Age excuses: conversational management of memory failures in older adults.
The social consequences of appealing to age to excuse memory failure were examined in 2 vignette-based studies. In Study 1, 75 older (M = 72 years) and 78 young (M = 22 years) adults evaluated forgetful older targets in their 70s who used their age, lack of ability, lack of effort, or the situation to explain forgetting. In Study 2, 105 older (M = 72 years) and 105 young participants (M = 19 years) evaluated forgetful targets with no specific age given in 4 excuse conditions (age, ability, situation, and no excuse). In support of the prediction of positive consequences, age excuses were rated as more believable than situation in both studies and more believable and socially fluent than effort in Study 1. In support of predictions of negative consequences, both groups in Study 2 rated target persons who used an age excuse to be much older than their peers and, along with ability excuse users, as eliciting more worry and frustration than the others. Moreover, young adults showed additional sensitivity to the negative aspects of age excuses in terms of worry and frustration in Study 1 and anticipated repeat forgetting in Study 2. These results suggest that although age excuses may relieve socially awkward situations, this strategy reinforces negative age stereotyping of the older forgetter.


Rate-pressure product and myocardial oxygen consumption during surgery for coronary artery bypass.
Rate-pressure product (RPP) is a sensitive index of myocardial oxygen consumption (mVO2) in awake people. We wished to determine whether this relationship persisted under anesthesia and in the face of concurrent large changes in myocardial contractility and left ventricular filling pressures. In 16 patients scheduled for coronary artery bypass surgery, we inserted coronary sinus and Swan-Ganz catheters, and a central aortic catheter via the brachial artery, before induction of anesthesia with either morphine (2 mg/kg) or halothane, chosen in random order. We measured aortic, pulmonary, and venous pressures, cardiac output, systolic time intervals, and thermodilution coronary sinus flow. We calculated mVO2 as coronary sinus flow times myocardial arteriovenous oxygen content difference. We found significant correlations between mVO2 and heart rate (r = 0.57), systolic blood pressure (r = 0.52), the index delta /delta T (r = 0.53, and RPP (r = 0.78). Multiple regression of RPP and delta P/delta T against mVO2 increased their correlation (r = 0.86), while multiple regression of RPP and pulmonary wedge pressure against mVo2 did not significantly improve the correlation of RPP alone (r = 0.75). We conclude that hemodynamic changes anesthesia and surgery do not decrease the sensitivity of RPP as an index of mVO2.


It is not just memory: propositional thinking influences performance on the autobiographical IAT.
The autobiographical Implicit Association Test (aIAT) is a variant of the Implicit Association Test reportedly capable of detecting an individual's concealed autobiographical event with very high accuracy. A previous attempt to utilize this measurement technique for the identification of cocaine users rendered an alarming rate of false positives. In this study, we aimed to explore the potential reasons behind the measurement's inaccuracy. Two versions of the cocaine aIAT were devised with different category labels (descriptive 'guilty/innocent' and self-referenced 'as if you were/were not'). Forty-one cocaine abstinent participants (43.9% male; mean age = 28.17 ± 7.36) were randomly assigned to one of the two conditions. Self-declared cocaine abstinence was confirmed for the 12-month period preceding data collection through hair analysis. Participants were also administered bespoke implicit and explicit cocaine user attitude measures, the self-esteem IAT and the Rosenberg self-esteem scale. The category labels which elicited self-referenced knowledge showed low accuracy (19%) compared to the 65% of the 'guilty/innocent' labels proposed by original authors. The self-referenced aIAT version significantly correlated with the self-concept measures. The aIAT outcomes were independent from attitudes toward cocaine users. Category labels play an influential role in determining the test's accuracy, demonstrating that participants' propositional knowledge and self-concept are involved during test performance. The aIAT does not appear to tap directly into an individual's implicit memory when relevant memory is not available. Although the test cannot be recommended for detecting drug use, further research should investigate underlying mechanisms and other potentials of the technique.


Clinical manifestations of dengue hemorrhagic fever in Puerto Rico, 1990-1991. Puerto Rico Association of Epidemiologists.
The aim of the study reported here was to demonstrate that dengue hemorrhagic fever occurs in Puerto Rico, that it is underreported, and that this underreporting is due partly to underdiagnosis in hospitals. Surveillance for severe dengue identified 986 hospitalizations for suspected dengue in 1990-1991. At the time, on the basis of available clinical and laboratory data, the surveillance system routinely identified 20 DHF cases, including three with dengue shock syndrome (DSS). Our subsequent review of these 986 patients' hospital records identified 102 whose records supported a clinical diagnosis of DHF (88) or DSS (14). Of the 102, there were 57 with positive virologic or serologic results for dengue and that met the World Health Organization criteria for DHF (fever, hemorrhagic manifestations, thrombocytopenia, and excessive capillary permeability). This group of 57 patients had a mean age of 38 years, contained a preponderance of males (34, 59.3%), included eight cases of DSS, and involved two (3.5%) fatalities (in females 16 and 55 years old). Hemorrhagic manifestations were mild; hemoconcentration, hypoalbuminemia, and elevated aspartate and alanine aminotransferase (AST and ALT) levels were frequently encountered. The median duration of hospitalization was five days. The clinical description of these laboratory-positive DHF cases in Puerto Rico is consistent with previous descriptions of DHF in the medical literature; but the patients' age distribution is similar to the pattern typically found in the Americas (where all age groups tend to be affected), as opposed to Southeast Asia (where mostly younger children are affected). The number of DHF cases identified by our study was nearly three times that reported through the established surveillance system. Our findings indicate that recognition and reporting of DHF by local clinicians needs to be improved.


Chemically synthesized dicarba H2 relaxin analogues retain strong RXFP1 receptor activity but show an unexpected loss of in vitro serum stability.
Peptides and proteins are now acknowledged as viable alternatives to small molecules as potential therapeutic agents. A primary limitation to their more widespread acceptance is their generally short in vivo half-lives due to serum enzyme susceptibility and rapid renal clearance. Numerous chemical approaches to address this concern have been undertaken in recent years. The replacement of disulfide bonds with non-reducible elements has been demonstrated to be one effective means by eliminating the deleterious effect of serum reductases. In particular, substitution with dicarba bonds via ring closure metathesis has been increasingly applied to many bioactive cystine-rich peptides. We used this approach for the replacement of the A-chain intramolecular disulfide bond of human relaxin 2 (H2 relaxin), an insulin-like peptide that has important regulatory roles in cardiovascular and connective tissue homeostasis that has led to successful Phase IIIa clinical trials for the treatment of acute heart failure. Use of efficient solid phase synthesis of the two peptide chains was followed by on-resin ring closure metathesis and formation of the dicarba bond within the A-chain and then by off-resin combination with the B-chain via sequential directed inter-chain disulfide bond formation. After purification and comprehensive chemical characterization, the two isomeric synthetic H2 relaxin analogues were shown to retain near-equipotent RXFP1 receptor binding and activation propensity. Unexpectedly, the in vitro serum stability of the analogues was greatly reduced compared with the native peptide. Circular dichroism spectroscopy studies showed subtle differences in the secondary structures between dicarba analogues and H2 relaxin suggesting that, although the overall fold is retained, it may be destabilized which could account for rapid degradation of dicarba analogues in serum. Caution is therefore recommended when using ring closure metathesis as a general approach to enhance peptide stability.


The effects of iodination on the polypeptide heterogeneity of thyroglobulin.
19 S thyroglobulins from several mammals were prepared under conditions designed to minimize endogenous proteolytic activities. The purified iodoproteins were then fractionated by RbCl isopycnic gradient centrifugation and fractions of varying iodine content analyzed by SDS-polyacrylamide gel electrophoresis. The dependence on the iodination level of molecular dissociability, previously reported in preparations "markedly' differing in their iodination degree, has been now ultimately assessed in all species investigated and demonstrated even for fraction differing from each other only by a few iodine atoms. Upon reduction fractions across the isopycnic gradients showed the occurrence of discrete electrophoretic bands faster than the 300,000 Da subunit: the relative amount of these peptides has been found to be linearly related to the iodine content of the molecules analyzed. This behaviour has been observed in all animal species investigated. In conclusion, our data suggest that iodination, beside the well-documented effects on thyroglobulin conformational properties, may also affect its "apparent' polypeptide chain composition. The origin of such heterogeneity is discussed.


Effect on bladder function of diversion of the contents of the small intestine to the urinary bladder in dogs.
The function of the lower part of the urinary tract after diversion of the contents of the small intestine to the bladder was studied in seven mongrel dogs. Cystometries and isobaric bladder volume were recorded. The observation time varied between six and 48 months. An initial decrease of the bladder volume was noted postoperatively. This decrease was more pronounced at the cystometrographic recordings on awake dogs than at the isobaric bladder volume registrations done under general anesthesia. At the six month examination, the bladder volume was unchanged or increased. The initial reduction in the bladder volume could be explained partly by the construction of the ileovesical anastomosis and, to some extent, by an inflammatory reaction of the bladder wall. No signs of progressive inflammatory reaction, leading to contraction of the bladder, were observed in any dog.


Activation of endothelial toll-like receptor 3 impairs endothelial function.
Endothelial dysfunction and atherosclerosis are chronic inflammatory diseases characterized by activation of the innate and acquired immune system. Specialized protein receptors of the innate immune system recognize products of microorganisms and endogenous ligands such as nucleic acids. Toll-like receptor 3 (TLR3), for example, detects long double-stranded RNA and is abundantly expressed in endothelial cells. Whether innate immunity contributes to atherogenic mechanisms in endothelial cells is poorly understood. We sought to determine the effects of TLR3 activation in endothelial cells. We first investigated whether stimulation of TLR3 influences endothelial biology in mice. Intravenous injection of polyinosine polycytidylic acid, a synthetic double-stranded RNA analog and TLR3 ligand, impaired endothelium-dependent vasodilation, increased vascular production of reactive oxygen species, and reduced reendothelialization after carotid artery injury in wild-type mice compared with controls but had no effect in TLR3(-/-) animals. TLR3 stimulation not only induced endothelial dysfunction but also enhanced the formation of atherosclerotic plaques in apolipoprotein E-deficient mice. In vitro incubation of endothelial cells with polyinosine polycytidylic acid induced production of the proinflammatory cytokines interleukin-8 and interferon-γ-induced protein 10, increased formation of reactive oxygen species, diminished proliferation, and increased apoptosis, which suggests that endothelial cells are able to directly detect and respond to TLR3 ligands. Neutralization of interleukin-8 and interferon-γ-induced protein 10 antagonizes the observed negative effects of polyinosine polycytidylic acid. We found elevated levels of circulating endothelial progenitor cells in polyinosine polycytidylic acid-treated mice, although they displayed increased endothelial dysfunction. Stimulation of TLR3 in cultured endothelial progenitor cells, however, led to increased formation of reactive oxygen species, increased apoptosis, and reduced migration. Injection of endothelial progenitor cells that had been incubated with polyinosine polycytidylic acid ex vivo hindered reendothelialization after carotid artery injury. Therefore, endothelial progenitor cell function was affected by TLR3 stimulation. Finally, apolipoprotein E-deficient/TLR3-deficient mice exhibited improved endothelial function compared with apolipoprotein E-deficient/TLR3(+/+) littermates. Immunorecognition of long double-stranded RNA by endothelial cells may be an important mechanism involved in endothelial cell activation and development of endothelial dysfunction.


Organochlorine pesticides in follicular fluid of women undergoing assisted reproductive technologies from central China.
Female infertility rates have increased by approximately 4% since the 1980s. There is evidence of adverse effects on female fertility in relation to exposure of chemical pollution in recent years. Follicular fluid samples were collected from 127 woman patients (aged 20-35) who underwent assisted reproductive technologies (ART) and had no records indicating occupational exposure to OCPs. Seventeen OCPs were analyzed in this study. The results showed that methoxychlor was dominant, accounted for 13.4% of total OCPs with a mean concentration of 167.9 ± 33.9 ng/g lipid weight (lw), followed by heptachlor-epoxide, hexachlorocyclohexanes, endrin and DDT. The concentrations of OCPs in the follicular fluid samples in the present study were moderate in comparison with those reported from developed or industrialized countries. All these pollutants can accumulate in different tissues of human body through diet, drinking water and respiration. No correlation between patient age and OCP concentrations was observed in this study.


A large population of galaxies 9 to 12 billion years back in the history of the Universe.
To understand the evolution of galaxies, we need to know as accurately as possible how many galaxies were present in the Universe at different epochs. Galaxies in the young Universe have hitherto mainly been identified using their expected optical colours, but this leaves open the possibility that a significant population remains undetected because their colours are the result of a complex mix of stars, gas, dust or active galactic nuclei. Here we report the results of a flux-limited I-band survey of galaxies at look-back times of 9 to 12 billion years. We find 970 galaxies with spectroscopic redshifts between 1.4 and 5. This population is 1.6 to 6.2 times larger than previous estimates, with the difference increasing towards brighter magnitudes. Strong ultraviolet continua (in the rest frame of the galaxies) indicate vigorous star formation rates of more than 10-100 solar masses per year. As a consequence, the cosmic star formation rate representing the volume-averaged production of stars is higher than previously measured at redshifts of 3 to 4.


Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI.
To evaluate the renal oxygenation in type 2 diabetes by blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI). Forty-eight patients with type 2 diabetes and 67 healthy controls were recruited. All patients were further divided into four subgroups based on renal functional level. Bilateral renal cortical R2* (CR2*) and medullary R2* (MR2*) values were extracted and quantified on BOLD-MRI, then R2* ratio between medulla and cortex (MCR) was calculated. CR2*, MR2* and MCR were compared among the groups separately. The relationships were analyzed between R2* values and clinical index of renal function. Compared with controls, MR2* and CR2* in diabetes were significantly increased. The positive relationship was found between MR2* and estimated glomerular filtration rate (eGFR), and CR2* was negatively correlated with eGFR. Interestingly, the MCR increased in early stage of diabetes and decreased along with the aggravation of diabetic nephropathy (DN). BOLD-MRI can non-invasively detect and assess the renal hypoxia in diabetes. Our findings suggest that hypoxia in medulla is more apparent and earlier than in cortex. During the progression of DN, a reversion of corticomedullary oxygenation gradient can be detected, thus, MCR would be adopted to suppose the progression and prognosis of DN.


Breaking aggregation in a tetrathiafulvalene-fused zinc porphyrin by metal-ligand coordination to form a donor-acceptor hybrid for ultrafast charge separation and charge stabilization.
A novel electron rich, tetrathiafulvalene fused zinc porphyrin, (TTF)4PZn, has been newly synthesized and characterized using spectral and electrochemical methods. In spite of the presence of eight t-butyl groups, (TTF)4PZn exhibited appreciable aggregation in solution. Scanning electron microscopic (SEM) imaging of the aggregates revealed their spherical particulate morphology. Attenuation of intermolecular aggregation was possible by metal-ligand coordination of a nitrogenous ligand. Further, using this strategy, a donor-acceptor hybrid was formed by coordinating imidazole functionalized fullerene as an electron acceptor. The occurrence of intrasupramolecular ultrafast photoinduced charge separation has been established using fluorescence and transient absorption spectroscopic techniques. The determined rate of charge separation, kCS, and rate of charge recombination, kCR were found to be 1.4 × 10(11) s(-1) and 2.5 × 10(6) s(-1), respectively. The lower kCR values indicate charge stabilization in the assembled donor-acceptor conjugate via an electron transfer-hole transfer mechanism.


Toxicology of deoxynivalenol (vomitoxin).
Trichothecene mycotoxins are a group of structurally similar fungal metabolites that are capable of producing a wide range of toxic effects. Deoxynivalenol (DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used for food and feed production, including in Canada and the United States. Although DON is one of the least acutely toxic trichothecenes, it should be treated as an important food safety issue because it is a very common contaminant of grain. This review focuses on the ability of DON to induce toxicologic and immunotoxic effects in a variety of cell systems and animal species. At the cellular level, the main toxic effect is inhibition of protein synthesis via binding to the ribosome. In animals, moderate to low ingestion of toxin can cause a number of as yet poorly defined effects associated with reduced performance and immune function. The main overt effect at low dietary concentrations appears to be a reduction in food consumption (anorexia), while higher doses induce vomiting (emesis). DON is known to alter brain neurochemicals. The serotoninergic system appears to play a role in mediation of the feeding behavior and emetic response. Animals fed low to moderate doses are able to recover from initial weight losses, while higher doses induce more long-term changes in feeding behavior. At low dosages of DON, hematological, clinical, and immunological changes are also transitory and decrease as compensatory/adaptation mechanisms are established. Swine are more sensitive to DON than mice, poultry, and ruminants, in part because of differences in metabolism of DON, with males being more sensitive than females. The capacity of DON to alter normal immune function has been of particular interest. There is extensive evidence that DON can be immunosuppressive or immunostimulatory, depending upon the dose and duration of exposure. While immunosuppression can be explained by the inhibition of translation, immunostimulation can be related to interference with normal regulatory mechanisms. In vivo, DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects which are similar to human immunoglobulin A (IgA) nephropathy. Other effects include superinduction of cytokine production by T helper cells (in vitro) and activation of macrophages and T cells to produce a proinflammatory cytokine wave that is analogous to that found in lipopolysaccharide-induced shock (in vivo). To what extent the elevation of cytokines contributes to metabolic effects such as decreased feed intake remains to be established. Although these effects have been largely characterized in the mouse, several investigations with DON suggest that immunotoxic effects are also likely in domestic animals. Further toxicology studies and an assessment of the potential of DON to be an etiologic agent in human disease are warranted.


Optimized expanded ensembles for simulations involving molecular insertions and deletions. I. Closed systems.
Monte Carlo simulation methods that involve the insertion-deletion of molecules are of wide spread use for the study of thermophysical behavior of complex systems; e.g., for the estimation of chemical potentials in closed-system ensembles. In this work, efficient expanded ensemble methods are described to overcome the lack of ergodicity that often plagues such molecular moves, wherein an arbitrary physical parameter Lambda is used to gradually couple and decouple a partial molecule to and from the system. In particular, we describe the use of (1) acceptance ratio methods for the robust estimation of free-energy changes associated with transitions between Lambda states of the partial molecule, (2) non-Boltzmann sampling of the probability density of Lambda states so that one can achieve either a flat histogram or an optimized histogram based on the maximization of round trips between the Lambda bounds, and (3) an approach to select suitable intermediate stages of the Lambda parameter that maximizes such round trips. The validity of the advocated methods is demonstrated by their application to two model systems, namely, the solvation of large hard spheres into a fluid of small spheres, and the mesophase formation of a block copolymer-homopolymer mixture.


[The hematological status of rats born and raised under increased gravitational force].
Blood and bone marrow morphology of the rats the pre- and postnatal development of which up to the ages of 60 and 75 days took place under 2g environments induced by a continuous centrifuge rotation. The response to a reduced gravity was studied in 60-day-old rats on post-rotation days 2 and 15. Immediately post-rotation, these animals exhibited: an intensified erythropoiesis resulting in an elevated erythroid cell counts, an activated eosinophilopoiesis and decreased level of neutrophilopoiesis. Return of the animals to a terrestrial environment during a 2-week period has caused a greater increase of erythroid production and the tendency toward normalizing granulocytopoiesis. In the 75-day-old rats developed under 2g, erythro- and granulocytopoiesis have tended to be recovered and bone marrow population of lymphoid and plasma cells was significantly decreased. The results point to the fact that hemopoiesis adaptation to an increased gravity during the studied period of time is not accomplished and this hematologic status depends on a changed status, of the controlling systems.


Admission heart rate in relation to presentation and prognosis in patients with acute myocardial infarction. Treatment regimens in German chest pain units.
Higher heart rates on admission have been associated with poor outcomes in patients with an acute coronary syndrome in previous cohorts. Whether such a linear relationship still exists in contemporary high-level care is unclear. Prospectively collected data from patients presenting with myocardial infarction (MI) in centers participating in the Chest Pain Unit (CPU) Registry between December 2008 and July 2014 were analyzed. Patients were classified according to their initial heart rate (I: < 50; II: 50-69; III: 70-89; IV: ≥ 90 bpm). A total of 6,168 patients out of 30,339 patients presenting to 38 centers were included in the study. Patients in group IV had more comorbidities, while patients in group I more often had a history of MI. Patients in the lowest heart rate group presented significantly earlier to the hospital (4 h 31 min vs. 7 h 37 min; p < 0.05) and had the highest rate of interventions. The overall survival after 3 months was significantly worse in group IV after adjusting for baseline variables. In the subgroup analysis, heart rate was a prognostic factor in the non-ST-segment elevation MI group but not in the ST-segment elevation MI group. The correlation between heart rate and major adverse cardiac events followed a J-shaped curve with worst outcomes in the lowest and highest heart rate groups. Patients admitted to a dedicated CPU with the diagnosis of MI and a heart rate > 90 bpm experience reduced survival at 3 months despite optimal treatment. Patients with bradycardia also seem to be at increased risk for cardiovascular events despite much earlier presentation and treatment.


Weightlifting, weight training and injuries.
Although millions of men and women in the United States are regularly involved in some form of weightlifting, the average physician knows, and frequently cares, little about the sports involved. As a result, his or her knowledge of the medical and physiological issues involved is limited This article attempts to address this lack by beginning with a brief introductory section outlining some of the similarities differences between the major weight lifting approaches (power lifting, olympic lifting, weight training and body building). Next it reviews major issues and controversies such as age restrictions for lifters, physiological effects, drug use, potential strength gains and hypertrophy. Finally, it discusses some of the more frequent and unique injuries that can occur in lifters.


Evidence of a thiamine deficiency in sheep fed maize silage.
Two groups of Merino sheep (with or without rumen fistulae) were used to study the effect of feeding maize-silage (compared to hay) on: thiamine concentrations in rumen fluid, tissues and organ; blood transketolase activity; microbial fermentation in the rumen. After sheep were transferred from a hay diet to maize-silage, thiamine concentrations in ruminal fluid fell to about 25% of control values on hay. Thiamine levels greatly decreased in kidney, heart, liver, rumen tissue and large intestine. Blood transketolase and TPP effect significantly decreased (P less than 0.01). Ruminal ammonia nitrogen and total volatile fatty acid (VFA) concentrations were not affected by the two diets. However, both butyric acid and isovaleric acid were significantly higher (P less than 0.001) in rumen fluid of sheep fed maize-silage. No significant differences were detected between diets for ruminal thiaminase activity regardless of the time of sampling. Relationships between butyric fermentation, thiaminase activity in maize-silage diet and a possible role of Clostridium are discussed. It was concluded that there is a marked thiamine deficiency in sheep fed maize-silage; the factors involved need further study.


Osteochondral distal metatarsal allograft reconstruction: a case series and surgical technique.
Painful degenerative diseases of the metatarsophalangeal joints (MTPJs) are frequently progressive and difficult to treat. Traditional operative treatments such as debridement, distal metatarsal osteotomies, and arthroplasty present a unique set of complications, and pain and deformity may still occur. Osteochondral distal metatarsal allograft reconstruction (ODMAR) is presented as a salvage procedure, reserved for patients with significant bone loss or avascular necrosis in whom traditional interventions have failed or are inadequate to address the underlying joint deformity. A retrospective review identified all ODMAR cases performed by the senior author over the past 10 years. Patient symptoms, satisfaction, and MTPJ range of motion were measured at each postoperative evaluation. Graft healing and subsequent degenerative changes at the MTPJ were observed at each visit with foot radiographs. The surgical techniques for both first and lesser metatarsal reconstructions are described. Six patients were identified with average follow-up interval of 36 months (range, 6-66). Preoperative diagnoses included infection (1), fracture (1), and avascular necrosis (4). Mean total arc of motion was 40 degrees (range, 30-50). All patients maintained viability of the allograft metatarsal head and joint space was normal or Kellgren-Lawrence grade 1 in 5 of 6 patients at final follow-up. All patients demonstrated osseous union of the metatarsal osteotomy site. No patients have undergone revision surgery to date. ODMAR is a safe and effective procedure for treatment of painful, degenerative conditions of the MTPJs. Further studies are required to determine the definitive indications and long-term outcomes for this procedure. Level IV, retrospective case series.


Studies on seasonal dynamics of soil-higher fungal communities in Mongolian oak-dominant Gwangneung forest in Korea.
We surveyed macrofungi biweekly at defined plots from April to December in 2014, in the Mongolian oak-dominant forest, Gwangneung Forest, Pochen-si, Korea, and analyzed a soilhigher fungal diversity during four seasons (represented by April, August, October, and December). Based on morphological observation of collected specimens, the collected macrofungi were classified into 2 phyla 3 classes 7 orders, 14 families, 21 genera, and 33 species (36 specimens). DNA-based community analyses indicated that soil-higher fungi were classified into 2 phyla, 18 classes, 49 orders, 101 families, and 155 genera (83,360 sequence reads), defined herein as 155 genus-level operational taxonomic units (GOTUs). In the present study, we evaluated and discussed the fungal diversity in seasonal dynamics and soil layers based on collected macrofungi and pyrosequencing data while considering environmental parameters (pH, exchangeable K, T-P, NH 4 (+) , NO 3 (-) , OM, WR, TOC, and T-N). Moreover, principal components analysis (PCA) showed distinct clusters of the GOTU assemblage associated with the seasons.


Disease-modifying anti-rheumatic drugs: strategies for screening.
Rheumatoid arthritis, a disease of unknown aetiology, has a multifactorial pathogenesis which may result in irreversible connective tissue destruction and loss of joint function. The search for drugs which offer more than symptomatic relief is a long term, largely unachieved aim of many pharmaceutical companies. This review briefly outlines those features of the aetiopathogenesis which appear to offer targets for therapeutic intervention and the structured strategy and test systems that can be used to detect drugs which may be capable of halting disease progression.


Essential oils of culinary herbs and spices activate PXR and induce CYP3A4 in human intestinal and hepatic in vitro models.
Essential oils (EOs) are extensively used in food industry, gastronomy and alternative medicine. They are multicomponent mixtures of bioactive compounds; hence, their potential for food-drug interactions is substantial. In this study, we investigated the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of pregnane X receptor (PXR) and expression of cytochrome P450 3A4 (CYP3A4), using human intestinal and hepatic in vitro models. All tested EOs activated PXR in intestinal LS180 cells transiently transfected with PXR, as revealed by a reporter gene assay. Consistently, all EOs induced CYP3A4 mRNA expression in PXR-transfected LS180 cells, primary human hepatocytes and wild-type hepatic progenitor HepaRG cells. EO-mediated induction of CYP3A4 mRNA expression was nullified in PXR-knock out HepaRG cells, suggesting the involvement of PXR in these effects. Collectively, we showed that EOs of culinary herbs and spices might be common activators of PXR and inducers of CYP3A4 at doses present in foods, thereby, they might have a potential for food-drug interactions. Follow-up studies are warranted to identify the bioactive constituents in the tested EOs.


[Iron deficiency and anemia in professional working women].
The hematological indices (Hb, Ht, MCHC) and iron status (serum iron, TIBC, LIBC, transferrin saturation), the prevalence of iron deficiency anemia in 224 women aged 31 to 47 years, working in textile industry in Lódź were examined. Nutritional status was evaluated as follow: body height and weight, body mass index (BMI kg/m2) and body fat content (%) calculated from the four skinfolds sum. Anemia (Hb < 12 g/dl) was stated in 11.2% participating women, evident iron deficiency (Fes < 60 micrograms/dl, Sat % < 16) in 13.4% of population. The positive correlation was found among hematological indices and body weight, body mass index and body fat content and relationships among iron status indices (Fes mu/dl, Sat%-positive correlation; TIBC microgram/dl, LIBC microgram/dl-negative relationship) and body fat content (%). The prevalence of iron deficiency and anemia were lower than in other women population in Poland examined in 1974-1986. The relationships among energy and protein nutrition and iron status and iron deficiency anemia suggest, that the menstruating overweight women or with obesity may be the group with lower risk of iron deficiency anemia.


[Clinical analysis of postoperative hyperbilirubinemia following resection of esophageal cancer].
Postoperative hyperbilirubinemia (Bil greater than or equal to 2, II greater than or equal to 15) was observed in 46.9% of 239 cases of esophageal cancer, since 1969. The incidence increased significantly from 31 to 55.9% after introducing total parenteral nutrition (TPN) for pre-postoperative nutritional support. In retrosternal reconstruction it was significantly higher (57.8%) than any other operative procedures. Further investigation was done in recent 128 cases since 1979. Postoperative hyperbilirubinemia was observed in 59%. The incidence was not different among operative procedures. It was significantly higher in esophagectomy than in total gastrectomy (28%) and in colectomy (12%). Lower nutritional states and longer operative time were predictive factors. Patients with higher bilirubin level (group A: greater than or equal to 3,5) had higher incidence of associated complications than patients with lower bilirubin level (group B: 3.5 greater than greater tha or equal to 2) and patients in control (group C: less than 2). Patients with hyperbilirubinemia alone as a postoperative complication were studied in group A and B. Bilirubin level in both groups reached maximum on 6-7th postoperative days (POD) as gamma GTP and ALP increased rapidly after 3rd-4th POD. The second elevation of GOT and GPT, and incidence of leukocytosis were marked in group A. Thus it was conceived that TPN, malnutrition, effects of extensive operation, postoperative cholestatic change, and infection might contribute to postoperative hyperbilirubinemia.


Tracing the Biotransformation of PCBs and PBDEs in Common Carp (Cyprinus carpio) Using Compound-Specific and Enantiomer-Specific Stable Carbon Isotope Analysis.
Compound-specific and enantiomer-specific carbon isotope composition was investigated in terms of biotransformation of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) as well as atropisomers of chiral PCB congeners in fish by exposing common carp (Cyprinus carpio) to certain PCB and PBDE congeners. The calculated carbon isotope enrichment factors (εC) for PCB 8, 18, and 45 were -1.99, -1.84, and -1.70‰, respectively, providing evidence of the metabolism of these congeners in fish. The stable carbon isotopic compositions of PBDE congeners clearly reflect the debromination of PBDEs in carp. Significant isotopic fractionation was also observed during the debromination process of BDE 153 (εC = -0.86‰). Stereoselective elimination of chiral PCB congeners 45, 91, and 95 was observed, indicating a stereoselective biotransformation process. The similar εC values for E1-PCB 45 (-1.63‰) and E2-PCB 45 (-1.74‰) indicated that both atropisomers were metabolized by the same reaction mechanisms and stereoselection did not occur at carbon bond cleavage. However, the εC values of (+)-PCB 91 (-1.5‰) and (-)-PCB 95 (-0.77‰) were significantly different from those of (-)-PCB 91 and (+)-PCB 95, respectively. In the latter, no significant isotopic fractionations were observed, indicating that the stereoselective elimination of PCB 91 and 95 could be caused by a different reaction mechanism in the two atropisomers.


Distribution of somatostatin mRNA in the rat nervous system as visualized by a novel non-radioactive in situ hybridization histochemistry procedure.
The cellular localization of preprosomatostatin mRNA in the rat brain and sensory ganglia has been examined in detail using a newly developed highly sensitive non-radioactive in situ hybridization histochemistry procedure. An alkaline phosphatase labelled anti-sense 30mer oligodeoxynucleotide probe was used for detection of somatostatin mRNA. This probe readily demonstrated somatostatin gene expression throughout the rat CNS with very high contrast and good cellular localization. As a result, we visualized numerous somatostatin mRNA-positive cells in many CNS areas which had previously not been shown to contain a mRNA signal. This method detected a number of somatostatin mRNA-positive cells, in the mitral cell layer of accessory olfactory bulb, the glomerular layer of the main olfactory bulb, the dorsal part of the lateral septum, superficial gray layer of superior colliculus, inferior colliculus, anterior ventral cochlear nucleus, granular layer and Purkinje cell layer of cerebellum, and substantia gelatinosa of medulla and spinal cord, all areas where signal detection using radiolabelled in situ probes has previously been rather difficult. The principle advantages of the present method include the very precise cellular resolution of signal, the rapid reaction time and low background. The sensitivity of the present method seems to be at least equivalent to most immunocytochemical procedures and more sensitive than most isotopic in situ hybridization methods.


Recovery of poliovirus from cut surface of stored fresh papaya fruit.
Poliovirus kept on the cut surfaces of fully ripe papaya cubes placed in an ice box showed a sharp and significant reduction in the recovery of infectious virus about 15 minutes after exposure. Thereafter, a very gradual decrease ensued and infectious residual virus was detected up to the end of the 6-hour exposure period. Papaya cubes washed or kept overnight before virus inoculation, and from less ripe fruits produced a similar survival pattern. A very small proportion of the inoculum was recovered from the mashed content of the inoculated papaya cubes thus suggesting that most of the non-recovered virus particles were inactivated. The results suggest that the importance of poliovirus-contaminated cut papayas as a transmission vehicle for the virus is greatly reduced by the rapid decline in the infectivity of a large proportion of the virus soon after contamination. Nevertheless, the potential to transmit remains as a small residual pool of infectious poliovirus is able to survive for a relatively long period.


A strategy combining flow sorting and comparative genomic hybridization for studying genetic aberrations at different stages of colorectal tumorigenesis in ulcerative colitis.
DNA aneuploidy has been shown to increase the risk of developing dysplasia in ulcerative colitis (UC) and is related to tumorigenesis in the colorectum. Therefore, it is of particular interest to study genetic aberrations behind DNA aneuploidization during colorectal carcinogenesis. We wanted to elucidate further the relationship between mucosal morphology and DNA aberrations in UC. DNA flow cytometry was applied to multiple lesions including regenerative, dysplastic, and carcinomatous mucosa from the colectomy specimen of a male patient with long-standing UC. The lesions harbored multiple DNA aneuploid stemlines that were subjected to flow sorting. We analyzed gene alterations by degenerate oligonucleotide primer (DOP; universal primers) polymerase chain reaction (PCR)-based comparative genomic hybridization (CGH) and fluorescent in situ hybridization (FISH) in diploid and aneuploid sorted cells. DOP-PCR-based CGH shows gains and losses that can be verified by FISH. We show that with this approach one can study genetic evolution of distinct DNA diploid and aberrant subpopulations through defined stages of colorectal tumorigenesis. This includes getting information related to tumor heterogeneity that cannot be obtained by CGH with DNA extracted from nonsorted cell populations. Genetic imbalance was also detected in diploid nondysplastic flow-sorted mucosal cells from the same bowel. Similar gains and losses were found in aneuploid dysplasias and carcinomas at widely separated locations in the same bowel, indicating a common selection pressure in different areas of the same bowel. The common aberrations may be of importance for progression from dysplasia to carcinoma.


Three-dimensional activation sequence of cesium-induced ventricular arrhythmias.
To investigate the electrophysiological and electrocardiographic characteristics of ventricular arrhythmia due to abnormal repolarization, we studied the three-dimensional activation sequence of cesium-induced ventricular tachycardia (VT) in 10 anesthetized dogs using a 384-channel recording system. Seventeen monomorphic VT (mVT) and eight polymorphic VT (pVT) episodes induced by cesium chloride (2 or 3 mM/kg) were analyzed. Only a single arrhythmogenic focus was detected in most beats of VT, whereas two competing foci were temporarily observed in two episodes of pVT. The site of arrhythmogenic focus of mVT was the endocardium (5 of 17), the midmyocardium (4 of 17), or undetermined (8 of 17). Both endocardial and midmyocardial arrhythmogenic foci were also found in pVT, and most pVT (6 of 8) were associated with the transition of the site of arrhythmogenic focus. These results are consistent with the view that both myocardial muscle fibers and Purkinje cells can cause ventricular arrhythmia due to abnormal repolarization and that changing the site of arrhythmogenic focus is the main mechanism of pVT.


Three-Dimensional Computerized Model Based on the Sonourethrogram: A Novel Technique to Evaluate Anterior Urethral Stricture.
The sonourethrogram is a useful alternative to the traditional retrograde urethrogram to evaluate anterior urethral strictures. With the development of 3-dimensional reconstructive techniques 3-dimensional urethral imaging can provide more accurate and useful information to enable the surgeon to make the best surgical decisions. We evaluated the accuracy and efficacy of a 3-dimensional reconstructed digital model of the urethra based on the sonourethrogram to assess anterior urethral disease. A total of 50 patients with an anterior urethral stricture and 10 healthy volunteers were enrolled in this study from April 2014 to January 2017. All patients and volunteers underwent sonourethrogram and retrograde urethrogram. Three-dimensional urethral models were reconstructed based on the sonourethrogram. Stricture length and location on retrograde urethrogram or sonourethrogram based images were compared with those found at operation. The 3-dimensional digital model revealed the entire anterior urethra, including the navicular fossa, and the penile and bulbar parts. The semitransparent model clearly demonstrated the structure of the corpus spongiosum and inside the urethral lumen. Further information on spongiofibrosis could also be seen in the 3-dimensional digital model. There was no significant difference in stricture length or location in the 3-dimensional model compared with retrograde urethrogram imaging and actual surgical findings. However, the latest technique could only reconstruct the short segment of the anterior urethra due to the probe width limitation. The 3-dimensional computerized model based on the sonourethrogram is a novel and effective technique of evaluating anterior urethral strictures.


Erythema elevatum diutinum.
A 53-year-old man with human-immunodeficiency-virus infection presents with a 2-year history of nodules on the extensor surfaces of his extremities. A biopsy confirmed the diagnosis of erythema elevatum diutinum. The clinical presentation, histopathology, etiology, and treatment options are reviewed.


3-Methoxalylchromone--a novel versatile reagent for the regioselective purine isostere synthesis.
The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminoheterocycles afforded a set of heteroannelated pyridines bearing a CO(2)Me substituent located at the α-position of the pyridine core.


Spontaneous disappearance of a normal adnexa associated with a contralateral polycystic-appearing ovary.
Absence of the adnexa may be congenital or acquired. However, the etiology is often uncertain. A 27-year-old woman presented with a 3-year history of subfertility. Her irregular menstruation was associated with acne vulgaris, alopecia, and elevated body mass index. Transvaginal ultrasonography of the pelvis showed a normal uterus, a normal right ovary, but a polycystic-appearing left ovary. A hysterosalpingogram demonstrated a normal uterine cavity, prompt filling and spilling of contrast material from the left fallopian tube, but no filling on the right. Subsequent laparoscopy showed an unexpected absence of right adnexa and presence of a solitary rounded free-floating mass enshrouded in the omentum. She did not have a history of abdominal pain or surgery. The evidence suggests that the patient might have had an asymptomatic infarction of the right adnexa.


Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP.
The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. In the presence of antibodies to either the ULBPs or their receptor NKG2D on NK cells, GPI-expressing cells were as less NK sensitive as GPI-deficient cells. NK cells therefore spared ULBP-deficient cells in vitro. The ULBPs were identified only on GPI-expressing blood cells of a proportion of patients with PNH but none of healthy individuals. Granulocytes of the patients partly underwent killing by autologous cytotoxic cells, implying ULBP-associated blood cell injury. In this setting, the lack of ULBPs may allow immunoselection of PNH clones.


Surface EMG power spectrum and intramuscular pH in human vastus lateralis muscle during dynamic exercise.
The relationship between intramuscular pH and the frequency components of the surface electromyographic (EMG) power spectrum from the vastus lateralis muscle was studied in eight healthy male subjects during brief dynamic exercise. The studies were carried out in placebo control and metabolic alkalosis induced by oral administration of NaHCO3. At the onset of exercise, blood pH was 0.08 units higher in alkalosis compared with placebo. Muscle lactate accumulation during exercise was higher in alkalosis (32 +/- 5 mmol/kg wet wt) than in placebo (17 +/- 4 mmol/kg wet wt), but no difference in intramuscular pH was found between the two conditions. The EMG power spectrum was shifted toward lower frequencies during fatigue in the control condition (10.1 +/- 0.9%), and these spectral shifts, evaluated from changes in the mean power frequency (MPF) of the EMG power spectrum, were further accentuated in alkalosis (19 +/- 2%). Although the changes in frequency components of EMG correlated with muscle lactate accumulation (r = 0.68, P less than 0.01), no direct relationship with muscle pH was observed. We conclude that alkalosis results in a greater reduction in MPF associated with a higher muscle lactate accumulation. However, the good correlation observed between the two variables is not likely causative, and a dissociation between intramuscular pH and the increase in the low-frequency content of EMG power spectrum appears during muscle fatigue.


Safety and efficacy of video-assisted retroperitoneal debridement for infected pancreatic collections: a multicenter, prospective, single-arm phase 2 study.
The feasibility of video-assisted retroperitoneal debridement (VARD) for infected pancreatic walled-off necrosis is established. We provide prospective data on the safety and efficacy of VARD. Multicenter, prospective, single-arm phase 2 study. Six academic medical centers. We evaluated 40 patients with pancreatic necrosis who had infection determined using Gram stain or culture. Percutaneous drains were placed at enrollment, and computed tomographic scans were repeated at 10 days. Patients who had more than a 75% reduction in collection size were treated with drains. Other patients were treated with VARD. Crossover to open surgery was performed for technical reasons and/or according to surgeon judgment. Efficacy (ie, successful VARD treatment without crossover to open surgery or death) and safety (based on mortality and complication rates). Patients received follow-up care for 6 months. We enrolled 40 patients (24 men and 16 women) during a 51-month period. Median age was 53 years (range, 32-82 years). Mean (SD) Acute Physiology and Chronic Health Evaluation II score at enrollment was 8.0 (5.1), and median computed tomography severity index score was 8. Of the 40 patients, 24 (60%) were treated with minimally invasive intervention (drains with or without VARD). Nine patients (23%) did not require surgery (drains only). For 31 surgical patients, VARD was possible in 60% of patients. Most patients (81%) required 1 operation. In-hospital 30-day mortality was 2.5% (intent-to-treat). Bleeding complications occurred in 7.5% of patients; enteric fistulas occurred in 17.5%. This prospective cohort study supports the safety and efficacy of VARD for infected pancreatic walled-off necrosis. Of the patients, 85% were eligible for a minimally invasive approach. We were able to use VARD in 60% of surgical patients. The low mortality and complication rates compare favorably with open debridement. An unexpected finding was that a reduction in collection size of 75% according to the results of computed tomographic scans at 10 to 14 days predicted the success of percutaneous drainage alone.


[Postoperative pseudosarcomas of the genitourinary tract. A diagnostic trap. Presentation of 4 cases of which 2 were studied immunohistochemically and review of the literature].
Four cases of postoperative pseudosarcomatous nodules of the genitourinary tract are reported. Two occurred in the vagina of 38 and 57 year-old women, 1 and 3 months after vaginal hysterectomy. The third one occurred in the bladder of a 60-year-old man, 1 and 1/2 months after prostatic adenomectomy. The fourth one occurred in the bladder of a 60-year-old woman, 2 months after transurethral cystoscopy with biopsies. On microscopic examination, the lesions were cellular spindle cell proliferations with numerous mitoses and minimal or no cytonuclear atypia. They mimicked sarcoma, with an overall appearance suggestive of leiomyosarcoma. Immunohistochemical studies performed on 2 cases showed strong reactivity of the cells with vimentin. Cytokeratins, desmin, smooth muscle myosin, smooth and striated muscle actins and factor VIII were negative. Despite simple, sometimes partial, local excision of the nodules, there was neither recurrence nor metastasis 8 months to 5 years later.


Endovascular microcatheter provocation test for the diagnosis of glossopharyngeal neuralgia.
Glossopharyngeal neuralgia (GN) is a rare disease often clinically misdiagnosed as trigeminal neuralgia. An endovascular provocative test has been applied to assist in making the diagnosis of GN caused by vascular compression. We similarly used endovascular provocative techniques to identify the causative vessel and to evaluate the indication for microvascular decompression (MVD) in two patients. Two patients had severe retroauricular and pharyngeal pain that could not be controlled by medical therapy. Magnetic resonance imaging and magnetic resonance angiography showed a high-riding right posterior inferior cerebellar artery (PICA). We decided to apply the endovascular provocation test to prove the assumed GN and identify potential indications for MVD. A loop of the PICA appeared to compress the glossopharyngeal nerve in the first patient. In this patient, a microcatheter was inserted into the right PICA, decreasing the GN. The patient underwent MVD, resulting in complete pain relief. In the second patient, a microcatheter was inserted into the right PICA, and an attack of typical GN occurred, with pain in the posterior region of the tongue, tonsils, oropharynx, and larynx. The patient's severe pain was clearly different from this typical GN caused by the microcatheter provocation test, and MVD was not performed. The diagnosis of GN is sometimes complex. The endovascular provocative technique may allow identification of GN caused by vascular compression.


Validated LC-MS-MS method for the determination of quetiapine in human plasma: application to a pharmacokinetic study.
A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the determination of quetiapine was developed and validated over the linearity range 1-1500 ng/mL with 0.1 mL of plasma using clozapine as the internal standard. Detection was performed on a triple-quadrupole tandem mass spectrometer using positive electrospray ionization and quantification was performed by selected reaction monitoring mode. The MS-MS ion transitions monitored were m/z 384.1 → 253.1 and 327.0 → 270.0 for quetiapine and clozapine, respectively. The between- and within-run precision was less than 7.44% and accuracy was less than 10.2%. The lower limit of quantification was 1 ng/mL. The extraction recoveries of quetiapine were over 90%. The method is proved to be accurate and specific, and was applied to the pharmacokinetic study in healthy Chinese volunteers.


Vitamin D Deficiency, Supplementation, and Cardiovascular Health.
Vitamin D has been traditionally recognized as a vitamin quintessential for bone-mineral health. In the past 2 decades, numerous experimental and observational studies have highlighted the role of vitamin D in immunity, metabolic syndrome (obesity and diabetes), cancers, renal disease, memory, and neurological dysfunction. In this article, we review important studies that focused on the impact of vitamin D on blood pressure, myocardial infarction, peripheral arterial disease, heart failure, and statin intolerance. Amidst the current pool of ambiguous evidence, we intend to discuss the role of vitamin D in "high-value cardiovascular health care".


G protein-coupled receptor kinase 2 involvement in desensitization of corticotropin-releasing factor (CRF) receptor type 1 by CRF in murine corticotrophs.
Hypothalamic CRF stimulates synthesis and secretion of ACTH via CRF receptor type 1 (CRFR1) in the anterior pituitary gland. After agonist-activated stimulation of receptor signaling, CRFR1 is down-regulated and desensitized. Generally, it is thought that G protein-coupled receptors may be desensitized by G protein-coupled receptor kinases (GRKs). However, the role of GRKs in corticotropic cells has not been determined. In this study we focused on involvement of GRKs in desensitization of CRFR1 by CRF in corticotropic cells. We found that GRK2 (but not GRK3) mRNA and protein were expressed in rat anterior pituitary cells and AtT-20 cells (a line of mouse corticotroph tumor cells). To determine the role of GRK2 in CRF-induced desensitization of CRFR1 in mouse corticotrophs, AtT-20 cells were transfected with a dominant-negative mutant GRK2 construct. CRF desensitized the cAMP-dependent response by CRFR1. Desensitization of CRFR1 by CRF was significantly less in AtT-20 cells transfected with the dominant-negative mutant GRK2 construct compared with desensitization in control (an empty vector-transfected) AtT-20 cells. Furthermore, pretreatment with a protein kinase A inhibitor also partially blocked desensitization of CRFR1 by CRF. These results suggest that GRK2 is involved in CRF-induced desensitization of CRFR1 in AtT-20 cells, and the protein kinase A pathway may also have an important role in desensitization of CRFR1 by CRF seen in corticotropic cells.


Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes.
A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes. Physically active, young adults (men and women) with type 1 diabetes (HbA1c 63.0 ± 16.0 mmol/mol [7.9% ± 1.5%]) and without type 1 diabetes (control), matched for sex, age, BMI and level of physical activity, were recruited (n = 12/group) to undergo vastus lateralis muscle microbiopsies. Mitochondrial respiration (high-resolution respirometry), site-specific mitochondrial H2O2 emission and Ca2+ retention capacity (CRC) (spectrofluorometry) were assessed using permeabilised myofibre bundles. Electron microscopy and tomography were used to quantify mitochondrial content and investigate muscle ultrastructure. Skeletal muscle microvasculature was assessed by immunofluorescence. Mitochondrial oxidative capacity was significantly lower in participants with type 1 diabetes vs the control group, specifically at Complex II of the electron transport chain, without differences in mitochondrial content between groups. Muscles of those with type 1 diabetes also exhibited increased mitochondrial H2O2 emission at Complex III and decreased CRC relative to control individuals. Electron tomography revealed an increase in the size and number of autophagic remnants in the muscles of participants with type 1 diabetes. Despite this, levels of the autophagic regulatory protein, phosphorylated AMP-activated protein kinase (p-AMPKαThr172), and its downstream targets, phosphorylated Unc-51 like autophagy activating kinase 1 (p-ULK1Ser555) and p62, was similar between groups. In addition, no differences in muscle capillary density or platelet aggregation were observed between the groups. Alterations in mitochondrial ultrastructure and bioenergetics are evident within the skeletal muscle of active young adults with type 1 diabetes. It is yet to be elucidated whether more rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.


Studying the performance of a job exposure matrix.
During the last decade, the use of job exposure matrices (JEM) in occupational studies has grown but uncertainty remains among epidemiologists and industrial hygienists regarding this methodology and appropriate methodological tools are needed to study the performance of JEM. It must first be emphasized that a true validation can rarely be achieved and that the performance of a JEM must be tested against the exposure evaluation of another method taken as a reference, such as expert assessment. This comparison comprises three main elements: the ability of the JEM to evaluate accurately the exposure itself, its statistical performances in terms of bias and power and its ability to detect known associations between risk factors and disease. When comparing JEM and experts, all aspects of the two methods have to be looked at and a balance struck between the advantages and shortcomings of each of them. The problem should not be reduced to a trade-off between the precision provided by experts and the cost savings possible by using JEM. Finally, it is important to avoid a systematic opposition between JEM and expert assessments, as one positive result of their comparison may be the improvement of both methods of exposure evaluation.


Attitude of women towards family planning methods and its use--study from a slum of Delhi.
To predict the need of family planning methods, family planning managers often rely on unmet need derived from measure of contraceptive demand. However women's intention and her background knowledge of family planning methods not received as much attention as a measure of family planning methods demand. To know the attitude of women regarding use of family planning methods and to find out the factors that restricts its use, and the change in pattern of use over a period of one year. This was a prospective study. One (Block G) out of eight blocks was selected randomly. Using convenient sample method, families were selected starting from a point in the selected block (Block G). 40 women of childbearing age group (15- 49 years) were enrolled. All women were followed for a period of one year. Weakness was narrated as the commonest side effect from all family planning methods. More than 70% women told that irregular menstruation from Oral Contraceptive pills and ill health from tubectomy as the other side effects. Demands for more children and for son preferences were the leading reason for not using any methods followed by afraid of side effects and health problems. There was negligible change in the use of family planning methods during the period of the study. Effective family planning methods use should be advocated through adequate counseling about the correct use, side effects and their proper management and their benefit in the back ground of custom and belief.


Platelet aggregation inhibitors for use in peripheral vascular interventions: what can we learn from the experience in the coronary arteries?
During the last decade, an enormous amount of information has been gathered about the function of the platelet and its impact on percutaneous vascular interventions. With the discovery of the GP IIb/IIIa receptor, which is responsible for platelet aggregation, new drug antagonists have been developed to prevent platelet aggregation that may result in arterial thrombosis or platelet microembolization. These drugs include the three GP IIb/IIIa receptor antagonists approved by the Food and Drug Administration: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These drugs have been used in several large studies to improve the outcome of coronary interventions and in conjunction with plasminogen activators to accelerate thrombolysis. In addition, because no oral GP IIb/IIIa inhibitor exists, other oral regimens have been developed with use of the thienopyridines, ticlopidine (Ticlid) and clopidogrel (Plavix), in combination with aspirin to prevent platelet aggregation and thrombosis. Because the majority of investigations have been performed in patients undergoing coronary interventions, knowledge of these data is necessary to attempt to translate the use of these antiplatelet drugs to peripheral vascular interventions. The goal of this article is to review the use of these agents in the percutaneous treatment of coronary artery disease and give insight to their potential utility in noncoronary interventions.


Aberrant expression of leukemia inhibitory factor receptor (LIFR) and leukemia inhibitory factor (LIF) is associated with tubal pregnancy occurrence.
Tubal pregnancy is a major cause of maternal death in the first trimester and exploration of its underlying molecular mechanism is of great importance. This study aimed to explore the association of tubal pregnancy with leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) expression in oviduct tissues. Immunohistochemistry was performed to probe the differential expression of LIF and LIFR in oviduct tissues among a control group (including NP group, n = 11; and IP group, n = 12), tubal pregnancy group (Ect-N group, n = 31; and Ect-A group, n = 40), and chronically inflamed group (including Inf-S group, n = 11; and Inf-P group, n = 9), followed by semiquantitative analysis. Semiquantitative immunohistochemical analysis demonstrated that there was no significant difference in LIF expression in either the epithelial or stromal cells of oviduct tissues between the tubal pregnancy group and the control group (P < 0.05). However, LIF expression was remarkably elevated in the Inf-S and Inf-P group compared to the other groups (P < 0.05). In the epithelial cells of the fallopian tubes, LIFR expression was highest in the chronically inflamed group, followed by the tubal pregnancy group, outnumbering the control group (P < 0.05). More interestingly, an opposite expression trend of LIFR was observed in the stromal cells of the fallopian tubes among these groups (P <0.05). Aberratn expression of LIF and LIFR might be associated with the occurrence of tubal pregnancy.


In vivo testing of an Enterococcus faecalis efaA mutant and use of efaA homologs for species identification.
Disruption of the previously described efaA (from Enterococcus faecalis antigen A) gene was generated in E. faecalis strain OG1RF and loss of an 37-kDa immunoreactive band from the mutant was demonstrated in Western blots. In a mouse peritonitis model, mice infected with the efaAfs (fs=from Enterococcus faecalis) mutant showed more prolonged survival than mice infected with the parent strain OG1RF. These results suggest that efaAfs encodes a function important for infection of mice by enterococci. An efaA-like gene was also identified in E. faecium DNA libraries and its deduced amino acid sequence showed 73% similarity to EfaA of E. faecalis and 42-63% similarities to a group of streptococcal virulence and adhesion associated proteins that are components of ATP-binding cassette transport systems. Intragenic probes representing efaAfs, recAfs, efaAfm (fm=from E. faecium) and gyrAfm were tested for their ability to identify E. faecalis and E. faecium using colony lysates of 133 enterococci and one Streptococcus sp. Probes of E. faecium and E. faecalis origin hybridized to all isolates of E. faecium and E. faecalis, respectively, regardless of their clinical source but not to any of 29 other enterococci. These results suggest that the use of gene probes may prove helpful in identification of isolates of E. faecium and E. faecalis.


Backward chromosome movement in crane-fly spermatocytes after UV microbeam irradiation of the interzone and a kinetochore.
Single anaphase chromosomes (in crane-fly spermatocytes) moved backwards after double irradiations with an ultraviolet light (UV) microbeam, first of the interzone and then of a kinetochore: the chromosome irradiated at the kinetochore moved backwards rapidly, across the equator and into the other half-spindle. High irradiation doses at the kinetochore were required to induce backward movement. Single irradiations of kinetochores or interzones were ineffective in inducing backward movements.


Photosynthetic characteristics of a multicellular green alga Volvox carteri in response to external CO2 levels possibly regulated by CCM1/CIA5 ortholog.
When CO(2) supply is limited, aquatic photosynthetic organisms induce a CO(2)-concentrating mechanism (CCM) and acclimate to the CO(2)-limiting environment. Although the CCM is well studied in unicellular green algae such as Chlamydomonas reinhardtii, physiological aspects of the CCM and its associated genes in multicellular algae are poorly understood. In this study, by measuring photosynthetic affinity for CO(2), we present physiological data in support of a CCM in a multicellular green alga, Volvox carteri. The low-CO(2)-grown Volvox cells showed much higher affinity for inorganic carbon compared with high-CO(2)-grown cells. Addition of ethoxyzolamide, a membrane-permeable carbonic anhydrase inhibitor, to the culture remarkably reduced the photosynthetic affinity of low-CO(2) grown Volvox cells, indicating that an intracellular carbonic anhydrase contributed to the Volvox CCM. We also isolated a gene encoding a protein orthologous to CCM1/CIA5, a master regulator of the CCM in Chlamydomonas, from Volvox carteri. Volvox CCM1 encoded a protein with 701 amino acid residues showing 51.1% sequence identity with Chlamydomonas CCM1. Comparison of Volvox and Chlamydomonas CCM1 revealed a highly conserved N-terminal region containing zinc-binding amino acid residues, putative nuclear localization and export signals, and a C-terminal region containing a putative LXXLL protein-protein interaction motif. Based on these results, we discuss the physiological and genetic aspects of the CCM in Chlamydomonas and Volvox.


Changes over time in attitudes towards the management of older patients with heart failure by general practitioners: a qualitative study.
Underdiagnosis and undertreatment of chronic heart failure (CHF) are common in older patients, who are usually treated by general practitioners (GPs). In 2007, the French ICAGE study explored GPs' attitudes to the management of this condition in older patients. To explore changes over time in GPs' attitudes towards the management of CHF in patients aged ≥75 and to identify barriers to optimal management. In 2015, we performed a qualitative study of 20 French GPs via semi-structured interviews and a thematic content analysis. The results were compared with the findings of a 2007 study. In 2015, the perceived barriers to diagnosis were the same as in 2007. Echocardiography was still the preferred diagnostic method but the GPs relied on the cardiologist to confirm the diagnosis. Many GPs were still unaware of the different types of CHF. In contrast, they reported greater knowledge of decompensation factors and the ultrasound criteria for CHF. They also prescribed a brain natriuretic peptide assay more frequently. Angiotensin-converting enzyme inhibitors and beta blockers were more strongly perceived to be core treatments. Few GPs initiated drug treatments and optimized dosages. Although patient education was never mentioned, the importance of multidisciplinary care was emphasized. Our results evidenced a small recent improvement in the management of older patients with CHF. Appropriate guidelines and training for GPs, patient education and multidisciplinary collaboration might further improve the care given to this population.


What is the impact of endoscopic vein harvesting on clinical outcomes following coronary artery bypass graft surgery?
Objective Endoscopic vein harvesting (EVH) is increasingly used as an alternative to open vein harvesting (OVH) for coronary artery bypass graft (CABG) surgery. Concerns about the safety of EVH with regard to midterm clinical outcomes following CABG have been raised. The objective of this study was to assess the impact of EVH on short-term and midterm clinical outcomes following CABG. Design This was a retrospective analysis of prospectively collected multi-centre data. A propensity score was developed for EVH and used to match patients who underwent EVH to those who underwent OVH. Setting Blackpool Victoria Hospital, Plymouth Derriford Hospital and the University Hospital of South Manchester were the main study settings. Patients There were 4709 consecutive patients who underwent isolated CABG using EVH or OVH between January 2008 and July 2010. Main outcome measures The main outcome measure was a combined end point of death, repeat revascularisation or myocardial infarction. Secondary outcome measures included in-hospital morbidity, in-hospital mortality and midterm mortality. Results Compared to OVH, EVH was not associated with an increased risk of the main outcome measure at a median follow-up of 22 months (HR 1.15; 95% CI 0.76 to 1.74). EVH was also not associated with an increased risk of in-hospital morbidity, in-hospital mortality (0.9% vs 1.1%, p=0.71) or midterm mortality (HR 1.04; 95% CI 0.65 to 1.66). Conclusions This multi-centre study demonstrates that at a median follow-up of 22 months, EVH was not associated with adverse short-term or midterm clinical outcomes. However, before the safety of EVH can be clearly determined, further analyses of long-term clinical outcomes are required.


Mountain Biking: Does Rough Terrain Make Rugged Riders?
All-terrain bikes are gaining ground on their streamlined counterparts, the enormously popular road bikes. But does the fact that they can handle rougher countryside increase their riders' fitness benefits or their injury risks?


Microglial cell responses to fetal ventral mesencephalic tissue grafting and to active and adoptive immunizations.
Microglia express cytokines, major histocompatibility (MHC) loci, and several other immunologically important constituents. The aim of this study was to detect immunological responses of microglial cells following allogeneic dopaminergic transplantation using active and adoptive immunizations. Adult inbred Fisher 344 (F344 RT1) rats were unilaterally dopamine (DA) depleted in striatum by injection of 6-hydroxydopamine. The degree of degeneration was assessed by recording the rotational response to apomorphine. Fetal ventral mesencephalic tissue containing DA neuroblasts from Wistar-Furth (WF, RT1u) rat donors (9-12 mm CRL) were later implanted in striatum on the lesioned side. Lymph nodes and spleen cells were collected aseptically, resuspended, and diluted for isovolumetric injections. Animals selected for active immunization were injected intraperitoneally with varying amounts of WF lymphocytes. Animals selected for adoptive immunization (transferred immunity) were intraperitoneally injected with 10(8) F344 lymphocytes prepared from animals actively immunized 3 weeks previously. Monoclonal antibodies against CD4 (OX38), CD8 (OX8), CD11b (OX42), MHC class I (OX18), monomorphic MHC class II (OX-6), and ED1 and polyclonal antibodies against tyrosine hydroxylase (TH) were used for immunohistochemistry. We found that the degree of ED1-positive cell proliferation was well correlated to the immunization patterns. Groups that were actively immunized with or without prior adoptive immunization had a larger amount of reactive microglial proliferation. ED1 immunohistochemistry revealed patterns of immunolabeling of engrafted areas: 8-12 weeks after grafting in nonimmunized and adoptively immunized groups reactive microglial proliferation occurred only at the graft periphery. Active and adoptive + active immunization led to ED1-IR within the grafts themselves. At early stages nonimmunized groups had an ED1 pattern which was partially inside the grafts. At early time points nonimmunized groups contained ameboid microglial cells within the grafts which disappeared at later stages and were absent in the immunized groups. ED1-positive ameboid microglial cells within the grafts may be of graft origin and constitute a part of a continued normal development of the fetal tissue.


Determination of the spectral-dependent refractive index of a single layer in a natural multilayer system: comparison of different approaches.
By means of heuristic optimization techniques, we estimate the unknown refractive index of one layer of a periodic natural multilayer system from far-field reflectance data. To take into account the dispersive characteristics of the material, we employ two different strategies. The first is based on the retrieval of Lorentz model-related parameters, to describe the unknown dielectric permittivity within a specific spectral range. The second strategy, based on a wavelength-by-wavelength approach, takes into account the reflectance values for each wavelength at a time. Through some examples, we compare the performance of both strategies when they look for the best estimates and analyze the error involved in each case. The applicability of both approaches to the case of noisy reflectance spectra is also explored.


Long-term survival after radical resection of advanced pancreatic cancer: a case report with special reference to CD8+ T-cell infiltration.
A 65-yr-old man who underwent pancreaticoduodenectomy with portal vein resection for pancreatic cancer is alive 8 yr after surgery. Originally, computed tomography (CT) revealed an 8-cm tumor in the pancreatic head. The tumor had infiltrated the portal vein, but grew expansively, so there was neither biliary obstruction nor jaundice. Pancreaticoduodenectomy with resection of the portal vein was performed for pancreatic cancer. Many tumor-infiltrating lymphocytes were seen within cancer cell nests on routine histopathology. We performed immunostaining for CD8, and found that a large number of the lymphocytes were CD8+ T cells. The patient's prognosis was considered poor because the tumor was large and had infiltrated the portal vein. We suspect that long-term survival may be related to the response of CD8+ T cells to the cancer.


Characteristics of aggregation in aqueous solutions of dialkylpyrrolidinium bromides.
Three pyrrolidinium-based ionic liquids-N-dodecyl-N-methylpyrrolidinium bromide, N-butyl-N-octylpyrrolidinium bromide, and N-butyl-N-dodecylpyrrolodinium bromide-were synthesized and characterized by their decomposition temperatures (T(d)) measured by thermogravimetric analysis, and by their melting point (T(m)), glass transition (T(g)) and crystallization temperatures (T(cryst)) determined by differential scanning calorimetry. Their self-aggregation properties in aqueous solution were studied and their behavior is compared with that of analogous conventional cationic surfactants, namely tetra-alkylammonium bromide salts. The critical micellar concentration, cmcs were obtained by isothermal titration calorimetry (ITC); which were further validated by measurements of interfacial tension, fluorescence and NMR spectroscopy. Enthalpies of micellization were measured at three different temperatures using ITC. The Taylor dispersion method and DOSY NMR were used to determine diffusion coefficients of the ionic liquid surfactants in aqueous solution at 298.15K. Several correlations between structural features of the surfactant species, such as the number and size of their alkyl chains, and the thermodynamic quantities of micellization-expressed by experimental values of cmc, counter-ion binding fraction, Δ(mic)G°, Δ(mic)°, and Δ(mic)S°-are established. We could interpret the different contributions of the two alkyl side chains to the aggregation properties in terms of the balance of interactions in homogeneous and micellar phases, contributing to understanding the aggregation behavior of ionic liquids in water and the parallel between these systems and traditional ionic surfactants.


On-line ultrasonic velocity monitoring of alcoholic fermentation kinetics.
In this work, fundamental aspects on the ultrasonic velocity monitoring of alcoholic fermentations in synthetic broths (glucose, fructose and sucrose) and natural media (must and wort) are reported. Results are explained in terms of monosaccharide catabolism, polysaccharide hydrolysis, gas production and microorganism growth. The effect of each one of these subprocesses upon ultrasonic velocity has been independently studied. It is shown that, regarding the sound propagation, the simplest systems behave as ternary dissolutions of sugar and ethanol in water, where, in the course of time, substrates are transformed into metabolites according to the fermentation reaction. A semi-empirical approach, based on the excess volume concept and the density and velocity measurements of binary mixtures, has been used to calculate these magnitudes in the ternary mixtures and to obtain the concentrations of the main solutes throughout the fermentations, reaching a good correlation (especially for the media of simplest composition). In all the processes analyzed, the data obtained from the ultrasonic measurements followed the changes caused by the yeast metabolism, asserting the potential of mechanical waves to monitor fermentations and, in general, biotechnological processes.


Absence of gut microbiota affects lipid metabolism in the prefrontal cortex of mice.
Objectives: Lipid metabolism is closely associated with many important biological functions. Here, we conducted this study to explore the effects of gut microbiota on the lipid metabolism in the prefrontal cortex of mice. Methods: Germ-free (GF) mice, specific pathogen-free (SPF) and colonized GF (CGF) mice were used in this study. The open field test (OFT), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were conducted to assess the changes in general behavioral activity. The liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was used to obtain the lipid metabolites. Both one-way analysis of variance (one-way ANOVA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to obtain the key differential lipid metabolites. Results: The behavioral tests showed that compared to SPF mice, GF mice had more center distance, more center time, less immobility time and less latency to familiar food. Meanwhile, 142 key differential lipid metabolites between SPF mice and GF mice were identified. These lipid metabolites mainly belonged to glycerophospholipids, glycerolipids, sphingolipids, and saccharolipids. The gut microbiota colonization did not reverse these changed behavioral phenotypes, but could restore 25 key differential lipid metabolites. Discussion: These results showed that the absence of gut microbiota could influence host behaviors and lipid metabolism. Our findings could provide original and valuable data for future studies to further investigate the microbiota-gut-brain axis.


Glassy cell carcinoma of the endometrium.
A case of glassy cell carcinoma of the endometrium in a 62-year-old woman is reported. Microscopically, a cytoplasm of ground-glass appearance was observed with a distinct cell wall and large nuclei containing prominent nucleoli. These histologic characteristics are consistent with those of glassy cell carcinoma of the cervix. Treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic lymph node dissection followed by external irradiation to the whole pelvis. The patient was alive without evidence of disease at 5 1/2 years.


Laryngeal carcinoma: transoral treatment utilizing the CO2 laser.
The CO2 laser has been found to be a useful adjunct in our efforts to treat laryngeal carcinoma. Utilized endoscopically, it has been of help in establishing the proper staging, in diagnosing recurrence after radiation therapy, in reestablishing airways blocked with tumor, in debulking tumor mass prior to radiation and/or chemotherapy, and as a primary mode of excisional therapy, all accomplished with minimal morbidity. Most patients may return home the first postoperative day, eating, with serviceable voice, and requiring no tracheotomy or analgesics, all of which provide a significant cost benefit.


[Chemical constituents of Lysimachia paridiformis].
To study the chemical constituents from Lysimachia paridiformis. The column chromatographic techniques were applied to isolate the chemical constituents of Lysimachia paridiformis. EI-MS and NMR were used to identify the structures. Seven compounds were isolated and identified from the extract of L. paridiformis, and their structures were elucidated as stigmasterol (1), oleanolic aicd (2), beta-amyrin (3), quercetin (4), luteolin (5), quercetin-3-O-beta-D-galactoside (6) and beta-daucosterol (7). Compound 1 -7 are isolated from this plant for the first time.


Biomolecular index of therapeutic efficacy in psoriasis treated with anti-TNF-α agents.
Clinical or quality of life assessments are currently available for psoriasis severity evaluation and therapeutic response. Laboratory scores focused to measure and follow treatment efficacy are lacking at present. A microscopic and biomolecular score was designed to monitor skin disease severity and clinical response to anti-psoriatic treatments. A susceptibility gene analysis on cellular retinoic acid binding protein-II (CRABP-II), acting on keratinocyte differentiation, was also performed. A Molecular Index of Therapeutic Efficacy (MITE) was defined by assembling morphometric/semiquantitative measurement of epidermal thickness, immunohistochemical Ki-67, keratin 17 and CRABP-II expression of lesional and non-lesional psoriatic skin biopsies before and after anti-tumor necrosis factor (TNF) α therapies. A 0-12 MITE score was correlated with Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI) scores and inflammation. Three CRABP-II SNPs were analyzed by TaqMan assay. All parameters were highly expressed in psoriatic lesions and reduced after 12 weeks of anti-TNF-α treatments. MITE score strongly correlated with PASI and PDI values either before or after therapies (P<0.001 and P<0.001, respectively). Conversely, MITE values did not change after treatments of non-responder patients. CRABP-II did not result in a psoriatic susceptibility gene for the SNPs probes analyzed. MITE score variations corresponded to the patients' clinical improvement following anti-TNF-α treatments, with significant statistical correlation among MITE, PASI and PDI scores. If confirmed in a larger series and/or in different hyperproliferative and inflammatory dermatoses, MITE score could be proposed as additional monitoring system to evaluate treatment protocols in skin disorders and targeted biomolecular pathways supporting clinical efficacy.


Macrocyclic inhibitors of beta-secretase: functional activity in an animal model.
A macrocyclic inhibitor of beta-secretase was designed by covalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency and physical properties when compared to the initial lead structures. More importantly, these macrocyclic inhibitors also displayed in vivo amyloid lowering when dosed in a murine model.


Mainstream Experiences for Learning Disabled students (Project MELD): preliminary report.
Mainstream Experiences for the Learning Disabled (MELD) was developed to accommodate students with learning disabilities in the mainstream. This article reports the progress of 13 students at the end of 1 year of planning and 1 year of implementing the MELD model in one urban elementary school. Observational and school adjustment data from the implementation year suggest that although the MELD model was not fully incorporated into the mainstream classes, students with learning disabilities adjusted well to a less individualized and more demanding mainstream program. They came to school regularly, did not present serious behavior problems, and spent as much of reading class and more of math class on task as they had in special education. These students in the mainstream were assigned more opportunities to work with text materials rather than workbooks in reading and spent significantly more reading time in teacher-directed lessions. Nevertheless, the students made no significant progress in reading or math and earned lower grades during the implementation year. The authors suggest that students with learning disabilities will not succeed in the mainstream if teachers continue "business as usual" in mainstream classes.


Interaction of a novel GDP exchange inhibitor with the Ras protein.
Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit tumorigenic Ras function may be useful in the treatment of Ras-related tumors. The interaction of a novel GDP exchange inhibitor (SCH-54292) with the Ras-GDP protein was studied by NMR spectroscopy. The binding of the inhibitor to the Ras protein was enhanced at low Mg2+ concentrations, which enabled the preparation of a stable complex for NMR study. To understand the enhanced inhibitor binding and the increased GDP dissociation rates of the Ras protein, the conformational changes of the Ras protein at low Mg2+ concentrations was investigated using two-dimensional 1H-15N HSQC experiments. The Ras protein existed in two conformations in slow exchange on the NMR time scale under such conditions. The conformational changes mainly occurred in the GDP binding pocket, in the switch I and the switch II regions, and were reversible. The Ras protein resumed its regular conformation after an excess amount of Mg2+ was added. A model of the inhibitor in complex with the Ras-GDP protein was derived from intra- and intermolecular NOE distance constraints, and revealed that the inhibitor bound to the critical switch II region of the Ras protein.


[Practice guidelines--legal aspects].
Medical guidelines of professional institutions establish rules for good medical treatment (quality of care). They take the form of international, national, regional and local guidelines and are set up by international and national medical organisations, mainly by medical societies but also by regional (e.g. medical associations in the states) and local institutions (up to hospital departments). The rules of good medical treatment (guidelines) conform to the corresponding medical standard which is defined by scientific knowledge (evidence based medicine), practical experience and professional acceptance. The binding character of the standard for medical practice increases with the reliability of scientific evidence and practical experience. Insofar, medical guidelines which correspond to the standard fulfil a quality assurance function for medical treatment as a means of communication in the medical profession, an implementation function for the enforcement of standards and thus also a protective function for patients. Furthermore, they rationalize decisions of the courts by increasing the transparency of their medical basis and thus also contribute to the quality improvement of legal decisions on medical malpractice. Medical guidelines can also influence social law directives. On principle. Medical guidelines do not include any economic considerations (efficiency) and should be strictly separated from these (principle of separation and transparency). Medical guidelines have to be differentiated from health insurance law directives and recommendations. In addition to the quality assurance function, the function of guaranteeing the efficiency of treatment is a priority for health insurances. These objectives may be in conflict with each other. This paper is mainly concerned with the significance of medical guidelines for medical malpractice law.


Parallel vectors criteria for unsteady flow vortices.
Feature-based flow visualization is naturally dependent on feature extraction. To extract flow features, often higher-order properties of the flow data are used such as the Jacobian or curvature properties, implicitly describing the flow features in terms of their inherent flow characteristics (e.g., collinear flow and vorticity vectors). In this paper we present recent research which leads to the (not really surprising) conclusion that feature extraction algorithms need to be extended to a time-dependent analysis framework (in terms of time derivatives) when dealing with unsteady flow data. Accordingly, we present two extensions of the parallel vectors based vortex extraction criteria to the time-dependent domain and show the improvements of feature-based flow visualization in comparison to the steady versions of this extraction algorithm both in the context of a high-resolution dataset, i.e., a simulation specifically designed to evaluate our new approach, as well as for a real-world dataset from a concrete application.


Metabolism of 4-14 C-progesterone in the adult female chimpanzee.
The metabolism of 4- 14-C-progesterone was studied in two adult female chimpanzees (Pan troglodytes). After intravenous injection of 4- 14-C-progesterone, urine was collected for 5 days. The urinary conjugates were hydrolyzed with Glusulase and the extracts purified by chromatography on silica gel, paper and alumina and then crystallized to constant specific activity with or without carrier steroid. The major metabolite in both experiments was pregnanediol which accounted for 39.8% and 49.5% of the recovered dose respectively. Pregnanolone (0.6% and 2.1%) and pregnanetriol (0.1% and 1.5%) were also isolated in smaller quantities. These data suggest that the pattern of progesterone metabolism in the chimpanzee is similar to that of man in that pregnanediol is the major metabolite whereas androsterone is not.


Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer.
Cochlear gene transfer is a promising new approach for inner ear therapy. Previous studies have demonstrated hair cell protection with cochlear gene transfer not only in the inoculated, but also in the uninoculated ear. To characterize the kinetics of viral spread, we investigated the extent of transgene expression in the contralateral (uninoculated) cochlea after unilateral adenoviral cochlear gene transfer. We used a lacZ reporter gene vector, and demonstrated spread of the adenovirus into the cerebrospinal fluid (CSF) after cochlear inoculation of 25 microl viral vector. Direct virus application into the CSF resulted in transduction of both cochleae, whereas virus inoculation into the bloodstream did not. The cochlear aqueduct was identified as the most likely route of virus spread to the contralateral cochlea. These data enhance our understanding of the kinetics of virus-mediated transgene expression in the inner ear, and assist in the development of clinical applications for inner ear gene therapy. Our results showed a functional communication between the CSF and the perilymphatic space of the inner ear, that is not only of importance for otological gene transfer, but also for CNS gene transfer. Gene Therapy (2000) 7, 377-383.


The influence of endophenotypic, disease-specific, and environmental variables on the expression of anxiety in pediatric epilepsy.
Children and adolescents with epilepsy often show higher rates of anxiety, which carries an increased risk for reduced health-related quality of life (HRQOL). The current study assessed the role of parental psychiatric history (i.e., anxiety, depression, and/or bipolar disorder) on the rate of anxiety features in youth seen in a tertiary epilepsy clinic. Data included parental ratings on the Behavior Assessment System for Children (BASC-2) and the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire for 180 children and adolescents (mean age=11.40, SD=3.98). Our results identified clinically elevated anxiety ratings in nearly half the sample (47%) with previous psychiatric history endorsed by 48% of parents. The effect of parental psychiatric history on youth anxiety was found to be significant and associated with a threefold increase in the rate of youth anxiety features. This risk increased to fourfold in refractory epilepsy, and the impact of family psychiatric history is greater in adolescent females and in families that report higher levels of stress. In those families who reported no psychiatric history, anxiety was best predicted by epilepsy-specific factors above and beyond sociodemographic factors. Parental psychiatric history was also identified as a significant risk factor for diminished patient HRQOL, even after accounting for seizure control. These findings highlight the impact of family and epilepsy factors on psychological functioning and offer further support for the strong relationship between parental adjustment and child outcome in pediatric epilepsy.


Assessment of Populus wood chemistry following the introduction of a Bt toxin gene.
Unintended changes in plant physiology, anatomy and metabolism as a result of genetic engineering are a concern as more transgenic plants are commercially deployed in the ecosystem. We compared the cell wall chemical composition of three Populus lines (Populus trichocarpa Torr. & A. Gray x Populus trichocarpa Bartr. ex Marsh., Populus trichocarpa x Populus nigra L. and Populus deltoides x Populus nigra) genetically modified to express the Cry3A or Cry3B2 protein of Bacillus thuringiensis (Bt) with the cell wall chemistry of non-transformed isogenic control lines. Three genetically modified clones, each represented by 10 independent transgenic lines, were analyzed by pyrolysis molecular beam mass spectrometry, gas chromatography/mass spectrometry and traditional wet chemical analytical methods to assess changes in cell wall composition. Based on the outcome of these techniques, there were no comprehensive differences in chemical composition between the transgenic and control lines for any of the studied clones.


Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids.
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.