Usefulness of bioclimatic models for studying climate change and invasive species.
Bioclimatic models (also known as envelope models or, more broadly, ecological niche models or species distribution models) are used to predict geographic ranges of organisms as a function of climate. They are widely used to forecast range shifts of organisms due to climate change, predict the eventual ranges of invasive species, infer paleoclimate from data on species occurrences, and so forth. Several statistical techniques (including general linear models, general additive models, climate envelope models, classification and regression trees, and genetic algorithms) have been used in bioclimatic modeling. Recently developed techniques tend to perform better than older techniques, although it is unlikely that any single statistical approach will be optimal for all applications and species. Proponents of bioclimatic models have stressed their apparent predictive power, whereas opponents have identified the following unreasonable model assumptions: biotic interactions are unimportant in determining geographic ranges or are constant over space and time; the genetic and phenotypic composition of species is constant over space and time; and species are unlimited in their dispersal. In spite of these problematic assumptions, bioclimatic models often successfully fit present-day ranges of species. Their ability to forecast the effects of climate change or the spread of invaders has rarely been tested adequately, however, and we urge researchers to tie the evaluation of bioclimatic models more closely to their intended uses.


Effect of long-term, low-level noise exposure on hearing thresholds, DPOAE and suppression of DPOAE in rats.
Loss of adaptability rather than loss of sensitivity may be one of the initial signs of auditory impairment following exposure to noise. One way to examine the adaptability of hearing in experimental investigation is to measure the magnitude of the suppression, exerted by the medial olivocochlear efferent system, on the ipsilateral otoacoustic emissions in response to contralateral sound stimulation. Thus, in order to test the hypothesis it was decided to measure hearing thresholds (HT), the cubic DPOAE and suppression of cubic DPOAE by contralateral wide band noise in rats exposed to long-term, low level noise (90 days of 90 dBlin 4-20 kHz wide band noise 4 hours/day, 5 days/week). Measurements of HT were performed by assessment of the ABR, elicited by tone-pips from the same probe assembly used in the measurements of DPOAE. The suppression of the cubic distortion product (CDP) was determined in ketamine/xylazine anaesthesia, allowing a stable response for a minimum of 20 min. Of the frequencies tested, the rats exposed to noise had an increase in HT at 12.8 kHz only (6.8 dB, P<0.05), while a reduction on the CDP was evident with f2 going from 9.2 kHz to the upper limit at 17.4 kHz. Further, the rats exposed to noise had little suppression of the CDP at low levels of contralateral noise (CN), but no difference from the control animals was seen as the CN noise level was increased. The measurement of DPOAE suppression did not reveal any effects of the low level noise exposure that was not paralleled also by shifts in hearing thresholds. The most sensitive assessment of the auditory changes in the study was the measurements of DPOAE, and further elaboration on the bandwidth and frequency distribution of the CN is necessary, before auditory changes in the high frequency range can be probably assessed.


Effect of pacing on oxygen supply-to-consumption ratio in ischemic myocardium.
This study was performed to determine if the partially occluded myocardium could maintain its O2 supply-to-consumption ratio during atrial pacing. In 14 open-chest anesthetized dogs, the left anterior descending coronary artery was occluded to 50% of base-line flow, and in half of the dogs the hearts were paced to 50% above base-line heart rate. Blood flows were determined by use of microspheres before and after occlusion, and O2 supply-consumption variables were determined by use of microspectrophotometry. After occlusion in control and paced groups, blood flow was depressed in the ischemic region compared with the nonischemic region. In paced animals, blood flows in all regions were significantly higher compared with their respective values in nonpaced animals. After pacing, mean O2 consumption was 34% higher (53% in the occluded region) compared with control animals. The O2 supply-to-consumption ratio was similar in the occluded region of paced animals compared with the same region in controls. This ratio was lower in ischemic regions of both groups compared with their respective nonischemic regions. This indicates that, despite a reduced O2 supply-to-consumption ratio in the ischemic area, an unutilized reserve of flow exists.


Key questions resulting from the JUPITER trial assessing cardiovascular disease intervention with rosuvastatin.
THIS PAPER PRESENTS AN ANALYSIS OF THE RECENTLY PUBLISHED JUSTIFICATION FOR THE USE OF STATINS IN PREVENTION (JUPITER: an intervention trial evaluating rosuvastatin) trial, which tested the statin rosuvastatin in apparently healthy individuals with no prior cardiovascular (CVD) disease and with normal plasma low density lipoprotein (LDL) cholesterol concentrations but with raised plasma high sensitivity C-reactive protein (hsCRP) levels. The rate of the combined primary CVD endpoint was significantly reduced in the treatment arm after a median of under 2 years. The JUPITER trial is distinct from previous studies examining statin use in primary prevention groups because the target group for drug therapy was apparently healthy men and women at low or intermediate risk for developing CVD. On the basis of JUPITER's findings, there are key questions that should be assessed on the therapeutic intervention of CVD regarding: the primary prevention groups that should be targeted for statin therapy, the utility of targets in addition to plasma LDL cholesterol levels, and the need to consider the metabolic state of individuals targeted for therapy (including the presence of obesity and inflammation). The conclusion from the current analysis is that the JUPITER results warrant further LDL cholesterol lowering than is currently targeted in primary prevention groups that have a pre-existing condition or lifestyle that elevates CVD risk but still do not have a high global CVD risk (as assessed with current algorithms). This group is not captured in current widely used CVD risk calculations, however, with the identification of useful biomarkers, such as hsCRP, this group can be better identified and targeted for intervention.


Chorea gravidarum in systemic lupus erythematosus.
A case of chorea gravidarum in a patient with systemic lupus erythematosus (SLE) is described. Review of the literature on chorea gravidarum suggests that SLE may be a more common cause than previously reported. Treatment of chorea gravidarum in SLE patients is discussed.


Improvement of stress LVEF rather than rest LVEF after coronary revascularisation in patients with ischaemic cardiomyopathy and viable myocardium.
To evaluate prospectively the response of left ventricular ejection fraction (LVEF) to high dose dobutamine infusion in patients showing substantial viability, with and without improved resting LVEF after revascularisation. Before and 9-12 months after revascularisation, 50 patients with ischaemic cardiomyopathy (LVEF 32 (8)%) and substantial myocardial viability (> or = 4 viable segments) underwent radionuclide ventriculography and dobutamine stress echocardiography. Patients were divided into group 1, patients with, and group 2, patients without significant improvement in resting LVEF (> or = 5% by radionuclide ventriculography) after revascularisation. The response of LVEF during dobutamine stress echocardiography was compared in these two groups. Groups 1 and 2 were comparable in baseline characteristics, resting LVEF, and number of viable segments (mean (SD) 7 (4) v 6 (2), not significant). After revascularisation, the LVEF response during dobutamine stress echocardiography improved significantly in both groups (group 1, 34 (10)% to 56 (8)%; group 2, 32 (10)% to 46 (11)%; both p < 0.001). Interestingly, although resting LVEF did not improve in group 2, peak stress LVEF after revascularisation did (p < 0.001). Group 1 patients had, however, a greater increase in peak stress LVEF (group 1, 22 (10)%; group 2, 13 (9)%; p < 0.01). New York Heart Association and Canadian Cardiovascular Society classes decreased in both groups. Although patients with viable myocardium did not always have improved rest LVEF after revascularisation, peak stress LVEF improved. Assessment of improvement of resting function may not be the ideal end point to evaluate successful revascularisation.


Endogenous caloric sources and nitrogen balance: regulation in postoperative patients.
Twenty-three postoperative patients were divided into three groups to evaluate the peripheral vein administration of solutions containing glucose, amino acids, or glucose and amino acids. Serum insulin, glucose, and nitrogen balances were monitored in each patient. Serum insulin concentrations rose on the first postoperative day in all three groups, then fell to near preoperative levels by the third day after surgery. Negative nitrogen balance was most pronounced in patients recieving glucose only. Patients receiving only amino acids had a reduction in nitrogen balance, but some protein catabolism was present. The mean nitrogen balance in patients who received a combination of these solutions was positive on days one and two after surgery and slightly negative on the third postoperative day. These changes were not significantly better than the amino acid group. However, the combination group had 12 to 21 days of positive balance, as compared to seven of 20 days in the amino acid group. Since starvation adaptation accurs gradually, it is concluded that the simplest and safest way to reduce protein catabolism in the immediate postoperative period is by the peripheral intravenous administration of both glucose and amino acids.


Exercise Training Mitigates Multisystem Deconditioning during Bed Rest.
This study investigated the safety and effectiveness of a new integrated aerobic and resistance exercise training prescription (SPRINT) using two different sets of exercise equipment: a suite of large International Space Station-like exercise equipment similar to what is found on the International Space Station and a single device with aerobic and resistance exercise capability in the spaceflight analog of bed rest (BR). Subjects (n = 34) completed 70 d of 6° head down tilt BR: 9 were randomized to remain sedentary (CONT), 9 to exercise training using traditional equipment (EX), 8 to exercise using traditional equipment and low-dose testosterone supplementation (ExT), and 8 to exercise using a combined resistance and aerobic flywheel device. Peak aerobic capacity, ventilatory threshold, cardiac morphology and function (echocardiography), muscle mass (magnetic resonance imaging) and strength/power (isokinetic, leg press, and vertical jump), and bone health (bone mineral density, blood and urine bone markers) were assessed before and after BR. The SPRINT protocol mitigated BR-induced muscle and cardiac deconditioning regardless of the exercise device used. Molecular markers of bone did not change in the CONT or EX groups. Peak aerobic capacity was maintained from pre- to post-BR in all exercise groups similarly, whereas significant declines were observed in the CONT group (~10%). Significant interaction effects between the CONT group and all EX groups were observed for muscle performance including leg press total work, isokinetic upper and lower leg strength, vertical jump power, and maximal jump height as well as muscle size. This is the first trial to evaluate multisystem deconditioning and the role of an integrated exercise countermeasure. These findings have important implications for the design and implementation of exercise-based countermeasures on future long-duration spaceflight missions.


Efficacy of anti-fungal but not anti-bacterial prophylaxis in intensive primary AML therapy: a real-world, retrospective comparative single-centre study.
The optimal strategy of anti-infectious prophylaxis in patients with acute leukaemia undergoing intensive chemotherapy remains a matter of debate. We assessed the impact of primary prophylaxis with posaconazole and levofloxacin on the incidence of invasive fungal infections (IFI) and bacteraemia. A retrospective single-centre study including two groups of adult patients with AML receiving intensive chemotherapy. Group one without anti-infective prophylaxis (September 2008 - February 2010), and group two with anti-infective prophyalaxis (March 2010 - April 2011). The primary end-point was IFI according to the EORTC/MSG 2008 definitions and bacteraemia. Baseline characteristics were similar in the non-prophylaxis (n = 43 patients; 99 chemotherapy cycles) and the prophylaxis (n = 45; 104 chemotherapy cycles) group. IFI were significantly reduced in the prophylaxis group (55.3% vs. 88.9%; p = 0.0032) and there was a trend of the projected IFI-free survival at 100 days to be increased (50.1% vs. 25%; p = 0.0526). One-hundred day overall survival (84.4% and 88.4%, p = 0.35) and 2-year overall survival (64.4% and 58.1%; p = 0.64) were unaffected. No difference in the occurrence of bacteraemia was observed (32.3% vs. 34.6%; p = 0.8). A total of two (3.6%) patients in the non-prophylaxis and three (6.7%) in the prophylaxis group died due to IFI, and two (3.6%) in the non-prophylaxis and none in the prophylaxis group patients had to stop leukaemia treatment due to IFI. The anti-infective prophylaxis with posaconazole and levofloxacin resulted in a significant reduction of 'possible' IFI with a number-needed to treat to prevent one IFI of only 3 but did not result in a reduction of the incidence of bacteraemia.


Paediatric oropharyngeal and cutaneous candidiasis with special reference to Candida dubliniensis.
Mucocutaneous and cutaneous candidiasis, though common in children, is often under-reported. The prevalence of Candida dubliniensis in causing these infections in this age group is also largely unknown. A prospective epidemiological cross-sectional study for candidiasis was performed in paediatric patients clinically suspected of candidiasis with oropharyngeal lesions (75 patients), cutaneous lesions (18 patients) and lesions at both sites (2 patients). Candida species were identified by conventional tests. For C. dubliniensis, chlamydospore production, growth on tobacco agar and growth at 45 °C were performed. Nine isolates were confirmed at a reference centre. The rates of candidiasis were 77.3 % (58 out of 75 patients clinically suspected of candidiasis) and 83.3 % (15/18) in oropharyngeal and cutaneous lesions respectively, and 1 of the 2 children with lesions at both sites was diagnosed as having chronic mucocutaneous candidiasis due to C. dubliniensis. The commonest species isolated was Candida albicans, in 41 (70.7 %) patients with oropharyngeal candidiasis and 11 (73.3 %) with cutaneous lesions; C. dubliniensis was isolated from 11 and 3 children respectively. In the paediatric population, C. albicans predominates in mucocutaneous and cutaneous candidiasis, with C. dubliniensis also contributing substantially.


Trends in antiviral therapy of adults hospitalized with influenza in Canada since the end of the 2009 pandemic.
Multiple observational studies have associated antiviral treatment of patients hospitalized with influenza with improved outcome, including reduced mortality. During the 2009-2010 H1N1 pandemic increased use of antiviral treatment of hospital patients was reported. We have carried out prospective surveillance for influenza in patients in a large network of Canadian hospitals since 2006. We wished to assess trends in antiviral use in the two seasons (2010-2011 and 2011-2012) since the end of the pandemic. Adults (>16 years) testing positive for influenza at the time of or during admission to participating Canadian hospitals were prospectively reviewed. In 2009-2010 there were 1132 confirmed cases, 1107 in 2010-2011 and 631 in 2011-2012. Information on antiviral therapy was available in >95% in each year. Rising to 89.6% in 2009, the proportion of adult patients treated with antiviral therapy fell to 79.9% and 65.7% in the two subsequent seasons (p < 0.001). Oseltamivir was the antiviral agent used in >98% of cases in each year. The median time from onset of symptoms to initiation of antiviral therapy was three days. The treatment proportion fell across all age groups, co-morbid conditions and disease severity. Despite evidence for benefit of antiviral therapy, and clinical practice guidelines recommending treatment of this population, antiviral therapy of Canadian adults hospitalized with influenza has progressively fallen in the two seasons since the end of the 2009-2010 influenza pandemic.


Age at menarche and risks of all-cause and cardiovascular death: a systematic review and meta-analysis.
We conducted a systematic review and meta-analysis to investigate the associations between menarcheal age and all-cause and cardiovascular death. Medline, Embase, Scopus, and Web of Knowledge were searched for articles published prior to March 2013 reporting on the associations between menarcheal age and death from all causes or from cardiovascular disease (total cardiovascular disease, ischemic heart disease (IHD), and stroke) in adult women. Nine articles were eligible for inclusion; these reported 5 estimates each for death from all causes and total cardiovascular death, 6 estimates for IHD, and 7 estimates for death from stroke. Our meta-analysis showed that each 1-year increase in age at menarche was associated with a 3% lower relative risk of death from all causes (pooled hazard ratio = 0.97, 95% confidence interval: 0.96, 0.98) with low heterogeneity (I(2) = 32.2%). Meta-analysis of 2 cohorts showed a higher risk of death from all causes for women who experienced early menarche (at <12 years of age) versus "not early" menarche (at ≥ 12 years of age) (pooled hazard ratio = 1.23, 95% confidence interval: 1.10, 1.38; I(2) = 0%). An inverse association between age at menarche and death from IHD was observed only among nonsmoking populations or populations with low prevalence of smoking. We found no evidence of association between age at menarche and death from all cardiovascular diseases or stroke. Early menarche was consistently associated with higher risk of death from all causes. Further studies are needed to clarify the role of menarcheal age on cardiovascular outcomes and to investigate the potential modifying role of smoking.


Veterinary attitudes towards pre-pubertal gonadectomy of cats: a comparison of samples from New Zealand, Australia and the United Kingdom.
To compare the attitudes and practices of a sample of veterinarians in New Zealand, Australia and the United Kingdom (UK) towards pre-pubertal gonadectomy of cats. Respondents' demographics were gathered using an electronic questionnaire distributed via professional veterinary associations in the target countries, as were minimum age at gonadectomy and typical age of puberty. Desirability of prepubertal gonadectomy was gauged using three response categories ('yes', 'no' or 'sometimes'), respondents were then able to justify the response given. Two-way Analyses of Variance (ANOVA) followed by post hoc Tukey HSD tests were used to test whether there were differences in minimum ages for gonadectomy within and between countries and between providers and non-providers of services to pounds (or animal welfare centres). Views on the desirability of prepubertal gonadectomy relative to demographics were explored using a Likelihood Ratio Test. The survey received 717 responses. Most respondents believed pre-pubertal gonadectomy was either entirely or 'sometimes' desirable (556/621), few thought it was undesirable (65/621). Minimum age at gonadectomy was significantly affected by country surveyed and provision or non-provision of services for pounds. Post hoc Tukey HSD analysis indicated the mean age of both spaying and castration (4.3 months) in the UK was significantly different from both Australia (spaying: 3.4 months, castration: 3.2 months) and New Zealand (spaying: 3.4 months, castration: 3.2 months) (all p<0.001). Mean ages at spaying and castration were also significantly different (p= 0.008; p= 0.019, respectively) for non-providers (spaying: 3.9 months, castration: 3.8 months) of services to pounds when compared to providers (spaying and castration: both 3.6 months). Likelihood Ratio Tests indicated significant effects amongst countries and between genders relative to the desirability of pre- pubertal gonadectomy. Respondents from the UK were more likely to answer 'no' (p = 0.004) or 'sometimes' (p = 0.050) as compared to those from New Zealand or Australia. Females were more likely to respond with 'sometimes' as opposed to 'yes' than males. Reasons for considering pre-pubertal gonadectomy desirable or sometimes desirable focussed on reducing unwanted pregnancies and improving population control, as well as improving rates of adoption, owner compliance and cat behaviour and health. In general, pre-pubertal gonadectomy is considered a desirable procedure by those practitioners that responded to the survey. However age at which any such procedure occurs differs depending upon a number of factors. Differences among countries may relate to the specific veterinary association's guidelines or possibly differences in social discourse which affect perception of cats. There is substantial overlap between the reported minimum age of gonadectomy and the age at which cats can enter early puberty, allowing a window for unintentional pregnancy when pre-pubertal gonadectomy does not occur.


Quantitative Imaging and Radiomics in Multiple Myeloma: A Potential Opportunity?
Multiple Myeloma (MM) is the second most common type of hematological disease and, although it is rare among patients under 40 years of age, its incidence rises in elderly subjects. MM manifestations are usually identified through hyperCalcemia, Renal failure, Anaemia, and lytic Bone lesions (CRAB). In particular, the extent of the bone disease is negatively related to a decreased quality of life in patients and, in general, bone disease in MM increases both morbidity and mortality. The detection of lytic bone lesions on imaging, especially computerized tomography (CT) and Magnetic Resonance Imaging (MRI), is becoming crucial from the clinical viewpoint to separate asymptomatic from symptomatic MM patients and the detection of focal lytic lesions in these imaging data is becoming relevant even when no clinical symptoms are present. Therefore, radiology is pivotal in the staging and accurate management of patients with MM even in early phases of the disease. In this review, we describe the opportunities offered by quantitative imaging and radiomics in multiple myeloma. At the present time there is still high variability in the choice between various imaging methods to study MM patients and high variability in image interpretation with suboptimal agreement among readers even in tertiary centers. Therefore, the potential of medical imaging for patients affected by MM is still to be completely unveiled. In the coming years, new insights to study MM with medical imaging will derive from artificial intelligence (AI) and radiomics usage in different bone lesions and from the wide implementations of quantitative methods to report CT and MRI. Eventually, medical imaging data can be integrated with the patient's outcomes with the purpose of finding radiological biomarkers for predicting the prognostic flow and therapeutic response of the disease.


Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method.
Measuring muscle mass is an important component of the nutritional assessment examination and a suggested index of this body space is the 24-h urinary excretion of creatinine. The method originated from studies in a variety of animal species in whom early workers found a parallelism between total body creatine and urinary excretion of creatinine. Assuming that nearly all creatine was within muscle tissue, that muscle creatine content remained constant and that creatinine was excreted at a uniform rate, an obvious "corollary" was that urinary creatinine was proportional to muscle mass. The so-called "creatinine equivalence" (kg muscle mass/g urinary creatinine) ranged experimentally from 17 to 22. One of the limiting factors in firmly establishing this constant and its associated variability was (and is) the lack of another totally acceptable noninvasive technique of measuring muscle mass to which the creatinine method could (or would) be compared. An improved understanding of creatine metabolism and a variety of clinical studies in recent years has tended to support the general validity of this approach. However, specific conditions have also been established in which the method becomes either inaccurate or invalid. While creatinine excretion may serve as a useful approximation of muscle mass in carefully selected subjects, there remains a need for accurate and practical indices of muscle mass for use in the individuals in whom the method cannot be reliably applied.


X-ray photoelectron spectroscopic investigation of conducting polymer blends.
Electrochemically prepared films of conducting polymers of polypyrrole and polythiophene and their blends with polyamide have been investigated by X-ray photoelectron spectroscopy. In the N1s region of the spectra of films containing polypyrrole the peak corresponding to N(+) at 402.0 eV is separated from that of neutral N. The intensity of the N(+) peak can be correlated with the electrical conductivity of the films and the spectroscopically derived ratio of F/N(+) is close to 4 indicating that one BF(-)(4) dopant ion is incorporated for every oxidized nitrogen center. In the spectra of films of polythiophene and its blends peaks corresponding to S and S(+) can not be resolved but again the F/C ratio correlates with the electrical conductivity.


Trends among pathogens reported as causing bacteraemia in England, 2004-2008.
The Health Protection Agency in England operates a voluntary surveillance system that collects data on bacteraemias reported by over 90% of laboratories in England. Trends in causative microorganisms reported between 2004 and 2008 were analyzed using a generalized linear model with a log link function for Poisson distribution. In 2008, 101,276 episodes of bacteraemia were reported; a rate of 189 per 100,000 population. More than one-half occurred in those aged over 65 years and males. The most common organisms reported were Escherichia coli (23%), coagulase-negative staphylococci (CNS) (16.9%) and Staphylococcus aureus (11.4%). Between 2004 and 2008, E. coli bacteraemia increased by 33% (p < 0.001); the species now accounts for more than 30% of bacteraemia in those aged over 75 years. There also were significant increases in bacteraemia caused by other Gram-negative pathogens and marked seasonal variation. Bacteraemia caused by S. aureus increased until 2005, with a decline after 2006 (p < 0.001) entirely due to methicillin-resistant strains. CNS bacteraemia have declined significantly since 2007. The renewed dominance of Gram-negative pathogens as major causes of bacteraemia in England is of particular concern because they are associated with a high morbidity and increasing resistance to antibiotics. Further investigation of the underlying causes and prevention strategies is a public health priority. Recent declines in methicillin-resistant S. aureus bacteraemia have not been reflected in other pathogens, including methicillin-susceptible S. aureus.


Unintended pregnancy among newly married couples in Shanghai.
Though contraceptive failure and induced abortion in China have both attracted research attention, the somewhat broader topic of unintended pregnancy has been neglected. A total of 7,872 newly married couples, enrolled between 1987 and 1988, were followed up until 1994-1995; only 2% were lost to follow-up. During face-to-face interviews, background and fertility-related data were collected. Chi-square tests and logistic regression were used to assess associations with unintended pregnancy. By three months after marriage, 461 couples had conceived; 57% of nonpregnant wives said that their preferred interval between marriage and conception was no more than three months. Twenty-one percent of pregnancies occurring between marriage and first birth were reported as unintended; 81% of these resulted from contraceptive failure. The majority of unintended pregnancies were carried to term; 13% were aborted. The younger the wife and the greater her desired interval between marriage and conception, the greater the likelihood that a pregnancy occurring before first birth was unintended. After first birth, 43% of couples experienced one or more unintended pregnancies, 98% of which were aborted in accordance with the one-child policy. The majority of these pregnancies occurred in the 12 months after first birth, when couples tend to rely on ineffective methods of contraception. The odds of having an unintended pregnancy after first birth were slightly elevated if at least one spouse desired a second child. Unintended pregnancies are common among married couples in Shanghai. Policies to reduce unintended pregnancies, and abortions, should focus particularly on postpartum contraception.


Detection of oral squamous cell carcinoma metastasis with cathepsin D: An immunohistochemical approach.
The lysosomal protease cathepsin D (CD) has been associated with tumor progression in malignant tumors including oral squamous cell carcinoma (OSCC). The purpose of this study was to find out any association between the CD and lymph node metastasis and to study the correlation of CD with various clinicopathological parameters to aid in assessment of its role as a prognostic indicator. Immunohistochemical staining was performed on 20 OSCC samples with polyclonal antibody against CD. Positive results indicative of the presence of CD were further analyzed to determine any correlation between the CD and other clinicopathological parameters. Pearson Chi-square analyses, Spearsman correlation coefficient, Mann-Whitney test, Kruskal Wallis test and student t test were used for statistical analysis (P < 0.05). Patients with lymph node metastasis showed statistically significant increase in CD expression (P < 0.01). Increasing tumor size seemed to correlate with increased CD expression (P < 0.05). Based on its association with other clinicopathological variables, CD expression can be used for the assessment of patient survival in cases of OSCC.


Hydrophilic versus non-coated catheters for intermittent catheterization.
Since Lapides reintroduced clean intermittent catheterization (CIC) in 1972, this procedure has been used routinely in individualized programmes for bladder evacuation in various bladder disorders. It has been suggested that in clinical practice hydrophilic catheters are preferable to non-coated catheters. In reviewing the literature on CIC, many of the reports were found to rely on data from non-randomized retrospective studies. In some recent prospective studies, involving a limited number of patients, hydrophilic and non-coated catheters have been evaluated and compared, especially with regard to bacteriuria and urethral irritation. The available data indicate that using hydrophilic catheters for CIC may induce lower rates of bacteriuria and long-term urethral complications such as urethral strictures. However, to reach a reliable conclusion about the supposed advantage of the hydrophilic catheters, there is a need for a prospective, randomized long-term multicentre study. It is important in such a study to define patient characteristics including age, gender, diagnosis of bladder dysfunction, reason for CIC, physical and mental handicap, manual dexterity and previous treatments. Effect parameters should include number of catheterizations, urinary tract infection, early and long-term urethral complications, patient satisfaction, preferences and dropout rates. It is obligatory to include factors such as cost-benefit and cost-effectiveness.


Demographic predictors of wellbeing in Carers of people with psychosis: secondary analysis of trial data.
Carers of people with psychosis are at a greater risk of physical and mental health problems compared to the general population. Yet, not all carers will experience a decline in health. This predicament has provided the rationale for research studies exploring what factors predict poor wellbeing in carers of people with psychosis. Our study builds on previous research by testing the predictive value of demographic variables on carer wellbeing within a single regression model. To achieve this aim, we conducted secondary analysis on two trial data sets that were merged and recoded for the purposes of this study. Contrary to our hypotheses, only carer gender and age predicted carer wellbeing; with lower levels of carer wellbeing being associated with being female or younger (aged under 50). However, the final regression model explained only 11% of the total variance. Suggestions for future research are discussed in light of the limitations inherent in secondary analysis studies. Further research is needed where sample sizes are sufficient to explore the interactive and additive impact of other predictor variables.


Preclinical Development of CD38-Targeted [89Zr]Zr-DFO-Daratumumab for Imaging Multiple Myeloma.
Multiple myeloma (MM) is a plasma B-cell hematologic cancer that causes significant skeletal morbidity. Despite improvements in survival, heterogeneity in response remains a major challenge in MM. Cluster of differentiation 38 (CD38) is a type II transmembrane glycoprotein overexpressed in myeloma cells and is implicated in MM cell signaling. Daratumumab is a U.S. Food and Drug Administration-approved high-affinity monoclonal antibody targeting CD38 that is clinically benefiting refractory MM patients. Here, we evaluated [89Zr]Zr-desferrioxamine (DFO)-daratumumab PET/CT imaging in MM tumor models. Methods: Daratumumab was conjugated to DFO-p-benzyl-isothiocyanate (DFO-Bz-NCS) for radiolabeling with 89Zr. Chelator conjugation was confirmed by electrospray ionization-mass spectrometry, and radiolabeling was monitored by instant thin-layer chromatography. Daratumumab was conjugated to Cyanine5 (Cy5) dye for cell microscopy. In vitro and in vivo evaluation of [89Zr]Zr-DFO-daratumumab was performed using CD38+ human myeloma MM1.S-luciferase (MM1.S) cells. Cellular studies determined the affinity, immunoreactivity, and specificity of [89Zr]Zr-DFO-daratumumab. A 5TGM1-luciferase (5TGM1)/KaLwRij MM mouse model served as control for imaging background noise. [89Zr]Zr-DFO-daratumumab PET/CT small-animal imaging was performed in severe combined immunodeficient mice bearing solid and disseminated MM tumors. Tissue biodistribution (7 d after tracer administration, 1.11 MBq/animal, n = 4-6/group) was performed in wild-type and MM1.S tumor-bearing mice. Results: A specific activity of 55.5 MBq/nmol (0.37 MBq/μg) was reproducibly obtained with [89Zr]Zr-daratumumab-DFO. Flow cytometry confirmed CD38 expression (>99%) on the surface of MM1.S cells. Confocal microscopy with daratumumab-Cy5 demonstrated specific cell binding. Dissociation constant, 3.3 nM (±0.58), and receptor density, 10.1 fmol/mg (±0.64), was obtained with a saturation binding assay. [89Zr]Zr-DFO-daratumumab/PET demonstrated specificity and sensitivity for detecting CD38+ myeloma tumors of variable sizes (8.5-128 mm3) with standardized uptake values ranging from 2.1 to 9.3. Discrete medullar lesions, confirmed by bioluminescence images, were efficiently imaged with [89Zr]Zr-DFO-daratumumab/PET. Biodistribution at 7 d after administration of [89Zr]Zr-DFO-daratumumab showed prominent tumor uptake (27.7 ± 7.6 percentage injected dose per gram). In vivo blocking was achieved with a 200-fold excess of unlabeled daratumumab. Conclusion: [89Zr]Zr-DFO- and Cy5-daratumumab demonstrated superb binding to CD38+ human MM cells and significantly low binding to CD38low cells. Daratumumab bioconjugates are being evaluated for image-guided delivery of therapeutic radionuclides.


Do well-publicized risk-adjusted outcomes reports affect hospital volume?
Report cards on hospital performance are common but have uncertain impact. The objective of this study was to determine whether hospitals recognized as performance outliers experience volume changes after publication of a report card. Secondary objectives were to test whether favorable outliers attract more patients with related conditions, or from outside their catchment areas; and whether disadvantaged groups are less responsive to report cards. We used a time-series analysis using linear and autoregressive models. We studied patients admitted to nonfederal hospitals designated as outliers in reports on coronary bypass surgery (CABG) mortality in New York, acute myocardial infarction (AMI) mortality in California, and postdiskectomy complications in California. We studied observed versus expected hospital volume for topic and related conditions and procedures, by month/quarter after a report card, with and without stratification by age, race/ethnicity, insurance, and catchment area. Potential confounders included statewide prevalence, prereport hospital volume and market share, and unrelated volume. In California, low-mortality and high-mortality outliers did not experience changes in AMI volume after adjusting for autocorrelation. Low-complication outliers for lumbar diskectomy experienced slightly increased volume in autoregressive models. No other cohorts demonstrated consistent trends. In New York, low-mortality outliers experienced significantly increased CABG volume in the first month after publication, whereas high-mortality outliers experienced decreased volume in the second month. The strongest effects were among white patients and those with HMO coverage in California, and among white or other patients and those with Medicare in New York. Volume effects were modest, transient, and largely limited to white Medicare patients in New York.


Fully-Online, Interoperable Clinical Trial Management System for Multi-Interventional RCT: Maintain Your Brain Digital Platform.
Maintain Your Brain (MYB)i is a randomised controlled trial (RCT) of multiple online interventions designed to target modifiable risk factors for Alzheimer's disease and dementia. Traditional clinical trial management systems (CTMS) requirements consist of features such as management of the study, site, subject (participant), clinical outcomes, external and internal requests, education, data extraction and reporting, security, and privacy. In addition to fulfilling these traditional requirements, MYB has a specific set of features that needs to be fulfilled. These specific requirements include: (i) support for multiple interventions within a study, (ii) flexible interoperability options with third-party software providers, (iii) study participants being able to engage in online activities via web-based interfaces throughout the trial (from screening to follow-up), (iv) ability to algorithmically personalize trial activities based on the needs of the participant, and (v) the ability to handle large volumes of data over a long period. This paper outlines how the existing CTMSs fall short in meeting these specific requirements. The presented system architecture, development approach and lessons learned in the implementation of the MYB digital platform will inform researchers attempting to implement CTMSs for trials comparable to MYB in the future.


An unexpected cascade reaction of 3-hydroxyoxindoles with coumarin-3-carboxylates to construct 2,3-dihydrobenzofuran spirooxindoles.
An unexpected Michael addition-inspired ring-opening/closure cascade reaction of 3-hydroxyoxindoles with coumarin-3-carboxylates was developed to access new dihydrobenzofuran or dihydrobenzothiophene spirooxindoles in 68-98% yields. This reaction not only provides an expedient and convenient method to assemble dihydrobenzofuran spirooxindoles, but also establishes a new reaction mode of coumarin-3-carboxylates. Moreover, it represents the first example of 3-hydroxyoxindoles serving as a C1 synthon possessing dual nucleophilic and electrophilic character with the hydroxyl group as a leaving group. Importantly, this methodology provides a rapid and robust approach to XEN907 analogues.


Is pre-emptive administration of ketamine a significant adjunction to intravenous morphine analgesia for controlling postoperative pain? A randomized, double-blind, placebo-controlled clinical trial.
To evaluate if the pre-emptive administration of ketamine would potentiate the effect of intravenous morphine analgesia in the management of post-thoracotomy pain. This was a unicentre, double-blind, placebo-controlled, parallel-group, prospective study. Patients were randomly assigned to receive 1 mg/kg ketamine (ketamine group) or an equivalent dose of normal saline (placebo group) before thoracotomy in 1:1 ratio. All patients received postoperatively intravenous morphine administration as additional analgesic regimen. Primary end-point was the pain relief measured with Visual Analogue Scale at rest. The secondary end-points were the reduction of inflammatory response expressed by plasma C-reactive protein levels, the morphine consumption and the rate of side effects. The measurements were carried out 6, 12, 24, 36 and 48 hours postoperatively. A total of 75 patients were randomized of whom 38 were allocated to ketamine group and 37 to placebo group. Baseline characteristics were comparable. Ketamine compared with placebo group showed a significant reduction of pain scores (P = 0.01), C-reactive protein (P < 0.001) and morphine consumption (P < 0.001). No acute psychological side effects related to the use of ketamine were registered. The administration of ketamine before surgery may be an effective adjunct to intravenous morphine analgesia in acute post-thoracotomy pain management. In ketamine group, satisfaction of pain relief was significantly higher with a significant reduction of inflammatory response and morphine consumption compared with placebo group. Our results, if confirmed by larger studies, may be of clinical relevance in situations where epidural analgesia or other analgesic procedures different from systemic opioid analgesia are unavailable or contraindicated.


Salient objects dominate the central fixation bias when orienting toward images.
Short-latency saccades are often biased toward salient objects or toward the center of images, for example, when inspecting photographs of natural scenes. Here, we measured the contribution of salient objects and central fixation bias to visual selection over time. Participants made saccades to images containing one salient object on a structured background and were instructed to either look at (i) the image center, (ii) the salient object, or (iii) at a cued position halfway in between the two. Results revealed, first, an early involuntary bias toward the image center irrespective of strategic behavior or the location of objects in the image. Second, the salient object bias was stronger than the center bias and prevailed over the latter when they directly competed for visual selection. In a second experiment, we tested whether the center bias depends on how well the image can be segregated from the monitor background. We asked participants to explore images that either did or did not contain a salient object while we manipulated the contrast between image background and monitor background to make the image borders more or less visible. The initial orienting toward the image was not affected by the image-monitor contrast, but only by the presence of objects-with a strong bias toward the center of images containing no object. Yet, a low image-monitor contrast reduced this center bias during the subsequent image exploration.


[Magnetic resonance tomography of a thoracic aortic aneurysm].
The results of magnetic resonance imaging in 16 patients with non-dissecting aneurysm of the thoracic aorta are presented. Scans with ECG-gated spin-echo sequences in transversal, coronal, and left anterior oblique views demonstrated the size and extent of the aneurysms. Measurements of the maximum aneurysmal diameter differed by less than 5 mm from measurements obtained with computed tomography. In 6 of 7 patients with presence of wall adherent intraluminal signal, phase images were able to differentiate accurately between mural thrombus and slow blood flow.


Validity and reliability of eye healthcare professionals in the assessment of glaucoma - a systematic review.
To explore the validity and reliability of eye healthcare professionals with different levels of training in diagnosing and/or identifying glaucomatous progression. Substantial pressure is being placed on our current eye healthcare workforce by chronic diseases such as glaucoma. Shared care schemes and role expansion of professionals other than ophthalmologists are being proposed to alleviate this pressure. A sound evidence base is imperative to determine whether other allied health professionals are skilled and clinically competent, when it comes to taking on these new roles in glaucoma management. A systematic review of research articles identified in MEDLINE, CINAHL, Embase, Scopus and Cochrane Library was performed. Studies which investigated rater reliability of various health professionals in diagnosing and/or identifying glaucoma progression against a reference standard were included. Of the 4088 publications identified by the initial database search, 32 met the inclusion criteria. The majority of studies demonstrated positive results, with most finding moderate to substantial agreement for inter- and intra-rater reliability across all testing modalities. The eye health professionals with ophthalmology training consistently attained the greatest agreement. When allied health professionals with different levels of training were compared, those who had completed residency training were significantly better than those who had not. The studies included in this review show promising results, including those raters without ophthalmology training. A lack of power calculations, unequal sample sizes in some studies and the diversity of the testing procedures used make it difficult to make sound inferences.


A gel aspiration-ejection system for the controlled production and delivery of injectable dense collagen scaffolds.
A gel aspiration-ejection (GAE) system has been developed for the advanced production and delivery of injectable dense collagen (I-DC) gels of unique collagen fibrillar densities (CFDs). Through the creation of negative pressure, GAE aspirates prefabricated highly hydrated collagen gels into a needle, simultaneously inducing compaction and meso-scale anisotropy (i.e., fibrillar alignment) on the gels, and by subsequent reversal of the pressure, I-DC gels can be controllably ejected. The system generates I-DC gels with CFDs ranging from 5 to 32 wt%, controlling the initial scaffold microstructure, anisotropy, hydraulic permeability, and mechanical properties. These features could potentially enable the minimally invasive delivery of more stable hydrogels. The viability, metabolic activity, and differentiation of seeded mesenchymal stem cells (MSCs) was investigated in the I-DC gels of distinct CFDs and extents of anisotropy produced through two different gauge needles. MSC osteoblastic differentiation was found to be relatively accelerated in I-DC gels that combined physiologically relevant CFDs and increased fibrillar alignment. The ability to not only support homogenous cell seeding, but also to direct and accelerate their differentiation through tissue-equivalent anisotropy, creates numerous opportunities in regenerative medicine.


Inhibition of influenza A virus (H1N1) fusion by benzenesulfonamide derivatives targeting viral hemagglutinin.
Hemagglutinin (HA) of the influenza virus plays a crucial role in the early stage of the viral life cycle by binding to sialic acid on the surface of host epithelial cells and mediating fusion between virus envelope and endosome membrane for the release of viral genomes into the cytoplasm. To initiate virus fusion, endosome pH is lowered by acidification causing an irreversible conformational change of HA, which in turn results in a fusogenic HA. In this study, we describe characterization of an HA inhibitor of influenza H1N1 viruses, RO5464466. One-cycle time course study in MDCK cells showed that this compound acted at an early step of influenza virus replication. Results from HA-mediated hemolysis of chicken red blood cells and trypsin sensitivity assay of isolated HA clearly showed that RO5464466 targeted HA. In cell-based assays involving multiple rounds of virus infection and replication, RO5464466 inhibited an established influenza infection. The overall production of progeny viruses, as a result of the compound's inhibitory effect on fusion, was dramatically reduced by 8 log units when compared with a negative control. Furthermore, RO5487624, a close analogue of RO5464466, with pharmacokinetic properties suitable for in vivo efficacy studies displayed a protective effect on mice that were lethally challenged with influenza H1N1 virus. These results might benefit further characterization and development of novel anti-influenza agents by targeting viral hemagglutinin.


Predictors of efficacy of GLP-1 agonists and DPP-4 inhibitors: A systematic review.
To identify the determinants of efficacy of glucagon-like peptide-1 receptor agonists (GLP-1A) and dipeptidyl peptidase-4 inhibitors (DPP-4I). MEDLINE and EMBASE were searched between 01/01/2011 and 15/08/2014 for randomized controlled trials of 12-52weeks' duration, which reported the change in glycated hemoglobin (HbA1c) from baseline as the primary end point, and reported data about predictors of efficacy of incretins. Among 4172 studies found, 77 studies reported data on baseline HbA1c, age, sex, ethnicity, body mass index (BMI), and history of diabetes in relation to change in HbA1c. For DPP-4I, 37 out of 47 studies reported a greater decrease in HbA1c among patients with higher baseline HbA1c. Most DPP-4I studies reported no variation in efficacy in regard to demographic characteristics or BMI. Among 17 studies reporting on GLP-1A, baseline higher HbA1c was reported as predictive of a greater response in 7 out of 9 studies; 13 studies reported data about other factors, without consistent findings. Current evidence suggests that higher baseline HbA1c is associated with a greater efficacy of both DPP-4I and GLP-1A therapies in lowering HbA1c. The roles of other potential predictors are less consistent across studies and require further investigation.


Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep.
A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.


From 'lactose intolerance' to 'lactose nutrition'.
The concept of lactose intolerance has become embedded in Western medicine and developing economy medicine. It is based on evidence that intestinal lactase activity persists into later childhood and throughout life in only a minority of the world's population, notably northern European-derived populations. These people have the T single nucleotide polymorphism (SNP) of the rs49882359 allele (C/T), also known as C/T-13910, the MCM6 gene which positively influences the lactase LCT gene. Other lactase persistent (LP) populations are found in Africa and the Middle East with different genetic variants. These SNPs represent co-evolution with dairying since the agricultural revolution and nutrient-dependent ecological adaptation. That said, gastrointestinal symptoms considered due to small intestinal lactose malabsorption are poorly correlated with lactase non-persistence (LNP), the situation for most people. With LNP, colonic microbiome lactase enables lactose fermentation to occur so that none is found in faeces. Whether the short chain fatty acids (SCFAs) and gases (hydrogen, carbon dioxide and methane) produced cause symptoms is dose-dependent. Up to 25 g of lactose at any one time can usually be consumed by a LNP person, but its food and meal pattern context, the microbiomic characteristics, age and other factors may alter tolerance. Thus, the notion that lactose intolerance is a disorder or disease of LNP people is misplaced and has been one of cultural perspective. What actually matters is whether a particular dairy product as normally consumed give rise to symptoms. It is, therefore, proposed that lactose tolerance tests be replaced with dairy food tolerance tests.


Studies on preparation of inactivated vaccines from cell cultures of mink enteritis virus (MEV) and their immunity.
In this paper, superhigh reproductive rate strains of MEV with titre more than HA8192x or TCID50 log10(9.7) have been achieved both by cultivation in cell lines with different susceptibility to MEV and by isolating and identifying in field by the author. The systematic tests proved that S18 and L12 strains of MEV are the best strains for vaccine preparation. In this study, the best means for the tissue cultivation of MEV and the most advanced technological process for the production and detection of serum-free cell-cultured MEV fluids with super-high HA titre in batches in large quantities have been established for the first time. Optimum conditions for MEV inactivation were determined, and safe and effective inactivated vaccines with mineral oil or Al(OH)3 gel adjuvant were successfully prepared with serum-free cell-cultured MEV fluids. Both vaccines with different adjuvants can be manufactured in batches in large quantities and have been widely used all over China since 1986. The change laws of the immune response kinetics of the MEV vaccines have been determined by the tests, and the indexes and laboratory animal models for monitoring humoral immune efficiency and immune protective rate of parvovirus vaccines have been established for the first time. The manufacturing and monitoring operation rules of the MEV vaccines with different adjuvants have been laid down by the author.


New drugs targeting calcitonin gene-related peptide for the management of migraines.
Significant advances in migraine research have contributed to the development of new drugs for the treatment of migraine. Monoclonal antibodies (mAbs) against Calcitonin Gene-Related Peptide (CGRP) or its receptor and CGRP receptor antagonists (gepants) have been associated with a good safety profile and resulted in an overall efficacy in reducing the number of monthly migraine days both in episodic and chronic forms of migraine. The results from main investigation studies (phase 2 or 3) of CGRP-targeting drugs (both anti-CGRP mAbs and gepants) are reported in this expert-opinion review. The introduction of new drugs targeting CGRP is a significant breakthrough in the migraine field, and represents a new generation of therapeutic agents that are available to manage migraine. The evaluation of efficacy and safety in the long-term follow-up and the development of trials comparing the available drugs could improve the current knowledge. The economic sustainability of these drugs remains to be clarified, and a cost-cutting campaign should be promoted based on the high burden of migraine.


White light endoscopy, narrow band imaging and chromoendoscopy with magnification in diagnosing colorectal neoplasia.
To evaluate the sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of 3 different techniques: high resolution white light endoscopy (WLE), Narrow Band Imaging (NBI) and Chromoendoscopy (CHR), all with magnification in differentiating adenocarcinomas, adenomatous and hyperplastic colorectal polyps. Each polyp was sequentially assessed first by WLE, followed by NBI and finally by CHR. Digital images of each polyp with each modality were taken and stored. Biopsies or polypectomies were then performed followed by blinded histopathological analysis. Each image was blindly graded based on the Kudo's pit pattern (KPP). In the assessment with NBI, the mesh brown capillary network pattern (MBCN) of each polyp was also described. The Sn, Sp, PPV and NPV of differentiating hyperplastic (Type I & II-KPP, Type I-MBCN) adenomatous (Types III, IV-KPP, Type II-MBCN) and carcinomatous polyps (Type V-KPP, Type III-MCBN) was then compared with reference to the final histopathological diagnosis. A total of 50 colorectal polyps (5 adenocarcinomas, 38 adenomas, 7 hyperplastic) were assessed. CHR and NBI [KPP, MBCN or the combined classification (KPP & MBCN)] were superior to WLE in the prediction of polyp histology (P < 0.001, P = 0.002, P = 0.001 and P < 0.001, respectively). NBI, using the MBCN pattern or the combined classification showed higher numerical accuracies compared to CHR, but this was not statistically significant (P = 0.625, 0.250). This feasibility study demonstrated that this combined classification with NBI could potentially be useful in routine clinical practice, allowing the endoscopist to predict histology with higher accuracies using a less cumbersome and technically less challenging method.


[Usefulness of positron tomography (PET) in lung cancer].
Lung carcinoma is one on the leading causes of death from cancer in all parts of the world. The frequency of this tumor is increasing; at present, accounts for approximately 25% of all cancer deaths. The majority of lung cancers are initially detected on chest radiographs, but many benign lesions have radiologic characteristics similar to malignant lesions. Computed tomography (CT) is most frequently used to provide additional anatomic and morphologic information on lesions, but it is limited in distinguishing between benign and malignant abnormalities. Fluorodeoxyglucose-Positron emission tomography (PET-FDG) imaging provides physiologic and metabolic information that characterizes lesions indeterminate by CT, is used clinically to-differentiate benign from malignant focal pulmonary abnormalities, to stage mediastinal and extrathoracic metastases, and to identify recurrence. It is the gold standard that define the therapeutic strategy.


Anti-inflammatory and anti-granuloma activity of Berberis aristata DC. in experimental models of inflammation.
Berberis aristata (Berberidaceae) is an important medicinal plant used in traditional system of medicine for the treatment of rheumatoid arthritis and other inflammatory disorders. The aim of the present study is to scientifically validate the traditional use of BA in the treatment of inflammatory disorders. Anti-inflammatory and anti-granuloma activity of BA hydroalcoholic extract (BAHE) were evaluated in experimental models, viz., carrageenan-induced paw edema, cotton pellet-induced granuloma formation, and complete Freund's adjuvant-induced stimulation of peritoneal macrophages in rats. Expression of inflammatory mediators, viz., tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, TNF-R1, and cyclooxygenase-2 (COX-2) was carried out in serum and peritoneal macrophages to derive the plausible mechanism of BAHE in activated peritoneal macrophages. Pretreatment with BAHE produced a dose-dependent reduction (P < 0.01) in carrageenan-induced paw edema and cotton pellet-induced granuloma model. BAHE treatment produced significant (P < 0.01) reduction in serum inflammatory cytokine levels as compared to control. Protein expression of pro-inflammatory markers, IL-1β, IL-6, TNF-R1, and COX-2, was found to be reduced in stimulated macrophages whereas anti-inflammatory cytokine, IL-10, was upregulated in peritoneal macrophages. The result of the present study thus demonstrates the anti-inflammatory and anti-granuloma activity of BAHE which may be attributed to its inhibitory activity on macrophage-derived cytokine and mediators.


Bitter taste of Brassica vegetables: The role of genetic factors, receptors, isothiocyanates, glucosinolates, and flavor context.
It is well known that consumption of Brassica vegetables has beneficial effect on human's health. The greatest interest is focused on glucosinolates and their hydrolysis products isothiocyanates, due to their potential as cancer preventing compounds. Brassica vegetables are also rich in flavor compounds belonging to many chemical groups. The main sensory sensation related to these vegetable is their characteristic sharp and bitter taste, and unique aroma. Because of these features this group of vegetables is often rejected by consumers. Interestingly, for some people unpleasant sensations are not perceived, suggesting a potential role of inter-individual variability in bitter taste perception and sensibility. Receptors responsible for bitter sensation with the emphasis on Brassica are reviewed, as well as genetic predisposition for bitterness perception by consumers. Also the role of glucosinolates and isothiocyanates as compounds responsible for bitter taste is discussed based on data from the field of food science and molecular biology. Isothiocyanates are shown in broaded context of flavor compounds also contributing to the aroma of Brassica vegetables.


Vascular permeability in the fibrotic lung.
Idiopathic pulmonary fibrosis (IPF) is thought to result from aberrant tissue repair processes in response to chronic or repetitive lung injury. The origin and nature of the injury, as well as its cellular and molecular targets, are likely heterogeneous, which complicates accurate pre-clinical modelling of the disease and makes therapeutic targeting a challenge. Efforts are underway to identify central pathways in fibrogenesis which may allow targeting of aberrant repair processes regardless of the initial injury stimulus. Dysregulated endothelial permeability and vascular leak have long been studied for their role in acute lung injury and repair. Evidence that these processes are of importance to the pathogenesis of fibrotic lung disease is growing. Endothelial permeability is increased in non-fibrosing lung diseases, but it resolves in a self-limited fashion in conditions such as bacterial pneumonia and acute respiratory distress syndrome. In progressive fibrosing diseases such as IPF, permeability appears to persist, however, and may also predict mortality. In this hypothesis-generating review, we summarise available data on the role of endothelial permeability in IPF and focus on the deleterious consequences of sustained endothelial hyperpermeability in response to and during pulmonary inflammation and fibrosis. We propose that persistent permeability and vascular leak in the lung have the potential to establish and amplify the pro-fibrotic environment. Therapeutic interventions aimed at recognising and "plugging" the leak may therefore be of significant benefit for preventing the transition from lung injury to fibrosis and should be areas for future research.


Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study.
Patients with Addison's disease (AD) have increased cardiovascular mortality. To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. A cross-sectional, single-center, case-control study. Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. The mean ± standard deviation age of all subjects was 53 ± 14 years; mean BMI, 25 ± 4 kg/m2; and mean duration of AD, 17 ± 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P < 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC), >1] and vasodilatory protective marker was decreased (FC, <1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.


The use of short segment free jejunal transfer as salvage surgery for cervical esophageal and hypopharyngeal cancer.
Salvage surgery after definitive chemoradiotherapy for cervical esophageal cancer and hypopharyngeal cancer remains a challenge because of the high rate of complications. The purpose of this study was to evaluate the safety and efficacy of free jejunal transfer as salvage surgery for cervical esophageal cancer and hypopharyngeal cancer after definitive chemoradiotherapy. We enrolled eight patients with cervical esophageal cancer and 11 patients with hypopharyngeal cancer who underwent free jejunal transfer as salvage surgery following radiotherapy or chemoradiotherapy. In this study, we reviewed the surgical procedures, perioperative complications, and survival rates. The median duration of surgery was 514 min, and the median blood loss was 439 ml. In surgical procedures, the recipient vessels for the anastomosis of the free jejunum consisted of one artery and one vein (63 %), one artery and two veins (5 %), and two arteries and two veins (31 %). The postoperative morbidity rate was 57.9 % (11 patients), with six cases of partial necrosis of the tracheal margin and no cases of graft necrosis or postoperative in-hospital death. The overall 5-year survival rate after surgery was 58.1 %. Our findings suggest that with careful attention to the potential development of necrosis of the tracheal margin, pharyngolaryngoesophagectomy and free jejunal transfer can be safely performed, even in patients who received radiotherapy or chemoradiotherapy.


A domain of the even-skipped protein represses transcription by preventing TFIID binding to a promoter: repression by cooperative blocking.
We examined the mechanism by which the C-terminal 236 amino acids of the even-skipped protein (region CD) repress transcription. A fusion protein, CDGB, was created that contains region CD fused to the glucocorticoid receptor DNA binding domain. This protein repressed transcription in an in vitro system containing purified fractions of the RNA polymerase II general transcription factors, and repression was dependent upon the presence of high-affinity glucocorticoid receptor binding sites in the promoter. Repression by CDGB was prevented when the promoter DNA was preincubated with TFIID or TBP, whereas preincubation of the template DNA with CDGB prevented TFIID binding. Together, these results strongly imply that CDGB represses transcription by inhibiting TFIID binding, and further experiments suggested a mechanism by which this may occur. Region CD can mediate cooperative interactions between repressor molecules such that molecules bound at the glucocorticoid receptor binding sites stabilize binding of additional CDGB molecules to low-affinity binding sites throughout the basal promoter. Binding to some of these low-affinity sites was shown to contribute to repression. Further experiments suggested that the full-length eve protein also represses transcription by the same mechanism. We speculate that occupancy of secondary sites within the basal promoter by CDGB or the eve protein inhibits subsequent TFIID binding to repress transcription, a mechanism we term cooperative blocking.


Analysis of prognostic factors in patients with multiple recurrences of papillary thyroid carcinoma.
Numerous studies in the past have mentioned various factors that influence the recurrence of papillary thyroid carcinoma, including age, tumor size, advanced stage, extrathyroidal extension, and distant metastasis, and attempts have been made to classify the disease into low-risk and high-risk group based on these clinicopathological factors. However, there has been relatively scarce study on patients with multiple recurrent papillary thyroid carcinoma. This study analyzed the risk factors associated with such cases. This study investigated various clinicopathological factors of 416 patients who were diagnosed with papillary thyroid carcinoma and received primary surgery at Yonsei University Wonju College of Medicine, Department of Surgery, from January 1983 to December 2006 and were followed up until October 2010. An investigation of factors associated with patients showing multiple recurrences was made. Patients were divided into 3 groups: group 1 (no recurrence, n=380), group 2 (1 recurrence only, n=21), and group 3 (multiple recurrences, n=15). The univariate analysis on risk factors revealed tumor size greater than 2 cm, multifocality, clinical apparent lymph node metastasis to be risk factors associated with multiple recurrences of papillary thyroid carcinoma. A multivariate analysis performed on variables selected from univariate analysis demonstrated no significant risk factor. The 10-year disease-specific survival for 3 different patient groups (group 1, 2, and 3) was 100%, 100%, and 83.1%, respectively, and patients in more clinically advanced group demonstrated poorer prognosis (p<0.001). The 10-year overall survival rate for the 3 patient groups was 93.9%, 100%, and 92%, respectively, and clinically advanced groups tended to show poorer overall survival rate as well (p=0.046). A more aggressive and extensive surgery, as well as closer follow up, is to be required when operating on patients with tumor size greater than 2 cm, multifocality, clinical apparent lymph node metastasis. The use of imaging modalities, such as ultrasonography and PET-CT scan, may be desirable when monitoring such patients.


Arrhythmogenic potential of diuretic induced hypokalaemia in patients with mild hypertension and ischaemic heart disease.
In view of evidence suggesting an association of mild hypokalaemia with cardiac arrhythmia, the arrhythmogenic potentials of potassium losing and potassium sparing diuretic treatments were compared in a controlled prospective crossover study of 10 patients with mild hypertension and ischaemic heart disease. Mean (SEM) plasma potassium was 4.3(0.06) mmol/l and 3.3(0.07) mmol/l after potassium sparing and potassium losing treatments respectively. Blood pressure and volume depletion as assessed by weight change, plasma renin activity, and noradrenaline concentrations did not differ significantly in the two treatment periods. The potassium losing treatment phase was associated with an increased frequency of ventricular extrasystoles, a higher Lown grading during ambulatory electrocardiographic monitoring, prolonged duration and decreased phase 0 velocity of the monophasic action potential, a prolonged ventricular effective refractory period, and increased myocardial electrical instability as assessed by programmed ventricular stimulation. It is concluded that minor changes in plasma potassium concentration are associated with increased ventricular electrical instability in patients with ischaemic heart disease. Mild hypokalaemia in such patients may predispose to life threatening arrhythmias and should be avoided.


Neural Mechanisms of Perceiving and Subsequently Recollecting Emotional Facial Expressions in Young and Older Adults.
It is known that emotional facial expressions modulate the perception and subsequent recollection of faces and that aging alters these modulatory effects. Yet, the underlying neural mechanisms are not well understood, and they were the focus of the current fMRI study. We scanned healthy young and older adults while perceiving happy, neutral, or angry faces paired with names. Participants were then provided with the names of the faces and asked to recall the facial expression of each face. fMRI analyses focused on the fusiform face area (FFA), the posterior superior temporal sulcus (pSTS), the OFC, the amygdala (AMY), and the hippocampus (HC). Univariate activity, multivariate pattern (MVPA), and functional connectivity analyses were performed. The study yielded two main sets of findings. First, in pSTS and AMY, univariate activity and MVPA discrimination during the processing of facial expressions were similar in young and older adults, whereas in FFA and OFC, MVPA discriminated facial expressions less accurately in older than young adults. These findings suggest that facial expression representations in FFA and OFC reflect age-related dedifferentiation and positivity effect. Second, HC-OFC connectivity showed subsequent memory effects (SMEs) for happy expressions in both age groups, HC-FFA connectivity exhibited SMEs for happy and neutral expressions in young adults, and HC-pSTS interactions displayed SMEs for happy expressions in older adults. These results could be related to compensatory mechanisms and positivity effects in older adults. Taken together, the results clarify the effects of aging on the neural mechanisms in perceiving and encoding facial expressions.


Effects of turmeric on the activities of benzo(a)pyrene-induced cytochrome P-450 isozymes.
Turmeric and/or its main coloring component, curcumin (diferuloylmethane), have been shown to inhibit benzo(a)pyrene [B(a)P]-induced forestomach papillomas in mice. However, the mechanisms of turmeric-mediated chemoprevention are not well understood. To study the mechanisms of turmeric-mediated chemoprevention, we investigated the effects of turmeric feeding on the activities of isozymes of cytochrome P-450 (CYP450)--namely, ethoxyresorufin O-deethylase (EROD, CYP1A1) and methoxyresorufin O-demethylase (MROD, CYP1A2)--which are predominantly involved in the metabolism of B(a)P. We determined the activities of EROD and MROD by monitoring the formation of resorufin from respective substrates in the presence of microsomal proteins obtained from tissues of control, 1% turmeric, 1 mg B(a)P, and 1% turmeric + 1 mg B(a)P-fed Swiss mice. The results indicate that the administration of turmeric through diet significantly inhibited the activities of both EROD and MROD in forestomach (target organ), liver, and lung. In vitro studies employing curcumin, demethoxycurcumin, and bis-demethoxycurcumin suggest that curcumins are the inhibitors in turmeric. Inhibition of B(a)P metabolizing phase I enzymes (EROD, MROD) may be at least in part one of the possible modes of chemopreventive action of turmeric/curcumin.


Trust, conflict, and cooperation: a meta-analysis.
Many theories of trust emphasize that trust is most relevant to behavior in situations involving a conflict of interests. However, it is not clear how trust relates to behavior across situations that differ in the degree of conflicting interest: Does trust matter more when the conflict of interest is small or large? According to an interdependence perspective, trust becomes an especially important determinant of behavior in situations involving larger, compared to smaller, degrees of conflicting interests. To examine this perspective, we conducted a meta-analysis involving 212 effect sizes on the relation between trust (both state and dispositional trust in others) and cooperation in social dilemmas-situations that involve varying degrees of conflict between self-interest and collective interest. Results revealed that the positive relation between trust and cooperation is stronger when there is a larger, compared to smaller, degree of conflict. We also examined several other possible moderators of the relation between trust and cooperation. The relation between trust and cooperation was stronger during individual, compared to intergroup, interactions but did not vary as a function of the situation being either a one-shot or repeated interaction. We also find differences across countries in the extent that people condition their own cooperation based on their trust in others. We discuss how the results support an emerging consensus about trust being limited to situations of conflict and address some theoretical and societal implications for our understanding of how and why trust is so important to social interactions and relationships.


Peer influence and physical activity behavior in young children: an experimental study.
There is evidence that the presence of a friend increases physical activity behavior in school-aged children (≥ 8 years old) and in young adolescents. Little is known about the developmental trajectory of the effects of peer influences on children's physical activity. Therefore, we sought to test the effect of the presence versus absence of a friend on physical activity in young children (≤ 6 years old). Physical activity was assessed, via accelerometery, in 3- to 6-year-old children, during 2 social conditions: alone and in the presence of a friend. During each condition, children were taken to a gymnasium and had free access to physical and sedentary activities for 30 minutes. In one condition children were tested alone (solo play), whereas in the other they were tested in the presence of a friend who had access to the same activities. Children exhibited 54% greater (P < .02) average accelerometer counts during the friend condition (mean = 2629, SD = 1080 or 5.7 METs) than during the solo play condition (mean = 1707, SD = 1009 or 4.5 METs). The presence of a friend contributes to increased physical activity behavior in young children.


Comparative RNA-seq analysis of early-infected peach leaves by the invasive phytopathogen Xanthomonas arboricola pv. pruni.
Xanthomonas arboricola pv. pruni is a quarantine bacterial pathogen that threatens peach production by causing necrotic spots on leaves and fruits, thus with the potential of severely reducing yields. The current understanding of the host plant defense responses to the pathogen is very limited. Using whole transcriptome sequencing, differential gene expression was analyzed at two time points, 2 h and 12 h post inoculation (hpi), by comparing the inoculated samples to their respective controls. On the total of 19,781 known peach genes that were expressed in all time points and conditions, 34 and 263 were differentially expressed at 2 and 12 hpi, respectively. Of those, 82% and 40% were up-regulated, respectively; and 18% and 60% were down-regulated, respectively. The functional annotation based on gene ontology (GO) analysis highlighted that genes involved in metabolic process and response to stress were particularly represented at 2 hpi whereas at 12 hpi cellular and metabolic processes were the categories with the highest number of genes differentially expressed. Of particular interest among the differentially expressed genes identified were several pathogen-associated molecular pattern (PAMP) receptors, disease resistance genes including several RPM1-like and pathogenesis related thaumatin encoding genes. Other genes involved in photosynthesis, in cell wall reorganization, in hormone signaling pathways or encoding cytochrome were also differentially expressed. In addition, novel transcripts were identified, providing another basis for further characterization of plant defense-related genes. Overall, this study gives a first insight of the peach defense mechanisms during the very early stages of infection with a bacterial disease in the case of a compatible interaction.


2-¹⁸fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: a retrospective validation of the SEMPET trial.
2-¹⁸fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P=0.032). Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.


Improving Quantitative EDS Chemical Analysis of Alloy Nanoparticles by PCA Denoising: Part II. Uncertainty Intervals.
Analytical studies of nanoparticles (NPs) are frequently based on huge datasets derived from hyperspectral images acquired using scanning transmission electron microscopy. These large datasets require machine learning computational tools to reduce dimensionality and extract relevant information. Principal component analysis (PCA) is a commonly used procedure to reconstruct information and generate a denoised dataset; however, several open questions remain regarding the accuracy and precision of reconstructions. Here, we use experiments and simulations to test the effect of PCA processing on data obtained from AuAg alloy NPs a few nanometers wide with different compositions. This study aims to address the reliability of chemical quantification after PCA processing. Our results show that the PCA treatment mitigates the contribution of Poisson noise and leads to better quantification, indicating that denoised results may be reliable from the point of view of both uncertainty and accuracy for properly planned experiments. However, the initial data need to be of sufficient quality: these results can only be obtained if the signal-to-noise ratio of input data exceeds a minimal value to avoid the occurrence of random noise bias in the PCA reconstructions.


Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy.
Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p<0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p<0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p<0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02-229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03-2.06), with no differences in major bleeding rate. Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations.


Restoration in Its Natural Context: How Ecological Momentary Assessment Can Advance Restoration Research.
More and more people use self-tracking technologies to track their psychological states, physiology, and behaviors to gain a better understanding of themselves or to achieve a certain goal. Ecological Momentary Assessment (EMA) also offers an excellent opportunity for restorative environments research, which examines how our physical environment (especially nature) can positively influence health and wellbeing. It enables investigating restorative health effects in everyday life, providing not only high ecological validity but also opportunities to study in more detail the dynamic processes playing out over time on recovery, thereby bridging the gap between laboratory (i.e., short-term effects) and epidemiological (long-term effects) research. We have identified four main areas in which self-tracking could help advance restoration research: (1) capturing a rich set of environment types and restorative characteristics; (2) distinguishing intra-individual from inter-individual effects; (3) bridging the gap between laboratory and epidemiological research; and (4) advancing theoretical insights by measuring a more broad range of effects in everyday life. This paper briefly introduces restorative environments research, then reviews the state of the art of self-tracking technologies and methodologies, discusses how these can be implemented to advance restoration research, and presents some examples of pioneering work in this area.


[Classification of psychopathological conditions associated with perceptual disorders in narcolepsy].
Based on a clinical analysis of psychopathological conditions associated with perceptive disorders in patients with narcolepsy, an attempt was made of their syndromal qualification. The constituents of the syndrome distinguished (orientation disturbances, theatrical effectiveness of hallucinations with fantastic plot, participation of the patient in the capacity of an active character in the play, episodes of relatively short duration, their relation to the sleep-consciousness cycle, and so forth) permit one to specify it as oneiric.


Pharmacokinetics of rituximab in patients with CD20 positive B-cell malignancies.
In this study, we investigated the pharmacokinetics of rituximab in patients with CD20 positive non-Hodgkin lymphoma, to get more insight into the factors that influence the pharmacokinetics of rituximab. This may aid to understand variability of treatment outcome, in patients with a CD20 positive malignancy treated with rituximab. In this study, patients with a CD20 positive B-cell malignancy who were treated with rituximab containing regimens were included. Induction treatment schedules consisted of a combination of rituximab with chemotherapy for 4-8 cycles. Maintenance treatment consisted of a 2 or 3-monthly dose of 375 mg/m2 rituximab intravenously for 2 years. On the day of the treatment with rituximab, preinfusion blood samples were taken. Also, after the end of treatment, selected blood samples were taken. Rituximab levels were measured with a validated enzyme-linked immunosorbent assay (ELISA). An antigen binding assay was applied for determination of human-antibodies against chimeric-antibodies (HACAs). Eight patients were on induction therapy. Rituximab levels of one patient on induction therapy remained very low after the first course. This patient had a chronic lymphoid leukemia with circulating tumor cells and a high tumor burden. Apart from one patient with mantle cell lymphoma, all patients on induction therapy had a complete response. Five patients were on maintenance therapy. Trough levels of 4 patients on three-monthly schedule maintenance therapy remained constant, with a median concentration of 6 mu g/mL (range 0.5-11.7 microg/mL). One patient had a relapse during his maintenance treatment. The elimination half-life at steady state of rituximab in all patients was estimated to be 19.2 (+/- 15.2%) days with a between-subject variability of 54%, indicating wide variability. Possible pharmacokinetic-pharmacodynamic relationship was observed as rituximab levels of the non-responders remained low compared to the rituximab levels of the responders. For all patients, concentration of HACAs remained below the quantification limit. Considerable inter-individual variability of rituximab levels was observed. Although the patient population was small, the results support the need for more research into the pharmacokinetics and factors that might influence the pharmacokinetic-pharmacodynamic relationships of rituximab in patients with non-Hodgkin lymphoma.


Increased serum nitrate concentration in cardiac transplant patients. A marker for acute allograft cellular rejection.
The purpose of the present study was to investigate whether nitrate serum level, reflecting total body production of nitric oxide in vivo, could serve as a noninvasive marker for acute human cardiac rejection. Serum nitrate concentration was determined by an enzymatic method. During routine right ventricular endomyocardial biopsies in 59 recipients, 145 tissue samples were obtained. Two groups of biopsy specimen were considered on the basis of posttransplant delay: group 1, < or = 90 days (n=47; 12-90 days); and group 2, >90 days (n=98; 3-81 months). All patients had normal ventricular systolic function on the day of biopsy and none had evidence of infection. Rejection grade correlated closely with serum nitrate concentration (P<0.001). In both groups, nitrate serum concentrations differed significantly (P<0.001) among cases without rejection, those with mild ongoing rejection (grade 1A/1B), and those with focal or diffuse aggressive infiltrates (grade 2 or higher). A cutoff value of 20 micromol/L, was determined that was positively predictive for grade 2 or higher rejection in 62% cases of early episodes of rejection and in 68% cases of late rejection. Conversely, a serum nitrate level below 20 micromol/L was negatively predictive in 97% and 94% of early and late cases, respectively. We conclude that the acute rejection process of the human transplanted heart is accompanied by a significant increase in serum nitrate level, reflecting increased nitric oxide production during the immune response. Because of its high negative predictive value, irrespective of the posttransplantation delay, nitrate serum determination may have clinical utility in the noninvasive monitoring of the cardiac transplant patient and could also add important information to endomyocardial biopsy analysis for treatment decision making.


Comparison of some representative density functional theory and wave function theory methods for the studies of amino acids.
Energies of different conformers of 22 amino acid molecules and their protonated and deprotonated species were calculated by some density functional theory (DFT; SVWN, B3LYP, B3PW91, MPWB1K, BHandHLYP) and wave function theory (WFT; HF, MP2) methods with the 6-311++G(d,p) basis set to obtain the relative conformer energies, vertical electron detachment energies, deprotonation energies, and proton affinities. Taking the CCSD/6-311++G(d,p) results as the references, the performances of the tested DFT and WFT methods for amino acids with various intramolecular hydrogen bonds were determined. The BHandHLYP method was the best overall performer among the tested DFT methods, and its accuracy was even better than that of the more expensive MP2 method. The computational dependencies of the five DFT methods and the HF and MP2 methods on the basis sets were further examined with the 6-31G(d,p), 6-311++G(d,p), aug-cc-pVDZ, 6-311++G(2df,p), and aug-cc-pVTZ basis sets. The differences between the small and large basis set results have decreased quickly for the hybrid generalized gradient approximation (GGA) methods. The basis set convergence of the MP2 results has been, however, very slow. Considering both the cost and the accuracy, the BHandHLYP functional with the 6-311++G(d,p) basis set is the best choice for the amino acid systems that are rich in hydrogen bonds.


Increased ratio of galactolipid MGDG : DGDG induces jasmonic acid overproduction and changes chloroplast shape.
Galactolipids monogalactosyl diacylglycerol (MGDG) and digalactosyl diacylglycerol (DGDG) constitute c. 50% and c. 30% of chloroplast membrane lipids, respectively. They are important for photosynthesis and stress tolerance. Mutations in DGD1, the major DGDG-synthesizing enzyme, severely reduce DGDG content and induce jasmonic acid (JA) overproduction, resulting in stunted growth. However, how DGDG reduction leads to JA overproduction is unknown. We introduced an inducible microRNA (ami-MGD1) into an Arabidopsis dgd1 mutant to reduce MGDG synthesis, thereby further diminishing galactolipid content, but partially restoring the MGDG : DGDG ratio. Galactolipid and Chl contents, expression of JA-biosynthesis and JA-responsive genes, photosystem II (PSII) maximum quantum efficiency, and chloroplast shape were investigated. Expression of JA-biosynthesis and JA-responsive genes were reduced in amiR-MGD1-transformed dgd1 plants. Stunted growth caused by JA overproduction was also partially rescued, but Chl reduction and PSII impairment remained similar to the original dgd1 mutant. Altered chloroplast shape, which is another defect observed in dgd1 but is not caused by JA overproduction, was also partially rescued. Our results reveal that an increased MGDG : DGDG ratio is the primary cause of JA overproduction. The ratio is also important for determining chloroplast shapes, whereas reduced Chl and photosynthesis are most likely a direct consequence of insufficient DGDG.


Simulating the impact of medical savings accounts on small business.
To simulate whether allowing small businesses to offer employer-funded medical savings accounts (MSAs) would change the amount or type of insurance coverage. Economic policy evaluation using a national probability sample of nonelderly non-institutionalized Americans from the 1993 Current Population Survey (CPS). We used a behavioral simulation model to predict the effect of MSAs on the insurance choices of employees of small businesses (and their families). The model predicts spending by each family in a FFS plan, an HMO plan, an MSA, and no insurance. These predictions allow us to compute community-rated premiums for each plan, but with firm-specific load fees. Within each firm, employees then evaluate each option, and the firm decides whether to offer insurance-and what type-based on these evaluations. If firms offer insurance, we consider two scenarios: (1) all workers elect coverage; and (2) workers can decline the coverage in return for a wage increase. In the long run, under simulated conditions, tax-advantaged MSAs could attract 56 percent of all employees offered a plan by small businesses. However, the fraction of small-business employees offered insurance increases only from 41 percent to 43 percent when MSAs become an option. Many employees now signing up for a FFS plan would switch to MSAs if they were universally available. Our simulations suggest that MSAs will provide a limited impetus to businesses that do not currently cover insurance. However, MSAs could be desirable to workers in firms that already offer HMOs or standard FFS plans. As a result, expanding MSA availability could make it a major form of insurance for covered workers in small businesses. Overall welfare would increase slightly.


Objective measures to investigate turning impairments and freezing of gait in people with Parkinson's disease.
Turning is impaired in people with Parkinson's Disease (PD) and it is a common trigger for freezing of gait (FoG). Recent evidence suggests that people with PD who freeze (PD+FoG) have worse turning performance than those who don't have freezing (non-freezers, PD-FoG), and the freezing episodes are exacerbated by increasing the turn angular amplitude. We investigated the difference between turning 180° while walking versus turning 360° in place, in both single- and dual-task conditions, by means of objective measures in people with PD with and without FoG. Twenty-four PD+FoG and eighteen PD-FoG performed 180° turns while walking and 360° turns in place during single- and dual-task conditions. Quantitative measures of turning and the dual-task cost were computed. Differences were investigated between groups and within turning types using ANOVA. Associations between turn measures and clinical scales were examined with Spearman correlations. Turn duration and the number of steps were greater, and peak angular velocity slower, in PD+FoG compared to PD-FoG (p < 0.001). Dual-task costs were similar across groups, but turn duration showed significant interaction (p = 0.03). Posture Instability and Gait Disability (PIGD) subscore was associated with all turn measures in PD-FoG; whereas PIGD was mainly associated with turning while walking in PD+FoG. Objective measures of turning revealed differences between people with and without FoG, specifically, people with FoG showed more impairments in 360° turning in place compared to 180° turning while walking. However, as the turning challenges were increased by adding a dual-task, results from PD+FoG were similar to those from PD-FoG.