Cutting back malaria: CRISPR/Cas9 genome editing of Plasmodium.
CRISPR/Cas9 approaches are revolutionizing our ability to perform functional genomics across a wide range of organisms, including the Plasmodium parasites that cause malaria. The ability to deliver single point mutations, epitope tags and gene deletions at increased speed and scale is enabling our understanding of the biology of these complex parasites, and pointing to potential new therapeutic targets. In this review, we describe some of the biological and technical considerations for designing CRISPR-based experiments, and discuss potential future developments that broaden the applications for CRISPR/Cas9 interrogation of the malaria parasite genome.


An aminopeptidase nutritionally important to Fusobacterium nucleatum.
The properties of an aminopeptidase (AP) from Fusobacterium nucleatum were studied in view of the fact that this organism, along with other Gram-negative anaerobes involved in periodontal diseases, survives in the subgingival environment by obtaining energy via the fermentation of a small number of peptide-derived amino acids. The AP was found to be cell-associated and was isolated from disrupted chemostat-grown cells. It was purified by (NH4)2SO4 fractionation, two column chromatographic steps and IEF. The enzyme was found to have a molecular mass of 54 kDa, a pI of 5.1, a pH optimum between 7.5 and 8.0 and, using Leu-Ala as substrate, it gave K(m) and Vmax values of 0.66 mM and 0.12 mumol min-1 mg-1, respectively. No complete homology was found between the N-terminal sequence of the first 20 amino acids (MDXKXYVDLKERFLRYVKFN...) and any other published sequence, but residues 8-20 gave a 62% match with residues 9-21 of an AP from Haemophilus influenzae. The enzyme was inactivated by chelating agents, bestatin, p-hydroxymercuribenzoate and some heavy metals. Cobalt ions restored EDTA-inactivated activity but did not reverse inhibition by 1,10-phenanthroline. In addition, bestatin and 1,10-phenanthroline had an inhibitory effect on the batch growth of F. nucleatum in a complex medium in which peptidase activities would be nutritionally essential. No such inhibition was observed in a chemically defined medium in which growth was not dependent upon peptidase activities. The peptidase described in this paper therefore appears to be a cobalt-activated metallo-AP which, together with other peptidases, is considered to be important in the survival of F. nucleatum in the subgingival environment of the mouth.


The effect of flumazenil on the recovery time of dental patients sedated with diazepam.
Flumazenil is an imidazobenzodiazepine that binds specifically to the central benzodiazepine receptor and antagonizes the actions of diazepam and other benzodiazepines. Previous studies in Europe have shown flumazenil at doses of 2 to 30 mg IV to reverse sedation in patients sedated with flunitrazepam, midazolam, and diazepam when evaluated by subjective criteria. The purpose of this study was to determine if flumazenil at 0.015 mg/kg IV was efficacious in shortening the recovery time of young, healthy dental patients sedated with diazepam (0.15 mg/kg IV) and restoring their psychomotor function to presedation levels. A total of 21 patients were randomized to placebo or flumazenil, sedated with diazepam, underwent a restorative dental procedure, and were then administered the test drug. Evaluations of psychomotor function by the Trieger test, Digit-Symbol Substitution test, Romberg test, and nurse questioning were carried out before sedation and at 10-minute intervals after test drug. Observations by the patients and nurses were not significantly different before versus after test drug. The investigator, however, found that flumazenil resulted in more rapid awakening. Patients treated with placebo exhibited significantly greater deficits in the number of dots missed and sum of deviations on the Trieger test than flumazenil-treated patients. Similar time-related deficits were recorded for the Digit-Symbol Substitution test. Flumazenil, at a dose of 0.015 mg/kg, was found to be efficacious in reducing the recovery time after diazepam sedation in dental patients.


Time for a change? The process of lengthening booking intervals in general practice.
Longer booking intervals between appointments in general practice are generally seen as 'a good thing', and have a strong 'evidence base' to support them. Changing to longer booking intervals is regarded as a pipe dream by many general practitioners (GPs). This paper reports the process and outcomes of a change to longer booking intervals in one practice, identifies the key elements of the change, and examines lessons learned for the practice, to help other practices to do similarly. The most important factor in bringing about change was the influence of facilitation by outside parties; first, by management consultants who identified solutions to the practice's problems, and secondly, by recruitment to a research study. Other outside influences were an awareness of the success of other practices in changing to 10-minute booking intervals, and the increasing 'evidence base' to support such change. Internal influences on the process were a desire to change as a result a perception that the practice was under-performing, and the stress associated with this. As a result of the change, the number of doctor consultations fell and the number of nurse consultations rose, fewer patients reconsulted, and marginal improvements were reported on doctor and patient satisfaction. Other practices may benefit from such change; the use of management consultants as facilitators may instigate such change.


Application of the convergence of the control net of box splines to scale-space filtering.
In this correspondence, we propose a new approach to scale-space filtering using a box spline representation of multidimensional signals. The use of box splines is motivated by their ability to handle complex geometries better than tensor-product B-splines. The box spline we use is defined by a set of vectors invariant under the multiplication by a sampling matrix. We show that such a box spline satisfies a dilation equation which is the basis for the scale-space filtering we propose. Several numerical applications in 2-D conclude the correspondence.


What is the psychological impact of self-weighing? A meta-analysis.
Many people self-weigh and many interventions addressing weight-related problems such as obesity promote self-weighing. However, while self-weighing has been associated with weight loss, there is mixed evidence regarding the psychological impact of this behaviour. The present review aimed to quantify the relationship between self-weighing and: (i) affect (e.g., anxiety, depression); (ii) psychological functioning (e.g., self-esteem); (iii) body-related attitudes and (iv) disordered eating. A computerized search of scientific databases in September 2014 and subsequent ancestry and citation searches identified 29 independent tests of the relationship between self-weighing on psychological outcomes. Meta-analysis was used to quantify the size of the association across the tests. Results indicated that there was no association between self-weighing and affect, body-related attitudes or disordered eating. There was, however, a small-sized negative association between self-weighing and psychological functioning. The age of participants, obesity status, the extent of weight loss, duration of self-weighing and study design (RCT versus correlational) were found to influence at least some of the psychological outcomes of self-weighing. The findings suggest that, for the most part, self-weighing is not associated with adverse psychological outcomes. However, in some cases the association between self-weighing and psychological outcomes may be more negative than in others.


Gabapentin: An update of its pharmacological properties and therapeutic use in epilepsy.
The new antiepileptic medications are prescribed for the treatment of patients with seizure disorders since 17 years ago. Gabapentin (GBP) was approved on January 1994 as adjunctive treatment in patients 12 years or older with partial seizures, with or devoid of secondary generalization. GBP, was formerly known as an anticonvulsant γ-aminobutyric acid (GABA) mimetic, is considered as a safe and well-tolerated antiepileptic drug (AED) with promising pharmacokinetic properties and a wide therapeutic index. GBP is useful for the therapy of mixed seizure disorders and refractory partial seizures in children. GBP must be regarded as the first treatment for older patients with recently diagnosed seizures. GBP has a well recognized clinical efficacy in those types of focal epilepsy which were resistant to the traditional AEDs. The main object of this review was to evaluate the efficacy, tolerability, dosing schedules and safety of GBP that have been investigated in peer-reviewed journals.


Hemodynamic Response to Treatment and Outcomes in Pulmonary Hypertension Associated With Interstitial Lung Disease Versus Pulmonary Arterial Hypertension in Systemic Sclerosis: Data From a Study Identifying Prognostic Factors in Pulmonary Hypertension Associated With Interstitial Lung Disease.
Patients with systemic sclerosis and both pulmonary hypertension and interstitial lung disease (SSc-PH-ILD) generally carry a worse prognosis than patients with SSc and pulmonary arterial hypertension (SSc-PAH) without ILD. There is no evidence of the efficacy of PAH therapies in SSc-PH-ILD. We undertook this study to compare survival of and response to treatment in patients with SSc-PH-ILD and those with SSc-PAH. We analyzed 128 patients (66 with SSc-PH-ILD and 62 with SSc-PAH) from 15 centers, in whom PH was diagnosed by right-sided heart catheterization; they were prospectively included in the PH registry. All patients received PAH-specific therapy. Computed tomography of the chest was used to confirm or exclude ILD. At baseline, patients with SSc-PH-ILD had less severe hemodynamic impairment than those with SSc-PAH (pulmonary vascular resistance 5.7 Wood units versus 8.7 Wood units; P = 0.0005) and lower diffusing capacity for carbon monoxide (median 25% [interquartile range (IQR) 18%, 35%] versus 40% [IQR 31%, 51%]; P = 0.0005). Additionally, patients with SSc-PH-ILD had increased mortality (8.1% at 1 year, 21.2% at 2 years, and 41.5% at 3 years) compared to those with SSc-PAH (4.1%, 8.7%, and 21.4%, respectively; P = 0.04). Upon treatment with PAH-targeted therapy, no improvement in the 6-minute walk distance was observed in either group. Improvement in the World Health Organization functional class was observed less frequently in patients with SSc-ILD-PH compared to those with SSc-PAH (13.6% versus 33.3%; P = 0.02). Hemodynamics improved similarly in both groups. ILD confers a worse prognosis to SSc-PH. Response to PAH-specific therapy is clinically poor in SSc-PH-ILD but was not found to be hemodynamically different from the response observed in SSc-PAH.


Selective ablation of astrocytes by intracerebral injections of alpha-aminoadipate.
The efficacy and the specificity of the putative astrotoxin, alpha-aminoadipate, were examined in this study. The integrity of astrocytes was evaluated at several time points following a single injection of alpha-aminoadipate into amygdala of adult rats using immunohistochemistry. The density and the morphological appearance of neurons and the response of microglia were also examined. The injection of alpha-aminoadipate disrupted the astrocytic network in that region. There was a profound loss of glial fibrillary acidic protein-positive and S100 beta-positive astrocytes, normally present in the region, while vimentin immunohistochemistry revealed the presence of deformed cell processes, presumably astrocytic. The presence of reactive microglia at the injection site was suggestive of an active degenerative process, while the normal neuronal density and appearance, as compared to controls, suggested that the damage was confined to astrocytes. The confirmed effectiveness and cellular specificity of alpha-aminoadipate in vivo makes it a potentially important experimental tool for attempting to decipher the functional significance of astrocytes.


Effects of nitroglycerin on cardiac function and regional blood flow distribution in conscious dogs.
The effects of intravenous infusion of nitroglycerin (NTG), 8 and 32 microgram/kg.min for 7 min, and of sublingual NTG, 1.2 mg, were examined on direct and continuous measurements of systemic, coronary, and regional hemodynamics, left ventricular (LV) dimensions, pressures, and myocardial contractility in conscious dogs. NTG induced sustained reductions in LV dimensions and transient increases in heart rate and dP/dt, and decreases in mean arterial pressure. Initially NTG increased cardiac output and flows to the coronary, mesenteric, renal, and iliac beds, while systemic and regional vascular resistances fell. Later, cardiac output, cardiac work, and mesenteric and iliac flows fell significantly below control, and significant vasoconstriction in the systemic as well as mesenteric, iliac, and coronary beds was observed at a time when LV end-diastolic dimensions were still significantly reduced. Peripheral vasoconstriction was not observed with systemic NTG in deafferented dogs or when NTG, 1 microgram/kg.min, was infused intra-arterially into the iliac bed. Thus, systemic NTG induces a biphasic response consisting of initial arteriolar vasodilation followed by vasoconstriction in the mesenteric, iliac, coronary and systemic beds, which is presumably due to longer lasting effects on preload and to secondary reflex responses to the drug.


Evaluation of high-performance liquid chromatography and mass spectrometry method for pharmacokinetic study of local anesthetic ropivacaine in plasma.
We studied the viability of high-performance liquid chromatography and mass spectrometry (LC/MS) as a selective and sensitive analytical method for measuring blood concentrations of the local anesthetic ropivacaine. Ropivacaine was effectively separated using a reverse-phase column and monitored at 275 m/z ion. The LC/MS method allowed measurement of concentrations of ropivacaine of lower than 75 ng/mL. The standard curve was linear and in the range of <1.5 microg/mL. Recovery of ropivacaine in plasma samples was over 90% after precipitation of plasma protein with trichloroacetic acid. The method was tested on the pharmacokinetics of plasma ropivacaine after single intravenous or subcutaneous administration in rabbits. The pharmacokinetic parameters showed a one-compartment model and a mean elimination half-life of 0.54+/-0.05 h and 2.83+/-0.51 h after administration at doses of 0.4 mg/kg, i.v. and 5 mg/kg, s.c., respectively. These values were in approximate agreement with previously obtained results in dogs. The results of the present study demonstrated that the LC/MS method was highly selective and sensitive for the measurement of ropivacaine, indicating that it offers a useful tool for monitoring the therapeutic effects and determining the pharmacokinetic parameters of this drug in blood.


Construction and evaluation of a pertactin-deficient live attenuated pertussis vaccine candidate BPZE1 derivative.
Pertussis, mainly caused by Bordetella pertussis, is a severe respiratory disease that can be fatal, especially in young infants. Vaccines, massively implemented since the middle of the last century, have substantially reduced the pertussis incidence, but have not been able to fully control the disease. One of the shortcomings of current pertussis vaccines is their inability to prevent infection by and transmission of B. pertussis, in contrast to immunity following natural infection. We have developed the live attenuated nasal vaccine BPZE1 and have shown that it prevents both disease and B. pertussis infection in preclinical models. This vaccine is now in clinical development. However, the initial clinical studies have suggested that vaccine take is hampered by pre-existing antibodies to pertactin. Here, we have constructed a pertactin-deficient BPZE1 derivative called BPZE1P in order to overcome this limitation. BPZE1P colonized the murine respiratory tract as efficiently as BPZE1 and induced antibodies at levels similar to those elicited by BPZE1. In the presence of pre-existing antibodies induced by acellular pertussis vaccination, BPZE1P colonized the mouse respiratory tract more efficiently than BPZE1. Both vaccines protected equally well the murine lungs and noses from challenge with laboratory and clinical strains of B. pertussis, including pertactin-deficient strains, against which current acellular pertussis vaccines are less efficient. BPZE1P may thus be an interesting alternative to BPZE1 to overcome vaccine take limitations due to pre-existing antibodies to pertactin.


[Activation of tyrosine kinases during induction of mammary gland tumors in GR mice by ovarian hormones].
In GR mice, the induction of proliferative processes in mammary tumours with ovarian hormones (estrone and progesterone) is accompanied by the activation of phosphorylation of plasma membrane, cytosolic and nuclear proteins by endogenous protein kinases. The hormones stimulate tyrosine kinases of tumour cells whose activity is as high as 14.9-17.9% of the total phosphorylation in plasma membranes and 9.5-10.4% in cell nuclei. The ovarian hormones stimulate tyrosine kinases of tumour cells which phosphorylate proteins with Mr of 110-230 and 15 kD (plasma membranes), 170, 52 and 13 kD (cytosol) and 32 kD (nuclei) which are resistant to alkaline hydrolysis. Apart from tyrosine kinases, the ovarian hormones also stimulate serine and threonine protein kinases which seems to be due to the activation of protein kinase C and other protein kinases.


Floral signposts: testing the significance of visual 'nectar guides' for pollinator behaviour and plant fitness.
Nectar guides, contrasting patterns on flowers that supposedly direct pollinators towards a concealed nectar reward, are taxonomically widespread. However, there have been few studies of their functional significance and effects on plant fitness. Most previous studies focused on pollinator behaviour and used artificial flowers in laboratory settings. We experimentally investigated the role of putative nectar guides in a natural system: the South African iris Lapeirousia oreogena, whose flowers have a clearly visible pattern of six white arrow-markings pointing towards the narrow entrance of the long corolla tube, and its sole pollinator, a long-proboscid nemestrinid fly. We painted over none, some or all of the white arrow-markings with ink that matched the colour of the corolla background. Although arrow-marking removal had little effect on the approaches by flies to flowers from a distance, it dramatically reduced the likelihood of proboscis insertion. Export of pollen dye analogue (an estimate of male fitness) was reduced to almost zero in flowers from which all nectar guides had been removed, and fruit set (a measure of female fitness) was also significantly reduced. Our results confirm that the markings on L. oreogena flowers serve as nectar guides and suggest that they are under strong selective maintenance through both male and female fitness components in this pollination system.


Biosynthesis of a complex yersiniabactin-like natural product via the mic locus in phytopathogen Ralstonia solanacearum.
A genome mining study in the plant pathogenic bacterium Ralstonia solanacearum GMI1000 unveiled a polyketide synthase/nonribosomal peptide synthetase gene cluster putatively involved in siderophore biosynthesis. Insertional mutagenesis confirmed the respective locus to be operational under iron-deficient conditions and spurred the isolation of the associated natural product. Bioinformatic analyses of the gene cluster facilitated the structural characterization of this compound, which was subsequently identified as the antimycoplasma agent micacocidin. The metal-chelating properties of micacocidin were evaluated in competition experiments, and the cellular uptake of gallium-micacocidin complexes was demonstrated in R. solanacearum GMI1000, indicating a possible siderophore role. Comparative genomics revealed a conservation of the micacocidin gene cluster in defined, but globally dispersed phylotypes of R. solanacearum.


Spouse and Patient Beliefs and Perceptions About Chronic Pain: Effects on Couple Interactions and Patient Pain Behavior.
Patient beliefs and perceptions about the causes and meaning of their chronic pain are related to their psychosocial functioning. Beliefs and perceptions about chronic pain held by spouses may also be related to patient functioning. We used a laboratory procedure to evaluate whether spouse beliefs about and perceptions of chronic pain were related to spouse negative responses toward patients with chronic low back pain during a conflictual discussion and to their attributions about patient pain behavior during a subsequent pain-induction task. Patients (n = 71) and their spouses (n = 71) participated in a 10-minute discussion followed by the patient undergoing a 10-minute structured pain behavior task. Findings were that a) spouse perceptions that patient's pain was a mystery were significantly related to greater patient perceived spouse critical/invalidating responses toward the patient during the discussion; and b) spouse perceptions that patient's pain was a mystery were related to internal and negative attributions spouses made while observing patients display pain behaviors during the structured pain behavior task. Inasmuch as both spouse critical/invalidating speech toward patients and negative attributions regarding the cause of patient behavior are related to poor patient functioning, spouse uncertainty about the source and potential legitimacy of their partner's pain may play crucial roles in affecting patient well-being. PERSPECTIVE: Spouse beliefs about and perceptions of patient chronic pain were related to spouse behavior toward patients during a discussion and to attributions explaining patient pain during physical activity. If spouse confusion and doubt about patient pain is related to negative behavior and attributions, then modifying these perceptions may be a fundamental intervention target.


[Elastic properties of triclinic crystals of lysozyme in anhydric acetonitrile].
Measurements of lysozyme crystal elastic properties in anhydrous acetonitrile were performed in order to investigate the role of water in protein elasticity. It was shown that triclinic crystals of lysozyme are suitable for such kind of investigation because of being placed in acetonitrile they save crystal lattice parameters. The observed changes of lysozyme crystals elastic properties are close to those found earlier for partially dehydrated protein. These results point to water influence on intramolecular conformational mobility of protein. The water-protein electrostatic interaction and Laplase's pressure as possible mechanisms of this influence are discussed.


Phase II trial of gemcitabine plus cisplatin in non-small cell lung cancer: a Hoosier Oncology Group study.
Although non-small cell lung cancer accounts for a majority of lung cancer cases in the United States, overall response rates of only 20% have been obtained with cisplatin-based therapy. However, new agents such as the nucleoside analog gemcitabine have demonstrated single-agent response rates of approximately 20%. The synergistic growth inhibition of several tumor cell lines seen in vitro with cisplatin and gemcitabine has led to clinical trials incorporating this drug combination. Recent phase I trials revealed that administration of gemcitabine 1,000 mg/m2 weekly x 3, with cisplatin 100 mg/m2 on day 15, every 28 days, was well tolerated. This regimen was used in the present Hoosier Oncology Group phase II trial of patients with advanced non-small cell lung cancer, except that cisplatin was administered on day 1. Five patients had stage IIIB and 25 had stage IV disease, with a mean Karnofsky performance status of 90. Toxicity observed was primarily hematologic, notably, granulocytopenia and thrombocytopenia. Responses were seen in 10 of 27 patients, for an overall response rate of 37%. Median overall survival was 8.4 months; it was 10.2 months for patients with stage IV disease. These favorable results and manageable side effects suggest that future trials incorporating gemcitabine and cisplatin are indicated.


Hair, encoding a single C2H2 zinc-finger protein, regulates multicellular trichome formation in tomato.
Trichomes originate from the epidermal cells of nearly all terrestrial plants, which are specialized unicellular or multicellular structures. Although the molecular mechanism regulating unicellular trichome formation has been extensively characterized, most of the genes essential for multicellular trichome formation remain unknown. In this study, we identified an associated locus on the long arm of chromosome 10 using a genome-wide association study (GWAS) on type-I trichomes of 180 diverse Solanum lycopersicum (tomato) accessions. Using map-based cloning we then cloned the key gene controlling the initiation of this type of trichome, named Hair (H), which encodes a single C2H2 zinc-finger protein. Transgenic experiments showed that hair-absent phenotype is caused by the deletion of the entire coding region of H. We identified three alleles of H containing several missense mutations and a nucleotide deletion, which result in amino acid substitutions and a reading frame shift, respectively. In addition, knockdown of H or Woolly (Wo) represses the formation of type-I trichomes, suggesting that both regulators may function as a heterodimer. Direct protein-protein interaction between them was further detected through pull-down and yeast two-hybrid assays. In addition, ectopic expression of H in Nicotiana tabacum (tobacco) and expression of its homologs from Capsicum annuum (pepper) and tobacco in tomato can trigger trichome formation. Taken together, these findings suggest that the H gene may be functionally conserved in multicellular trichome formation in Solanaceae species.


Carbohydrate nutrition and development of adiposity during adolescence.
To examine the prospective association between glycemic index, glycemic load (GL) of diets and intakes of carbohydrates, sugars, fiber, and the main carbohydrate containing food groups (e.g., soft drinks) with changes in percent body fat, body mass index (BMI), and waist circumference among adolescents. Students aged 12 at baseline (n = 856) were examined both in 2004-2005 and 2009-2011. A semiquantitative food frequency questionnaire was administered. Anthropometric parameters were measured and defined using standardized protocols. After multivariable adjustment, in girls, each 1-SD increase in dietary GL was associated with concurrent 0.77 kg/m2 and 1.45 cm increase in BMI and waist circumference, respectively (both P = 0.01). Conversely, each 1-SD increase in dietary fiber intake was associated with a concurrent 0.44 kg/m2 decrease in mean BMI in girls (P = 0.02) and 1.45 cm decrease in waist circumference in boys (P = 0.002). Girls who consumed soft drinks once or more per day versus those who never/rarely consumed soft drinks, had a 4.45% increase in percent body fat after 5 years (Ptrend = 0.01). High-GL foods might adversely influence development of body composition, particularly in girls, whereas fiber-rich diets could limit excess weight during adolescence.


[Existence of Biofilm and Biofilm-Associated Virulence Genes in Multi-Drug Resistant Invasive Acinetobacter baumannii Isolates].
Acinetobacter baumannii is a multi-drug resistant (MDR) gram-negative pathogen leading to nosocomial infections. Hospital-acquired infections due to A.baumannii occur especially in patients hospitalized in intensive care units. Important infections related to this bacterium are pneumonia, bacteremia, endocarditis, skin and soft tissue, urinary tract infections and meningitis. Human transmission is usually through the hospital environment or through medical personnel. A.baumannii isolates increases their virulence not only being multiple resistance to antibiotics but as well as the ability to form biofilm. The biofilm formation of A.baumannii isolates were mostly related with genes encoding curli fiber (csgA), the chaperone-usher fimbria (csuE) and the outer membrane (ompA). The aim of this study was to demonstrate biofilm production and virulence genes in MDR invasive A.baumannii isolates. MDR and similarity status previously known invasive A.baumannii (n= 156) isolates were included in the study. Biofilm production was determined by quantitative microplate biofilm method. Virulence genes csgA, csuE, fimH, ompA and blaPER-1 were investigated by polymerase chain reaction (PCR). It was determined that 60.3% (94/156) of all the isolates formed biofilm. Of these 94 isolates, 17 were weak, 33 were medium and 44 were strong. The mean biomass forming capacity of the isolates was found to be 2.23 ± 0.0033. Among the isolates included in the study (n= 156) the frequency of csgA, csuE, ompA, fimH and blaPER-1 genes were 71.2%, 32.1%, 21.8%, 7.1% and 3.2% respectively. The frequency of csgA, ompA, bap, csuE, fimH virulence genes were found to be 41.5%, 24.5%, 20.2% and 5.3% among biofilm positive isolates respectively. Biofilm-forming isolates were most commonly found in pulsotype II 19.1% (18/94), pulsotype IX 17.0% (16/94) and pulsotype VI 12.8% (12/94). In this study, when the distribution of virulence genes were compAred with the isolates that have weak, medium and strong biofilm, all of the studied genes were found to be more abundant in isolates with strong and medium positive biofilm production. This has shown that excluding fimH gene, csgA, csuE and ompA genes have contributed to the biofilm formation in invasive A.baumannii isolates, respectively.


Rates of ultrasonic vocalizations are more strongly related than acoustic features to non-vocal behaviors in mouse pups.
Mouse pups produce. ultrasonic vocalizations (USVs) in response to isolation from the nest (i.e., isolation USVs). Rates and acoustic features of isolation USVs change dramatically over the first two weeks of life, and there is also substantial variability in the rates and acoustic features of isolation USVs at a given postnatal age. The factors that contribute to within age variability in isolation USVs remain largely unknown. Here, we explore the extent to which non-vocal behaviors of mouse pups relate to the within age variability in rates and acoustic features of their USVs. We recorded non-vocal behaviors of isolated C57BL/6J mouse pups at four postnatal ages (postnatal days 5, 10, 15, and 20), measured rates of isolation USV production, and applied a combination of pre-defined acoustic feature measurements and an unsupervised machine learning-based vocal analysis method to examine USV acoustic features. When we considered different categories of non-vocal behavior, our analyses revealed that mice in all postnatal age groups produce higher rates of isolation USVs during active non-vocal behaviors than when lying still. Moreover, rates of isolation USVs are correlated with the intensity (i.e., magnitude) of non-vocal body and limb movements within a given trial. In contrast, USVs produced during different categories of non-vocal behaviors and during different intensities of non-vocal movement do not differ substantially in their acoustic features. Our findings suggest that levels of behavioral arousal contribute to within age variability in rates, but not acoustic features, of mouse isolation USVs.


Versatile DIY Route for Incorporation of a Wide Range of Electrode Materials into Rotating Ring Disk Electrodes.
Rotating ring disk electrodes (RRDEs) are a powerful and versatile tool for mechanistically investigating electrochemical reactions at electrode surfaces, particularly in the area of electroanalysis and catalysis. Despite their importance, only limited electrode materials (typically glassy carbon, platinum, and gold) and combinations thereof are available commercially. In this work, we present a method employing three-dimensional (3D) printing in conjunction with machined brass components to produce housing, which can accommodate any electrode material in, e.g., pressed powdered pellet, wafer, rod, foil, or vapor deposited onto a conductive substrate form. In this way, the range and usability of RRDEs is extended. This custom do-it-yourself (DIY) approach to fabricating RRDEs also enables RRDEs to be produced at a significant fraction of the cost of commercial RRDEs. To illustrate the versatility of our approach, coplanar boron-doped diamond (BDD) RRDEs are fabricated for the first time using the approach described. Experimental collection efficiencies for the redox couple FcTMA+/FcTMA2+ are found to be very close to those predicted theoretically. BDD electrodes serve as an ideal electrocatalyst support due to their low background currents, wide solvent potential window in aqueous solution, and chemical and electrochemical stability in acid and alkali solutions. The BDD RRDE configuration is employed to investigate the importance of surface-incorporated nondiamond carbon in BDD on hydrogen peroxide generation via the oxygen reduction reaction in acid solutions.


[Congenital cystic dilatation of the intrahepatic bile ducts (Caroli syndrome)].
Caroli's syndrome is a rare disease, six cases of which were under the authors' care between 1979 and 1986. None had associated congenital hepatic fibrosis; one had an associated choledochal anomaly. Endoscopic retrograde cholangiography proved to be the most sensitive diagnostic method. Liver abscess and secondary biliary cirrhosis of the liver developed as complications. Partial liver resection was possible in two patients in whom only one lobe had been affected.


Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers.
This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.


Human monoclonal antibody-drug conjugates in the experimental treatment of malignant gliomas--studies in vitro and in vivo.
The chemotherapeutic agents doxorubicin (DXR) and 4'-epi-doxorubicin were separately conjugated to the human monoclonal antibody CLNIgG, which binds strongly to human malignant glioma cells. The antibody-drug conjugates were more potent than the free drugs in killing human glioma cells in vitro and in vivo (subcutaneous glioma model). A biodistribution study using [14-14C]DXR-CLNIgG conjugate indicated that immunoconjugates delivered at least five times more DXR to glioma tissues than free DXR alone in nude mice without increasing the concentration in other tissues. In a nude rat intracerebral glioma model, intracarotid hyperosmolar perfusion to achieve blood-brain barrier (BBB) opening caused a 640% increase in the DXR-CLNIgG concentration in intracerebral tumor tissue. Human monoclonal antibody-drug conjugates in combination with BBB opening is a potential new approach to the treatment of malignant gliomas.


An ongoing case-control study to evaluate the NHS Bowel Cancer Screening Programme.
Colorectal cancer is the third most common cause of cancer death in both males and females in England. A national bowel cancer screening programme was rolled out in England between 2006 and 2010. In the post-randomised controlled trials epoch, assessment of the impact of the programme using observational studies is needed. This study protocol was set up at the request of the UK Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis to evaluate the effect of the current bowel cancer screening programme on incidence of advanced primary colorectal cancer. All incident cases of primary colorectal cancer in England will be included. Cases will be matched to controls with respect to sex, age, area of registration and year of first invitation to screening. Each evaluation round will cover a 2-year period, starting from January 2012, and ongoing thereafter. In the first instance, a pilot will be carried out in a single region. Variables related to colorectal tumour pathology will be obtained to enable selection and matching of cases and controls, and to allow analyses stratification by anatomical subsite within the bowel. Cases at Duke's stage B or worse will be considered as "advanced stage". The influence of sex will also be investigated. The incidence ratio observed in randomised controlled trials between controls (not invited) and non-attender invitees will be used to correct for self-selection bias overall. Screening participation at other national screening programmes (cervical, breast) will also be collected to derive a more contemporaneous adjustment factor for self-selection bias and assess consistency in self-selection correction in female patients.Full ethical approval was obtained from the Health Research Authority. The case-control design is potentially prone to a number of biases. The size of the planned study, the design specifications and the development of analytical strategies to cope with bias should enable us to obtain accurate estimates of reduction in incidence of advanced stage disease. The results of analyses by sex and anatomical subsite may highlight the potential need for sex-specific recommendations in the programme.


[A drowsy child: benzodiazepine poisoning?].
In The Netherlands accidental intoxications in children due to benzodiazepines are regularly encountered. In 1987 of 1630 requests for information at the National Poison Control Centre about probable benzodiazepine intoxications 144 (8.8%) concerned children 0-12 years of age. The symptoms of this type of intoxication are non-specific and if the physician does not think of benzodiazepine intoxication extensive diagnostic procedures may be performed. If children show symptoms e.g. unconsciousness, ataxia and hypotonia, the physician should always think of benzodiazepine intoxication and try to confirm or to exclude this possibility by toxicological analysis. We discuss ways and means of the diagnosis and how to avoid pitfalls on the way.


Live birth in Cretaceous marine lizards (mosasauroids).
Although live-bearing (viviparity) has evolved around 100 times within reptiles, evidence of it is almost never preserved in the fossil record. Here, we report viviparity in mosasauroids, a group of Cretaceous marine lizards. This is the only known fossil record of live-bearing in squamates (lizards and snakes), and might represent the oldest occurrence of the trait in this diverse group; it is also the only known fossil record of viviparity in reptiles other than ichthyosaurs. An exceptionally preserved gravid female of the aigialosaur Carsosaurus (a primitive mosasauroid) contains at least four advanced embryos distributed along the posterior two-thirds of the long trunk region (dorsal vertebrae 9-21). Their orientation suggests that they were born tail-first (the nostrils emerging last) to reduce the possibility of drowning, an adaptation shared with other highly aquatic amniotes such as cetaceans, sirenians and ichthyosaurs; the orientation of the embryos also suggests that they were not gut contents because swallowed prey are usually consumed head-first. One embryo is located within the pelvis, raising the possibility that the adult died during parturition. Viviparity in early medium-sized amphibious aigialosaurs may have freed them from the need to return to land to deposit eggs, and permitted the subsequent evolution of gigantic totally marine mosasaurs.


Head and Neck Reconstruction: Does Surgical Specialty Affect Complication Rates?
Reconstruction of head and neck defects resulting from resection of head and neck masses is performed by both plastic surgeons and otolaryngologists. The American College of Surgeons National Surgical Quality Improvement (NSQIP) database allows one to directly compare the outcomes for a given procedure based upon specialty. The purpose of this study is to compare outcomes and resource utilization of microvascular head and neck reconstruction between plastic surgery and otolaryngology. Institutional review board approval was obtained and NSQIP was queried from 2005 to 2015 with inclusion of Current Procedural Terminology codes for free tissue transfer performed for head and neck reconstruction. Outcomes were compared between cases having otolaryngology and plastic surgery as performing the free flap reconstruction. During 2005 to 2015, a total of 2,322 flaps were performed, 893 by plastic surgery and 1,429 by otolaryngology. Average length of stay (LOS) was 13.7 and 11.4 days for plastic surgery and otolaryngology, respectively. It was found that plastic surgery performed more osteocutaneous flaps than otolaryngology. Higher rates of superficial surgical site infection, deep surgical site infections, wound dehiscence, myocardial infarction, bleeding complications, sepsis, unplanned return to the operating room, and unplanned readmission were observed for patients treated by otolaryngology (p < 0.05). This study shows plastic surgery patients have superior outcomes with regards to free tissue transfers of the head and neck when compared with otolaryngology patients. Although plastic surgery patients experienced a longer LOS, the significantly lower complication rate supports an overall more optimal resource utilization. Future studies may elucidate potential cost savings in patients treated by plastic surgery.


School-Based Tobacco Control and Smoking in Adolescents: Evidence from Multilevel Analyses.
Since 2015, universal comprehensive school-based tobacco control programs have been provided in all primary and secondary schools in Korea. This study explored the association of school-level tobacco control with adolescent smoking, and the interactions to investigate whether gender moderates the impact of school tobacco control programs and school-level norms. Both school- and individual-level data were drawn from the 2015 School-Based Tobacco Prevention Program Survey. Multilevel logistic regression analyses were performed using data from 4631 students (ages 10-18 years) who were nested in 62 secondary schools in Seoul, Korea. Students who participated in more prevention programs were less likely to smoke (OR = 0.47, 95% CI 0.30-0.74). The effect of the programs was significantly moderated by gender. For boys, exposure to a greater number of programs decreased the risk of smoking (OR = 0.32, 95% CI 0.18-0.57) but not for girls. At the school level, the school norm regarding tobacco control regulations was negatively associated with smoking (OR = 0.28, 95% CI 0.11-0.76), and its effect was significant for girls only (OR = 0.35, 95% CI 0.17-0.76). This study highlights how the school environment is associated with adolescent smoking behavior, and the effects of programs and norms are different by gender. The findings suggest the need to develop strategies to enhance school-based tobacco control programs and the school norm considering gender differences.


Impact of neighbourhood food environment on food consumption in children aged 9-10 years in the UK SPEEDY (Sport, Physical Activity and Eating behaviour: Environmental Determinants in Young people) study.
Poor diet in childhood increases risk of obesity but the relationship between access to food and children's food choice is underexplored. We determined relationships between distance to and density of food outlets on children's food choice. Children (n 1721) aged 9-10 years who participated in a cross-sectional study from a sample of state and private schools across urban and rural areas. Food consumption was reported using a short validated FFQ. A Geographic Information System was used to determine proximity to local food outlets. Multivariable regression analyses were performed to determine associations between food consumption and distance to and density of local food outlets. Norfolk, England. Boys (n 754) and girls (n 967) aged 9-10 years. The impact of distance to or density of food outlets on food choice was small after adjustment. Living further away from a supermarket increased portions of fruit (0.11 portions/week per 1 km increase in distance to nearest supermarket, P < 0.05) and vegetables (0.11 portions/week, P < 0.05) consumed. Living closer to convenience stores was also associated with an increased consumption of crisps, chocolate and white bread. Density of supermarkets was associated with both an increase in vegetable intake (0.31 portions/week, P < 0.05) and unhealthy foods. Distance to and density of food outlets are both associated with children's food choice, although the impact appears to be small and the relationship is complex. However, the effects of individual foods combined could be important, particularly as even small differences in intake can impact on body weight over time.


Up-regulated miR-500a enhances hepatocarcinoma metastasis by repressing PTEN expression.
It has been shown that miR-500a may play an important role in the metastasis of hepatocarcinoma. The present study is to explore the influence of miR-500a on hepatocarcinoma proliferation and metastasis, and the related molecular mechanism. The levels of miR-500a in the serum and tissues of patients with metastatic or non-metastatic hepatocarcinoma or normal people were determined by quantitative reverse transcription-PCR (qRT-PCR). The proliferation, invasion, and cloning of hepatocarcinoma cell lines SMMC-7721 after transfection with mimic miR-500a or inhibitor miR-500a were determined. Luciferase reported assay was used to explore the relationship between miR-500a and phosphatase and tensin homologue (PTEN). Then, the protein expression of PTEN, p-Akt (S473), p-Akt (T308), Akt, p-mTOR, mTOR, p-4E-BP1, 4E-BP1, p-S6K, and S6K in SMMC-7721 cells were also determined by Western blotting. The expression of miR-500a in patients with metastatic hepatocarcinoma was significantly higher than the non-metastatic hepatocarcinoma. Overexpression of miR-500a promoted the proliferation, invasion, and cloning of SMMC-7721 cells. Luciferase reported assay showed miR-500a could directly target at 3'-UTR of PTEN. Overexpression of miR-500a significantly reduced the expression of PTEN, and enhanced phosphorylation of Akt, mTOR, S6K, and 4E-BP1. In conclusion, the expression of miR-500a was related to the proliferation and metastasis of hepatocarcinoma, which may be partly because of the activation of AKT/mTOR pathway through targetting PTEN.


Nanoheterostructure cation exchange: anionic framework conservation.
In ionic nanocrystals the cationic sublattice can be replaced with a different metal ion via a fast, simple, and reversible place exchange, allowing postsynthetic modification of the composition of the nanocrystal, while preserving its size and shape. Here, we demonstrate that, during such an exchange, the anionic framework of the crystal is preserved. When applied to nanoheterostructures, this phenomenon ensures that compositional interfaces within the heterostructure are conserved throughout the transformation. For instance, a morphology composed of a CdSe nanocrystal embedded in a CdS rod (CdSe/CdS) was exchanged to a PbSe/PbS nanorod via a Cu(2)Se/Cu(2)S structure. During every exchange cycle, the seed size and position within the nanorod were preserved, as evident by excitonic features, Z-contrast imaging, and elemental line scans. Anionic framework conservation extends the domain of cation exchange to the design of more complex and unique nanostructures.


Epidermal lipids, barrier function, and desquamation.
Based on recent morphologic, histochemical, and biochemical data, we propose a heterogeneous two-compartment model of the stratum corneum that ascribes a special role for intercellular lipids in the regulation of stratum corneum barrier function and desquamation. The evidence in favor of the model and several predictions based on the model are surveyed in this review.


[Immune response and immune tolerance to the O-antigen of Shigella flexneri VI].
The method for the determination of the number of cells synthetizing antibodies to S. flexneri VI O-antigen in the spleen of mice has been developed. Primary immune response to this antigen has been studied with the use of the new method. Immune response to the optimum immunogenic dose of O-antigen has a manifest variable character. The intensity of primary immune response has been shown to rise with the increase of the dose of O-antigen from 0.004 to 50 micrograms. The preliminary injection of 200 micrograms of O-antigen, followed by the injection of cyclophosphamide 2 days later, leads to the development of specific immunological tolerance to O-antigen in experimental animals.


Bright and dark helices of light.
Laser beams can be made to form bright and dark intensity helices of light. Such helices have a pitch length on the order of a wavelength and may have applications in lithography and the manipulation of particles through optical forces. The formation of bright helices is more strongly constrained by optical resolution limits than that of dark helices, corresponding scaling laws are derived and their relevance for photo-lithography pointed out. It is shown how to arrange dark helices on a grid in massively parallel fashion in order to create handed materials using photo-lithographic techniques.


Liposomes: an overview of manufacturing techniques.
During the last few decades liposomes have attracted great interest as ideal models for biological membranes as well as efficient carriers for drugs, diagnostics, vaccines, nutrients and other bioactive agents. The extensive and ever increasing literature covering the field of liposomology written by researchers with diverse backgrounds is an indication of increasing interest in this field. Many techniques and methodologies have evolved for the manufacture of liposomes, on small and large scales, since their introduction to the scientific community around 40 years ago. This article intends to provide an overview of the advantages and disadvantages of liposome preparation methods in general with particular emphasis on the heating method, developed in our laboratory, as a model technique for fast production of the lipid vesicles.


Phase-shifting with computer-generated holograms written on a spatial light modulator.
We propose a new computer-controlled phase-shifting method based on computer-generated holograms (CGHs) displayed on a spatial light modulator (SLM). In this method the accurate phase shifts required in phase-shifting digital holography or interferometry are induced by a suitable transformation of the encoding patterns of the CGH displayed on a SLM. Both the theoretical analysis and the experimental results demonstrate the feasibility of this approach. We also discuss possible applications of this method in the field of interferometric null testing of aspheres.


[The risk of fracture with taking alpha blockers for treating benign prostatic hyperplasia].
We evaluated the risk of fracture associated with hypotension-related adverse drug reaction caused by taking alpha blockers to treat benign prostatic hyperplasia (BPH). We used the Health Insurance Review and Assessment Service database from January 1st 2005 to June 30th 2006 for this study. The male patients with BPH and who had a prescription for alpha blockers following any fractures were defined as the cases. We set the 20 day long hazard period prior to the index date and the four control periods whose lengths were same with hazard period. After 1:4 matching of the hazard and control periods, conditional logistic regression was used to calculate the odds ratios for the risk of fractures as related to the alpha blocker exposure. Doxazosin and tamsulosin showed the increased risk of fractures, whereas terazosin did not. After stratification using the defined daily doses, a protective effect was shown for the patients who took terazosin at the doses lower than 0.4 DDD and the hazardous effect at the doses higher than or equal to 0.4 DDD. There was no significant difference for the risk of patients taking tamsulosin at the doses higher than 1.0 DDD but there was a statistically significant increase in the risk at the doses higher than or equal to 1.0 DDD. Alpha blockers for BPH may increase the risk of fracture in elderly patients who have comorbidities and take the concomitant medications. Alpha blockers need to be prescribed with caution, although some have high prostate specificity.


Attention impairment following traumatic brain injury.
The incidence of traumatic brain injury (TBI) is approximately 2,000,000 cases annually, and approximately 5.3 million Americans are currently living with some degree of cognitive-linguistic impairment secondary to TBI. One frequent aspect of that impairment is disordered attention. Attention is a complex system comprised of several component skills, each of which may be compromised by TBI and thus must be carefully assessed to design appropriate treatment protocols. Attention treatments for patients with TBI frequently involve implementing environmental controls and designing individualized therapy tasks that vary in terms of information processing demands. This article provides a summary of those attention impairments frequently associated with TBI and outlines assessment and treatment guidelines for clinicians serving TBI patients with attention problems.


Terbium (lithium zinc) distannide, TbLi(1-x)Zn(x)Sn(2) (x = 0.2).
The new terbium (lithium zinc) distannide, TbLi(1-x)Zn(x)Sn(2) (x = 0.2) crystallizes in the ortho-rhom-bic CeNiSi(2) structure type with space group Cmcm and Pearson symbol oS16. Of the four independent 4c atom positions (m2m site symmetry), three are fully occupied by individual atoms (two by Sn and one by Tb atoms) and the fourth is occupied by Li and Zn atoms with a statistical distribution. The Tb coordination polyhedron is a 21-vertex pseudo-Frank-Kasper polyhedron. One Sn atom is enclosed in a tricapped trigonal prism, the second Sn atom is in a cubocta-hedron and the statistically distributed (Li,Zn) site is in a tetra-gonal anti-prism with one added atom. Electronic structure calculations were used for the elucidation of reasons for and the ability of mutual substitution of lithium and transition metals. Positive charge density was observed around the rare earth atom and the Li and Zn atoms, the negative charge density in the proximity of the Sn atoms.


Activities of daily living, social support, and future health of older Americans.
The authors investigated the relation of activities of daily living (ADL) and social support satisfaction to illness status 10 years later among 4,870 married older adults in the Health and Retirement Study (F. Juster & R. Suzman, 1995). The authors tested the direct and indirect effects of 1992 ADL, as well as family and friends support satisfaction and spousal social support satisfaction on 2002 illness status. The hierarchical multiple regressions found, controlling for 1992 illness status, ADL protected against future illness, and family and friends and spousal support satisfaction had small, surprisingly positive, effects on greater 2002 illness. The ADL x Family and Friends Support Satisfaction and the ADL x Spousal Support Satisfaction crossproduct interactions were also small positive predictors of later illness. The authors discuss several possible mechanisms that explained this unexpected result. The authors concluded that, depending on whether the recipient is in need of support and depending on the source of the support, the older adults do or do not benefit from the support.


Possible Roles of New Mutations Shared by Asian and American Zika Viruses.
Originating in Africa, the Zika virus (ZIKV) has spread to Asia, Pacific Islands and now to the Americas and beyond. Since the first isolation in 1947, ZIKV strains have been sampled at various times in the last 69 years, but this history has not been reflected in studying the patterns of mutation accumulation in their genomes. Implementing the viral history, we show that the ZIKV ancestor appeared sometime in 1930-1945 and, at that point, its mutation rate was probably less than 0.2 × 10-3/nucleotide site/year and subsequently increased significantly in most of its descendants. Sustaining a high mutation rate of 4 × 10-3/site/year throughout its evolution, the Ancestral Asian strain, which was sampled from a mosquito in Malaysia, accumulated 13 mutations in the 3'-untranslated region of RNA stem-loops prior to 1963, seven of which generate more stable stem-loop structures and are likely to inhibit cellular antiviral activities, including immune and RNA interference (RNAi) pathways. The seven mutations have been maintained in all Asian and American strains and may be responsible for serious medical problems we are facing today and offer testable hypotheses to examine their roles in molecular interactions during brain development.


Effects of static vs. tidal hydrology on pollutant transformation in wetland sediments.
This work addressed effects of hydrology on biogeochemical processes relevant to pollutant chemical transformation in wetland sediments. Microcosms were designed to impose three hydrologic conditions on salt marsh sediments: (i) drained-oxidized redox potenial (Eh); (ii) flooded-reduced Eh and, (iii) diurnal tide-oscillating Eh. The test chemicals were N- and/or S-heterocycles (NSHs) including quinoxaline (1,4-benzodiazine), 2-methylquinoxaline(2-methyl-1,4-benzodiazine), 2,3-dimethylquinoxalinen (2,3-dimethyl-1,4-benzodiazine), phenazine (2,3,5,6-dibenzo-1,4-diazine), acridine (2,3,5,6-dibenzopyridine), dibenzothiophene (2,3,5-dibenzothiophene), phenothiazine (dibenzo-1,4-thiazine), and phenanthridine (2,3-benzoisoquinoline). Biogeochemical processes reflected the hydrologic conditions in ways analogous to field settings, e.g., Eh characteristics were drastically different: static (flooded and drained) systems had reduced (mu = -428 mV +/- 57) and oxidized (mu = +73 mV +/- 32) values, respectively, with no evidence of periodic variation while the tidal systems exhibited regularly oscillating Eh (amplitudes 40-250 mV). Sediment trace gases also corresponded to the Eh, with the major species detected being CO2 and H2O (drained, tidal) vs. CO2 + H2O + sulfides + methane (flooded). The NSH transformation rates were different in each hydrologic regime and decreased as follows: tidal > or = drained >> flooded. These results indicated that there were subtle differences in NSH processing in drained and tidal systems, but both of these systems transformed NSHs faster and to lower levels than flooded sediments. These data suggest that in situ remediation options that preserve wetland integrity and tidal hydrology can be as or more effective than static conditions that obtain in approaches such as impoundment and excavation-upland placement.


Prevalence of antibody to hantaviruses in humans and rodents in the Caribbean region of Colombia determined using Araraquara and Maciel virus antigens.
We tested sera from 286 agricultural workers and 322 rodents in the department of Córdoba, northeastern Colombia, for antibodies against two hantaviruses. The sera were analysed by indirect ELISA using the lysate of Vero E6 cells infected with Maciel virus (MACV) or the N protein of Araraquara virus (ARAV) as antigens for the detection of antibodies against hantaviruses. Twenty-four human sera were IgG positive using one or both antigens. We detected anti-MACV IgG antibodies in 10 sera (3.5%) and anti-ARAV antibodies in 21 sera (7.34%). Of the 10 samples that were positive for MACV, seven (70%) were cross-reactive with ARAV; seven of the 21 ARAV-positive samples were cross-reactive with MACV. Using an ARAV IgM ELISA, two of the 24 human sera (8.4%) were positive. We captured 322 rodents, including 210 Cricetidae (181 Zygodontomys brevicauda, 28 Oligoryzomys fulvescens and 1 Oecomys trinitatis), six Heteromys anomalus (Heteromyidae), one Proechimys sp. (Echimyidae) and 105 Muridae (34 Rattus rattus and 71 Mus musculus). All rodent sera were negative for both antigens. The 8.4% detection rate of hantavirus antibodies in humans is much higher than previously found in serosurveys in North America, suggesting that rural agricultural workers in northeastern Colombia are frequently exposed to hantaviruses. Our results also indicate that tests conducted with South American hantavirus antigens could have predictive value and could represent a useful alternative for the diagnosis of hantavirus infection in Colombia.


Pathways Home: comparing voluntary IT and non-IT users participating in a mentored self-management project.
This research paper examines the challenges in the development and adoption of an electronic patient diary within the Pathways Home for Respiratory Illness Project. This project supported community-based patients suffering from chronic obstructive pulmonary disease (COPD) to achieve increased levels of self-management and self-efficacy using electronic-monitoring techniques and mentoring by community health nurses. Participants had the option of voluntarily adopting an electronic patient diary to support their self-monitoring, which provided patients, nurses and clinicians with access to symptom and psycho-social data. This aimed to improve the identification, comprehension and initiation of early action in relation to alterations in their conditions. The paper presents data on technology adoption, electronic diary usage and, self-reported data quality, as well as examining the impact of the technology on hospitalisations (frequency and duration). The participants who chose to use the online patient diary continued their involvement with the project for the entire trial period (85% vs 54% completion). Participants were more likely to maintain use of the online patient diary than the paper diary. Both the groups experienced a positive improvement in their self-efficacy to self-manage their condition scores. The data highlight the problems implicit in some of the assumptions underpinning existing information systems models, especially in evaluating impact and the end-points presumed to be relevant in systems development life cycles.


Responses of rabbit superior colliculus neurons to repeated visual stimuli.
It has been shown that cells in the superficial layers of the superior colliculus exhibit response decrements when a visual stimulus is repeated. These response decrements have some of the properties associated with habituation, in particular, 1) spontaneous recovery and 2) habituation rate dependent on stimulus frequency. These observations have been made in two classes of neurons; direction-selective cells and so-called modified concentric cells. All of these neurons had small receptive fields and well-defined response properties. Some neurons in both the direction-selective and modified concentric groups do not show habituation. On the basis of area-threshold curves and other observations, it is suggested that those neurons which habituate possess strong inhibitory inputs which are weak or lacking in thenonhabituating neurons. This generalization leads to a hypothesis that inhibition in the superior colliculus has a long decay time and that a response to a given stimulus is affected by inhibition activated by preceding stimuli.


Breast DWI Analyzed Before and After Gadolinium Contrast Administration-An Intrapatient Analysis on 1.5 T and 3.0 T.
Diffusion-weighted magnetic resonance imaging (MRI) is gaining popularity as an addition to standard dynamic contrast-enhanced breast MRI. Although adding diffusion-weighted imaging (DWI) to the standard protocol design would require increased scanning-time, implementation during the contrast-enhanced phase could offer a multiparametric MRI protocol without any additional scanning time. However, gadolinium within a region of interest (ROI) might affect assessments of DWI. This study aims to determine if acquiring DWI postcontrast, incorporated in an abbreviated MRI protocol, would statistically significantly affect lesion classification. In addition, the effect of postcontrast DWI on breast parenchyma was studied. Screening or preoperative MRIs (1.5 T/3 T) were included for this study. Diffusion-weighted imaging was acquired with single-shot spin echo-echo planar imaging before and at approximately 2 minutes after gadoterate meglumine injection. Apparent diffusion coefficients (ADCs) based on 2-dimensional ROIs of fibroglandular tissue, as well as benign and malignant lesions at 1.5 T/3.0 T, were compared with a Wilcoxon signed rank test. Diffusivity levels were compared between precontrast and postcontrast DWI with weighted κ. An overall P ≤ 0.05 was considered statistically significant. No significant changes were observed in ADC mean after contrast administration in 21 patients with 37 ROI of healthy fibroglandular tissue and in the 93 patients with 93 (malignant and benign) lesions. This effect remained after stratification on B 0 . In 18% of all lesions, a diffusion level shift was observed, with an overall weighted κ of 0.75. This study supports incorporating DWI at 2 minutes postcontrast when ADC is calculated based on b150-b800 with 15 mL 0.5 M gadoterate meglumine in an abbreviated multiparametric MRI protocol without requiring extra scan time.


Characterization of influenza a outbreaks in Minnesota swine herds and measures taken to reduce the risk of zoonotic transmission.
Influenza A virus infections commonly cause respiratory disease in swine and can be transmitted between people and pigs, with potentially novel strains introduced into herds and spilling back into the human population. The goals of this study were to characterize influenza infections in Minnesota pigs and assess biosecurity measures used by swine workers. Veterinarians submitting influenza-positive swine samples to the University of Minnesota Veterinary Diagnostic Laboratory between October 2007 and April 2009 were surveyed regarding disease-related information and biosecurity procedures at each farm. Influenza-positive samples were submitted year-round, peaking in spring and fall. H1N1 was the most commonly detected subtype (56%), followed by H3N2 (14%) and H1N2 (12%). Most positive submissions were associated with illness in growing pigs (median age 8.8 weeks, IQR 5-15). Median morbidity and mortality were 25% (IQR 10-48) and 2% (IQR 0.5-3.5), respectively. Vaccination of sows and growing pigs was conducted at 71% and 7.9% of the swine farms, respectively. Specialized footwear was reported as the most common form of protective equipment used by workers. Employee vaccination for seasonal influenza was 19%. The sow vaccination rate in this study is consistent with national data, although growing pig vaccination is lower than the national average. Seasonal and age trends identified here may provide diagnostic guidance when growing pigs experience respiratory disease. Inconsistent use of protective equipment and employee vaccination at swine farms indicates the need for further discussion and research of approaches to minimize interspecies influenza transmission on swine farms.


Nucleoskeleton and initiation of DNA replication in metazoan cells.
To determine whether or not initiation sites for DNA replication in mammalian cells are defined by association with nuclear structure, attachments between the nucleoskeleton and the hamster DHFR gene initiation zone were examined. Nucleoskeletons were prepared by encapsulating cells in agarose and then extracting them with a nonionic detergent in a physiological buffer. The fraction of DNA that remained following endonuclease digestion was resistant to salt, sensitive to Sarkosyl, and essentially unchanged by glutaraldehyde crosslinking. Although newly replicated DNA was preferentially attached to the nucleoskeleton, no specific sequence was preferentially attached within a 65 kb locus containing the DHFR gene, two origins of bi-directional replication and at least one nuclear matrix attachment region. Instead, the entire region went from preferentially unattached to preferentially attached as cells progressed from G1 to late S-phase. Thus, initiation sites in mammalian chromosomes are not defined by attachments to the nucleoskeleton. To further assess the relationship between the nucleoskeleton and DNA replication, plasmid DNA containing the DHFR initiation region was replicated in a Xenopus egg extract. All of the DNA associated with the nucleoskeleton prior to S-phase without preference for a particular sequence and was released upon mitosis. However, about half of this DNA was trapped rather than bound to the nucleoskeleton. Thus, attachments to the nucleoskeleton can form in the absence of either DNA replication or transcription, but if they are required for replication, they are not maintained once replication is completed.


Acute leukemias in Piauí: comparison with features observed in other regions of Brazil.
Differences in age and sex distribution as well as FAB (French-American-British classification) types have been reported for acute leukemias in several countries. We studied the demographics and response to treatment of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) between 1989 and 2000 in Teresina, Piau , and compared these results with reports from Brazil and other countries. Complete data concerning 345 patients (230 ALL, 115 AML) were reviewed. AML occurred predominantly in adults (77%), with a median age of 34 years, similar to that found in the southeast of Brazil but lower than the median age in the United States and Europe (52 years). FAB distribution was similar in children and adults and FAB-M2 was the most common type, as also found in Japan. The high frequency of FAB-M3 described in most Brazilian studies and for Hispanics in the United States was not observed. Overall survival for adults was 40%, similar to other studies in Brazil. A high mortality rate was observed during induction. No clinical or hematological parameter influenced survival in the Cox model. ALL presented the characteristic peak of incidence between 2-8 years. Most of the cases were CD10+ pre-B ALL. In 25%, abnormal expression of myeloid antigens was observed. Only 10% of the patients were older than 30 years. Overall survival was better for children. Age and leukocyte count were independent prognostic factors. These data demonstrate that, although there are regional peculiarities, the application of standardized treatments and good supportive care make it possible to achieve results observed in other countries for the same chemotherapy protocols.


Strangulation of intraperitoneal kidney transplant by fallopian tube.
Renal allograft strangulation is a rare complication following simultaneous kidney pancreas transplant, often causing graft loss. This case report represents the first documented case of a 35-year-old female who developed renal graft strangulation around the left fallopian tube. Our case outlines a new complication that contributes to graft loss concerning iliac fossa anatomy and variations in female patients, as well as surgical considerations that need to be made prior to transplantation. We recommend measurement of the grafted renal vessels within the iliac fossa and respective surroundings structures to allow for the ideal positioning of the grafted organ.


Changes in enzymic activities of nucleoside diphosphate sugar interconversions during differentiation of cambium to xylem in pine and fir.
A protein fraction [precipitate obtained between 40 and 65% (NH4)2SO4 satn.] prepared from cambial cells, differentiating xylem cells and differentiated xylem cells of pine and fir trees contained all the enzymes required for the nucleoside diphosphate sugar interconversions. By using UDP-D-[U-14C]glucose or UDP-D-[U-14C]galactose, UDP-D-[U-14C-]glucuronic acid and UDP-D-[U-14C]xylose as substrates, the activities of UDP-D-galactose 4-epimerase (DC 22.214.171.124), UDP-D-xylose 4-epimerase(EC 220.127.116.11), UDP-D-glucose dehydrogenase (EC 22.214.171.124) and UDP-D-glucuronate 4-epimerase (EC184.108.40.206), UDP-d-glucuronate decarboxylase (EC 126.96.36.199) were measured at different stages of cell-wall development. The specific activities and the activities per cell of these enzymes varied during differentiation of cambium to xylem according to the type polysaccharide synthesized. Variations were also found between the two species investigated. These data, compared with those obtained in out previous work on angiosperms [see the preceding paper, Dalessandro & Northcote (1977) Biochem. J. 162, 267-279], suggest that some control of polysaccharide synthesis operates at the level of the formation of the precursors of pectin and hemicellulose syntheses.


Severe alcohol hand rub overdose inducing coma, watch after H1N1 pandemic.
Alcoholic hand rubs (AHRs) have been proven effective in preventing nosocomial infections, and healthcare authorities include AHRs use among quality-of-care criteria. Since the onset of the influenza A (H1N1) pandemic, AHRs have gained considerable popularity among the general public. We report a case of intentional AHRs self-poisoning inducing rapid coma with hyperlactatemia, and a full recovery. The relevant literature was reviewed. To our knowledge, this is the third reported case of intentional AHRs poisoning. 3 patients presented with a picture of acute alcohol intoxication, of variable severity depending on the amount ingested and speed of ingestion. The blood alcohol level was 414 mg/dl and tests for other drugs were performed 30 min after admission. The blood lactate level increased briefly to 4.8 mmol/l, without renal or hepatic function disturbances. She regained consciousness after 6 h then achieved a full recovery allowing extubation and readmission to the psychiatric ward after 24 h. She reported gulping down the entire contents of the Aniosgel bottle. Whereas overdrinking in social settings (wine and liquor) leads to a gradual increase in blood alcohol levels, AHRs poisoning is usually characterized by a sudden massive alcohol load. The unusual nature of the alcohol source may lead to diagnostic wanderings. AHRs are currently available in bottles that facilitate the ingestion of large amounts. Unit-dose packaging or dispensing might decrease the risk of AHRs poisoning.


Actions of ethanol on epidermal growth factor receptor activated luteinizing hormone secretion.
Activation of the epidermal growth factor receptor (EGF-R) stimulates prepubertal luteinizing hormone-releasing hormone (LHRH) release, which in turn induces luteinizing hormone (LH) secretion. Although ethanol (ETOH) diminishes LHRH secretion and delays the onset of female puberty, its actions following EGF-R activation are unknown. We therefore investigated the effects of ETOH on EGF-induced LHRH and LH release, both in vivo and in vitro. Basal blood samples were taken every 15 minutes from immature female rats, which then received ETOH (3 g/kg) or saline by gastric gavage. After a 90-minute ETOH absorption period, a single blood sample was drawn from each rat. Finally, EGF (200 ng/3 microl) was injected into the third ventricle of all animals and postinjection samples were drawn every 15 minutes. A similar experimental design was performed except no blood samples were taken. After ETOH exposure, EGF was administered, and 45 minutes later the animals were killed and their medial basal hypothalamus and pituitary were removed and analyzed for EGF-R and cyclooxygenase (COX) 1 and 2 by western blot analysis. For in vitro experiment, median eminence fragments from immature female rats were exposed to ETOH in a static incubation system, and prostaglandin-E, (PGE2) and LHRH were measured. EGF stimulated LH release, and this release was blunted (p < .05) by ETOH. Western blot analysis revealed that ETOH did not alter the EGF-R protein levels in the hypothalamus. ETOH blocked EGF-induced PGE2 and LHRH released from isolated median eminences. EGF administration increased both COX-1 (p < .001) and COX-2 (p < .01), but both enzymes were blocked by ETOH. The ETOH-induced decrease in EGF-stimulated LH release is due to a reduction in the formation of hypothalamic PGE2 and, subsequently, suppressed LHRH release.


Heart rate variability parameters and fetal movement complement fetal behavioral states detection via magnetography to monitor neurovegetative development.
Fetal behavioral states are defined by fetal movement and heart rate variability (HRV). At 32 weeks of gestational age (GA) the distinction of four fetal behavioral states represented by combinations of quiet or active sleep or awakeness is possible. Prior to 32 weeks, only periods of fetal activity and quiesence can be distinguished. The increasing synchronization of fetal movement and HRV reflects the development of the autonomic nervous system (ANS) control. Fetal magnetocardiography (fMCG) detects fetal heart activity at high temporal resolution, enabling the calculation of HRV parameters. This study combined the criteria of fetal movement with the HRV analysis to complete the criteria for fetal state detection. HRV parameters were calculated including the standard deviation of the normal-to-normal R-R interval (SDNN), the mean square of successive differences of the R-R intervals (RMSSD, SDNN/RMSSD ratio, and permutation entropy (PE) to gain information about the developing influence of the ANS within each fetal state. In this study, 55 magnetocardiograms from healthy fetuses of 24-41 weeks' GA were recorded for up to 45 min using a fetal biomagnetometer. Fetal states were classified based on HRV and movement detection. HRV parameters were calculated for each state. Before GA 32 weeks, 58.4% quiescence and 41.6% activity cycles were observed. Later, 24% quiet sleep state (1F), 65.4% active sleep state (2F), and 10.6% active awake state (4F) were observed. SDNN increased over gestation. Changes of HRV parameters between the fetal behavioral states, especially between 1F and 4F, were statistically significant. Increasing fetal activity was confirmed by a decrease in PE complexity measures. The fHRV parameters support the differentiation between states and indicate the development of autonomous nervous control of heart rate function.


Using economic and social data to improve veterinary vaccine development: Learning lessons from human vaccinology.
The drivers of vaccine development are many and varied. They include, for example, recognition of the burden of a vaccine-targeted disease, prioritisation of the multiple problems associated with a disease, consideration of the differing socio-economic situations under which vaccines are used, the influence of advocacy groups, and assessment of the feasibility of large-scale vaccine manufacture and distribution. In the field of human health, data-driven development of vaccines is becoming increasingly common through the availability of reliable information on the Global Burden of Disease (GBD) and stringent evaluations of vaccination programmes utilising empirical data on costing and effectiveness, and standardised cost-effectiveness thresholds. The data generated from such analyses allow policymakers, implementing partners, industries and researchers to make decisions based on the best, and most contextually relevant, available evidence. In this paper, we wish to explore the current use of economic and social data for the development of veterinary vaccines. Through comparison with the development of human vaccines, we will look for opportunities in animal health sciences to better integrate socio-economic data and analyses into the process of veterinary vaccine selection, development, and field implementation. We believe that more robust animal health impact assessments could add value to veterinary vaccine development by improving resource allocation and animal disease management.


Erythropoietin metabolism and pharmacokinetics in experimental nephrosis.
We studied erythropoietin (EPO) metabolism, regulation, and pharmacokinetics in rats with nephrotic syndrome. Sprague-Dawley rats were randomized into nephrotic (puromycin-induced) and pair-fed control groups. Animals were studied at baseline and after induction of anemia or exposure to hypobaric conditions (32 cmHg). The nephrotic group showed a reduced hematocrit (P < 0.05), a significant urinary EPO excretion, and an inappropriately low plasma EPO. Induction of anemia and exposure to hypoxia resulted in a less pronounced elevation of plasma EPO in the nephrotic group than in the control group (P < 0.05). The blunted plasma EPO response to hypoxia in nephrotic animals was associated with a marked rise in urinary EPO excretion. Pharmacokinetic studies following intravenous injection of recombinant EPO, 100 U/kg, revealed a shorter plasma half-life (t1/2) (P < 0.05), larger apparent volume of distribution (P < 0.05), and greater clearance (P < 0.02) in the nephrotic group than in the controls. Estimated endogenous EPO production rate in nephrotic rats with severe anemia was significantly lower (P < 0.05) than that of equally anemic controls. Thus puromycin-induced nephrotic syndrome is associated with marked urinary loss of EPO, relatively depressed plasma EPO response to anemia and hypoxia, as well as reduced plasma t1/2, increased volume of distribution, and clearance of exogenous EPO.


Tungiasis Stigma and Control Practices in a Hyperendemic Region in Northeastern Uganda.
Neglected tropical diseases are known to be highly stigmatized conditions. This study investigates tungiasis-related stigma and control practices in the impoverished Napak District in rural northeastern Uganda, where tungiasis is hyperendemic and effective treatment is unavailable. We conducted a questionnaire survey with the main household caretakers (n = 1329) in 17 villages and examined them for tungiasis. The prevalence of tungiasis among our respondents was 61.0%. Questionnaire responses showed that tungiasis was perceived as a potentially serious and debilitating condition and that tungiasis-related stigma and embarrassment were common. Among the respondents, 42.0% expressed judging attitudes, associating tungiasis with laziness, carelessness, and dirtiness, and 36.3% showed compassionate attitudes towards people with tungiasis. Questionnaire responses further indicated that people made an effort to keep their feet and house floors clean (important tungiasis prevention measures), but lack of water was a common problem in the area. The most frequent local treatment practices were hazardous manual extraction of sand fleas with sharp instruments and application of various and sometimes toxic substances. Reliable access to safe and effective treatment and water are therefore key to reducing the need for dangerous treatment attempts and breaking the vicious cycle of tungiasis stigma in this setting marked by poverty.


Hypocholesterolemic and Anticarcinogenic Effect of Vicia faba Protein Hydrolyzates.
In recent years, the consumption of vegetal-source proteins has been studied to determine their preventing effect on the development of several chronic diseases. The initial purpose of this report was to determine the effect of a hypercholesterolemic diet (HCD) given to mice, alone or with azoxymethane (AOM), on various obesity biochemical biomarkers, as well as on the induction of colon aberrant crypts (aberrant crypt foci; ACF). At the end of the 5-week assay, animals fed the HCD showed alterations in the level of total cholesterol, high- and low-density lipoproteins, and in the Atherogenic Index; besides, a significant elevation was observed in the number of ACF. Our second aim was to examine the effect of a Faba Protein Hydrolyzate (FPH) on mice fed the HCD. We first obtained protein hydrolyzates from the seeds of Vicia faba, determined the in vitro antioxidant potential with two tests, and, subsequently, evaluated the effect on obesity biomarkers and on the number of ACF. In the first case, we found that, generally, the best protective effect was obtained with the low dose of FPH (10 mg/kg) administered to animals fed the HCD, and injected AOM. With respect to the number of ACF, we observed that this dose was more effective, inhibiting such lesions to almost the level determined for the normocholesterolemic diet (NCD). Therefore, our results demonstrated the relevance of a HCD to develop anomalies in obesity biomarkers in mouse, as well as to increase the number of precarcinogenic lesions. Our results also showed a protective response with the administration of FPH, particularly with a specific dose, suggesting the need for extending research on the matter by widening the spectra of doses, in order to clearly define its potential to counteract the damage induced by the HCD, as well as to confirm if antioxidation in mice was involved in such an effect.


Disinfection of gutta-percha cones using three reagents and their residual effects.
The purpose of this study was to compare the efficacy of 5.25% sodium hypochlorite, 2% chlorehexidine and MTAD in disinfecting gutta-percha cones and to analyze the surface topography of gutta-percha cones after the rapid chemical disinfection procedure. Gutta-percha cones were immersed in suspensions of Enterococcus faecalis and Staphylococcus aureus separately. The cones were then immersed in 5.25% NaOCl, 2% CHX and MTAD for 30 seconds, 1 minute and 5 minutes separately. The disinfected cones were then incubated in thioglycollate media for 7 days. The thioglycolate media was sub-cultured and colony forming units were counted. For topographical examination of gutta-percha cones, the cones were immersed in respective solutions for one minute and allowed to air dry for 30 minutes after rinsing or without rinsing the cones with distilled water. The topography of the cones were then analyzed under SEM. Data was statistically analyzed using one way anova. MTAD was found to be the most effective disinfecting solution. The topographical examination of GP cones found some deposits after the disinfection procedure in every group. These deposits were removed when the GP cones were rinsed with distilled water. MTAD possesses superior bactericidal activity when compared with NaOCl and CHX and a final rinse with distilled water is essential after the disinfection procedure.


Fatigue crack localization using noncontact laser ultrasonics and state space attractors.
A fatigue crack and its precursor often serves as a source of nonlinear mechanism for ultrasonic waves, and the resulting nonlinear features are often much more sensitive to the fatigue crack than their linear counterparts. Among various nonlinear ultrasonic techniques, the proposed laser nonlinear wave modulation spectroscopy (LNWMS) is unique in that (1) it utilizes a pulse laser to exert a single broadband input instead of conventional two distinctive sinusoidal waves, and (2) a complete noncontact measurement can be realized based on LNWMS. Under a broadband excitation, a nonlinear source exhibits modulations due to interactions among various input frequency components. These modulations are often weak and can be hardly directly detected. In this paper, a damage feature called Bhattacharyya distance is extracted from the ultrasonic time signal corresponding to a pulse laser input and used to quantify the degree of damage-induced nonlinearity and localize the crack. This feature is a measure of a statistical distance used to detect the geometrical changes between state space attractors reconstructed before and after damage formation. It has been successfully used for localizing fatigue cracks in metallic plates.


Unique structure of Ascaris suum b5-type cytochrome: an additional alpha-helix and positively charged residues on the surface domain interact with redox partners.
Cytochrome b5 of the body wall of adult Ascaris suum, a porcine parasitic nematode, is a soluble protein that lacks a C-terminal membrane-anchoring domain, but possesses an N-terminal pre-sequence of 30 amino acids. During the maturation of cytochrome b5, the N-terminal pre-sequence is proteolytically cleaved to form the mature protein of 82 amino acid residues. A. suum cytochrome b5 is a basic protein containing more lysine residues and exhibiting a higher midpoint redox potential than its mammalian counterparts. We developed an expression system for the production of the recombinant nematode cytochrome b5, which is chemically and functionally identical with the native protein. Using this recombinant protein, we have determined the X-ray crystal structure of A. suum cytochrome b5 at 1.8 A (1 A=0.1 nm) resolution, and we have shown that this protein is involved in the reduction of nematode body-wall metmyoglobin. The crystal structure of A. suum cytochrome b5 consists of six alpha-helices and five beta-strands. It differs from its mammalian counterparts by having a head-to-tail disulphide bridge, as well as a four-residue insertion in the vicinity of the sixth ligating histidine, which forms an additional alpha-helix, alpha4A, between helices alpha4 and alpha5. A. suum cytochrome b5 exists predominantly as a haem-orientation B isomer. Furthermore, the haem plane is rotated approx. 80 degrees relative to the axis formed by haem-Fe and N atoms of the two histidine residues that are ligated to haem-Fe. The charge distribution around the haem crevice of A. suum cytochrome b5 is remarkably different from that of mammalian cytochrome b5 in that the nematode protein bears positively charged lysine residues surrounding the haem crevice. Using immunohistochemistry, we found that A. suum cytochrome b5 is present in the nematode hypodermis. Based on this histochemical and structural information, the physiological function of A. suum cytochrome b5 and its interaction with nematode metmyoglobin can be hypothesized.


Hyperforin, a bio-active compound of St. John's Wort, is a new inhibitor of angiogenesis targeting several key steps of the process.
Hyperforin, a phloroglucinol derivative found in St. John's wort related mainly to its antidepressant effects, has been reported recently to induce apoptosis in tumour cells and to inhibit cancer invasion and metastasis. We show that hyperforin inhibits angiogenesis in vitro in bovine aortic endothelial cells and in vivo in the chorioallantoic membrane assay. In a variety of experimental systems representing the sequential events of the angiogenic process, hyperforin treatment of endothelial cells resulted in strong inhibitory effects. Hyperforin inhibited the growth of endothelial cells in culture. Capillary tube formation on Matrigel was abrogated completely by addition of hypeforin at the low micromolar range. Hyperforin also exhibited a clear inhibitory effect on the invasive capabilities of endothelial cells. Zymographic assays showed that hyperforin treatment produced a complete inhibition of urokinase and a remarkable inhibition of matrix metalloproteinase 2. Our data indicates that hyperforin is a compound that interferes with key events in angiogenesis, confirming the recent and growing evidence about a potential role of this compound in cancer and metastasis inhibition and making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies.


Observer design for switched recurrent neural networks: an average dwell time approach.
This paper is concerned with the problem of observer design for switched recurrent neural networks with time-varying delay. The attention is focused on designing the full-order observers that guarantee the global exponential stability of the error dynamic system. Based on the average dwell time approach and the free-weighting matrix technique, delay-dependent sufficient conditions are developed for the solvability of such problem and formulated as linear matrix inequalities. The error-state decay estimate is also given. Then, the stability analysis problem for the switched recurrent neural networks can be covered as a special case of our results. Finally, four illustrative examples are provided to demonstrate the effectiveness and the superiority of the proposed methods.


A Large Solitary Fibrous Tumor of the Nasal Cavity and Paranasal Sinuses Involving the Anterior Frontal Fossa: A Case Report and Review of the Literature.
The Solitary Fibrous Tumor (SFT) is a rare mesenchymal neoplasm that arises mainly from the pleura. The sinonasal tract is generally not affected by SFT, and less than 100 cases have been reported in the English literature to date. We report an extremely rare SFT of the nasal cavity and paranasal sinuses extending into the anterior frontal fossa through the floor of the anterior skull base. To our knowledge, this case is the fourth SFT of the sinonasal tract involving the anterior frontal fossa in the world. Meanwhile, the tumor, measuring 13 × 6 cm in images, is the largest SFT of the sinonasal tract compared to previously reported cases. Three surgical procedures, including a transcranial one, were performed for the patient to achieve complete removal of the tumor. The diagnosis of SFT was established primarily by immunohistochemical positivity for CD34, STAT6, and negativity for S-100 protein. We emphasize the possibility of recurrence in SFT, and close follow-up is necessary with the help of nasal endoscopy and imaging approaches.


The Temporal Voice Areas are not "just" Speech Areas.
The Temporal Voice Areas (TVAs) respond more strongly to speech sounds than to non-speech vocal sounds, but does this make them Temporal "Speech" Areas? We provide a perspective on this issue by combining univariate, multivariate, and representational similarity analyses of fMRI activations to a balanced set of speech and non-speech vocal sounds. We find that while speech sounds activate the TVAs more than non-speech vocal sounds, which is likely related to their larger temporal modulations in syllabic rate, they do not appear to activate additional areas nor are they segregated from the non-speech vocal sounds when their higher activation is controlled. It seems safe, then, to continue calling these regions the Temporal Voice Areas.


Glycine insertion makes yellow fluorescent protein sensitive to hydrostatic pressure.
Fluorescent protein-based indicators for intracellular environment conditions such as pH and ion concentrations are commonly used to study the status and dynamics of living cells. Despite being an important factor in many biological processes, the development of an indicator for the physicochemical state of water, such as pressure, viscosity and temperature, however, has been neglected. We here found a novel mutation that dramatically enhances the pressure dependency of the yellow fluorescent protein (YFP) by inserting several glycines into it. The crystal structure of the mutant showed that the tyrosine near the chromophore flipped toward the outside of the β-can structure, resulting in the entry of a few water molecules near the chromophore. In response to changes in hydrostatic pressure, a spectrum shift and an intensity change of the fluorescence were observed. By measuring the fluorescence of the YFP mutant, we succeeded in measuring the intracellular pressure change in living cell. This study shows a new strategy of design to engineer fluorescent protein indicators to sense hydrostatic pressure.