Processes of incremental message planning during conversation.
Speaking begins with the formulation of an intended preverbal message and linguistic encoding of this information. The transition from thought to speech occurs incrementally, with cascading planning at subsequent levels of production. In this article, we aim to specify the mechanisms that support incremental message preparation. We contrast two hypotheses about the mechanisms responsible for incorporating message-level information into a linguistic plan. According to the Initial Preparation view, messages can be encoded as fluent utterances if all information is ready before speaking begins. By contrast, on the Continuous Incrementality view, messages can be continually prepared and updated throughout the production process, allowing for fluent production even if new information is added to the message while speaking is underway. Testing these hypotheses, eye-tracked speakers in two experiments produced unscripted, conjoined noun phrases with modifiers. Both experiments showed that new message elements can be incrementally incorporated into the utterance even after articulation begins, consistent with a Continuous Incrementality view of message planning, in which messages percolate to linguistic encoding immediately as that information becomes available in the mind of the speaker. We conclude by discussing the functional role of incremental message planning in conversational speech and the situations in which this continuous incremental planning would be most likely to be observed.


Estradiol regulation of follistatin and inhibin alpha- and beta(B)-subunit mRNA in avian granulosa cells.
Estradiol modulation of granulosa cell growth and regulation of follistatin and inhibin alpha- and beta(B)-subunit mRNA were investigated in cultured chicken granulosa cells. Granulosa cells were isolated and pooled according to size from the F(4) + F(5), small yellow (SYF), and large white (LWF) follicles. Isolated and dispersed granulosa cells were then cultured in the absence or presence of 1 x 10(-5) M 17 beta-estradiol. In Experiment 1 (n = 4 replications) the effect of estradiol on the growth of granulosa cells from the different-sized follicles was examined at 24 and 48 h of culture. Untreated and treated granulosa cells from all three follicle sizes proliferated during culture, and cell viability for all cultures was over 95% throughout the experiment. After 48 h the untreated cultures for all follicle types had 1.6 to 2.2 times (P < 0.05) more cells than the estradiol-treated cultures. In Experiment 2 (n = 3 replications), the cultures were terminated at 4 and 24 h after plating. Follistatin mRNA levels were higher in estradiol-treated cells at 24 h in F(4) + F(5) follicles, at 4 and 24 h in the SYF, and at 4 h in the LWF. beta(B)-subunit mRNA levels were also increased by estradiol at 4 h in F(4) + F(5) cells and at 4 and 24 h in the LWF. Steady state mRNA levels for the alpha-subunit were higher (P < 0.05) in estradiol-treated cultures at 4 and 24 h in F(4) + F(5) follicles and at 24 h in the SYF. Immunoreactive alpha-subunit protein, however, was not increased by estradiol treatment. Thus, whereas estradiol inhibited granulosa cell growth, it exerted a generally stimulatory effect on the expression of FS and the inhibin alpha- and beta(B)-subunit mRNA.


Development, evaluation, and laboratory validation of immunoassays for the diagnosis of equine infectious anemia (EIA) using recombinant protein produced from a synthetic p26 gene of EIA virus.
Equine infectious anemia (EIA)-a retroviral disease caused by equine infectious anemia virus (EIAV)-is a chronic, debilitating disease of horses, mules, and donkeys. EIAV infection has been reported worldwide and is recognized as pathogen of significant economic importance to the horse industry. This disease falls under regulatory control program in many countries including India. Control of EIA is based on identification of inapparent carriers by detection of antibodies to EIAV in serologic tests and "Stamping Out" policy. The current internationally accepted test for diagnosis of EIA is the agar gel immune-diffusion test (AGID), which detects antibodies to the major gag gene (p26) product. The objective of this study was to develop recombinant p26 based in-house immunoassays [enzyme linked immunosorbent assays (ELISA), and AGID] for EIA diagnosis. The synthetic p26 gene of EIAV was expressed in Escherichia coli and diagnostic potential of recombinant p26 protein were evaluated in ELISA and AGID on 7,150 and 1,200 equine serum samples, respectively, and compared with commercial standard AGID kit. The relative sensitivity and specificity of the newly developed ELISA were 100 and 98.6 %, respectively. Whereas, relative sensitivity and specificity of the newly developed AGID were in complete agreement in respect to commercial AGID kit. Here, we have reported the validation of an ELISA and AGID on large number of equine serum samples using recombinant p26 protein produced from synthetic gene which does not require handling of pathogenic EIAV. Since the indigenously developed reagents would be economical than commercial diagnostic kit, the rp26 based-immunoassays could be adopted for the sero-diagnosis and control of EIA in India.


Choroidal thickness following extrafoveal photodynamic treatment with verteporfin in patients with central serous chorioretinopathy.
To evaluate the effect of verteporfin photodynamic treatment (PDT) on choroidal thickness in patients with central serous chorioretinopathy (CSC). Choroidal thickness was measured with enhanced depth imaging- optical coherence tomography (EDI-OCT) before and after verteporfin PDT (full-dose verteporfin, half-light dose) in 16 eyes in 16 patients with serous detachment of the fovea secondary to extrafoveal angiographic fluorescein leakage. Treatment was confined to the area of leakage, whereas choroidal thickness before and after treatment was assessed over a larger area of the fundus using OCT. Complete resolution of the serous detachment was seen in all 16 eyes within 1 month of extrafoveal PDT, while choroidal thickness in the area where PDT was applied decreased from 407 μm [mean; 95% confidence interval (CI(95) ) 356-458 μm] to 349 μm (mean; CI(95) 300-399 μm; p < 0.0001), and subfoveal choroidal thickness was reduced from 421 μm (mean; CI(95) 352-489 μm) to 346 μm (mean; CI(95) 278-414 μm; p = 0.0001). Initially, subfoveal choroidal thickness was significantly increased in the treated eye compared with the healthy fellow eye (mean 324 μm; CI(95) 273-376 μm; p = 0.0003), but after treatment, the difference was not significant. Photodynamic therapy of active CSC was followed by choroidal thickness reduction, not only locally but also at considerable distance from the treated area. Thus, the process that causes choroidal thickening in CSC appears to spread laterally within the choroid.


A dual function alpha-dioxygenase-peroxidase and NAD(+) oxidoreductase active enzyme from germinating pea rationalizing alpha-oxidation of fatty acids in plants.
An enzyme with fatty acid alpha-oxidation activity (49 nkat mg(-1); substrate: lauric acid) was purified from germinating pea (Pisum sativum) by a five-step procedure to apparent homogeneity. The purified protein was found to be a 230-kD oligomer with two dominant subunits, i.e. a 50-kD subunit with NAD(+) oxidoreductase activity and a 70-kD subunit, homolog to a pathogen-induced oxygenase, which in turn shows significant homology to animal cyclooxygenase. On-line liquid chromatography-electrospray ionization-tandem mass spectrometry revealed rapid alpha-oxidation of palmitic acid incubated at 0 degrees C with the purified alpha-oxidation enzyme, leading to (R)-2-hydroperoxypalmitic acid as the major product together with (R)-2-hydroxypalmitic acid, 1-pentadecanal, and pentadecanoic acid. Inherent peroxidase activity of the 70-kD fraction decreased the amount of the (R)-2-hydroperoxy product rapidly and increased the level of (R)-2-hydroxypalmitic acid. Incubations at room temperature accelerated the decline toward the chain-shortened aldehyde. With the identification of the dual function alpha-dioxygenase-peroxidase (70-kD unit) and the related NAD(+) oxidoreductase (50-kD unit) we provided novel data to rationalize all steps of the classical scheme of alpha-oxidation in plants.


[Microalbuminuria and clinical proteinuria as the main predictive factors of cardiovascular morbidity and mortality in patients with type 2 diabetes].
[corrected] The principal objective was that of evaluating the independent contribution of microalbuminuria and clinical proteinuria to the cardiovascular morbidity and mortality in patients with type 2 diabetes. A prospective cohort study with selection of patients with type 2 diabetes evaluated in hospital outpatient consultations. Through the Cox proportional risks model the predictive importance of the presence of microalbuminuria and clinical proteinuria on the appearance of fatal and non-fatal cardiovascular complications (angina, fatal and non-fatal myocardial infarction, sudden death, transitory ischemic attack, fatal and non-fatal stroke, or amputation of lower limbs) was analyzed. The monitoring of 463 patients was done during an average period of 4.64 years (SD: 1.56). There were 330 patients (71.3%) with normoalbuminuria, 106 (22.9%) with microalbuminuria and 27 (5.8%) with proteinuria. The global cardiovascular morbidity and mortality rate was 3.7% annual (2.46% annual for the patients with normoalbuminuria, 5.6% for the patients with microalbuminuria and 14.42% for the patients with proteinuria; p < 0.0001). After multiple adjustment, both microalbuminuria (RR: 1.91; 95% CI: 1.05-3.48; p = 0.032) and proteinuria (RR: 4.15; 95% CI: 1.77-9.75; p = 0.0011) were the main independent predictive factores of appearance of cardiovascular complications. Other predictive variables were age (RR: 1.06; 95% CI: 1.02-1.10; p = 0.0014), HDL cholesterol (RR = 0.96; 95% CI: 0.93-0.98; p = 0.001), LDL cholesterol (RR: 1.01; 95% CI: 1.002-1.02; p = 0.016) and initial presence of ischemic cardiopathy (RR: 1.97; 95% CI: 1.03-3.76; p = 0.041). The increase in the rate of excretion of urinary albumin is the main independent predictive factor of cardiovascular morbidity and mortality in patiens with type 2 diabetes.


Environmental cadmium levels increase phytochelatin and glutathione in lettuce grown in a chelator-buffered nutrient solution.
Phytochelatins are enzymatically synthesized peptides involved in metal detoxification and have been measured in plants grown at very high Cd concentrations, but few studies have examined the response of plants at lower environmentally relevant Cd concentrations. Using an ethylenediaminetetraacetic acid (EDTA)-buffered nutrient medium, we have varied Cd exposure and measured phytochelatin and glutathione concentrations in romaine lettuce (Lactuca sativa L. var. longifolia Lam. var. Parris Island) grown in a flow-through hydroponic (FTH) system. Very low free ionic Cd (10(-9.6) M) increased average phytochelatin concentrations above those of controls, and increasing Cd resulted in increased phytochelatin production, though increases were tissue dependent. Glutathione concentrations also increased with increasing Cd. In other standard hydroponic experiments, the media were manipulated to vary total Cd concentration while the ionic Cd was fixed. We found that the total amount of Cd (primarily EDTA bound) in the medium altered thiol production in roots, whereas thiols in leaves remained constant. The Cd uptake into roots and translocation to old leaves was also influenced by the total concentration in the medium. Cadmium in all tissues was lower and in some tissues thiol concentrations were higher than in FTH-grown plants grown in identical medium, suggesting that nutrient delivery technique is also an important variable. Though phytochelatin and glutathione production can be sensitive to changes in bioavailable Cd, thiol concentrations will not necessarily reflect the Cd content of the plant tissues.


Correlation between anthracycline structure and human DNA ligase inhibition.
A total of 19 anthracycline derivatives were tested for their ability to interfere in vitro with the action of the human replicative DNA ligase. Only those with the sugar devoid of unmodified amino groups or with large configurational modifications were found to be inactive. Maximal inhibition of DNA-joining activity was found to require a 4'-deoxy-3'-amino sugar. Self-adenylation of DNA ligase was largely insensitive to these drugs. An important general finding is that slight modifications of the anthracycline structure have pronounced effects on DNA-ligase-inhibitory activity and might be related to the specificity of anthracycline anti-tumour activity.


Controlled release solid dosage forms using combinations of (meth)acrylate copolymers.
Controlled release solid oral dosage forms have been widely used for decades, enabling drugs to be administered more comfortably while at the same time providing a sustained and reproducible method of release. (Meth)acrylate copolymers are one of the options available when considering a sustained release solid form. Due to their different functionalities it is possible to achieve various different release profiles. The electrical character of these copolymers and their pH-dependent solubility can result in new and modified patterns when these polymers are combined. This review sheds light on various studies involving combinations of (meth)acrylate copolymers for use in multi-unit systems and matrix tablets, and also on several analytical methods that help to identify possible interactions between these polymers.


Comparative metabolic study of the chloroform fraction of three Cystoseira species based on UPLC/ESI/MS analysis and biological activities.
This study aims to investigate the phytoconstituents of the chloroform fraction of three Cystoseira spp. namely C. myrica, C. trinodis, and C. tamariscifolia using UPLC/ESI/MS technique. The results revealed the identification of 19, 20 and 11 metabolites in C. myrica, C. trinodis, and C. tamariscifolia, respectively mainly terpenoids, flavonoids, phenolic acids and fatty acids. Also, an in vitro antioxidant study using FRAP and DPPH assays was conducted where the chloroform fraction of C. trinodis displayed the highest antioxidant activity in both assays, which would be attributed to its highest total phenolics and total flavonoids. Besides, the investigation of COX-1, α-glucosidase and α-amylase inhibitory activities were performed. Regarding C. trinodis, it showed the strongest inhibitory activity towards COX-1. Moreover, it showed potent inhibitory activity towards α-glucosidase and α-amylase enzymes. According to the molecular docking studies, the major compounds characterised showed efficient binding to the active sites of the target enzymes.


Diet-treated gestational diabetes mellitus: comparison of early vs routine diagnosis.
The purpose of this study was to compare pregnancy outcomes in women with diet-treated gestational diabetes mellitus (GDM) that was diagnosed at < 24 weeks of gestation to those women who received the diagnosis at > or = 24 weeks of gestation. This was a retrospective cohort study of 2596 women with diet-treated GDM who delivered between December 1999 and June 2005 at Parkland Hospital. Women with risk factors for GDM underwent immediate glucose screening; women without risk factors underwent universal glucose screening between 24 and 28 weeks of gestation. Women with diet-treated GDM that was diagnosed at < 24 weeks of gestation (n = 339; 13.1%) were compared with those women who received the diagnosis at > or = 24 weeks of gestation. Women with an earlier diagnosis of diet-treated GDM were at increased risk of preeclampsia and the delivery of large infants. Even after adjustment for differences in maternal characteristics and glycemic control, the risk of preeclampsia persisted (odds ratio, 2.4; 95% CI, 1.5, 3.8). Women with an early diagnosis of diet-treated GDM have a 2-fold increased risk of preeclampsia.


Inhaled corticosteroids compared to placebo for prevention of exercise induced bronchoconstriction.
The pathogenesis of exercise induced bronchoconstriction is likely multifactorial and is not completely understood. Inflammation plays an important role in the pathogenesis of exercise induced bronchoconstriction in asthmatic subjects but the evidence seems less strong in non-asthmatic subjects. The management of exercise induced bronchoconstriction focuses on prevention, through both pharmacologic and non-pharmacologic interventions. The objectives of this review were to evaluate the use of inhaled corticosteroids in the treatment of exercise induced bronchoconstriction in a systematic way. Specifically, the review was designed to: determine whether inhaled corticosteroids (compared to placebo) has an attenuating effect on exercise induced bronchoconstriction in adult and pediatric asthmatic patients; estimate the magnitude of the attenuating effect. We searched the Cochrane Airways Review Group Specialised Register of trials, the Cochrane Central Register of Controlled Trials, review articles, textbooks and reference list of articles. Randomised trials in adults or children comparing inhaled corticosteroids with placebo to prevent bronchoconstriction in patients with exercise induced bronchoconstriction. Trial quality assessment and data extraction were conducted independently by two reviewers. The results from six randomised controlled trials involving 123 participants were analyzed (two trials involving adults and four involving children). Combining results from the two parallel studies with at least 4 weeks duration of inhaled corticosteroids, the use of inhaled corticosteroids significantly attenuated the percent fall index in forced expiratory volume in 1 second (WMD = 14.07%; 95% CI: 11.62% to 16.52%). The result from one crossover study with duration of inhaled corticosteroids of 4 weeks revealed significant attenuation of percent fall in forced expiratory volume in 1 second ( WMD = 6.90%; 95% CI: 1.40% to 12.40%) and the percent fall in peak expiratory flow ( WMD =11.50%; 95% CI: 6.31% to 16.69%). The small amount of data from placebo-controlled trials using a single treatment do not currently allow conclusions to be drawn. Inhaled corticosteroids used for 4 weeks or more before exercise testing significantly attenuated exercise-induced bronchoconstriction. The relative benefits of inhaled corticosteroids compared to other forms of exercise induced bronchoconstriction treatment (sodium cromoglycate, nedocromil sodium, salbutamol, and other anti-inflammatory agents) remains unclear.


Hierarchical multi-resolution mesh networks for brain decoding.
Human brain is supposed to process information in multiple frequency bands. Therefore, we can extract diverse information from functional Magnetic Resonance Imaging (fMRI) data by processing it at multiple resolutions. We propose a framework, called Hierarchical Multi-resolution Mesh Networks (HMMNs), which establishes a set of brain networks at multiple resolutions of fMRI signal to represent the underlying cognitive process. Our framework, first, decomposes the fMRI signal into various frequency subbands using wavelet transform. Then, a brain network is formed at each subband by ensembling a set of local meshes. Arc weights of each local mesh are estimated by ridge regression. Finally, adjacency matrices of mesh networks obtained at different subbands are used to train classifiers in an ensemble learning architecture, called fuzzy stacked generalization (FSG). Our decoding performances on Human Connectome Project task-fMRI dataset reflect that HMMNs can successfully discriminate tasks with 99% accuracy, across 808 subjects. Diversity of information embedded in mesh networks of multiple subbands enables the ensemble of classifiers to collaborate with each other for brain decoding. The suggested HMMNs decode the cognitive tasks better than a single classifier applied to any subband. Also mesh networks have a better representation power compared to pairwise correlations or average voxel time series. Moreover, fusion of diverse information using FSG outperforms fusion with majority voting. We conclude that, fMRI data, recorded during a cognitive task, provide diverse information in multi-resolution mesh networks. Our framework fuses this complementary information and boosts the brain decoding performances obtained at individual subbands.


The mechanism of manganese dissolution on Li1.6Mn1.6O4 ion sieves with HCl.
Li1.6Mn1.6O4 is a representative ion sieve material that is used to recover lithium from salt brines and bitterns owing to its high lithium ion adsorption capacity reaching 11.9-44 mg g-1. However, manganese dissolution during acid treatment hinders the industrial application of the material. For investigating the mechanism of manganese dissolution, the precursor Li1.6Mn1.6O4 and ion sieve H1.6Mn1.6O4 were prepared and characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), chemical content analyses, diffuse reflectance infrared Fourier-transform spectroscopy (DRIFTS), and X-ray photoelectron spectroscopy (XPS). The results of XRD, SEM, and FT-IR showed that the bulk phase of Li1.6Mn1.6O4 retained the spinel structure, whereas the lattice diminished during acid treatment. The results of chemical content analyses showed that the bulk phase of Li1.6Mn1.6O4 contained a few trivalent manganese atoms and that the mean valence of manganese in the material increased during acid treatment. DRIFTS and XPS exhibited that the surface of Li1.6Mn1.6O4 was mostly full of tetravalent manganese and retained the spinel structure during acid treatment. In the proposed mechanism of manganese dissolution, an electron of trivalent manganese in the bulk phase transfers to the surface and is captured by tetravalent manganese within the acidic environment. Then, tetravalent manganese is converted to bivalent manganese after acquiring sufficient electrons, and dissolution occurs simultaneously.


[Acute fever due to rats].
The bite of a rat can transmit diverse micro-organisms; however, the development of health measures and the improved conditions of habitability of homes have meant that the infectious diseases transmitted by the aggressions of these animals are infrequent in industrialised countries. In occasional circumstances this type of aggression can still take place, especially in depressed areas on the periphery of big cities and in uninhabited premises, this being a possibility that it is advisable to bear in mind. The case is presented of fever due to a rat bite in a patient who was attacked while cleaning an industrial premise. The evolution of the clinical picture was typical, with Streptobacillus moniliformis isolated as the causal agent, and the picture was controlled with doxicycline without complications arising.


Can Better Emotion Regulation Protect against Suicidality in Traumatized Homeless Youth?
A substantial majority of homeless youth and young adults (HYA) experience abuse prior to and during homelessness. HYA also have high rates of posttraumatic stress disorder (PTSD) and suicidal behavior. This study investigated relationships between traumatic experiences, PTSD symptoms, substance use, and the protective effects of emotion regulation on outcome variables suicidal ideation and suicide attempts. Data were drawn from a sample of 398 HYA interviewed at 3 drop-in centers in Los Angeles County. A bivariate logistic regression modeling strategy was employed to examine relationships among demographic characteristics and dependent and independent variables. Trauma prior to homelessness and trauma prior to and after homelessness were positively associated with suicidal ideation, whereas emotional awareness and control demonstrated negative associations. PTSD symptoms were positively associated with suicide attempts, whereas emotional awareness and control demonstrated negative associations. Better emotion regulation is associated with reduced odds of suicidal ideation and attempts in HYA and may protect against effects of traumatic experiences. Interventions targeting emotion regulation skills in HYA to reduce suicidality associated with traumatic experiences merit additional investigation.


Serum-soluble interleukin-2 receptor (sIL-2R) is an extremely strong prognostic factor for patients with peripheral T-cell lymphoma, unspecified (PTCL-U).
The aim of this study was to assess the prognostic factors of peripheral T-cell lymphoma, unspecified (PTCL-U). We retrospectively analyzed 30 cases fulfilling the criteria of PTCL-U defined by the World Health Organization classification. The patients were treated with 6-8 cycles of a CHOP or THP (pirarubicin)-COP regimen. A high serum sIL-2R level (> or =2,000 U/ml) at onset was associated with a low complete remission rate. Patients with high sIL-2R had significantly lower survival rates (5 year, 15.1%) than those with low sIL-2R (<2,000 U/ml) (100%) (P < 0.005). Factors associated with worse overall survival in a univariate analysis were high sIL-2R (P < 0.005), high age (>60 years) (P < 0.05), poor performance status (P < 0.01) and poor international prognostic index (P < 0.05). No correlation was observed between sIL-2R and other markers. Multivariate analysis showed that only sIL-2R was a prognostic factor for overall survival (P < 0.01). The results suggest that a high serum sIL-2R level predicts a poor prognosis in PTCL-U.


The Impact of a Foot-Toe Orthosis on Dynamic Balance: An Exploratory Randomized Control Trial.
The influence of custom and over-the-counter foot orthoses on dynamic balance has been investigated in the past. However, there has not been an exploration of the use of a foot-toe orthosis for improving balance. The ability of clinicians to influence balance could have important implications for injury prevention and rehabilitation. To determine the impact of a foot-toe orthosis on dynamic balance in healthy, young adults. Randomized control trial. Athletic training laboratory. In total, 64 healthy, recreationally active participants aged 18-29 years were randomly allocated to one of the following groups: the foot-toe orthosis and laboratory-issued shoe group, the laboratory-issued shoe only (SO) group, or the control group. Subjects in the intervention group wore the foot-toe orthosis and laboratory-issued shoe with activities of daily living for 4 weeks. Subjects in the SO intervention group wore the laboratory-issued shoe with activities of daily living for 4 weeks. Participants in the control group did not receive any intervention. The instrumented version of the Star Excursion Balance Test, known as the Lower Quarter Y-Balance Test, was used to quantify the dynamic balance at baseline and follow-up. Reaches were normalized for leg length. There were statistically significant differences in postintervention scores on the Lower Quarter Y-Balance Test for both the dominant (P = .03, effect size = 0.84; 95% confidence interval, 0.25 to 1.43) and nondominant (P = .002, effect size = 0.74; 95% confidence interval, 0.15 to 1.32) legs when comparing dynamic balance scores of the foot-toe orthosis and laboratory-issued shoe group with the SO and control groups. No significant differences were observed when comparing dynamic balance between the SO and control groups. A 4-week intervention with a foot-toe orthosis and laboratory-issued shoe resulted in improved dynamic balance in a healthy young adult population. These findings suggest a novel intervention for increasing balance.


Cost-Saving Early Diagnosis of Functional Pain in Nonmalignant Pain: A Noninferiority Study of Diagnostic Accuracy.
Objectives. We compared two index screening tests for early diagnosis of functional pain: pressure pain measurement by electronic diagnostic equipment, which is accurate but too specialized for primary health care, versus peg testing, which is cost-saving and more easily manageable but of unknown sensitivity and specificity. Early distinction of functional (altered pain perception; nervous sensitization) from neuropathic or nociceptive pain improves pain management. Methods. Clinicians blinded for the index screening tests assessed the reference standard of this noninferiority diagnostic accuracy study, namely, comprehensive medical history taking with all previous findings and treatment outcomes. All consenting patients referred to a university hospital for nonmalignant musculoskeletal pain participated. The main analysis compared the receiver operating characteristic (ROC) curves of both index screening tests. Results. The area under the ROC curve for peg testing was not inferior to that of electronic equipment: it was at least 95% as large for finger measures (two-sided p = 0.038) and at least equally as large for ear measures (two-sided p = 0.003). Conclusions. Routine diagnostic testing by peg, which is accessible for general practitioners, is at least as accurate as specialized equipment. This may shorten time-to-treatment in general practices, thereby improving the prognosis and quality of life.


Malignant hyperpyrexia. A study of an affected family.
Our purpose was to determine whether an apparently healthy patient who died under general anaesthesia had malignant hyperpyrexia by examining her relatives and to suggest protective measures for the relatives of the deceased patient against this complication during future general anaesthetics. The family members of the deceased patient were examined systematically to determine whether or not they were prone to develop malignant hyperpyrexia. Raised serum CPK and aldolase levels, EMG changes, histopathological examination of the striated muscle, diminished muscle power during an ergometric test, and subjective symptoms revealed that other members of her family had muscular dystrophy. Our results support the theory that during general anaesthesia patients with muscular dystrophy are prone to develop malignant hyperpyrexia. Although muscular dystrophy is uncommon in Finland, affected persons should be catalogued, and preventive measures against malignant hyperpyrexia taken if they ever have to have a general anaesthetic.


Changes in the metabolome of rats after exposure to arginine and N-carbamylglutamate in combination with diquat, a compound that causes oxidative stress, assessed by 1H NMR spectroscopy.
Numerous factors can induce oxidative stress in animal production and lead to growth retardation, disease, and even death. Arginine and N-carbamylglutamate can alleviate the effects of oxidative stress. However, the systematic changes in metabolic biochemistry linked to oxidative stress and arginine and N-carbamylglutamate treatment remain largely unknown. This study aims to examine the effects of arginine and N-carbamylglutamate on rat metabolism under oxidative stress. Thirty rats were randomly divided into three dietary groups (n = 10 each). The rats were fed a basal diet supplemented with 0 (control), 1% arginine, or 0.1% N-carbamylglutamate for 30 days. On day 28, the rats in each treatment were intraperitoneally injected with diquat at 12 mg per kg body weight or sterile solution. Urine and plasma samples were analyzed by metabolomics. Compared with the diquat group, the arginine + diquat group had significantly lower levels of acetamide, alanine, lysine, pyruvate, tyrosine, α-glucose, and β-glucose in plasma; N-carbamylglutamate + diquat had higher levels of 3-hydroxybutyrate, 3-methylhistidine, acetone, allantoin, asparagine, citrate, phenylalanine, trimethylamine-N-oxide, and tyrosine, and lower levels of low density lipoprotein, lipid, lysine, threonine, unsaturated lipid, urea, and very low density lipoprotein (P < 0.05) in plasma. Compared with the diquat group, the arginine + diquat group had significantly higher levels of citrate, creatinine, homogentisate, and α-ketoglutarate while lower levels of acetamide, citrulline, ethanol, glycine, isobutyrate, lactate, malonate, methymalonate, N-acetylglutamate, N-methylnicotinamide, propionate, and β-glucose (P < 0.05) in urine. Compared with the diquat group, the N-carbamylglutamate + diquat group had significantly higher levels of allantoin, citrate, homogentisate, phenylacetylglycine, α-ketoglutarate, and β-glucose while lower levels of acetamide, acetate, acetone, benzoate, citrulline, ethanol, hippurate, lactate, N-acetylglutamate, nicotinamide, ornithine, and trigonelline (P < 0.05) in urine. Overall, these results suggest that arginine and N-carbamylglutamate can alter the metabolome associated with energy metabolism, amino acid metabolism, and gut microbiota metabolism under oxidative stress.


Competition and Symmetry in an Artificial Word Learning Task.
Natural language involves competition. The sentences we choose to utter activate alternative sentences (those we chose not to utter), which hearers typically infer to be false. Hence, as a first approximation, the more alternatives a sentence activates, the more inferences it will trigger. But a closer look at the theory of competition shows that this is not quite true and that under specific circumstances, so-called symmetric alternatives cancel each other out. We present an artificial word learning experiment in which participants learn words that may enter into competition with one another. The results show that a mechanism of competition takes place, and that the subtle prediction that alternatives trigger inferences, and may stop triggering them after a point due to symmetry, is borne out. This study provides a minimal testing paradigm to reveal competition and some of its subtle characteristics in human languages and beyond.


P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A.
Spatial and temporal changes in intracellular calcium concentrations are critical for controlling gene expression in neurons. In many neurons, activity-dependent calcium influx through L-type channels stimulates transcription that depends on the transcription factor CREB by activating a calmodulin-dependent pathway. Here we show that selective influx of calcium through P/Q-type channels is responsible for activating expression of syntaxin-1A, a presynaptic protein that mediates vesicle docking, fusion and neurotransmitter release. The initial P/Q-type calcium signal is amplified by release of calcium from intracellular stores and acts through phosphorylation that is dependent on the calmodulin-dependent kinase CaM K II/IV, protein kinase A and mitogen-activated protein kinase kinase. Initiation of syntaxin-1A expression is rapid and short-lived, with syntaxin-1A ultimately interacting with the P/Q-type calcium channel to decrease channel availability. Our results define an activity-dependent feedback pathway that may regulate synaptic efficacy and function in the nervous system.


Use of single (4B-2) and repetitive copy (pS4) deoxyribonucleic acid (DNA) probes to characterize translocated Y DNA in a pedigree with recurrent abortion.
Probes for unique and repetitive copy deoxyribonucleic acid (DNA) are available to detect and characterize Y DNA. The probe pS4 detects repetitive copy DNA mapped to Yq12. The upper limits of the pS4 sequences are defined by the upper limits of C-banding. The probe 4B-2 is a recombinant phage construct developed from a Y library and contains a unique copy 3.3 kb Eco RI fragment mapped to Yq11. A family was ascertained through a pregnant female who had a history of four consecutive abortions and two normal daughters. Cytogenetic analysis revealed the mother and one of her daughters to have a 46,XX,15p+ karyotype. Amniocytes were karyotyped as 46,XY,15p+. Genomic DNA from controls, mother, daughters, and amniocytes was digested with Mbo I and hybridized to 32P-labeled pS4 probe. DNAs from both 46,XX,15p+ females and 46,XY,15p+ amniocytes demonstrated a clear male-specific 2.3 kb band. Digestion of the same genomic DNAs with Eco RI and blot hybridization to 32P-labeled 4B-2 probe revealed the 3.3 kb male-specific band only in the 46,XY,15p+ amniocyte DNA. The additional sequences located on 15p segregating in the female members of this family correspond to Yq12. The effect of this additional DNA on gametogenesis is unknown.


Thermocells Driven by Phase Transition of Hydrogel Nanoparticles.
Thermoelectric conversion of low temperature, delocalized, and abundant thermal sources is crucial for the development of the Internet of Things (IoT) and/or a carbon-free society. Thermocells are of great interest in thermoelectric conversion of low-temperature heat due to the low cost and flexibility of components. However, significant improvement of the conversion efficiency is required for the practical use of the cells. Here, we report thermo-electrochemical cells driven by volume phase transition (VPT) of hydrogel nanoparticles (NPs). Entropically driven VPT of poly(N-isopropylacrylamide) NPs containing carboxylic acids and amines generates a pH gradient of up to 0.049 and -0.053 pH K-1, respectively, around physiological temperature. The pH gradient triggers the proton-coupled electron transfer (PCET) reactions of quinhydrone on the electrodes, resulting in the highly efficient thermoelectric conversion with a Seebeck coefficient (Se) of -6.7 and +6.1 mV K-1. Thermocells driven by phase transition of hydrogels provide a nontoxic, flexible, and inexpensive charger that harvests carbon-free energy from abundant energy sources such as solar, body and waste heat.


Adult chicken alpha-globin gene expression in transfected QT6 quail cells: evidence for a negative regulatory element in the alpha D gene region.
The chicken adult alpha-globin genes, alpha A and alpha D, are closely linked in chromosomal DNA and are coordinately expressed in vivo in an approximate 3:1 ratio, respectively. When subcloned DNAs containing one or the other gene are stably transfected into QT6 quail fibroblasts, the alpha A-globin gene is expressed at measurable RNA levels, but the alpha D gene is not. The alpha A gene expression can be considerably increased by the presence of a linked Rous sarcoma virus long terminal repeat enhancer, but that of the alpha D gene remains undetectable. Transfection with subclones containing both genes, either in cis or in trans, leads to considerably reduced alpha A RNA levels and still no observable alpha D gene expression. Transfection with deleted subclones suggests that maximal expression levels in this system require the alpha A-globin gene promoter, as opposed to that of the alpha D gene, but that such expression is greatly reduced by one or more DNA sequences which lie approximately 2,000 base pairs upstream of the alpha A gene, within the body of the alpha D gene.


Prognostic value of red blood cell distribution width in hepatocellular carcinoma.
Red blood cell distribution width (RDW) is a simple, inexpensive, routinely measured and automatically reported blood test parameter, which reflects the degree of anisocytosis of red blood cells in peripheral blood. RDW was found to be associated with and retain clinical significance for assessing disease severity and outcomes in a number of hematological and solid malignancies. Motley of interacting clinical and biochemical factors have an impact on the red cell population biology. Malignancies per se can act as a causative factor, or anisocytosis may develop as a result of chronic inflammation. RDW has also been shown to be affected by nutritional status, which is typically deranged in malignancies. RDW is shown to be a clinically useful marker of disease severity and level of fibrosis in liver cirrhosis of various causes such as hepatitis B, hepatitis C and non-alcoholic fatty liver disease. Whether liver cirrhosis patients with higher RDW are at increased risk of hepatocellular cancer is yet to be determined, but several lines of evidence confirm that RDW has clinical significance in hepatocellular carcinoma (HCC). In this review, we specifically discuss the current literature about the association between RDW and HCC. The available evidences were summarized and the potential underlying mechanisms were analyzed.


Mitochondrial processes are impaired in hereditary inclusion body myopathy.
Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared with 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile data sets by the intersection of three statistic methods (Student's t-test, TNoM and Info score), we found that the HIBM-specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of nine additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism.


Taller-Than-Wide Shape: A New Definition Improves the Specificity of TIRADS Systems.
A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio >1. An intraobserver variability of up to 18% in AP diameter evaluations has been described, which may lead to overreporting of this feature. To potentially improve the reliability of the TTW definition, we propose an arbitrary ratio of ≥1.2. The aim of this study was to estimate the impact of this definition on diagnostic performance. We prospectively analyzed 553 thyroid nodules referred for cytology evaluation at an academic center. Before fine-needle aspiration, two examiners jointly defined all sonographic features considered in risk stratification systems developed by the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), the American College of Radiology (ACR TIRADS), the European Thyroid Association (EU-TIRADS), and the Korean Society of Thyroid Radiology (K-TIRADS). TTW was defined according to the current definition (AP/T diameter ratio >1) and an arbitrary alternative definition (AP/T ratio >1.2). The alternative definition classified fewer nodules as TTW (28, 5.1% vs. 94, 17%). The current and proposed definitions have a sensitivity of 26.2 and 11.9% (p = 0.03) and a specificity of 83.8 and 95.5% (p < 0.001). Thus, as a single feature, the arbitrary definition has a lower sensitivity and a higher specificity. When applied to sonographic risk stratification systems, however, the proposed definition would increase the number of avoided biopsies (up to 58.2% for ACR TIRADS) and the specificity of all systems, without negative impact on sensitivity or diagnostic odds ratio. Re-defining TTW nodules as those with an AP/T ratio ≥1.2 improves this marker's specificity for malignancy. Using this definition in risk stratification systems will increase their specificity, reducing the number of suggested biopsies without significantly diminishing their overall diagnostic performance.


Regulatory evolution in proteins by turnover and lineage-specific changes of cyclin-dependent kinase consensus sites.
Evolutionary change in gene regulation is a key mechanism underlying the genetic component of organismal diversity. Here, we study evolution of regulation at the posttranslational level by examining the evolution of cyclin-dependent kinase (CDK) consensus phosphorylation sites in the protein subunits of the pre-replicative complex (RC). The pre-RC, an assembly of proteins formed during an early stage of DNA replication, is believed to be regulated by CDKs throughout the animals and fungi. Interestingly, although orthologous pre-RC components often contain clusters of CDK consensus sites, the positions and numbers of sites do not seem conserved. By analyzing protein sequences from both distantly and closely related species, we confirm that consensus sites can turn over rapidly even when the local cluster of sites is preserved, consistent with the notion that precise positioning of phosphorylation events is not required for regulation. We also identify evolutionary changes in the clusters of sites and further examine one replication protein, Mcm3, where a cluster of consensus sites near a nucleocytoplasmic transport signal is confined to a specific lineage. We show that the presence or absence of the cluster of sites in different species is associated with differential regulation of the transport signal. These findings suggest that the CDK regulation of MCM nuclear localization was acquired in the lineage leading to Saccharomyces cerevisiae after the divergence with Candida albicans. Our results begin to explore the dynamics of regulatory evolution at the posttranslational level and show interesting similarities to recent observations of regulatory evolution at the level of transcription.


Bending of layer-by-layer films driven by an external magnetic field.
We report on optimized architectures containing layer-by-layer (LbL) films of natural rubber latex (NRL), carboxymethyl-chitosan (CMC) and magnetite (Fe3O4) nanoparticles (MNPs) deposited on flexible substrates, which could be easily bent by an external magnetic field. The mechanical response depended on the number of deposited layers and was explained semi-quantitatively with a fully atomistic model, where the LbL film was represented as superposing layers of hexagonal graphene-like atomic arrangements deposited on a stiffer substrate. The bending with no direct current or voltage being applied to a supramolecular structure containing biocompatible and antimicrobial materials represents a proof-of-principle experiment that is promising for tissue engineering applications in biomedicine.


Partitioned exhaled nitric oxide to non-invasively assess asthma.
Asthma is a chronic inflammatory disease of the lungs, characterized by airway hyperresponsiveness. Chronic repetitive bouts of acute inflammation lead to airway wall remodeling and possibly the sequelae of fixed airflow obstruction. Nitric oxide (NO) is a reactive molecule synthesized by NO synthases (NOS). NOS are expressed by cells within the airway wall and functionally, two NOS isoforms exist: constitutive and inducible. In asthma, the inducible isoform is over expressed, leading to increased production of NO, which diffuses into the airway lumen, where it can be detected in the exhaled breath. The exhaled NO signal can be partitioned into airway and alveolar components by measuring exhaled NO at multiple flows and applying mathematical models of pulmonary NO dynamics. The airway NO flux and alveolar NO concentration can be elevated in adults and children with asthma and have been correlated with markers of airway inflammation and airflow obstruction in cross-sectional studies. Longitudinal studies which specifically address the clinical potential of partitioning exhaled NO for diagnosis, managing therapy, and predicting exacerbation are needed.


Design and implementation of a community-based exercise program for breast cancer patients.
Research has indicated that exercise is critical in the recovery process for breast cancer patients, and yet this evidence has infrequently been translated into sustainable community programming. The present article describes the processes and operations of beauty (the Breast Cancer Patients Engaging in Activity and Undergoing Treatment program). This evidence-based 12-week exercise program, with an optional 12-week maintenance component, is supported by the Wings of Hope Foundation, allowing the program to be delivered at no cost to participants. The program was designed to restore and improve the physical well-being of women living with breast cancer as they undergo chemotherapy or radiation treatments. Evaluations measure safety and adherence to the program and the effects of the program on physiologic and psychological outcomes and quality of life. The beauty program addresses the gap between the level of evidence for the benefits of exercise after a cancer diagnosis and translation of that evidence into community programming by providing an accessible, individualized, and safe physical activity program for women during treatment for breast cancer.


Swallowing and dysphagia in neurological disorders.
Neurologists are often confronted with swallowing disorders in routine practice. Swallowing impairments carry serious health consequences if they are overlooked or inappropriately managed. Swallowing problems usually develop in patients with established neurological conditions, although on occasion they may be a presenting symptom of a neurological disorder. Prompt recognition of dysphagia and early diagnosis can often be accomplished through a systematic clinical history and examination. This article reviews the physiology and neuroanatomy of normal swallowing and discusses pertinent clinical approaches toward evaluating a patient with neurogenical dysphagia. Important neurological conditions causing dysphagia are also discussed in this context.


Protracted Treponema pallidum-induced cutaneous chancres in rabbits infected with human T-cell leukemia virus type I.
In a preliminary study, two of four rabbits infected with human T-cell leukemia virus type I (HTLV-I) demonstrated prolonged primary chancres following superinfection with Treponema pallidum, the causative agent of syphilis. Two rabbits inoculated with 1 x 10(7) HTLV-I-infected human MT-2 cells and two with infected rabbit cells from a line established in this laboratory (RLT-P), developed latent HTLV-I infection as detected by seroconversion 10 weeks after infection and by detection of HTLV-I sequences in the DNA of peripheral blood lymphocytes after amplification by polymerase chair reaction (PCR) 15 weeks after infection. The rabbits remained clinically normal and had normal blood counts. Six months after infection, the four HTLV-infected rabbits and two noninfected controls were challenged by the intradermal inoculation of 1 x 10(6) Treponema pallidum into eight sites on the shaved back. The lesions of two of the HTLV-I-infected rabbits had a time course similar to non-HTLV-I-infected controls and were completely healed by 4 weeks. The lesions of one of the other two rabbits with progressive disease began to heal about 7 weeks after T. pallidum challenge. The cutaneous lesions in the other rabbit remained dark-field positive and became a confluent eschar at 8 weeks; healing only after treatment with penicillin. Four months after the primary challenge none of the six rabbits previously challenged with T. pallidum had developed lesions after rechallenge and thus expressed chancre immunity. These results demonstrate that rabbits with latent HTLV-I infections may have defective cell-mediated immunity.


The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.
Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α-responsive, heparan sulfate-specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.


The Lipid Transfer Protein 1 from Nicotiana benthamiana Assists Bamboo mosaic virus Accumulation.
Host factors play a pivotal role in regulating virus infection. Uncovering the mechanism of how host factors are involved in virus infection could pave the way to defeat viral disease. In this study, we characterized a lipid transfer protein, designated NbLTP1 in Nicotiana benthamiana, which was downregulated after Bamboo mosaic virus (BaMV) inoculation. BaMV accumulation significantly decreased in NbLTP1-knockdown leaves and protoplasts compared with the controls. The subcellular localization of the NbLTP1-orange fluorescent protein (OFP) was mainly the extracellular matrix. However, when we removed the signal peptide (NbLTP1/ΔSP-OFP), most of the expressed protein targeted chloroplasts. Both NbLTP1-OFP and NbLTP1/ΔSP-OFP were localized in chloroplasts when we removed the cell wall. These results suggest that NbLTP1 may have a secondary targeting signal. Transient overexpression of NbLTP1 had no effect on BaMV accumulation, but that of NbLTP1/ΔSP significantly increased BaMV expression. NbLTP1 may be a positive regulator of BaMV accumulation especially when its expression is associated with chloroplasts, where BaMV replicates. The mutation was introduced to the predicted phosphorylation site to simulate the phosphorylated status, NbLTP/ΔSP/P(+), which could still assist BaMV accumulation. By contrast, a mutant lacking calmodulin-binding or simulates the phosphorylation-negative status could not support BaMV accumulation. The lipid-binding activity of LTP1 was reported to be associated with calmodulin-binding and phosphorylation, by which the C-terminus functional domain of NbLTP1 may play a critical role in BaMV accumulation.


Creating a more quit-friendly national workforce? Individual layoff history and voluntary turnover.
Although Bureau of Labor Statistics data reveal that U.S. employers laid off over 30 million employees since 1994, virtually no research has addressed the behavior of layoff victims upon reemployment. In a first step, we investigate how layoffs shape voluntary turnover behavior in subsequent jobs. Utilizing a recently developed fixed effects specification of survival analysis, we find that a layoff history is positively associated with quit behavior. This effect is partially mediated by underemployment and job satisfaction in the postlayoff job. The remaining direct effect is consistent with the notion that layoffs produce a psychological spillover to postlayoff employment, which then manifests in quit behavior. We also find that layoff effects on turnover attenuate as an individual's layoffs accumulate and vary in magnitude according to the turnover "path" followed by the leaver.


Clinical significance of p53 in non-small-cell lung cancer.
p53 abnormalities appear to play critical roles in human carcinogenesis. Many studies have indicated that p53 alteration is responsible for the differences in clinical characteristics of non-small cell lung cancer (NSCLC). The purpose of this review is to evaluate and summarize the significance of p53 alteration in the diagnosis and therapy of NSCLC. After assessing the principles of each approach to detecting p53 alteration, we reviewed the literature describing the impact of p53 alteration on clinical modalities such as diagnosis, prediction of prognosis, and response to treatment. We also reviewed p53 gene replacement therapy for NSCLC. Although p53 appears to be the most important gene in the development of NSCLC, it is not known whether p53 abnormalities are useful markers for clinicians. A multicenter, prospective study of p53 immunohistochemistry should therefore be performed. Replacement of the p53 gene has been shown to be effective in a clinical trial for patients with NSCLC. In addition to simple gene replacement, combination treatments of gene transfer and chemotherapy are now being tested in clinical trials.


Computational investigation of microgels: synthesis and effect of the microstructure on the deswelling behavior.
We present computer simulations of a realistic model of microgels. Unlike the regular network frameworks usually assumed in the simulation literature, we model and simulate a realistic and efficient synthesis route, mimicking cross-linking of functionalized chains inside a cavity. This model is inspired, e.g., by microfluidic fabrication of microgels from macromolecular precursors and is different from standard polymerization routes. The assembly of the chains is mediated by a low fraction of interchain crosslinks. The microgels are polydisperse in size and shape but globally spherical objects. In order to deeply understand the microgel structure and eventually improve the synthesis protocol we characterize their conformational properties and deswelling kinetics, and compare them with the results found for microgels obtained via underlying regular (diamond-like) structures. For the same molecular weight, monomer concentration and effective degree of cross-linking, the specific microstructure of the microgel has no significant effect on the locus of the volume phase transition (VPT). However, it strongly affects the deswelling kinetics, as revealed by a consistent analysis of the domain growth during the microgel collapse. Though both the disordered and the regular networks exhibit a similar early growth of the domains, an acceleration is observed in the regular network at the late stage of the collapse. Similar trends are found for the dynamic correlations coupled to the domain growth. As a consequence, the fast late processes for the domain growth and the dynamic correlations in the regular network are compensated, and the dynamic correlations follow a power-law dependence on the growing length scale that is independent of the microgel microstructure.


Long-term trends in migratory behavior in a developing country: the case of Mexico.
Comparable lifetime migration relationships are estimated for Mexico for 1950, 1960, and 1970. Moreover, migration flows from each state to every other state are separately examined for each year. A number of significant changes over time are evident in the responsiveness of Mexican internal migrants to various socioeconomic stimuli, and appreciable differences are also evident across space. Moreover, a threshold is observed such that up to about 340 miles higher origin earnings deter migration, but beyond this distance higher earnings actually encourage migration.


Large-scale eradication of rabies using recombinant vaccinia-rabies vaccine.
Rabies infection of domestic and wild animals is a serious problem throughout the world. The major disease vector in Europe is the red fox (Vulpes vulpes) and rabies control has focused on vaccinating and/or culling foxes. Culling has not been effective, and the distribution of five vaccine baits is the only appropriate method for the vaccination of wild foxes. Although some European countries have conducted field vaccination campaigns using attenuated rabies virus strains, their use has not been extensively approved because they retain pathogenicity for rodents and can revert to virulence. These strains cannot be used in North America because they are pathogenic for the striped skunk (Mephitis mephitis) and are ineffective in the raccoon (Procyon lotor). We have constructed a recombinant vaccinia virus, VVTGgRAB, expressing the surface glycoprotein (G) of rabies virus (ERA strain). The recombinant was a highly effective vaccine in experimental animals, in captive foxes and in raccoons. We report here the results of a large-scale campaign of fox vaccination in a 2,200 km2 region of southern Belgium, an area in which rabies is prevalent. After distribution, 81% of foxes inspected were positive for tetracycline, a biomarker included in the vaccine bait and, other than one rabid fox detected close to the periphery of the treated area, no case of rabies, either in foxes or in domestic livestock, has been reported in the area.


Evaluation of the use of venous thromboembolism prophylaxis in hospitalised medical patients.
Venous thromboembolism (VTE) prophylaxis is effective in the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in medical patients. A retrospective chart review was performed on medical inpatients at two academic hospitals in Hamilton, Ontario to investigate if patients received VTE prophylaxis as per current guidelines. An analysis was performed on 762 patient charts and 170 met inclusion criteria for use of pharmacological VTE prophylaxis. Of these, 91 (54%) received pharmacological VTE prophylaxis. In 63 patients with a contraindication to pharmacological VTE prophylaxis, 16 (25%) received non-pharmacological VTE prophylaxis. The provision rate of pharmacological VTE prophylaxis in hospitalised medical patients who met pre-defined clinical criteria for prophylaxis was 54%. The rate of prophylaxis increased with additional VTE risk factors to a peak rate of 67%. There is room for the development of strategies to improve the use of VTE prophylaxis in hospitalised medical patients.


Aortic arch (pseudo) aneurysm complicating cardiac catheterization.
The development of an infected aortic (pseudo)aneurysm which occurred after placement of a coronary artery stent is reported. Complications of cardiac catheterization and coronary artery stent placement are infrequent and this complication has not yet been reported in the literature.


The Core Promoter and Redox-sensitive Cis-elements as Key Targets for Inactivation of the Lysyl Oxidase Gene by Cadmium.
Exposure of humans to cadmium (Cd) either from environmental contamination or from cigarette smoke, often induces lung emphysema and cancers. Lysyl oxidase (LOX), a copper-dependent enzyme essential for crosslinking of the extracellular matrix, displays antagonistic effects on emphysema and cancer pathogenesis. Our previous studies showed down-regulation of LOX in Cd-resistant (CdR) rat fetal lung fibroblasts (RFL6) derived from parental cells via long-term Cd exposure. The cloned rat LOX gene promoter -804/-1 (relative to ATG) with the maximal promoter activity contains the Inr-DPE core promoter, putative NFI binding sites, metal response elements (MRE) and antioxidant response elements (ARE). ChIP assays reported here further characterize the rat LOX gene promoter in response to Cd. CdR cells exhibited enhanced methylation of CpG at the LOX core promoter region and reduced activities of the NFI binding sites and MRE, but increased activity of the ARE in a dose-dependent manner. The collective effect of Cd on the LOX promoter is trans-inhibition of the LOX gene as shown by suppression of histone H3 acetylation in the LOX core promoter region. Thus, the LOX core promoter and redox-sensitive cis-elements are key Cd targets for down-regulation of LOX relevant to mechanisms for Cd-induced emphysema and lung cancers.


Pycnodysostosis. A report of 3 clinical cases.
Pycnodysostosis is a rare clinical entity, first described in 1962 by Maroteaux and Lamy. It is a genetic disorder, usually diagnosed at an early age. However, the diagnosis is sometimes late, made as a result of bone fracture, given the severe bone fragility resulting from increased bone density. Oral and maxillofacial manifestations of this disease are very clear. The head is usually large, the nose beaked, the mandibular angle obtuse, and both maxilla and mandible hypoplastic. Dental abnormalities and impaction are observed, as well as alterations in eruption and frequent dental crowding. The differential diagnosis is established with osteopetrosis, cleidocranial dysplasia and idiopathic acro-osteolysis. This article reviews the clinical and radiographic characteristics of pycnodysostosis based on three clinical cases of patients with this disease.


Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection.
Arterial dissections account for 2% of strokes in all age groups, and up to 25% in patients aged 45 years or younger. The safety of endovascular intervention in this patient population is not well characterized. We identified all patients in the Merci registry - a prospective, multi-center post-market database enrolling patients treated with the Merci Retriever thrombectomy device - with arterial dissection as the most likely stroke etiology. Stroke presentation and procedural details were obtained prospectively; data regarding procedural complications, intracerebral hemorrhage (ICH), and the use of stenting of the dissected artery were obtained retrospectively. Of 980 patients in the registry, ten were identified with arterial dissection (8/10 ICA; 2/10 vertebrobasilar). The median age was 48 years with a baseline NIH stroke scale score of 16 and median time to treatment of 4.9 h. The procedure resulted in thrombolysis in cerebral ischemia (TICI) scores of 2a or better in eight out of ten and TICI 2b or better in six out of ten patients. Stenting of the dissection was performed in four of nine (44%). The single complication (1/9; 11%) - extension of a dissected carotid artery - was treated effectively with stenting. No symptomatic ICH or stroke in a previously unaffected territory occurred. A favorable functional outcome was observed in eight out of ten patients. Despite severe strokes on presentation, high rates of recanalization (8/10) and favorable functional outcomes (8/10) were observed. These results suggest that mechanical thrombectomy in patients with acute stroke resulting from arterial dissection is feasible, safe, and may be associated with favorable functional outcomes.


Junctional communication of pancreatic beta cells contributes to the control of insulin secretion and glucose tolerance.
Proper insulin secretion requires the coordinated functioning of the numerous beta cells that form pancreatic islets. This coordination depends on a network of communication mechanisms whereby beta cells interact with extracellular signals and adjacent cells via connexin channels. To assess whether connexin-dependent communication plays a role in vivo, we have developed transgenic mice in which connexin 32 (Cx32), one of the vertebrate connexins found in the pancreas, is expressed in beta cells. We show that the altered beta-cell coupling that results from this expression causes reduced insulin secretion in response to physiologically relevant concentrations of glucose and abnormal tolerance to the sugar. These alterations were observed in spite of normal numbers of islets, increased insulin content, and preserved secretory response to glucose by individual beta cells. Moreover, glucose-stimulated islets showed improved electrical synchronization of these cells and increased cytosolic levels of Ca(2+). The results show that connexins contribute to the control of beta cells in vivo and that their excess is detrimental for insulin secretion.


[Drug treatment of myocardial ischemia].
Nitrates are the basic medication of patients suffering from coronary heart disease. Frequently they are combined with calcium-antagonists or beta-receptor-blocking agents. The dose of 20 mg non-retarded dinitrates or mononitrates three times a day have the same effect as retarded nitrates once a day but of a higher dose (60-120 mg). The meaning of this drug has increased because of new results on the mechanism of action: nitric oxide is able to substitute the missing EDRF in the injured intima and leads to dilatation of the stenosis. This mechanism is the basis for the antianginal effect. Already minimal doses (0.025 mg nitroglycerine i.v. 1.25 mg isosorbide dinitrate oral) are effective independent of the dilatation of peripheral venous and arterial vessels. The antiaggregatory effect decrease thrombus formation in patients with unstable angina and the risk of infarction and produce a kind of rinsing effect in the stenosis. The size of infarction becomes smaller, the expansion of the ventricle is less and the prognosis improved. Concerning the calcium-antagonists dihydropiridine-preparations, verapamil and diltiazem have to be separated. Arterial vasodilatation of nifedipine may increase heart rate during exercise and rarely coronary steel phaenonemen. In contrast verapamil (3 x 120 mg) and gallopamil (3 x 50 mg) have strong antianginal effects and reduce the ischemic reaction during exercise about 50%. Heart rate is reduced during physical exercise, similar to the beta-receptor-blocking agents. AV-blocks are rare. Obstipation is more frequent with verapamil than with gallopamil. Verapamil decreases the infarct size and improves the prognosis after infarction in patients without left ventricular failure.(ABSTRACT TRUNCATED AT 250 WORDS)


Pasteurella species isolated from the bovine respiratory tract and their antimicrobial sensitivity patterns.
Pasteurella haemolytica biotype A, serotype 1 (P haemolytica A1) was the most commonly isolated Pasteurella species from 80 calves examined at necropsy from 40 outbreaks of respiratory disease, the majority of which were pathologically confirmed as bovine pneumonic pasteurellosis (transit fever; shipping fever). Similarly, nasopharyngeal swabs from in-contact and apparently healthy calves indicated the widespread presence of P haemolytica A1. Pasteurella multocida and other serotypes of P haemolytica A1 were found including six isolations of P haemolytica T10, a fairly common pathogen in sheep. Approximately two-thirds of the isolates were tested for their antimicrobial sensitivity patterns and the degree of sensitivity for P haemolytica A1, the most frequently isolated serotype, was chloramphenicol (100 per cent), sulphamethoxazole trimethoprim (98 per cent), oxytetracycline (80 per cent), ampicillin (85 per cent), penicillin (82 per cent), streptomycin (3 per cent) and lincomycin (1 per cent).


Genetic relationships among species of Contracaecum Railliet & Henry, 1912 and Phocascaris Höst, 1932 (Nematoda: Anisakidae) from pinnipeds inferred from mitochondrial cox2 sequences, and congruence with allozyme data.
The genetic relationships among 11 taxa, belonging to the genus Contracaecum (C. osculatum A, C. osculatum B, C. osculatum (s.s.), C. osculatum D, C. osculatum E, C. osculatum baicalensis, C. mirounga, C. radiatum, C. ogmorhini (s.s.), C. margolisi) and Phocascoris (Phocoscris cystophorae), parasites as adults of seals, were inferred from sequence analysis 1519 bp) of the mitochondrial cytochrome c oxidase subunit II (mtDNA cox2) gene. Phylogenetic analyses obtained from Parsimony (MP) and Neighbour-Joining (NJ) K2P distance values generated similar topologies, each well supported at major nodes. All analyses delineated two main clades: the first encompassing the parasites of the phocid seals, i.e. the C. osculatum species complex, C. osculatum boicolensis, C. mirounga and C. radiatum, with the latter two species forming a separate subclade; the second including the parasites of otarids, i.e. C. ogmorhini (s.s.) and C. margolisi. An overall high congruence between mtDNA inferred tree topologies and those produced from nuclear data sets (20 allozyme loci) was observed. Comparison of the phylogenetic hypothesis here produced for Controcaecum spp. plus Phocascaris with those currently available for their definitive hosts (pinnipeds) suggests parallelism between hosts and parasite phylogenetic tree topologies.


Direct-Acting Antiviral Agents for HCV-Associated Glomerular Disease and the Current Evidence.
Glomerular disease is an extra-hepatic manifestation of hepatitis C virus infection (HCV) and membranoproliferative glomerulonephritis is the most frequent glomerular disease associated with HCV. It occurs commonly in patients with HCV-related mixed cryoglobulinemia syndrome. Patients with HCV-related glomerular disease have been historically a difficult-to-treat group. The therapeutic armamentarium for HCV-related glomerular disease now includes antiviral regimens, selective or non-specific immunosuppressive drugs, immunomodulators, and symptomatic agents. The treatment of HCV-associated glomerular disease is dependent on the clinical presentation of the patient. The recent introduction of all-oral, interferon (IFN)-free/ribavirin (RBV)-free regimens is dramatically changing the course of HCV in the general population, and some regimens have been approved for HCV even in patients with advanced chronic kidney disease. According to a systematic review of the medical literature, the evidence concerning the efficacy/safety of direct-acting antiviral agents (DAAs) of HCV-induced glomerular disease is limited. The frequency of sustained virological response was 92.5% (62/67). Full or partial clinical remission was demonstrated in many patients (n = 46, 68.5%) after DAAs. There were no reports of deterioration of kidney function in patients on DAAs. Many patients (n = 29, 43%) underwent immunosuppression while on DAAs. A few cases of new onset or relapsing glomerular disease in patients with HCV successfully treated with DAAs have been observed. In summary, DAA-based combinations are making easier the management of HCV. However, patients with HCV-induced glomerular disease are still a difficult-to-treat group even at the time of DAAs.


Histological and immunohistological investigation of lymphoid tissue in the platypus (Ornithorhynchus anatinus).
The gross and histological appearance and the distribution of T and B lymphocytes and plasma cells are described for lymphoid tissues obtained from 15 platypuses. The spleen was bilobed and surrounded by a thick capsule of collagen, elastic fibres and little smooth muscle. White pulp was prominent and included germinal centres and periarterial lymphoid sheaths. Red pulp contained haematopoietic tissue. A thin lobulated thymus was located within the mediastinum overlying the heart. The cortex of lobules consisted of dense aggregates of small and medium lymphocytes, scattered macrophages and few reticular epithelial cells. In the medulla, Hassall's corpuscles were numerous, lymphocytes were small and less abundant, and reticular cells were more abundant than in the cortex. Lymphoid nodules scattered throughout loose connective tissue in cervical, pharyngeal, thoracic, mesenteric and pelvic sites measured 790 +/- 370 microm (mean +/- S.D., n = 39) in diameter, the larger of which could be observed macroscopically. These consisted of single primary or secondary follicles supported by a framework of reticular fibres. Macrophages were common in the germinal centres. The platypus had a full range of gut-associated lymphoid tissue. No tonsils were observed macroscopically but histologically they consisted of submucosal follicles and intraepithelial lymphocytes. Peyer's patches were not observed macroscopically but histologically they consisted of several prominent submucosal secondary follicles in the antimesenteric wall of the intestine. Caecal lymphoid tissue consisted of numerous secondary follicles in the submucosa and densely packed lymphocytes in the lamina propria. Bronchus-associated lymphoid tissue was not observed macroscopically but was identified in 7 of 11 platypus lungs assessed histologically. Lymphoid cells were present as primary follicles associated with bronchi, as aggregates adjacent to blood vessels and as intraepithelial lymphocytes. The distribution of T lymphocytes, identified with antihuman CD3 and CD5, and B lymphocytes and plasma cells, identified with antihuman CD79a and CD79b and antiplatypus immunoglobulin, within lymphoid tissues in the platypus was similar to that described in therian mammals except for an apparent relative paucity of B lymphocytes. This study establishes that the platypus has a well-developed lymphoid system which is comparable in histological structure to that in therian mammals. It also confirms the distinctiveness of its peripheral lymphoid tissue, namely lymphoid nodules. Platypus lymphoid tissue has all the essential cell types, namely T and B lymphocytes and plasma cells, to mount an effective immune response against foreign antigens.


4-Hydroxynonenal induces apoptosis in human osteoarthritic chondrocytes: the protective role of glutathione-S-transferase.
4-Hydroxynonenal (HNE) is one of the most abundant and reactive aldehydes of lipid peroxidation products and exerts various effects on intracellular and extracellular signalling cascades. We have previously shown that HNE at low concentrations could be considered as an important mediator of catabolic and inflammatory processes in osteoarthritis (OA). In the present study, we focused on characterizing the signalling cascade induced by high HNE concentration involved in cell death in human OA chondrocytes. Markers of apoptosis were quantified with commercial kits. Protein levels were evaluated by Western blotting. Glutathione (GSH) and ATP levels were measured with commercial kits. Glucose uptake was assessed by 2-deoxy-D-[3H]-glucose. The role of GSH-S-transferase A4-4 (GSTA4-4) in controlling HNE-induced chondrocyte apoptosis was investigated by chondrocyte transfection with small interfering RNA (siRNA) or with the expression vector of GSTA4-4. Our data showed that HNE at concentrations of up to 10 microM did not alter cell viability but was cytotoxic at concentrations of greater than or equal to 20 microM. HNE-induced chondrocyte death exhibited several classical hallmarks of apoptosis, including caspase activation, cytochrome c and apoptosis-induced factor release from mitochondria, poly (ADP-ribose) polymerase cleavage, Bcl-2 downregulation, Bax upregulation, and DNA fragmentation. Our study of signalling pathways revealed that HNE suppressed pro-survival Akt kinase activity but, in contrast, induced Fas/CD95 and p53 expression in chondrocytes. All of these effects were inhibited by an antioxidant, N-acetyl-cysteine. Analysis of cellular energy and redox status showed that HNE induced ATP, NADPH, and GSH depletion and inhibited glucose uptake and citric acid cycle activity. GSTA4-4 ablation by the siRNA method augmented HNE cytotoxicity, but, conversely, its overexpression efficiently protected chondrocytes from HNE-induced cell death. Our study provides novel insights into the potential mechanisms of cell death in OA cartilage and suggests the potential role of HNE in OA pathophysiology. GSTA4-4 expression is critically important for cellular defence against oxidative stress-induced cell death in OA cartilage, possibly by HNE elimination.


ALMS1-deficient fibroblasts over-express extra-cellular matrix components, display cell cycle delay and are resistant to apoptosis.
Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.


A Hybrid Automata Approach for Monitoring the Patient in the Loop in Artificial Pancreas Systems.
The use of automated insulin delivery systems has become a reality for people with type 1 diabetes (T1D), with several hybrid systems already on the market. One of the particularities of this technology is that the patient is in the loop. People with T1D are the plant to control and also a plant operator, because they may have to provide information to the control loop. The most immediate information provided by patients that affects performance and safety are the announcement of meals and exercise. Therefore, to ensure safety and performance, the human factor impact needs to be addressed by designing fault monitoring strategies. In this paper, a monitoring system is developed to diagnose potential patient modes and faults. The monitoring system is based on the residual generation of a bank of observers. To that aim, a linear parameter varying (LPV) polytopic representation of the system is adopted and a bank of Kalman filters is designed using linear matrix inequalities (LMI). The system uncertainty is propagated using a zonotopic-set representation, which allows determining confidence bounds for each of the observer outputs and residuals. For the detection of modes, a hybrid automaton model is generated and diagnosis is performed by interpreting the events and transitions within the automaton. The developed system is tested in simulation, showing the potential benefits of using the proposed approach for artificial pancreas systems.


New evidence on the suggestibility of memory: the role of retrieval-induced forgetting in misinformation effects.
Extending recent work that has demonstrated that the act of remembering can result in the inhibition of related items in memory, the present research examined whether retrieval-induced forgetting could provide a mechanism for explaining misinformation effects. Specifically, the authors found in their first study that the inhibition of critical items rendered the recollection of postevent information more likely in a subsequent test of memory. The authors established in their second study that when guided retrieval practice and final recall tests were separated by 24 hr, retrieval-induced forgetting failed to emerge and misinformation effects were absent. In contrast, a delay of 24 hr between initial encoding and guided retrieval practice produced not only retrieval-induced forgetting but also misinformation effects.


Negotiation and appeasement can be more effective drivers of sociality than kin selection.
Two alternative frameworks explain the evolution of cooperation in the face of conflicting interests. Conflicts can be alleviated by kinship, the alignment of interests by virtue of shared genes, or by negotiation strategies, allowing mutually beneficial trading of services or commodities. Although negotiation often occurs in kin-structured populations, the interplay of kin- and negotiation-based mechanisms in the evolution of cooperation remains an unresolved issue. Inspired by the biology of a cooperatively breeding fish, we developed an individual-based simulation model to study the evolution of negotiation-based cooperation in relation to different levels of genetic relatedness. We show that the evolution of negotiation strategies leads to an equilibrium where subordinates appease dominants by conditional cooperation, resulting in high levels of help and low levels of aggression. This negotiation-based equilibrium can be reached both in the absence of relatedness and in a kin-structured population. However, when relatedness is high, evolution often ends up in an alternative equilibrium where subordinates help their kin unconditionally. The level of help at this kin-selected equilibrium is considerably lower than at the negotiation-based equilibrium, and it corresponds to a level reached when responsiveness is prevented from evolving in the simulations. A mathematical invasion analysis reveals that, quite generally, the alignment of payoffs due to the relatedness of interaction partners tends to impede selection for harsh but effective punishment of defectors. Hence kin structure will often hamper rather than facilitate the evolution of productive cooperation.


The coenzyme specificity of Candida tenuis xylose reductase (AKR2B5) explored by site-directed mutagenesis and X-ray crystallography.
CtXR (xylose reductase from the yeast Candida tenuis; AKR2B5) can utilize NADPH or NADH as co-substrate for the reduction of D-xylose into xylitol, NADPH being preferred approx. 33-fold. X-ray structures of CtXR bound to NADP+ and NAD+ have revealed two different protein conformations capable of accommodating the presence or absence of the coenzyme 2'-phosphate group. Here we have used site-directed mutagenesis to replace interactions specific to the enzyme-NADP+ complex with the aim of engineering the co-substrate-dependent conformational switch towards improved NADH selectivity. Purified single-site mutants K274R (Lys274-->Arg), K274M, K274G, S275A, N276D, R280H and the double mutant K274R-N276D were characterized by steady-state kinetic analysis of enzymic D-xylose reductions with NADH and NADPH at 25 degrees C (pH 7.0). The results reveal between 2- and 193-fold increases in NADH versus NADPH selectivity in the mutants, compared with the wild-type, with only modest alterations of the original NADH-linked xylose specificity and catalytic-centre activity. Catalytic reaction profile analysis demonstrated that all mutations produced parallel effects of similar magnitude on ground-state binding of coenzyme and transition state stabilization. The crystal structure of the double mutant showing the best improvement of coenzyme selectivity versus wild-type and exhibiting a 5-fold preference for NADH over NADPH was determined in a binary complex with NAD+ at 2.2 A resolution.


Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier.
There is an increasing need to develop improved systems for predicting the safety of xenobiotics. However, to move beyond hazard identification the available concentration of the test compounds needs to be incorporated. In this study cyclosporine A (CsA) was used as a model compound to assess the kinetic profiles in two rodent brain cell cultures after single and repeated exposures. CsA induced-cyclophilin B (Cyp-B) secretion was also determined as CsA-specific pharmacodynamic endpoint. Since CsA is a potent p-glycoprotein substrate, the ability of this compound to cross the blood-brain barrier (BBB) was also investigated using an in vitro bovine model with repeated exposures up to 14 days. Finally, CsA uptake mechanisms were studied using a parallel artificial membrane assay (PAMPA) in combination with a Caco-2 model. Kinetic results indicate a low intracellular CsA uptake, with no marked bioaccumulation or biotransformation. In addition, only low CsA amounts crossed the BBB. PAMPA and Caco-2 experiments revealed that CsA is mostly trapped to lipophilic compartments and exits the cell apically via active transport. Thus, although CsA is unlikely to enter the brain at cytotoxic concentrations, it may cause alterations in electrical activity and is likely to increase the CNS concentration of other compounds by occupying the BBBs extrusion capacity. Such an integrated testing system, incorporating BBB, brain culture models and kinetics could be applied for assessing neurotoxicity potential of compounds.


Characterization of the secretory activity of leukotriene B4 toward rabbit neutrophils.
We have described in det ail the secretory activity of leukotriene B4 toward rabbit neutrophils. Leukotriene B4 rapidly and vigorously degranulates rabbit neutrophils. This activity is stereospecific, cytochalasin B-dependent, and is enhanced by extracellular calcium. Pretreatment with leukotriene B4 deactivates rabbit neutrophils, i.e., cells so treated do not respond to stimulation by an additional bolus of leukotriene B4. In addition, the secretory activity of leukotriene B4 is sharply dependent on the simultaneous presence of cytochalasin B. Rabbit neutrophils therefore exhibit the previously described desensitization to the effect of cytochalasin B. In these and other discussed respects the characteristics of the leukotriene B4-induced degranulation of rabbit neutrophils are strikingly similar to those of the chemotactic factors. These results support the hypothesis that leukotriene B4 mediates, at least in part, the secretory, and possibly other, activities of chemotactic factors.


Is transition to disability pension in young people associated with changes in risk of attempted suicide?
The aim of the present study was to investigate trajectories of suicide attempt risks before and after granting of disability pension in young people. The analytic sample consisted of all persons 16-30 years old and living in Sweden who were granted a disability pension in the years 1995-1997; 2000-2002 as well as 2005-2006 (n = 26,624). Crude risks and adjusted odds ratios for suicide attempt were computed for the 9-year window around the year of disability pension receipt by repeated-measures logistic regressions. The risk of suicide attempt was found to increase continuously up to the year preceding the granting of disability pension in young people, after which the risk declined. These trajectories were similar for women and men and for disability pension due to mental and somatic diagnoses. Still, the multivariate odds ratios for suicide attempts for women and for disability pension due to mental disorders were 2.5- and 3.8-fold increased compared with the odds ratios for men and disability pension due to somatic disorders, respectively. Trajectories of suicide attempts differed for young individuals granted a disability pension during 2005-2006 compared with those granted during 1995-1997 and 2000-2002. We found an increasing risk of suicide attempt up until the granting of a disability pension in young individuals, after which the risk decreased. It is of clinical importance to monitor suicide attempt risk among young people waiting for the granting of a disability pension.


A photoperiod-insensitive barley line contains a light-labile phytochrome B
Barley (Hordeum vulgare L.) is a long-day plant whose flowering is enhanced when the photoperiod is supplemented with far-red light, and this promotion is mediated by phytochrome. A chemically mutagenized dwarf cultivar of barley was selected for early flowering time (barley maturity daylength response [BMDR]-1) and was made isogenic with the cultivar Shabet (BMDR-8) by backcrossing. BMDR-1 was found to contain higher levels of both phytochrome A and phytochrome B in the dark on immunoblots with monoclonal antibodies from oat (Avena sativa L.) that are specific to different members of the phytochrome gene family. Phytochrome A was light labile in both BMDR-1 and BMDR-8, decreasing to very low levels after 4 d of growth in the light. Phytochrome B was light stable in BMDR-8, being equal in both light and darkness. However, phytochrome B became light labile in BMDR-1 and this destabilization of phytochrome B appeared to make BMDR-1 insensitive to photoperiod. In addition, both the mutant and the wild type lacked any significant promotion of flowering in response to a pulse of far-red light given at the end of day, and the end-of-day, far-red inhibition of tillering is normal in both, suggesting that phytochrome B is not involved with these responses in barley.


Metabolic Syndrome and Its Components in Young Adults Conceived by ICSI.
Intracytoplasmic sperm injection (ICSI) conception presents the early embryo with a radically different environment, which may lead to permanent alterations to key cardiometabolic processes. Blood pressure, indicators of insulin resistance, and lipid profiles have previously been studied in offspring born after in vitro fertilisation (IVF) and ICSI, with conflicting findings. Also, results in young adults born after ICSI are lacking. We investigated if young adult men and women conceived by ICSI more frequently have metabolic syndrome and its individual features in comparison to spontaneously conceived controls. Cardiometabolic and anthropometric parameters from 126 longitudinally followed young adults conceived by ICSI were compared to those of 133 controls. At age 18 years, only 1 of the participants displayed the metabolic syndrome (1 control woman). Mean concentrations of total cholesterol, triglycerides, insulin, HOMA-IR, and blood pressure were comparable between the ICSI conceived and control participants. A higher proportion (19.6%) of men conceived by ICSI had low (<40 mg/dl) HDL cholesterol compared to controls (5.6%). While men conceived by ICSI, but not women, had lower mean HDL cholesterol concentrations in comparison to controls, other markers of the metabolic syndrome were not affected by the mode of conception.


Rivastigmine-loaded L-lactide-depsipeptide polymeric nanoparticles: decisive formulation variable optimization.
The main aim of the investigation was to explore a novel L-lactide-depsipeptide copolymer for the development of rivastigmine-loaded polymeric nanoparticles. L-lactide-depsipeptide synthesis was based on the ring opening polymerization reaction of L-lactide with the cyclodepsipeptide, cyclo(Glc-Leu), using tin 2-ethyl hexanoate as an initiator. Rivastigmine-loaded nanoparticles were prepared by the single emulsion-solvent evaporation technique. The influence of various critical formulation variables like sonication time, amount of polymer, amount of drug, stabilizer concentration, drug-to-polymer ratio, and organic-to-aqueous phase ratio on particle size and entrapment efficiency was studied. The optimized formulation having a particle size of 142.2 ± 21.3 nm with an entrapment efficiency of 60.72 ± 3.72% was obtained. Increased rivastigmine entrapment within the polymer matrix was obtained with a relatively low organic-to-aqueous phase ratio and high drug-to-polymer ratio. A decrease in the average size of the nanoparticles was observed with a decrease in the amount of polymer added and an increase in the sonication time. Prolonged sonication time, however, decreased rivastigmine entrapment. From the different lyoprotectant tested, only trehalose was found to prevent nanoparticle aggregation upon application of the freeze-thaw cycle. Drug incorporation into the polymeric matrix was confirmed by the DSC and XRD study. The spherical nature of the nanoparticles was confirmed by the SEM study. The in vitro drug release study showed the sustained release of more than 90% of the drug up to 72 h. Thus, L-lactide-depsipeptide can be used as an efficient carrier for the nanoparticle preparation of rivastigmine.


Sir Hugh Cairns and World War II British advances in head injury management, diffuse brain injury, and concussion: an Oxford tale.
The authors trace the Oxford, England, roots of World War II (WWII)-related advances in head injury management, the biomechanics of concussion and brain injury, and postwar delineation of pathological findings in severe concussion and diffuse brain injury in man. The prominent figure in these developments was the charismatic and innovative Harvey Cushing-trained neurosurgeon Sir Hugh Cairns. Cairns, who was to closely emulate Cushing's surgical and scholarly approach, is credited with saving thousands of lives during WWII by introducing and implementing innovative programs such as helmets for motorcyclists, mobile neurosurgical units near battle zones, and the military usage of penicillin. In addition, he inspired and taught a generation of neurosurgeons, neurologists, and neurological nurses in the care of brain and spinal cord injuries at Oxford's Military Hospital for Head Injuries. During this time Cairns also trained the first full-time female neurosurgeon. Pivotal in supporting animal research demonstrating the critical role of acceleration in the causation of concussion, Cairns recruited the physicist Hylas Holbourn, whose research implicated rotary acceleration and shear strains as particularly damaging. Cairns' work in military medicine and head injury remain highly influential in efforts to mitigate and manage brain injury.