Selected Plant Triterpenoids and Their Derivatives as Antiviral Agents.
The results of the most recent investigation of triterpenoid-based antiviral agents namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key historical achievements are included to stress consequences and continuity in this research. Most of the agents studied belong to a series of compounds derived from betulin or betulinic acid, and their synthetic derivative is called bevirimat. A termination of clinical trials of bevirimat in Phase IIb initiated a search for more successful compounds partly derived from bevirimat or designed independently of bevirimat structure. Surprisingly, a majority of bevirimat mimics are derivatives of betulinic acid, while other plant triterpenoids, such as ursolic acid, oleanolic acid, glycyrrhetinic acid, or other miscellaneous triterpenoids, are relatively rarely involved in a search for a novel antiviral agent. Therefore, this review article is divided into three parts based on the leading triterpenoid core structure.


New screening system for selective blockers of voltage-gated K(+) channels using recombinant cell lines dying upon single action potential.
To develop a simple screening system for blockers of voltage-gated Kv1.3 and Kv1.5 channels, new cell lines co-expressing mutated Nav1.5 (IFM/Q3), Kir2.1 (Kir), and Kv1.3 or Kv1.5 were introduced as IFM/Q3+Kir+Kv1.3 and IFM/Q3+Kir+Kv1.5, respectively. Electrical stimulation (ES) of a cell line, IFM/Q3+Kir, induced prolonged action potentials due to the slow inactivation of IFM/Q3 and subsequent cell death. Additional co-expression of Kv1.3 or Kv1.5 to IFM/Q3+Kir shortened the evoked action potentials and prevented cell death. In the presence of margatoxin, a selective Kv1.3-blocker, ES induced cell death in IFM/Q3+Kir+Kv1.3, but not in IFM/Q3+Kir+Kv1.5. In the presence of 4-aminopyridine, a non-selective Kv-channel blocker, ES application elicited cell death in both cell lines. The IC50s of acacetin, a Kv1.5-blocker, was 10.2 μM in IFM/Q3+Kir+Kv1.3 and almost identical to that in IFM/Q3+Kir+Kv1.5 (7.6 μM). The IC50s of citalopram, a 5-HT uptake-inhibitor, were 1.8 μM in IFM/Q3+Kir+Kv1.3 and 1.5 μM in IFM/Q3+Kir+Kv1.5, respectively. These IC50s were comparable to those determined electrophysiologically. In conclusion, acacetin and citalopram block both Kv1.3 and Kv1.5 without selectivity. The Kv1.3 or Kv1.5 channel inhibition assay using these new cell lines may be applicable to high-throughput screening because of its simplicity, accuracy, and high cost-performance.


A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/β-Catenin Signaling Promotes Metastasis of Colon Cancer.
We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic β-catenin impeded casein kinase 1 (CK1)-induced β-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, β-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear β-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with β-catenin, and the positive feed-forward circuit of CYTOR-β-catenin might be a useful therapeutic target in antimetastatic strategy.


Rapid and efficient incorporation of tissue factor into liposomes.
Tissue factor (TF), the physiological trigger of the blood clotting cascade, is also the active ingredient in thromboplastin preparations which are widely used in clotting assays such as the prothrombin time (PT) test. A type I integral membrane protein, TF must be incorporated into suitable phospholipid membranes for full procoagulant activity. Several methods exist for incorporating TF into phospholipid vesicles, typically employing the formation of mixed micelles containing detergent, phospholipid and TF, followed by detergent removal or dilution below the critical micelle concentration (CMC). These methods have certain drawbacks: they may take several days to complete, employ expensive detergents, are difficult to scale up, and do not always result in complete detergent removal. In this study we have investigated the use of a variety of detergents [Triton X-100, octaethylene glycol monododecyl ether (C(12)E(8)), cholate, deoxycholate, and n-octyl-beta-D-glucopyranoside], and the use of adsorbent beads (Bio-Beads SM-2) for removing detergent, in processes to incorporate TF into proteoliposomes with high specific activity in coagulation assays. The method we have developed is rapid and readily scalable, yielding thromboplastin preparations with specific activities in plasma clotting assays that are at least as high as those made with detergent dialysis.


Developing a QSAR model for hepatotoxicity screening of the active compounds in traditional Chinese medicines.
The perception that natural substances are deemed safe has made traditional Chinese medicine (TCM) popular in the treatment and prevention of disease globally. However, such an assumption is often misleading owing to a lack of scientific validation. To assess the safety of TCM, in silico screening provides major advantages over the classical laboratory approaches in terms of resource- and time-saving and full reproducibility. To screen the hepatotoxicity of the active compounds of TCMs, a quantitative structure-activity relationship (QSAR) model was firstly established by utilizing drugs from the Liver Toxicity Knowledge Base. These drugs were annotated with drug-induced liver injury information obtained from clinical trials and post-marketing surveillance. The performance of the model after nested 10-fold cross-validation was 79.1%, 91.2%, 53.8% for accuracy, sensitivity, and specificity, respectively. The external validation of 91 well-known ingredients of common herbal medicines yielded a high accuracy (87%). After screening the TCM Database@Taiwan, the world's largest TCM database, a total of 6853 (74.8%) ingredients were predicted to have hepatotoxic potential. The one-hundred chemical ingredients predicted to have the highest hepatotoxic potential by our model were further verified by published literatures. Our study indicated that this model can serve as a complementary tool to evaluate the safety of TCM.


Relationship between Leadership among Peers and Burnout in Sports Teams.
This study has been conducted with the aim of ascertaining the relationship between peer leaders in sport teams and the levels of burnout experienced by their team-mates. A total of 219 Spanish athletes involved in football and basketball participated in the study. To measure leadership among peers, we employed the Sports Peer Leadership Scale, which comprises 24 items, grouped into 6 primary factors: empathy, influence on decision making, sports values, social support, training orientation and competition orientation. And to measure burnout, we employed the Athlete Burnout Questionnaire, which comprises 15 items which are indicators of physical and emotional exhaustion, devaluation and reduced sense of accomplishment among athletes. The results led to the conclusion that there is a statistically significant negative relationship between perceived leadership capacity and the levels of burnout experience by a team. The greater the level of leadership capacity perceived, the lower the levels of burnout will be. A multiple regression analysis with total burnout as dependent variable and social and task orientations of the leader as predictors showed standardized regression coefficients of -.241 (p = .010) and -.076 (p = .413), respectively for social and task orientation, being the effect size equal to .089.


Alcohol Binge Drinking and Executive Functioning during Adolescent Brain Development.
Alcohol consumption in adolescents causes negative effects on familiar, social, academic life, as well as neurocognitive alterations. The binge drinking (BD) pattern of alcohol is characterized by the alternation of episodes of heavy drinking in a short interval of time, and periods of abstinence, a practice that can result in important brain alterations; even more than regular alcohol consumption. The prefrontal cortex, which acts as neural support for the executive processes, is particularly affected by alcohol; however, not all studies are in agreement about how BD alcohol consumption affects executive functioning. Some research has found that alcohol consumption in adolescence does not significantly affect executive functioning while others found it does. It is possible that these discrepancies could be due to the history of alcohol consumption, that is, at what age the subjects started drinking. The aim of our study is to assess the performance on executive functioning tasks of 13-19-year-old adolescents according to their pattern of alcohol consumption. We hypothesize that BD adolescents will perform worse than non-BD subjects in tasks that evaluate executive functions, and these differences will increase depending on how long they have been consuming alcohol. Three hundred and twenty-two students (48.14% females; age range 13-22 years; mean aged 16.7 ± 2.59) participated in the study; all of them had begun drinking at the age of 13 years. Participant were divided into three groups, according to their age range (13-15, 16-18, and 19-22 years) and divided according to their pattern of alcohol consumption (BD and control groups). Then, the subjects were evaluated with neuropsychological tasks that assess executive functions like working memory, inhibition, cognitive flexibility, or self-control among others. The entire sample showed a normal improvement in their executive performance, but this improvement was more stable and robust in the control group. Regarding the executive performance among age groups, control subjects only obtained better results than BDs in the 19-22-year-old range, whereas the performance was quite similar at younger ages. Considering that all the BD subjects started drinking at the same age (13 years old), it is possible that a kind of compensation mechanism exists in the adolescent brain which allows them to reach a normal performance in executive tasks. This theoretical mechanism would depend upon neuronal labor, which could lose efficacy over time with further alcohol ingestion. This process would account for the differences in neuropsychological performance, which were only observed in older students with a longer history of alcohol consumption.


Achromatic combinations of hologram optical elements.
Two- and three-element combinations of hologram optical elements are considered, and analytical conditions are obtained for absence of longitudinal dispersion. Solutions of the conditional equations are compared with another author's computed design results. A simple doublet design is considered for an eyepiece, and its performance is described.


Relationship among state reopening policies, health outcomes and economic recovery through first wave of the COVID-19 pandemic in the U.S.
State governments in the U.S. have been facing difficult decisions involving tradeoffs between economic and health-related outcomes during the COVID-19 pandemic. Despite evidence of the effectiveness of government-mandated restrictions mitigating the spread of contagion, these orders are stigmatized due to undesirable economic consequences. This tradeoff resulted in state governments employing mandates at widely different ways. We compare the different policies states implemented during periods of restriction ("lockdown") and reopening with indicators of COVID-19 spread and consumer card spending at each state during the first "wave" of the pandemic in the U.S. between March and August 2020. We find that while some states enacted reopening decisions when the incidence rate of COVID-19 was minimal or sustained in its relative decline, other states relaxed socioeconomic restrictions near their highest incidence and prevalence rates experienced so far. Nevertheless, all states experienced similar trends in consumer card spending recovery, which was strongly correlated with reopening policies following the lockdowns and relatively independent from COVID-19 incidence rates at the time. Our findings suggest that consumer card spending patterns can be attributed to government mandates rather than COVID-19 incidence in the states. We estimate the recovery in states that reopened in late April was more than the recovery in states that did not reopen in the same period- 15% for consumer card spending and 18% for spending by high income households. This result highlights the important role of state policies in minimizing health impacts while promoting economic recovery and helps planning effective interventions in subsequent waves and immunization efforts.


Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus.
More than three decades ago, the Framingham study revealed that cardiovascular risk is elevated for all diabetics and that this jeopardy is substantially accentuated for women in particular. Numerous studies have subsequently documented worsened cardiac outcomes for women. Given that estrogen and insulin exert major regulatory effects through common intracellular signaling pathways prominent in maintenance of cardiomyocyte function, a sex-hormone:diabetic-disease interaction is plausible. Underlying aspects of female cardiovascular pathophysiology that exaggerate cardiovascular diabetic risk may be identified, including increased vulnerability to coronary microvascular disease, age-dependent impairment of insulin-sensitivity, and differential susceptibility to hyperglycemia. Since Framingham, considerable progress has been made in the development of experimental models of diabetic disease states, including a diversity of genetic rodent models. Ample evidence indicates that animal models of both type 1 and 2 diabetes variably recapitulate aspects of diabetic cardiomyopathy including diastolic and systolic dysfunction, and cardiac structural pathology including fibrosis, loss of compliance, and in some instances ventricular hypertrophy. Perplexingly, little of this work has explored the relevance and mechanisms of sexual dimorphism in diabetic cardiomyopathy. Only a small number of experimental studies have addressed this question, yet the prospects for gaining important mechanistic insights from further experimental enquiry are considerable. The case for experimental interrogation of sex differences, and of sex steroid influences in the aetiology of diabetic cardiomyopathy, is particularly compelling-providing incentive for future investigation with ultimate therapeutic potential.


Body composition estimation from selected slices: equations computed from a new semi-automatic thresholding method developed on whole-body CT scans.
Estimating volumes and masses of total body components is important for the study and treatment monitoring of nutrition and nutrition-related disorders, cancer, joint replacement, energy-expenditure and exercise physiology. While several equations have been offered for estimating total body components from MRI slices, no reliable and tested method exists for CT scans. For the first time, body composition data was derived from 41 high-resolution whole-body CT scans. From these data, we defined equations for estimating volumes and masses of total body AT and LT from corresponding tissue areas measured in selected CT scan slices. We present a new semi-automatic approach to defining the density cutoff between adipose tissue (AT) and lean tissue (LT) in such material. An intra-class correlation coefficient (ICC) was used to validate the method. The equations for estimating the whole-body composition volume and mass from areas measured in selected slices were modeled with ordinary least squares (OLS) linear regressions and support vector machine regression (SVMR). The best predictive equation for total body AT volume was based on the AT area of a single slice located between the 4th and 5th lumbar vertebrae (L4-L5) and produced lower prediction errors (|PE| = 1.86 liters, %PE = 8.77) than previous equations also based on CT scans. The LT area of the mid-thigh provided the lowest prediction errors (|PE| = 2.52 liters, %PE = 7.08) for estimating whole-body LT volume. We also present equations to predict total body AT and LT masses from a slice located at L4-L5 that resulted in reduced error compared with the previously published equations based on CT scans. The multislice SVMR predictor gave the theoretical upper limit for prediction precision of volumes and cross-validated the results.


Genetic Diversity on the Human X Chromosome Does Not Support a Strict Pseudoautosomal Boundary.
Unlike the autosomes, recombination between the X chromosome and the Y chromosome is often thought to be constrained to two small pseudoautosomal regions (PARs) at the tips of each sex chromosome. PAR1 spans the first 2.7 Mb of the proximal arm of the human sex chromosomes, whereas the much smaller PAR2 encompasses the distal 320 kb of the long arm of each sex chromosome. In addition to PAR1 and PAR2, there is a human-specific X-transposed region that was duplicated from the X to the Y chromosome. The X-transposed region is often not excluded from X-specific analyses, unlike the PARs, because it is not thought to routinely recombine. Genetic diversity is expected to be higher in recombining regions than in nonrecombining regions because recombination reduces the effect of linked selection. In this study, we investigated patterns of genetic diversity in noncoding regions across the entire X chromosome of a global sample of 26 unrelated genetic females. We found that genetic diversity in PAR1 is significantly greater than in the nonrecombining regions (nonPARs). However, rather than an abrupt drop in diversity at the pseudoautosomal boundary, there is a gradual reduction in diversity from the recombining through the nonrecombining regions, suggesting that recombination between the human sex chromosomes spans across the currently defined pseudoautosomal boundary. A consequence of recombination spanning this boundary potentially includes increasing the rate of sex-linked disorders (e.g., de la Chapelle) and sex chromosome aneuploidies. In contrast, diversity in PAR2 is not significantly elevated compared to the nonPARs, suggesting that recombination is not obligatory in PAR2. Finally, diversity in the X-transposed region is higher than in the surrounding nonPARs, providing evidence that recombination may occur with some frequency between the X and Y chromosomes in the X-transposed region.


Toleration and the Design of Norms.
One of the pressing challenges we face today-in a post-Westphalian order (emergence of the state as the modern, political information agent) and post-Bretton Woods world (emergence of non-state multiagent systems or MASs as "hyperhistorical" players in the global economy and politics)-is how to design the right kind of MAS that can take full advantage of the socio-economic and political progress made so far, while dealing successfully with the new global challenges that are undermining the best legacy of that very progress. This is the topic of the article. In it, I argue that (i) in order to design the right kind of MAS, we need to design the right kind of norms that constitute them; (ii) in order to design the right kind of constitutive norms, we need to identify and adopt the right kind of principles of normative design; (iii) toleration is one of those principles; (iv) unfortunately, its role as a foundation for the design of norms has been undermined by the "paradox of toleration"; (v) however, the paradox can be solved; (vi) so toleration can be re-instated as the right kind of foundational principle for the design of the right kind of norms that can constitute the right kind of MAS that can operate across cultures, societies and states, to help us to tackle the new global challenges facing us.


A randomized comparison of branded sodium stibogluconate and generic sodium stibogluconate for the treatment of visceral leishmaniasis under field conditions in Sudan.
To compare the outcome of treatment of Sudanese kala-azar patients treated under field conditions with either branded sodium stibogluconate (SSG) (Pentostam GlaxoWellcome) or generic SSG (Albert David Ltd, Calcutta, supplied by International Dispensary Association, Amsterdam). Randomised comparison. 271 patients were treated with Pentostam and 245 with generic SSG. No statistically significant differences in cure rate or mortality were detected between Pentostam and generic SSG. No differences in side-effects between the two drugs were noted. The initial cure rate at the time of discharge was 93.7 and 97.6%, respectively; the death rate during treatment 5.9 and 2.4%. Six months follow up was achieved in 88.5% of the discharged patients. Two patients had died in the Pentostam group and two had died in the generic SSG group, giving a final death rate of 7.5 and 3.7%. The number of relapses in the Pentostam and generic SSG groups were 3 and 1, respectively. The final cure rates, calculated at 6 months after discharge, were 91.3% and 95.9%. No difference was observed in the performance of generic SSG compared to Pentostam for the treatment of visceral leishmaniasis in Sudan. Generic SSG can be routinely and safely used for the treatment of kala-azar. Generic SSG costs only 1/14 of the price of Pentostam. The use of generic SSG may make treatment of kala-azar affordable for national governments in Africa.


Tailored semiconductors for high-harmonic optoelectronics.
The advent of high-harmonic generation in gases 30 years ago set the foundation for attosecond science and facilitated ultrafast spectroscopy in atoms, molecules, and solids. We explore high-harmonic generation in the solid state by means of nanostructured and ion-implanted semiconductors. We use wavelength-selective microscopic imaging to map enhanced harmonic emission and show that the generation medium and the driving field can be locally tailored in solids by modifying the chemical composition and morphology. This enables the control of high-harmonic technology within precisely engineered solid targets. We demonstrate customized high-harmonic wave fields with wavelengths down to 225 nanometers (ninth-harmonic order of 2-micrometer laser pulses) and present an integrated Fresnel zone plate target in silicon, which leads to diffraction-limited self-focusing of the generated harmonics down to 1-micrometer spot sizes.


Efficient two-step conversion of alpha,beta-unsaturated aldehydes to optically active gamma-oxy-alpha,beta-unsaturated nitriles and its application to the total synthesis of (+)-patulolide C.
[reaction: see text] An efficient two-step conversion of alpha,beta-unsaturated aldehydes into optically active gamma-oxy-alpha,beta-unsaturated nitriles is described. First, catalytic asymmetric cyanation-ethoxycarbonylation using (S)-YLi(3)tris(binaphthoxide) (YLB) afforded chiral allylic cyanohydrin carbonate. Second, a [3,3]-sigmatropic rearrangement proceeded without racemization under thermal conditions to give gamma-oxy-alpha,beta-unsaturated nitriles. Lewis acids were also effective for the rearrangement, and the reaction proceeded smoothly under mild conditions. To demonstrate the utility of the conversion, concise catalytic enantioselective total synthesis of (+)-patulolide C was performed.


Nutrient content of milk and milk products: water soluble vitamins in baby milk formulae.
A study of the content of water soluble vitamins in the 12 baby milk formulae available in the UK in April 1983 showed that levels of vitamins in the individual brands were generally in excess of those declared by the manufacturer. For cows' milk based formulae the mean excess of vitamins over the declared level was 94%. Vitamin levels in prepared formulae averaged three times the minimum recommended level. The average level of B vitamins in prepared cows' milk based formulae was six times higher than in mature human milk. For the two soya based products, the levels of vitamins were generally in excess of the declared level and levels of vitamin B12, biotin and, in one sample, vitamin B6 were considerably in excess of those found in mature human milk.


Portable ultrasound for remote environments, part II: current indications.
With recent advances in ultrasound technology, it is now possible to deploy lightweight portable imaging devices in the field. Techniques and studies initially developed for hospital use have been extrapolated out of the hospital setting in a wide variety of environments in an effort to increase diagnostic accuracy in austere or prehospital environments. This review summarizes current ultrasound applications used in out-of-hospital arenas and highlights existing evidence for such use. The diversity of applications and environments is organized by indication to better inform equipment selection as well as future directions for research and development. Trauma evaluation, casualty triage, and assessment for pneumothorax, acute mountain sickness, and other applications have been studied by field medical teams. A wide range of outcomes have been reported, from alterations in patient care to determinations of accuracy compared to clinical judgment or other diagnostic modalities. The use of lightweight portable ultrasound shows great promise in augmenting clinical assessment for field medical operations. Although some studies of diagnostic accuracy exist in this setting, further research focused on clinically relevant outcomes data is needed.


Stabilizing Perovskite Light-Emitting Diodes by Incorporation of Binary Alkali Cations.
The poor stability of perovskite light-emitting diodes (PeLEDs) is a key bottleneck that hinders commercialization of this technology. Here, the degradation process of formamidinium lead iodide (FAPbI3 )-based PeLEDs is carefully investigated and the device stability is improved through binary-alkalication incorporation. Using time-of-flight secondary-ion mass spectrometry, it is found that the degradation of FAPbI3 -based PeLEDs during operation is directly associated with ion migration, and incorporation of binary alkali cations, i.e., Cs+ and Rb+ , in FAPbI3 can suppress ion migration and significantly enhance the lifetime of PeLEDs. Combining experimental and theoretical approaches, it is further revealed that Cs+ and Rb+ ions stabilize the perovskite films by locating at different lattice positions, with Cs+ ions present relatively uniformly throughout the bulk perovskite, while Rb+ ions are found preferentially on the surface and grain boundaries. Further chemical bonding analysis shows that both Cs+ and Rb+ ions raise the net atomic charge of the surrounding I anions, leading to stronger Coulomb interactions between the cations and the inorganic framework. As a result, the Cs+ -Rb+ -incorporated PeLEDs exhibit an external quantum efficiency of 15.84%, the highest among alkali cation-incorporated FAPbI3 devices. More importantly, the PeLEDs show significantly enhanced operation stability, achieving a half-lifetime over 3600 min.


Feasibility of Isokinetic Training to Modify Coupling of Upper Limb Muscle Synergy Activation in Stroke-affected Upper Limb.
Abnormal intermuscular coordination in stroke-affected upper limbs contributes to motor deficits after stroke. In particular, abnormalities in the activation of upper limb muscle synergies after stroke were demonstrated for endpoint force control during isokinetic exercises. This study aimed to investigate the feasibility of isokinetic training to alter these abnormal synergy activations and improve motor control. Muscle synergies and Wolf Motor Function Test Functional Ability Scale (WMFT-FAS) score were compared before and after three weeks of electromyography-based training. The proposed training changed the synergy activation and improved the WMFT-FAS score in a chronic stroke survivor while preserving the muscle weights of the synergies.Clinical Relevance- This study presents the feasibility of neuromuscular training to modify the activation of upper limb muscle synergies against stroke-specific patterns of intermuscular coordination and improve WMFT-FAS score.


Brain-computer symbiosis.
The theoretical groundwork of the 1930s and 1940s and the technical advance of computers in the following decades provided the basis for dramatic increases in human efficiency. While computers continue to evolve, and we can still expect increasing benefits from their use, the interface between humans and computers has begun to present a serious impediment to full realization of the potential payoff. This paper is about the theoretical and practical possibility that direct communication between the brain and the computer can be used to overcome this impediment by improving or augmenting conventional forms of human communication. It is about the opportunity that the limitations of our body's input and output capacities can be overcome using direct interaction with the brain, and it discusses the assumptions, possible limitations and implications of a technology that I anticipate will be a major source of pervasive changes in the coming decades.


Nationwide cohort study identifies clinical outcomes of angioectasia in patients with acute hematochezia.
While angioectasia is an important cause of acute hematochezia, relevant clinical features remain unclear. This study aims to reveal risk factors, clinical outcomes, and the effectiveness of therapeutic endoscopy for patients with acute hematochezia due to angioectasia. This retrospective cohort study was conducted at 49 Japanese hospitals between January 2010 and December 2019, enrolling patients hospitalized for acute hematochezia (CODE BLUE-J study). Baseline factors and clinical outcomes for angioectasia were analyzed. Among 10,342 patients with acute hematochezia, 129 patients (1.2%) were diagnosed with angioectasia by colonoscopy. The following factors were significantly associated with angioectasia: chronic kidney disease, liver disease, female, body mass index < 25, and anticoagulant use. Patients with angioectasia were at a significant increased risk of blood transfusions compared to those without angioectasia (odds ratio [OR] 2.61; 95% confidence interval [CI] 1.69-4.02). Among patients with angioectasia, 36 patients (28%) experienced rebleeding during 1-year follow-up. The 1-year cumulative rebleeding rates were 37.0% in the endoscopic clipping group, 14.3% in the coagulation group, and 32.8% in the conservative management group. Compared to conservative management, coagulation therapy significantly reduced rebleeding risk (P = 0.038), while clipping did not (P = 0.81). Multivariate analysis showed coagulation therapy was an independent factor for reducing rebleeding risk (hazard ratio [HR] 0.40; 95% CI 0.16-0.96). Our data showed patients with angioectasia had a greater comorbidity burden and needed more blood transfusions in comparison with those without angioectasia. To reduce rebleeding risk, coagulation therapy can be superior for controlling hematochezia secondary to angioectasia.


A microfluidic cell-migration assay for the prediction of progression-free survival and recurrence time of patients with glioblastoma.
Clinical scores, molecular markers and cellular phenotypes have been used to predict the clinical outcomes of patients with glioblastoma. However, their clinical use has been hampered by confounders such as patient co-morbidities, by the tumoral heterogeneity of molecular and cellular markers, and by the complexity and cost of high-throughput single-cell analysis. Here, we show that a microfluidic assay for the quantification of cell migration and proliferation can categorize patients with glioblastoma according to progression-free survival. We quantified with a composite score the ability of primary glioblastoma cells to proliferate (via the protein biomarker Ki-67) and to squeeze through microfluidic channels, mimicking aspects of the tight perivascular conduits and white-matter tracts in brain parenchyma. The assay retrospectively categorized 28 patients according to progression-free survival (short-term or long-term) with an accuracy of 86%, predicted time to recurrence and correctly categorized five additional patients on the basis of survival prospectively. RNA sequencing of the highly motile cells revealed differentially expressed genes that correlated with poor prognosis. Our findings suggest that cell-migration and proliferation levels can predict patient-specific clinical outcomes.


Metabolic-associated Fatty Liver Disease as Assessed by the Fatty Liver Index Among Migrant and Non-migrant Ghanaian Populations.
Metabolic-associated fatty liver disease (MAFLD) is driven by high caloric intake and sedentary lifestyle. Migration towards high income countries may induce these driving factors; yet, the influence of such on the prevalence of MAFLD is clearly understudied. Here, we investigated the Fatty Liver Index (FLI), a proxy of steatosis in MAFLD, after migration of Ghanaian subjects. Cross-sectional data of 5282 rural, urban and migrant participants from the Research on Obesity and Diabetes among African Migrants (also known as RODAM) study were analyzed with logistic regression for geographical differences in FLI and associations with type 2 diabetes mellitus (T2DM), waist-to-hip ratio, and 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD). Both FLI and the proportion with an FLI indicative of MAFLD steatosis (FLI ≥60) were higher in migrants compared with non-migrants. Prevalence of elevated FLI (FLI ≥60) in non-migrant males was 4.2% compared to 28.9% in migrants. For females, a similar gradient was observed, from 13.6% to 36.6% respectively. Compared to rural residents, the odds for a FLI ≥60 were higher in migrants living in urban Europe (odds ratio [OR] 9.02, 95% confidence interval [CI]: 5.02-16.20 for men, and 4.00, 95% CI: 3.00-5.34 for women). Compared to controls, the ORs for FLI ≥60 were 2.43 (95% CI: 1.73-3.41) for male T2DM cases and 2.02 (95% CI: 1.52-2.69) for female T2DM cases. One-unit higher FLI was associated with an elevated (≥7.5%) 10-year ASCVD risk (OR: 1.051, 95% CI: 1.041-1.062 for men, and 1.020, 95% CI: 1.015-1.026 for women). FLI as a proxy for MAFLD increased stepwise in Ghanaians from rural areas, through urban areas, to Europe. Our results clearly warrant awareness for MAFLD in migrant population as well as confirmation with imaging modalities.


Assessment of the accuracy of portion size reports using computer-based food photographs aids in the development of an automated self-administered 24-hour recall.
To assess the accuracy of portion-size estimates and participant preferences using various presentations of digital images. Two observational feeding studies were conducted. In both, each participant selected and consumed foods for breakfast and lunch, buffet style, serving themselves portions of nine foods representing five forms (eg, amorphous, pieces). Serving containers were weighed unobtrusively before and after selection as was plate waste. The next day, participants used a computer software program to select photographs representing portion sizes of foods consumed the previous day. Preference information was also collected. In Study 1 (n=29), participants were presented with four different types of images (aerial photographs, angled photographs, images of mounds, and household measures) and two types of screen presentations (simultaneous images vs an empty plate that filled with images of food portions when clicked). In Study 2 (n=20), images were presented in two ways that varied by size (large vs small) and number (4 vs 8). Convenience sample of volunteers of varying background in an office setting. Repeated-measures analysis of variance of absolute differences between actual and reported portions sizes by presentation methods. Accuracy results were largely not statistically significant, indicating that no one image type was most accurate. Accuracy results indicated the use of eight vs four images was more accurate. Strong participant preferences supported presenting simultaneous vs sequential images. These findings support the use of aerial photographs in the automated self-administered 24-hour recall. For some food forms, images of mounds or household measures are as accurate as images of food and, therefore, are a cost-effective alternative to photographs of foods.


Implementation and outcomes of the Balanced Living with Diabetes program conducted by Cooperative Extension in rural communities in Virginia.
Adult onset diabetes is a significant health issue in rural communities that are disproportionately suffering from the health, social and financial costs of the disease. Despite this, over half of rural counties in the USA lack access to diabetes self-management programs, which are effective at improving diabetes management. The Cooperative Extension System (CES) is a nationwide education network that provides research-based information and programs in nearly 3000 counties in the USA to improve the health and wellbeing of rural and urban communities. This study evaluated the implementation and outcomes of a lifestyle management program, Balanced Living with Diabetes (BLD) conducted by community-based educators who are part of the CES in rural Virginia, to address the gap in diabetes education in these communities. BLD is grounded in social cognitive theory and has shown efficacy to modify dietary and physical activity behaviors resulting in improved glycemic control in people with type 2 diabetes. The study evaluated the implementation and effectiveness of BLD programs conducted by the CES in 16 rural counties over 2 years. Program adoption, reach, context, and barriers and facilitators to implementation were evaluated through program outcome data and extension educator interviews. Program outcomes included change in weight, glycosylated hemoglobin (A1C), diabetes knowledge, self-management practices, diet and physical activity behaviors, and self-efficacy from baseline to 12-week assessment. Extension educators conducted 30 programs, reaching 290 residents, with a 58% mean retention rate. The program resulted in a significant increase in diabetes and food knowledge, fruit, vegetable, and whole grain intake, use of the plate method, exercise, and diabetes management self-efficacy. A1C decreased significantly in participants with diabetes (mean reduction=0.345±1.013; p=0.001). The program was conducted twice in 11 counties, and once in five counties. Barriers to program adoption in the five counties included limited community interest, competing program priorities of the extension educator, and loss of extension personnel to conduct the program. Participant communication materials and systems to enhance program sustainability were developed in response to educator feedback. Process evaluation indicated that the program was highly acceptable to extension educators and program participants. The CES is an effective network for implementation of diabetes lifestyle-management programs in underserved communities, and the BLD program is effective at increasing lifestyle behaviors and self-efficacy that improve glycemic control in people with type 2 diabetes. Collaboration by Virginia's CES with a variety of community partners, including healthcare and social service providers, increases the reach and sustainability of extension diabetes programs. The CES in the USA is well positioned to fill the gap in diabetes education in rural communities as part of a chronic care model.


Arterial stiffness indices in healthy volunteers using non-invasive digital photoplethysmography.
Increased arterial stiffness is a marker of cardiovascular damage, even in the absence of clinically apparent disease. It is likely to become an important clinical tool in cardiovascular risk assessment. We studied a group of healthy subjects and measured their arterial stiffness by digital photoplethysmography. We aimed to obtain a range of arterial stiffness values, and investigated the influence of age, gender, race, body mass index, fasting lipids and haemodynamic factors. One hundred and fifty-two healthy subjects, aged between 18 and 67 years, on no medications and with no significant medical illnesses were recruited. The population was predominantly Caucasian (n = 112). Two measures of arterial stiffness were obtained: stiffness index (SI), a measure of large arterial stiffness, and reflection index (RI), a measure of small to medium-sized arterial stiffness. SI and RI were significantly correlated with age, total cholesterol, low-density lipoprotein-cholesterol, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Race was a significant independent predictor of SI. Digital photoplethysmography is a portable, operator-independent, reproducible and simple method of measuring arterial stiffness. Ranges of normality of arterial stiffness will depend on the individual's age, race, lipid levels, HR and blood pressure.


Isolation and structural characterization of an insulin-related molecule, a predominant neuropeptide from Locusta migratoria.
Neurohaemal lobes of corpora cardiaca of Locusta migratoria are an established storage site for neurohormones produced by the neurosecretory cells of the brain. As previously reported [Hietter, H., Van Dorsselaer, A., Green, B., Denoroy, L., Hoffmann, J.A. & Luu, B. (1990) Eur. J. Biochem. 187, 241-247], the isolation and characterization of a novel 5-kDa peptide from these lobes served as the basis for oligonucleotide screening of cDNA libraries prepared from poly(A) RNA from neurosecretory cells of the central nervous system. From subsequent cDNA cloning studies [Lagueux, M., Lwoff, L., Meister, M., Goltzené, F. & Hoffmann, J.A. (1990) Eur. J. Biochem. 187, 249-254], the existence of a 145-residue precursor protein was deduced, which contained, in addition to the 5-kDa peptide, amino-acid sequences with homology to the A and B chains of an insulin-related peptide. In the present study we have isolated the native molecule from corpora cardiaca of Locusta and characterized, by Edman degradation and plasma-desorption mass spectrometry, the two chains as follows: A chain, Gly-Val-Phe-Asp-Glu-Cys-Cys-Arg-Lys-Ser-Cys-Ser-Ile-Ser-Glu-Leu-Gln-Thr- Tyr-Cys - Gly (Ile, isoleucine); B chain, Ser-Gly-Ala-Pro-Gln-Pro-Val-Ala-Arg-Tyr-Cys-Gly-Glu-Lys-Leu-Ser-Asn-Ala- Leu-Lys - Leu-Val-Cys-Arg-Gly-Asn-Tyr-Asn-Thr-Met-Phe. Taken in conjunction with the previous cloning studies, our data lead to a clear picture of the processing of Locusta preproinsulin. They indicate that locusta corpora cardiaca contain remarkably large amounts of one single insulin form, in contrast to multiple insulin isoforms of Bombyx mori, the only other insect species from which insulin-related peptides have been isolated and characterized [Nagasawa, H., Kataoka, H., Isogai, A., Tamura, S., Suzuki, A., Mizoguchi, A., Fujiwara, Y., Suzuki, A., Takahashi, S. & Ishizaki, H. (1986) Proc. Natl Acad. Sci. USA 83, 5840-5843].


Bilateral Serous Macular Detachment After Attempted Suicide with Pregabalin.
A 24-year-old female presented with bilateral vision loss following attempted suicide with pregabalin. Her best-corrected visual acuity (BCVA) was 20/40 in the right eye and 20/50 in the left eye. The bilateral visual disturbance was associated with serous macular detachment. Fundus examination of both eyes showed foveal serous retinal detachment, which was confirmed by optical coherence tomography. Topical nepafenac 0.1% eye drops were started as single drop every 8 hours for 4 weeks. One month later, the serous macular detachment had regressed and BCVA increased to 20/20 in both eyes. To the best of our knowledge, this is the first reported case of bilateral serous macular detachment presumably caused by pregabalin intoxication.


Body mass index has a curvilinear relationship with the percentage of body fat among children.
Body Mass Index (BMI), which is defined as the ratio between weight (in kg) and height (in m2), is often used in clinical practice as well as in large scale epidemiological studies to classify subjects as underweight, normal weight, overweight or obese. Although BMI does not directly measure the percentage of Body Fat (BF%), it is widely applied because it is strongly related with BF%, it is easy to measure and it is an important predictor of mortality. Among children, age and sex-specific reference values of BMI, known as percentiles, are used. However, it is not clear how strong the relationship between BMI and BF% is among children and whether the association is linear. We performed a cross-sectional study aiming at evaluating the strength and shape of the relationship between BMI and BF% among school-aged children aged 6-12 years. The study was conducted on a sample of 361 football-playing male children aged 6 to 12 years in Rome, Italy. Age, weight, height and skinfold thickness were collected. BF% was estimated using 4 skinfold equations whereas BMI was converted into BMI-for-age z-score. The relationship between these variables was examined using linear regression analyses. Mean BMI was 18.2 (± 2.8), whereas BF% was influenced by the skinfold equation used, with mean values ranging from 15.6% to 23.0%. A curvilinear relationship between BMI-for-age zscore and BF % was found, with the regression line being convex. The association between BMI-for-age zscore and BF% was stronger among overweight/obese children than among normal/underweight children. This curvilinear pattern was evident in all 4 skinfold equations used. The association between BMI-for-age zscore and BF% is not linear among male children aged 6-12 years and it is stronger among overweight and obese subjects than among normal and underweight subjects. In this age group, BMI is a valid index of adiposity only among overweight and obese subjects.


Transformation of lamotrigine by white-rot fungus Pleurotus ostreatus.
One of the most persistent pharmaceutical compounds commonly found in treated wastewater is lamotrigine (LTG). It has also been detected in soils and crops irrigated with treated wastewater. Here we focused on the ability of the white-rot edible mushroom Pleurotus ostreatus to remove and transform LTG in liquid cultures. At concentrations of environmental relevance (1 and 10 μg L-1) LTG was almost completely removed from the culture medium within 20 days. To elucidate the mechanism of LTG removal and transformation, we applied a physiological-based approach using inhibitors and a competing agent. These experiments were conducted at a higher concentration for metabolites detection. Based on identification of sulfur-containing metabolites and LTG N2-oxide and the effect of specific inhibitors, cytochrome P450 oxidation is suggested as one of the reaction mechanisms leading to LTG transformation. The variety and number of transformation products (i.e., conjugates) found in the current study were larger than reported in mammals. Moreover, known conjugates with glucuronide, glutathione, or cysteine/glycine, were not found in our system. Since the majority of the identified transformation products were conjugates of LTG, this study highlights the persistence of LTG as an organic pollutant in ecosystems exposed to wastewater.


Increased serum interleukin-1beta and interleukin-6 in elderly, chronic schizophrenic patients on stable antipsychotic medication.
In schizophrenia, alterations of proinflammatory cytokine levels have been reported and related to the disease and psychopathology. However, only limited conclusions can be drawn in view of confounding factors such as infection, age, sex, smoking, and antipsychotic medication. Chronic schizophrenic patients with a long-term disease process and medication period have not been investigated so far. We have measured serum levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)alpha in 41 elderly, chronic schizophrenic patients and 23 age- and sex-matched controls using enzyme-linked immunosorbent assay (ELISA). We assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine, and the two main clozapine metabolites, desmethylclozapine and clozapine metabolite N-oxide, by high-pressure liquid chromatography (HPLC). IL-1beta and IL-6 levels were increased in treatment-resistant schizophrenic patients compared with healthy controls, whereas TNFalpha showed no difference. We did not find statistically significant differences of cytokine levels between medication groups and there was no correlation with serum levels of antipsychotics or psychopathological rating scores. Elevations of IL-1beta and IL-6 in elderly chronic schizophrenic patients may be related to an active disease process lasting until old age. Despite missing correlations, long-term treatment effects in treatment-resistant patients may have affected TNFalpha, leading to control levels. Post-mortem and animal studies should clarify the presence of altered immune function in the brain as well as the effect of cytokine levels in relation to neurodevelopmental disturbances and schizophrenia-associated behavior.


Stereotactic radiosurgery for postgeniculate visual pathway arteriovenous malformations.
Arteriovenous malformations (AVMs) that are located within the postgeniculate optic radiations or striate cortex are difficult to resect without creating postoperative visual defects. To reduce the risk of an AVM hemorrhage and to enhance the possibility of preserving visual function, the authors performed stereotactic radiosurgery in 34 patients with newly diagnosed or residual AVMs of the visual pathways. The mean AVM volume was 4.7 ml, and the average radiation dose to the AVM margin was 21 Gy. The median follow up was 47 months (range 16-83 months). Two (6%) of 34 patients had documented new visual field defects (central scotoma in one, and partial hemianopsia in one) after single-stage radiosurgery, but no patient developed a new permanent homonymous hemianopsia. Angiography was performed in all patients at a median of 26 months after radiosurgery: 22 (65%) had complete obliteration, 10 (29%) had a significant decrease in AVM volume, one (3%) had only a persistent early draining vein without residual nidus, and one (3%) had no change in the AVM. Thirteen (81%) of 16 patients with AVMs less of than 4 ml had complete obliteration. Five patients had second-stage stereotactic radiosurgery after angiography revealed a persistent AVM nidus; two patients eligible for follow-up angiography had complete obliteration, thereby increasing the overall series obliteration rate to 71%. The calculated annual risk of AVM bleeding (before radiographic evidence of obliteration) was 2.4%. No patient bled after angiographically confirmed obliteration. In most patients stereotactic radiosurgery obliterates visual pathway AVMs and also preserves preoperative visual function. Multimodality management (embolization, microsurgery, or staged radiosurgery) enhances AVM obliteration and visual preservation rates.


Vitamin C uptake and recycling among normal and tumor cells from the central nervous system.
Specialized cells transport vitamin C in its reduced form using sodium-dependent cotransporters (SVCT1 and SVCT2). Additionally, different cells transport the oxidized form of vitamin C, dehydroascorbic acid, through glucose transporters (GLUTs). We have proposed recently a model for vitamin C uptake that resolves the apparent contradiction that although only ascorbic acid is detectable in vivo, there are cells that transport only dehydroascorbic acid. We carried out a detailed kinetic analysis to compare the mechanisms of vitamin C uptake in normal human melanocytes, neurons isolated from brain cortex, hypothalamic ependymal-glial cells, and astrocytes. Uptake of ascorbic acid was also analyzed in the human oligodendroglioma cell line TC620, in human choroid plexus papilloma cells (HCPPC-1), and in the neuroblastoma cell line Neuro-2a. Melanocytes were used to carry out a detailed analysis of vitamin C uptake. Analysis of the transport data by the Lineweaver-Burk plot revealed the presence of one functional component (K(m) 20 microM) involved in ascorbic acid transport by melanocytes. Vitamin C sodium-dependent saturable uptake was also observed in neurons and hypothalamic tanycytes. We confirmed SVCT2 expression in neurons by in situ hybridization; however, SVCT2 expression was not detected in astrocytes in situ. Functional data indicate that astrocytes transport mainly dehydroascorbic acid, using the glucose transporter GLUT1. Our functional uptake analyses support the hypothesis that astrocytes are involved in vitamin C recycling in the nervous system. This recycling model may work as an efficient system for the salvage of vitamin C by avoiding the hydrolysis of dehydroascorbic acid produced by antioxidative protection.


[Results of combined therapy for 1260 patients with small cell lung cancer].
To evaluate the efficacy of combined modality treatment and determine the prognostic factors for small cell lung cancer (SCLC). From January 1974 to December 1995, 1260 patients with SCLC treated were retrospectively evaluated, with limited lesions in 732 patients, extensive lesions in 500 and stage unrecorded in 28. 553 patients were alloted into chemotherapy + radiotherapy (C + R) group, 355 into C + R + C group, 97 into R + C group, 126 into C group, 64 into R group and 65 into surgery (S + C + R) group. Patients with limited lesions received 2 - 4 cycles of chemotherapy including COMC, COMP, COMVP and CE-CAP. Radiotherapy was given to a dose of 40 - 70 Gy/4 - 7 w. Radiation portals for patients with limited lesions encompassed the primary tumor, hilar lymphatic drainage areas, partial mediastinum and bilateral supraclavicular regions. Patients with extensive lesions mainly received chemotherapy with or without palliative irradiation. The overall CR and PR rates were 26.7% and 52.3%. Local recurrence and distant metastasis rates were 58.8% and 61.5%. The 1-, 3- and 5-year survival rates were 50.2%, 14.7% and 11.7%, with median survival time of 12 months. The era, sex, age, tumor stage and treatment modality were all significant prognostic factors by both uni-variate and multi-variate analyses (P < 0.05). The result of S + C + R rated the best among these modalities and the result of C + R + C was superior to C + R, though the difference of which was not significant. Surgical resection should be considered as one part of comprehensive therapy for small cell lung cancer patients with limited lesions whenever possible. On top of routine chemotherapy early administration of radiotherapy is advisable.


Electron paramagnetic resonance characterization of tetrahydrobiopterin radical formation in bacterial nitric oxide synthase compared to mammalian nitric oxide synthase.
H(4)B is an essential catalytic cofactor of the mNOSs. It acts as an electron donor and activates the ferrous heme-oxygen complex intermediate during Arg oxidation (first step) and NOHA oxidation (second step) leading to nitric oxide and citrulline as final products. However, its role as a proton donor is still debated. Furthermore, its exact involvement has never been explored for other NOSs such as NOS-like proteins from bacteria. This article proposes a comparative study of the role of H(4)B between iNOS and bsNOS. In this work, we have used freeze-quench to stop the arginine and NOHA oxidation reactions and trap reaction intermediates. We have characterized these intermediates using multifrequency electron paramagnetic resonance. For the first time, to our knowledge, we report a radical formation for a nonmammalian NOS. The results indicate that bsNOS, like iNOS, has the capacity to generate a pterin radical during Arg oxidation. Our current electron paramagnetic resonance data suggest that this radical is protonated indicating that H(4)B may not transfer any proton. In the 2nd step, the radical trapped for iNOS is also suggested to be protonated as in the 1st step, whereas it was not possible to trap a radical for the bsNOS 2nd step. Our data highlight potential differences for the catalytic mechanism of NOHA oxidation between mammalian and bacterial NOSs.


Arterial Wave Separation Analysis and Reflection Wave Transit Time Estimation using a Double Rayleigh Flow Rate Model.
Arterial pulse wave separation analysis (WSA) requires simultaneously measured pressure and flow rate waveform from the same arterial site. Modelling approaches to flow rate waveforms offers a methodological and instrumentational advantage. However, current techniques are limited to the aortic site. For non-aortic sites such as carotid artery, modelling methods that were developed for aortic sites are not likely to capture the intrinsic differences in the carotid flow rate. In this work, a double-Rayleigh flow rate model for the carotid artery is developed to separate the forward and backward pressure waves using WSA (DRMWSA). The model parameters are optimally found based on characteristic features - obtained from the pressure waveform. The DRMWSA was validated using a database of 4374 virtual (healthy) subjects, and its performance was compared with actual flow rate based WSA (REFWSA) at the carotid artery. An RMSE < 2 mmHg were obtained for forward and backward pressure waveforms. The reflection quantification indices (ΔPF, ΔPB), (RM, RI) obtained from DRMWSA demonstrated strong and statistically significant correlation (r > 0.96, p < 0.001) and (r > 0.80, p < 0.001) respectively, with insignificant bias (p > 0.05), upon comparing with counterparts in REFWSA. A moderate correlation (r = 0.64, p < 0.001) was obtained for reflection wave transit time between both methods. The proposed method minimises the measurements required for WSA and has the potential to widen the vascular screening procedures incorporating carotid pulse wave dynamics.Clinical Relevance-This methodology quantifies arterial pressure wave reflections in terms of pressure augmentation and reflection transit time. The methodological advantage of using only a single waveform helps easy translation to technological solutions for clinical research.


Advances in the management of low-grade gliomas.
Low-grade gliomas (LGGs) represent the most common childhood brain tumors and are a histologically heterogenous group of tumors. Most LGGs are surgically resectable with excellent 10-year overall survival outcomes of more than 90 % with surgery alone. Tumors not amenable to surgical resection and those with an aggressive biology are more challenging to treat. Conventional radiotherapy is a more efficacious method of long-term tumor control than chemotherapy. However, radiation is associated with significant cognitive, endocrine, and cerebrovascular late effects, making chemotherapy an often-preferred modality over radiotherapy, especially in younger children. Multiple chemotherapy regimens have been evaluated over the past few decades with comparable survival outcomes and differing toxicity profiles. Newer regimens containing antiangiogenic agents also show promise. Recent molecular studies have implicated the BRAF oncogene, a key regulator of the MAPK pathway, and the AKT/mTOR pathway in pediatric LGG tumorigenesis. This has opened up promising new avenues for targeted therapy, with many agents currently under investigation.


Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing.
Understanding genetic aberrations in cancer leads to discovery of new targets for cancer therapies. The genomic landscape of hepatocellular carcinoma (HCC) has not been fully described. Therefore, patients with refractory advanced/metastatic HCC referred for experimental therapies, who had adequate tumor tissue available, had targeted next generation sequencing (NGS) of their tumor samples using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA) and their treatment outcomes were analyzed. In total, NGS was obtained for 14 patients (median number of prior therapies, 1) with advanced/metastatic HCC. Of these 14 patients, 10 (71%) were men, 4 (29%) women, 6 (43%) had hepatitis B or C-related HCC. NGS revealed at least 1 molecular abnormality in 12 patients (range 0-8, median 2). Detected molecular aberrations led to putative activation of the PI3K/AKT/mTOR pathway (n=3 [mTOR, PIK3CA, NF1]), Wnt pathway (n=6 [CTNNA1, CTNNB1]), MAPK pathway (n=2 [MAP2K1, NRAS]), and aberrant DNA repair mechanisms, cell cycle control and apoptosis (n=18 [ATM, ATR, BAP1, CCND1, CDKN2A, CDK4, FGF3, FGF4, FGF19, MCL1, MDM2, RB1, TP53]). Of the 3 patients with molecular aberrations putatively activating the PI3K/AKT/mTOR pathway, 2 received therapies including a mTOR inhibitor and all demonstrated therapeutic benefit ranging from a partial response to minor shrinkage per RECIST (-30%, -15%; respectively). In conclusion, genomic alterations are common in advanced HCC. Refractory patients with alterations putatively activating the PI3K/AKT/mTOR pathway demonstrated early signals of clinical activity when treated with therapies targeting mTOR.


Cyclohexane bis-urea compounds for the gelation of water and aqueous solutions.
A new class of efficient hydrogelators has been developed by a simple modification of the peripheral substituents of cyclohexane bis-urea organogelators with hydrophilic hydroxy or amino functionalities. These bis-urea hydrogelators were synthesised in two or three steps using an alternative procedure to the common isocyanate method. Gelation was obtained with organic solvents, water and strongly basic aqueous solutions like 25% ammonia. Hydrogelation was found to depend on a delicate balance between the hydrophobicity of the alkyl chains, hydrophilicity of the terminal substituents and the enantiomeric purity of the compound. The hydrogels consisted of a network of fibers, in which all urea groups are involved in intermolecular hydrogen bonding. Most likely, gelation is driven by hydrophobic interactions of the methylene units, whereas hydrogen bond formation between the urea groups provides the necessary anisotropy of the aggregation and the high thermal stability of the gels.


Elucidating the Mechanisms of Sodium Benzoate in Alzheimer's Disease: Insights from Quantitative Proteomics Analysis of Serum Samples.
N-methyl-D-aspartate receptors (NMDARs) are crucial components of brain function involved in memory and neurotransmission. Sodium benzoate is a promising NMDAR enhancer and has been proven to be a novel, safe and efficient therapy for patients with Alzheimer's disease (AD). However, in addition to the role of sodium benzoate as an NMDA enhancer, other mechanisms of sodium benzoate in treating AD are still unclear. To elucidate the potential mechanisms of sodium benzoate in Alzheimer's disease, this study employed label-free quantitative proteomics to analyze serum samples from AD cohorts with and without sodium benzoate treatment. The serum proteins from each patient were separated into 24 fractions using an immobilized pH gradient, digested with trypsin and then subjected to nanoLC‒MS/MS to analyze the proteome of all patients. The nanoLC‒MS/MS data were obtained with a label-free quantitative proteomic approach. Proteins with fold changes were analyzed with STRING and Cytoscape to find key protein networks/processes and hub proteins. Our analysis identified 861 and 927 protein groups in the benzoate-treatment cohort and the placebo cohort, respectively. The results demonstrated that sodium benzoate had the most significant effect on the complement and coagulation cascade pathways, amyloidosis disease, immune responses and lipid metabolic processes. Moreover, Transthyretin (TTR), Fibrinogen alpha chain (FGA), Haptoglobin (HP), Apolipoprotein B-100 (APOB), Fibrinogen beta chain (FGB), Apolipoprotein E (APOE) and Alpha-1-acid glycoprotein 1 (ORM1) were identified as hub proteins in the protein‒protein interaction networks. These findings suggest that sodium benzoate may exert its influence on important pathways associated with AD, thus contributing to the improvement in the pathogenesis of the disease.


Effects of long-term corticosteroid usage on functional disability in patients with early rheumatoid arthritis, regardless of controlled disease activity.
We investigated the effect of long-term corticosteroid usage in suppressing the progression of functional disability in patients with early rheumatoid arthritis (RA). We studied 3,982 RA patients, who had continuous enrollment for at least 3 years, among 9,132 RA patients enrolled in an observational cohort study, IORRA, in Tokyo, Japan, from 2000 to 2007. The DAS28 and Japanese version of Health Assessment Questionnaire (J-HAQ) scores were collected at 6-month intervals (each phase). Among these patients, those with DAS28 values under 3.2 in all phases and RA disease duration under 2 years at study entry were selected as "early RA patients with well-controlled disease". These patients were further classified into 3 groups based on average months of steroid usage per year: Non-users, Medium-users, and Frequent-users. Multiple linear regression analysis was used to study the relationship between steroid usage and the final J-HAQ scores. Among the 3,982 patients, 109 had DAS28 values under 3.2 in all the phases and were selected as study cohort. The average Final J-HAQ in Non-user (N = 64), in Medium-user (N = 25), in Frequent-user group (N = 20) was 0.04, 0.06, and 0.33, respectively. Multiple linear regression analysis after adjusting for all potential covariates confirmed that frequent steroid usage was the most significant factor associated with higher final J-HAQ scores (P < 0.05). Frequent steroid usage was associated with significantly higher final J-HAQ scores in early RA patients, even though their disease was managed efficiently by maintaining the DAS28 values under 3.2 over a long-term period.


Nanomatrix Coated Stent Enhances Endothelialization but Reduces Platelet, Smooth Muscle Cell, and Monocyte Adhesion under Physiologic Conditions.
Cardiovascular disease is presently the number one cause of death worldwide. Current stents used to treat cardiovascular disease have a litany of unacceptable shortcomings: adverse clinical events including restenosis, neointimal hyperplasia, thrombosis, inflammation, and poor re-endothelialization. We have developed a biocompatible, multifunctional, peptide amphiphile-based nanomatrix coating for stents. In this study, we evaluated the ability of the nanomatrix coated stent to simultaneously address the issues facing current stents under physiological flow conditions in vitro. We found that the nanomatrix coated stent could increase endothelial cell migration, adhesion, and proliferation (potential for re-endothelialization), discourage smooth muscle cell migration and adhesion (potential to reduce neointimal hyperplasia and restenosis), and decrease both platelet activation and adhesion (potential to prevent thrombosis) as well as monocyte adhesion (potential to attenuate inflammatory responses) under physiological flow conditions in vitro. These promising results demonstrate the potential clinical utility of this nanomatrix stent coating, and highlight the importance of biocompatibility, multifunctionality, and bioactivity in cardiovascular device design.


Review of multimodal treatment for type 2 diabetes: combining metabolic surgery and pharmacotherapy.
Treating type 2 diabetes mellitus (T2DM) in patients with obesity remains a challenge for physicians, endocrinologists and surgeons, a fact supported by uncontroverted evidence from studies looking at mortality and associated morbidity. Metabolic surgery remains the most effective treatment for obesity and T2DM with evidence demonstrating an improvement or resolution of symptoms of T2DM and a reduction in a mortality and rates of cardiovascular events compared with pharmacotherapy alone. While these results are promising, two important limitations must be recognized and addressed. With regards to long-term remission of T2DM, the metabolic benefits of bariatric surgery appear to fatigue with time and a proportion of patients will not maintain normoglycaemia without pharmacotherapy. Second, there has been noteworthy progress in the development of several classes of medications for the treatment of T2DM which were unavailable when the original studies comparing the effects of bariatric surgery with pharmacotherapy were conducted. Recognizing the need for further treatment following metabolic surgery for long-term disease control in conjunction with the availability of newer medications offering more effective, nonsurgical treatment presents a critical turning point in treatment treating obesity. While the traditional approach would be to determine the superiority (or non-inferiority) of these agents compared with surgery, clinicians and surgeons must acknowledge the limitations of this attitude towards treatment given evidence from fields such as cancer, where a combinational approach is the gold standard. Recent advances in pharmacotherapy, present not only a novel approach to medical therapy but a renewed impetus to investigate what can be achieved through multimodal care.


Identification and characterization of recD, a gene affecting plasmid maintenance and recombination in Escherichia coli.
We isolated mutations that reduce plasmid stability in dividing cell populations and mapped these mutations to a previously undescribed gene, recD, that affects recombination frequency and consequently the formation of plasmid concatemers. Insertions of the transposable element Tn10 into recD resulted in increased concatemerization and loss of pSC101 and ColE1-like replicons during nonselective growth. Both concatemer formation and plasmid instability in recD mutants require a functional recA gene. Mutations in recD are recessive to recD+ and map to a small region of the Escherichia coli chromosome located between recB and argA. Although the recD locus is distinct from loci encoding the two previously identified subunits of the RecBC enzyme, mutations in recD appear to affect the exonuclease activity of this enzyme.


Smart magnetic resonance imaging-based theranostics for cancer.
Smart theranostics are dynamic platforms that integrate multiple functions, including at least imaging, therapy, and responsiveness, in a single agent. This review showcases a variety of responsive theranostic agents developed specifically for magnetic resonance imaging (MRI), due to the privileged position this non-invasive, non-ionising imaging modality continues to hold within the clinical imaging field. Different MRI smart theranostic designs have been devised in the search for more efficient cancer therapy, and improved diagnostic efficiency, through the increase of the local concentration of therapeutic effectors and MRI signal intensity in pathological tissues. This review explores novel small-molecule and nanosized MRI theranostic agents for cancer that exhibit responsiveness to endogenous (change in pH, redox environment, or enzymes) or exogenous (temperature, ultrasound, or light) stimuli. The challenges and obstacles in the design and in vivo application of responsive theranostics are also discussed to guide future research in this interdisciplinary field towards more controllable, efficient, and diagnostically relevant smart theranostics agents.


Jumbo phages are active against extensively drug-resistant eyedrop-associated Pseudomonas aeruginosa infections.
Antibiotic-resistant bacteria present an emerging challenge to human health. Their prevalence has been increasing across the globe due in part to the liberal use of antibiotics that has pressured them to develop resistance. Those bacteria that acquire mobile genetic elements are especially concerning because those plasmids may be shared readily with other microbes that can then also become antibiotic resistant. Serious infections have recently been related to the contamination of preservative-free eyedrops with extensively drug-resistant (XDR) isolates of Pseudomonas aeruginosa, already resulting in three deaths. These drug-resistant isolates cannot be managed with most conventional antibiotics. We sought to identify alternatives to conventional antibiotics for the lysis of these XDR isolates and identified multiple bacteriophages (viruses that attack bacteria) that killed them efficiently. We found both jumbo phages (>200 kb in genome size) and non-jumbo phages that were active against these isolates, the former killing more efficiently. Jumbo phages effectively killed the three separate XDR P. aeruginosa isolates both on solid and liquid medium. Given the ongoing nature of the XDR P. aeruginosa eyedrop outbreak, the identification of phages active against them provides physicians with several novel potential alternatives for treatment.


Sustained colonoscopy quality improvement using a simple intervention bundle.
Unacceptable variation in colonoscopy quality exists. The Quality Improvement in Colonoscopy (QIC) study in 2011 improved quality by introducing an evidence-based "bundle" of measures into routine colonoscopy practice. The QIC bundle included: minimal cecal withdrawal time of ≥ 6 minutes; hyoscine butylbromide use; supine patient position for transverse colon examination; rectal retroflexion. Colonoscopy quality was measured by adenoma detection rate (ADR). The current study measured whether these effects led to a sustained change in practice 3 years following implementation. This observational study collected data from eight hospital trusts (sites) in the United Kingdom for a 6-month period, 3 years following QIC bundle implementation. Use of the antispasmodic, hyoscine butylbromide, was measured as a marker of bundle uptake. Bundle effectiveness was measured by ADR change. Comparisons were made between data before and immediately after implementation of the bundle. 28 615 colonoscopies by 188 colonoscopists were studied. Hyoscine butylbromide use increased from 15.8 % pre-implementation to 47.4 % in the sustainability phase (P < 0.01) indicating sustained engagement with QIC measures. ADR was higher in the sustainability period compared with pre-intervention, but only reached statistical significance among the poorest-performing colonoscopists. The introduction of a simple, inexpensive, pragmatic intervention significantly changed practice over a sustained period, improving colonoscopy quality as measured by ADR, particularly in poorer performers. QIC demonstrates that an easy-to-implement quality improvement approach can deliver a sustained change in practice for many years post intervention.


Molecular dynamics simulations of shock waves in hydroxyl-terminated polybutadiene melts: mechanical and structural responses.
The mechanical and structural responses of hydroxyl-terminated cis-1,4-polybutadiene melts to shock waves were investigated by means of all-atom non-reactive molecular dynamics simulations. The simulations were performed using the OPLS-AA force field but with the standard 12-6 Lennard-Jones potential replaced by the Buckingham exponential-6 potential to better represent the interactions at high compression. Monodisperse systems containing 64, 128, and 256 backbone carbon atoms were studied. Supported shock waves were generated by impacting the samples onto stationary pistons at impact velocities of 1.0, 1.5, 2.0, and 2.5 km s(-1), yielding shock pressures between approximately 2.8 GPa and 12.5 GPa. Single-molecule structural properties (squared radii of gyration, asphericity parameters, and orientational order parameters) and mechanical properties (density, shock pressure, shock temperature, and shear stress) were analyzed using a geometric binning scheme to obtain spatio-temporal resolution in the reference frame centered on the shock front. Our results indicate that while shear stress behind the shock front is relieved on a ∼0.5 ps time scale, a shock-induced transition to a glass-like state occurs with a concomitant increase of structural relaxation times by several orders of magnitude.


Robustness of performance during domain change in an esport: A study of within-expertise transfer.
Research on the transfer of skill from the circumstances in which it was learned to partially or completely novel tasks or situations is a foundational topic in the study of learning, memory, education, and expertise. A long history of transfer research has led to the conclusion that skill learning is generally domain specific. One important transfer problem occurs when a domain of expertise undergoes a fundamental shift, as when experts must adapt to changes in technology, rules, or professional practice. Here we examine skill maintenance in StarCraft 2, a video game of skills which undergoes frequent changes due to updates and includes a variety of gameplay options. Of particular interest are two competing predictions about how transfer will interact with expertise in this domain. The first approach emphasizes perceived similarity of the domains and predicts that skilled individuals will exhibit more favourable transfer than novices as these people will know enough to avoid processes, methods, and strategies which no longer apply after a domain change. The second emphasizes maximal adaptation to task constraints and predicts that experts will suffer the most during a domain change because of the loss of exploitable affordances. Neither approach did a good job explaining behaviour after the major game update called 'StarCraft 2: Heart of the Swarm,' perhaps because transfer was generally strong across all players. However, when examining transfer in the context of larger changes to gameplay, transfer seemed slightly better in more experienced players. The theoretical implications of this apparent interaction effect, and of the apparent resilience of more experienced StarCraft 2 players to transfer costs, are discussed.


Sequential appetite suppression by oral and visceral feedback to the brainstem.
The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1-4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.


[Hepatocellular carcinoma: occurrence, risk factors, biomarkers].
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Primary hepatocellular carcinoma can be found most frequently (80-90 %) in patients with liver cirrhosis. The most frequent causes of liver cirrhosis are chronic hepatitis B and C virus infections and chronic alcohol consumption. The occurrence of hepatocellular carcinoma is about 3-15 % in patients with alcoholic liver disease. Other predisposing causes can be: non-alcoholic steatohepatitis (NASH), obesity, diabetes mellitus, autoimmune hepatitis, intrahepatic biliary inflammations (primary biliary cirrhosis, primary sclerosing cholangitis), copper and iron metabolic diseases (Wilson-disease, haemochromatosis), congenital alpha-1-antitripsin deficiency. The causative role of hepatitis B és C viruses have been well established in the pathogenesis of liver cancer. Other pathogenic factors are smoking, and different chemical agents. Treatment options for these patients have previously been limited to best supportive care and palliative therapy. Beside surgical treatment (resection, liver transplantation) the invasive radiologic therapy also has been widely used. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In year 2007, sorafenib, a multitargeted kinase inhibitor was introduced to clinical practice and found to prolong survival significantly for patients with advanced HCC.


Heart failure with preserved left ventricular ejection fraction: concepts, misconceptions and future directions.
Heart failure with preserved left ventricular ejection fraction (HFPEF) represents a huge medical problem, especially in light of an increasing elderly population. Dysfunction of both left ventricular filling and ejection, combined with adverse loading conditions related to advanced age, arterial hypertension, diabetes mellitus, obesity and atrial fibrillation are fundamental pathophysiological mechanisms. Hypertension is probably the most important modifiable risk factor. The diagnosis has largely been based on signs of increased left ventricular filling pressure. Additional matters of debate are the interpretation of left ventricular ejection fraction in concentric remodelling and the cut-off used for the definition of HFPEF, as well as inconsistencies related to prevalence and prognosis, and lack of benefit of drugs in randomized trials.


Bacterial adhesion at synthetic surfaces.
A systematic investigation into the effect of surface chemistry on bacterial adhesion was carried out. In particular, a number of physicochemical factors important in defining the surface at the molecular level were assessed for their effect on the adhesion of Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli. The primary experiments involved the grafting of groups varying in hydrophilicity, hydrophobicity, chain length, and chemical functionality onto glass substrates such that the surfaces were homogeneous and densely packed with functional groups. All of the surfaces were found to be chemically well defined, and their measured surface energies varied from 15 to 41 mJ. m(-2). Protein adsorption experiments were performed with (3)H-labelled bovine serum albumin and cytochrome c prior to bacterial attachment studies. Hydrophilic uncharged surfaces showed the greatest resistance to protein adsorption; however, our studies also showed that the effectiveness of poly(ethyleneoxide) (PEO) polymers was not simply a result of its hydrophilicity and molecular weight alone. The adsorption of the two proteins approximately correlated with short-term cell adhesion, and bacterial attachment for L. monocytogenes and E. coli also correlated with the chemistry of the underlying substrate. However, for S. aureus and S. typhimurium a different pattern of attachment occurred, suggesting a dissimilar mechanism of cell attachment, although high-molecular-weight PEO was still the least-cell-adsorbing surface. The implications of this for in vivo attachment of cells suggest that hydrophilic passivating groups may be the best method for preventing cell adsorption to synthetic substrates provided they can be grafted uniformly and in sufficient density at the surface.


[Urological terminology in Francisco Díaz: an example in the history of the Spanish language].
The work "Tratado nuevamente impreso de todas las enfermedades de los riñones, vejiga y carnosidades de la verga y orina" from Francisco Diaz is the first Urology treaty and the main urologic text from the spanish renaissance. The idea that prompted our work was to collect the Romance language from a text about urology dated at the end of the XVI century. Its interest consists, on the one hand in the lack of similar studies, and on the other in the novelty resulting from the fact that the author decided to write in Romance language at a moment in which scientific treaties were written in Latin. We performed a meticulous reading of the treaty on a facsimile edition of the original of the same title edited in Madrid in 1588. We extract 1.288 medical terms that we consulted in three modern dictionaries to analyze the lexicon used by Diaz in its composition. We analyze the words from the point of view of their make up and ethimology; we review the meaning of the medical terms in relation to their current use--meaning conservation or loss--, and also the date of appearance of those terms in the spanish language, to know how many of them appeared in the work of Diaz for the first time, and to know the conservation or loss of the meaning that Diaz gave them currently. We extract 1.288 medical terms, 195 of them have been conserved with the same meaning from their origin to date; on the contrary, 35.5% are not found in either of the three dictionaries, so that they are medical terms used by Francisco Diaz for the first time and that were erased by time. 543 medical terms were contributions from Diaz in their first written appearance. The author performs a magnificent study in which he analyzes and explains his experience, his knowledge, and his deductions on everything referred to urinary tract diseases, with great expertise, offering at the same time an extraordinary living document of his time. It is also an extensive source of medical and general knowledge, provided from the great culture, maturity, and classic education of the author. It is a pleasant-to-read and easy-to-understand work thanks to its exquisite composition and perfect use of the the Romance language, well defined syntax, rich vocabulary, and abundance of practical examples.


Increased skeletal muscle volume in women with familial partial lipodystrophy, Dunnigan variety.
Familial partial lipodystrophy, Dunnigan variety (FPLD), an autosomal dominant disorder caused by LMNA mutations, is characterized by fat loss from the extremities. However, it is unclear whether these patients appear muscular because of a lack of subcutaneous fat or have an actual increase in muscle mass. Therefore, we compared muscle mass and volume of selected muscles in women with FPLD and control subjects using dual-emission x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Whole-body axial MRI and DXA scans were obtained on 39 women, aged 18 to 65 years, with FPLD and 17 healthy women matched for body mass index and age (group 1). Volumes of muscles in both the thighs, calves, and psoas were calculated from MRI scans and muscle mass in extremities were calculated from DXA. In addition, abdominal MRI and DXA scans were analyzed from 129 healthy, frequency-matched women (group 2). Comparisons between women with FPLD and control subjects were made using ANOVA, adjusting for height, body mass index, and age. Patients with FPLD, compared with control subjects had significantly greater volumes of the thigh muscles, (6358 ± 1491 vs 5198 ± 716 mL, P = .002), calf muscles (3133 ± 713 vs 2397 ± 335 mL; P < .001), and psoas muscles (210 ± 51 vs 175 ± 34 [group 1] and 165 ± 38 mL [group 2], P < .001). Patients with FPLD also had significantly increased arm and leg muscle masses when measured by DXA (P < .001). Insulin sensitivity, assessed by insulin tolerance tests, was negatively correlated to the calf muscle volume. Female patients with FPLD have increased skeletal muscle volume and mass compared with those of normal women.


Cogan's syndrome: clinical significance of antibodies against the inner ear and cornea.
The aim of this study was to evaluate the pathological significance of antibodies against cornea and inner ear tissue in the development of audiovestibular and ocular symptoms in patients with Cogan's syndrome (CS). We analysed the serum of 5 CS patients for binding of IgM and IgG to fresh cryosections of rat labyrinth (semicircular canals, ampulla, utricle, saccule) and cornea by indirect immunofluorescence (IF). The predominant pattern of anti-corneal IgM was staining of the superficial cell layer of the non-keratinizing squamous epithelium. IgM against cornea was found in 3 patients, all of whom had bilateral inflammatory eye signs at the start of the disease. However, IgM was also detected in the chronic stage of the disease when no clinical signs of eye involvement were apparent. The study includes the first follow-up examination of anti-corneal IgM and IgG antibodies during a complete episode of active CS. During the first episode of CS in 1 patient, anti-corneal IgM became detectable 1 week after the onset of interstitial keratitis and 3 weeks after the onset of audiovestibular symptoms. It increased over several weeks and then fell to very low levels. However, at no time was anti-corneal IgG found. In the course of follow-up examinations, the serum of 4 patients intermittently contained low titre IgG antibodies against inner ear labyrinthine tissue, but without any clear correlation with the active stages of CS. In addition, high-resolution MRI (HR-MRI) of the inner ear was performed in the acute and chronic stages of CS to evaluate the activity of CS. In the acute stage, HR-MRI revealed abnormal MRI signals in the vestibule, semicircular canals, vestibular nerve, or cochlea. In the chronic stage, patients showed narrowing or occlusion of semicircular canals and the cochlea on the 3D-CISS images, but no high signal lesions (T1) and no enhancement. Antibodies against cornea or labyrinthine tissue were not consistently detected in CS and the level of organ-specific antibodies did not correlate with the activity of the disease.


[Technic of optical mixing spectroscopy in the diagnosis of blood microcirculations].
Optical mixing spectroscopy was used to measure the correlation function of helium-neon laser light (wavelength 0.633 micron) scattered in the finger skin. The mean blood flow velocity was evaluated from the data obtained. It was shown that application of the method to the diagnosis of blood microcirculations demands that vascular reactions of laser light be taken into consideration. In most cases the mean blood velocity was observed to rise 1.5-3-fold within the first-second minute of irradiation at 0.6 W/cm2.


Effect of degree of conversion on in vivo biocompatibility of flowable resin used for bioprotection of mini-implants.
To test the hypothesis that there is no difference between the biocompatibility and degree of monomer conversion of flowable resins used as bioprotective materials of orthodontic mini-implants. Forty-eight male Wistar rats were divided into four groups (n = 12). Group Control (polyethylene), Group Wave, Group Top Comfort, and Group Filtek. The animals were sacrificed after time intervals of 7, 15, and 30 days and tissues were analyzed under optical microscopy for inflammatory infiltrate, edema, necrosis, granulation tissue, multinucleated giant cells, and collagen formation. The degree of conversion was evaluated by the Fourier method. Biocompatibility and degree of conversion were evaluated by the Kruskal-Wallis and Dunn tests, and analysis of variance and the Tukey test, respectively (P < .05). An intense inflammatory infiltrate was observed on the seventh day, with Groups Top Comfort and Filtek differing statistically from Group Control (P = .016). Edema, necrosis, granulation tissue, and giant cells showed greater expressiveness at 7 days, without statistical difference between them (P > .05). For the presence of collagen fibers, Group Top Comfort was shown to differ statistically from Group Control (P = .037) at 15 days and from Groups Filtek and Control (P = .008) at 30 days. Monomer conversion ranged from 62.3% in Group Top Comfort at 7 days to 79.1% in Group Filtek at 30 days. The hypothesis was rejected. The resin Top Comfort demonstrated lower tissue repair capacity with a lower number of collagen fibers compared with Filtek and Wave resins. The resin Top Comfort showed the lowest conversion values during the experiment.


Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions.
Recent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis. Patients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology. According to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups). The choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis.


Epidemiological studies on the expectation of life for cats computed from animal cemetery records.
Based on the Chiang's method, the life table for cats was constructed from the death data of 3936 cats. They died in the Kanto area and were buried in an animal cemetery in Tokyo from June 1981 through May 1982. This life table seems to be the first one for domestic pet cats. The expectation of life for cats was 4.2 years at age 0, 5.0 years at age 1, 5.4 years at age 4, 5.3 years at age 5, 3.5 years at age 10, and 2.2 years at age 15. The maximum age at death was 22 years. From age 0 to age 5, the probability of dying for cats was higher than that for dogs, but over 6 years of age it seemed that Gompertz's equation was applicable to this life table for cats. From these results, if the probability of dying for cats at early ages decreases, the fundamental pattern of dying curve for cats seems to be a similar figure of dogs. The life table was constructed for different breeds and localities. Comparing the expectation of life at age 1 (e1) of the two populations divided by breeds or localities, there was significant difference in the e1 among different localities but not among different breeds. These facts suggest the existence of some factors which may influence the life span of cats among different localities.


Microbial infections, immunomodulation, and drugs of abuse.
The use of recreational drugs of abuse has generated serious health concerns. There is a long-recognized relationship between addictive drugs and increased levels of infections. Studies of the mechanisms of actions of these drugs became more urgent with the advent of AIDS and its correlation with abused substances. The nature and mechanisms of immunomodulation by marijuana, opiates, cocaine, nicotine, and alcohol are described in this review. Recent studies of the effects of opiates or marijuana on the immune system have demonstrated that they are receptor mediated, occurring both directly via specific receptors on immune cells and indirectly through similar receptors on cells of the nervous system. Findings are also discussed that demonstrate that cocaine and nicotine have similar immunomodulatory effects, which are also apparently receptor mediated. Finally, the nature and mechanisms of immunomodulation by alcohol are described. Although no specific alcohol receptors have been identified, it is widely recognized that alcohol enhances susceptibility to opportunistic microbes. The review covers recent studies of the effects of these drugs on immunity and on increased susceptibility to infectious diseases, including AIDS.