The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing.
To develop a questionnaire that is sensitive to changes in the symptomatology of the female lower urinary tract, particularly urinary incontinence, providing an instrument that can characterize symptom severity, impact on quality of life and evaluate treatment outcome. Items covering as wide a range of urinary symptoms as possible were devised after consultation with clinicians and a health scientist, a literature review and discussion with patients. Additional items assessed the degree of 'bother' that symptoms were causing. Eighty-five women with clinical symptoms attending for urodynamic assessment and 20 women with none were asked to self-complete the questionnaire. The instrument's validity was assessed by interviewing patients and measuring levels of missing data, comparing symptom scores between clinical and non-clinical populations and comparison with frequency/volume charts and data from pad tests. The instrument's reliability was assessed by measuring both internal consistency and stability, using a 2-week test-retest analysis. The questionnaire was completed by the patients with a mean of only 2% of items missing; most questions were easily understood. Construct validity was good, with the instrument easily differentiating clinical and non-clinical populations. Criterion validity, as tested against frequency/volume charts and pad-test data, was acceptable, with Kappa coefficients of 0.29-0.79 for frequency/volume data and Spearman rank correlations of 0.50-0.97 and 0.31-0.67 for frequency/volume and pad-test data, respectively. The reliability of the instrument was good; a Cronbach's alpha of 0.78 indicated that the symptom questions had high internal consistency, while stability was excellent, with 78% of symptoms and problems answered identically on two occasions, and Spearman rank correlations of 0.86 and 0.90, respectively. The instrument has good psychometric validity and reliability. The stability demonstrated at baseline and the ability to differentiate clearly between community and clinical populations suggest that it should be ideal for measuring changes following therapeutic intervention. The addition of life-impact items and a 'bother' factor may provide the opportunity to identify those women who wish treatment for their symptoms; this dimension requires further exploration.


Investigating the Impact of Control Modes to Competency and Engagement in Serious Game Play for Children with ADHD.
Serious games are designed to reduce symptoms of attention deficit among children with Attention Deficit/Hyperactivity Disorder (ADHD). These games predominantly use touchscreen interfaces that children with ADHD play in a sitting position, which contributes to already-problematic sedentary behaviors. In an effort to mitigate negative impacts of sedentary behavior, we set out to investigate the use of Dance Dance Revolution (DDR) mats with serious games to induce gross movements. To that end, we designed and implemented Breathtaking Glass Bridge to investigate the impact of interface (DDR vs. touchscreen) on competency and engagement in children with ADHD. Our investigation with 30 children with ADHD reveal that the DDR mat was as engaging as the conventional touchscreen interface despite relatively lower competence shown by our participants. Our study opens new research opportunities for developing and strategically using movement-based control interfaces to encourage gross movements while reducing attention deficit symptoms among children with ADHD.


Synergetic Self-Assembly of Liquid Crystalline Block Copolymer with Amphiphiles for Fabrication of Hierarchical Assemblies.
Novel functions and advanced structure, where each single component could not be produced individually, can exhibit from the collective and synergistic behavior of component systems. This synergetic strategy has been successfully demonstrated for co-assembly of polymer-polymer to construct hierarchical nanomaterials. However, differences in the natures of polymer and small molecules impose challenges in the construction of sophisticated co-assemblies with geometrical and compositional control. Herein, a synergetic self-assembly strategy is proposed to prepare organic-organic hybrid colloidal mesostructures by blending a liquid crystalline block copolymer (LC-BCP) with small molecular amphiphiles. Through a classic solvent-exchange process, amphiphiles embedded with LC-BCP realize multi-component nucleation and hierarchical assembly driven by anisotropic interaction from the LC ordering alignment of the core-forming block. 1D nanofibers with a periodic striped structure are formed by further LC component fusion and refinement. In addition, LC ordering effect of LC-BCP can be regulated by selecting appropriate solvents and leads to the formation of vesicular co-micelles. By means of the thermal-responsive behavior of amphiphiles, hexagonal pore arrays are finally generated on the surface of those vesicles.


Modelling the genesis and treatment of cancer: the potential role of physiologically based pharmacodynamics.
Physiologically based modelling of pharmacodynamics/toxicodynamics requires an a priori knowledge on the underlying mechanisms causing toxicity or causing the disease. In the context of cancer, the objective of the expert meeting was to discuss the molecular understanding of the disease, modelling approaches used so far to describe the process, preclinical models of cancer treatment and to evaluate modelling approaches developed based on improved knowledge. Molecular events in cancerogenesis can be detected using 'omics' technology, a tool applied in experimental carcinogenesis, but also for diagnostics and prognosis. The molecular understanding forms the basis for new drugs, for example targeting protein kinases specifically expressed in cancer. At present, empirical preclinical models of tumour growth are in great use as the development of physiological models is cost and resource intensive. Although a major challenge in PKPD modelling in oncology patients is the complexity of the system, based in part on preclinical models, successful models have been constructed describing the mechanism of action and providing a tool to establish levels of biomarker associated with efficacy and assisting in defining biologically effective dose range selection for first dose in man. To follow the concentration in the tumour compartment enables to link kinetics and dynamics. In order to obtain a reliable model of tumour growth dynamics and drug effects, specific aspects of the modelling of the concentration-effect relationship in cancer treatment that need to be accounted for include: the physiological/circadian rhythms of the cell cycle; the treatment with combinations and the need to optimally choose appropriate combinations of the multiple agents to study; and the schedule dependence of the response in the clinical situation.


Soluble CD146, a novel endothelial marker, is related to the severity of liver disease.
Angiogenesis and inflammation have been involved in the progression of fibrosis in patients with chronic liver disease (CLD). Soluble CD146 (sCD146), a biomarker that was recently characterized as a novel component of the endothelial junction is implicated in endothelial proliferation. Our study evaluates the performance of sCD146 in assessing liver fibrosis and cirrhosis, and determines if its levels are related to the severity of liver disease in patients with cirrhosis. sCD146 levels were determined by a commercially available immunoenzymatic technique in 62 consecutive patients with cirrhosis, 43 patients with CLD and 27 healthy controls. Patients with cirrhosis compared to non-cirrhotics with CLD had a higher median sCD146 concentration (639 vs. 317 ng/ml). In receiver operating characteristic (ROC) curve analysis, the cut-off of 412 ng/ml showed a sensitivity of 78% and a specificity of 75% for diagnosis of cirrhosis, offering good diagnostic accuracy (area under the ROC curve [AUROC: 0.838]). Patients with compensated compared to those with decompensated cirrhosis had a lower median sCD146 concentration (399 vs. 848 ng/ml, respectively). A cut-off of 534 ng/ml offered a sensitivity of 83% and a specificity of 78% for differentiating compensated from decompensated cirrhosis (AUROC: 0.866). Furthermore, in cirrhotics, sCD146 correlated positively with AST, bilirubin levels and most importantly with international normalized ratio and model for end-stage liver disease (r = 0.648, p < 0.001 and r = 0.567, p < 0.001, respectively). sCD146 can be used as a surrogate, inexpensive biomarker for the diagnosis of cirrhosis. It is also well correlated with severity of liver disease in cirrhotic patients. Further studies are needed to define its role in clinical practice.


Urologist-Level Correlation in the Use of Observation for Low- and High-Risk Prostate Cancer.
The reporting of individual urologist rates of observation for localized prostate cancer may be a valuable performance measure with important downstream implications for patient and payer stakeholder groups. However, few studies have examined the urologist-level variation in the use of observation across all risk strata of prostate cancer. To measure variation in the use of observation at the urologist level by disease risk strata and to evaluate the association between the urologist-level rates of observation for men with low-risk and high-risk prostate cancer. With the use of linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, a population-based study of men diagnosed with prostate cancer from January 1, 2004, to December 31, 2009, was performed in SEER catchment areas of the United States. A total of 57 639 men with prostate cancer with 1884 diagnosing urologists were identified. Data were analyzed from October 1 to December 31, 2015. The main outcome was observation, which is defined as the absence of definitive treatment within 1 year of diagnosis. In each risk stratum, a multivariable mixed-effects model was fit to characterize associations between observation and selected patient characteristics. From these models, the estimated probability of observation was calculated for each urologist within each risk stratum, and the association between the physician-level estimated rates of observation for low-risk and high-risk disease was assessed. Among the 57 639 men included in the study, the estimated probability of observation for low-risk disease varied impressively (mean, 27.8%; range, 5.1%-71.2%) at the individual urologist level. Considerably less urologist-level variation was seen in the use of observation for intermediate-risk disease (11.1%; range, 4.8%-31.5%) and high-risk disease (5.8%; range, 3.2%-16.5%). Furthermore, the estimated rates of observation for low- and high-risk disease were correlated at the urologist level (Spearman ρ = 0.17; P < .001). A comparable correlation was likewise observed among urologists with high-volume prostate cancer practices (Spearman ρ = 0.24; P < .001). Considerable urologist-level variation is seen in the use of observation for men with low-risk prostate cancer. More important, the use of observation for low-risk and high-risk patients with prostate cancer is correlated at the urologist level. This study reveals the strikingly variable use of observation among US urologists and establishes a framework for the use of urologist-level treatment signatures as a quality measure in the emerging value-based health care environment.


Clinical Features and Long-term Prognosis of Retinoblastoma according to Age at Diagnosis.
We aimed to study the clinical characteristics and long-term prognoses of retinoblastoma according to the age at diagnosis. A retrospective chart review of non-screened patients newly diagnosed with retinoblastoma between January 2007 and February 2018. Among the 20 patients analyzed, 11 were diagnosed at an age younger than 1 year (group 1) and nine at 1 year or older (group 2). The mean lag times until diagnosis were 1.0 ± 0.4 and 5.0 ± 2.1 months for groups 1 and 2, respectively (p = 0.056). The mean follow-up durations were 49.4 ± 12.7 and 58.3 ± 8.8 months, respectively (p = 0.412). Group 1 had a significantly higher proportion of bilateral retinoblastoma than did group 2 (72.7% vs. 11.1%, p = 0.010). Four of five patients (80.0%) with germline RB1 mutations were diagnosed with retinoblastoma at age 3 months or younger. The eyes of patients in group 2 had significantly higher International Intraocular Retinoblastoma Classification stages than did those of patients in group 1 (p for trend = 0.010). The proportion of eyes with optic nerve invasion and those that had undergone enucleation were significantly higher in group 2 (p = 0.033 and 0.046, respectively). Survival did not differ according to the age at diagnosis. Early onset retinoblastoma does not seem to indicate poor ocular or survival prognosis in Korean children with retinoblastoma.


Measuring biomass and carbon stock in resprouting woody plants.
Resprouting multi-stemmed woody plants form an important component of the woody vegetation in many ecosystems, but a clear methodology for reliable measurement of their size and quick, non-destructive estimation of their woody biomass and carbon stock is lacking. Our goal was to find a minimum number of sprouts, i.e., the most easily obtainable, and sprout parameters that should be measured for accurate sprout biomass and carbon stock estimates. Using data for 5 common temperate woody species, we modelled carbon stock and sprout biomass as a function of an increasing number of sprouts in an interaction with different sprout parameters. The mean basal diameter of only two to five of the thickest sprouts and the basal diameter and DBH of the thickest sprouts per stump proved to be accurate estimators for the total sprout biomass of the individual resprouters and the populations of resprouters, respectively. Carbon stock estimates were strongly correlated with biomass estimates, but relative carbon content varied among species. Our study demonstrated that the size of the resprouters can be easily measured, and their biomass and carbon stock estimated; therefore, resprouters can be simply incorporated into studies of woody vegetation.


Production of weanling rat ventromedial and dorsomedial hypothalamic syndromes by electrolytic lesions with platinum-iridium electrodes.
Weanling Sprague-Dawley rats received bilateral anodic electrolytic lesions with platinum-iridium (PtIr) electrodes in the ventromedial (VMN) and dorsomedial (DMN) hypothalamic areas. Sham-operated rats served as controls. The rats were maintained for 48 days (experiment 1) and 33 days (experiment 2) and food intake, body weight (b.w.), nose-tail length and obesity index were recorded. The data of both experiments indicate that all parameters change in the same direction, as they do when lesions are produced with anodic stainless steel electrodes: in the VMN-P-lesioned animals, b.w. gains and overall mean food intake were normal, carcass fat increased and linear growth was reduced. In experiment 2, however, there was a temporary hyperphagia during the 1st 2 weeks of the study. In the DMN-lesioned rats, both ponderal and linear growth and food intake were decreased but body composition was normal. Plasma obtained at sacrifice in experiment 2 showed slight but significant hyperinsulinemia in the VMN rats (p less than 0.02 vs control and p less than 0.05 vs DMN rats). Prolactin (PRL) levels, on the other hand, were higher in the DMN-lesioned rats (p less than 0.05 vs control and p less than 0.02 vs VMN rats). The data indicate that the changes characteristic of the weanling rat VMN and DMN syndrmes are due to 'true' tissue destruction rather than to artifactitious side effects of the lesions. They also suggest, therefore, than an 'irritative focus' hypothesis is not required to account for the observed alterations. They further suggest that the DMN may play role in the control of PRL release.


Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior.
Inhibitor of κB kinase (IκK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IκK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IκK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IκK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IκK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IκK (IκKca), or a dominant negative form of IκK into the NAc. Of all three experimental groups, only mice expressing IκKca show a behavioral phenotype. Expression of IκKca results in a decrease in the time spent in the non-periphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IκK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IκKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.


[Assessment values of procalcitonin, lactic acid, and disease severity scores in patients with sepsis].
To investigate the assessment values of procalcitonin (PCT), lactic acid (LAC), sequential organ failure assessment (SOFA) score and acute physiology and chronic health evaluation II (APACHE II) score in patients with sepsis. 140 patients with suspicious bacterial infection admitted to emergency department of Beijing Chaoyang Hospital of the Capital Medical University from August 2017 to June 2018 were enrolled. They were divided into three groups according to diagnostic criteria of Sepsis-3: non-sepsis group (n = 58), sepsis group (n = 66) and septic shock group (n = 16). The PCT, LAC, SOFA score, APACHE II score, 28-day prognosis, and positive detection rate of PCT and LAC were compared among three groups. Independent predictors of 28-day mortality were analyzed by Logistic regression; predictive values of PCT, LAC, SOFA score and APACHE II score for 28-day mortality in sepsis patients were analyzed by receiver operating characteristic (ROC) curve. PCT, LAC, SOFA score, APACHE II score at admission, and 28-day mortality in sepsis group and septic shock group were significantly higher than those in non-sepsis group, and PCT, LAC, APACHE II score, and 28-day mortality in sepsis shock group were further higher than those in sepsis group [PCT (μg/L): 38.1±12.6 vs. 4.6±2.3, LAC (mmol/L): 3.3±2.1 vs. 2.4±2.1, APACHE II score: 14.9±2.4 vs. 9.5±4.3, 28-day mortality: 75.0% vs. 24.2%, all P < 0.05]. The positive detection rate of PCT and LAC in sepsis group and septic shock group were higher than those in non-sepsis group (positive detection rate of PCT: 56.1%, 81.3% vs. 32.8%; positive detection rate of LAC: 42.4%, 62.5% vs. 13.7%; all P < 0.01). Logistic regression analysis showed that PCT, LAC, SOFA score and APACHE II score were independent predictors of 28-day mortality [PCT: odds ratio (OR) = 0.933, 95% confidence interval (95%CI) = 0.878-0.991; LAC: OR = 0.539, 95%CI = 0.347-0.838; SOFA score: OR = 0.291, 95%CI = 0.514-0.741; APACHE II score: OR = 0.808, 95%CI = 0.669-0.976; all P < 0.05]. ROC curve analysis showed that the area under ROC curve (AUC) of PCT, LAC, SOFA score and APACHE II score predicting 28-day mortality was 0.76, 0.86, 0.81 and 0.87, respectively. The assessment values of APACHE II score and LAC were higher than PCT in predicting 28-day mortality (Z1 = 2.56, Z2 = 2.45, both P < 0.01), and the performance of SOFA score was similar to PCT. PCT, LAC, SOFA score and APACHE II score were reliable indexes to evaluate disease severity for patients diagnosed with infection. The assessment values of APACHE II score and LAC in 28-day mortality were superior to SOFA score and PCT.


Pulmonary deportation of hydatidiform mole: a 12-year, single tertiary center experience in China.
Pulmonary deportation of hydatidiform mole is an exceedingly rare entity. The underlying mechanisms and proper management strategies remain unclear based on sporadic case reports over the past six decades. This study aimed to investigate the clinical features and rational treatment of patients with benign molar pregnancies with pulmonary deportation based on our experience. Medical records of 20 cases of hydatidiform mole with pulmonary deportation were retrospectively reviewed at Peking Union Medical College Hospital from November 2006 to May 2019. The detailed information of all patients was recorded and analyzed. Patients were divided into different groups according to their characteristics and Mann-Whitney U test was used to compare the duration to achieve a normal β-human chorionic gonadotrophin (β-hCG) level after the first evacuation among groups. Initial pulmonary computed tomography scans showed suspected bilateral, left and right chest deportation of hydatidiform mole in 12, four, and four patients, respectively, with the maximum nodular diameter ranging from 0.6 to 1.2 cm. Ten patients achieved lesion resolution while the remaining ten patients achieved decreases in the size of their pulmonary lesions. The median duration to achieve a normal β-hCG level after the first evacuation was 15.5 (13.0, 21.9) weeks. There was no significant difference in the duration to achieve a normal β-hCG level after the first evacuation between two groups based on age (≥40 years vs. < 40 years: 15.8 [12.2, 21.5] weeks vs. 15.5 [12.9, 23.0] weeks, Z = 0.094, P = 0.925), type of antecedent mole (partial mole vs. complete mole: 15.2 [12.5, 27.4] weeks vs. 15.9 [12.9, 21.5] weeks, Z = 0.165, P = 0.869), distribution of pulmonary nodules (bilateral lungs vs. unilateral lung: 15.2 [12.8, 22.5] weeks vs. 15.9 [13.2, 22.2] weeks, Z = 0.386, P = 0.700), maximum size of pulmonary nodules (>0.5 cm vs. ≤0.5 cm: 13.0 [11.3, 17.2] weeks vs. 16.0 [14.5, 23.8] weeks, Z = 1.815, P = 0.070), and number of uterine evacuations (once vs. twice or three times: 15.0 [13.0, 16.3] weeks vs. 16.0 [12.8, 23.9] weeks, Z = 0.832, P = 0.405). The post-molar cohort was followed up for 17 to 139 months, and no gestational trophoblastic neoplasia was observed. No surgeries other than uterine evacuation and no chemotherapy regimens are recommended for such patients if they achieve satisfactory decreases in the level of hCG and gradual decrease or disappearance of pulmonary deportation nodules. Patients should be informed about the necessity of long-term follow-up. More collaborative international studies on this exceedingly rare condition may guide decisions regarding optimal management strategies.


Chemometrics applications in biotech processes: a review.
Biotech unit operations are often characterized by a large number of inputs (operational parameters) and outputs (performance parameters) along with complex correlations amongst them. A typical biotech process starts with the vial of the cell bank, ends with the final product, and has anywhere from 15 to 30 such unit operations in series. The aforementioned parameters can impact process performance and product quality and also interact amongst each other. Chemometrics presents one effective approach to gather process understanding from such complex data sets. The increasing use of chemometrics is fuelled by the gradual acceptance of quality by design and process analytical technology amongst the regulators and the biotech industry, which require enhanced process and product understanding. In this article, we review the topic of chemometrics applications in biotech processes with a special focus on recent major developments. Case studies have been used to highlight some of the significant applications.


Very early discharge from hospital after normal deliveries.
The aim of the present study was to investigate, in a descriptive study, how healthy women experienced early discharge from hospital, 6-12 hours, after normal deliveries. Expecting couples were prepared for early discharge during pregnancy. The women delivered at the University Hospital in Uppsala. All infants had two obligatory medical examinations, one before leaving the hospital and one for metabolic screening after four or five days. Both mothers and infants received postpartum care at home by midwives. One hundred and three women participated and answered a questionnaire four to five days after delivery. Twenty of the women were additionally interviewed by telephone four months after delivery. The average length of stay at the hospital after delivery was 8 hours. The families had, on average, 1.9 visits at home. All women considered that they had received sufficient care and advice from the midwives, although 40 percent felt uncertainty about something in the postpartum period. Questions frequently raised concerned breast-feeding. Two infants were readmitted to hospital due to mild neonatal hyperbilirubinemia. All but three women wanted to repeat very early discharge after a future uncomplicated delivery. Ninety-five percent of the women were still breast-feeding after four months. We conclude, that antenatal preparation and a well-organised, adequate postpartum home-care is of the greatest importance, to establish safe early discharge after uncomplicated deliveries. This concept of early discharge from hospital, with midwifery home care provided, is safe and appreciated by the new parents.


[Findings of standard and high-frequency audiometry in workers exposed to occupational noise for long durations].
Changes in hearing thresholds were determined by standard and high-frequency audiometry in subjects exposed to occupational noise for long durations. Hearing thresholds were measured between 250 and 16000 Hz frequencies by standard and high-frequency audiometry in 64 male workers (mean age 42 years; range 31 to 55 years) of a hydroelectric power plant and in 30 age- and sex-matched controls with no hearing problems. The workers were divided into three groups according to the noise level and into four groups according to the duration of exposure. The mean hearing thresholds of workers showed significant increases in all frequencies from 4000 to 16000 Hz (p<0.005), the most affected frequencies being 4000, 6000, 14000, and 16000 Hz (p<0.0005). Increases in hearing thresholds were significantly correlated with the noise level and duration of exposure to noise (p<0.05). The results suggest that high-frequency audiometry should be used together with standard audiometry in the detection and follow-up of individuals who are at potential risks for hearing losses.


Synthesis, characterization and electrochemiluminescent properties of cyclometalated platinum(II) complexes with substituted 2-phenylpyridine ligands.
Two neutral cyclometalated platinum(II) complexes, Pt(DPP)(acac) and Pt(BPP)(acac) (DPP = 2,4-diphenylpyridine, BPP = 2-(4-tert-butylphenyl)-4-phenylpyridine, acac = acetylacetone), have been synthesized and characterized by (1)H NMR spectroscopy, mass spectrometry, elemental analyses and by X-ray crystallography for Pt(DPP)(acac). Electrogenerated chemiluminescence (ECL) of the two complexes in the absence or presence of coreactant tri-n-propylamine (TPrA) in different solvents (CH(3)CN, CH(2)Cl(2), DMF, CH(3)CN/H(2)O (V, 50 : 50)) has been studied. The ECL spectra are identical to their own PL spectra, indicating that ECL processes lead to the same metal-to-ligand charge-transfer ((3)MLCT) excited state that is generated by light excitation. The ECL potentials of Pt(DPP)(acac) and Pt(BPP)(acac)/TPrA in CH(3)CN and CH(3)CN/H(2)O solution were at ~0.75 V vs. SCE, and significantly negatively shifted by about 0.6 V compared to that of the Ru(bpy)(3)(2+)/TPrA system. The ECL quantum efficiencies of the complexes are comparable to that of the Ru(bpy)(3)(2+)/TPrA system. The significant increase of the ECL signal in the coreactant system is due to the formation of the strongly reducing intermediate TPrA˙. It is noteworthy that the ECL efficiencies of the synthesized compounds are much higher than that of the tridentate polypyridyl ligands.


Bayesian model selection framework for identifying growth patterns in filamentous fungi.
This paper describes a rigorous methodology for quantification of model errors in fungal growth models. This is essential to choose the model that best describes the data and guide modeling efforts. Mathematical modeling of growth of filamentous fungi is necessary in fungal biology for gaining systems level understanding on hyphal and colony behaviors in different environments. A critical challenge in the development of these mathematical models arises from the indeterminate nature of their colony architecture, which is a result of processing diverse intracellular signals induced in response to a heterogeneous set of physical and nutritional factors. There exists a practical gap in connecting fungal growth models with measurement data. Here, we address this gap by introducing the first unified computational framework based on Bayesian inference that can quantify individual model errors and rank the statistical models based on their descriptive power against data. We show that this Bayesian model comparison is just a natural formalization of Occam׳s razor. The application of this framework is discussed in comparing three models in the context of synthetic data generated from a known true fungal growth model. This framework of model comparison achieves a trade-off between data fitness and model complexity and the quantified model error not only helps in calibrating and comparing the models, but also in making better predictions and guiding model refinements.


Recombinant human interferon-gamma as prophylaxis against rhinovirus colds in volunteers.
The first evaluation of intranasal (i.n.) recombinant human interferon-gamma (rHuIFN-gamma) as prophylaxis against experimental rhinovirus (RV) infection and illness in volunteers is reported. In two studies, 7 of 27 (26%) of the volunteers who received rHuIFN-gamma (2 Mu i.n. 3 x /day) had either blood stained nasal secretions or nose bleeding which was not observed in any of the 26 placebo recipients. Some volunteers given rHuIFN-gamma showed increased nasal secretion and the majority complained of slight nasal stuffiness, whereas only a few of those receiving placebo complained of these symptoms. In the prophylactic study, 17 volunteers were given the above regimen of rHuIFN-gamma and 17 placebo; after the fourth dose all were challenged with RV9, followed 1 h later with RV14 (100 TCID50 of each virus). Compared with the placebo-treated controls, interferon recipients showed no significant reduction in the proportion who developed colds or became infected, and there was an increase in both their mean clinical scores and mean nasal secretion weights. Thus i.n. rHuIFN-gamma did not prevent rhinovirus infection or illness and may enhance the symptoms.


Idiopathic fibrous mediastinitis--a case report.
A rare case of idiopathic fibrous mediastinitis is reported. Symptoms, etiology, diagnostic and therapeutic aspects are discussed with reference to the literature. In this case in which dysphagia and hoarseness were the presenting symptoms, a successful oesophageal myotomy was performed.


Body composition, energy, protein and iron intake of Nigerian female nursing students.
100 apparently healthy female nursing students (aged 20-30 years) were studied. A 24 hours dietary recall was recorded. Additionally a questionnaire was elaborated to collect dietary parameters for 3 days. From the mean daily food intake the energy, protein and iron intake was calculated. A series of anthropometric measurements, i.e. body weight, body height and skinfold thickness (triceps, breast, scapula, abdomen) were used to determine total body fat, lean body mass, optimum weight, and relation weight. The mean total body fat of the 100 subjects was (21.3 +/- 5.1) % and (12.7 +/- 4.4) kg, respectively, the optimum weight (56.6 +/- 6.3) kg and the mean relative weight (101 +/- 12.4) %. 11% of the 100 subjects studied was underweight, 73% showed normal weight, 10% was overweight and 6% obese. All the age groups met their energy and protein requirements as well as the iron intake.


[Reduction of cigarette consumption: an intermediate stage before a total stop?].
Reduction of cigarette consumption is a natural tendency of many undecided smokers and can be an intermediate stage before a total stop. It does not offer proven benefits regarding smoking-associated morbidity or mortality but seems to increase the motivation of smokers without intention to quit and the long-term chance of cessation. Smoking reduction can be offered to some smokers with smoking-related diseases as a transition before complete cessation. It can be obtained more easily with the use of nicotine replacement therapy.


Determinants of patronage of traditional bone setters in the middle belt of Nigeria.
Traditional bone setting is a practice that is common in our environment. This is a community based survey of opinions concerning orthodox and traditional fracture management in four states of the middle belt of Nigeria. We set out to ascertain the factors influencing preference of treatment of fractures among populations in the middle belt of Nigeria. A community based questionnaire survey of randomly selected adults regarding preference of choice of treatment between orthodox and traditional fracture management. One hundred and eighty-six questionnaires were found analyzable with a male to female ratio of 2:1. There was a preponderance of preference for orthodox fracture management (70.4%). Decisions were mainly collegiate, outside the influence of the individual; only 9.9% decided to attend traditional bone setters on their own. Reasons adduced for preference of traditional bone setters were incongruous and inconsistent. A fixated cultural outlook was recognized as being the motivating factor for patronage of traditional bone setters. Need for enlightenment campaign of the public against patronage of traditional bone setters is emphasized. A gradual phasing out of traditional bone setting with a road map towards making orthodox fracture management available to all is advocated.


Selective determination of total vanadium in water samples by cloud point extraction of its ternary complex.
A highly sensitive micelle-mediated extraction methodology for the preconcentration of trace levels of vanadium as a prior step to its determination by flame atomic absorption spectrometry (FAAS) has been developed. Vanadium was complexed with 1-(2-pyridylazo)-2-naphthol (PAN) and hydrogen peroxide in acidic medium (0.2 mol L(-1) phosphoric acid) using Triton X-100 as surfactant and quantitatively extracted into a small volume of the surfactant-rich phase after centrifugation. The color reaction of vanadium ions with hydrogen peroxide and PAN in phosphoric acid medium is highly selective. The chemical variables affecting cloud point extraction (CPE) were evaluated and optimized. The R.S.D. for 5 replicate determinations at the 20 microg L(-1)V level was 3.6%. The calibration graph using the preconcentration system for vanadium was linear with a correlation coefficient of 0.99 at levels near the detection limits up to at least 0.6 microg L(-1). The method has good sensitivity and selectivity and was applied to the determination of trace amounts of vanadium in water samples with satisfactory result. The proposed method is a rare application of CPE-atomic spectrometry to vanadium assay, and is superior to most other similar methods, because its useful pH range is in the moderately acidic range achieved with phosphoric acid. At this pH, many potential interferents are not chelated with PAN, and iron(III) as the major interferent is bound in a stable phosphate complex.


In situ regeneration of inner hair cells in the damaged cochlea by temporally regulated co-expression of Atoh1 and Tbx2.
Cochlear inner hair cells (IHCs) are primary sound receptors, and are therefore a target for developing treatments for hearing impairment. IHC regeneration in vivo has been widely attempted, although not yet in the IHC-damaged cochlea. Moreover, the extent to which new IHCs resemble wild-type IHCs remains unclear, as is the ability of new IHCs to improve hearing. Here, we have developed an in vivo mouse model wherein wild-type IHCs were pre-damaged and nonsensory supporting cells were transformed into IHCs by ectopically expressing Atoh1 transiently and Tbx2 permanently. Notably, the new IHCs expressed the functional marker vGlut3 and presented similar transcriptomic and electrophysiological properties to wild-type IHCs. Furthermore, the formation efficiency and maturity of new IHCs were higher than those previously reported, although marked hearing improvement was not achieved, at least partly due to defective mechanoelectrical transduction (MET) in new IHCs. Thus, we have successfully regenerated new IHCs resembling wild-type IHCs in many respects in the damaged cochlea. Our findings suggest that the defective MET is a critical barrier that prevents the restoration of hearing capacity and should thus facilitate future IHC regeneration studies.


Omega-3 polyunsaturated fatty acids and non-communicable diseases: meta-analysis based systematic review.
The aim of this updated systematic review is to summarize the evidence of the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on non-communicable diseases (NCDs). Publications of meta-analysis up to August 2014 were systematically searched from PubMed, the Cochrane and EMBASE databases. N-3 PUFAs have the following beneficial effects; cardio-protective effects, reduce ischemic stroke risk in both men and women and total stroke risk in women, increase insulin sensitivity in Asians, decrease risk of breast cancer and colorectal cancer in men. However, n-3 PUFAs may have unfavourable effects on type 2 diabetes in Caucasians. In conclusion, n-3 PUFA plays a crucial role in the prevention of NCDs, however, unfavourable effects should be considered in subjects with certain clinical conditions. Cross-cultural studies on the effect of n-3 PUFA on type 2 diabetes are needed to verify why diabetic patients with different ancestries have a different response to n-3 PUFA.


Hepatitis A virus in the liver and intestine of marmosets after oral inoculation.
A total of 12 seronegative marmosets (Saguinus mystax) were inoculated orally with hepatitis A virus (HAV) and sacrificed at 3- to 4-day intervals. Tissues from the livers, intestines, mesenteric lymph nodes, and spleens were obtained for immunofluorescence studies, and bile and intestinal contents were obtained for enzyme-linked immunosorbent assay studies. Two marmosets sacrificed on days 34 and 41 after inoculation developed antibody to HAV and demonstrated HAV in their livers but not in any part of their intestinal tissues. None of the remaining marmosets sacrificed from days -3 to 31 survived long enough to develop antibody to HAV, but an additional two marmosets, which were sacrificed on days 21 and 31, demonstrated HAV in their livers and also in bile but not in the intestinal tissues or their contents. The mesenteric lymph nodes and spleens were negative for HAV by immunofluorescence in all the marmosets. No evidence of HAV replication was demonstrated in any part of the intestine at any time during the incubation period or during acute illness in the marmosets inoculated orally with HAV. The shedding of HAV in stools in the late incubation period can be explained by excretion of HAV from the livers with the bile.


Vectorial transcytosis of dimeric IgA by the Calu-3 human lung epithelial cell line: upregulation by IFN-gamma.
We have developed an in vitro airway epithelial cell model for dimeric immunoglobulin (Ig) A (dIgA) transcytosis that allows the assessment of polymeric Ig receptor (pIgR) gene expression and actual dIgA transport. Tight monolayers of human lung-derived Calu-3 adenocarcinoma cells grown on permeable membranes expressed pIgR mRNA and released more secretory component (SC; P < 0.01) and secretory IgA (sIgA; P < 0.02) into the apical medium than into the basolateral medium. Transcytosis of dIgA was not due to paracellular leakage and was inhibited to approximately 20 and 30% of control values by anti-pIgR antibodies and the competitive ligand pentameric IgM, respectively. Interferon-gamma (IFN-gamma; 200 U/ml) induced pIgR mRNA expression and increased apical release of free SC and sIgA in a dose-dependent fashion (P < 0.0001). Basolateral addition of increasing amounts of dIgA dose dependently increased apical sIgA release (P < 0.0001). These data indicate that Calu-3 monolayers are capable of translocating dIgA through the pIgR. In addition, we show the integrated stimulatory effect of IFN-gamma on pIgR mRNA and protein expression and dIgA transcytosis.


Fully Electrically Controlled van der Waals Multiferroic Tunnel Junctions.
The fully electrical control of the magnetic states in magnetic tunnel junctions is highly pursued for the development of the next generation of low-power and high-density information technology. However, achieving this functionality remains a formidable challenge at present. Here we propose an effective strategy by constructing a trilayer van der Waals multiferroic structure, consisting of CrI3-AgBiPSe6 and Cr2Ge2Te6-In2Se3, to achieve full-electrical control of multiferroic tunnel junctions. Within this structure, two different magnetic states of the magnetic bilayers (CrI3/Cr2Ge2Te6) can be modulated and switched in response to the polarization direction of the adjacent ferroelectric materials (AgBiPSe6/In2Se3). The intriguing magnetization reversal is mainly attributed to the polarization-field-induced band structure shift and interfacial charge transfer. On this basis, we further design two multiferroic tunnel junction devices, namely, graphene/CrI3-AgBiPSe6/graphene and graphene/Cr2Ge2Te6-In2Se3/graphene. In these devices, good interfacial Ohmic contacts are successfully obtained between the graphene electrode and the heterojunction, leading to an ultimate tunneling magnetoresistance of 9.3 × 106%. This study not only proposes a feasible strategy and identifies a promising candidate for achieving fully electrically controlled multiferroic tunnel junctions but also provides insights for designing other advanced spintronic devices.


A preliminary investigation of short-term cytokine expression in gingival crevicular fluid secondary to high-level orthodontic forces and the associated root resorption: case series analytical study.
Orthodontically induced iatrogenic root resorption (OIIRR) is an unavoidable inflammatory process. Several factors claimed to be related to the severity of OIIRR. Orthodontic forces cause micro-trauma to the periodontal ligament and activate a cascade of cellular events associated with local periodontal inflammation. The purpose of this split-mouth study were (1) to investigate the changes in cytokine profile in the gingival crevicular fluid (GCF) secondary to heavy orthodontic forces and (2) to compare the cytokine expression between participants showing high and low root resorption. Eight participants requiring maxillary first premolar extractions involved in this study. The teeth on the tested side (TS) received 225 g of controlled buccal tipping force for 28 days, while the contralateral teeth act as a control (CS). GCF was collected from both TS and CS teeth at 0 h (prior to application of force) and 3 h, 1 day, 3 days, 7 days and 28 days after the application of force, and analysed with multiplex bead immunoassay to determine the cytokine levels. Statistically significant temporal increase was found in the TS teeth for tumour necrosis factor alpha (TNF-α) at 3 h and 28 days (p = 0.01). Interleukin 7 (IL-7) significantly peaked at the 28th day. Comparing cytokine profile for participants with high and low root resorption (>0.35 and <0.15 mm3, respectively), the levels of GM-CSF was significantly greater in low root resorption cases (p < 0.05). The amounts of root resorption which craters on mesial, distal surfaces and middle third region were significant in the TS teeth (p < 0.05). IL-7 and TNF-α (pro-resorptive cytokine) increased significantly secondary to a high-level of orthodontic force application. Significantly high levels of granulocyte macrophage colony-stimulating factor (anti-resorptive cytokine) were detected in mild root resorption cases secondary to high-level orthodontic force application. A future long-term randomised clinical trial with larger sample taking in consideration gender, age and growth pattern distribution would be recommended.


Thiopurines: factors influencing toxicity and response.
Thiopurines are the backbone of current anti-leukemia regimens and have also been effective immunosuppressive agents for the past half a century. Extensive research on their mechanism of action has been undertaken, yet many issues remain to be addressed to resolve unexplained cases of thiopurine toxicity or treatment failure. The aim of this review is to summarize current knowledge of the mechanism of thiopurine action in experimental models and put into context with clinical observations. Clear understanding of their metabolism will contribute to maximizing efficacy and minimizing toxicity by individually tailoring therapy according to the expression profile of relevant factors involved in thiopurine activation pathway.


In the Real World: Infections Associated with Biologic and Small Molecule Therapies in Psoriatic Arthritis and Psoriasis.
To summarize our most current understanding of the real world risk of infections associated with biologic and small molecule therapies in the setting of psoriatic disease. Patients with psoriasis or psoriatic arthritis are at increased risk for infection from both their disease and some of their therapies. There is little real world data for biologic and small molecule therapies; however, ustekinumab and biologics inhibiting IL-17 or IL-23 appear to have reduced risk estimates compared to anti-TNF therapies. Apremilast seems to have little infectious signal with limited real world data, and for JAK inhibitors, limited real world data suggest a higher risk of herpes zoster. Recently approved targeted and small molecule therapies for psoriasis carry infectious risks for patients, although they appear to vary across mechanism of action. As these treatments become more widespread, and additional therapies are approved, it will be imperative to evaluate their safety in the context of real world data.


Quantitative proteome and phosphoproteome analyses of cultured cells based on SILAC labeling without requirement of serum dialysis.
The use of dialyzed serum is essential in the application of the conventional stable isotope labeling by amino acids in cell culture (SILAC) approach to achieve complete labeling of proteins for quantitative proteomics. Here, we first evaluated the impact of dialyzed serum on the proteome and phosphoproteome of hormone-sensitive breast cancer MCF-7 cells and found that dialyzed serum influenced the expression of proteins related to signaling systems via hormone receptors, inducing a marked change of the phosphoproteome compared with the use of non-dialyzed serum. We also evaluated 9 other cell lines, including HeLa, HEK293 and Panc1, and found that the influence of serum dialysis on the expression profiles of the proteome and phosphoproteome varied, depending on the cell type. To avoid these problems, we established a SILAC-based quantification approach without the requirement of serum dialysis. Our simple approach is based on dual labeling of two populations of cells with two kinds of heavy amino acids of different mass, using non-dialyzed serum. Using our SILAC approach with non-dialyzed serum, we successfully quantified the phosphoproteome of MCF-7 cells induced by lapatinib, an EGFR1/Her2 dual kinase inhibitor. Because of the dual labeling approach, our method is widely applicable to cultured cells in which protein labeling is incomplete for any reason, e.g., owing to the use of non-dialyzed serum or a low growth rate.


Biobased Terpene Derivatives: Stiff and Biocompatible Compounds to Tune Biodegradability and Properties of Poly(butylene succinate).
Different copolymers incorporating terpene oxide units (e.g., limonene oxide) have been evaluated considering thermal properties, degradability, and biocompatibility. Thus, polycarbonates and polyesters derived from aromatic, monocyclic and bicyclic anhydrides have been considered. Furthermore, ring substitution with myrcene terpene has been evaluated. All polymers were amorphous when evaluated directly from synthesis. However, spherulites could be observed after the slow evaporation of diluted chloroform solutions of polylimonene carbonate, with all isopropene units possessing an R configuration. This feature was surprising considering the reported information that suggested only the racemic polymer was able to crystallize. All polymers were thermally stable and showed a dependence of the maximum degradation rate temperature (from 242 °C to 342 °C) with the type of terpene oxide. The graduation of glass transition temperatures (from 44 °C to 172 °C) was also observed, being higher than those corresponding to the unsubstituted polymers. The chain stiffness of the studied polymers hindered both hydrolytic and enzymatic degradation while a higher rate was detected when an oxidative medium was assayed (e.g., weight losses around 12% after 21 days of exposure). All samples were biocompatible according to the adhesion and proliferation tests performed with fibroblast cells. Hydrophobic and mechanically consistent films (i.e., contact angles between 90° and 110°) were obtained after the evaporation of chloroform from the solutions, having different ratios of the studied biobased polyterpenes and poly(butylene succinate) (PBS). The blend films were comparable in tensile modulus and tensile strength with the pure PBS (e.g., values of 330 MPa and 7 MPa were determined for samples incorporating 30 wt.% of poly(PA-LO), the copolyester derived from limonene oxide and phthalic anhydride. Blends were degradable, biocompatible and appropriate to produce oriented-pore and random-pore scaffolds via a thermally-induced phase separation (TIPS) method and using 1,4-dioxane as solvent. The best results were attained with the blend composed of 70 wt.% PBS and 30 wt.% poly(PA-LO). In summary, the studied biobased terpene derivatives showed promising properties to be used in a blended form for biomedical applications such as scaffolds for tissue engineering.


[The relationship between hydrolases and invasion of gastric carcinoma].
In order to clarify the relationship between hydrolases and the invasion of gastric carcinoma, both fibronectin and proteoglycan in pericancerous matrix and beta-galactosidase activity in gastric carcinoma were investigated by means of histochemical, immunohistochemical and ruthenium red electrocytochemical stains. The results showed that the activity of beta-galactosidase in mucous cell carcinoma was more intensive than that in well-differentiated and poorly-differentiated adenocarcinoma. RR granules and fibronectin were not found in the pericancerous matrix close to the mucous cell carcinoma, but were obtained in the region far from the mucous cell carcinoma. Nevertheless, both of them were present and intact near the well-differentiated adenocarcinoma. The result of this study suggests that mucous cell carcinoma may secrete beta-galactosidase into the surrounding matrix, inducing degradation of proteoglycan and fibronectin in favour of further infiltration and metastasis.


Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2.
A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.


In vivo metabotropic glutamate receptor 5 (mGluR5) antagonism prevents cocaine-induced disruption of postsynaptically maintained mGluR5-dependent long-term depression.
Metabotropic glutamate receptor 5 (mGluR5) plays a critical role in psychostimulant-induced behavior, yet it is unclear whether mGluR5 is activated by psychostimulant administration, or whether its role is constitutive. We previously reported that activation of mGluR5 with the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) can induce a long-term depression (DHPG-LTD) of glutamatergic transmission in the bed nucleus of the stria terminalis (BNST), and that ex vivo induction of this LTD is disrupted by repeated in vivo administration of cocaine. Here we demonstrate that DHPG-LTD is not maintained by alterations in glutamate release, and that postsynaptic endocytosis is necessary. Furthermore, we find that a single administration of cocaine produces a transient disruption of DHPG-LTD, and the duration of this disruption was increased by repeated days of cocaine administration. The disruption produced by cocaine was not permanent, because DHPG-LTD could be induced 10 d after cocaine administration. To test the role of mGluR5 in vivo in the cocaine-induced disruption of DHPG-LTD, we injected mice with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine before cocaine. mGluR5 antagonism during in vivo cocaine administration rescued subsequent ex vivo induction of DHPG-LTD. The effects of in vivo cocaine could be mimicked by application of cocaine to BNST-containing slices, suggesting that the actions of cocaine are local. Thus, using a novel strategy of in vivo antagonist-induced rescue of ex vivo agonist effects for the same receptor, we provide evidence suggesting that mGluR5 activation is actively recruited by in vivo cocaine.


Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision.
The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored. In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1beta, IL-6, G-CSF, KC and TNFalpha after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone. The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.


Depression increases the risk of mortality among people living with diabetes: Results from national health and nutrition examination survey, USA.
Type 2 Diabetes (T2D) and depression are leading global public health problems associated with profound disability and lower quality of life. Extensive evidence suggests that the two disorders are frequently comorbid. However, long-term effects such as the risk of mortality due to depression among people living with T2D are not well explored. Data from the National Health and Nutrition Examination Survey, 2005-2010 were linked with mortality files from the National Death Index up to December 31st, 2019. A total of 14,920 American adults were included in the study sample; nearly a tenth of them had depression (9.08 %) or T2D (10 %). In adjusted analysis, individuals with T2D were 1.70 times more likely (95 % CI = 1.42-2.03) to die than those without T2D. Among people living with T2D without depression, the risk of mortality was 1.55 times higher, but those with both T2D and depression had a 4.24 times higher risk of mortality. Given the greater risk of morbidity and premature mortality with cooccurring T2D and depression, widespread screening is warranted with a focus on high-risk groups. Integrated and collaborative care models can help address the psychosocial needs of people with T2D and should be widely implemented with the sensitization of clinicians and care teams in primary and specialist care for T2D.


Analysis of PET parameters predicting response to radiotherapy for myeloid sarcoma.
Positron-emission tomography (PET)-CT has recently been used for diagnostic imaging and radiotherapy for myeloid sarcoma, but there is little research on predicting the response of radiotherapy. The aim of this study was to analyze the association between PET-CT variables and the response to radiotherapy in patients with myeloid sarcoma. This study was conducted in myeloid sarcoma patients who received radiotherapy and PET-CT before and after radiotherapy. The response to radiotherapy was evaluated based on the European Organization for Research and Treatment of Cancer PET response criteria, and binary regression analysis was performed to assess the factors predicting reductions in the maximum standardized uptake value (SUVmax). Twenty-seven sites in 12 patients were included in the study. Complete metabolic responses were seen in 24 patients after radiotherapy, a partial metabolic response in one, and progressive metabolic disease in two patients. The prescribed dose of more than 3000 cGy10 was significantly greater in the treatment control group (P = 0.024). In binary logistic regression analysis predicting reductions in the SUVmax of more than 70% after radiotherapy, the pretreatment SUVmax (≥ 7.5) and further chemotherapy after radiotherapy showed significant differences in univariate and multivariate analyses. Good metabolic responses (complete or partial) to radiotherapy were achieved in 92.6% of the myeloid sarcoma patients. Radiation doses < 3000 cGy10 and increased SUVmax were related to treatment failure and high SUVmax before radiotherapy was a factor influencing SUVmax reduction. Further large-scale studies are needed.


Stat3-mTOR signaling mediates the stimulation of GLP-1 production induced by IL-27.
GLP-1 is a potent glucose-dependent insulinotropic hormone derived from intestinal L cells. Inflammatory Interleukin-27 (IL-27), a pleiotropic two-chain cytokine, is composed of EBI3 and IL-27 p28 subunits. IL-27 has a protective effect on pancreatic β-cell function. The relationship between IL-27 and GLP-1 is still unexplored. Here we showed interleukin-27-stimulated GLP-1 production via the Stat3-mTOR-dependent mechanism. Interleukin 27 receptor subunit alpha (IL-27 Rα) was detected in ileum and STC-1 cells. Co-localization of EBI3 and GLP-1 was observed not only in mouse ileums but also in human ileums and colons. Third-ventricular infusion of IL-27 increased ileal and plasma GLP-1 in both lean C57BL/6J mice and diet-induced obese and diabetic mice. These changes were associated with a significant increase in Stat3-mTOR activity. Treatment of STC-1 cells with IL-27 contributed to the increments of Stat3-mTOR signaling and GLP-1. Interference of mTOR activity by mTOR siRNA or rapamycin abolished the stimulation of GLP-1 production induced by IL-27 in STC-1 cells. Stat3 siRNA also blocked the stimulus effect of IL-27 on GLP-1. IL-27 increased the interaction of mTOR and Stat3 in STC-1 cells. Our results identify Stat3-mTOR as a critical signaling pathway for the stimulation of GLP-1 induced by IL-27.


[Forensic chemical investigation of alcohol-containing liquids contained polyhexamethylene guanidine hydrochloride and diethylphthalate].
Alcoholism remains one of the main causes of premature death in the population of Russia. Hence, the importance of the problem of uncontrolled distribution and consumption of surrogate alcoholic products, such as alcohol-containing liquids of uncertain origin. The objective of the present study was to detect ethyl alcohol, polyhexamethylene guanidine hydrochloride, and diethylphthalate in disinfectant liquids, biological fluids and human tissues and to analyse qualitative and quantitative composition of these materials.


Cannabis use among treatment-seeking smokers: motives and the moderating effects of anxiety sensitivity.
Concurrent use of cannabis and tobacco is associated with poor tobacco cessation outcomes. As little research has examined why treatment-seeking tobacco users engage in cannabis use, the objective of this study was to discover if emotional vulnerability and cannabis use motives are associated with concurrent users' cannabis use. One hundred thirty-eight (n = 138) daily cigarette smokers seeking smoking cessation treatment completed measures of anxiety sensitivity, cannabis use motives, and cannabis use. Stronger coping, enhancement, social, and expansion motives were associated with using greater amounts of cannabis per use occasion. In a model accounting for all these motives, anxiety sensitivity moderated the relationship between enhancement motives and cannabis use. Clinical interventions for concurrent tobacco-cannabis users may be advanced by targeting low anxiety sensitive individuals' use of cannabis to increase excitement and fun. Such an approach may consist of having clients identify and engage in healthier pleasurable activities and by teaching clients to accept the trade-off between perceived less pleasurable, but healthier activities and cannabis use.


Single-molecule analysis of the rotation of F₁-ATPase under high hydrostatic pressure.
F1-ATPase is the water-soluble part of ATP synthase and is an ATP-driven rotary molecular motor that rotates the rotary shaft against the surrounding stator ring, hydrolyzing ATP. Although the mechanochemical coupling mechanism of F1-ATPase has been well studied, the molecular details of individual reaction steps remain unclear. In this study, we conducted a single-molecule rotation assay of F1 from thermophilic bacteria under various pressures from 0.1 to 140 MPa. Even at 140 MPa, F1 actively rotated with regular 120° steps in a counterclockwise direction, showing high conformational stability and retention of native properties. Rotational torque was also not affected. However, high hydrostatic pressure induced a distinct intervening pause at the ATP-binding angles during continuous rotation. The pause was observed under both ATP-limiting and ATP-saturating conditions, suggesting that F1 has two pressure-sensitive reactions, one of which is evidently ATP binding. The rotation assay using a mutant F1(βE190D) suggested that the other pressure-sensitive reaction occurs at the same angle at which ATP binding occurs. The activation volumes were determined from the pressure dependence of the rate constants to be +100 Å(3) and +88 Å(3) for ATP binding and the other pressure-sensitive reaction, respectively. These results are discussed in relation to recent single-molecule studies of F1 and pressure-induced protein unfolding.


The Pioneering and Unknown Stereotactic Approach of Roeder and Orthner from Göttingen. Part II: Long-Term Outcome and Postmortem Analysis of Bilateral Pallidotomy in the Pre-Levodopa Era.
Before the advent of levodopa, pallidotomy was initially the most effective treatment for Parkinson disease, but it was soon superseded by thalamotomy. It is widely unknown that, similar to Leksell, 2 neurologists from Göttingen, Orthner and Roeder, perpetuated pallidotomy against the mainstream of their time. Postmortem studies demonstrated that true posterior and ventral pallidoansotomy sparing the overwhelming mass of the pallidum was accomplished. This was due to a unique and individually tailored stereotactic technique even allowing bilateral staged pallidotomies. In 1962, the long-term effects (3-year follow-up on average) of the first 18 out of 36 patients with staged bilateral pallidotomies were reported in great detail. Meticulous descriptions of each case indicate long-term improvements in parkinsonian rigidity and associated pain, as well as posture, gait, and akinesia (e.g., improved repetitive movements and arm swinging). Alleviation of tremor was found to require larger lesions than needed for suppression of rigidity. No improvement in speech, drooling, or seborrhea was observed. By 1962, the team had operated 13 patients with postencephalitic oculogyric crises with remarkable results (mean follow-up: 5 years). They also described alleviation of nonparkinsonian hyperkinetic disorders (e.g., hemiballism and chorea) with pallidotomy. The reported rates for surgical mortality and other complications had been remarkably low, even if compared to those reported after the revival of pallidotomy by Laitinen in the post-levodopa era. This applies also to bilateral pallidotomy performed with a positive risk-benefit ratio that has remained unparalleled to date. The intricate history of pallidotomy for movement disorders is incomplete without an appreciation of the achievements of the Göttingen group.


Using the electronic health record for genomics research.
Although primarily designed for medical documentation and billing purposes, the electronic health record (EHR) has significant potential for translational research. In this article, we provide an overview of the use of the EHR for genomics research with a focus on heritable lipid disorders. Linking the EHR to genomic data enables repurposing of vast phenotype data for genomic discovery. EHR data can be used to study the genetic basis of common and rare disorders, identify subphenotypes of diseases, assess pathogenicity of novel genomic variants, investigate pleiotropy, and rapidly assemble cohorts for genomic medicine clinical trials. EHR-based discovery can inform clinical practice; examples include use of polygenic risk scores for assessing disease risk and use of phenotype data to interpret rare variants. Despite limitations such as missing data, variable use of standards and poor interoperablility between disparate systems, the EHR is a powerful resource for genomic research. When linked to genomic data, the EHR can be leveraged for genomic discovery, which in turn can inform clinical care, exemplifying the virtuous cycle of a learning healthcare system.


Changes in Transcriptome of Yersinia pseudotuberculosis IP32953 Grown at 3 and 28°C Detected by RNA Sequencing Shed Light on Cold Adaptation.
Yersinia pseudotuberculosis is a bacterium that not only survives, but also thrives, proliferates, and remains infective at cold-storage temperatures, making it an adept foodborne pathogen. We analyzed the differences in gene expression between Y. pseudotuberculosis IP32953 grown at 3 and 28°C to investigate which genes were significantly more expressed at low temperature at different phases of growth. We isolated and sequenced the RNA from six distinct corresponding growth points at both temperatures to also outline the expression patterns of the differentially expressed genes. Genes involved in motility, chemotaxis, phosphotransferase systems (PTS), and ATP-binding cassette (ABC) transporters of different nutrients such as fructose and mannose showed higher levels of transcripts at 3°C. At the beginning of growth, especially genes involved in securing nutrients, glycolysis, transcription, and translation were upregulated at 3°C. To thrive as well as it does at low temperature, Y. pseudotuberculosis seems to require certain cold shock proteins, especially those encoded by yptb3585, yptb3586, yptb2414, yptb2950, and yptb1423, and transcription factors, like Rho, IF-1, and RbfA, to maintain its protein synthesis. We also found that genes encoding RNA-helicases CsdA (yptb0468), RhlE (yptb1214), and DbpA (yptb1652), which unwind frozen secondary structures of nucleic acids with cold shock proteins, were significantly more expressed at 3°C, indicating that these RNA-helicases are important or even necessary during cold. Genes involved in excreting poisonous spermidine and acquiring compatible solute glycine betaine, by either uptake or biosynthesis, showed higher levels of transcripts at low temperatures. This is the first finding of a strong connection between the aforementioned genes and the cold adaptation of Y. pseudotuberculosis. Understanding the mechanisms behind the cold adaptation of Y. pseudotuberculosis is crucial for controlling its growth during cold storage of food, and will also shed light on microbial cold adaptation in general.


Can network attention effectively stimulate corporate ESG practices?-Evidence from China.
Environmental, social, and governance (ESG) has emerged as a widespread concern for all societal segments. This study aims to explore the influence of network attention on corporate ESG practices from an investor perspective. We find that rising network attention significantly increases corporate ESG practices. Specifically, network attention plays the role of external monitoring, image promotion incentives, and mitigation of financing constraints to make companies willing to challenge ESG practices. Additionally, the promoting effect of network attention on firms' ESG practices was more significant in higher marketization processes, severely competitive industries, and non-state enterprises. In the internet era, companies must pay attention to the flow effect caused by network attention, meet stakeholder demands, and pursue long-term sustainable development.


Role of histidine 932 of the human mitochondrial DNA polymerase in nucleotide discrimination and inherited disease.
The human mitochondrial DNA polymerase (pol γ) is nuclearly encoded and is solely responsible for the replication and repair of the mitochondrial genome. The progressive accumulation of mutations within the mitochondrial genome is thought to be related to aging, and mutations in the pol γ gene are responsible for numerous heritable disorders including progressive external opthalmoplegia, Alpers syndrome, and parkinsonism. Here we investigate the kinetic effect of H932Y, a mutation associated with opthalmoplegia. Mutations H932Y and H932A reduce the specificity constant governing correct nucleotide incorporation 150- and 70-fold, respectively, without significantly affecting fidelity of incorporation or the maximum rate of incorporation. However, this leads to only a 2-fold reduction in rate of incorporation at a physiological nucleotide concentration (∼100 μm). Surprisingly, incorporation of T:T or C:T mismatches catalyzed by either H932Y or H932A mutants was followed by slow pyrophosphate release (or fast pyrophosphate rebinding). Also, H932Y readily catalyzed incorporation of multiple mismatches, which may have a profound physiological impact over time. His-932 is thought to contact the β-phosphate of the incoming nucleotide, so it is perhaps surprising that H932Y appears to slow rather than accelerate pyrophosphate release.


Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Surgical Techniques and Technologies for the Management of Patients With Nonfunctioning Pituitary Adenomas.
Numerous technological adjuncts are used during transsphenoidal surgery for nonfunctioning pituitary adenomas (NFPAs), including endoscopy, neuronavigation, intraoperative magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) diversion, and dural closure techniques. To generate evidence-based guidelines for the use of NFPA surgical techniques and technologies. An extensive literature search spanning January 1, 1966, to October 1, 2014, was performed, and only articles pertaining to technological adjuncts for NFPA resection were included. The clinical assessment evidence-based classification was used to ascertain the class of evidence. Fifty-six studies met the inclusion criteria, and evidence-based guidelines were formulated on the use of endoscopy, neuronavigation, intraoperative MRI, CSF diversion, and dural closure techniques. Both endoscopic and microscopic transsphenoidal approaches are recommended for symptom relief in patients with NFPAs, with the extent of tumor resection improved by adequate bony exposure and endoscopic visualization. In select cases, combined transcranial and transsphenoidal approaches are recommended. Although intraoperative MRI can improve gross total resection, its use is associated with an increased false-positive rate and is thus not recommended. There is insufficient evidence to recommend the use of neuronavigation, CSF diversion, intrathecal injection, or specific dural closure techniques. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter_6. CSF, cerebrospinal fluidNFPA, nonfunctioning pituitary adenoma.


Pain and health status of primary care patients with low back pain.
In addition to the pain caused by low back problems, suffering may also adversely affect other aspects of patients' lives. Since there is little knowledge about the suffering caused by low back pain, a prospective cohort study was undertaken to study pain intensity, perceived health, and daily functioning of consecutive patients with low back pain presenting in general practice. During a period of 2 years, 15 general practitioners enlisted consecutive patients with both chronic and recent-onset low back pain in the study. From the initial visit, each patient was monitored for a period of 6 months prospectively. The follow-up consisted of questionnaires mailed every 4 weeks to determine the intensity of the pain, perceived health, and daily functioning. Of the 605 patients identified, 430 were included in the follow-up; 6 months after the initial visit, 167 patients were lost to follow-up. At baseline, the analyses did not reveal any important differences between acute, subacute, and chronic low back pain. Pain intensity, perceived health, and daily functioning in all patients tended to resolve over time. This tendency was strongest in patients with acute low back pain. The change in pain intensity was not strongly correlated with changes in perceived health and daily functioning. All aspects of suffering caused by low back pain tend to diminish and resolve over time. No evidence was found of a relationship between perceived health or daily functioning and the duration of the low back pain.


Changing trends of histopathology in childhood nephrotic syndrome in western Saudi Arabia.
It is widely accepted that minimal change nephrotic syndrome is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis in adults and children. This study was conducted to analyze the trend of histopathologic subtypes in idiopathic nephrotic syndrome in the western area of the Kingdom of Saudi Arabia. To determine the possible changes in the etiology of childhood nephrosis, the clinical charts of 46 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1997 and 2001, group A, were reviewed. Results were compared with our initial published data of 132 patients with idiopathic nephrotic syndrome diagnosed between 1983 and 1992, group B. There was no difference in the percentage of biopsies between group A (43%) and group B (31.8%), P= 0.9. There was a decline in the incidence of minimal change nephrotic syndrome in recent years. Even if we assume that all patients without a histological diagnosis had minimal change nephrotic syndrome, presumptive minimal change nephrotic syndrome, the total incidence of minimal change nephrotic syndrome (biopsy proven + presumptive) in group A, was only 65% compared to 79.5% in group B, P=0.02. The incidence of focal segmental glomerulosclerosis was significantly greater in biopsies performed in the recent period, group A, 35% versus group B, 16.7%, P=0.05, and in the total number when we included the presumptive minimal change nephrotic syndrome, group A, 15.2% and group B, 5.3%, P<0.0001. Similarly we found an increased incidence of membranoprolifrative glomerulonephritis in total patients when we included the presumptive minimal change nephrotic syndrome, group A, 13.0% and group B, 5.3%, P=0.02. There is a shift toward an increasing prevalence of focal segmental glomerulosclerosis and membranoprolifrative glomerulonephritis over the years in the western area of the Kingdom of Saudi Arabia. These findings may have significant implications in the management of childhood nephrotic syndrome.


An Assessment of the Importance of Chaotic Stirring and Turbulent Mixing on the West Florida Shelf.
Application of dynamical systems tools has recently revealed in surface ocean currents produced by a Hybrid-Coordinate Ocean Model (HYCOM) simulation the presence of a persistent large-scale Lagrangian coherent structure (LCS) on the southern portion of the west Florida shelf (WFS). Consistent with satellite-tracked drifter trajectories, this LCS constitutes a cross-shelf barrier for the lateral transport of passive tracers. Because of the constraints that the above LCS, as well as smaller-scale LCSs lying shoreside, can impose on pollutant dispersal and its potentially very important biological consequences, a study was carried out on the nature of the surface ocean Lagrangian motion on the WFS. The analysis is based on the same simulated surface ocean velocity field that has been able to sustain the aforementioned persistent cross-shelf transport barrier. Examination of several diagnostics suggests that chaotic stirring dominates over turbulent mixing on time scales of up to two months or so. More specifically, it is found on those time scales that tracer evolution at a given length scale is governed to a nonnegligible extent by coarser-scale velocity field features, fluid particle dispersion is spatially inhomogeneous, and the Lagrangian evolution is more irregular than the driving Eulerian flow.


Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
To investigate whether sclerosing cholangitis with an autoimmune serology characteristic of autoimmune hepatitis (AIH) and AIH are distinct entities, we studied 55 consecutive children with clinical and/or biochemical evidence of liver disease and circulating antinuclear (ANA), anti-smooth muscle (SMA), and/or liver-kidney-microsomal type 1 (LKM1) autoantibodies. They underwent liver biopsy, direct cholangiography, sigmoidoscopy, and rectal biopsy at presentation. Twenty-eight were diagnosed as AIH in the absence and 27 autoimmune sclerosing cholangitis (ASC) in the presence of radiological features of cholangiopathy. Twenty-six ASC and 20 AIH had ANA and/or SMA; 1 ASC and 8 AIH LKM1 autoantibody. Similarities between the 2 conditions included most clinical and biochemical parameters and a lower frequency of HLA DR4. Inflammatory bowel disease and histological biliary changes were more common in ASC; coagulopathy, hypoalbuminemia, lymphocytic periportal hepatitis, and HLA DR3 were more common in AIH. Histological biliary changes were observed in 65% of ASC and 31% of AIH patients. Eighty-nine percent responded to immunosuppression. Follow-up liver biopsies from 17 ASC and 18 AIH patients had similarly reduced inflammatory activity and no progression to cirrhosis. Sixteen follow-up cholangiograms from AIH patients and 9 from ASC patients were unchanged, while 8 ASC patients showed a progressive cholangiopathy. One child with AIH and ulcerative colitis developed sclerosing cholangitis 8 years after presentation. At 2 to 16 years (median, 7 years) from presentation, all patients are alive, including 4 ASC patients who underwent liver transplantation. In conclusion, ASC and AIH are similarly prevalent in childhood; cholangiography is often needed to distinguish between these 2 entities, which are likely to lie within the same disease process.


Agriculture, Aid, and Economic Growth in Africa.
How can foreign aid to agriculture support economic growth in Africa? This paper constructs a geographically indexed applied general equilibrium model that considers pathways through which aid might affect growth and structural transformation of labor markets in the context of soil nutrient variation, minimum subsistence consumption requirements, domestic transport costs, labor mobility, and constraints to self-financing of agricultural inputs.Using plausible parameters, the model is presented for Uganda as an illustrative case.We present three stylized scenarios to demonstrate the potential economy-wide impacts of both soil nutrient loss and replenishment, and how foreign aid can be targeted to support agricultural inputs that boost rural productivity and shift labor to boost real wages. One simulation shows how a temporary program of targeted official development assistance (ODA) for agriculture could generate, contrary to traditional Dutch disease concerns, an expansion in the primary tradable sector and positive permanent productivity and welfare effects, leading to a steady decline in the need for complementary ODA for budget support.


Premaxillary augmentation using autologous costal cartilage as an adjunct to rhinoplasty.
Premaxillary augmentation is a widely adopted procedure used as an independent facial contouring operation or as an adjunct to rhinoplasty. Insufficient projection of the praemaxilla is a relatively common deformity, especially in the Asian population. We performed two cases of premaxillary augmentation using autologous costal cartilage as an adjunct to rhinoplasty. The first case was a 17-year-old man, who had had an underprojected and over-rotated nose with a bulbous tip since birth. He underwent bilateral premaxillary augmentation using autologous costal cartilage and a rhinoplasty with unilateral extended spreader graft in conjunction with columella strut insertion and dorsal augmentation with Goretex. The second case was a 22-year-old male, who had a repaired left cleft lip and palate. He underwent a revision unilateral premaxillary augmentation and rhinoplasty with columella strut insertion, nasal tip cap graft and dorsal augmentation using autologous costal cartilage. The two patients were satisfied with the results of both the premaxillary augmentations and the rhinoplasties. In both patients, we performed a correction of the acute nasolabial angle and the midface was augmented, which resulted in a more pronounced nasal tip augmentation and a more natural appearance of the midface. We suggest that autologous costal cartilage block could be satisfactory graft material for premaxillary augmentation.


Protective effect of poly(ADP-ribose) synthetase inhibition on multiple organ failure after zymosan-induced peritonitis in the rat.
In the present study, we tested the hypothesis that peroxynitrite and subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) play a role in the pathogenesis of multiple organ failure induced by peritoneal injection of zymosan in the rat. Animals were randomly divided into six groups (ten rats for each group). The first group was treated with ip administration of saline solution (0.9% NaCl) and served as the sham group. The second group was treated with ip administration of zymosan (500 mg/kg suspended in saline solution). In the third and fourth groups, rats received ip administration of 3-aminobenzamide (10 mg/kg) 1 and 6 hrs after zymosan or saline administration, respectively. In the fifth and sixth groups, rats received ip administration of nicotinamide (50 mg/kg) 1 and 6 hrs after zymosan or saline administration, respectively. After zymosan or saline injection, animals were monitored for 72 hrs to evaluate systemic toxicity (conjunctivitis, ruffled fur, diarrhea, and lethargy), loss of body weight, and mortality. A severe inflammatory response, characterized by peritoneal exudation, high plasma and peritoneal levels of nitrate/nitrite (the breakdown products of nitric oxide), and leukocyte infiltration into peritoneal exudate, was induced by zymosan administration. This inflammatory process coincided with the damage of lung, small intestine, and liver as assessed by histologic examination and by an increase of myeloperoxidase activity, which is indicative of neutrophil infiltration. Zymosan-treated rats showed signs of systemic illness, significant loss of body weight, and high mortality rates. Peritoneal administration of zymosan in the rat also induced a significant increase in the plasma levels of peroxynitrite as measured by the oxidation of the fluorescent dihydrorhodamine 123. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the lung of zymosan-shocked rats. In vivo treatment with ip administration of 3-aminobenzamide (10 mg/kg, 1 and 6 hrs after zymosan injection) or nicotinamide (50 mg/kg, 1 and 6 hrs after zymosan injection) significantly decreased mortality, inhibited the development of peritonitis, and reduced peroxynitrite formation. In addition, PARS inhibitors were effective in preventing the development of organ failure because tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, were reduced in the lung, small intestine, and liver. In conclusion, the major findings of our study are that peroxynitrite and the consequent PARS activation exert a role in the development of multiple organ failure and that PARS inhibition is an effective anti-inflammatory therapeutic tool.


Predictors for resectability and survival in locally advanced pancreatic cancer after gemcitabine-based neoadjuvant therapy.
To evaluate the predictors for resectability and survival of patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based neoadjuvant therapy (GBNAT). Between May 2003 and Dec 2009, 41 tissue-proved LAPC were treated with GBNAT. The location of pancreatic cancer in the head, body and tail was 17, 18 and 6 patients respectively. The treatment response was evaluated by RECIST criteria. Surgical exploration was based on the response and the clear plan between tumor and celiac artery/superior mesentery artery. Kaplan-Meier analysis and Cox Model were used to calculate the resectability and survival rates. Finally, 25 patients received chemotherapy (CT) and 16 patients received concurrent chemoradiation therapy (CRT). The response rate was 51% (21 patients), 2 CR (1 in CT and 1 in CRT) and 19 PR (10 in CT and 9 in CRT). 20 patients (48.8%) were assessed as surgically resectable, in which 17 (41.5%) underwent successful resection with a 17.6% positive-margin rate and 3 failed explorations were pancreatic head cancer for dense adhesion. Two pancreatic neck cancer turned fibrosis only. Patients with surgical intervention had significant actuarial overall survival. Tumor location and post-GBNAT CA199 < 152 were predictors for resectability. Post-GBNAT CA-199 < 152 and post-GBNAT CA-125 < 32.8 were predictors for longer disease progression-free survival. Pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, and post-op CEA < 6 were predictors for longer overall survival. Tumor location and post-GBNAT CA199 < 152 are predictors for resectability while pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, post-GBNAT CA-199 < 152 and post-op CEA < 6 are survival predictors in LAPC patients with GBNAT.


Concentration and M/G ratio influence the physiochemical and mechanical properties of alginate constructs for tissue engineering.
The diffusion and mechanical properties of calcium alginate gels were determined using constructs of different alginate concentrations and guluronic acid contents. It was found that the diffusion of small molecules such as sulphate, glucose and thymidine was not impeded by any of the alginates tested at concentrations of 1% and 3% (w/v). By contrast, the diffusion of large molecules, including insulin like growth factor-1 (IGF-1), human growth hormone and bovine serum albumin was impeded by alginate. This effect was enhanced with increasing alginate concentration, but was less evident for alginates with increased guluronic acid content. These findings have significant implications in tissue engineering where cells such as chondrocytes depend on the supply of factors such as IGF-1 to remain viable. An increase in both alginate concentration and guluronic acid content also increased the compressive properties, as determined by both tangent and equilibrium modulus, of alginate constructs. Although the 3% alginate constructs exhibited enhanced stiffness compared to some reported cartilage substitute biomaterials, such as PGA, their absolute values were still appreciably less stiff than articular cartilage.


Mgat1-dependent N-glycosylation of membrane components primes Drosophila melanogaster blood cells for the cellular encapsulation response.
In nature, larvae of the fruitfly Drosophila melanogaster are commonly infected by parasitoid wasps, and so have evolved a robust immune response to counter wasp infection. In this response, fly immune cells form a multilayered capsule surrounding the wasp egg, leading to death of the parasite. Many of the molecular mechanisms underlying this encapsulation response are conserved with human immune responses. Our findings suggest that protein N-glycosylation, a common protein post-translational modification of human immune proteins, may be one such conserved mechanism. We found that membrane proteins on Drosophila immune cells are N-glycosylated in a temporally specific manner following wasp infection. Furthermore we have identified mutations in eight genes encoding enzymes of the N-glycosylation pathway that decrease fly resistance to wasp infection. More specifically, loss of protein N-glycosylation in immune cells following wasp infection led to the formation of defective capsules, which disintegrated over time and were thereby unsuccessful at preventing wasp development. Interestingly, we also found that one species of Drosophila parasitoid wasp, Leptopilina victoriae, targets protein N-glycosylation as part of its virulence mechanism, and that overexpression of an N-glycosylation enzyme could confer resistance against this wasp species to otherwise susceptible flies. Taken together, these findings demonstrate that protein N-glycosylation is a key player in Drosophila cellular encapsulation and suggest that this response may provide a novel model to study conserved roles of protein glycosylation in immunity.


Identification of a colorectal tumor-associated antigen (COA-1) recognized by CD4(+) T lymphocytes.
Only a limited number of target molecules have been shown to be recognized by colon tumor-reactive T cells, limiting the options for the development of immunotherapies for patients with colon cancer. The current studies were undertaken in an attempt to generate tumor-reactive T cells that could be used to identify and characterize novel colon tumor-associated antigens. Multiple CD4(+) T-cell clones isolated either from tumor-infiltrating lymphocytes or peripheral blood mononuclear cells that were sensitized in vitro with autologous tumor cells from a colon cancer patient, 1869, recognized autologous tumor cells in a class II HLA-DR-restricted manner. One of the peripheral blood mononuclear cell clones, clone C111, was used to screen pools of clones that were generated from an autologous colon tumor cell line cDNA library. A cDNA clone that was isolated encoded a protein that was termed colorectal tumor-associated antigen-1 (COA-1). This product was recognized in the context of the two autologous HLA-DRbeta1 alleles, HLA-DRbeta1*0402 and DRbeta1*1301. The nucleotide sequence of the COA-1 transcript was nearly identical to multiple expressed sequence tag sequences that encode variants of Socius, a protein that was found recently to bind to members of the Rnd family of GTPases. The COA-1 gene was expressed at relatively comparable levels in colorectal and melanoma tumor cells, EBV-infected B cells, normal B cells, and cultured fibroblast cell lines. However, the gene that was isolated from normal cell types contained a single nucleotide substitution, resulting in an amino acid change near the COOH terminus of the protein. Although the minimal epitope recognized by CD4(+) cells was encoded by sequences that were upstream from this substitution, C111 T cells did not appear to recognize the normal gene product. Therefore, this alteration may either affect the localization or the processing of this gene product, which may at least in part be responsible for the differential recognition of tumor and normal cells.


Comparison of growth patterns in healthy dogs and dogs in abnormal body condition using growth standards.
In dogs, optimal growth is critical for future health and wellbeing. Recently, a series of evidence-based growth standards, based on bodyweight, were developed for male and female dogs across 5 different size categories. The aim of the current study was to compare growth curves depicted by the standards with patterns of growth in dogs that were either healthy, had abnormal body condition, or had various diseases with the potential to affect growth. The data came from 2 research colonies in Europe (France and UK), and a large corporate network of primary care veterinary hospitals across the USA. Age and bodyweight data were used to model growth in healthy dogs, in dogs that became overweight or underweight by 3 years of age, and in dogs with diseases associated with altered growth. Centile line crossing during the growth phase was uncommon in healthy dogs, with <5% of dogs crossing >2 centile lines. In contrast, centile line crossing was more frequent in dogs with abnormal growth patterns or abnormal body condition. Dogs that developed obesity by 3 years grew faster than the growth standards predicted, and 68% crossed ≥2 centile lines in an upwards direction. Dogs with conditions associated with accelerated growth also grew faster than expected, and 54% crossed ≥2 centile lines. In contrast dogs that became underweight by 3 years gained weight slower than expected, and 49% crossed ≥2 centile lines in a downwards direction. These results suggest that the growth standards are useful for monitoring healthy growth in dogs. Prospective studies are now required to confirm these findings and to determine whether early intervention can prevent the development of diseases.


The Neuropsychiatric Side of Cerebral Venous Thrombosis: A Case of Delirium and Catatonia.
We report a patient with cerebral venous thrombosis who initially presented with psychosis and who then progressed to delirium and catatonia within a few days. Upon treatment and resolution of the thrombosis, she presented complete remission of the psychiatric disturbances. This case highlights a specific neuropsychiatric presentation of cerebral venous thrombosis involving psychosis, catatonia, and delirium, which, to our best knowledge, has not been reported in the neurological or psychiatric literature. However, it reminds us of mental status and behavioral abnormalities which are not infrequent features of cerebral venous thrombosis. This leads to a discussion regarding the psychopathology, etiology, and pathophysiology of the case.