Development of CYP3A4 inhibition models: comparisons of machine-learning techniques and molecular descriptors.
Computational models of cytochrome P450 3A4 inhibition were developed based on high-throughput screening data for 4470 proprietary compounds. Multiple models differentiating inhibitors (IC(50) <3 microM) and noninhibitors were generated using various machine-learning algorithms (recursive partitioning [RP], Bayesian classifier, logistic regression, k-nearest-neighbor, and support vector machine [SVM]) with structural fingerprints and topological indices. Nineteen models were evaluated by internal 10-fold cross-validation and also by an independent test set. Three most predictive models, Barnard Chemical Information (BCI)-fingerprint/SVM, MDL-keyset/SVM, and topological indices/RP, correctly classified 249, 248, and 236 compounds of 291 noninhibitors and 135, 137, and 147 compounds of 179 inhibitors in the validation set. Their overall accuracies were 82%, 82%, and 81%, respectively. Investigating applicability of the BCI/SVM model found a strong correlation between the predictive performance and the structural similarity to the training set. Using Tanimoto similarity index as a confidence measurement for the predictions, the limitation of the extrapolation was 0.7 in the case of the BCI/SVM model. Taking consensus of the 3 best models yielded a further improvement in predictive capability, kappa = 0.65 and accuracy = 83%. The consensus model could also be tuned to minimize either false positives or false negatives depending on the emphasis of the screening.


Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir.
The latent reservoir for HIV-1 in resting CD4+ T cells persists despite antiretroviral therapy (ART) and precludes cure. Reservoir-targeting interventions are evaluated in ART-treated macaques infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV). Efficacy is determined by reservoir measurements before and after the intervention. However, most proviruses persisting in the setting of ART are defective. In addition, intact HIV-1 and SIV genomes undergo complex, multiphasic decay observable when new infection events are blocked by ART. Intervention-induced elimination of latently infected cells must be distinguished from natural decay. Here, we address these issues for SHIV. We describe an intact proviral DNA assay that allows digital counting of SHIV genomes lacking common fatal defects. We show that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase (t1/2 = 30.1 d) and a slower second phase (t1/2 = 8.1 mo) that is still more rapid that the slow decay observed in people with HIV-1 on long-term ART (t1/2 = 3.7 y). In SHIV models, most interventions are tested during 2nd phase decay. Natural 2nd phase decay must be considered in evaluating interventions as most infected cells present at this time do not become part of the stable reservoir. In addition, for interventions tested during 2nd phase decay, a caveat is that the intervention may not be equally effective in people with HIV on long-term ART whose reservoirs are dominated by latently infected cells with a slower decay rate.


Nursing diagnosis in older adults at risk for pressure injury.
To develop nursing diagnoses and care plans for older adults with pressure injuries based on risk factors, aiming at preventing their occurrence in hospitalized older adults. Exploratory, descriptive, cross-sectional, quantitative study conducted with 87 medical records at the Medical Clinic Unit of a University Hospital. Among older adults at some risk for the development of pressure injury, there was a prevalence of the female sex, age over 80 years and moderate risk classification on the Braden Scale. Nursing interventions that encourage patient mobility, pressure control, skin supervision, nutrition, incontinence and hygiene stood out. Nursing has an important role in maintaining the integrity of patients' skin. It is worth highlighting the use of injury predictive scales as a complement to clinical practice in order to assist in the nursing diagnosis with a view to interventions aimed at risk factors.


Determinants of mammography use in rural and urban regions of Canada.
National guidelines advocate biennial mammography screening for asymptomatic women aged 50-69 years. Unfortunately many women do not abide by such recommendations, and evidence indicates that compliance rates are lower in rural areas. We estimated logistic regression models using data from the Canadian Community Health Survey for 2002/03 and 2004/05. We identified the extent of regional variation within and between Canadian provinces using a new and more detailed set of rural indicators based on economic zones of influence, after accounting for a range of demographic and socio-economic factors. The odds of asymptomatic women aged 50-69 years having undergone mammography during the previous 2 years were significantly lower for those residing in relatively remote and rural areas than for those residing in census metropolitan areas (odds ratio [OR] 0.58, confidence interval [CI] 0.42-0.80). This was also true of women residing in certain other rural areas that had some limited labour market attachment to larger urban areas (OR 0.81, CI 0.70-0.93), but there were no significant differences between smaller and larger urban areas. We also found variation in mammography use among women living in rural and urban areas across provinces. Mammography use is significantly lower in rural and remote areas, even after a range of other demographic and socio-economic factors are accounted for. One important factor underpinning this result appears to be differences in attitude about the importance of regular mammography screening between women residing in rural and urban areas. Information campaigns raising awareness about the importance of mammography screening should be targeted, in particular, at women residing in rural and remote areas.


Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival.
In addition to its role as a survival factor, nerve growth factor (NGF) has been implicated in initiating apoptosis in restricted cell types both during development and after terminal cell differentiation. NGF binds to the TrkA tyrosine kinase and the p75 neurotrophin receptor, a member of the tumor necrosis factor cytokine family. To understand the mechanisms underlying survival versus death decisions, the TrkA receptor was introduced into oligodendrocyte cell cultures that undergo apoptosis in a p75-dependent manner. Here we report that activation of the TrkA NGF receptor in oligodendrocytes negates cell death by the p75 receptor. TrkA-mediated rescue from apoptosis correlated with mitogen-activated protein kinase activation. Concurrently, activation of TrkA in oligodendrocytes resulted in suppression of c-jun kinase activity initiated by p75, whereas induction of NFkappaB activity by p75 was unaffected. These results indicate that TrkA-mediated rescue involves not only activation of survival signals but also simultaneous suppression of a death signal by p75. The selective interplay between tyrosine kinase and cytokine receptors provides a novel mechanism that achieves alternative cellular responses by merging signals from different ligand-receptor systems.


Gonadal dysgenesis: associations between clinical features and sex of rearing.
The purpose of this study was to review the phenotypic and endocrine features or a series of patients with ambiguous genitalia or sex-reversal due to gonadal dysgenesis (GD) and to analyse the impact of these on the decision about sex of rearing. This study is a retrospective analysis of 22 patients with GD treated between 1964 and 1994. We assessed external genitalia, internal genitalia, internal genital structures, gonadal morphology (n = 22), basal and human CG (hCG) stimulated serum testosterone levels (n = 11) and serum gonadotropin levels (n = 13) in patients with GD. Basal and hCG stimulated testosterone levels were also measured for 43 control patients. There were no significant associations or correlations between internal or external genital phenotype, endocrine function and gonadal morphology. There was a significant association between sex of rearing and external genitalia (P = 0.03). Patients with gonadal dysgenesis had significantly lower stimulated/basal testosterone levels than the controls (P = 0.0001). Given that the clinical features of various forms of GD overlap considerably, gonadal biopsy should remain the investigation of choice when attempting to define the pathology.


Effect of solvation on the aggregation-induced luminescence of tetraphenylethene derivatives.
The compound TPE-(α-NH2)2 was synthesized. In the water-THF mixture (fw = 90%), a relatively stable non-emission aggregate with ultrasound-responsive emission properties could be obtained. It was found that the preferential solvation of THF plays an essential role in the emission properties through controlling the aggregation patterns.


Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+).
To test the association of distinct neuropathologic features of Alzheimer disease (AD) with risk loci identified in genome-wide association studies. Vantaa 85+ is a population-based study that includes 601 participants aged ≥85 years, of which 256 were neuropathologically examined. We analyzed 29 AD risk loci in addition to APOE ε4, which was studied separately and used as a covariate. Genotyping was performed using a single nucleotide polymorphism (SNP) array (341 variants) and imputation (6,038 variants). Participants with Consortium to Establish a Registry for Alzheimer Disease (CERAD) (neuritic Aβ plaques) scores 0 (n = 65) vs score M + F (n = 171) and Braak (neurofibrillary tangle pathology) stages 0-II (n = 74) vs stages IV-VI (n = 119), and with capillary Aβ (CapAβ, n = 77) vs without (n = 179) were compared. Cerebral amyloid angiopathy (CAA) percentage was analyzed as a continuous variable. Altogether, 24 of the 29 loci were associated (at p < 0.05) with one or more AD-related neuropathologic features in either SNP array or imputation data. Fifteen loci associated with CERAD score, smallest p = 0.0002122, odds ratio (OR) 2.67 (1.58-4.49) at MEF2C locus. Fifteen loci associated with Braak stage, smallest p = 0.004372, OR 0.31 (0.14-0.69) at GAB2 locus. Twenty loci associated with CAA, smallest p = 7.17E-07, β 14.4 (8.88-20) at CR1 locus. Fifteen loci associated with CapAβ smallest p = 0.002594, OR 0.54 (0.37-0.81) at HLA-DRB1 locus. Certain loci associated with specific neuropathologic features. CASS4, CLU, and ZCWPW1 associated only with CAA, while TREM2 and HLA-DRB5 associated only with CapAβ. AD risk loci differ in their association with neuropathologic features, and we show for the first time distinct risk loci for CAA and CapAβ.


Patterns of Adherence to Secondary Prevention Measures Among Chinese Patients With Coronary Artery Disease: A Longitudinal Study.
Adherence to secondary prevention measures among patients with coronary artery disease (CAD) affects patient prognosis, whereas patients' adherence behaviors change over time. The aims of this study were to identify adherence trajectories to secondary prevention measures including medication-taking and a heart-healthy lifestyle and to estimate predictors of adherence trajectories among patients with CAD. This longitudinal study enrolled 698 patients with CAD who received a percutaneous coronary intervention in China. Demographics, clinical characteristics, adherence to secondary prevention measures, and patient-related factors including disease knowledge, self-efficacy, and health literacy were measured during hospitalization. Adherence behaviors were followed at 1, 3, and 6 months, and 1 year after discharge. Group-based trajectory models estimated adherence trajectories, and multinomial logistic regression identified trajectory group predictors. Four trajectory groups were identified for medication-taking adherence: sustained adherence (39.9%), increasing and then decreasing adherence (23.1%), increasing adherence (23.4%), and nonadherence (13.6%). The 3 adherence trajectory groups for a heart-healthy lifestyle were sustained adherence (59.7%), increasing adherence (28.3%), and nonadherence (12.0%). Married patients were more likely (odds ratio [OR], 3.42; 95% confidence interval [CI], 1.56-7.52) to have sustained adherence to medication-taking. However, patients with higher disease knowledge were less likely (OR, 0.93; 95% CI, 0.87-0.99) to be adherent. Patients who were not working (OR, 2.25; 95% CI, 1.03-4.92) had higher self-efficacy (OR, 1.21; 95% CI, 1.08-1.37). Those with higher health literacy (OR, 1.18; 95% CI, 1.01-1.38) were more likely to have sustained adherence to a heart-healthy lifestyle. However, patients having no coronary stents (OR, 0.36; 95% CI, 0.19-0.70) were less likely to have done so. Trajectories of adherence to secondary prevention measures among mainland Chinese patients with CAD are multipatterned. Healthcare providers should formulate targeted adherence support, which considers the influence of disease knowledge, self-efficacy, and health literacy.


Overall reductions in functional brain activation are associated with falls in older adults: an fMRI study.
Falls are a common geriatric condition, and while impaired cognitive function has been identified as a key risk factor, the neural correlates that contribute to reduced executive functioning and falls currently remain unknown. In this study, community-dwelling adults aged 65-75 years were divided into two groups based on their recent history of falls (fallers versus non-fallers). All participants completed the Flanker task during functional magnetic resonance imaging (fMRI). We examined the hemodynamic response of congruent and incongruent trials separately in order to separate the relative contribution of each trial type as a function of falls history. We found that fallers exhibited a smaller difference in functional activation between congruent and incongruent trials relative to non-fallers, as well as an overall reduction in level of blood-oxygen-level dependent response. Of particular note, the medial frontal gyrus - a region implicated in motor planning - demonstrated hypo-activation in fallers, providing evidence that the prefrontal cortex might play a central role in falls risk in older adults.


[Screening and cloning genes transactivated by TGF beta 1 in hepatic stellate cells using suppression subtractive hybridization technique].
To construct a cDNA subtractive library of genes transactivated by TGF beta 1 in LX02 hepatic stellate cells (HSC); to screen and to clone the regulated genes transactivated by TGF beta 1; and to elucidate the molecular biological mechanism of hepatic fibrosis mediated by TGF beta 1. mRNA was isolated from HSC treated with TGF beta 1 or with PBS (as controls). Suppression subtractive hybridization (SSH) technique was employed to analyze the differentially expressed DNA sequence between the two groups. After restriction enzyme Rsa I digestion, small size cDNAs were obtained. Then tester cDNA was divided into two groups and ligated to specific adaptor 1 and adaptor 2, respectively. After tester cDNA was hybridized with driver cDNA twice and underwent polymerase chain reaction twice it then was subcloned into pGEM-Teasy plasmid vectors to set up the subtractive library. Amplification of the library was carried out with E. coli strain DH5a. The cDNA was sequenced and analyzed in GenBank with Blast search. The subtractive cDNA library of genes transactivated by TGF beta 1 in HSC was constructed successfully. The amplified library contained 146 positive clones, which contained 200-1000 bp of inserts. Randomly, thirty clones were analyzed by sequencing and bioinformatics, consisting of 28 known genes and 2 unknown genes. The subtractive cDNA library of genes transactivated by TGF beta 1 in HSC using SSH technique was constructed successfully. Some gene coding proteins are those involved in cell growth regulation, protein synthesis, signal transduction, extracellular matrix metabolism, and anti-lipid peroxidative, which gives us some new clues for the study of the mechanism of liver fibrosis.


Actions of BW540C in an equine model of acute inflammation: a preliminary study.
An equine model of acute non-immune inflammation has been developed to facilitate studies of the inflammatory process and the actions of novel anti-inflammatory drugs. Five polyester sponge strips soaked in sterile 2% carrageenin solution were placed in subcutaneous pouches prepared under local anaesthesia in the necks of conscious ponies. Serial removal of the strips and harvesting of the exudate enabled studies to be made of the cellular, biochemical and mediator aspects of the localised, acute inflammation, and the heat generated by the lesion was monitored by infra-red thermometry. Maximal concentrations of the eicosanoids 6-keto-prostaglandin F1 alpha, thromboxane B2 and leukotriene B4 occurred at 9 h, whereas leukocyte numbers, lactate dehydrogenase (LDH) and total protein concentrations were greatest at 24 h. Lesional skin temperature was increased by approximately 4 degrees C throughout the 24 h period. The novel anti-inflammatory agent BW540C, administered orally at a dose-rate of 20 mg/kg, did not affect leukocyte infiltration or the concentrations of protein, LDH and eicosanoids in exudate but serum thromboxane B2 levels were reduced. Skin temperature rises were greater in drug-treated animals. It is concluded that higher doses of BW540C will be required for a clinically useful anti-inflammatory action in horses.


Dosimetric comparison of stopping power calibration with dual-energy CT and single-energy CT in proton therapy treatment planning.
The accuracy of proton dose calculation is dependent on the ability to correctly characterize patient tissues with medical imaging. The most common method is to correlate computed tomography (CT) numbers obtained via single-energy CT (SECT) with proton stopping power ratio (SPR). CT numbers, however, cannot discriminate between a change in mass density and change in chemical composition of patient tissues. This limitation can have consequences on SPR calibration accuracy. Dual-energy CT (DECT) is receiving increasing interest as an alternative imaging modality for proton therapy treatment planning due to its ability to discriminate between changes in patient density and chemical composition. In the current work we use a phantom of known composition to demonstrate the dosimetric advantages of proton therapy treatment planning with DECT over SECT. A phantom of known composition was scanned with a clinical SECT radiotherapy CT-simulator. The phantom was rescanned at a lower X-ray tube potential to generate a complimentary DECT image set. A set of reference materials similar in composition to the phantom was used to perform a stoichiometric calibration of SECT CT number to proton SPRs. The same set of reference materials was used to perform a DECT stoichiometric calibration based on effective atomic number. The known composition of the phantom was used to assess the accuracy of SPR calibration with SECT and DECT. Intensity modulated proton therapy (IMPT) treatment plans were generated with the SECT and DECT image sets to assess the dosimetric effect of the imaging modality. Isodose difference maps and root mean square (RMS) error calculations were used to assess dose calculation accuracy. SPR calculation accuracy was found to be superior, on average, with DECT relative to SECT. Maximum errors of 12.8% and 2.2% were found for SECT and DECT, respectively. Qualitative examination of dose difference maps clearly showed the dosimetric advantages of DECT imaging, compared to SECT imaging for IMPT dose calculation for the case investigated. Quantitatively, the maximum dose calculation error in the SECT plan was 7.8%, compared to a value of 1.4% in the DECT plan. When considering the high dose target region, the root mean square (RMS) error in dose calculation was 2.1% and 0.4% for SECT and DECT, respectively. DECT-based proton treatment planning in a commercial treatment planning system was successfully demonstrated for the first time. DECT is an attractive imaging modality for proton therapy treatment planning owing to its ability to characterize density and chemical composition of patient tissues. SECT and DECT scans of a phantom of known composition have been used to demonstrate the dosimetric advantages obtainable in proton therapy treatment planning with DECT over the current approach based on SECT.


Identification of gastric H,K-ATPase in an early vertebrate, the Atlantic stingray Dasyatis sabina.
Virtually all vertebrates acidify their gastric contents to a pH between 0.8 and 2.0. In mammals, acid secretion is mediated by a K-stimulated proton-translocating adenosine triphosphatase (H,K-ATPase), which establishes a million-fold gradient of protons across the apical membrane of the gastric parietal cell. The earliest phylogenetic appearance of gastric acid secretion is in cartilaginous fish, and we sought to verify in this class (Chondrichthyes) the presence and distribution of H,K-ATPase in gastric epithelial cells. An antibody against a synthetic peptide based on the C-terminus of pig H,K-ATPase alpha-subunit was localized in the gastric glands of the Atlantic stingray Dasyatis sabina. The C-terminal antibody stained all cells with tubulovesicles and the apical membrane domain of mucous neck cells. In proximal stomach, gastric glands showed the strongest immunoreactivity in cells close to the isthmus; in the distal stomach, strongest immunoreactivity was found in cells at the base of the glands. Oxyntic cells were more intensely immunoreactive than oxynticopeptic cells. This antibody labeled a single band of M(r) 100,600 on immunoblots of D. sabina gastric microsomes. These results show the earliest phylogenetic occurrence of a gastric ATPase in putative acid-secreting cells and suggest that this enzyme shares structural features with mammalian H,K-ATPase.


The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.


Gait Variability Structure Linked to Worse Cartilage Composition Post-ACL Reconstruction.
Aberrant gait variability has been observed after anterior cruciate ligament reconstruction (ACLR), yet it remains unknown if gait variability is associated with early changes in cartilage composition linked to osteoarthritis development. Our purpose was to determine the association between femoral articular cartilage T1ρ magnetic resonance imaging relaxation times and gait variability. T1ρ magnetic resonance imaging and gait kinematics were collected in 22 ACLR participants (13 women; 21 ± 4 yr old; 7.52 ± 1.43 months post-ACLR). Femoral articular cartilage from the ACLR and uninjured limbs were segmented into anterior, central, and posterior regions from the weight-bearing portions of the medial and lateral condyles. Mean T1ρ relaxation times were extracted from each region and interlimb ratios (ILR) were calculated (i.e., ACLR/uninjured limb). Greater T1ρ ILR values were interpreted as less proteoglycan density (worse cartilage composition) in the injured limb compared with the uninjured limb. Knee kinematics were collected at a self-selected comfortable walking speed on a treadmill with an eight-camera three-dimensional motion capture system. Frontal and sagittal plane kinematics were extracted, and sample entropy was used to calculate kinematic variability structure (KV structure ). Pearson's product-moment correlations were conducted to determine the associations between T1ρ and KV structure variables. Lesser frontal plane KV structure was associated with greater mean T1ρ ILR in the anterior lateral ( r = - 0.44, P = 0.04) and anterior medial condyles ( r = - 0.47, P = 0 .03). Lesser sagittal plane KV structure was associated with greater mean T1ρ ILR in the anterior lateral condyle ( r = - 0.47, P = 0.03). The association between less KV structure and worse femoral articular cartilage proteoglycan density suggests a link between less variable knee kinematics and deleterious changes joint tissue changes. The findings suggest that less knee kinematic variability structure is a mechanism linking aberrant gait to early osteoarthritis development.


A direct method for locating minimum-energy crossing points (MECPs) in spin-forbidden transitions and nonadiabatic reactions.
An efficient computational method for locating minimum-energy crossing points (MECPs) between potential-energy surfaces in spin-crossover transitions and nonadiabatic spin-forbidden (bio)chemical reactions is introduced. The method has been tested on the phenyl cation and the computed MECP associated with its radiationless singlet-triplet spin crossover is in good agreement with available data. However, the convergence behavior of the present method is significantly more efficient than some alternative methods which allows us to study nonadiabatic processes in larger systems such as spin crossover in metal-containing compounds. The convergence rate of the method obeys a fast logarithmic law which has been verified on the phenyl cation. As an application of this new methodology, the MECPs of the ferrous complex [Fe(ptz)(6)](BF(4))(2), which exhibits light-induced excited spin state trapping, have been computed to identify their geometric and energetic parameters during spin crossover. Our calculations, in conjunction with spin-unrestricted density-functional calculations, show that the transition from the singlet ground state to a triplet intermediate and to the quintet metastable state of [Fe(ptz)(6)](BF(4))(2) is accompanied by unusually large bond-length elongations of the axial ligands ( approximately 0.26 and 0.23 A, respectively). Our results are consistent with crystallographic data available for the metastable quintet but also predict new structural and energetic information about the triplet intermediate and at the MECPs which is currently not available from experiment.


Comparative Evaluation of Three Preprocessing Methods for Extraction and Detection of Influenza A Virus Nucleic Acids from Sputum.
Viscous sputum specimens usually cannot undergo automated extraction, and thus, a pre-homogenization process is desirable before isolating nucleic acids for real-time reverse transcription PCR. In this study, we compared three preprocessing methods [preprocessing with normal saline (NS), dithiothreitol (DTT), and proteinase K (PK)] of sputum specimens on the extraction and detection of influenza A virus (IAV) nucleic acids. Based on the experimental results of 217 specimens, we found that DTT and PK could be used to improve the homogenization effects of sputum and increase the positive rates by 5.53-6.91% higher than that of the NS group. Comparison of 49 positive specimens in all of the three groups demonstrated that the threshold cycle values of the DTT group and PK group were significantly lower and their nucleic acid concentration and A260/A280 ratio within 1.8-2.0 were higher than those of the NS group. Thus, sputum homogenization before nucleic acid extraction is essential for the accurate diagnosis of IAV infection.


Treatment of clinical solid waste using a steam autoclave as a possible alternative technology to incineration.
A steam autoclave was used to sterilize bacteria in clinical solid waste in order to determine an alternative to incineration technology in clinical solid waste management. The influence of contact time (0, 5, 15, 30 and 60 min) and temperature (111 °C, 121 °C and 131 °C) at automated saturated steam pressure was investigated. Results showed that with increasing contact time and temperature, the number of surviving bacteria decreased. The optimum experimental conditions as measured by degree of inactivation of bacteria were 121 °C for 15 minutes (min) for Gram negative bacteria, 121 °C and 131 °C for 60 and 30 min for Gram positive bacteria, respectively. The re-growth of bacteria in sterilized waste was also evaluated in the present study. It was found that bacterial re-growth started two days after the inactivation. The present study recommends that the steam autoclave cannot be considered as an alternative technology to incineration in clinical solid waste management.


Facile synthesis of AgInS₂ hierarchical flowerlike nanoarchitectures composed of ultrathin nanowires.
In this work, AgInS(2) hierarchical flowerlike nanoarchitectures, which are composed of ultrathin nanowires, were synthesized by thermolysis of a mixed solution of AgNO(3), InCl(3)·4H(2)O and n-dodecanethiol at elevated temperature. The average diameter and length of the nanowires composing the nanoarchitectures can reach 5 nm and ∼300 nm, respectively. We investigated the growth process of the nanoarchitectures and the effects of reaction parameters by XRD, SEM and TEM. In particular, the use of InCl(3)·4H(2)O played a decisive role in the synthesis of the nanoarchitectures. Moreover, it was found that polyhedra formed in the initial reaction time, and then the nanowires grew on the facets of these polyhedra, which resulted in the nanoarchitectures. The reaction temperature and the concentration of metal salts could influence the size of the nanowires.


Indomethacin-induced gastroduodenal damage is not affected by cotreatment with ranitidine.
A randomized, double-blind, placebo-controlled study was conducted to determine whether concomitant administration of ranitidine reduces gastroduodenal mucosal damage associated with 1 week of indomethacin treatment. One hundred ten subjects with acute musculoskeletal conditions and who received indomethacin 150 mg/day completed the trial: 55 were treated with ranitidine 150 mg b.i.d. and 51 subjects received placebo b.i.d. Endoscopic gastric and duodenal injury were assessed before and after one week of treatment. There was no statistically significant difference in the percentage of patients with gastroduodenal damage or in the severity of the lesions in both treatment groups. Ranitidine did not ameliorate indomethacin-induced gastrointestinal symptoms and there was no correlation between upper gastrointestinal symptoms and endoscopic findings.


Clonal generation of multipotent and unipotent hemopoietic blast cell colonies in vitro.
Colonies with a unique compact morphology and displaying high replating potential develop in methycellulose cultures when bone marrow cells from hydroxyurea- or 5-fluorouracil-treated mice are cultured in the presence of syngeneic thymocytes. These compact colonies are clonal, originating from a single unit, the compact-colony-forming unit (CFU). Based on replating analysis, at least three groups of compact colonies exist: (1) those that do not replate, (2) those that replate and give only GM colonies, and (3) those that give rise to granulocyte-macrophage (GM), erythroid (E), and mixed-erythroid (MIX/E) colonies. Colonies in the last group have a mean size of 2,060 cells and generate an average of 244 colonies in secondary cultures. Velocity sedimentation studies showed the compact-CFU to be similar in size to the MIX/E-CFU, sedimenting at rates between 3.5 and 7 mm/hour. In addition to giving rise to large numbers of in vitro CFU, compact-CFU are also able to generate day 8 spleen colony-forming units (CFU-S).


Clinical Considerations of Obstructive Sleep Apnea with Little REM Sleep.
Obstructive sleep apnea (OSA) is more severe during rapid eye movement (REM) sleep than during non-REM sleep. We aimed to determine the features of patients with OSA who experience little REM sleep. Patients with a chief complaint of sleep-disordered breathing were enrolled. All subjects underwent overnight polysomnography (PSG) and completed questionnaires on sleep quality. Patients were divided into the following three groups according to the proportion of REM sleep detected in overnight PSG: little REM sleep [REM sleep <20% of total sleep time (TST)], normal REM sleep (20-25% of TST), and excessive REM sleep (>25% of TST). Multiple logistic regression analyses were applied to the data. The success rate of continuous positive airway pressure (CPAP) titration was estimated in these groups. The age and body mass index of the patients were 47.9±15.9 years (mean±SD) and 25.2±4.1 kg/m², respectively. The 902 patients comprised 684 (76%) men and 218 (24%) women. The apnea-hypopnea index (AHI) in the little-REM-sleep group was 22.1±24.4 events/hour, which was significantly higher than those in the other two groups (p<0.05). Multiple logistic regression showed that a higher AHI (p<0.001; odds ratio, 1.512; 95% confidence interval, 1.020-1.812) was independently predictive of little REM sleep. The titration success rate was lower in the little-REM-sleep group than in the normal-REM-sleep group (p=0.038). The AHI is higher and the success rate of CPAP titration is lower in OSA patients with little REM sleep than those with normal REM sleep.


Effect of miR-203 expression on myocardial fibrosis.
Cardiovascular disease is one of the diseases threatening human health. Myocardial fibrosis is a major cause of cardiovascular diseases. Studies have shown that over expression of miR-203 can inhibit the fibrosis. Therefore, in this study, the effect of differential expression of miR-203 on fibrosis of cultured mouse cardiomyocytes was investigated. Activators and inhibitors of miR-203 were designed according to the sequence of miR-203, synthesized, and transfected into mouse cardiomyocytes to establish activator group, inhibitor group, and control group. The expression levels of fibrosis-related factors including FN, CTGF, and TGF-β1 were measured by Western blot and RT-PCR 24 h and 36 h after transfection. Over-expression of miR-203 in mouse cardiomyocytes significantly decreased the expression levels of TGF-β1, CTGF, and FN in a time-dependent manner, compared with that in the control group (p <0.05). Inhibition of miR-203 expression in mouse cardiomyocytes significantly increased the expression levels of TGF-β1, CTGF, and FN 36 h after transfection, compared with that in the control group (p < 0.05). No significant differences were seen in the expression levels of TGF-β1, CTGF, and FN 24 h after transfection, compared with that in the control group (p >0.05). Over-expression of miR-203 in mouse cardiomyocytes significantly decreased the expression levels of TGF-β1, CTGF, and FN, which might be used as a detection index for prediction of fibrosis.


Temporary uterine artery occlusion for treatment of menorrhagia and uterine fibroids using an incisionless Doppler-guided transvaginal clamp: case report.
We report the successful treatment of a 43-year-old woman with menorrhagia and multiple uterine fibroids by temporary uterine artery occlusion. Using a Doppler-guided transvaginal clamp, her uterine arteries were non-invasively identified and occluded by mechanical compression against the cervix for 6 h. Following removal of the clamp, blood flow in the uterine arteries returned immediately. Menorrhagia symptoms were tracked with the Ruta Menorrhagia Severity Scale. Uterine and fibroid volumes were measured by analysis of magnetic resonance images. The patient's self-reported menorrhagia symptoms were significantly reduced at 6 months (70% reduction in Ruta score) and both uterine volume and fibroid volume had decreased by more than 44% at 6 months. This case report illustrates the potential applicability of a simple-to-use, non-surgical device for the treatment of menorrhagia and uterine fibroids by temporary uterine artery occlusion.


Help seeking for mental health problems in an adolescent population: the effect of gender.
Background: While the onset of many mental health problems occurs in adolescence, these problems are severely undertreated in this age group. To inform early intervention for adolescents, we investigated the effect of gender and education type on perception of barriers to help seeking, mental health literacy, and the awareness and use of mental health services. Method: A web-based survey using vignettes, open-ended and multiple choice items was administered to upper secondary school students in two counties in Norway. Results: The survey was completed by 1249 students (88% response rate) with an average age of 17.6 years and 56% were female. Compared to males, the females were better in identifying psychological problems of anxiety and trauma, awareness of mental health services (p < 0.001) and perceived more barriers for seeking help (cost and waiting time; p < 0.001). For use of all mental health services, the effect of education type was greater than the effect of gender. Conclusion: For adolescents, gender appears to play a significant, but not exclusive, role in the inclination to seek professional help for mental health problems. We hypothesise that the observed gender difference in use of services is related to the gender difference in awareness of referral pathway services and the influence of parents in help-seeking process.


Treatment of acne scarring with fractional CO2 laser.
Fractional ablative CO(2) laser therapy is based on the theory of fractional photothermolysis. It can be effective in treating acne scars in a less invasive fashion than conventional ablative CO(2) laser therapy. In this clinical study, the safety and efficacy of a novel CO(2) fractional ablative laser was investigated for the treatment of facial atrophic acne scarring in Chinese individuals. A total of 31 patients (11 females, 20 males, Fitzpatrick skin phototypes III-IV) with facial acne scarring received three sequential fractional treatments over a 6-month period. Outcome measurements included blinded evaluations of before and after photographs by two physicians at 3 and 12 months after the final treatment. Global improvement was noted as well as any untoward events. At the 12 months follow-up time period, 12.9% of the patients showed excellent improvement in their acne scars, while 38.71% noted good to fair results. The clinical response at the 12-month follow-up visit tended to be better than at the 3-month follow-up visit, but was not statistically significant. Four patients experienced post-treatment and transient PIH but three patients were noted to have prolonged erythema. There was no evidence hypopigmentation or worsening of the scarring in any of the study patients. This high-energy pulsed and cool-scanned fractional ablative CO(2) laser system is safe and effective for facial atrophic acne scarring. Improvement in scarring was noted in the majority of patients with minimal discomfort and minimal downtime. Continued improvement over time is also an important clinical finding.


Evidence of a distinct lipid fraction in historical parchments: a potential role in degradation?
Parchment, a biologically based material obtained from the processed hides of animals such as cattle and sheep, has been used for millennia as a writing medium. Although numerous studies have concentrated on the structure and degradation of collagen within parchment, little attention has been paid to noncollagenous components, such as lipids. In this study, we present the results of biochemical and structural analyses of historical and newly manufactured parchment to examine the potential role that lipid plays in parchment stability. The lipid fraction extracted from the parchments displayed different fatty acid compositions between historical and reference materials. Gas chromatography, small-angle X-ray scattering, and solid-state NMR were used to identify and investigate the lipid fraction from parchment samples and to study its contribution to collagen structure and degradation. We hypothesize that the origin of this lipid fraction is either intrinsic, attributable to incomplete fat removal in the manufacturing process, or extrinsic, attributable to microbiological attack on the proteinaceous component of parchments. Furthermore, we consider that the possible formation of protein-lipid complexes in parchment over the course of oxidative degradation may be mediated by reactive oxygen species formed by lipid peroxidation.


Radiological manifestations of COVID-19: key points for the physician.
The emergence of the SARS-CoV-2 virus at the end of 2019 has led to unprecedented demand on healthcare systems around the world. Healthcare workers, including doctors, have found themselves having to work in unfamiliar environments in the effort to control this pandemic. This article gives the hospital physician an overview of the radiological manifestations of COVID-19 disease, to improve knowledge and increase familiarity when reviewing radiographic images.


Pathogenicity of aseptic Bursaphelenchus xylophilus.
Pine wilt is a disease of pine (Pinus spp.) caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus. However, the pathogenic mechanism of pine wilt disease (PWD) remains unclear. Although the PWN was thought to be the only pathogenic agent associated with this disease, a potential role for bacterial symbionts in the disease process was recently proposed. Studies have indicated that aseptic PWNs do not cause PWD in aseptic pine trees, while PWNs associated with bacteria cause wilting symptoms. To investigate the pathogenicity of the PWN and its associated bacteria, 3-month-old microcuttings derived from certain clones of Pinus densiflora Siebold & Zucc. produced in vitro were inoculated under aseptic conditions with aseptic PWNs, non-aseptic PWNs and bacteria isolated from the nematodes. Six-month-old aseptic P. densiflora microcuttings and 7-month-old P. massoniana seedlings were also inoculated under aseptic conditions with aseptic PWNs and non-aseptic PWNs. The results showed that the aseptic microcuttings and seedlings inoculated with aseptic PWNs or non-aseptic PWNs wilted, while those inoculated with bacterial isolates did not wilt. Nematodes were recovered from wilted microcuttings and seedlings inoculated with aseptic PWNs and non-aseptic PWNs, and the asepsis of nematodes recovered from aseptic PWN-inoculated microcuttings and seedlings was reconfirmed by culturing them in NB liquid medium at 30°C for more than 7 days. Taken together, the results indicate that the asepsis of PWN did not cause the loss of pathogenicity.


Fluorescence of yeast vitally stained with ethidium bromide and propidium iodide.
Both ethidium bromide and propidium iodide stain growing yeast. As visualized in the fluorescence microscope, ethidium stains the nucleus and cytoplasm in wild type yeast and in those grown in 10% dextrose, with brightly fluorescent cytoplasmic granules being present in both. Under the latter conditions, the mitochondria are repressed but not absent. In rho 0 cells, in which the mitochondrial DNA is absent, ethidium appears to bind to the cell wall or membrane preferentially with no cytoplasmic granules being visible. In all cell types, propidium appears to bind the cell wall or membrane with no cytoplasmic granules being visible in any cell. The staining patterns thus suggest greater differences in the binding of these two types to mitochondrial DNA in situ than is suggested by their in vitro behavior. These differences in binding could explain their different mutagenic capacities..


From Elemental Sulfur to Hydrogen Sulfide in Agricultural Soils and Plants.
Sulfur is an essential element in determining the productivity and quality of agricultural products. It is also an element associated with tolerance to biotic and abiotic stress in plants. In agricultural practice, sulfur has broad use in the form of sulfate fertilizers and, to a lesser extent, as sulfite biostimulants. When used in the form of bulk elemental sulfur, or micro- or nano-sulfur, applied both to the soil and to the canopy, the element undergoes a series of changes in its oxidation state, produced by various intermediaries that apparently act as biostimulants and promoters of stress tolerance. The final result is sulfate S+6, which is the source of sulfur that all soil organisms assimilate and that plants absorb by their root cells. The changes in the oxidation states of sulfur S0 to S+6 depend on the action of specific groups of edaphic bacteria. In plant cells, S+6 sulfate is reduced to S-2 and incorporated into biological molecules. S-2 is also absorbed by stomata from H2S, COS, and other atmospheric sources. S-2 is the precursor of inorganic polysulfides, organic polysulfanes, and H2S, the action of which has been described in cell signaling and biostimulation in plants. S-2 is also the basis of essential biological molecules in signaling, metabolism, and stress tolerance, such as reactive sulfur species (RSS), SAM, glutathione, and phytochelatins. The present review describes the dynamics of sulfur in soil and plants, considering elemental sulfur as the starting point, and, as a final point, the sulfur accumulated as S-2 in biological structures. The factors that modify the behavior of the different components of the sulfur cycle in the soil-plant-atmosphere system, and how these influences the productivity, quality, and stress tolerance of crops, are described. The internal and external factors that influence the cellular production of S-2 and polysulfides vs. other S species are also described. The impact of elemental sulfur is compared with that of sulfates, in the context of proper soil management. The conclusion is that the use of elemental sulfur is recommended over that of sulfates, since it is beneficial for the soil microbiome, for productivity and nutritional quality of crops, and also allows the increased tolerance of plants to environmental stresses.


Coumarin-Spiropyran Dyad with a Hydrogenated Pyran Moiety for Rapid, Selective, and Sensitive Fluorometric Detection of Cyanide Anion.
We synthesized a coumarin-spiropyran dyad with a hydrogenated pyran moiety (2), behaving as an off-on type fluorescent receptor for rapid, selective, and sensitive detection of cyanide anion (CN(-)) in aqueous media. The receptor itself shows almost no fluorescence with a quantum yield < 0.01, due to the delocalization of π-electrons over the molecule. Selective nucleophilic addition of CN(-) to the spirocarbon of the molecule rapidly promotes spirocycle opening within only 3 min. This leads to localization of π-electrons on the coumarin moiety and exhibits strong light-blue fluorescence at 459 nm with very high quantum yield (0.52). As a result of this, the receptor facilitates rapid, selective, and sensitive fluorometric detection of CN(-) as low as 1.0 μM.


[Diagnostic Possibilities of Speckle-Tracking Echocardiography].
The review is devoted to merits and demerits of a new method of assessment of condition of the heart - speckle-tracking echocardiography. Speckle-tracking echocardiography is a perspective method allowing to register disorders of both global and regional contractile motion.


Expression of fibronectin and a fibronectin-binding molecule during preimplantation development in the mouse.
Using an indirect immunofluorescent technique, expression of cell surface fibronectin and a cell surface fibronectin-binding molecule was studied during mouse embryo preimplantation development. We also studied the expression of fibronectin on immunosurgically isolated inner cell masses (ICMs) and regenerated mouse blastocysts. Fibronectin and the fibronectin-binding molecule were not detected at the morula stage. From the early to late blastocyst stage, fibronectin expression increased on the trophectoderm. Expression of the fibronectin-binding molecule was found only in the polar trophectoderm region of the early blastocyst, then in the polar and mural trophectoderm regions of the middle blastocyst. In the late blastocyst stage, this fibronectin-binding molecule was only present in the mural trophectoderm. Fibronectin expression by ICMs of early blastocysts was more intense than that of late blastocysts. After 24 h of culture, 10% of ICMs isolated from early blastocysts regenerated a trophectoderm which stained intensively for fibronectin in the mural and polar trophectoderm regions. After 48 h of culture, regenerated blastocyst-like structures closely resembled the normally obtained late blastocysts and stained for fibronectin in the mural and polar trophectoderm regions. The significance of the results is discussed in relation to mouse embryo development, trophectoderm formation and blastocyst implantation.


The Effect of Teach-Back Combined with King Interactive Standard Mode on the Life of COPD Patients.
COPD is a common clinical chronic airway inflammatory disease that occurs mostly in middle-aged and older adults over the age of 40. The incidence of COPD is increasing year by year and the onset of age is gradually becoming younger. To observe the effect of teach-back combined with king interaction on the life of patients with chronic obstructive pulmonary disease (COPD). A total of 100 COPD patients admitted to our hospital from Jan 2021 to Jan 2022 were retrospectively selected to be divided into 50 cases in the control group and 50 cases in the observation group according to the nursing methods. The control group was treated with routine nursing intervention, while the observation group was treated with teach-back combined with king interactive standard mode intervention. The differences in Self-Care Ability Assessment Scale (ESCA) score, St. George's Respiratory Questionnaire (SGRQ) score, Mental State Assessment Scale (MSSNS) score, 6-minute walking distance (6MWD), and pulmonary function indexes were compared between the two groups before and after the intervention. The success rate and patient compliance of each index in the groups were also recorded. After 3 months and 6 months of intervention, the total SGRO score and its factor scores of self-care skills, self-care responsibility, self-concept, health knowledge level in them were all higher than those before the intervention, while the total SGRO score and its factor scores of respiratory symptoms, activity limitation, disease influence, and so on were all decreased compared with those before the intervention. The ESCA score of the observation group was significantly higher than that of the control one after 3 months and 6 months of intervention, while the SGRQ score was significantly lower than that of the control one, with statistical significance (P < 0.05). After 3 months of intervention, the total score of MSSNS and the scores of anxiety, depression, loneliness, and other factors in both groups were decreased compared with those before intervention. After 6 months of intervention, the total score of MSSNS and scores of each factor in both groups were decreased compared with those before intervention, and the MSSNS scores in the observation group were significantly lower than those in the control group after the intervention, which was statistically significant (P < 0.05). After 3 months and 6 months of intervention, 6MWD, forced vital capacity (FVC), forced expiratory value in 1 second (FEV1), and FVC/FEV1 in them were all higher than those before intervention, and 6MWD and pulmonary function were significantly higher in the observation group than in the control group after 3 and 6 months of intervention, which was statistically significant (P < 0.05). The ESCA score, SGRQ score, MSSNS score, pulmonary function compliance rate, and compliance rate in the observation group were significantly higher than those in the control group, which was statistically significant (P < 0.05). The use of teach-back combined with king interactive standard mode in COPD patients can improve the patient's self-care ability, reduce psychological negative emotions, and improve the quality of life.


Using the Referral Decision Scale to screen mentally ill jail detainees: validity and implementation issues.
The prevalence of serious mental illnesses in jail populations is significantly greater than in the general population. Identifying individuals who warrant psychiatric evaluations is important and benefits correctional staff as well as detainees. One widely used screening instrument intended for this task is the Referral Decision Scale (RDS). This paper reviews the development and validation of the RDS. Using data from a multisite study which assessed postrelease outcomes for detainees with mental illness, various types of validity are addressed. The results confirm that the RDS has some inherent characteristics that seriously limit its practical application as a screening instrument for use by correctional staff.


Development of color tunable aqueous CdS-cysteine quantum dots with improved efficiency and investigation of cytotoxicity.
Cysteine capped aqueous CdS quantum dots with improved luminescence and excellent colloidal-luminescence stability were developed in a simple one pot aqueous method from safer precursors at low temperatures. Investigation of size and luminescence as a function of cysteine amount, pH and temperature revealed an optimum value for all these variables to maximize the quantum yield. Cysteine:Cd ratio of 2, reaction pH of 9.5 and synthesis at room temperature-30 degrees C emerged as the best conditions for the highest QY of 19%. Yet, QY can be improved up to 55% if QDs are cleaned from excess cysteine and ions and redispersed in pH 7 medium. Size of the QDs, therefore the color of luminescence, can be tuned by the reaction temperature in this simple process. Higher temperatures provide larger particles. Cell uptake and cell viability studies in a wide range of doses and different incubation times with MCF-7 and HeLa cell lines revealed cell dependent differences. MCF-7 cells uptake more QDs but are much more viable than HeLa cells. At low doses such as 0.025 mg QD/ml all cells are viable. At 24 h incubation times MCF-7 cells demonstrate viability above 75% up to 0.15 mg QD/mI. On the other hand HeLa cells loose viability with increasing dose.


[A comparison of respiratory muscle strength, pulmonary function tests and endurance in patients with early and late stage ankylosing spodylitis].
Ankylosing spondylitis (AS) is a multisystemic disease in which pulmonary function is altered owing mainly to the restriction of chest wall involvement. A restrictive ventilatory defect has been extensively reported. This has been suggested to be a consequence of reduced mobility of the thoracic cage. Respiratory function in AS shows a typical restrictive pattern but pulmonary compliance, diffusion capacity, and arterial blood gases are normal. The objective of the present study was to compare pulmonary function tests (PFT), respiratory muscle strength (MIP, MEP) and endurance (MVV) in early and late AS. A total of 35 patients (30 males, 5 females) took part, all of whom met the New York criteria for AS. Patients were divided into two groups for the comparison of early (disease duration <10 years, 20 patients) and late (disease duration >10 years, 15 patients) manifestations in pulmonary function tests, respiratory muscle strength and endurance, dyspnea score, chest expansion, and BASFI score. In addition, 21 healthy controls were compared with the AS patients. Measurement of chest expansion was performed in all subjects. Pulmonary function tests were performed by spirometry. Respiratory muscle strength was evaluated by a mouth pressure meter (MPM). Functional status was assessed by BASFI in all AS patients. There was no significant difference in body mass index between the groups. The FVC and FEV(1) were significantly lower in late AS (p=0.003, p=0.03, restrictive ventilatory defect ). Chest expansion was significantly lower in late AS (p<0.05). There was no significant difference for MIP or MEP values between late AS, early AS and the controls (p>0.05). Endurance (MVV) was significantly lower in late AS patients (p=0.05). Although the BASFI and dyspnea scores were higher in late AS, they did not reach significant levels. In addition, age was negatively correlated with MIP and MEP in late AS (r=-0.733; p=0.02, r=-0.667; p=0.05). This study demonstrates that FVC and FEV(1) (hallmarks of a restrictive pattern), MVV (endurance) and chest expansion are especially involved in long-standing AS. Therefore, improvement of the thoracic cage should be taken into consideration, especially in early AS. These patients should be encouraged to make regular respiratory exercises for preventing the limitation of chest expansion and also improving cardiopulmonary fitness and respiratory endurance.


Eyelid abscess as a presenting sign of occult sinusitis.
To describe 5 patients who presented with eyelid abscesses whose subsequent workup revealed occult sinusitis. We reviewed the medical records of 5 patients who presented with eyelid abscess. Common presenting signs and symptoms were identified. Successful diagnosis and treatment was accomplished in each case. All patients were in good general health and did not appear to be systemically ill. Eyelid swelling was the chief presenting complaint of each patient. None of the patients complained of fevers or chills. Each patient had an upper eyelid abscess. Symptoms suggestive of sinusitis included purulent nasal discharge and headache. With appropriate radiologic studies, extensive occult sinusitis was identified in each case. Two patients demonstrated a small defect in the bone between the infected frontal sinus and the eyelid. All patients received intravenous antibiotics followed by oral antibiotics, incision and drainage of the abscess, and, after ENT consultation, functional endoscopic sinus surgery. All patients improved after treatment, and none had permanent visual loss. Clinical suspicion of sinusitis may be aroused with a thorough history and examination. Radiographic evaluation and prompt treatment of both the eyelid abscess and the sinusitis can result in good outcomes for such patients.


Wrong-Patient Orders in Obstetrics.
To compare rates of wrong-patient orders among patients on obstetric units compared with reproductive-aged women admitted to medical-surgical units. This was an observational study conducted in a large health system in New York between January 1, 2016, and December 31, 2018. The primary outcome was near-miss wrong-patient orders identified using the National Quality Forum-endorsed Wrong-Patient Retract-and-Reorder measure. All electronic orders placed for eligible patients during the study period were extracted retrospectively from the health system data warehouse, and the unit of analysis was the order session (consecutive orders placed by a single clinician for a patient within 60 minutes). Multilevel logistic regression models were used to estimate odds ratios (ORs) and 95% CIs comparing the probability of retract-and-reorder events in obstetric and medical-surgical units, overall, and in subgroups defined by clinician type and order timing. Overall, 1,329,463 order sessions were placed during the study period, including 676,643 obstetric order sessions (from 45,436 patients) and 652,820 medical-surgical order sessions (from 12,915 patients). The rate of 79.5 retract-and-reorder events per 100,000 order sessions in obstetric units was significantly higher than the rate in the general medical-surgical population of 42.3 per 100,000 order sessions (OR 1.98, 95% CI 1.64-2.39). The obstetric retract-and-reorder event rate was significantly higher for attending physicians and house staff compared with advanced practice clinicians. There were no significant differences in error rates between day and night shifts. Order errors occurred more frequently on obstetric units compared with medical-surgical units. Systems strategies shown to decrease these events in other high-risk specialties should be explored in obstetrics to render safer maternity care.


Phallic narcissism, anal sadism, and oral discord: the case of Yukio Mishima, Part I.
Thus far I have explored Mishima's traumatic childhood and the experiences leading him toward misogyny, phallic narcissism, and the drive to murder his own weakness and sexual vulnerability. Mishima suffered the extraordinary trauma of being separated from his parents and sequestered to the sickroom of a psychotic grandmother for the first twelve years of his life. Intense rage over abandonment and impingement engendered a disgust for femininity and the need to escape feminine messiness through homosexual pursuits. Mishima's entrenched feelings of shame and weakness gave rise to phallic narcissistic tendencies, as he idealized powerful men and eventually strove to become a powerful and beautiful male. In pursuing this erotic masculine image Mishima continued to fantasize about murdering his weak and shameful self-image, and commingled this sadistic impulse with fantasies of sexual merger with murdered love objects. Finally Mishima was the murderer erotically eradicating his sexual vulnerability as both subject and object. His suicide was a repetition of this erotic sadistic fantasy. In a further article I will continue the discussion by examining Mishima's fantasies of murdering beautiful and abandoning love objects. I will also address the complex nature of his ritual suicide as fantasy of rebirth, sexual merger, the murder of toxic introjects, and escape from death, decay, and regression to helpless infancy.


[Autologous blood transfusion in transurethral resection of the prostate].
With the purpose to avoid the risk of transfusion mediated infection and complication, predeposited autologous blood transfusion was performed. From April 1990 to March 1991, transurethral resection of the prostate (TUR-P) were performed in 27 patients (mean age: 72.5 years) with benign prostatic hypertrophy (BPH). Autologous blood (200-400 ml, mean 244 ml) was predeposited 3 weeks prior to TUR-P in 18 patients (mean age: 73.9 years) and transfused during or just after the operation in 16 (five patients required some homologous blood in addition to their own banked blood). Another three patients were transfused with homologous blood only. The mean values for hemoglobin concentration were 13.7 +/- 0.4 g/dl before blood deposition and 12.8 +/- 0.5 g/dl on the day of operation (recovery rate: 92.5 +/- 2.7%). Although no complication was found in autologous blood transfusion group (11 patients), one case of systemic exanthema and one case of type C hepatitis were observed in homologous blood transfusion group (8 patients). In TUR-P, positive correlations were observed among resected prostate weight (Pro-wt), blood loss (B.) and operation time (Op-T.). Correlation efficient between Pro-wt. and B. was 0.80, that of B. and Op-T. was 0.77 and that of Pro-wt. and Op-T. was 0.85. From these results and ultransomographic measurement of the prostate weight, the amount of blood loss can be calculated preoperatively, there by the amount of blood needed for transfusion will be estimated.(ABSTRACT TRUNCATED AT 250 WORDS)


Update on biphasic anaphylaxis.
Biphasic anaphylaxis is a well documented complication of anaphylaxis, but it has been inconsistently defined in the literature. Analysis of contemporary studies of biphasic anaphylaxis based on modern definitions is needed. The rate of biphasic reactions in contemporary literature ranges from 0.4 to 14.7% depending on the study population. Observational studies have reported risk factors associated with the development of biphasic reactions; however, findings have been inconsistent and of questionable generalizability. Although life-threatening biphasic reactions are rare, up to 50% of biphasic reactions will require treatment with epinephrine. Early epinephrine administration may have a role in prevention of biphasic reactions, but the role of steroids needs further investigation. The optimal duration of observation is yet to be determined. Given the relative rarity of life-threatening biphasic anaphylaxis and the new context of the NIAID/FAAN standardized definition, further research regarding biphasic anaphylaxis is needed to better elucidate the care model for anaphylaxis patients with a focus on: prevention of biphasic reactions; identification of patients at increased risk of a biphasic reaction; determination of appropriate observation strategies for anaphylaxis patients; and patient education and preparation for management of potential biphasic reactions.


Bastion6: a bioinformatics approach for accurate prediction of type VI secreted effectors.
Many Gram-negative bacteria use type VI secretion systems (T6SS) to export effector proteins into adjacent target cells. These secreted effectors (T6SEs) play vital roles in the competitive survival in bacterial populations, as well as pathogenesis of bacteria. Although various computational analyses have been previously applied to identify effectors secreted by certain bacterial species, there is no universal method available to accurately predict T6SS effector proteins from the growing tide of bacterial genome sequence data. We extracted a wide range of features from T6SE protein sequences and comprehensively analyzed the prediction performance of these features through unsupervised and supervised learning. By integrating these features, we subsequently developed a two-layer SVM-based ensemble model with fine-grain optimized parameters, to identify potential T6SEs. We further validated the predictive model using an independent dataset, which showed that the proposed model achieved an impressive performance in terms of ACC (0.943), F-value (0.946), MCC (0.892) and AUC (0.976). To demonstrate applicability, we employed this method to correctly identify two very recently validated T6SE proteins, which represent challenging prediction targets because they significantly differed from previously known T6SEs in terms of their sequence similarity and cellular function. Furthermore, a genome-wide prediction across 12 bacterial species, involving in total 54 212 protein sequences, was carried out to distinguish 94 putative T6SE candidates. We envisage both this information and our publicly accessible web server will facilitate future discoveries of novel T6SEs. http://bastion6.erc.monash.edu/. Supplementary data are available at Bioinformatics online.


Turkey Hemorrhagic Enteritis Virus Can Be Titrated but Not Propagated in Chicken Embryos.
This study aimed to investigate the feasibility of propagating and titrating hemorrhagic enteritis virus (HEV) in chicken embryos. A total of 308 embryonated eggs were used. At 10 days of embryonic age, eggs were inoculated via allantoic sac or chorioallantoic membrane routes with non-heat-treated (live) HEV or heat-treated (dead) HEV or served as negative controls. Allantoic fluid retrieved at 0, 1, 3, 5, and 7 days postinoculation (dpi) was tested for HEV by quantitative PCR. Inoculation with HEV did not cause visible growth impairment or lesions in the chicken embryos. Overall, there was no difference in postinoculation mortality rates among groups sham-inoculated (6/30, 20.0%) or inoculated with live (34/252, 13.4%) or dead (3/ 26, 6.9%) HEV (P = 0.58). The amount of HEV DNA detected in allantoic fluid at 7 dpi in eggs inoculated with live virus was similar to the inoculated dose, indicating that virus propagation in chicken embryos is not efficient. No HEV DNA was detected after 3 dpi in eggs inoculated with dead virus. Inoculation of chicken embryos combined with qualitative PCR can be used for titration of HEV virus stocks and presents a high correlation with in vivo titration using chickens (R2 0.98, P = 0.007). This method may be relevant in countries in which specific-pathogen-free turkeys are unavailable and in which the importation of RP19 cells, the only cell that supports effective propagation of HEV, is not permitted.


Hairy cell leukemia and allied chronic lymphoid leukemias: current knowledge and new therapeutic options.
This review deals mainly with the essentials of hairy cell leukemia (HCL) detailing clinical aspects, laboratory findings and morphology. Rare manifestations of HCL are listed. Newer aspects relating to cytokines, soluble interleukin receptors and TNF are reviewed. Differential diagnosis including HCL-variant, SLVL, PLL and CLL/PLL are discussed. Prognostic factors and in particular therapeutic aspects are detailed with particular emphasis on the new purine analogues Pentostatin and 2-CdA. A list of suggested reading is offered.


Simplified northern blot hybridization using 5% sodium dodecyl sulfate.
We describe a simplified Northern blot hybridization procedure. This procedure eliminates the need for many reagents commonly used in RNA hybridization and replaces them with two buffers containing 5% sodium dodecyl sulfate for pre-hybridization, hybridization and all post-hybridization washes.


A case of partial congenital pericardial defect presenting as acute coronary syndrome.
Congenital pericardial defects are rare and asymptomatic for both partial and complete defects. However, some patients can experience syncope, arrhythmia, and chest pain. When a patient experiences a symptom, it may be caused by herniation and dynamic compression or torsion of a heart structure including the coronary arteries. Diagnosis of a congenital pericardial defect may be difficult, especially in old patients with concomitant coronary artery disease. The clinical importance of congenital pericardial defect has not been stressed and congenital pericardial defects are regarded as benign, but in this case, pericardial defect was responsible for myocardial ischemia. The authors report a case of partial congenital pericardial defect causing herniation and dynamic compression of the coronary arteries, presenting as an acute coronary syndrome in an old man, with an emphasis on the unique features of the coronary angiogram that support the diagnosis of partial pericardial defects.


Concerted genomic and epigenomic changes accompany stabilization of Arabidopsis allopolyploids.
During evolution successful allopolyploids must overcome 'genome shock' between hybridizing species but the underlying process remains elusive. Here, we report concerted genomic and epigenomic changes in resynthesized and natural Arabidopsis suecica (TTAA) allotetraploids derived from Arabidopsis thaliana (TT) and Arabidopsis arenosa (AA). A. suecica shows conserved gene synteny and content with more gene family gain and loss in the A and T subgenomes than respective progenitors, although A. arenosa-derived subgenome has more structural variation and transposon distributions than A. thaliana-derived subgenome. These balanced genomic variations are accompanied by pervasive convergent and concerted changes in DNA methylation and gene expression among allotetraploids. The A subgenome is hypomethylated rapidly from F1 to resynthesized allotetraploids and convergently to the T-subgenome level in natural A. suecica, despite many other methylated loci being inherited from F1 to all allotetraploids. These changes in DNA methylation, including small RNAs, in allotetraploids may affect gene expression and phenotypic variation, including flowering, silencing of self-incompatibility and upregulation of meiosis- and mitosis-related genes. In conclusion, concerted genomic and epigenomic changes may improve stability and adaptation during polyploid evolution.


Distinct Roles for Interfacial Hydration in Site-Specific DNA Recognition by ETS-Family Transcription Factors.
The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. Unlike other ETS homologues, such as Ets-1, DNA recognition by PU.1 is highly sensitive to its osmotic environment due to excess interfacial hydration in the complex. To investigate interfacial hydration in the two homologues, we mutated a conserved tyrosine residue, which is exclusively engaged in coordinating a well-defined water contact between the protein and DNA among ETS proteins, to phenylalanine. The loss of this water-mediated contact blunted the osmotic sensitivity of PU.1/DNA binding, but did not alter binding under normo-osmotic conditions, suggesting that PU.1 has evolved to maximize osmotic sensitivity. The homologous mutation in Ets-1, which was minimally sensitive to osmotic stress due to a sparsely hydrated interface, reduced DNA-binding affinity at normal osmolality but the complex became stabilized by osmotic stress. Molecular dynamics simulations of wildtype and mutant PU.1 and Ets-1 in their free and DNA-bound states, which recapitulated experimental features of the proteins, showed that abrogation of this tyrosine-mediated water contact perturbed the Ets-1/DNA complex not through disruption of interfacial hydration, but by inhibiting local dynamics induced specifically in the bound state. Thus, a configurationally identical water-mediated contact plays mechanistically distinct roles in mediating DNA recognition by structurally homologous ETS transcription factors.


Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice.
To examine further the genetic determinants of cholesterol gallstone susceptibility in inbred mice, we performed quantitative trait locus (QTL) analysis of an intercross of gallstone-susceptible PERA/EiJ and gallstone-resistant DBA/2J inbred mice. Three hundred twenty-four F2 offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers. Linkage analysis was performed by interval mapping. In addition, we analyzed the combined datasets from this cross and from an independent cross of strain PERA and gallstone-resistant I/Ln mice. QTL mapping detected one significant new gallstone susceptibility (Lith) locus on Chromosome 13 (Lith15). A second significant QTL on Chr 6 (Lith16) confirmed a previous QTL. Furthermore, suggestive QTLs confirmed Lith loci from previous crosses on Chromosomes 1, 2, 5, 16 and X. QTL analysis of the dataset derived from the combined crosses increased the detection power and narrowed confidence intervals of Lith loci on Chromosomes 2, 6, 13, and 16. Moreover, the analysis of combined datasets revealed a shared QTL between both crosses on Chromosome 17 (Lith9). Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9.


Mathematical Model for the Industrial SMTO Reactor with a SAPO-34 Catalyst.
The methanol-to-olefins (MTO) technology creates a new non-oil route to produce light olefins. This paper reports a 14-lump MTO kinetic model for SAPO-34 catalyst, combined with the hydrodynamic model for the fast fluidized bed reactor of the industrial SMTO process. Selective deactivation is considered to quantify the product selectivity and abrupt catalytic activity change. Moreover, referring to the parallel compartment (PC) model, the activity difference between the circulating spent catalyst and the regenerated catalyst is considered. The validation results with the optimized kinetic parameters showed good agreement between the calculated value and the actual value. Sensitivity analysis of the industrial SMTO process was performed. According to the results, the established mathematical model can provide guidance for industrial production operations.


Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing.
Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain processing is present in many chronic pain conditions and can influence responses to specific therapies. Thus, the ability to precisely describe the state of central pain processing has profound clinical significance in both prognosis and prediction. Because it is not practical to record neuronal firings directly in the human spinal cord, surrogate behavior tests become an important tool to assess the state of central pain processing. Dynamic QST is one such test, and can probe both the ascending facilitation and descending modulation of incoming nociceptive signals via TS and CPM, respectively. Due to the large between-individual variability in the sensitivity to noxious signals, standardized TS and CPM tests may not yield any meaningful data in up to 50% of the population due to floor or ceiling effects. We present methodologies to individualize TS and CPM so we can capture these measures in a broader range of individuals than previously possible. We have used these methods successfully in several studies at the lab, and data from one ongoing study will be presented to demonstrate feasibility and potential applications of the methods.


Plants under attack II.
In many diseases of plants there is a well defined genetic relationship between host and pathogen, the host possessing resistance genes and the pathogen possessing avirulence genes. Where these are cognate their products interact and trigger a variety of resistance responses, resulting in an incompatible interaction. Where they are not cognate the pathogen is not recognised and invades the host causing a compatible interaction. A few resistance genes and a larger number of avirulence genes have been cloned and this information has afforded us new perspectives of the recognition phenomenon itself and the means by which virulent pathogens avoid being recognised. Mechanisms of resistance range from preformed antimicrobial compounds to a series of components that are induced as a response to microbial challenge. Most of these induced reactions are preceded by and may be triggered by an oxidative burst which results in the cross-linking of cell wall proteins and also causes the death of one to several cells. This localized death of host cells, termed the hypersensitive response, provides an explanation for resistance to obligate parasites which require living host tissue but not for resistance to facultative parasites which colonise dying or dead tissue. However, the hypersensitive response appears to be intimately involved with several other defence responses such as the synthesis and accumulation of phytoalexins, lignification and the production of hydrolase enzymes that attack the invader. Salicylic acid has proved fundamental to the effecting of these defence responses and also to the phenomenon of systemic acquired resistance whereby a previous challenge from a pathogen induces the expression of enhanced resistance to a second challenge by the same or another organism. Despite these sophisticated defences plants still succumb to attack. Two of the weapons to which they are vulnerable and which are produced by many successful pathogens are toxins and enzymes. In some instances an understanding of these has pointed to novel methods of control supplementary to that obtained by conventional breeding for resistance.


TAVR Through Heavily Calcified Aorta Following Atheroma Retrieval With the "Elevator" Technique.
An 86-year-old Caucasian female with severe symptomatic, inoperable aortic stenosis was accepted for high-risk transfemoral transcatheter aortic valve replacement (TAVR) approach due to severe calcification of the aorta. During initial passage of a 22 Fr sheath, there was dislodgment with proximal migration of a circumferential tunnel of calcium from the infrarenal aorta. A novel "elevator" technique was used to secure and retrieve the dislodged aorta en bloc back to its original infrarenal aortic position and allow in situ fixation with stenting. A new TAVR system was then successfully placed through the stent and a 23 mm Edwards Sapien valve (Edwards Lifesciences) was implanted as planned. In case of calcification protruding into the lumen of the aorta and limiting the passage of the large valve delivery system sheath, the obstruction can be managed by stenting the calcification against the luminal wall under fluoroscopic and intravascular-ultrasound guidance, allowing successful passage of the valve delivery system. The elevator technique allows axial transportation of any calcified vascular fragments, should they become dislodged.


Risk of chemotherapy-induced pulmonary fibrosis is associated with polymorphic tumour necrosis factor-a2 gene.
In some patients, chemotherapy (CHT) of cancer can result in pulmonary inflammation and fibrosis, eventually leading to respiratory insufficiency. As animal studies have underlined the importance of major histocompatibility complex (MHC) genes in the susceptibility to bleomycin (BLM)-induced pulmonary fibrosis, the authors typed human leukocyte antigen-DR (HLA-DR) and tumor necrosis factor (TNF) genes in patients treated for Hodgkin's disease by a therapy including bleomycin. Patients were divided into pulmonary responders (PR) (n=21) or nonresponders (PNR) (n=20) on the basis of pulmonary alterations detected on chest radiography and the cumulated amount of BLM injected. The incidence of TNFa2, a microsatellite allele in the promoter region of the TNFB gene reported to be associated with increased TNF-a production, was significantly higher in PR than PNR (65% versus 19%). HLA-DRB1*15 showed a weak but nonsignificant association with the PR phenotype (50% versus 14%), as well as HLA-DRB1*03 (30% versus 19%) and TNFA-308*2 (30% versus 14%). TNFa2 and DR15 were independent risk factors and the occurrence of either genetic marker was 85% versus 29% in the PR and PNR groups respectively. Thus, the polymorphic TNFa2 microsatellite is associated with a risk of chemotherapy-induced pulmonary fibrosis.


A Multi-Mode Education Program to Enhance Asthma Care by Pharmacists.
Objective. To provide optimal asthma care, community pharmacists must have advanced, contemporary knowledge, and the skills to translate that knowledge into practice. The development and evaluation of an innovative multi-mode education program to enhance pharmacists' clinical knowledge and practical skills is described.Methods. The online education modules were collaboratively developed alongside asthma and pharmacy organizations. The education program was comprised of five evidence-based education modules delivered online and a skills review conducted either in-person with real-time feedback (urban pharmacists) or via video upload and scheduled video-conference feedback (regional and remote pharmacists). A mixed methods approach was used to evaluate the feedback obtained from pharmacists to assess the content, efficacy, and applicability of the education.Results. Ninety-seven pharmacists opted into the program and successfully completed all education requirements. A larger proportion of pharmacists did not pass trial protocol-based education modules on their first attempts compared to the number that passed the asthma and medication knowledge-based modules. Prior to skills review, the proportion of pharmacists demonstrating device technique competency was suboptimal. Pharmacists rated the education modules highly in both quantitative and qualitative evaluations and reported that the program adequately prepared them to better deliver care to asthma patients.Conclusion. We developed, implemented, and evaluated a novel multi-mode asthma education program for community pharmacists that supports knowledge and practical skill development in this crucial area of patient care. The education program was well received by pharmacists. This form of education could be used more broadly in international collaborative trials.


Personal Health Train Architecture with Dynamic Cloud Staging.
Scientific advances, especially in the healthcare domain, can be accelerated by making data available for analysis. However, in traditional data analysis systems, data need to be moved to a central processing unit that performs analyses, which may be undesirable, e.g. due to privacy regulations in case these data contain personal information. This paper discusses the Personal Health Train (PHT) approach in which data processing is brought to the (personal health) data rather than the other way around, allowing (private) data accessed to be controlled, and to observe ethical and legal concerns. This paper introduces the PHT architecture and discusses the data staging solution that allows processing to be delegated to components spawned in a private cloud environment in case the (health) organisation hosting the data has limited resources to execute the required processing. This paper shows the feasibility and suitability of the solution with a relatively simple, yet representative, case study of data analysis of Covid-19 infections, which is performed by components that are created on demand and run in the Amazon Web Services platform. This paper also shows that the performance of our solution is acceptable, and that our solution is scalable. This paper demonstrates that the PHT approach enables data analysis with controlled access, preserving privacy and complying with regulations such as GDPR, while the solution is deployed in a private cloud environment.


A hydrophobic domain in glutamate transporters forms an extracellular helix associated with the permeation pathway for substrates.
Recent work has shown that cysteine residues introduced into domain 10, a highly hydrophobic segment in the excitatory amino acid transporter 1, react readily when hydrophilic sulfhydryl-modifying reagents are applied extracellularly. To investigate the functional contributions of this region, we mutated each residue in domain 10 (Ala(446)-Gly(459)) to cysteine and assessed the transport kinetics and inhibitor sensitivities of the mutant carriers. Modification of the introduced sulfhydryl group with membrane-impermeant methanethiosulfonate derivatives inhibited substrate transport by all but one functional cysteine mutant. Substrates and/or non-transported inhibitors block thiol modification of most mutants within this region, implying that access to the domain becomes restricted as a consequence of the binding of substrates and substrate analogs. An examination of the temperature dependence of substrate protection for one mutant (I453C) indicates that substrates prevent modification at a step prior to the large conformational changes associated with translocation. When superimposed on a helical model, mutants with similar attributes are positioned in close proximity. Our data are consistent with a model in which domain 10 exists as an alpha-helix at an aqueous interface of the translocation pathway, which can be directly occluded by substrates and inhibitors at an early step in the transport cycle.


Design and implementation of a core EPA-based acting internship curriculum.
The Association of American Medical Colleges published Core Entrustable Professional Activities (Core EPAs), expected independent clinical skills for first-day interns. We sought to determine whether a required acting internship (AI) in the fourth-year curriculum could be used for summative assessment of students' mastery of Core EPAs to a predefined level that would readily generalize across disciplines and campuses. The University of North Dakota School of Medicine and Health Sciences MD Program created a standardized, required Core EPA-based AI curriculum for multiple specialties at multiple geographic sites providing a final entrustability assessment for 10 EPAs in a single course. The course was successfully designed and launched for all students in a single class. During the AI, students functioned at the level of an acting intern, rated the courses as superior, and performed at satisfactory exit-level competence for 10 Core EPAs. A standardized, EPA-based AI curriculum can provide an opportunity for exit level EPA assessment in the medical curriculum. This model functions well within multiple specialties and at diverse community-based, volunteer faculty teaching sites.


Critical role of interleukin-1beta for transcriptional regulation of endothelial 6-pyruvoyltetrahydropterin synthase.
Synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases, is strongly induced on immunostimulation in vascular endothelial cells (VECs). Expression of GTP cyclohydrolase I (GTPCH), the first enzyme in BH4 biosynthesis, is regulated by cytokines and considered rate-limiting. Herein we investigated the molecular mechanism and relevance of cytokine-dependent regulation of 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme in BH4 synthesis, in human coronary artery endothelial cells (HCAECs). Real-time polymerase chain reaction revealed a 4-fold induction of PTPS and a 300-fold induction of GTPCH expression by interleukin (IL)-1beta/tumor necrosis factor-alpha/interferon-gamma, mainly through de novo transcription. On immunostimulation, PTPS became rate-limiting. Importantly, IL-1beta induced PTPS rather than GTPCH. As a result, IL-1beta contributed significantly to the amount of BH4 produced (+40%) but concomitantly reduced the accumulation of the GTPCH intermediate, 7,8-dihydroneopterin triphosphate (-50%). Our data show that PTPS induction is necessary for optimized BH4 synthesis in cytokine-stimulated HCAECs and point to IL-1beta as a leading cytokine in this process.


Adrenergic receptors in inner and outer layers of human myometrium near term: characterization of beta-adrenergic receptor sites by [125I]-iodocyanopindolol binding.
The beta-adrenergic receptors present in inner and outer layers of human myometrium near term were characterized using the radioiodinated antagonist iodocyanopindolol (ICYP). In both layers ICYP binding is saturable, rapidly reversible, stereoselective, and appears to occur in a single class of sites with a KD of 30 pmol/l. Adrenergic agonists compete for ICYP binding sites with an order of potency consistent with beta 2-adrenergic potencies: isoproterenol greater than epinephrine much greater than norepinephrine. Studies in which CGP 20712 A, a beta 1-adrenergic antagonist, competes for ICYP binding sites in human myometrium reveal that at least 65% of the beta-receptors present are beta 2-subtype, whatever the layer considered. At the 35th week of pregnancy, the density of beta-adrenergic receptors in the inner layer (15.2 fmol/mg of protein) is about 50% higher than in the outer layer. At term, the densities of beta-adrenergic receptors are reduced and exhibit the same values for both layers (5 fmol/mg of protein). These results indicate that the beta-adrenergic receptors in the two layers diminish during pregnancy and reach, at term, an equal and low level of density.


A twenty-year experience with endoscopic therapy for symptomatic primary sclerosing cholangitis.
The current study presents 1 tertiary endoscopy center's 20-year experience using endoscopic therapy to treat patients with symptomatic primary sclerosing cholangitis (PSC). Endoscopic therapy for patients with PSC and dominant strictures has been used for more than 20 years, but there is concern that instrumenting a sclerotic biliary tree induces risks that outweigh anticipated benefits. In this retrospective chart review, 117 patients with PSC were identified using ICD-9 codes. Patients had a mean age of 47 years (range: 15 to 86 y). Mean duration of follow-up was 8 years (range: 2 to 20 y). Of the 117 identified patients, 106 underwent endoscopic retrograde cholangiopancreatography on one or more occasions (for a total of 317 endoscopic retrograde cholangiopancreatographies), and a subset of 84 patients received endoscopic therapy for treatment of dominant strictures and/or deteriorating clinical status. Actual survival for endoscopically treated patients was compared with predicted survival using the Mayo Clinic natural history model for PSC. Our chart review revealed 23 recognized complications among the 317 procedures performed (7.3%), and no procedure-related deaths. Observed patient survival at years 3 and 4 was significantly higher than that predicted by the Mayo Clinic natural history model for PSC (P=0.021). Patients with PSC who have a deteriorating clinical course benefited from endoscopic therapy to provide drainage of bile ducts, removal of stones, and/or temporary relief from obstructions, with acceptable procedure-related complications and higher than expected 3-year and 4-year survival.


[Introduction and PDCA-Management of a Liaison-Clinical Pathway with Cancer Patients after a Curative Operation].
Our hospital was appointed as an Osaka designated cancer care hospital in April 2012. At that time, we introduced the same liaison-clinical pathway with cancer patients after a curative operation in all of Osaka. Based on the management of the plan-do-check-act cycle, we found problems in the clinical pathway. These problems included the following: the clinical pathway was not known, was complicated, was troubling for patients, and not well understood by doctors. To solve these problems, we planned and carried out the following five measures. The first was public information, followed by practice processes, informed consent, patient referral documents, and clinical pathway investigation reports. We were able to promote the use of the liaison-clinical pathway by constantly improving these measures.


Structure Modeling of Human Tyrosyl-DNA Phosphodiesterase 1 and Screening for Its Inhibitors.
The DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) represents a potential molecular target for anticancer therapy. A human Tdp1 model has been constructed using the methods of quantum and molecular mechanics, taking into account the ionization states of the amino acid residues in the active site and their interactions with the substrate and competitive inhibitors. The oligonucleotide- and phosphotyrosine-binding cavities important for the inhibitor design have been identified in the enzyme's active site. The developed molecular model allowed us to uncover new Tdp1 inhibitors whose sulfo group is capable of occupying the position of the 3'-phosphate group of the substrate and forming hydrogen bonds with Lys265, Lys495, and other amino acid residues in the phosphotyrosine binding site.


Soluble ST2 and CD163 as Potential Biomarkers to Differentiate Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome.
The differentiation of primary hemophagocytic lymphohistiocytosis (pHLH) and macrophage activation syndrome (MAS) poses a challenge to hematologists. The aim of this study was (1) to compare the levels of soluble ST2 (sST2), sCD163, IFN-γ, IL-10, IL-18, TNF-α and Serum soluble interleukin-2 receptor (sCD25) in patients with pHLH and MAS and (2) to investigate whether they can help differentiate the two diseases. A total of 52 participants were recruited in this study, including 12 pHLH patients, 20 MAS patients, and 20 healthy subjects. We measured the levels of sST2, sCD163 and sCD25 in serum by ELISA. The serum levels of IFN-γ, IL-10, IL-18, and TNF-α were detected using a Luminex 200 instrument. The serum levels of sST2 and sCD163 in MAS patients were markedly higher than that in pHLH patients (363.13 ± 307.24 ng/ml vs 80.75 ± 87.04 ng/ml, P = 0.004; 3532.72 ± 2479.68 ng/ml vs 1731.96 ± 1262.07 ng/ml, P = 0.046). There was no significant difference in the expression of IFN-γ (306.89 ± 281.60 pg/ml vs 562.43 ± 399.86 pg/ml), IL-10 (20.40 ± 30.49 pg/ml vs 8.3 ± 13.14 pg/ml), IL-18 (463.33 ± 597.04 pg/ml vs 1247.82 ± 1318.58 pg/ml), TNF-α (61.48 ± 84.69 pg/ml vs 106.10 ± 77.21 pg/ml), and sCD25 (21062.1 ± 18515.26 pg/ml vs 11074.78 ± 11149.96 pg/ml) between pHLH and MAS. Patients with pHLH and MAS show some differences in cytokine profiles. The elevated levels of IFN-γ, IL-10, TNF-α, IL-18, and sCD25 can contribute to the diagnosis of HLH, but may not discriminate pHLH from MAS. Levels of sST2 and sCD163 may serve as markers to distinguish pHLH from MAS.


Penetration of ciprofloxacin and ofloxacin into human allograft pancreatic juice.
The penetration of ciprofloxacin (500 mg) and ofloxacin (400 mg) into pancreatic juice following a single oral dose, was investigated in seven patients who had undergone pancreatic transplantation. With a special technique for segmental pancreatic transplantation it was possible to collect pure pancreatic juice at regular intervals for up to 24 h after drug intake. The antibiotic concentrations were determined by the agar-well diffusion method. The concentration of ciprofloxacin in pancreatic juice was 36% of that in serum. The same figure for ofloxacin was 92%. The mean peak level in pancreatic juice was 0.5 +/- 0.0 mg/l (+/- S.E.) for ciprofloxacin and occurred at 4 h after drug intake. The same figure for ofloxacin was 2.7 +/- 0.7 mg/l (+/- S.E.) occurring at 3.6 h. The decrease in concentrations with time was parallel to the serum concentration curves for both antibiotics. The concentrations of ofloxacin in pancreatic juice exceeded the MIC values for most of the organisms causing infections in the pancreas for several hours after an oral dose. The concentrations of ciprofloxacin only briefly exceeded the MIC for the same organisms.