Mechanisms of ionophore-induced stimulation of renin secretion with special reference to a chemiosmotic hypothesis.
The effects of several ionophores on renin secretion were investigated in rabbit renal cortical slices. When slices were incubated in the absence of Ca++, the K+ ionophore valinomycin (10(-5) approximately 5 x 10(-4) M) or the monovalent cation ionophore nonactin (10(-4) M) stimulated renin secretion about 2-fold. The renin secretion stimulated by valinomycin was further increased by inclusion of the H+ ionophore, carbonylcyanide m-chlorophenylhydrazone. The electroneutral K+/H+ exchange ionophore nigericin (10(-5) approximately 5 x 10(-4) M) stimulated renin secretion in a dose-dependent manner, producing a maximal stimulation of about 17-fold. Another electroneutral exchange ionophore, monensin, also significantly stimulated secretion. The stimulation by both valinomycin and nigericin was apparent whether slices were incubated in Na(+)-rich or K(+)-rich media. The extent of stimulation by the two ionophores was dependent upon the presence of anion with acetate greater than Cl greater than isethionate greater than thiocyanate. Thiocyanate itself markedly inhibited renin secretion. Incubating of slices in an iso-osmotic ammonium acetate medium which is known to induce rapid swelling of secretory granules, stimulated renin secretion to the magnitude comparable to that of maximal stimulation by nigericin in a potassium acetate medium. The pattern of response to these ionophores indicates that changes in K+, H+ and anion gradients across the renin secretory granule may modulate renin secretory rate. It is proposed that conditions which allow accumulation of K+ and anion within acidic renin secretory granules lead to osmotic swelling of the granules and that granule swelling may promote exocytosis.


Ultrasound-Guided Treatment of Extrusive Medial Meniscopathy: A 3-Step Protocol.
Medial knee pain is commonplace in clinical practice and can be related to several pathologic conditions: ie, medial plica syndrome, saphenous nerve entrapment, pes anserine syndrome, medial collateral ligament injury, and medial meniscus disorders. Ultrasound (US) imaging represents a valuable first-line diagnostic approach to adequately visualize the superficial structures in the medial compartment of the knee to easily plan for prompt treatment. Currently, the management of chronic degenerative diseases involving the menisci, and causing their extrusion, consists of surgery (arthroscopic partial meniscectomy). This procedure often allows only a partial resolution of pain and functional impairment. In the pertinent literature, US-guided interventions for the medial meniscus are proposed, mainly to decrease pain and inflammation or to induce regeneration. Likewise, this Technical Innovation describes in detail the US findings of medial extrusive meniscopathy and also illustrates a novel US-guided technique to treat the bursa of the medial collateral ligament, the extruded fragment of the medial meniscus, and the synovial parameniscal recesses simultaneously.


A Gaussian Approximation Approach for Value of Information Analysis.
Most decisions are associated with uncertainty. Value of information (VOI) analysis quantifies the opportunity loss associated with choosing a suboptimal intervention based on current imperfect information. VOI can inform the value of collecting additional information, resource allocation, research prioritization, and future research designs. However, in practice, VOI remains underused due to many conceptual and computational challenges associated with its application. Expected value of sample information (EVSI) is rooted in Bayesian statistical decision theory and measures the value of information from a finite sample. The past few years have witnessed a dramatic growth in computationally efficient methods to calculate EVSI, including metamodeling. However, little research has been done to simplify the experimental data collection step inherent to all EVSI computations, especially for correlated model parameters. This article proposes a general Gaussian approximation (GA) of the traditional Bayesian updating approach based on the original work by Raiffa and Schlaifer to compute EVSI. The proposed approach uses a single probabilistic sensitivity analysis (PSA) data set and involves 2 steps: 1) a linear metamodel step to compute the EVSI on the preposterior distributions and 2) a GA step to compute the preposterior distribution of the parameters of interest. The proposed approach is efficient and can be applied for a wide range of data collection designs involving multiple non-Gaussian parameters and unbalanced study designs. Our approach is particularly useful when the parameters of an economic evaluation are correlated or interact.


Hemoglobinopathy gone astray-three novel forms of α-thalassemia in Norwegian patients characterized by quantitative real-time PCR and DNA sequencing.
α-thalassemia is one of the most common monogenic diseases worldwide and is caused by reduced or absent synthesis of α-globin chains, most commonly due to deletions of one or more of the α-globin genes. α-thalassemia occurs with high frequency in tropical and subtropical regions of the world and are very rarely found in the indigenous Scandinavian population. Here, we describe four rare forms of α-thalassemia out of which three are novel, found in together 20 patients of Norwegian origin. The study patients were diagnosed during routine hemoglobinopathy evaluation carried out at the Department of Medical Biochemistry, Oslo University Hospital, Norway. The patients were selected for their thalassemic phenotype, despite Norway as country of origin. All samples went through standard hemoglobinopathy evaluation. DNA sequencing and copy number variation (CNV) analysis using quantitative real-time polymerase chain reaction (qPCR) was applied to detect sequence variants and uncommon deletions in the α-globin gene cluster, respectively. Deletion breakpoints were characterized using gap-PCR and DNA sequencing. DNA sequencing revealed a single nucleotide deletion in exon 3 of the HBA2 gene (NM_000517.4(HBA2):c.345del) and a novel deletion of 20 nucleotides in exon 2 of the HBA2 gene (NM_000517.4(HBA2):c.142_161del). qPCR CNV analysis detected two novel large deletions in the α-globin gene cluster, -(NOR) deletion covering both α-globin genes and (αα)Aurora Borealis affecting the regulatory region, leaving the downstream α-globin genes intact. Even though inherited globin gene disorders are extremely rare in indigenous Scandinavians, the possibility of a carrier state should not be ignored.


The enigma of fetal alcohol neurotoxicity.
The neurotoxic effects of ethanol on the human fetal brain (fetal alcohol syndrome, FAS) have been recognized for three decades, but the underlying mechanisms have remained elusive. Recently, we discovered that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neurodegeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis, also known as the brain growth-spurt period, which in rodents is a postnatal event, but in humans extends from the sixth month of gestation to several years after birth. We propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, in that we have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABA(A) receptors also trigger apoptotic neurodegeneration in the developing brain. Our findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).


Virtual patients for assessment of clinical reasoning in nursing -- a pilot study.
In different nursing programmes, one important learning outcome is clinical reasoning (CR) skills. However, to date, there is limited number of methods available for assessment of CR skills; especially for distance-based courses. This study investigates students' opinions about the feasibility of using Virtual Patients (VPs) for assessing CR in nursing education. VPs were introduced as an assessment tool in three different nursing courses at two universities, comprising 77 students in total. Students' overall acceptance of this assessment tool, including its applicability to the practise of nursing and the potential of VP-based assessment as a learning experience, were investigated using questionnaires. Course directors used the Web-SP system to assess students' interactions with VPs and their answers regarding diagnoses, caring procedures and their justifications. Students' found the VP cases to be realistic and engaging, and indicate a high level of acceptance for this assessment method. In addition, the students' indicated that VPs were good for practising their clinical skills, although some would prefer that the VP system be less "medical" and asked for more focus on nursing. Although most students supplied correct diagnoses and made adequate clinical decisions, there was a wide range in their ability to explain their clinical reasoning processes.


Investigation of the binding of isoform-selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy.
Prostaglandin endoperoxide synthase (PGHS) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis. Two isoforms of PGHS exist, a constitutive form termed PGHS-1 and an inducible form termed PGHS-2. We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with PGHS-1 and PGHS-2. By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS, we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for PGHS-1 with the PGHS-1 inhibitor and an R0 of 21 A for PGHS-2 with the PGHS-2 inhibitor. The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme. Time-resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in PGHS-1 and 18 A in PGHS-2. Preliminary stopped-flow kinetic studies reveal that the rate of quenching is limited by a first-order protein transition, which is slow, and that bound inhibitor undergoes rapid exchange.


Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.


Young-adult compared to adolescent onset of regular cannabis use: A 20-year prospective cohort study of later consequences.
This paper compares consequences of cannabis use initiated after high school with those of cannabis initiation in adolescence, with estimates of the proportion of adverse consequences accounted for by adult-onset and adolescent-onset cannabis users. A state-representative sample in Victoria, Australia (n = 1792) participated in a 10-wave longitudinal study and was followed from age 15 to 35 years. Exposure variable: Patterns of cannabis use across 20 years. Outcomes at age 35: Alcohol use, smoking, illicit drug use, relationship status, financial hardship, depression, anxiety and employment status. Substantially more participants (13.6%) initiated regular use after high school (young-adult onset) than in adolescence (7.7%, adolescent onset). By the mid-30s, both young-adult and adolescent-onset regular users were more likely than minimal/non-users (63.5%) to have used other illicit drugs (odds ratio [OR] > 20.4), be a high-risk alcohol drinker (OR > 3.7), smoked daily (OR > 7.2) and less likely to be in relationships (OR < 0.4). As the prevalence of the young-adult-onset group was nearly double of the adolescent-onset group, it accounted for a higher proportion of adverse consequences than the adolescent-onset group. Cannabis users who began regular use in their teens had poorer later life outcomes than non-using peers. The larger group who began regular cannabis use after leaving high school accounted for most cannabis-related harms in adulthood. Given the legalisation of cannabis use in an increasing number of jurisdictions, we should increasingly expect harms from cannabis use to lie in those commencing use in young adulthood.


Blood pressure response to exercise in normotensives and hypertensives.
Hypertensive patients have lower cardiac outputs and stroke volumes, higher heart rates, and a markedly higher peripheral resistance than normotensive individuals at the same intensity of exercise. Even patients with mildly elevated resting blood pressures have a markedly increased myocardial oxygen demand during exercise; since demand is determined not only by the pressure load but also by the degree of ventricular hypertrophy, three therapeutic inferences may be drawn: (a) Endurance training offers hypertensive patients a means of lowering exercise heart rate, reducing the systolic blood pressure and myocardial oxygen consumption, and also improving physical work capacity. (b) Besides avoiding isometric exercise, due to possible excessive peaks of blood pressure, all patients should be evaluated by ergometric testing before beginning an exercise training programme. (c) If ergometry reveals a marked rise in blood pressure at low levels of exertion, then appropriate antihypertensive medication (beta-blockers, calcium antagonists) should be prescribed prior to training.


Improved chips for sequencing by hybridization.
The SHOM method (Sequencing by Hybridization with Oligonucleotide Matrix) developed in 1988 is a new approach to nucleic acid sequencing by hybridization to an oligonucleotide matrix composed of an array of immobilized oligonucleotides. The original matrix proposed for sequencing by SHOM had to contain at least 65,536 octanucleotides. The present work describes a new family of matrices, which allows one to reduce the number of synthesized oligonucleotides 5-15 times without essentially decreasing the resolving power of the method.


Effects of chronic ethanol administration on hepatic glycoprotein secretion in the rat.
The effects of chronic ethanol feeding on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Liver slices from rats fed ethanol for 4-5 wk showed a decreased ability to incorporate [14C]glucosamine into medium trichloracetic acid-precipitable proteins when compared to the pair-fed controls; however, the labeling of hepatocellular glycoproteins was unaffected by chronic ethanol treatment. Immunoprecipitation of radiolabeled secretory (serum) glycoproteins with antiserum against rat serum proteins showed a similar marked inhibition in the appearance of glucosamine-labeled proteins in the medium of slices from ethanol-fed rats. Minimal effects, however, were noted in the labeling of intracellular secretory glycoproteins. Protein synthesis, as determined by measuring [14C]leucine incorporation into medium and liver proteins, was decreased in liver slices from ethanol-fed rats as compared to the pair-fed controls. This was the case for both total proteins as well as immunoprecipitable secretory proteins, although the labeling of secretory proteins retained in the liver slices was reduced to a lesser extent than total radiolabeled hepatic proteins. When the terminal sugar, [14C]fucose, was employed as a precursor in order to more closely focus on the final steps of hepatic glycoprotein secretion, liver slices obtained from chronic ethanol-fed rats exhibited impaired secretion of fucose-labeled proteins into the medium. When ethanol (5 or 10 mM) was added to the incubation medium containing liver slices from the ethanol-fed rats, the alterations in protein and glycoprotein synthesis and secretion caused by the chronic ethanol treatment were further potentiated. The results of this study indicate that liver slices prepared from chronic ethanol-fed rats exhibit both impaired synthesis and secretion of proteins and glycoproteins, and these defects are further potentiated by acute ethanol administration.


On the validity of the integral localized approximation for Bessel beams and associated radiation pressure forces.
In this paper we investigate the integral version of the localized approximation (ILA)-a powerful technique for evaluating the beam shape coefficients in the framework of the generalized Lorenz-Mie theory-as applied to ideal scalar Bessel beams (BBs). Originally conceived for arbitrary shaped beams with a propagating factor exp(±ikz), it has recently been shown that care must be taken when applying the ILA for the case of ideal scalar BBs, since they carry a propagating factor exp(±ikz cos α), with α being the axicon angle, which cannot be smoothly accommodated into its mathematical formalism. Comparisons are established between the beam shape coefficients calculated from both ILA and exact approaches, assuming paraxial approximation and both on- and off-axis beams. Particular simulations of radiation pressure forces are provided based on the existing data in the literature. This work helps us in elucidating that ILA provides adequate beam shape coefficients and descriptions of ideal scalar BBs up to certain limits and, even when it fails to do so, reliable information on the physical optical properties of interest can still be inferred, depending on specific geometric and electromagnetic aspects of the scatterer.


[In-vivo assessment of multiple sclerosis pathology: the role of neuroimaging techniques].
Although the correlations between magnetic resonance imaging (MRI) findings and long-term disease evolution range from poor to moderate', conventional pre- and post-contrast MRI provides sensitive and reliable measures to monitor multiple sclerosis (MS) activity over time. The application of non-conventional techniques, such as magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI), can increase the pathological specificity of MRI findings and, as a consequence, improve the relationship with the clinical evolution of the disease. These techniques also enable us to quantify the subtle abnormalities occurring in the so-called normal-appearing white matter, thus allowing to achieve a more accurate assessment of MS burden. Some of the aforementioned techniques have already shown their value for assessing MS dynamics, whereas other still need to go through a more complete validation process prior to any extensive clinical application in MS. The use of multiparametric MRI approaches, including both conventional techniques and new methods able to assess the macro- and microscopic disease burden and to characterize the individual lesion intrinsic nature, should improve our ability to study in vivo the pathology of MS.


The Role of Vitamin D in Multiple Sclerosis: Biology and Biochemistry, Epidemiology and Potential Roles in Treatment.
Multiple sclerosis (MS) is a progressive, demyelinating condition of the central nervous system, manifesting in loss or alterations in function of sensory, motor and cognitive function. Of the various environmental and behavioural risk factors identified as playing a role in MS onset and progression, perhaps none has been as consistent as vitamin D. In this review, we will endeavour to present a general background on the role of vitamin D in human health and particularly in MS, as well as the substantial epidemiological evidence in support of vitamin D's role in MS. Initially identified via the oft-noted latitudinal gradient in MS prevalence and incidence, vitamin D has since been demonstrated to have a strong and consistent inverse association with MS risk and clinical course. Cases have much lower levels of the diagnostic metabolite of vitamin D, 25- hydroxyvitamin D (25(OH)D) compared to healthy controls, while those with more active disease have lower levels of 25(OH)D than other cases with less active disease. These case-control and crosssectional study results led the way to cohort studies which indicated significant inverse associations between serum 25(OH)D and clinical activity in MS. The combined weight of indirect and direct observational evidence have been the impetus for completed and ongoing randomised trials of vitamin D supplementation, alone or in addition to standard immunomodulatory medications, as an intervention in MS onset and clinical course. Moreover, in addition to being a distinct factor in MS aetiology, vitamin D has been demonstrated to interact with a variety of other risk factors, from genetic predictors like HLA-DR1 genotype to behavioural factors like smoking. There is an abundance of epidemiological evidence, both direct and indirect, as well as significant biological plausibility substantiating a role for vitamin D in the onset and progression of multiple sclerosis.


Is atomised intranasal cocaine systemically absorbed during endoscopic sinus surgery?
In order to perform endoscopic sinus surgery (ESS) safely and efficiently, preparation of the nasal mucosa with vasoconstrictor agents is crucial to minimise bleeding. There is no single best method, although traditionally cocaine has been the agent of choice. However, there have been concerns over the potential for systemic side effects when applied topically. With this concern in mind, there exists limited contemporary research looking at cocaine absorption in the context of ESS. This study aims to determine the amount and duration of systemic cocaine absorption after intranasal atomised administration of modified Moffett's solution prior to ESS. Twelve adults undergoing ESS were enrolled. Modified Moffett's solution containing 100 mg cocaine hydrochloride and 1 mg of adrenaline was administered topically 5 minutes prior to surgery. Serum cocaine and the cocaine degradation product, benzoylecgonine, were measured at specific time points up to 12 hrs post administration. Peak plasma cocaine concentration occurred between 60 and 120 minutes post-administration (range 13-31 micrograms/L). The mean peak plasma concentration was 20.35 micrograms/L occurring at 120 minutes post-administration. Benzoylecgonine was detected in 11 subjects at 60 minutes post-administration and in all subjects 12 hours post-administration of cocaine. This study demonstrates that there are low levels of systemic absorption of cocaine when administered in an atomised modified Moffett's formulation prior to endoscopic sinus surgery.


Childhood asthma and mental retardation.
Four hundred consecutive outpatients seen at the Children's Psychiatric Research Institute, London, Ont., were investigated to determine whether there is a negative correlation between childhood asthma and mental retardation. Of these, 380 were mentally retarded and 20 were of normal intelligence. Only two cases of childhood asthma were found. One of these had an I.Q. of 108 and the other 78, so that no case of asthma was found in the mentally retarded group. On the basis of a reported prevalence rate for asthma of 1.76%, one would expect six or seven cases among the 400. By contrast, among the approximately 800 parents there were 11 cases of chronic asthma, a figure which is approximately the expected number.


Navigating the rapids: the development of regulated next-generation sequencing-based clinical trial assays and companion diagnostics.
Over the past decade, next-generation sequencing (NGS) technology has experienced meteoric growth in the aspects of platform, technology, and supporting bioinformatics development allowing its widespread and rapid uptake in research settings. More recently, NGS-based genomic data have been exploited to better understand disease development and patient characteristics that influence response to a given therapeutic intervention. Cancer, as a disease characterized by and driven by the tumor genetic landscape, is particularly amenable to NGS-based diagnostic (Dx) approaches. NGS-based technologies are particularly well suited to studying cancer disease development, progression and emergence of resistance, all key factors in the development of next-generation cancer Dxs. Yet, to achieve the promise of NGS-based patient treatment, drug developers will need to overcome a number of operational, technical, regulatory, and strategic challenges. Here, we provide a succinct overview of the state of the clinical NGS field in terms of the available clinically targeted platforms and sequencing technologies. We discuss the various operational and practical aspects of clinical NGS testing that will facilitate or limit the uptake of such assays in routine clinical care. We examine the current strategies for analytical validation and Food and Drug Administration (FDA)-approval of NGS-based assays and ongoing efforts to standardize clinical NGS and build quality control standards for the same. The rapidly evolving companion diagnostic (CDx) landscape for NGS-based assays will be reviewed, highlighting the key areas of concern and suggesting strategies to mitigate risk. The review will conclude with a series of strategic questions that face drug developers and a discussion of the likely future course of NGS-based CDx development efforts.


Gonadal tumor in Frasier syndrome: a review and classification.
Frasier syndrome is a rare inherited disease characterized by steroid-resistant nephrotic syndrome, gonadal tumor, and male pseudohermaphroditism (female external genitalia with sex chromosomes XY), which is based on a splice site mutation of Wilms tumor-suppressor gene 1 (WT1). Several unusual Frasier syndrome cases have been reported in which male pseudohermaphroditism was absent. We reviewed 88 Frasier syndrome cases in the literature and classified them into three types (type 1-3) according to external genitalia and sex chromosomes, and described their clinical phenotypes. Type 1 Frasier syndrome is characterized by female external genitalia with 46,XY (n = 72); type 2 by male external genitalia with 46,XY (n = 8); and type 3 by female external genitalia with 46,XX (n = 8). Clinical course differs markedly among the types. Although type 1 is noticed at the mean age of 16 due to mainly primary amenorrhea, type 2 and 3 do not present delayed secondary sex characteristics, making diagnosis difficult. The prevalence of gonadal tumor is high in type 1 (67%) and also found in 3 of the 8 type 2 cases, but not in any type 3 cases, which emphasize that preventive gonadectomy is unnecessary in type 3. On the basis of our findings, we propose a new diagnostic algorithm for Frasier syndrome.


Déjà vu experiences in anxiety.
Déjà vu occurs when a novel event is experienced with an erroneous sense of familiarity. Memory researchers theorise that this arises due to an error in the processes underlying the recognition memory system. Research has indicated that there may be a link between high levels of anxiety and increased frequency and intensity of déjà vu, however, there has been a comparatively little characterisation of déjà vu as experienced by individuals with clinical anxiety. We used an online questionnaire to collect data from individuals self-reporting a clinical diagnosis of anxiety, as well as from age-matched controls. The Anxiety Group reported a significantly higher frequency of déjà vu episodes over the previous month than controls. They also reported experiencing déjà vu more frequently and with higher intensity during periods of high anxiety. In addition, the Anxiety Group reported finding déjà vu episodes significantly more distressing than the Control Group. The findings indicate that there are differences in déjà vu experienced by people reporting high levels of anxiety compared to healthy controls without an anxiety diagnosis. We discuss structural and neural mechanisms thought to underpin déjà vu in relation to these results.


Progressive perinatal bowel obstruction--a rare cause of short-bowel syndrome.
A girl was born after an uneventful pregnancy of 36 weeks. Prenatally, distended bowel loops had been seen on ultrasound. Multiple small-bowel atresia was diagnosed and treated surgically. In the course of the next eleven weeks, previously patent segments of small bowel became obstructed. In 4 separate operative sessions, several segments of jejunum and ileum were resected, leaving 23 cm of ileum with the ileocecal valve in place. On microscopic examination of all resected material, necrosis of the mucosa was found consistent with ischemia. The child survived and tolerated full enteral feeding at the age of 8.5 months. The origin of the progressive obliterating process remains unknown.


[The oblique effect revealed by optical imaging in primary visual cortex of cats].
The oblique effect is a ubiquitous visual psychological effect. To explore its underlying neural basis, we quantitatively analyzed the proportion and response amplitude of the cardinal preferred areas and the oblique preferred areas in a fairly large region of the primary visual cortex of cats, using optical imaging based on intrinsic signals. The results show that cardinal preferred areas were larger than oblique preferred areas, with a mean difference of 4.7%. Overall, the responses evoked by cardinal stimuli were generally greater than those by oblique stimuli. The present work provides an explanation for the differences in electrophysiological results reported for this issue, and gives a new insight into the neural basis of the oblique effect.


Consensus Genotyper for Exome Sequencing (CGES): improving the quality of exome variant genotypes.
The development of cost-effective next-generation sequencing methods has spurred the development of high-throughput bioinformatics tools for detection of sequence variation. With many disparate variant-calling algorithms available, investigators must ask, 'Which method is best for my data?' Machine learning research has shown that so-called ensemble methods that combine the output of multiple models can dramatically improve classifier performance. Here we describe a novel variant-calling approach based on an ensemble of variant-calling algorithms, which we term the Consensus Genotyper for Exome Sequencing (CGES). CGES uses a two-stage voting scheme among four algorithm implementations. While our ensemble method can accept variants generated by any variant-calling algorithm, we used GATK2.8, SAMtools, FreeBayes and Atlas-SNP2 in building CGES because of their performance, widespread adoption and diverse but complementary algorithms. We apply CGES to 132 samples sequenced at the Hudson Alpha Institute for Biotechnology (HAIB, Huntsville, AL) using the Nimblegen Exome Capture and Illumina sequencing technology. Our sample set consisted of 40 complete trios, two families of four, one parent-child duo and two unrelated individuals. CGES yielded the fewest total variant calls (N(CGES) = 139° 897), the highest Ts/Tv ratio (3.02), the lowest Mendelian error rate across all genotypes (0.028%), the highest rediscovery rate from the Exome Variant Server (EVS; 89.3%) and 1000 Genomes (1KG; 84.1%) and the highest positive predictive value (PPV; 96.1%) for a random sample of previously validated de novo variants. We describe these and other quality control (QC) metrics from consensus data and explain how the CGES pipeline can be used to generate call sets of varying quality stringency, including consensus calls present across all four algorithms, calls that are consistent across any three out of four algorithms, calls that are consistent across any two out of four algorithms or a more liberal set of all calls made by any algorithm. To enable accessible, efficient and reproducible analysis, we implement CGES both as a stand-alone command line tool available for download in GitHub and as a set of Galaxy tools and workflows configured to execute on parallel computers. Supplementary data are available at Bioinformatics online.


[The characteristics of the peripheral blood monocytes in diabetics].
The study was aimed at laboratory evaluation of monocytes in peripheral blood of patients with insulin-dependent and non-insulin-dependent diabetes mellitus. Irrespective of the disease type and clinical features, monocytes count at the expense of Fc-positive monocytes was increased, activity of monocytes in the test NBT reduction was inhibited. The problem of monocyte involvement in diabetic angiopathy genesis and the role of insulin in this process are discussed. The findings justify introduction of immunomodulating therapy of diabetes mellitus patients with drugs acting on monocytes.


[Modern treatment options for Zenker's diverticulum: indications and results].
Conventional transcervical therapy of Zenker's diverticulum comprises diverticulectomy, invagination, diverticulopexy and myotomy, which may be combined with the aforementioned methods. Transoral diverticuloesophagostomy is performed by diathermy, lasers or staplers through a rigid esophagoscope, or more recently by diathermy applied via a flexible endoscope. Morbidity of transcervical procedures ranges between 3 (myotomy) and 23 % (diverticulectomy + myotomy). The percentage of patients with at least significantly improved symptoms is 92 % or more, while recurrences occur in 5.7 (diverticulectomy alone) to 21 % (invagination). Transoral procedures have a morbidity of 9 (stapler) to 26 % (Laser), while symptoms improve in 91 (diathermy through rigid esophagoscope) to 99 % (diathermy via flexible endoscope), however in up to 64 % of patients reoperations are necessary. Small diverticula (Brombart I/II) can be treated by diverticulectomy (with/without myotomy) or flexible endoscopy, larger diverticula in general by all methods. Patients younger than 60 years should undergo diverticulectomy, elderly multimorbid patients should be treated by transoral procedures.


Chronotropic incompetence in persons with down syndrome.
To investigate the chronotropic response to exercise through peak heart rate and the Chronotropic Response Index (CRI) in participants with Down syndrome (DS) and in nondisabled control participants. Comparative study describing the acute exercise heart rate response. University sports medicine facility. Twenty participants with DS (mean age +/- standard deviation, 24.2+/-3.5y) and 20 control participants without disabilities (age, 21.2+/-2.8y). Not applicable. Maximal treadmill exercise tests with metabolic and heart rate measurements. Maximal heart rate and the CRI were considered main outcomes. The peak oxygen consumption (41.7 vs 31.8mL. kg(-1).min(-1)) and peak heart rate (165+/-14.7 vs 192+/-7.7 beats/min) were significantly lower in participants with DS than in controls (P<.05). The CRI was below normal (.84+/-.25) in participants with DS and was normal (.97+/-.07) in controls. Both the CRI and the peak heart rates were indicative of chronotropic incompetence in participants with DS, but not in controls. The CRI of the participants with DS was similar to that reported for nondisabled populations who have a true chronotropic response to exercise. The CRI indicated that the low peak heart rate in our participants with DS was a true chronotropic response.


Report-Biochemical and molecular characterization of catalase enzyme in the saprobic fungus: Sordaria fimicola.
Fungi have been used in modern scientific research due to their high potential for different enzymes production based on genomic features. The great proportion of soil mycoflora represented by saprobic fungi plays an important role in decomposition, thus contribute to the global carbon cycle. Sordaria fimicola strains (n= 61) collected from different environments were evaluated for catalase enzyme activity at first stage. Among all 61 isolates of S. fimicola, five strains viz. S1, S2, N7, N6 and SF13 were found to be most efficient in catalase enzyme activity. The complete catalase gene including exons and introns was amplified and sequenced from the most efficient strains of S. fimicola and then submitted in the NCBI data base under accession numbers KM282183, KM282184, KM282186, KM282185 and KM282182 for strains S1, S2, N7, N6 and SF13 respectively. The significant differences in the genes sequences and theoretically translated proteins were observed for all five strains of S. fimicola. As regards catalase enzyme activity, S. fimicola strains were found comparable to the Aspergillus niger strains, therefore being a saprophytic fungus with short life cycle S. fimicola can become a fungus of choice to produce catalase enzyme at large scale.


The Scientometric Bubble Considered Harmful.
This article deals with a modern disease of academic science that consists of an enormous increase in the number of scientific publications without a corresponding advance of knowledge. Findings are sliced as thin as salami and submitted to different journals to produce more papers. If we consider academic papers as a kind of scientific 'currency' that is backed by gold bullion in the central bank of 'true' science, then we are witnessing an article-inflation phenomenon, a scientometric bubble that is most harmful for science and promotes an unethical and antiscientific culture among researchers. The main problem behind the scenes is that the impact factor is used as a proxy for quality. Therefore, not only for convenience, but also based on ethical principles of scientific research, we adhere to the San Francisco Declaration on Research Assessment when it emphasizes "the need to eliminate the use of journal-based metrics in funding, appointment and promotion considerations; and the need to assess research on its own merits rather on the journal in which the research is published". Our message is mainly addressed to the funding agencies and universities that award tenures or grants and manage research programmes, especially in developing countries. The message is also addressed to well-established scientists who have the power to change things when they participate in committees for grants and jobs.


Measurement of scapular asymetry and assessment of shoulder dysfunction using the Lateral Scapular Slide Test: a reliability and validity study.
The Lateral Scapular Slide Test (LSST) is used to determine scapular position with the arm abducted 0, 45, and 90 degrees in the coronal plane. Assessment of scapular position is based on the derived difference measurement of bilateral scapular distances. The purpose of this study was to assess the reliability of measurements obtained using the LSST and whether they could be used to identify people with and without shoulder impairments. Subjects. Forty-six subjects ranging in age from 18 to 65 years (X=30.0, SD=11.1) participated in this study. One group consisted of 20 subjects being treated for shoulder impairments, and one group consisted of 26 subjects without shoulder impairments. Two measurements in each test position were obtained bilaterally. From the bilateral measurements, we derived the difference measurement. Intraclass correlation coefficients (ICC [1,1]) and the standard error of measurement (SEM) were calculated for intrarater and interrater reliability of the difference in side-to-side measures of scapular distance. Sensitivity and specificity of the LSST for classifying subjects with and without shoulder impairments were also determined. The ICCs for intrarater reliability were .75, .77, and .80 and .52, .66, and .62, respectively, for subjects without and with shoulder impairments in 0, 45, and 90 degrees of abduction. The ICCs for interrater reliability were .67, .43, and .74 and .79, .45, and .57, respectively, for subjects without and with shoulder impairments in 0,45 and 90 degrees of abduction. The SEMs ranged from 0.57 to 0.86 cm for intrarater reliability and from 0.79 to 1.20 cm for interrater reliability. Using the criterion of greater than 1.0 cm difference, sensitivity and specificity were 35% and 48%, 41% and 54%, and 43% and 56%, respectively, for 0, 45, and 90 degrees of abduction. Sensitivity and specificity based on the criterion of greater than 1.5 cm difference were 28% and 53%, 50% and 58%, and 34% and 52%, respectively, for the 3 scapular positions. Our results suggest that measurements of scapular positioning based on the difference in side-to-side scapular distance measures are not reliable. Furthermore, the results suggest that sensitivity and specificity of the LSST measurements are poor and that the LSST should not be used to identify people with and without shoulder dysfunction.


Laboratory demonstration of spatial-coherence analysis of a blackbody through an up-conversion interferometer.
In the field of high resolution imaging in astronomy, we experimentally demonstrate the spatial-coherence analysis of a blackbody using an up-conversion interferometer in the photon counting regime. The infrared radiation of the blackbody is converted to a visible one in both arms of the interferometer thanks to the sum-frequency generation processes achieved in Ti-diffused periodically poled lithium niobate waveguides. The coherence analysis is performed through a dedicated imaging stage which mimics a classical telescope array analyzing an astrophysical source. The validity of these measurements is confirmed by the comparison with spatial-coherence analysis through a reference interferometer working at infrared wavelengths.


A comparative study of marital status on the academic performance of the female medical undergraduate in a Nigerian university.
To examine the effect of marriage, pregnancy and child bearing on the academic performance of the Nigerian female medical student. Self administered cross sectional questionnaires were distributed to female and male medical students of Ebonyi State University, Nigeria. Academic records were examined, and data obtained analysed using the Epi info statistical software package. Sixteen (19.3%) of the female students were married, thirteen after admission into the Faculty. Fourteen of these had children and mean parity was 2. The married female students were older, had more resit examinations than their male and single female counterparts. The difference was statistically significant. Marriage and child bearing which play a central and prominent role in the traditional African culture, may serve as an additional burden on the Nigerian female medical student, affecting her academic performance. The specific problems associated with marriage, pregnancy and childbirth need to be recognised, addressed and reflected in a modern medical curriculum.


[Study of Skip Metastasis to Lateral Lymph Nodes in Low Rectal Cancer].
We reviewed the clinical records of 302 patients with low rectal carcinoma to evaluate the effectiveness of lateral lymph node(LLN)dissection in cases of skip metastases to the LLN. Patients were divided into 4 groups according to nodal status: group N(133 cases), no metastasis in both the mesorectum lymph node(MLN)and LLN; groupM(100 cases), metastasis in the MLN and no LLN metastasis; group L(15 cases), which was defined as skip metastasis, with no metastasis in the MLN and LLN metastasis; and group ML(54 cases), node metastases in both the MLN and LLN. LLN metastasis was found in 22.8% of all patients, and skip metastasis was found in 10.1%. The recurrence rate in group L(40.0%, 6 cases)was significantly lower than that in group ML(75.9%, 41 cases)and not different from that in group M(43.0%, 43 cases). The initial recurrence sites in group L were the lung(3 cases)and local recurrence(3 cases). In group L, 20.0% had hematogenous recurrence, which was lower than in group ML. There was no significant difference between group L(5-year survival rate: 57.1%)and group M(71.7%)in terms of prognosis. Multivariate analysis revealed that histology was a risk factor for LLN metastasis in lowrectal cancer without MLN metastasis. The positive predictive value of LLN metastasis based on computed tomography was 43.9%. It was believed that LLN dissection was important, especially for non-differentiated cancer, in consideration of skip metastases to the LLN.


Folding of a donor-acceptor polyrotaxane by using noncovalent bonding interactions.
Mechanically interlocked compounds, such as bistable catenanes and bistable rotaxanes, have been used to bring about actuation in nanoelectromechanical systems (NEMS) and molecular electronic devices (MEDs). The elaboration of the structural features of such rotaxanes into macromolecular materials might allow the utilization of molecular motion to impact their bulk properties. We report here the synthesis and characterization of polymers that contain pi electron-donating 1,5-dioxynaphthalene (DNP) units encircled by cyclobis(paraquat-p-phenylene) (CBPQT(4+)), a pi electron-accepting tetracationic cyclophane, synthesized by using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The polyrotaxanes adopt a well defined "folded" secondary structure by virtue of the judicious design of two DNP-containing monomers with different binding affinities for CBPQT(4+). This efficient approach to the preparation of polyrotaxanes, taken alongside the initial investigations of their chemical properties, sets the stage for the preparation of a previously undescribed class of macromolecular architectures.


Uniform Mesoporous Amorphous Cobalt-Inherent Silicon Oxide as a Highly Active Heterogeneous Catalyst in the Activation of Peroxymonosulfate for Rapid Oxidation of 2,4-Dichlorophenol: The Important Role of Inherent Cobalt in the Catalytic Mechanism.
Amorphous cobalt-inherent silicon oxide (Co-SiOx) was synthesized for the first time and employed as a highly active catalyst in the activation of peroxymonosulfate (PMS) for the rapid oxidation of 2,4-dichlorophenol (2,4-DCP). The characterization results revealed that the 0.15Co-SiOx possessed a high specific surface area of 607.95 m2/g with a uniform mesoporous structure (24.33 nm). The X-ray diffraction patterns indicate that the substituted cobalt atoms enlarge the unit cell parameter of the original SiO2, and the selected area electron diffraction pattern confirmed the amorphous nature of Co-SiOx. More bulk oxygen vacancies (Ov) existing in the Co-SiOx were identified to be one of the primary contributors to the significantly enhanced catalytic activation of PMS. The cobalt substitution both creates and stabilizes the surficial Ov and forms the adequately active Co(II)-Ov pairs which engine the electron transfer process during the catalytic activities. The active Co(II)-Ov pairs weaken the average electronegativity of Co/Si and Co/O sites, resulting in the prevalent changes in final state energy, which is the main driving cause of the binding energy shifts in the X-ray photoelectron spectroscopy (XPS) spectra of Si and O among all samples. The increase of the relative proportion of Co(III) in the spent Co-SiOx probably causes the binding energy shifts of the Co XPS spectrum compared to that of the Co-SiOx. The amorphous Co-SiOx outperforms stable and quick 2,4-DCP degradation, achieving a much higher kinetic rate of 0.7139 min-1 at pH = 7.02 than others via sulfate radical advanced oxidation processes (AOPs), photo-Fenton AOPs, H2O2 reagent AOPs, and other AOP approaches. The efficient degradation performance makes the amorphous Co-SiOx as a promising catalyst in removing 2,4-DCP or organic-rich pollutants.


Prevalence of inappropriate tuberculosis treatment regimens: a systematic review.
A potential threat to the success of new tuberculosis (TB) drugs is the development of resistance. Using drugs in appropriate regimens, such as those recommended in the World Health Organization (WHO) treatment guidelines, prevents the development of resistance. We performed a systematic review to assess the prevalence of inappropriate prescription of TB drugs for the treatment of TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Observational studies published from 2000 that included TB patients receiving treatment were selected. A treatment regimen was considered inappropriate if the regimen was not a WHO recommended regimen. 37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies. The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%. In 19 studies the quality of treatment regimen reporting was low. Despite the fact that assessment of inappropriate treatment was hampered by low quality of reporting, our data indicate a reasonable amount of inappropriate prescription of TB treatment regimens. Thus, there is a risk that new drugs will be used in inappropriate treatment regimens, even with WHO guidelines in place, introducing the risk of resistance development. This article highlights the need to improve implementation of the WHO treatment of TB guidelines.


Carboxyfluorescein. A probe of the blood-ocular barriers with lower membrane permeability than fluorescein.
We have examined the permeability of the blood-ocular barriers to carboxyfluorescein, a dye similar in spectral properties but more polar than fluorescein. Octanol-buffer partition ratios of carboxyfluorescein, measured as an indication of lipid solubility, were approximately 1,000 times lower than those of fluorescein at pH values between 6.40 and 8.03. The partition ratios of both dyes show pronounced pH dependence. We also evaluated intraocular dye distribution by fluorescence microscopy after intravenous (IV) injection in rats. Carboxyfluorescein does not penetrate ciliary or iris epithelial cells, whereas fluorescein prominently stains these cells. Quantitative measurement of fluorescence intensity demonstrates that carboxyfluorescein does not enter the retina even when high doses are administered. Fluorescein, in contrast, can be detected throughout the retina with fluorescence intensity levels proportional to the IV dose administered. The relative inability of carboxyfluorescein to penetrate the blood-ocular barriers is not caused by greater binding to plasma proteins, since the plasma concentration of free carboxyfluorescein is greater than that of fluorescein. We conclude that carboxyfluorescein has potential experimental and clinical use as a probe of the blood-ocular barriers. Because of its low membrane permeability, it may yield a better definition of the nature of barrier abnormalities than is now possible with fluorescein.


Factors associated with disease severity of COVID‑19 in patients with type 2 diabetes mellitus.
Diabetes mellitus causes a decline in immunological function, an increase in proinflammatory cytokines, and a prothrombotic state, thus providing risk factors for the severity of coronavirus disease 2019 (COVID-19) in patients with type 2 diabetes mellitus (T2DM). The aim of the present study was to analyze the risk factors associated with the severity of COVID-19 in patients with T2DM. A cross-sectional observational study was performed on 201 patients with T2DM from May 1 to August 31, 2020 and admitted to the isolation ward of Dr Soetomo General Hospital (Surabaya, Indonesia). The patients were divided into severe (108 cases; 53.7%) and non-severe (93 cases; 46.3%) groups, which were considered the dependent variables. Univariate and multivariate analysis was performed. The independent variables were age, sex, diabetes onset, chronic complications, presence of hypertension, randomized blood glucose, HbA1c, albumin, and neutrophil-lymphocyte ratio (NLR). A P-value <0.05 was considered to be statistically significant. The median age of the 201 subjects was 56 years, with 70.1% <60 years old, 52.7% male, 76.1% with diabetes onset <10 years, and 108 patients (53.7%) in severe condition. The results of the bivariate analysis revealed that diabetes onset >10 years (OR 2.5; P=0.011) was associated with severity of COVID-19 in patients with T2DM, however hypoalbumin (OR 1.93; P=0.054) was not associated with disease severity. Furthermore, multivariate analysis revealed that male sex (OR 2.07; P=0.042), age (≥60 years) (OR 2.92; P=0.008), HbA1c (≥8%) (OR 3.55; P=0.001), hypertension (OR 4.07; P=0.001), and an NLR ≥7.36 (OR 6.39; P=0.001) were associated with severe COVID-19. Collectively, it was revealed that increased NLR, hypertension, poor glycemic control, older age, and male sex were risk factors associated with the severity of COVID-19 among diabetic patients.


Exercise following Mental Work Prevented Overeating.
Mental work may promote caloric intake, whereas exercise may offset positive energy balance by decreasing energy intake and increasing energy expenditure. This study aimed to replicate previous findings that mental work increases caloric intake compared with a rest condition and assess whether exercise after mental work can offset this effect. Thirty-eight male and female university students were randomly assigned to mental work + rest (MW + R) or mental work + exercise (MW + E). Participants also completed a baseline rest (BR) visit consisting of no mental work or exercise. Visit order was counterbalanced. During the MW + R or MW + E visit, participants completed a 20-min mental task and either a 15-min rest (MW + R) or a 15-min interval exercise (MW + E). Each visit ended with an ad libitum pizza lunch. A two-way repeated-measures ANOVA was used to compare eating behavior between groups. Participants in the MW + R condition consumed an average of 100 more kilocalories compared with BR (633.3 ± 72.9 and 533.9 ± 67.7, respectively, P = 0.02), and participants in MW + E consumed an average of 25 kcal less compared with BR (432.3 ± 69.2 and 456.5 ± 64.2, respectively, P > 0.05). When including the estimated energy expenditure of exercise in the MW + E conditions, participants were in negative energy balance by an average of 98.5 ± 41.5 kcal, resulting in a significant difference in energy balance between the two groups (P = 0.001). An acute bout of interval exercise after mental work resulted in significantly decreased food consumption compared with a nonexercise condition. These results suggest that an acute bout of exercise may be used to offset positive energy balance induced by mental tasks.


Low plasma zinc levels and immunological responses to zinc supplementation in HIV-infected patients with immunological discordance after antiretroviral therapy.
Immunological discordance in HIV-infected patients is associated with a higher risk of mortality and disease progression. Zinc is an essential micronutrient for immune function. A two-phase pilot study including a cross-sectional study to determine plasma zinc levels and a prospective, randomized, placebo-controlled trial to determine immunological responses after zinc supplementation was conducted in HIV-infected patients with immunological discordance in a medical school hospital. Immunological discordance was defined in patients who received antiretroviral therapy, had HIV RNA < 40 copies/mL, and a CD4(+) cell count < 200 cells/mm(3) that increased <30% from baseline after receiving ART with undetectable HIV RNA for 12 months. Of 31 patients, 12 (39%) had low plasma zinc levels (<75 μg/dL). Five of 12 patients with low plasma zinc levels and 8 of 19 patients with normal plasma zinc levels were randomized to receive zinc supplementation. The median changes in plasma zinc levels after supplementation versus placebo in patients with low plasma zinc levels were 29 versus 4.5 μg/dL, respectively. The CD4(+) cell count significantly increased (176 versus 250 cells/mm(3), P = 0.042) after zinc supplementation in patients with low plasma zinc levels. Further large-scale studies to determine long-term benefits of zinc supplementation in patients with immunological discordance are required.


The role of environmental exposures and the epigenome in health and disease.
The genetic material of every organism exists within the context of regulatory networks that govern gene expression, collectively called the epigenome. Epigenetics has taken center stage in the study of diseases such as cancer and diabetes, but its integration into the field of environmental health is still emerging. As the Environmental Mutagenesis and Genomics Society (EMGS) celebrates its 50th Anniversary this year, we have come together to review and summarize the seminal advances in the field of environmental epigenomics. Specifically, we focus on the role epigenetics may play in multigenerational and transgenerational transmission of environmentally induced health effects. We also summarize state of the art techniques for evaluating the epigenome, environmental epigenetic analysis, and the emerging field of epigenome editing. Finally, we evaluate transposon epigenetics as they relate to environmental exposures and explore the role of noncoding RNA as biomarkers of environmental exposures. Although the field has advanced over the past several decades, including being recognized by EMGS with its own Special Interest Group, recently renamed Epigenomics, we are excited about the opportunities for environmental epigenetic science in the next 50 years. Environ. Mol. Mutagen. 61:176-192, 2020. © 2019 Wiley Periodicals, Inc.


Biosynthesis of the C(7)-cyclitol moiety of acarbose in Actinoplanes species SE50/110. 7-O-phosphorylation of the initial cyclitol precursor leads to proposal of a new biosynthetic pathway.
We have previously demonstrated that the biosynthesis of the C(7)-cyclitol, called valienol (or valienamine), of the alpha-glucosidase inhibitor acarbose starts from the cyclization of sedo-heptulose 7-phosphate to 2-epi-5-epi-valiolone (Stratmann, A., Mahmud, T., Lee, S., Distler, J., Floss, H. G., and Piepersberg, W. (1999) J. Biol. Chem. 274, 10889-10896). Synthesis of the intermediate 2-epi-5-epi-valiolone is catalyzed by the cyclase AcbC encoded in the biosynthetic (acb) gene cluster of Actinoplanes sp. SE50/110. The acbC gene lies in a possible transcription unit, acbKLMNOC, cluster encompassing putative biosynthetic genes for cyclitol conversion. All genes were heterologously expressed in strains of Streptomyces lividans 66 strains 1326, TK23, and TK64. The AcbK protein was identified as the acarbose 7-kinase, which had been described earlier (Drepper, A., and Pape, H. (1996) J. Antibiot. (Tokyo) 49, 664-668). The multistep conversion of 2-epi-5-epi-valiolone to the final cyclitol moiety was studied by testing enzymatic mechanisms such as dehydration, reduction, epimerization, and phosphorylation. Thus, a phosphotransferase activity was identified modifying 2-epi-5-epi-valiolone by ATP-dependent phosphorylation. This activity could be attributed to the AcbM protein by verifying this activity in S. lividans strain TK64/pCW4123M, expressing His-tagged AcbM. The His-tagged AcbM protein was purified and subsequently characterized as a 2-epi-5-epi-valiolone 7-kinase, presumably catalyzing the first enzyme reaction in the biosynthetic route, leading to an activated form of the intermediate 1-epi-valienol. The AcbK protein could not catalyze the same reaction nor convert any of the other C(7)-cyclitol monomers tested. The 2-epi-5-epi-valiolone 7-phosphate was further converted by the AcbO protein to another isomeric and phosphorylated intermediate, which was likely to be the 2-epimer 5-epi-valiolone 7-phosphate. The products of both enzyme reactions were characterized by mass spectrometric methods. The product of the AcbM-catalyzed reaction, 2-epi-5-epi-valiolone 7-phosphate, was purified on a preparative scale and identified by NMR spectroscopy. A biosynthetic pathway for the pseudodisaccharidic acarviosyl moiety of acarbose is proposed on the basis of these data.


[Single tooth replacement with a removable partial denture].
The indication of removable partial dentures in cases of single tooth replacement is limited. This is due to a number of disadvantages closely connected to the use of removable partial denture. An often applied use is that of a mucosa-borne transitional acrylic denture to improve patients aesthetics until the definitive denture can be made. Acrylic dentures may be indicated as a definitive denture when limited financial resources are available. A metal frame removable partial denture can be applied to lengthen a shortened dental arch or in specific cases in which fixed partial dentures are not the preferable treatment option. The success of the treatment with a removable partial denture is highly dependent on the follow-up service and the oral hygiene awareness.


Sustainable Cellulose Nanofibers-Mediated Synthesis of Uniform Spinel Zn-Ferrites Nanocorals for High Performances in Supercapacitors.
Spinel ferrites are versatile, low-cost, and abundant metal oxides with remarkable electronic and magnetic properties, which find several applications. Among them, they have been considered part of the next generation of electrochemical energy storage materials due to their variable oxidation states, low environmental toxicity, and possible synthesis through simple green chemical processing. However, most traditional procedures lead to the formation of poorly controlled materials (in terms of size, shape, composition, and/or crystalline structure). Thus, we report herein a cellulose nanofibers-mediated green procedure to prepare controlled highly porous nanocorals comprised of spinel Zn-ferrites. Then, they presented remarkable applications as electrodes in supercapacitors, which were thoroughly and critically discussed. The spinel Zn-ferrites nanocorals supercapacitor showed a much higher maximum specific capacitance (2031.81 F g-1 at a current density of 1 A g-1) than Fe2O3 and ZnO counterparts prepared by a similar approach (189.74 and 24.39 F g-1 at a current density of 1 A g-1). Its cyclic stability was also scrutinized via galvanostatic charging/discharging and electrochemical impedance spectroscopy, indicating excellent long-term stability. In addition, we manufactured an asymmetric supercapacitor device, which offered a high energy density value of 18.1 Wh kg-1 at a power density of 2609.2 W kg-1 (at 1 A g-1 in 2.0 mol L-1 KOH electrolyte). Based on our findings, we believe that higher performances observed for spinel Zn-ferrites nanocorals could be explained by their unique crystal structure and electronic configuration based on crystal field stabilization energy, which provides an electrostatic repulsion between the d electrons and the p orbitals of the surrounding oxygen anions, creating a level of energy that determines their final supercapacitance then evidenced, which is a very interesting property that could be explored for the production of clean energy storage devices.


Antitumor activity of Src inhibitor saracatinib (AZD-0530) in preclinical models of biliary tract carcinomas.
Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is, therefore, an urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the nonreceptor tyrosine kinase Src, observing promising antitumor effects of its small-molecule inhibitor saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from patients with BTC. Upon saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28, and TGBC1-TKB. The effect of saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G(0)-G(1) phase, and inhibited cell migration. At high concentrations (median dose from 2.26-6.99 μmol/L), saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. Here, we provide a demonstration that the targeted inhibition of Src kinase by saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of saracatinib-based clinical applications.


[Features of the hemodynamics of myocardial infarct patients undergoing the most widely used rehabilitation programs].
Integrated body rheography, radiocardiography and radionuclide ventriculography were used to investigate hemodynamic changes in 101 myocardial infarction patients during the hospital stage of the disease. Changes in major hemodynamic parameters were demonstrated by the end of the 1st week and when walking was resumed. At the resumed-walking stage, the mechanism of declining stroke and cardiac indices was shown to depend on physical activation rates. Hemodynamic response is mostly conditioned by myocardial insufficiency when walking is resumed rapidly during the 2nd week, and by smaller venous return due to hypovolemia where it is resumed slowly during the 4th week. Expanding motion regimens at slow rates results in persistent hemodynamic disturbances in myocardial infarction patients.


[Thrombocytopenia, arthritis and enteropathy: a casual association or the expression of a unique entity?].
The arthropathy of inflammatory bowel disease (IBD) is a noninfectious arthritis occurring before or during the course of either regional enteritis or ulcerative colitis. Two patterns of joint disease are described: a chronic asymmetric oligoarthritis affecting peripheral joints, and a spondylo-sacroiliitis similar to the idiopathic type. Different criteria for diagnosis and classification (ACR and EULAR) of arthropathies associated with IBD are used and this is not helpful in order to a correct nosography. An unusual case of ulcerative colitis with thrombocytopenia and oligoarticular arthritis at onset, 4 and 2 years before the assessment of IBD, is reported. Moreover the arthritis had characteristics much more similar to a juvenile chronic arthritis (JCA) with pauciarticular onset of type I (FR-; ANA+) than to an enteropathic arthropathy.


[Clinical and organizational assessment of endovascular care accessibility at the regional level].
The world health care system´s concern of inequalities in treatment of receiving the necessary medical care. The purpose of article to evaluate the availability of endovascular care (EVC) for patients at regional level in Russia and to develop a system for its improvement. As a result the low availability of EVC for the population at the regional level in Russia with coronary heart disease, atherosclerosis of the brachiocephalic arteries and critical lower limb ischemia (CLLI) was funded. The main reasons for the difficulties in obtaining EVC in the regions of Russia are the low frequency of diagnosing a critical stage of cardiovascular disease (CVD) requiring surgical treatment, the absence of cardiovascular surgeons and cardiologists in the medical care organizations, the failure in information to patients attending a regular doctor´s appointment about effectiveness and safety of endovascular treatment technology. More old-school traditional methods remain in place like bypass or endarterectomy surgery. Further obstacles are prolonged waiting list at the regional level for the provision of high-tech care in cardiovascular surgery, choice of conservative treatment methods or amputation of lower limbs for patients with CLLI 3 and 4 st. (p<0.05). In Conclusion the Clinical and organizational assessment of the endovascular care accessibility in CVD for the population in regions of Russia elaborated. One way to improve the situation is the introduction of the cardiovascular care clinical management. A dual-circuit clinical and organizational system was developed and proposed to increase endovascular care accessibility in regions.


Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation.
Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 VL domain and stabilise an unexpected partially open LC dimer in which the two VL domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.


Molecular Dynamics and MM-PBSA Analysis of the SARS-CoV-2 Gamma Variant in Complex with the hACE-2 Receptor.
The SARS-CoV-2 virus, since its appearance in 2019, has caused millions of cases and deaths. To date, there is no effective treatment or a vaccine that is fully protective. Despite the efforts made by governments and health institutions around the globe to control its propagation, the evolution of the virus has accelerated, diverging into hundreds of variants. However, not all of them are variants of concern (VoC's). VoC's have appeared in different regions and throughout the two years of the pandemic they have spread around the world. Specifically, in South America, the gamma variant (previously known as P.1) appeared in early 2021, bringing with it a second wave of infections. This variant contains the N501Y, E484K and K417T mutations in the receptor binding domain (RBD) of the spike protein. Although these mutations have been described experimentally, there is still no clarity regarding their role in the stabilization of the complex with the human angiotensin converting enzyme 2 (hACE-2) receptor. In this article we dissect the influence of mutations on the interaction with the hACE-2 receptor using molecular dynamics and estimations of binding affinity through a screened version of the molecular mechanics Poisson Boltzmann surface area (MM-PBSA) and interaction entropy. Our results indicate that mutations E484K and K417T compensate each other in terms of binding affinity, while the mutation N501Y promotes a more convoluted effect. This effect consists in the adoption of a cis configuration in the backbone of residue Y495 within the RBD, which in turn promotes polar interactions with the hACE-2 receptor. These results not only correlate with experimental observations and complement previous knowledge, but also expose new features associated with the specific contribution of concerned mutations. Additionally, we propose a recipe to assess the residue-specific contribution to the interaction entropy.


The immunopathology of acute experimental allergic encephalomyelitis. IV. An ultrastructural immunocytochemical study of class II major histocompatibility complex molecule (Ia) expression.
Cell surface expression of Class II major histocompatibility complex (Ia) molecules is required for antigen recognition by T cells. To determine the ultrastructural cellular distribution of Ia molecules in the autoimmune disease model acute experimental allergic encephalomyelitis (EAE) we studied central nervous system (CNS) tissues from adult Strain 13 guinea pigs (GP). Experimental allergic encephalomyelitis was induced by sensitization with GP spinal cord homogenate in complete Freund's adjuvant (CFA). Nine of 11 sensitized GP had clinical and histologic EAE whereas unsensitized and CFA-sensitized controls were normal. Central nervous system tissues were reacted with monoclonal antibodies to either GP Ia or T cell surface antigen using an avidin-biotin immunoperoxidase technique and studied by electron microscopy; Ia was found on luminal but not abluminal surfaces of many meningeal and parenchymal vascular endothelial cells in GP with EAE. In EAE perivascular lymphocytes and macrophages and processes of unidentified cells in the parenchyma expressed surface Ia and Ia+ macrophages encircled and phagocytosed myelin. T cells were found predominantly in perivascular inflammatory cuffs. These observations indicate that following immunologic challenge Ia is expressed on luminal surfaces of vascular endothelium and on resident CNS cells, suggesting the possibility that these cells may have active antigen-presenting functions in CNS inflammatory reactions.


Selective dysfunction of the crural diaphragm in patients with chronic restrictive and obstructive lung disease.
Gastroesophageal reflux (GER) is known to be associated with chronic lung diseases. The driving force of GER is the transdiaphragmatic pressure (Pdi) generated mainly by costal and crural diaphragm contraction. The latter also enhances the esophagogastric junction (EGJ) pressure to guard against GER. The relationship between Pdi and EGJ pressure was determined using high resolution esophageal manometry in patients with interstitial lung disease (ILD, n = 26), obstructive lung disease (OLD, n- = 24), and healthy subjects (n = 20). The patient groups did not differ with respect to age, gender, BMI, and pulmonary rehabilitation history. Patients with ILD had significantly higher Pdi but lower EGJ pressures as compared to controls and OLD patients (p < 0.001). In control subjects, the increase in EGJ pressure at all-time points during inspiration was greater than Pdi. In contrast, the EGJ pressure during inspiration was less than Pdi in 14 patients with ILD and 7 patients with OLD. The drop in EGJ pressure was usually seen after the peak Pdi in ILD group (p < 0.0001) and before the peak Pdi in OLD group, (p = 0.08). Nine patients in the ILD group had sliding hiatus hernia, compared to none in control subjects (p = 0.003) and two patients in the OLD, (p = 0.04). A higher Pdi and low EGJ pressure, and dissociation between Pdi and EGJ pressure temporal relationship suggests selective dysfunction of the crural diaphragm in patients with chronic lung diseases and may explain the higher prevalence of GERD in ILD as seen in previous studies.


A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron degeneration in the motor cortex, brainstem and spinal cord. It is generally accepted that ALS is caused by death of motor neurons, however the exact temporal cascade of degenerative processes is not yet completely known. To identify the early pathological changes in spinal cord of G93A-SOD1 ALS mice we performed a comprehensive longitudinal analysis employing diffusion-tensor magnetic resonance imaging alongside histology and electron microscopy, in parallel with peripheral nerve histology. We showed the gradient of degeneration appearance in spinal cord white and gray matter, starting earliest in the ventral white matter, due to a cascade of pathological events including axon dysfunction and mitochondrial changes. Notably, we found that even the main sensory regions are affected by the neurodegenerative process at symptomatic disease phase. Overall our results attest the applicability of DTI in determining disease progression in ALS mice. These findings suggest that DTI could be potentially adapted in humans to aid the assessment of ALS progression and eventually the evaluation of treatment efficacy.


Revised scored Sensory Perception Quotient reveals sensory hypersensitivity in women with autism.
Previous research using the Sensory Perception Quotient (SPQ) has reported greater sensory hypersensitivity in people with autism spectrum condition (ASC) compared to controls, consistent with other research. However, current scoring of the SPQ does not differentiate between hyper and hyposensitivity, making it uncertain whether individuals with ASC might also show differences in hyposensitivity. Furthermore, no research to date has focused on sensory differences in females, and whether differences in sensory sensitivity extend to the broader autism phenotype (BAP). The present study aimed to fill these gaps. The present study developed and validated a Revised Scoring of the Sensory Perception Quotient (SPQ-RS) in order to investigate self-reported hypersensitivity and hyposensitivity in three groups of adults: a female ASC group (n = 152), mothers of children with ASC (BAP mothers group; n = 103), and a control mothers group (n = 74). All participants completed the SPQ as a self-report measure of sensory processing and the Autism-Spectrum Quotient (AQ) as a measure of the degree of autism traits. The female ASC group reported significantly more hypersensitivity, but not more hyposensitivity, compared to the control female and BAP mothers groups. The BAP mothers group did not differ from the control mothers group in either reported hypersensitivity (p = .365) or hyposensitivity (p = .075), suggesting atypical sensory sensitivity is not a BAP trait within females. SPQ-RS hypersensitivity scores positively correlated with autistic traits in the female ASC (r = .266) and BAP mothers groups (r = .350). The present findings revealed greater sensory hypersensitivity, but not hyposensitivity, in females with ASC compared to BAP and control female groups, and that a greater degree of autism traits relates to higher hypersensitivity in ASC females. The results offer support for the enhanced perceptual functioning model using large samples of females, who are an understudied population, and demonstrate the validity of the SPQ-RS as a valuable new research tool for exploring self-reported hypersensitivity and hyposensitivity.


Bundling dynamics regulates the active mechanics and transport in carbon nanotube networks and their nanocomposites.
High-density carbon nanotube networks (CNNs) continue to attract interest as active elements in nanoelectronic devices, nanoelectromechanical systems (NEMS) and multifunctional nanocomposites. The interplay between the network nanostructure and its properties is crucial, yet current understanding remains limited to the passive response. Here, we employ a novel superstructure consisting of millimeter-long vertically aligned single walled carbon nanotubes (SWCNTs) sandwiched between polydimethylsiloxane (PDMS) layers to quantify the effect of two classes of mechanical stimuli, film densification and stretching, on the electronic and thermal transport across the network. The network deforms easily with an increase in the electrical and thermal conductivities, suggestive of a floppy yet highly reconfigurable network. Insight from atomistically informed coarse-grained simulations uncover an interplay between the extent of lateral assembly of the bundles, modulated by surface zipping/unzipping, and the elastic energy associated with the bent conformations of the nanotubes/bundles. During densification, the network becomes highly interconnected yet we observe a modest increase in bundling primarily due to the reduced spacing between the SWCNTs. The stretching, on the other hand, is characterized by an initial debundling regime as the strain accommodation occurs via unzipping of the branched interconnects, followed by rapid rebundling as the strain transfers to the increasingly aligned bundles. In both cases, the increase in the electrical and thermal conductivity is primarily due to the increase in bundle size; the changes in network connectivity have a minor effect on the transport. Our results have broad implications for filamentous networks of inorganic nanoassemblies composed of interacting tubes, wires and ribbons/belts.


Can Transcranial Direct Current Stimulation Enhance Poststroke Motor Recovery? Development of a Theoretical Patient-Tailored Model.
New treatments that can facilitate neural repair and reduce persistent impairments have significant value in promoting recovery following stroke. One technique that has gained interest is transcranial direct current stimulation (tDCS) as early research suggested it could enhance plasticity and enable greater behavioral recovery. However, several studies have now identified substantial intersubject variability in response to tDCS and clinical trials revealed insufficient evidence of treatment effectiveness. A possible explanation for the varied and negative findings is that the physiologic model of stroke recovery that researchers have used to guide the application of tDCS-based treatments in stroke is overly simplistic and does not account for stroke heterogeneity or known determinants that affect the tDCS response. Here, we propose that tDCS could have a more clearly beneficial role in enhancing stroke recovery if greater consideration is given to individualizing treatment. By critically reviewing the proposed mechanisms of tDCS, stroke physiology across the recovery continuum, and known determinants of tDCS response, we propose a new, theoretical, patient-tailored approach to delivering tDCS after stroke. The proposed model includes a step-by-step principled selection strategy for identifying optimal neuromodulation targets and outlines key areas for further investigation. Tailoring tDCS treatment to individual neuroanatomy and physiology is likely our best chance at producing robust and meaningful clinical benefit for people with stroke and would therefore accelerate opportunities for clinical translation.


A replication-dependent passive mechanism modulates DNA demethylation in mouse primordial germ cells.
Germline cells reprogramme extensive epigenetic modifications to ensure the cellular totipotency of subsequent generations and to prevent the accumulation of epimutations. Notably, primordial germ cells (PGCs) erase genome-wide DNA methylation and H3K9 dimethylation marks in a stepwise manner during migration and gonadal periods. In this study, we profiled DNA and histone methylation on transposable elements during PGC development, and examined the role of DNA replication in DNA demethylation in gonadal PGCs. CpGs in short interspersed nuclear elements (SINEs) B1 and B2 were substantially demethylated in migrating PGCs, whereas CpGs in long interspersed nuclear elements (LINEs), such as LINE-1, were resistant to early demethylation. By contrast, CpGs in both LINE-1 and SINEs were rapidly demethylated in gonadal PGCs. Four major modifiers of DNA and histone methylation, Dnmt3a, Dnmt3b, Glp and Uhrf1, were actively repressed at distinct stages of PGC development. DNMT1 was localised at replication foci in nascent PGCs, whereas the efficiency of recruitment of DNMT1 into replication foci was severely impaired in gonadal PGCs. Hairpin bisulphite sequencing analysis showed that strand-specific hemi-methylated CpGs on LINE-1 were predominant in gonadal PGCs. Furthermore, DNA demethylation in SINEs and LINE-1 was impaired in Cbx3-deficient PGCs, indicating abnormalities in G1 to S phase progression. We propose that PGCs employ active and passive mechanisms for efficient and widespread erasure of genomic DNA methylation.


Effectiveness of computer-tailored Smoking Cessation Advice in Primary Care (ESCAPE): a randomised trial.
Smoking remains a major public health problem; developing effective interventions to encourage more quit attempts, and to improve the success rate of self-quit attempts, is essential to reduce the numbers of people who smoke. Interventions for smoking cessation can be characterised in two extremes: the intensive face-to face therapy of the clinical approach, and large-scale, public health interventions and policy initiatives. Computer-based systems offer a method for generating highly tailored behavioural feedback letters, and can bridge the gap between these two extremes. Proactive mailing and recruitment can also serve as a prompt to motivate smokers to make quit attempts or to seek more intensive help. The aim of this study is to evaluate the effect of personally tailored feedback reports, sent to smokers identified from general practitioners lists on quit rates and quitting activity. The trial uses a modified version of a computer-based system developed by two of the authors to generate individually tailored feedback reports. A random sample of cigarette smokers, aged between 18 and 65, identified from GP records at a representative selection of practices registered with the GPRF are sent a questionnaire. Smokers returning the questionnaire are randomly allocated to a control group to receive usual care and standard information, or to an intervention group to receive usual care and standard information plus tailored feedback reports. Smoking status and cognitive change will be assessed by postal questionnaire at 6-months. Computer tailored personal feedback, adapted to reading levels and motivation to quit, is a simple and inexpensive intervention which could be widely replicated and delivered cost effectively to a large proportion of the smoking population. Given its recruitment potential, a modest success rate could have a large effect on public health. The intervention also fits into the broader scope of tobacco control, by prompting more quit attempts, and increasing referrals to specialised services. The provision of this option to smokers in primary care can complement existing services, and work synergistically with other measures to produce more quitters and reduce the prevalence of smoking in the UK. Current Controlled Trials ISRCTN05385712.


Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing.
Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning. The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for. Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities. The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.


Proton pumping mechanism in cytochrome c oxidase.
Two different issues, important for the pumping mechanism of cyctochrome c oxidase, have been addressed in the present study. One of them concerns the nature of two key proton transfer transition states. A simple electrostatic model is used to suggest that the transition state (TS) for transfer to the pump-site should be positively charged, while the one for transfer to the binuclear center should be charge-neutral. The character of the former TS will guarantee that the protons will be pumped to the outside and not return to the inside, while the neutral character of the latter one will allow transfer with a sufficiently low barrier. In the simple electrostatic analysis, leading to this qualitative picture of the pumping process, the results from the kinetic experiments are strictly followed, but it is at least as important to follow the fundamental requirements for pumping. In this perspective, the uncertainties in the quantitative analysis should be rather unimportant for the emerging qualitative picture of the pumping mechanism. The second problem addressed concerns the purpose of the K-channel. It is argued that the reason for the presence of the K-channel could be that protons cannot pass through the binuclear center at some stage of pumping. Barriers and water binding energies were computed using hybrid density functional theory (DFT) to investigate this question.


Successful catheter ablation of accessory pathway from noncoronary cusp of aorta: an alternative approach.
Anteroseptal accessory pathways are relatively rare. Because of the close proximity of the atrioventricular (AV) node, ablation of these accessory pathways has the potential to result in AV block. The anteroseptal region is adjacent to the noncoronary cusp, allowing anteroseptal accessory pathways to be ablated from the noncoronary cusp. A 34 year-old male patient with recurrent episodes of palpitation for approximately ten years was admitted to our department. Twelve lead-ECG was consistent with anteroseptal accessory pathway. Intracardiac recordings were also consistent with anteroseptal accessory pathway. In this case, we found an excellent AV relation while mapping the noncoronary cusp. Radiofrequency (RF) ablation was applied to this region. Pre-excitation was immediately disappeared during RF application. After RF ablation, there was no pre-excitation detectable by ECG. In this report, we present a case of anteroseptal accessory pathway that was successfully ablated from the noncoronary cusp.


Pharmacy Travel Health Services in Canada: Experience of Early Adopters.
Since 2007, community pharmacists in Canada have become increasingly involved in delivering Travel Health services, including the recommendation and administration of vaccines. This qualitative scoping survey examines some of the activities and opinions of those early pharmacist adopters delivering these services. A Survey Monkey free text questionnaire was emailed to pharmacists who were involved in delivering travel medicine services. 21 pharmacists responding represented seven Canadian provinces. Only 5 pharmacists estimated that they were seeing five or more patients a week on average. Amongst the challenges they faced the most quoted was lack of time when running a busy pharmacy (62%) a lack of prescribing authority, (52%), and lack of access to public health vaccines (52%). 'Word of mouth' was widely quoted as a means of developing the service, indicating a good patient satisfaction. Also expressed were the advantages of convenience in terms of being a 'one stop shop', ease of billing to insurance companies and convenient appointment times. There are a number of challenges which are still to be faced which may be resolved by further legislation allowing access to public health vaccines and more widespread prescribing rights. The relatively low level of consultations reported by some is of concern if those pharmacists are to maintain competence.


Cyclophilin D as a potential target for antioxidants in neurodegeneration: the X-ALD case.
X-linked adrenoleukodystrophy (X-ALD) is a severe inherited neurodegenerative disorder characterized by adrenal insufficiency and graded damage in the nervous system. Loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long-chain fatty acids in organs and plasma, is the genetic cause. Treatment with a combination of antioxidants halts the axonal degeneration and locomotor impairment displayed by the animal model of X-ALD, and is a proof of concept that oxidative stress contributes to axonal damage. New evidence demonstrates that metabolic failure and the opening of the mitochondrial permeability transition pore orchestrated by cyclophilin D underlies oxidative stress-induced axonal degeneration. Thus, cyclophilin D could serve as a therapeutic target for the treatment of X-ALD and cyclophilin D-dependent neurodegenerative and non-neurodegenerative diseases.


Ischemic enterocolitis examined by colonoscopy and selective angiography.
To study the value of colonoscopy and selective angiography in diagnosing ischemic enterocolitis. Among the 16 cases under study, 10 cases had hypertension and a history of coronary artery disease (one was hospitalized for sub-ventricular-wall infarction). The blood pressure of 10 of the 16 cases ranged from 13.9-23.8 to 13.3-14.6 kPa (170-180/100-110 mmHg). Two cases had chronic auricular fibrillation, and in four cases, a cardiogram showed left-front branch conduction block. Sixteen patients were examined by colonoscopy. Among them, 14 cases had a long course of angiocardiac disease, and were further examined by selective mesenteric inferior angiography. The colonoscopy revealed local mucous hyperemia edema and blood on contact. Lesions were found in the sigmoid colon in four cases, in the descending colon in eight cases and in splenic flexure in four cases, which suggests that the lesion always appeared in the left part of colon. There were different degrees of inflammatory cell infiltration, submucous bleeding, edema, fibro-embolism and hemosiderosis by biopsy in the 16 patients whose membranes affect part of the enteral wall. Of the 14 patients examined by mesenteric inferior angiography, 3 cases showed mesenteric amphraxis inferior and formation of collateral circulation. There were different degrees of stenosis in the other 11 subjects' mesenteric inferior cavities which grew slim and their branches were stenotic, so the radiographic image was not complete and the ends of some branches even cannot be seen. The colonoscopy and the selective mesenteric inferior angiography are both helpful in the diagnosis of ischemic enterocolitis.


Translating national childhood immunization guidelines to a computer-based reminder recall system within an immunization registry.
To translate national childhood immunization guidelines to a computer-based reminder recall system, hierarchical system architecture design and combined approach of tabular and procedural knowledge representation are taken. Nested branches with hierarchical combinations of single antecedent variables are used to avoid logical incompleteness, redundancy and inconsistency. Mapping to the local electronic medical vocabulary is implemented to facilitate the integration with the local information system architecture. 26 second-level modules with 195 original branches and 121 final branches after pruning are encoded. 99.67% of the reminders are confirmed to be correct by SQL query.


Obtaining lignocellulosic biomass-based catalysts and their catalytic activity in cellobiose hydrolysis and acetic acid esterification reactions.
Global challenges prompt the world to modify its strategies and shift from a fossil-fuel-based economy to a bio-resource-based one with the production of renewable biomass chemicals. Different processes exist that allow the transformation of raw biomass into desirable bio-based products and/or energy. In this work different biochars that were obtained as a by-product from birch chip fast pyrolysis and carbonization were used as is or chemically/physically treated. These sulfonated carbon catalysts were compared to a commercially available sulfonated styrene-divinylbenzene macroreticular resin (Dowex 50W X8). Characterisation (water content and pH value, FTIR, base titration, element analysis and N2 desorption) was done to evaluate the obtained sulfonated biocarbon catalysts. Catalytic activity was tested using cellobiose (CB) hydrolysis and acetic acid esterification. For the catalytic CB hydrolysis, we tested the reaction temperature, time and CB and catalyst mass ratios. The determined optimal conditions were 120 °C and 24 h, with CB and catalyst mass ratio 1 : 5. The highest glucose yield was observed for biochar obtained from the birch chip fast pyrolysis process (BC_Py-H2SO4) - 92% within 24 h for 120 °C. Comparably high glucose yield was observed for biochar that was obtained in birch chip carbonization (BC_Carbon-H2SO4) - 86% within 24 h for 120 °C.


Effects of cell wall inhibitors on cell division in Streptococcus mutans.
The addition of inhibitors of cell wall biosynthesis to exponential-phase cultures of Streptococcus mutans may do one of three things, depending on the concentrations used: (i) prevent cell division at a time coincident with the onset of chromosome replication, (ii) prevent cell division later in the cell cycle coincident with or near completion of septation, or (iii) lead to limited cell lysis. The relative tolerance of S. mutans to inhibitors of cell wall biosynthesis may be due to the fact that S. mutans cultures treated with low levels of cell wall antibiotics seem to be blocked at a stage before initiation of autolytic activity, whereas cultures treated with high levels of these antibiotics seem to be blocked after termination of the autolytic phase. Thus, the cells escape the lytic death that is seen in other streptococci exposed to inhibitors of cell wall biosynthesis.