[Medical emergency teams: current situation and perspectives of preventive in-hospital intensive care medicine].
Severe clinical incidents occur in up to 10% of all non-intensive care unit (ICU) patients, which have an estimated mortality of 5-8%. As in the prehospital setting, early clinical warning signs can be identified in the majority of cases. Studies suggest that introduction of an in-hospital medical emergency team (MET) which responds to objective criteria of physiological deterioration, may effectively reduce the incidence of in-hospital cardiac arrests as well as unanticipated or readmissions to the ICU. According to this concept, METs would evaluate and treat non-ICU patients at risk at an early stage before a potentially fatal deterioration of cardiorespiratory parameters occurs. This article reviews available data on preventive in-hospital intensive care medicine and reflects on the circumstances for an implementation of METs in Germany, Austria and Switzerland.


Right ventricular diastolic dysfunction in patients with left ventricular hypertrophy: analysis of right ventricular myocardial relaxation using two-dimensional speckle tracking imaging.
Although several previous studies have suggested the presence of right ventricular (RV) diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM) and those with hypertensive left ventricular hypertrophy (HT-LVH), the mechanisms are still unclear. This study aimed to clarify the relationship between the RV global diastolic dysfunction in these patients and the regional myocardial diastolic function, including synchronicity of the interventricular septum and RV free wall. In 20 age-matched patients with HT-LVH, 20 patients with HCM and 22 control subjects without pulmonary hypertension, RV isovolumic relaxation time (IRTR) was measured using continuous-wave Doppler echocardiography. The early diastolic peak strain rate (E SR) and time from QRS to E SR (T-E SR) were measured in the apical, mid-ventricular and basal segments of the interventricular septum and RV free wall using two-dimensional speckle tracking imaging (2DST). IRTR was more prolonged both in HT-LVH and in HCM than in the controls. The averaged septal E SR was reduced both in HT-LVH and in HCM (P < 0.0001, respectively), but the averaged RV free wall E SR was decreased only in HCM (P = 0.0007). E SR averaged for six septal and RV free wall segments was correlated with IRTR (r = -0.46, P = 0.0001). Neither intergroup difference nor correlation with IRTR was observed in a coefficient of variation of T-E SR for the six segments. RV global diastolic function is impaired in patients with HT-LVH and HCM due to relaxation abnormalities, not an asynchrony, of the myocardium surrounding the RV cavity. The detection of RV free wall relaxation abnormality using 2DST may be useful to differentiate HCM from HT-LVH.


Sedation with dexmedetomidine for conducting electroencephalogram in a patient with Angelman syndrome: a case report.
Angelman syndrome is characterized by severe mental retardation and speech and seizure disorders. This rare genetic condition is associated with changes in GABAA receptor. Patients with Angelman syndrome need to be sedated during an electroencephalogram ordered for diagnostic purposes or evolutionary control. Dexmedetomidine, whose action is independent of GABA receptor, promotes a sleep similar to physiological sleep and can facilitate the performing of this examination in patients with Angelman syndrome. Female patient, 14 years old, with Angelman syndrome; electroencephalogram done under sedation with dexmedetomidine. The procedure was uneventful and bradycardia or respiratory depression was not recorded. The examination was successfully interpreted and epileptiform activity was not observed. Dexmedetomidine promoted satisfactory sedation, was well tolerated and enabled the interpretation of the electroencephalogram in a patient with Angelman syndrome and seizure disorder.


A comprehensive study of novel microcapsules incorporating gliclazide and a permeation enhancing bile acid: hypoglycemic effect in an animal model of Type-1 diabetes.
Gliclazide (G) is a commonly prescribed drug for Type 2 diabetes (T2D). In a recent study, we found that when G was combined with a primary bile acid, and gavaged to an animal model of Type 1 diabetes (T1D), it exerted a hypoglycemic effect. We hypothesized this to be due to metabolic activation of the primary bile acid into a secondary or a tertiary bile acid, which enhanced G solubility and absorption. The tertiary bile acid, taurocholic acid (TCA), has shown strong permeation-enhancing effects in vivo. Thus, we aimed to design, characterize, and test microcapsules incorporating G and TCA in an animal model of T1D. Microcapsules were prepared using the polymer sodium alginate (SA). G-SA microcapsules (control) and G-TCA-SA microcapsules (test) were extensively examined (in-vitro) at different pH and temperatures. The microcapsules were gavaged to diabetic rats, and blood glucose and G concentrations in serum were examined. Ex-vivo studies were also performed using a muscle cell line (C2C12), and cell viability and glucose intake post-treatment were examined. G-TCA-SA microcapsules showed good stability, uniformity, and thermal and chemical excipient compatibilities. TCA did not change the size or the shape of the microcapsules, but it enhanced their mechanical resistance and reduced their swelling properties. G-TCA-SA enhanced the viability of C2C12 cells over 24 hours, and exerted a hypoglycemic effect in alloxan-induced type-1 diabetic rats. The incorporation of TCA into G-microcapsules resulted in functionally improved microcapsules with a positive effect on cell viability and glycemic control in Type-1 diabetic animals.


Rationally design and chemical modification: Getting a new and efficient biocatalyst for Henry reaction.
A robust biocatalyst for green Henry reaction was achieved. Based on the fact that Henry reaction requires a base for proton transfer, we firstly proposed that the catalytic triad of lipase could play this role. The distance between the substrate and the catalytic center and the surrounding amino acid interaction network were used as the criterion. Benzaldehyde and nitromethane were used as the model reaction, RNL (Lipase from Rhizopus niveus) was considered to be the best Henry reaction catalyst via a molecular dynamics simulation. Then experiments demonstrated that RNL has a yield of 48 % using model substrate in water. Further, in order to increase product yield, the chemical modifier 1, 2-cyclohexanedione (CHD) was used to modify Arg on RNL. As a result, RNL (CHD) increased the activity of catalyzing Henry reaction and had a broad spectrum of substrates, the yield of the product was as high as 67-99 %.


STAR proteins quaking-6 and GLD-1 regulate translation of the homologues GLI1 and tra-1 through a conserved RNA 3'UTR-based mechanism.
The binding of the STAR protein GLD-1 to an element in the tra-2 3' untranslated region (3'UTR), called the TGE (tra GLI element), represses tra-2 translation, allowing for hermaphrodite spermatogenesis in Caenorhabditis elegans. GLD-1 is a member of the STAR family that includes the mammalian quaking (Qk) proteins. Here, we show that the 3'UTR of the nematode homologue of GLI1, called tra-1, also contains a TGE, through which translation is regulated by GLD-1. We find that GLD-1 activity is required for proper TRA-1 protein expression in hermaphrodites. RNA gel shift assays show that GLD-1 binds the predicted sites. Using reporter transgenes, we show that the human GLI1 (hGLI1) 3'UTR controls translation in the mouse embryo. We demonstrate that the addition of the mouse QK isoform-6 (QKI-6) protein to a mammalian cell line that lacks QKI-6 can confer regulation on reporter and GLI1 mRNAs in a TGE-specific manner, and reduction of QKI-6 activity with siRNA disrupts translational control. Further, siRNA knockdown of QKI-6 increases the activity of a reporter transgene that monitors the transcriptional activity of mouse Gli1 (mGli1) and increases mouse Gli1 protein. We show by immunoprecipitation that QKI-6 antibody specifically co-purifies TGE-containing mRNAs in ribonucleoproteins. Thus, we find that the mouse QKI-6 protein acts through the mGli1 and hGLI1 RNAs to repress translation. Our results suggest that STAR family-dependent translational control of GLI mRNAs is ancient, and that it existed before the division of nematodes and mammals.


Association of Body Mass Index and Outcome in Acutely Ill Patients With Chronic Kidney Disease Requiring Intensive Care Therapy.
An association of body mass index (BMI) and outcome, the "obesity paradox," has been described in patients with chronic kidney disease (CKD) and end-stage renal disease. We sought to assess whether a potential beneficial effect of a high body mass is also seen in CKD patients with critical illness. In a retrospective analysis of a prospectively collected database of 123,416 patients from 107 Austrian intensive care units (ICUs) in whom BMI was available, the association of 6 groups of BMI and hospital mortality was assessed in 12,206 patients with CKD 3-5 by univariate and multivariate logistic regression analyses. Patients with CKD were sicker, had a longer ICU stay, and had a higher ICU and hospital mortality than those without. The association of BMI and outcome in CKD patients indicated a U-shaped curve with the highest mortality in patients with BMI <20 and ≥40, and the lowest with a BMI between ≥25 and <40. This relationship was also significant in a multivariate analysis adjusted for severity of illness assessed by Simplified Acute Physiology Score III score, age, gender, admission diagnosis, and pre-existing comorbidities. It was not found in patients with CKD 5 on renal replacement therapy, in patients below 60 years of age, and those with diabetes mellitus requiring insulin treatment. BMI is associated with better outcomes in CKD 3-5 patients who have acquired acute intermittent diseases and are admitted to an ICU, but not those requiring renal replacement therapy. This higher tolerance to acute disease processes may in part explain the "obesity paradox" observed in CKD patients.


2006 CSEP Annual Scientific Conference, Halifax, Nova Scotia, 1-4 November 2006. Pediatric exercise physiology symposium: a tribute to Oded Bar-Or. Introduction.
Dr. Oded Bar-Or was a pioneer in the study of children's physical activity, exercise, and health. His diverse research interests led to numerous scientific explorations on thermoregulation, aerobic and anaerobic capacity, physical activity, economy of movement, obesity, neuromuscular diseases, asthma, cystic fibrosis (CF), and many more. To commemorate the extraordinary contributions that Dr. Bar-Or made to the study of exercise and youth, a symposium on pediatric exercise physiology was held at the CSEP's 2006 Annual Meeting in Halifax. The papers in the following pages include the four papers presented by international colleagues in his memory.


Triggering multiple sclerosis at conception and early gestation: The variation in ultraviolet radiation is as important as its intensity.
Medical science needs to further elucidate the role of ultraviolet radiation (UVR), geographic latitude, and the role of vitamin D in the autoimmune disease multiple sclerosis (MS). We separated several papers into categories out of the thousands published and used their conclusions to explore the relationship between UVR and MS. MS is increasing in incidence, particularly in women where MS is two to three times that in men and particularly severe in African Americans. We collected UVR data at our observatory in Central Maine and calculated the average coefficient of variation (CVUVR) for each month for 15 years (2007-2021, inclusive). The month of conception (MOC) is more important than the month of birth (MOB) in explaining how UVR triggers the variable genetic predisposition to MS. We hypothesize that the rapidly increasing CVUVR is important in preventing an increase in the activity of the vitamin D receptor (VDR) from August to December, which then requires a higher intensity of UVR later in life to suppress the immune system, therefore predisposing to more MS. One observatory at about 44° latitude. While variation in UVR is important at the MOC if UVR exceeds a threshold (e.g., if the sunspot number equals or is greater than 90, usually at a solar cycle MAX, or at elevations above approximately 3,000 feet above sea level), the MS mitigating vitamin D-VDR mechanism is overwhelmed and the genotoxic effects of higher-intensity UVR promote MS in those with a genetic predisposition. This paper offers a new concept in MS research.


Energy limitation of hummingbird populations in tropical and temperate communities.
Regular censuses were conducted at both a temperate alpine and a tropical lowland site to determine seasonal changes in the composition of hummingbird communities and the availability of their food. From these data we calculated the total daily energy demand by the hummingbirds (Daily Energy Expenditure; DEE) and the daily energy supply available from floral nectar (Daily Energy Production; DEP) for each community census. Despite differences in habitat type and hummingbird community structure between these two sites, the hummingbird populations were often at or near carrying capacity. On average, all of the daily nectar production was cropped by the birds. We suggest that the supply/demand economics of coevolved mutualisms favour the evolution of complete resource use.


Acute up-regulation of the rat brain somatostatin receptor-effector system by leptin is related to activation of insulin signaling and may counteract central leptin actions.
Leptin and somatostatin (SRIF) have opposite effects on food seeking and ingestive behaviors, functions partially regulated by the frontoparietal cortex and hippocampus. Although it is known that the acute suppression of food intake mediated by leptin decreases with time, the counter-regulatory mechanisms remain unclear. Our aims were to analyze the effect of acute central leptin infusion on the SRIF receptor-effector system in these areas and the implication of related intracellular signaling mechanisms in this response. We studied 20 adult male Wister rats including controls and those treated intracerebroventricularly with a single dose of 5 μg of leptin and sacrificed 1 or 6h later. Density of SRIF receptors was unchanged at 1h, whereas leptin increased the density of SRIF receptors at 6h, which was correlated with an elevated capacity of SRIF to inhibit forskolin-stimulated adenylyl cyclase activity in both areas. The functional capacity of SRIF receptors was unaltered as cell membrane levels of αi1 and αi2 subunits of G inhibitory proteins were unaffected in both brain areas. The increased density of SRIF receptors was due to enhanced SRIF receptor subtype 2 (sst2) protein levels that correlated with higher mRNA levels for this receptor. These changes in sst2 mRNA levels were concomitant with increased activation of the insulin signaling, c-Jun and cyclic AMP response element-binding protein (CREB); however, activation of signal transducer and activator of transcription 3 was reduced in the cortex and unchanged in the hippocampus and suppressor of cytokine signaling 3 remained unchanged in these areas. In addition, the leptin antagonist L39A/D40A/F41A blocked the leptin-induced changes in SRIF receptors, leptin signaling and CREB activation. In conclusion, increased activation of insulin signaling after leptin infusion is related to acute up-regulation of the SRIF receptor-effector system that may antagonize short-term leptin actions in the rat brain.


Protective effects of curcumin against lithium-pilocarpine induced status epilepticus, cognitive dysfunction and oxidative stress in young rats.
Status epilepticus (SE), one of the most severe forms of epilepsy is regarded a medical emergency with considerable morbidity and mortality. Due to the limited efficacy and enormous side effects of currently available drugs, a search for new safe and effective therapeutic agents is critical using experimentally induced SE in animals. The lithium-pilocarpine (Li-Pc) model of SE is most suitable and frequently used for pathophysiological and management strategies of SE. Recent studies have shown significant potential of pharmacological, prophylactic or therapeutic use of curcumin (Cur) in many beneficial activities in the body including neuroprotection in neurodegenerative diseases and antioxidant properties. The present study describes anticonvulsive effects of Cur in Li-Pc induced SE in young rats. The effect of Cur was examined on the intensity and frequency of SE, cognitive behavior in water maze as well as on oxidative stress related enzymes in the brain. Besides its anticonvulsant effect, Cur significantly ameliorates SE-induced cognitive dysfunction and oxidative damages in the hippocampus and striatum areas of the brain. Possible therapeutic application of Cur as an anticonvulsant and as an antioxidant for the treatment of SE has a great potential and warrants further studies.


Nationwide survey of alcohol screening and brief intervention practices at US Level I trauma centers.
In 2007, the American College of Surgeons (ACS) Committee on Trauma implemented a requirement that Level I trauma centers must have a mechanism to identify patients who are problem drinkers and the capacity to provide an intervention for patients who screen positive. Although the landmark alcohol screening and brief intervention (SBI) mandate is anticipated to impact trauma practice nationwide, a literature review revealed no studies that have systematically documented SBI practice pre-ACS requirement. Trauma programs at all US Level I trauma centers were contacted and asked to complete a survey about pre-ACS requirement trauma center SBI practice. One hundred forty-eight of 204 (73%) Level I trauma centers responded to the survey. More than 70% of responding centers routinely used laboratory tests (eg, blood alcohol concentration) to screen patients for alcohol and 39% routinely used a screening question or standardized screening instrument. Screen-positive patients received a formal alcohol consult or had an informal alcohol discussion with staff members approximately 25% of the time. The investigation observed marked variability across Level I centers in the percentage of patients screened and in the nature and extent of intervention delivery in screen-positive patients. In the wake of the ACS Committee on Trauma requirement, future research could systematically implement and evaluate training in the delivery of evidence-based alcohol interventions and training in development of trauma center organizational capacity for sustained delivery of SBI.


Prospective international validation of the predisposition, infection, response and organ dysfunction (PIRO) clinical staging system among intensive care and general ward patients.
Stratifying patients with sepsis was the basis of the predisposition, infection, response and organ dysfunction (PIRO) concept, an attempt to resolve the heterogeneity in treatment response. The purpose of this study is to perform an independent validation of the PIRO staging system in an international cohort and explore its utility in the identification of patients in whom time to antibiotic treatment is particularly important. Prospective international cohort study, conducted over a 6-month period in five Portuguese hospitals and one Australian institution. All consecutive adult patients admitted to selected wards or the intensive care, with infections that met the CDC criteria for lower respiratory tract, urinary, intra-abdominal and bloodstream infections were included. There were 1638 patients included in the study. Patients who died in hospital presented with a higher PIRO score (10 ± 3 vs 8 ± 4, p < 0.001). The observed mortality was 3%, 15%, 24% and 34% in stage I, II, III and IV, respectively, which was within the predicted intervals of the original model, except for stage IV patients that presented a lower mortality. The hospital survival rate was 84%. The application of the PIRO staging system to the validation cohort resulted in a positive predictive value of 97% for stage I, 91% for stage II, 85% for stage III and 66% for stage IV. The area under the receiver operating characteristics curve (AUROC) was 0.75 for the all cohort and 0.70 if only patients with bacteremia were considered. Patients in stage III and IV who did not have antibiotic therapy administered within the desired time frame had higher mortality rate than those who have timely administration of antibiotic. To our knowledge, this is the first external validation of this PIRO staging system and it performed well on different patient wards within the hospital and in different types of hospitals. Future studies could apply the PIRO system to decision-making about specific therapeutic interventions and enrollment in clinical trials based on disease stage.


Radiographic appearance of frontal osteomyelitis in two patients with extradural abscess.
Extradural abscess can be a complication of frontal sinusitis. The chronicity of this condition can give rise to extreme frontal hyperostosis which can be an important radiological sign in a condition which may be clinically obscure.


Three-dimensional motion analysis for comprehensive understanding of gait characteristics after sciatic nerve lesion in rodents.
Rodent models of sciatic nerve lesion are regularly used to assess functional deficits in nerves. Impaired locomotor functions induced by sciatic nerve lesion are currently evaluated with scoring systems despite their limitations. To overcome these shortcomings, which includes low sensitivity, little significance, and the representation of only marginal components of motion profiles, some additional metrics have been introduced. However, a quantitative determination of motion deficits is yet to be established. We used a three-dimensional motion analysis to investigate gait deficits after sciatic nerve lesion in rats. This enabled us to depict the distorted gait motion using both traditional parameters and novel readouts that are specific for the three-dimensional analysis. Our results suggest that three-dimensional motion analysis facilitates a comprehensive understanding of the gait impairment specifically, but not limited to, a sciatic lesion rat model. A broad application of these methods will improve understanding and standardized motor assessment.


Sequence Type Changes Associated with Decreasing Macrolide-Resistant Mycoplasma pneumoniae, Japan.
We compared sequence types (STs) of Mycoplasma pneumoniae isolates from Japan during 2002-2019. ST3 and ST14 dominated during 2002-2016, and ST7 and ST33 dominated during 2018-2019. These STs were associated with a decrease in macrolide-resistant strains after an epidemic of infection with M. pneumoniae during 2011-2012.


Existence of hybrid structures in cationic liposome/DNA complexes revealed by their interaction with plasma proteins.
The self-assembling of cationic liposomes (CLs) and DNA can give rise to a variety of nanostructures and morphologies. Multilamellar complexes are made of DNA intercalated between opposing lipid bilayers, while clusters formed by intact vesicles may exist as 'beads-on-a-string' (i.e. CLs attached to a string of DNA). Precise knowledge of the structure and morphology of complexes is relevant in many biological important processes such as gene delivery. Here dynamic light scattering, zeta potential, synchrotron small angle X-ray scattering and one-dimensional polyacrylamide gel electrophoresis were performed to investigate the equilibrium structure, morphology and interactions with plasma proteins of lipoplexes made of the cationic lipid (3β-[N-(N',N'-dimethylaminoethane)-carbamoyl])-cholesterol (DC-Chol), the zwitterionic lipid dioleoylphosphatidylethanolamine (DOPE) and DNA. Results show that DC-Chol-DOPE/DNA complexes are multilamellar systems with DNA protected by cationic lipids. On the other hand, the 'protein corona' associated to lipoplexes after interaction with human plasma was found to be much richer in basic immunoglobulins gamma proteins (Ig-Gs) than that of pure lipid vesicles in the absence of DNA. According to the most recent evidences reported in the literature, this finding would suggest the existence of hybrid structures made of multilamellar complexes either stuck together by DNA or coexisting with DNA-loaded intact vesicles. Because surface properties of lipoplexes may determine their interaction with cells and tissues, these results may be important for predicting biological responses in vivo.


High levels of plasma atrial natriuretic factor and impaired left ventricular diastolic function in hypertensives without left ventricular hypertrophy.
To seek possible correlations between plasma atrial natriuretic factor (ANF) and left ventricular diastolic function (LVDF) in hypertensive patients. Since LVDF abnormalities can be detected in patients with normal left ventricular mass, we studied a group of hypertensive patients without left ventricular hypertrophy. Untreated hypertensive patients (n = 23) and normotensive control subjects (n = 19) were studied. LVDF indices were obtained by M-mode and pulsed Doppler echocardiography. Blood samples for plasma ANF were taken in the recumbent position from subjects on normal-sodium intake. Plasma ANF levels were significantly higher in hypertensive patients than in normotensive subjects. All indices for systolic function were normal in both normotensive subjects and hypertensive patients. Left atrial diameter was significantly higher for hypertensive patients than for normotensive subjects. Considering LVDF, all indices for ventricular filling were found to be altered, on average, in hypertensive patients, the only exception being peak early velocity. In addition, significant correlations were found between plasma ANF and the pulsed Doppler parameters of left ventricular filling, peak atrial velocity and the peak early:peak atrial velocity ratio. Overall correlations between plasma ANF and left atrial diameter, and between left atrial diameter and left ventricular mass index were also observed. The high levels of plasma ANF observed in our hypertensive patients and their correlation with the LVDF indices (which mainly reflect the atrial contribution to ventricular filling) could be the result of an increased atrial stretch due to diastolic ventricular dysfunction. This may exist in hypertensive patients before the development of ventricular hypertrophy.


Candida lyxosophila sp. nov., a new D-xylose fermenting yeast from southern Africa.
Six strains of an undescribed Candida species which ferment D-xylose tardily, were isolated from soil. A description of the new species, Candida lyxosophila, is given.


Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viremic pregnant women: a case series.
Despite appropriate immunoprophylaxis, up to 10 % of infants born to highly viremic hepatitis B virus (HBV-DNA ≥ 7 log IU/mL) mothers are infected with HBV. Use of TDF to prevent vertical transmission (VT) by such mothers has not been evaluated. To evaluate the efficacy and safety of TDF in preventing VT from highly viremic HBV-infected mothers. Data were collected retrospectively from HBV mono-infected, hepatitis B e antigen (HBeAg) positive, pregnant women between 6/2008 and 11/2010. Cases enrolled were HBV mono-infected mothers who received TDF (300 mg orally once a day) in the third trimester. Those with pregnancy complications or an abnormal fetus on sonography were excluded from use of TDF. All infants received hepatitis B immunoglobulin and vaccination at birth and subsequently. Eleven Asian mothers received TDF at the median gestational age of 29 (28-32) weeks and the median duration of TDF use before delivery was 10 (7-12) weeks. A significant reduction in serum HBV-DNA was achieved at delivery compared with baseline (mean 5.25 ± 1.79 vs. 8.87 ± 0.45 log(10) copies/mL, respectively; p < 0.01). Three had serum ALT levels more than 1.5 times the upper limit of normal and two of these normalized before delivery. The 11 infants were born with no obstetric complication or birth defects. Five infants were breastfed. All infants were hepatitis B surface antigen negative 28-36 weeks after birth. Our preliminary data suggest that TDF use in the third trimester is safe, and effectively prevents VT of HBV from high viremic HBeAg-positive mothers.


Aortic aneurysm secondary to umbilical artery catheterization.
A 14-month-girl presented with an asymptomatic posterior mediastinal mass. She had a history of prematurity, umbilical artery catheterization, and sepsis. The diagnosis of aortic aneurysm was made by dynamic computed tomography. The aneurysm was successfully resected.


Structural degeneration of Aspergillus fumigatus after exposure to saperconazole.
Saperconazole is a newly synthesized triazole antifungal with potent activity against Aspergillus fumigatus. Exposure of spores inoculated into BHI agar medium to saperconazole doses as low as 35 ng ml-1, resulted in complete suppression of germination (hyphal outgrowth) when treatment started simultaneously with inoculation. Cultures which were grown for 24 or 48 h in the absence of drug and were then exposed to saperconazole showed a block in the development of hyphae, sporophores, vesicles, sterigmata and spores. Moreover, a substantial proportion of the pre-existent hyphae became necrotic during exposure to the drug. The latter was most obvious with the 70 ng ml-1 dose. Although treatment with lower doses yielded severely altered but non-necrotic cells, an abolishment of further outgrowth and differentiation was achieved.


Different modes of word recognition in the left and right visual fields.
We confirm previous evidence indicating that word length has a substantial effect on word recognition in the LVF but a much weaker effect in both the RVF and fovea. The nature of encoding in the LVF is not altered when the words are vertically displayed (Experiment 2), and the effect cannot therefore be entirely due to scanning artefact or acuity gradients in peripheral vision. We provide evidence that links the asymmetrical influence of word length directly to hemispheric specialization: left-handers, who as a group are much less consistently lateralized than right-handers are also less affected by word length in the LVF on the average (Experiment 3). This occurs because the asymmetry for certain left-handers is either very weak or, in some cases, is the complete reverse of the asymmetry observed in right-handers. Finally, we demonstrate that the length x field interaction is observed in lexical decisions (Experiment 4) which do not entail pronunciation of written words. There is some indication that concrete, high-imageable words produce a smaller effect of length in the LVF than abstract, low-imageable words, and we discuss this outcome in relation to the proposal that the right hemisphere can sometimes extract a lexical code from letter information. The concept of distinct modes of word recognition in the LVF and RVF clarifies a number of issues in laterality research, and suggests a new approach to evaluating group differences in half-field performance.


A sulfated glycosaminoglycan array for molecular interactions between glycosaminoglycans and growth factors or anti-glycosaminoglycan antibodies.
Glycosaminoglycans (GAGs) take part in numerous biological processes by binding to protein molecules and functionally regulating protein-ligand interactions; therefore, molecular interactions of GAGs have been studied by several methods, including surface plasmon resonance, enzyme-linked immunosorbent assays (ELISAs), and GAG microarrays. To achieve rapid, sensitive, and high-throughput screening of GAG interactions, we have developed a novel microarray in which GAGs, including chondroitin sulfate, heparan sulfate, and heparin, were immobilized. The microarray is made from cyclic polyolefin substrate coated with metacrylate polymers, which have phospholipid groups as side chains. The polymer also has aminooxy groups that react specifically with aldehyde groups at the reducing termini of GAG chains, whereas the phospholipid groups prevent nonspecific adsorption of proteins. Thus, minute amounts of GAGs can be chemically immobilized on the surface with low nonspecific binding of proteins. Using this array, interactions between GAGs and antibodies against chondroitin or heparan sulfate and heparin-binding growth factors were examined. The results were in agreement with previously reported specificities, suggesting that the GAG array is useful for high-throughput interaction analyses between GAGs and functional proteins in miniscule amounts and can be applied to both basic studies of GAGs and the development of diagnostic methods for metabolic diseases involving GAGs.


Utility and accuracy of duplex ultrasonography in evaluating in-stent restenosis after carotid stenting.
Stents alter flow velocities after carotid artery stenting (CAS). To identify criteria for in-stent restenosis (ISR), velocities obtained by duplex ultrasonography (DU) after CAS were analyzed. Carotid angiography and DU were performed after 129 CAS procedures. The 2 x 2 table method and receiver operating characteristic curves were used to assess the ability of DU to detect ISR. The median follow-up period was 21.2 months (interquartile range 14-32 months). Overall, 6 patients (4.7%) had significant ISR by angiography. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the validated criteria for nonstented arteries were 100%, 85%, 25%, and 100%, respectively, to determine ISR. Newly validated criteria revealed optimal detection of ISR, with 100% sensitivity, 99% specificity, PPV of 66%, and NPV of 100%. Patients with abnormal findings on initial DU revealed increased velocities by >80% when ISR occurred. DU can accurately detect ISR after CAS, but velocity criteria require modification and validation at each vascular laboratory. For patients with abnormal findings on initial DU, significant changes in velocities suggest ISR.


Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function.
The pathophysiological mechanisms in non-ulcer dyspepsia are incompletely understood. To compare gastric motor and sensory functions in Helicobacter pylori positive or negative patients with non-ulcer dyspepsia. Seventeen patients with non-ulcer dyspepsia and 16 asymptomatic controls. The following were evaluated: gastrointestinal symptoms; gastric emptying and orocaecal transit of solids; abdominal vagal function; gastric compliance; fasting and postprandial gastric tone and phasic contractions; symptoms during ingestion of cold water and during the distension of an intragastric bag; and somatic sensitivity and personality profile (Minnesota Multiphasic Personality Inventory, MMPI). Gastric accommodation was reduced in H pylori negative dyspeptics relative to controls; the degree of accommodation was unrelated to H pylori status in dyspeptics. Increased postprandial gastric sensation was more frequent among H pylori positive patients (4/5 H pylori positive versus 4/12 H pylori negative patients). Intragastric meal distribution and orocaecal transit were normal; gastric emptying at four hours was abnormal in 4/17 patients. Vagal dysfunction was rare. Eight of 17 patients had somatisation or depression on MMPI. Impaired gastric accommodation is frequent in non-ulcer dyspepsia and seems to be unrelated to vagal efferent dysfunction. H pylori infection does not seem to influence gastric accommodation, but is associated with heightened sensitivity in dyspeptics. Therapeutic approaches that restore normal postprandial accommodation and gastric sensitivity should be tested in non-ulcer dyspepsia.


Information and the Umwelt: A theoretical framework for the evolution of play.
Play is phylogenetically widespread, and there are many proposed theories and fitness benefits of play. However, we still need a theoretical framework that unifies our understanding of the benefits that facilitated the evolution of play in so many diverse species. Starting with von Uexküll's theory of the Umwelt (i.e., the sensory-motor worlds of animals), together with the behavior systems approach, we propose that the Umwelt is an information processing system that serves basic biological functions. During development, the Umwelt undergoes a rapid expansion in the sensory and motor stimuli it processes. We argue that play is a process that converts surplus resources into information. By increasing the information content of the developing Umwelt, play confers fitness benefits. To demonstrate that play could evolve based on its information benefits, we present a model and simulation results of the evolution of a social play learning process that provides fitness-enhancing information in adult cooperative and competitive situations. Finally, we discuss this information-theoretic framework in relation to proposed hypotheses and fitness benefits of play.


PARENTAL PERCEPTION OF BODY WEIGHT IN PRESCHOOL CHILDREN AND AN ANALYSIS OF THE CONNECTION BETWEEN SELECTED PARENT-RELATED FACTORS AND THE ASSESSMENT OF THEIR CHILDREN'S WEIGHT.
The efforts parents make to maintain the correct body weight in children indicates parental awareness of overweight and obesity-related health risks. The objective of the analysis was to define the accuracy of the appraisal of weight-to-height proportions in preschool children, as assessed by their parents and to analyse the connection of selected parental factors with the assessment conducted. Data were collected from 230 children (121 males and 109 females aged 6.28 ± 0.56 years) attending preschools in the city of Wroclaw, Poland. Body height and weight were measured to calculate BMI; cut-offs referenced by the International Obesity Task Force were used to determine weight status (underweight, overweight, obese). The participants' parents completed a weight-height assessment of their child and provided information on how often the child's body weight was checked. Cohen's kappa coefficient was used as a statistical measure of inter-rater agreement between actual child weight and parental perception of child weight. Selected parental factors influencing the correctness of assessing child body weight was tested using the chi-square test. This study showed that 42.1% of underweight children and 60.9% overweight and obese children are perceived as having normal weight. In the group of children with normal weight-to-height proportions, 13.3% of the parents declared their normal-weight children to be underweight. No relationship was found in the study between the correct assessment of body weight and the parents' own body weight, their education, or such factors as sex and the frequency of checking the child's body weight. The incompatibility between actual and perceived weight status indicates the need for health education among parents in assessing and monitoring the child's body weight during the developmental period.


[Small fibre neuropathy: Diagnostic approach and therapeutic issues, and its association with primary Sjögren's syndrome].
This article reviews the diagnostic issues and the therapeutic management of small fibre neuropathy (SFN), and a detailed literature analysis of its association with primary Sjögren's syndrome (pSS). A diagnosis of SFN should be raised in the presence of diffuse neuropathic painful manifestations (burning sensation, paresthesia, pricking, allodynia or hyperesthesia) and neurovegetative signs. The neurological examination and the electroneuromyogram are usually normal. The diagnosis of SFN can be confirmed by the evidence of decreased intra-epidermal nerve fibre density after a skin punch biopsy or the presence of abnormal nonconventional neurophysiological tests exploring the A-delta and C small nerve fibres (laser-evoked potentials, quantitative sensory tests, cutaneous sympathic reflex, autonomic function tests). The association of SFN and pSS has been scarcely evaluated, probably because of its lack of awareness and the low availability of the required diagnostic procedures. According to our literature review, pSS may be present in 9 to 30% of patients with SFN. Conversely, a pure SFN is present in 3 to 9% of patients with pSS where it may represent 25 to 35% of pSS-associated peripheral neuropathies. The treatment of SFN is mainly symptomatic and based on antalgic neuropsychotropic drugs and conventional analgesics. Corticosteroids and immunosuppressive drugs are usually unsuccessful. The effectiveness of intravenous immunoglobulins is only supported by a few case reports. SFN deserves to be separately evaluated among pSS-associated peripheral neuropathies. This requires a better availability of the appropriate diagnostic procedures, the investigation of underlying immunopathological mechanisms and the assessment of the new treatments recently proposed in pSS, mainly rituximab.


Propionyl-L-carnitine improves hemodynamics and metabolic markers of cardiac perfusion during coronary surgery in diabetic patients.
Diabetic hearts are particularly vulnerable to ischemia-reperfusion injury during cardiac surgery. Application of carnitine derivatives could be beneficial not only because of metabolic effects but also by protecting vasculature. This study aimed to evaluate hemodynamic changes associated with propionyl-L-carnitine and L-carnitine administration and its correlation with biochemical markers of cardiac vascular function. Sixty-eight diabetic patients undergoing cardiopulmonary bypass coronary operation were given intravenously 20 mg/kg b.w. L-carnitine (LC), 24 mg/kg b.w. propionyl-L-carnitine (PC), or placebo (Cont). Endothelin and nucleotide metabolites were determined intraoperatively in arterial and coronary sinus blood and heart biopsies. Cardiac index at 6 and 12 h after cardiopulmonary bypass was significantly higher in PC (3.30 +/- 0.12 and 3.47 +/- 0.15 L/min/m2) as compared to Cont (2.92 +/- 0.13 and 2.91 +/- 0.16 L/min/m2; P = 0.04 and P = 0.01, respectively). Mean pulmonary artery pressure was lower in PC at 6 (20.8 +/- 0.91 mmHg) and 12 h (20.7 +/- 0.81 mmHg) in comparison to Cont (23.5 +/- 0.75 and 23.4 +/- 0.75 mmHg; P = 0.03 and P = 0.02, respectively). Trans-cardiac endothelin difference on reperfusion was higher in Cont (0.33 +/- 0.26 pmol/L) than in LC (-0.61 +/- 0.24 pmol/L, P = 0.012) and tended to be higher than in PC (-0.29 +/- 0.17 pmol/L, P = 0.056). Trans-cardiac hypoxanthine difference after 10 min reperfusion was significantly higher in Cont (6.22 +/- 1.08 micromol/L) in comparison to LC (3.17 +/- 0.66 micromol/L, P = 0.025) and PC (2.36 +/- 0.73 micromol/L, P = 0.006). Myocardial hypoxanthine concentration was lowest in PC. Significant improvement of hemodynamics following propionyl-L-carnitine administration in diabetic patients undergoing on-bypass coronary surgery was accompanied by reduced trans-cardiac endothelin difference and rapid hypoxanthine washout during reperfusion suggesting improvement of metabolism or vascular function.


Functional IL-10 deficiency in the lung of cystic fibrosis (cftr(-/-)) and IL-10 knockout mice causes increased expression and function of B7 costimulatory molecules on alveolar macrophages.
Alveolar macrophages are poor APCs that only minimally express B7 costimulatory molecules. Because our previous data suggest that bronchial epithelial cells constitutively secrete IL-10, and IL-10 inhibits B7 expression in vitro, we hypothesized that this IL-10 is responsible for suppressing B7 expression on macrophages that enter the airways. Furthermore, because we have shown that cystic fibrosis (CF) lungs are deficient in IL-10, we hypothesized that bronchoalveolar macrophages (BALMs) from cystic fibrosis transmembrane conductance regulator (CFTR)(-/-) as well as IL-10(-/-) mice might express increased B7. Immunofluorescence for B7 was positive on BALMs from CF patients and CFTR(-/-) and IL-10(-/-) mice, but was negative on controls. FACS showed that 63.9% of BALMs from IL-10(-/-) mice were B7-1 positive, as were 67.4% of BALMs from CFTR(-/-) mice, whereas <7% of BALMs from wild-type controls were positive. Using BALMs to costimulate splenic T cells with anti-CD3 as a mitogen showed 9202 +/- 2107 cpm [(3)H]thymidine incorporation for BALMs from IL-10(-/-) mice and 4082 +/- 1036 cpm for BALMs from CFTR(-/-) mice, but <200 cpm with BALMs from either type of +/+ mouse. Treatment of CFTR(-/-) mice with recombinant mouse IL-10 reduced the B7 expression and costimulatory activity of the BALMs. These data suggest that the IL-10 secreted in the healthy lung may be responsible for the absence of B7 and poor costimulatory activity of BALMs and that reductions of pulmonary IL-10 in CF may enhance B7 expression and local immune responses.


Urocortin 2 Gene Transfer Improves Heart Function in Aged Mice.
Prevalence of left ventricular (LV) systolic and diastolic dysfunction increases with aging. We previously reported that urocortin 2 (Ucn2) gene transfer increases heart function in mice with heart failure with reduced ejection fraction. Here, we test the hypotheses that (1) Ucn2 gene transfer will increase LV function in aged mice and that (2) Ucn2 gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2 gene transfer or saline. LV function was examined 3-4 months (treatment study) or 20 months (prevention study) after Ucn2 gene transfer or saline injection. In both the treatment and prevention strategies, Ucn2 gene transfer increased ejection fraction, reduced LV volume, increased LV peak -dP/dt and peak +dP/dt, and reduced global longitudinal strain. Ucn2 gene transfer-in both treatment and prevention strategies-was associated with higher levels of LV SERCA2a protein, reduced phosphorylation of LV CaMKIIa, and reduced LV α-skeletal actin mRNA expression (reflecting reduced cardiac stress). In conclusion, Ucn2 gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction.


A monolithic patch-clamping amplifier with capacitive feedback.
Patch-clamping is an established method for directly measuring ionic transport through cellular membranes with sufficient resolution to observe open/close transitions of individual channel molecules. This paper describes an alternative technique for patch-clamping which uses a capacitor as the transimpedance element. This approach eliminates bandwidth and saturation limitations experienced with resistive patch-clamping amplifiers. A complete monolithic design featuring an on-chip operational amplifier, a capacitor array with gain-ranging from 30 pF down to 0.03 pF, and reset and gain ranging switches has been fabricated using 5 microns CMOS technology. It is shown that the voltage noise of the CMOS operational amplifier limits the overall noise performance, but that performance competitive with conventional instruments can be achieved over a 10 kHz bandwidth, at least for small input capacitances (less than or equal to 5 pF). Results are presented along with an analysis and comparison of noise performance using both resistive and capacitive elements.


Direct detection using the Drosophila DNA-repair test and isolation of a DNA-damaging mycotoxin, 5,6-dihydropenicillic acid, in fungal culture.
The Drosophila DNA-repair test was used in an attempt to detect fungal production of DNA-damaging mycotoxins without an extraction process. 29 species of fungi, 13 Aspergillus, 12 Penicillium and four Fusarium were inoculated directly to a Drosophila medium, and the larvae were then bred in the mouldy medium. Production of DNA-damaging mycotoxin was detected directly by counting the decrease in the survival of DNA-repair-deficient flies. With the direct detection method, Aspergillus ochraceus, A. parasiticus and A. versicolor produced DNA-damaging mycotoxins. The same results were obtained with the mouldy medium extract using the standard DNA-repair test. The direct detection method was convenient for surveying the fungal production of DNA-damaging mycotoxins. The extracts of A. parasiticus and A. versicolor contained aflatoxin B1 and sterigmatocystin, respectively. The DNA-damaging compound in the extract of A. ochraceus was isolated and purified to clear, colourless 'needles'. With nuclear magnetic resonance-mass spectroscopy spectra, the compound was confirmed to be 5,6-dihydropenicillic acid, the DNA-damaging potency of which has not been previously reported.


[The components of the phenotypic dispersion of the basic typological traits and of work capacity in horses of the Ukrainian saddle breed].
The indexes of standardized deviations by the measured characters (probits) are expedient to be used for distribution of horses according to classes M-, M0 and M+, under these conditions one can select individuals M0 for to rise their capacity for work and expressivity of the type of breed.


Are Synonymous Substitutions in Flowering Plant Mitochondria Neutral?
Angiosperm mitochondrial genes appear to have very low mutation rates, while non-gene regions expand, diverge, and rearrange quickly. One possible explanation for this disparity is that synonymous substitutions in plant mitochondrial genes are not truly neutral and selection keeps their occurrence low. If this were true, the explanation for the disparity in mutation rates in genes and non-genes needs to consider selection as well as mechanisms of DNA repair. Rps14 is co-transcribed with cob and rpl5 in most plant mitochondrial genomes, but in some genomes, rps14 has been duplicated to the nucleus leaving a pseudogene in the mitochondria. This provides an opportunity to compare neutral substitution rates in pseudogenes with synonymous substitution rates in the orthologs. Genes and pseudogenes of rps14 have been aligned among different species and the mutation rates have been calculated. Neutral substitution rates in pseudogenes and synonymous substitution rates in genes are significantly different, providing evidence that synonymous substitutions in plant mitochondrial genes are not completely neutral. The non-neutrality is not sufficient to completely explain the exceptionally low mutation rates in land plant mitochondrial genomes, but selective forces appear to play a small role.


Profiles of cognitive impairment in chronic heart failure-A cluster analytic approach.
Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. The prospective cohort study "Cognition.Matters-HF" recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the "global deficits" cluster and the "no deficits" group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.


Cross-reactivity of antibodies against T-2 with deepoxide T-2 toxin.
Two types of antibodies raised against T-2 toxin, namely anti-T-2-HS-BSA and anti-3 -Ac -NEOS-HS -BSA, showed good cross-reactivity with deepoxy T-2 toxin. Our results indicate that the epoxide is not an important epitope for the production of antibody against T-2 toxin.


Early mortality in myeloma patients treated with first-generation novel agents thalidomide, lenalidomide, bortezomib at diagnosis: A pooled analysis.
Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity. We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib. During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients <80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death. First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.


Estradiol via estrogen receptor beta inhibits chondrogenesis of mouse vertebral growth plate in vitro.
Abnormal growth of vertebral growth plate (VGP) was considered as one of the etiologic factors in adolescent idiopathic scoliosis (AIS). Previous studies described that estrogen played an important role in the pathogenesis of AIS. The present study was aimed to investigate the effect of estrogen/estrogen receptor axis on mouse VGP chondrocytes in vitro. Chondrocytes were isolated from mouse VGP and treated with or without 17β-estradiol (E2). Cell proliferation was measured by the cell growth rate assay. Gene expression of collagen type II and aggrecan were evaluated by real-time PCR. Expression of the proliferating cell nuclear antigen (PCNA), Sox9, and Smad4 were detected by Western blotting. Estradiol inhibited the proliferation of VGP chondrocytes and the gene expression of collagen type II and aggrecan and downregulated the protein expression of PCNA, Sox9, and Smad4. In addition, the inhibitory effect of estradiol was reversed by ERβ small interfering RNA (siRNA) or PHTPP, an ERβ antagonist. Estradiol via estrogen/estrogen receptor β axis inhibits the proliferation and differentiation of VGP chondrocytes, which might give some new insight into the regulatory mechanism of bone development.


Supramolecular organization of lysophosphatidylcholine-packaged Gramicidin A.
Heat derived gramicidin A'/L-alpha-lysophosphatidylcholine complexes were separated on a sucrose gradient to form two fractions: Fraction A which had an approximately constant Gramicidin A' to phospholipid ratio of 8 to 10 lipid molecules per Gramicidin A' molecule and Fraction B which had a larger but variable ratio. Fluorescence and circular dichroism studies confirmed Fraction A to be a lipid-incorporated channel state. Electron microscopic studies, using uranyl acetate negative staining, showed fraction A to be a membranous state with the formation of bilayer vesicles, that is, the interaction of peptide and phospholipid micelles causes the lipid to reorganize into a bilayer structure. Freeze-fracture replicas of the channel incorporated state demonstrated the presence of a supramolecular organization of particles exhibiting a tendency to form rows with a 50-60 A periodicity along the row and with 70-80 A distance between rows. An idealized working model for the incorporated state is presented.


Terminal deletion of chromosome 10q and its clinical features.
A male case with terminal deletion of chromosome 10q has growth retardation, craniofacial dysmorphism, congenital heart disease and other minor anomalies. The karyotypic formula is 46, XY, del (10), (q26.1----qter) by a high resolution G-banding staining. There are few differences in clinical features between our case and the previously reported cases.


[Complete (R0) resection is the only valid prognostic factor in abdominoperineal resection for recurrent cancer of the anal canal (a consecutive series of 95 patients)].
When radiation therapy fails to control cancer of the anal canal, the only therapeutic alternative is salvage abdomino-perineal resection (APR). Its role remains debatable since very few long-term survivals have been reported. No prognostic factors have yet been identified in the limited series of reported cases. 95 APR's performed over a 20 year period are reviewed and analyzed. Median follow-up was 5.5 years. Only one prognostic factor was identified: an R0 resection (n=76) versus either R1 (n=9) or R2 (n=9) resection. Median survival for R0 APR was more than 10 years versus 1 year for R1 and R2 resections (p=0.001). There was no prognostic difference between salvage APR for disease progression (n=55) or for late recurrence (n=40). The sub-group of women<45 years of age (n=5) had a particularly poor prognosis with no survivors beyond 2 years. When anal cancer recurs after radiation therapy, a salvage APR is indicated. If an R0 resection can be achieved, median survival is greater than 10 years. However, the justification for APR when only an R1 or R2 resection can be achieved is much less clear; in such cases there was no survival beyond 3 years.


Aqueous root extract of Lecaniodiscus cupanioides restores nitric oxide/cyclic guanosine monophosphate pathway in sexually impaired male rats.
Aqueous root extract of Lecaniodiscus cupanioides is widely used in the management of sexual dysfunction in Nigeria. The effect of aqueous root extract of L. cupanioides root on the concentrations of penile cyclic Guanosine Monophosphate (cGMP) and plasma nitric oxide in paroxetine-induced sexually impaired male rats was evaluated. Thirty (30) albino rats were assigned into six groups (A, B, C, D, E and F) of five rats each such that animals in Group A (control) received distilled water while those in Groups B, C, D, E and F which were induced into sexual dysfunction (p.o 10mg/kg of paroxetine hydrochloride suspension in Tween-80) and in addition received distilled water, 7.14 mg/kg body weight of a reference herbal drug (PowmaxM), 25, 50 and 100mg/kg body weight of the extract respectively, orally, once daily for five days. Administration of paroxetine significantly reduced the levels of penile cyclic Guanosine Monophosphate (cGMP) and plasma nitric oxide. These decreases were dose dependently reversed by the aqueous extract of L. cupanioides root. The reversal by the 25 and 50mg/kg body weight of the extract compared favorably with the PowmaxM, whereas the 100mg/kg body weight of the extract compared favorably with the non-sexually impaired distilled water treated control animals. The results of this study show that aqueous extract of L. cupanioides root restored the levels of cGMP and nitric oxide in sexually impaired rats. This study further lends credence to the use of aqueous root extract of L. cupanioides in the management of sexual dysfunction in Nigeria.


Immune mechanisms shape the clonal landscape during early progression of prostate cancer.
Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Using multicolor lineage tracing in genetically engineered mouse models and single-cell transcriptomics, we show that slowly progressing tumors contain a multiclonal landscape of relatively homogeneous subpopulations within a well-organized tumor microenvironment. In more advanced and aggressive tumors, however, the multiclonal landscape develops into competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that this dominant/minor landscape is associated with differential immunoediting, in which minor clones are marked by an increased expression of IFNγ-response genes and the T cell-activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. Notably, the immune-specific gene signature of minor clones exhibits a prognostic value for biochemical recurrence-free survival in human prostate cancer. These findings suggest new immunotherapy approaches for modulating clonal fitness and tumor progression in prostate cancer.


Posterior capsular vacuuming to avoid PCO formation.
To retrospectively evaluate the effectiveness of the capsular vacuuming technique in reducing posterior capsule opacification (PCO). Group 1 of the study consisted of 2752 eyes of 2752 patients with a cataract who had undergone phacoemulsification and IOL implantation surgery with anterior, equatorial, and posterior capsular polishing between January 2010 and December 2014. Group 2 consisted of 2761 eyes of 2761 patients with a cataract who had undergone phacoemulsification and IOL implantation surgery with anterior, equatorial, and posterior capsular polishing as well as posterior capsular vacuuming between January 2010 and December 2014. The mean patient age was 63.45 ± 12.23 years (range, 43-89) in Group 1 and 64.02 ± 13.36 years (range, 40-91) in Group 2. The two groups did not significantly differ with respect to age, sex, preoperative and postoperative uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and intraocular pressure (IOP) measurements (p > 0.05). At the 5-year follow-up, 253 eyes (9.19%) in Group 1 developed PCO requiring Nd:YAG laser capsulotomy, whereas 24 eyes (0.86%) in Group 2 developed PCO requiring Nd:YAG laser capsulotomy (p < 0.001). During capsular vacuuming, posterior capsule rupture was observed in the shape of a hole in only 2 eyes in Group 2. But the IOLs were implanted in the capsular bag in all eyes in both groups. PCO is the most common complication of cataract surgery; therefore, surgical technique is important in preventing PCO formation. We recommend posterior capsular vacuuming together with anterior, equatorial, and posterior capsular polishing, as this method significantly reduced the PCO rate.


Action of somatostatin, levodopa and pyridoxine on growth hormone (GH) secretion in newborn infants.
We studied the effect of i.v. levodopa, pyridoxine and synthetic somatostatin in 28 normal babies during the first hours of life. Somatostatin caused a decrease in GH levels in all infants; in addition, both levodopa and pyridoxine infection paradoxically suppressed GH secretion in all subjects. It is concluded that in the first hours of life GH secretion can be suppressed by synthetic somatostatin as well as by levodopa and pyridoxine administration.


Ensuring respiratory phase consistency to improve cardiac function quantification in real-time CMR.
To develop an automatic method for selecting heartbeats with consistent respiratory phase to improve accuracy of cardiac function quantification in real-time (RT) cardiac MRI. The respiratory signal is extracted by a principal component analysis method from RT cine images. Then, a two-step procedure is used to determine the directionality (sign) of the respiratory signal. With the motion in a manually selected region-of-interest as a reference, the quality of the extracted respiratory signal is assessed using multislice RT cine data from 11 volunteers and 10 patients. In addition, the impact of selecting heartbeats with consistent respiratory phase on the cardiac function quantification is evaluated. The extracted respiratory signal using the proposed method exhibits a high, positive correlation with the reference in all cases and is more robust compared to a recently proposed method. Also, for right ventricular function quantification, selecting heartbeats at expiratory position improves agreement between RT cine and breath-held reference. The proposed method enables fully automatic extraction and directionality determinations of respiratory signal from RT cardiac cine images, allowing accurate cardiac function quantification.


Synergistically reinforced poly(ethylene oxide)-based composite electrolyte for high-temperature lithium metal batteries.
Traditional liquid lithium-ion batteries are not applicable for extreme temperatures, due to the shrinkage of separators and volatility of electrolytes. It is necessary to develop advanced electrolytes with desirable characteristics in terms of thermal stability, electrochemical stability and mechanical properties. Solid-state electrolytes, such as polyethylene oxide (PEO), outperform other types and bring the opportunity to realize the high-temperature lithium-ion batteries. However, the softness of PEO at elevated temperatures leads to battery failure. In this work, a three-dimensional fiber-network-reinforced PEO-based composite polymer electrolyte is prepared. The introduced polyimide (PI) framework and trimethyl phosphate (TMP) plasticizer decrease the crystallinity of PEO and increase the ionic conductivity at 30 °C from 8.79 × 10-6 S cm-1 to 4.70 × 10-5 S cm-1. In addition, the PEO bonds tightly with PI fiber network, improving both the mechanical strength and thermal stability of the prepared electrolyte. With the above strategies, the working temperature range of the PEO-based electrolytes is greatly expanded. The LiFePO4/Li cell assembled with the PI-PEO-TMP electrolyte stably performs over 300 cycles at 120 °C. Even at 140 °C, the cell still survives 80 cycles. These excellent performances demonstrate the potential application of the PI-PEO-TMP electrolyte in developing safe and high-temperature lithium batteries.


Emotional dysregulation as a mediator linking sleep disturbance with aggressive behaviors: Disentangling between- and within-person associations.
Sleep problems and aggressive behaviors are two prevalent and highly related problems among adolescents and emerging adults worldwide. This longitudinal study examined the reciprocal relations between sleep disturbance with aggressive behaviors and whether emotional dysregulation functioned as mediator of the relations, after separating within-person effects from between-person effects. A total of 4352 freshman students participated in a five-wave longitudinal study across two and half years. Data from the second wave to the fourth wave was used in this study. Random intercept cross-lagged panel models (RI-CLPM) were utilized to separate between- and within-person effects. Results from RI-CLPM showed: (a) Sleep disturbance and aggressive behaviors bidirectionally predicted each other at the within-person level; (b) Emotional dysregulation functioned as a mediator of the associations from sleep disturbance to aggressive behaviors at the within-person level. These findings advanced the literature by elucidating longitudinal associations among sleep disturbance, emotional dysregulation, and aggressive behaviors at the within-person level, suggesting that prevention and intervention programs targeted at improving emotional regulation skills may be helpful to prevent the developmental pathway from sleep disturbance to aggressive behaviors among college students.


Prolonged treatment with the proteasome inhibitor MG-132 induces apoptosis in PC12 rat pheochromocytoma cells.
Rat pheochromocytoma (PC12) cells were treated with the proteasome inhibitor MG-132 and morphological changes were recorded. Initially, neuronal differentiation was induced but after 24 h signs of morphological deterioration became apparent. We performed nuclear staining, flow cytometry and WST-1 assay then analyzed signal transduction pathways involving Akt, p38 MAPK (Mitogen-Activated Protein Kinase), JNK (c-Jun N-terminal Kinase), c-Jun and caspase-3. Stress signaling via p38, JNK and c-Jun was active even after 24 h of MG-132 treatment, while the survival-mediating Akt phosphorylation declined and the executor of apoptosis (caspase-3) was activated by that time and apoptosis was also observable. We examined subcellular localization of stress signaling components, applied kinase inhibitors and dominant negative H-Ras mutant-expressing PC12 cells in order to decipher connections of stress-mediating pathways. Our results are suggestive of that treatment with the proteasome inhibitor MG-132 has a biphasic nature in PC12 cells. Initially, it induces neuronal differentiation but prolonged treatments lead to apoptosis.


Proposed Sheffield quantitative criteria in cervical cytology to assist the grading of squamous cell dyskaryosis, as the British Society for Clinical Cytology definitions require amendment.
In 1986, the British Society for Clinical Cytology (BSCC) published quantitative criteria to assist diagnosis in a three-tier grading system of squamous cell dyskaryosis. In dyskaryotic cells, area nuclear to cytoplasmic (NC) ratios below 50%, between 50% and 66% and over 66% were defined as equating with mild, moderate and severe grades respectively. Following the Terminology Conference in 2002, however, the BSCC recommended on their website that the three-tier model should be replaced by a new two-tier system of low- and high-grade squamous abnormalities. The latter broadly equate with the two-grade Bethesda System (TBS) for reporting squamous intraepithelial lesions. The purpose of this study was to assess the accuracy and reproducibility of the BSCC three-tier quantitative definitions, to investigate if they were applicable to liquid-based cytology (LBC) and to see how they related to the proposed new two-tier BSCC system. Quantitative image analysis was undertaken on illustrations from the 1986 BSCC terminology publication and on microscope slides from external quality assessment and Cytology Training Centre teaching sets. Analysis of mean NC ratios showed that mild, moderate and severe dyskaryosis exist as statistically different populations. Overlap of NC ratio ranges, however, limits their practical application in the three-tier model, although interestingly no overlap was noted between mild and severe dyskaryosis. No grade of dyskaryosis had a mean area NC ratio over 50%, indicating that the BSCC quantitative definitions are incorrect. The mean diameter NC ratios for mild, moderate and severe dyskaryosis were found to be 40%, 49% and 66% respectively. Accordingly it is possible that those reporting cervical cytology could be interpreting the BSCC NC ratios as meaning diameter rather than area. Amalgamation of the three-tier results into the proposed two-tier model shows that the resulting mean NC area and diameter ratios identify statistically different low- and high-grade populations. The reduced degree of overlap, however, of NC ratio ranges in the two-tier model implies that NC ratios could have a useful practical role in the separation of the low- and high-grade categories. The two categories were reasonably well separated by mean area and diameter NC ratios of 25% and 50% respectively. A two-tier model combining mild with moderate rather than severe dyskaryosis was found to be a statistically valid alternative but gave rise to NC ratios that would be difficult to use in practice. Except for moderate dyskaryosis, no significant differences were identified between the mean NC ratios of either conventional and LBC preparations or LBC preparations using two different commercial methodologies (SurePath and ThinPrep). Differences, however, were noted in area measurements between SurePath and ThinPrep and this has potential implications for classifications (such as TBS) using area comparisons as their basis. In addition, it was found that the increased NC ratio, associated with higher grades of dyskaryosis is more a consequence of progressive cytoplasmic area reduction rather than nuclear area increase. The similar NC ratios of borderline nuclear changes associated with human papilloma virus and mild dyskaryosis support the BSCC proposal that these can be combined to constitute a low-grade category. This study shows that the BSCC area NC ratio criteria of grading squamous cell dyskaryosis require amendment. In addition, this study supports the new BSCC recommendation of low- and high-grade squamous cell categories. The study proposes Sheffield quantitative criteria to assist the grading of squamous cell abnormalities. Quantitative diameter NC ratio measurements, however, must always be accompanied by detailed assessment of qualitative morphological features and in particular those relating to nuclear chromatin. This is equally relevant to both two- and three-tier models.


Ki-67 labeling: a more sensitive indicator of malignant phenotype than mitotic count or tumor size?
The Ki-67 index has been incorporated into The World Health Organization's classification system of pancreatic neuroendocrine tumors. However, pathologists continue to question the utility of Ki-67 index over that of mitotic count as an indicator of proliferative activity. The intent of the current study is to compare K-i67 index with tumor size and mitotic rate for the association of each with lymph node metastasis and survival. The current study is a review of 24 patients with pancreatic neuroendocrine tumors. Regional LNM were present in 100% of tumors with Ki-67 index >10%, while only 25% of tumors with <10% Ki-67 had LNM (P = 0.003). No tumors <2 cm had >10% Ki-67 labeling. Of patients with tumors showing ≥ 10% Ki-67 labeling, 80% died during the observation period of this study, while during the same time period, no patients with <10% Ki-67 labeling died. Ki-67 index of >10% is a sensitive indicator of malignant behavior and mortality. Future advances in management of pNETs will require development of staging guidelines with higher predictive value. Inclusion of Ki-67 labeling >10% as an indicator of aggressive disease may contribute to such improvements.


High frequency stimulation and pharmacological inactivation of the subthalamic nucleus reduces 'compulsive' lever-pressing in rats.
In recent years there have been several attempts to establish high frequency stimulation (HFS) as an additional treatment strategy for obsessive-compulsive disorder (OCD). Two studies reported that bilateral HFS of the subthalamic nucleus (STN) dramatically alleviated compulsions and improved obsessions in three patients with co-morbid Parkinson's disease and OCD. A recent study reported that HFS as well as pharmacological inactivation of the STN alleviate compulsive checking in the quinpirole rat model of OCD. As the quinpirole model is based on a dopaminergic manipulation, the aim of the present study was to test whether HFS and pharmacological inactivation of the STN exert an anti-compulsive effect also in the drug-naive brain, using the signal attenuation rat model of OCD. The main finding of the present study is that both HFS and pharmacological inactivation of the STN exerted an anti-compulsive effect, although the two manipulations differed in their effects on other behavioral measures. These findings support the possibility that HFS of the STN may provide an additional therapeutic strategy for OCD.


Novel Utility of Amplatzer Septal Occlusion Device to Treat Persistent Aortocaval Fistula following Ruptured Endovascular Aortic Aneurysm Repair (rEVAR).
Aortocaval fistulas following endovascular repair of ruptured abdominal aortic aneurysms (rAAA) are rare. We herein describe repair using an Amplatzer Septal Occluder in a 68-year-old male who presented to the emergency department 6 months after ruptured endovascular aneurysm repair (rEVAR) with right heart failure. With the assistance of diagnostic angiography and intravascular ultrasound, the patient was found to have a 1.2 cm diameter aortocaval fistula and a type-II endoleak. His aortocaval fistula was successfully closed using an Amplatzer septal occluder device after failure of attempted closure with an Amplatzer plug and coiling of the aneurysm sac. His symptoms of heart failure improved, and he was discharged to an acute rehabilitation unit. Follow-up at 3 months demonstrated continued improvement in heart failure symptoms, and a small persistent type II endoleak. Aortocaval fistulae are a potentially fatal complication of rAAA. We discuss the sequelae and treatment strategies of aortocaval fistulas following rEVAR including the use of the Amplatzer Septal Occluder.


Progressive fibrosing interstitial lung disease: prevalence and clinical outcome.
The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DLCO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.


The replication domain model: regulating replicon firing in the context of large-scale chromosome architecture.
The "Replicon Theory" of Jacob, Brenner, and Cuzin has reliably served as the paradigm for regulating the sites where individual replicons initiate replication. Concurrent with the replicon model was Taylor's demonstration that plant and animal chromosomes replicate segmentally in a defined temporal sequence, via cytologically defined units too large to be accounted for by a single replicon. Instead, there seemed to be a program to choreograph when chromosome units replicate during S phase, executed by initiation at clusters of individual replicons within each segment. Here, we summarize recent molecular evidence for the existence of such units, now known as "replication domains", and discuss how the organization of large chromosomes into structural units has added additional layers of regulation to the original replicon model.


High reproductive potential of the commercially exploited shark Squalus suckleyi in the major fishing grounds of the western North Pacific.
The present study examined body length (precaudal length, PCL) and age at sexual maturity, as well as fecundity and maternal investment in the Pacific spiny dogfish Squalus suckleyi, a long-term commercially exploited shark in the western North Pacific, using samples caught in several fisheries and across seasons. The PCL and age at 50% sexual maturity of males were 60.6 cm and 9.4 years, respectively, and those of females were 73.1 cm and 17.8 years, respectively. The PCL and age at 50% maternity were 77.4 cm and 19.7 years, respectively. General or generalized linear models revealed that capture by different fishing method did not significantly correlate with sexual maturity and maternity rates or litter size. Other general linear models revealed an increase in offspring size with maternal size, but litter size was not affected by embryonic development. These findings indicate that the reproductive potential of Pacific spiny dogfish is relatively high throughout the whole North Pacific region because of a smaller size and earlier age at sexual maturation in both sexes. In addition, pregnant females displayed no resting phase and produced 0.45 more embryos per centimetre of PCL in their lifetime after the onset of maturity, which is higher than in the eastern North Pacific. We suggest that these qualities are not a consequence of stock decline associated with the long-term exploitation of the species, but that its high reproductive potential has likely contributed to the long-term stability of the landings in Japan. SIGNIFICANCE STATEMENT: While reproductive potential has been determined for many fish species, such information is scarce for Pacific spiny dogfish. We evaluated the reproductive characteristics of this species in the major fishing grounds of the western North Pacific. The productivity and rebound potential of sharks is extremely low compared with those of bony fishes. However, our results indicate that even if the reproductive potential has a small effect on the population dynamics, it should not be ignored for sustainable stock utilisation.


Synthesis, Characterization and Adsorption Properties of Magnetic γ-Fe2O3/C Nanocomposite.
γ-Fe2O3/C nanocomposite was prepared through a convenient method by which one-pot synthesized Fe3O4/Starch was oxidized and carbonized by calcining at 250 °C. The γ-Fe2O3/C displayed strong magnetism and could adsorb organic molecules from aqueous solution effectively, thus it showed promising application in the dislodgement of organic pollutants in sewage. Adsorption isotherms and kinetics of methylene blue (MB) onto γ-Fe2O3/C were studied in a batch system. The adsorption process reached equilibrium in about 15 min, and the maximum adsorption capacity of MB was found to be 64.9 mg g-1 at 303 K. Adsorption isotherms were well fitted to Langmuir model and the adsorption kinetics could be described by the pseudo-second order kinetic equation. The findings of the present work highlight a new facile method to fabricate magnetic carbon-based composites and the obtained γ-Fe2O3/C with excellent magnetic property and adsorption performance hold great promise for practical application in water treatment.


Acute infectious diarrhoea in children: new insights in antisecretory treatment with racecadotril.
In developing countries acute infectious diarrhoea remains one of the leading causes of death among young children, especially those under 1 year of age. In contrast, in industrialized nations the death rate is very low, although the disease is an important cause of morbidity and consumes substantial healthcare costs. A variety of viral, bacterial and parasitic organisms have been implicated in the pathogenesis of acute diarrhoea. The primary objectives of treatment of acute infectious diarrhoea are correction of dehydration with oral replacement therapy (ORT) and maintenance of good nutritional status via food intake. With regards drug therapy antimicrobial agents are not usually recommended since the disease is generally self-limiting. Racecadotril is powerful and selective enkephalinase inhibitor and has emerged as a promising drug in the antisecretory therapy of acute infectious diarrhoea in children. There is encouraging evidence that treatment with racecadotril can provide clinically relevant symptomatic relief by reducing the severity and duration of diarrhoeal episodes. The drug is well tolerated and has a favourable safety profile. However, further comparative studies and cost-effectiveness analyses are needed to define the position of the drug in the management of diarrhoeal illness in children.


Short-term toxicity studies of loline alkaloids in mice.
Epichloë endophytes have been used successfully in pastoral systems to reduce the impact of insect pests through the expression of secondary metabolites. The use of endophytes could be extended to other plant species, such as cereal crops, where the production of bioactive secondary metabolites would reduce the reliance on pesticides for insect control. The success of this approach is dependent on the selection of an appropriate secondary metabolite target which must not only be effective against insect pests but also be safe for grazing and monogastric animals. The loline alkaloids have been identified as possible target metabolites as they are associated with potent effects on insects and low toxicity to grazing animals. The purpose of the current study was to generate toxicological data on the loline alkaloids in a monogastric system using mice. Male and female mice were fed 415 mg/kg/day total lolines for a 3-week period. The loline treatment caused no statistically significant effect on gross pathology, histology, haematology, blood chemistry, heart rate, blood pressure or motor coordination. Reduced weight gain and food consumption were noted in the loline groups during the initial stages of the experiment. This experiment raises no food safety concerns for the loline alkaloids.


Multiple globoid meningiomas associated with craniomandibular fibrous dysplasia: case report.
A 20-year-old male with craniomandibular deformity and almost total visual loss of the right eye due to bilateral optic atrophy underwent cerebral nonenhanced computed tomography (NECT) examinations. He had multiple sphenoidal-temporoparietal meningiomas, with adjacent hyperostoses and distant calvarial hyperdense lesions, as well as sclerotic expansion of right mandibular condyle. History, clinical and imaging findings were suggestive of associated fibrous dysplasia (FD), which explained the visual loss due to optic nerve compression through sphenoidal optic foramens. Cranial and mandibular FD and concurrent multiple globoid meningiomas in this case may suggest a mutual influence, which may explain the etiopathogenesis of FD lesions and/or bone hyperdensities adjacent or distant to meningiomas.


Mutational bias of Turnip Yellow Mosaic Virus in the context of host anti-viral gene silencing.
Plant Dicer-like (DCL) enzymes exhibit a GC-preference during anti-viral post-transcriptional gene silencing (PTGS), delivering an evolutionary selection pressure resulting in plant viruses with GC-poor genomes. However, some viruses, e.g. Turnip Yellow Mosaic Virus (TYMV, genus Tymovirus) have GC-rich genomes, raising the question as to whether or not DCL derived selection pressure affects these viruses. In this study we analyzed the virus-derived small interfering RNAs from TYMV-infected leaves of Brassica juncea showed that the TYMV population accumulated a mutational bias with AU replacing GC (GC-AU), demonstrating PTGS pressure. Interestingly, at the highly polymorphic sites the GC-AU bias was no longer observed. This suggests the presence of an unknown mechanism preventing mutational drift of the viral population and maintaining viral genome stability, despite the host PTGS pressure.


A novel PAK4 inhibitor suppresses pancreatic cancer growth and enhances the inhibitory effect of gemcitabine.
Over 95% of Pancreatic ductal adenocarcinomas (PDA) carry mutations in the oncogene KRas which has been proven to be a difficult drug target. P21-activated kinase 4 (PAK4), acts downstream of KRas, and is overexpressed in PDA contributing to its growth and chemoresistance, and thus becomes an attractive therapeutic target. We have developed a new PAK4 inhibitor, PAKib and tested its effect on pancreatic cancer (PC) cell growth in vitro and in a syngeneic mouse model of PC. PAKib suppressed PC cell growth by inducing cell death and cycle arrest. PAKib inhibited PC growth and enhanced the inhibition by gemcitabine of PC in cell culture and in PC mouse model. PAKib acted through multiple signaling pathways involved in cell cycle checkpoints, apoptosis, cell junction, and focal adhesion. These proof-of-concept studies demonstrated the anti-cancer effect of PAKib alone and in combination with gemcitabine and warrant a further clinical investigation.


Looking beyond the Wnt pathway for the deep nature of β-catenin.
After two decades of stardom, one would think that β-catenin has revealed all of its most intimate details. Yet the essence of its duality has remained mysterious--how can a single protein both be the core link between cadherins and the cytoskeleton, and the nuclear messenger for Wnt signalling? On the basis of the available evidence and on molecular and evolutionary considerations, I propose that β-catenin was a born nuclear transport receptor, which by interacting with adhesion molecules acquired the property to coordinate nuclear functions with cell-cell adhesion. While Wnt signalling diverted this activity, the original pathway might still function in modern eukaryotes.


[Drownings].
The epidemiology of drowning is described discussing the pathological mechanism of death during drowning, mentioning the characteristic types of drowning and outlining the main principles of treatment of drowned subjects.


High production of erythritol from Candida sorbosivorans SSE-24 and its inhibitory effect on biofilm formation of Streptococcus mutans.
Amongst different isolates screened for erythritol production, isolate no. SSE-24 was found to be the best erythritol producer and identified as Candida sorbosivorans SSE-24. Statistical optimization was used to determine the optimum level of the significant variables for maximum erythritol production. The interactive effects of glucose, inoculum level and yeast extract were determined to be significant. The optimum medium composition for erythritol production was 160 g/L glucose, 12 g/L yeast extract, 10% inoculum level and 0.35 g/L FeSO4⋅7H2O. The production of erythritol was successfully scaled up to a 30 L level, where 60.20 g/L of erythritol was produced, with a yield of 0.38 g/g. The fermentation broth was purified by activated charcoal followed by vacuum concentration, ion exchange chromatography and crystallization. Purity of erythritol was further determined by NMR. Significant inhibitory effect of erythritol on growth (>78%) and biofilm formation (40.2%) of Streptococcus mutans enhances the importance of this study.


Simultaneous soot combustion and nitrogen oxides storage on potassium-promoted hydrotalcite-based CoMgAlO catalysts.
A series of potassium-promoted hydrotalcite-based CoMgAlO mixed oxide catalysts used for simultaneous soot combustion and nitrogen oxides storage were prepared by impregnation method. The techniques of TG/DTA, XRD, H2-TPR and in situ DRIFTS were employed for catalyst characterization. Over the catalyst containing 7.5% or 10% K, the soot ignition temperature (Ti=260 degrees C) and total removal temperature (Tf=390 degrees C) are decreased by 180 degrees C and 273 degrees C, respectively, as compared with the uncatalyzed reaction. The results of kinetic calculation show that the presence of K-promoted catalysts decreases the activation energy of soot combustion from 207kJ/mol to about 160kJ/mol. When 400ppm NO is introduced, lower characteristic temperatures or higher reaction rate for soot oxidation is achieved. Simultaneously, relatively larger nitrogen oxides storage capacity is obtained. It is revealed by H2-TPR that the addition of K increases the amount of active Co sites and the mobility of bulk lattice oxygen due to the low melting point of K-containing compounds, the low valence of K+ and the strong interaction between K and Mg(Al). For nitrogen oxides storage, different routes via chelating bidentate nitrates, monodentate nitrates and ionic nitrates are confirmed by in situ DRIFTS over the CoMgAlO catalysts with potassium loadings of 0, 1.5 and 7.5%, respectively.


Antiepileptic drug therapy in pregnancy I: gestation-induced effects on AED pharmacokinetics.
The ideal management of women with epilepsy during pregnancy involves achieving an optimal balance between minimizing fetal exposure to the deleterious influences of both antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiological changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Many of the AEDs are characterized by significant increases in clearance during pregnancy. Studies performed thus far provide convincing findings for significant increases in the clearance of lamotrigine and phenytoin during pregnancy; other studies support that phenobarbital, oxcarbazepine, and levetiracetam clearances also most likely increase during pregnancy. Therapeutic drug monitoring of lamotrigine with adjustment of dosages during pregnancy to maintain that individual's target concentration has been shown to decrease the risk for increased seizure frequency. Reports of seizure worsening with decreased concentrations of other AEDs have been reported but not studied in similar formal protocols. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy, with assessment of maternal and fetal/newborn consequences, could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but at the same time minimize fetal drug exposure.


T-cell phenotypes in chemically induced leukemia in mice.
T-cell leukemias were induced in adult BDF mice by a single i.v. injection of 50 mg kg-1 of methylnitrosourea (MNU). Leukemic cells from the thymus and other organ sites showed the theta antigen and were peanut-negative, but were heterogeneous with respect to Lyt-1 and Lyt-2. The acute cytotoxic effect of the MNU showed no preferential toxicity to a special T-cell subset in the thymus. During the latency period of leukemogenesis a continuous fall in peanut-positive cells in the thymus was found.


Levels of true thymidine kinase and nucleoside phosphotransferase in two strains of Tetrahymena pyriformis under different growth conditions.
Activities of typical thymidine kinase and nucleoside phosphotransferase are both present in logarithmically growing tetrahymena pyriformis, GL-1 and ST strains, contrary to previous reports. 2. Activities of thymidine kinase and nucleoside phosphotransferase are also found in both GL-1 and ST strains grown in the defined medium, PPL medium and Neff's medium. 3. The specific activities of both enzymes are very much influenced by the growth state. Both the specific activities of thymidine kinase and nucleoside phosphotransferase decrease steadily from the start of the experiments when the cell numbers were about 2-3 x 10(4) cells/ml in the PPL medium, while in the Neff's medium, the specific activities of thymidine kinase increase up to when the cell numbers reached 3-5 x 10(5) cells/ml and then decreased, but the specific activities of nucleoside phosphotransferase continuously decreased when the cell concentrations were 2-6 x 10(4) cells/ml. 4. In the PPL medium, the final cell numbers reached are about 6.5 x 10(5) cells/ml, while in the Neff's medium, the cell numbers increase further (to about 2 x 10(6) cells/ml). 5. No striking difference in activities of thymidine kinase and nucleoside phosphotransferase was observed when the cells were transferred from the defined medium to the Neff's medium, contrary to that reported by others for the activity of thymidylate synthetase.


Optical platelet aggregometry does not appear useful as a means of assessing the risk of recurrent vascular events in aspirin-treated patients.
To investigate whether the results of optical platelet aggregometry indicate the risk of recurrent ischemic events. Cerebro- and cardiovascular patients taking aspirin for at least 30 days were studied retrospectively. Ischemic vascular events occurring prior to testing and the presence of vascular risk factors were recorded. 241 subjects were included. Among the 78 patients (32.4%) who displayed recurrent vascular episodes, the age (62.5 +/- 10.6 vs. 58.4 +/- 11.6, P = 0.009) and the proportion of hypertensives (80.8% vs. 68.1%, P = 0.040) were significantly higher when compared with the participants who exhibited single events. The degree of platelet aggregation did not differ significantly between the patients with and those without recurrent episodes. Logistic regression analysis identified only age (OR 1.033, 95% CI 1.008-1.058, P = 0.010), and not aggregation values, as a risk condition for recurrent vascular episodes. Results of optical platelet aggregometry were not indicative of the risk of recurrent vascular events. The role of conventional risk factors appeared to be more important.