastomeric 2D grating and hemispherical optofluidic chamber for multifunctional fluidic sensing.
We present an optofluidic sensor based on an elastomeric two-dimensional (2D) grating integrated inside a hemispherical fluid chamber. A laser beam is diffracted before (reflection) and after (transmission) going through the grating and liquid in the dome chamber. The sensing mechanism is investigated and simulated with a finite-difference time-domain-based electromagnetic method. For the experiment, by analyzing the size, power, and shape of the 2D diffraction patterns, we can retrieve multiple parameters of the liquid, including the refractive index, pressure, and opacity with high sensitivity. We demonstrate that the glucose concentration can be monitored when mixed in a different concentrated phosphate-buffered saline solution. The free-solution binding of bovine serum albumin (BSA) and anti-BSA IgG is detected with this optical sensor. This low-cost, multifunctional, and reliable optofluidic sensor has the potential to be used as a monitor of biofluid, such as blood in hemodialysis.


Self-assembly of hairy disks in two dimensions - insights from molecular simulations.
We report the results of large scale molecular dynamics simulations conducted for sparsely grafted disks in two-dimensional systems. The main goal of this work is to show how the ligand mobility influences the self-assembly of particles decorated with short chains. We also analyze the impact of the chain length on the structure of dense phases. A crossover between the systems controlled by the core-core or by the segment-segment interactions is discussed. We prove that the ligand mobility determines the structure of the system. The particles with fixed tethers are found to order into different structures, an amorphous phase, hexagonal or honeycomb lattices, and a "spaghetti"-like phase containing single strings of cores, depending on the length of attached chains. The disks with mobile monomers assemble into a hexagonal structure, while the particles with longer mobile chains attached to them form a lamellar phase consisting of double strings of cores.


Communicating with the public about the risks of naturally occurring asbestos.
To explore the application of evidence based risk communication to community messaging about naturally occurring asbestos (NOA). Type of program or service: Risk communication education about NOA. We apply principles and determinants of risk communication to the topic of NOA. We emphasise the importance of erring on the side of transparency and trust, even when officials may be concerned about inadvertently heightening needless public concern. We offer a range of practical suggestions for how to lower public concern and outrage relating to the issue of NOA when it arises in local contexts. Public concern and outrage can be reduced by favouring early and frequent communication, awareness and use of the 'rule of threes' in media communication, open acknowledgement of uncertainty, prioritising response to community concern above narrow myth-busting strategies, and supporting community action.


Open saphenectomy complications following lower extremity revascularization.
A review of saphenectomy site complications following lower extremity revascularization was conducted. Leg incisions used for 133 consecutive infrainguinal bypass procedures were categorized by location. Patient and procedural risk factors were analyzed for risk of wound complications. Procedure, limb and patient outcome were reported via life table analysis. Incisional wound complications followed 32/133 procedures (24%), including 15 groin, eight saphenectomy, five distal and four vein/distal incisions. There were five grade I and three grade II saphenectomy complications. Only weight (body mass index) predicted the likelihood of wound complication (P < 0.05). The 6-month primary patency rate was 79% (mean follow-up 22 months). Four-year assisted primary patency, limb salvage and survival rates were 75, 87 and 57%, respectively. Most bypass-related wound complications (24/32, 75%) involve arterial access incisions. Incisional complications are related to body mass index. Only 6% of GS vein bypass procedures develop saphenectomy site complications. Limiting saphenectomy size may not significantly reduce incisional morbidity following bypass grafting.


Warfarin initiation nomograms for venous thromboembolism.
Venous thromboembolism (VTE) is a common condition in hospital patients. Considerable controversy is ongoing regarding optimal initial warfarin dosing for patients with acute deep venous thrombosis (DVT) and pulmonary embolism (PE). Achieving a therapeutic international normalized ratio (INR) with warfarin as soon as possible is important because this minimizes the duration of parenteral medication necessary to attain immediate anticoagulation, and it potentially decreases the cost and inconvenience of treatment. Although a 5-mg loading-dose nomogram tends to prevent excessive anticoagulation, a 10-mg loading-dose nomogram may achieve a therapeutic INR more quickly. To evaluate the efficacy of a 10-mg warfarin nomogram compared with a 5-mg warfarin nomogram among patients with VTE. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12). The review authors searched PubMed (last searched 10 April 2013) and LILACS (last searched 28 February 2013). In addition, the review authors contacted pharmaceutical companies. Randomized controlled studies comparing warfarin initiation nomograms of 10 and 5 mg in patients with VTE. Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information. Four trials involving 494 participants were included. Three studies involving 383 participants provided data on the proportion of participants who had achieved a therapeutic INR by day five. Significant benefit of a 10-mg warfarin nomogram was observed (risk ratio [RR] 1.27, 95% confidence interval [CI] 1.05 to 1.54), although with substantial heterogeneity (I(2) = 90%). The review authors analyzed each study separately because it was not possible to perform a subgroup analysis. One study showed significant benefit of a 10-mg warfarin nomogram for the proportion of outpatients with VTE who had achieved a therapeutic INR by day five (RR 1.78, 95% CI 1.41 to 2.25), with the number needed to treat for an additional beneficial outcome (NNTB = 3, 95% CI 2 to 4); another study showed significant benefit of a 5-mg warfarin nomogram in outpatients with VTE (RR 0.58, 95% CI 0.36 to 0.93) with NNTB = 5 (95% CI 3 to 28); a third study showed no difference (RR 1.08, 95% CI 0.65 to 1.80). No difference was observed in recurrent venous thromboembolism (RVTE) at 90 days when the warfarin nomogram of 10 mg was compared with the warfarin nomogram of 5 mg (RR 1.48, 95% CI 0.39 to 5.56); no difference was observed in major bleeding at 14 days (RR 1.69, 95% CI 0.22 to 13.04) and at 90 days (RR 0.62, 95% CI 0.10 to 3.78). No difference was observed in minor bleeding at 14 to 90 days (RR 0.32, 95% CI 0.15 to 1.83) or in length of hospital stay (mean difference [MD] -2.30 days, 95% CI -7.96 to 3.36). In patients with acute thromboembolism (DVT or PE) aged 18 years or older, considerable uncertainty surrounds the use of a 10-mg or a 5-mg loading dose for initiation of warfarin to achieve an INR of 2.0 to 3.0 on the fifth day of therapy. Heterogeneity among analyzed studies limits certainty surrounding optimal warfarin initiation nomograms.


VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis.
VEGF-C and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly understood. Here, we have studied the effects of VEGF-C and VEGF-D on tumor development in the murine multistep chemical carcinogenesis model of squamous cell carcinoma by using a soluble VEGF-C/VEGF-D inhibitor. After topical treatment with a tumor initiator and repeated tumor promoter applications, transgenic mice expressing a soluble VEGF-C/VEGF-D receptor (sVEGFR-3) in the skin developed significantly fewer squamous cell tumors with a delayed onset when compared with wild-type mice or mice expressing sVEGFR-3 lacking the ligand-binding site. Epidermal proliferation was reduced in the carcinogen-treated transgenic skin, whereas epidermal keratinocyte proliferation in vitro was not affected by VEGF-C or VEGF-D, indicating indirect effects of sVEGFR-3 expression. Importantly, transgenic mouse skin was less sensitive to tumor promoter-induced inflammation, with reduced angiogenesis and blood vessel leakage. Cutaneous leukocytes, especially macrophages, were reduced in transgenic skin without major changes in macrophage polarization or blood monocyte numbers. Several macrophage-associated cytokines were also reduced in transgenic papillomas, although the dermal macrophages themselves did not express VEGFR-3. These findings indicate that VEGF-C/VEGF-D are involved in shaping the inflammatory tumor microenvironment that regulates early tumor progression. Our results support the use of VEGF-C/VEGF-D-blocking agents not only to inhibit metastatic progression, but also during the early stages of tumor growth.


eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response.
The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a guanosine triphosphatase that becomes activated by eIF2B, a two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from a substrate into an inhibitor of eIF2B. We report cryo-electron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2α, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequestering it into a nonproductive complex.


Vitamin A deficiency associated with enhanced proliferation of bile duct epithelial cells in the rat.
Vitamin A and its derivative retinoic acid regulate various aspects of cell behavior as growth, differentiation, and proliferation. Retinoic acid derivative have been suggested to play a role in processes such as hepatic regeneration and fibrosis. To evaluate the influence of vitamin A on rat liver epithelial cell proliferation. We performed common bile duct ligation in rats that had been subjected to differing vitamin A diets and compared their livers to control rats. Proliferation, apoptosis, and retinoic acid receptors were evaluated by histology and immunohistochemistry in bile duct cells and hepatocytes. Vitamin A deficiency was found to be associated with enhanced proliferation of bile duct epithelial cells following CBD ligation. The proliferation was manifested by increased numbers of ducts, by aberrant extended ductal morphology, and by elevated numbers of nuclei expressing the proliferation marker Ki67. The amount of vitamin A in the rat diet did not affect detectably ductal cell apoptosis. We observed up-regulated expression of the retinoid X receptor-alpha in the biliary epithelium of vitamin A-deficient rats that had undergone CBD ligation, but not in vitamin A-sufficient rats. We speculate that the mechanism underlying the ductal proliferation response involves differential expression of RXR-alpha. Our observations suggest that deficiency of vitamin A may exacerbate cholestasis, due to excessive intrahepatic bile duct proliferation.


Structure-function relationships of human JmjC oxygenases-demethylases versus hydroxylases.
The Jumonji-C (JmjC) subfamily of 2-oxoglutarate (2OG)-dependent oxygenases are of biomedical interest because of their roles in the regulation of gene expression and protein biosynthesis. Human JmjC 2OG oxygenases catalyze oxidative modifications to give either chemically stable alcohol products, or in the case of Nɛ-methyl lysine demethylation, relatively unstable hemiaminals that fragment to give formaldehyde and the demethylated product. Recent work has yielded conflicting reports as to whether some JmjC oxygenases catalyze N-methyl group demethylation or hydroxylation reactions. We review JmjC oxygenase-catalyzed reactions within the context of structural knowledge, highlighting key differences between hydroxylases and demethylases, which have the potential to inform on the possible type(s) of reactions catalyzed by partially characterized or un-characterized JmjC oxygenases in humans and other organisms.


Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock.
The Institute of Medicine has called for the development of clinical guidelines and practice parameters to develop "best practice" and potentially improve patient outcome. To provide American College of Critical Care Medicine clinical guidelines for hemodynamic support of neonates and children with septic shock. Individual members of the Society of Critical Care Medicine with special interest in neonatal and pediatric septic shock were identified from literature review and general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (1998-2001). The MEDLINE literature database was searched with the following age-specific keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, and extracorporeal membrane oxygenation. More than 30 experts graded literature and drafted specific recommendations by using a modified Delphi method. More than 30 more experts then reviewed the compiled recommendations. The task-force chairman modified the document until <10% of experts disagreed with the recommendations. Only four randomized controlled trials in children with septic shock could be identified. None of these randomized trials led to a change in practice. Clinical practice has been based, for the most part, on physiologic experiments, case series, and cohort studies. Despite relatively low American College of Critical Care Medicine-graded evidence in the pediatric literature, outcomes in children have improved from 97% mortality in the 1960s to 60% in the 1980s and 9% mortality in 1999. U.S. hospital survival was three-fold better in children compared with adults (9% vs. 27% mortality) in 1999. Shock pathophysiology and response to therapies is age specific. For example, cardiac failure is a predominant cause of death in neonates and children, but vascular failure is a predominant cause of death in adults. Inotropes, vasodilators (children), inhaled nitric oxide (neonates), and extracorporeal membrane oxygenation can be more important contributors to survival in the pediatric populations, whereas vasopressors can be more important contributors to adult survival. American College of Critical Care Medicine adult guidelines for hemodynamic support of septic shock have little application to the management of pediatric or neonatal septic shock. Studies are required to determine whether American College of Critical Care Medicine guidelines for hemodynamic support of pediatric and neonatal septic shock will be implemented and associated with improved outcome.


A strong host response and lack of MYC expression are characteristic for diffuse large B cell lymphoma transformed from nodular lymphocyte predominant Hodgkin lymphoma.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.


Morphology and distribution of primary afferent fibres expressing alpha-galactose extended oligosaccharides in the spinal cord and brainstem of the rat. Light microscopy.
The light microscopic morphology and distribution of non-substance P-containing small primary afferent fibres were studied. These fibres were labelled using LD2 and LA4 monoclonal antibodies which recognize alpha-galactose extended oligosaccharides expressed by primary afferent neurons. The LD2 and LA4 antibodies immunostained small primary afferent fibres ending mainly in lamina II of the spinal cord dorsal horn and trigeminal subnucleus caudalis of the rat. The lamination pattern of both types of primary afferents was assessed using an image analysis system. The highest density of LD2-immunoreactive fibres was located in a patchy band located in lamina II outer, while LA4-immunoreactive fibres were distributed mainly through lamina II inner. In lateral regions of cervical and lumbar dorsal horn the LA4-immunoreactive band is broader and comprises almost all lamina II. In contrast to substance P-containing primary afferents, a low density of LD2- or LA4-immunoreactive fibres was found in lamina I, and no terminal fields were found in lamina V or lamina X of the spinal cord or in levels of the trigeminal system outside the subnucleus caudalis. Both antibodies also labelled the parent fibres in the white matter fasciles. LD2-immunoreactive fibres were located in the dorsal roots, medial regions of the Lissauer tract, dorsal columns of the spinal cord, outer regions of the spinal trigeminal tract and dorsal to the cuneatus and gracilis nuclei. In contrast, LA4-immunoreactive fibres were restricted to the dorsal roots, medial and lateral regions of the Lissauer tract and the outer regions of the trigeminal tract. Immunostained fibres in the rootlets of the X and IX nerves and immunoreactive terminal arborizations in various subnuclei of the nucleus tractus solitarius were seen using both antibodies. These results show that subpopulations of small primary afferents stained by LD2 and LA4 antibodies have distinct patterns of central distribution and are consistent with a subdivision of small primary afferents into peptide- and non-peptide-containing groups.


Two industrial cohorts: baseline characteristics and factors associated with obesity.
To describe demographic and health characteristics, and factors associated with obesity among production workers. This cross-sectional study analyzed baseline data from two occupational cohorts. Regression modeling was used to assess associations between worker characteristics and obesity. A total of 1974 subjects were included in these analyses. The mean body mass index was 29.5 kg/m (SD = 6.5). Having smoked in the past and currently smoking decreased the odds of being obese in the WISTAH Distal Upper Extremity cohort, whereas those feeling depressed had increased odds of being obese. Being a Pacific Islander/Native Hawaiian and married increased the odds of obesity in the BackWorks Low Back Pain cohort. Factors associated with obesity differed substantially between the two cohorts. Recognizing factors associated with obesity in specific work settings may provide opportunities for optimizing preventive workplace interventions.


Prioritization of HCV treatment in the direct-acting antiviral era: An economic evaluation.
We determined the optimal HCV treatment prioritization strategy for interferon-free (IFN-free) HCV direct-acting antivirals (DAAs) by disease stage and risk status incorporating treatment of people who inject drugs (PWID). A dynamic HCV transmission and progression model compared the cost-effectiveness of treating patients early vs. delaying until cirrhosis for patients with mild or moderate fibrosis, where PWID chronic HCV prevalence was 20, 40 or 60%. Treatment duration was 12weeks at £3300/wk, to achieve a 95% sustained viral response and was varied by genotype/stage in alternative scenarios. We estimated long-term health costs (in £UK=€1.3=$1.5) and outcomes as quality adjusted life-years (QALYs) gained using a £20,000 willingness to pay per QALY threshold. We ranked strategies with net monetary benefit (NMB); negative NMB implies delay treatment. The most cost-effective group to treat were PWID with moderate fibrosis (mean NMB per early treatment £60,640/£23,968 at 20/40% chronic prevalence, respectively), followed by PWID with mild fibrosis (NMB £59,258 and £19,421, respectively) then ex-PWID/non-PWID with moderate fibrosis (NMB £9,404). Treatment of ex-PWID/non-PWID with mild fibrosis could be delayed (NMB -£3,650). In populations with 60% chronic HCV among PWID it was only cost-effective to prioritize DAAs to ex-PWID/non-PWID with moderate fibrosis. For every one PWID in the 20% chronic HCV setting, 2 new HCV infections were averted. One extra HCV-related death was averted per 13 people with moderate disease treated. Rankings were unchanged with reduced drug costs or varied sustained virological response/duration by genotype/fibrosis stage. Treating PWID with moderate or mild HCV with IFN-free DAAs is cost-effective compared to delay until cirrhosis, except when chronic HCV prevalence and reinfection risk is very high.


Dynamics of recovery from anaesthesia-induced unconsciousness across primate neocortex.
How the brain recovers from general anaesthesia is poorly understood. Neurocognitive problems during anaesthesia recovery are associated with an increase in morbidity and mortality in patients. We studied intracortical neuronal dynamics during transitions from propofol-induced unconsciousness into consciousness by directly recording local field potentials and single neuron activity in a functionally and anatomically interconnecting somatosensory (S1, S2) and ventral premotor (PMv) network in primates. Macaque monkeys were trained for a behavioural task designed to determine trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We found that neuronal dynamics were dissociated between S1 and higher-order PMv prior to return of consciousness. The return of consciousness was distinguishable by a distinctive return of interregionally coherent beta oscillations and disruption of the slow-delta oscillations. Clustering analysis demonstrated that these state transitions between wakefulness and unconsciousness were rapid and unstable. In contrast, return of pre-anaesthetic task performance was observed with a gradual increase in the coherent beta oscillations. We also found that recovery end points significantly varied intra-individually across sessions, as compared to a rather consistent loss of consciousness time. Recovery of single neuron multisensory responses appeared to be associated with the time of full performance recovery rather than the length of recovery time. Similar to loss of consciousness, return of consciousness was identified with an abrupt shift of dynamics and the regions were dissociated temporarily during the transition. However, the actual dynamics change during return of consciousness is not simply an inverse of loss of consciousness, suggesting a unique process.


The local density of optical states of a metasurface.
While metamaterials are often desirable for near-field functions, such as perfect lensing, or cloaking, they are often quantified by their response to plane waves from the far field. Here, we present a theoretical analysis of the local density of states near lattices of discrete magnetic scatterers, i.e., the response to near field excitation by a point source. Based on a pointdipole theory using Ewald summation and an array scanning method, we can swiftly and semi-analytically evaluate the local density of states (LDOS) for magnetoelectric point sources in front of an infinite two-dimensional (2D) lattice composed of arbitrary magnetoelectric dipole scatterers. The method takes into account radiation damping as well as all retarded electrodynamic interactions in a self-consistent manner. We show that a lattice of magnetic scatterers evidences characteristic Drexhage oscillations. However, the oscillations are phase shifted relative to the electrically scattering lattice consistent with the difference expected for reflection off homogeneous magnetic respectively electric mirrors. Furthermore, we identify in which source-surface separation regimes the metasurface may be treated as a homogeneous interface, and in which homogenization fails. A strong frequency and in-plane position dependence of the LDOS close to the lattice reveals coupling to guided modes supported by the lattice.


Api6/AIM/Spα/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma.
Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remain poorly understood. Apoptosis inhibitor 6 (Api6, also known as AIM, Sp-α, and CD5L) is a downstream target gene of neutral lipids and peroxisome proliferator-activated receptor gamma in lung alveolar type II (AT II) epithelial cells. An association among increased expression of Api6 in certain settings of pathogenic lung inflammation in mice prompted us to hypothesize a possible role in cancer. Here, we report that Api6 promotes malignant transformation by limiting lung epithelial cell apoptosis and promoting immune escape. The specific function of Api6 in AT II cells was determined by using a doxycycline-inducible Api6 mouse model. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. In addition, Api6 overexpression in AT II cells increased the concentrations of proinflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, promoting expansion of myeloid-derived suppressor cells (MDSC) in lung and blood but not in bone marrow or spleen. Lung MDSCs suppressed T-cell proliferation and activity in vitro and reduced levels of T cells in vivo following doxycycline treatment to activate Api6. Together, our findings establish that Api6 promotes lung tumorigenesis by blocking a mechanism of epithelial apoptosis that would normally support immunosurveillance.