scRNA-seq Analysis of Hemocytes of Penaeid Shrimp Under Virus Infection.
The classification of cells in non-model organisms has lagged behind the classification of cells in model organisms that have established cluster of differentiation marker sets. To reduce fish diseases, research is needed to better understand immune-related cells, or hemocytes, in non-model organisms like shrimp and other marine invertebrates. In this study, we used Drop-seq to examine how virus infection affected the populations of hemocytes in kuruma shrimp, Penaeus japonicus, which had been artificially infected with a virus. The findings demonstrated that virus infection reduced particular cell populations in circulating hemolymph and inhibited the expression of antimicrobial peptides. We also identified the gene sets that are likely to be responsible for this reduction. Additionally, we identified functionally unknown genes as novel antimicrobial peptides, and we supported this assumption by the fact that these genes were expressed in the population of hemocytes that expressed other antimicrobial peptides. In addition, we aimed to improve the operability of the experiment by conducting Drop-seq with fixed cells as a source and discussed the impact of methanol fixation on Drop-seq data in comparison to previous results obtained without fixation. These results not only deepen our understanding of the immune system of crustaceans but also demonstrate that single-cell analysis can accelerate research on non-model organisms.


[Presence of Tarebia granifera (Lamarck) (Mollusca: prosobranchia) in several fresh water bodies in the municipality of Sancti Spiritus].
The distribution of T. granifera in bodies of sweet water in Sancti Spiritus municipality is studied. It was found that it is widely distributed and that it occupies very varied biotopes, except in places with a high organic contamination.


Ontogenetic changes in forager polymorphism and foraging ecology in the leaf-cutting ant Atta cephalotes.
In the leaf-cutting ant Atta cephalotes (L.) small colonies produce a relatively narrow size-range of small workers, whereas large colonies produce a much wider size-range of workers. In this study, I compared the foraging of four small A. cephalotes colonies (fewer than 5000 workers) with published data on foraging of large colonies to examine how colony size and worker size-range may be related to foraging ecology in leaf-cutting ants. I found that the foraging ecology of small A. cephalotes colonies is very different from that of large colonies. In small colonies, a relatively narrow size-range of foragers (1.4-6.7 mg, mean 3.3 mg) cut primarily "herbs" (ferns, grasses, and other small herbaceous plants) located within 7 m of the nest. In contrast, in large colonies, a broader size-range of workers (1.4-30 mg, mean 7.3 mg) participate in foraging, generally harvesting from trees 20-80 m from the nest, with larger workers cutting on trees with thicker and tougher leaves. Small colonies' dependence on small herbaceous plants near the nest may have a profound impact on distribution of A. cephalotes. A. cephalotes colonies are rarely found in primary forest, where the low occurrence of small herbaceous plants in the understory may preclude the establishment of young colonies.


[Medical therapy of urinary tract infection].
Urinary tract infections (UTI) are the most common bacterial infectious diseases seen in the community, in most cases caused by E. coli. The treatment strategy differs depending on localization (lower vs. upper UT), acute uncomplicated vs. complicated infection, as well as for chronic disease and asymptomatic bacteriuria, the known or susceptible causative uropathogen with the (local) resistance pattern and the morbidity of the patient. There is a considerable worrying increase in the resistance rate of E. coli to TMP/SMX, quinolones and others. Most patients with uncomplicated, in the community acquired UTI are treated safely and effectively as out-patients. The available data support a short-course therapy with 3 days as the current standard therapy for lower UTI, but with a 7-14 days treatment for upper and complicated UTI. Recurrent UTI is best managed by low-dose antimicrobial prophylaxis for 3-6 (12 ore more) months. Besides that, new approaches to preventive strategies must prove their value in specific patient groups.


Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.
Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).


Antimalarial troponoids, puberulic acid and viticolins; divergent synthesis and structure-activity relationship studies.
Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved utilizing the total synthetic route of puberulic acid. Structure-activity relationships of natural products and simple troponoids inspired us to explore more detailed properties of this class of compounds. Access to new derivatives was facilitated through intermediate compounds generated during the total synthesis of puberulic acid by a stepwise oxidation-aromatization sequence to provide 7-hydroxytropolones and bromination for conversion of the carboxylic acid moiety. The first total synthesis of viticolin A, as well as the synthesis of different methyl-substituted derivatives, has also been achieved. In vitro antimalarial activity and cytotoxicity of novel derivatives were evaluated and fundamental information to facilitate the discovery of more promising antimalarials was obtained.


1-Hydroxypyrene as an indicator of the mutagenicity of coal tar after activation with human liver preparations.
Liver S9 fractions were prepared from male Wistar rats, either non-induced or induced with Aroclor 1254 and from 5 human kidney transplant donors. The preparations were compared for their ability to metabolize the premutagens present in coal tar to mutagenic metabolites in the Salmonella mutagenicity assay towards strain TA98. Low levels of mutagenicity of coal tar were seen with human S9 preparations. The differences between the S9 mix of the 5 donors in capacity to activate premutagens were approximately 6-fold. The activation of coal tar by rat liver S9 preparations was higher than by the human S9 preparations. The metabolic conversion of pyrene in coal tar to 1-hydroxypyrene by the same human S9 preparations was determined in a parallel assay. 3 human preparations showed a high correlation between the formation of 1-hydroxypyrene and bioactivation of coal tar to mutagenic metabolites. The slope values of the individual regression lines were equal, suggesting that 1-hydroxypyrene is a good indicator for the activation of premutagens present in coal tar.


Antimicrobial therapy against Staphylococcus aureus, Pseudomonas aeruginosa, and Pseudomonas cepacia.
The aims of antimicrobial therapy extend beyond short-term bacterial killing to long-term maintenance of weight and lung function. A review of antimicrobial drug trials shows that empiricism is still ahead of science and more studies are needed both to justify current practice and to make future changes logical.


Distribution, alkylation, and migration of mercury in soil discharged from the Itomuka mercury mine.
The purpose of this study was to investigate the behavior of previously discharged mercury (Hg) released from the Itomuka Hg mine into the surrounding environment, especially into soil. Total-Hg (T-Hg), methylmercury (MeHg), and ethylmercury (EtHg) concentrations in the surface soil at eight sample sites around the mine were 3.8-64.2 mg/kg, 6.0-54.7 μg/kg, and undetected to 4.5 μg/kg, respectively. Core samples collected from seven of the eight sample sites showed that the vertical distribution of T-Hg was the highest in the surface soil layer and decreased rapidly in the lower layers. A strong positive correlation was observed between T-Hg and MeHg concentrations in the core samples; however, the slope of the regression line varied considerably for each core. This suggests that Hg and MeHg were not supplied from the atmosphere simultaneously, but rather that MeHg was produced on-site. Further, the formation of MeHg and EtHg in soil was considered in terms of the total organic carbon/total nitrogen ratio, which is a decomposition index of soil organic matter. The strong positive correlation between T-Hg and MeHg can be attributed to the migration of organic matter containing Hg species to the lower layers. There was no relationship between T-Hg and MeHg at the riverbed sample site because of the high T-Hg in the lower soil layers, suggesting that Hg was supplied by ore at this sample site. These assumptions of the formation change and migration of Hg in soil were supported by the results of the fractionation experiment and the elution test. To understand the current conditions in this area, measurements of Hg in the water, sediment, atmosphere, and plants were also conducted.


Claudin-14 regulates renal Ca⁺⁺ transport in response to CaSR signalling via a novel microRNA pathway.
The paracellular claudin channel of the thick ascending limb (TAL) of Henle is critical for Ca(++) reabsorption in the kidney. Genome-wide association studies (GWASs) have identified claudin-14 associated with hypercalciuric nephrolithiasis. Here, we show that claudin-14 promoter activity and transcript are exclusively localized in the TAL. Under normal dietary condition, claudin-14 proteins are suppressed by two microRNA molecules (miR-9 and miR-374). Both microRNAs directly target the 3'-UTR of claudin-14 mRNA; induce its mRNA decay and translational repression in a synergistic manner. Through physical interaction, claudin-14 blocks the paracellular cation channel made of claudin-16 and -19, critical for Ca(++) reabsorption in the TAL. The transcript and protein levels of claudin-14 are upregulated by high Ca(++) diet, while downregulated by low Ca(++) diet. Claudin-14 knockout animals develop hypermagnesaemia, hypomagnesiuria, and hypocalciuria under high Ca(++) dietary condition. MiR-9 and miR-374 transcript levels are regulated by extracellular Ca(++) in a reciprocal manner as claudin-14. The Ca(++) sensing receptor (CaSR) acts upstream of the microRNA-claudin-14 axis. Together, these data have established a key regulatory role for claudin-14 in renal Ca(++) homeostasis.


The preoptic area in the sexually immature pig. Morphological study.
The preoptic area was investigated in 5 immature pigs. This area is composed of three nuclei: lateral, medial, and median. The largest is the lateral nucleus.


Gender differences in traditional Chinese medicine use among adults in Taiwan.
The increasing use of complementary, alternative medicine (CAM) and traditional Chinese medicine (TCM) has attracted attention. We report on the gender difference in TCM use among the general population in Taiwan in a population-based, cross-sectional study. We collected data on socio-demographic factors, lifestyle and health behavior from the 2001 Taiwan National Health Interview Survey. The medical records of interviewees aged 20-69 years were obtained from National Health Insurance claims data with informed consent. The prevalence of TCM use and the average frequency of TCM use were compared between women and men. Among 14,064 eligible participants, the one-year prevalence of TCM use for women and men was 31.8% and 22.4%, respectively. Compared with men, women had a higher average TCM use frequency (1.55 visits vs. 1.04 visits, p<0.001). This significant difference remained evident after excluding gender-specific diseases (1.43 visits vs. 1.03 visits, p<0.001). The average TCM use frequency was significantly higher in women than in men across all age groups. TCM use correlates differed for women and men. Marital status (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.30-1.85), family income and unhealthy lifestyle (OR = 1.50, 95% CI = 1.30-1.74) were factors associated with TCM use in men but not in women. In Taiwan, women used more TCM services than men and the gender differences in the TCM use profile persisted across age groups.


Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors.
Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)-camouflaged hollow MnO2 (HMnO2 ) catalytic nanosystem embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long-circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O2 , which can be produced during the decomposition of endogenous H2 O2 catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti-PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.


The Cryptosporidium parvum kinome.
Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the Cryptosporidium parvum kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase. The C. parvum kinome comprises over 70 members, some of which may be promising drug targets. These C. parvum protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of Cryptosporidium spp. Comparison of specific kinases with their Plasmodium falciparum and Toxoplasma gondii orthologues revealed some distinct characteristics within the C. parvum kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening CpCDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC₅₀ values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of CpCDPK1. In addition, structural analysis of CpCDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation. Identification and comparison of the C. parvum protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.


The distribution of hauled-out ringed seals and an interpretation of Taylor's law.
The sizes of the groups in which ringed seals (Phoca hispida) haul out were studied from aerial survey data from a wide area of the Canadian Arctic. Densities of hauled-out ringed seals varied over a wide range, but the mean group size was comparatively constant. Ringed seal distribution data obeyed Taylor's law of variation; about half the increase in aggregation with density was due to change in group size, and half to increasingly clumpy distribution of groups.


Correction: A Rehabilitation Program for Individuals With Chronic Low Back Pain: Protocol for a Randomized Clinical Trial.
[This corrects the article DOI: 10.2196/31345.].


Growth of colorectal carcinoma cells: regulation in vitro by gastrin, pentagastrin and the gastrin-receptor antagonist proglumide.
The growth-regulating effects of pentagastrin, gastrin and the gastrin-receptor antagonist proglumide were investigated in three established cell lines derived from human colorectal carcinomas in vitro and after transplantation into nude mice. In vitro a significant increase of cell growth in the SW 403 cell line incubated with pentagastrin or gastrin was observed. In the Lovo cell line this effect was only detected after synchronization of cell growth. Pentagastrin and gastrin had no effect on the growth of the Ls 174 T cell line. Proglumide reduced cell proliferation in all three cell lines as well as in the L929S cell line derived from fibroblasts, which served as control. After transplantation into nude mice all tumor cell lines increased, Lovo and Ls 174 T as undifferentiated tumor, SW 403 as differentiated. Pentagastrin increased and proglumide decreased growth in SW 403 tumors, whereas no effect was observed on Ls 174 T and Lovo tumors. We therefore conclude that growth of some colorectal carcinomas is regulated by gastrin, but that the effect of proglumide is unspecific rather than related to blockage of gastrin receptors. The growth-regulating effect of gastrin could be due to tumor differentiation.


Relationship between postvaccinal anti-influenza antibodies, blood magnesium levels, and HLA antigens.
Seventy-eight healthy subjects belonging to 16 different families were submitted to an anti-influenza vaccination. The antibody titers and the red blood cell and plasma Mg concentrations were determined before and 30 days after vaccination. The population study performed on 32 subjects showed the occurrence of a higher antibody response (P less than 0.01) and a lower red blood cell Mg level, among the Bw35 individuals. These findings are confirmed by family studies: HLA identical sibs have values much closer to those of the propositi than to those of the HLA different sibs. The relationships between HLA, immune response, and Mg revealed by the present investigation are discussed in light of the literature together with the known associations between HLA Bw35 antigen and diseases.


Transcriptome analysis and physiological responses of the potato plantlets in vitro under red, blue, and white light conditions.
Light is an important factor for plant development and has serious effects on the growth, production and quality of potatoes. However, the physical and molecular mechanisms by which potato plantlets cope with different light qualities are not understood. In this study, the potato "Zhuanxinwu", which is a germplasm potato resource with a high anthocyanin content, was used for physiological and transcriptome profiling analyses to uncover the different mechanisms that occur in response to blue, red and white light conditions, with the white light condition serving as the control. Multiple growth indexes, protective enzyme activity and metabolite accumulation were measured. The results indicated that white light promoted a shift in biomass allocation away from tubers to leaves to enhance dry leaf matter and reduce tuber fresh/dry weight relative to the effects of blue or red light. The leaf area and anthocyanin content values were greater for plants grown in blue light than those grown in white or red light, suggesting that combinations of different spectra were more conducive to regulating potato growth. A total of 2220 differentially expressed genes (DEGs) were found among the three samples, and the DEGs in the three comparison sets were analyzed. A total of 1180 and 984 DEGs were identified in the red light (Red) and blue light (Blue) conditions compared to the control condition, respectively, and 359 DEGs overlapped between the two comparison sets (Blue_vs_White and Red_vs_White). Interestingly, the 24 most common overlapped DEGs were involved in photosynthesis, respiration, and reactive oxygen species (ROS) scavenging. Of these DEGs, four genes involved in photosynthesis and two genes involved in pigment synthesis were highly expressed, implying that some genes could be implemented to cope with different light spectra by regulating the expression of DEGs involved in the corresponding metabolic pathways. In conclusion, our study characterizes physiological responses of potato to different light qualities and identifies potential pathways and candidate genes involved in these responses, thus providing a basis for further research on artificial light regulation of potato plant growth.


Prevalence of osteoporosis in osteoarthritis: a systematic review and meta-analysis.
Data are contradictory regarding the relationship between osteoarthritis (OA) and osteoporosis (OP) with some studies showing the increased risk of OP in OA. The study was conducted to determine whether OP prevalence is increased in patients with OA, compared to age and sex-matched population. MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library (inception-2019) were searched for studies reporting the frequency, rate, prevalence, incidence, risk, or excess risk of OP in patients with OA compared to age and sex-matched population. Estimates were combined using a random effects model. Consistency was evaluated using the I2 statistic. Articles with fewer than 200 participants were excluded. Of 2772 articles, 49 had full article screening, and 8 articles met the inclusion criteria. Other articles reporting mean BMD and not OP were excluded. In women, 998 participants with OA were compared with 1903 controls. The pooled estimate of the odds ratio for prevalence of OP vs general matched population was not statistically different. In men, 136 participants with OA were compared with 682 controls. The results did not show a statistically significant difference in the frequency of OP in OA in men. According to the site of bone mineral density measurement, a higher prevalence of OP at lumbar spine was found in both men and women. The frequency of OP overall in participants with OA was not different, except for a higher prevalence of OP in lumbar spine in both men and women compared to the matched controls.


Multiple doses of paracetamol plus codeine taken immediately after oral surgery.
A double-blind randomized analgesic trial was carried out in 180 patients undergoing surgical removal of an impacted lower wisdom tooth. The patients received the first dose of either paracetamol 1000 mg plus codeine 60 mg, paracetamol 500 mg plus codeine 30 mg or placebo immediately after surgery during the effect of the local anaesthetic. The mean pain intensity, the duration of effect and the number of patients needing additional analgesics were all significantly dose related. In the evaluation procedure a pain intensity index was defined which took into account both the efficacy and the duration of effect. In addition, the analgesic efficacy was calculated over a 12 hour period after first medication and thereby including the efficacy of a second dose, if taken. Paracetamol 1000 mg plus codeine 60 mg followed by paracetamol 500 mg plus codeine 30 mg after around 5 hours was a very effective treatment and over 40% of these patients did not need any further pain relief during the evaluation period. In conclusion, an effective analgesic taken immediately after oral surgery reduces the total pain and diminishes the need of analgesics.


Screening and monitoring for albuminuria: the performance of the HemoCue point-of-care system.
Obtaining immediate results makes testing for albuminuria at the point of care far superior to central laboratory assays. Here we determined if a quantitative desk-top system could identify and monitor patients with microalbuminuria. Urinary albumin excretion was measured in 259 patients of a population cohort study where they collected 24-h urines and first morning void samples prior to three clinic visits at three week intervals. The albumin concentration was determined with both an in-office HemoCue Albumin 201 system and a central laboratory BNII nephelometer. The median (interquartile-range) urinary albumin concentration in the first morning void, intra-individual variability in patients excreting more than 30 mg/day and the prediction of microalbuminuria in subsequent 24-h collections measured by each technique were statistically indistinguishable. The HemoCue system met the FDA criterion for precision while being at its border for accuracy. Our study shows that determination of urinary albumin concentration in a first morning void by the HemoCue point-of-care system provides a good alternative to central laboratory analysis identifying and monitoring patients with microalbuminuria.


Thermodynamics of micellization of nonionic surfactants - The effect of incorporating CO2 moieties into the head group.
The micellization behavior of nonionic surfactants is significantly influenced by substituting ethylene oxide (EO) units with CO2 in the head group of nonionic C12EOj surfactants. Incorporating hydrophobic units has a major effect on the driving forces of the micellization process by a reduced hydration affinity. Hence, the incorporation of CO2 moieties is favoring micellization and thereby adding a further tuning parameter. The micellization of the surfactants was characterized in terms of thermodynamics and the assembly properties on the water/air interface by isothermal titration calorimetry (ITC) and surface tension measurements. The incorporation of CO2 moieties was compared to the effect of propylene oxide (PO) and propiolactone (PL) over the temperature range of 25-50 °C. From ITC measurements and the van't Hoff relation, we determined the thermodynamic parameters of micellization: enthalpy (ΔHmic), entropy (ΔSmic), and Gibbs free energy (ΔGmic). The incorporation of CO2 moieties reduces the critical micellization concentration (cmc) and a transfer energy of -0.36 kT/CO2 unit quantifies favored micellization for CO2 surfactants. The presence of PO or CO2 in the head group has a similar effect on the cmc, but for CO2 ΔHmic is substantially decreased, resulting in a largely reduced temperature sensitivity of the micellization process and indicating a reduced hydration affinity. This thermodynamic analysis reveals that CO2 and PO behave very differently concerning their effect on the micellization process.


Perioperative antibiotic prophylaxis in cardiovascular surgery: a prospective randomized comparative trial of cefazolin versus ceftriaxone.
With a view of possible reduction in antibiotic dosage, several prospective randomized comparative trials performed in our institution showed that a 4-day prophylactic antimicrobial regimen with cefazolin was equally effective as a 2-day prophylaxis with cefuroxime and that the best regimen was equally as effective as a double dose of ceftriaxone prophylaxis in major cardiovascular surgery. In this prospective randomized comparative study, 1-day cefazolin prophylaxis (4 X 0.5 g intravenously) was compared with a single dose of ceftriaxone prophylaxis (2 g intravenously). Of the 900 patients enrolled in the study, 17 were subsequently excluded. Of the remaining 883 patients, 439 were in the cefazolin group and 444 were in the ceftriaxone group. The overall postoperative infection rate was 5.0% in the cefazolin group and 4.5% in the ceftriaxone group. In view of the almost identical infection rates in both groups, we considered that a single 2 g dose of ceftriaxone offers patients a reliable antimicrobial prophylaxis. The single-dose prophylaxis has the additional advantage of reducing the dosage administered and the costs of administration.


Normal Echocardiographic Measurements in a Korean Population Study: Part I. Cardiac Chamber and Great Artery Evaluation.
Measurement of the cardiac chamber is essential, and current guidelines recommend measuring and reporting values for both sides of the cardiac chamber during echocardiographic evaluation. Normal echocardiographic reference values have been suggested previously, but detailed information about right-sided chambers and values according to gender was not included. This is a prospective multicenter (23 centers) study evaluating normal Korean adult subjects using comprehensive echocardiography. We included normal adult subjects (age; 20-79 years old) who had no significant cardiac disorders or illnesses, such as hypertension or diabetes, which could affect cardiac structure and function. We measured the cardiac chamber including both right and left ventricles as well as atria according to current echocardiography guidelines and compared values according to gender and age groups. A total of 1003 subjects were evaluated and the mean age was 48 ± 16 years. Left ventricular (LV) dimensions increased, but LV volume decreased in older subjects. Right ventricular (RV) area decreased in women and older subjects, and the RV long-axis dimension showed a similar trend. Left atrial (LA) volume increased in men but there were no differences in LA volume index between men and women. The dimension of great arteries increased in men and older subjects. Since there were considerable differences between men and women and in the different age groups, and the trends differed significantly between different echo variables, normal echocardiographic cutoff values should be differentially applied based on age and gender.


Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence.
Glutamate is the primary excitatory neurotransmitter in neurons and glia. N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors are major ionotropic glutamate receptors. Glutamatergic neurotransmission is strongly linked with Ca2+ homeostasis. Research has provided ample evidence that brain aging is associated with altered glutamatergic neurotransmission and Ca2+ dysregulation. Much of the work has focused on the hippocampus, a brain region critically involved in learning and memory, which is particularly susceptible to dysfunction during senescence. The current review examines Ca2+ regulation with a focus on the NMDA receptors in the hippocampus. Integrating the knowledge of the complexity of age-related alterations in Ca2+ homeostasis and NMDA receptor-mediated glutamatergic neurotransmission will positively shape the development of highly effective therapeutics to treat brain disorders including cognitive impairment.


Induction of endogenous avian tumor virus gene expression by pyrrolizidine alkaloids.
The pyrrolizidine alkaloids (PA) are toxic compounds which occur naturally in plant species throughout the world. They have been implicated as both carcinogenic and mutagenic agents. An active metabolite of the alkaloids, the pyrrole, which is a strong alkylating agent, is thought to be the toxicant. The naturally occurring alkaloid, jacobine , is able to induce the production of endogenous avian RNA tumor virus particles in cultured chick embryo fibroblasts (CEF). When jacobine was modified to form retronecine it no longer induced virus particles. Conversion of retronecine to its pyrrole resulted in a compound capable of inducing virus particle production. The isobutyryl monoester of retronecine was also able to induce virus particle production, but the isobutyryl monoester pyrrole was unexpectedly inactive as an inducer. This type of viral induction system is useful for studying the effect of modification of the inducer on its biological activity.


A novel ex vivo tracheobronchomalacia model for airway stent testing and in vivo model refinement.
We sought to develop an ex vivo trachea model capable of producing mild, moderate, and severe tracheobronchomalacia for optimizing airway stent design. We also aimed to determine the amount of cartilage resection required for achieving different tracheobronchomalacia grades that can be used in animal models. We developed an ex vivo trachea test system that enabled video-based measurement of internal cross-sectional area as intratracheal pressure was cyclically varied for peak negative pressures of 20 to 80 cm H2O. Fresh ovine tracheas were induced with tracheobronchomalacia by single mid-anterior incision (n = 4), mid-anterior circumferential cartilage resection of 25% (n = 4), and 50% per cartilage ring (n = 4) along an approximately 3-cm length. Intact tracheas (n = 4) were used as control. All experimental tracheas were mounted and experimentally evaluated. In addition, helical stents of 2 different pitches (6 mm and 12 mm) and wire diameters (0.52 mm and 0.6 mm) were tested in tracheas with 25% (n = 3) and 50% (n = 3) circumferentially resected cartilage rings. The percentage collapse in tracheal cross-sectional area was calculated from the recorded video contours for each experiment. Ex vivo tracheas compromised by single incision and 25% and 50% circumferential cartilage resection produce tracheal collapse corresponding to clinical grades of mild, moderate, and severe tracheobronchomalacia, respectively. A single anterior cartilage incision produces saber-sheath type tracheobronchomalacia, whereas 25% and 50% circumferential cartilage resection produce circumferential tracheobronchomalacia. Stent testing enabled the selection of stent design parameters such that airway collapse associated with moderate and severe tracheobronchomalacia could be reduced to conform to, but not exceed, that of intact tracheas (12-mm pitch, 0.6-mm wire diameter). The ex vivo trachea model is a robust platform that enables systematic study and treatment of different grades and morphologies of airway collapse and tracheobronchomalacia. It is a novel tool for optimization of stent design before advancing to in vivo animal models.


Electrical Stimulation of the Spinal Dorsal Root Inhibits Reflex Bladder Contraction and External Urethra Sphincter Activity: Is This How Sacral Neuromodulation Works?
Using a rat model, we aimed to confirm the inhibitory effect of dorsal spinal root (afferent) stimulation and test if bilateral stimulation is more effective than unilateral stimulation. External urethral sphincter (EUS) electromyography (EMG) is also assessed in conjunction with cystometrogram. Eighteen female Sprague-Dawley rats were tested following urethane anesthesia. Via urethral catheterization, the bladder was infused with normal saline to evoke rhythmic bladder reflex contractions (BRC). L6 spinal nerves were isolated and stimulated. L6 stimulation was effective in inhibiting BRC. L6 bilateral dorsal root (DR) stimulation of 50% intensity was required to cause inhibition as compared to unilateral stimulation. In EUS EMG recordings, there was a strong association between EUS EMG activities and bladder contraction. When the bladder contraction was inhibited effectively by L6 DR stimulation, a considerable reduction was also found in the EUS EMG activities. L6 DR stimulation abolished BRC in our rat model. Bilateral L6 DR stimulation produced a 50% reduction in stimulation intensity, providing a similar BRC block. Abolishing BRC also appeared to coincide with a reduction in EUS EMG, implicating that sacral neuromodulation might act centrally, at least rostrally at the T8-9 spinal level.


Decrease in plasma tryptophan after tryptophan-free amino acid mixtures in man.
Male healthy subjects, fasting 12 hours, ingested increasing amounts of a mixture containing a fixed proportion of seven essential amino acids (L-isoleucine 11.5%, L-leucine 18.0%, L-lysine 13.1%, L-methionine 18.0%, L-phenylalanine 18.0%, L-threonine 8.2%, L-valine 13.1%) and lacking tryptophan. The diets produced a rapid fall in plasma tryptophan which was proportional to the total amount of the amino acids ingested. Following the highest dose administered (36.6 g) plasma tryptophan fell to a minimum of about 35% the initial level and remained markedly reduced at 6 hours after treatment. The mechanism of this decrease and its potential clinical relevance are discussed.


The anti-neoplastic and novel topoisomerase II-mediated cytotoxicity of neoamphimedine, a marine pyridoacridine.
Topoisomerase IIalpha (top2) is a target of some of the most useful anticancer drugs. All clinically approved top2 drugs act to stabilize a drug-enzyme-DNA cleavable complex. Here we report the novel top2 activity of neoamphimedine, an isomer of the marine pyridoacridine amphimedine. Neoamphimedine was cytotoxic in yeast and mammalian cell lines. Neoamphimedine exhibited enhanced toxicity in top2 over-expressing yeast cells and was toxic in every mammalian cell line tested. However, neoamphimedine did not possess enhanced toxicity in a mammalian cell line sensitive to stabilized cleavable complexes. Therefore, we hypothesized that neoamphimedine is a top2-dependent drug, whose primary mechanism of action is not the stabilization of cleavable complexes. Top2-directed activity was determined in purified enzyme systems. Neoamphimedine-induced catenation of plasmid DNA only in the presence of active top2. This catenation correlated with the ability of neoamphimedine to aggregate DNA. Catenation was also observed using a filter-binding assay and transmission electron microscopy. Catenation was confirmed when only restriction enzyme digestion could resolve the catenated plasmid complex to monomer length plasmid DNA. Neoamphimedine also showed potent anti-neoplastic activity in human xenograft tumors in athymic mice. Neoamphimedine was as effective as etoposide in mice bearing KB tumors and as effective as 9-aminocamptothecin in mice bearing HCT-116 tumors. Amphimedine did not induce DNA aggregation or catenation in vitro, nor did it display any significant anti-neoplastic activity. These results suggest that neoamphimedine has a novel top2-mediated mechanism of cytotoxicity and anticancer potential.


Increased Effects of Extracorporeal Shock Waves Combined with Gentamicin against Staphylococcus aureus Biofilms In Vitro and In Vivo.
An implant-associated bacterial infection is one of the most common and costly complications of orthopedic surgery. Once biofilms develop, it is extremely difficult to cure infections with antimicrobial agents. High-energy extracorporeal shock wave (ESW) treatment has been used for orthopedic-related diseases and has been found to be an effective bactericidal agent that is tolerable both in vitro and in vivo. The broad-spectrum antibiotic gentamicin exhibits bactericidal activity against Staphylococcus aureus, and bacterial resistance to gentamicin is lower. We tested the effectiveness of gentamicin in combination with ESW treatment against S. aureus biofilms in vivo and in vitro. The spread plate method, crystal violet staining, confocal laser scanning microscopy, scanning electron microscopy and microbiologic evaluation were used to compare the effects of combined treatment with those of either treatment alone. The results revealed statistically significant differences between the group treated with ESWs combined with gentamicin and all other groups. Our findings indicate that use of the combination of ESWs with gentamicin is more effective against S. aureus biofilms in vitro and in vivo.


Convex output feedback model predictive control for mitigation of COVID-19 pandemic.
In this paper, a model predictive control approach is proposed for epidemic mitigation. The disease spreading dynamics is described by an 8-compartment smooth nonlinear model of the COVID-19 pandemic in Hungary known from the literature, where the manipulable control input is the stringency of the introduced non-pharmaceutical measures. It is assumed that only the number of hospitalized people is measured on-line, and the other state variables are computed using a state observer which is based on the dynamic inversion of a linear sub-system of the model. The objective function contains a measure of the direct harmful consequences of the restrictions, and the constraints refer to input bounds and to the capacity of the healthcare system. By exploiting the special properties of the model, the nonlinear optimization problem required by the control design is reformulated to convex tasks, allowing a computationally efficient solution. Two approaches are proposed: the first finds a suboptimal solution by geometric programming, while the second one further simplifies the problem and transforms it to a linear programming task. Simulations show that both suboptimal solutions fulfill the design specifications even in the presence of parameter uncertainties.


"A Sick Child is Always the Mother's Property": The Jane Austen Pediatric Trauma Management Protocol.
Two pediatric accidents in Jane Austen's Persuasion (1818) and one in Margaret Oliphant's The Doctor's Family (1863) are examined from the point of view of trauma management with analysis of contributing risk factors, medical management, concerns of parents and bystanders, and course of recovery. Risk factors for injury are impulsivity, poor supervision, and parents who are unable to set limits. Medical attention is swift and competent, but no heroic measures are used; the management of the injuries, concussion with loss of consciousness and dislocation of the collar bone, is consistent with the way these conditions are, for the most part, still managed today, and successful recovery depends on careful nursing and rest. Louisa Musgrove, who suffers a severe head injury, requires ten weeks of convalescence and undergoes a marked personality change, which we might today attribute in part to post-concussion syndrome but which may reflect contemporary debate about the biological basis of personality and behavior. A sudden traumatic injury to a child or adolescent changes the narrative abruptly, in fiction or in life, dividing a story into before and after, introducing grief and anxiety, and requiring that plans be rethought and personal relationships reshuffled with decisions about caretaking and nursing.


[Hypotension, mental disorders and changes in catecholamine excretion observed during the administration of disulfiram in a case of pheochromocytoma].
A case of pheocromocytoma treated with disulfiram during ten days in described. Hypotensive and psychiatric effects were observed, which disappeared upon discontinuation of the drug. Urinary amines decreased while the drug was used, and upon interruption of its administration dopamine increased, as a rebound phenomena probably due to availability of tissue dopamine previously blocked by DBH inhibition. The effect of simultaneous administration of alpha-methyldopa is considered.


Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia.
Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with the risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that interleukin-10 (IL-10) deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, macrophage inflammatory protein-1β/CCL4, and granulocyte colony-stimulating factor). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B-cell neoplasms in a dose-dependent manner and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create a risk for leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.


An application of in-vehicle recording technologies to analyze injury severity in crashes between taxis and two-wheelers.
Conventionally, the crash data used in traffic safety analysis have been collected by the police dispatched to the crash scene. Therefore, crash information inevitably includes errors that influence traffic safety analysis. Such errors can include the crash speed, crash time, crash location, and other crash characteristics. The advances in in-vehicle video recording (IVVR) technologies have recently enabled traffic safety professionals to use more accurate crash information based on crash data reconstruction methods. Although a few studies have been conducted to identify the factors affecting the crash injury severity using such detailed crash data, there was no effort to analyze the factors affecting the injury severity in crashes between taxis and two-wheelers (TWs), including bicycles and motorcycles. Therefore, this study analyzes the injury severity of TW riders in taxi-TW crashes with the accurate crash data collected by taxis equipped with IVVR devices in Incheon, Korea. Two hundred and forty-eight crash data from two years (2010-2011) were used to perform this objective. The factors affecting the injury severity to TW riders were identified based on a partial proportional odds model for these data. Seven variables were found to affect the injury severity significantly: crash speed, second collision, third collision, Delta-V, crashes that occurred with a non-helmeted motorcycle rider, crashes where the collision type was sideswipe, and crashes under rainy or snowy weather conditions. On the other hand, two variables regarding crashes, where the taxi driver behavior helped reduce visible and severe injuries, were changing lanes and the young TW riders (<18 years).


Target biorecognition-triggered assembly of a G-quadruplex DNAzyme-decorated nanotree for the convenient and ultrasensitive detection of antibiotic residues.
The abuse of kanamycin (Kana) in many fields has led to increasing antibiotic pollution problems and serious threats to public health. Therefore, determining how to develop methods to realize the convenient detection of antibiotics in complicated environmental matrices is highly desirable. In this study, we utilized a target biorecognition-triggered hybridization chain reaction (HCR) assembly of a G-quadruplex DNAzyme (G-DNAzyme)-decorated nanotree to develop a novel homogeneous colorimetric biosensing method for the convenient and ultrasensitive detection of Kana antibiotic residues in real samples. Through the designed aptamer-recognition reaction, an Mg2+-dependent DNAzyme (MNAzyme) strand can be liberated. Thus, its catalyzed cleavage of the hairpin substrates anchored at a DNA nanowire will cause the assembled formation of an HCR-initiator; this process can be greatly amplified by the exonuclease III-assisted target recycling and the MNAzyme-catalyzed release of another MNAzyme strand. Based on the DNA-nanowire-accelerated HCR assembly of many G-DNAzyme-decorated DNA duplexes on the two sides of the nanowire, a DNA nanotree decorated by numerous G-DNAzymes will form to realize the ultrasensitive colorimetric signal output. Under the optimal conditions, this method exhibited a wide five-order-of-magnitude linear range and a very low detection limit of 28 fg mL-1. In addition, excellent selectivity, repeatability, and reliability were also demonstrated for this homogeneous bioassay method. These unique features along with its automatic manipulation and low assay cost show promise for practical applications.


Topical application of metformin accelerates cutaneous wound healing in streptozotocin-induced diabetic rats.
Diabetic chronic wound, which is one of the diabetic complications caused by hyperglycemia, characterized by prolonged inflammation has become one of the most serious challenges in the clinic. Hyperglycemia during diabetes not only causes prolonged inflammation and delayed wound healing but also modulates the activation of nuclear factor-kappa B (NF-κB) and the expression of matrix metalloproteinases (MMPs). Although metformin is the oldest oral antihyperglycemic drug commonly used for treating type 2 diabetes, few studies have explored the molecular mechanism of its topical effect on wound healing. Therefore, we aimed to investigate the molecular effects of topical metformin application on delayed wound healing, which's common in diabetes. In this context, we created a full-thickness excisional wound model in Wistar albino rats and, investigated NF-κB p65 DNA-binding activity and expression levels of RELA (p65), MMP2 and MMP9 in wound samples taken on days 0, 3, 7, and 14 from diabetic/non-diabetic rats treated with metformin and saline. As a result of our study, we showed that topically applied metformin accelerates wound healing by suppressing NF-κB p65 activity and diminishing the expression of MMP2 and MMP9. Diabetic wounds treated with metformin healed even faster than those in the control group that mimicked standard wound healing.


Transplacental mutagenesis of products formed in the stomach of golden hamsters given sodium nitrite and morpholine.
Hamster embryos were exposed in utero to the action of sodium nitrite (NaNO2) and morpholine (Mo) administered simultaneously by stomach tube to the mothers on the 11th or 12th day of pregnancy. Embryo cells were examined for chromosomal aberrations, micronuclear formation, morphological or malignant transformation and drug resistance mutations. For detection of induced mutations, the embryo cells were cultured in normal medium for 72 h and then transferred to medium containing 10 or 20 micrograms/ml of 8-azaguanine (8AG) or 1m7 ouabain (Oua). The number of 8AG-, Ouaresistant colonies was markedly increased after administration of NaNO2 and Mo. The embryonic fibroblasts also showed a markedly increased frequency of micronucleation and a slight increase in chromosome aberrations. This treatment also caused morphological or malignant transformation of fetal cells. After cultivation in vitro, cells from some transformed colonies produced tumors when inoculated into the cheek pouch of young golden hamsters. Orally administered N-nitroso-morpholine (N-Mo), as a positive control, had the same transplacental biological actions on embryonic fibroblasts. However, transplacentally Mo alone was ineffective. A single administration of 500 mg/kg NaNO2 had only slight biological effects. N-Mo was produced in the stomachs of animals treated simultaneously with NaNO2 and Mo. A small amount of a nitrosamine, N-nitrosodimethylamine (DMN), was detected in the stomach after a single dose of NaNO2.


What is the therapeutically active ingredient of homeopathic potencies?
The nature of the 'active ingredient', in homeopathic high dilutions is investigated. A model for every degree of dilution is introduced; within this the active ingredient can be dealt with in physical terms. In mathematical terms this model has features which correspond to the axioms of weak quantum theory. Features which are similar to entanglement in ordinary quantum theory are discussed in particular.


Life-Course Trajectories of Risk-Taking Propensity: A Coordinated Analysis of Longitudinal Studies.
How does risk preference change across the life span? We address this question by conducting a coordinated analysis to obtain the first meta-analytic estimates of adult longitudinal age differences in risk-taking propensity in different domains. We report results from 26 longitudinal samples (12 panels; 187,733 unique respondents; 19 countries) covering general and domain-specific risk-taking propensity (financial, driving, recreational, occupational, health) across 3 or more waves. Results revealed a negative relation between age and both general and domain-specific risk-taking propensity. Furthermore, females consistently reported lower levels of risk taking across the life span than males in all domains, but there is little support for the idea of an age by gender interaction. Although we found evidence of systematic and universal age differences, we also detected considerable heterogeneity across domains and samples. Our work suggests a need to understand the nature of heterogeneity of age differences in risk-taking propensity and recommends the use of domain-specific and population estimates for applications interested in modeling heterogeneity in risk preference for economic and policy-making purposes.


The effects of different MNNG (N-methyl-N'-nitro-N-nitrosoguanidine)-doses on the stomach and the upper small intestine of the rat. II. The frequency of intestinal metaplasia.
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was given to 3 groups of male Wistar rats in different doses of 25 micrograms/ml, 50 micrograms/ml and 100 micrograms/ml with their drinking water for 32 weeks. After 50 weeks the antrum region of the stomach was investigated by serial sections. All animals showed tubules with metaplastic intestinal epithelium. The different values of metaplastic glands in the antrum region of the stomach were 187 (25 micrograms MNNG), 76 (50 micrograms MNNG) and 51 (100 micrograms MNNG). They indicate an inverse relationship of the frequency of intestinal metaplasia and the MNNG dose. As opposed to this dose-response pattern, cytotoxic alterations, regenerative hyperplastic lesions and tumours of the stomach are more frequent after medium of high MNNG doses. It is therefore suggested that the induction of intestinal metaplasia is a specific effect of the carcinogen mainly in the low dose range.


Organic-Solvent-Free "Lego-Like" Modular Preparation of Fab-Nondestructive Antibody-Drug Conjugates with Ultrahigh Drug-to-Antibody Ratio.
Antibody-drug conjugates (ADCs) have exciting possibilities in targeted tumor therapy. However, in the existing ADC preparation processes, the random attachment of the payloads to the antigen-binding fragments (Fab) greatly increases the risk of disrupting its antigen recognition ability, while the drug-antibody ratio (DAR) is low, leading to a cumbersome preparation process and low drug delivery efficiency. Herein, poly(glutamic acid) is used to expand the number of drug binding sites, based on the "click chemistry" of azide and DBCO, and the high affinity of Fc-III-4C peptide to the crystalline fragment (Fc) of the monoclonal antibodies. Various antibody-polymer-drug conjugates are obtained with ultrahigh DAR using this organic-solvent-free "Lego-like" modular construction. Among them, aHER2-P-MMAE with DAR of 41.6 achieves tumor growth inhibition (TGI) of 99.7% for both medium-sized and large SKOV-3 ovarian tumors, and aPDL1-P-MMAE (DAR = 40.7) achieves TGI of 98.5% for MC38 colon tumors. In summary, a universal platform is created to prepare Fab-nondestructive ADCs with ultrahigh DAR, which can be used to develop precision medicine for personalized anticancer therapy.


Image preprocessing to improve the accuracy and robustness of mutual-information-based automatic image registration in proton therapy.
We propose a method that potentially improves the outcome of mutual-information-based automatic image registration by using the contrast enhancement filter (CEF). Seventy-six pairs of two-dimensional X-ray images and digitally reconstructed radiographs for 20 head and neck and nine lung cancer patients were analyzed retrospectively. Automatic image registration was performed using the mutual-information-based algorithm in VeriSuite®. Images were preprocessed using the CEF in VeriSuite®. The correction vector for translation and rotation error was calculated and manual image registration was compared with automatic image registration, with and without CEF. In addition, the normalized mutual information (NMI) distribution between two-dimensional images was compared, with and without CEF. In the correction vector comparison between manual and automatic image registration, the average differences in translation error were < 1 mm in most cases in the head and neck region. The average differences in rotation error were 0.71 and 0.16 degrees without and with CEF, respectively, in the head and neck region; they were 2.67 and 1.64 degrees, respectively, in the chest region. When used with oblique projection, the average rotation error was 0.39 degrees with CEF. CEF improved the NMI by 17.9 % in head and neck images and 18.2 % in chest images. CEF preprocessing improved the NMI and registration accuracy of mutual-information-based automatic image registration on the medical images. The proposed method achieved accuracy equivalent to that achieved by experienced therapists and it will significantly contribute to the standardization of image registration quality.


After you Roux, what do you do? A systematic review of most successful advanced assisted ERCP techniques in patients with various altered upper gastrointestinal surgical anatomical reconstructions with particular focus on RYGB (last 10 years).
Access to the Common Bile Duct in patients with surgically altered UGI anatomy such as RYGB is exceptionally challenging. Previously, these patients could only be treated by open surgery; however, multiple new advanced assisted ERCP techniques such as EDGE, LA-ERCP, and DEA-ERCP have now been developed and indeed successfully used to treat these patients. Despite growing experience, these techniques have yet to become part of our mainstream practice and many clinicians remain unfamiliar or even unaware of them; as a result, they are unfortunately often overlooked. We conducted this systematic review to try and shed more light on them and understand which of these techniques resulted in the best patient outcomes. We conducted a systematic review of PubMed database publications between December 2008 and December 2018. Keyword variants of "EDGE, Enteroscopy-assisted & laparoscopy-assisted ERCP" and "altered surgical anatomy" were combined to identify relevant papers for inclusion. We identified 34 studies, comprising a total of 1848 advanced assisted ERCPs in patients with altered UGI anatomy from 12 different countries. These papers were critically appraised, summarised, and presented in table format. EDGE and LA-ERCP were associated with both the highest overall combined CBD cannulation rates (99.3% for both vs 74.6% for DEA-ERCP) and ERCP interventional success (98.3% for EDGE vs 97.4% for LA-ERCP and 67.6% for DEA-ERCP). Advanced ERCP is associated with excellent success rates and a higher safety profile than surgery; however, patient selection and identification of the exact surgical anatomy are key.


Shape recognition in amblyopia.
The results of recent investigations of supra-threshold spatial vision in amblyopia have indicated that the amblyopic eye may be more disadvantaged than acuity or contrast detection measurements have suggested. We report here on the sensitivity of the amblyopic eye when performing tasks requiring the recognition of small spatial differences in thin bright line stimuli displayed in a variety of 2-D configurations. Amblyopes were able to perform these tasks, but their amblyopic eye was generally poorer than their normal eye by a multiplicative factor. It is argued that this pattern of results indicates that spatial scrambling rather than blurring is an appropriate model for amblyopia.


Lack of an Exposure Response and Interaction With HLA-DPβ1 and DRβ1 Polymorphisms in the Development of Beryllium Toxicity in a High Beryllium Exposure Cohort.
To evaluate interaction of HLA-DPβ1 and DRβ1 polymorphisms with metrics of beryllium exposure, in the development of beryllium sensitization (BeS) and chronic beryllium disease (CBD). A matched case-control study of 61 CBD, 41 BeS, and 259 controls from two beryllium-processing facilities. BES and CBD were significantly associated with presence of DPβE69. Dose response of exposure was not observed for the development of BES and CBD with/without adjustment for DPβE69 (P > 0.05). The DRβE71 polymorphism was more common in BeS than CBD after adjusting for exposure and maybe a protective factor (aOR 0.4, 95% CI 0.2 to 0.9) against the progression of BeS to CBD. No exposure-response association was found, which may reflect that the workers in this high exposure cohort were above a threshold level where an exposure-response could be observed.


Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase.
The vitamins phylloquinone (K1), menadione (K3) and various menaquinones (K2) were compared for their ability to serve as a cofactor for the hepatic vitamin K-dependent carboxylase. It was found that the cofactor activity of the menaquinones varied with the length of the aliphatic side-chain and showed an optimum at MK-3. Menadione was not active at all. The concentration required for half-maximal reaction velocity (K 1/2) was determined for the various menaquinones and decreased at increasing chain length. The K 1/2 value for MK-4 was 3-times lower than that for vitamin K1. Under our in vitro conditions both vitamin K1 and the K2 vitamins were rapidly metabolized into a mixture of the quinone, the hydroquinone and the epoxide form. The fact that at equilibrium the level of these three metabolites was independent of the starting material shows that the vitamin K cycle is operational for vitamin K1 as well as for K2.


The effect on transcription efficiency of the apolipoprotein AI gene of DNA variants at the 5' untranslated region.
Elevated circulating levels of high-density lipoprotein and apolipoprotein AI are associated with reduced coronary artery disease risk. We have shown that a C to T substitution at +83 bp and a G to A substitution at -75 bp of the apolipoprotein AI gene are both related to increased high-density lipoprotein levels in a healthy population but not in a coronary population, among whom the same mutations are associated with increased disease severity. In the present study, we explored the effects of these base changes on transcriptional efficiency in vitro. We directionally cloned (using polymerase chain reaction) the 5' region of the apolipoprotein AI gene (-281 to +330 bp) with GC, GT, and AC haplotypes into a pGL3-luciferase reporter gene basic vector, and transfected the constructed vectors into HepG2 cells. The cells carrying the T allele at the +83 bp site (GT 112.3 +/- 12.4) had the same transcriptional efficiency as those bearing the C allele (GC 126.3 +/- 9.6). However, for cells with the A allele at -75 bp there was a twofold decrease in transcription (AC 63.1 +/- 9.3) accompanied by similar changes in Luc+ mRNA levels; this reduced transcription was only present if the apolipoprotein AI leader sequence was included in the insert. While the findings are inconsistent with the T or A allele being associated with higher high-density lipoprotein levels, they are consistent with the finding that the alleles are associated with an increased coronary artery disease risk, and demonstrate that the 5' leader region of the apolipoprotein AI gene participates in regulating apolipoprotein AI transcription. They also suggest that other regions of the apolipoprotein AI gene may have an active role in such regulation, and that environmental effects may influence allele-specific expression.


Preparation of Pd/Fe3O4 nanoparticles by use of Euphorbia stracheyi Boiss root extract: A magnetically recoverable catalyst for one-pot reductive amination of aldehydes at room temperature.
We describe a method for supporting palladium nanoparticles on magnetic nanoparticles using Euphorbia stracheyi Boiss root extract as the natural source of reducing and stabilizing agent. The progress of the reaction was monitored using UV-visible spectroscopy. The nanocatalyst was characterized by FE-SEM, TEM, XRD, EDS, FT-IR spectroscopy and ICP. The nanocatalyst was applied as an efficient, magnetically recoverable, highly reusable and heterogeneous catalyst for one-pot reductive amination of aldehydes at room temperature. The nanocatalyst was easily recovered by applying an external magnet and reused several times without considerable loss of activity.


[Development of national guidelines for depression].
Depressive disorders rank among the most frequent causes of consultation and diseases in health care. Although they are treatable, there is further need to optimize diagnostics and therapy, despite sizable progress in recent years. The implementation of evidence- and consensus-based guidelines is an appropriate measure to improve care for depressive patients. An evidence-based guideline for depression is currently being developed for Germany. In order to ensure its acceptance and a wide dissemination, this guideline will be adopted in consensus by all relevant health care providers in this field. According to this, it is a future challenge to anchor guideline-based diagnostics and treatment in routine care.


Antioxidant and hepatoprotective properties of dried fig against oxidative stress and hepatotoxicity in rats.
The aim of this study was to investigate the hepatoprotective effect and antioxidant role of dried fig (DF) (Ficus carica L.) against ethanol-induced oxidative stress. Experiment was designed as normal Control, 20% ethanol, 10% DF and 10% DF+20% ethanol groups. The hepatoprotective and antioxidant role of the dried DF supplementation feed against ethanol induced oxidatif stress were evaluated by liver histopathological changes, measuring liver damage serum enzymes (LDSE), antioxidant defense system (ADS) and malondialdehyde (MDA) content in various tissues of rats following the exposure of experimental for 50days. The biochemical analysis showed a considerable increase the LDSE in the ethanol group as compared to that of control group whereas, decreased in 10% DF+20% ethanol group as compared to that of ethanol group. In addition, the DF supplementation diet restored the ethanol-induced MDA and ADS towards to control. The hepatoprotection of DF is further substantiated by the almost normal histologic findings of liver in 10% DF+20% ethanol group against degenerative changes in ethanol group. The results indicated that the DF could be as important as diet-derived antioxidants and antihepatotoxicity in preventing oxidative damage in the tissues by inhibiting the production of ethanol-induced free radicals and hepatotoxicity in rats.


The emergence of doing "nothing" as a viable paradigm design.
Resting state fMRI has become widely accepted as a viable technique for investigating functional connectivity of the human brain. I review from a personal perspective the events of the first 8-10 years after the initial report of resting state functional connectivity, focusing on the events that led to eventual acceptance of the method. During this time there were important studies, both in MRI and other modalities, that were critical to the eventual acceptance of the resting state as a viable research tool in fMRI.


System-level responses of lake ecosystems to chemical stresses using exergy and structural exergy as ecological indicators.
This paper presents the system-level responses of experimental lake ecosystems to three chemical stresses (acidification, copper and pesticide contamination) using exergy and structural exergy as ecological indicators. The results indicate that the doses or toxicity of the three chemical stressors contributed to changes in both exergy and structural exergy. Remarkable changes in exergy and structural exergy occurred under acidic conditions and in the presence of Dursban, 24D-DMA, permethrin, bifenthrin, Carbaryl, TCP, PCP, trichlorethylene, benzene, and high doses of Cu, oil, and hexazinone. This seemed to indicate that the subject ecosystems were seriously contaminated by these chemical stressors. For low doses of Cu, oil, atrazine, HCBP, and hexazinone, exergy and structural exergy were either unchanged or only slightly changed, suggesting that the lake ecosystems were not significantly impacted by these chemical stressors. Discussion of the relationships between ecosystem-level changes and structural and functional changes in stressed lake ecosystems indicates that the above-mentioned ecosystem-level changes were in accordance with the changes in structure and function. The observed changes in exergy and structural exergy were also consistent with Odum's predictions of shortened food chains, reduced resource use efficiency, poor stability, low information, and high entropy in stressed aquatic ecosystems. The findings lead the authors to conclude that it is feasible for exergy and structural exergy to serve as ecological indicators when characterizing the system-level responses of experimental lake ecosystems to chemical stress. These results for experimental lake ecosystems would be extrapolated to actual lakes.


Synaptic reorganization in explanted cultures of rat hippocampus.
Due to loss of afferent innervation, synaptic reorganization occurs in organotypic hippocampal slice cultures. With extra- and intracellular recordings, we confirm that the excitatory loop from the dentate gyrus (DG) to CA3 and further to CA1 is preserved. However, hilar stimulation evoked antidromic population spikes in the DG which were followed by a population postsynaptic potential (PPSP); intracellularly, an antidromic spike with a broad shoulder or EPSP/IPSP sequences were induced. Synaptic responses were blocked by glutamate receptor antagonists. Stimulation of CA1 induced a PPSP in DG. Dextranamine stained pyramidal cells of CA1 were shown to project to DG. After removal of area CA3, DG's and mossy fibers' (MF) stimulation still elicited PPSPs and EPSP/IPSP sequences in area CA1 which disappeared when a cut was made through the hippocampal fissure. During bicuculline perfusion, hilar stimulation caused EPSPs in granule cells and spontaneous and evoked repetitive firing appeared even after its isolation from areas CA3 and CA1. Collateral excitatory synaptic coupling between granule cells was confirmed by paired recordings. Besides the preservation of the trisynaptic pathway in this preparation, new functional synaptic contacts appear, presumably due to MF collateral sprouting and formation of pathways between areas CA1 and DG.


Thymic volume in healthy, small for gestational age and growth restricted fetuses.
The aim of this study was to verify the hypothesis that a difference in thymic size exists between small for gestational age (SGA) fetuses, likely constitutional, and intrauterine growth restricted (IUGR) fetuses because of placental causes. We studied 27 SGA and 36 control fetuses. SGA was defined as fetal abdominal circumference (AC) and birthweight <10th percentile for gestational age. We defined as constitutional SGA those with normal uterine and umbilical artery Doppler flow velocity waveforms (FVW), and as IUGR those with abnormal uterine FVW. IUGR were further divided based on normal or abnormal umbilical FVW. Fetal thymic volume (TV) was acquired by three-dimensional ultrasound and reconstructed with virtual organ computer-aided analysis. To correct for the influence of fetal size on thymic dimension, TV/AC ratio was calculated. Controls presented a higher TV/AC compared with each group of SGA (p < 0.001). TV/AC was significantly lower in IUGR with abnormal umbilical FVW compared with both constitutional SGA (p = 0.01) and IUGR with normal umbilical FVW (p = 0.01). The differences in TV/AC between constitutional SGA and IUGR with abnormal umbilical FVW suggest that, in the latter, a specific 'trigger' might compromise trophoblastic invasion and thymic development; however, some kind of alteration of the immune system might occur in all SGA fetuses.


Should a Mechanical or Biological Prosthesis Be Used for a Tricuspid Valve Replacement? A Meta-Analysis.
The prosthesis of choice for a tricuspid valve replacement is still unkown. This meta-analysis was undertaken to review the results of mechanical and bioprosthetic valves in the tricuspid position. We identified all relevant studies published in the past 20 years (from January 1, 1995 to December 31, 2014) through the Embase, Current Contents, and PubMed databases. The hazard ratio and its 95% confidence limits were utilized to evaluate time-to-event related effects of surgical procedures. The Q-statistic, Index of Inconsistency test, funnel plots, and Egger's test were used to assess the degree of heterogeneity and publication bias. Random effects models were used, and study quality was also assessed. In our meta-analysis, 22 studies published from 1995 to 2014 were reviewed and 2630 patients and 14,694 follow-up years were analyzed. No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, and prosthetic valve failure. The respective pooled hazard ratio estimates were 0.95 (0.79 to 1.16, p = 0.62, I(2) = 29%), 1.20 (0.84 to 1.71, p = 0.33, I(2) = 0%), and 0.35 (0.06 to 2.01, p = 0.24, I(2) = 0%). A higher risk of thrombosis was found in mechanical tricuspid valve prostheses (3.86, 1.38 to 10.82, p = 0.01, I(2) = 0%). No statistically significant difference was identified between mechanical and biological valves in terms of survival, reoperation, or prosthetic valve failure, but mechanical tricuspid valve prostheses had a higher risk of thrombosis. doi: 10.1111/jocs.12730 (J Card Surg 2016;31:294-302).


Significance and Surgical Options for Nontranssexual Phalloplasty: A Retrospective Single-Center Analysis of 166 Patients.
This study aimed to evaluate the long-term outcomes of phalloplasty and explore the clinical significance and selection of methods for penile reconstruction. The same surgical team performed primary phalloplasty in 166 nontranssexual patients using different surgical approaches between September 2000 and September 2020. All patients had at least 6 months of follow-up. Surgical techniques, complications, and outcomes were retrospectively recorded. A total of 166 patients with indications such as penile trauma (n = 68 [41%]), amputation injury (n = 15 [9%]), iatrogenic (n = 13 [8%]), penile aplasia (n = 54 [32%]), genital ambiguity (n = 15 [9%]), and Peyronie disease (n = 1 [0.6%]) underwent different techniques of phalloplasty. Four patients (2.4%) had total flap necrosis, and 17 (10%) had partial flap necrosis. The total urethral complications rate was 32.5% (54 of 166); however, all the patients were able to void while standing after successful corrective surgery. Individualized selection of appropriate penile reconstruction methods tailored to the cause of penile defect, patients' personal needs, thickness of donor site, and the blood supply of the flap are conducive to achieving satisfactory treatment results, reducing complications, and improving patient satisfaction. We believe that a scapular flap has certain advantages in nontranssexual patients, whereas other flaps also have their own indications.


Pyelosinus extravasation and urinoma associated with malignancy. Computed tomography demonstration.
We report 3 cases of abdominal malignancy with urinary tract obstruction and pyelosinus extravasation. Urinomas were present in 2 cases. The computed tomographic findings are emphasized, including the distribution of the extravasated urine reflecting the partitioning in the perirenal space. The cases presented within an eighteen-month period suggest pyelosinus extravasation and urinoma formation may not be uncommon in malignant disease affecting the retroperitoneum and pelvis.


A spatial web/agent-based model to support stakeholders' negotiation regarding land development.
Decision making in land management can be greatly enhanced if the perspectives of concerned stakeholders are taken into consideration. This often implies negotiation in order to reach an agreement based on the examination of multiple alternatives. This paper describes a spatial web/agent-based modeling system that was developed to support the negotiation process of stakeholders regarding land development in southern Alberta, Canada. This system integrates a fuzzy analytic hierarchy procedure within an agent-based model in an interactive visualization environment provided through a web interface to facilitate the learning and negotiation of the stakeholders. In the pre-negotiation phase, the stakeholders compare their evaluation criteria using linguistic expressions. Due to the uncertainty and fuzzy nature of such comparisons, a fuzzy Analytic Hierarchy Process is then used to prioritize the criteria. The negotiation starts by a development plan being submitted by a user (stakeholder) through the web interface. An agent called the proposer, which represents the proposer of the plan, receives this plan and starts negotiating with all other agents. The negotiation is conducted in a step-wise manner where the agents change their attitudes by assigning a new set of weights to their criteria. If an agreement is not achieved, a new location for development is proposed by the proposer agent. This process is repeated until a location is found that satisfies all agents to a certain predefined degree. To evaluate the performance of the model, the negotiation was simulated with four agents, one of which being the proposer agent, using two hypothetical development plans. The first plan was selected randomly; the other one was chosen in an area that is of high importance to one of the agents. While the agents managed to achieve an agreement about the location of the land development after three rounds of negotiation in the first scenario, seven rounds were required in the second scenario. The proposed web/agent-based model facilitates the interaction and learning among stakeholders when facing multiple alternatives.


Bone ingrowth around porous-coated acetabular implant: a three-dimensional finite element study using mechanoregulatory algorithm.
Fixation of uncemented implant is influenced by peri-prosthetic bone ingrowth, which is dependent on the mechanical environment of the implant-bone structure. The objective of the study is to gain an insight into the tissue differentiation around an acetabular component. A mapping framework has been developed to simulate appropriate mechanical environment in the three-dimensional microscale model, implement the mechanoregulatory tissue differentiation algorithm and subsequently assess spatial distribution of bone ingrowth around an acetabular component, quantitatively. The FE model of implanted pelvis subjected to eight static load cases during a normal walking cycle was first solved. Thereafter, a mapping algorithm has been employed to include the variations in implant-bone relative displacement and host bone material properties from the macroscale FE model of implanted pelvis to the microscale FE model of the beaded implant-bone interface. The evolutionary tissue differentiation was observed in each of the 13 microscale models corresponding to 13 acetabular regions. The total implant-bone relative displacements, averaged over each region of the acetabulum, were found to vary between 10 and 60 μm. Both the linear elastic and biphasic poroelastic models predicted similar mechanoregulatory peri-prosthetic tissue differentiation. Considerable variations in bone ingrowth (13-88%), interdigitation depth (0.2-0.82 mm) and average tissue Young's modulus (970-3430 MPa) were predicted around the acetabular cup. A progressive increase in the average Young's modulus, interdigitation depth and decrease in average radial strains of newly formed tissue layer were also observed. This scheme can be extended to investigate tissue differentiation for different surface texture designs on the implants.


Late-onset axial jerky dystonia due to the DYT1 deletion.
We describe a 71-year-old woman who presented to the neurology department late in life with a jerky axial dystonia due to the DYT1 GAG deletion. She recalled that her symptoms began 62 years prior to study and remained unchanged for 40 years, illustrating the broad phenotype of DYT1 idiopathic torsion dystonia.


A review of esophageal disc battery ingestions and a protocol for management.
To review our experience with esophageal disc battery requiring endoscopic retrieval and describe a protocol for management. Retrospective medical chart review. Pediatric patients who underwent endoscopic retrieval of an esophageal disc battery over a 10-year period. Ten pediatric patients had ingested an esophageal disc battery that required endoscopic removal. Three patients had minimal esophageal damage; the other 7 sustained severe and extensive esophageal damage involving the muscularis (n = 5) or developed a perforation (n = 2). One of these patients had an extensive injury that extended into the trachea resulting in a tracheoesophageal fistula. Two case reports are presented, outlining the management approach to esophageal perforations from esophageal battery ingestion. Severe injury can occur rapidly following disc battery ingestion. A high index of suspicion for an esophageal disc battery is necessary to expeditiously diagnose this condition. Emergency endoscopic removal is necessary. We outline a protocol for the management of this hazardous problem.


On the possible involvement of ascorbic acid and copper proteins in leukemia. III. ESR investigations on the interaction between ascorbic acid and some transition metal ions.
The interaction between lyophilized samples of ascorbic acid and Cu2+, Fe3+ or Mn2+ has been investigated by means of ESR spectroscopy. All of the three transition metal ions form complexes with vitamin C, but only in the case of Cu2+ and Fe3+ the interaction results in a reduction of the metal ions. Cu2+ and ascorbic acid seem to form 2 : 1 complexes with an equilibrium constant of about K = 1 X 10(7) mol-1. None of these metal ion complexes exhibits, however, the ESR spectrum obtained with leukemic blood.


Severe maternal morbidity in pregnant patients with SARS-CoV-2 infection.
Although the increased risk for severe illness and adverse pregnancy outcomes associated with SARS-CoV-2 infection during pregnancy is well described, the association of infection with severe maternal morbidity has not been well characterized. This study aimed to evaluate the risk for severe maternal morbidity associated with SARS-CoV-2 infection during pregnancy. This was a multicenter retrospective cohort study of all pregnant patients who had a SARS-CoV-2 test done and who delivered in a New York health system between March 1, 2020 and March 1, 2021. Patients with missing test results were excluded. The primary outcome of severe maternal morbidity, derived from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine example list of diagnoses and complications, was compared between the following 2 groups: patients who tested positive for SARS-CoV-2 during pregnancy and patients who tested negative. Secondary outcomes included subgroups of severe maternal morbidity. Multivariable logistic regression was used to adjust for potential confounders such as maternal demographics, neighborhood socioeconomic status, hospital location, and pregnancy-related complications. A subanalysis was performed to determine if the risk for severe obstetrical hemorrhage and hypertension-associated or neurologic morbidity differed based on the timing of SARS-CoV-2 infection between those who tested positive for SARS-CoV-2 at their delivery hospitalization (ie, active infection) and those who tested positive during pregnancy but negative at their delivery hospitalization (ie, resolved infection). Of the 22,483 patients included, 1653 (7.4%) tested positive for SARS-CoV-2 infection. Patients with SARS-CoV-2 infection were more commonly Black, multiracial, Hispanic, non-English speaking, used Medicaid insurance, were multiparous, and from neighborhoods with a lower socioeconomic status. Patients with SARS-CoV-2 infection were at an increased risk for severe maternal morbidity when compared with those without infection (9.3 vs 6.5%; adjusted odds ratio, 1.52; 95% confidence interval, 1.21-1.88). Patients with SARS-CoV-2 infection were also at an increased risk for severe obstetrical hemorrhage (1.1% vs 0.5%; adjusted odds ratio, 1.78; 95% confidence interval, 1.04-2.88), pulmonary morbidity (2.0% vs 0.5%; adjusted odds ratio, 3.90; 95% confidence interval, 2.52-5.89), and intensive care unit admission (1.8% vs 0.5%; adjusted odds ratio, 3.29; 95% confidence interval, 2.09-5.04) when compared with those without infection. The risk for hypertension-associated or neurologic morbidity was similar between the 2 groups. The timing of SARS-CoV-2 infection (whether active or resolved at time of delivery) was not associated with the risk for severe obstetrical hemorrhage or hypertension-associated or neurologic morbidity when compared with those without infection. SARS-CoV-2 infection during pregnancy was associated with an increased risk for severe maternal morbidity, severe obstetrical hemorrhage, pulmonary morbidity, and intensive care unit admission. These data highlight the need for obstetrical unit preparedness in caring for patients with SARS-CoV-2 infection, continued public health efforts aimed at minimizing the risk for infection, and support in including this select population in investigational therapy and vaccine trials.


Phenylethynyl-butyltellurium inhibits the sulfhydryl enzyme Na+, K+ -ATPase: an effect dependent on the tellurium atom.
Organotellurium compounds are known for their toxicological effects. These effects may be associated with the chemical structure of these compounds and the oxidation state of the tellurium atom. In this context, 2-phenylethynyl-butyltellurium (PEBT) inhibits the activity of the sulfhydryl enzyme, δ-aminolevulinate dehydratase. The present study investigated on the importance of the tellurium atom in the PEBT ability to oxidize mono- and dithiols of low molecular weight and sulfhydryl enzymes in vitro. PEBT, at high micromolar concentrations, oxidized dithiothreitol (DTT) and inhibited cerebral Na(+), K(+)-ATPase activity, but did not alter the lactate dehydrogenase activity. The inhibition of cerebral Na(+), K(+)-ATPase activity was completely restored by DTT. By contrast, 2-phenylethynyl-butyl, a molecule without the tellurium atom, neither oxidized DTT nor altered the Na(+), K(+)-ATPase activity. In conclusion, the tellurium atom of PEBT is crucial for the catalytic oxidation of sulfhydryl groups from thiols of low molecular weight and from Na(+), K(+)-ATPase.


Treadmill walking with body weight support effect of treadmill, harness and body weight support systems.
This study aims to provide new knowledge on the principles of treadmill walking with body weight support (BWS) by qualifying and quantifying the effects on gait in 28 healthy individuals. Gait assessment included measuring trunk movements during different conditions. Walking overground and on a treadmill with and without harness, and on a treadmill with 30% dynamic and static body weight support, was assessed. Gait variables for all conditions were compared at 1.2m/s. On the treadmill, cadence increased, the trunk tilted more forwards, vertical acceleration increased and anteroposterior acceleration became more variable. Wearing a harness resulted in more restricted vertical acceleration. Walking with body weight support restricted acceleration in all directions. It also produced variable interstride trunk acceleration in the anteroposterior and vertical directions, but more consistent interstride trunk acceleration in the mediolateral direction. Static BWS gave larger differences than dynamic BWS.


Antimicrobial activity of Ro 24-6778, a covalent bonding of desmethylfleroxacin and desacetylcefotaxime.
A new "dual action" cephalosporin (Ro 24-6778), representing an ester-linked desacetylcefotaxime and desmethylfleroxacin was tested against 287 aerobic bacteria. Ro 24-6778 was found to be very active (minimal inhibitory concentrations [MIC90], less than or equal to 0.5 micrograms/ml) against Enterobacteriaceae, Streptococcus spp., and Aeromonas hydrophila. Moderate Ro 24-6778 activity (MIC90, 1-8 micrograms/ml) was demonstrated against Bacillus spp., Staphylococcus spp. (including oxacillin-resistant strains), Flavobacterium spp., Enterococcus durans, and Acinetobacter anitratus. More Ro 24-6778-resistant strains (MIC90, 16- greater than 32 micrograms/ml) were usually found among the enterococci, Xanthomonas hydrophila, Pseudomonas spp., and Achromobacter xyloxidans isolates. These preliminary Ro 24-6778 MIC test results show a spectrum superior (93.4% of strains susceptible at less than or equal to 8 micrograms/ml) to the comparison drugs (cefotaxime or fleroxacin) and possible clinical utility for therapy of many fluoroquinolone- or cephalosporin-resistant strains.


Combination of APACHE-II score and an obesity score (APACHE-O) for the prediction of severe acute pancreatitis.
The advent of specific therapeutic or preventive treatments for severe acute pancreatitis creates a need to determine the risk of complications for each individual. Scoring systems used in acute pancreatitis identify groups of patients at risk of complications, but the pancreatitis-specific scores require 48 h of hospital admission to give full information. The APACHE-II score is useful within 24 h, but ignores simple clinical features, such as obesity, known to predict severity. The aim of this study was to evaluate a combination of the APACHE-II score with an obesity score in patients with acute pancreatitis, to predict severity using information available during the first 24 h of hospital admission. Data were collected prospectively from 186 consecutive patients with acute pancreatitis, to allow calculation of the APACHE-II score and body mass index (BMI). BMI was categorised as normal (score = 0), overweight (BMI 26-30: score = 1), or obese (BMI >30: score = 2). A logistic regression model was used to identify factors significantly associated with complications (Atlanta criteria; 104 complications in 60 patients). Age, BMI and the acute physiology score independently predicted complications. Addition of the score for obesity to the APACHE-II score gave a composite score (APACHE-O) with greater predictive accuracy. At cut-off of >8, APACHE-O had sensitivity 82%, specificity 86%, positive predictive value 74%, negative predictive value 91% and overall accuracy 85%. This study confirms that age, obesity and APACHE-II measured in the first 24 h of hospital admission can predict complications in acute pancreatitis. Combination of the APACHE-II and obesity scores by simple addition improved categorical prediction of severity (mild or severe) in patients with acute pancreatitis.


Determination of enantiomeric purity of the new D-2 dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) by reversed-phase high-performance liquid chromatography after pre-column derivatization with D(+)-glucuronic acid.
This paper describes an enzymic derivatization procedure that allows accurate determination of very small amounts of enantiomeric impurities in the D-2 dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437). After pre-column glucuronidation of the individual enantiomers, two diastereoisomers were formed which were separated by reversed-phase high-performance liquid chromatography. An enantiomeric purity of 99.84% was calculated for the (-)-enantiomer, against 99.89% for the (+)-enantiomer. The assay was validated by spiking 1% of the (-)-enantiomer in the (+)-enantiomer. A high accuracy (error 4.5%) and precision (coefficient of variation 2.9%, n = 5) of the method were established.


High blood pressure as risk factor in diabetic retinopathy development in NIDDM patients.
The correlation between diabetic retinopathy and blood pressure was analyzed in 742 type II diabetic patients. Systolic and pulse blood pressures were significantly higher in the patients with retinopathy than in those without (mean systolic pressure 142 vs. 139 mmHg, P less than .01; mean pulse pressure 60.5 vs. 56.4 mmHg, P less than .001). There was no difference in the diastolic blood pressure between these two groups. The correlation between blood pressure and the components of retinopathy (including microaneurysms, hemorrhages, and exudates) was also analyzed. Even when the patient with microaneurysms or dot hemorrhages, blot hemorrhages, or hard or soft exudates were separately evaluated, systolic and pulse blood pressures were higher in those with one of these diabetic changes than in patients without them. To avoid the influence of nephropathy, the patients were divided into nonproteinuric or proteinuric groups. In the nonproteinuric group, pulse blood pressure was higher in patients with retinopathy than in those without. In the proteinuric group, systolic blood pressure was also higher in patients with retinopathy than in those without. However, these observed differences in blood pressure were slight after the division of the patients. With respect to the components of retinopathy, systolic and pulse blood pressures were significantly higher in the patient with blot hemorrhages than in those without in both nonproteinuric and proteinuric groups (nonproteinuric: systolic pressure 142 vs. 137 mmHg, P less than .005, and pulse pressure 60.4 vs. 55.5 mmHg, P less than .001; proteinuric: systolic pressure 155 vs. 146 mmHg, P less than 0.01, and pulse pressure 69.0 vs. 63.5 mmHg, P less than .05).


Use of adenosine 5'-0-(2-thiotriphosphate) for revealing of newly initiated transcripts in isolated rat liver nuclei.
Initiation of DNA-dependent RNA synthesis in isolated rat liver nuclei was studied with adenosine 5'-0-(2-thiotriphosphate), (beta-S-ATP), as a precursor. The newly made RNA labelled with sulfur at 5'-triphosphate termini (thio-RNA) was isolated by affinity chromatography on a mercury-agarose column. Sulfur label can be removed from thio-RNA by digestion with phosphodiesterase I and nucleotide pyrophosphatase. Gel electrophoresis revealed that thio-RNA synthesized during 30 min was composed of 4S-35S molecules with three prevailing classes grouped around 4S-5S, 16S and approximately 35S. Differential sensitivity of the thio-RNA classes to low (1 microgram/ml) and high (200 micrograms/ml) concentrations of alpha-amanitin disclosed that beta-S-ATP was used for initiation of transcription by all three classes of RNA polymerases, and that thio-RNA included molecules as large as 18S initiated by RNA polymerase II. Thio-RNA resistant even to high doses of alpha-amanitin represents probably a product of RNA polymerase I which was initiated and elongated up to 35S.


Proteomic analysis reveals that Xbp1s promotes hypoxic pulmonary hypertension through the p-JNK MAPK pathway.
Hypoxic pulmonary hypertension (HPH) is characterized by elevated pulmonary artery resistance and vascular remodeling. Endoplasmic reticulum stress (ERS) is reported to be involved in HPH, but the underlying mechanisms remain uncertain. We found that Xbp1s, a potent transcription factor during ERS, was elevated in hypoxic-cultured rat PASMCs and lung tissues from HPH rats. Our in vitro experiments demonstrated that overexpressing Xbp1s can promote proliferation, cell viability, and migration and inhibit the apoptosis of PASMCs, while silencing Xbp1s led to the opposite. Through data-independent acquisition (DIA) mass spectrometry, we identified extensive proteomic alterations regulated by hypoxia and Xbp1s. Further validation revealed that p-JNK, rather than p-ERK or p-p38, was the downstream effector of Xbp1s. p-JNK inhibition reversed the biological effects of Xbp1s overexpression in vitro. In the animal HPH model, rats were randomly assigned to five groups: normoxia, hypoxia, hypoxia+AAV-CTL (control), hypoxia+AAV-Xbp1s (prevention), and hypoxia+AAV-Xbp1s (therapy). Adeno-associated virus (AAV) serotype 1-mediated Xbp1s knockdown in the prevention and therapy groups significantly reduced right ventricular systolic pressure, total pulmonary resistance, right ventricular hypertrophy, and the medial wall thickness of muscularized distal pulmonary arterioles; AAV-Xbp1s also decreased proliferating cell nuclear antigen expression and increased apoptosis in pulmonary arterioles. Collectively, our findings demonstrated that the Xbp1s-p-JNK pathway is important in hypoxic vascular remodeling and that targeting this pathway could be an effective strategy to prevent and alleviate HPH development.