[Clarithromycin, a new macrolide antibiotic. Effectiveness in puerperal infections and pharmacokinetics in breast milk].
The aims of this study were, to determine the pharmacokinetic parameters of clarithromycin and to study the passage of the drug into breast milk. Twelve patients (age 24 to 38; weight 44 to 83 kg), suffering from puerperal infections, were treated orally with 250 mg clarithromycin b.i.d. for 6 days. Samples of blood and breast milk were taken at timed intervals. The specimens were assayed for clarithromycin and its active metabolite 14-hydroxy-clarithromycin by HPLC and electrochemical detection. Serum concentrations of clarithromycin in the investigated patients were higher than those reported in healthy volunteers. The mean peak concentrations of clarithromycin and 14-hydroxy-clarithromycin in breast milk were about 25%, and 75% respectively of the corresponding serum concentrations. All patients recovered within 2 to 4 days and no drug-associated side effects (eg. gastrointestinal) were noted. Clarithromycin appears to be an appropriate antibiotic for the treatment of puerperal infections and (because of its considerable concentrations in breast milk) for puerperal mastitis as well.


A dialogue on occupational therapy, culture, and families.
This paper, based on a broad body of relevant data, presents a dialogue that explores and integrates two important concepts: family and culture. An understanding of these concepts is important for enhancing occupational therapy practice, in particular a practice that claims to be client-centered and holistic. The dialogue focuses particularly on issues students involved in the Intercultural Interaction Project, The University of Sydney, Australia, in 2002 identified as important. These include: a lack of understanding of the concept of culture, the confounding of culture and ethnicity, considering culture as an issue only in families from "other" cultural backgrounds, assumptions about the nature of families and therapists' points of reference for making these assumptions, differences in client or family and therapist expectations, and how these expectations affect what happens in therapy and participants' level of satisfaction with the outcomes of the interactions involved. The information suggests that there is a need for a better understanding of how culture influences ideas about families and how to work with them.


Alterations in beta adrenergic physiological response characteristics after long-term treatment with desmethylimipramine: interaction between norepinephrine and gamma-aminobutyric acid in rat cerebellum.
Changes in beta adrenergically mediated responses of cerebellar Purkinje cells to norepinephrine (NE) were assessed in rats chronically treated with desmethylimipramine (DMI). A decreased efficacy of NE action after DMI pretreatment was manifested in both a higher mean iontophoretic current dose of the catecholamine required to induce threshold depressions of Purkinje cell spontaneous activity and a markedly diminished ability of NE to enhance inhibitory responses to gamma-aminobutyric acid. No significant differences were found in the responsiveness of Purkinje cells to gamma-aminobutyric acid alone between control and DMI-pretreated animals. However, in a significant portion of the Purkinje cells tested in the DMI-pretreated group, concurrent NE application resulted in an antagonism rather than an enhanced responsiveness to gamma-aminobutyric acid. The results of this electrophysiological study provide evidence for a "modulatory subsensitivity" toward noradrenergic actions in the cerebellum after a decrease in beta receptor number induced by prolonged treatment with DMI.


Dirichlet Diffusion Score Model for Biological Sequence Generation.
Designing biological sequences is an important challenge that requires satisfying complex constraints and thus is a natural problem to address with deep generative modeling. Diffusion generative models have achieved considerable success in many applications. Score-based generative stochastic differential equations (SDE) model is a continuous-time diffusion model framework that enjoys many benefits, but the originally proposed SDEs are not naturally designed for modeling discrete data. To develop generative SDE models for discrete data such as biological sequences, here we introduce a diffusion process defined in the probability simplex space with stationary distribution being the Dirichlet distribution. This makes diffusion in continuous space natural for modeling discrete data. We refer to this approach as Dirchlet diffusion score model. We demonstrate that this technique can generate samples that satisfy hard constraints using a Sudoku generation task. This generative model can also solve Sudoku, including hard puzzles, without additional training. Finally, we applied this approach to develop the first human promoter DNA sequence design model and showed that designed sequences share similar properties with natural promoter sequences.


Immunocytochemical study of the distribution of a 16-kDa galectin in the chicken retina.
To compare the distribution of a developmentally regulated 16-kDa galectin in the chicken retina at two different developmental stages: embryonic day 13 (ED13) and postnatal day 10 (PD10) retinas, by immunocytochemical analysis using light and transmission electron microscopy. Semi-thin and thin sections from ED13 and PD10 retinas were incubated with the IgG fraction purified from a rabbit antiserum raised against the 16-kDa chicken galectin. After incubation with colloidal gold particle-labeled goat anti-rabbit IgGs, tissue sections were analyzed by light and transmission electron microscopy. To improve the observation by light microscopy, semi-thin immunostained sections were intensified by silver enhancement. In ED13 retinas a specific galectin labeling was detected in the region corresponding to the outer limiting membrane by light microscopy. This labeling seemed to be associated with the apical villi of Muller glial cells and their specialized junctions, as judged by transmission electron microscopy. In PD10 retinas, the more relevant finding revealed by light microscopy was the detection of a widespread immunostaining at the level of all retinal layers. The ultrastructural analysis indicated that the galectin labeling was detected at the cytoplasmic and nuclear compartments of Muller cells throughout the different retinal layers. Moreover, the labeling was detected in the inner limiting membrane in structures that resemble the end feet of Muller cells. The apical villi, and the specialized junctions of these glial cells, appeared more strongly stained in PD10 retinas than in ED13 retinas. Finally, highly intense labeling in a group of mitochondria localized in the inner segments of cone cells was observed. The present study clearly supports the idea that the subcellular distribution of the 16-kDa galectin changes during the development of the chicken retina. Morphologic changes associated with developmentally regulated expression and subcellular compartmentalization of the retinal galectin suggest that this lectin may be involved in the modulation of several processes in the visual system. Its presence in the apical villi of Miller cells may be related by modulatory functions between retina and pigment epithelium, but its presence in the cytoplasm and nucleus of these glial cells suggests a potential immunomodulatory role and its involvement in different metabolic processes between Muller and the other retinal cells. Finally, although the presence of galectins inside mitochondria has not been described before, this localization gives rise to the idea that this lectin may be involved in the modulation of mitochondrial processes.


A naturally evolved mutation (Ser59Gly) in glutamine synthetase confers glufosinate resistance in plants.
Glufosinate is an important and widely used non-selective herbicide active on a wide range of plant species. Evolution of resistance to glufosinate in weedy plant species (including the global weed Eleusine indica) is underway. Here, we established the molecular basis of target site glufosinate resistance in Eleusine indica. Full-length E. indica glutamine synthetase (GS) iso-genes (EiGS1-1, 1-2, 1-3, and EiGS2) were cloned, and expression of EiGS1-1 and EiGS1-2 was higher than that of EiGS2. A novel point mutation resulting in a Ser59Gly substitution in EiGS1-1 was identified in glufosinate-resistant plants. Rice calli and seedlings transformed with the mutant EiGS1-1 gene were resistant to glufosinate. Purified mutant EiGS1-1 expressed in yeast was more tolerant to glufosinate than the wild-type variant. These transgenic results correlate with a more glufosinate-resistant GS in the crude tissue extract of resistant versus susceptible E. indica plants. Structural modelling of the mutant EiGS1-1 revealed that Ser59 is not directly involved in glufosinate binding but is in contact with some important binding residues (e.g. Glu297) and especially with Asp56 that forms an intratoroidal contact interface. Importantly, the same Ser59Gly mutation was also found in geographically isolated glufosinate-resistant populations from Malaysia and China, suggesting parallel evolution of this resistance mutation.


[Plasticity of motor maps in primates: recent advances and therapeutical perspectives].
In the past decade, there have been considerable advances in understanding the neuronal bases of sensory and motor map reorganisation in adults and it is now clear that cortical representations are not invariant and stable, but rather, are dynamic and can continuously be modified. In human subjects, substantial advances in this field have been possible because of the spectacular development of non-invasive imaging and brain stimulation techniques. This review addresses specific questions about the capacity of motor maps in adult primates, including man, to change in response to behaviourally relevant experiences or as a result of central or peripheral lesion. The first part of this review deals with recent progress in understanding the role of the primary motor cortex (M1) in both motor control and cognition. The organisation and function of multiple "non-primary" motor areas located rostrally to the primary motor cortex and in the cingulate cortex are also discussed. This review then focuses on advances made in understanding motor cortex plasticity in different conditions. Firstly, since representations in M1 have been shown to change after motor learning, the contribution of M1 in motor learning has been insinuated; arguments against and in favour of this view are discussed. In addition, data suggesting that intracortical circuitry of M1 may play a role in map reorganisation following motor learning are also evaluated. Secondly, a large body of evidence from both animal and human observations is reviewed that confirms that M1 representations can also be altered as a result of changes in availability of effectors or following sensory deprivation. The mechanisms underlying such a plasticity of cortical maps following peripheral lesions are increasingly well understood. Thirdly, we discuss data showing that a corticospinal system lesion can lead to a complete reorganisation of the area allocated to the hand representation in the primary motor cortex or to a reorganization of the whole network of motor areas responsible for voluntary movements. As a conclusion, therapeutical perspectives that result from a better understanding of those various mechanisms responsible for motor map plasticity are briefly discussed.


CRISPR Screen Reveals that EHEC's T3SS and Shiga Toxin Rely on Shared Host Factors for Infection.
Enterohemorrhagic Escherichia coli (EHEC) has two critical virulence factors-a type III secretion system (T3SS) and Shiga toxins (Stxs)-that are required for the pathogen to colonize the intestine and cause diarrheal disease. Here, we carried out a genome-wide CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats with Cas9) loss-of-function screen to identify host loci that facilitate EHEC infection of intestinal epithelial cells. Many of the guide RNAs identified targeted loci known to be associated with sphingolipid biosynthesis, particularly for production of globotriaosylceramide (Gb3), the Stx receptor. Two loci (TM9SF2 and LAPTM4A) with largely unknown functions were also targeted. Mutations in these loci not only rescued cells from Stx-mediated cell death, but also prevented cytotoxicity associated with the EHEC T3SS. These mutations interfered with early events associated with T3SS and Stx pathogenicity, markedly reducing entry of T3SS effectors into host cells and binding of Stx. The convergence of Stx and T3SS onto overlapping host targets provides guidance for design of new host-directed therapeutic agents to counter EHEC infection.IMPORTANCE Enterohemorrhagic Escherichia coli (EHEC) has two critical virulence factors-a type III secretion system (T3SS) and Shiga toxins (Stxs)-that are required for colonizing the intestine and causing diarrheal disease. We screened a genome-wide collection of CRISPR mutants derived from intestinal epithelial cells and identified mutants with enhanced survival following EHEC infection. Many had mutations that disrupted synthesis of a subset of lipids (sphingolipids) that includes the Stx receptor globotriaosylceramide (Gb3) and hence protect against Stx intoxication. Unexpectedly, we found that sphingolipids also mediate early events associated with T3SS pathogenicity. Since antibiotics are contraindicated for the treatment of EHEC, therapeutics targeting sphingolipid biosynthesis are a promising alternative, as they could provide protection against both of the pathogen's key virulence factors.


[Targeting of PP2A enzymes by viral proteins and cancer signalling].
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. PP2A proteins are made of a core dimer, composed of a catalytic (C) subunit and a structural (A) subunit, in association with a third variable -regulatory (B) subunit. Although initially considered as a constitutive housekeeping enzyme, PP2A is indeed highly regulated by post-translational modifications of its catalytic subunit or by the identity of a regulatory type B subunit, which determines substrate specificity, subcellular localization and enzymatic activity of a defined holoenzyme. During the two last decades, multiple studies of structural and functional regulation of PP2A holoenzymes by viral proteins led to the identification of critical pathways for both viral biology and tumorigenesis. To date a dozen of different viruses (ADN/ARN or retrovirus) have been identified that encode viral proteins associated to PP2A. In this review, we analyze a biological strategy, used by various viruses based on the targeting of PP2A enzymes by viral proteins, in order to specifically deregulate cellular pathways of their hosts. The impact of such PP2A targeting for biomedical search, and in further therapeutic developments against cancer, will also be discussed.


Supramolecular gels - a panorama of low-molecular-weight gelators from ancient origins to next-generation technologies.
Supramolecular gels, self-assembled from low-molecular-weight gelators (LMWGs), have a long history and a bright future. This review provides an overview of these materials, from their use in lubrication and personal care in the ancient world, through to next-generation technologies. In academic terms, colloid scientists in the 19th and early 20th centuries first understood such gels as being physically assembled as a result of weak interactions, combining a solid-like network having a degree of crystalline order with a highly mobile liquid-like phase. During the 20th century, industrial scientists began using these materials in new applications in the polymer, oil and food industries. The advent of supramolecular chemistry in the late 20th century, with its focus on non-covalent interactions and controlled self-assembly, saw the horizons for these materials shifted significantly beyond their historic rheological applications, expanding their potential. The ability to tune the LMWG chemical structure, manipulate hierarchical assembly, develop multi-component systems, and introduce new types of responsive and interactive behaviour, has been transformative. Furthermore, the dynamics of these materials are increasingly understood, creating metastable gels and transiently-fueled systems. New approaches to shaping and patterning gels are providing a unique opportunity for more sophisticated uses. These supramolecular advances are increasingly underpinning and informing next-generation applications - from drug delivery and regenerative medicine to environmental remediation and sustainable energy. In summary, this article presents a panorama over the field of supramolecular gels, emphasising how both academic and industrial scientists are building on the past, and engaging new fundamental insights and innovative concepts to open up exciting horizons for their future use.


The phylogenetics of the global population of potato virus Y and its necrogenic recombinants.
Potato virus Y (PVY) is a major pathogen of potatoes and other solanaceous crops worldwide. It is most closely related to potyviruses first or only found in the Americas, and it almost certainly originated in the Andes, where its hosts were domesticated. We have inferred the phylogeny of the published genomic sequences of 240 PVY isolates collected since 1938 worldwide, but not the Andes. All fall into five groupings, which mostly, but not exclusively, correspond with groupings already devised using biological and taxonomic data. Only 42 percent of the sequences are not recombinant, and all these fall into one or other of three phylogroups; the previously named C (common), O (ordinary), and N (necrotic) groups. There are also two other distinct groups of isolates all of which are recombinant; the R-1 isolates have N (5' terminal minor) and O (major) parents, and the R-2 isolates have R-1 (major) and N (3' terminal minor) parents. Many isolates also have additional minor intra- and inter-group recombinant genomic regions. The complex interrelationships between the genomes were resolved by progressively identifying and removing recombinants using partitioned sequences of synonymous codons. Least squared dating and BEAST analyses of two datasets of gene sequences from non-recombinant heterochronously-sampled isolates (seventy-three non-recombinant major ORFs and 166 partial ORFs) found the 95% confidence intervals of the TMRCA estimates overlap around 1,000 CE (Common Era; AD). We attempted to identify the most accurate datings by comparing the estimated phylogenetic dates with historical events in the worldwide adoption of potato and other PVY hosts as crops, but found that more evidence from gene sequences of non-potato isolates, especially from South America, was required.


Murine cytomegalovirus induces a Sjögren's syndrome-like disease in C57Bl/6-lpr/lpr mice.
To analyze Fas and tumor necrosis factor receptor I (TNFRI) apoptosis pathways in salivary gland inflammatory disease induced by murine cytomegalovirus (MCMV) infection. Four different strains of mice (C57BI/6 [B6]-+/+, Fas-deficient B6-lpr/lpr, TNFRI-deficient B6-tnfr1(0/0), and B6-tnfr1(0/0)-lpr/lpr mice) were infected intraperitoneally with the Smith strain of MCMV (1 x 10(5) plaque-forming units). Viral load was determined by a plaque assay, inflammation and apoptosis by immunohistochemistry and staining with terminal dUTP nickend labeling, and autoantibodies by enzyme-linked immunosorbent assay. Infectious MCMV was not detectable by day 100. Although all MCMV-infected mice developed acute sialadenitis by day 28, a chronic (>100 days), severe salivary gland inflammation and anti-Ro and anti-La antibodies developed only in the B6-lpr/lpr mice. Apoptotic cells were detected during the acute, but not the chronic, phase of inflammation. Both Fas- and TNFRI-mediated apoptosis contribute to the clearance of MCMV-infected cells in the salivary glands. However, because Fas-mediated apoptosis is necessary for the down-modulation of the immune response, a defect in this process can lead to a postinfection, chronic inflammatory response that resembles Sjögren's syndrome.


Influenza vaccine refusal in Israeli young adults.
The purpose of this study was to identify correlates of noncompliance with influenza immunization among young adults and to determine the reasons leading to immunization refusal. Self-administered questionnaires were distributed in 10 military bases during two consecutive annual Israel Defense Force influenza vaccination campaigns. Multivariate logistic regression was performed to identify independent correlates. Of 2,000 questionnaires distributed over two seasons, 942 were completed and returned. Of those, 401 respondents were not vaccinated either because of medical contraindication or for administrative reasons. The remaining 541 respondents who reported either receiving the vaccine or refusing to receive it were analyzed. Risk groups for vaccine refusal included older age (17.9% vs. 3.5% refusal rate) and officer rank (25.9% vs. 13.8% refusal rate). The main reasons for vaccine refusal differed significantly between officers and nonofficers (chi2 = 7.587, p = 0.023). Officers refused mainly (60%) because of fear of possible vaccine adverse effects, whereas nonofficers refused mainly (44.2%) because of disbelief in the vaccine's efficacy in preventing illness. Officers serve as a negative role model in this case, and efforts directed toward dissemination of evidence-based information regarding vaccine-related adverse effects should be introduced to increase vaccination rates in this group.


Ex Vivo Porcine Model for Robot-Assisted Partial Nephrectomy Simulation at a High-Volume Tertiary Center: Resident Perception and Validation Assessment Using the Global Evaluative Assessment of Robotic Skills Tool.
Introduction: With increased demands on surgeon productivity and outcomes, residency robotics training increasingly relies on simulations. The objective of this study is to assess the validity and effectiveness of an ex vivo porcine training model as a useful tool to improve surgical skill and confidence with robot-assisted partial nephrectomy (RAPN) among urology residents. Methods: A 2.5 cm circular area of ex vivo porcine kidneys was marked as the area of the tumor. Tumor excision and renorrhaphy was performed by trainees using a da Vinci Si robot. All residents ranging from postgraduate year (PGY) 2 to 5 participated in four training sessions during the 2017 to 2018 academic year. Each session was videorecorded and scored using the global evaluative assessment of robotic skills (GEARS) by faculty members. Results: Twelve residents completed the program. Initial mean GEARS score was 16.7 and improved by +1.4 with each subsequent session (p = 0.008). Initial mean excision, renorrhaphy, and total times were 8.2, 13.9, and 22.1 minutes, which improved by 1.6, 2.0, and 3.6 minutes, respectively (all p < 0.001). Residents' confidence at performing RAPN and robotic surgery increased after completing the courses (p = 0.012 and p < 0.001, respectively). Overall, residents rated that this program has greatly contributed to their skill (4/5) and confidence (4.1/5) in robotic surgery. Conclusions: An ex vivo porcine simulation model for RAPN and robotic surgery provides measurable improvement in GEARS score and reduction in procedural time, although significant differences for all PGY levels need to be confirmed with larger study participation. Adoption of this simulation in a urology residency curriculum may improve residents' skill and confidence in robotic surgery.


SIFT Meets CNN: A Decade Survey of Instance Retrieval.
In the early days, content-based image retrieval (CBIR) was studied with global features. Since 2003, image retrieval based on local descriptors (de facto SIFT) has been extensively studied for over a decade due to the advantage of SIFT in dealing with image transformations. Recently, image representations based on the convolutional neural network (CNN) have attracted increasing interest in the community and demonstrated impressive performance. Given this time of rapid evolution, this article provides a comprehensive survey of instance retrieval over the last decade. Two broad categories, SIFT-based and CNN-based methods, are presented. For the former, according to the codebook size, we organize the literature into using large/medium-sized/small codebooks. For the latter, we discuss three lines of methods, i.e., using pre-trained or fine-tuned CNN models, and hybrid methods. The first two perform a single-pass of an image to the network, while the last category employs a patch-based feature extraction scheme. This survey presents milestones in modern instance retrieval, reviews a broad selection of previous works in different categories, and provides insights on the connection between SIFT and CNN-based methods. After analyzing and comparing retrieval performance of different categories on several datasets, we discuss promising directions towards generic and specialized instance retrieval.


Candidate gene association analysis of acute lymphoblastic leukemia identifies new susceptibility locus at 11p15 (LMO1).
To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 × 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis.


Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study.
Plasma soluble Receptor for Advanced Glycation End-products (sRAGE) is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001). The T (vs. C) allele of rs2070600, a missense variant in AGER, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10-16; minor allele frequency (MAF) = 0.04) and blacks (N = 581; P = 0.02; MAF = 0.01). In blacks, the T (vs. C) allele of rs2071288, intronic to AGER, was associated with 43% lower sRAGE levels (P = 2.22x10-8; MAF = 0.10) and was nearly absent in whites. These AGER SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130-9,017) or blacks (N = 2,293-2,871) (median follow up ~20 years). We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.


Local destabilization of the tropomyosin coiled coil gives the molecular flexibility required for actin binding.
Tropomyosin, a coiled coil protein that binds along the length of actin filaments, contains 40 uninterrupted heptapeptide repeats characteristic of coiled coils. Yet, it is flexible. Regions of tropomyosin that may be important for binding to the filament and for interacting with troponin deviate from canonical coiled coil structure in subtle ways, altering the local conformation or energetics without interrupting the coiled coil. In a region rich in interface alanines (an Ala cluster), the chains pack closer than in canonical coiled coils, and are staggered, resulting in a bend [Brown et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 8496-8501]. Brown et al. suggested that bends at alanine clusters allow tropomyosin to wind on the actin filament helix. Another explanation is that local destabilization of the coiled coil, rather than close packing of the chains at Ala clusters per se, allows flexibility. Changing three Ala residues to canonical interface residues, A74L-A78V-A81L, greatly stabilized tropomyosin, measured using circular dichroism and differential scanning calorimetry, and reduced actin affinity >10-fold. Normal actin affinity and stability were restored in a mutant A74Q-A78N-A81Q that mimicked the stability of the Ala cluster but not the close packing of the chains. Analysis and modeling of comparable mutations introduced closer to the N-terminus show that the effects on stability and function depend on context. Models based on tropomyosin crystal structures give insight into possible effects of the mutations on the structure. We conclude that the significance of the Ala clusters in allowing flexibility of tropomyosin is stability-driven.


Systemic Manifestations in Pyridox(am)ine 5'-Phosphate Oxidase Deficiency.
Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency. A series of six patients with homozygous mutations of PNPO, the gene coding pyridox(am)ine 5'-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations. Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A). In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5'-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy.


Porcine NAMPT gene: search for polymorphism, mapping and association studies.
NAMPT encodes an enzyme catalysing the rate-limiting step in NAD biosynthesis. The extracellular form of the enzyme is known as adipokine visfatin. We detected SNP AM999341:g.669T>C (referred to as 669T>C) in intron 9 and SNP FN392209:g.358A>G (referred to as 358A>G) in the promoter of the gene. RH mapping linked the gene to microsatellite SW944. Linkage analysis placed the gene on the current USDA – USMARC linkage map at position 92 cM on SSC9. Association analyses were performed in a wild boar × Meishan F2 family (W × M), with 45 traits recorded (growth and fattening, fat deposition, muscling, meat quality, stress resistance and other traits), and in a commercial Landrace × Chinese-European (LCE) synthetic population with records for 15 traits (growth, fat deposition, muscling, intramuscular fat, meat colour and backfat fatty acid content). In the W × M, SNP 669T>C was associated with muscling, fat deposition, growth and fattening, meat quality and other traits and in the LCE with muscling, meat quality and backfat fatty acid composition. In the W × M, SNP 358A>G was associated with muscling, fat deposition, growth and other traits. After correction for multiple testing, the NAMPT haplotypes were associated in the W × M with, in descending order, muscling (q = 0.0056), growth (q = 0.0056), fat deposition (q = 0.0109), fat-to-meat ratio (q = 0.0135), cooling losses (q = 0.0568) and longissimus pHU (q = 0.0695). The SNPs are hypothesized to be in linkage disequilibrium with a causative mutation affecting energy metabolism as a whole rather than fat metabolism alone.


Structure and genetic diversity of Canadian Maritimes wild hops.
Studies on the northeastern American native hops (Humulus lupulus ssp. lupuloides) from the Canadian Maritimes are scarce. This study aimed to evaluate the genetic structure and diversity among 25 wild-collected hops from three Canadian Maritime provinces using microsatellite (simple sequence repeat (SSR)) markers. Based on 43 SSR markers, four distinct subgroups were found, with a low molecular variance (19%) between subgroups and a high variance (81%) within subgroups. The Nei's unbiased genetic distance between clusters ranged from 0.01 to 0.08, the genetic distance between clusters 2 and 3 being the farthest and that between clusters 1 and 2 the closest. Cluster 2 captured the highest overall diversity. A total of 18 SSR markers clearly discriminated hop clones by detecting putative subspecies-specific haplotypes, differentiating clones of native-wild H. lupulus ssp. lupuloides from the naturalized old and modern hop cultivars. Seven of the 18 SSR markers also differentiated two clones from the same site from one another. The study is the first, using molecular markers, to identify SSR markers with potential for intellectual property protection in Canadian Maritimes hops. The SSR markers herein used can be prime tools for hop breeders and growers in the region.


Enhancement of phorbol diester-induced HL-60-mediated cytotoxicity by retinoic acid, dimethyl sulfoxide, and 5-azacytidine.
Both peripheral blood monocytes and neutrophils are known to be capable of lysing a variety of extracellular tumor and non-tumor cell targets. The HL-60 human promyelocytic leukemia cell line has served as a useful model of human granulocyte and macrophage differentiation in studies from many laboratories. We have previously reported that phorbol diesters, which induce differentiation along the macrophage pathway, stimulate HL-60 cells to become strikingly cytotoxic to a variety of red cell targets. We now report that agents known to differentiate HL-60 along the granulocyte pathway (retinoic acid, dimethyl sulfoxide, 5-azacytidine) do not, in themselves, induce HL-60 to become cytotoxic. However, previous exposure (3-5 days) to these granulocyte pathway active agents markedly enhances phorbol diester-triggered killing. This enhancement is particularly striking at decreased effector:target ratios (as low as one effector per five targets) and is also demonstrated by a shift to lower concentrations of the phorbol diester dose-response curve. Retinoic acid is the most effective of the three agents tested, although priming (previous exposure) with dimethyl sulfoxide or 5-azacytidine also markedly enhances killing. These studies demonstrate that HL-60-mediated killing may be dissected pharmacologically into at least two distinct steps and further support the utility of this model system in studies of the development of macrophage-like cytotoxic cells. This system has also proven to be useful in the characterization of cytokines which mimic the differentiation effects of retinoic acid and dimethyl sulfoxide (J. A. Leftwich and R. E. Hall, manuscript in preparation).


Diadenosine polyphosphate receptors. from rat and guinea-pig brain to human nervous system.
Diadenosine polyphosphates are a family of naturally occurring nucleotidic compounds present in secretory vesicles together with other chemical messengers. The exocytotic release of these compounds permits them to stimulate receptors termed "purinoceptors" or "ATP receptors." Purinoceptors for nucleotides are named P2 in contrast with those sensitive to nucleosides (P1). P2 receptors are further subdivided into metabotropic P2Y receptors, further divided into 5 subtypes, and ionotropic P2X receptors, with 7 different subtypes. Diadenosine polyphosphates can activate recombinant P2Y(1), P2Y(2), and P2Y(4) and recombinant homomeric P2X(1), P2X(2), P2X(3), P2X(4), and P2X(6). Heteromeric P2X receptors change their sensitivity to diadenosine polyphosphates when co-assembly between different subunits occurs. Diadenosine polyphosphates can activate specific receptors termed dinucleotide receptors or P4 receptors, which are insensitive to other nucleosides or nucleotides. The P4 receptor is a receptor-operated Ca(2)+ channel present in rat brain synaptic terminals, stimulated by diadenosine pentaphosphate and diadenosine tetraphosphate. This receptor is strongly modulated by protein kinases A and C and protein phosphatases. The dinucleotide receptor is present in different brain areas, such as midbrain (in rat and guinea-pig), cerebellum (in guinea-pig), and cortex (in human).


[The administrative function of the nurse in the newborn unit].
Considerations are made about the neonatal service of the hospital with special attention to the newborn unit. The authors describe the role of the nurse as a most valuable element of the functional group and emphasize her administrative function in the newborn.


Interleukin-15 induces rapid tyrosine phosphorylation of STAT6 and the expression of interleukin-4 in mouse mast cells.
Interleukin (IL)-4 plays an important role in the differentiation of naive T helper (Th) cells into Th2. Mast cells can produce a significant amount of IL-4 and have been proposed to play a major role in the induction of Th2 responses. Recently, it has been reported that mast cells have a distinct IL-15 receptor system different from that of T or natural killer cells. In the present study, we demonstrated that IL-15 induced IL-4 production from a mouse mast cell line, MC/9, and bone marrow-derived mast cells. IL-4 mRNA expression was increased by IL-15, suggesting that IL-15 promotes IL-4 expression at the transcriptional level. In these mast cells, signal transducer and activator of transcription (STAT) 6 were rapidly tyrosine-phosphorylated in response to IL-15. In MC/9 cells, the expression of a C-terminally truncated dominant negative form of STAT6 significantly suppressed the IL-4 mRNA up-regulation by IL-15, suggesting that STAT6 activation is essential for the IL-15-mediated IL-4 production. Additionally, tyrosine phosphorylation of Tyk2 was rapidly increased by IL-15 treatment in this cell line. Altogether, our results suggest that IL-15 plays an important role in stimulating early IL-4 production in mast cells that may be responsible for the initiation of Th2 response.


Laparoscopic inguinal hernia repair (LIHR): the benefit of the double stitch in the largest single-center experience.
To review our experience of laparoscopic inguinal hernia repair (LIHR) regarding complication rates, the practice of closing the asymptomatic patent processes vaginalis (PPV), and comparison of complication rates between pre-term (< 37 week gestation) and term infants. Retrospective review of LIHR performed between 2009 and 2021. Repair was performed by intracorporal single or double purse string/purse string + Z-stitch using a non-absorbable suture. Data were analyzed using Chi-squared/Mann-Whitney and are quoted as median (range). 1855 inguinal rings were closed in 1195 patients (943 (79%) male). 1378 rings (74%) were symptomatic. 492 (41%) patients were pre-term. Corrected gestational age at surgery was 55 weeks (31 weeks-14.6 years) and weight 5.9 kg (1-65.5). Closure of contralateral PPV was higher in the premature group (210/397 [53%] vs. 265/613 [43%] p = 0.003). There were 23 recurrences in 20 patients, of whom 10 had been born prematurely. The only factor significantly associated with a lower recurrence was use of a second stitch (p = 0.011). This is the largest single-center reported series of LIHR. LIHR is safe at any age, the risk of recurrence is low, and can be corrected by re-laparoscopy. Use of a Z-stitch or second purse string is associated with a significantly lower rate of recurrence.


The Missing=Smoking Assumption: A Fallacy in Internet-Based Smoking Cessation Trials?
In this study, penalized imputation (PI), a common approach to handle missing smoking status data and sometimes referred to as "missing=smoking," is compared with other missing data approaches using data from internet-based smoking cessation trials. Two hypotheses were tested: (1) PI leads to more conservative effect estimates than complete observations analysis; and (2) PI and multiple imputation (MI) lead to similar effect estimates under balanced (equal missingness proportions among the trial arms) and unbalanced missingness. First, the outcomes of 22 trials included in a recent Cochrane review on internet-based smoking cessation interventions were reanalyzed using only the complete observations, and after applying PI. Second, in a simulation study outcomes under PI, complete observations analysis, and two types of MI were compared. For this purpose, individual patient data from one of the Cochrane review trials were used. Results of the missing data approaches were compared with reference data without missing observations, upon which balanced and unbalanced missingness scenarios were imposed. In the reanalysis of 22 trials, relative risks (RR = 1.15 [1.00; 1.33]) after PI were nearly identical to those under complete observations analysis (RR = 1.14 [0.98; 1.32]). In the simulation study, PI was the only approach that led to deviations from the reference data beyond its 95% confidence interval. Analyses after PI led to pooled results equivalent to complete observations analyses. PI also led to significant deviations from the reference in the simulation studies. PI biases the reported effects of interventions, favoring the condition with the lowest proportion of missingness. Therefore, more sophisticated missing data approaches than PI should be applied.


Resurfaced allograft-prosthetic composite for proximal tibial reconstruction in children: intermediate-term results of an original technique.
Reconstruction of the proximal part of the tibia in children with megaprostheses or standard composite devices removes the distal femoral physis, and osteoarticular allografts have a high incidence of mechanical failure. We evaluated the results of an alternative original technique for proximal tibial reconstruction after tumor resection. Nineteen children, ranging in age from six to sixteen years, who underwent surgical resection and reconstruction with a resurfaced allograft-prosthetic composite were retrospectively reviewed at a mean follow-up time of seventy-eight months. Eighteen children had high-grade sarcoma (fourteen had osteosarcoma and four had Ewing sarcoma), and one child had an aggressive giant cell tumor of the proximal part of the tibia. Surgical resection and its complications, disease-free survival of the patients, implant survival, and functional results according to the Musculoskeletal Tumor Society scoring system were analyzed at the time of the latest follow-up. In all patients, wide surgical margins were obtained and no local recurrence was observed. At the time of the latest follow-up, nine of the eighteen patients with a high-grade malignant tumor were continually disease-free, another six had had metastases but had no evidence of disease, and three had died of the disease. The patient with a giant cell tumor was continually disease-free after 168 months. The mean implant survival was sixty-eight months (range, six to 188 months). The major complications were one deep infection; two nonunions, which healed after surgical revision; and six allograft fractures. Limb-length discrepancy was the most frequent complication but, following contralateral epiphysiodesis, resulted in a mean discrepancy of 1.9 cm at the time of the latest follow-up. At the time of the latest follow-up, eight patients had a Musculoskeletal Tumor Society score deemed as excellent or good. In children and young teenagers with bone tumors of the proximal part of the tibia requiring an intra-articular resection, knee reconstruction with a resurfaced allograft-prosthetic composite may represent a valid alternative to conventional megaprostheses or to osteoarticular allograft.


Extensor tendon injuries of the hand.
Extensor tendon injuries are often initially evaluated and diagnosed in the Emergency Department. These injuries may be painfully obvious or frightfully subtle, but if the emergency physician has a firm understanding of the anatomy involved and he or she embarks on a careful and complete history and physical examination, the diagnosis should be made. There are various considerations in the ultimate treatment and outcome for the patient, and the patient's best interests are served when the emergency physician provides the initial appropriate treatment and proper disposition.


3D printed swelling-driven shape-morphing pH-responsive hydrogel gripper.
Stimuli-responsive soft robots have provided new directions for obtaining advanced biomedical healthcare systems, such as targeted drug delivery capsules, less-invasive biopsy tools, and untethered microsurgical robots. We designed, 3D printed, and tested diverse time-dependent shape changeable 3D pH-responsive soft grippers consisting of N-isopropylacrylamide (NIPAM) and N-isopropylacrylamide-co-acrylic acid (NIPAM-AAc) bilayer. We found that the swelling/deswelling-driven actuation of the pH-responsive NIPAM/NIPAM-AAc gripper is primarily affected by the volume percent (% v/v) of the acrylic acid (AAc) and intensity of UV light. We expect that this study can be applied to untethered pH-responsive soft grippers as smart drug delivery capsules or biopsy tools in biomedical healthcare systems.


Molecular basis of endocrine regulation by orphan nuclear receptor Small Heterodimer Partner.
Nuclear receptors (NRs) are a unique superfamily of transcription factors (TFs) which are involved in and play a crucial role in almost all aspects of mammalian physiology. Small Heterodimer Partner (SHP; NR0B2), an exceptional member of this superfamily of NRs, have been identified as a key regulatory factor of the transcription of a variety of genes involved in diverse metabolic pathways, and are thereby an important factor in a variety of physiological functions. Since its discovery a decade ago, considerable progress has been made in the elucidation of the underlying mechanism by which SHP regulates various metabolic processes, and the results of previous studies support its importance in the maintenance of metabolic homeostasis. In this review, we have evaluated the current state of understanding of the molecular mechanisms and the resultant physiological interpretations governed by SHP.


A Novel Bis-Thiourea Organocatalyst for the Asymmetric Aza-Henry Reaction.
A novel bis-thiourea BINAM-based catalyst for the asymmetric aza-Henry reaction has been developed. This catalyst promotes the reaction of N-Boc imines with nitroalkanes to afford β-nitroamines with good yields and high enantioselectivities. This catalyst has the advantage that it can be prepared in a single step from commercially available materials. A model is proposed for the catalyst action where the both components of the reaction are activated simultaneously by hydrogen bonding. Regardless of the mechanism, the success of the present catalyst demonstrates the potential of bis-thioureas as an interesting class of relatively unexplored catalysts.


[Fundamental and clinical studies on T-1982 (cefbuperzone), a new cephamycin antibiotic, in the field of pediatrics].
Studies on T-1982 (cefbuperazone), a new cephamycin antibiotic, were carried out in the field of pediatrics, and the following results were obtained. 1. Peak MIC of T-1982 against S. pyogenes (group A) lately isolated was 0.39 micrograms/ml, and the drug was active even against highly resistant strains of macrolides, lincomycin, tetracycline and chloramphenicol. 2. Peak MICs of T-1982 were 0.78 microgram/ml against B. pertussis, 0.2 microgram/ml against E. coli and less than or equal to 0.05 microgram/ml against K. oxytoca, and the drug was also active against ampicillin-resistant bacteria. 3. Serum levels and urinary excretions of T-1982 were investigated in 6 cases. When given at a dose of 20-28 mg/kg by 1 hour intravenous drip infusion, serum concentrations of T-1982 attained the peak level of 63.5-75.9 micrograms/ml at the end of administration and sustained the level of 0.9-2.6 micrograms/ml at 6 hours, the serum half-life (T 1/2) ranging 70-82 minutes. Approximately 20-72% of the dose were excreted in the active form into urine within 6 hours. 4. Twenty-seven cases of acute pediatric infections were treated with T-1982 mainly by intravenous drip infusion, and satisfactory clinical results were obtained in all the cases of angina lacunaris, bronchitis, bronchopneumonia, pertussis, sepsis caused by Serratia and acute urinary tract infections caused by ampicillin-resistant E. coli. The efficacy rate was 96.3%. In this study the drug was administered chiefly at a daily dose of 50-70 mg/kg 2-3 times a day for 2-12 days. 5. Gram-positive cocci (S. aureus, S. pneumoniae, S. pyogenes) and Gram-negative rods (H. influenzae, H. parainfluenzae P. vulgaris, B. pertussis, S. marcescens, E. coli) were eradicated by the treatment with T-1982. 6. No noticeable side effects were observed, except for temporary increase of eosinophil in 2 cases and slight elevation of GOT in 1 case.


Clinicopathological study of multiple gliomas--report of three cases.
Three cases of multiple gliomas with postmortem findings including a rare case of multicentric glioma are presented. A 59-year-old female was hospitalized with decreased mental activity and gait disturbance. Computed tomographic (CT) scans and magnetic resonance (MR) images showed two independent mass lesions in the left frontal and the right temporal lobes, shown by postmortem to have no communication. Histologically, they were a gemistocytic astrocytoma and an anaplastic astrocytoma, respectively. Therefore, multicentric glioma was diagnosed. A 66-year-old male was admitted with slow mentation and gait disturbance. CT scans and MR images demonstrated two mass lesions; one overriding the bilateral frontal lobes through the corpus callosum and the other in the left temporal lobe. Postmortem examination showed that both lesions were glioblastoma and the left temporal tumor was accompanied by subarachnoid dissemination. A 29-year-old male was hospitalized with gustatory hallucination and convulsions of the right upper extremity. CT scans revealed two mass lesions in the right frontal and the left temporal lobes. MR images demonstrated communication between the two lesions through the corpus callosum. The left temporal tumor developed into the occipital lobe and another new lesion appeared in the right temporal lobe despite chemotherapy and irradiation. Postmortem examination revealed communication between the three masses through the corpus callosum. Histologically, all three tumors were glioblastoma. Multicentric gliomas have been reported at various incidences from 2.3 to 9.1%. However, multicentric gliomas with multiple tumors of different histologies are very rare and only 16 cases have been reported. MR imaging is more valuable than CT scanning to detect communication between two or more lesions.


[Construction of a deprivation index by Basic Healthcare Area in Aragon using Population and Housing Census 2011].
The measurement of inequalities using composite indicators facilitates the prioritization and implementation of public health actions. The most commonly source of information used for this has been the Population and Housing Census of 2011 (PCH_2011).The objective of this study was to evaluate the use of PHC_2011 and develop a deprivation index (DI) by Basic Healthcare Area (BHA) and to analyse its association with mortality in Aragon. Ecological study by BHA. Since PHC_2011 was a sample of the population it was validated by the Chi-square test for homogeneity. 26 socioeconomic indicators were calculated. Spearman correlation coefficients were used to evaluate the relationship between socioeconomic indicators and Standardized Mortality Ratios (SMR). Principal Component Analyses (PCA) were conducted using the indicators in which a significant correlation was found. Components with eigenvalues higher than 1 were extracted, and the rotated matrix (Varimax) was obtained. PCA from each component were conducted, extracting only one factor. BHA were grouped into, according to the deprivation index values. Mortality rates adjusted to the European Standard Population by age, sex and quartile were calculated. The most discriminant factor by quartiles was considered DI. A different DI for urban areas was obtained from the same variables. The validation of PHC sample detected 4 underrepresented BHA. 17 socioeconomic indicators were significatively correlated with SMR. From the first PCA, 3 components were obtained. The DI included %unemployment, %eventual workers, % insufficient education 16-64 years old and %foreigners. The % of variance explained by the DI was 59.7% and 73.8% in urban areas. In men, mortality in the quartile with the lowest deprivation (544,7 per 105; CI95%: 515,8-573,6) was significatively lower than in the most deprivated areas(618,7 per 105;CI95%:589,4-648,0). This new DI allows us to identify deprived BHA. This is a useful tool to bring to light health inequalities and to plan interventions according to population´s needs.


Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort.
If most adults with mental disorders are found to have a juvenile psychiatric history, this would shift etiologic research and prevention policy to focus more on childhood mental disorders. Our prospective longitudinal study followed up a representative birth cohort (N = 1037). We made psychiatric diagnoses according to DSM criteria at 11, 13, 15, 18, 21, and 26 years of age. Adult disorders were defined in the following 3 ways: (1) cases diagnosed using a standardized diagnostic interview, (2) the subset using treatment, and (3) the subset receiving intensive mental health services. Follow-back analyses ascertained the proportion of adult cases who had juvenile diagnoses and the types of juvenile diagnoses they had. Among adult cases defined via the Diagnostic Interview Schedule, 73.9% had received a diagnosis before 18 years of age and 50.0% before 15 years of age. Among treatment-using cases, 76.5% received a diagnosis before 18 years of age and 57.5% before 15 years of age. Among cases receiving intensive mental health services, 77.9% received a diagnosis before 18 years of age and 60.3% before 15 years of age. Adult disorders were generally preceded by their juvenile counterparts (eg, adult anxiety was preceded by juvenile anxiety), but also by different disorders. Specifically, adult anxiety and schizophreniform disorders were preceded by a broad array of juvenile disorders. For all adult disorders, 25% to 60% of cases had a history of conduct and/or oppositional defiant disorder. Most adult disorders should be reframed as extensions of juvenile disorders. In particular, juvenile conduct disorder is a priority prevention target for reducing psychiatric disorder in the adult population.


ADAM10 is Expressed by Ameloblasts, Cleaves the RELT TNF Receptor Extracellular Domain and Facilitates Enamel Development.
MMP20 cleaves cadherins and may facilitate cell movement, however MMP20 is not known to cleave tight junction or desmosome proteins. Ameloblasts had not previously been screened for membrane anchored proteases that could contribute to cell movement. Here we performed a PCR screen for proteolyticlly active A Disintegrin And Metalloproteinase (ADAM) family members. These proteinases are termed sheddases because they have a transmembrane domain and their catalytic domain on the cell surface can function to release anchored proteins. Significantly, ADAMs can be targeted to specific substrates on the cell membrane through their interaction with tetraspanins. Six ADAMs (ADAM8, 9, 10, 15, 17, 19) were expressed in mouse enamel organs. We show that Adam10 expression begins in the apical loop, continues through the secretory stage and abruptly ends at the transition stage when ameloblast migration ceases. ADAM10 cleaves cadherins and tight junction plus desmosome proteins and is well characterized for its role in cell movement. ADAM10 facilitated LS8 cell migration/invasion through a Matrigel coated membrane and we demonstrate that ADAM10, but not ADAM17 cleaves the RELT extracellular domain. This striking result is significant because RELT mutations cause amelogenesis imperfecta (AI) and this directly links ADAM10 to an important role in enamel development.


Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins.
Elderly individuals are susceptible to pneumococcal infections. Although factors contributing to the increased susceptibility of the elderly to bacterial infections may be several, compromised immune function, a consequence of normal human ageing, is widely accepted to play a role. We evaluated the effect of ageing on the concentrations of naturally acquired antibodies to pneumococcal capsular polysaccharides (PPS) and protein antigens. The concentrations of immunoglobulin G (IgG) and IgM antibodies to the PPS of serotypes 3, 4, 6B, 9V, 14, and 23F and IgG antibodies to the pneumococcal virulence-associated proteins CbpA, LytC, PhtD and its C-terminal fragment (PhtD C), NanA, PspA fam1, and PspA fam2 were measured by enzyme immunoassay in the sera of younger (30 to 64 years of age) and elderly (65 to 97 years of age) adults. The concentrations of anti-PPS IgG against serotypes 3 and 6B, of anti-PPS IgM against serotypes 3, 4, 6B, 9V, and 23F, and of anti-protein IgG against all tested antigens were significantly lower in the elderly than in younger adults. A stronger decline in anti-PPS antibody concentrations was seen with age in women compared to men, while anti-protein antibody concentrations were mainly similar between the genders. Age, gender, and the nature of the antigen have substantial and varying effects on the antibody concentrations in the sera of adults.


The expression of creatine kinase isoenzymes in neocortex of patients with neurodegenerative disorders: Alzheimer's and Pick's disease.
Creatine kinase (CK) activity was found decreased in the brains of patients with Alzheimer's disease (AD) and Pick's disease (PD). However, the decrease of total CK activity in AD was more pronounced than in PD. Analysis of the activity of two CK isoforms, BCK and ubiquitous mitochondrial CK, demonstrated that the decrease of total CK activity in AD and PD was related to the decrease of BCK activity. The decline of CK activity both in AD and PD correlated well with the decline of the content of immunoreactive BCK in brain extracts. The BCK mRNA level in AD and PD was not significantly different from control patients and could not be the primary reason for decreases in CK content and activity. The decreased level of BCK in AD and PD brains might be caused by posttranscriptional events, which could affect the translation of BCK mRNA and/or lead to the inactivation and degradation of the enzyme. Because CK is sensitive to oxidative modification, it is possible that the changes observed in this study result from free radical damage.


Local steroid injection for moderately severe idiopathic carpal tunnel syndrome: protocol of a randomized double-blind placebo-controlled trial (NCT 00806871).
Patients with idiopathic carpal tunnel syndrome (CTS) are commonly treated with steroid injection into or proximal to the carpal tunnel. However, evidence for its efficacy beyond one month has not been established in randomized placebo-controlled trials. The primary aim of this randomized trial is to assess the efficacy of steroid injection into the carpal tunnel in relieving symptoms of CTS in patients with symptoms of such severity to warrant surgical treatment but have not been treated with steroid injection. The study is a randomized double-blind placebo-controlled trial. Patients referred to one orthopedic department because of CTS are screened. Eligibility criteria are age 18 to 70 years, clinical diagnosis of primary idiopathic CTS and abnormal nerve conduction tests or clinical diagnosis made independently by two orthopedic surgeons, failed treatment with wrist splinting, symptom severity of such magnitude that the patient is willing to undergo surgery, no severe sensory loss or thenar muscle atrophy, and no previous steroid injection for CTS. A total of 120 patients will be randomized to injection of 80 mg Methylprednisolone, 40 mg Methylprednisolone, or normal saline, each also containing 10 mg Lidocaine. Evaluation at baseline and at 5, 10, 24 and 52 weeks after injection includes validated questionnaires (CTS symptom severity scale, QuickDASH and SF-6D), adverse events, physical examination by a blinded assessor, and nerve conduction tests. The primary outcome measures are change in the CTS symptom severity score at 10 weeks and the rate of surgery at 52 weeks. The secondary outcome measures are the score change in the CTS symptom severity scale at 52 weeks, time to surgery, and change in QuickDASH and SF-6D scores and patient satisfaction at 10 and 52 weeks. The primary analysis will be carried out using mixed model analysis of repeated measures. This paper describes the rationale and design of a double-blind, randomized placebo-controlled trial that aims to determine the efficacy of two different doses of steroid injected into the carpal tunnel in patients with moderately severe idiopathic CTS. Clinicaltrials.gov identifier NCT00806871.


Prognostic factors associated with radiotherapy for cervical cancer with computed tomography-detected para-aortic lymph node metastasis.
Patients with cervical cancer diagnosed with a para-aortic lymph node (PALN) metastasis by computed tomography (CT) scan were analyzed to identify associated prognostic factors. A total of 55 patients were reviewed, and 27 of these patients underwent extended-field radiotherapy (EFRT). The median PALN dose in patients receiving EFRT was 45 Gy (range, 27-57.6 Gy). Of the 55 patients, 28 underwent pelvic radiotherapy (RT); concurrent chemoradiotherapy (CCRT) was administered to 41 patients. The Kaplan-Meier method was used to calculate the actuarial rate. Multivariate analysis was performed using the Cox proportional hazards model. Five-year overall survival (OS) rates were 41% and 17.9% in patients undergoing EFRT and pelvic RT (P = 0.030), respectively. Age < 53 years (P = 0.023), FIGO Stage I-II (P = 0.002), and treatment with EFRT (P = 0.003) were independent predictors of better OS. The use of CCRT (P = 0.014), Stage I-II (P = 0.002), and treatment using EFRT (P = 0.036) were independent predictors of distant metastasis. In patients undergoing EFRT plus CCRT, the 5-year OS was 50%. Three-year PALN disease-free rates were 8.8%, 57.9% and 100% (P < 0.001) in CCRT patients who received PALN doses of 0 Gy, ≤45 Gy and ≥50.4 Gy, respectively. Although PALN metastasis is thought to be distant metastasis in cervical cancer, EFRT plus CCRT shows a good outcome, particularly in younger patients in an early FIGO stage. Cervical cancer with a PALN metastasis should not be considered incurable. Doses ≥50.4 Gy for treating PALN may result in better disease control.


Clinical manifestations associated with the aberrant expression of the soluble granulocyte-macrophage colony-stimulating factor receptor in patients presenting with haematological malignancies.
The receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) can exist as both transmembrane (tmGMRalpha) and soluble (solGMRalpha) isoforms, and the latter, is a normal constituent of human plasma. We investigated if aberrant solGMRalpha expression occurs in haematopoietic malignancies and whether or not solGMRalpha expression levels correlated with clinical presentation. Compared with the normal population, patients with acute lymphoblastic leukaemia (ALL) had low levels of solGMRalpha whereas clonal disorders of the myeloid lineage demonstrated higher levels of solGMRalpha. Patients with acute myelogenous leukaemia (AML) and high levels of solGMRalpha presented with a distinct clinical picture. These patients were older, predominantly belonged to the M4 and M5 French-American-British (FAB) subtypes, and they had higher white blood cell counts at presentation including myeloid precursors and myeloblasts. They often presented with either unexplained lung infiltrates or hypoxia and lower rates of microbiologically defined infections. Elevated solGMRalpha levels were not associated with decreased relapse-free and overall survival in the AML population. On multivariate analysis, the correlation between elevated solGMRalpha levels and age, M4 and M5 FAB subtypes and decreased numbers of infections persisted. Our study is the first to describe that distinct clinical presentations are associated with aberrant solGMRalpha levels in haematological malignancies.


Improving the stability of recombinant anthrax protective antigen vaccine.
Development of recombinant protective antigen (rPA)-based anthrax vaccines has been hindered by a lack of stability of the vaccines associated with spontaneous deamidation of asparagine (Asn) residues of the rPA antigen during storage. In this study, we explored the role that two deamidation-prone Asn residues located directly adjacent to the receptor binding site of PA, Asn713 and Asn719, play in the stability of rPA-based anthrax vaccines. We modified these residues to glutamine (Gln) and generated rPA(N713Q/N719Q), since Gln would not be expected to deamidate on a time scale relevant to vaccine storage. While wild-type rPA vaccine formulated with aluminum hydroxide lost immunogenicity upon storage, as measured by induction of toxin-neutralizing antibodies in mice, the rPA(N713Q/N719Q) vaccine did not exhibit a significant loss in immunogenicity. This finding suggests that modification of Asn713 and Asn719 of rPA to deamidation-resistant amino acids may improve the stability of rPA-based anthrax vaccines.


A Kirigami Approach of Patterning Membrane Actuators.
Ionic electroactive polymer actuators are typically implemented as bending trilayer laminates. While showing high displacements, such designs are not straightforward to implement for useful applications. To enable practical uses in actuators with ionic electroactive polymers, membrane-type film designs can be considered. The significantly lower displacement of the membrane actuators due to the lack of freedom of motion has been the main limiting factor for their application, resulting in just a few works considering such devices. However, bioinspired patterning designs have been shown to significantly increase the freedom of motion of such membranes. In this work, we apply computer simulations to design cutting patterns for increasing the performance of membrane actuators based on polypyrrole doped with dodecylbenzenesulfonate (PPy/DBS) in trilayer arrangements with a polyvinylidene fluoride membrane as the separator. A dedicated custom-designed device was built to consistently measure the response of the membrane actuators, demonstrating significant and pattern-specific enhancements of the response in terms of displacement, exchanged charge and force.


An acute care surgeon's dilemma: Operative vs. non-operative management of emergency general surgery conditions in patients with recent colorectal cancer treatment.
This comparative effectiveness study examined outcomes of operative vs. non-operative management for emergency general surgery (EGS) conditions in patients with recent cancer treatment (RT). Medicare beneficiaries with a history of colorectal cancer hospitalized for an EGS condition (2016-2018) were identified. RT was defined as chemotherapy/radiation within 3 months prior to admission. Instrumental variable analysis assessed the impact of management on mortality and readmissions among survivors (30d, 60d, and 90d), for patients in whom there was clinical equipoise regarding optimal management strategy. Of 26,097 patients, 13% had undergone RT. In both the RT and non-RT groups, the optimal management strategy was uncertain in 14%. Operative management conferred increased risk of mortality but not readmission in patients with RT compared to those without (90d mortality:+43%, p = 0.03; 90d readmission:+7.1%, p = 0.776). In patients with RT for whom there is clinical equipoise regarding EGS management, operative intervention increases risk of mortality.


The inflammatory effect of cardiopulmonary bypass on leukocyte extravasation in vivo.
Extravascular trafficking of leukocytes into organs is thought to play a major role in the pathophysiologic mechanisms of the inflammatory response to cardiopulmonary bypass, yet leukocyte extravasation is difficult to study clinically. Here we have tested the hypothesis that leukocyte emigration into skin blisters can provide a way to monitor the inflammatory effect of cardiopulmonary bypass that allows testing of anti-inflammatory interventions (exemplified by aprotinin). Patients undergoing primary elective coronary artery bypass grafting (n = 14) were randomized into 2 equal groups to receive saline infusion during cardiopulmonary bypass (control group) or high-dose aprotinin. Experimental skin blisters (in duplicate) were induced on the forearm by means of topical application of the vesicant cantharidin, and blister fluid was sampled at 5 hours postoperatively. Inflammatory leukocyte subsets in blister fluid were analyzed by means of flow cytometry by using expression of CD11b and CD62L as a phenotypic marker of activation. In the control group of patients, cardiopulmonary bypass surgery triggered a 381% increase in leukocyte extravasation into the skin compared with reference blisters carried out before surgical intervention, with neutrophil (P = .014), monocyte (P = .014), and eosinophil (P = .009) levels all statistically significantly increased. In the aprotinin group there was no statistically significant increase during cardiopulmonary bypass surgery in any inflammatory leukocyte subset. The activation phenotype of extravascular leukocytes was not significantly altered between surgical groups. This study introduces the cantharidin blister technique as a powerful new research tool for analyzing the inflammatory effect of cardiopulmonary bypass in vivo. It has provided detailed molecular insight into the extravascular leukocyte population during cardiopulmonary bypass. Although aprotinin blocked cardiopulmonary bypass-dependent extravasation of leukocytes, there was no change in their CD11b/CD62L activation status. The cantharidin skin test thus represents a novel research tool for evaluating future anti-inflammatory interventions in cardiothoracic surgery.


Multifractal vector fields and stochastic Clifford algebra.
In the mid 1980s, the development of multifractal concepts and techniques was an important breakthrough for complex system analysis and simulation, in particular, in turbulence and hydrology. Multifractals indeed aimed to track and simulate the scaling singularities of the underlying equations instead of relying on numerical, scale truncated simulations or on simplified conceptual models. However, this development has been rather limited to deal with scalar fields, whereas most of the fields of interest are vector-valued or even manifold-valued. We show in this paper that the combination of stable Lévy processes with Clifford algebra is a good candidate to bridge up the present gap between theory and applications. We show that it indeed defines a convenient framework to generate multifractal vector fields, possibly multifractal manifold-valued fields, based on a few fundamental and complementary properties of Lévy processes and Clifford algebra. In particular, the vector structure of these algebra is much more tractable than the manifold structure of symmetry groups while the Lévy stability grants a given statistical universality.


Incomplete reproductive isolation following host shift in brood parasitic indigobirds.
Behavioural and molecular studies suggest that brood parasitic indigobirds (Vidua spp.) rapidly diversified through a process of speciation by host shift. However, behavioural imprinting on host song, the key mechanism promoting speciation in this system, may also lead to hybridization and gene flow among established indigobird species when and if female indigobirds parasitize hosts already associated with other indigobird species. It is therefore not clear to what extent the low level of genetic differentiation among indigobird species is due to recent common ancestry versus ongoing gene flow. We tested for reproductive isolation among three indigobird species in Cameroon, one of which comprises two morphologically indistinguishable host races. Mimicry of host songs corresponded with plumage colour in 184 male indigobirds, suggesting that females rarely parasitize the host of another indigobird species. Paternity analyses, however, suggest that imperfect specificity in host and/or mate choice allows for continuing gene flow between recently formed host races of the Cameroon Indigobird Vidua camerunensis; while 63 pairs of close relatives were associated with the same host, two strongly supported father-son pairs included males mimicking the songs of the two different hosts of V. camerunensis. Thus, complete reproductive isolation is not necessarily an automatic consequence of host shifts, a result that suggests an important role for natural and/or sexual selection in indigobird speciation.


Nutritional Composition, Fatty Acids Profile, Mineral Content, Antioxidant Activity and Acute Toxicity of the Flesh of Helix aspesra Müller.
Humans consume snail flesh as part of their diet. To assess its nutritional value and toxicity, chemical analyses were conducted to confirm the presence of protein, total and reduced carbohydrates, fat, fatty acid composition and mineral components. Furthermore, an acute toxicity study was carried out to determine the safety of Helix aspersa Müller snail flesh. H. aspersa Müller snail flesh exhibits a high nutritional content, a good ω3/ω6 ratio and higher levels of unsaturated fatty acids. Various minerals have been found in the flesh of H. aspersa Müller. Around 76.91 kcal, or 3.84% of the energy of a daily meal of 2000 kcal, are present in 100 g of this flesh. The evaluation of the antioxidant capacity indicated that the flesh's extracts contained a large quantity of antioxidant biomolecules. Administration of the aqueous extract of H. aspersa Müller flesh didn't cause death in laboratory rats, indicating that the lethal dose 50 is greater than 2000 mg·kg-1 body weight. The consumption of the flesh of H. aspersa Müller is highly recommended for human consumption due to its high concentration of nutrients and essential elements, as well as unsaturated fats, and due to its safety.


Effect of hyperthermia on normal tissue toxicity and on adriamycin pharmacokinetics in dogs.
This study examined the effects of Adriamycin (ADR) (30 mg/m2), whole-body hyperthermia (WBH) (42 degrees C for 1 h), and the combination of the two (ADR plus WBH) on gastrointestinal and hematopoietic toxicity and the effects of WBH on ADR pharmacokinetics in the normal dog (n = 5/treatment group). Duodenal biopsies were collected from animals in each group via endoscopy and were incubated in the presence of [3H]thymidine as an index of cell turnover. Additional duodenal biopsies were assayed for the enzymes gamma-glutamyltranspeptidase, N-acetyl-beta-D-glucosaminidase, and succinate dehydrogenase. Complete blood chemistry profiles and differential blood cell counts were done prior to and following treatment. Cell turnover was most depressed 3 days after ADR or ADR plus WBH; WBH alone had little effect on cell turnover. Neither gamma-glutamyltranspeptidase, N-acetyl-beta-D-glucosaminidase, nor succinate dehydrogenase activities were significantly altered by any of the treatment protocols. High performance liquid chromatography was used to quantify Adriamycin and adriamycinol in samples collected up to 6 h after drug administration. Duodenal biopsies were collected immediately and 1 h after drug administration for measurement of tissue concentrations of Adriamycin. A significant increase in the apparent volume of distribution and whole-body clearance and decrease in area under the plasma Adriamycin concentration versus time curve occurred when drug was administered concurrently with WBH. This differs from results reported in some other mammalian species.


Anemia in the treatment of hepatitis C virus infection.
Hepatitis C virus (HCV) infection is a significant worldwide health care problem. Nearly one-third of all patients infected with human immunodeficiency virus (HIV) are coinfected with HCV. Compared with HIV-monoinfected persons, coinfected individuals experience more rapid progression of fibrosis and higher incidence of cirrhosis and death as a result of liver disease. Treatment for HCV infection includes ribavirin (RBV) plus interferon alfa (IFN-alpha) or pegylated IFN, a combination treatment associated with anemia that may require RBV dose reduction or discontinuation. IFN-RBV-associated anemia is more profound among coinfected patients, who have a high prevalence of pretreatment anemia and may also be taking other medications causing anemia. Epoetin alfa administration to HCV-infected patients with IFN-RBV-related anemia can significantly increase hemoglobin levels and maintain significantly higher RBV doses compared with patients treated with RBV dose reduction alone. Higher RBV doses and adherence to HCV therapy have been associated with higher sustained virologic response (SVR) rates. Maintenance of RBV dose with epoetin alfa may improve adherence, thereby affecting SVR.


MIR159 regulates multiple aspects of stamen and carpel development and requires dissection and delimitation of differential downstream regulatory network for manipulating fertility traits.
Unravelling genetic networks regulating developmental programs are key to devising and implementing genomics assisted trait modification strategies. It is crucial to understand the role of small RNAs, and the basis of their ability to modify traits. MIR159 has been previously reported to cause defects in anther development in Arabidopsis; however, the complete spectrum and basis of the defects remained unclear. The present study was therefore undertaken to comprehensively investigate the role of miR159 from Brassica juncea in modulating vegetative and reproductive traits. Owing to the polyploid nature of Brassica, paralogous and homeologous copies of MIR159A, MIR159B, and, MIR159C were identified and analysis of the precursor uncovered extensive structural and sequence variation. The MIR159 locus with mature miR159 with perfect target complimentarily with MYB65, was cloned from Brassica juncea var. Varuna for functional characterization by generating constitutively over-expressing lines in Arabidopsis thaliana Col-0. Apart from statistically significant difference in multiple vegetative traits, drastic differences were observed in stamen and pistil. Over-expression of miR159a led to shortening of filament length and loss of tetradynamous condition. Anthers were apiculate, with improper lobe formation, and unsynchronized cellular growth between connective tissue and another lobe development. Analysis revealed arrested meiosis/cytokinesis in microspores, and altered lignin deposition pattern in endothecial walls thus affecting anther dehiscence. In the gynoecium, flaccid, dry stigmatic papillae, and large embryo sac in the female gametophyte was observed. Over-expression of miR159a thus severely affected pollination and seed-set. Analysis of the transcriptome data revealed components of regulatory networks of anther and carpel developmental pathway, and lignin metabolism that are affected. Expression analysis allowed us to position the miR159a-MYB65 module in the genetic network of stamen development, involved in pollen-grain maturation; in GA-mediated regulation of stamen development, and in lignin metabolism. The study, on one hand indicates role of miR159a-MYB65 in regulating multiple aspects of reproductive organ development that can be manipulated for trait modification, but also raises several unaddressed questions such as relationship between miR159a and male-meiosis, miR159a and filament elongation for future investigations. Accession numbers: KC204951-KC204960. Project number PRJNA1035268. The online version contains supplementary material available at 10.1007/s12298-023-01377-7.


Operando XAS Study of the Surface Oxidation State on a Monolayer IrOx on RuOx and Ru Oxide Based Nanoparticles for Oxygen Evolution in Acidic Media.
Herein we present surface sensitive operando XAS L-edge measurements on IrOx/RuO2 thin films as well as mass-selected RuOx and Ru nanoparticles. We observed shifts of the white line XAS peak toward higher energies with applied electrochemical potential. Apart from the case of the metallic Ru nanoparticles, the observed potential dependencies were purely core-level shifts caused by a change in oxidation state, which indicates no structural changes. These findings can be explained by different binding energies of oxygenated species on the surface of IrOx and RuOx. Simulated XAS spectra show that the average Ir oxidation state change is strongly affected by the coverage of atomic O. The observed shifts in oxidation state suggest that the surface has a high coverage of O at potentials just below the potential where oxygen evolution is exergonic in free energy. This observation is consistent with the notion that the metal-oxygen bond is stronger than ideal.


Plasticity of myenteric neurons.
The nervous system exerts a profound influence on all digestive processes. The wall of digestive system is endowed with its own, local nervous system referred to as the enteric or intrinsic nervous system which is responsible for the modulation of the rhythmic gastrointestinal peristaltic activities along with other functions. The principal components of the enteric nervous system are two neuronal networks: myenteric and submucosal, embedded in the wall of the digestive tract and extend from esophagus to anus. The musculature of different parts of gastrointestinal tract is differently disposed to perform different functions. Thus the aim of present study was to demonstrate the presence of neurons and to quantify the number of collections of neurons, number of neurons in each collection and area of the neurons of the plexus. One cm piece from all the parts of GIT containing entire wall was taken from the same region of 5 adult cadavers of postmortem cases which were embalmed in the Department ofAnatomy, Postgraduate Institute of Medical Sciences and Research, Chandigarh and were processed for paraffin sectioning. 5 and 10 micro thick serial sections were obtained and 6th and 7th slides were stained with: Hematoxylin and Eosin and Marsland, Glees and Erikson's silver stain. The slides were photomicrographed using digital camera. The morphometrical analysis was done using Image Pro Express software. Aggregations of 1-31 neurons present in myenteric network located between longitudinal and circular muscle layers of the GIT whose size varied from 10.263-259.660 microm2. They were oval or round; multipolar, arranged in two rows and dispersed in groups in connective tissue of muscularis propria. The collections of neurons were appeared to be more numerous in appendix and ileoceacal valve.


Pharmacological approach to therapy of glomerulonephritis.
Since glomerulonephritis is a typical inflammation, we are approaching the time when inhibitors of the mediators of inflammation will be used to modify the course of nephritides. In this category are thromboxane synthetase inhibitors and thromboxane antagonists as well as anti-leukotriene and anti-platelet activating factor agents. Corticosteroids are often limited by their side effects. Other approaches include the use of heparins, endothelin antagonists and E prostaglandins. This article presents the background knowledge to these considerations.


Rates of reactions catalysed by a dimeric enzyme. Effects of the reaction scheme and the kinetic parameters on co-operativity.
For the reaction S in equilibrium P catalysed by a dimeric enzyme, the reaction schemes are considered on the basis of the KNF model. For each of the ten possible schemes, the rate equation is derived on the basis of the combined steady-state and rapid-equilibrium assumptions. The curves of the plots of initial velocity v versus the substrate concentration [S] and the Hill coefficients h calculated from the rate equations depend strongly on the reaction scheme and the parameter X1. This parameter is defined by log (KS2/KS1) and is a measure of the relative affinities of the first and second protomers for the substrate. When X1 less than 0, v-[S] curves for some schemes exhibit negative co-operativity (h less than 1.0) and v-[S] curves for other schemes are similar to that of the Michaelis-Menten scheme, indicating that, even if there is interaction between the distinct protomers, sigmoidal rate behaviour is not necessarily observed. When X1 greater than 0, all the reaction schemes except one, which shows substrate-inhibition kinetic behaviour, exhibit sigmoidal kinetic behaviour (h greater than 1.0), and at the limit of X1 much greater than 0 the Hill coefficients attain the maximum possible value of 2.0. Furthermore, we have found that, even if X1 = 0, the v-[S] curve for almost all the schemes considered in the present work does not necessarily agree with that for the Michaelis-Menten scheme. This means that the deviation of the v-[S] curve from a hyperbola can be observed even if there is no interaction between the distinct protomers.


Acral myxoinflammatory fibroblastic sarcoma fine needle aspiration: a case report.
Cytological diagnosis of low grade sarcomas can be a daunting task, owing to the varied cytomorphological appearances possible. We report a case of acral myxoinflammatory fibroblastic sarcoma (AMIFS) in a woman who presented with a longstanding mass on the dorsum of her left foot. The diagnosis was suggested by fine needle aspiration cytology and established by wide excision. Microscopic examination showed that fine needle aspirate smears of this lesion contained the characteristic features seen in the surgical excision of this AMIFS: myxoid material, spindled to epithelioid cells with variably prominent nucleoli, nuclear pseudoinclusions, bipolar cytoplasmic extensions, globules of extracellular material, and bizarre virocyte or ganglion-like giant cells.


[Life-threatening emergencies at the office: implications for medical education and equipment of the primary care physician].
Every medical practitioner is confronted on a daily basis with emergencies. Among these, life-threatening emergencies can have disastrous consequences in term of morbidity and mortality; 22 cardiac arrests and 10 deaths were reported among the 1,650 Swiss practices during a 5 year period. The occurrence of life-threatening emergencies at the office necessitates, according to the type and place of the practice, the skills of the practitioner and the organization of his practice, the implementation of procedures, equipments (for example room equipped with a defibrillator, respiratory nebulizer, splints, emergency drugs) and specific continuous education programs that should be encouraged and made available to the whole medical corporation.


p53 Family: Role of Protein Isoforms in Human Cancer.
TP53, TP63, and TP73 genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and its role in cancer.


Dated co-occurrence of Homo erectus and Gigantopithecus from Tham Khuyen Cave, Vietnam.
Tham Khuyen Cave (Lang Son Province, northern Vietnam) is one of the more significant sites to yield fossil vertebrates in east Asia. During the mid-1960s, excavation in a suite of deposits produced important hominoid dental remains of middle Pleistocene age. We undertake more rigorous analyses of these sediments to understand the fluvial dynamics of Pleistocene cave infilling as they determine how skeletal elements accumulate within Tham Khuyen and other east Asian sites. Uranium/thorium series analysis of speleothems brackets the Pleistocene chronology for breaching, infilling, and exhuming the regional paleokarst. Clast analysis indicates sedimentary constituents, including hominoid teeth and cranial fragments accumulated from very short distances and under low fluvial energy. Electron spin resonance analysis of vertebrate tooth enamel and sediments shows that the main fossil-bearing suite (S1-S3) was deposited about 475 thousand years ago. Among the hominoid teeth excavated from S1-S3, some represent Homo erectus and Gigantopithecus blacki. Criteria are defined to differentiate these teeth from more numerous Pongo pygmaeus elements. The dated co-occurrence of Homo erectus and Gigantopithecus blacki at Tham Khuyen helps to establish the long co-existence of these two species throughout east Asia during the Early and Middle Pleistocene.


Breeding phenology of birds: mechanisms underlying seasonal declines in the risk of nest predation.
Seasonal declines in avian clutch size are well documented, but seasonal variation in other reproductive parameters has received less attention. For example, the probability of complete brood mortality typically explains much of the variation in reproductive success and often varies seasonally, but we know little about the underlying cause of that variation. This oversight is surprising given that nest predation influences many other life-history traits and varies throughout the breeding season in many songbirds. To determine the underlying causes of observed seasonal decreases in risk of nest predation, we modeled nest predation of Dusky Flycatchers (Empidonax oberholseri) in northern California as a function of foliage phenology, energetic demand, developmental stage, conspecific nest density, food availability for nest predators, and nest predator abundance. Seasonal variation in the risk of nest predation was not associated with seasonal changes in energetic demand, conspecific nest density, or predator abundance. Instead, seasonal variation in the risk of nest predation was associated with foliage density (early, but not late, in the breeding season) and seasonal changes in food available to nest predators. Supplemental food provided to nest predators resulted in a numerical response by nest predators, increasing the risk of nest predation at nests that were near supplemental feeders. Our results suggest that seasonal changes in foliage density and factors associated with changes in food availability for nest predators are important drivers of temporal patterns in risk of avian nest predation.


Discrete melanocortin-sensitive neuroanatomical pathway linking the ventral premmamillary nucleus to the paraventricular hypothalamus.
The physiological effects of melanocortin-4 receptor (MC4-R) on metabolism have been hypothesized to be mediated individually or collectively by neuronal groups innervating the paraventricular nucleus of the hypothalamus (PVH). The present study was designed to identify MC4-R-expressing neurons that innervate the PVH using retrograde tract tracing techniques in the MC4-R-GFP reporter mice. Our initial mapping identified very limited projections from MC4-R-expressing neurons to the PVH. This included a defined population of MC4-R-positive neurons located in the ventral premmamillary nucleus (PMv). Anterograde tracing experiments confirmed projections from PMv neurons to the medial parvicellular subdivision of the PVH, in close proximity to oxytocin neurons and β-endorphin-containing fibers. Given the known stimulatory effects of leptin and sexual odorants exposure on many PMv neurons, it was expected that MC4-R-expressing neurons in the PMv might be responsive to leptin and activated by odors exposure. Contrary to expectation, MC4-R-GFP neurons in the PMv do not respond to leptin as demonstrated by double labeling for GFP and leptin-induced phosphorylated STAT3. However, we found that Fos expression is induced in a large subset of MC4-R-GFP neurons in the PMv in response to opposite sex odors. Collectively, these results provide evidence for a previous unrecognized role of MC4-R expressed by neurons innervating the PVH that are also sensitive to reproductive cues.


Antibiotic Use and New-Onset Inflammatory Bowel Disease in Olmsted County, Minnesota: A Population-Based Case-Control Study.
Several studies have suggested significant associations between environmental factors and the risk of developing inflammatory bowel disease [IBD]. However, data supporting the role of antibiotics are conflicting. The aim of this study was to evaluate the association between antibiotic use and new-onset IBD. We conducted a population-based case-control study using the Rochester Epidemiology Project of Olmsted County, Minnesota. We identified 736 county residents diagnosed with IBD between 1980 and 2010 who were matched to 1472 controls, based on age, sex and date of IBD diagnosis. Data on antibiotic use between 3 months and 5 years before IBD diagnosis were collected. Logistic regression models were used to estimate associations between antibiotic use and IBD, and were expressed as adjusted odds ratio [AOR] with 95% confidence interval [CI]. Antibiotic use occurred in 455 IBD cases [61.8%] and 495 controls [33.6%] [p < 0.001]. In multivariate analysis, there were statistically significant associations between antibiotic use and new-onset IBD [AOR, 2.93; 95% CI, 2.40-3.58], Crohn's disease [CD] [AOR, 3.01; 2.27-4.00] and ulcerative colitis [UC] [AOR, 2.94; 95% CI, 2.23-3.88]. A cumulative duration of antibiotic use ≥ 30 days had the strongest AOR [6.01; 95% CI, 4.34-8.45]. AOR for those receiving antibiotics under the age of 18 years was 4.27 [95% CI, 2.39-7.91], 2.97 for age 18-60 years [2.36-3.75] and 2.72 for age > 60 years [1.60-4.67]. This population-based case-control study suggests a strong association between antibiotic use and the risk of both new-onset CD and new-onset UC. The risk was increased among all age-onset IBD.


Novel HIV-1 long terminal repeat (LTR) sequences of subtype B and mosaic intersubtype B/C recombinants in North India.
Although the HIV-1 epidemic in India is mainly due to subtype C, other subtypes have also been reported from different parts of India. HIV-1 LTR sequence analysis from six HIV-1 infected individuals from North India was carried out to determine the nature and extent of variations. Four out of six samples formed a unique phylogenetic cluster which was close to subtype B. The other two samples (A3 and S3) turned out to be novel mosaic recombinants showing resemblance to subtypes B, B/C-India and B/C-Myanmar gene segments. All four subtype B LTR samples and the two B/C recombinants showed conserved as well as unique polymorphisms in all of the putative transcription factor binding sites (TFBS). These changes may potentially alter basal as well as Tat-mediated HIV-1 LTR promoter activation. The two recombinants possessed three copies of the NF-kappaB TFBS as seen with the majority of subtype C and recombinant B/C isolates reported earlier, but the other four non-recombinant B-LTRs showed only two copies of the NF-kappaB site. This is the first study to show a dominance of unique subtype B-LTRs and strongly suggests that this region could also be a hot spot for the formation of highly complex inter subtype B/C recombinants.