Comparison of tear function tests and impression cytology with the ocular findings in acne rosacea.
The aim of this study was to determine the correlation between tear function tests and impression cytology results and the clinical findings in ocular rosacea. Patients with a histopathologic and clinical diagnosis of acne rosacea were studied. Ocular examination consisted of best-corrected visual acuity measurement, slitlamp examination, tear break-up time (BUT), basal Schirmer test, and rose Bengal staining. Impression cytology was done two days later. Ocular findings and symptoms were checked and scored. Age-matched controls were assessed using the same parameters. The most frequent symptoms were itching (80%), redness (68%), burning (64%), and photophobia (60%). The most frequent clinical findings were meibomitis (92%), telangiectasis (88%), blepharitis (84%), superficial punctate keratopathy (72%), and hyperemia (60%). Mean tear BUT was 9.6+/-3.1 (SD) seconds (range 5-17 seconds). Mean Schirmer test measured 11.4+/-1.6 mm (SD) (range 8-15 mm). Mean rose Bengal staining scored 1.8+/-0.1. Mean tear BUT, Schirmer test and rose Bengal staining scores were lower in the rosacea group than the control group (p<0.003, p=0.04, p< or =0.038, respectively). Staining was pathologic in 18 patients (36%) and the highest staining score was 4. No significant difference was found between the stages of the nasal and temporal conjunctival impression cytologies in each eye, and there was no relationship between impression cytology stages and rose Bengal scores (p>0.05). A significant relation was observed between the stages of impression cytology and the severity of meibomitis (Fisher's test, chi2=9.625, p=0.001). The Schirmer test gave lower results in patients with severe blepharitis (Mann-Whitney U Test, U=180.5, p=0.034). Early diagnosis prevents serious ocular complications and chronic dry eye in rosacea. We suggest that in addition to tear function tests, rose Bengal staining and impression cytology can be successfully used in the early diagnosis of dry eye and in monitoring medical treatment in ocular rosacea. Meibomian glands play an important role in the pathogenesis of the ocular disease.


A novel machine learning-based approach for the risk assessment of nitrate groundwater contamination.
This study aimed to develop a novel framework for risk assessment of nitrate groundwater contamination by integrating chemical and statistical analysis for an arid region. A standard method was applied for assessing the vulnerability of groundwater to nitrate pollution in Lenjanat plain, Iran. Nitrate concentration were collected from 102 wells of the plain and used to provide pollution occurrence and probability maps. Three machine learning models including boosted regression trees (BRT), multivariate discriminant analysis (MDA), and support vector machine (SVM) were used for the probability of groundwater pollution occurrence. Afterwards, an ensemble modeling approach was applied for production of the groundwater pollution occurrence probability map. Validation of the models was carried out using area under the receiver operating characteristic curve method (AUC); values above 80% were selected to contribute in ensembling process. Results indicated that accuracy for the three models ranged from 0.81 to 0.87, therefore all models were considered for ensemble modeling process. The resultant groundwater pollution risk (produced by vulnerability, pollution, and probability maps) indicated that the central regions of the plain have high and very high risk of nitrate pollution further confirmed by the exiting landuse map. The findings may provide very helpful information in decision making for groundwater pollution risk management especially in semi-arid regions.


Green synthesis of bioactive polysaccharide-capped gold nanoparticles for lymph node CT imaging.
The development of biologically targeted contrast agents for X-ray computed tomography (CT) imaging remains a major challenge. Here, we investigated a green chemistry-based synthesis of lymph node-targeted mannan-capped gold nanoparticles (M-GNPs) as a CT contrast agent. In this study, mannan was used as a reducing and stabilizing agent for gold nanoparticles (AuNPs). M-GNPs were readily internalized by antigen-presenting cells (APCs) through mannose receptors-mediated endocytosis. The M-GNPs, which had a spherical morphology, had an average diameter of 9.18±0.71nm and surface plasmon resonance (SPR) absorption spectra with maximal absorption at 522nm. The M-GNPs displayed a concentration-based X-ray attenuation property with a maximum Hounsfield unit (HU) value of 303.2±10.83. The local administration of M-GNPs led to significantly enhanced X-ray contrast for the imaging of popliteal lymph nodes. These findings demonstrated that M-GNPs can be used as biologically targeted contrast agents for CT imaging.


Oxytocin and sexual behavior.
The neurohypophyseal hormone oxytocin has been implicated in many aspects of reproduction including sexual behavior. This review considers the hypotheses that oxytocin and/or the neural events surrounding the release of oxytocin may have behavioral effects during sexual arousal, orgasm, sexual satiety and other aspects of sociosexual interactions.


Topography and instability of monolayers near domain boundaries.
We theoretically study the topography of a biphasic surfactant monolayer in the vicinity of domain boundaries. The differing elastic properties of the two phases generally lead to a nonflat topography of "mesas," where domains of one phase are elevated with respect to the other phase. The mesas are steep but low, having heights of up to 10 nm. As the monolayer is laterally compressed, the mesas develop overhangs and eventually become unstable at a surface tension of about K(deltac(0))(2) (deltac(0) being the difference in spontaneous curvature and K a bending modulus). In addition, the boundary is found to undergo a topography-induced rippling instability upon compression, if its line tension is smaller than about Kdeltac(0). The effect of diffuse boundaries on these features and the topographic behavior near a critical point are also examined. We discuss the relevance of our findings to several experimental observations related to surfactant monolayers: (i) small topographic features recently found near domain boundaries; (ii) folding behavior observed in mixed phospholipid monolayers and model lung surfactants; (iii) roughening of domain boundaries seen under lateral compression; (iv) the absence of biphasic structures in tensionless surfactant films.


Familial aggregation of multiple myeloma and central nervous system diseases.
Degenerative central nervous system diseases such as Alzheimer's disease and lymphoreticular malignancies such as multiple myeloma occur with increased frequency with advancing age. Relatives of early-onset Alzheimer's disease patients may have an increased risk of lymphoreticular malignancies. This led us to evaluate the family history of central nervous system diseases in a case-control study of multiple myeloma. Thirteen of 439 multiple myeloma cases had one or more first-degree relatives with degenerative or demyelinating central nervous system disease. In comparison, there were nine "positive" family histories in 1,317 matched hospital controls (relative risk = 4.4, 95% confidence interval = 1.9-10.3). Relative risks for the component categories of Parkinson's disease, multiple sclerosis, and miscellaneous degenerative central nervous system diseases were 3.0, 4.0 and 11.9, respectively. Our findings suggest that the degenerative and demyelinating central nervous system diseases and the lymphoreticular malignancies may comprise an etiologically related group of "protean diseases." These diseases may have a shared genetic susceptibility, possibly an immunologic abnormality. The varied disease manifestation in family members suggests a second necessary etiologic step of a variable and possibly environmental nature.


Resolution of Inflammatory Responses: a brief introduction.
Resolution of inflammatory responses is the regulatory process that prevents prolonged inflammation, thus avoiding diseases such as atherosclerosis, rheumatoid arthritis and transplant rejection. There are various different aspects to this process which are discussed briefly here and in the accompanying papers from this Focused Meeting.


Can the Virtual Labels Obtained by Traditional LP Approaches Be Well Encoded in WLR?
Semisupervised dimension reduction via virtual label regression first derives the virtual labels of unlabeled data by employing a newly designed label propagation (LP) approach (called Special random walk (SRW)) and then encodes them in a weighted linear regression model. Nie et al. (2011) highlighted two important characteristics of SRW nonexistent in the previous LP approaches: outlier detection and probability value output, which guarantee the elegant encoding of the resultant virtual labels in the weighted label regression. However, in this brief, we show that the relationship between the SRW and the previous work on LP is very close. Naturally, a problem deserving investigation is whether traditional LP approaches are indeed unable to share the above two characteristics of SRW. We aim to address this problem.


Docetaxel plus gemcitabine as first-line treatment in malignant pleural mesothelioma: a single institution phase II study.
The cisplatin-pemetrexed and cisplatin-gemcitabine combinations are considered the standard treatment for malignant pleural mesothelioma. The purpose of this study was to examine the efficacy of gemcitabine plus docetaxel in the first-line setting, as this combination has not been investigated in mesothelioma before. Twenty-five consecutive patients with malignant pleural mesothelioma were enrolled. They received 80 mg/m(2) of docetaxel and 1,000 mg/m(2) of gemcitabine on days 1 and 14 of a 28-day cycle. The treatment was scheduled for a maximum of 6 cycles or until disease progression or unacceptable toxicity. A total of 7 out of our 25 patients (28%) responded to treatment. In 14 patients (56%), the disease remained stable, while in 4 (16%) it progressed. The median time to progression was 7 months (range: 5.4-8.6 months) and the median overall survival was 15 months (range: 12.4-17.5 months). The administration of gemcitabine and doctaxel appears to be promising first-line therapy for patients with mesothelioma, as it is well tolerated and appears to improve survival.


Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes.
The relentless decline in beta-cell function frequently observed in type 2 diabetic patients, despite optimal drug management, has variously been attributed to glucose toxicity and lipotoxicity. The former theory posits hyperglycemia, an outcome of the disease, as a secondary force that further damages beta-cells. The latter theory suggests that the often-associated defect of hyperlipidemia is a primary cause of beta-cell dysfunction. We review evidence that patients with type 2 diabetes continually undergo oxidative stress, that elevated glucose concentrations increase levels of reactive oxygen species in beta-cells, that islets have intrinsically low antioxidant enzyme defenses, that antioxidant drugs and overexpression of antioxidant enzymes protect beta-cells from glucose toxicity, and that lipotoxicity, to the extent it can be attributable to hyperlipidemia, occurs only in the context of preexisting hyperglycemia, whereas glucose toxicity can occur in the absence of hyperlipidemia.


First molecular assessment of the interrelationships of cladorchiid digeneans (Digenea: Paramphistomoidea), parasites of Neotropical fishes, including descriptions of three new species and new host and geographical records.
The first molecular assessment of phylogenetic relationships of cladorchiid digeneans (superfamily Paramphistomoidea Fischoeder, 1901) from freshwater fishes based on 28S rDNA, ITS2 and cox1 sequences reveals the subfamilies Dadayiinae Fukui, 1929 and Kalitrematinae Travassos, 1933 as non-monophyletic, whereas Dadaytrema Travassos, 1931 represented by three species is monophyletic. Fourteen species of cladorchiids were found in characiform, perciform and siluriform fishes in the Neotropical Region (Brazil and Peru), with numerous new host and geographical records. The first scanning electron micrographs of seven species are presented. Two new species of dadayiine and one new species of kalitrematine paramphistomes are described. Microrchis macrovarium sp. n. from Pimelodella cristata (Müller et Troschel) (type host), Tetranematichthys quadrifilis (Kner) and Pterodoras granulosus (Valenciennes) in Brazil and Peru differs from all three congeners in that the testes are directly tandem, not oblique, and that the ovary, between the caecal ends, is widely separated from the testes. Pronamphistoma philippei sp. n. from Heros sp. in Brazil is distinguished from the type and only species, Pronamphistoma cichlasomae Thatcher, 1992, by the absence of the anterior collar-like expansion present in the type species, the presence of extramural rather than intramural pharyngeal sacs, and the unusual development of the dorsal and ventral exterior circular muscle fibre series in the acetabulum. Pseudocladorchis romani sp. n. from P. granulosus (type host), Brachyplatystoma vaillantii (Valenciennes), Calophysus macropterus (Lichtenstein), Megalodoras uranoscopus (Eigenmann et Eigenmann) and Oxydoras niger (Valenciennes) in Brazil and Peru, is most similar to Pseudocladorchis nephrodorchis Daday, 1907 but differs in the shape of the testes (irregular, versus reniform in the latter species) and the size of the ovary (as large as, or larger than, the testes in the new species). The generic diagnosis of Pronamphistoma Thatcher, 1992 is amended. Dadaytremoides parauchenipteri Lunaschi, 1989 is transferred to Doradamphistoma Thatcher, 1979 as D. parauchenipteri (Lunaschi, 1989) comb. n. based on morphological and molecular evidence.


Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action.
In recent years, public and scientific interest in plant flavonoids has tremendously increased because of their postulated health benefits. This review was mainly focuses on the flavone chrysin (5,7-dihydroxyflavone), which occurs naturally in many plants, honey, and propolis. A number of in vitro and in vivo studies have revealed the therapeutic effects of chrysin against various diseases. In general, chrysin exhibits many biological activities and pharmacological effects, including antioxidant, anti-inflammatory, anticancer, and antiviral activities. Moreover, many studies have reported on the bioavailability of chrysin. Because of its compromised bioavailability and enhanced protein stability, chrysin solid lipid nanoparticle (SLN) synthesis avoids proteolytic degradation and sustained release of drug delivery. To clarify the mechanism of action of chrysin, researchers have investigated the structural binding relationship of chrysin through the docking computation method.


A reporter gene system for the hyperthermophilic archaeon Sulfolobus solfataricus based on a selectable and integrative shuttle vector.
Sulfolobus solfataricus has developed into an important model organism for molecular and biochemical studies of hyperthermophilic archaea. Although a number of in vitro systems have been established for the organism, efficient tools for genetic manipulations have not yet been available for any hyperthermophile. In this work, we have developed a stable and selectable shuttle vector based on the virus SSV1 of Sulfolobus shibatae. We have introduced pUC18 for propagation in Escherichia coli and the genes pyrEF coding for orotidine-5'-monophosphate pyrophosphorylase and orotidine-5'-monophosphate decarboxylase of Sulfolobus solfataricus as selectable marker to complement pyrimidine auxotrophic mutants. Furthermore, the beta-galactosidase gene (lacS) was introduced into this vector as a reporter under the control of the strong and heat-inducible promoter of the Sulfolobus chaperonin (thermosome). After transformation of a S. solfataricus pyrEF/lacS double mutant, the vector was found to reside as a single-copy vector, stably integrated into the host chromosome via the site-specific recombination system of SSV1. Specific beta-galactosidase activities in transformants were found to be fourfold higher than in wild-type S. solfataricus cells, and increased to more than 10-fold after heat shock. Greatly increased levels of lacS mRNA were detected in Northern analyses, demonstrating that this reporter gene system is suitable for the study of regulated promoters in Sulfolobus and that the vector can also be used for the high-level expression of genes from hyperthermophilic archaea.


Cholecystostomy for noninflammatory disease.
Cholecystostomy in patients with noninflammatory disease of the biliary tract has rarely been evaluated. Our experience with 124 patients suggests that, in addition to being helpful in inflammatory conditions, cholecystostomy is helpful in performing cholangiography, in removing stones and in decompressing an otherwise obstructed biliary tree. The mortality associated with this procedure is minimal, and the morbidity is 4.5 percent.


[A case in which palatal squamous cell carcinoma responded to UFT therapy].
We administered UFT to a 70-year-old female with squamous cell carcinoma of the palatal mucosa (T1 N0 M0) who had not consented to radical surgical treatment. The tumor disappeared grossly and histopathologically after 1 month, and no adverse reaction to oral administration of UFT was noted. The patient remains under observation.


Physical illness and suicide risk in rural residents of contemporary China: a psychological autopsy case-control study.
Physical illness is linked with an increased risk of suicide; however, evidence from China is limited. To assess the influence of physical illness on risk of suicide among rural residents of China, and to examine the differences in the characteristics of people completing suicide with physical illness from those without physical illness. In all, 200 suicide cases and 200 control subjects, 1:1 pair-matched on sex and age, were included from 25 townships of three randomly selected counties in Shandong Province, China. One informant for each suicide or control subject was interviewed to collect data on the physical health condition and psychological and sociodemographic status. The prevalence of physical illness in suicide cases (63.0%) was significantly higher than that in paired controls (41.0%; χ² = 19.39, p < .001). Compared with suicide cases without physical illness, people who were physically ill and completed suicide were generally older, less educated, had lower family income, and reported a mental disorder less often. Physical illness denoted a significant risk factor for suicide with an associated odds ratio of 3.23 (95% CI: 1.85-5.62) after adjusted for important covariates. The elevated risk of suicide increased progressively with the number of comorbid illnesses. Cancer, stroke, and a group of illnesses comprising dementia, hemiplegia, and encephalatrophy had a particularly strong effect among the commonly reported diagnoses in this study population. Physical illness is an important risk factor for suicide in rural residents of China. Efforts for suicide prevention are needed and should be integrated with national strategies of health care in rural China.


Database mining using soft computing techniques. An integrated neural network-fuzzy logic-genetic algorithm approach.
Two different soft computing (SC) techniques (a competitive learning neural network and an integrated neural network-fuzzy logic-genetic algorithm approach) are employed in the analysis of a database subset obtained from the Cambridge Structural Database. The chemical problem chosen for study is relevant to the relationship between various metric parameters in transition metal imido (LnMdNZ, Z = carbon-based substituent) complexes and the chemical consequences of such relationships. The SC techniques confirmed and quantified the suspected relationship between the metal-nitrogen bond length and the metal-nitrogen-substituent bond angle for transition metal imidos: increased metal-nitrogen-carbon angles correlate with shortened metal-nitrogen distances. The mining effort also yielded an unexpected correlation between the NC distance and the MNC angle-shorter NC correlate with larger MNC. A fuzzy inference system is used to construct an MNred-NC-MNC hypersurface. This hypersurface suggests a complicated interdependence among NC, MNred, and the angle subtended by these two bonds. Also, major portions of the hypersurface are very flat, in regions where MNC is approaching linearity. The relationships are also seen to be influenced by whether the imido substituent is an alkyl or aryl group. Computationally, the present results are of particular interest in two respects. First, SC classification was able to isolate an "outlier" cluster. Identification of outliers is important as they may correspond to unreported experimental errors in the database or novel chemical entities, both of which warrant further investigation. Second, the SC database mining not only confirmed and quantified a suspected relationship (MNred versus MNC) within the data but also yielded a trend that was not suspected (NC versus MNC).


Silicon deposition in the root reduces sodium uptake in rice (Oryza sativa L.) seedlings by reducing bypass flow.
Sodium chloride reduces the growth of rice seedlings, which accumulate excessive concentrations of sodium and chloride ions in their leaves. In this paper, we describe how silicon decreases transpirational bypass flow and ion concentrations in the xylem sap in rice (Oryza sativa L.) seedlings growing under NaCl stress. Salt (50 mM NaCl) reduced the growth of shoots and roots: adding silicate (3 mM) to the saline culture solution improved the growth of the shoots, but not roots. The improvement of shoot growth in the presence of silicate was correlated with reduced sodium concentration in the shoot. The net transport rate of Na from the root to shoot (expressed per unit of root mass) was also decreased by added silicate. There was, however, no effect of silicate on the net transport of potassium. Furthermore, in salt-stressed plants, silicate did not decrease the transpiration, and even increased it in seedlings pre-treated with silicate for 7 d prior to salt treatment, indicating that the reduction of sodium uptake by silicate was not simply through a reduction in volume flow from root to shoot. Experiments using trisodium-8-hydroxy-1,3,6-pyrenetrisulphonic acid (PTS), an apoplastic tracer, showed that silicate dramatically decreased transpirational bypass flow in rice (from about 4.2 to 0.8%), while the apparent sodium concentration in the xylem, which was estimated indirectly from the flux data, decreased from 6.2 to 2.8 mM. Direct measurements of the concentration of sodium in xylem sap sampled using Philaenus spumarius confirmed that the apparent reduction was not a consequence of sodium recycling. X-ray microanalysis showed that silicon was deposited in the outer part of the root and in the endodermis, being more obvious in the latter than in the former. The results suggest that silicon deposition in the exodermis and endodermis reduced sodium uptake in rice (Oryza sativa L.) seedlings under NaCl stress through a reduction in apoplastic transport across the root.


Simulation of the economic impact of transmissible gastroenteritis on commercial pig production in Australia.
A simulation model (AUSPIG) was used to predict the effect of an increase in piglet deaths, and a reduction in growth rate and an increase in feed conversion ratio of grower pigs on the profitability of two herds representative of the Australian pig industry caused by the introduction of transmissible gastroenteritis virus (TGE) into those herds. For each herd, mortality rates for piglets under 1 week of age of 50% and 95% were assumed to represent a 'moderate' and a 'severe' outbreak, respectively. A reduction in net revenue of 70% was predicted to occur in the 6 months after a 'moderate' outbreak of TGE (100% for a 'severe' outbreak). This represents a total loss of between $260 and $330 per breeding sow in the 12 months after infection with the TGE virus. The likely financial impact of an outbreak of TGE on an Australian piggery is substantial and should be considered when addressing quarantine issues.


Respiratory syncytial virus fusion inhibitors. Part 3: Water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo.
The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.


Bias in topoisomerase (TOPO)-cloning of multitemplate PCR products using locked nucleic acid (LNA)-substituted primers.
Locked nucleic acid (LNA) modifications help to improve nucleic acid recognition in molecular biology applications. We report that LNA-substituted primers in PCR reactions may cause considerable cloning bias when the widely used topoisomerase-based ligation is used for cloning of multitemplate PCR products.


Case Investigation and Forensic Evidence for a New Plant Disease: The Case of Lettuce Corky Root.
The process of disease diagnosis reminds of the process of solving a crime. This starts with a so-called 'crime scene investigation' (CSI) carried out in a highly systematic manner. The CSI is followed by 'forensic investigation' in specialized laboratories. The final step in solving a crime is the 'crime scene reconstruction' process, which involves systematic elimination of unlikely scenarios and comparison of results from the analysis of physical evidence with eye witness accounts. If more evidence becomes available, an 'old case may be reactivated'. In this review, the same sequence of activities is followed to solve a plant disease problem using a case study of a disease that was difficult to diagnose, namely the 'case' of corky root of lettuce.


Differential Off-line LC-NMR (DOLC-NMR) Metabolomics To Monitor Tyrosine-Induced Metabolome Alterations in Saccharomyces cerevisiae.
A novel differential off-line LC-NMR approach (DOLC-NMR) was developed to capture and quantify nutrient-induced metabolome alterations in Saccharomyces cerevisiae. Off-line coupling of HPLC separation and 1H NMR spectroscopy supported by automated comparative bucket analyses, followed by quantitative 1H NMR using ERETIC 2 (electronic reference to access in vivo concentrations), has been successfully used to quantitatively record changes in the metabolome of S. cerevisiae upon intervention with the aromatic amino acid l-tyrosine. Among the 33 metabolites identified, glyceryl succinate, tyrosol acetate, tyrosol lactate, tyrosol succinate, and N-acyl-tyrosine derivatives such as N-(1-oxooctyl)-tyrosine are reported for the first time as yeast metabolites. Depending on the chain length, N-(1-oxooctyl)-, N-(1-oxodecanyl)-, N-(1-oxododecanyl)-, N-(1-oxomyristinyl)-, N-(1-oxopalmityl)-, and N-(1-oxooleoyl)-l-tyrosine imparted a kokumi taste enhancement above their recognition thresholds ranging between 145 and 1432 μmol/L (model broth). Finally, carbon module labeling (CAMOLA) and carbon bond labeling (CABOLA) experiments with 13C6-glucose as the carbon source confirmed the biosynthetic pathway leading to the key metabolites; for example, the aliphatic side chain of N-(1-oxooctyl)-tyrosine could be shown to be generated via de novo fatty acid biosynthesis from four C2-carbon modules (acetyl-CoA) originating from glucose.


Effect of flunarizine on micro-regional distributions of intravascular HbO2 saturations in RIF-1 and KHT sarcomas.
Flunarizine, a calcium channel-blocker, preferentially active on peripheral blood vessels and red blood cells, has previously been shown to increase not only tumor blood flow, but also both chemosensitivity and radiosensitivity. The mechanisms behind these effects are not clear at present, and different tumor lines have been demonstrated to respond quite differently to the same flunarizine treatment. To clarify the underlying mechanisms at the micro-regional level, the present investigation examined the effects of flunarizine on spatially-resolved distributions of intravascular oxyhemoglobin (HbO2) saturations. Tumors were implanted s.c. in the flanks of C3H mice and grown to a volume of 500-1000 mm3. Flunarizine was injected i.p. at 5 mg/kg; animals were anesthetized, and following a 20 min delay, tumors were quick-frozen. HbO2 saturations were determined cryospectrophotometrically at systematically selected sites across each tumor cross-section. Three primary questions were addressed: (a) Does flunarizine have a direct effect on tumor oxygen delivery as measured by intravascular HbO2 saturations? (b) Are changes in oxygen delivery uniformly distributed throughout the tumor volume? (c) Are HbO2 distributions for tumor lines of dissimilar radiobiological hypoxic fraction affected similarly by flunarizine? For KHT tumors, flunarizine substantially increased the % vessels greater than or equal to 10% saturated throughout the tumor volume, with a somewhat larger increase for the interior vessels than for the peripheral vessels. In contrast, for the RIF-1 tumors, HbO2 saturations following flunarizine remained near control levels. These results indicate that fundamental differences in vascular geometry, hemodynamics, or blood rheology may exist between the KHT and RIF-1 tumor lines, and furthermore, that the response of one tumor line to a given blood-flow modifier may be completely unrelated to that of another.


Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.
The clinical pharmacology of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine), a structural analogue of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine, was assessed in 14 patients with various malignancies during a phase I trial. Since the starting dose for the protocol was low (0.2 mg/m2/hr over a 72-hr continuous iv infusion), a radioimmunoassay (RIA) using commercially available ara-C antibody and [3H]ara-C was developed to measure the anticipated low plasma drug levels. The assay could be used to measure fazarabine accurately in plasma and urine with a sensitivity of 0.08 ng/ml. The RIA does not require extraction of samples. Using both RIA and HPLC, similar results were obtained in plasma samples from a patient receiving a high dose (180 mg/m2/hr) of fazarabine. The assay is simple, sensitive, reproducible, and specific. Following the infusion, plasma levels declined triphasically with a terminal half-life of 5.7 +/- 2.0 hr. The AUC was linearly related to dose. When the various doses were normalized to 1.75 mg/m2/hr (the maximum tolerated dose as determined from the phase I trial) the mean AUC value was 4232 +/- 987 (ng/ml)hr. Plasma steady-state drug levels (CPss) were achieved in 2-4 hr and were linearly dependent to dose. Also, when normalized, the mean CPss was 58 +/- 13 ng/ml, which is within the reported concentration range necessary for inhibiting malignant cell growth. Total clearance was rapid, 528 +/- 138 ml/(m2.min), and not dose-related.


Missing relationship of moyamoya and persistent primitive artery in Europeans. Another distinctive feature or artifact?
Previous studies found higher incidence of persistent primitive arteries in Asian moyamoya (MM) patients than in the general population, which was thought to be a characteristic trait of the MM entity in general. We analyzed incidence of persistent primitive arteries and demographics of patients with European MM treated in one single center. First, we compared our large dataset to existing literature and second, we raised the question whether European MM demonstrates similar high prevalence of persistent primitive arteries as it was previously presented within Asian MM. All European MM on whom revascularization surgery was performed from 1999 to 2013 were included. Demographics and associated diseases were obtained by retrospective chart review. Two independent readers evaluated 122 MM angiograms to determine the occurrence of persistent primitive arteries as well as the Suzuki score. We identified 112 cases with MM disease, 10 with MM syndrome. Mean age at time of diagnosis was 38.2 (range 6-64 years); a peak incidence in early childhood was not observed. Ninety (73.8%) were women, associated systemic diseases were found in four patients. Seven cases (5.7%) presented with unilaterally affected vessels. The majority of patients (71; 58.2%) were graded Suzuki Score 3. One 14-year-old boy with moyamoya presented with a primitive trigeminal artery (0.89%). We did not find a bimodal age distribution, but only a second peak during adulthood. Unlike previous studies on Asian moyamoya patients, our collective does not exhibit a higher prevalence of persistent primitive arteries than the normal population.


Cognitive effects of topiramate in migraine patients aged 12 through 17 years.
Neuropsychologic data are presented from a randomized, double-blind, placebo-controlled, multicenter study with placebo, topiramate 50 mg/day, and topiramate 100 mg/day. The Cambridge Neuropsychological Test Automated Battery (CANTAB) and cognitive adverse events were used to evaluate neurocognitive effects of topiramate. Topiramate 100 mg/day vs placebo was associated with slight statistically significant score increases, indicating slowing, from baseline vs placebo in three CANTAB measures: five-choice reaction time (P = 0.028), pattern recognition memory mean correct latency (P = 0.027), and rapid visual information processing mean latency (P = 0.040). No other patterns related to topiramate treatment were observed in measurements of learning, memory, and visual information processing, except for potential improvement with topiramate 100 mg/day vs placebo in spatial span total errors (accuracy test) (P = 0.040). The most common cognitive and neuropsychiatric adverse events with a higher incidence in the topiramate 50 and 100 mg/day groups vs placebo were anorexia (9% and 11% vs 3%), insomnia (9% and 3% vs 3%), fatigue (6% and 9% vs 6%), and dizziness (6% and 9% vs 0%). Thus, topiramate 100 mg/day was associated with modest increases in psychomotor reaction times. Learning, memory, and executive function were unchanged. The tolerability profile, including cognitive adverse events, appeared to be acceptable.


Specificity of antipeptide antibodies produced against V2 and V3 regions of the external envelope of human immunodeficiency virus type 2.
The V2 region of simian immunodeficiency virus (SIV) and V3 region of human immunodeficiency virus type 1 (HIV-1) have been reported to be neutralization epitopes. We analysed the corresponding regions in HIV-2. Synthetic peptides modeling the V2 (aa 149-168) and V3 (CV3: aa 298-315 and NV3: aa 306-324) regions of the HIV-2 external envelope glycoprotein were coupled to KLH and used as immunogens in rabbits. We characterized the resulting antiV2 and antiV3 antibodies for their ability to recognize native and deglycosylated HIV-2 envelope glycoprotein, to block gp-CD4 interaction and to inhibit syncytium formation in vitro. The three synthetic peptides induced antibodies able to recognize specifically the native HIV-2 envelope glycoprotein with a significant avidity (K0.5 between 6 x 10(-7) and 8 x 10(-9) M). Interestingly, the reactivity of antibodies produced against the V2 peptide, which contains two potential sites of N-glycosylation, was higher against the fully deglycosylated than glycosylated HIV-2 external envelope glycoprotein (gp105). The antipeptide antibodies were used to investigate the topography of these regions in the preformed gp-CD4 complex in indirect immunofluorescence assays. The V2 and V3 regions in the complex remained accessible to their respective antibodies. Moreover, preincubation of gp105 with anti V2 or anti V3 antibodies did not prevent gp-CD4 interaction. Thus the V2 and V3 regions are not directly involved in the gp105 binding site for the CD4 receptor. Finally, in contrast with results obtained with antibodies produced against the V3 region of HIV-1 gp120 and monoclonal antibodies produced against the V3 of SIV, antibodies produced against V2 and V3 of HIV-2 were unable to inhibit syncytium formation induced by HIV-2 in vitro.


Decreasing medical malpractice: toward an organizational systems approach.
Using a systems model, the authors offer malpractice reduction strategies and actions in five subsystems of the organization: technical, structural, psychosocial, managerial, and cultural (goals and values).


Damage to the esophagus after atrial fibrillation ablation: Just the tip of the iceberg? High prevalence of mediastinal changes diagnosed by endosonography.
Radiofrequency catheter ablation is increasingly used in the treatment of atrial fibrillation. Esophageal wall changes varying from erythema to ulcers have been described by endoscopy in up to 47% of patients following pulmonary vein isolation (PVI). Although esophageal changes are frequently reported, the development of a left atrial (LA)-esophageal fistula is fortunately rare. Nevertheless, mucosal changes may just represent "the tip of the iceberg." The aim of this study was, therefore, to investigate the more subtle changes of and injuries to the posterior wall of the LA, the periesophageal and mediastinal connective tissue, and the whole wall of the esophagus, including mucosal changes by esophagogastroduodenoscopy (EGD) combined with radial endosonography (EUS). Twenty-nine patients (7 females; mean age, 57.7+/-10.5 years [range, 23-75 years]) underwent EGD and EUS before and after PVI within 48 hours. PVI was performed as a circumferential antral isolation of the septal and lateral pulmonary veins guided by a decapolar circular mapping catheter using a 3-dimensional mapping system with the integration of a preprocedurally acquired computed tomography scan of the left atrium. The maximum power applied was 30 W, with an open-irrigated catheter using a maximum flow rate of 30 mL/min. In all patients, the esophagus was reconstructed using the same computed tomography scan and displayed during the ablation procedure. In case of newly detected periesophageal changes, EGD and EUS were repeated 1 week after the PVI. In all patients, a regular contact area between the LA and the esophagus could be demonstrated before PVI. The mean vertical contact length was 4.4+/-1.5 cm (range, 2-10 cm); and the mean distance between the anterior wall of the esophagus and the endocardium was 2.6+/-0.8 mm (range, 1.4-4.0 mm). After PVI, morphological changes of the periesophageal connective tissue and the posterior wall of the LA were diagnosed by endosonography in 8 patients (27%; 95% confidence interval, 12.73-47.24). No mucosal changes of the esophagus in terms of erythema or ulcers were found. In all but one patient (who refused the control), all periesophageal and atrial changes had resolved within 1 week. No atrioesophageal fistula occurred during follow-up (mean follow-up, 294+/-110 days [range, 36-431 days]). Mucosal changes of the esophagus after PVI-like ulcers or erythema could not be demonstrated, yet structural changes of the mediastinum, which were only visible by endosonography, occurred in 27% of patients in the present study. This may indicate a higher than expected periesophageal injury because of PV ablation. Endosonography might prove to be a sensitive and reliable tool in the follow-up after PVI.


Impaired skeletal muscle fatigue resistance in rats with pressure overload-induced left ventricular hypertrophy.
In rats with left ventricular (LV) hypertrophy, we investigated whether abnormalities of skeletal muscle could result in reduced exercise tolerance in the absence of reduced cardiac function. LV pressure overload was induced by partial constriction of the abdominal aorta (AC) with controls subjected to sham operation. Cardiac and skeletal muscle function and blood flow were assessed in vivo 3 and 6 weeks later. AC induced LV hypertrophy of 41% and 37% at 3 and 6 weeks post-operation. In AC rats, cardiac index was 31 +/- 8 and 35 +/- 4 ml/min/100 g at 3 and 6 weeks compared to 38 +/- 4 and 34 +/- 2 ml/min/100 g in controls (N.S.). Fatigue index of the soleus (type-I rich) muscle in AC rats was reduced by 14% (P < 0.05) at both time points, while that of the tibialis anterior (mixed fiber) muscle was unchanged at 3 weeks but reduced by 18% (P < 0.05) at 6 weeks. Function of the extensor digitorum longus (type-IIB rich) muscle was unaltered at both time points. Blood flow at rest was paradoxically increased in muscles which exhibited increased fatigue susceptibility. At 3 weeks, blood flow during fatigue stimulation was reduced by 33% in the soleus muscle; the only muscle to exhibit impaired fatigue resistance at this time point. Blood flow during stimulation remained unaltered in the EDL and TA muscles. Thus, impaired fatigue resistance was observed in skeletal muscle with high oxidative and oxidative glycolytic fiber content during the compensatory phase of LV hypertrophy, prior to overt cardiac dysfunction. A selective impairment of blood flow to these muscles during exercise may play a causal role in exercise intolerance.


Combining robust state estimation with nonlinear model predictive control to regulate the acute inflammatory response to pathogen.
The inflammatory response aims to restore homeostasis by means of removing a biological stress, such as an invading bacterial pathogen. In cases of acute systemic inflammation, the possibility of collateral tissue damage arises, which leads to a necessary down-regulation of the response. A reduced ordinary differential equations (ODE) model of acute inflammation was presented and investigated in [10]. That system contains multiple positive and negative feedback loops and is a highly coupled and nonlinear ODE. The implementation of nonlinear model predictive control (NMPC) as a methodology for determining proper therapeutic intervention for in silico patients displaying complex inflammatory states was initially explored in [5]. Since direct measurements of the bacterial population and the magnitude of tissue damage/dysfunction are not readily available or biologically feasible, the need for robust state estimation was evident. In this present work, we present results on the nonlinear reachability of the underlying model, and then focus our attention on improving the predictability of the underlying model by coupling the NMPC with a particle filter. The results, though comparable to the initial exploratory study, show that robust state estimation of this highly nonlinear model can provide an alternative to prior updating strategies used when only partial access to the unmeasurable states of the system are available.


Reflections on the Design of Exertion Games.
The design of exertion games (i.e., digital games that require physical effort from players) is a difficult intertwined challenge of combining digital games and physical effort. To aid designers in facing this challenge, we describe our experiences of designing exertion games. We outline personal reflections on our design processes and articulate analyses of players' experiences. These reflections and analyses serve to highlight the unique opportunities of combining digital games and physical effort. The insights we seek aim to enhance the understanding of exertion game design, contributing to the advancement of the field, and ultimately resulting in better games and associated player experiences.


Direct determination of the base-pair force constant of DNA from the acoustic phonon dispersion of the double helix.
Quantifying the molecular elasticity of DNA is fundamental to our understanding of its biological functions. Recently different groups, through experiments on tailored DNA samples and numerical models, have reported a range of stretching force constants (0.3 to 3 N/m). However, the most direct, microscopic measurement of DNA stiffness is obtained from the dispersion of its vibrations. A new neutron scattering spectrometer and aligned, wet spun samples have enabled such measurements, which provide the first data of collective excitations of DNA and yield a force constant of 83 N/m. Structural and dynamic order persists unchanged to within 15 K of the melting point of the sample, precluding the formation of bubbles. These findings are supported by large scale phonon and molecular dynamics calculations, which reconcile hard and soft force constants.


Nucleosome surface containing nucleosomal DNA entry/exit site regulates H3-K36me3 via association with RNA polymerase II and Set2.
A nucleosome is composed of intrinsically disordered histone tails and a structured nucleosome core surrounded by DNA. A variety of modifiable residues on the intrinsically disordered histone tails have been identified in the last decade. Mapping of the functional residues on the structured nucleosome core surface was recently initiated by global analysis of a comprehensive histone point mutant library (histone-GLibrary). It stands to reason that a functional relationship exists between modifiable residues on the intrinsically disordered histone tails and functional residues on the structured nucleosome core; however, this matter has been poorly explored. During transcription elongation, trimethylation of histone H3 at lysine 36 (H3-K36me3) is mediated by histone methyltransferase Set2, which binds to RNA polymerase II. Here, we used a histone-GLibrary that encompasses the nucleosomal DNA entry/exit site to show that six residues (H2A-G107, H2A-I112, H2A-L117, H3-T45, H3-R49 and H3-R52) form a surface on the structured nucleosome core and regulate H3-K36me3. Trimethylation at H3-K4 introduced by histone methyltransferase Set1 was not affected by the mutation of any of the six residues. Chromatin immunoprecipitation analysis showed that most of these residues are critical for the chromatin association of RNA polymerase II and Set2, suggesting that these components regulate H3-K36me3 through functional interactions with the structured nucleosome core surface.


Diagnosis of imported malaria by Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein 2 (PfHRP-2)-based immunocapture assays.
This study was conducted to evaluate the performance of two rapid non-microscopic assays: Plasmodium lactate dehydrogenase (pLDH) assay (OptiMAL) and Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) assay (ICT Malaria). The assays were used to detect malaria infection in 515 immigrants living in Kuwait. The performance of both assays was compared to that of microscopy of Giemsa-stained thick blood films and to each other. Of the 515 patients tested, 163 were positive for malaria parasites by microscopy of thick blood film. Of these, 87 were infected with Plasmodium vivax parasites, 63 with P. falciparum, 1 with Plasmodium malariae, and 12 had mixed infections of P. falciparum and P. vivax. The PfHRP-2 assay detected 53 P. falciparum infections and, as expected, failed to detect all but one case of P. vivax. Three cases of mixed infections were also not detected by this assay. The pLDH assay detected 56 P. falciparum cases and 77 P. vivax infections but failed to detect 4 cases of mixed infections. Compared to microscopy, the performance of both the assays to diagnose P. falciparum infection was comparable. The sensitivity for the PfHRP-2 assay was 82% with a specificity of 99.0% and for the pLDH assay the sensitivity was 89% with a specificity of 99.5%. The PfHRP-2 assay detected 4 false positive cases, 2 of which were also detected by the pLDH assay. These patients reported treatment with chloroquine in the last 2-5 weeks. Though the immunocapture diagnostic assays may be helpful in certain situations, microscopy of thick blood film is still the method of choice in diagnosing imported malaria.


Might stopping smoking reduce injury death risks? A meta-analysis of randomized, controlled trials.
Smokers have excesses of injuries. Randomized, controlled trials (RCT) could assess whether cigarette smoking (smoking) causes (and smoking cessation (cessation) prevents) those injuries. We analyzed injury, accident, suicide, and homicide deaths as secondary endpoints in RCT that induced cessation. RCT were sought via MEDLINE, bibliographies, the CDC Smoking and Health database, and the GLOBALink Tobacco listserver. RCT were included if (1) net (intervention minus control) cessation totaled over 10% of all intervention smokers and (2) injury data were available. Relative risks (RR) were summarized by fixed effects modeling. Three trials were located (the Lung Health Study, MRFIT, and Whitehall RCT). In-trial annual point prevalence cessation averaged 41, 46, and 59% in the intervention group smokers versus 17, 22, and 28% in the respective controls. Intervention (cessation) was associated with pooled injury RR of 0.65 within the trials (95% confidence interval (CI) 0.36-1.19) and 0.68 (95% CI 0.43-1.09) with additional follow-up in the Lung Health and MRFIT populations. The smoking/injury death association is of borderline statistical significance in currently available RCT data. It modestly supports the significant forensic, cohort, case-control, cross-sectional, challenge-rechallenge, in vitro, and animal data suggesting that smoking may cause injury. Direct tests of the hypothesis could strengthen this inference.


Quantum and classical dynamics of water dissociation on Ni(111): A test of the site-averaging model in dissociative chemisorption of polyatomic molecules.
Recently, we reported the first highly accurate nine-dimensional global potential energy surface (PES) for water interacting with a rigid Ni(111) surface, built on a large number of density functional theory points [B. Jiang and H. Guo, Phys. Rev. Lett. 114, 166101 (2015)]. Here, we investigate site-specific reaction probabilities on this PES using a quasi-seven-dimensional quantum dynamical model. It is shown that the site-specific reactivity is largely controlled by the topography of the PES instead of the barrier height alone, underscoring the importance of multidimensional dynamics. In addition, the full-dimensional dissociation probability is estimated by averaging fixed-site reaction probabilities with appropriate weights. To validate this model and gain insights into the dynamics, additional quasi-classical trajectory calculations in both full and reduced dimensions have also been performed and important dynamical factors such as the steering effect are discussed.


Analysis of immunostimulatory activity of Porphyromonas gingivalis fimbriae conferred by Toll-like receptor 2.
Bacterial fimbriae are an important pathogenic factor. It has been demonstrated that fimbrial protein encoded by fimA gene (FimA fimbriae) of Porphyromonas gingivalis not only contributes to the abilities of bacterial adhesion and invasion to host cells, but also strongly stimulates host innate immune responses. However, FimA fimbriae separated from P. gingivalis ATCC 33277 using a gentle procedure showed very weak proinflammatory activity compared with previous reports. Therefore, in the present study, biological characteristics of FimA fimbriae were further analyzed in terms of proinflammatory activity in macrophages. Macrophages differentiated from THP-1 cells were stimulated with native, heat-denatured, or either proteinase- or lipoprotein lipase-treated FimA fimbriae of P. gingivalis ATCC 33277. Stimulating activities of these FimA fimbriae were evaluated by TNF-alpha-inducing activity in the macrophages. To clarify the mode of action of FimA fimbriae, anti-Toll-like receptor (TLR) 2 blocking antibody was added prior to stimulation. Weak stimulatory activity of native FimA fimbriae was enhanced by heat treatment and low-dose proteinase K treatment. Higher dose of proteinase K treatment abrogated this up-regulation. The activity of treated FimA fimbriae was suppressed by anti-TLR2 antibody, and more substantially by lipoprotein lipase treatment. These results suggest that lipoproteins or lipopeptides associated with FimA fimbriae could at least in part account for signaling via TLR2 and subsequent TNF-alpha production in macrophages.


Etched graphite with internally grown Si nanowires from pores as an anode for high density Li-ion batteries.
A novel architecture consisting of Si nanowires internally grown from porous graphite is synthesized by etching of graphite with a lamellar structure via a VLS (vapor-liquid-solid) process. This strategy gives the high electrode density of 1.5 g/cm(3), which is comparable with practical anode of the Li-ion battery. Our product demonstrates a high volumetric capacity density of 1363 mAh/cm(3) with 91% Coulombic efficiency and high rate capability of 568 mAh/cm(3) even at a 5C rate. This good electrochemical performance allows porous graphite to offer free space to accommodate the volume change of Si nanowires during cycling and the electron transport to efficiently be improved between active materials.


Intensive glucose-lowering and the risk of vascular events and premature death in patients with decreased kidney function: The ADVANCE trial.
To assess the effects of intensive glucose control on the risk of major clinical outcomes according to estimated glomerular filtration rate (eGFR) levels in people with type 2 diabetes. Of 11 140 ADVANCE trial participants, 11 096 with baseline eGFR measurements were included, and classified into three eGFR groups: ≥90 mL/min/1.73 m2 ; 60 to 89 mL/min/1.73 m2 ; and < 60 mL/min/1.73 m2 . Relative risk reduction of randomized intensive glucose control with regard to the composite outcome of major macro- and microvascular events, all-cause death and cardiovascular death did not significantly vary by eGFR level (P for heterogeneity ≥0.49). The risk of severe hypoglycaemia increased with intensive glucose control; however, this risk did not vary across eGFR groups (P for heterogeneity = 0.83). The risk-benefit profile of intensive glucose control in patients with type 2 diabetes and impaired kidney function appears similar to that observed in those with preserved kidney function.


Interleukin-1beta gene in orange-spotted grouper, Epinephelus coioides: molecular cloning, expression, biological activities and signal transduction.
IL-1beta, a key mediator of inflammation, orchestrates a variety of immune responses by initiating gene expression. Herein, we have cloned and sequenced the IL-1beta in orange-spotted grouper (Epinephelus coioides), produced soluble mature recombinant IL-1beta in Escherichia coli, and characterized its biological properties and downstream signal transduction. The grouper IL-1beta cDNA was 1364bp in length, containing an open reading frame of 765bp. The predicted protein of 254 amino acids revealed the presence of the IL-1 family signature motif and the absence of a conventional ICE cut site. Phylogenetically, the grouper IL-1beta clustered closely with those of teleost belonging to Perciformes and apart from those of mammals. The grouper IL-1beta was constitutively expressed in almost all tissues examined, and was augmented in PBL after the addition of LPS or Poly I:C in vitro. The prokaryotically produced rIL-1beta significantly stimulated the proliferation of grouper head kidney cells, and activated gene expression of IL-1beta and COX-2. Moreover, the rIL-1beta-induced IL-1beta and COX-2 expression were reduced by p38 MAPK inhibitor (SB203580) and JNK inhibitor (SP600125), respectively. Taken together, the present study indicated that grouper IL-1beta may have an important role in grouper immune system and activate similar downstream cascades as its mammalian counterparts.


Prospective ECG-triggered, axial 4-D imaging of the aortic root, valvular, and left ventricular structures: a lower radiation dose option for preprocedural TAVR imaging.
Transcatheter valve interventions rely on imaging for patient selection, preprocedural planning, and intraprocedural guidance. We explored the use of prospective electrocardiogram (ECG)-triggered 4-dimensional (4-D) CT imaging in patients evaluated for transcatheter aortic valve replacement (TAVR). A total of 47 consecutive patients underwent 128-slice dual-source CT with wide-window dose-modulated prospective ECG-triggered, axial acquisition of the aortic root, reconstructed during diastolic and systolic cardiac phases. Image quality was evaluated, aortic root and left ventricular (LV) geometry and function were analyzed, and radiation exposure was estimated. Image quality was generally good, with 41 of 47 (87%) patients scored as good or excellent. The mean aortic valve area was 0.93 ± 0.24 cm(2). Mean LV ejection fraction was 56.8% ± 16.4%, and mean LV mass was 130.4 ± 43.8 g. The minor diameter of the annulus was larger in systole (systole, 2.29 ± 0.24 cm; diastole, 2.14 ± 0.25 cm; P = 0.006), but the mean and major diameters did not vary significantly between systole and diastole. The mean estimated effective dose was 5.9 ± 2.4 mSv. Multiphase, prospective ECG-triggered axial image acquisition is a lower dose acquisition technique for 4-D aortic root imaging in patients being considered for TAVR.


Effect of postural and load variation on the coordination of the leg muscles in rebound jumping movement.
The aim of the study was to investigate the coordination of the activity of the leg muscles during performance conditions simulating vertical jumping. Jumps were carried out in different body postures with no balance requirement. Five skilled male subjects performed maximum drop jumps with small (QDJ) and large stretching amplitude (DDJ) on a special sledge dynamometer. The inclination of the dynamometer could be adjusted to vary the load to between 40% and 110% of body weight. Increased load produced a higher negative angular velocity of the knee joint and higher maximum peak force (P < 0.001). The QDJ conditions caused significantly higher force results than the DDJ (p < 0.001). The main result of the present study was that the leg muscle activity coordination model was found to be consistent in all the different test conditions. The maximum peak activity of the agonist muscles was characterized in the model by a sequential proximodistal chain. The QDJ conditions potentiated muscle activity in the hip, knee and ankle joint during the eccentric work phase but decreased it after the transient point (p < 0.05). Especially in the eccentric phase, increased agonist activity in the hip and knee joint and, inversely, decreased activity in the ankle joint was linked to heavier load (p < 0.05). The present results suggest that the coordination program of the vertical jumping model had been so highly practiced that it had become an automatic reflex-like movement now named "skill-reflex". The programmed skill-reflex seemed to guid the execution of the jump irrespective of temporary voluntary orders from the central nervous system.


Environmental Goals Addressed in Assessments of Contaminated Sediments.
Environmental management often aims at sustainability and at implementing goals such as the UN Sustainable Development Goals (SDG). Several of these goals rely upon healthy sediments, implying that contaminated sediments need to be addressed in environmental management. In Sweden, the SDGs and national environmental objectives are meant to be central in environmental management. However, in Environmental Risk Assessment (ERA) for contaminated sediments, it is not clear to assessors or authorities in Sweden which goals to consider and how. In the current study, we explore which environmental goals ERAs of contaminated sediment should consider, according to representatives from Swedish authorities, and to what extent ERAs consider those goals in practice in Sweden. The identified goals indicated that protection of aquatic ecosystems and associated services is a main priority for the authorities. The ERAs analyzed showed that most identified goals were addressed, albeit not consistently. Furthermore, risk assessors seem to put less weight on ecological aspects than authorities do. This indicates that authorities need to stress the importance of environmental aspects and provide guidance on how to address them. Several environmental goals were found to be directly relevant to contaminated sediments and ERAs can contribute to their fulfillment, as ERA is a basis for management decisions. However, practitioners need clearer guidance on which goals to address and how. Finally, there seems to be good potential for implementation of the SDGs in environmental management in Sweden, due to existing legislation based on sustainable development and well-anchored national environmental objectives that overlap with the SDGs. This article is protected by copyright. All rights reserved.


[Strategy and tactic in the treatment of local advanced rectal cancer].
In local advanced rectal cancer (LARC) was defined at the work group in rectal cancer as a tumour what invade the serosa or neighbouring organs, associated with invaded perirectal or mezorectal nodes, with internal fistulae, peritoneal carcinomatosis and locoregional recidives. On a trial of 97 patients, the authors present personal experience, in comparison with literature data regarding therapeutic strategy and tactic of parameters: operability and the moment of operation, indication of preoperative radiotherapy, the type of operation, excision of the metastasis, adjuvant therapy and attitude of locoregional recidives. The survival of the patients was 21.6% at 3 years and 15.4% at 5 years.


IKKalpha and IKKbeta function in TNFalpha-stimulated adhesion molecule expression in human aortic smooth muscle cells.
The role of NFkappaB and it's upstream kinases in regulating adhesion molecule expression in the smooth muscle of the vasculature remains controversial. We therefore examined the effect of blocking the NFkappaB pathway on TNFalpha-stimulated ICAM-1 and VCAM-1 expression in primary cultures of human aortic smooth muscle cells using an adenoviral wild-type IkappaB alpha construct (Ad.IkappaB alpha) and dominant-negative IKKalpha (Ad.IKKalpha+/-) and IKKbeta (Ad.IKKbeta+/-) constructs. Ad.IkappaB alpha treatment was found to block NFkappaB DNA-binding, and thereby completely prevent TNFalpha-stimulated ICAM-1 and VCAM-1 expression without influencing IKK activity. Ad.IKKbeta+/- treatment completely inhibited TNFalpha-stimulated IKK kinase activity, IkappaB alpha degradation and NFkappaB DNA-binding in addition to completely blocking TNFalpha-stimulated ICAM-1 and VCAM-1 expression. Ad.IKKalpha+/- treatment however had no detectable effect on NFkappaB DNA-binding or ICAM-1 and VCAM-1 expression. Our results demonstrate that TNFalpha-stimulated ICAM-1 and VCAM-1 expression in human aortic smooth muscle cells is NFkappaB-dependent, that IKKbeta is a suitable target for drug therapy and Ad.IKKbeta+/- an effective inhibitor of TNFalpha-stimulated ICAM-1 and VCAM-1 expression.


Mental health and well-being of parents caring for a ventilator-dependent child.
An integrative literature review was undertaken to determine the social and emotional effects on the mental health and well-being of parents of children requiring long-term ventilation at home. Six studies were included. Recurrent themes reported in the literature included lack of formal and informal support, financial adversity, limited access to respite care and feelings of social isolation. These themes were associated with depressive symptoms and were consistently reported to have a negative effect on parental mental health and well-being. Healthcare professionals have a part to play in improving parents' coping skills, resilience and resourcefulness to help reduce adverse social and emotional effects on their mental health and well-being.


Carcinoma of the urachus.
Two cases of carcinoma of the urachus are reported, 1 involving the dome of the bladder and 1 occurring beneath the peritoneum of the anterior abdominal wall below the umbilicus at the apex of an elongated bladder. Both patients died shortly after diagnosis, a fact which emphasizes the poor prognosis of this group of patients. The poor prognosis and need for more than local resection of the tumour may not be widely appreciated. Tumours arising above the bladder have a different mode of presentation from those arising within the bladder wall. Bladder wall tumours are most frequently mucus-secreting adenocarcinomas; tumours arising above the bladder may be more variable in their histological type, and include squamous and undifferentiated cancer. A simple classification into vesicle and supra-vesical tumours is proposed, to replace an early classification into 7 groups.


[Immobilization of N-acetyl-1,6-diaminohexane(NADAH) on diol-silica and study of mechanism of NADAH and hexamethylene bisacetamide(HMBA) inducing tumor cells differentiation].
A method for separating NADAH and its immobilization onto diol-silica have been developed. HMBA and its meabolite NADAH were used as the inducers for many types of tumor cells' differentiation. The inducing mechanism of HMBA is not clear yet. Experiments show that HMBA and NADAH have a relatively strong hydrophobic reaction and hardly ion-exchange with some DNA and some proteins of the cytosolic fraction of HL-60 human acute progranulocytic leukemia cells, BIU-87 human bladder carcinoma cells and the human erythrocyte membrane, when utilizing immobilization of NADAH. The retention time of the proteins and DNA was longer than that of the phosphatides. These results show that the adsorption of HMBA and NADAH with some proteins and DNA is higher than that with the phosphatides. The expected receptor binding biospecifically with HMBA has not been found.


Red blood cell distribution width, relative lymphocyte count, and type 2 diabetes predict all‑cause mortality in patients with advanced heart failure.
INTRODUCTION Early identification of patients with advanced heart failure (HF) who are at higher risk of poor outcome is an important element of patient management, both from the medical and economic standpoint. OBJECTIVES We sought to determine the association between hematologic parameters assessed on admission and within a 3‑year follow‑up in consecutive patients with advanced HF. We also investigated the association between baseline demographic and clinical data and mortality. PATIENTS AND METHODS We analyzed the data of consecutive patients with advanced HF from the single‑center registry COMMIT‑HF. Patients with hematologic and autoimmune disorders, acute or chronic inflammatory diseases, malignant diseases, incomplete clinical and laboratory data, and those receiving glucocorticoids were excluded from the study. RESULTS We analyzed 785 patients with advanced HF out of the total number of 1798 patients included in the COMMIT‑HF registry between 2009 and 2013. The mean (SD) age of the patients was 61.9 (12.4) years, and 76.8% of them were male. Diabetes (hazard ratio [HR], 1.46; 95% CI, 1.15-1.86; P = 0.002), elevated red blood cell distribution width (RDW; HR, 1.05; 95% CI, 1.04-1.07; P <0.0001), and a low relative lymphocyte count (RLC%; HR, 0.942; 95% CI, 0.928-0.956; P <0.0001) were shown to be independent predictors of death. CONCLUSIONS Our study showed that diabetes is a strong independent predictor of death in patients with advanced HF. RDW and RLC% are simple, accurate, and widely available markers predicting mortality at 3 years in patients with advanced HF.


Antagonism of vascular endothelial growth factor for macular edema caused by retinal vein occlusions: two-year outcomes.
To determine the long-term effects of intraocular antagonism of vascular endothelial growth factor (VEGF) in patients with macular edema caused by retinal vein occlusions (RVOs). Prospective randomized trial. Twenty patients with macular edema caused by branch RVOs (BRVOs) and 20 patients with central RVOs (CRVOs). After the month 3 primary end point, patients were seen every 2 months and received injections of an anti-VEGF agent as needed for recurrent edema. Mean change from baseline best-corrected visual acuity (BCVA) at month 24 with assessment of other parameters of visual function and center subfield thickness (foveal thickness [FTH]). For 17 patients with BRVO who completed 2 years of follow-up, the mean improvement from baseline in BCVA at month 24 was 17.8 letters compared with 15.6 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 18%, 59%, and 76% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients. With an average of 2 injections of ranibizumab during year 2, the mean FTH at month 24 was 245.8 μm compared with 217.1 μm at month 3 and 481.5 μm at baseline. For 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 14%, 21%, and 43% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients. With an average of 3.5 injections of ranibizumab in year 2, mean FTH at month 24 was 338 μm compared with 278 μm at month 3 and 533 μm at baseline. Duration of RVO >1 year at study entry and nonperfusion of perifoveal capillaries for 360 degrees correlated with reduced visual outcomes. Antagonism of VEGF provides substantial long-term benefit to patients with macular edema caused by RVO, but frequent injections are required in some patients with BRVO and most patients with CRVO.


Effects of energy demand in ischemic and in hypoxemic isolated rat hearts.
Aim of this study was to assess the role of O2, lactate and energy demand in the regulation of myocardial work during severe dysoxia. For this purpose, we measured function and metabolism in isolated Langendorff-perfused rat hearts exposed to either ischemia or hypoxemia (matched for the O2 supply, 10% of baseline) with/out electrical stimulation. When hearts could adjust their HR, hypoxemia demanded more energy than ischemia (p < 0.05) despite same O2 supply. Venous PO2 was 12 +/- 2 or 139 +/- 20 mmHg (p < 0.0001), respectively, but VO2 was the same. After 10 min at HR = 300 min-1, myocardial performance increased in ischemic but not in hypoxemic hearts. PvO2 and VO2 were not affected by pacing. In contrast, both venous [lactate] and lactate production rate increased, but in ischemic hearts only. We conclude that ischemic hearts were downregulated while hypoxemic hearts were not. Likely, depressed washout of lactate during ischemia could offset the effects of O2 in severely dysoxic hearts. Anaerobic glycolysis provided the energy necessary to meet increased energy demand in ischemic hearts, but could not exploit this action in hypoxemic hearts probably because in these hearts it was already working near maximum.


Successful treatment of six patients with neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure.
Neuroleptic malignant syndrome is a rare but potentially lethal, rare reaction to neuroleptics which is characterized by altered levels of consciousness, extrapyramidal effects, autonomic instability, hyperthermia, and elevated serum creatine phosphokinase levels. The most serious complication of neuroleptic malignant syndrome is acute renal failure. We investigated six cases of neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure due to rhabdomyolysis and effect of hemodialysis or hemodiafiltration. The patients were five males and one female with a mean age of 43.5 yr. All of the patients, who developed acute renal failure induced from rhabdomyolysis, had previously received butyrophenone (haloperidol), phenothiazine, benzamide, iminomide, benzisoxazole, antidepressants, and hypnotics (benzodiazepine and barbiturate) for the treatment of schizophrenia. The clinical manifestations of neuroleptic malignant syndrome were characterized by altered consciousness, muscle rigidity and weakness, fever, and excessive perspiration. The peak laboratory data were blood urea nitrogen 102 +/- 26 (mean +/- SD) mg/dL, serum creatinine 9.1 +/- 2.1 mg/dL, serum creatine phosphokinase 229,720 +/- 289,940 IU/L, and all of them developed oliguric acute renal failure. Dantrolene sodium administration was given to five cases and hemodialysis or hemodiafiltration was performed in all of them. The serum creatinine level after hemodialysis or hemodiafiltration was 1.4 +/- 1.0 mg/dL. All patients were successfully cured of acute renal failure by hemodialysis or hemodiafiltration. As a result, myoglobulinemic acute renal failure associated with neuroleptic malignant syndrome was successfully treated by hemodialysis or hemodiafiltration.


Intestinal permeability to inert sugars and different-sized polyethyleneglycols in children with celiac disease.
Intestinal permeability was measured in a total of 42 children, 29 of whom had celiac disease. The celiac children were studied at presentation, during gluten-free diet, and/or at gluten challenge. The permeability was assessed by oral lactulose/L-rhamnose in all 42 children and also by different-sized polyethylene glycols (PEG) in 36 children. Results were compared with the findings of small intestinal biopsy. The mean of the permeability tests in children with enteropathy was significantly abnormal compared with the result in children with a normal mucosal morphology. The lactulose/L-rhamnose test and the PEG test gave equivalent results in the same child. In the celiac children abnormal permeability properties at presentation normalized during gluten-free diet and reappeared during gluten challenge. It is concluded that measurement of intestinal permeability may be a valuable tool in monitoring children with celiac disease, preferably when serial measurements are available in the same child.


Free and membrane-bound polysomes from rat liver. 1. Improvements of subcellular fractionation.
Substantial improvements of cellular fractionation in ionic conditions allowing preservation of polysome structure and polysome-membrane interactions are reported. They consist primarily in minimizing the lysosomal content of fractions containing endoplasmic reticulum by isolating a lysosome-rich fraction with little loss (6%) of RNA. Endoplasmic reticulum membranes were recovered in high yield, mainly in association with mitochondria, the remainder being found in the post-lysosomal supernatant. The latter also contained practically all the free polysomes, as judged by metrizamide gradient analyses. The distributions of various constituents (RNA, DNA, protein and marker enzymes) among cell fractions is presented.


Breath-to-breath variations in rate and depth of ventilation in sleeping infants.
Ventilatory measurements were made noninvasively over 2- to 3-h periods during sleep in each of nine normal infants at 1 mo of age. To assess the changes that occur in ventilation on a breath-to-breath basis, we 1) examined the variations of each of tidal volume (VT), respiratory cycle time (Ttot), expiratory time (TE), and inspiratory time (TI) and 2) studied their interrelationships. We found that the variations of VT, Ttot, and TE but not of TI were significantly greater in rapid-eye-movement (REM) than in quiet sleep. In addition, on a breath-to-breath basis, VT had a positive linear relationship and strong correlation with TI; however, the correlation between VT and TE was weak in both sleep states. VT/Ttot was found to be moderately and negatively correlated with Ttot in both REM and quiet sleep. VT was weakly correlated with Ttot in REM sleep and was, on the average, more correlated with Ttot in quiet sleep. We suggest that in infants 1) on a breath-to-breath basis, VT/Ttot is likely to drop if respiratory frequency is decreased and 2) VT is nonlinearly related to Ttot during sleep; this lack of linearity depends on the lack of constancy of VT/Ttot, which is in turn closely related to the variability of the "on-switching" of inspiratory activity.


Technical considerations in the use of external condom catheter systems.
Since the advent of rehabilitation engineering new advances have been made that have revolutionized condom catheter drainage systems (CCDS). An innovative CCDS has been designed that ensures unobstructed urine flow. Its condom catheter has several unique design features. It has a double row of convolutions near the catheter tip that prevent kinking and twisting so that the pathway remains open. The condom catheter features a unique inner flap that fits snugly on the glans to prevent backflow of urine on the shaft. This condom catheter is connected to a vented leg bag that eliminates the development of a partial vacuum in the connecting tube. This vacuum can create siphoning, which in turn interferes with urine flow into the leg bag. In addition, a new rechargeable battery-operated clipper has been developed that makes nick-free hair removal from the genitals exceptionally easy. This atraumatic hair removal eliminates the pubic hair that becomes trapped under the condom catheter. The clinical impact of these new advances in CCDS requires further investigation.


Health insurance status and outcomes of critically ill obstetric patients: a prospective cohort study in Argentina.
In Argentina, uninsured patients receive public health care, and the insured receive private health care. Our aim was to compare different outcomes between critically ill obstetric patients from both sectors. This is a prospective cohort, including pregnant/postpartum patients requiring admission to 1 intensive care unit in the public sector (uninsured) and 1 in the private (insured) from January 1, 2008, to September 30, 2011. A total of 151 patients were included in the study. In uninsured (n = 63) vs insured (n = 88) patients, Acute Physiology and Chronic Evaluation II (APACHE II) and Sequential Organ Failure Assessment scores were 11 ± 6.5 vs 8 ± 4 and 3 (2-7) vs 1 (0-2), respectively, and 84% vs 100% received prenatal care (P = .001 for all). Multiple organ dysfunction syndrome (MODS) was present in 32 (54%) uninsured vs 9 (10%) insured patients (P = .001), and acute respiratory distress syndrome developed in 18 (30.5%) of 59 vs 2(2%) of 88 (P = .001). Neonatal survival was 80% vs 96% (P = .003). Variables independently associated with the development of MODS were APACHE II (odds ratio, 1.30 [1.13-1.49]), referral from another hospital (odds ratio, 11.43 [1.86-70.20]), lack of health insurance (odds ratio 6.75 [2.17-20.09]), and shock (odds ratio 4.82 [1.54-15.06]). Three patients died, all uninsured. Uninsured critically ill obstetric patients (public sector) were more severely ill on admission and experienced worse outcomes than insured patients (private sector). Variables independently associated with MODS were APACHE II, shock, referral from another hospital, and lack of insurance.


Polymorphism of GSTM1 and GSTT1 genes in bladder cancer: a study from North India.
The present study was conducted (1) to examine whether the GSTT1- and GSTM1-null genotypes are risk factors for bladder cancer, and (2) to study possible association of tobacco usage and age strata with genotype of these patients. This case control study was undertaken over a period of 19 months and included 106 bladder cancer patients and 182 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. Genotype frequencies among patients and controls were assessed and the association of the genotypes with smoking habits and gender of the patients were statistically determined by the chi(2) test. Frequencies of null genotypes in GSTT1 and GSTM1, were 16% (29/182) and 30% (54/182), respectively, in control individuals. The frequencies of GSTT1- and GSTM1-null genotypes in bladder cancer patients were 26% (28/106) and 40% (42/106), respectively. In conclusion, our study demonstrated that the null genotypes of GSTT1 and GSTM1 were substantially at higher risk for bladder carcinoma compared to the normal healthy controls. The GSTT1- and GSTM1-null genotypes did not show significant association with tobacco usage in bladder cancer patients. However, the null genotypes were statistically significant in female relative to male bladder cancer patients.


Of dilemmas and tensions: a qualitative study of palliative care physicians' positions regarding voluntary active euthanasia in Quebec, Canada.
In 2015, the Province of Quebec, Canada passed a law that allowed voluntary active euthanasia (VAE). Palliative care stakeholders in Canada have been largely opposed to euthanasia, yet there is little research about their views. The research question guiding this study was the following: How do palliative care physicians in Quebec position themselves regarding the practice of VAE in the context of the new provincial legislation? We used interpretive description, an inductive methodology to answer research questions about clinical practice. A total of 18 palliative care physicians participated in semistructured interviews at two university-affiliated hospitals in Quebec. Participants positioned themselves in opposition to euthanasia. Their justifications were framed within their professional commitment to not hasten death, which sat in tension with the value of patients' autonomy to choose how to die. Participants described VAE as unacceptable if it impeded opportunities to evaluate and alleviate suffering. Further, they contested government rhetoric that positioned VAE as a way to improve end-of-life care. Participants felt that VAE would diminish the potential of palliative care to relieve suffering. Dilemmas were apparent in their narratives, about reconciling respect for patient autonomy with broader palliative care values, and the value of accompanying and not abandoning patients who make requests for VAE while being committed to neither prolonging nor hastening death. This study provides insight into nuanced positions of experienced palliative care physicians in Quebec and confirms expected tensions between an important stakeholder and the practice of VAE as guided by the new legislation.


Improved semisupervised adaptation for a small training dataset in the brain-computer interface.
One problem in the development of brain-computer interface (BCI) systems is to minimize the amount of subject training on the premise of accurate classification. Hence, the challenge is how to train the BCI system effectively especially in the scenario with small amount of training data. In this paper, we introduce improved semisupervised adaptation based on common spatial pattern (CSP) features. The feature extraction and classification are performed jointly and iteratively. In the iteration step, training data are expanded by part of the testing data with labels which are predicted by a linear discriminant analysis classifier and/or a Bayesian linear discriminant analysis classifier in the previous iteration. Then CSP features are reextracted from the expanded training data, and the classifiers are retrained. Both self-training and cotraining paradigms are proposed for the improved semisupervised adaptation. Throughout the investigation on different number of initial training trials, we find that when a small number of training trials are used, e.g., a training session contains no more than 30 trials, similar classification performance to that of large training data items (40-50 trials) can be achieved. Effectiveness of the algorithms is verified by two competition datasets. Compared with several existing algorithms, the proposed semisupervised algorithms show improvements in classification accuracy for most of the competition datasets especially in the case of small training data.


Aqueous outflow pathway complex carbohydrate synthesis in vitro.
A technique is described for examining the in vitro synthesis of glycosaminoglycans and glycoproteins in the aqueous outflow pathway (AOP). New Zealand red rabbit eyes were maintained at near-physiologic conditions and were infused by anterior chamber exchange with 30 muCi [3H] glucosamine and 100 muCi [35S] sulfate. At 0.5, 1.0, and 2.0 hours, the anterior segment tissues were dissected, isolated, and fractionated by gel filtration chromatography on Sephadex G-50 columns. The elution profiles demonstrated an increase of labeled material with time in the glycosaminoglycan (GAG) fractions and in the glycopeptide fractions. The relative rate of synthesis of labeled material was: central cornea greater than peripheral cornea greater than iris-ciliary body greater than AOP greater than anterior sclera. In order to characterize the profiles of each tissue, the isolated material was analyzed for hexosamine, hexuronic acid, and sulfate. The AOP cells synthesized a heterogenous mixture of GAGs and glycoproteins which biochemically appeared to be distinct from other anterior segment tissues. In addition, the percent distribution of GAG polymers in each tissue was determined by selective GAG degradative procedures and by gel filtration chromatography. The AOP cells synthesized four types of GAGs, and the percent distribution of the labeled GAGs was different from the other tissues. The present results suggest that this technique may provide a well-controlled method to probe the metabolic activity of complex carbohydrates in the AOP and in the anterior segment.


Adaptations to daily exercise in hot and humid ambient conditions in trained thoroughbred horses.
The objectives of this study were to: 1) determine the effects of heat and high relative humidity (RH) on the clinical and physiological responses of horses during and after daily exercise training and 2) determine whether repeated exposure to, and exercise in, the heat would result in improved thermal tolerance (heat acclimation). Six trained Thoroughbred horses completed 1 h of submaximal exercise in cool, dry conditions (CD) and during a daily 4 h period of exposure to high heat and humidity (HH, room temperature = 33-35 degrees C, RH = 80-85%) for 22 days. Rectal temperature (Tre) and heart rate (HR) were measured before, during and after exercise and respiratory rate (RR) was measured before exercise and during a 2 h recovery. In HH, the rate of rise in Tre was significantly higher than in CD. However, by HH Day 5, Tre before, during and after exercise was significantly lower than on HH Day 1. The day-to-day decrease in Tre during exercise was reflected in significant decreases in heat storage following exercise by HH Day 10 (910 +/- 47 kcal) when compared to HH Day 1 (1211 +/- 75 kcal). At rest, RR was initially higher in HH than CD, and a further increase in pre-exercise RR from HH Day 1 to Day 10 may have contributed to the lower pre-exercise Tre. Recovery RR was higher after HH Day 1 and was associated with a lower end-of-exercise HR did not change in the 1 h before exercise in CD and did not differ from HH Days 1-22. By HH Day 10, mean HR during the latter part of exercise was lower than HH Day 1 and was not different from pre-exercise by 60 min of recovery. Pre-exercise body mass did not change during the 3 wk period and the decrease in body mass that occurred during the 4 h training period was significantly attenuated by HH Day 15 (9.8 +/- 0.8 kg) when compared to HH Day 1 (12.5 +/- 0.8 kg). Over the 3 week period of HH, mean 24 h water consumption increased from 26.0 +/- 2.1 litres to 39.5 +/- 3.2 litres, largely reflecting a 2-fold increase in water intake during the 4 h period of heat exposure. It is concluded that 3 weeks of daily exposure to, and exercise in, hot and humid ambient conditions resulted in a progressive reduction in thermal and cardiovascular strain. Furthermore, the reported physiological adaptations are consistent with an improved thermal tolerance (heat acclimation).


Should we prefer different drugs to treat hypertension in older and younger adults? Practical implications of clinical trials: European perspective.
Guidelines for the management of hypertension almost invariably include sections where the evidence for or against treatment or for certain types of treatment in certain types of patients is inconclusive. This is especially the case of older patients with hypertension. As a consequence, although a large number of randomized trials including hypertensive patients aged > or = 60 years showed that antihypertensive drugs reduce cardiovascular morbidity and mortality, health care professionals who take care of older adults have been often reluctant to provide adequate antihypertensive therapy. In a recent meta-analysis, the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) compared the effects of different drugs for reducing blood pressure (BP) in older and younger adults; the reduction in BP levels and the relative risk reduction of a cardiovascular event with various antihypertensive drugs occurred independently of the patients' ages, and the benefits of antihypertensive regimens based on different drug classes were widely comparable across age groups. The BPLTTC analysis strongly suggests an early and aggressive management of hypertension irrespectively of age; more myocardial infarctions, strokes, heart failures and deaths will be prevented by treating hypertensive patients aged > or = 65 years than by treating patients < or = 50 years with the same BP levels. Antihypertensive treatment should be embedded within the management of global cardiovascular risk, with the use of charts for stratifying risk based on additional risk factors, target organ damage or additional clinical conditions.


In vive effects of gliclazide and metformin on the plasma concentration of caffeine in healthy rats.
The in vivo effects of gliclazide and metformin HCl on plasma concentration of caffeine have been studied in rats. The plasma concentration of caffeine was determined by UV spectrophotometry after oral single administration of caffeine alone and with gliclazide and metformin HCl. The in vivo study for determination of plasma concentration of caffeine showed that concurrent administration of caffeine and gliclazide have not made noticeable changes in plasma concentration of caffeine. But administration of caffeine and metformin HCl has showed a significant change in plasma concentration of caffeine. So, a competitive inhibition of the binding to plasma protein by metformin HCI increases the plasma concentration of caffeine. Thus any change in plasma concentration may affect the pharmacological or toxic effects of the drug.


[Tricyclic antidepressants and therapeutic monitoring. An experience with trimipramine].
Now it is not possible to choose an efficacious dosage of trimipramine when measuring serum drug concentrations. At once those measurement are useful to assure the long term surveillance of the treatment. That's why we propose to define a personal therapeutic interval that allows to limit the area in which the drug concentrations must be found.


The rise and fall of mercury methylation in an experimental reservoir.
For the past 9 years, we experimentally flooded a wetland complex (peatland surrounding an open water pond) at the Experimental Lakes Area (ELA), northwestern Ontario, Canada, to examine the biogeochemical cycling of methyl mercury (MeHg) in reservoirs. Using input-output budgets, we found that prior to flooding, the wetland complex was a net source of approximately 1.7 mg MeHg ha(-1) yr(-1) to downstream ecosystems. In the first year of flooding, net yields of MeHg from the reservoir increased 40-fold to approximately 70 mg MeHg ha(-1) yr(-1). Subsequently, annual net yields of MeHg from the reservoir declined (10-50 mg MeHg ha(-1) yr(-1)) but have remained well above natural levels. The magnitude and timing of Hg methylation in the flooded peat portion of the wetland reservoir were very different than in the open water region of the reservoir. In terms of magnitude, net Hg methylation rates in the peat in the first 2 years of flooding were 2700 mg ha(-1) yr(-1), constituting over 97% of the MeHg produced at the whole-ecosystem level. But in the following 3 years, there was a large decrease in the mass of MeHg in the flooded peat due to microbial demethylation. In contrast, concentrations of MeHg in the open water region and in zooplankton, and body burdens of Hg in cyprinid fish, remained high for the full 9 years of this study. Microbial activity in the open water region also remained high, as evidenced by continued high concentrations of dissolved CO2 and CH4. Thus, the large short-term accumulation of MeHg mass in the peat appeared to have only a small influence on concentrations of MeHg in the biota; rather MeHg accumulation in biota was sustained by the comparatively small ongoing net methylation of Hg in the flooded pond where microbial activity remained high. In large reservoirs, where the effects of wind and fetch are greater than in the small experimental reservoir we constructed, differences can occur in the timing and extent of peat and soil erosion, effecting either transport of MeHg to the food chain or the fueling of microbial activity in open water sediments, both of which could have important long-term implications for MeHg concentrations in predatory fish.


Experimental hypoglycemizing tumor of B-cells of Langerhans islets produced by the combined action of streptozotocin annd nicotinamide in the rat.
Young male and female Wistar-Velaz rats were treated with streptozotocin-nicotinamide combination according to the method of Rakieten and examined periodically for 23 months for fasting and postprandial glycemia, by intravenous, intraperitoneal or intragastric glucose tolerance and tolbutamide tests with the aim to detect in vivo the experimentally produced nesidiomas. One male rat with severe hypoglycemia, apparent first on tolbutamide test after twelve months, later also on glucose tolerance test and fasting hypoglycemia associated with paraplegia with macroscopically and microscopically documented nesidioma is described. The exstirpation of this nesidioma was followed first by normalization and later by development of latent diabetes.


Bilateral periodic lateralized epileptiform discharges in Mycoplasma encephalitis.
Status epilepticus and prolonged coma developed in two patients with respiratory tract infections caused by Mycoplasma pneumoniae. Serial electroencephalography initially revealed bilateral, independent, periodic, lateralized epileptiform discharges. This pattern was replaced several days later by other electroencephalographic abnormalities.


Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury.
We have shown recently that endothelial Grb-2-associated binder 1 (Gab1), an intracellular scaffolding adaptor, has a protective effect against limb ischemia via mediating angiogenic signaling pathways. However, the role of Gab1 in cardiac ischemia/reperfusion (I/R) injury remains unknown. In this study, we show that Gab1 is required for cardioprotection against I/R injury. I/R injury led to remarkable phosphorylation of Gab1 in cardiomyocytes. Compared with controls, the mice with cardiomyocyte-specific deletion of Gab1 gene (CGKO mice) exhibited an increase in infarct size and a decrease in cardiac function after I/R injury. Consistently, in hearts of CGKO mice subjected to I/R, the activation of caspase 3 and myocardial apoptosis was markedly enhanced whereas the activation of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), which are critical for cardiomyocyte survival, was attenuated. Oxidative stress is regarded as a major contributor to myocardial I/R injury. To examine the role of Gab1 in oxidative stress directly, isolated adult cardiomyocytes were subject to oxidant hydrogen peroxide and the cardioprotective effects of Gab1 were confirmed. Furthermore, we found that the phosphorylation of Gab1 and Gab1-mediated activation of Akt and MAPK by oxidative stress was suppressed by ErbB receptor and Src kinase inhibitors, accompanied by an increase in apoptotic cell death. In conclusion, our results suggest that Gab1 is essential for cardioprotection against I/R oxidative injury via mediating survival signaling.