Variations in management of A3 and A4 cervical spine fractures as designated by the AO Spine Subaxial Injury Classification System.
Optimal management of A3 and A4 cervical spine fractures, as defined by the AO Spine Subaxial Injury Classification System, remains controversial. The objectives of this study were to determine whether significant management variations exist with respect to 1) fracture location across the upper, middle, and lower subaxial cervical spine and 2) geographic region, experience, or specialty. A survey was internationally distributed to 272 AO Spine members across six geographic regions (North America, South America, Europe, Africa, Asia, and the Middle East). Participants' management of A3 and A4 subaxial cervical fractures across cervical regions was assessed in four clinical scenarios. Key characteristics considered in the vignettes included degree of neurological deficit, pain severity, cervical spine stability, presence of comorbidities, and fitness for surgery. Respondents were also directly asked about their preferences for operative management and misalignment acceptance across the subaxial cervical spine. In total, 155 (57.0%) participants completed the survey. Pooled analysis demonstrated that surgeons were more likely to offer operative intervention for both A3 (p < 0.001) and A4 (p < 0.001) fractures located at the cervicothoracic junction compared with fractures at the upper or middle subaxial cervical regions. There were no significant variations in management for junctional incomplete (p = 0.116) or complete (p = 0.342) burst fractures between geographic regions. Surgeons with more than 10 years of experience were more likely to operatively manage A3 (p < 0.001) and A4 (p < 0.001) fractures than their younger counterparts. Neurosurgeons were more likely to offer surgical stabilization of A3 (p < 0.001) and A4 (p < 0.001) fractures than their orthopedic colleagues. Clinicians from both specialties agreed regarding their preference for fixation of lower junctional A3 (p = 0.866) and A4 (p = 0.368) fractures. Overall, surgical fixation was recommended more often for A4 than A3 fractures in all four scenarios (p < 0.001). The subaxial cervical spine should not be considered a single unified entity. Both A3 and A4 fracture subtypes were more likely to be surgically managed at the cervicothoracic junction than the upper or middle subaxial cervical regions. The authors also determined that treatment strategies for A3 and A4 subaxial cervical spine fractures varied significantly, with the latter demonstrating a greater likelihood of operative management. These findings should be reflected in future subaxial cervical spine trauma algorithms.


Efficacy of Neoseiulus californicus and Phytoseiulus persimilis in suppression of Tetranychus urticae in young clementine plants.
Tetranychus urticae is one of the most damaging tetranychid mites affecting clementine orchards in Spain, where natural control is insufficient. Furthermore, in clementine nurseries, tender foliage is highly susceptible to attack and natural enemies are almost always absent. Therefore, acaricides are often used indiscriminately. Alternative control measures are necessary, both in commercial orchards and clementine nurseries. In order to assess the efficacy of inoculative releases of N. californicus and P. persimilis to reduce T. urticae populations in young Spanish clementine plants, a semi-field experiment was conducted and repeated in three seasons (spring, summer and autumn). Phytoseiulus persimilis was highly effective in reducing both T. urticae infestations and the damage level inflicted on plants at both release rates evaluated (40 and 80 phytoseiids/plant) and all three periods considered. By contrast, N. californicus demonstrated low performance under certain conditions. The results of this study could be adapted and transferred to nurseries and young citrus plantations.


Social Laughter Triggers Endogenous Opioid Release in Humans.
The size of human social networks significantly exceeds the network that can be maintained by social grooming or touching in other primates. It has been proposed that endogenous opioid release after social laughter would provide a neurochemical pathway supporting long-term relationships in humans (Dunbar, 2012), yet this hypothesis currently lacks direct neurophysiological support. We used PET and the μ-opioid-receptor (MOR)-specific ligand [11C]carfentanil to quantify laughter-induced endogenous opioid release in 12 healthy males. Before the social laughter scan, the subjects watched laughter-inducing comedy clips with their close friends for 30 min. Before the baseline scan, subjects spent 30 min alone in the testing room. Social laughter increased pleasurable sensations and triggered endogenous opioid release in thalamus, caudate nucleus, and anterior insula. In addition, baseline MOR availability in the cingulate and orbitofrontal cortices was associated with the rate of social laughter. In a behavioral control experiment, pain threshold-a proxy of endogenous opioidergic activation-was elevated significantly more in both male and female volunteers after watching laughter-inducing comedy versus non-laughter-inducing drama in groups. Modulation of the opioidergic activity by social laughter may be an important neurochemical pathway that supports the formation, reinforcement, and maintenance of human social bonds.SIGNIFICANCE STATEMENT Social contacts are vital to humans. The size of human social networks significantly exceeds the network that can be maintained by social grooming in other primates. Here, we used PET to show that endogenous opioid release after social laughter may provide a neurochemical mechanism supporting long-term relationships in humans. Participants were scanned twice: after a 30 min social laughter session and after spending 30 min alone in the testing room (baseline). Endogenous opioid release was stronger after laughter versus the baseline scan. Opioid receptor density in the frontal cortex predicted social laughter rates. Modulation of the opioidergic activity by social laughter may be an important neurochemical mechanism reinforcing and maintaining social bonds between humans.


Response of single leukemic cells to peptidase inhibitor therapy across time and dose using a microfluidic device.
Single-cell methodologies are revealing cellular heterogeneity in numerous biological processes and pathologies. For example, cancer cells are characterized by substantial heterogeneity in basal signaling and in response to perturbations, such as drug treatment. In this work, we examined the response of 678 individual U937 (human acute myeloid leukemia) cells to an aminopeptidase-inhibiting chemotherapeutic drug (Tosedostat) over the course of 95 days. Using a fluorescent reporter peptide and a microfluidic device, we quantified the rate of reporter degradation as a function of dose. While the single-cell measurements reflected ensemble results, they added a layer of detail by revealing unique degradation patterns and outliers within the larger population. Regression modeling of the data allowed us to quantitatively explore the relationships between reporter loading, incubation time, and drug dose on peptidase activity in individual cells. Incubation time was negatively correlated with the number of peptide fragment peaks observed, while peak area (which was proportional to reporter loading) was positively correlated with both the number of fragment peaks observed and the degradation rate. Notably, a statistically significant change in the number of peaks observed was identified as dose increased from 2 to 4 μM. Similarly, a significant difference in degradation rate as a function of reporter loading was observed for doses ≥2 μM compared to the 1 μM dose. These results suggest that additional enzymes may become inhibited at doses >1 μM and >2 μM, demonstrating the utility of single-cell data to yield novel biological hypotheses.


Credit where credit's due: accounting for co-authorship in citation counts.
I propose a new method (Pareto weights) to objectively attribute citations to co-authors. Previous methods either profess ignorance about the seniority of co-authors (egalitarian weights) or are based in an ad hoc way on the order of authors (rank weights). Pareto weights are based on the respective citation records of the co-authors. Pareto weights are proportional to the probability of observing the number of citations obtained. Assuming a Pareto distribution, such weights can be computed with a simple, closed-form equation but require a few iterations and data on a scholar, her co-authors, and her co-authors' co-authors. The use of Pareto weights is illustrated with a group of prominent economists. In this case, Pareto weights are very different from rank weights. Pareto weights are more similar to egalitarian weights but can deviate up to a quarter in either direction (for reasons that are intuitive).


Toward an understanding of the effective mechanisms of alcohol brief interventions.
Research on effective mechanisms of alcohol brief interventions has been neglected, but Bertholet and colleagues provide an example of such research in a re-analysis of combined data from 3 trials of brief motivational interviewing (BMI). However, it is disappointing that, in a well-designed and well-conducted analysis, little support was found for highly plausible hypotheses relating treatment processes to outcome of intervention. It is argued here that, because BMI must be assumed to work by increasing client motivation to cut down drinking, some measure of overall motivation before and after intervention is necessary to elucidate the pathway by which treatment processes are translated into positive outcomes. In pioneering research on physician advice on smoking cessation by Russell and colleagues, it was possible to distinguish between whether intervention worked by motivating more people to try to stop smoking, by increasing the success rate among those who did try, or by reducing the relapse rate among those who quit. It is recommended that similar measures be employed in research on how alcohol brief interventions work. A further consideration bearing on the relationship between treatment processes and outcome is whether or not individuals are dependent on alcohol and this is reminiscent of a dispute in the literature concerning the relative priority that should be given to motivational or dependence variables in the prediction of smoking cessation. In order to improve the effectiveness of alcohol brief interventions, future research should focus more on effective mechanisms of behavior change.


Noninvasive approach for the management of hemolytic disease of the fetus.
Hemolytic disease of the fetus and newborn (HDFN) is due to maternal alloantibodies directed against paternally inherited antigens on fetal red cells, and it is still a problem in affected pregnancies despite the routine use of anti-D immunoglobulin during pregnancy and shortly after delivery. The current noninvasive management of HDFN starts with the determination of fetal RhD genotype by use of cell-free fetal DNA in maternal plasma. When the fetus is antigen positive, the follow-up is performed by Doppler ultrasonography for the detection of moderate or severe anemia on the basis of an increase peak velocity of systolic blood in the middle cerebral artery. Finally, if anemia is suspected, an invasive approach is required in order to perform an intrauterine blood transfusion, which should only be attempted when the fetus needs transfusion. This approach reduces the iatrogenic conversion of mild-to-severe disease, which occurred as a result of the previous invasive management, and prevents unnecessary administration of human-derived blood products. These changes represent one of the genuine successes of fetal therapy.


Silica-induced pulmonary inflammation and fibrosis in mice is altered by acute exposure to nitrogen dioxide.
The biologic impact of consecutive exposures to two environmental pollutants was examined in mice exposed to silica crystals (SI) by intratracheal (IT) injection followed by an inhalation exposure to nitrogen dioxide (NO2). C57Bl/6 mice received an IT injection of 2 mg SI or sterile saline (SAL) followed by a 2-h inhalation exposure to NO2 at 20 ppm either within 2 h of or 24 h after SI instillation. During acute inflammation (d 3 postsilica), mice exposed to NO2 at either time showed a dramatic and significant reduction in the number of lavaged alveolar neutrophils (PMN) when compared to silica/air-exposed mice. Animals exposed to NO2 24 h after silica also evidenced significant decreases in levels of lavage albumin and lactate dehydrogenase (LDH) 3 d after silica, as well as significant decreases in hydroxyproline content of the lung 30 and 60 d postsilica injection when compared to silica/air-exposed animals. NO2 administration 24 h after silica appeared to shift the appearance of PMN in the lung from d 3 to d 14, but did not otherwise alter chronic cellular inflammation. These data suggest that the marked neutrophil response and collagen deposition induced by SI can be modulated by NO2 exposure and that the time of oxidant gas exposure after silica administration is critical to this modulation.


Epidural and intramuscular pethidine--a pharmacokinetic study.
Epidural preservative-free pethidine hydrochloride 0,75 mg/kg is rapidly absorbed into the blood. At 1,5 mg/kg the plasma levels reached are similar to those achieved by intramuscular preservative-free pethidine hydrochloride, as is the time course. Plasma levels fall more rapidly after epidural pethidine. Since the plasma levels lag behind the analgesic effects, they are unlikely to be of importance as regards clinical analgesia.


Australasian Resuscitation In Sepsis Evaluation trial statistical analysis plan.
The Australasian Resuscitation In Sepsis Evaluation (ARISE) study is an international, multicentre, randomised, controlled trial designed to evaluate the effectiveness of early goal-directed therapy compared with standard care for patients presenting to the ED with severe sepsis. In keeping with current practice, and taking into considerations aspects of trial design and reporting specific to non-pharmacologic interventions, this document outlines the principles and methods for analysing and reporting the trial results. The document is prepared prior to completion of recruitment into the ARISE study, without knowledge of the results of the interim analysis conducted by the data safety and monitoring committee and prior to completion of the two related international studies. The statistical analysis plan was designed by the ARISE chief investigators, and reviewed and approved by the ARISE steering committee. The data collected by the research team as specified in the study protocol, and detailed in the study case report form were reviewed. Information related to baseline characteristics, characteristics of delivery of the trial interventions, details of resuscitation and other related therapies, and other relevant data are described with appropriate comparisons between groups. The primary, secondary and tertiary outcomes for the study are defined, with description of the planned statistical analyses. A statistical analysis plan was developed, along with a trial profile, mock-up tables and figures. A plan for presenting baseline characteristics, microbiological and antibiotic therapy, details of the interventions, processes of care and concomitant therapies, along with adverse events are described. The primary, secondary and tertiary outcomes are described along with identification of subgroups to be analysed. A statistical analysis plan for the ARISE study has been developed, and is available in the public domain, prior to the completion of recruitment into the study. This will minimise analytic bias and conforms to current best practice in conducting clinical trials.


Prevalence and impact of chronic widespread pain in the Bangladeshi and White populations of Tower Hamlets, East London.
The prevalence and impact of chronic pain differ between ethnic groups. We report a study of the comparative prevalence and impact of chronic pain in Bangladeshi, British Bangladeshi and White British/Irish people. We posted a short questionnaire to a random sample of 4,480 patients registered with 16 general practices in the London Borough of Tower Hamlets and conducted a longer questionnaire with patients in the waiting areas at those practices. We distinguished between Bangladeshi participants who were born in the UK or had arrived in the UK at the age of 14 or under (British Bangladeshi) and those who arrived in UK at the age of over 14 (Bangladeshi). We obtained 1,223/4,480 (27 %) responses to the short survey and 600/637 (94 %) to the long survey. From the former, the prevalence of chronic pain in the White, British Bangladeshi and Bangladeshi groups was 55, 54 and 72 %, respectively. The corresponding figures from the long survey were 49, 45 and 70 %. Chronic widespread pain was commoner in the Bangladeshi (16 %) than in the White (10 %) or British Bangladeshi (9 %) groups. People with chronic pain experienced poorer quality of life (odds ratio for scoring best possible health vs. good health (or good vs. poor health) 5.6 (95 % confidence interval 3.4 to 9.8)), but we found no evidence of differences between ethnic groups in the impact of chronic pain on the quality of life. Chronic pain is commoner and, of greater severity, in Bangladeshis than in Whites. On most measures in this study, British Bangladeshis resembled the Whites more than the Bangladeshis.


On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer.
Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC.


Comparing the Noncomparable: The Need for Equivalence Measures That Make Sense in Health-Economic Evaluations.
The popularity of quality-adjusted life years (QALYs) has been resistant to concerns about validity and reliability. Utility-theoretic outcome equivalents are widely used in other areas of applied economics. Equivalence values can be derived for time, money, risk, and other metrics. These equivalence measures preserve all available information about individual preferences and are valid measures of individual welfare changes. The objective of this study was to derive alternative generalized equivalence measures from first principles and illustrate their application in an empirical comparative-effectiveness example. We specify a general-equilibrium model incorporating neoclassical utility functions, health production function, severity-duration preferences, and labor-market tradeoff function. The empirical implementation takes advantage of discrete-choice experiment methods that are widely accepted in other areas of applied economics and increasingly in health economics. We illustrate the practical significance of restrictive QALY assumptions using comparative-effectiveness results based on both QALYs and estimates of welfare-theoretic time-equivalent values for anti-tumor necrosis factor and prolonged corticosteroid treatments for Crohn's disease in three distinct preference classes. The QALY difference between the two treatments is 0.2 months, while time-equivalent values range between 0.5 and 1.3 months for aggregate and class-specific differences. Thus, the QALY-based analysis understates welfare-theoretic values by 60%-85%. These results suggest that using disease-specific equivalence values offer a meaningful alternative to QALYs to compare global outcomes across treatments. The equivalence values approach is consistent with principles of welfare economics and offers several features not represented in QALYs, including accounting for preference nonlinearities in disease severity and duration, inclusion of preference-relevant nonclinical healthcare factors, representing preferences of clinically-relevant patient subpopulations, and including utility losses related to risk aversion.


Visualization of doxorubicin-induced oxidative stress in isolated cardiac myocytes.
The paper presents high-resolution fluorescence images obtained using laser-scanning confocal microscopy. Isolated cells from adult rat hearts were preloaded with 2',7'-dichlorofluorescin (an oxidant-sensitive fluorescent probe) and exposed to doxo- rubicin, an important anticancer drug with prominent cardioxicity. Fluorescence images were collected from live cells simultaneously on two channels: 1) 515-530 nm emission range was used to monitor an increase in dichlorofluorescein, the oxidized product of dichlorofluorescein, and 2) emission > 610 nm was used to visualize the intracellular distribution of doxorubicin. The images reveal intracellular oxidation close to the mitochondria after only 20 min of exposure of isolated cardiomyocytes to 40-160 microM doxorubicin. The data confirm an oxidative mechanism of doxorubicin cardiotoxicity and demonstrate the capability of a new technique to monitor intracellular oxidation in living cardiomyocytes.


Cutaneous Ulcers as Initial Presentation of Localized Granulomatosis with Polyangiitis: A Case Report and Review of the Literature.
Background. Granulomatosis with polyangiitis (GPA) is an ANCA associated small vessel vasculitis characterized by necrotizing granulomatous inflammation involving the upper and the lower respiratory tract and the kidneys. The disease has a broad clinical spectrum that ranges from limited/localized involvement of a single organ system to a generalized systemic vasculitis that affects several organs with evidence of end organ damage. Atypical forms of the disease have been recognized with or without respiratory tract involvement with a long protracted course before manifesting as generalized disease. Case Presentation. We describe a 57-year-old woman who presented with recurrent fever and cutaneous ulcers on her legs who was diagnosed to have granulomatosis with polyangiitis (GPA) after an extensive evaluation which excluded infectious, other vasculitides, connective tissue disease and malignant etiologies. Conclusion. In the absence of typical manifestations, granulomatosis with polyangiitis (GPA) is indeed a diagnostic challenge to the physician. Atypical manifestations like unexplained recurrent fever and cutaneous ulcers nevertheless call for keeping a low threshold for the diagnosis of GPA as the disease can initially present in localized form before heralding into a generalized disease.


Therapeutic dilemma in a case of acute coronary syndrome (ACS).
An adult male labourer, a smoker and alcoholic was admitted to our hospital with a short history of fever, myalgia, breathlessness and oliguria. On examination he was icteric and hypotensive. Calf muscle tenderness was present. A provisional diagnosis of leptospirosis was made and he was started on treatment with crystalline penicillin. Blood pressure (BP) did not improve with fluids. Inotropes were started. The patient was taken for Slow Low Efficiency Daily Dialysis (SLEDD) during which he developed chest pain. ECG showed an anterolateral myocardial infarction (MI). He also complained of breathlessness and haemoptysis. Antiplatelets were withheld in view of thrombocytopaenia and haemoptysis; heparin could not be given because of the deranged coagulation parameters. The patient was managed symptomatically with nitrates. After the BP improved SLEDD was restarted. On day 3 of admission the patient became tachypnoeic and hypoxic, bilateral coarse crackles were present on auscultation. He was intubated and mechanically ventilated. Suctioning of endotracheal tube revealed fresh blood, and chest CT revealed alveolar haemorrhage. In spite of aggressive resuscitative measures, mechanical ventilation and antibiotics, the patient expired on the 12th day following admission.


Photoreceptor Transplantation in Late Stage Retinal Degeneration.
The recent advances in cell-based therapies for the repair of the pigmented epithelium is providing additional impetus for the translation of photoreceptor transplantation to eventual clinical trials. The prospects for transplantation of photoreceptors as a potential therapy for the treatment of photoreceptor degeneration will depend on successfully addressing many critical issues in preclinical studies. Although most of the studies that have carried out transplants of photoreceptors have primarily used normal mice, there have been recent reports that have also shown some success following transplantation to mouse models of retinitis pigmentosa. However, while these results are promising, there are several key issues that require further investigation in order to better understand the optimum timing for transplantation, given the extensive remodeling of the retina that occurs in late stage disease.


Distribution of algal aggregates under summer sea ice in the Central Arctic.
The sea ice cover of the Arctic Ocean has changed dramatically in the last decades, and the resulting consequences for the sea-ice-associated ecosystem remain difficult to assess. Algal aggregates underneath sea ice are of great importance for the ice-associated ecosystem and the pelagic-benthic coupling. However, the frequency and distribution of their occurrence is not well quantified. During the IceArc expedition (ARK-27/3) of RV Polarstern in late summer 2012, we observed different types of algal aggregates floating underneath various ice types in the Central Arctic basins. We investigated the spatial distribution of ice algal aggregates and quantified their biomass, using under-ice image surveys obtained by an upward-looking camera on a remotely operated vehicle. On basin scale, filamentous aggregates of Melosira arctica are more frequently found in the inner part of the Central Arctic pack ice, while rounded aggregates mainly formed by pennate diatoms are found closer to the ice edge, under melting sea ice. On the scale of an ice floe, the distribution of algal aggregates in late summer is mainly regulated by the topography of the ice underside, with aggregates accumulating in dome-shaped structures and at the edges of pressure ridges. The average biomass of the aggregates from our sites and season was 0.1-6.0 mg C m-2. However, depending on the approach used, differences in orders of magnitude for biomass estimates may occur. This highlights the difficulties of upscaling observations and comparing results from surveys conducted using different methods or on different spatial scales.


Bone Material Properties and Skeletal Fragility.
Deformations of vertebrae and sudden fractures of long bones caused by essentially normal loading are a characteristic problem in osteoporosis. If the loading is normal, then the explanation for and prediction of unexpected bone failure lies in understanding the mechanical properties of the whole bone-which come from its internal and external geometry, the mechanical properties of the hard tissue, and from how well the tissue repairs damage. Modern QCT and MRI imaging systems can measure the geometry of the mineralized tissue quite well in vivo-leaving the mechanical properties of the hard tissue and the ability of bone to repair damage as important unknown factors in predicting fractures. This review explains which material properties must be measured to understand why some bones fail unexpectedly despite our current ability to determine bone geometry and bone mineral content in vivo. Examples of how to measure the important mechanical properties are presented along with some analysis of potential drawbacks of each method. Particular attention is given to methods useful to characterize the loss of bone toughness caused by mechanical fatigue, drug side effects, and damage to the bone matrix.


Characterization of ion channel and transporter mRNA expressions in isolated gill chloride and pavement cells of seawater acclimating eels.
Ion channels and transporters (i.e. cystic fibrosis transmembrane regulator (CFTR), inward rectifier potassium channel (eKir), Na/K-ATPase, Na/K/Cl2 co-transporter (NKCC), aquaporin-3 (AQP-3), and Na/H exchanger-1 (NHE-1)) are known to be expressed in gill epithelia of teleost fish. Owing to the anatomical complexity of gill structures, their temporal expression profile in seawater acclimating gill pavement (PVCs) and chloride cells (CCs) are limited. In this study, we isolated the gill PVCs and CCs from seawater acclimating Japanese eels to address the issue. In the gill epithelia of freshwater adapted eels, CCs expressed the highest mRNA and/or protein levels of Na/K-ATPase, NKCC, and eKir as demonstrated by real-time PCR and/or immunohistochemical staining. AQP-3 mRNA was highly expressed in freshwater PVCs and its protein was in general expressed in all gill cells. The NHE-1 transcripts were expressed in similar levels in both PVCs and CCs. CFTR mRNA transcript was almost undetectable in all the freshwater gill cell samples. Seawater acclimation induced the transcript and/or protein levels of Na/K-ATPase, NKCC, CFTR, and eKir in CCs. The upregulation and the coexpression of these transporters in CCs suggested their cohort function in mediating Na+, K+, and Cl- transport. The expression of CFTR was found to be tightly regulated as its expression was restricted only in "seawater CCs". AQP-3 transcript and protein levels in PVCs reduced significantly during the acclimation. Interestingly immunocytochemical (ICC) staining of seawater gill epithelia revealed that AQP-3 immunoreactivities were mainly localized in seawater CCs. In the acclimation, there was no significant reduction of NHE-1 mRNA in both PVCs and CCs, however its protein level dropped significantly in the seawater condition. The present study is the first to demonstrate the activation of the mRNA transcripts for the ion channels and transporters in isolated gill CCs during seawater acclimation. The activating mechanism is found to be confined primarily in CCs. These results indicated that in addition to the increase in size and number of CCs, the molecular remodeling and the functional plasticity of CCs were essential in the ion transport process during seawater acclimation.


Understanding and expectation towards pharmaceutical care among patients, caregivers and pharmacy service providers: a qualitative study.
Over the past decades, the pharmacist's role has changed from being 'compounders and dispensers' to one of 'medication therapy manager' providing pharmaceutical care (PC). The transformation of pharmacy practice and its benefits, however, seem to be poorly understood by patients and caregivers (consumers) even in advanced health systems. This study aims to assess the comprehension of consumers in Singapore towards PC and expectations on the scope of pharmacy services today. This qualitative study was conducted among 51 consumers and pharmacy staff (pharmacy providers) in a tertiary acute care hospital in Singapore through 45 semi-structured interviews. Participants were sampled from inpatient and outpatient settings. Data were transcribed, coded and analysed by thematic analysis. Thirteen pharmacy technicians, 14 pharmacists and 14 out of 24 patients and caregivers, agreed to be interviewed. Reasons such as minimal English and unsure of pharmacy services were cited for declining interviews. From the interviews, the majority of the consumers did not understand the differences in roles between pharmacists and doctors beyond the basics of doctors diagnosing and pharmacists dispensing. Eighteen (75%) consumers remain unaware that pharmacists are trained to provide additional services such as medication enquiry services and optimisation of drug therapy. In addition, consumer expectations have expanded beyond transactional encounters, with 15 (63%) consumers expecting personalised services. Five (19%) pharmacy providers also expect the use of automation to boost efficiency and improve patients' convenience. Seven (15%) of the participants hope to see better prediction with analytics and, therefore, pre-emptive management of medication errors. There is an incomplete understanding regarding PC and the roles of pharmacy providers among healthcare consumers today. Beyond basic service provisions, expectations of pharmacy practice have become more experience-oriented. Policy changes that expand pharmacists' roles must be matched with corresponding publicity and education efforts to encourage service utilisation.


Removing brakes on adult brain plasticity: from molecular to behavioral interventions.
Adult brain plasticity, although possible, remains more restricted in scope than during development. Here, we address conditions under which circuit rewiring may be facilitated in the mature brain. At a cellular and molecular level, adult plasticity is actively limited. Some of these "brakes" are structural, such as perineuronal nets or myelin, which inhibit neurite outgrowth. Others are functional, acting directly upon excitatory-inhibitory balance within local circuits. Plasticity in adulthood can be induced either by lifting these brakes through invasive interventions or by exploiting endogenous permissive factors, such as neuromodulators. Using the amblyopic visual system as a model, we discuss genetic, pharmacological, and environmental removal of brakes to enable recovery of vision in adult rodents. Although these mechanisms remain largely uncharted in the human, we consider how they may provide a biological foundation for the remarkable increase in plasticity after action video game play by amblyopic subjects.


Characterizing Speech Phenotype in Individuals With Craniofacial Microsomia: A Scoping Review.
Craniofacial microsomia (CFM) is a complex congenital condition primarily affecting the ear, mandible, facial nerve and muscles, and tongue. Individuals with CFM are at increased risk of hearing loss, obstructive sleep apnea, and feeding/swallowing difficulties. The purpose of this scoping review was to summarize evidence pertaining to speech production in CFM. All articles reporting any characteristic of speech production in CFM were included and screened by two independent reviewers by title, abstract, and full text. Data charting captured details related to study population and design, CFM diagnostic criteria, speech outcome measurement, and key findings. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist guided reporting of results. Our protocol was registered on the Open Science Framework (https://osf.io/npr94/) and published elsewhere. Forty-five articles were included in the detailed review. Most articles originated from the United States, were published in the past decade, and utilized case report/series study design. A speech-language pathologist authored 29%. The prevalence of velopharyngeal insufficiency ranged from 19% to 55% among studies. Oral distortion of alveolar and palatal fricatives and affricates primarily characterized articulation errors. Studies identified increased disordered speech and lower intelligibility in adolescents with CFM compared to unaffected peers. Evidence pertaining to phonatory and respiratory speech findings is limited. Evidence supports that individuals with CFM are at increased risk of both velopharyngeal and articulatory speech differences. Additional information is needed to develop speech screening guidelines for children with CFM. Heterogeneity in study design and outcome measurement precludes comparisons across studies. https://doi.org/10.23641/asha.24424555.


pH-sensitive dispersion and debundling of single-walled carbon nanotubes: lysozyme as a tool.
Highly dispersed and debundled carbon nanotubes were prepared in an aqueous solution of lysozyme using a combination of ultrasonication and ultracentrifugation. The product is a pH-sensitive dispersion, which remains in a highly dispersed state at pH<8 and pH>11, but in an aggregated state at pH 8-11. Photoluminescence measurements show that by changing the pH value, a reversible conversion of the highly dispersed state to the aggregated state (or vice versa) could be observed. Circular dichromism analysis confirmed that the secondary structure, as well as the majority of the tertiary structure, remains intact. Some lysozyme molecules were irreversibly bound to the nanotubes, which is possibly due to pi-pi or hydrophobic interactions. However, these interactions alone are not enough to produce fine dispersions of the nanotubes. Protonated amine interactions on the defect sites of the nanotubes play a vital role in the stabilization of the nanotubes below the isoelectric point and amine adsorption on the sidewalls of nanotubes occurs in cases where the pH value is higher than the isoelectric point.


A Methodological Perspective on the Longitudinal Cognitive Change after Stroke.
Most studies of poststroke cognitive impairment (PSCI) have analyzed cognitive levels at specific time points rather than their changes over time. Furthermore, they seldom consider correlations between cognitive domains. We aimed to investigate the effects of these methodological considerations on determining significant PSCI predictors in a longitudinal stroke cohort. In patients who underwent neuropsychological tests at least twice after stroke, we adopted a multilevel hierarchical mixed-effects model with domain-specific cognitive changes and a multivariate model for multiple outcomes to reflect their correlations. We enrolled 375 patients (median follow-up of 34.1 months). Known predictors of PSCI were generally associated with cognitive levels; however, most of the statistical significances disappeared when cognitive changes were set as outcomes, except age for memory, prior stroke and baseline cognition for executive/attention domain, and baseline cognition for visuospatial function. The multivariate analysis which considered multiple outcomes simultaneously further altered these associations. This study shows that defining outcomes as changes over time and reflecting correlations between outcomes may affect the identification of predictors of PSCI.


Caspases--their role in apoptosis and other physiological processes as revealed by knock-out studies.
Caspases are crucial mediators of apoptosis, a form of physiological cell death. Their activation is carefully controlled by a philogenetically conserved death program, which is indispensable for the homeostasis and development of higher organisms. Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. In vitro studies have demonstrated the requirement of caspase activity for both the triggering phase as well as the execution of apoptosis, thus providing a molecular base for the fine-tuning of this process by pharmacological agents. The precise roles of the individual caspases in vivo and their functional relation to each other have been best demonstrated in genetically modified animals. The generation of single caspase-deficient mice have confirmed most of the data obtained in vitro and exposed some new aspects previously undetected in the cell culture system. Interestingly, inactivation of many caspases revealed not only their expected participation in apoptotic events as well as in the maturation of cytokines, but also provided hints about the role of at least some caspases in cell differentiation and stimulatory responses. In this review we will discuss what these studies have unveiled about the role of individual caspases in development, apoptosis, and inflammation, with particular focus on their role beyond the apoptotic process.


HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events.
A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk. In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux. We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.


Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.
There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between "normal" and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.


Human schistosomiasis.
Human schistosomiasis--or bilharzia--is a parasitic disease caused by trematode flukes of the genus Schistosoma. By conservative estimates, at least 230 million people worldwide are infected with Schistosoma spp. Adult schistosome worms colonise human blood vessels for years, successfully evading the immune system while excreting hundreds to thousands of eggs daily, which must either leave the body in excreta or become trapped in nearby tissues. Trapped eggs induce a distinct immune-mediated granulomatous response that causes local and systemic pathological effects ranging from anaemia, growth stunting, impaired cognition, and decreased physical fitness, to organ-specific effects such as severe hepatosplenism, periportal fibrosis with portal hypertension, and urogenital inflammation and scarring. At present, preventive public health measures in endemic regions consist of treatment once every 1 or 2 years with the isoquinolinone drug, praziquantel, to suppress morbidity. In some locations, elimination of transmission is now the goal; however, more sensitive diagnostics are needed in both the field and clinics, and integrated environmental and health-care management will be needed to ensure elimination.


A far-red emitting fluorescent marker protein, mGarnet2, for microscopy and STED nanoscopy.
Here we present mGarnet2, a monomeric, far-red fluorescent marker protein derived from mRuby, with absorption and emission bands peaking at 598 and 671 nm, respectively. The protein shows excellent performance as a live-cell fusion marker for STED nanoscopy with 640 nm excitation and 780 nm depletion wavelengths.


[Comorbidity on axis I and treatment outcome].
Clinical practice shows that patients with complicated psychopathology are more difficult to treat than those with simple psychopathology. Comorbidity may be the complicating factor involved here. The prognostic value that comorbidity on axis I has on treatment outcome may be relevant for establishing the treatment plan for a patient and may also be relevant for the evaluation of aggregated treatment outcomes achieved by clinicians, treatment teams or institutes.
 AIM: To investigate whether comorbidity on axis I can explain disappointing results and whether we should correct for comorbidity when comparing the aggregated treatment results achieved by clinicians, treatment teams or institutes.
 METHOD: Our observational study involved a large group of patients (n = 25,651). Outcome data for a subgroup of patients (n = 7754) were available. Comorbidity in this subgroup was established by means of a structured diagnostic interview (MINI-Plus) performed by trained research nurses.
 RESULTS: Comorbidity appeared to have some association with the treatment outcome, but the severity of symptoms seemed to be a much more powerful predictor of treatment outcome.
 CONCLUSION: After correcting for baseline severity, we found that comorbidity had very little prognostic value as far as the treatment outcome was concerned.


Radioactive iodine remnant uptake after completion thyroidectomy: not such a complete cancer operation.
Given limitations in preoperative diagnostics, thyroid lobectomy followed by completion thyroidectomy (CT) for differentiated thyroid cancer (DTC) may be required. It is unclear whether resection quality by CT differs from that by total thyroidectomy (TT). Additional surgeon or patient factors may also influence the "completeness" of resection. This study evaluated how CT and surgeon volume influence the adequacy of resection as measured by radioactive iodine (RAI) remnant uptake. A retrospective review of a prospectively collected thyroid database was queried for patients treated for DTC with TT or CT followed by RAI ablation. CT patients were matched 1:2 by age, sex, and tumor size to TT patients. Surgeon volume, time to completion, and continuity of surgeon care were reviewed. Over 18 years, 45 patients with DTC had CT and RAI. Mean age was 48 ± 2 years, and 76 % were female, with a tumor size of 2.7 ± 0.3 cm. CT had higher remnant uptake than TT (0.07 vs. 0.04 %; p = 0.04). CT performed by a high-volume surgeon had much lower remnant uptakes (0.06 vs. 0.22 %; p = 0.04). Remnant uptake followed a stepwise decrease with involvement of a high-volume surgeon for part or all of the surgical management (p = 0.11). Multiple regression analysis found CT (p = 0.02) and surgeon volume (p = 0.04) to significantly influence uptake after controlling for other factors. Single-stage TT provides a better resection based on smaller thyroid remnant uptakes than CT for patients with thyroid cancer. If a staged operation for cancer is necessary, surgeon volume may affect the completeness of resection.


Practice structure improves unconscious transitional memories by increasing synchrony in a premotor network.
Sequence learning relies on formation of unconscious transitional and conscious ordinal memories. The influence of practice type on formation of these memories that compose skill and systems level neural substrates is not known. Here, we studied learning of transitional and ordinal memories in participants trained on motor sequences while scanned using fMRI. Practice structure was varied or grouped (mixing or grouping sequences during training, respectively). Memory was assessed 30 min and 1 week later. Varied practice improved transitional memory and enhanced coupling of the dorsal premotor cortex with thalamus, cerebellum, and lingual and cingulate regions and greater transitional memory correlated with this coupling. Thus, varied practice improves unconscious transitional memories in proportion to coupling within a cortico-subcortical network linked to premotor cortex. This result indicates that practice structure influences unconscious transitional memory formation and identifies underlying systems level mechanisms.


Molecular and biochemical characterization of a novel β-N-acetyl-D-hexosaminidase with broad substrate-spectrum from the Aisan corn borer, Ostrinia furnacalis.
Insect β-N-acetyl-D-hexosaminidases with broad substrate-spectrum (IBS-Hex) are the homologues of human β-N-acetyl-D-hexosaminidase A/B (HsHex A/ B). These enzymes are distributed in most insect species and vary in physiological roles. In this study, the gene encoding an IBS-Hex, OfHEX2, was cloned from the Asian corn borer, Ostrinia furnacalis. Recombinant OfHex2 was expressed in Pichia pastoris and purified to homogeneity. By structure-based sequence alignment, three sequence segments with high diversity among IBS-Hexs were firstly concluded. Furthermore, the residue pair N423-R424/ D452-L453 important for the specificity of human β-N-acetyl-D-hexosaminidase subunits α/β toward charged/ non-charged substrates was not conserved in OfHex2 and other IBS-Hexs. Unlike HsHex A, OfHex2 could not degrade charged substrates such as 4-methylumbelliferyl-6-sulfo-N-acetyl-β-D-glucosaminide, ganglioside GM2 and peptidoglycan. OfHex2 showed a broad substrate-spectrum by hydrolyzing β1-2 linked N-acetyl-D-glucosamines from both α3 and α6 branches of biantennary N-glycan and β1-4 linked GlcNAc from chitooligosaccharides as well as β1-3 linked or β1-4 linked N-acetyl-D-galactosamine from oligosaccharides of glycolipids. Real-time PCR analysis demonstrated that the expression of OfHEX2 was up-regulated in the intermolt stages (both larva and pupa), and mainly occurred in the carcass rather than in the midgut during the feeding stage of fifth (final) instar larva. This study reported a novel IBS-Hex with specific biochemical properties, suggesting biodiversity of this class of enzymes.


Investigate the risk factors of stunting, wasting, and underweight among under-five Bangladeshi children and its prediction based on machine learning approach.
Malnutrition is a major health issue among Bangladeshi under-five (U5) children. Children are malnourished if the calories and proteins they take through their diet are not sufficient for their growth and maintenance. The goal of the research was to use machine learning (ML) algorithms to detect the risk factors of malnutrition (stunted, wasted, and underweight) as well as their prediction. This work utilized malnutrition data that was derived from Bangladesh Demographic and Health Survey which was conducted in 2014. The selected dataset consisted of 7079 children with 13 factors. The potential risks of malnutrition have been identified by logistic regression (LR). Moreover, 3 ML classifiers (support vector machine (SVM), random forest (RF), and LR) have been implemented for predicting malnutrition and the performance of these ML algorithms were assessed on the basis of accuracy. The average prevalence of stunted, wasted, and underweight was 35.4%, 15.4%, and 32.8%, respectively. It was noted that LR identified five risk factors for stunting and underweight, as well as four factors for wasting. Results illustrated that RF can be accurately classified as stunted, wasted, and underweight children and obtained the highest accuracy of 88.3% for stunted, 87.7% for wasted, and 85.7% for underweight. This research focused on the identification and prediction of major risk factors for stunting, wasting, and underweight using ML algorithms which will aid policymakers in reducing malnutrition among Bangladesh's U5 children.


Increased performance in genetic manipulation by modeling the dielectric properties of the rodent brain.
Genetic approaches to control DNA expression in different brain areas have provided an excellent system to characterize gene function in health and disease of animal models. With respect to others, in utero electroporation of exogenous DNA into progenitor cells committed to specific brain areas is the optimal solution in terms of simplicity and velocity. Indeed, this method entails one quick and easy surgical procedure aimed at DNA injection in the embryonic brain followed by brief exposure to a strong electric field by a bipolar electrode. Nevertheless, the technique is still lacking the necessary control and reliability in addressing the field. Moving from a theoretical model that accounts for the morphology and the dielectric properties of the embryonic brain, we developed here a set of novel and reliable experimental configurations based on the use of three electrodes for electroporation in mouse. Indeed, by means of a full 3D model of the embryonic brain and the surrounding environment, we showed that the distribution of the electric field can be finely tuned in order to target specific brain regions at a desired temporal window by proper placement of the three electrodes. In the light of this theoretical background, we manufactured a three-electrode device and performed model-guided experimental sessions. The result was an increased spatial control, extended time frames and unprecedented reliability of the genetic manipulation, with respect to the current state of the art. In particular, the outcomes of this method applied into the mouse model are reported here for the first time.


Characterization of stimulated Brillouin scattering in a circular-core two-mode fiber using optical time-domain analysis.
We show characterization of stimulated Brillouin scattering (SBS) in a circular-core two-mode fiber (c-TMF) using Brillouin optical time-domain analysis (BOTDA) with a pulsed pump and a counterpropagating continuous wave probe. By using two free-space mode combiners (FSMCs), we can launch any combination of spatial modes into both ends of the c-TMF. Combined with coherent detection, measurement of distributed Brillouin gain spectra (BGS) is achieved for all possible counter-propagating spatial mode pairs with high spectral resolution and stability. Both intra- and inter-modal SBS are investigated for the c-TMF. The inter-modal SBS between two degenerate LP11 modes (LP11a/LP11b) is demonstrated for the first time. From the Brillouin frequency shift (BFS) measured in each intra-modal SBS, the distributed modal birefringence between non-degenerate modes (LP01/LP11) and degenerate LP11 modes is obtained. The proposed setup can potentially be used as a c-TMF based distributed Brillouin sensor.


Genetic variants of the copy number polymorphic beta-defensin locus are associated with sporadic prostate cancer.
Prostate cancer represents the cancer with the highest worldwide prevalence in men. Chromosome 8p23 has shown suggestive genetic linkage to early-onset familial prostate cancer and is frequently deleted in cancer cells of the urogenital tract. Within this locus some beta-defensin genes (among them DEFB4, DEFB103, DEFB104) are localized, which are arranged in a gene cluster shown to exhibit an extensive copy number variation in the population. This structural variation considerably hampers genetic studies. In a new approach considering both sequence as well as copy number variations we aimed to compare the defensin locus at 8p23 in prostate cancer patients and controls. We apply PCR/cloning-based haplotyping and high-throughput copy number determination methods which allow assessment of both individual haplotypes and gene copy numbers not accessible to conventional SNP-based genotyping. We demonstrate association of four common DEFB104 haplotypes with the risk of prostate cancer in two independent patient cohorts. Moreover, we show that high copy numbers (>9) of the defensin gene cluster are significantly underrepresented in both patient samples. Our findings imply a role of the antibacterial defensins in prostate cancerogenesis qualifying distinct gene variants and copy numbers as potential tumor markers.


Urinary tract infections in adults.
Urinary tract infections remain a significant cause of morbidity in all age groups. Recent studies have helped to better define the population groups at risk for these infections, as well as the most cost-effective management strategies. Initially, a urinary tract infection should be categorized as complicated or uncomplicated. Further categorization of the infection by clinical syndrome and by host (i.e., acute cystitis in young women, acute pyelonephritis, catheter-related infection, infection in men, asymptomatic bacteriuria in the elderly) helps the physician determine the appropriate diagnostic and management strategies. Uncomplicated urinary tract infections are caused by a predictable group of susceptible organisms. These infections can be empirically treated without the need for urine cultures. The most effective therapy for an uncomplicated infection is a three-day course of trimethoprim-sulfamethoxazole. Complicated infections are diagnosed by quantitative urine cultures and require a more prolonged course of therapy. Asymptomatic bacteriuria rarely requires treatment and is not associated with increased morbidity in elderly patients.


Adolescence is characterized by more sedentary behaviour and less physical activity even among highly active forager-farmers.
Over 80% of adolescents worldwide are insufficiently active, posing massive public health and economic challenges. Declining physical activity (PA) and sex differences in PA consistently accompany transitions from childhood to adulthood in post-industrialized populations and are attributed to psychosocial and environmental factors. An overarching evolutionary theoretical framework and data from pre-industrialized populations are lacking. This cross-sectional study tests hypotheses from life history theory, that adolescent PA is inversely related to age, but this association is mediated by Tanner stage, reflecting higher and sex-specific energetic demands for growth and reproductive maturation. Detailed measures of PA and pubertal maturation are assessed among Tsimane forager-farmers (age: 7-22 years; 50% female, n = 110). Most Tsimane sampled (71%) meet World Health Organization PA guidelines (greater than or equal to 60 min/day of moderate-to-vigorous PA). Like post-industrialized populations, sex differences and inverse age-activity associations were observed. Tanner stage significantly mediated age-activity associations. Adolescence presents difficulties to PA engagement that warrant further consideration in PA intervention approaches to improve public health.


A Review of Protein Structure Prediction Using Lattice Model.
The prediction of the tertiary structure of a protein from its primary sequence is a long-standing problem for life science researchers. Solutions to this problem have a direct impact on other research areas such as design and discovery of new drugs, understanding the sequenced genomic data, solving the puzzle of protein structure, and understanding the folding mechanism. Solving protein structure prediction (PSP) is considered a cornerstone for life science research to reveal the mechanism of cellular processes; it has been an open problem for past six decades. Globally, various research institutes are working toward a solution to PSP with different methods. In this paper, we present a review of de novo PSP using hydrophobic-polar lattice model. In the hydrophobic-polar model, the PSP problem is defined as a combinatorial optimization problem with an objective of finding the protein structure having the lowest free energy. This study is bounded to two key factors. The first is application of the evolutionary search algorithms for PSP, and the second is the evolution of the modeling method and its corresponding potential energy function. The goal of this paper is to give sufficient biological background to understand the fundamentals of proteins, their structure, and available computational methods.


Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy.
The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre-existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health-related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the child's health being better, was significantly greater for the transfusion group than the observation group (difference estimate = -0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy.


A Voucher Flora of Diatoms from Fens in the Tanana River Floodplain, Alaska.
Climate change and human activities may alter the structure and function of boreal peatlands by warming waters and changing their hydrology. Diatoms can be used to assess or track these changes. However, effective biomonitoring requires consistent, reliable identification. To address this need, this study developed a diatom voucher flora of species found across a boreal fen gradient (e.g., vegetation) in interior Alaskan peatlands. Composite diatom samples were collected bi-weekly from three peatland complexes over the 2017 summer. The morphological range of each taxon was imaged. The fens contained 184 taxa across 38 genera. Eunotia (45), Gomphonema (23), and Pinnularia (20) commonly occurred in each peatland. Tabellaria was common in the rich and moderate fen but sparse in the poor fen. Eunotia showed the opposite trend. Approximately 11% of species are potentially novel and 25% percent matched those at risk or declining in status on the diatom Red List (developed in Germany), highlighting the conservation value of boreal wetlands. This voucher flora expands knowledge of regional diatom biodiversity and provides updated, verifiable taxonomic information for inland Alaskan diatoms, building on Foged's 1981 treatment. This flora strengthens the potential to effectively track changes in boreal waterways sensitive to climate change and anthropogenic stressors.


Thromboembolic complications of elective coil embolization of unruptured aneurysms: the effect of oral antiplatelet preparation on periprocedural thromboembolic complication.
We retrospectively evaluated whether antiplatelet preparation lowered the thromboembolic complication rate during the perioperative period. We reviewed 328 elective coil embolization procedures in which only microcatheters were used for coiling. No antiplatelet medication was prescribed before the procedure in 95 cases (29%, group 1), whereas antiplatelet therapy was used in 233 cases (71%, group 2; 61 [18.6%] with a single agent [aspirin or clopidogrel] and 172 [52.4%] with both agents). Antiplatelet agents were not given after coiling unless atherosclerosis, severe coil protrusion, or a thromboembolic complication occurred during the procedure. A thromboembolic complication was defined as a procedural thromboembolic event or transient ischemic attack or stroke occurring within 2 days of embolization. Thromboembolic complications occurred in 11 cases (3.4%): 6 (6.3%) in group 1 and 5 (2.1%) in group 2 (P = .085). In 195 cases (59.5%) treated by the single microcatheter technique, the risk of thromboembolic complications was low and not affected by antiplatelet preparation (1.8% [no preparation] vs 2.2% [preparation]; P = 1.000). However, in 133 cases (40.5%) treated by the multiple microcatheter technique, antiplatelet preparation significantly reduced the thromboembolic complication risk by 85.2% (12.8% [no preparation] vs 2.1% [preparation]; odds ratio, 0.148; 95% confidence interval, 0.027-0.798; P = .023). The aneurysms treated by the multiple microcatheter technique had more complex configurations for coiling (P < .001). The risk of hemorrhage was not increased by antiplatelet preparation (P = .171). Antiplatelet preparation lowered the periprocedural thromboembolic complication rate in unruptured aneurysms treated by the multiple microcatheter technique and did not increase the risk of hemorrhage. Therefore, antiplatelet preparation can help to reduce complications in patients in whom technical difficulties are expected without the risk of hemorrhage.


Normal adrenocortical response to adrenocorticotrophic hormone in patients with homozygous familial hypercholesterolaemia.
1. Plasma cortisol concentration was measured in three subjects with homozygous familial hypercholesterolaemia immediately before, and 30 and 60 min after, an intramuscular injection of adrenocorticotrophic hormone. The baseline values and the values at 30 and 60 min were within the normal range. 2. We conclude that in the presence of a genetic deficiency of low-density lipoprotein receptors, the human adrenal cortex can respond to a single injection of adrenocorticotrophic hormone with a normal increase in corticosteroid production.


Out of Asia: mitochondrial evolutionary history of the globally introduced supralittoral isopod Ligia exotica.
The native ranges and invasion histories of many marine species remain elusive due to a dynamic dispersal process via marine vessels. Molecular markers can aid in identification of native ranges and elucidation of the introduction and establishment process. The supralittoral isopod Ligia exotica has a wide tropical and subtropical distribution, frequently found in harbors and ports around the globe. This isopod is hypothesized to have an Old World origin, from where it was unintentionally introduced to other regions via wooden ships and solid ballast. Its native range, however, remains uncertain. Recent molecular studies uncovered the presence of two highly divergent lineages of L. exotica in East Asia, and suggest this region is a source of nonindigenous populations. In this study, we conducted phylogenetic analyses (Maximum Likelihood and Bayesian) of a fragment of the mitochondrial 16S ribosomal (r)DNA gene using a dataset of this isopod that greatly expanded previous representation from Asia and putative nonindigenous populations around the world. For a subset of samples, sequences of 12S rDNA and NaK were also obtained and analyzed together with 16S rDNA. Our results show that L. exotica is comprised of several highly divergent genetic lineages, which probably represent different species. Most of the 16S rDNA genetic diversity (48 haplotypes) was detected in East and Southeast Asia. Only seven haplotypes were observed outside this region (in the Americas, Hawai'i, Africa and India), which were identical or closely related to haplotypes found in East and Southeast Asia. Phylogenetic patterns indicate the L. exotica clade originated and diversified in East and Southeast Asia, and only members of one of the divergent lineages have spread out of this region, recently, suggesting the potential to become invasive is phylogenetically constrained.


Presence of clonal T cell populations in chronic B lymphocytic leukemia and smoldering myeloma.
Clonality in the non-neoplastic T cell population was investigated in 21 patients with B cell chronic leukemic (B-CLL) or multiple myeloma (MM) by probing for TCR beta chain gene rearrangements using Southern blot analysis. In three patients with a benign form of B-CLL (stage 0), and in one patient with smoldering MM, evidence was found for predominant T cell clones. As cellular immunity against the malignant cells may be important in leukemia, the results are discussed in view of the potential role of T cell immunity in B-CLL and MM.


Social media: opportunities for quality improvement and lessons for providers-a networked model for patient-centered care through digital engagement.
Social media brings a new dimension to health care for patients, providers, and their support networks. Increasing evidence demonstrates that patients who are more actively involved in their healthcare experience have better health outcomes and incur lower costs. In the field of cardiology, social media are proposed as innovative tools for the education and update of clinicians, physicians, nurses, and medical students. This article reviews the use of social media by healthcare providers and patients and proposes a model of "networked care" that integrates the use of digital social networks and platforms by both patients and providers and offers recommendations for providers to optimize their use and understanding of social media for quality improvement.


trans-Cinnamaldehyde Inhibits Microglial Activation and Improves Neuronal Survival against Neuroinflammation in BV2 Microglial Cells with Lipopolysaccharide Stimulation.
Microglial activation contributes to neuroinflammation and neuronal damage in neurodegenerative disorders including Alzheimer's and Parkinson's diseases. It has been suggested that neurodegenerative disorders may be improved if neuroinflammation can be controlled. trans-cinnamaldehyde (TCA) isolated from the stem bark of Cinnamomum cassia possesses potent anti-inflammatory capability; we thus tested whether TCA presents neuroprotective effects on improving neuronal survival by inhibiting neuroinflammatory responses in BV2 microglial cells. To determine the molecular mechanism behind TCA-mediated neuroprotective effects, we assessed the effects of TCA on lipopolysaccharide- (LPS-) induced proinflammatory responses in BV2 microglial cells. While LPS potently induced the production and expression upregulation of proinflammatory mediators, including NO, iNOS, COX-2, IL-1β, and TNF-α, TCA pretreatment significantly inhibited LPS-induced production of NO and expression of iNOS, COX-2, and IL-1β and recovered the morphological changes in BV2 cells. TCA markedly attenuated microglial activation and neuroinflammation by blocking nuclear factor kappa B (NF-κB) signaling pathway. With the aid of microglia and neuron coculture system, we showed that TCA greatly reduced LPS-elicited neuronal death and exerted neuroprotective effects. Our results suggest that TCA, a natural product, has the potential of being used as a therapeutic agent against neuroinflammation for ameliorating neurodegenerative disorders.


10 x 112Gb/s PDM-QPSK transmission over 5032 km in few-mode fibers.
Few-mode fibers (FMFs) are used for the first time to transmit over 5000 km. Ten WDM channels with 50GHz channel spacing at 112 Gb/s per channel using PDM-QPSK are launched into the fundamental mode of the FMFs by splicing single-mode fibers directly to the FMFs. Even though few-mode fibers can support an additional spatial mode LP(11) at 1550 nm, the signal remains in the fundamental mode and does not experience mode coupling throughout fiber transmission. After each span the signal is collected by a second single-mode fiber which is also spliced to the FMF. Span loss is compensated by single-mode EDFAs before it is launched to the next FMF span. The lack of mode coupling ensures that the signal does not suffer any impairments that may result from differential mode delay or excess loss. Therefore the FMFs used in this "single-mode operation" have the same bandwidth as single-mode fibers. Experimental results verified that FMFs have the significant advantage of large core size which reduces the nonlinear impairments suffered by the signal. It is shown that FMFs with an effective area of 130 μm(2), have an optimum launch power 2 dB higher compared to standard single-mode fibers and as a result a 1.1 dB improvement in the Q-factor is obtained after 3000 km.


Experiences of accessing and using breast cancer services in Vietnam: a descriptive qualitative study.
To understand, describe and analyse the experiences of women with breast cancer in Vietnam when accessing and using breast cancer services. Descriptive qualitative study. Women were interviewed about their experiences from the first time they became aware of symptoms or changes to their body through treatment and post-treatment. This study is the first descriptive study on breast cancer in Vietnam from the perspective of women with a breast cancer diagnosis. Women (n=13) who had completed or were still receiving treatment for breast cancer, purposively recruited from the north and south of Vietnam. An analysis of the experiences of women with breast cancer in Vietnam revealed a lack of awareness and knowledge about breast cancer and symptoms. Family and social support were described as key factors influencing whether a woman accesses and uses breast cancer services. Cost of treatment and out-of-pocket expenditures limited access to services and resulted in significant financial challenges for women and their families. Vietnam has made huge strides in improving cancer care, and is tackling a complex and expanding public health challenge, however, there are a number of areas requiring strengthening and future research. While Vietnam has successfully expanded social health insurance coverage, changes that increase the percentage of costs covered for specific treatments, such as chemotherapy or radiotherapy, could benefit women and their families.


The importance of DNA methylation in prostate cancer development.
After briefly reviewing the nature of DNA methylation, its general role in cancer and the tools available to interrogate it, we consider the literature surrounding DNA methylation as relating to prostate cancer. Specific consideration is given to recurrent alterations. A list of frequently reported genes is synthesized from 17 studies that have reported on methylation changes in malignant prostate tissue, and we chart the timing of those changes in the diseases history through amalgamation of several previously published data sets. We also review associations with genetic alterations and hormone signalling, before the practicalities of investigating prostate cancer methylation using cell lines are assessed. We conclude by outlining the interplay between DNA methylation and prostate cancer metabolism and their regulation by androgen receptor, with a specific discussion of the mitochondria and their associations with DNA methylation.


Building Complex Kondo Impurities by Manipulating Entangled Spin Chains.
The creation of molecule-like structures in which magnetic atoms interact controllably is full of potential for the study of complex or strongly correlated systems. Here, we create spin chains in which a strongly correlated Kondo state emerges from magnetic coupling of transition-metal atoms. We build chains up to ten atoms in length by placing Fe and Mn atoms on a Cu2N surface with a scanning tunneling microscope. The atoms couple antiferromagnetically via superexchange interaction through the nitrogen atom network of the surface. The emergent Kondo resonance is spatially distributed along the chain. Its strength can be controlled by mixing atoms of different transition metal elements and manipulating their spatial distribution. We show that the Kondo screening of the full chain by the electrons of the nonmagnetic substrate depends on the interatomic entanglement of the spins in the chain, demonstrating the prerequisites to build and probe spatially extended strongly correlated nanostructures.


Haloperidol-associated stealth liposomes: a potent carrier for delivering genes to human breast cancer cells.
Sigma receptors are membrane-bound proteins that are overexpressed in certain human malignancies including breast cancer. These receptors show very high affinity for various sigma ligands including neuroleptics like haloperidol. We hypothesized that in associating haloperidol-linked lipid into the cationic lipid-DNA complex, we can specifically target and deliver genes to breast cancer cells that overexpress sigma receptors. In the present study, haloperidol was chemically modified to conjugate at the distal end of the polyethylene glycollinked phospholipid, which was then incorporated into the cationic liposome known to condense and deliver genes inside cells. The resulting haloperidol-conjugated targeted lipoplex showed at least 10-fold higher (p < 0.001) reporter gene expression in MCF-7 cells than control lipoplex. The reporter gene expression of the targeted lipoplex was significantly blocked by haloperidol (p < 0.001) and by another sigma ligand, 1,3-ditolylguanidine (p < 0.001) in the majority of cationic lipid to DNA charge ratios (+/-). Spironolactone-mediated sigma receptor down-regulation enabled MCF-7 to show 10-fold lower transgene expression with targeted lipoplex compared with that obtained in spironolactone-untreated cells. The targeted lipoplex generated nonspecific gene expression in sigma receptor-nonexpressing human cancer cells such as Hela, KB, HepG2, and Chinese hamster ovary cells. Moreover, the transgene expression remained unabated in physiologically relevant serum concentrations. This is the first study to demonstrate that haloperidol-targeted gene delivery systems can mediate efficient targeting of genes to sigma receptor-overexpressing breast cancer cells, thereby becoming a novel class of therapeutics for the treatment of human cancers.


Evolution of Protein Domain Architectures.
This chapter reviews current research on how protein domain architectures evolve. We begin by summarizing work on the phylogenetic distribution of proteins, as this will directly impact which domain architectures can be formed in different species. Studies relating domain family size to occurrence have shown that they generally follow power law distributions, both within genomes and larger evolutionary groups. These findings were subsequently extended to multi-domain architectures. Genome evolution models that have been suggested to explain the shape of these distributions are reviewed, as well as evidence for selective pressure to expand certain domain families more than others. Each domain has an intrinsic combinatorial propensity, and the effects of this have been studied using measures of domain versatility or promiscuity. Next, we study the principles of protein domain architecture evolution and how these have been inferred from distributions of extant domain arrangements. Following this, we review inferences of ancestral domain architecture and the conclusions concerning domain architecture evolution mechanisms that can be drawn from these. Finally, we examine whether all known cases of a given domain architecture can be assumed to have a single common origin (monophyly) or have evolved convergently (polyphyly). We end by a discussion of some available tools for computational analysis or exploitation of protein domain architectures and their evolution.


Cloning and characterization of DNA polymerase eta from Trypanosoma cruzi: roles for translesion bypass of oxidative damage.
We report the cloning and characterization of the DNA polymerase eta gene from Trypanosoma cruzi (TcPoleta), the causative agent of Chagas disease. This protein, which can bypass cyclobutane pyrimidine dimers, contains motifs that are conserved between Y family polymerases. In vitro assays showed that the recombinant protein is capable of synthesizing DNA in undamaged primer-templates. Intriguingly, T. cruzi overexpressing TcPoleta does not increase its resistance to UV-light (with or without caffeine) or cisplatin, despite the ability of the protein to enhance UV resistance in a RAD30 mutant of Saccharomyces cerevisiae. Parasites overexpressing TcPoleta are also unable to restore growth after treatment with zeocin or gamma irradiation. T. cruzi overexpressing TcPoleta are more resistant to treatment with hydrogen peroxide (H(2)O(2)) compared to nontransfected cells. The observed H(2)O(2) resistance could be associated with its ability to bypass 8-oxoguanine lesions in vitro. The results presented here suggest that TcPoleta is able to bypass UV and oxidative lesions. However the overexpression of the gene only interferes in response to oxidative lesions, possibly due to the presence of these lesions during the S phase.


Occipital ganglio-neuroblastoma in an adult.
Ganglioneuroblastomas (GNBs) are embryonic neoplasms, whose behaviour are not well established; 80% of cases occur in the first decade, while only two cases in the adulthood had been reported. This 60-year-old female presented with a 2-month history of headache, vertigo, amnesia. A right brachio-crural hemiparesis, right homonymous hemianopsia and sensorial dysphasia was evident. A CT scan revealed a left occipital lesion. MRI scan was not performed because the patient had an anal sphincter stimulator. Three years before thyroidectomy for a follicular carcinoma was performed. A total body CT scan was negative. A left occipital craniotomy was carried out and a solid mass was totally excised. A diagnosis of GNB was made from histopathological examination and immunohistochemistry. Post-operatively the patient recovered from the hemiparesis while the visual disturbances persisted. She underwent fractioned radiotherapy (60 Gy) and chemotherapy with Temozolomide. She remained disease free 18 months after diagnosis. A CT scan showed no evidence of recurrence. Recent observations suggest that in spite of an embryonal appearance, these tumours are circumscribed and have a better prognosis than malignant gliomas.


The effect of injection therapy and operation of coccydynia on the schooling and physical activity of adolescent patients.
Pain while sitting is the most common complaint among patients with Coccydynia. In young patients this may seriously affect their schooling which usually involves long periods of sitting. We studied if this improved after either injection therapy or surgery. During a seven-year period 32 adolescents with a mean age of 15 (range: 11-17) years were treated in our department because of coccydynia. They were followed up with mailed questionnaires at a minimum of 12 months after treatment and 28 (88%) responded. Three were no longer attending school and were excluded. Of the remainder, 12 received only injection therapy while 13 were operated upon. Mean follow-up time was 36 (14-66) months. Eight reported absence from school during the month before treatment, but only one during the week before review (pÃ0.01). There was significant improvement in sitting during class and physical exercise at school and when engaging in general sports (pÃ0.01). We can not exclude that improvements would have occurred spontaneously, but this seems unlikely as symptoms had persisted for more than two years before treatment. We conclude that in juveniles, an additional benefit of treating coccydynia with corticosteroid injection or operative resection is that their ability to attend school and take part in sports improves significantly.


Air Pollution and Neuropsychological Development: A Review of the Latest Evidence.
For the last decade, literature on the detrimental impacts of air pollution on brain, cognition and behavior has exponentially increased. Our aim is to review the latest epidemiologic literature on the association between outdoor air pollution and neuropsychological developmental in children. Two independent researchers searched for published studies between January 1, 2012 and June 12, 2015 in MEDLINE, Web of Science, and Science direct using defined keywords on outdoor air pollution and neuropsychological development. Selection of articles was based on study eligibility criteria. We encountered sufficient evidence of detrimental effects of pre- or postnatal exposure to polycyclic aromatic hydrocarbons on global intelligence quotient. The evidence was also sufficient for the association between pre- or postnatal exposure to fine particulate matter (PM2.5) and autism spectrum disorder, and limited evidence was encountered between nitrogen oxides and autism spectrum disorder. For other exposure-outcome associations reviewed, the evidence was inadequate or insufficient. Although evidence is not yet conclusive and further research is needed, the latest epidemiological studies support the hypothesis that pre- or postnatal exposure to ambient pollution, particularly polycyclic aromatic hydrocarbons, PM2.5, and nitrogen oxides has a negative impact on the neuropsychological development of children. The public health impact of air pollutants cannot be ignored and the precautionary principle should be applied to protect children.


Controlled exposures to air pollutants and risk of cardiac arrhythmia.
Epidemiological studies have reported associations between air pollution exposure and increases in cardiovascular morbidity and mortality. Exposure to air pollutants can influence cardiac autonomic tone and reduce heart rate variability, and may increase the risk of cardiac arrhythmias, particularly in susceptible patient groups. We investigated the incidence of cardiac arrhythmias during and after controlled exposure to air pollutants in healthy volunteers and patients with coronary heart disease. We analyzed data from 13 double-blind randomized crossover studies including 282 participants (140 healthy volunteers and 142 patients with stable coronary heart disease) from whom continuous electrocardiograms were available. The incidence of cardiac arrhythmias was recorded for each exposure and study population. There were no increases in any cardiac arrhythmia during or after exposure to dilute diesel exhaust, wood smoke, ozone, concentrated ambient particles, engineered carbon nanoparticles, or high ambient levels of air pollution in either healthy volunteers or patients with coronary heart disease. Acute controlled exposure to air pollutants did not increase the short-term risk of arrhythmia in participants. Research employing these techniques remains crucial in identifying the important pathophysiological pathways involved in the adverse effects of air pollution, and is vital to inform environmental and public health policy decisions.


Sodium/proton antiporter in the euryhaline crab Carcinus maenas: molecular cloning, expression and tissue distribution.
Gill epithelial cells of euryhaline crustaceans demonstrate net inward transport of sodium ions, possibly via apical Na+/H+ antiporters, Na+/K+/2Cl- cotransporters or Na+ channels working in series with the basolateral Na(+) + K(+)-ATPase. We have identified and sequenced the cDNA coding for a crustacean Na+/H+ antiporter, starting with mRNA isolated from gills of the euryhaline green shore crab Carcinus maenas. The complete 2595-base-pair cDNA includes an open reading frame coding for a 673-amino-acid protein. A search of GenBank revealed more than 20 high-scoring matches, all Na+/H+ antiporter sequences from mammalian, amphibian, teleost and nematode species. Injection of Xenopus laevis oocytes with cRNA transcribed from the cloned crab sequence substantially enhanced Na(+)-dependent H+ efflux from the oocytes. Analysis of crab tissue antiporter mRNA levels by semi-quantitative reverse transcription-polymerase chain reaction revealed that posterior and anterior gills of Carcinus maenas expressed this antiporter the most strongly, followed in decreasing order by skeletal muscle, hepatopancreas, hypodermis and heart. Hydropathy and transmembrane alpha-helix analysis suggested a 10-helix membrane-spanning topology of the antiporter protein. It is clear from this study that Carcinus maenas gills vigorously transcribe a gene coding for a Na+/H+ antiporter. Whether these gills also express a gene coding for an epithelial Na+ channel or Na+/K+/2Cl- cotransporter remains to be demonstrated.


SU-E-T-10: Monte Carlo Study of the Dose Enhancement Factor (DEF) for Gold Nano-Particle (GNP) on the Cellular Level.
In megavoltage external beam radiotherapy, in vivo cell experiments suggest GNP could be used as a radiosensitizer by having radiation dose enhancement factor (DEF) significantly larger than 1. However, Monte Carlo (MC) simulations published in the literature failed to give prove, in which most of them only simulated the interactions between the radiation beams and a single GNP. In this study, we built a multi-GNPs model considering possible spatial arrangements of GNPs relative to a cell to calculate the DEFs of GNPs. Geant4 MC code with G4DNA physics model which can trace electrons down to eV level was used. Two types of geometry models representing different GNP-cell binding were created with each GNP modeled individually: (1) shell model with GNPs randomly and sparsely distributed in a shell in water mimicking when the GNPs were binding to the cell membrane, and (2) sphere model with GNPs randomly and sparsely distributed in a sphere in water mimicking when GNPs were floating inside the cytoplasm. Photon and electron spectrum at 5 cm in depth in water from a Varian 6MV beam was used as the radiation source. Dose to water inside the shell or the sphere representing cytoplasm were scored and compared to situations without GNPs to calculate the DEF. We also looked into the variation of DEFs due to different GNP sizes and concentrations. A 35 um water cubic were successfully built in Geant4 with spatial resolution of 100 nm. Preliminary results shown under 200 keV electron irradiation, 100 nm GNPs in the shell model shown increased dose to cell at the beam entrance (DEF = 1.08). The computation is undergoing for different GNP sizes and concentrations. Meaningful results are expected on the completion of this study.


Influence of phthalates on cytokine production in monocytes and macrophages: a systematic review of experimental trials.
Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which could affect both pro- and anti-inflammatory abilities of these cells. A systematic search was performed in Medline, Embase and Toxline in June 2013, last updated 3rd of August 2014. Criteria used to select studies were described and published beforehand online on Prospero (http://www.crd.york.ac.uk/NIHR_PROSPERO, registration number CRD42013004236). In vivo, ex vivo and in vitro studies investigating the influence of phthalates on cytokine mRNA expression and cytokine secretion in animals and humans were included. A total of 11 reports, containing 12 studies, were found eligible for inclusion. In these, a total of four different phthalate diesters, six primary metabolites (phthalate monoesters) and seven different cytokines were investigated. Though all studies varied greatly in study design and species sources, four out of five studies that investigated di-2-ethylhexyl phthalate found an increased tumour necrosis factor-α secretion/production from monocytes or macrophages. A summary of cytokine measurements was not possible since few studies were comparable in study design and due to insufficient reporting of raw data for most of the included studies. Results from this review have suggested that at least one phthalate (di-2-ethylhexyl phthalate) has the ability to enhance tumour necrosis factor-α production/secretion from monocytes/macrophages in vitro, but also observed ex vivo. Influence of other phthalates on other cytokines has only been investigated in few studies. Thus, in vitro studies on primary human monocytes/macrophages as well as more in vivo studies are needed to confirm or dispute these findings.


Carers' Motivations for, and Experiences of, Participating in Suicide Research.
(1) Background: First-hand accounts of lived experience of suicide remain rare in the research literature. Increasing interest in the lived experience of suicide is resulting in more opportunities for people to participate in research based on their personal experience. How individuals choose to participate in research, and their experience of doing so, are important considerations in the ethical conduct of research. (2) Methods: To understand the experience of providing care for someone who has previously attempted suicide, a cross-sectional online community survey was conducted. This survey concluded with questions regarding motivation to participate and the experience of doing so. Of the 758 individuals who participated in the survey, 545 provided open-ended text responses to questions regarding motivation and 523 did so for questions regarding the experience of participating. It is these responses that are the focus of this paper. Data were analysed thematically. (3) Results: Motivations to participate were expressed as primarily altruistic in nature, with a future focus on improving the experience of the person who had attempted suicide alongside carers to ease distress. The experience of participating was difficult yet manageable, for all but a few participants. (4) Conclusions: With the increasing interest in first-hand accounts of suicide, how individuals experience participation in research is an important focus that requires further attention.


Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology.
TH is a tetrahydrobiopterin-requiring, iron-containing monooxygenase. It catalyses the conversion of L-tyrosine to L-dopa, which is the first, rate-limiting step in the biosynthesis of catecholamines (dopamine, noradrenaline and adrenaline), the central and sympathetic neurotransmitters and adrenomedullary hormones. The cofactor of TH is tetrahydrobiopterin, which is synthesized from GTP in three steps. The TH gene consists of 14 exons only in humans and 13 exons in animals. Human TH exists in four isoforms (hTH1-4) that are produced by alternative mRNA splicing from a single gene. A single mRNA and protein corresponding to hTH1 exists in non-primates. Monkey TH exists in two isoforms, corresponding to hTH1 and hTH2. TH activity is regulated in the short term by feedback inhibition of catecholamines in competition with tetrahydrobiopterin, and by activation and deactivation due to phosphorylation and dephosphorylation, mainly at Ser-19 and Ser-40 of hTH1. The multiple TH isoforms in humans and monkeys have additional phosphorylation, resulting in more subtle regulation. In long-term regulation under stress conditions, TH protein is induced. CRE and AP1 in the 5' flanking region of the TH gene may be the main functional elements for TH gene expression. TH may be closely related to the pathogenesis of neurological diseases, such as dystonia and Parkinson's disease, psychiatric diseases, such as affective disorders and schizophrenia, as well as cardiovascular diseases. The TH gene may prove useful in gene therapy to compensate for decreased levels of catecholamines in neurological diseases, for example, for supplementation of dopamine in Parkinson's disease.