[Effect of Cynaropicrin on 2,3,4,7,8-Pentachlorodibenzofuran-induced Wasting Syndrome and Oxidative Stress].
The effect of cynaropicrin that is the major component of an edible plant, artichoke (Cynara scolymus) on 2,3,4,7,8-pentachlorodibenzofuran (PenCDF)-induced toxicity in mice was studied. We evaluated the effect of cynaropicrin on the wasting syndrome and oxidative stress elicited by PenCDF. However, the PenCDF dose-response relationship on the wasting syndrome has been superficial. Therefore, we determined the dose which causes wasting syndrome in C57BL/6J mice, a responsive strain to dioxins. Since 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 mg/kg, p.o.) induces hepatic ethoxyresorfin O-deethylase (EROD) activity in mice, we set the doses of PenCDF at 0.3, 1.0, 3.0, 5.0 and 10 mg/kg (once, p.o.) on the basis of its toxic-eqivalency factor (0.3). The wasting syndrome was evaluated by measuring the daily changes of body weight. Thiobarbituric acid-reactive substances were used as an index of oxidative stress. Of PenCDF doses examined, wasting syndrome and oxidative stress took place most markedly in 5 mg/kg. In disagreement with this, EROD activity which is the marker of the aryl hydrocarbon receptor-dependent induction of cytochrome P450 1a1 was elevated most abundantly at 0.3 mg/kg. Then, we examined the effect of cynaropicrin on the wasting syndrome and oxidative stress provoked by PenCDF at 5 mg/kg. However, this compound up to 20 mg/kg (p.o.) did not attenuate PenCDF-induced wasting syndrome. On the contray, PenCDF-induced oxidateive stress was suppressed by cynaropicrin at the highest dose (20 mg/kg), although EROD activity was increased rather than reduced by cynaropicrin at lower doses. Thus, it is suggested that cynaropicrin has an ability to reduce oxidative stress caused by PenCDF.


Tunable Excited-State Properties and Dynamics as a Function of Pt-Pt Distance in Pyrazolate-Bridged Pt(II) Dimers.
The influence of molecular structure on excited-state properties and dynamics of a series of cyclometalated platinum dimers was investigated through a combined experimental and theoretical approach using femtosecond transient absorption (fs TA) spectroscopy and density functional theory (DFT) calculations. The molecules have the general formula [Pt(ppy)(μ-R2pz)]2, where ppy = 2-phenylpyridine, pz = pyrazolate, and R = H, Me, Ph, or (t)Bu, and are strongly photoluminescent at room temperature. The distance between the platinum centers in this A-frame geometry can be varied depending on the steric bulk of the bridging pyrazolate ligands that exert structural constraints and compress the Pt-Pt distance. At large Pt-Pt distances there is little interaction between the subunits, and the chromophore behaves similar to a monomer with excited states described as mixtures of ligand-centered and metal-to-ligand charge transfer (LC/MLCT) transitions. When the Pt(II) centers are brought closer together with bulky bridging ligands, they interact through their dz(2) orbitals and the S1 and T1 states are best characterized as metal-metal-to-ligand charge transfer (MMLCT) in character. The results of the femtoseconds TA experiments reveal that intersystem crossing (ISC) occurs on ultrafast time scales (τS1 < 200 fs), while there are two relaxation processes occurring within the triplet manifold, τ1 = 0.5-3.2 ps and τ2 = 20-70 ps; the longer time constants correspond to the presence of bulkier bridging ligands. DFT calculations illustrate that the Pt-Pt distances further contract in the T1 (3)MMLCT states; therefore, slower relaxation may be related to a larger structural reorganization. Subsequent investigations using faster time resolution are planned to measure the ISC process as well as to identify any potential coherent interaction(s) between the platinum centers that may occur.


Immune Checkpoint Inhibitors in Advanced-Stage Non-small Cell Lung Cancer.
More than half of non-small cell lung cancer (NSCLC) patients are at an advanced stage at the time of diagnosis, and they have a poor prognosis. Systemic treatment is the basic treatment approach for advanced-stage NSCLC, and chemotherapy and targeted treatments are commonly used based on the molecular characteristics. Although targeted therapies have led to a significant level of improvement in terms of survival, the results are still unsatisfactory. However, considerable attention has been focused to the immunotherapy with recent positive results reported by studies on this field. In this context, a certain portion of clinical studies have shown dramatic results, and these have involved inhibitors developed particularly against the immune checkpoint protein programmed death receptor-1 and its ligand (programmed death ligand-1). This review aims to present the significance of immune checkpoint inhibitors in NSCLC and to summarize the findings of relevant contemporary clinical studies.


Passive administration of monoclonal antibodies against H. capsulatum and other fungal pathogens.
The purpose of the use of this methodology is 1) to advance our capacity to protect individuals with antibody or vaccine for preventing or treating histoplasmosis caused by the fungus Histoplasma capsulatum and 2) to examine the role of virulence factors as target for therapy. To generate mAbs, mice are immunized, the immune responses are assessed using a solid phase ELISA system developed in our laboratory, and the best responder mice are selected for isolation of splenocytes for fusion with hybridoma cells. C57BL/6 mice have been extensively used to study H. capsulatum pathogenesis and provide the best model for obtaining the data required. In order to assess the role of the mAbs in infection, mice are intraperitoneally administered with either mAb to H. capsulatum or isotype matched control mAb and then infected by either intravenous (i.v.), intraperitoneal (i.p.), or intranasal (i.n.) routes. In the scientific literature, efficacy of mAbs for fungal infections in mice relies on mortality as an end point, in conjunction with colony forming units (CFU) assessments at earlier time points. Survival (time to death) studies are necessary as they best represent human disease. Thus, efficacy of our intervention would not adequately be established without survival curves. This is also true for establishing efficacy of vaccine or testing of mutants for virulence. With histoplasmosis, the mice often go from being energetic to dead over several hours. The capacity of an intervention such as the administration of a mAb may initially protect an animal from disease, but the disease can relapse which would not be realized in short CFU experiments. In addition to survival and fungal burden assays, we examine the inflammatory responses to infection (histology, cellular recruitment, cytokine responses). For survival/time to death experiments, the mice are infected and monitored at least twice daily for signs of morbidity. To assess fungal burden, histopathology, and cytokine responses, the mice are euthanized at various times after infection. Animal experiments are performed according to the guidelines of the Institute for Animal Studies of the Albert Einstein College of Medicine.


SMART STEP - SMARTphone-driven exercise and pedometer-based STEP intervention to promote physical activity among desk-based employees: Study protocol for a three-arm cluster randomized controlled trial.
Prolonged sitting in desk-based office workers is found to be associated with increased cardiometabolic risk and poor cognitive performance. Technology-based physical activity (PA) interventions using smartphone applications (SmPh app) to promote PA levels might be effective in reducing cardiometabolic risk among sedentary population but the evidence remains inconclusive. The objective is to investigate the effects of a technology-based PA intervention compared to PA education with a worksite manual or no intervention on PA levels, cardiometabolic risk, cognitive performance, and work productivity among desk-based employees. A three-arm clustered randomized trial will be conducted. The study will be conducted among various administrative offices of a multifaceted university in India. Desk-based employees aged between 30 and 50 years (n = 159; 53 in each arm) will be recruited. Employees from various constituent institutions (clusters) of the university will be randomized into one of the three following groups - SMART: SmPh app-driven break reminders (visual exercise prompts) plus pedometer-based step intervention, TRADE: worksite PA education with a manual plus American College of Sports Medicine guided PA prescription, or CONTROL: usual work group. At baseline and after the 1st, 3rd and 6th month of the trial period, accelerometer-measured sitting time and PA levels, cardiometabolic risk (fasting blood glucose, triglycerides, insulin, blood pressure, heart rate variability, functional capacity, and subcutaneous fat), cognitive performance (executive function), sickness absenteeism and work limitations will be assessed by a blinded assessor. Therapist delivering interventions will not be blinded. This trial will determine whether a combined SmPh-app and pedometer-based intervention is more effective than education or no intervention in altering PA levels, cardiometabolic risk and cognitive performance among desk-based employees in India. This study has the potential to foster institutional recommendations for using SmPh-based technology and pedometers to promote PA and reduce sedentary behavior at work.


Association of persistent pain with the incidence of chronic conditions following a disabling work-related injury.
In a cohort of workers disabled by a work-related injury or illness, this study aimed to: (i) compare pre-injury prevalence estimates for common chronic conditions to chronic condition prevalence in a representative sample of working adults; (ii) calculate the incidence of chronic conditions post-injury; and (iii) estimate the association between persistent pain symptoms and the incidence of common chronic conditions. Eighteen months post-injury, 1832 workers disabled by a work-related injury or illness in Ontario, Canada, completed an interviewer-administered survey. Participants reported pre- and post-injury prevalence of seven physician-diagnosed chronic conditions, and demographic, employment, and health characteristics. Pre-injury prevalence estimates were compared to estimates from a representative sample of workers. Multivariable logistic regression was used to examine the association of persistent pain with post-injury chronic condition incidence. Age-standardized pre-injury prevalence rates for diabetes, hypertension, arthritis, and back problems were similar to prevalence rates observed among working adults in Ontario, while prevalence rates for mood disorder, asthma and migraine were moderately elevated. Post-injury prevalence rates of mood disorder, migraine, hypertension, arthritis, and back problems were elevated substantially in this cohort. High persistent pain symptoms were strongly associated with the 18-month incidence of these conditions. The incidence of five chronic conditions over an 18-month follow-up period post injury was substantial. Persistent pain at 18 months was associated with this elevated incidence, with population attributable fraction estimates suggesting that 37-39% of incident conditions may be attributed to exposure to high levels of persistent pain.


High levels of Y-chromosome nucleotide diversity in the genus Pan.
Although some mitochondrial, X chromosome, and autosomal sequence diversity data are available for our closest relatives, Pan troglodytes and Pan paniscus, data from the nonrecombining portion of the Y chromosome (NRY) are more limited. We examined approximately 3 kb of NRY DNA from 101 chimpanzees, seven bonobos, and 42 humans to investigate: (i) relative levels of intraspecific diversity; (ii) the degree of paternal lineage sorting among species and subspecies of the genus Pan; and (iii) the date of the chimpanzee/bonobo divergence. We identified 10 informative sequence-tagged sites associated with 23 polymorphisms on the NRY from the genus Pan. Nucleotide diversity was significantly higher on the NRY of chimpanzees and bonobos than on the human NRY. Similar to mtDNA, but unlike X-linked and autosomal loci, lineages defined by mutations on the NRY were not shared among subspecies of P. troglodytes. Comparisons with mtDNA ND2 sequences from some of the same individuals revealed a larger female versus male effective population size for chimpanzees. The NRY-based divergence time between chimpanzees and bonobos was estimated at approximately 1.8 million years ago. In contrast to human populations who appear to have had a low effective size and a recent origin with subsequent population growth, some taxa within the genus Pan may be characterized by large populations of relatively constant size, more ancient origins, and high levels of subdivision.


Developing a nursing database system in Kenya.
To describe the development, initial findings, and implications of a national nursing workforce database system in Kenya. Creating a national electronic nursing workforce database provides more reliable information on nurse demographics, migration patterns, and workforce capacity. Data analyses are most useful for human resources for health (HRH) planning when workforce capacity data can be linked to worksite staffing requirements. As a result of establishing this database, the Kenya Ministry of Health has improved capability to assess its nursing workforce and document important workforce trends, such as out-migration. Current data identify the United States as the leading recipient country of Kenyan nurses. The overwhelming majority of Kenyan nurses who elect to out-migrate are among Kenya's most qualified. The Kenya nursing database is a first step toward facilitating evidence-based decision making in HRH. This database is unique to developing countries in sub-Saharan Africa. Establishing an electronic workforce database requires long-term investment and sustained support by national and global stakeholders.


Wheat-dependent exercise-induced anaphylaxis: a retrospective case review from a tertiary hospital.
Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy caused by the combination of wheat ingestion and physical exercise and has been reported in other parts of Asia. At present, there are no published reports of WDEIA in Singapore. The objective of this study is to characterise the common local clinical and laboratory manifestations of WDEIA. This was a retrospective descriptive study of all WDEIA who presented to a tertiary Singaporean Hospital over a 5-year-period from 1 January 2009 to 30 June 2013. Eight patients aged 9-41 years old were characterised. Six were males and the majority (5) was of Chinese ethnicity. An atopic history was found in four patients. The symptoms of anaphylaxis included cutaneous manifestations such as urticaria (n=7), angioedema (n=6), respiratory symptoms of dyspnoea and wheezing (n=5) and hypotension (n=5). The symptoms occurred 20-75 min after consumption of wheat-based products, often upon cessation of exercise [running (n=3), walking (n=4) and swimming (n=1)]. The WDEIA was recurrent in seven patients. The skin prick tests were positive to wheat in seven patients, and ω-5 gliadin test to wheat was positive in five patients. With the emergence of wheat allergy in East Asian countries, WDEIA has become an important condition for physicians and Singapore is no exception. Under-recognition combined with life-threatening symptoms warrants better public awareness measures. In addition, further studies are necessary to identify possible unique genetic and environmental exposures that could explain the inter-regional differences of WDEIA.


Molecular mapping and improvement of leaf rust resistance in wheat breeding lines.
Leaf rust, caused by Puccinia triticina, is the most common and widespread disease of wheat (Triticum aestivum) worldwide. Deployment of host-plant resistance is one of the strategies to reduce losses due to leaf rust disease. The objective of this study was to map genes for adult-plant resistance to leaf rust in a recombinant inbred line (RIL) population originating from MN98550-5/MN99394-1. The mapping population of 139 RILs and five checks were evaluated in 2005, 2009, and 2010 in five environments. Natural infection occurred in the 2005 trials and trials in 2009 and 2010 were inoculated with leaf rust. Four quantitative trait loci (QTL) on chromosomes 2BS, 2DS, 7AL, and 7DS were detected. The QTL on 2BS explained up to 33.6% of the phenotypic variation in leaf rust response, whereas the QTL on 2DS, 7AL, and 7DS explained up to 15.7, 8.1, and 34.2%, respectively. Seedling infection type tests conducted with P. triticina races BBBD and SBDG confirmed that the QTL on 2BS and 2DS were Lr16 and Lr2a, respectively, and these genes were expressed in the seedling and field plot tests. The Lr2a gene mapped at the same location as Sr6. The QTL on 7DS was Lr34. The QTL on 7AL is a new QTL for leaf rust resistance. The joint effects of all four QTL explained 74% of the total phenotypic variation in leaf rust severity. Analysis of different combinations of QTL showed that the RILs containing all four or three of the QTL had the lowest average leaf rust severity in all five environments. Deployment of these QTL in combination or with other effective genes will lead to successful control of leaf rust.


Non-medical prescription opioid use, prescription opioid-related harms and public health in Canada: an update 5 years later.
Five years ago, we highlighted Canada's emerging problem of prescription opioid (PO)-related harms and emphasized the need for targeted surveillance, research and interventions. Overall levels of PO use in the Canadian population have grown by 70% since then, while at the same time levels of non-medical PO use (NMPOU) in general and in key risk populations have continued to be high; furthermore, PO-related harms - specifically morbidity (e.g., treatment admissions) and mortality (e.g., overdose deaths) - have risen substantively. Unfortunately, major knowledge gaps related to systematic monitoring of PO-related harms continue to exist; for example, no national morbidity or mortality statistics are available. Investigator-driven research has generated important insights into the epidemiology and impacts of PO-related harms: high correlations between population-level PO dispensing and/or PO dosing and harms; high rates of co-occurrence of NMPOU and co-morbidities; and distinct NMPOU-related risk dynamics among street drug users. Select policy measures have been implemented only recently at the federal and provincial levels; these interventions remain to be systematically evaluated, especially given preliminary indications of reductions in PO-related harms (e.g., NMPOU) unfolding prior to the interventions. For these purposes, improvements in surveillance tools and research resources devoted to the extensive public health problem of PO-related harms in Canada continue to be urgently needed.


TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Accumulations of aggregated proteins are a key feature of the pathology of all of the major neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) was brought into this fold quite recently with the discovery of TDP-43 (TAR DNA binding protein, 43 kDa) inclusions in nearly all ALS cases. In part this discovery was fueled by the recognition of the clinical overlap between ALS and frontotemporal lobar degeneration, where ubiquitinated TDP-43 inclusions were first identified. Later the identification of TDP-43 mutations in rare familial forms of ALS confirmed that altered TDP-43 function can be a primary cause of the disease. However, the simple concept that TDP-43 is an aggregation-prone protein that forms toxic inclusions capable of promoting neurodegeneration has not been upheld by initial investigations. This review discusses observations from human pathology, cell culture and animal model systems, to highlight our somewhat murky understanding of the relationship between TDP-43 aggregation and neurodegeneration.


Internet gaming addiction: current perspectives.
In the 2000s, online games became popular, while studies of Internet gaming addiction emerged, outlining the negative consequences of excessive gaming, its prevalence, and associated risk factors. The establishment of specialized treatment centers in South-East Asia, the US, and Europe reflects the growing need for professional help. It is argued that only by understanding the appeal of Internet gaming, its context, and neurobiologic correlates can the phenomenon of Internet gaming addiction be understood comprehensively. The aim of this review is to provide an insight into current perspectives on Internet gaming addiction using a holistic approach, taking into consideration the mass appeal of online games, the context of Internet gaming addiction, and associated neuroimaging findings, as well as the current diagnostic framework adopted by the American Psychiatric Association. The cited research indicates that the individual's context is a significant factor that marks the dividing line between excessive gaming and gaming addiction, and the game context can gain particular importance for players, depending on their life situation and gaming preferences. Moreover, the cultural context is significant because it embeds the gamer in a community with shared beliefs and practices, endowing their gaming with particular meaning. The cited neuroimaging studies indicate that Internet gaming addiction shares similarities with other addictions, including substance dependence, at the molecular, neurocircuitry, and behavioral levels. The findings provide support for the current perspective of understanding Internet gaming addiction from a disease framework. The benefits of an Internet gaming addiction diagnosis include reliability across research, destigmatization of individuals, development of efficacious treatments, and the creation of an incentive for public health care and insurance providers. The holistic approach adopted here not only highlights empirical research that evidences neurobiologic correlates of Internet gaming addiction and the establishment of a preliminary diagnosis, but also emphasizes the necessity of an indepth understanding of the meaning, context, and practices associated with gaming.


Assembly of membrane-bound respiratory complexes by the Tat protein-transport system.
The Tat protein-export system serves to translocate folded proteins, often containing redox cofactors, across the bacterial inner membrane. Substrate proteins are directed to the Tat apparatus by distinctive N-terminal signal peptides containing a consensus SRRxFLK 'twin-arginine' motif. Here we review recent studies of the Tat system with particular emphasis on the assembly of membrane-bound respiratory complexes. We discuss the connection between Tat targeting and topological organisation of the complexes and consider the role of chaperone proteins in cofactor insertion and Tat targeting. The crystal structure of Escherichia coli formate dehydrogenase-N demonstrates that some Tat substrates are integral membrane proteins. Sequence analysis suggests that one-quarter of all traffic on the E. coli Tat pathway is inner-membrane proteins.


A Review of the Development and Application of Generic Multi-Attribute Utility Instruments for Paediatric Populations.
Multi-attribute utility instruments (MAUIs) are increasingly being used as a means of quantifying utility for the calculation of quality-adjusted life-years within the context of cost utility analysis. Traditionally, MAUIs have been developed and applied in adult populations. However, increasingly, researchers in health economics and other disciplines are recognising the importance of the measurement and valuation of health in both children and adolescents. Presently, there are nine generic MAUIs available internationally that have been used in paediatric populations: the Quality of Well-Being Scale (QWB), the Health Utility Index Mark 2 (HUI2), the HUI3, the Sixteen-dimensional measure of health-related quality of life (HRQoL) (16D), the Seventeen-dimensional measure of HRQoL (17D), the Assessment of Quality of Life 6-Dimension (AQoL-6D) Adolescent, the Child Health Utility 9D (CHU9D), the EQ-5D Youth version (EQ-5D-Y) and the Adolescent Health Utility Measure (AHUM). This paper critically reviews the development and application of the above nine MAUIs and discusses the specific challenges of health utility measurement in children and adolescents. Areas for further research relating to the development and application of generic MAUIs in paediatric populations are highlighted.


Accentuation of ethanol-induced fatty liver by phenobarbitone.
1. Four groups of rats received a liquid formula diet, given alone (control), or supplemented with either ethanol or phenobarbitone, or both together. 2. The ethanol-treated group showed a fall in plasma triglyceride and a rise in liver triglyceride, as compared with the control rats. 3. The phenobarbitone-treated group showed a marked rise in plasma triglyceride but not in liver triglyceride. 4. The group receiving both ethanol and phenobarbitone also showed a rise in plasma triglyceride, but this was accompanied by a striking increase in liver triglyceride. 5. These results suggest that ethanol and phenobarbitone each stimulate triglyceride synthesis but that in addition ethanol has an inhibitory effect on hepatic triglyceride secretion.


Diffraction from polymerized membranes.
Flexible polymerized membranes in a good solvent are expected to exhibit a remarkable low-temperature flat phase, characterized by a diverging bending rigidity, vanishing elastic constants, and large fluctuations both parallel and perpendicular to the surface. A theory of the equilibrium structure factor provides a good fit to extensive molecular dynamics simulations of simplified "tethered surface" models of these materials. These results show how information about the size, thickness, and internal structure of polymerized membranes can be extracted from diffraction experiments.


CD200-Fc, a novel antiarthritic biologic agent that targets proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis.
The CD200 receptor (CD200R) is an inhibitory receptor expressed by myeloid cells that is postulated to play an important role in regulation of the immune system. The purpose of this study was to evaluate the efficacy of a soluble ligand of CD200R in established collagen-induced arthritis (CIA) in mice and to analyze changes in cytokine expression following therapy in order to understand its primary mechanism of action. Arthritis was induced in DBA/1 mice, and CD200-Fc fusion protein, an isotype control monoclonal antibody, or TNFR-Fc fusion protein was administered over a period of 10 days (total of 4 doses). Cytokine expression in the joint was assessed by flow cytometry, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. CD200-Fc significantly reduced the severity of established arthritis at the clinical and histologic levels. The therapeutic effect of CD200-Fc at 1 mg/kg was comparable with that of TNFR-Fc at 4 mg/kg. CD200R was found to be expressed in arthritic synovia and in lymph nodes, yet no changes in T cell cytokine levels (interferon-gamma, interleukin-5 [IL-5], IL-10, IL-17) were detected after CD200-Fc therapy. There was no evidence of an expansion of forkhead box P3-positive regulatory T cells or a change in serum anticollagen IgG1 and IgG2a levels. However, administration of CD200-Fc markedly decreased the expression of messenger RNA for tumor necrosis factor alpha, IL-1beta, IL-10, and matrix metalloproteinase 13 in the joint to the same extent as administration of TNFR-Fc. CD200-Fc is an effective therapeutic agent in established CIA that targets proinflammatory cytokine expression in the joint without any obvious systemic immunosuppressive effects. Our findings indicate that CD200-Fc has considerable potential as a novel therapeutic agent in rheumatoid arthritis in humans.


Perception of pain in the minimally conscious state with PET activation: an observational study.
Patients in a minimally conscious state (MCS) show restricted self or environment awareness but are unable to communicate consistently and reliably. Therefore, better understanding of cerebral noxious processing in these patients is of clinical, therapeutic, and ethical relevance. We studied brain activation induced by bilateral electrical stimulation of the median nerve in five patients in MCS (aged 18-74 years) compared with 15 controls (19-64 years) and 15 patients (19-75 years) in a persistent vegetative state (PVS) with (15)O-radiolabelled water PET. By way of psychophysiological interaction analysis, we also investigated the functional connectivity of the primary somatosensory cortex (S1) in patients and controls. Patients in MCS were scanned 57 (SD 33) days after admission, and patients in PVS 36 (9) days after admission. Stimulation intensities were 8.6 (SD 6.7) mA in patients in MCS, 7.4 (5.9) mA in controls, and 14.2 (8.7) mA in patients in PVS. Significant results were thresholded at p values of less than 0.05 and corrected for multiple comparisons. In patients in MCS and in controls, noxious stimulation activated the thalamus, S1, and the secondary somatosensory or insular, frontoparietal, and anterior cingulate cortices (known as the pain matrix). No area was less activated in the patients in MCS than in the controls. All areas of the cortical pain matrix showed greater activation in patients in MCS than in those in PVS. Finally, in contrast with patients in PVS, those in MCS had preserved functional connectivity between S1 and a widespread cortical network that includes the frontoparietal associative cortices. Cerebral correlates of pain processing are found in a similar network in controls and patients in MCS but are much more widespread than in patients in PVS. These findings might be objective evidence of a potential pain perception capacity in patients in MCS, which supports the idea that these patients need analgesic treatment.


Complicated surgical resection of malignant tumors in the upper cervical spine after failed ion-beam radiation therapy.
Case report. To report 3 cases of malignant tumors in the upper cervical spine that were treated surgically by a combination of posterior tumor resection and stabilization and anterior tumor resection through a mandible-splitting approach after failed ion-beam radiation therapy. Few clinical reports have described in detail the postoperative complications associated with transoral surgical resection of tumors in the upper cervical spine after unsuccessful ion-beam radiation therapy. Three patients with malignant tumors in the upper cervical spine who had undergone ion-beam radiotherapy and experienced tumor recurrence were treated by a combination of posterior and anterior surgery through a mandible-splitting approach. One patient (patient 1, a 32-year-old man) had a hemangioendothelioma at the C2 and C3 level, whereas the other 2 patients (patient 2, a 66-year-old woman and patient 3, a 65-year-old man) had a chordoma at the C2 and C3 level. The intralesional but macroscopic total resection of the tumors was achieved in all 3 patients. However, serious complications developed after surgery, including deep wound infection, cerebrospinal fluid leakage, and meningitis in patient 1, prolonged swallowing difficulty, subsidence of the strut graft, and recurrence in patient 2, and deep wound infection and discitis causing progressive paralysis in patient 3. All patients underwent salvage surgery, including debridement of the wound in patient 1, posterior reinforcement using instrumentation and posterior tumor resection for the recurrent tumor in patient 2, and anterior debridement of the wound with a pedicle flap using the pectoral major muscle in patient 3 to address these problems. Patients 1 and 3 had no signs of recurrence at the time of a follow-up examination. Severe complications, mainly associated with the disturbance in healing of the retropharyngeal wall, were observed in all 3 patients. A preventive method, such as primary repair of the retropharyngeal wall using muscular/musculocutaneous flaps, should be considered for patients undergoing resection through a transoral approach after ion-beam irradiation.


Ginseng for the Management of Cancer-Related Fatigue: An Integrative Review.
Cancer-related fatigue (CRF) is one of the most prevalent, debilitating symptoms affecting a majority of patients with cancer worldwide. It can lead to poor compliance with anticancer therapy and discontinuation of treatment. Current management strategies for CRF center around activity and exercise; however, these strategies can be challenging for many patients undergoing active treatment. Ginseng has been shown to improve CRF and may provide benefit for patients suffering from CRF. A systematic review was completed by searching PubMed and Scopus databases. 115 search results were reduced to a final sample of five articles after applying inclusion and exclusion criteria. Published results suggest that 2,000 mg of American ginseng once daily improves symptoms of CRF. Minimal side effects or drug interactions are observed. Additional research is needed to further evaluate the role of ginseng for CRF. There are data to support the use of American ginseng to treat CRF. Large-scale randomized controlled trials are needed to validate these findings and determine optimal dosage and duration of therapy.


Elbow nerves: MR findings in 60 asymptomatic subjects--normal anatomy, variants, and pitfalls.
To prospectively evaluate the signal intensity (SI), course, and diameter of elbow nerves and to identify anatomic variants that are potentially associated with nerve compression syndromes on magnetic resonance (MR) images of asymptomatic elbows. This study was approved by the institutional review board. Informed consent was obtained from each volunteer. Sixty subjects with asymptomatic elbows (age range, 22.4-51.7 years; median age, 32.8 years) underwent MR imaging. Increased SI compared with surrounding muscles on fluid-sensitive MR images, anatomic course, anatomic nerve and muscle variants potentially associated with nerve compression syndromes, and qualitative changes in nerve diameters were evaluated. Quantitative data on the shortest and longest nerve diameters were obtained. Increased SI on fluid-sensitive MR images was seen in the ulnar nerve in 60% (36 of 60) of subjects but was never observed in the median and radial nerves. An atypical intermuscular course of the median nerve between the brachialis and pronator muscles was detected in 17% (10 of 60) of subjects. Ulnar nerve subluxation at the level of the cubital tunnel was seen in 2% (one of 60) of subjects; an anconeus epitrochlearis muscle, in 23% (14 of 60); and a hypertrophic leash of Henry, in 15% (nine of 60). Median nerve dimensions were 2.4 x 4.0 mm (range, 1.0-4.0 x 3.0-7.0 mm) for the ulnar nerve, 1.0 x 1.9 mm (range, 0.8-2.0 x 0.9-5.0 mm) for the radial nerve, and 3.0 x 5.4 mm (range, 1.0-5.0 x 3.0-9.0 mm) for the median nerve. Increased SI of the ulnar nerve on fluid-sensitive images (60%), an atypical intermuscular course of the median nerve (17%), and an anconeus epitrochlearis muscle (23%) are common MR findings in asymptomatic elbows.


Tissue distribution and efficacy of gold nanorods coupled with laser induced photoplasmonic therapy in ehrlich carcinoma solid tumor model.
Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment.


Neuropsychological performance following staged bilateral pallidal or subthalamic nucleus deep brain stimulation for Parkinson's disease.
Deep brain stimulation (DBS) has the potential to significantly reduce motor symptoms in advanced Parkinson's disease (PD). Controversy remains about non-motor effects of DBS and the relative advantages of treatment at two brain targets, the globus pallidus internus (GPi) and the subthalamic nucleus (STN). We investigated effects of DBS on neuropsychological functioning in 42 patients with advanced PD randomly assigned to receive staged bilateral DBS surgery of either the GPi or STN. Patients underwent neuropsychological assessment prior to and 6 months after unilateral surgery. Twenty-nine subsequently underwent surgery to the contralateral side and completed a second follow-up neuropsychological evaluation 15 months later. Unilateral treatment resulted in small but statistically significant reductions in performance on several measures, including verbal fluency and working memory. A similar pattern was observed after bilateral treatment. Reductions in verbal associative fluency were significant only after left-sided treatment. There were few significant differences related to treatment at the two surgical targets. Supplementary analyses suggested that decrements in select neuropsychological domains following DBS are unrelated to age or post-surgical reduction in dopaminergic medication dose. Findings are discussed with reference to possible causes of neuropsychological decline and the need for further controlled studies of specific neuropsychological effects of DBS.


Protobacco Media Exposure and Youth Susceptibility to Smoking Cigarettes, Cigarette Experimentation, and Current Tobacco Use among US Youth.
Youth are exposed to many types of protobacco influences, including smoking in movies, which has been shown to cause initiation. This study investigates associations between different channels of protobacco media and susceptibility to smoking cigarettes, cigarette experimentation, and current tobacco use among US middle and high school students. By using data from the 2012 National Youth Tobacco Survey, structural equation modeling was performed in 2013. The analyses examined exposure to tobacco use in different channels of protobacco media on smoking susceptibility, experimentation, and current tobacco use, accounting for perceived peer tobacco use. In 2012, 27.9% of respondents were never-smokers who reported being susceptible to trying cigarette smoking. Cigarette experimentation increased from 6.3% in 6th grade to 37.1% in 12th grade. Likewise, current tobacco use increased from 5.2% in 6th grade to 33.2% in 12th grade. Structural equation modeling supported a model in which current tobacco use is associated with exposure to static advertising through perception of peer use, and by exposure to tobacco use depicted on TV and in movies, both directly and through perception of peer use. Exposure to static advertising appears to directly increase smoking susceptibility but indirectly (through increased perceptions of peer use) to increase cigarette experimentation. Models that explicitly incorporate peer use as a mediator can better discern the direct and indirect effects of exposure to static advertising on youth tobacco use initiation. These findings underscore the importance of reducing youth exposure to smoking in TV, movies, and static advertising.


Idiopathic pulmonary fibrosis and lung cancer: a clinical and pathogenesis update.
About one out of 10 patients with idiopathic pulmonary fibrosis (IPF) develop lung cancer. This review provides an epidemiology and clinical update of the association of these two lethal diseases. In addition, we focus on the emerging overlapping epigenetic mechanisms in both diseases. In a vast majority of cases, lung cancer is diagnosed during the clinical and radiological follow-up for the fibrosis. The risk of development of lung cancer in IPF is higher for older male smokers and there is a significantly higher prevalence of lung cancer in the combined IPF and emphysema syndrome compared with fibrosis only. The association of two lethal diseases, such as IPF and lung cancer, carries a very poor outcome and the correct treatment strategy, particularly for advanced forms of lung cancer, is still unclear. The two novel drugs approved for IPF, pirfenidone and nintedanib, open a new scenario in which treated patients with fibrosis will live longer, and possibly have a lower incidence of lung cancer. However, prospective studies are urgently needed to definitively clarify the role of lung cancer treatment in the management of IPF patients. Furthermore, common epigenetic alterations may represent a promising target for therapeutic approaches in the near future.


The incidence of postoperative endophthalmitis after cataract surgery in China: a multicenter investigation of 2006-2011.
To estimate the cumulative incidence of postoperative endophthalmitis, identify risk factors and determine clinical outcomes in China. Medical records were reviewed for all patients with acute-onset endophthalmitis after cataract surgery from January 2006 to December 2011 at eight eye centres of tertiary care hospitals in China. Sixty-six cases of presumed endophthalmitis occurred after 201 757 cataract surgeries, yielding a cumulative incidence of 0.033% (95% CI 0.025 to 0.041). Logistic regression analysis revealed that the risk of endophthalmitis increased with intraoperative communication with vitreous (multivariate OR 9.96; 95% CI 4.54 to 21.84; p<0.001). After a median follow-up of 153 days, best-corrected visual acuity in the affected eye was more than 20/70 in 29/65 (44.6%) patients, and more than 20/40 in 20/65 (30.8%). A predictor of good visual acuity was baseline acuity of counting fingers or better (OR 6.25; 95% CI 2.13 to 18.33). Of 64 cases, 25 (39.1%) were culture positive. Coagulase-negative Staphylococcus and Pseudomonas species were the most common organisms isolated, accounting for 72.0% of the culture-positive cases (18/25). Two eye centres that used a combination of a high concentration vancomycin (1 mg/0.1 mL intracameral vancomycin injection or 100 µg/mL vancomycin in irrigating solution) and tobramycin as infection prophylaxis achieved a lower incidence of endophthalmitis than other centres (p<0.001). The incidence of acute postoperative endophthalmitis after cataract surgery in tertiary care hospitals of China was 0.033%. Intraoperative communication with vitreous was a major risk factor for developing endophthalmitis. Prophylactic use of a high-concentration vancomycin and tobramycin may play a positive role in the prevention of postoperative endophthalmitis after cataract surgery.


Förster energy transfer in an optical microcavity.
By studying the transfer of excitation energy between dye molecules confined within an optical microcavity, we demonstrate experimentally that Förster energy transfer is influenced by the local photonic mode density. Locating donor and acceptor molecules at well-defined positions allows the transfer rate to be determined as a function of both mutual separation and cavity length. The results show that the Förster transfer rate depends linearly on the donor emission rate and hence photonic mode density, providing the potential to control energy transfer by modification of the optical environment.


Low temperature protein refolding suggested by molecular simulation.
The function of critical biological materials, such as proteins, is intrinsically tied to their structure, and this structure is in turn heavily dependent on the properties of the solvent, most commonly water or dilute aqueous solutions. As water is known to exhibit anomalous properties, especially at supercooled temperatures, it is natural to ask how these properties might impact the thermodynamics of protein folding. To investigate this question, we use molecular simulation to explore the behavior of a model miniprotein, Trp-cage, as low as 70 K below the freezing point of the solvent at ambient pressure. Surprisingly, we find that while the expected cold denaturation of the protein is observed at moderate supercooling, further cooling to more than 55 K below the freezing point leads to cold refolding of the protein. Structural and hydrogen bonding analysis suggests that this refolding is driven by the desolvation of the protein's hydrophobic core, likely related to the pronounced decrease in density at this temperature. Beyond their intrinsic fundamental interest, these results have implications for cryomicroscopy and cryopreservation, where biological materials are often transiently subjected to these extreme conditions.


Circulating levels of adiponectin, resistin, and visfatin after mud-bath therapy in patients with bilateral knee osteoarthritis.
Adipocytokines, including adiponectin, resistin, and visfatin may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether a cycle of mud-bath therapy (MBT) influences the serum levels of adiponectin, resistin, and visfatin in patients with knee OA. As part of a prospective randomized, single blind-controlled trial evaluating the efficacy of MBT in knee OA, we included in this study 95 outpatients. One group (n = 49) received a cycle of MBT at the spa center of Chianciano Terme (Italy) in addition to the usual treatment, and one group (control group; n = 46) continued their regular care routine alone. Patients were assessed at basal time and at the end of the study (15 days) for clinical and biochemical parameters. Clinical assessments included spontaneous pain on a visual analog scale (VAS) score and the Western Ontario and McMaster Universities index (WOMAC) subscores for knee OA evaluated as total pain score (W-TPS), total stiffness score (W-TSS), and total physical function score (W-TPFS). Adiponectin, resistin and visfatin serum levels were assessed by enzyme immunoassay methods. At the end of the mud-bath therapy, serum adiponectin levels showed a significant decrease (p < 0.001), while no significant modifications were found in the control group at day 15. Serum resistin showed a significant decrease (p < 0.0001) in the MBT group at the end of the study and a significant increase in the control patients (p < 0.001). No significant modifications of visfatin were found in MBT. Furthermore, we tested the relationships between demographic and clinical parameters and adipocytokine concentrations measured in the MBT group at basal and at the end of the study. In conclusion, the present study shows that a cycle of MBT can modify serum levels of adiponectin and resistin but not the circulating levels of visfatin. In view of the recent evidences about the involvement of adiponectin and resistin in the pathogenesis and progression of OA, the decrease of these adipokines after mud-bath therapy may play a protective role in the course of the disease. However, it remains to be clarified which of the mechanisms of action of MBT may have determined the changes in serum levels of adiponectin and resistin that we observed.


Aging and health status of elderly in Latin America and the Caribbean: preliminary findings.
Aging in Latin America and the Caribbean will not proceed along known paths already followed by more developed countries. In particular, the health profile of the future elderly population is less predictable due to factors associated with their demographic past that may haunt them for a long time and make them more vulnerable, even if economic and institutional conditions turn out to be better than what they are likely to be. This paper answers a set of questions regarding the nature and determinants of health status among the elderly in Latin America and the Caribbean using SABE (Survey on Health and Well-Being of Elders), a cross-sectional representative sample of over 10,000 elderly aged 60 and above in private homes in seven major cities in Latin America and the Caribbean. We examine health outcomes such as self-reported health, functional limitations-Activities of Daily Living (ADL's) and Instrumental Activities of Daily Living (IADL's), obesity (ratio of weight in kilograms to the square of height in centimeters), and self-reported chronic conditions (including diabetes). The findings include: (a) Countries differ in self-reported health but exhibit much less differences in terms of functional limitations. The number of chronic conditions increase with age and is higher among females than among males; (b) On average SABE countries display levels of self-reported diabetes (and obesity) that are as high if not higher than those found in the US; (c) There is evidence, albeit weaker than expected, suggesting deteriorated health and functional status in the region; (d) There is important evidence pointing toward rather strong inequalities (by education and income) in selected health outcomes. Preliminary findings from SABE confirm that Latin America and the Caribbean display peculiarities in the health profile of elderly, particularly with regard to diabetes and obesity. It is important that new policy initiatives begin to seriously target the region's elderly, especially with an emphasis on the prevention and treatment of diabetes and obesity.


Müller-cell-derived leukaemia inhibitory factor arrests rod photoreceptor differentiation at a postmitotic pre-rod stage of development.
In the present study, we examine rod photoreceptor development in dissociated-cell cultures of neonatal mouse retina. We show that, although very few rhodopsin+ rods develop in the presence of 10% foetal calf serum (FCS), large numbers develop in the absence of serum, but only if the cell density in the cultures is high. The rods all develop from nondividing rhodopsin- cells, and new rods continue to develop from rhodopsin- cells for at least 6-8 days, indicating that there can be a long delay between when a precursor cell withdraws from the cell cycle and when it becomes a rhodopsin+ rod. We show that FCS arrests rod development in these cultures at a postmitotic, rhodopsin-, pre-rod stage. We present evidence that FCS acts indirectly by stimulating the proliferation of Müller cells, which arrest rod differentiation by releasing leukaemia inhibitory factor (LIF). These findings identify an inhibitory cell-cell interaction, which may help to explain the long delay that can occur both in vitro and in vivo between cell-cycle withdrawal and rhodopsin expression during rod development.


Data on proteome of Mycoplasma hominis cultivated with arginine or thymidine as a carbon source.
Mycoplasma hominis is an opportunistic bacterium that can cause acute and chronic infections of the urogenital tract. This bacterium, like all other Mycoplasma species, is characterized by the reduced genome size, and, consequently, reduction of the main metabolic pathways. M. hominis cells cannot effectively use glucose as a carbon and energy source. Therefore, the main pathway of energy metabolism is the arginine dihydrolase pathway. However, several bacteria can use nucleosides as the sole energy source. Biochemical studies using Salmonella typhimurium have shown that three enzymes (thymidine phosphorylase, phosphopentose mutase and deoxyribose-phosphate aldolase) are involved in the thymidine catabolic pathway. All these enzymes are present in M. hominis. For understanding changes in the energy metabolism of M. hominis we performed shotgun proteome analysis of M. hominis cells in liquid medium with arginine or thymidine as a carbon source. LC-MS analysis was performed with an Ultimate 3000 Nano LC System (Thermo Fisher Scientific) coupled to a Q Exactive HF benchtop Orbitrap mass spectrometer (Thermo Fisher Scientific) via a nanoelectrospray source (Thermo Fisher Scientific). Data are available via ProteomeXchange with identifier PXD018714 (https://www.ebi.ac.uk/pride/archive/projects/PXD018714).


Perceived barriers in accessing sexual and reproductive health services for youth in Lao People's Democratic Republic.
Sexual activity during youth is common in Lao PDR. However, young people seldom utilize sexual and reproductive health services and subsequently suffer from poor sexual and reproductive health. The aim of this qualitative study was to explore the barriers perceived by youth that prevent their access to sexual and reproductive health services. Twenty-nine semi-structured interviews were conducted with 22 participants aged 15-25 years, from urban and rural areas. A vignette was used during interviews with those who had no experience with sexual and reproductive health services. Additionally, seven semi-structured interviews were conducted with health providers from youth-friendly health clinics and from public sexual and reproductive health services. Data were analyzed using a thematic approach. The main barriers preventing young people from accessing sexual and reproductive health services were related to cognitive accessibility and psychosocial accessibility. The cognitive accessibility barriers were a lack of sexual knowledge and a lack of awareness of services. Perceived barriers in psychosocial accessibility were the feelings of shyness and shame caused by negative cultural attitudes to premarital sex, and the fear of parents finding out about visits to public sexual and reproductive health services, due to lack of confidentiality in the services and among health providers. In addition, the barriers of geographical accessibility, mainly insufficient availability of youth-friendly health clinics. To improve access to services, a multi-component strategy is needed: promotion of youth-friendly health clinics; sexual education in schools; a formal referral system between schools and youth-friendly health clinics; and community support interventions. Prior to implementation, more research should be done on the applicability of these methods in the Laos context. Future research should try to determine the cost-effectiveness of youth-friendly health clinics integrated in a district hospital and stand-alone clinics, to provide insight into which form should be further developed.


From "under" to "over" social cognition in schizophrenia: Is there distinct profiles of impairments according to negative and positive symptoms?
Interactions between social cognition and symptoms of schizophrenia have been investigated, but mostly component by component. Here we tested the assumption that two categories of deficits exist depending on clinical profiles, one corresponding to a defect in social cognition - "under-social cognition" - and one corresponding to excessive attributions leading to social cognitive impairments - "over-social cognition". To conduct the investigation, we performed a Hierarchical Clustering Analysis using positive and negative symptoms in seventy patients with schizophrenia and we compared the clusters obtained to a group of healthy controls on social cognitive measures. We distinguished two social cognitive profiles based on prevailing symptoms for emotion processes and Theory of Mind. Actually, patients with negative symptoms showed lower performances in emotion recognition task than both those with positive symptoms and controls. Concerning Theory of Mind, patients with positive symptoms had a significant tendency to make over interpretative errors than both patients with negative symptoms and controls. For other processes assessed, further explorations are needed. Actually, concerning social perception and knowledge both patients' groups presented significant impairments compared to controls. Assessment of attribution bias showed that patients in the positive group presented a significant hostility bias and a higher intentionality score compared to healthy controls. These results favor the existence of different categories of impairments depending more on the clinical characteristics of patients than on nosographical categories, but further investigations are now necessary to specify these profiles. It nevertheless showed the importance of assessing symptoms in relationship with cognitive functioning.


Ultrafast Imaging of the Jahn-Teller Topography in Carbon Tetrachloride.
We report the direct time-domain observation of ultrafast dynamics driven by the Jahn-Teller effect. Using time-resolved photoelectron spectroscopy with a vacuum-ultraviolet femtosecond source to prepare high-lying Rydberg states of carbon tetrachloride, our measurements reveal the local topography of a Jahn-Teller conical intersection. The pump pulse prepares a configurationally mixed superposition of the degenerate 1T2 4p-Rydberg states, which then distorts through spontaneous symmetry breaking that we identify to follow the t2 bending motion. Photoionization of these states to three cationic states 2T1, 2T2, and 2E reveals a shift in the center-of-mass of the photoelectron peaks associated with the 2Tn states which reveals the local topography of the Jahn-Teller conical intersection region prepared by the pump pulse. Time-dependent density functional theory calculations confirm that the dominant nuclear motion observed in the spectrum is the CCl4 t2 bending mode. The large density of states in the VUV spectral region at 9.33 eV of carbon tetrachloride and strong vibronic coupling result in ultrafast decay of the excited-state signal with a time constant of 75(4) fs.


Tumor regression dynamics with external radiotherapy in cancer cervix and its implications.
To study the external radiotherapy (EXTRT) regression patterns in cancer of the cervix. Evaluate EXTRT tumor regression doses (TRD) for 50% (TRD50), 80% response (TRD80), normalized dose response gradient (g50) and slope (slope50) with clinical outcome. Patients, treated solely with radiotherapy and enrolled for other prospective studies having weekly tumor regressions recorded were considered. Seventy-seven patients received 50Gy of EXTRT at 2 Gy/fraction followed by 18Gy of high-dose rate intracavitary brachytherapy at 6 Gy/fraction. Loco-regional regressions were assessed clinically at weekly intervals during EXTRT to generate EXTRT dose-response curves. Student's t test, logistic regression, Kaplan Meier and Cox's proportional hazard model. Scatter plots were fitted using cubic fit. Age (P=0.052) and absence or presence of gross residual tumor (AGRT and PGRT respectively) following EXTRT (P<0.001) were the only determinants for complete response (CR) at 1 month following completion of radiotherapy. EXTRT tumor regression sigmoid curves obtained for various patient characteristics differed only for those with AGRT and PGRT with differences in TRD50, (P<0.001); TRD80 (P<0.001) and slope50 (P=0.001). Response status to EXTRT was a prognosticator for loco-regional disease free survival (LDFS) (AGRT vs. PGRT; P=0.046). On multivariate analysis, both TRD50 and TRD80 emerged as significant predictors for tumor status at end of EXTRT while TRD80 was the sole determinant of LDFS. Extent of tumor regression to EXTRT is an important predictor for treatment outcome in cancer cervix as evident from TRD50 and TRD80 values of EXTRT tumor regression curves.


Development and validation of cross-transferable and polymorphic DNA markers for detecting alien genome introgression in Oryza sativa from Oryza brachyantha.
African wild rice Oryza brachyantha (FF), a distant relative of cultivated rice Oryza sativa (AA), carries genes for pests and disease resistance. Molecular marker assisted alien gene introgression from this wild species to its domesticated counterpart is largely impeded due to the scarce availability of cross-transferable and polymorphic molecular markers that can clearly distinguish these two species. Availability of the whole genome sequence (WGS) of both the species provides a unique opportunity to develop markers, which are cross-transferable. We observed poor cross-transferability (~0.75 %) of O. sativa specific sequence tagged microsatellite (STMS) markers to O. brachyantha. By utilizing the genome sequence information, we developed a set of 45 low cost PCR based co-dominant polymorphic markers (STS and CAPS). These markers were found cross-transferrable (84.78 %) between the two species and could distinguish them from each other and thus allowed tracing alien genome introgression. Finally, we validated a Monosomic Alien Addition Line (MAAL) carrying chromosome 1 of O. brachyantha in O. sativa background using these markers, as a proof of concept. Hence, in this study, we have identified a set molecular marker (comprising of STMS, STS and CAPS) that are capable of detecting alien genome introgression from O. brachyantha to O. sativa.


Temporal localization of actions with actoms.
We address the problem of localizing actions, such as opening a door, in hours of challenging video data. We propose a model based on a sequence of atomic action units, termed "actoms," that are semantically meaningful and characteristic for the action. Our actom sequence model (ASM) represents an action as a sequence of histograms of actom-anchored visual features, which can be seen as a temporally structured extension of the bag-of-features. Training requires the annotation of actoms for action examples. At test time, actoms are localized automatically based on a nonparametric model of the distribution of actoms, which also acts as a prior on an action's temporal structure. We present experimental results on two recent benchmarks for action localization "Coffee and Cigarettes" and the "DLSBP" dataset. We also adapt our approach to a classification-by-localization set-up and demonstrate its applicability on the challenging "Hollywood 2" dataset. We show that our ASM method outperforms the current state of the art in temporal action localization, as well as baselines that localize actions with a sliding window method.


Post-traumatic stress disorder amongst children aged 8-18 affected by the 2011 northern-Namibia floods.
Extreme flooding in the northern parts of Namibia occurred in 2011, impacting many school-going children in the region. The rationale for the current research is to assess post-traumatic stress disorder (PTSD) on school children as a result of the floods. A self-administered Child Trauma Screening Questionnaire (CTSQ) with closed-ended questions was administered to 480 children between the ages of eight and 18 years at their respective schools. The CTSQ consists of five items assessing re-experiencing and five items assessing hyper-arousal symptoms. The results show that 55.2% of learners aged 12 and below and 72.8% of learners aged 13 and above reported experiencing symptoms of trauma from the floods 2 years after the event. These percentages were quite high and are therefore a cause for concern. Given the magnitude of this problem, it is important for the government and other stakeholders to provide the necessary psychological and/or emotional support in the event of future floods or similar disasters.


Optical coherence tomography based microangiography provides an ability to longitudinally image arteriogenesis in vivo.
Arteriogenesis describes the active growth of the pre-existing collateral arterioles, which is a crucial tissue-saving process in occlusive vascular diseases. We propose to use optical coherence tomography (OCT)-based microangiography (OMAG) to monitor arteriogenesis following artery transection in mouse ear and focal stroke in mouse brain. Our longitudinal mouse ear study shows that the growth phase of arteriogenesis, indicated by changes in collateral vessel diameter and velocity, occurs between 12 and 24h after vessel transection. Additionally, the magnitude of local inflammation is consistent with the time course of arteriogenesis, judging by the tissue thickness measurement and lymphatic vessel signals in OCT. In the mouse brain study, collateral vessel morphology, blood flow velocity and directionality are identified, and an activation of the collateral flow at the arteriolo-arteriolar anastomoses (AAA) is observed during stroke. In comparison with histology and fluorescence imaging, OCT/OMAG is completely non-invasive and capable of producing consistent results of longitudinal changes in collateral vessel morphology and vasodynamics. OCT/OMAG is a promising imaging tool for longitudinal study of collateral vessel remodeling in small animals. This technique can be applied in guiding the in vivo experiments of arteriogenesis stimulation to treat occlusive vascular diseases, including stroke.


Predictors of severe H1N1 infection in children presenting within Pediatric Emergency Research Networks (PERN): retrospective case-control study.
To identify historical and clinical findings at emergency department presentation associated with severe H1N1 outcome in children presenting with influenza-like illness. Multicentre retrospective case-control study. 79 emergency departments of hospitals associated with the Pediatric Emergency Research Networks in 12 countries. 265 children (<16 years), presenting between 16 April and 31 December 2009, who fulfilled Centers for Disease Control and Prevention criteria for influenza-like illness and developed severe outcomes from laboratory confirmed H1N1 infection. For each case, two controls presenting with influenza-like illness but without severe outcomes were included: one random control and one age matched control. Severe outcomes included death or admission to intensive care for assisted ventilation, inotropic support, or both. Multivariable conditional logistic regression was used to compare cases and controls, with effect sizes measured as adjusted odds ratios. 151 (57%) of the 265 cases were male, the median age was 6 (interquartile range 2.3-10.0) years, and 27 (10%) died. Six factors were associated with severe outcomes in children presenting with influenza-like illness: history of chronic lung disease (odds ratio 10.3, 95% confidence interval 1.5 to 69.8), history of cerebral palsy/developmental delay (10.2, 2.0 to 51.4), signs of chest retractions (9.6, 3.2 to 29.0), signs of dehydration (8.8, 1.6 to 49.3), requirement for oxygen (5.8, 2.0 to 16.2), and tachycardia relative to age). These independent risk factors may alert clinicians to children at risk of severe outcomes when presenting with influenza-like illness during future pandemics.


Quantized surface transport in topological Dirac semimetal films.
Unconventional surface states protected by non-trivial bulk orders are sources of various exotic quantum transport in topological materials. One prominent example is the unique magnetic orbit, so-called Weyl orbit, in topological semimetals where two spatially separated surface Fermi-arcs are interconnected across the bulk. The recent observation of quantum Hall states in Dirac semimetal Cd3As2 bulks have drawn attention to the novel quantization phenomena possibly evolving from the Weyl orbit. Here we report surface quantum oscillation and its evolution into quantum Hall states in Cd3As2 thin film samples, where bulk dimensionality, Fermi energy, and band topology are systematically controlled. We reveal essential involvement of bulk states in the quantized surface transport and the resultant quantum Hall degeneracy depending on the bulk occupation. Our demonstration of surface transport controlled in film samples also paves a way for engineering Fermi-arc-mediated transport in topological semimetals.


64-qubit quantum circuit simulation.
Classical simulations of quantum circuits are limited in both space and time when the qubit count is above 50, the realm where quantum supremacy reigns. However, recently, for the low depth circuit with more than 50 qubits, there are several methods of simulation proposed by teams at Google and IBM. Here, we present a scheme of simulation which can extract a large amount of measurement outcomes within a short time, achieving a 64-qubit simulation of a universal random circuit of depth 22 using a 128-node cluster, and 56- and 42-qubit circuits on a single PC. We also estimate that a 72-qubit circuit of depth 23 can be simulated in about 16 h on a supercomputer identical to that used by the IBM team. Moreover, the simulation processes are exceedingly separable, hence parallelizable, involving just a few inter-process communications. Our work enables simulating more qubits with less hardware burden and provides a new perspective for classical simulations.


Chronic cranberry juice consumption restores cholesterol profiles and improves endothelial function in ovariectomized rats.
Postmenopausal women experience higher risks for cardiovascular diseases than age-matched men and pre-menopausal women. There is a need for better treatment strategy for estrogen-deficient-related cardiovascular complications. We and others have recently reported that activated renin-angiotensin system and the associated oxidative stress impaired endothelium-dependent relaxation in ovariectomized rat, while angiotensin receptor blocker rescues endothelial dysfunction. Dietary supplements and lifestyle modifications provide an alternative way to improve cardiovascular health. The present study tests the hypothesis that chronic cranberry juice consumption improves cholesterol profiles and vascular functions in estrogen-deficient animal model. The effect of cranberry consumption on expression and activity of renin-angiotensin system in the vasculature will be determined. Ovariectomized rats were treated daily with commercial cranberry juice at 7 mg/kg for 8 weeks, a dosage comparable to recent clinical studies. Serum was collected for measuring cholesterol levels while aorta was isolated for isometric force assay and expression studies. Cranberry juice consumption reduced circulating levels of total cholesterol, triacylglycerols, HDL, nHDL, and nHDL/HDL ratio. Meanwhile, cranberry juice consumption improved endothelium-dependent relaxation in aorta of ovariectomized rats by restoring p-eNOS level (endothelial nitric oxide synthase phosphorylated at ser-1177), reversing the up-regulated levels of renin-angiotensin system markers (angiotensin-converting enzyme, angiotensin II, and angiotensin II type 1 receptor), and normalizing the elevated NAD(P)H oxidase expression and oxidative stress. Our data demonstrate the novel cardiovascular benefits of cranberry juice consumption in improving both vascular functions and cholesterol profiles, providing insight into developing cranberry products into useful dietary supplements for postmenopausal women.


Sphingolipid biosynthesis by rat liver cells: effects of serine, fatty acids and lipoproteins.
The effects of circulating factors that might influence de novo sphingolipid biosynthesis were examined with rat liver cells by following the incorporation of [14C]serine into sphingosine and sphinganine, the predominant long-chain base backbones of hepatic sphingolipids. The rate of long-chain base formation depended on the concentration of [14C]serine in the medium and exhibited saturation kinetics. Long-chain base formation was stimulated by another precursor, palmitic acid, but stearic, oleic, linoleic and linolenic acids were inhibitory. This kinetic behavior indicates that long-chain base formation in liver is affected by the availability of the substrates of the initial enzyme of this pathway, serine palmitoyltransferase. Since liver is also exposed to sphingolipids associated with circulating lipoproteins, the effects of various lipoprotein fractions were determined and each appeared to decrease long-chain base formation. These results suggest that hepatic long-chain base biosynthesis can be stimulated by increases in the circulating levels of the precursors serine and palmitic acid whereas some other fatty acids and lipoproteins decrease the flux through this pathway.


The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium.
Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants. The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition. Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44). This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.


Physical activity levels of adolescent girls during dance classes.
The aims of this study were to describe the physical activity levels of girls during dance classes and to identify factors associated with moderate-to-vigorous physical activity (MVPA) in those classes. Participants were 137 girls (11 to 18 years-old) enrolled in ballet, jazz, or tap dance classes from 11 dance studios. Participants wore an accelerometer during the selected dance class on 2 separate days. Factors hypothesized to be associated with MVPA were dance style, instructional level, instructor's experience, percent of class time spent in choreography, and participants' age, race/ethnicity, BMI-for-age percentile, and years of dance training. Data were analyzed using generalized linear mixed models. Girls engaged in 9.8 minutes of MVPA, 6.0 minutes of moderate, 3.8 minutes of vigorous, 39.3 minutes of light, and 10.9 minutes of sedentary behavior per hour of dance class participation. Jazz/tap classes provided more MVPA than ballet classes, and intermediate level classes provided more MVPA than advanced level classes. Girls with more dance training obtained more MVPA than girls with less dance training. Dance classes provide valuable opportunities for adolescent girls to be physically active.


Psychometric properties of a revised version of the Assisting Hand Assessment (Kids-AHA 5.0).
The aim of this study was to scrutinize the Assisting Hand Assessment (AHA) version 4.4 for possible improvements and to evaluate the psychometric properties regarding internal scale validity and aspects of reliability of a revised version of the AHA. In collaboration with experts, scoring criteria were changed for four items, and one fully new item was constructed. Twenty-two original, one new, and four revised items were scored for 164 assessments of children with unilateral cerebral palsy aged 18 months to 12 years. Rasch measurement analysis was used to evaluate internal scale validity by exploring rating-scale functioning, item and person goodness-of-fit, and principal component analysis. Targeting and scale reliability were also evaluated. After removal of misfitting items, a 20-item scale showed satisfactory goodness-of-fit. Unidimensionality was confirmed by principal component analysis. The rating scale functioned well for the 20 items, and the item difficulty was well suited to the ability level of the sample. The person reliability coefficient was 0.98, indicating high separation ability of the scale. A conversion table of AHA scores between the previous version (4.4) and the new version (5.0) was constructed. The new, 20-item version of the Kids-AHA (version 5.0), demonstrated excellent internal scale validity, suggesting improved responsiveness to changes and shortened scoring time. For comparison of scores from version 4.4 to 5.0, a transformation table is presented.


Non-invasive study of the three-dimensional structure of nanoporous triblock terpolymer membranes.
Nanoporous media are of great importance for drug delivery or filtration. Typically the pore structure of such media is characterized using high-resolution techniques such as electron microscopy or atomic force microscopy. However, these techniques are restricted to the surface of the material and/or are highly invasive. In a proof-of-concept experiment we have employed three-dimensional single-particle orbit tracking for testing the three-dimensional pore structure of a liquid filled nanoporous polystyrene-block-polyisoprene-block-poly(N-isopropylacrylamide) (PS-b-PI-b-PNiPAAm) triblock terpolymer membrane. Using fluorescent tracers with a diameter of about 10% of the relevant void structures, the tracking experiments yielded results that were comparable to those obtained from reference experiments using environmental scanning electron microscopy (eSEM). This testifies that single-particle orbit tracking can serve as a useful non-invasive alternative for characterising the structure of nanoporous materials.


Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant.
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579-91. ©2016 AACR.


Oxidative stress markers, trace elements, and endocrine disrupting chemicals in children with Hashimoto's thyroiditis.
In this study, we aimed to investigate whether bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) exposure have any association with Hashimoto's thyroiditis (HT) and its biomarkers and to determine whether oxidative stress biomarkers and trace element levels showed any alterations in children with HT. We found that superoxide dismutase and glutathione peroxidase activities are lower in HT group from control (24% and 46%, respectively, p < 0.05). Zinc levels were significantly lower in HT group vs. control. In addition, the levels of mono-(2-ethylhexyl) phthalate (MEHP) which is the primary metabolite for DEHP, were markedly higher in HT group compared to control (p < 0.05). A negative correlation was observed between urinary BPA levels and fT4. In children with HT, oxidant/antioxidant balance is changed and these differences may be related by EDC exposure, the importance of which should be elucidated with further studies.


Chromosome mapping of the genes for murine arylamine N-acetyltransferases (NATs), enzymes involved in the metabolism of carcinogens: identification of a novel upstream noncoding exon for murine Nat2.
Arylamine N-acetyltransferases (NATs) catalyse acetylation reactions which can result in either detoxification or activation of arylamine carcinogens. The human NAT loci (NAT1, NAT2, and a pseudogene, NATP) have been mapped to human chromosome 8p22, a region frequently deleted in tumours. There are three functional genes in mice (Nat1, Nat2, and Nat3) encoding for three NAT isoenzymes. Different alleles at the Nat2 locus are responsible for the acetylation polymorphism identified in different mouse strains. We show that Nat3 is close to Nat1 and Nat2, by screening of a P1 artificial chromosome (PAC) library and provide cytogenetic evidence for co-localisation of the three genes in chromosome region 8 B3.1-B3.3. The Nat region of mouse and human is homologous. We also provide sequence information and a restriction map in the vicinity of Nat1 and Nat2 and describe a noncoding exon located 6 kb upstream of the Nat2 coding region.


The chronic ischaemic cardiovascular disease ESC Pilot Registry: Results of the six-month follow-up.
Aim Chronic ischaemic cardiovascular disease (CICD) remains a leading cause of morbidity and mortality worldwide. The CICD Pilot Registry enrolled 2420 patients across 10 European Society of Cardiology countries prospectively to describe characteristics, management strategies and clinical outcomes in this setting. We report here the six-month outcomes. Methods and results From the overall population, 2203 patients were analysed at six months. Fifty-eight patients (2.6%) died after inclusion; 522 patients (23.7%) experienced all-cause hospitalisation or death. The rate of prescription of angiotensin-converting enzyme inhibitors, beta-blockers and aspirin was mildly decreased at six months (all P < 0.02). Patients who experienced all-cause hospitalisation or death were older, more often had a history of non-ST-segment elevation myocardial infarction, of chronic kidney disease, peripheral revascularisation and/or chronic obstructive pulmonary disease than those without events. Independent predictors of all-cause mortality/hospitalisation were age (hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27) per 10 years, and a history of previous peripheral revascularisation (HR 1.45, 95% CI 1.03-2.03), chronic kidney disease (HR 1.31, 95% CI 1.0-1.68) or chronic obstructive pulmonary disease (HR 1.42, 95% CI 1.06-1.91, all P < 0.05). We observed a higher rate of events in eastern, western and northern countries compared to southern countries and in cohort 1. Conclusion In this contemporary European registry of CICD patients, the rate of severe clinical outcomes at six months was high and was influenced by age, heart rate and comorbidities. The medical management of this condition remains suboptimal, emphasising the need for larger registries with long-term follow-up. Ad-hoc programmes aimed at implementing guidelines adherence and follow-up procedures are necessary, in order to improve quality of care and patient outcomes.


The acinar-ductal tango in the pathogenesis of acute pancreatitis.
There is an unacceptably high mortality in acute pancreatitis, which is due to the lack of specific treatments for the disease. A major reason stated to account for the inability to develop effective treatments is that there are multiple pathobiologic pathways activated in the acinar cell mediating pancreatitis making it difficult to choose molecular targets for therapeutic strategies. However, this reasoning limits opportunities for therapeutic development because it does include another important participant in pancreatitis - the pancreatic duct cells. The most recent advance in pancreatitis research is that depletion of both glycolytic and oxidative ATP synthesis is a common event in both acinar and ductal cells. Although ATP has a very short half-life in the blood and is hydrolysed to ADP, there is clear evidence that encapsulating ATP into liposomes can effectively drive ATP into the cells which can be effective in protecting them from necrosis. In this review, we will examine the effects of different insults associated with pancreatitis on both the acinar and ductal components of the exocrine pancreas pointing out the role of the ductal epithelial responses in both attenuating and increasing the severity of pancreatitis. In addition, we propose that exogenous ATP administration may restore ductal and acinar function providing therapeutic benefit.


Analytical model and stability analysis of the leading edge spar of a passively morphing ornithopter wing.
This paper presents the stability analysis of the leading edge spar of a flapping wing unmanned air vehicle with a compliant spine inserted in it. The compliant spine is a mechanism that was designed to be flexible during the upstroke and stiff during the downstroke. Inserting a variable stiffness mechanism into the leading edge spar affects its structural stability. The model for the spar-spine system was formulated in terms of the well-known Mathieu's equation, in which the compliant spine was modeled as a torsional spring with a sinusoidal stiffness function. Experimental data was used to validate the model and results show agreement within 11%. The structural stability of the leading edge spar-spine system was determined analytically and graphically using a phase plane plot and Strutt diagrams. Lastly, a torsional viscous damper was added to the leading edge spar-spine model to investigate the effect of damping on stability. Results show that for the un-damped case, the leading edge spar-spine response was stable and bounded; however, there were areas of instability that appear for a range of spine upstroke and downstroke stiffnesses. Results also show that there exist a damping ratio between 0.2 and 0.5, for which the leading edge spar-spine system was stable for all values of spine upstroke and downstroke stiffnesses.


Ethnicity and differences between clinic and ambulatory blood pressure measurements.
This study investigated the relationship of ethnicity to the differences between blood pressure (BP) measured in a clinic setting and by ambulatory blood pressure monitoring (ABPM) in individuals with a previous diagnosis of hypertension (HT) and without a previous diagnosis of hypertension (NHT). A cross-sectional comparison of BP measurement was performed in 770 participants (white British (WB, 39%), South Asian (SA, 31%), and African Caribbean (AC, 30%)) in 28 primary care clinics in West Midlands, United Kingdom. Mean differences between daytime ABPM, standardized clinic (mean of 3 occasions), casual clinic (first reading on first occasion), and last routine BP taken at the general practitioner practice were compared in HT and NHT individuals. Daytime systolic and diastolic ABPM readings were similar to standardized clinic BP (systolic: 128 (SE 0.9) vs. 125 (SE 0.9) mm Hg (NHT) and 132 (SE 0.7) vs. 131 (SE 0.7) mm Hg (HT)) and were not associated with ethnicity to a clinically important extent. When BP was taken less carefully, differences emerged: casual clinic readings were higher than ABPM, particularly in the HT group where the systolic differences approached clinical relevance (131 (SE 1.2) vs. 129 (SE 1.0) mm Hg (NHT) and 139 (SE 0.9) vs. 133 (SE 0.7) mm Hg (HT)) and were larger in SA and AC hypertensive individuals (136 (SE 1.5) vs. 133 (SE 1.2) mm Hg (WB), 141 (SE 1.7) vs. 133 (SE 1.4) mm Hg (SA), and 142 (SE 1.6) vs. 134 (SE 1.3) mm Hg (AC); mean differences: 3 (0-7), P = 0.03 and 4 (1-7), P = 0.01, respectively). Differences were also observed for the last practice reading in SA and ACs. BP differences between ethnic groups where BP is carefully measured on multiple occasions are small and unlikely to alter clinical management. When BP is measured casually on a single occasion or in routine care, differences appear that could approach clinical relevance.


2'-O-methoxyethyl splice-switching oligos correct splicing from IVS2-745 β-thalassemia patient cells restoring HbA production and chain rebalance.
β-thalassemia is a disorder caused by altered hemoglobin protein synthesis and affects individuals worldwide. Severe forms of the disease, left untreated, can result in death before the age of 3 years (1). The standard of care consists of chronic and costly palliative treatment by blood transfusion combined with iron chelation. This dual approach suppresses anemia and reduces iron-related toxicities in patients. Allogeneic bone marrow transplant is an option, but limited by the availability of a highly compatible HSC donor. While gene therapy is been explored in several trials, its use is highly limited to developed regions with centers of excellence and well-established healthcare systems (2). Hence, there remains a tremendous unmet medical need to develop alternative treatment strategies for β-thalassemia (3). Occurrence of aberrant splicing is one of the processes that affects β-globin synthesis in β-thalassemia. The (C>G) IVS-2-745 is a splicing mutation within intron 2 of the β-globin gene. It leads to an aberrantly spliced mRNA that incorporates an intron fragment. This results in an in-frame premature termination codon that inhibits β-globin production. Here, we propose the use of uniform 2'-O-methoxyethyl (2'-MOE) splice switching oligos (SSOs) to reverse this aberrant splicing in the pre-mRNA. With these lead SSOs we show aberrant to wild type splice switching. This switching leads to an increase of adult hemoglobin (HbA) up to 80% in erythroid cells from patients with the IVS-2-745 mutation. Furthermore, we demonstrate a restoration of the balance between β-like- and α-globin chains, and up to an 87% reduction in toxic α-heme aggregates. While examining the potential benefit of 2'-MOE-SSOs in a mixed sickle-thalassemic phenotypic setting, we found reduced HbS synthesis and sickle cell formation due to HbA induction. In summary, 2'-MOE-SSOs are a promising therapy for forms of β-thalassemia caused by mutations leading to aberrant splicing.


Pharmacognostical studies of the plant drug Mimosae tenuiflorae cortex.
The bark of the Mimosa tenuiflora (Willd.) Poiret (Leguminoseae) tree, known as tepescohuite in Mexico, is commonly used in this country and in Central America to elaborate different products for the treatment of skin burns and lesions. The cicatrizing properties of extracts obtained from this bark have been scientifically studied, attributing the main biological activity to its tannin and saponin content. Studies include clinical trials of phytodrugs based on Mimosae tenuiflora bark extracts for treatment of venous leg ulcerations. Recent commercialization of the plant drug Mimosae tenuiflorae cortex requires pharmacognostical information to develop quality-control methods for raw materials and extracts produced with this plant drug. The present paper reports a group of ethnobotanical, morphological, chemical, and molecular studies performed with Mimosae tenuiflora materials obtained by collection in the southeastern Mexican state of Chiapas. Macro- and micro-morphological parameters were established to authenticate the genuine drug that allowed detection of adulterants usually found in commercial samples of this plant material. These morphological characteristics can be used for rapid identification of the drug and are particularly useful in the case of powdered materials. The chemical studies performed demonstrated that tannins represent the major component group in the bark. Its content in genuine tepescohuite is 16% and is mainly composed of proanthocyanidins, a condition permitting a tannin-based chemical-control method for fingerprinting the plant drug. Contrariwise, the saponin concentration in Mimosae tenuiflora bark is extremely low, and its isolation and content evaluation represent a complex procedure that is unsuitable for routine control purposes. Finally, random amplified DNA (RAPD) analysis results a useful tool for obtaining DNA specific markers of Mimosae tenuiflora species which should be useful in future studies involving raw material authentication by molecular methods.


A cell-cell communication system regulates protease production during sporulation in bacteria of the Bacillus cereus group.
In sporulating Bacillus, major processes like virulence gene expression and sporulation are regulated by communication systems involving signalling peptides and regulators of the RNPP family. We investigated the role of one such regulator, NprR, in bacteria of the Bacillus cereus group. We show that NprR is a transcriptional regulator whose activity depends on the NprX signalling peptide. In association with NprX, NprR activates the transcription of an extracellular protease gene (nprA) during the first stage of the sporulation process. The transcription start site of the nprA gene has been identified and the minimal region necessary for full activation has been characterized by promoter mutagenesis. We demonstrate that the NprX peptide is secreted, processed and then reimported within the bacterial cell. Once inside the cell, the mature form of NprX, presumably the SKPDIVG heptapeptide, directly binds to NprR allowing nprA transcription. Alignment of available NprR sequences from different species of the B. cereus group defines seven NprR clusters associated with seven NprX heptapeptide classes. This cell-cell communication system was found to be strain-specific with a possible cross-talk between some pherotypes. The phylogenic relationship between NprR and NprX suggests a coevolution of the regulatory protein and its signalling peptide.


Modeling Challenges of Ebola Virus-Host Dynamics during Infection and Treatment.
Mathematical modeling of Ebola virus (EBOV)-host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model's predictions. We also explored the model's predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV-host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment.


Recognition of a peptide antigen by heat shock--reactive gamma delta T lymphocytes.
Small synthetic peptides that correspond to different portions of the 65-kilodalton mycobacterial heat shock protein (Hsp65) were used to identify a putative antigenic epitope for gamma delta cells. Weaker gamma delta responses to the equivalent portion of the autologous homolog, mouse Hsp63, were also seen. The stimulatory epitope overlaps with an epitope recognized by arthritogenic alpha beta T cell clones. The data suggest that gamma delta cells have a role in autoimmune disorders and imply that these cells recognize ligands by a mechanism similar to that of alpha beta T lymphocytes, that is, in the form of small processed protein fragments bound to antigen-presenting molecules.


Kazantsev dynamo in turbulent compressible flows.
We consider the kinematic fluctuation dynamo problem in a flow that is random, white-in-time, with both solenoidal and potential components. This model is a generalization of the well-studied Kazantsev model. If both the solenoidal and potential parts have the same scaling exponent, then, as the compressibility of the flow increases, the growth rate decreases but remains positive. If the scaling exponents for the solenoidal and potential parts differ, in particular if they correspond to typical Kolmogorov and Burgers values, we again find that an increase in compressibility slows down the growth rate but does not turn it off. The slow down is, however, weaker and the critical magnetic Reynolds number is lower than when both the solenoidal and potential components display the Kolmogorov scaling. Intriguingly, we find that there exist cases, when the potential part is smoother than the solenoidal part, for which an increase in compressibility increases the growth rate. We also find that the critical value of the scaling exponent above which a dynamo is seen is unity irrespective of the compressibility. Finally, we realize that the dimension d = 3 is special, as for all other values of d the critical exponent is higher and depends on the compressibility.