[Faecal calprotectin is a useful biomarker for intestinal inflammation].
Faecal calprotectin is a biomarker for inflammation in the intestinal mucosa. Faecal calprotectin has the ability to detect inflammatory causes of gastrointestinal symptoms and to distinguish these from irritable bowel syndrome. The test is very sensitive but not specific to any particular gastrointestinal disease. In inflammatory bowel disease, faecal calprotectin correlates with symptoms, biochemical markers and the endoscopic findings. It can be used to monitor disease activity, treatment response and mucosal healing as well as predict relapse. We propose an algorithm for the use of faecal calprotectin in patients with unspecific abdominal complaints.


Hemodialysis versus cross hemodialysis in experimental hepatic coma.
In this study, the effects of conventional hemodialysis on experimental hepatic coma have been compared with those of hemodialysis against blood from a normal donor which allows exchanges without mixing of blood. cuprophan and polyacrylonitrile membranes were compared. Cross hemodialysis with a donor resulted in rpompt but transient recovery of consciousness, whichever membrane was used. Cuprophan hemodialysis without donor had no effect. Polacrylonitrile hemodialysis without donor allowed progressive and prolonged improvement in the consciusness level and the electroencephalograms. Therefore, clearance of middle molecular weight substances was more effective than exchange with a donor. Preliminary results in man showed total recovery of consciousness in six of ten patients with acute liver failure and coma and partial recovery from complete grade IV coma to grade II encephalopathy in two patients. These two patients reacted when called by their name by opening their eyes and obeying simple orders.


Changes in the Morphology of Hypoglossal Motor Neurons in the Brainstem of Developing Rats.
The autonomic brainstem generates breathing rhythm by integrating inputs from chemosensors and mechanosensors in the viscera and coordinating descending outputs from higher structures in the central nervous system. Hypoglossal motoneurons (XII MNs) receive inputs from respiratory premotor neurons, important for maintaining airway patency. Previous studies in rodents report significant changes in breathing control during the first 3 weeks of life, with a sensitive period at 10 to 13 days postbirth (P10-P13) characterized by pronounced changes in neurotransmitters, excitation-inhibition balance, and breathing physiology. However, age-dependent morphological changes of XII MNs during the first 3 weeks postbirth and especially this sensitive period are under-studied. Here, we comprehensively characterize and quantify the early morphological changes in rat XII MNs. We hypothesized that morphological changes in XII MNs correspond to the functionally defined sensitive period observed at postnatal day 10-13 (P10-P13). To test this hypothesis, we used an innovative contemporary statistical approach to analyze Golgi-Cox stained XII MNs at nine postnatal ages between P1 and P21. Our findings reveal two subpopulations of XII MNs, which are dependent on age and morphological features. Soma size increased approximately 40% from P1 to P21, without changing shape. However, dendritic arborization increased in extent/distance and complexity. Dendritic branching of developing neurons significantly increased from P1 through P13, with the greatest increase at P10-P13 based on the Sholl method. Our detailed characterization of XII MN morphological development establishes a foundation for the study and elucidation of morphological changes caused by maternal and perinatal conditions. Anat Rec, 302:869-892, 2019. © 2018 Wiley Periodicals, Inc.


Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus.
Our aim was to review recent studies that address the increased risk of atherosclerosis and coronary heart disease in patients with rheumatoid arthritis and systemic lupus erythematosus. We examine the strength of this association, how inflammation mediates this increased risk and what impact therapies may have. Atherosclerosis is more prevalent and accelerated in both conditions. Indeed the process may actually precede the onset of clinical inflammatory disease. Metabolic alterations include insulin resistance and the generation of proinflammatory HDL. In addition, inflammatory mechanisms central to both rheumatoid arthritis and systemic lupus erythematosus such as macrophage activation, interferon-1 and complement deficiency may contribute to atherogenesis. There is still no consensus as to the value of primary preventive strategies in these conditions. However, drugs such as hydroxychloroquine seem to modify coronary heart disease risk and may improve survival. The recently developed antitumour necrosis factor drugs may also reduce coronary heart disease risk but biomarker studies to date have been inconclusive. There is an urgent need for clinical trials to examine both the lipid-lowering and inflammatory hypotheses of atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Novel targeted therapies in development may also have a major impact on future coronary heart disease risk in these conditions.


Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation.
To study the influence of immunoglobulin heavy-chain (HC) and light-chain (LC) expression in promoting B-cell differentiation, we have introduced functional immunoglobulin HC and/or LC transgenes into the recombinase activating gene-2-deficient background (RAG-2-/-). RAG-2-/- mice do not undergo endogenous V(D)J rearrangement events and, therefore, are blocked in B- and T-cell development at the early pro-B- and pro-T-cell stages. Introduction of immunoglobulin HC transgenes into the RAG-2-/- background promotes the development of a B-lineage cell population that phenotypically has the characteristics of pre-B cells. We have shown further that this population has altered growth characteristics as measured by interleukin-7 responsiveness in culture. Bone marrow cells from immunoglobulin HC transgenic RAG-2-/- mice have up-regulated expression of germ-line kappa LC gene transcripts and down-regulated expression of lambda 5 surrogate LCs (SLCs). Although mu HC/SLC complexes are detectable intracellularly in HC/RAG-2-/- pre-B-cell populations, HC expression is not readily detectable on the surface of these cells. lambda LC RAG-2-/- mice had a bone marrow B-lineage cell phenotype indistinguishable from that of RAG-2-/- littermates, indicating that LC expression by itself has no influence on pro-B cell differentiation. Strikingly, simultaneous introduction of mu HC and lambda LC transgenes into RAG-2-/- mice led to the generation of a substantial population of "monoclonal" peripheral B-cells that were functional with regard to immunoglobulin secretion, indicating that T cells or diverse immunoglobulin repertoires are not necessary for peripheral B-cell development.


Maximum likelihood estimates of diffusion coefficients from single-particle tracking experiments.
Single-molecule localization microscopy allows practitioners to locate and track labeled molecules in biological systems. When extracting diffusion coefficients from the resulting trajectories, it is common practice to perform a linear fit on mean-squared-displacement curves. However, this strategy is suboptimal and prone to errors. Recently, it was shown that the increments between the observed positions provide a good estimate for the diffusion coefficient, and their statistics are well-suited for likelihood-based analysis methods. Here, we revisit the problem of extracting diffusion coefficients from single-particle tracking experiments subject to static noise and dynamic motion blur using the principle of maximum likelihood. Taking advantage of an efficient real-space formulation, we extend the model to mixtures of subpopulations differing in their diffusion coefficients, which we estimate with the help of the expectation-maximization algorithm. This formulation naturally leads to a probabilistic assignment of trajectories to subpopulations. We employ the theory to analyze experimental tracking data that cannot be explained with a single diffusion coefficient. We test how well a dataset conforms to the assumptions of a diffusion model and determine the optimal number of subpopulations with the help of a quality factor of known analytical distribution. To facilitate use by practitioners, we provide a fast open-source implementation of the theory for the efficient analysis of multiple trajectories in arbitrary dimensions simultaneously.


Bioaccumulation of tetrabromobisphenol A in a laboratory-based fish-water system based on selective magnetic molecularly imprinted solid-phase extraction.
Recently, magnetic solid-phase extraction (MSPE) using magnetic molecularly imprinted polymers (MMIPs), which is a simple process with excellent selectivity, has attracted much attention for the determination of environmental pollutants. In this study, MMIPs were used as an adsorbent to establish a selective MSPE method coupled with high-performance liquid chromatography using ultraviolet detection (HPLC-UV) for the determination of tetrabromobisphenol A (TBBPA) levels in water and fish samples. The samples were collected from a laboratory-based fish-water system after 0, 2, 5, 8, 11, 20, 30, and 50 days. We found that the concentrations of TBBPA in the sample group spiked with TBBPA decreased in the water samples over time and increased in the fish samples from 2 to 30 days, then finally decreased. The calculated bioconcentration factor (BCF) increased over time, reaching 33.98 L/kg after 50 days exposure to TBBPA. Linear and exponential kinetic models were applied to fit the correlation between BCF and exposure time, and the constant of the time-dependent BCF (Ku) ranged from 0.0364 to 1.5250 L/kg per day with a corresponding R2 of 0.6786 to 0.9985. Simplified mathematical models to evaluate the transfer characteristics of TBBPA in a laboratory-based fish-water system have been developed.


The characteristics of missed pharyngeal and laryngeal cancers at gastrointestinal endoscopy.
Understanding the miss rate and characteristics of missed pharyngeal and laryngeal cancers during upper gastrointestinal endoscopy may aid in reducing the endoscopic miss rate of this cancer type. However, little is known regarding the miss rate and characteristics of such cancers. Therefore, the aim of this study was to investigate the upper gastrointestinal endoscopic miss rate of oro-hypopharyngeal and laryngeal cancers, the characteristics of the missed cancers, and risk factors associated with the missed cancers. Patients who underwent upper gastrointestinal endoscopy and were pathologically diagnosed with oro-hypopharyngeal and laryngeal squamous cell carcinoma from January 2019 to November 2020 at our institution were retrospectively evaluated. Missed cancers were defined as those diagnosed within 15 months after a negative upper gastrointestinal endoscopy. A total of 240 lesions were finally included. Eighty-five lesions were classified as missed cancers, and 155 lesions as non-missed cancers. The upper gastrointestinal endoscopic miss rate for oro-hypopharyngeal and laryngeal cancers was 35.4%. Multivariate analysis revealed that a tumor size of <13 mm (odds ratio: 1.96, P=0.026), tumors located on the anterior surface of the epiglottis/valleculae (odds ratio: 2.98, P=0.045) and inside of the pyriform sinus (odds ratio: 2.28, P=0.046) were associated with missed cancers. This study revealed a high miss rate of oro-hypopharyngeal and laryngeal cancers during endoscopic observations. High-quality upper gastrointestinal endoscopic observation and awareness of missed cancer may help reduce this rate.


Pan-cancer evaluation of clinical value of mitotic network activity index (MNAI) and its predictive value for immunotherapy.
Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types, 10,061 patients) and validation on other publicly available cohorts (23 tumor types, 9,209 patients) confirmed the significant association of MNAI with overall survival, progression-free survival, and other prognostic endpoints in multiple cancer types, including lower-grade gliomas (LGG), breast invasive carcinoma (BRCA), as well as many others. We also showed significant association between MNAI and genetic instability, which provides a biological explanation of its prognostic impact at pan-cancer landscape. Our association analysis revealed that patients with high MNAI benefitted more from anti-PD-1 and Anti-CTLA-4 treatment. In addition, we demonstrated that multimodal integration of MNAI and the AI-empowered Cellular Morphometric Subtypes (CMS) significantly improved the predictive power of prognosis compared to using MNAI and CMS alone. Our results suggest that MNAI can be used as a potential prognostic biomarker for different tumor types toward different clinical endpoints, and multimodal integration of MNAI and CMS exceeds individual biomarker for precision prognosis.


Learning curves for three specific procedures by anesthesiology residents using the learning curve cumulative sum (LC-CUSUM) test.
The learning curve cumulative sum (LC-CUSUM) test is an innovative tool that allows quantitative monitoring of individual medical performance during the learning process by determining when a predefined acceptable level of performance is reached. This study used the LC-CUSUM test to monitor the learning process and failure rate of anesthesia residents training for specific subspecialty anesthesia procedures. The study included 490 tracheal punctures (TP) for jet ventilation, 340 thoracic epidural analgesia (TEA) procedures, and 246 fiberoptic nasal intubations (FONI) performed by 18 residents during their single 6-month rotation. Overall, 27 (14-52), 19 (5-41), and 14 (6-33) TP, TEA, and FONI procedures were performed, respectively, by each resident. In total, 2 of 18 residents achieved an acceptable failure rate for TEA according to the literature and 4 of 18 achieved an acceptable failure rate for FONI, while none of the residents attained an acceptable rate for TP. A single 6-month rotation in a reference teaching center may not be sufficient to train residents to perform specific or sub-specialty procedures as required. A regional learning network may be useful. More patient-based data are necessary to conduct a risk adjustment analysis for such specific procedures.


Novel cycloaddition of nitriles with monolithio- and dilithiobutadienes.
Two novel and synthetically useful reaction patterns of organolithium compounds with nitriles are reported to afford pyridine derivatives as the final products. Both 1-lithio-1,3-dienes and 1,4-dilithio-1,3-dienes, which can be easily generated in situ by lithiation of their corresponding iodo compounds, react with nitriles in the presence of HMPA to form substituted pyridines including 2,2'-bipyridines and tetrahydroisoquinolines in high yields.


Using the mood disorder questionnaire and bipolar spectrum diagnostic scale to detect bipolar disorder and borderline personality disorder among eating disorder patients.
Screening scales for bipolar disorder including the Mood Disorder Questionnaire (MDQ) and Bipolar Spectrum Diagnostic Scale (BSDS) have been plagued by high false positive rates confounded by presence of borderline personality disorder. This study examined the accuracy of these scales for detecting bipolar disorder among patients referred for eating disorders and explored the possibility of simultaneous assessment of co-morbid borderline personality disorder. Participants were 78 consecutive female patients who were referred for evaluation of an eating disorder. All participants completed the mood and eating disorder sections of the SCID-I/P and the borderline personality disorder section of the SCID-II, in addition to the MDQ and BSDS. Predictive validity of the MDQ and BSDS was evaluated by Receiver Operating Characteristic analysis of the Area Under the Curve (AUC). Fifteen (19%) and twelve (15%) patients fulfilled criteria for bipolar II disorder and borderline personality disorder, respectively. The AUCs for bipolar II disorder were 0.78 (MDQ) and 0.78 (BDSD), and the AUCs for borderline personality disorder were 0.75 (MDQ) and 0.79 (BSDS). Among patients being evaluated for eating disorders, the MDQ and BSDS show promise as screening questionnaires for both bipolar disorder and borderline personality disorder.


Impact of new data for neutron-rich heavy nuclei on theoretical models for r-process nucleosynthesis.
Current models for the r process are summarized with an emphasis on the key constraints from both nuclear physics measurements and astronomical observations. In particular, we analyze the importance of nuclear physics input such as beta-decay rates; nuclear masses; neutron-capture cross sections; beta-delayed neutron emission; probability of spontaneous fission, beta- and neutron-induced fission, fission fragment mass distributions; neutrino-induced reaction cross sections, etc. We highlight the effects on models for r-process nucleosynthesis of newly measured β-decay half-lives, masses, and spectroscopy of neutron-rich nuclei near the r-process path. We overview r-process nucleosynthesis in the neutrino driven wind above the proto-neutron star in core collapse supernovae along with the possibility of magneto-hydrodynamic jets from rotating supernova explosion models. We also consider the possibility of neutron star mergers as an r-process environment. A key outcome of newly measured nuclear properties far from stability is the degree of shell quenching for neutron rich isotopes near the closed neutron shells. This leads to important constraints on the sites for r-process nucleosynthesis in which freezeout occurs on a rapid timescale.


Inventorizing the modern benthic foraminiferal assemblage from marginal marine environments across the North West coast of Bay of Bengal.
Modern benthic foraminiferal assemblages are instrumental in providing information regarding changes in relative sea level as well as prevailing environmental conditions in marine environments. Marginal marine environments are coastal environments that are in most cases characterized by high influx of terrestrially originated nutrients. Inventorizing of modern benthic foraminiferal assemblages from such habitats can act as biotic indicators of water quality variations along with any changes in relative sea level. The present study documents the modern benthic foraminiferal assemblage from three major marginal marine habitats located along the North West coast of Bay of Bengal, in the Indian Ocean. Sediment samples for the purpose were thus collected from the Indian Sundarbans Delta, Chilika lagoon and the Gautami Godavari estuarine zone which encompasses the Kakinada bay. A total of 32 species of benthic foraminifera were documented during the study. The present observations were compared with previous reports of benthic foraminiferal diversity from these habitats and exhibited variability.


A point mutation in the nuclease domain of MLH3 eliminates repeat expansions in a mouse stem cell model of the Fragile X-related disorders.
The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases, genetic disorders that result from the expansion of a disease-specific microsatellite. In those Repeat Expansion Disease models where it has been examined, expansion is dependent on functional mismatch repair (MMR) factors, including MutLγ, a heterodimer of MLH1/MLH3, one of the three MutL complexes found in mammals and a minor player in MMR. In contrast, MutLα, a much more abundant MutL complex that is the major contributor to MMR, is either not required for expansion or plays a limited role in expansion in many model systems. How MutLγ acts to generate expansions is unclear given its normal role in protecting against microsatellite instability and while MLH3 does have an associated endonuclease activity, whether that contributes to repeat expansion is uncertain. We show here, using a gene-editing approach, that a point mutation that eliminates the endonuclease activity of MLH3 eliminates expansions in an FXD mouse embryonic stem cell model. This restricts the number of possible models for repeat expansion and supports the idea that MutLγ may be a useful druggable target to reduce somatic expansion in those disorders where it contributes to disease pathology.


Binding of noble gas atoms by superhalogens.
Because of their closed shells, noble gas (Ng) atoms (Ng = Ne, Ar, Kr, and Xe) seldom take part in chemical reactions, yet finding such mechanisms not only is of scientific interest but also has practical significance. Following a recent work by Mayer et al. [Proc. Natl. Acad. Sci. U. S. A. 116, 8167-8172 (2019)] on the room temperature binding of Ar to a superelectrophilic boron site embedded in a negative ion complex, B12(CN)11 -, we have systematically studied the effect of cluster size and terminal ligands on the interaction of Ng by focusing on B12X11(Ng) (X = H, CN, and BO) and B12X10(Ng)2 (X = CN and BO) whose stabilities are governed by the Wade-Mingos rule and on C5BX5(Ng) (X = H, F, and CN) and C4B2(CN)4(Ng)2 whose stabilities are governed by the Huckel's aromaticity rule. Our conclusion, based on density functional theory, is that both the cluster size and the terminal ligands matter-the interaction between the cluster and the Ng atoms becomes stronger with increasing cluster size and the electron affinity of the terminal ligands. Our studies also led to a counter-intuitive finding-removing multiple terminal ligands can enable electrophilic centers to bind multiple Ng atoms simultaneously without compromising their binding strength.


Altered Neurovascular Coupling in Unilateral Pulsatile Tinnitus.
Altered cerebral blood flow (CBF) and regional homogeneity (ReHo) have been reported in pulsatile tinnitus (PT) patients. We aimed to explore regional neurovascular coupling changes in PT patients. Twenty-four right PT patients and 25 sex- and age-matched normal controls were included in this study. All subjects received arterial spin labeling imaging to measure CBF and functional MRI to compute ReHo. CBF/ReHo ratio was used to assess regional neurovascular coupling between the two groups. We also analyzed the correlation between CBF/ReHo ratio and clinical data from the PT patients. PT patients exhibited increased CBF/ReHo ratio in left middle temporal gyrus and right angular gyrus than normal controls, and no decreased CBF/ReHo ratio was found. CBF/ReHo ratio in the left middle temporal gyrus of PT patients was positively correlated with Tinnitus Handicap Inventory score (r = 0.433, p = 0.035). These findings indicated that patients with PT exhibit abnormal neurovascular coupling, which provides new information for understanding the neuropathological mechanisms underlying PT.


Radiation-induced cytochrome c release and the neuroprotective effects of the pan-caspase inhibitor z-VAD-fmk in the hypoglossal nucleus.
Numerous studies have demonstrated that neuronal cell death occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Radiation induces caspase activation fundamentally via the mitochondrial pathway. To investigate the role of caspase, a cell permeable pan-caspase inhibitor, z-VAD-fmk [N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone], was used to investigate the effects of caspase blockade in vivo following irradiation. Adult male Sprague-Dawley rats (weight, 250-300 g) underwent irradiation at room temperature with a 4-Gy dose of radiation. Since z-VAD-fmk does not penetrate the blood-brain barrier, it was applied intracerebroventricularly via a bolus injection (0.2 μg/h for 1 h). Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) demonstrated that z-VAD-fmk reduced the numbers of TUNEL-positive cells within the hypoglossal nucleus, suggesting that intervention in the caspase cascade following radiation may have therapeutic applications. The caspase inhibitor z-VAD-fmk reduced the expression and activation of caspase-3, caspase-8 and caspase-9 in the irradiated rats, indicating that caspase may be a potential therapeutic target in the treatment of brain radiation injury. Treatment with z-VAD-fmk also reduced the appearance of cytochrome c within the cytosolic fraction following radiation. The hypoglossal nucleus may be used as a model of radiation-induced injury in the central nervous system, providing visual information and displaying apoptotic nuclear morphology.


Topics on the Na+/Ca2+ exchanger: involvement of Na+/Ca2+ exchanger in the vasodilator-induced vasorelaxation.
Many kinds of vasodilators induce relaxation of the vascular smooth muscle cells (VSMCs) through the production of cyclic AMP (cAMP) or cyclic GMP (cGMP). The relaxant effects mediated by these second messengers are thought to be mainly due to the decrease in intracellular Ca(2+) concentration ([Ca(2+)](i)), as well as the decrease in Ca(2+) sensitivity of the contractile apparatus of VSMCs. To explain the cAMP- or cGMP-mediated decrease in [Ca(2+)](i), several mechanisms have been proposed, including the inhibition of Ca(2+) influx due to a hyperpolarization, a stimulation of Ca(2+) uptake into the intracellular store, and an increase in Ca(2+) extrusion from VSMCs by stimulation of sarcolemmal Ca(2+)-pump. VSMCs have two major systems for Ca(2+) extrusion, namely, sarcolemmal Ca(2+)-pump and Na(+)/Ca(2+) exchanger (NCX). However, the involvement of NCX in the vasodilator-induced relaxation of VSMCs has not been well established. In this article, the possible involvement of NCX in the vasodilator-induced relaxation of VSMCs will be reviewed.


Epidemiology of Pediatric Severe Sepsis in Main PICU Centers in Southwest China.
To estimate the prevalence, management, and outcomes of pediatric severe sepsis in the main PICUs in Southwest China. A prospective, observational, and multicenter study. Eight PICUs in Southwest China with 19 (13-24) beds and 1,322 (1,066-1,452) annual admissions each. A total of 10,598 patients (29 d to 18 yr old) were consecutively admitted between September 1, 2016, and August 31, 2017. All patients were screened and evaluated for severe sepsis or septic shock. Of them, 10,353 patients were excluded due to incomplete data or not meeting the consensus criteria for severe sepsis or septic shock; 245 patients were included with complete data. None. Finally, 245 patients who were diagnosed with severe sepsis or septic shock were included in the study, with an incidence rate of 2.3%. Of them, 64.0% of the enrolled patients were male with 80.8% being less than 5 years old and 60.8% being from rural areas. The respiratory system was the most common organ system in which dysfunction was observed (76.7%) as well as the most frequently infected site (37.6%). The primary therapies were antibiotics (99.0%), immunoglobulin (88.3%), mechanical ventilation (78.4%), vasoactive infusions (59.6%), and corticosteroids (46.1%). Among the 188 patients who had respiratory dysfunction, 173(92%) required mechanical ventilation and 39 (20.7%) met the criteria for pediatric acute respiratory distress syndrome. Seven of the patients with pediatric acute respiratory distress syndrome died (7/39, 17.9%). The median durations for mechanical ventilation and vasoactive medications were 123.5 hours (35.25-226.00 hr) and 2 days (1-5 d), respectively. Eighty-six percent of patients had multiple organ dysfunction syndrome at the point at which severe sepsis was recognized, and 31% had underlying conditions. The hospital mortality rate was 18.8%. This report is the first to present the prevalence, treatment, and outcomes of pediatric severe sepsis in the main PICU centers in Southwest China. The mortality rate remains high; therefore, improved clinical management and implementation of large-scale clinical trials are necessary to improve early diagnoses and treatment.


[Investigation of serum resistance for Pseudomonas aeruginosa and Acinetobacter baumannii strains].
Serum resistance is one of the major virulence factors of Gram negative bacteria. The aim of this study was to investigate the serum resistance of Pseudomonas aeruginosa and Acinetobacter baumannii strains isolated from various clinical samples (19 tracheal aspirates, 14 urine, 7 sputum, 7 wound and one peritoneal fluid specimens). Forty-eight P. aeuginosa and 48 A. baumannii strains were tested for human serum bactericidal effect by using Benge's method. Thirty-five (72.9%), 9 (18.7%), and 4 (8.3%) of P. aeruginosa strains were found to be resistant, intermediate sensitive and sensitive to serum, respectively. These rates were detected as 81.2% (39/48), 14.5% (7/48), and 4.1% (2/48) for A. baumannii strains, respectively. It can be concluded that, high serum resistance rates of P. aeruginosa and A. baumannii isolates might have an important role in the pathogenesis of infections of these bacteria.


T cell receptor delta repertoire in inflamed and noninflamed colon of patients with IBD analyzed by CDR3 spectratyping.
Gamma/delta T cells might play an important role in autoimmune conditions like inflammatory bowel disease (IBD). In the present study, we characterized the T cell receptor (TCR)-delta repertoire by complementarity determining region 3 (CDR3) spectratyping in the inflamed and noninflamed mucosa and in the peripheral blood of subjects with Crohn's disease and ulcerative colitis. In contrast to previously published data about alpha/beta T cells, we rarely found oligoclonal expansions of gamma/delta T cells specific only for the inflamed mucosa. The same dominant gamma/delta T cell expansions were also present in the noninflamed colon. Furthermore, the peripheral gamma/delta TCR repertoire was oligoclonal but clearly distinct from that in the inflamed intestine. Thus our results do not support a role for antigen-specific gamma/delta T cells in IBD, and dominant gamma/delta T cells of the peripheral blood are not likely to be derived from the inflamed gut. However, in several patients, the TCR-delta-repertoire was highly diversified, whereas in others we observed a loss of dominant gamma/delta T cell clones when inflamed and noninflamed mucosa were compared. In conclusion, those changes indicate that gamma/delta T cells might play an important role in a subset of patients with IBD.


Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension.
Despite the development of several lung transplantation procedures, the most advantageous for pulmonary hypertension remains controversial. Between 1986 and February 1992, 30 patients with end-stage primary pulmonary hypertension (n = 24), chronic pulmonary embolism (n = 4), and hystiocytosis X (n = 2) underwent heart-lung (n = 21), double lung (n = 8), or single lung (n = 1) transplantation. Indications for double lung transplantation were similar to those for heart-lung transplantation, and the preoperative clinical and hemodynamic parameters were not significantly different between the two groups. There were no intraoperative deaths, but two reoperations were needed for pleural hematoma. Five early deaths were related to graft failure (two heart-lung transplantations), mediastinitis (one heart-lung transplantation), multiorgan failure (one double lung transplantation), and aspergillosis (one double lung transplantation). There was a similar improvement in early (days 0 and 2) and late (6 months postoperatively) right-sided hemodynamic function in patients undergoing heart-lung and double lung transplantation. Three double lung transplant recipients had early and reversible left ventricular-failure. The early postoperative course of the one patient who had single lung transplantation was characterized by severe pulmonary edema, left ventricular failure, and persistent desaturation and later on by moderate pulmonary hypertension and an important ventilation/perfusion mismatch. The pulmonary function results were also similar in the heart-lung and double lung transplantation groups. The overall projected 2- and 4-year survivals were 49% and 41%, respectively, and were not significantly different between the heart-lung and double lung recipients. Results demonstrate that heart-lung and double lung transplantation are equally effective in obtaining early and durable right-sided hemodynamic and respiratory improvement and similar respiratory function. In patients with pulmonary hypertension, double lung transplantation should be preferred to single lung transplantation because of the critical postoperative course and the uncertain long-term results of single lung transplantation.


SWCNTs/PEDOT:PSS-Modified Microelectrode Arrays for Dual-Mode Detection of Electrophysiological Signals and Dopamine Concentration in the Striatum under Isoflurane Anesthesia.
Accurate detection of the degree of isoflurane anesthesia during a surgery is important to avoid the risk of overdose isoflurane anesthesia timely. To address this challenge, a four-shank implantable microelectrode array (MEA) was fabricated for the synchronous real-time detection of dual-mode signals [electrophysiological signal and dopamine (DA) concentration] in rat striatum. The SWCNTs/PEDOT:PSS nanocomposites were modified onto the MEAs, which significantly improved the electrical and electrochemical performances of the MEAs. The electrical performance of the modified MEAs with a low impedance (16.20 ± 1.68 kΩ) and a small phase delay (-27.76 ± 0.82°) enabled the MEAs to detect spike firing with a high signal-to-noise ratio (> 3). The electrochemical performance of the modified MEAs with a low oxidation potential (160 mV), a low detection limit (10 nM), high sensitivity (217 pA/μM), and a wide linear range (10 nM-72 μM) met the specific requirements for DA detection in vivo. The anesthetic effect of isoflurane was mediated by inhibiting the spike firing of D2_SPNs (spiny projection neurons expressing the D2-type DA receptor) and the broadband oscillation rhythm of the local field potential (LFP). Therefore, the spike firing rate of D2_SPNs and the power of LFP could reflect the degree of isoflurane anesthesia together. During the isoflurane anesthesia-induced death procedure, we found that electrophysiological activities and DA release were strongly inhibited, and changes in the DA concentration provided more details regarding this procedure. The dual-mode recording MEA provided a detection method for the degree of isoflurane anesthesia and a prediction method for fatal overdose isoflurane anesthesia.


Corticosteroids: sculptors of the hippocampal formation.
The influence of corticosteroids on hippocampus-dependent learning and memory processes is now indisputable. On the other hand, closer scrutiny of early studies together with interpretations from newer studies would suggest that the proposition that corticosteroid-induced hippocampal cell death accounts fully for the associated cognitive deficits is only partially correct. Firstly, it is now clear that a specific sub-population of hippocampal neurons, the granule cells of the dentate gyrus, is more sensitive to changes in the corticosteroid environment; this fact raises the interesting question of what might be the unique properties of granule cells that render them more vulnerable to these hormones, since virtually all hippocampal cells express corticosteroid receptors. Secondly, from a critical analysis of the available data, the picture that emerges is that corticosteroids, by acting through two distinct receptors, influence not only cell birth and death, but probably also cell differentiation. Mineralocorticoid receptor (MR) occupation appears to be essential for the survival of existing and newly generated granule neurons. In contrast, while glucocorticoid receptors (GR) can induce loss of neurons in the absence of MR activation, it appears that their occupation usually results in less drastic effects involving only dendritic atrophy and loss of synaptic contacts. This revised scheme of corticosteroid actions on hippocampal structure should explain earlier observations that many of the cognition- impairing effects of corticosteroids are reversible.


Pre-exposure prophylaxis among Brazilian men who have sex with men: a comparative study between migrants and non-migrants.
Investigating the use and adherence to pre-exposure prophylaxis (PrEP) in MSM is a global health priority in the fight against HIV. Strategies must be capable of increasing usage and reaching not only the population living in the country but also those who immigrate, who face additional vulnerabilities. Based on this, in this observational, cross-sectional, and analytical study, our aim is to analyze the use of PrEP among Brazilian men who have sex with men, whether they are migrants or not. We aim to highlight preventive opportunities and strategies for the global health scenario. We utilized a sample of Brazilians living in the country and Brazilian immigrants residing in Portugal, one of the main destinations for Brazilians in recent years. To estimate the prevalence ratio (PR) of PrEP use, we employed the Poisson regression model with robust variance estimation using a covariance matrix. A total of 1,117 Brazilian MSM PrEP users participated in this study, with 788 residing in Brazil and 328 in Portugal. Multivariate analysis was conducted in three stages: overall, and for subgroups of residents in Brazil and immigrants in Portugal. We identified four convergent factors that increased the prevalence of PrEP use in Brazilians regardless of migration status: having two or more casual sexual partners per month, engaging in challenging sexual practices as the receptive partner, disclosing serological status on apps, and being single. Among native Brazilians, four unique factors stood out: being in a polyamorous relationship, having sexual relations with unknown casual partners, and having higher levels of education. This study highlights the need to implement strategies to strengthen PrEP adherence in Brazil and create international programs that facilitate its usage among populations migrating between these two countries.


Predicting the outcome of surgical treatment of vulvar vestibulitis.
To identify predictive factors for success or failure of perineoplasty for severe vulvar vestibulitis. Seventy-nine women with severe vulvar vestibulitis underwent perineoplasty by a single surgeon during 1992-1994. Sixty (76%) who experienced a complete response were compared with 19 (24%) who had an incomplete response. Using univariate and then multivariate (logistic regression) analysis, the two groups were compared with regard to preoperative demographic, social, and medical variables, as well as physical findings in the vestibule. The complete- and incomplete-response groups were similar in all comparisons except for constant vulvar pain of vestibular origin (in addition to dyspareunia) and the presence of symptoms since first coitus. On multiple logistic regression, these characteristics had odds ratios (and 95% confidence intervals) of 4.97 (1.49, 16.63) and 5.83 (1.74, 19.55), respectively. An incomplete response to perineoplasty may be anticipated in women with vulvar vestibulitis associated with dyspareunia since their first episode of intercourse and in those with associated persistent vulvar pain. Treatment approaches other than surgery should be considered for such patients.


Open Abdomen in Obese Patients: Pay Attention! New Evidences from IROA, the International Register of Open Abdomen.
Open abdomen is the cornerstone of damage control strategies in acute care and trauma surgery. The role of BMI has not been well investigated. The aim of the study was to assess the role of BMI in determining outcomes after open abdomen. This is an analysis of patients recorded into the International Register of Open Abdomen; patients were classified in two groups according to BMI using a cutoff of 30 kg/m2. The primary outcome was in-hospital mortality; secondary outcomes were primary fascia closure rate, length of treatment, complication rate, entero-atmospheric fistula rate and length of ICU stay. A total of 591 patients were enrolled from 57 centers, and obese patients were 127 (21.5%). There was no difference in mortality between the two groups; complications developed during the open treatment were higher in obese patients (63.8% vs. 53.4%, p = 0.038) while post-closure complications rate was similar. Obese patients had a significantly longer duration of the open treatment (9.1 ± 11.5 days vs. 6.3 ± 7.5 days; p = 0,002) and lower primary fascia closure rate (75.5% vs. 89.5%; p < 0,001). No differences in fistula rate were found. There was a linear correlation between the duration of open abdomen and the BMI (Pearson's linear correlation coefficient = 0,201; p < 0,001). Open abdomen in obese patients seems to be safe as in non-obese patients with similar mortality; however, in obese patients the length of open abdomen is significantly higher with higher complication rate, longer ICU length of stay and lower primary fascia closure rate. ClinicalTrials.gov, Identifier: NCT02382770.


Time on previous renal replacement therapy is associated with worse outcomes of COVID-19 in a regional cohort of kidney transplant and dialysis patients.
Chronic renal replacement therapy by either a kidney transplant (KTX) or hemodialysis (HD) predisposes patients to an increased risk for adverse outcomes of COVID-19. However, details on this interaction remain incomplete. To provide further characterization, we undertook a retrospective observational cohort analysis of the majority of the hemodialysis and renal transplant population affected by the first regional outbreak of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) in Germany. In a region of 250,000 inhabitants we identified a total of 21 cases with SARS-CoV-2 among 100 KTX and 260 HD patients, that is, 7 KTX with COVID-19, 14 HD with COVID-19, and 3 HD with asymptomatic carrier status. As a first observation, KTX recipients exhibited trends for a higher mortality (43 vs 18%) and a higher proportion of acute respiratory distress syndrome (ARDS) (57 vs 27%) when compared to their HD counterparts. As a novel finding, development of ARDS was significantly associated with the time spent on previous renal replacement therapy (RRT), defined as the composite of dialysis time and time on the transplant (non-ARDS 4.3 vs ARDS 10.6 years, P = .016). Multivariate logistic regression analysis showed an OR of 1.7 per year of RRT. The association remained robust when analysis was confined to KTX patients (5.1 vs 13.2 years, P = .002) or when correlating the time spent on a renal transplant alone (P = .038). Similarly, longer RRT correlated with death vs survival (P = .0002). In conclusion our data suggest renal replacement vintage as a novel risk factor for COVID-19-associated ARDS and death. The findings should be validated by larger cohorts.


Cre-lox-regulated conditional RNA interference from transgenes.
We have generated two lentiviral vectors for conditional, Cre-lox-regulated, RNA interference. One vector allows for conditional activation, whereas the other permits conditional inactivation of short hairpin RNA (shRNA) expression. The former is based on a strategy in which the mouse U6 promoter has been modified by including a hybrid between a LoxP site and a TATA box. The ability to efficiently control shRNA expression by using these vectors was shown in cell-based experiments by knocking down p53, nucleophosmin and DNA methyltransferase 1. We also demonstrate the usefulness of this approach to achieve conditional, tissue-specific RNA interference in Cre-expressing transgenic mice. Combined with the growing array of Cre expression strategies, these vectors allow spatial and temporal control of shRNA expression in vivo and should facilitate functional genetic analysis in mammals.


Long-chain acyl-CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of KATP channels by the same mechanism.
Phosphatidylinositol phosphates (PIPs, e.g. PIP2) and long-chain acyl-CoA esters (e.g. oleoyl-CoA) are potent activators of KATP channels that are thought to link KATP channel activity to the cellular metabolism of PIPs and fatty acids. Here we show that the two types of lipid act by the same mechanism: oleoyl-CoA potently reduced the ATP sensitivity of cardiac (Kir6.2/SUR2A) and pancreatic (Kir6.2/SUR1) KATP channels in a way very similar to PIP2. Mutations (R54Q, R176A) in the C- and N-terminus of Kir6.2 that greatly reduced the PIP2 modulation of ATP sensitivity likewise reduced the modulation by oleoyl-CoA, indicating that the two lipids interact with the same site. Polyvalent cations reduced the effect of oleoyl-CoA and PIP2 on the ATP sensitivity with similar potency suggesting that electrostatic interactions are of similar importance. However, experiments with differently charged inhibitory adenosine phosphates (ATP4-, ADP3- and 2'(3')-O-(2,4,6-trinitrophenyl)adenosine 5'-monophosphate (TNP-AMP2-)) and diadenosine tetraphosphate (Ap4A5-) ruled out a mechanism where oleoyl-CoA or PIP2 attenuate ATP inhibition by reducing ATP binding through electrostatic repulsion. Surprisingly, CoA (the head group of oleoyl-CoA) did not activate but inhibited KATP channels (IC50 = 265 +/- 33 muM). We provide evidence that CoA and diadenosine polyphosphates (e.g. Ap4A) are ligands of the inhibitory ATP-binding site on Kir6.2.


Low-temperature dormancy in fish.
The importance of low ambient temperature in the physiology of winter dormancy was studied in the brown bullhead (Ictalurus nebulosus) and the largemouth bass (Micropterus salmoides). The bullheads frequently entered a sleep-like state at low temperatures; the likelihood of being aroused from this state was inversely proportional to the ambient temperature. Spontaneous activity for both species was relatively constant from 17 to 7 degrees C; at lower temperatures activity decreased. The selected temperature was lowered in both species as a consequence of acclimation to 3 degrees C; if given the opportunity, fish of both species moved to temperatures above 25 degrees C within 1 day in spite of the consequent acid-base and metabolic imbalances. In bass, food intake was very low for acclimation temperatures of 8 degrees C and below; at higher temperatures the relationship between food intake and acclimation temperature required 4 wk to stabilize. Quiescent brown bullheads exhibited discontinuous breathing. Alteration of brain temperature with implanted thermodes indicated that the main locus of control of this breathing pattern is in the medulla; lesser influences emanate from the anterior hypothalamus and the midbrain. Metabolism was measured at a series of acclimation temperatures between 3 and 17 degrees C for both species. No evidence of a discontinuous function (metabolic shutdown) was seen for either species.


Molecular Characterization of the Complete Genome of Three Basal-BR Isolates of Turnip mosaic virus Infecting Raphanus sativus in China.
Turnip mosaic virus (TuMV) infects crops of plant species in the family Brassicaceae worldwide. TuMV isolates were clustered to five lineages corresponding to basal-B, basal-BR, Asian-BR, world-B and OMs. Here, we determined the complete genome sequences of three TuMV basal-BR isolates infecting radish from Shandong and Jilin Provinces in China. Their genomes were all composed of 9833 nucleotides, excluding the 3'-terminal poly(A) tail. They contained two open reading frames (ORFs), with the large one encoding a polyprotein of 3164 amino acids and the small overlapping ORF encoding a PIPO protein of 61 amino acids, which contained the typically conserved motifs found in members of the genus Potyvirus. In pairwise comparison with 30 other TuMV genome sequences, these three isolates shared their highest identities with isolates from Eurasian countries (Germany, Italy, Turkey and China). Recombination analysis showed that the three isolates in this study had no "clear" recombination. The analyses of conserved amino acids changed between groups showed that the codons in the TuMV out group (OGp) and OMs group were the same at three codon sites (852, 1006, 1548), and the other TuMV groups (basal-B, basal-BR, Asian-BR, world-B) were different. This pattern suggests that the codon in the OMs progenitor did not change but that in the other TuMV groups the progenitor sequence did change at divergence. Genetic diversity analyses indicate that the PIPO gene was under the highest selection pressure and the selection pressure on P3N-PIPO and P3 was almost the same. It suggests that most of the selection pressure on P3 was probably imposed through P3N-PIPO.


(3E,5E)-3,5-Dibenzyl-idene-1-[3-(piperidin-1-yl)propano-yl]piperidin-4-one.
The asymmetric unit of the title compound, C(27)H(30)N(2)O(2), comprises two independent mol-ecules. The dihedral angles between the phenyl rings in the two mol-ecules are 55.59 (8) and 55.39 (8)°. The piperidine rings adopt chair conformations. The crystal structure is stabilized by weak inter-molecular C-H⋯O and C-H⋯N hydrogen bonds. The crystal studied was a non-merohedral twin with a domian ratio of 0.75 (2):0.25 (2).


Patient-Reported Outcomes Measurement Information System: Translation and Linguistic Validation of Six Profile Domains for Korean Adults.
The purpose of the study was to translate and linguistically validate a Korean language version of the PROMIS (K-PROMIS) for the six profile adult domains: Fatigue, Pain Intensity, Pain Interference, Physical Function, Sleep Disturbance, and Ability to Participate in Social Roles and Activities. A total of 268 items were translated into Korean according to the Functional Assessment of Chronic Illness Therapy multilingual translation methodology. Participants first completed approximately 27 to 35 items and were then interviewed to evaluate the conceptual equivalence of the translation to the original English language source. The K-PROMIS items that met the a priori threshold of ≥ 20% of respondents with comprehension difficulties in the cognitive interview. 54 of the 268 items were identified as difficult items to comprehend for at least 20% of respondents in Round 1. The most frequently identified K-PROMIS domain on difficult items to comprehend was the Physical function (24.5%). Most items with linguistic difficulties were Fatigue and Physical function. Cultural difficulties were only included the Physical function and Ability to Participate in Social Roles and Activities domains. 25 of 54 items were slightly revised, and then these revised items were tested with additional six participants in Round 2, and most participants had no problems to understand modified items. The six profile adult domains of K-PROMIS have been linguistically validated. Further psychometric validation of the K-PROMIS items will provide additional information of meaningful outcomes for chronic disease and clinical setting.


[The technique of army nursing in the Meiji period].
It was in the nineteenth year of Meiji that Japan introduced the modern nursing system from Europe on the nation-wide level. But the Japanese army introduced the new nursing system from the sixth year of Meiji. For that reason, I studied whether the technique of the army nursing system was modern or not. Since the technical level of the nursing system is represented by the teaching methods and text books, I studied these aspects of the Japanese army nursing system. As the result, I confirmed that the army nursing system was modern. The Japanese army was the first to introduce the modern nursing system from Europe in Japan.


Alcohol, aviation, and safety revisited: a historical review and a suggestion.
A 1964 study by Harper and Albers initiated a new era of alcohol, aviation, and safety interest. Studies by the author agreed with the Harper and Albers data. Educational efforts that followed, and the apparent effects, are described. A study commissioned by the author confirmed the effect of low levels of alcohol on flying performance. Impairment from other effects of alcohol, such as alcohol-induced hypoglycemia (AIH), post-alcohol impairment (PAI), and positional alcohol nystagmus (PAN) are mentioned. It is suggested that the effects of PAN may play a role in spatial disorientation. It is also suggested that the ingestion of alcohol days before an accident may be demonstrated by laboratory procedures. The feasibility and implementation of this should be established. If the association between previous alcohol ingestion, and spatial disorientation or other impairment becomes evident, it should provide a basis for extensive education regarding aviation and safety.


Recent advances in positive allosteric modulators of the AMPA receptor.
The alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propioic acid (AMPA) subtype of glutamate receptors mediate fast excitatory neurotransmission throughout the mammalian nervous system and participate in the forms of synaptic plasticity that are considered to underlie learning and memory. Positive allosteric modulators of these receptors are the subject of much investigation because of their emerging therapeutic potential for a range of psychiatric and neurological disorders such as schizophrenia and Alzheimer's disease. This review focuses on the most recent developments in preclinical and clinical research on novel classes of AMPA receptor positive modulators and highlights how the application of biostructural studies has increased our understanding of the biophysical effects produced by these drugs.


Fitness change and subsequent academic performance in adolescents.
This study examined the association between fitness change and subsequent academic performance in Taiwanese schoolchildren from 7th grade to 9th grade. The 7th graders from 1 junior high school district participated in this study (N = 669). Academic performance was extracted from school records at the end of each grade. Cardiovascular (CV) fitness, sit-and-reach flexibility, bent-leg curl-ups, and height and weight for calculating body mass index (BMI) were assessed at the start of each grade. The results showed that improvement in CV fitness, but not muscular endurance or flexibility, is significantly related to greater academic performance. A weak and nonsignificant academic-BMI relationship was seen. CV fitness exhibits stronger longitudinal associations with academic performance than other forms of fitness or BMI for adolescents.


Preoperative autologous blood deposition in support of gynaecological repair procedures.
Autologous blood transfusion was evaluated in gynaecological repair procedures including abdominal/ vaginal hysterectomy with vaginal repair, post-hysterectomy vaginal suspension and fixation, uni/bilateral salpingo-oophorectomy with vaginal colpopexy and sling procedures. A total of 247 autologous units were collected from 95 patients at the regional blood centre with 1-3 units (mean 2-6 units) deposition from each patient. One hundred and ninety of all collected units were transfused (collection/transfusion ratio = 1.3). Of these patients, 86 (90.5%) received autologous blood; 12 (13%) being transfused with 1 unit, 44 (46%) with 2 units and 30 (32%) with 3 units. Two of these patients received additional homologous blood. The average preoperative haemoglobin level was 119 g L-1 and average post-operative haemoglobin level was 105 gL-1. The post-operative Hb level was used as a retrospective indicator for the requirement for blood transfusion. The results show that overall 75% of patients had post-operative haemoglobin levels < or = 110 and 33% of patients with Hb levels < 100, respectively. These results suggest that preoperative autologous blood deposition may be appropriate in the patients undergoing reconstructive gynaecological repair procedures since there was a high rate of usage of autologous blood and low post-operative haemoglobin in a significant proportion of patients.


[Dynamic changes of matrix metalloproteinase 9 in heterotopic ossification of rat model].
To explore the value of matrix metalloproteinase 9 (MMP-9) in predicting the occurrence of heterotopic ossification by observing the expression of MMP-9 in heterotopic ossification of the early trauma rat model. A total of 132 male Sprague Dawley rats, aged 4-5 weeks, weighing (135.0 ± 6.5) g, were randomly divided into experimental group and control group (n = 66). In experimental group, the Achilles tendon was cut off and clamped to prepare heterotopic ossification model; in control group, only Achilles tendon was exposed by making a incision. The general condition of the rats was observed after operation; at 2, 3, 4, 5, 6, 7, and 8 days after operation, the Achilles tendon tissue was harvested for gross observation, histological observation, and immunohistochemical staining observation; the serum and Achilles tendon tissue were harvested to detect the expressions of MMP-9 protein and mRNA by ELISA and RT-PCR. The X-ray films at 5 and 10 weeks and histological examination at 10 weeks after operation were used to observe heterotopic ossification. All rats survived to the end of the experiment. The Achilles tendon had no significant change in control group at each time point, showing normal tendon structure. In experimental group, the hardness of Achilles tendon tissue gradually increased with the time; there were a large number of irregular connective tissue and cartilage cells; and immunohistochemical staining for MMP-9 was positive results. The MMP-9 protein and mRNA expression levels of experimental group were significantly higher than those of the control group at each time point (P < 0.05). MMP-9 protein and mRNA expression levels of experimental group showed an increasing tendency (P < 0.05). According to the results of X-ray films and histological observation, heterotopic ossification occurred at 10 weeks after operation in experimental group, but no heterotopic ossification was observed in control group. In early heterotopic ossification of rat Achilles tendon, the expression of MMP-9 increases significantly, indicating that it has reference significance in predicting heterotopic ossification.


Transmaxillary exploration of the intracranial portion of the maxillary nerve in malignant perineural disease. Technical note.
Achieving microscopically tumor-free margins during resection of skull base malignancies has consistently been identified as a positive prognostic factor for patient survival. When malignancies extend perineurally into the major nerves traversing the skull base and entering the cavernous sinus, achieving tumor-free margins can be challenging and typically necessitates performing a craniotomy to access the lateral wall of the cavernous sinus. This report describes a novel technique used to access and resect malignancy extending perineurally into the intracranial portion of V2 via the maxillary sinus. Seven patients with maxillary sinus tumors and perineural extensions along V2, who underwent resection of the primary tumor and transmaxillary intracranial exposure and dissection of the maxillary nerve to achieve maximal tumor resection, were analyzed. Prospectively collected data, including symptoms, clinical signs, diagnostic imaging data, pathological diagnosis, incidence and nature of complications, adjuvant therapies, and oncological outcomes, were retrospectively analyzed. All patients in this cohort had trigeminal nerve symptomatology as well as abnormal enhancement in the pterygopalatine fissure as noted on magnetic resonance imaging. The transmaxillary exploration of the maxillary nerve technique was used in all seven patients, resulting in gross-total resection of the tumors in every patient. At the last follow-up (mean 30 months, range 13-58 months, in four of seven patients for > 2 years), six patients were alive without evidence of local disease. One patient with squamous cell carcinoma died of progressive infratemporal fossa and regional neck disease 26 months after resection. No intracranial or cavernous sinus disease was present. This technique extended the limits of resection without the need for a craniotomy and improved local tumor control in this patient cohort.


Properties of the major classes of mechanoreceptors in the guinea pig bladder.
Sensory neurons represent an attractive target for pharmacological treatment of various bladder disorders. However the properties of major classes of mechano-sensory neurons projecting to the bladder have not been systematically established. An in vitro bladder preparation was used to examine the effects of a range of mechanical stimuli (stretch, von Frey hair stroking and focal compression of receptive fields) and chemical stimuli (1 mm alpha,beta-methylene ATP, hypertonic solutions (500 mm NaCl) and 3 microm capsaicin) during electrophysiological recordings from guinea pig bladder afferents. Four functionally distinct populations of bladder sensory neurons were distinguished by these stimuli. The first class, muscle mechanoreceptors, were activated by stretch but not by mucosal stroking with light (0.05-0.1 mN) von Frey hairs or by hypertonic saline, alpha,beta-methylene ATP or capsaicin. Removal of the urothelium did not affect their stretch-induced firing. The second class, muscle-mucosal mechanoreceptors, were activated by both stretch and mucosal stroking with light von Frey hairs or by hypertonic saline and by alpha,beta-methylene ATP, but not by capsaicin. Removal of the urothelium reduced their stretch- and stroking-induced firing. The third class, mucosal high-responding mechanoreceptors, were stretch-insensitive but could be activated by mucosal stroking with light von Frey hairs or by hypertonic saline, alpha,beta-methylene ATP and capsaicin. Stroking-induced firing was significantly reduced by removal of the urothelium. The fourth class, mucosal low-responding mechanoreceptors, were stretch insensitive but could be weakly activated by mucosal stroking with light von Frey hairs but not by hypertonic saline, alpha,beta-methylene ATP or capsaicin. Removal of the urothelium reduced mucosal stroking-induced firing. All four populations of afferents conducted in the C-fibre range and showed class-dependent differences in spike amplitude and duration. At least four functional classes of bladder mechanoreceptors can be readily distinguished by different mechanisms of activation and are likely to transmit different types of information to the central nervous system.


The effect of radiofrequency thermal ablation method on nasal mucociliary activity in patients with inferior turbinate hypertrophy.
This study aims to investigate the effect of radiofrequency thermal ablation (RFTA) treatment on nasal mucociliary activity before and after treatment in inferior turbinate hypertrophy. Thirty-nine patients (21 males, 18 females; mean age 36.3±13.9 years; range 16 to 67 years) admitted to our clinic with complaint of nasal obstruction and diagnosed with stromal inferior turbinate hypertrophy were included in this study. Effect of RFTA treatment on nasal mucociliary activity was investigated by saccharine test before treatment and two months after treatment. Grade of nasal obstruction was evaluated by visual analog scale (VAS) before treatment and two months after treatment. Results were compared with paired t-test. Mean mucociliary activity times were 9.8±4.4 minutes before treatment and 9.6±4.1 minutes two months after treatment, and the difference between two tests was not statistically significant (p=0.3). Mean VAS scores for nasal obstruction were 6.5±1.2 before treatment and 3.8±1.0 two months after treatment, and the difference between two results was statistically significant (p=0.001). Difference between sexes in terms of saccharine transit time and VAS values before and after treatment was not statistically significant (p>0.05). It was detected that RFTA has no adverse effect on mucociliary activity in the treatment of inferior turbinate hypertrophy, and this method is notably effective in relieving the nasal obstruction caused by inferior turbinate hypertrophy.


The cognitive adaptability and resiliency employment screener (CARES): tool development and testing.
To decrease psychological risk for content moderators, the study initiated the first steps of developing a robust employment screening tool, namely, the Cognitive Adaptability and Resiliency Employment Screener. The study consisted of three phases with 4,839 total participants. In Phase 1, a set of 76 items were developed and tested via exploratory factor analysis, yielding three factors (i.e., Psychological Perseverance & Agility, Rumination & Emotional Lingering, and Expressiveness & Sociability) and also reducing the scale to 68 items. In Phase 2 through confirmatory factor analysis, the three-factor structure showed good fit (CFI = 0.92, RMSEA = 0.05) and demonstrated sufficient overall reliability. In Phase 3, the convergent validity and divergent validity of the tool were established relative to constructs such as resilience, cognitive control and flexibility, emotion regulation, and optimism. Altogether, the findings revealed that the scale demonstrated good psychometric properties that, pending future studies, may serve as a promising employment screener for content moderators.


Fractional Feynman-Kac equation for non-brownian functionals.
We derive backward and forward fractional Feynman-Kac equations for the distribution of functionals of the path of a particle undergoing anomalous diffusion. Fractional substantial derivatives introduced by Friedrich and co-workers [Phys. Rev. Lett. 96, 230601 (2006)10.1103/PhysRevLett.96.230601] provide the correct fractional framework for the problem. For applications, we calculate the distribution of occupation times in half space and show how the statistics of anomalous functionals is related to weak ergodicity breaking.


Function of heterologous and truncated RNase P proteins in Bacillus subtilis.
Bacterial RNase P is composed of an RNA subunit and a single protein (encoded by the rnpB and rnpA genes respectively). The Bacillus subtilis rnpA knockdown strain d7 was used to screen for functional conservation among bacterial RNase P proteins from a representative spectrum of bacterial subphyla. We demonstrate conserved function of bacterial RNase P (RnpA) proteins despite low sequence conservation. Even rnpA genes from psychrophilic and thermophilic bacteria rescued growth of B. subtilis d7 bacteria; likewise, terminal extensions and insertions between beta strands 2 and 3, in the so-called metal binding loop, were compatible with RnpA function in B. subtilis. A deletion analysis of B. subtilis RnpA defined the structural elements essential for bacterial RNase P function in vivo. We further extended our complementation analysis in B. subtilis strain d7 to the four individual RNase P protein subunits from three different Archaea, as well as to human Rpp21 and Rpp29 as representatives of eukaryal RNase P. None of these non-bacterial RNase P proteins showed any evidence of being able to replace the B. subtilis RNase P protein in vivo, supporting the notion that archaeal/eukaryal RNase P proteins are evolutionary unrelated to the bacterial RnpA protein.


[Response of Na+/Ca2+ antiporter to ischemia and glial/neuronal death].
Brain ischemia produces morphologic and biochemical alterations in astrocytes. This mini-review summarizes astrocytic responses to brain ischemia including our studies on the neuronal and astrocytic Na(+)-Ca2+ exchanger (NCX). NCX is considered to cause Ca2+ efflux (forward mode) or Ca2+ influx (reverse mode), depending on the electrochemical gradient of Na+ across the plasma membranes and membrane potential. We demonstrated that NCX is present in cultured neurons and astrocytes and that there are differences in their properties and distribution ratio of the isoforms between neurons and astrocytes. We also found that Ca2+ depletion followed by reperfusion with Ca(2+)-containing medium caused cell death in cultured astrocytes (Ca2+ paradox-like injury), but not in neurons. The study, carried out by the use of a specific antisense oligomer, provides direct evidence that Ca2+ paradox-like injury is mediated by NCX in the reverse mode. The injury was attenuated by inhibitors of the Na(+)-Ca2+ exchanger, heat shock protein and the calcineurin inhibitor FK506. In a preliminary experiment, we found that brain ischemia decreases the mRNA level of NCX in the hippocampus. Further studies on activation and cell injury of astrocytes will contribute to development of new drugs that modulate the function of astrocytes.


"Try it; it's good and it's good for you": effects of taste and nutrition information on willingness to try novel foods.
In an attempt to understand the effects of information on willingness to taste foods, we presented college students with a variety of familiar and novel foods of animal and vegetable origin. Participants received one of four types of information about the foods: none, they tasted good, they were high in vitamins, or they were high in vitamins and might soon be available in the college cafeteria. The information manipulation had no effect on willingness to taste familiar foods. Willingness to taste novel non-animal foods was increased by both taste and vitamin-plus-availability information, while willingness to taste animal foods was not affected by information. Willingness to taste novel foods was also predicted by a measure of trait neophobia. The results suggest that (a) emotional reactions to animal foods may block information effects, and (b) nutrition information is more effective in a context where the food is believed to be available.


Clostridium thermobutyricum: growth studies and stimulation of butyrate formation by acetate supplementation.
Clostridium thermobutyricum produces butyrate as the main fermentation product from glucose, and from yeast extract, which is required for substantial growth. After sequential transfer in the presence of increasing butyrate concentrations, strain JW 171 K grew in the presence of up to 350 mM butyrate either at pH 5.5 or at pH 8.0 and at 40 degrees C as well as at 60 degrees C. This result indicated that butyrate-dependent growth inhibition was independent from the concentration of undissociated butyric acid. Increased butyrate concentration decreased the level of tolerated glucose from above 15% to below 10%. At 0.05 and 2.0% (wt/vol) yeast extract, the Y(Glucose) was 30 and 55 g dry weight cells per mole glucose, respectively. Y(ATP) values between 18 and 21 g weight cells per mole ATP, obtained after growth in the presence of 2% yeast extract, indicate that the butyrate fermentation under thermophilic growth conditions is as energy efficient as it is under mesophilic conditions. Externally added acetate stimulated the production of butyrate. Supplemented 14C-acetate was converted to butyrate, resulting in the formation of 44% labeled butyrate (i.e. formed from 14C-acetate) and 56% unlabeled butyrate (formed from glucose and yeast extract). Continuous removal of H2 in batch cultures led to a shift in the fermentation products from more butyrate to the more oxidized and more energy yielding acetate.


Responses of the rabbit epicardial coronary artery to acetylcholine and adrenoceptor agonists.
The aim was to identify the role of the endothelium in mediating the responses to acetylcholine in the rabbit coronary artery, and to determine whether alpha or beta adrenergic stimulation may cause relaxation via endothelial receptors in the coronary arteries of this species. Responses to acetylcholine and adrenoceptor agonists were compared in isolated ring preparations with and without endothelium. The adrenoceptor agonists were examined in the presence of phentolamine or propranolol to block alpha and beta adrenoceptors, respectively. 30 New Zealand white rabbits (2.3-3.4 kg) were killed by an overdose of barbiturate and exsanguination, and the left epicardial coronary artery was dissected free. Ring preparations were suspended in organ baths under isometric tension and, where required, the tone of the preparations was raised by KC1. Concentrations of acetylcholine up to 10(-6) mol.litre-1 produced dose dependent relaxation of the preparations with endothelium intact, but no relaxation in preparations denuded of endothelium. At higher concentrations, a marked vasoconstrictor response was seen in all preparations regardless of the presence of endothelium. At basal tone, acetylcholine produced vasoconstriction which reached a maximum of 1.0 (SEM 0.14)g tension in preparations with endothelium and 1.74(0.27) g tension in those without endothelium (p less than 0.05). In coronary arteries pretreated with 50 mumol.litre-1 phenoxybenzamine to block alpha adrenoceptors, noradrenaline, isoprenaline, and salbutamol produced dose dependent relaxation of the preparations; this was unaffected by the absence of endothelium. In vessels not pretreated with phenoxybenzamine, propranolol inhibited the relaxation to noradrenaline and isoprenaline but again there was no difference between vessels with and without endothelium. In the rabbit isolated epicardial coronary artery, acetylcholine produces an endothelium dependent relaxant response over a limited concentration range; a vasoconstrictor response via smooth muscle dominates at higher concentrations. beta Adrenoceptors mediating relaxation are present on the smooth muscle, but there was no evidence for either alpha or beta adrenoceptor mediated responses via the endothelium. Important differences with coronary arteries from other species are discussed.


Brain Metastases of Non-Small Cell Lung Cancer: Prognostic Factors in Patients with Surgical Resection.
Bronchogenic carcinoma is the cancer that most commonly metastasizes to the brain. The standard treatment schedule for these patients is still unclear, although recommendation level 1 class I advocates for surgical resection together with postoperative whole-brain radiotherapy for patients with good Karnofsky performance status (KPS). We performed a study to identify prognostic factors for the long-term survival of patients with brain metastases from non-small cell lung cancer (NSCLC). This retrospective single-center study included 71 patients with brain metastases from NSCLC having undergone surgical metastasectomy between January 2002 and January 2015. The average age was 58.8 years. A total of 85.9% of the lesions were located in the supratentorial region, 61.9% of the lesions were < 3 cm, and 80.3% of cases were solitary brain metastases. Complete resection was achieved in 90.1% of patients. Clinical debut with motor involvement was associated with higher rates of incomplete surgical resection. Patients with motor deficits had a worse preoperative KPS. The preoperative KPS was > 70 in 74.6% of patients, and the postoperative KPS was > 70 in 85.9% of patients. Overall, 84.5% of the brain surgeries had no complications. Brain metastases were diagnosed as a synchronous presentation in 64.7% of patients.The average survival after brain surgery was 20.38 months. The survival rate was 66.2% at 6 months, 45.1% at 12 months, 22.5% at 24 months, 14.1% at 36 months, and 8.5% at 48 months. Patients < 55 years of age showed a higher survival rate at 12 months and 48 months. Patients > 70 years of age showed a higher mortality rate at 6 months. Complete surgical brain metastasis resection was associated with an increased survival at 6 months, and patients undergoing primary lung surgery had better survival rates at 48 months. A preoperative KPS > 70% improved the prognosis of patients at 6 and 24 months. Surgical complications reduced survival at 6 and 12 months. Surgical resection may be beneficial for a given group of patients: a preoperative KPS > 70; age < 55 years, complete surgical brain metastasis resection, no surgical complications, patients with primary lung surgery, and complete radiotherapy treatment. We did not find any significant difference regarding further factors that probably affect survival rates such as size or number of metastases.


Immunotherapy in Melanoma, Gastrointestinal (GI), and Pulmonary Malignancies.
Oncologic immunotherapy involves stimulating the immune system to more effectively identify and eradicate tumor cells that have successfully adapted to survive the body's natural immune defenses. Immunotherapy has shown great promise thus far by prolonging the lives of patients with a variety of malignancies, and has added a crucial new set of tools to the oncologists' armamentarium. The aim of this paper is to provide an overview of immunotherapy treatment options that are currently available and under active research for melanoma, gastrointestinal (esophageal, gastric, pancreatic, and colorectal), and pulmonary malignancies. Potential biomarkers that may predict favorable responses to immunotherapies are discussed where applicable, as are future avenues of research in this rapidly evolving field.


Motion Plan of Maritime Autonomous Surface Ships by Dynamic Programming for Collision Avoidance and Speed Optimization.
Maritime Autonomous Surface Ships (MASS) with advanced guidance, navigation, and control capabilities have attracted great attention in recent years. Sailing safely and efficiently are critical requirements for autonomous control of MASS. The MASS utilizes the information collected by the radar, camera, and Autonomous Identification System (AIS) with which it is equipped. This paper investigates the problem of optimal motion planning for MASS, so it can accomplish its sailing task early and safely when it sails together with other conventional ships. We develop velocity obstacle models for both dynamic and static obstacles to represent the potential conflict-free region with other objects. A greedy interval-based motion-planning algorithm is proposed based on the Velocity Obstacle (VO) model, and we show that the greedy approach may fail to avoid collisions in the successive intervals. A way-blocking metric is proposed to evaluate the risk of collision to improve the greedy algorithm. Then, by assuming constant velocities of the surrounding ships, a novel Dynamic Programming (DP) method is proposed to generate the optimal multiple interval motion plan for MASS. These proposed algorithms are verified by extensive simulations, which show that the DP algorithm provides the lowest collision rate overall and better sailing efficiency than the greedy approaches.


[Carboxycryobiopsy and carboxycryoextraction of bladder tumor. Experimental study].
To evaluate the possibility of performing transurethral carboxycryobiopsy (CCB) and carboxycryoextraction (CCE) of a bladder tumor for pathomorphological examination, as well as to perform a comparative analysis of the safety (quality) of biopsy material (tumor tissue) during standard transurethral biopsy and carboxycryobiopsy. In the first experiment in vitro, CCE of bladder tumor fragments obtained after transurethral resection was performed. In the second pilot study, cystoscopy followed by CCB and CCE in a patient with multiple bladder tumors was done. The procedure was performed by transurethral access. During cryopreservation of the bladder tumor, a biopsy was performed. After freezing, the tumor was removed from the bladder and sent for histological examination. The first experiment showed that cryoextraction of the fragments of a bladder tumor using carbon dioxide (CCE) in vitro is a feasible procedure and allows the evacuation of tumor tissues of various sizes. According to the second experiment, CCB and CCE of the bladder tumor using carbon dioxide allows to obtain a biopsy of a bladder tumor of sufficient size without compression or coagulation artifacts, which contributes to a more accurate histological evaluation. Our experiments showed that CCB and CCE of a bladder tumor using carbon dioxide are feasible procedures that contribute to obtaining better biopsy material for pathomorphological examination, and also allows to evaluate the effect of low temperatures of carbon dioxide on the biopsy material (tumor tissue).


Cytotoxic T lymphocyte antigen-4 (CTLA-4) A49G polymorphism and autoimmune blood diseases.
The cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is expressed on T lymphocytes, and inhibits the T-cell responses. In animal models, it has been shown that complete CTLA-4 deficiency was lethal due to massive infiltration of tissues by polyclonally proliferating lymphocytes. CTLA-4 A49G polymorphism, which has been suggested to reduce the inhibitory function of the CTLA-4 molecule, was found to be associated with various autoimmune diseases in recent studies. In this study, we evaluated the frequency of CTLA-4 A49G polymorphism in 46 patients with autoimmune hemolytic anemia (AIHA), 62 patients with immune thrombocytopenic purpura (ITP), and 150 healthy individuals. Allele frequencies and genotype distributions were similar in both ITP and AIHA patients compared to healthy individuals. In subgroup analysis, however, we found that in chronic lymphocytic leukemia (CLL) patients with AIHA (n=4), all patients had CTLA-4 A49G polymorphism (3 had AG, 1 had GG). There was no significant statistical association between G allele and systemic lupus erythematosus (SLE) or AIHA. These data suggest that CTLA-4 A49G polymorphism does not contribute to the pathogenesis of lymphoproliferative diseases itself, nor does it increase the risk of autoimmune complications in patients with lymphoproliferative disease.


Cold stress provokes sympathoinhibitory presyncope in healthy subjects and hemodialysis patients with low cardiac output.
Sudden hypotension in progressive hypovolemia or during hemodialysis is attributed to sudden inhibition of sympathetic activity. Critical ventricular underfilling seems responsible for this paradox, but it is unknown why the transition from sympathoactivation accompanying hypovolemia to sympathoinhibition is so abrupt. We studied whether brief fluctuation of sympathetic activity induced by cold pressor test (CPT) evokes sympathoinhibition if applied during low cardiac output. Fourteen healthy subjects underwent CPT, lower-body negative pressure (LBNP; -45 mm Hg for 60 minutes), or the combination thereof. CPT alone caused vasoconstriction and increased muscle sympathetic nerve activity, followed by uneventful relaxation. When applied during reduced cardiac output, tachycardia, and vasoconstriction induced by prior LBNP for 6 minutes, CPT again caused vasoconstriction, now followed by acute hypotension in 10 subjects, and was associated with vasorelaxation, relative bradycardia, and fall in muscle sympathetic nerve activity. Eight subjects also experienced acute LBNP-induced hypotension in the absence of CPT, but not until 17 +/- 6 minutes of LBNP. We also performed CPT before and in the final phase of hemodialysis in 8 patients. Before dialysis, the patients tolerated CPT uneventfully, but during hemodialysis, CPT provoked acute hypotension in 5 cases, showing similar withdrawal of vasoconstriction. This is the first study showing that brief cold stress, tolerated well in normal circulatory conditions, can provoke sudden sympathoinhibition and hypotension when applied during decreased cardiac output induced by LBNP or hemodialysis. We suggest that during conditions of a decreased cardiac output, subtle sympathetic relaxation such as follows cold stress triggers self-enhancing relaxation that cannot be controlled.


Multicentre study of the efficacy and tolerance of acebutolol versus atenolol in the long term treatment of mild arterial hypertension.
The efficacy, tolerance and effect on serum lipids of acebutolol were compared with those of atenolol over a 6-month period in a large group of patients with mild arterial hypertension. Both drugs were equally effective in reducing blood pressure, and tolerance was generally excellent. High density lipoprotein (HDL)-cholesterol concentrations were reduced to a similar extent by both treatments at 2 months and this change was reflected in measurements of the total cholesterol concentrations. However, no significant changes occurred in serum triglyceride levels and at 6 months all serum lipid parameters had returned to baseline values. These observations suggest that cardioselective beta-blockers have no adverse effects on serum lipids at 6 months, after a temporary reduction of HDL-cholesterol at 2 months.


Innovations in national nutrition surveys.
The aim of this paper is to describe innovations taking place in national nutrition surveys in the UK and the challenges of undertaking innovations in such settings. National nutrition surveys must be representative of the overall population in characteristics such as socio-economic circumstances, age, sex and region. High response rates are critical. Dietary assessment innovations must therefore be suitable for all types of individuals, from the very young to the very old, for variable literacy and/or technical skills, different ethnic backgrounds and life circumstances, such as multiple carers and frequent travel. At the same time, national surveys need details on foods consumed. Current advances in dietary assessment use either technological innovations or simplified methods; neither lend themselves to national surveys. The National Diet and Nutrition Survey (NDNS) rolling programme, and the Diet and Nutrition Survey of Infants and Young Children (DNSIYC), currently use the 4-d estimated diary, a compromise for detail and respondent burden. Collection of food packaging enables identification of specific products. Providing space for location of eating, others eating, the television being on and eating at a table, adds to eating context information. Disaggregation of mixed dishes enables determination of true intakes of meat and fruit and vegetables. Measurement of nutritional status requires blood sampling and processing in DNSIYC clinics throughout the country and mobile units were used to optimise response. Hence, innovations in national surveys can and are being made but must take into account the paramount concerns of detail and response rate.


Interdisciplinary education on discussing end-of-life care.
The interactions and observations of residents speaking with patients and family members about end-of-life decisions indicated a need for more empathy. Nursing and medical students have been called to learn and work together so they can work more effectively. A review of the evidence on interdisciplinary education of residents concerning end-of-life care and communicating with patients and their family members was the inspiration for this study. This article applies evidence related to interdisciplinary education in critical care settings. This pilot project was a collaboration of medical education between a critical care service in a public hospital and baccalaureate nursing students assisting family members in making end-of-life decisions. As nursing students, we were able to effectively present content on end-of-life decision making to medical residents.


Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation.
Infections caused by metallo-β-lactamase (MBL)-producing bacteria are emerging and carry a significant impact on patients' outcome. MBL producers are spread worldwide, both in community and hospital setting, with increasingly reported epidemic clusters and the search for MBL inhibitors is an important topic for public health. MBLs are zinc-dependent enzymes whose functioning can be hampered by zinc chelators. We evaluated the potential of six zinc chelators (disulfiram, nitroxoline, 5-amino-8-hydroxyquinoline, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA], cyclam, and N,N,N',N'-tetrakis (2-pyridymethyl) ethylenediamine [TPEN]) in restoring carbapenem activity against MBL producers. Zinc chelators alone or in combination with meropenem against MBL-producing Klebsiella pneumoniae, Chryseobacterium indologenes, Elizabethkingia meningoseptica, and Stenotrophomonas maltophilia isolates were tested in vitro and in vivo (Galleria mellonella). In vitro experiments showed a synergistic activity between TPEN and meropenem toward all the strains. Nitroxoline alone retained activity against S. maltophilia, C. indologenes, and E. meningoseptica. In vivo experiments showed that TPEN or nitroxoline in combination with meropenem increased survival in larvae infected with E. meningoseptica, S. maltophilia, and K. pneumoniae. Based on our data, zinc chelators are potential carbapenem adjuvants molecules (restoring carbapenem activity) against MBL-sustained infections and could represent an interesting option for infections induced by these microorganisms.


PLANT HOMOLOGOUS TO PARAFIBROMIN is a component of the PAF1 complex and assists in regulating expression of genes within H3K27ME3-enriched chromatin.
The human Paf1 complex (Paf1C) subunit Parafibromin assists in mediating output from the Wingless/Int signaling pathway, and dysfunction of the encoding gene HRPT2 conditions specific cancer-related disease phenotypes. Here, we characterize the organismal and molecular roles of PLANT HOMOLOGOUS TO PARAFIBROMIN (PHP), the Arabidopsis (Arabidopsis thaliana) homolog of Parafibromin. PHP resides in an approximately 670-kD protein complex in nuclear extracts, and physically interacts with other known Paf1C-related proteins in vivo. In striking contrast to the developmental pleiotropy conferred by mutation in other plant Paf1C component genes in Arabidopsis, loss of PHP specifically conditioned accelerated phase transition from vegetative growth to flowering and resulted in misregulation of a very limited subset of genes that included the flowering repressor FLOWERING LOCUS C. Those genes targeted by PHP were distinguished from the bulk of Arabidopsis genes and other plant Paf1C targets by strong enrichment for trimethylation of lysine-27 on histone H3 (H3K27me3) within chromatin. These findings suggest that PHP is a component of a plant Paf1C protein in Arabidopsis, but has a more specialized role in modulating expression of a subset of Paf1C targets.


Adenoid squamous cell carcinoma of the oral mucosa: report of two autopsy cases.
Two autopsy cases of adenoid squamous cell carcinoma of the oral mucosa proper are presented. Consecutive histologic examinations confirmed that adenoid transformation had occurred directly from within the pre-existing usual squamous cell carcinoma during the course of the disease. The adenoid pattern was reproduced in the lymph node metastases in both cases. The behavior and autopsy findings were not significantly different from those of usual squamous cell carcinoma of the oral mucosa.


Binary vectors and super-binary vectors.
A binary vector is a standard tool in the transformation of higher plants mediated by Agrobacterium tumefaciens. It is composed of the borders of T-DNA, multiple cloning sites, replication functions for Escherichia coli and A. tumefaciens, selectable marker genes, reporter genes, and other accessory elements that can improve the efficiency of and/or give further capability to the system. A super-binary vector carries additional virulence genes from a Ti plasmid, and exhibits very high frequency of transformation, which is valuable for recalcitrant plants such as cereals. A number of useful vectors are widely circulated. Whereas vectors with compatible selectable markers and convenient cloning sites are usually the top criteria when inserting gene fragments shorter than 15 kb, the capability of maintaining a large DNA piece is more important for consideration when introducing DNA fragments larger than 15 kb. Because no vector is perfect for every project, it is recommended that modification or construction of vectors should be made according to the objective of the experiments. Existing vectors serve as good sources of components.


EVALUATION OF THE SYNTHESIS AND STRUCTURE OF NEW AZETIDIN-2-ONES OF FERULIC ACID.
To synthesize some new azetidin-2-ones of ferulic acid and to evaluate them from physicochemical and spectral point of view. The synthesis was carried out in several steps: (i) obtaining the ferulic acid chloride; (ii) obtaining the ferulic acid hydrazide with hydrazine hydrate (98%); (iii) condensation of ferulic acid hydrazide with different benzaldehydes (2-hydroxy-/2-nitro-/4-chloro-/4- fluoro-/4-bromo-benzaldehyde) in order to obtain the corresponding hydrazones; (iv) cy- clization of ferulic acid hydrazones with chloroacethyl chloride in freshly distilled toluene medium and in the presence of triethylamine, resulting in the corresponding azetidin-2-ones. Six new azetidin-2-ones of ferulic acid were synthesized. They were characterized in terms of their physicochemical properties and their structure was confirmed by IR and 1H-NMR spectroscopy. Six new azetidin-2-ones of ferulic acid were synthesized, physicochemically characterized and validated spectrally. A


LaCyTools: A Targeted Liquid Chromatography-Mass Spectrometry Data Processing Package for Relative Quantitation of Glycopeptides.
Bottom-up glycoproteomics by liquid chromatography-mass spectrometry (LC-MS) is an established approach for assessing glycosylation in a protein- and site-specific manner. Consequently, tools are needed to automatically align, calibrate, and integrate LC-MS glycoproteomics data. We developed a modular software package designed to tackle the individual aspects of an LC-MS experiment, called LaCyTools. Targeted alignment is performed using user defined m/z and retention time (tr) combinations. Subsequently, sum spectra are created for each user defined analyte group. Quantitation is performed on the sum spectra, where each user defined analyte can have its own tr, minimum, and maximum charge states. Consequently, LaCyTools deals with multiple charge states, which gives an output per charge state if desired, and offers various analyte and spectra quality criteria. We compared throughput and performance of LaCyTools to combinations of available tools that deal with individual processing steps. LaCyTools yielded relative quantitation of equal precision (relative standard deviation <0.5%) and higher trueness due to the use of MS peak area instead of MS peak intensity. In conclusion, LaCyTools is an accurate automated data processing tool for high-throughput analysis of LC-MS glycoproteomics data. Released under the Apache 2.0 license, it is freely available on GitHub ( https://github.com/Tarskin/LaCyTools ).


Diurnal rhythms of the neuroendocrine system in professional riveters with different constitutional types.
In our earlier investigations it have been shown that experimental vibration exposure causes different endocrine reactions in hypothalamo-pituitary-adrenocortical (HPA) and hypothalamo-pituitary-gonadal (HPG) systems in men of different constitutional types. The present study was carried out to determine diurnal rhythms of HPA and HPG systems in professional male riveters during a working day under industrial conditions. The state of HPA and HPG systems was evaluated according to the concentration of hormones cortisol (Cort.) and testosterone (T) in saliva. Mixed saliva was collected without stimulation at 7.00, 11.00, 15.00, 19.00 and 23.00 h. The concentration of hormones was determined by radio-immunoassay. Only healthy workers with a long working time under vibration exposure were chosen for participation in the investigation. The workers were divided into three groups of abdominal (A), muscular (M) and pectoral (P) somatotypes according to the antropometric signs (Bunaris classification, 1941). The results of investigating the HPA system have shown that usual diurnal rhythm of Cort, was observed in 60% of all cases. This rhythm is characterised by the maximum concentration of Cort, at 7.00 h with subsequent lowering during the day. In 10% of all cases we observed very low concentration of Cort, at 7.00 h and in 30% there was a significant increase of the level of Cort, at 15.00 and 19.00 h. Another change of diurnal rhythm was revealed in the HPG system. The diurnal rhythm of T completely corresponds to the rhythm of Cort. The accordance of T concentration to the diurnal rhythm we observed only in 27% of all cases. In 47% of all cases the increase of T took place at 15.00 and 19.00 h and in 20% the "monotonous" curve of T concentration without any changes of rhythm and with a low concentration at 7.00 h was observed. We also revealed different distribution of A, M and P somatotypes in connection with various diurnal rhythms of hormone curves. The result allows us to suppose that constitutional dependence of changes of diurnal rhythm of HPA and HPG systems probably underlines the adaptive processes to long time vibration exposure.


A MODEL FOR INTEGRATING ACTUAL NEUROTIC OR UNREPRESENTED STATES AND SYMBOLIZED ASPECTS OF INTRAPSYCHIC CONFLICT.
In psychoanalytic theory, the importance of actual neuroses-considered to be devoid of psychic content-diminished as Freud and subsequent analysts focused on unconscious intrapsychic conflict. This paper explores the relationship between actual neurotic and unrepresented states, which are believed to be best addressed through attention to countertransference, intersubjectivity, and enactments rather than interpretation of intrapsychic conflict. Models suggesting how actual neurotic states and symbolized intrapsychic conflict may interact with each other and environmental stressors are described. Symbolizing actual neurotic states and establishing meaningful linkages between somatic/affective experiences and intrapsychic conflict are viewed as necessary for effective treatment of many disorders.