Inter-fraction heart displacement during voluntary deep inspiration breath hold radiation therapy without visual feedback measured by daily CBCT.
Deep Inspiration Breath Hold (DIBH) is now considered as the standard of care for many breast cancer patients. However, there are still uncertainties about the dose given to the heart, and it is unknown if patients may improve voluntary DIBH depth by gaining experience during treatment. In this study, we will examine the interfractional three-dimensional (3D) heart displacement throughout voluntary DIBH (vDIBH) radiotherapy by means of daily cone-beam computed tomography (CBCT). Two hundred twenty-five unique CBCTs from 15 patients treated in 15 fractions were analyzed. During CBCT, a vDIBH was conducted without any visual feedback. Patients performed their DIBH freely after receiving explanations and training. After daily CBCT matching to the chest wall (CW), surface-guided radiation therapy (SGRT) tracked DIBH depth to ensure that the CW position was the same as the daily acquired CBCT. The CBCTs were retrospectively registered to the DIBH planning-CT to calculate daily changes in heart displacement relative to the CW. The mean displacement of the heart during DIBH treatment relative to the DIBH planning-CT was as follows: 1.1 mm to the right, interquartile range (IQR) 8.0; 0.5 mm superiorly, IQR 4.8; and 0 mm posteriorly, IQR 6.4. The Spearman correlation coefficients (rs) were -0.15 (p=0.025), 0.04 (p=0.549), and 0.03 (p=0.612) for the X, Y, and Z directions, respectively. The differences in median heart displacement were significant: Friedmann rank sum test p=0.031 and pairwise comparison using the Wilcoxon rank-sum test were p=0.008 for X and Y; p=0.33 for X and Z; and p=0.07 for Y and Z. The total median heart motion was δtot median= 7.26 mm, IQR= 6.86 mm. During DIBH, clinicians must be aware of the wide range of intra- and inter-individual heart position variations. The inter-individual heterogeneity shown in our study should be investigated further in order to avoid unexpected cardiac overexposure and to develop a more accurate heart dose-volume model.


[Results of laser photocoagulation in diabetic retinopathy with maculopathy].
Examined were 91 eyes with non-proliferative and proliferative retinopathy with coexisting maculopathy in 51 patients in whom segmental or retinal pan-photocoagulation were performed. The period of observation--3 to 4.5 years. Stabilization of the pathological process was observed in 37.3 p.c. of cases, 54.9 p.c. of patients showed further deterioration and 7.6 p.c. loss of vision. The most frequent cause of deterioration was the progression of the macular lesions (72 p.c.), a smaller number of cases (28 p.c.) was due to other changes.


[Secondary osteoporosis. Secondary osteoporosis by primary hyperparathyroidism.]
Primary hyperparathyroidism(PHPT)is one of the common endocrine disorders, which results clinically in secondary osteoporosis. PHPT also occurs nephrolithiasis, muscle weakness, cardiac and psychiatric abnormalities even in a mild or asymptomatic disease. Parathyroidectomy(PTX)is the only definitive treatment for PHPT. In the case PTX is not choose, these patients may require intervention for management of osteoporosis and/or hypercalcemia.


Lidar receivers without overlap of the photomultiplier's single pulses.
Lidar receivers of linear performance without overlap of the single pulses are analyzed. The statistics of output signals are investigated by using a model of the photoreceiving system that is based on the conversion of secondary electron trains into single-frequency decayed oscillations. I show that the lidar profile can be separated into nonuniform and uniform parts and a background and sampled by low-speed analog-to-digital converters (12-16 bits/0.01-100 kHz) to provide high amplitude and temporal resolution. The nonstationary background is reduced without chopping to the square root of its intensity. The use of the lidar receivers is discussed.


Retroviral vector backbone immunogenicity: identification of cytotoxic T-cell epitopes in retroviral vector-packaging sequences.
Retroviral vectors are the frequently applied gene delivery vehicles for clinical gene therapy, but specificity of the immunogenicity to the protein encoded by the inserted gene of interest is a problem which needs to be overcome. Here, we describe human cytotoxic T-lymphocyte (CTL) clones recognizing epitopes derived from the protein encoded by the retroviral vector backbone, which were established during the course of our attempts to generate CTLs against cytomegalovirus (CMV) or human papilloma virus (HPV) in vitro. In the case of healthy CMV-seronegative donors, CTL lines specific for retrovirally transduced cells were generated in four out of eight donors by stimulating CD8 T cells with CD40-activated B (CD40-B) cells retrovirally transduced with CMV-pp65. Two CTL clones derived from one of the CTL lines were found to recognize epitopes from gag in the context of HLA-B(*)4403 and -B(*)4601, respectively. Similarly, an HLA-B(*)3501-restricted CTL clone from a cervical cancer patient recognized an epitope located in the junctional regions of the gag and pol sequences. These results show that polypeptides encoded by components of the retroviral vector backbone are in fact immunogenic, generating CTLs in vitro in human cells. Thus, potential CTL responses to retroviral products should also be considered in clinical settings.


Purification, NMR study and immunostimulating property of a fucogalactan from the fruiting bodies of Ganoderma lucidum.
A water-soluble polysaccharide (LZ-D-1) was isolated from Ganoderma lucidum fruiting bodies by DEAE-Sepharose Fast Flow and Sephacryl S-300 high-resolution chromatography. The polysaccharide had a molecular weight of 2.8 x 10(4) Da and was mainly composed of L-Fuc, D-Glc and D-Gal in a molar ratio of ca.1 : 1 : 5. LZ-D-1 had a sugar content of 98.7 % as measured using the phenol-sulfuric acid method. On the basis of methylation analysis, FT-IR spectrum and NMR experiments, the structure of the repeating unit of the polysaccharide was established. LZ-D-1 had a backbone composed of 1,6-disubstituted alpha-D-galactopyranosyl, 1,2,6-trisubstituted alpha-D-galactopyranosyl and had a branch composed of fucose attached to O-2 of a 1,2,6-trisubstituted alpha-D-galactopyranosyl residue. At the same time, the polysaccharide contained some 1,6-disubstituted glucopyranosyl residues and 1,3-disubstituted glucopyranosyl residues. An immunostimulating experiment in vitro indicated that LZ-D-1 stimulated proliferation of mouse spleen lymphocytes.


Photic maculopathy in young males with intraocular foreign body.
A young male with intraocular foreign body (IOFB) and clear media had successful removal of the IOFB but sustained macular damage and permanent loss of vision secondary to operating microscope phototoxicity. Light damage to the eye can be thermal, mechanical, or photochemical and is dependent on source and wavelength of light, filters, and host factors. Removal of IOFB is important, but surgeons must be aware of potential light damage to the macula in lengthy surgical procedures and take appropriate precautions.


Disease resistance results from foreign phytoalexin expression in a novel plant.
Although phytoalexins have long been inferred to be important in the defence of plants against fungal infection, there are few reports showing that they provide resistance to infection. Several plants, including grapevine, synthesize the stilbene-type phytoalexin resveratrol when attacked by pathogens. Stilbenes with fungicidal potential are formed in several unrelated plant species, such as peanut (Arachis hypogaea), grapevine (Vitis vinifera) and pine (Pinus sylvestris). Stilbene biosynthesis only specifically requires the presence of stilbene synthase. Furthermore, the precursor molecules for the formation of hydroxy-stilbenes are malonyl-CoA and p-coumaroyl-CoA, both present in plants. To investigate the potential of stilbene biosynthetic genes in a strategy of engineering pathogen resistance, we isolated stilbene synthase genes from grapevine, where they are expressed at a high level, and transferred them into tobacco. We report here that regenerated tobacco plants containing these genes are more resistant to infection by Botrytis cinerea. This is, to our knowledge, the first report of increased disease resistance in transgenic plants based on an additional foreign phytoalexin.


Biventricular Outflow Obstruction Associated With Atrioventricular Septal Defects and Patent Ductus Arteriosus: An Extremely Rare Combination.
We present an extremely rare combination of biventricular outflow obstruction associated with atrioventricular septal defects and patent ductus arteriosus (PDA). Almost all the other published cases, including ours, were associated with other congenital cardiac lesions other than biventricular outflow obstruction. Most cases ended with poor outcomes. Our patient was a 55-day-old term female infant. She was managed by successful aortic balloon valvuloplasty with successful early outcome.


Spontaneous formation of the unlocked state of the ribosome is a multistep process.
The mechanism of substrate translocation through the ribosome is central to the rapid and faithful translation of mRNA into proteins. The rate-limiting step in translocation is an unlocking process that includes the formation of an "unlocked" intermediate state, which requires the convergence of large-scale conformational events within the ribosome including tRNA hybrid states formation, closure of the ribosomal L1 stalk domain, and subunit ratcheting. Here, by imaging of the pretranslocation ribosome complex from multiple structural perspectives using two- and three-color single-molecule fluorescence resonance energy transfer, we observe that tRNA hybrid states formation and L1 stalk closure, events central to the unlocking mechanism, are not tightly coupled. These findings reveal that the unlocked state is achieved through a stochastic-multistep process, where the extent of conformational coupling depends on the nature of tRNA substrates. These data suggest that cellular mechanisms affecting the coupling of conformational processes on the ribosome may regulate the process of translation elongation.


Phylogeny, floral evolution, and inter-island dispersal in Hawaiian Clermontia (Campanulaceae) based on ISSR variation and plastid spacer sequences.
Previous studies based on DNA restriction-site and sequence variation have shown that the Hawaiian lobeliads are monophyletic and that the two largest genera, Cyanea and Clermontia, diverged from each other ca. 9.7 Mya. Sequence divergence among species of Clermontia is quite limited, however, and extensive hybridization is suspected, which has interfered with production of a well-resolved molecular phylogeny for the genus. Clermontia is of considerable interest because several species posses petal-like sepals, raising the question of whether such a homeotic mutation has arisen once or several times. In addition, morphological and molecular studies have implied different patterns of inter-island dispersal within the genus. Here we use nuclear ISSRs (inter-simple sequence repeat polymorphisms) and five plastid non-coding sequences to derive biparental and maternal phylogenies for Clermontia. Our findings imply that (1) Clermontia is not monophyletic, with Cl. pyrularia nested within Cyanea and apparently an intergeneric hybrid; (2) the earliest divergent clades within Clermontia are native to Kauài, then Òahu, then Maui, supporting the progression rule of dispersal down the chain toward progressively younger islands, although that rule is violated in later-evolving taxa in the ISSR tree; (3) almost no sequence divergence among several Clermontia species in 4.5 kb of rapidly evolving plastid DNA; (4) several apparent cases of hybridization/introgression or incomplete lineage sorting (i.e., Cl. oblongifolia, peleana, persicifolia, pyrularia, samuelii, tuberculata), based on extensive conflict between the ISSR and plastid phylogenies; and (5) two origins and two losses of petaloid sepals, or--perhaps more plausibly--a single origin and two losses of this homeotic mutation, with its introgression into Cl. persicifolia. Our phylogenies are better resolved and geographically more informative than others based on ITS and 5S-NTS sequences and nuclear SNPs, but agree with them in supporting Clermontia's origin on Kauài or some older island and dispersal down the chain subsequently.


Antimicrobial activity of the surface coatings on TiAlZr implant biomaterial.
This study is devoted to antimicrobial activity of new surface coatings on TiAlZr. Ti alloys such as TiAlZr are used as implant biomaterials, but, despite the good behavior of such alloys in simulated conditions, bacterial infections appear after the introduction of an implant into the body. The infections are typically caused by the adherence and colonization of bacteria on the surfaces of the implants. The study presents preparation and surface morphology characterization of coatings obtained via anodizing, as well as biomimetic coatings with hydroxyapatite and silver ions with and without antibiotic. The percentage inhibition of Escherichia coli bacteria growth was evaluated for each of the studied coating, and a Trojan-horse model of silver nanoparticles (nAg) antibacterial activity at interface was proposed. Such coatings could be more important taking into account that antibacterial treatments with antibiotics are becoming less effective due to their intensive use.


[Expression patterns of ectodysplasin and ectodysplasin receptor during early dental development in zebrafish].
This study aims to study the expression patterns of ectodysplasin (EDA) and ectodysplasin receptor (EDAR) during the early development of zebrafish and provide a foundation for further research of the Eda signaling pathway in tooth development. Total RNA was extracted from zebrafish embryos at 48 hours postfertilization (hpf) and then reverse transcribed for cDNA library generation. The corresponding RNA polymerase was selected for the synthesis of the digoxin-labeled antisense mRNA probe of zebrafish pharyngeal tooth specific marker dlx2b and Eda signaling-associated genes eda and edar in vitro. The three sequences were ligated into a pGEMT vector with a TA cloning kit, and polymerase chain reaction (PCR) was applied to linearize the plasmid. The resultant PCR sequences were used as templates for synthesizing Dig-labeled mRNA probe dlx2b, eda, and edar. Zebrafish embryos were collected at 36, 48, 56, 60, 72, and 84 hpf, then whole mount in situ hybridization was performed for the detection of eda and edar expression patterns. Then, their expression patterns at 72 hpf were compared with the expression pattern of dlx2b. The mRNA antisense probes of dlx2b, eda, and edar were successfully obtained. The positive signals of eda and edar were observed in zebrafish pharyngeal tooth region at 48-72 hpf and thus conform to the signals of dlx2b in the positive regions. The ligand eda and edar, which are associated with the Eda signaling pathway, are strongly expressed only at the pharyngeal tooth region in zebrafish from tooth initiation to the morphogenesis stage. Thus, the Eda signaling pathway may be involved in the regulation of the early development of zebrafish pharyngeal teeth.


Cell death and mechanoprotection by filamin a in connective tissues after challenge by applied tensile forces.
Cells in mechanically challenged environments must cope with high amplitude forces to maintain cell viability and tissue homeostasis. Currently, force-induced cell death and the identity of mechanoprotective factors are not defined. We examined death in cultured periodontal fibroblasts, connective tissue cells that are exposed to heavy applied forces in vivo. Static tensile forces (0.48 piconewtons/microm2 cell area) were applied through magnetite beads coated with collagen or bovine serum albumin. There was a time-dependent increase of the percentage of propidium iodide-permeable cells in force-loaded cultures incubated with collagen but not bovine serum albumin beads, indicating a role for integrins. Cells exhibited reduced mitochondrial membrane potential, increased caspase-3 activation, nuclear condensation, terminal deoxynucleotidyl transferase nick end labeling staining, and detachment from the culture dish. The caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde reduced detachment 3-fold. There was a rapid (<10-s) decrease in plasma membrane potential after force application, which, in filamin A-deficient melanoma cells, contributed to irreversible cell depolarization. In fibroblast cultures, cells with increased permeability to propidium iodide exhibited approximately 2-fold less filamin A content than impermeable cells. Fibroblasts transfected with antisense filamin A constructs or with filamin A constructs without an actin-binding domain exhibited 2-3-fold increased proportions of dead cells relative to controls. We conclude that high amplitude forces delivered through integrins can promote apoptosis in a proportion of cells and that filamin A confers mechanoprotection by preventing membrane depolarization.


Renohepatic crosstalk: a review of the effects of acute kidney injury on the liver.
Several theories regarding acute kidney injury (AKI)-related mortality have been entertained, although mounting evidence supports the paradigm that impaired kidney function directly and adversely affects the function of several remote organs. The kidneys and liver are fundamental to human metabolism and detoxification, and it is therefore hardly surprising that critical illness complicated by hepatorenal dysfunction portends a poor prognosis. Several diseases can simultaneously impact the proper functioning of the liver and kidneys, although this review will address the impact of AKI on liver function. While evidence for this relationship in humans remains sparse, we present supportive studies and then discuss the most likely mechanisms by which AKI can cause liver dysfunction. These include 'traditional' complications of AKI (uremia, volume overload and acute metabolic acidosis, among others) as well as systemic inflammation, hepatic leukocyte infiltration, cytokine-mediated liver injury and hepatic oxidative stress. We conclude by addressing the therapeutic implications of these findings to clinical medicine.


New hope for children with Kawasaki disease.
Kawasaki disease is now the most common cause of acquired heart disease in America's children. It is an acute febrile illness that may cause coronary artery aneurysm formation in infected children. The results of a multicenter, randomized trial on the effect of intravenous administration of gamma globulin (IVGG) plus aspirin versus aspirin alone upon coronary aneurysm formation show a decrease in coronary aneurysm formation from the usual 20%-30% to 3%. Administration of IVGG presents some unique challenges for nurses. Also, the pediatric nurse must educate parents and children about this disease to prepare them for discharge and long-term follow-up care.


INHABIT: A web-based decision support tool for invasive plant species habitat visualization and assessment across the contiguous United States.
Narrowing the communication and knowledge gap between producers and users of scientific data is a longstanding problem in ecological conservation and land management. Decision support tools (DSTs), including websites or interactive web applications, provide platforms that can help bridge this gap. DSTs can most effectively disseminate and translate research results when producers and users collaboratively and iteratively design content and features. One data resource seldom incorporated into DSTs are species distribution models (SDMs), which can produce spatial predictions of habitat suitability. Outputs from SDMs can inform management decisions, but their complexity and inaccessibility can limit their use by resource managers or policy makers. To overcome these limitations, we present the Invasive Species Habitat Tool (INHABIT), a novel, web-based DST built with R Shiny to display spatial predictions and tabular summaries of habitat suitability from SDMs for invasive plants across the contiguous United States. INHABIT provides actionable science to support the prevention and management of invasive species. Two case studies demonstrate the important role of end user feedback in confirming INHABIT's credibility, utility, and relevance.


Upper eyelid contour symmetry measurement with Bézier curves.
The purpose of the present work is to measure the interocular upper lid contour symmetry using a new method of lid contour quantification. The Bézier curve tool of the Image J software was used to extract the right and left upper eyelid contours of 75 normal subjects. Inter-observer variability of 29 right lid contours obtained by two independent observers was estimated using the coefficient of overlap of two curves and an analysis of the differences of the contour peak location. A two-way analysis of variance was used to test the mean value of the coefficient of overlap of the right and left contours in males and females and lid segments. The same analysis was performed to compare the location of the contour peak of the right and left contours. The coefficient of contour overlap obtained by independent observers ranged from 93.5% to 98.8%, with a mean of 96.1% ± 1.6 SD. There was a mean difference of 0.02 mm in the location of the contour peak. Right and left contour symmetry did not differ between females and males and was within the range of the method variability for contour overlap and location of the contour peak. The upper eyelid contour is highly symmetrical. Bézier lines allow a quick and fast quantification of the lid contour, with a mean inter-observer variability of 3.9%.


Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor.
Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.


tRNAPyl: Structure, function, and applications.
Pyrrolysine is the 22nd proteinogenic amino acid encoded into proteins in response to amber (TAG) codons in a small number of archaea and bacteria. The incorporation of pyrrolysine is facilitated by a specialized aminoacyl-tRNA synthetase (PylRS) and its cognate tRNA (tRNAPyl). The secondary structure of tRNAPyl contains several unique features not found in canonical tRNAs. Numerous studies have demonstrated that the PylRS/tRNAPyl pair from archaea is orthogonal in E. coli and eukaryotic hosts, which has led to the widespread use of this pair for the genetic incorporation of non-canonical amino acids. In this brief review we examine the work that has been done to elucidate the structure of tRNAPyl, its interaction with PylRS, and survey recent progress on the use of tRNAPyl as a tool for genetic code expansion.


Experimental observation of Rabi oscillations in photonic lattices.
We demonstrate spatial Rabi oscillations in optical waveguide arrays. Adiabatic transitions between extended Floquet-Bloch modes associated with different bands are stimulated by periodic modulation of the photonic lattice in the propagation direction. When the stimulating modulation also carries transverse momentum, the transition becomes indirect, equivalent to phonon-assisted Rabi oscillations. In solid state physics such indirect Rabi oscillations necessitate coherent phonons and hence they have never been observed. Our experiments suggest that phonon-assisted Rabi oscillations are observable also with Bose-Einstein condensates, as well as with other wave systems-where coherence can be maintained for at least one period of the Rabi oscillation.


A General Three-Parameter Logistic Model With Time Effect.
Within the framework of item response theory, a new and flexible general three-parameter logistic model with response time (G3PLT) is proposed. The advantage of this model is that it can combine time effect, ability, and item difficulty to influence the correct-response probability. In contrast to the traditional response time models used in educational psychology, the new model incorporates the influence of the time effect on the correct-response probability directly, rather than linking them through a hierarchical method via latent and speed parameters as in van der Linden's model. In addition, the Metropolis-Hastings within Gibbs sampling algorithm is employed to estimate the model parameters. Based on Markov chain Monte Carlo output, two Bayesian model assessment methods are used to assess the goodness of fit between models. Finally, two simulation studies and a real data analysis are performed to further illustrate the advantages of the new model over the traditional three-parameter logistic model.


Domestication modulates the expression of genes involved in neurogenesis in high-quality eggs of Sander lucioperca.
Pikeperch, Sander lucioperca, is a species of high interest to the aquaculture. The expansion of its production can only be achieved by furthering domestication level. However, the mechanisms driving the domestication process in finfishes are poorly understood. Transcriptome profiling of eggs was found to be a useful tool allowing understanding of the domestication process in teleosts. In this study, using next-generation sequencing, the first pikeperch transcriptome has been generated as well as pikeperch-specific microarray comprising 35,343 unique probes. Next, we performed transcriptome profiling of eggs obtained from wild and domesticated populations. We found 710 differentially expressed genes that were linked mostly to nervous system development. These results provide new insights into processes that are directly involved in the domestication of finfishes. It can be suggested that all the identified processes were predetermined by the maternally derived set of genes contained in the unfertilized eggs. This allows us to suggest that fish behavior, along with many other processes, can be predetermined at the cellular level and may have significant implications on the adaptation of cultured fish to the natural environment. This also allows to suggest that fish behavior should be considered as a very important pikeperch aquaculture selection trait.


Complete mitochondrial genome of the mulberry psyllid Paurocephala sauteri Enderlein (Hemiptera: Psyllidae) and phylogenetic analysis.
Paurocephala sauteri (Enderlein, 1914) (Hemiptera: Psyllidae) is a species of a psyllid distributed in Asia. Mulberry is the only known host for P. sauteri until now. The complete mitogenome of P. sauteri (accession number: MT759765) 14,963 bp in size, including 13 protein-coding genes, 22 transfer RNAs, and two ribosomal RNAs genes. The base composition of the whole P. sauteri mitogenome is 40.26% for A, 7.86% for G, 34.07% for T, and 11.81% for C, with a high AT bias of 80.33%. The mitochondrial genome of P. sauteri was sequenced and annotated as the first representative of family Paurocephalidae. The present data could contribute to a detailed phylogeographic analysis of this valuable economic insect for further study in differentiating closely related species.


Eosinophilic granuloma of the mandible involving the periodontal tissues. A case report.
This case reports on a 14-year-old boy with multiple radiolucent lesions widely distributed in the mandible, particularly in the right side (body-angle-ascending ramus). The lesion was first diagnosed as early-onset periodontitis and treated accordingly. It continued to grow very quickly, however, over a 6-month period, resulting in involvement of the entire mandible, with complete destruction of the lingual cortical bone, erosion of the external cortex with expansion in the neighboring soft tissues, and with a periosteal reaction in some areas. This case may serve to illustrate the rapid progress of eosinophilic granuloma, the importance and the difficulties of an early diagnosis, and the consequences of late diagnosis and treatment.


Characterization of human epithelial resident memory regulatory T cells.
Human resident memory regulatory T cells (Tregs) exist in the normal, noninflamed skin. Except one, all previous studies analyzed skin Tregs using full-thickness human skin. Considering that thick dermis contains more Tregs than thin epidermis, the current understanding of skin Tregs might be biased toward dermal Tregs. Therefore, we sought to determine the phenotype and function of human epidermal and epithelial Tregs. Human epidermis and epithelium were allowed to float on a medium without adding any exogenous cytokines and stimulations for two days and then emigrants from the explants were analyzed. Foxp3 was selectively expressed in CD4+CD103- T cells in the various human epithelia, as it is highly demethylated. CD4+CD103-Foxp3+ cells suppressed proliferation of other resident memory T cells. The generation and maintenance of epithelial Tregs were independent of hair density and Langerhans cells. Collectively, immune-suppressive CD4+CD103-Foxp3+ Tregs are present in the normal, noninflamed human epidermis and mucosal epithelia.


PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK).
Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism.


Prevalence, clinical characteristics, and risk factors of Barrett esophagus in Vietnamese patients with upper gastrointestinal symptoms.
The current barrier for investigation of Barrett esophagus (BE) in Asia is diagnostic standardization, which is a challenge to identify its true risk factors. This study aimed to investigate the prevalence, clinical characteristics and risk factors of BE in Vietnamese patients with upper gastrointestinal symptoms.A cross-sectional study was conducted on consecutive outpatients who underwent upper gastrointestinal endoscopy. Endoscopically suspected esophageal metaplasia (ESEM) which was clearly visible at least 1 cm above the gastroesophageal junction at endoscopy was taken biopsy. At least 1 biopsy per 2 cm in tongues of ESEM and 4 biopsies per 2 cm of circumferential ESEM were taken. The diagnostic criterion for BE was replacement of the normal squamous epithelial lining by columnar epithelium confirmed by histology.A total of 1947 patients were recruited. Forty-seven out of 58 patients with ESEM were histologically confirmed BE. The prevalences of BE and hiatal hernia (HH) were 2.4% (95% confidence interval [CI], 1.7-3.1%) and 2.3% (95% CI, 1.6-2.9%), respectively. Heartburn and/or regurgitation presented in only 61.7% (95% CI, 46.4-75.5%) of patients with BE. In multivariate analysis, the only 2 factors significantly associated with BE were HH (OR 7.53; 95% CI, 3.13-18.11; P < .001) and typical reflux symptom (OR 2.07; 95% CI, 1.12-3.83; P = .020).BE is not uncommon in Vietnamese patients with upper gastrointestinal symptoms. In addition, typical reflux symptoms and HH are the risk factors for BE in Vietnamese.


Stimulation of hyphal growth in anaerobic cultures of Mucor rouxii by extracellular trehalose. Relevance of cell wall-bound activity of acid trehalase for trehalose utilization.
In fungi, the hydrolysis of extracellular trehalose is carried out by acid trehalases. These secretory glycoproteins may be more abundant either in the vacuolar compartment, like in yeast, or at the cell surface, such as in many filamentous fungi. The relative efficiency of these two compartments for the utilization of extracellular trehalose was investigated using as a model the dimorphic fungus Mucor rouxii, which produces yeast-like cells under a CO(2) atmosphere, or hyphae in the presence of air. Under CO(2), cultures supplemented with glucose produced yeast-like cells devoid of acid trehalase activity. On the other hand, trehalose-supplemented cultures developed hyphae exhibiting cell wall-bound and intracellular acid trehalase activity. Glucose-grown yeast-like cells supplemented with trehalose after glucose exhaustion, induced intracellular activity of acid trehalase, but no activity was detected at the cell surface. Even endowed of significant intracellular activity of acid trehalase, these cells did not grow further. When exposed to air these yeast-like produced germ tubes exhibiting cell wall-bound acid trehalase activity. These results suggest that the utilization of extracellular trehalose as a source of carbon for growth requires the localization of acid trehalase activity at the cell surface. Our results also show that extracellular trehalose elicits a morphogenetic phenomenon, inducing the formation of hyphae which are the physiological support for acid trehalase activity.


Prospective analysis of the distal margin of clearance in anterior resection for rectal carcinoma.
The distal resection margin measured in situ at operation, on the fresh specimen and on the fixed specimen was analysed prospectively in 55 consecutive patients undergoing anterior resection for carcinoma of the rectum. There was obvious contraction in length from the operative margin to the specimen margin and to the fixed margin. As measured by contraction coefficients, contraction was greater in more proximal tumours than in distal ones. Eight of 55 patients had microscopic intramural spread in the fixed distal margin and the maximum spread was 12 mm. Taking contraction of the fixed margin into account, the extrapolated microscopic spread in the operative margin ranged from 0 to 47 mm.


Subtraction of 16.67 Hz railroad net interference from the electrocardiogram: application for automatic external defibrillators.
The widespread application of automatic external defibrillators (AEDs) for treating out-of-hospital cardiac arrest incidents and their particular use at railway stations defines the task for 16.67 Hz power line interference elimination from the electrocardiogram (ECG). Although this problem exists only in five European countries, it has to be solved in all AEDs, which must comply with the European standard for medical equipment requirements for interchangeability and compatibility between rail systems. The elimination of the railroad interference requires a specific approach, since its frequency band overlaps with a significant part of the frequencies in the QRS spectra. We present a method based only on one channel ECG signal processing, which effectively subtracts the interference components. The computation procedure is based on simple signal processing tools, which include: (i) bi-directional band-pass filtering (13-23 Hz) of the analyzed ECG segment; (ii) estimation of adequate linearity thresholds; (iii) frequency measurement and calculation of dynamic interference buffer in linear segments and (iv) phase synchronization and subtraction technique in nonlinear segments. The developed method has proved advantageous in providing sufficient quality of the output interference free ECG signal for seven defined arrhythmia types (normal sinus rhythm, normal rhythm, supraventricular tachicardia, slow/rapid ventricular tachycardia, and coarse/fine ventricular fibrillation), and simulated interferences with constant or variable frequencies and amplitudes, which cover the entire amplitude range of the input channel. The procedure is suitable to be embedded in AEDs as a preprocessing branch, which proves reliable for analysis of ECG signals, thus guaranteeing the specified accuracy of the AED automatic rhythm analysis algorithms.


Highly enantioselective intramolecular cyanoamidation: (+)-horsfiline, (-)-coerulescine, and (-)-esermethole.
The first asymmetric cyanoamidation with synthetically useful enantioselectivity (ee up to 99%) to produce 3,3-disubstituted oxindoles is reported. Palladium catalysts with chiral phosphoramidite ligands activate the cyanoformamide C-CN bond, which is subsequently functionalized with a tethered alkene to give all-carbon quaternary stereocenters. The use of the N,N-(i-Pr)(2) derivative of octahydro-MonoPhos allowed the production of oxindoles with high enantioselectivities. Cyanoformamides bearing free N-H groups are now tolerated, potentially allowing protecting-group-free synthesis. Oxindole products of cyanoamidation are rapidly transformed into (+)-horsfiline, (-)-coerulescine, and (-)-esermethole.


[Clinical review of pneumothorax cases complicated with active pulmonary tuberculosis].
Pneumothorax is an important and dangerous complication of pulmonary tuberculosis. Forty-six pneumothorax cases complicated with active pulmonary tuberculosis at National Chiba-Higashi Hospital were studied retrospectively. From Jan. 1987 to Dec. 1997, we experienced 3611 patients with pulmonary tuberculosis, and among them 46 patients (18-90 years old, 38 males and 8 females) had pneumothorax. On admission, 33 out of 46 cases (71.7%) were smear positive by sputum examination of mycobacteria and 41 out of 46 cases (89.1%) had cavitary lesions on chest X-ray. Eleven cases had mild pneumothorax, thirty-two had moderate, and three had severe. Pneumothorax was present on admission in 23 patients and developed during treatment for tuberculosis in the other 23 patients. Eleven patients were treated with bed rest alone, four were thoracentesis and aspiration, twenty-four were intrathoracic tube drainage and seven were operated. Thirty-one patients were recovered, but fifteen passed away, among them 13 due to respiratory failure. The Prognostic nutritional index (PNI; 10 x serum albumin concentration +0.005 x peripheral lymphocyte count) which was proposed by Onodera, serum albumin level and Body mass index were lower in the fatal group than in the survival group. We consider these indices are useful to evaluate the prognosis of active tuberculosis patients complicated with pneumothorax.


[The changes in TNF alpha in plasma, organs and eschar of rats after thermal injury].
The TNF alpha (Tumor Necrosis Factor-alpha) contents in the plasma, five organs (heart, lung, liver, kidney and intestine) and burned skin were measured by ELISA method in Wistar rats with 35% TBSA III degrees. The animals were divided into eight different time groups. The experiment showed that TNF alpha contents were excessively high in early stage of burn (24 hours postburn) in plasma, eschar and the five organs. The contents of TNF alpha in eschar were 27.5-86.7 times higher than that in plasma and the five organs.


Management of adult rhinosinusitis.
Rhinosinusitis is an inflammation of the nasal mucosa and paranasal sinuses, affecting more than 31 million Americans. Acute rhinosinusitis lasts up to 4 weeks and results from infection. Chronic rhinosinusitis lasts 12 or more weeks and is caused by various inflammatory processes. Symptoms may be similar, but management options differ.


Sex-related differences in urinary excretion of egualen sodium in rats.
Egualen sodium (sodium 3-ethyl-7-isopropyl-1-azulenesulfonate 1/3 hydrate) is a new antiulcer drug. There has been no difference observed in absorption between male and female rats, the relative amount of metabolites in male plasma has been higher than that in females, and the excretion ratios of metabolites in males have been significantly higher than those in females. However, the plasma concentration profile of total radioactivity in males has been higher than that in females. To clarify this discrepancy, the renal clearances and plasma concentrations of the unchanged drug and its metabolites were determined. The renal clearance of the unchanged drug in males was 21 times lower than that in females, and the urinary excretions in males and females were 2.1 and 39.5% of dose, respectively. This indicates that the major factor in the sex-related difference observed in the plasma concentration of total radioactivity is due to the difference in the renal clearance of the unchanged drug between the sexes. The results of treatments with probenecid in normal and gonadectomized rats revealed that egualen sodium was mainly excreted into urine by secretion through the renal tubule. Furthermore, the results of treatments with testosterone in rats revealed that the excretion of egualen sodium was highly affected by androgens. These facts indicated that the sex-related difference observed in the plasma concentration of total radioactivity can be attributed to the inhibition of renal tubular secretion of the unchanged drug by androgens. This is the first example of sex-related differences in both metabolism and excretion.


Large-Beam Picosecond Interference Patterning of Metallic Substrates.
In this paper, we introduce a method to efficiently use a high-energy pulsed 1.7 ps HiLASE Perla laser system for two beam interference patterning. The newly developed method of large-beam interference patterning permits the production of micro and sub-micron sized features on a treated surface with increased processing throughputs by enlarging the interference area. The limits for beam enlarging are explained and calculated for the used laser source. The formation of a variety of surface micro and nanostructures and their combinations are reported on stainless steel, invar, and tungsten with the maximum fabrication speed of 206 cm2/min. The wettability of selected hierarchical structures combining interference patterns with 2.6 µm periodicity and the nanoscale surface structures on top were analyzed showing superhydrophobic behavior with contact angles of 164°, 156°, and 150° in the case of stainless steel, invar, and tungsten, respectively.


Homologous Cloning of Potassium Channel Genes From the Superior Apple Rootstock Line 12-2, Which is Tolerant to Apple Replant Disease.
Potassium channels are important ion channels that are responsible for the absorption of potassium in the plant nutrient uptake system. In this study, we used homologous molecular cloning to obtain 8 K+ channel genes from the superior apple rootstock line 12-2 (self-named): MsAKT1-1, MsKAT3-2, MsKAT1-3, MsK2P3-4, MsK2P3-5, MsK2P5-6, MsK2P3-7, and MsK2P3-8. Their lengths varied from 942 bp (MsK2P5-6) to 2625 bp (MsAKT1-1), and the number of encoded amino acids varied from 314 (MsK2P5-6) to 874 (MsAKT1-1). Subcellular localization predictions showed that MsAKT1-1, MsKAT3-2, and MsKAT1-3 were localized on the plasma membrane, and MsK2P3-4, MsK2P3-5, MsK2P5-6, MsK2P3-7, and MsK2P3-8 were localized on the vacuole and plasma membrane. The 8 K+ channel proteins contained α helices, extended strands, β turns, and random coils. MsKAT1-3 had four transmembrane structures, MsKAT3-2 had six, and the other six K+ channel genes had five. Protein structure domain analysis showed that MsAKT1-1 contained nine protein domains, followed by MsKAT3-2 with four, MsKAT1-3 with three, and the other five two-pore domain K+ channel proteins with two. Semi-quantitative RT-PCR detection of the K+ channel genes showed that their expression levels were high in roots. qRT-PCR analysis showed that the relative expression levels of the 8 genes changed after exposure to ARD stress. The above results provide a theoretical basis for further research on the functions of potassium channel genes in 12-2 and a scientific basis for the breeding of ARD-resistant rootstock.


Protein-linked glycans in periodontal bacteria: prevalence and role at the immune interface.
Protein modification with complex glycans is increasingly being recognized in many pathogenic and non-pathogenic bacteria, and is now thought to be central to the successful life-style of those species in their respective hosts. This review aims to convey current knowledge on the extent of protein glycosylation in periodontal pathogenic bacteria and its role in the modulation of the host immune responses. The available data show that surface glycans of periodontal bacteria orchestrate dendritic cell cytokine responses to drive T cell immunity in ways that facilitate bacterial persistence in the host and induce periodontal inflammation. In addition, surface glycans may help certain periodontal bacteria protect against serum complement attack or help them escape immune detection through glycomimicry. In this review we will focus mainly on the generalized surface-layer protein glycosylation system of the periodontal pathogen Tannerella forsythia in shaping innate and adaptive host immunity in the context of periodontal disease. In addition, we will also review the current state of knowledge of surface protein glycosylation and its potential for immune modulation in other periodontal pathogens.


The complete mitochondrial genome of Parabotia fasciata (Cypriniformes: Cobitidae).
Parabotia fasciata is a small-sized benthopelagic fish species in the family Cobitidae. In the present study, we reported the complete mitochondrial genome of P fasciata. The complete mitochondrial genome of P. fasciata was 16,590 bp in length, which contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, a control region, and an L-strand replication origin (OL). Besides, its overall nucleotide base composition of mitogenome was 31.28% for A, 25.83% for T, 15.72% for G and 27.17% for C, as well as an AT content of 57.11%.


Association of IL4 single-nucleotide polymorphisms with febrile seizures.
As of importance of interleukin-4 (IL-4) in inhibiting the production of proinflammatory cytokines, the IL4 gene polymorphisms were investigated in patients with febrile seizure. This association has not been investigated yet, except 1 study which has been done in Japanese population. Eighty-two patients with febrile seizure were enrolled in this study, compared with 139 controls. The allele and genotype frequency of 3 single-nucleotide polymorphisms of IL4 gene were determined. Frequency of the IL4-590/C allele in the patient group was significantly higher than in the control group (P < .0001). Frequency of the following genotypes was significantly lower in patients compared to controls: IL-4 (-590) TC (P = .0001) and IL-4 (-33) TC (P = .001). The most frequent IL-4 haplotype in the patient group was TCC (P = .00) haplotype. In contrast, frequencies of GCC (P = .01), TTT (P = .009), and TTC (P = .0007) haplotypes were significantly lower in febrile seizure patients. Certain alleles, genotypes, and haplotypes in the IL4 gene were overrepresented in Iranian patients with febrile seizure, which could predispose individuals to this disease, and further investigations in other ethnicities are required.


A huge intracardiac thrombus developed in the presence of antithrombin III deficiency in a patient with end-stage renal failure.
In this study, we report a 15-year-old female with end-stage renal disease undergoing hemodialysis, who admitted with acute respiratory failure and generalized edema. Abdominal tomography detected thrombi in the right renal vein, in the hepatic segment of the inferior vena cava and in iliac veins. Levels of proteins C and S, antinuclear antigen, anti-dsDNA, C3, and C4 were in normal limits. The thrombi persisted despite treatment with nadroparin, heparin with fresh frozen plasma and warfarin. Due to heparin resistance, antithrombin III levels were measured and were found abnormally low. The first echocardiographic examination was in normal limits but the second echocardiography revealed a huge thrombus occluding the tricuspid valve. Urgent thrombectomy was planned but the patient died in the intensive care unit due to severe pulmonary edema.


Breeding System and Response of the Pollinator to Floral Larceny and Florivory Define the Reproductive Success in Aerides odorata.
Consumption of pollination reward by felonious means in a plant species can influence the foraging behavior of its pollinator and eventually the reproductive success. So far, studies on this aspect are largely confined to interaction involving plant-pollinators and nectar robbers or thieves. However, a foraging guild in such interactions may also include floral herbivores or florivores. There is a paucity of information on the extent to which nectar larcenists may influence the foraging behavior of the pollinator and reproductive fitness of plants in the presence of a florivore. We investigated various forms of larceny in the natural populations of Aerides odorata, a pollinator-dependent and nectar-rewarding orchid. These populations differed in types of foraging guild, the extent of larceny (thieving/robbing), which can occur with or without florivory, and natural fruit-set pattern. The nectariferous spur of the flower serves as an organ of interest among the foraging insects. While florivory marked by excision of nectary dissuades the pollinator, nectar thieving and robbing significantly enhance visits of the pollinator and fruit-set. Experimental pollinations showed that the species is a preferential outbreeder and experiences inbreeding depression from selfing. Reproductive fitness of the orchid species varies significantly with the extent of floral larceny. Although nectar thieving or robbing is beneficial in this self-compatible species, the negative effects of florivory were stronger. Our findings suggest that net reproductive fitness in the affected plant species is determined by the overarching effect of its breeding system on the overall interacting framework of the foraging guild.


Single-dose ampicillin prophylaxis does not eradicate enterococcus from the lower genital tract.
To determine the carriage rate of enterococcus in the lower genital tract of women having a cesarean delivery and to determine whether a single 2-g intraoperative dose of ampicillin eradicates enterococcus from the lower genital tract. Lower genital tract cultures were taken in 84 women who were in labor or had ruptured membranes and who were about to have an indicated cesarean delivery. The subjects were randomized to receive either a single 2-g dose of ampicillin or a cephalosporin as prophylaxis. Cultures were repeated 24 hours postpartum. Enterococcus was isolated preoperatively in 33 subjects (39.3%) and postoperatively in 36 (42.9%). The enterococcus was eradicated in five of 17 women (29.5%) who received ampicillin. These results suggest that a single 2-g dose of ampicillin does not eradicate enterococcus from the lower genital tract.


Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and enalapril.
A 69-year-old woman with a history of diabetes and hypertension, was referred to the Hospital of Laredo because of hyponatraemia. She had weakness and slight dyspnoea with no evidence of extracellular fluid volume depletion or oedema. Serum sodium level on admission was 125 mol l-1, plasma osmolality 270 mosmol kg-1, simultaneous urine osmolality was 580 mosmol kg-1 and urine sodium 32.6 mmol l-1. She had been treated with enalapril (20 mg) daily for 4 months. She was diagnosed with the Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that was reversed after cessation of treatment with enalapril and reappeared on reintroduction of the drug at the same daily doses.


Immunoscintigraphy of the bone marrow: normal uptake values of technetium-99m-labeled monoclonal antigranulocyte antibodies.
The aim of our study was to determine the normal range of the 99mTc-labeled anti-NCA 95 antigranulocyte antibody (AGAb) uptake in the bone marrow using the sacroiliac-to-background uptake ratio in the posterior view. We made 169 planar bone marrow scans on 162 patients who were each injected with 555 MBq AGAb. Fifty patients with the diagnosis of infection/pyrexia of unknown origin (PUO) and with completely normal bone marrow scintigraphy were defined as the normal group. Uptake ratios were calculated drawing irregular regions of interest around the sacroiliac and a background area, respectively. The normal group revealed a mean uptake ratio of 7.3 +/- 2.3 (range 4.4-12.6). Similar uptake ratios were obtained in patients with the primary diagnosis of infection/PUO and bone marrow extension (7.4 +/- 2.2, range 4.2-11.7), suggesting that the bone marrow reacts on infection primarily by extension into the periphery, without any significant increase of the activity of the central hemopoietic/granulopoietic bone marrow. Mean uptake ratios also were not significantly different in patients with normal bone marrow scintigraphy and the primary diagnosis of solid malignant tumors, lymphomas and plasmacytomas, and in patients with focal lesions visible on bone marrow scintigraphy (soft tissue inflammation or cold lesions in the bone marrow but with normal sacroiliac regions). Mean uptake ratios in the normal group were significantly age related, amounting to 8.5 +/- 1.8, 7.5 +/- 1.9 and 6.1 +/- 2.0 in patients younger than 40 yr, between 40 and 59 yr, and 60 yr or older, respectively (p = 0.0025). The method revealed good inter- and intraobserver agreement with correlation coefficients of about r = 0.90 and r = 0.95, respectively. Inter- and intraobserver coefficients of variation were 6.6% and 4.6%, respectively. Determination of the bone marrow uptake ratio is simple and reproducible. The normal values established in this study were age dependent, which has to be considered when interpreting bone marrow uptake ratios. The presence of infection/PUO, solid malignant tumors, lymphomas and plasmacytomas does not seem to alter the AGAb uptake ratio significantly. The most important application of the quantitative analysis of bone marrow scintigraphy could be the diagnosis and follow-up of diseases with depression of the central hemopoietic activity.


The characteristics and outcomes of hospitalised and outpatient-treated first-onset schizophrenia patients: a 5-year register linkage study.
We compared the course and outcome of schizophrenia in two groups: (i) hospitalised patients (HP) (n = 5980) who were identified based on their first hospital admission for schizophrenia and (ii) outpatient-treated patients (OTP) who received disability pension because of schizophrenia but who had no hospital admissions for schizophrenia or other psychotic disorder before having been granted a disability pension for schizophrenia (n = 1220). Outcomes were compared using data on mortality, psychiatric hospital utilisation, relapse rate and occupational functioning. A nationwide register-based 5-year follow-up study of all first-onset schizophrenia cases between 1998 and 2003 in Finland. The data were linked with the register information of hospital admissions, disability pensions and National Causes of Death Registers. When outcome of treatment was evaluated using mortality rate, relapses, hospital treatment and involuntary admissions as outcome measures, results indicated that OTP group had got along better with their illnesses than HP group. The mortality rates, number of psychiatric treatment days and relapse rate during the 5-year follow up were significantly lower in OTP group. Within the OTP group, there was a notable subgroup of never HP (n = 737, 60.4%), who did not require any psychiatric hospitalisation during the 5-year follow up. Patients first identified as outpatients had better outcomes than patients first identified following a hospitalisation. Future studies are required to establish whether outpatient treatment is associated with more favourable prognosis, even after fully adjusting for severity of initial symptoms. The higher suicide mortality of hospital-treated patients suggests that hospital treatment of first-onset patients does not protect from suicide.


Interventional neuroangiography in neonates.
Two neonates with either vein of Calen aneurysmal malformation or dural sinus malformation (congenital dural arteriovenous fistula at the torcular herophili) are reported. In neonatal interventional neuroangiography, special attention should be paid to body temperature, contrast material, infusion fluid, heparin, and angio-equipment. In the neonatal period, the umbilical approach provides unique access routes to both arterial and venous sides of the cerebral circulation. Among them, transumbilical venous, transcardiac approach through the foramen ovale allows transarterial intervention from the venous side.


A survey of interfering shoulder pain in United States competitive swimmers.
The prevalence of shoulder pain in United States competitive swimmers has not been extensively surveyed but is perceived as common. To evaluate this concern, a questionnaire survey was conducted on 1262 United States swimmers: 993 age group, 198 senior development, and 71 national team athletes. We sought to identify the incidence of interfering shoulder pain in this population and how it is influenced by various training tasks. The prevalence of current shoulder pain in these groups varied between 10% (age group) to 26% (national team) and increased with time in the sport. In those athletes with a painful shoulder, weight training, use of hand paddles, kickboard use, stretching, and various resistance activities aggravated the painful shoulder. This survey has identified that interfering shoulder pain is present in a substantial number of competitive swimmers.


Comparison between thymidylate synthase B of Bacillus subtilis ATCC6633 and 168.
Bacillus subtilis 168 possesses two thymidylate synthase genes: thyA and thyB, encoding for a thermolabile and a thermostable enzyme respectively. B. subtilis ATCC6633 also possesses two thy genes, both producing thermostable enzymes. A comparison of the thymidylate synthase B amino acid sequences from the two strains shows, among others, a Pro to Ala mutation which may affect the dUMP binding site. The apparent Km and Vmax values for dUMP and tetrahydrofolate were determined at a permissive temperature for both enzymes. The kinetic data showed a significant difference in the Km, but not in the Vmax, for dUMP between the two enzymes. The Km and Vmax for tetrahydrofolate were very similar.


[Role of magnetic resonance imaging for response evaluation and predictive value of tumor biomarkers in the neoadjuvant chemotherapy for breast cancer:a multi-center prospective study].
To explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in monitoring therapy responses and analyze the predictive value of tumor biomarkers in neoadjuvant chemotherapy for breast cancer. From August 2010 to August 2013, the patients diagnosed as primary invasive breast cancer were admitted into this multi-center study. All of them received 6 cycles of neoadjuvant chemotherapy and DCE-MRI during the procedure and underwent surgery. The associations between clinical therapy response and pathologic response as well as predictive factors were analyzed. As for evaluating neoadjuvant treatment response, DCE-MRI had statistically significant correlations with histopathology. PR negativity, HER-2 over-expression and high Ki-67 index were statistically correlated with pathologic complete response (pCR) (P < 0.05). DCE-MRI is a reliable method of assessing the response of neoadjuvant therapy for breast cancer. And the immunohistochemistry status of PR, HER-2 and Ki-67 were related with pCR.


Analysis of the effects of candesartan in the mesenteric vascular bed of the cat.
The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 microg/kg i.v.. After administration of the AT1 receptor antagonist in a dose of 3 microg/kg i.v., the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT1 receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, alpha,beta-methylene ATP, adenosine, acetylcholine, and bradykinin. Treatment with the AT2 receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan on responses to angiotensin II. Candesartan also decreased pressor responses to angiotensin III and IV with a parallel shift at the low dose and a nonparallel shift to the right of the dose-response curve at the high dose. These results indicate that candesartan is a potent, selective, long-acting AT1 receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.


[Raman spectroscopy study of the effect of H+ on the oxygen affinity capacity of hemoglobin].
The hemoglobin was extracted from the blood which was provided by the healthy volunteers and the impact of the pH on hemoglobin oxygen binding capacity was studied with microscopic Raman spectroscopy. The results indicated that: under the excitation light of 514.5 nm, with the reducing of the oxygen partial pressure (PO2), the Raman peak intensity at 1 375, 1 562, 1 585 and 1 638 cm(-1) of the control hemoglobin (pH 7.4) reduced gradually, among which, the change of the 1 375 and 1 638 cm(-1) were the most significant and had a good relevance with the PO2. The curves were plotted by regarding the PO2 as the x-axis and the Raman absolute intensity as the y-axis, and the relationship between hemoglobin Raman absolute intensity of the 1 375 and 1 638 cm(-1) and their related PO2 levels when the pH was 5.7, 7.4 and 8.0 respectively were analyzed. The data was well linear fitted and the fitting equation was obtained. The relationship of the slope (Raman intensity/PO2 level) among them were K8.0 > K7.4 > K5.7, indicating that the lower the pH, the easier the release of the oxygen molecules. It was showed that the Raman spectroscopy technique could be used to detect the oxygen binding rate of hemoglobin quantitatively, and the effect of the PH on oxygen binding state of hemoglobin could be observed, which could provide a new method and make a foundation for the monitoring of the PO2 levels in the blood, as well as the research on the regulatory factors of the blood oxygen affinity, such as H+ and CO2.


[Cardiotoxic effects of breast cancer chemotherapy and their possible correction].
Clinical data are reported upon the examination of a group of 160 women aged 18-55, suffering of a breast cancer and subjected to polychemotherapy using various cytostatic schemes: (I) standard CAF scheme, course repetition each 4 weeks; (II) alternating CAF and AVCFM schemes (intermittent introductions), a total of 4 courses. For the reduction of the cardiotoxic effects of anthracyclines, one part of patients was given an antioxidant preparation of amber acid--Reamberin--whose administration substantially decreased both the frequency of cardial complaints and the expression of clinical manifestations of the astheno-neurotic syndrome and prevented the occurrence of systolic and diastolic dysfunction of myocardium and the heart rhythm and conductivity disturbances.


L-dopa in the treatment of negative schizophrenic symptoms: a single-subject experimental study.
Adjunctive Sinemet (L-DOPA plus carbidopa) therapy was assessed for a neuroleptic nonresponsive schizophrenic with a longstanding negative syndrome. A twenty-seven week double-blind placebo-controlled reversal design found significant improvement specifically for negative symptoms while treated with combined haloperidol-Sinemet as compared against haloperidol-placebo. The eight-week adjunctive treatment reversed a worsening trend in attention, abstract thinking, passive withdrawal, psychomotor retardation, and a cluster of seven negative parameters, while positive symptoms were unaffected. This seemed to represent more than simple reversal of drug-induced akinesia and underscores the importance of distinguishing between positive and negative syndromes in psychopharmacological research.


Autoimmune hepatitis and overlap syndromes.
Autoimmune hepatitis is a well-established chronic liver disease. It primarily affects women, is characterized by circulating autoantibodies and elevated gammaglobulins and is associated with extrahepatic immune-mediated syndromes. Treatment regimens have remained unchanged for a number of years because of the high efficacy of steroid monotherapy, or combination therapy of azathioprine and steroids. In approximately 90% of patients remission of the disease is reached by medical therapy, which is usually administered lifelong because long-term remission after drug withdrawal is achieved in only 17% of patients. In 10% of patients treatment failure is observed. The challenge of remission induction involves the use of transplant immunosuppressants such as cyclosporine, mycophenolate moffetil, and tacrolimus. The challenge of maintenance therapy minimizing steroid side-effects involves the evaluation of topical steroids and the use of azathioprine monotherapy. Overlap syndromes occur in approximately 20% of autoimmune liver diseases. The diagnosis is broadly based on serological, biochemical, clinical and histological parameters. Most common are the overlap of autoimmune hepatitis and primary biliary cirrhosis, as well as autoimmune hepatitis with primary sclerosing cholangitis. These yet incompletely defined syndromes are an important differential diagnosis in the difficult-to-treat patient with autoimmune hepatitis.


Characterization of monoclonal antibodies against the human immunodeficiency virus matrix protein, p17gag: identification of epitopes exposed at the surfaces of infected cells.
Eight monoclonal antibodies reactive with the matrix protein of human immunodeficiency virus type 1 (HIV-1), p17gag, were isolated from rats which had been immunized with solubilized HIV-1 lysate. The epitope specificities of these antibodies were determined with a series of synthetic peptides representing overlapping regions of p17. Six of the antibodies were mapped to three distinct regions of p17, while two antibodies (G11g1 and G11h3) reacted only with intact recombinant p17, suggesting that they were directed against conformational or discontinuous epitopes. All the antibodies bound to HIV-infected cells which had been permeabilized with acetone, but only G11g1 and G11h3 reacted with live HIV-infected cells. Specificity studies with diverse virus strains demonstrated that these two antibodies recognized distinct epitopes, one which was group specific for HIV-1, and one which was shared with HIV type 2 and simian immunodeficiency virus. Binding competition studies indicated that these epitopes were proximal in native p17. Despite their reactivity with intact cells, these two antibodies did not possess appreciable virus-neutralizing activity. These results indicate that a form of p17 is expressed on the surfaces of live HIV-infected cells which is accessible to some, but not all, antibodies against p17. These cell surface molecules may play a role in the generation of antibodies against p17gag that are characteristic of early stages of HIV infection, and they may act as natural targets for the immune system and as potential targets for immunotherapy of HIV-infected cells.


N-substituted Indole-2 and 3-carboxamide derivatives as inhibitors of human protein kinase CK2: in vitro assay and molecular modelling study.
Protein kinase CK2 (Casein Kinase 2) is involved in cell growth; proliferation and suppression of apoptosis. Hence, it strongly promotes cell survival and can be considered an important target for human cancers. In the present study, a series of N-substituted indole-2- and 3-carboxamide derivatives were tested for inhibitions of human recombinant protein kinase CK2 to evaluate their anticancer properties. The inhibition test revealed that the most active compound 4 (1-benzyl-N-(2,4-dichlorobenzyl)-1H-indole-2-carboxamide) showed an IC50 value of 14.6 µM towards human protein kinase CK2. A molecular docking study of the compounds with CK2 was performed and revealed the binding mode of the most active compound 4, underlying its inhibitory activity.


Characteristics and outcomes of patients with community-acquired and hospital-acquired sepsis.
To compare the clinical characteristics and outcomes of patients with community-acquired and hospital-acquired sepsis. This is a retrospective cohort study that included all patients with a diagnosis of sepsis detected between January 2010 and December 2015 at a private hospital in southern Brazil. Outcomes (mortality, intensive care unit and hospital lengths of stay) were measured by analyzing electronic records. There were 543 hospitalized patients with a diagnosis of sepsis, with a frequency of 90.5 (85 to 105) cases/year. Of these, 319 (58%) cases were classified as hospital-acquired sepsis. This group exhibited more severe disease and had a larger number of organ dysfunctions, with higher hospital [8 (8 - 10) versus 23 (20 - 27) days; p < 0.001] and intensive care unit [5 (4 - 7) versus 8.5 (7 - 10); p < 0.001] lengths of stay and higher in-hospital mortality (30.7% versus 15.6%; p < 0.001) than those with community-acquired sepsis. After adjusting for age, APACHE II scores, and hemodynamic and respiratory dysfunction, hospital-acquired sepsis remained associated with increased mortality (OR 1.96; 95%CI 1.15 - 3.32, p = 0.013). The present results contribute to the definition of the epidemiological profile of sepsis in the sample studied, in which hospital-acquired sepsis was more severe and was associated with higher mortality.


Assessing cost savings when unnecessary utilization of laboratory tests can be abolished.
The authors report on the theoretic cost savings that would be realized if presumed overutilization of selected laboratory tests could be eliminated. They limit the scope of this study to inpatients at the University Hospital and on a preselected subset of assays ordered in their institution. A baseline audit including the requests for 19 commonly ordered clinical chemistry tests made for all inpatients during three weekdays was performed at our 400-bed hospital. Eight of the 19 tests (the LYTES-Plus), were done on the ASTRA-8 selective multitest analyzer (Beckman Instruments Inc., Brea, CA 92621), while remaining 11 tests (MTA-11) were performed on the RA-1000 selective multitest system (Technicon Instruments Corp., Tarrytown, NY 10591). The average tests ordered per patient-day were 4.38 of the 19, and the average venipunctures were 0.67. The corresponding numbers for the intensive care patients were 16.6 tests and 2.45 venipunctures per patient-day. Although the intensive care units contributed approximately 8% of the patient days in the hospital, they represented more than 25% of the tests ordered. The authors noted that 5.89 of the eight possible LYTES-Plus assays were ordered per ASTRA-8 sample. The equivalent figure for MTA-11 was 4.55 of 11 possible tests. Using list prices of reagents and disposables, the savings in direct material costs resulting from implementing a number of rather conservative recommendations for decreasing overutilization was estimated to be $45,000 per annum or 31% of the total direct material costs.


Modeling to Evaluate Contribution of Oil and Gas Emissions to Air Pollution.
Oil and gas production in the Western United States has increased considerably over the past 10 years. While many of the still limited oil and gas impact assessments have focused on potential human health impacts, the typically remote locations of production in the Intermountain West suggests that the impacts of oil and gas production on national parks and wilderness areas (Class I and II areas) could also be important. To evaluate this, we utilize the Comprehensive Air quality Model with Extensions (CAMx) with a year-long modeling episode representing the best available representation of 2011 meteorology and emissions for the Western United States. The model inputs for the 2011 episodes were generated as part of the Three State Air Quality Study (3SAQS). The study includes a detailed assessment of oil and gas (O&G) emissions in Western States. The year-long modeling episode was run both with and without emissions from O&G production. The difference between these two runs provides an estimate of the contribution of the O&G production to air quality. These data were used to assess the contribution of O&G to the 8 hour average ozone concentrations, daily and annual fine particulate concentrations, annual nitrogen deposition totals and visibility in the modeling domain. We present the results for the Class I and II areas in the Western United States. Modeling results suggest that emissions from O&G activity are having a negative impact on air quality and ecosystem health in our National Parks and Class I areas. In this research, we use a modeling framework developed for oil and gas evaluation in the western United States to determine the modeled impacts of emissions associated with oil and gas production on air pollution metrics. We show that oil and gas production may have a significant negative impact on air quality and ecosystem health in some national parks and other Class I areas in the western United States. Our findings are of particular interest to federal land managers as well as regulators in states heavy in oil and gas production as they consider control strategies to reduce the impact of development.


Topical application of a vitamin D analogue exacerbates atopic dermatitis and induces the atopic dermatitis-like phenotype in Stat6VT mice.
Calcipotriene is a topical vitamin D3 analogue approved for the treatment of plaque and scalp psoriasis. We report the case of a 2-year-old boy whose atopic dermatitis (AD) flared in response to application of calcipotriene 0.005% cream and solution for a mistaken diagnosis of plaque and scalp psoriasis. We investigated whether the patient's eruption was secondary to an allergic contact dermatitis. In the Stat6VT mouse model of AD we tested whether calcipotriene could induce the otherwise-spontaneous AD-like phenotype. Closed patch testing was done on the patient with calcipotriene solution and cream, moisturizing cream, and 51% isopropanol. Stat6VT and wild-type (WT) mice were treated for 7 days with calcipotriene solution or vehicle (isopropanol) applied to the right and left upper back skin, respectively, after which mice were followed longitudinally for 10 weeks. Biopsy specimens from prior treatment sites were then collected for histology and RNA isolation. RNA was analyzed for interleukin (IL-4) expression using quantitative polymerase chain reaction. Patch testing was negative. Stat6VT mice, in contrast to WT mice, developed a persistent eczematous dermatitis at sites of calcipotriene application. Clinical and histologic features and high IL-4 transcript levels were consistent with the spontaneous AD-like phenotype seen in Stat6VT mice. At sites of active disease, calcipotriene can worsen a flare of AD. In Stat6VT mice, calcipotriene can induce the AD-like phenotype.


Utility of home blood pressure monitoring to evaluate postprandial blood pressure in treated hypertensive patients.
Postprandial hypotension, defined as a fall in systolic blood pressure (SBP) of 20 mmHg or greater within 2 hours after a meal, is a risk factor for stroke, coronary events and mortality. The clinical suspicion is typically raised by episodes of postprandial syncope or falls, whereas asymptomatic postprandial hypotension is mostly neglected. The magnitude of the postprandial fall in SBP, as detected by 24-hour recording in apparently healthy middle-aged to elderly subjects, was proportional to the severity of the silent cerebrovascular damage. Postprandial hypotension can also be detected by self-measured blood pressure before and within 2 hours after meals using automatic devices. The review highlights the value of home blood pressure monitoring (HBPM) as a screening test for asymptomatic postprandial hypotension in hypertensive patients. Using a HBPM protocol that included duplicated blood pressure measurements before and after three consecutive lunches, we detected unsuspected postprandial hypotension in 27.4% of the 230 hypertensive patients screened. The prevalence of postprandial hypotension was 13.2% in controlled and 42.2% in uncontrolled hypertensive patients (p < 0.001), raising the dilemma of further lowering blood pressure in the setting of postprandial hypotension. The inclusion of preprandial and postprandial measurements in the protocol of HBPM is useful to identify hypertensive patients with postprandial hypotension and may guide adjustments in antihypertensive treatment according to postprandial blood pressure.


Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.
Here we demonstrate that multiple tetraspanin (transmembrane 4 superfamily) proteins are palmitoylated, in either the Golgi or a post-Golgi compartment. Using CD151 as a model tetraspanin, we identified and mutated intracellular N-terminal and C-terminal cysteine palmitoylation sites. Simultaneous mutations of C11, C15, C242, and C243 (each to serine) eliminated >90% of CD151 palmitoylation. Notably, palmitoylation had minimal influence on the density of tetraspanin protein complexes, did not promote tetraspanin localization into detergent-resistant microdomains, and was not required for CD151-alpha 3 beta 1 integrin association. However, the CD151 tetra mutant showed markedly diminished associations with other cell surface proteins, including other transmembrane 4 superfamily proteins (CD9, CD63). Thus, palmitoylation may be critical for assembly of the large network of cell surface tetraspanin-protein interactions, sometimes called the "tetraspanin web." Also, compared with wild-type CD151, the tetra mutant was much more diffusely distributed and showed markedly diminished stability during biosynthesis. Finally, expression of the tetra-CD151 mutant profoundly altered alpha 3 integrin-deficient kidney epithelial cells, such that they converted from a dispersed, elongated morphology to an epithelium-like cobblestone clustering. These results point to novel biochemical and biological functions for tetraspanin palmitoylation.


An open trial of topical tacrolimus for erosive oral lichen planus.
Erosive oral lichen planus is a chronic, painful disease that is frequently refractory to treatment. We describe 6 patients with erosive oral lichen planus, not responsive to topical steroids, who showed substantial improvement with the use of topical tacrolimus ointment 0.1%. This medication was well tolerated and appears to be effective in controlling erosive oral lichen planus.


Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism.
Macrophage infiltration and polarization have been increasingly observed in intervertebral disc (IVD) degeneration (IDD). However, their biological roles in IDD are still unrevealed. We harvested conditioned media (CM) derived from a spectrum of macrophages induced from THP-1 cells, and examined how they affect nucleus pulposus cells (NPCs) in vitro, by studying cell proliferation, extracellular matrix (ECM) synthesis, and pro-inflammation expression; and in vivo by injection CM in a rat IDD model. Then, high-throughput sequencing was used to detect differentially expressed genes (DEGs). Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks were used to further analysis. Higher CCR7+ (M1 marker) and CD206+ (M2 marker) cell counts were found in the degenerated human IVD tissues as compared with the control. Furthermore, the cell co-culture model showed M1CM attenuated NPC proliferation, downregulated the expression of ECM anabolic genes encoding aggrecan and collagen IIα1, upregulated the expression of ECM catabolic genes encoding MMP-13, and inflammation-related genes encoding IL-1β, IL-6, and IL-12, while M2CM showed contrasting trends. In IDD model, higher histological scores and lower disc height index were found following M1CM treatment, while M2CM exhibited opposite results. M1CM injection decreased ECM anabolic and increased ECM catabolic, as well as the upregulation of inflammation-related genes after 8 weeks treatment, while M2CM slowed down these trends. Finally, a total of 637 upregulated and 655 downregulated genes were detected in M1CM treated NPCs, and 975 upregulated genes and 930 downregulated genes in the M2CM groups. The top 30 GO terms were shown and the most significant KEGG pathway was cell cycle in both groups. Based on the PPI analysis, the five most significant hub genes were PLK1, KIF20A, RRM2, CDC20, and UBE2C in the M1CM groups and RRM2, CCNB1, CDC20, PLK1, and UBE2C in the M2CM groups. In conclusion, macrophage polarization exhibited diverse roles in IDD progression, with M1CM exacerbating cell proliferation suppression and IVD degeneration, while M2CM attenuated IDD development. These findings may facilitate the further elucidation of the role of macrophage polarization in IDD, and provide novel insights into the therapeutic potential of macrophages.


Effects of antenatal hydrocortisone on tidal volumes in spontaneously breathing preterm newborn rabbits. Possible mediation by adrenal catecholamines.
Rabbit fetuses were injected on day 26 of gestation with hydrocortisone (2 mg) and delivered by hysterotomy 2 days later. The animals were tracheotomized at birth, and tidal volumes and esophageal pressures were recorded during spontaneous ventilation at standardized intervals from the first breath to the age of 2 h. In a subgroup of animals, the catecholamine content was measured in the adrenal glands. In comparison with littermate controls, tidal volumes were enlarged in hydrocortisone-treated neonates at the first breath and 60 min after birth; however, this effect was associated with an increased incidence of intra-alveolar hemorrhage. Hydrocortisone-treated animals also had a significantly increased adrenal content of adrenaline. Our data confirm a modest beneficial effect of antenatal hydrocortisone treatment on the fetal lung and suggest that this might in part be mediated by adrenal catecholamines. Stimulation of beta-adrenergic receptors could thus potentiate the effect induced by direct influence of glucocorticoids on fetal lung maturation.


Synthesis of Saxitoxin and Its Derivatives.
The chiral synthesis of (+)-saxitoxin and its derivatives is described. Two consecutive carbon-nitrogen bonds at C-5 and C-6 in saxitoxin were effectively installed by the sequential Overman rearrangement of an allylic vicinal diol derived from d-malic acid. The bicyclic guanidine unit was constructed by the intramolecular aminal formation of an acyclic bis-guanidine derivative possessing a ketone carbonyl at C-4. From the bicyclic aminal intermediate, (+)-saxitoxin, (+)-decarbamoyl-β-saxitoxinol [(+)-dc-β-saxitoxinol], and the unnatural skeletal isomer, (-)-iso-dc-saxitoxinol, were synthesized.


Excitons in monolayer transition metal dichalcogenides.
We theoretically investigate the exciton formed with two massive Dirac particles in monolayer [Formula: see text] and other transition metal dichalcogenides as well as two layers separated by a dielectric layer. In the low-energy limit, the separation of the center-of-mass and relative motions is obtained. Analytical solutions for the exciton wave function and energy dispersion are obtained including the Coulomb interaction between electron and hole, the exciton Bohr radius, binding energy and its effective mass are obtained in monolayer transition metal dichalcogenides. In the case of two monolayers separated by a dielectric layer, we find that the exciton effective mass can be continuously tuned by the interlayer separation.


Elucidating aromatic acid tolerance at low pH in Saccharomyces cerevisiae using adaptive laboratory evolution.
Toxicity from the external presence or internal production of compounds can reduce the growth and viability of microbial cell factories and compromise productivity. Aromatic compounds are generally toxic for microorganisms, which makes their production in microbial hosts challenging. Here we use adaptive laboratory evolution to generate Saccharomyces cerevisiae mutants tolerant to two aromatic acids, coumaric acid and ferulic acid. The evolution experiments were performed at low pH (3.5) to reproduce conditions typical of industrial processes. Mutant strains tolerant to levels of aromatic acids near the solubility limit were then analyzed by whole genome sequencing, which revealed prevalent point mutations in a transcriptional activator (Aro80) that is responsible for regulating the use of aromatic amino acids as the nitrogen source. Among the genes regulated by Aro80, ESBP6 was found to be responsible for increasing tolerance to aromatic acids by exporting them out of the cell. Further examination of the native function of Esbp6 revealed that this transporter can excrete fusel acids (byproducts of aromatic amino acid catabolism) and this role is shared with at least one additional transporter native to S. cerevisiae (Pdr12). Besides conferring tolerance to aromatic acids, ESBP6 overexpression was also shown to significantly improve the secretion in coumaric acid production strains. Overall, we showed that regulating the activity of transporters is a major mechanism to improve tolerance to aromatic acids. These findings can be used to modulate the intracellular concentration of aromatic compounds to optimize the excretion of such products while keeping precursor molecules inside the cell.


Clinicopathologic Features and Diagnostic Implications of Pyloric Gland Metaplasia in Intestinal Specimens.
Pyloric gland metaplasia (PGM) is a histopathologic change usually seen after inflammatory injury and, although described in association with inflammatory bowel disease (IBD) and particularly Crohn disease (CD), its significance is still debated. We evaluated long-term correlates of PGM in a large cohort of 601 intestinal specimens, 227 (37.8%) biopsies, and 374 (62.2%) resections, from 567 different patients, 328 (57.8%) male and 239 (42.2%) female, with a mean age of 43.4±15.8 years. During mean clinical follow-up of 83.5±48.1 months, 511 (90.1%) patients were diagnosed with IBD, 457 (89.4%) with CD, and 53 (10.4%) with ulcerative colitis. In multivariate analysis, IBD patients with PGM were younger (P<0.001) and more often had severely active inflammation (P=0.002) compared with non-IBD patients, whereas, among IBD patients, those with ulcerative colitis were more likely to have PGM in a biopsy (P<0.001) or in the colorectum (P=0.009), compared with CD patients. Kaplan-Meier analyses showed that incidental PGM in a biopsy was more likely to predict IBD in patients younger than 50 years (P<0.001) and those without a history of bowel surgery (P<0.001) and also more likely to signify CD in patients younger than 50 years (P=0.004), those without a history of bowel surgery (P=0.020), and when identified in the small intestine (P=0.032). In conclusion, intestinal PGM warrants a high suspicion for IBD and specifically CD, however, it should be interpreted with caution, especially in older patients or those with a history of prior intestinal surgery and in colorectal biopsies or specimens lacking severely active inflammation.


Coronary flow reserve assessed by myocardial contrast echocardiography predicts mortality in patients with heart failure.
the aim of the study was to assess whether myocardial contrast echocardiography (MCE) can predict mortality in patients with heart failure. Myocardial viability, ischaemia, and coronary flow reserve (CFR) are predictors of mortality in patients with heart failure. MCE can assess myocardial viability, ischaemia, and CFR at the bedside. However, its prognostic value is unknown in patients with heart failure. eighty-seven patients (age: 68 ± 10 years, 62% male) with heart failure [left ventricular ejection fraction (LVEF): 35% ± 13] underwent low-power intermittent MCE at rest and 2 min after dipyridamole infusion. Resting and stress perfusion score index were derived qualitatively. CFR (MBF at stress/MBF at rest) was calculated by a quantitative method. All patients underwent coronary arteriography. Patients were followed up for mortality. Of the 87 patients, 43 (49%) patients had coronary artery disease. There were 28 (32%) deaths during a mean follow-up of 4.1 ± 1.7 years. Type 2 diabetes [P = 0.02, hazard ratios (HR) 2.43, confidence interval (CI) 1.13-5.22] and CFR (P = 0.001, HR 0.15, CI 0.05-0.45) were independent predictors of mortality. A CFR ≤ 1.5 had a significantly (P < 0.0001) higher mortality of 49 vs. 10% in patients with CFR > 1.5 over the 4 year follow-up period. CFR determined by MCE is a powerful predictor of mortality in patients with heart failure.


A scenario-based study on information flow and collaboration patterns in disaster management.
Disaster management (DM) is a continuous, highly collaborative process involving governments, DM organisations, responders, the construction sector, and the general public. Most research approaches to DM include the development of information and communication technologies (ICT) to support the collaboration process rather than the creation of a collaboration process to provide information flows and patterns. An Intelligent Disaster Collaboration System (IDCS) is introduced in this paper as a conceptual model to integrate ICT into DM and the mitigation process and to enhance collaboration. The framework is applicable to the collaboration process at the local, regional and national levels. Within this context, the deployment of ICT tools in DM is explored and scenario-based case studies on flooding and terrorism--examples of natural and human-induced disasters, respectively--are presented. Conclusions are drawn regarding the differences found in collaboration patterns and ICT used during natural and human-induced disasters and the differences between currently available ICT and proposed ICT.


Traumatic Pseudoaneurysm of Anterior Tibial Artery Treated by Thrombin Injection.
Traumatic pseudoaneurysm of limb arteries are relatively rare. A 70-year-old gentleman, with history of mechanical aortic valve implantation on warfarin, presented to the emergency department with pain and swelling in the right leg. He had sustained blunt injury to the leg, a week prior to presentation. On examination, the lateral compartment of the leg was swollen, ecchymotic, and tense. Distal pulses were well palpable. An ultrasound Doppler evaluation revealed a large intramuscular hematoma in the lateral compartment with a pseudoaneurysm of a muscular branch of the anterior tibial artery. An ultrasound-guided compression of the pseudoaneurysm was initially attempted for 24 hours, which failed in closing off the pseudoaneurysm. He was subsequently taken up for thrombin injection into the pseudoaneurysm, which resulted in instant thrombosis of the pseudoaneurysm, with an uneventful clinical course thereafter. Thrombin injection is an effective and safe modality to treat pseudoaneurysms of limb arteries.


Air-borne microbial contamination of surfaces in a UK dental clinic.
Little is known about the number, type, or antibiotic resistance profiles, of air-borne microbes present in hospital settings yet such information is important in designing effective measures to reduce cross-infection. In this study settle plates were used to identify and quantify the air-borne microbes present in a dental clinic. All isolates were identified to species level using partial 16S ribosomal RNA gene sequencing and their susceptibility to ampicillin, chloramphenicol, erythromycin, gentamicin, penicillin, tetracycline or vancomycin was performed. The mean numbers of viable bacteria detected for each sampling occasion during periods of clinical activity and in the absence of such activity were 21.9 x 10(2 )cfu/m2/h and 2.3 x 10(2 )cfu/m2/h respectively. One hundred ninety-three distinct colony morphotypes, comprising 73 species, were isolated during the study and 48% of these were resistant to at least one antibiotic. The mean numbers of different morphotypes detected per sampling occasion were 14.3 and 5 during periods of clinical activity and inactivity respectively. Propionibacterium acnes, Micrococcus luteus and Staphylococcus epidermidis were frequently isolated regardless of whether any clinical activities were taking place. These findings highlight the importance of preventing surfaces from becoming reservoirs of antibiotic-resistant bacteria and thereby contributing to cross-infection in the dental clinic.


Evaluation of the Disconnect between Hepatocyte and Microsome Intrinsic Clearance and In Vitro In Vivo Extrapolation Performance.
The use of in vitro in vivo extrapolation (IVIVE) from human hepatocyte (HH) and human liver microsome (HLM) stability assays is a widely accepted predictive methodology for human metabolic clearance (CLmet). However, a systematic underprediction of CLmet from both matrices appears to be universally apparent, which can be corrected for via an empirical regression offset. After physiological scaling, intrinsic clearance (CLint) for compounds metabolized via the same enzymatic pathway should be equivalent for both matrices. Compounds demonstrating significantly higher HLM CLint relative to HH CLint have been encountered, raising questions regarding how to predict CLmet for such compounds. Here, we determined the HLM:HH CLint ratio for 140 marketed drugs/compounds, compared this ratio as a function of physiochemical properties and drug metabolism enzyme dependence, and examined methodologies to predict CLmet from both matrices. The majority (78%) of compounds displaying a high HLM:HH CLint ratio were CYP3A substrates. Using HH CLint for CYP3A substrates, the current IVIVE regression offset approach remains an appropriate strategy to predict CLmet (% compounds overpredicted/correctly predicted/underpredicted 27/62/11, respectively). However, using the same approach for HLM significantly overpredicts CLmet for CYP3A substrates (% compounds overpredicted/correctly predicted/underpredicted 56/33/11, respectively), highlighting that a different IVIVE offset is required for CYP3A substrates using HLM. This work furthers the understanding of compound properties associated with a disproportionately high HLM:HH CLint ratio and outlines a successful IVIVE approach for such compounds. SIGNIFICANCE STATEMENT: Oral drug discovery programs typically strive for low clearance compounds to ensure sufficient target engagement. Human liver microsomes and isolated human hepatocytes are used to optimize and predict human hepatic metabolic clearance. After physiological scaling, intrinsic clearance for compounds of the same metabolic pathway should be equivalent between matrices. However, a disconnect in intrinsic clearance is sometimes apparent. The work described attempts to further understand this phenomenon, and by achieving a mechanistic understanding, improvements in clearance predictions may be realized.