Relationship between serum bilirubin levels, urinary biopyrrin levels, and retinopathy in patients with diabetes.
Previous reports have indicated that serum bilirubin levels may be associated with diabetic retinopathy. However, the detailed mechanism is not fully understood. In this study, we evaluated the relationship between the severity of diabetic retinopathy and various factors including bilirubin levels and factors influencing bilirubin metabolism. The study participants consisted of 94 consecutive patients with diabetes mellitus admitted to Kyushu University Hospital from April 2011 to July 2012. The patients were classified into three groups: no retinopathy (NDR), simple retinopathy (SDR), and pre-proliferative or proliferative retinopathy (PDR). The relationship between the severity of retinopathy and various factors was evaluated using univariate and logistic regression analyses. In addition, multivariate regression analysis was performed to evaluate the significant determinants for bilirubin levels. In univariate analysis, a significant difference was found among NDR, SDR and PDR in bilirubin levels, duration of diabetes, systolic blood pressure, and macroalbuminuria. Logistic regression analysis showed that PDR was significantly associated with bilirubin levels, duration of diabetes, and systolic blood pressure (OR 0.737, 95% CI 0.570-0.952, P = 0.012; OR 1.085, 95% CI 1.024-1.149, P = 0.006; OR 1.036, 95% CI 1.011-1.062, P = 0.005, respectively). In turn, multivariate regression analysis showed that bilirubin levels were negatively associated with high-sensitivity C-reactive protein levels and PDR, but positively correlated with urinary biopyrrin levels, oxidized metabolites of bilirubin. PDR was negatively associated with bilirubin levels. This negative association may be due to a decreased production of bilirubin rather than its increased consumption considering the positive association between bilirubin and biopyrrin levels.


Translocation and assembly of mitochondrially coded Saccharomyces cerevisiae cytochrome c oxidase subunit Cox2 by Oxa1 and Yme1 in the absence of Cox18.
Members of the Oxa1/YidC/Alb3 family of protein translocases are essential for assembly of energy-transducing membrane complexes. In Saccharomyces cerevisiae, Oxa1 and its paralog, Cox18, are required for assembly of Cox2, a mitochondrially encoded subunit of cytochrome c oxidase. Oxa1 is known to be required for cotranslational export of the Cox2 N-terminal domain across the inner mitochondrial membrane, while Cox18 is known to be required for post-translational export of the Cox2 C-tail domain. We find that overexpression of Oxa1 does not compensate for the absence of Cox18 at the level of respiratory growth. However, it does promote some translocation of the Cox2 C-tail domain across the inner membrane and causes increased accumulation of Cox2, which remains unassembled. This result suggests that Cox18 not only translocates the C-tail, but also must deliver it in a distinct state competent for cytochrome oxidase assembly. We identified respiring mutants from a cox18Delta strain overexpressing OXA1, whose respiratory growth requires overexpression of OXA1. The recessive nuclear mutations allow some assembly of Cox2 into cytochrome c oxidase. After failing to identify these mutations by methods based on transformation, we successfully located them to MGR1 and MGR3 by comparative hybridization to whole-genome tiling arrays and microarray-assisted bulk segregant analysis followed by linkage mapping. While Mgr1 and Mgr3 are known to associate with the Yme1 mitochondrial inner membrane i-AAA protease and to participate in membrane protein degradation, their absence does not appear to stabilize Cox2 under these conditions. Instead, Yme1 probably chaperones the folding and/or assembly of Oxa1-exported Cox2 in the absence of Mrg1 or Mgr3, since respiratory growth and cytochrome c oxidase assembly in a cox18 mgr3 double-mutant strain overexpressing OXA1 is YME1 dependent.


[Study of the cultured human endothelial cells infected by epidemic hemorrhagic fever virus].
Virus antigen could be detected in the cytoplasm of infected human endothelial cells (HEC) by immunofluorescent assay (IFA) 2 to 10 days after the inoculation of epidemic hemorrhagic fever virus (EHFV), but no apparent histologic changes could be found by phase contrast light microscopy, as well as no mature virus particles could be detected under the transmission electron microscope. Reinoculation of the freeze-melt supernatant of HEC 8 days after the inoculation of EHFV to EHFV susceptible Vero E-6 cells, viral antigen could be detected in most of these cells and mature EHFV particles or viral inclusion bodies could also be obtained in the cytoplasm under transmission electron microscope. The results show that HEC is a susceptible target cell to EHFV and infection by this virus may not give apparent cytopathogenic effect in HEC.


Pharmacological interventions for pruritus in adult palliative care patients.
Pruritus is not the most prevalent but one of the most puzzling symptoms in palliative care patients. It can cause considerable discomfort and has a major impact on patients' quality of life. In the field of palliative care, pruritus is a symptom occurring in patients with disparate underlying diseases and based on different pathologic mechanisms but ending in the same phenomenon. The pathogenesis of pruritus is complex and not fully elucidated. Thus, it is still very difficult to treat pruritus effectively. Evidence-based treatment approaches are needed. The objective was to evaluate the efficacy of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. A systematic literature search up to January 2012 was performed and it was updated in August 2012. The following databases were searched: The Cochrane Library (CENTRAL, DARE, CDSR) (2012, issue 8 of 12); MEDLINE (1950 to August 2012); EMBASE (1980 to August 2012) and three other databases. In addition, we searched trials registries and checked the reference lists of all relevant studies, key textbooks, reviews, and websites, and contacted investigators and specialists in pruritus and palliative care regarding unpublished data. We included randomised controlled trials assessing the effects of different pharmacological treatments on preventing or treating pruritus in palliative care patients. Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies, data extraction, assessment of risk of bias and methodological quality. Results were summarised descriptively according to the different pharmacological interventions and the type of underlying pruritus. Where possible, results were presented in meta-analyses. In total, 38 reports comprising 40 studies and 1286 participants were included in the review. Altogether, 30 different treatments for pruritus in four different patient groups were included.The findings of this review indicated that the treatment of pruritus for palliative care patients is challenging and requires an individualistic approach. Results showed that effective therapeutic choices have to be guided by the pathophysiology of the pruritus. Various forms of pruritus occur, especially in the field of palliative care, and sometimes the origin of the pruritus is difficult to determine. Therefore, identifying the underlying cause of pruritus is of prime importance in order to develop tailored treatment plans, even if in palliative care the treatment is focused towards the symptom and not necessarily the underlying disease.Results show that in palliative care patients with pruritus of different natures, treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, may be beneficial. For patients suffering from pruritus associated with HIV infection, indomethacin was described as the most effective drug, although the evidence was weak. For patients suffering from chronic kidney disease-associated pruritus, gabapentin may be an option. An alternative treatment for this patient group seems to be the κ-opioid receptor agonist nalfurafine, which has shown significant amelioration of pruritus and acceptable adverse effects. As they have exhibited a low incidence of adverse effects, rifampicin and flumecinol may be recommended for patients with cholestatic pruritus. The opioid antagonist naltrexone has been shown to offer a therapeutic alternative for patients suffering from uraemic or cholestatic pruritus. However, these drugs are often inappropriate in the palliative population because of the risk of reducing analgesia when giving high doses of naltrexone. The findings of this review indicate that the number of systemic and topical drugs used for the different subforms of pruritus is increasing. Different interventions have been shown to be effective in the treatment of pruritus of different origins. Nevertheless, an optimal therapy for pruritus is constrained due to the limited understanding of crucial itch mediators and receptors in the various subforms of itch. Ideal antipruritic therapies are still lacking, especially for palliative care patients.This systematic review also indicates that there is insufficient evidence to give any concrete recommendations regarding treatment of pruritus in palliative care patients. Due to the very small sample sizes and poor methodological quality of the majority of studies that were included, the results of this review need to be interpreted with caution. Furthermore, the generalizability is questionable. Additional studies, and particularly carefully designed treatment trials, are needed to provide valid evidence for adequate treatment of pruritus in palliative care patients.


Urinary complications of cyclophosphamide therapy: etiology, prevention, and management.
Cyclophosphamide is a well established cytotoxic drug used in the treatment of lymphoproliferative disorders, certain solid tumors, and nonneoplastic disorders such as the nephrotic syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Hemorrhagic cystitis can be a complication of this drug in from 2% to 40% of patients so treated. At times, the hemorrhage may be severe, protracted, and life-threatening. Cyclophosphamide therapy has also been implicated as the causative agent in 32 cases of carcinoma of the bladder and three cases of carcinoma of the renal pelvis.


Unusually delayed presentation of persistent Descemet's membrane tear and detachment after cataract surgery.
A 51-year-old male who had undergone phacoemulsification in his left eye 11 months prior presented with complaint of sudden onset of blurred vision in the same eye. Review of his clinical course, slit-lamp exam, pachymetry, and specular endothelial microscopy led to the diagnosis of acute hydrops caused by Descemet's membrane dehiscence at the site of the incision. He was initially managed with medical treatment and observation. In the subsequent months of follow-up, the corneal edema and the patient's visual acuity did not improve. Intracameral gas injection was performed 7 months after presentation, but because of persistent corneal edema and nonattached Descemet's membrane, penetrating keratoplasty was performed. Histopathologic examination confirmed the diagnosis. The patient has had a clear corneal graft since then. Although Descemet's membrane detachment is a rather common complication after intraocular surgery, its unusually delayed presentation can also occur, and should not be confused with pseudophakic bullous keratopathy. Many mechanisms have been studied for the development of early tears and detachments after cataract surgery, but little is known about late presentations. The authors explore possible causes, and highlight the importance of instructing patients to avoid eye rubbing and any other type of trauma to the cornea after intraocular surgery.


ushr: Understanding suppression of HIV in R.
HIV/AIDS is responsible for the deaths of one million people every year. Although mathematical modeling has provided many insights into the dynamics of HIV infection, there is still a lack of accessible tools for researchers unfamiliar with modeling techniques to apply them to their own clinical data. Here we present ushr, a free and open-source R package that models the decline of HIV during antiretroviral treatment (ART) using a popular mathematical framework. ushr can be applied to longitudinal data of viral load measurements, and provides processing tools to prepare it for computational analysis. By mathematically fitting the data, important biological parameters can then be estimated, including the lifespans of short and long-lived infected cells, and the time to reach viral suppression below a defined detection threshold. The package also provides visualization and summary tools for fast assessment of model results. ushr enables researchers without a strong mathematical or computational background to model the dynamics of HIV using longitudinal clinical data. Increasing accessibility to such methods may facilitate quantitative analysis across a broader range of independent studies, so that greater insights on HIV infection and treatment dynamics may be gained.


A Valid and Precise Semiautomated Method for Quantifying Intermuscular Fat Intramuscular Fat in Lower Leg Magnetic Resonance Images.
The accumulation of INTERmuscular fat and INTRAmuscular fat (IMF) has been a hallmark of individuals with diabetes, those with mobility impairments such as spinal cord injuries and is known to increase with aging. An elevated amount of IMF has been associated with fractures and frailty, but the imprecision of IMF measurement has so far limited the ability to observe more consistent clinical associations. Magnetic resonance imaging has been recognized as the gold standard for portraying these features, yet reliable methods for quantifying IMF on magnetic resonance imaging is far from standardized. Previous investigators used manual segmentation guided by histogram-based region-growing, but these techniques are subjective and have not demonstrated reliability. Others applied fuzzy classification, machine learning, and atlas-based segmentation methods, but each is limited by the complexity of implementation or by the need for a learning set, which must be established each time a new disease cohort is examined. In this paper, a simple convergent iterative threshold-optimizing algorithm was explored. The goal of the algorithm is to enable IMF quantification from plain fast spin echo (FSE) T1-weighted MR images or from water-saturated images. The algorithm can be programmed into Matlab easily, and is semiautomated, thus minimizing the subjectivity of threshold-selection. In 110 participants from 3 cohort studies, IMF area measurement demonstrated a high degree of reproducibility with errors well within the 5% benchmark for intraobserver, interobserver, and test-retest analyses; in contrast to manual segmentation which already yielded over 20% error for intraobserver analysis. This algorithm showed validity against manual segmentations (r > 0.85). The simplicity of this technique lends itself to be applied to fast spin echo images commonly ordered as part of standard of care and does not require more advanced fat-water separated images.


Suicidal ideation in treatment-seeking Veterans of Operations Enduring Freedom and Iraqi Freedom: the role of coping strategies, resilience, and social support.
Recent epidemiologic studies have found an increased risk of suicide among Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF-OIF) with psychiatric disorders. However, little is known about whether variables other than psychiatric conditions, such as coping strategies, resilience, and social support, may be related to suicidality in this population. A total of 167 OEF-OIF Veterans seeking behavioral or primary care services completed a survey containing measures of combat exposure, psychopathology, pain, psychological resilience, social support, and cognitive coping strategies. Thirty-six respondents (21.6%) reported contemplating suicide in the two weeks prior to completing the survey. Compared to suicide non-contemplators, suicide contemplators were older, and more likely to screen positive for depression and posttraumatic stress disorder (PTSD), and to report a deployment-related pain condition or complaint. They also scored higher on measures of worry, self-punishment, and cognitive-behavioral avoidance strategies, and lower on measures of psychological resilience and postdeployment social support. Multivariate analysis revealed that a positive depression screen, and higher scores on measures of self-punishment and cognitive-social avoidance coping were positively associated with suicidal ideation, while higher scores on measures of psychological resilience (i.e., positive acceptance of change) were negatively related to suicidal ideation. Moderator analysis revealed that a positive screen for depression or PTSD significantly diminished the protective effect of postdeployment social support on suicidal ideation. 1 in 5 treatment-seeking OEF-OIF Veterans may contemplate suicide. Interventions to reduce depressive symptoms, and maladaptive cognitive-behavioral coping strategies of self-punishment and cognitive social avoidance, and to bolster psychological resilience may help mitigate suicidality in this population.


Anti-neuroinflammatory properties of synthetic cryptolepine in human neuroblastoma cells: possible involvement of NF-κB and p38 MAPK inhibition.
Cryptolepis sanguinolenta and its bioactive alkaloid, cryptolepine have shown anti-inflammatory activity. However, the underlying mechanism of anti-inflammatory action in neuronal cells has not been investigated. In the present study we evaluated an extract of C. sanguinolenta (CSE) and cryptolepine (CAS) on neuroinflammation induced with IL-1β in SK-N-SH neuroblastoma cells. We then attempted to elucidate the mechanisms underlying the anti-neuroinflammatory effects of CAS in SK-N-SH cells. Cells were stimulated with 10 U/ml of IL-1β in the presence or absence of different concentrations of CSE (25-200 μg/ml) and CAS (2.5-20 μM). After 24 h incubation, culture media were collected to measure the production of PGE2 and the pro-inflammatory cytokines (TNFα and IL-6). Protein and gene expressions of cyclooxygenase (COX-2) and microsomal prostaglandin synthase-1 (mPGES-1) were studied by immunoblotting and qPCR, respectively. CSE produced significant (p < 0.05) inhibition of TNFα, IL-6 and PGE2 production in SK-N-SH cells. Studies on CAS showed significant and dose-dependent inhibition of TNFα, IL-6 and PGE2 production in IL-1β-stimulated cells without affecting viability. Pre-treatment with CAS (10 and 20 μM) was also found to inhibit IL-1β-induced protein and gene expressions of COX-2 and mPGES-1. Further studies to determine the mechanism of action of CAS showed inhibition of NF-κBp65 nuclear translocation, but not IκB phosphorylation. At 10 and 20 μM, CAS inhibited IL-1β-induced phosphorylation of p38 MAPK. Studies on the downstream substrate of p38, MAPK-activated protein kinase 2 (MAPKAPK2) showed that CAS produced significant (p < 0.05) and dose dependent inhibition of MAPKAPK2 phosphorylation in IL-1β-stimulated SK-N-SH cells. This study clearly shows that cryptolepine (CAS) inhibits neuroinflammation through mechanisms involving inhibition of COX-2 and mPGES-1. It is suggested that these actions are probably mediated through NF-κB and p38 signalling.


Evaluation of a fast implicit solvent model for molecular dynamics simulations.
A solvation term based on the solvent accessible surface area (SASA) is combined with the CHARMM polar hydrogen force field for the efficient simulation of peptides and small proteins in aqueous solution. Only two atomic solvation parameters are used: one is negative for favoring the direct solvation of polar groups and the other positive for taking into account the hydrophobic effect on apolar groups. To approximate the water screening effects on the intrasolute electrostatic interactions, a distance-dependent dielectric function is used and ionic side chains are neutralized. The use of an analytical approximation of the SASA renders the model extremely efficient (i.e., only about 50% slower than in vacuo simulations). The limitations and range of applicability of the SASA model are assessed by simulations of proteins and structured peptides. For the latter, the present study and results reported elsewhere show that with the SASA model it is possible to sample a significant amount of folding/unfolding transitions, which permit the study of the thermodynamics and kinetics of folding at an atomic level of detail.


In silico approaches and the role of ontologies in aging research.
The 2013 Rostock Symposium on Systems Biology and Bioinformatics in Aging Research was again dedicated to dissecting the aging process using in silico means. A particular focus was on ontologies, because these are a key technology to systematically integrate heterogeneous information about the aging process. Related topics were databases and data integration. Other talks tackled modeling issues and applications, the latter including talks focused on marker development and cellular stress as well as on diseases, in particular on diseases of kidney and skin.


Non-invasive estimation of hyperthermia temperatures with ultrasound.
Ultrasound is an attractive modality for temperature monitoring because it is non-ionizing, convenient, inexpensive and has relatively simple signal processing requirements. This modality may be useful for temperature estimation if a temperature-dependent ultrasonic parameter can be identified, measured and calibrated. The most prominent methods for using ultrasound as a non-invasive thermometer exploit either (1) echo shifts due to changes in tissue thermal expansion and speed of sound (SOS), (2) variation in the attenuation coefficient or (3) change in backscattered energy from tissue inhomogeneities. The use of echo shifts has received the most attention in the last decade. By tracking scattering volumes and measuring the time shift of received echoes, investigators have been able to predict the temperature from a region of interest both theoretically and experimentally in phantoms, in isolated tissue regions in vitro and preliminary in vivo studies. A limitation of this method for general temperature monitoring is that prior knowledge of both SOS and thermal-expansion coefficients is necessary. Acoustic attenuation is dependent on temperature, but with significant changes occurring only at temperatures above 50 degrees C, which may lead to its use in thermal ablation therapies. Minimal change in attenuation, however, below this temperature range reduces its attractiveness for use in clinical hyperthermia. Models and measurements of the change in backscattered energy suggest that, over the clinical hyperthermia temperature range, changes in backscattered energy are dependent on the properties of individual scatterers or scattering regions. Calibration of the backscattered energy from different tissue regions is an important goal of this approach. All methods must be able to cope with motion of the image features on which temperature estimates are based. A crucial step in identifying a viable ultrasonic approach to temperature estimation is its performance during in vivo tests.


No Differences in Energy Cost of a Predetermined Exercise among Young Overweight/Obese and Undernourished Individuals.
Physical activity is an integral part of one's daily life. Obese (Ob) and undernourished (UN) persons are known to underperform physically as compared to normal weight (N) individuals. In this study, we have measured the energy spent to perform a prefixed exercise on treadmill walking and basal heart rate and blood pressure. Body mass index (BMI) and body fat of participating individuals were assessed. Fasting blood sugar and lipid profile were also evaluated. Eighty-three young individuals (male: 41; female: 42) of medical faculty, Universiti Sultan Zainal Abidin, who volunteered for the study, were recruited. The mean age of the individuals was 19.8 ± 0 years (P < 1.08). The individuals were grouped as N, UN/underweight, and overweight (Ow)/Ob based on BMI. The results of the study revealed that there were no differences in the energy spent on performing the predetermined treadmill walking of 20 min duration among the three groups (a mean of 78 and 70 calories in all male and female subgroups, respectively). The distance covered by the males was 1.6 km while the females covered 1.4 km on treadmill walking in 20 min time. Basal blood pressure and heart rate and fasting blood sugar did not reveal any significant difference among the groups. However, total cholesterol and triglyceride levels were marginally higher in the Ow/Ob groups of male and female individuals as compared to other groups. Since the study individuals were very young and competitive by nature and possibly had no major metabolic disturbances, the differences in physical activity performances were not obvious. Possibly, such differences would become apparent only at later stages of life as age advances or when the intensity and duration of exercise are set at higher levels.


Association of HLA class II genes with systemic sclerosis in Spanish patients.
To examine the role of HLA-DRB1 and HLA-DQB1 alleles in the susceptibility to systemic sclerosis (SSc) and its clinical expression in a Spanish population. One hundred Spanish Caucasian patients with SSc and 130 controls were studied. Molecular HLA-DRB1 and HLA-DQB1 typing was performed by polymerase chain reaction (PCR) sequence-based typing and PCR sequence-specific oligonucleotide. HLA-DRB1*11 was associated with genetic susceptibility to SSc, whereas HLA-DRB1*07 (HLA-DRB1*0701) showed a protective effect. A significant increase in the frequency of the DRB1*1104 allele was observed in patients with anti-topoisomerase I autoantibodies (anti-Topo I) while HLA-DRB1*01 and HLA-DQB1*05 alleles were significantly increased in patients with anti-centromere antibodies (ACA). The HLA-DRB1*11 allele was more frequent in patients with pulmonary fibrosis; however, no significant association with any HLA-DRB1 or DQB1 alleles was identified in patients with pulmonary arterial hypertension. HLA alleles play a role in genetic susceptibility to SSc in Spanish patients. Some alleles are more prevalent in patients with pulmonary fibrosis and in patients with certain SSc-specific autoantibodies (anti-Topo I and ACA).


Use and effects of implementation strategies for practice guidelines in nursing: a systematic review.
Practice guidelines can reduce variations in nursing practice and improve patient care. However, implementation of guidelines is complex and inconsistent in practice. It is unclear which strategies are effective at implementing guidelines in nursing. This review aimed to describe the use and effects of implementation strategies to facilitate the uptake of guidelines focused on nursing care. We conducted a systematic review of five electronic databases in addition to the Cochrane Effective Practice and Organization of Care (EPOC) Group specialized registry. Studies were included if implementation of a practice guideline in nursing and process or outcome of care provided by nurses were reported. Two reviewers independently screened studies, assessed study quality, extracted data, and coded data using the EPOC taxonomy of implementation strategies. For those strategies not included in the EPOC taxonomy, we inductively categorized these strategies and generated additional categories. We conducted a narrative synthesis to analyze results. The search identified 46 papers reporting on 41 studies. Thirty-six studies used a combination of educational materials and educational meetings. Review findings show that multicomponent implementation strategies that include educational meetings, in combination with other educational strategies, report positive effects on professional practice outcomes, professional knowledge outcomes, patient health status outcomes, and resource use/expenditures. Twenty-three of the 41 studies employed implementation strategies not listed within the EPOC taxonomy, including adaptation of practice guidelines to local context (n = 9), external facilitation (n = 14), and changes to organizational policy (n = 3). These implementation strategies also corresponded with positive trends in patient, provider, and health system outcomes. Nursing guideline implementation may benefit from using the identified implementation strategies described in this review, including participatory approaches such as facilitation, adaptation of guidelines, and organizational policy changes. Further research is needed to understand how different implementation strategy components work in a nursing context and to what effect. As the field is still emerging, future reviews should also explore guideline implementation strategies in nursing in quasi or non-experimental research designs and qualitative research studies.


Circulating Irisin and esRAGE as Early Biomarkers of Decline of Metabolic Health.
A decline in metabolic health may take place before observing any alteration in the levels of the traditional metabolic markers. New indicators of metabolic derangement are therefore compelling. Irisin is a myokine with important metabolic functions. The role of irisin as a metabolic biomarker in humans has not been fully established yet. We quantified plasma irisin and esRAGE in 106 apparently healthy individuals and we performed a cluster analysis to evaluate their associations with metabolic profile. Plasma levels of various traditional markers of metabolic risk (i.e., glucose and lipid levels) were all within the ranges of normality. We identified two clusters of individuals. Compared to cluster 2, individuals in cluster 1 had higher irisin levels, a metabolic profile shifted toward the limits of the reference ranges and lower esRAGE levels. The traditional metabolic blood tests seem not to be enough to identify a metabolic decline early. Irisin increase and esRAGE decrease may reflect a metabolic derangement at the beginning of its development. The role of these molecules as early biomarkers of decline of metabolic health seems an interesting topic to be further explored.


[EORTC QLQ-C30 questionnaire role as predictor for malnutrition risk in head and neck cancer Mexican patients].
Head and neck cancer treatment restricts oral intake and conditioning malnutrition. Adequate nutritional support during treatment can limit the impact of side effects. To describe EORTC QLQ-C30 role for malnutrition risk screening in head and neck cancer patients. Analytical and cross-sectional, diagnostic test study in head and neck cancer patients. We correlated malnutrition diagnosis with subjective global assessment (SGA) and score for the EORTC QLQ-C30 scales with Pearson and Spearman correlation. We realized COR (Receiver Operating Characteristic) curves to calculate cut point in the score for the EORTC QLQ-C30 scales; we calculated sensitivity, specificity, positive predictive value, negative predictive value and Odds Ratio through logistic regression. Functional scales (role, physic, global health status/QoL) showed limited utility to malnutrition risk estimation in people with head and neck cancer. Symptoms' scales with strong association were: pain (sensitivity 76.47%, specificity 69.23%), insomnia (sensitivity 88.24%, specificity 53.85%), fatigue (sensitivity 70.59%, specificity 76.92%). EORTC QLQ-C30 questionnaire is a useful tool to early malnutrition diagnosis in head and neck cancer patients with short term results in nutritional condition, treatment response and a better QoL in this kind of patients.


COMPARATIVE STUDIES ON RESPIRATION : XXVII. THE MECHANISM OF OXIDATION IN RELATION TO CHLOROFORM ANESTHESIA.
A mathematical analysis of the effects of chloroform on the production of carbon dioxide by living Ulva, killed Ulva, and unsaturated organic acids indicates that the same process is taking place in all three cases. On the basis of this interpretation it is reasonable to conclude that the action of chloroform on the oxidative mechanism of the cell is chemical in nature and that it acts either by catalysis or by the formation of a loose compound with some portion of the system.


Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting.
To assess the effects of antidiabetic drugs on the risk of heart failure in patients with type 2 diabetes. We conducted a retrospective cohort study with a newly diagnosed diabetes cohort of 25,690 patients registered in the U.K. General Practice Research Database, 1988-1999. We categorized person-time drug exposures to monotherapies in insulin, sulfonylureas (SUs), metformins, and other oral hypoglycemic agents (i.e., acarbose, guar gum) and combination therapy including insulin, combination therapy without insulin, and triple combination therapy with or without insulin. A drug-free time interval served as a reference category. Cox interval-wise (piece-wise) regression analyses were used. The main outcome was incident heart failure. Among 43,390 drug exposure intervals for 25,690 patients who had a mean follow-up period of 2.5 years, 1,409 patients developed heart failure. Heart failure occurred most frequently in SU monotherapy exposure. After adjusting for duration of diabetes, the timing and order of treatments received, and known risk factors for heart failure, we found no differential effects among type-specific therapies. Patients with any drug use within the first year after diabetes diagnosis had a 4.75-fold higher risk (hazard ratio) for heart failure than those with drug-free status but had no increased risk during subsequent years. In conclusion, the use of any pharmacological therapy for type 2 diabetes appears to be associated with an increased risk of heart failure. This risk does not persist beyond the first year after diagnosis of diabetes and does not appear to differ among the types of drug therapy examined. This observation suggests that the severity of diabetes or the preclinical duration of diabetes and the need for drug therapy, and not the therapy itself, is an explanation for heart failure in patients with type 2 diabetes.


Care-paradigm shift promoting smoking cessation treatment among cancer center patients via a low-burden strategy, Electronic Health Record-Enabled Evidence-Based Smoking Cessation Treatment.
Tobacco smoking is an important risk factor for cancer incidence, an effect modifier for cancer treatment, and a negative prognostic factor for disease outcomes. Inadequate implementation of evidence-based smoking cessation treatment in cancer centers, a consequence of numerous patient-, provider-, and system-level barriers, contributes to tobacco-related morbidity and mortality. This study provides data for a paradigm shift from a frequently used specialist referral model to a point-of-care treatment model for tobacco use assessment and cessation treatment for outpatients at a large cancer center. The point-of-care model is enabled by a low-burden strategy, the Electronic Health Record-Enabled Evidence-Based Smoking Cessation Treatment program, which was implemented in the cancer center clinics on June 2, 2018. Five-month pre- and post-implementation data from the electronic health record (EHR) were analyzed. The percentage of cancer patients assessed for tobacco use significantly increased from 48% to 90% (z = 126.57, p < .001), the percentage of smokers referred for cessation counseling increased from 0.72% to 1.91% (z = 3.81, p < .001), and the percentage of smokers with cessation medication significantly increased from 3% to 17% (z = 17.20, p < .001). EHR functionalities may significantly address barriers to point-of-care treatment delivery, improving its consistent implementation and thereby increasing access to and quality of smoking cessation care for cancer center patients.


The Short- and Long-Term Impacts of Hurricane Irma on Florida Agricultural Leaders as Early Emergency Responders: The Importance of Workplace Stability.
The impacts of hurricane-related disasters in agricultural communities include extensive losses of fields, orchards, and livestock, the recovery of which could span many years. Agricultural Extension Agents (EAs) try to manage and mitigate these losses, while simultaneously overseeing emergency shelter operations. These non-professional emergency responders face numerous potential stressors, the outcomes of which are minimally known. This study examined the short- and long-term medical and behavioral outcome of 36 University of Florida Agricultural Extension Agents within two months and one year after Hurricane Irma, Florida, USA, taking into consideration personal/home and work-related hurricane impacts. Regression analyses indicated that combined home and work hurricane impacts were associated with greater anxiety, depression, and medical symptoms controlling for age and number of prior hurricane experiences within two months of landfall. One year later, depression symptoms increased as well as the use of negative disengagement coping strategies for which stability of the work environment was protective. The findings suggest that advanced training in emergency response, organization and time management skills, time off and temporary replacement for personally impacted EAs, and workplace stability, including enhanced continuity of operations plans, represent critical elements of health prevention and early intervention for this occupational group.


Development of a Hazard Classification Scheme for Substances Used in the Fraudulent Adulteration of Foods.
Food fraud, the intentional misrepresentation of the true identity of a food product or ingredient for economic gain, is a threat to consumer confidence and public health and has received increased attention from both regulators and the food industry. Following updates to food safety certification standards and publication of new U.S. regulatory requirements, we undertook a project to (i) develop a scheme to classify food fraud-related adulterants based on their potential health hazard and (ii) apply this scheme to the adulterants in a database of 2,970 food fraud records. The classification scheme was developed by a panel of experts in food safety and toxicology from the food industry, academia, and the U.S. Food and Drug Administration. Categories and subcategories were created through an iterative process of proposal, review, and validation using a subset of substances known to be associated with the fraudulent adulteration of foods. Once developed, the scheme was applied to the adulterants in the database. The resulting scheme included three broad categories: 1, potentially hazardous adulterants; 2, adulterants that are unlikely to be hazardous; and 3, unclassifiable adulterants. Categories 1 and 2 consisted of seven subcategories intended to further define the range of hazard potential for adulterants. Application of the scheme to the 1,294 adulterants in the database resulted in 45% of adulterants classified in category 1 (potentially hazardous). Twenty-seven percent of the 1,294 adulterants had a history of causing consumer illness or death, were associated with safety-related regulatory action, or were classified as allergens. These results reinforce the importance of including a consideration of food fraud-related adulterants in food safety systems. This classification scheme supports food fraud mitigation efforts and hazard identification as required in the U.S. Food Safety Modernization Act Preventive Controls Rules.


ABCB1 C3435T and CYP2C19*2 polymorphisms in a Palestinian and Turkish population: A pharmacogenetic perspective to clopidogrel.
Clopidogrel is an antiplatelet drug used to prevent recurrent ischemic events after acute coronary syndrome and/or coronary stent implantation. Single nucleotide polymorphisms (SNPs) such as CYP2C19*2 and ABCB1 C3435T have been found to play a role in different individual responses to clopidogrel. Since the prevalence of these SNPs is generally known to differ from one population to another, the aim of this study was to examine their prevalence in both a Palestinian and Turkish population. One hundred unrelated Palestinian subjects and 100 unrelated Turkish subjects were analyzed for CYP2C19*2 and ABCB1 C3435T polymorphisms by the amplification refractory mutation system (ARMS). Results showed an ABCB1 3435 T allele frequency of 0.46 (95% CI 0.391 to 0.529) in the Palestinian sample and 0.535 (95% CI 0.4664 to 0.6036) in the Turkish sample. CYP2C19*2 allele frequency was 0.095 (95% CI 0.0558 to 0.134) in the Palestinian sample and 0.135 (95% CI 0.088 to 0.182) in the Turkish sample. Our results provide information about the prevalence of the polymorphisms related to clopidogrel response in both the Palestinian and Turkish populations, in order to improve the safety and efficacy of clopidogrel through use of genetically guided, individualized treatment. The prevalence of these clinically significant alleles shed light on the importance of testing them before prescribing clopidogrel.


Sequential liver-kidney transplantation in a boy with congenital hepatic fibrosis and nephronophthisis from a living donor.
A five-yr-old boy developed chronic liver failure and ESKD because of CHF and juvenile NPHP. He underwent sequential liver and kidney transplantation with a compatible blood type from his father, at five yr, seven months and five yr, 11 months old, respectively. Because the patient was not in ESKD, we initially performed LDLT because of significant portal hypertension. Even after LDLT, his ascites was not ameliorated, and he needed continuous drainage of ascites and daily albumin and gamma globulin infusion. Thereafter, he progressed to ESKD and needed hemodialysis for one month before LDKT. CDC crossmatch for donor B cells in the warm test, FCXM for B cell IgG, and flow PRA for donor class II were positive before LDKT. After pretreatment of three courses of plasma exchange and intravenous gamma globulin, LDKT was performed. Two weeks after LDKT, AIHA concomitant with autoimmune thrombocytopenia, also called Evans syndrome, occurred because of passenger lymphocytes from the donor; however, the patient was successfully treated with intravenous methylprednisolone. Eighteen months have passed since LDKT, and liver and kidney function in both the recipient and donor are normal.


External Hardware and Sensors, for Improved MRI.
Complex engineered systems are often equipped with suites of sensors and ancillary devices that monitor their performance and maintenance needs. MRI scanners are no different in this regard. Some of the ancillary devices available to support MRI equipment, the ones of particular interest here, have the distinction of actually participating in the image acquisition process itself. Most commonly, such devices are used to monitor physiological motion or variations in the scanner's imaging fields, allowing the imaging and/or reconstruction process to adapt as imaging conditions change. "Classic" examples include electrocardiography (ECG) leads and respiratory bellows to monitor cardiac and respiratory motion, which have been standard equipment in scan rooms since the early days of MRI. Since then, many additional sensors and devices have been proposed to support MRI acquisitions. The main physical properties that they measure may be primarily "mechanical" (eg acceleration, speed, and torque), "acoustic" (sound and ultrasound), "optical" (light and infrared), or "electromagnetic" in nature. A review of these ancillary devices, as currently available in clinical and research settings, is presented here. In our opinion, these devices are not in competition with each other: as long as they provide useful and unique information, do not interfere with each other and are not prohibitively cumbersome to use, they might find their proper place in future suites of sensors. In time, MRI acquisitions will likely include a plurality of complementary signals. A little like the microbiome that provides genetic diversity to organisms, these devices can provide signal diversity to MRI acquisitions and enrich measurements. Machine-learning (ML) algorithms are well suited at combining diverse input signals toward coherent outputs, and they could make use of all such information toward improved MRI capabilities. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.


Human Papillomavirus (HPV) Vaccine Effectiveness and Potential Herd Immunity for Reducing Oncogenic Oropharyngeal HPV-16 Prevalence in the United Kingdom: A Cross-sectional Study.
Oropharyngeal cancer incidence is rapidly rising due to human papillomavirus (HPV) type 16 infection. The dearth of data on effectiveness of national female-only vaccination programs in preventing oral HPV infection and potential herd immunity in unvaccinated males has resulted in considerable controversy regarding the need to vaccinate males, especially in countries with high female vaccination coverage. Subjects aged 0-65 years undergoing tonsillectomy for nonmalignant indications were recruited in 6 hospitals in the United Kingdom. Oral samples were collected as follows: oral rinse, tongue base, and pharyngeal wall brushes, then tonsil tissue (tonsillectomy). Vaccination data were obtained from regional health authorities. All samples were centrally tested for HPV DNA by polymerase chain reaction. Of 940 subjects, 243 females and 69 males were aged 12-24 years (median age, 18.6 years), with 189 (78%) females and no males vaccinated against HPV. Overall, oropharyngeal HPV-16 prevalence was significantly lower in vaccinated versus unvaccinated females (0.5% vs 5.6%, P = .04). In contrast, prevalence of any oropharyngeal HPV type was similar in vaccinated and unvaccinated females (19% vs 20%, P = .76). Oropharyngeal HPV-16 prevalence in unvaccinated males was similar to vaccinated females (0% vs 0.5%, P > .99), and lower than unvaccinated females (0% vs 5.6%, P = .08). Our findings indicate that the UK female-only vaccination program is associated with significant reductions in oropharyngeal HPV-16 infections. These are also the first data to suggest potential herd immunity from female-only vaccination against oropharyngeal HPV infection in contemporaneously aged males.


Efficacy and safety of apatinib as second-line therapy for advanced gastric cancer: a single-center observational study.
Apatinib has been proven to be effective and safe among patients in the third-line treatment of advanced gastric cancer in phase II and III trials. We aimed to evaluate its efficacy and safety in second-line practice, and to explore the factors associated with efficacy. Between April 2015 and May 2017, a total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of gastroesophageal junction were enrolled and followed up retrospectively after failing the first line of systemic therapy. The median progression-free survival was 4.43 months (95% confidence interval: 1.63-7.22) and the median overall survival was 9.11 months (95% confidence interval: 8.22-9.99). Two patients achieved a partial response and 14 patients achieved stable disease. The disease control rate was 69.6% and the objective response rate was 8.7%. The most common adverse events over grade 3 were hypertension (8.7%) and thrombocytopenia (8.7%). No treatment-related death was documented during the drug administration. Apatinib is an effective regimen for the second-line treatment of advanced gastric and gastroesophageal cancer with manageable toxicity.


Bile Acid and Cholesterol Metabolism in Atherosclerotic Cardiovascular Disease and Therapy.
Dysregulation of lipid metabolism is a major factor contributing to atherosclerotic cardiovascular disease (ACVD), which is the number one cause of death in western countries. The liver plays a central role in maintaining whole body cholesterol homeostasis via catabolism of cholesterol to bile acids, as well as biliary cholesterol excretion. The liver synthesizes lipoproteins that transport dietary cholesterol and fats to muscle and adipose tissue, directs reverse cholesterol transport of excess cholesterol from extrahepatic tissues and macrophages to the liver to convert to bile acids, and thus, protects against metabolism-related nonalcoholic fatty liver disease (NAFLD) and ACVD. Liver fibrosis/nonalcoholic steatohepatitis increases the risk and prevalence of cardiovascular disease morbidity and mortality. Bile acids are signaling molecules and metabolic regulators that activate farnesoid X receptor and G protein-coupled bile acid receptor-1 to regulate lipid, glucose, and energy metabolism. The bidirectional regulation of bile acids and the gut microbiota determine the rate of bile acid synthesis, the bile acid pool size, and the composition of the circulating bile acid pool. The liver-intestine-heart axis regulates lipid metabolism, inflammation, and the pathogenesis of metabolic diseases such as ACVD, NAFLD, diabetes, and obesity. This review focuses on the roles of liver-to-intestine, liver-to-heart and intestine-to-heart axes in cholesterol, lipoprotein, and bile acid metabolism; signaling in heart health and ACVD; and drug therapies for atherosclerosis.


Genetic variation and gene conversions within the bovine NK-lysin gene family.
In contrast to a single copy of the NK-lysin gene in humans and many other mammals, we previously identified a family of four expressed NK-lysin genes arising by tandem duplications on cattle chromosome 11. Here, we report two genetic variants in the bovine NK-lysin complex with potential importance in the bovine innate immune system. The first one is a 9-bp deletion causing a three-amino-acid deletion in the pro-region of the NK1 gene product. The second is a deletion of NK2B in some Holstein cattle, resulting in copy number variation that is in disequilibrium with a SNP from the bovine 770K HD SNP array. We also show evidence for gene conversions within the three new NK2 genes, which at least partially accounts for their high degree of sequence identity.


Dynamical simulations of DNA supercoiling and compression.
In the present article, we summarize our recent studies of DNA dynamics using the generalized immersed boundary method. Our analysis of the effects of electrostatic repulsion on the dynamics of DNA supercoiling revealed that, after perturbation, a pre-twisted DNA collapses into a compact supercoiled configuration that is sensitive to the initial excess link and ionic strength of the solvent. A stochastic extension of the generalized immersed boundary method shows that DNA in solution subjected to a constant electric field is compressed into a configuration with smaller radius of gyration and smaller ellipticity ratio than those expected for such a molecule in a thermodynamic equilibrium.


Solution structure of the third immunoglobulin domain of the neural cell adhesion molecule N-CAM: can solution studies define the mechanism of homophilic binding?
Homophilic binding of the neural cell adhesion molecule (N-CAM) mediates the calcium-independent cell-cell adhesion that is involved in neuronal development. Two hypotheses have been advanced for the mechanism of homophilic binding. Cell-based experiments have implicated each of the five extracellular immunoglobulin (Ig) domains of N-CAM in the homophilic adhesion interaction, and have predicted that the third domain (Ig III) self-associates. The alternative hypothesis is based on solution observations, which implicate a specific antiparallel interaction between the first two Ig domains (Ig I and Ig II). In order to test these hypotheses, we have determined a high-resolution solution structure of recombinant Ig III (sequence derived from chicken N-CAM) and examined the aggregation behavior of isolated Ig domains in solution. The structure shows that Ig III adopts a canonical Ig fold, in which the beta strands ABED and A'GFCC' form two beta sheets that are linked by a disulfide bond. In contrast to the demonstrated aggregation of Ig III on solid supports, we were unable to demonstrate self-association of Ig III under any of a variety of solution conditions. The structure shows that the surface of Ig III is dominated by two large acidic patches, which may explain our failure to observe self-association in solution. To evaluate the involvement of the Ig I-Ig II interaction in cell-cell adhesion, we designed a point mutation in Ig I (F19S) that proved sufficient to abrogate the Ig I-Ig II interaction seen in solution. However, the introduction of this mutation into full-length N-CAM expressed in COS-7 cells failed to affect N-CAM-mediated cell-cell adhesion. The inability to observe Ig III self-association in solution, combined with the failure of the F19S mutation to affect N-CAM-mediated cell-cell adhesion, suggests that, although solution studies can give important insights into the structures of individual domains, the interactions observed in solution between the domains may not be representative of the interactions that occur on the cell surface.


Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB).
To study the metabolic effects in vivo of L-2, 4 diaminobutyric acid (DAB) administered by retrograde microdialysis in glioblastoma and to evaluate the feasibility of the technique. In 10 patients with glioblastoma, a stereotactic biopsy was performed followed by implantation of microdialysis catheters. One or two catheters were implanted in tumor tissue and two reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue, respectively. Tumor catheters were perfused with 80 or 120 mmol/l DAB and reference catheters were perfused with a Ringer solution, all with a flow rate of 2.0 microl/min. Treatment was given for at mean 9.1 (5-19) days. The treatment was well tolerated by the patients with the exception of two patients in whom a transient brain edema appeared. No complications related to the technique were encountered. During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found demonstrating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident. The metabolism in normal brain was unaffected during treatment. Retrograde microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in patients with glioblastoma. We found it possible to deliver DAB to glioblastoma tumors in fully mobilized patients and to assess the metabolic effects induced by the treatment. The changes in extracellular amino acids were in concordance to what was expected from in vitro studies. Elevation of glutamate and taurine may be regarded as markers for an induced cellular toxicity while the unchanged level of glycerol may indicate no direct effects on phospholipase activity and membrane phospholipid composition. The effects were restricted to the tumor compartment. Although an improved survival could possibly be suspected no dramatic effect on outcome could be detected. However, the series was small and, most probably, the time for treatment was too short.


Cultivation and Live Imaging of Drosophila Imaginal Discs.
The ex vivo cultivation and live imaging of wing discs open exciting new research avenues by overcoming the limitations of end-point analysis of fixed tissues. Here we describe how to prepare an optimized wing disc culture medium (WM1) and how to dissect and arrange wing discs for cultivation and live imaging. This protocol enables the study of dynamic phenomena such as cell division and delamination as well as the use of pharmacological compounds and biosensors. Wing discs cultured and imaged as described here, maintain constant levels of proliferation during the first ten hours of culture.


Clinical Validation of Novel Digital Measures: Statistical Methods for Reliability Evaluation.
Assessment of reliability is one of the key components of the validation process designed to demonstrate that a novel clinical measure assessed by a digital health technology tool is fit-for-purpose in clinical research, care, and decision-making. Reliability assessment contributes to characterization of the signal-to-noise ratio and measurement error and is the first indicator of potential usefulness of the proposed clinical measure. Methodologies for reliability analyses are scattered across literature on validation of PROs, wet biomarkers, etc., yet are equally useful for digital clinical measures. We review a general modeling framework and statistical metrics typically used for reliability assessments as part of the clinical validation. We also present methods for the assessment of agreement and measurement error, alongside modified approaches for categorical measures. We illustrate the discussed techniques using physical activity data from a wearable device with an accelerometer sensor collected in clinical trial participants. This paper provides statisticians and data scientists, involved in development and validation of novel digital clinical measures, an overview of the statistical methodologies and analytical tools for reliability assessment.


Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case.
Noncovalent interactions underlie nearly all molecular processes in the condensed phase from solvation to catalysis. Their quantification within a physically consistent framework remains challenging. Experimental vibrational Stark effect (VSE)-based solvatochromism can be combined with molecular dynamics (MD) simulations to quantify the electrostatic forces in solute-solvent interactions for small rigid molecules and, by extension, when these solutes bind in enzyme active sites. While generalizing this approach toward more complex (bio)molecules, such as the conformationally flexible and charged penicillin G (PenG), we were surprised to observe inconsistencies in MD-based electric fields. Combining synthesis, VSE spectroscopy, and computational methods, we provide an intimate view on the origins of these discrepancies. We observe that the electric fields are correlated to conformation-dependent effects of the flexible PenG side chain, including both the local solvation structure and solute conformational sampling in MD. Additionally, we identified that MD-based electric fields are consistently overestimated in three-point water models in the vicinity of charged groups; this cannot be entirely ameliorated using polarizable force fields (AMOEBA) or advanced water models. This work demonstrates the value of the VSE as a direct method for experiment-guided refinements of MD force fields and establishes a general reductionist approach to calibrating vibrational probes for complex (bio)molecules.


First Report of Stalk Rot Disease of Sugarcane Caused by Phaeocytostroma sacchari in Mexico.
In April 2009 and 2010, severe symptoms of stalk rot of sugarcane (Saccharum officinarum L.) plants cvs. MEX-79-431, MEX-69-749, and RB-73-9735 were observed in commercials fields located in southeast Michoacan state, Mexico. The diseased plants exhibited complete discoloration of foliage, ascendant necrosis and rot in the internal stalk tissue, and disintegration of vascular tissue. Symptoms were most evident in the nodes with intense purple coloration. Dead plants were observed. Two diseased plants of each cultivar were collected. Pieces of symptomatic stem tissue were surface sterilized with 2% sodium hypochlorite solution for 1 min, washed with sterile distilled water, dried on sterilized paper, and plated onto potato dextrose agar (PDA). Petri dishes were incubated at 22°C under continuous white light for 72 h. A fungus was consistently isolated. On PDA, colonies had sparse aerial mycelium in the center and dense in the margins with black masses of conidia. The fungus isolated was grown on dishes containing 2% water agar (WA) overlaid with pine needles and incubated at 22°C under continuous white light for 2 weeks to induce the formation of fruiting bodies. Pycnidia produced in WA were black, up to 500 μm in diameter, usually globose, blister shaped without peaks, scattered, and multilocular. Conidiophores were cylindrical, hyaline, 5 to 20 × 1.5 to 2 μm, and formed in the pycnidial cavity. Conidia were ellipsoidal to oblong, unicellular, pale brown to dark brown, 8.5 to 12.5 × 3 to 4.5 μm, biguttulate, and non-septate. Paraphyses were hyaline, aseptate, occasionally branched, and flexuous. On the basis of cultural and morphological characteristics, the fungus was identified as Phaeocytostroma sp. DNA from an isolate was extracted and the internal transcribed spacer region (ITS1-5.8S-ITS2) of rDNA was amplified using primers ITS1 and ITS4 (2). PCR products were purified and sequenced. The resulting sequence of 536 bp was deposited in GenBank (Accession No. KC893550). BLAST analysis showed a 99% similarity with the sequence of Phaeocytostroma sacchari (FR748047). Pathogenicity tests of an isolate of P. sacchari were performed on 6-month-old sugarcane plants (cvs. MEX-79-431, MEX-69-749, and RB-73-9735). A 1-cm-deep wound near the base of the stem was created with a sterilized needle. Mycelial plugs (9 mm diameter) of 6-day-old PDA cultures were deposited on wounds and wrapped with Parafilm. Four plants of each cultivar were inoculated and 12 control plants were treated similarly with PDA plugs instead of fungal inoculum. Plants were placed at 28°C and 95% relative humidity for 72 h. All the inoculated plants exhibited typical wilt symptoms 4 weeks after inoculation, whereas control plants remained healthy. P. sacchari was consistently re-isolated from artificially inoculated plants. To our knowledge, this is the first report of P. sacchari on sugarcane in Mexico. The occurrence of stalk rot disease of sugarcane caused by P. sacchari has been described causing severe losses in sugarcane-producing countries such as South Africa and India (1). References: (1) R. Viswanathan et al. Sugar Tech. 5: 61, 2003. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.


Surgical vs nonsurgical treatments in patients with anterior open-bite have similar effects in occlusal function: A 2-year follow-up study.
This study aimed to investigate changes in bite force (BF) and occlusal contact area after anterior open-bite (AOB) treatment and compare the changes in surgical vs nonsurgical treatment. This retrospective study included patients with AOB compared with normal occlusion. AOB was corrected by either intrusion of the maxillary molars (intrusion group, n = 19) or orthognathic surgery (surgery group, n = 37). The control group (n = 35) had a normal overbite relationship. Records of lateral cephalograms, BF, and occlusal contact area taken before (T0), immediately after (T1), and 2 years after (T2) orthodontic treatment were compared within and among the 3 groups. The open-bite group, including intrusion and surgery groups, had a lower BF and less occlusal contact area than the control group at T0 and T1 (P <0.001). However, there were no significant differences among the 3 groups at T2 (P >0.05). The intrusion and surgery groups showed no significant differences throughout the observation period extending from T0 to T2 (P >0.05). Although BF and occlusal contact area decreased at T1 compared with T0, they increased during retention and showed higher values at T2 than at T0. Treatment of AOB improved BF and occlusal contact area 2 years posttreatment. Orthognathic surgery and molar intrusion using orthodontic miniscrews can improve occlusal function similarly. Orthodontists can select either method depending on malocclusion severity and patient demand.


Abomasal and duodenal motility in yearling cattle after administration of prokinetic drugs.
Effects of the following treatments on abomasal and duodenal myoelectric activity in yearling cattle were studied: 2 ml of 0.9% sodium chloride solution (NACL); 0.07 mg of bethanechol (BET)/kg of body weight; 0.1 mg of metoclopramide (MET)/kg; and 0.07 mg of bethanechol and 0.1 mg of metoclopramide (BETMET)/kg. All treatments were administered SC during the early part of phase I of the migrating myoelectric complex. Myoelectric signals were recorded for 4 hours after administration of the treatments from 1 electrode in the antrum and 3 electrodes in the duodenum. For the antral spike rate (ASR), there was no significant difference among treatments during the first hour, but the ASR was significantly (P < 0.05) greater during hours 2 to 4 after treatment with BETMET, compared with ASR for MET alone. The duodenal spike rate (DSR) was significantly (P < 0.05) greater during the first hour after administration of BETMET than after the other treatments. After administration of BET, DSR was significantly (P < 0.05) greater than after MET or NACL. There was no difference in DSR after MET, compared with DSR after NACL. There was no significant difference in DSR among treatments during the second and third hours. The total antegrade propagating spike (TAPS) count was greater after administration of BETMET in all hours, compared with the other treatments. The ratio of TAPS to total spikes on the orad-most duodenal electrode was significantly (P < 0.05) greater after BETMET during hours 1 and 2.


Disrupted Functional Rich-Club Organization of the Brain Networks in Children with Attention-Deficit/Hyperactivity Disorder, a Resting-State EEG Study.
Growing evidence indicates that disruptions in the brain's functional connectivity play an important role in the pathophysiology of ADHD. The present study investigates alterations in resting-state EEG source connectivity and rich-club organization in children with inattentive (ADHDI) and combined (ADHDC) ADHD compared with typically developing children (TD) under the eyes-closed condition. EEG source analysis was performed by eLORETA in different frequency bands. The lagged phase synchronization (LPS) and graph theoretical metrics were then used to examine group differences in the topological properties and rich-club organization of functional networks. Compared with the TD children, the ADHDI children were characterized by a widespread significant decrease in delta and beta LPS, as well as increased theta and alpha LPS in the left frontal and right occipital regions. The ADHDC children displayed significant increases in LPS in the central, temporal and posterior areas. Both ADHD groups showed small-worldness properties with significant increases and decreases in the network degree in the θ and β bands, respectively. Both subtypes also displayed reduced levels of network segregation. Group differences in rich-club distribution were found in the central and posterior areas. Our findings suggest that resting-state EEG source connectivity analysis can better characterize alterations in the rich-club organization of functional brain networks in ADHD patients.


Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.
The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.


Recent progress in black phosphorus and black-phosphorus-analogue materials: properties, synthesis and applications.
Black phosphorus (BP), a novel two-dimensional (2D) layered semiconductor material, has attracted tremendous attention since 2014 due to its prominent carrier mobility, thickness-dependent direct bandgap and in-plane anisotropic physical properties. BP has been considered as a promising material for many applications, such as in transistors, photonics, optoelectronics, sensors, batteries and catalysis. However, the development of BP was hampered by its instability under ambient conditions, as well as by the lack of methods to synthesize large-area and high quality 2D nanofilms. Recently, some BP-analogue materials such as binary phosphides (MPx), transition metal phosphorus trichalcogenides (MPX3), and 2D group V (pnictogens) and 2D group VI materials have attracted increasing interest for their unique and stable structures, and excellent physical and chemical properties. This article, which focuses on BP and BP-analogue materials, will present their crystal structure, properties, synthesis methods and applications. Also the similarity and difference between BP and BP-analogue materials will be discussed, and the presentation of the future opportunities and challenges of the materials are included at the end.


Role of VEGF-A gene in the formation of late effects after the Chornobyl accident.
To characterize the VEGF-A gene expression and its main effects on immune cells in the Chornobyl NPP accident clean-up workers. VEGF-A gene expression and its main effects on immune cells were studied in 55 persons by a real-time PCR analysis and immunophenotyping of immune competent cells. Disorders of regulation of neoangiogenesis were found in remote period upon radiation exposure. Elevated levels of VEGF-A gene expression correlated with TP53 gene expression in the ChNPP accident clean-up workers. Correlation was established between the percentage of the immunoregulatory T-cell subpopulations and VEGF-A expressing in the group of exposed persons and there was demonstrated a suppression of specific immune response of CD4⁻8⁺ T cells. Correlation between the percentage of CD4⁺25⁺ cells and radiation dose in a group of Chornobyl clean-up workers is not related to VEGF-A expression, so this type of immune response can be regarded as a manifestation of long-term effects after exposure. Some parameters were identified characterizing the state and abnormalities of the "immunity-angio-genesis" system. Those parameters could be promising in prediction of neoplastic process in remote period upon radiation exposure.


The naturally occurring rhythm of blues: winter depression.
Winter depression, a form of seasonal affective disorder, is a common condition that increases in prevalence in northern areas and in regions with a high proportion of overcast fall and winter days. Parts of Ohio are high-risk areas given the high percentage of overcast days. Winter depression is marked by the onset of recurrent episodes of major depression each fall or winter which spontaneously remit in the spring. The depressive syndrome is often characterized by sadness, anxiety, decreased involvement in work and social activities, increased appetite, carbohydrate craving, weight gain, hypersomnia and psychomotor retardation. This syndrome often responds to treatment with two to six hours per day of full-spectrum bright artificial light. The efficacy of drugs in the treatment of this condition is now being studied at The Ohio State University. A monoamine oxidase inhibitor is effective.


Aspects of innate immunity and Parkinson's disease.
Genetic studies on PARK genes have identified dysfunction in proteasomal, lysosomal, and mitochondrial enzymes as pathogenic for Parkinson's disease (PD). We review the role of these and similar enzymes in mediating innate immune signaling. In particular, we have identified that a number of PARK gene products as well as other enzymes have roles in innate immune signaling as well as DNA repair and regulation, ubiquitination, mitochondrial functioning, and synaptic trafficking. PD enzymatic dysfunction is likely to contribute to inadequate innate immune responses to a variety of extra- and intra-cellular stimuli, with a number of the innate immunity related enzymes found in the characteristic Lewy body pathology of PD. The decrease in innate immunity in PD is associated with an increase in markers of adaptive immunity, and recent GWAS studies have identified variants in human leukocyte antigen region as associated with late-onset sporadic PD (Hamza et al., 2010; Hill-Burns et al., 2011). Intriguing new data also suggest that peripheral immune responses may be involved, giving some potential to alleviate such peripheral dysfunction more directly in patients with PD. It is now important to identify the cell type specific immune responses contributing to the initial changes that occur in PD, as well as to the propagating immune responses important for the progression of PD pathology between cells and within the brain. Overall, a complex interplay between different types of immunity appear to be involved in the underlying pathology of PD.


Conventional Treatments plus Acupuncture for Asthma in Adults and Adolescent: A Systematic Review and Meta-Analysis.
The efficacy of conventional treatments plus acupuncture for asthma in adult and adolescent is uncertain. Literature reports are conflicting; therefore, the aim of this study was to determine the efficacy of conventional treatments plus acupuncture versus conventional treatments alone using a meta-analysis of all published randomized clinical trials (RCTs). Two reviewers independently performed a comprehensive literature search from multiple electronic sources (1990-2018), including PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WanFang databases. RCTs in which adult and adolescent patients with asthma (age ≥12 years) were divided into conventional treatments plus acupuncture and conventional treatments alone were included. Nine studies were included. The results showed that conventional treatments plus acupuncture as a complementary therapy could improve the symptom response rate (OR = 7.87, 95% CI = [4.13, 14.99], p < 0.00001) and significantly decrease interleukin-6 (IL-6) levels (MD = -11.42; 95% CI = [-15.28, -7.56], p < 0.00001). However, indices of pulmonary function, including the forced expiratory volume in one second (FEV1) (MD = 0.22, 95% CI = [-0.11, 0.56], p = 0.19) and FEV1/forced vital capacity (FVC) (MD = 8.62, 95% CI = [-0.35, 17.59], p = 0.06), failed to be improved with conventional treatments plus acupuncture. Conventional treatments plus acupuncture are associated with significant benefits for adult and adolescent patients with asthma. Therefore, we suggest the use of conventional treatments plus acupuncture for asthma patients.


Synthesis, structure, electrochemistry and magnetism of cobalt-, nickel- and zinc-containing [M4(OH)3(H2O)2(α-SiW10O36.5)2]13- (M = Co2+, Ni2+, and Zn2+).
Interaction of the trilacunary 9-tungstosilicate [A-α-SiW9O34]10- with cobalt(ii), nickel(ii) and zinc(ii) ions in pH 9 aqueous medium at room temperature led to the formation of the respective M4-containing heteropolytungstates [M4(OH)3(H2O)2(α-SiW10O36.5)2]13- (M = Co2+ (1), Ni2+ (2), and Zn2+ (3)). Polyanions 1-3 were characterized in the solid state by single-crystal XRD, FT-IR spectroscopy, and thermogravimetric and elemental analyses. Electrochemical studies showed that the Co2+ ions in 1 can be oxidized to Co3+ and the CVs of the WVI centers of the polyanions feature well-defined and chemically reversible reduction waves. Magnetic measurements on 1 and 2 showed paramagnetism with complex ferromagnetic and antiferromagnetic interactions. A model was presented for extracting the exchange constants for the magnetic exchange interaction.


SESAMs for high-power femtosecond modelocking: power scaling of an Yb:LuScO₃ thin disk laser to 23 W and 235 fs.
We report on power scaling of a modelocked thin disk laser based on the broadband mixed sesquioxide material Yb:LuScO₃. One of the key elements to achieve this result was an improved SESAM design with reduced two-photon-absorption (TPA) and high damage threshold. In a first experiment, using a standard antiresonant SESAM with no topcoating, we could demonstrate record short pulse durations of 195 fs at a moderate average power of 9.5 W. Furthermore, we were able to power scale our thin disk laser while keeping the pulses short reaching 23 W at a pulse duration of 235 fs. This was made possible by designing a new SESAM with multiple quantum wells (QW) and a suitable dielectric topcoating. We will present SESAM optimization guidelines for short pulse generation from high-power modelocked oscillators.


ACR Appropriateness Criteria® Clinically Suspected Adnexal Mass, No Acute Symptoms.
There are approximately 9.1 pelvic surgeries performed for every histologically confirmed adnexal malignancy in the United States, compared to 2.3 surgeries per malignancy (in oncology centers) and 5.9 surgeries per malignancy (in other centers) in Europe. An important prognostic factor in the long-term survival in patients with ovarian malignancy is the initial management by a gynecological oncologist. With high accuracy of imaging for adnexal mass characterization and consequent appropriate triage to subspecialty referral, the better use of gynecologic oncology can improve treatment outcomes. Ultrasound, including transabdominal, transvaginal, and duplex ultrasound, combined with MRI with contrast can diagnose adnexal masses as benign with specific features (ie, functional masses, dermoid, endometrioma, fibroma, pedunculated fibroid, hydrosalpinx, peritoneal inclusion cyst, Tarlov cyst), malignant, or indeterminate. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


The spatial and temporal distribution of polarizing activity in the flank of the pre-limb-bud stages in the chick embryo.
The presence of polarizing activity in the limb buds of developing avian embryos determines the pattern of the anteroposterior axis of the limbs in the adult. Maps of the spatial distribution and the strength of the signal within limb buds of different stages are well documented. Polarizing activity can also be found in Hensen's node in the early embryo. We have mapped the distribution of polarizing activity as it emerges from Hensen's node and spreads into the flank tissue of the embryo. There is a clear change in the local pattern of expression of polarizing activity between stage 8 and 18. Almost no activity is measured for stages 8 and 9. More or less uniform levels of around 10% are spread along the flank lateral to the unsegmented somitic mesoderm from somite position 12 to 22 in stage 10 embryos. Some 6 to 8 h later at stage 12, there is a distinct peak of activity at somite position 18, the middle of the wing field. This peak increases at stages 13 to 15 and its position traverses to the posterior edge of the wing field. Full strength of activity is reached shortly before the onset of limb bud formation at stage 16 to 17. Stages 16 to 18 were investigated for polarizing activity in the wing and the leg field. Low levels of polarizing activity are present in the anterior leg field at stages 16 and 17 but have disappeared by stage 18 and all activity is confined to the posterior part of the leg bud.


Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.


Evaluation of micronutrient levels in children with cerebral palsy.
Many studies evaluating the nutritional status of children with cerebral palsy (CP) have focused on energy requirements and protein intake. The present work aimed to assess nutritional status and micronutrient levels of children with (CP). This multicenter, cross-sectional and observational study was conducted in 10 different cities in Turkey. Data were available for 398 participants. Anthropometric measurements, feeding mode, nutritional status, and micronutrient levels were evaluated. The study was conducted with 398 participants (303 patients and 95 healthy controls). Statistical analysis showed that according to the Gomez Classification, weight-for-age (WFA) revealed malnutrition in 92.6% of children with CP, based on Centers for Disease Control and Prevention percentiles. Measurements of micronutrient levels showed that zinc levels were low in patients, whereas vitamin A levels were low in controls. Phosphorous and manganese levels were significantly lower in malnourished children than in typical children. The results revealed that children consuming enteral nutrition solutions had higher selenium and lower zinc levels than non-consumers. Malnutrition is not only a protein- or calorie-based problem; micronutrient deficiencies might cause severe health problems. Children with chronic neurological disabilities must be carefully evaluated for these issues. Therefore, nutritional interventions should be adapted to nutrition.


Association of alpha-dystrobrevin with reorganizing tight junctions.
Alpha-dystrobrevin (alpha-DB) has been described primarily as a cytoplasmic component of the dystrophin-glycoprotein complex in skeletal muscle cells. Isoforms of alpha-DB show different localization in cells and tissues; at basolateral membranes in epithelial cells, dystrobrevins mediate contact with the extracellular matrix, peripheral and transmembrane proteins and the filamentous actin cytoskeleton. Beside their structural role, alpha-DBs are assumed to be important in cell signalling and cell differentiation. We have primarily assessed the role of alpha-DB in two epithelial cell lines (MDCK I, HT 29), which represent different developmental stages and exhibit distinct permeability characteristics. Using a polyclonal anti-alpha-DB antibody, we have investigated its expression, localization and association with tight junction (TJ)- associated proteins (ZO-1, occludin) before and after protein kinase C (PKC) activation with phorbol myristate acetate. Distinct subsets of alpha-DB isoforms were detected in the two cell lines by immunoblotting. In both cell lines there was submembranous localization of alpha-DB both apically and basolaterally, shown with confocal imaging. PKC activation caused a reorganization of TJ, which was parallel to increased localization of alpha-DB to TJ areas, most pronounced in MDCK I cells. Moreover, actin and ZO-1 co-immunoprecipitated with a-DB, as displayed with immunoblotting. Our findings suggest that a-dystrobrevin specifically is associated with the tight junctions during their reorganization.


HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells.
Treatment of dopaminergic rat PC12 cells with human immunodeficiency virus, type 1 (HIV-1) Tat protein or tat cDNA inhibited the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme for the dopamine biosynthetic pathway, as well as the production and release of dopamine into the culture medium. Moreover, the Tat addition to PC12 cells up-regulated the expression of the inducible cAMP early repressor (ICER), a specific member of the cAMP-responsive element modulator transcription factor family, in a cAMP-dependent manner. In turn, ICER overexpression abrogated the transcription activity of the TH promoter in PC12 cells, strongly suggesting ICER involvement in Tat-mediated inhibition of TH gene expression. In vivo injection of synthetic HIV-1 Tat protein into the striatum of healthy rats induced a subclinical Parkinson's-like disease that became manifested only when the animals were treated with amphetamine. As early as one week postinjection, the histochemical examination of the rat substantia nigra showed a reduced staining of neurons expressing TH followed by a loss of TH(+) neurons at later time points. As Tat protein can be locally released into the central nervous system by HIV-1-infected microglial cells, our findings may contribute to the explanation of the pathogenesis of the motorial abnormalities often reported in HIV-1 seropositive individuals.


White shark genome reveals ancient elasmobranch adaptations associated with wound healing and the maintenance of genome stability.
The white shark (Carcharodon carcharias; Chondrichthyes, Elasmobranchii) is one of the most publicly recognized marine animals. Here we report the genome sequence of the white shark and comparative evolutionary genomic analyses to the chondrichthyans, whale shark (Elasmobranchii) and elephant shark (Holocephali), as well as various vertebrates. The 4.63-Gbp white shark genome contains 24,520 predicted genes, and has a repeat content of 58.5%. We provide evidence for a history of positive selection and gene-content enrichments regarding important genome stability-related genes and functional categories, particularly so for the two elasmobranchs. We hypothesize that the molecular adaptive emphasis on genome stability in white and whale sharks may reflect the combined selective pressure of large genome sizes, high repeat content, high long-interspersed element retrotransposon representation, large body size, and long lifespans, represented across these two species. Molecular adaptation for wound healing was also evident, with positive selection in key genes involved in the wound-healing process, as well as Gene Ontology enrichments in fundamental wound-healing pathways. Sharks, particularly apex predators such as the white shark, are believed to have an acute sense of smell. However, we found very few olfactory receptor genes, very few trace amine-associated receptors, and extremely low numbers of G protein-coupled receptors. We did however, identify 13 copies of vomeronasal type 2 (V2R) genes in white shark and 10 in whale shark; this, combined with the over 30 V2Rs reported previously for elephant shark, suggests this gene family may underlie the keen odorant reception of chondrichthyans.


Neural changes in extinction recall following prolonged exposure treatment for PTSD: A longitudinal fMRI study.
Neurobiological models of posttraumatic stress disorder (PTSD) implicate fear processing impairments in the maintenance of the disorder. Specific deficits in extinction recall, the retention of learned extinction, have been demonstrated. While deficient extinction recall, and the associated activation pattern of prefrontal and hippocampal regions, distinguishes individuals with PTSD from controls, research has not yet examined changes following treatment. We examined the behavioral and neural correlates of extinction recall before and after cognitive behavioral treatment of PTSD. Fifty-eight participants (30 with PTSD, 28 trauma-exposed matched controls) underwent a 2-day behavioral fear conditioning, extinction, and recall paradigm during functional magnetic resonance imaging (fMRI). The same procedures were repeated 10 weeks later, after PTSD patients had completed prolonged exposure treatment. We analyzed fMRI data from 32 subjects (16 PTSD; 16 controls) and skin conductance response (SCR) data from 33 subjects (16 PTSD; 17 controls). Neural activity during extinction recall, SCR, and PTSD symptoms were compared across groups and over time. PTSD patients exhibited pre- to post-treatment reduction in rostral anterior cingulate cortex (rACC) activation during extinction recall, and increase in functional coherence between the rACC and the ventromedial prefrontal cortex (vmPFC) and subgenual anterior cingulate cortex (sgACC). Reduced PTSD symptom severity from pre- to post-treatment was significantly associated with reduced subgenual ACC and parahippocampal activation during this task. SCR during the extinction recall phase did not significantly change with treatment in the PTSD group, but change in SCR was associated with reduction in PTSD symptom severity. Prolonged exposure treatment appears to alter neural activation in PTSD patients during recall of fear extinction, and change in extinction recall (measured by SCR) is associated with symptom reduction. We discuss results in the context of neural systems involved in response to affective stimuli.


Evidence from community level inputs to improve quality of care for maternal and newborn health: interventions and findings.
Annually around 40 million mothers give birth at home without any trained health worker. Consequently, most of the maternal and neonatal mortalities occur at the community level due to lack of good quality care during labour and birth. Interventions delivered at the community level have not only been advocated to improve access and coverage of essential interventions but also to reduce the existing disparities and reaching the hard to reach. In this paper, we have reviewed the effectiveness of care delivered through community level inputs for improving maternal and newborn health outcomes. We considered all available systematic reviews published before May 2013 on the pre-defined community level interventions and report findings from 43 systematic reviews. Findings suggest that home visitation significantly improved antenatal care, tetanus immunization coverage, referral and early initiation of breast feeding with reductions in antenatal hospital admission, cesarean-section rates birth, maternal morbidity, neonatal mortality and perinatal mortality. Task shifting to midwives and community health workers has shown to significantly improve immunization uptake and breast feeding initiation with reductions in antenatal hospitalization, episiotomy, instrumental delivery and hospital stay. Training of traditional birth attendants as a part of community based intervention package has significant impact on referrals, early breast feeding, maternal morbidity, neonatal mortality, and perinatal mortality. Formation of community based support groups decreased maternal morbidity, neonatal mortality, perinatal mortality with improved referrals and early breast feeding rates. At community level, home visitation, community mobilization and training of community health workers and traditional birth attendants have the maximum potential to improve a range of maternal and newborn health outcomes. There is lack of data to establish effectiveness of outreach services, mass media campaigns and community education as standalone interventions. Future efforts should be concerted on increasing the availability and training of the community based skilled health workers especially in resource limited settings where the highest burden exists with limited resources to mobilize.


Antioxidant and pancreatic lipase inhibitory effects of flavonoids from different citrus peel extracts: An in vitro study.
Obesity and oxidative damage are two important risk factors associated closely with metabolic syndrome. Utilization of functional food ingredients is considered as a feasible way to tackle these challenges. In the present study, eight representative species of citrus peel extracts (CPEs) were evaluated and compared for their flavonoid profiles, antioxidant activities, and pancreatic lipase (PL) inhibitory capacities and mechanisms. Results indicated that hesperidin, naringin, neohesperidin, narirutin and eriocitrin were the five major flavonoids in CPEs, among which hesperidin was the main active PL inhibitor. Moreover, hesperidin could interact with PL by hydrogen bonds and van der Waals forces, and the interaction would not obviously change the secondary structure of PL. Overall, ponkan peel extract, having the strongest overall antioxidant activity, the highest content of hesperidin and total phenolic compounds among all tested CPEs, is a promising natural ingredient to scavenge free radicals and manage obesity.


Sorafenib combined with TACE in advanced primary hepatocellular carcinoma.
To evaluate the effectiveness and safety of sorafenib combined with transarterial chemoembolization (TACE) in patients with advanced primary hepatocellular carcinoma. A retrospective analysis of 65 patients with advanced primary hepatocellular carcinoma who had been administered sorafenib for more than one month and treated by TACE was performed. The tumor response was evaluated according to the response evaluation criteria in solid tumors and any side effects were recorded. Twelve patients entered a partial remission, 42 entered a stable condition, and the disease progressed in 11 patients. The disease control and objective regression rates were 83.1% and 18.5%, respectively. The one-year survival rate was 63.1%. Among the cases, the median overall survival time was 17 months, and the median time to progression was 9 months. The overall side effects rate was 78.5% and most were relieved after treatment. Sorafenib combined with TACE is a safe and effective treatment of advanced primary hepatocellular carcinoma.


Active site dynamics of ribonuclease.
The stochastic boundary molecular dynamics method is used to study the structure, dynamics, and energetics of the solvated active site of bovine pancreatic ribonuclease A. Simulations of the native enzyme and of the enzyme complexed with the dinucleotide substrate CpA and the transition-state analog uridine vanadate are compared. Structural features and dynamical couplings for ribonuclease residues found in the simulation are consistent with experimental data. Water molecules, most of which are not observed in crystallographic studies, are shown to play an important role in the active site. Hydrogen bonding of residues with water molecules in the free enzyme is found to mimic the substrate-enzyme interactions of residues involved in binding. Networks of water stabilize the cluster of positively charged active site residues. Correlated fluctuations between the uridine vanadate complex and the distant lysine residues are mediated through water and may indicate a possible role for these residues in stabilizing the transition state.