Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031).
ZK-807834 (also known as CI-1031) is a small molecule that potently and selectively inhibits Factor Xa. Studies in animals have shown that ZK-807834 attenuates thrombosis and thrombus progression after fibrinolysis and exhibits an increased antithrombotic-to-bleeding risk ratio compared with conventional agents. The present study describes the human in vitro anticoagulant and pharmacodynamic profile ZK-807834. Consistent with its selective inhibition of Factor Xa, ZK-807834 in the range of 0.3-0.5 microM prolonged prothrombin time (PT) and activated partial thromboplastin time (aPPT) twofold without affecting thrombin time (TT). Intersubject variability of in vitro anticoagulant activity was nominal and gender-independent. ZK-807834 inhibited Factor Xa in clot-bound prothrombinase with an average IC50 of 10+/-7 (S.D.) nM. ZK-807834 exhibited no direct effect on ADP- or collagen-induced platelet aggregation. Based on the potency and specificity, ZK-807834 may represent an important advance in the development of selective and safe antithrombotics.


Intravenous immunoglobulin-based adjuvant therapy for severe COVID-19: a single-center retrospective cohort study.
Coronavirus disease 2019 (COVID-19) is a major challenge facing the world. Certain guidelines issued by National Health Commission of the People's Repubilic of China recommend intravenous immunoglobulin (IVIG) for adjuvant treatment of COVID-19. However, there is a lack of clinical evidence to support the use of IVIG. This single-center retrospective cohort study included all adult patients with laboratory-confirmed severe COVID-19 in the Respiratory and Critical Care Unit of Dabie Mountain Regional Medical Center, China. Patient information, including demographic data, laboratory indicators, the use of glucocorticoids and IVIG, hospital mortality, the application of mechanical ventilation, and the length of hospital stay was collected. The primary outcome was the composite end point, including death and the use of mechanical ventilation. The secondary outcome was the length of hospital stay. Of the 285 patients with confirmed COVID-19, 113 severely ill patients were included in this study. Compared to the non-IVIG group, more patients in the IVIG group reached the composite end point [12 (25.5%) vs 5 (7.6%), P = 0.008] and had longer hospital stay periods [23.0 (19.0-31.0) vs 16.0 (13.8-22.0), P < 0.001]. After adjusting for confounding factors, differences in primary outcomes between the two groups were not statistically significant (P = 0.167), however, patients in the IVIG group had longer hospital stay periods (P = 0.041). Adjuvant therapy with IVIG did not improve in-hospital mortality rates or the need for mechanical ventilation in severe COVID-19 patients. Our study does not support the use of immunoglobulin in patients with severe COVID-19 patients.


Year in review in Critical Care, 2003 and 2004: respirology and critical care.
We summarize all original research in the field of respirology and critical care published in 2003 and 2004 in Critical Care. Articles were grouped into the following categories to facilitate a rapid overview: pathophysiology, therapeutic approaches, and outcome in acute lung injury and acute respiratory distress syndrome; hypoxic pulmonary arterial hypertension; mechanical ventilation; liberation from mechanical ventilation and tracheostomy; ventilator-associated pneumonia; multidrug-resistant infections; pleural effusion; sedation and analgesia; asthma; and techniques and monitoring.


Real exposure: field measurement of chemical plumes in headwater streams.
In fluvial systems, organismic exposure to nonpoint source pollutants will fluctuate in frequency (exposure events), intensity (concentration), and duration. The reliance on lethal concentrations and static exposure in many laboratory studies does not adequately represent nor address exposure to in situ chemical plumes of fluvial habitats. To adequately address field exposure in a laboratory setting, one needs an understanding of the physics of chemical transmission within moving fluids. Because of the chaotic nature of turbulence, chemical plumes introduced to fluvial systems have a spatial and temporal microstructure with fluxes in chemical concentration. Consequently, time-averaged static exposure models are not ecologically relevant for the major reason of in situ distribution. The purpose of this study was to quantify in situ chemical distribution and dispersion within two physically different streams. Dopamine was introduced as a chemical tracer mimicking groundwater runoff. Chemical fluxes and stream hydrodynamics were simultaneously measured using a microelectrode and an acoustic Doppler velocimeter, respectively, at three heights of three downstream locations at each research site. Fine-scale measurements of the dopamine plume microstructure showed that organisms could be exposed to chemical fluctuations where concentrations are significantly greater than the overall time-averaged concentration. These measurements demonstrate that rather than relying on static exposure, standards for pollution must consider the concept of exposure being interdependently linked to flow of the fluid medium. The relationship between fluid dynamics, pollution exposure, and organism physiology are complex and must be evaluated in ways to mimic natural systems.


Lifestyle, Exercise and Activity Package for People living with Progressive Multiple Sclerosis (LEAP-MS): adaptions during the COVID-19 pandemic and remote delivery for improved efficiency.
The LEAP-MS (Lifestyle, Exercise and Activity Package for People living with Progressive Multiple Sclerosis) study has developed an individualised supported self-management approach for physical activity for people with progressive multiple sclerosis (MS) and severe disability. The intervention has been evaluated in a single-arm feasibility study with embedded process evaluation. The feasibility study was due to open to recruitment during the COVID-19 2020-2021 pandemic, 1 month into the first UK-wide lockdown. We worked rapidly to implement adaptions to the trial procedures and intervention delivery that we believe are applicable to randomised controlled trials. Recruitment became predominantly via self-referral. Electronic consent was employed, with consent discussions occurring over the telephone. Registration, consent, eligibility assessment and data collection as well as the intervention (online physical activity tool) were via a secure, encrypted multi-user web-based platform for participants, physiotherapists and researchers accessible via various hardware. Physiotherapy consultations, as well as the process evaluation, were conducted remotely using video conferencing software or the telephone. A remote training package for physiotherapists and site initiations was also developed and electronic site files employed. Our adaptions are extremely topical given the COVID-19 situation, and whilst not what we had originally planned, have enabled successful delivery of the feasibility study and are relevant to conducting randomised controlled trials and meeting the needs of people with MS who are far more isolated than ever before. TRIAL REGISTRATION: ClinicalTrials.gov NCT03951181 . Registered on 15 May 2019.


Pharmacists' thought processes in making a differential diagnosis using a gastro-intestinal case vignette.
Community pharmacists facilitate patient self-care and, in effect, provide a triage service to primary care medical services. Their ability to perform this role has been questioned, yet research has not explored how pharmacists make these decisions. Better understanding of the processes that shape pharmacists' clinical decisions will allow strategies to be developed to improve "diagnostic" performance. This study aimed to explore community pharmacists thought processes when making a differential diagnosis during referral and triage. Using a case vignette, community pharmacists were asked to establish the cause of a simulated patient's signs and symptoms. After each question asked by the pharmacist they were asked to 'think aloud' their thoughts. Pharmacists from the West Midlands, England were recruited through convenience and snowball sampling. The simulated consultations were recorded and transcribed verbatim. Questions asked were coded into pre-determined categories that captured the context of why the question was being asked, which was gained from the 'think aloud' process. Ten pharmacists were interviewed. Seven used an acronym approach to information gathering, and those who used it exclusively did not reach the expected outcome. Three pharmacists exhibited questioning that aligned to medical clinical decision-making and asked more questions that informed the diagnosis than those pharmacists relying on using an acronym; all three arrived at the expected outcome. All pharmacists asked 'safety net' type question/s early on in the consultation. This study was exploratory and the findings must be viewed with caution until larger studies are conducted. Pharmacists rarely exhibited clinical decision-making and relied heavily on protocol-led questioning strategies.


Floristic diversity in different urban ecological niches of a southern European city.
The present paper aimed at studying the vertical and horizontal spatial distribution, species richness and diversity of vascular plants in different urban ecological niches (urban habitats) by means of the case study of Bologna (Italy), a typical densely populated southern European city. A total of 477 species were found in the study area of the historical city centre, 30% of which were alien species. Alien plant species were mainly present among phanerophytes, while native plants were mainly therophytes and hemicryptophytes. The habitats that mostly contributed to the species total richness were semi-natural soils, followed by paved areas, walls, rooftops and manholes. The number of exclusive species decreased according to the selectiveness of the habitat, with manholes and rooftops being the most selective. The presence of hemicryptophytes constant decreased going from 27% of more humid habitats to 5% of more arid habitats, so that they can be considered a water availability biomarker. Urban habitat quality, measured by the number of native species, was directly proportional to the strength of selective factors and inversely proportional to the rate of disturbance, with roofs and semi-natural soils having, respectively, the highest and lowest quality. Finally, a relation between species richness and street characteristics, like width, orientation and type of flooring, was demonstrated.


Endoscopic transsphenoidal approach for resection of malignant pituitary blastoma in an 18-month-old infant: a technical note.
Sella and suprasellar tumors are increasingly managed via an endoscopic transsphenoidal approach, but infant endoscopic surgery has not been reported. Pituitary blastoma is a rare sellar malignant tumor that primarily occurs in infants and is managed by surgical resection (cytoreduction) followed by adjuvant therapy. To describe the technique and feasibility of resection of a pituitary blastoma via endoscopic endonasal transsphenoidal approach in an 18-month-old infant. Endoscopic endonasal transsphenoidal approach for resection of a pituitary malignant tumor in an infant. Near-total tumor resection was achieved. The skull base was reconstructed by using a nasoseptal flap with no cerebrospinal fluid leak or any other intraoperative complications. The postoperative course was uneventful. One-year follow-up showed complete resolution of the tumor. The endoscopic endonasal transsphenoidal approach with nasoseptal flap reconstruction could be used as a safe, yet minimally invasive and innovative technique for the resection of pituitary blastoma in infants.


[Alveolar proteinosis in a facade plasterer. A sequential study of bronchoalveolar lavage and thoracic computerized tomography].
Alveolar proteinosis is a rare disease. We report a case occurring in a patient who smoked and was a facade plasterer who was treated with repeated pulmonary lavage. A mineral analysis of the lavage fluid recovered a significant amount of silica and iron oxide confirming the massive exposure of the patient to these minerals. The favourable outcome over the next 7 years was associated as regards respiratory function, with a progressive improvement in lung volumes and pulmonary output and of CO diffusion capacity, as regards broncho-alveolar lavage there was a regular increase in the cellularity and finally as regards CT scanning (at high resolution) there was a progressive clearing of the alveolar opacities only leaving the persistent opacities in the interstitium.


A meta-analysis of microarray-based gene expression studies of olfactory bulb-derived olfactory ensheathing cells.
Genome wide transcriptional profiling and large scale proteomics have emerged as two powerful methods to dissect the molecular properties of specific neural tissues or cell types on a global scale. Several genome-wide transcriptional profiling and proteomics studies have been published on cultured olfactory ensheathing cells (OEC). In this article we present a meta-analysis of all five published and publicly available micro-array gene expression datasets of cultured early-passage-OB-OEC with other cell types (Schwann cells, late-passage-OB-OEC, mucosa-OEC, an OEC cell line, and acutely dissected OEC). The aim of this meta-analysis is to identify genes and molecular pathways that are found in multiple instead of one isolated study. 454 Genes were detected in at least three out of five microarray datasets. In this "Top-list", genes involved in the biological processes "growth of neurites", "blood vessel development", "migration of cells" and "immune response" were strongly overrepresented. By applying network analysis tools, molecular networks were constructed and Hub-genes were identified that may function as key genes in the above mentioned interrelated processes. We also identified 7 genes (ENTPD2, MATN2, CTSC, PTHLH, GLRX1, COL27A1 and ID2) with uniformly higher or lower expression in early-passage-OB-OEC in all five microarray comparisons. These genes have diverse but intriguing roles in neuroprotection, neurite extension and/or tissue repair. Our meta-analysis provides novel insights into the molecular basis of OB-OEC-mediated neural repair and can serve as a repository for investigators interested in the molecular biology of OEC. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.


[Effect of ultrasonics on isolated plasmalemmas from adult mouse liver: biochemistry and cytochemistry].
Ultrasonic irradiation is applied for different conditions on plasma membranes isolated from male adult Mouse liver. Investigations of plasma membrane structures and 5'-nucliotidase activity associated with it, are carried out to determine the effect of ultrasound treatment.


Stability in contractive nonlinear neural networks.
We consider models of the form mu chi = -x + p + WF(x) where x = x(t) is a vector whose entries represent the electrical activities in the units of a neural network. W is a matrix of synaptic weights, F is a nonlinear function, and p is a vector (constant or slowly varying over time) of inputs to the units. If the map WF(x) is a contraction, then the system has a unique equilibrium which is globally asymptotically stable; consequently the network acts as a stable encoder in that its steady-state response to an input is independent of the initial state of the network. We consider some relatively mild restrictions on W and F(x), involving the eigenvalues of W and the derivative of F, that are sufficient to ensure that WF(x) is a contraction. We show that in the linear case with spatially-homogeneous synaptic weight, the eigenvalues of W are simply related to the Fourier transform of the connection pattern. This relation makes it possible, given cortical activity patterns as measured by autoradiographic labeling, to construct a pattern of synaptic weights which produces steady state patterns showing similar frequency characteristics. Finally, we consider the relationships, in the spatial and frequency domains, between the equilibrium of the model and that of the linear approximation mu chi = -x + p + Wx; this latter equilibrium can be computed easily from p in the homogeneous case using discrete Fourier transforms.


Nanostructured raspberry-like gelatin microspheres for local delivery of multiple biomolecules.
Multicompartment particles, which are particles composed of smaller building units, have gained considerable interest during the past decade to facilitate simultaneous and differential delivery of several biomolecules in various applications. Supercritical carbon dioxide (CO2) processing is an industrial technology widely used for large-scale synthesis and processing of materials. However, the application of this technology for production of multicompartment particles from colloidal particles has not yet been explored. Here, we report the formation of raspberry-like gelatin (RLG) microparticles composed of gelatin nanoparticles as colloidal building blocks through supercritical CO2 processing. We show that these RLG microparticles exhibit a high stability upon dispersion in aqueous media without requiring chemical cross-linking. We further demonstrate that these microparticles are cytocompatible and facilitate differential release of two different model compounds. The strategy presented here can be utilized as a cost-effective route for production of various types of multicompartment particles using colloidal particles with suitable interparticle interactions. Multicompartment particles have gained considerable interest during the past decade to facilitate simultaneous and differential delivery of multiple biomolecules in various biomedical applications. Nevertheless, common methods employed for the production of such particles are often complex and only offer small-scale production. Here, we report the formation of raspberry-like gelatin (RLG) microparticles composed of gelatin nanoparticles as colloidal building blocks through supercritical CO2 processing. We show that these microparticles are cytocompatible and facilitate differential release of two model compounds with different molecular sizes, promising successful applications in various biomedical areas. Summarizing, this paper presents a novel strategy that can be utilized as a cost-effective route for production of various types of multicompartment particles using a wide range of colloidal building blocks.


Management of long-term failure after colon interposition for benign disease.
To assess causes and treatment of late failures of colon interposition. We reviewed the charts of 6 patients who underwent one or more revisions of a colonic interposition at a mean of 16 years after colon interposition (CI). Symptoms of problems with the CI were dysphagia (67%), regurgitation (67%), pneumonia (40%), and chest pain (33%). Findings that accounted for failure were colonic redundancy (67%), and gastrocolonic reflux (50%). Approach was resection of redundant colon or management of reflux. Four patients underwent segmental resection of the colon preserving blood supply. Three patients had gastric resection or diversion of bile and acid for management of reflux. Treatment was successful in all patients. Late failure of colon interposition is secondary to conduit redundancy and severe reflux. Resection of redundant colon will correct colonic redundancy. Gastric resection or diversion of bile and acid corrects gastrocolonic reflux.


Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.
A number of 2',3'-dideoxynucleosides have been shown to inhibit the in vitro infectivity and cytopathic effect of the human immunodeficiency virus (HIV). These compounds, as their 5'-triphosphates, inhibit viral reverse transcriptase by competing with the natural substrate at the same binding site on the enzyme. Dideoxynucleoside triphosphates can also be incorporated into growing DNA chains which then blocks further DNA elongation because they lack the 3'-hydroxyl group required for further polymerization. Among these nucleosides, 2', 3'-dideoxyadenosine 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) show promising in vitro activity. Because adenosine is rapidly converted to inosine by adenosine deaminase, the in vivo conversion of ddA to ddI was studied to determine suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of ddA. This report describes and compares the pharmacokinetics of ddA and ddI in the mouse.


Pandemic coronavirus disease (Covid-19): World effects analysis and prediction using machine-learning techniques.
Pandemic novel Coronavirus (Covid-19) is an infectious disease that primarily spreads by droplets of nose discharge when sneezing and saliva from the mouth when coughing, that had first been reported in Wuhan, China in December 2019. Covid-19 became a global pandemic, which led to a harmful impact on the world. Many predictive models of Covid-19 are being proposed by academic researchers around the world to take the foremost decisions and enforce the appropriate control measures. Due to the lack of accurate Covid-19 records and uncertainty, the standard techniques are being failed to correctly predict the epidemic global effects. To address this issue, we present an Artificial Intelligence (AI)-based meta-analysis to predict the trend of epidemic Covid-19 over the world. The powerful machine learning algorithms namely Naïve Bayes, Support Vector Machine (SVM) and Linear Regression were applied on real time-series dataset, which holds the global record of confirmed, recovered, deaths and active cases of Covid-19 outbreak. Statistical analysis has also been conducted to present various facts regarding Covid-19 observed symptoms, a list of Top-20 Coronavirus affected countries and a number of coactive cases over the world. Among the three machine learning techniques investigated, Naïve Bayes produced promising results to predict Covid-19 future trends with less Mean Absolute Error (MAE) and Mean Squared Error (MSE). The less value of MAE and MSE strongly represent the effectiveness of the Naïve Bayes regression technique. Although, the global footprint of this pandemic is still uncertain. This study demonstrates the various trends and future growth of the global pandemic for a proactive response from the citizens and governments of countries. This paper sets the initial benchmark to demonstrate the capability of machine learning for outbreak prediction.


Glucose and protein metabolism during late pregnancy in triplet-bearing ewes given fresh forages ad lib. 1. Voluntary intake and birth weight.
Ewes of the Booroola X Romney genotype carrying triplet lambs were given fresh forages ad lib. in late pregnancy. In Expt 1, groups of three ewes were given kale (Brassica oleracea), perennial ryegrass (Lolium perenne) or perennial ryegrass (0.75)-barley (0.25). In Expt 2, groups of two or three ewes were given fresh perennial ryegrass and infused into the abomasum with iso-energetic quantities of casein and glucose in a 2 x 2 factorial arrangement. Post-lambing ewe live weights were 40-50 kg. Glucose irreversible loss (GIL) was determined from dilution of D-[U-14C]glucose. For ewes given kale, perennial ryegrass and perennial ryegrass-barley in Expt 1, mean metabolizable energy (ME) intakes were 0.50, 0.82 and 0.83 MJ/kg live weight 0.75 per d, GIL was 112, 142 and 157 g/d, and mean birth weight 2.22, 3.05 and 2.95 kg/lamb. In Expt 2, infusion of glucose, casein, and glucose + casein depressed herbage ME intake respectively by 1.6, 0.9 and 0.3 times the amount of ME infused. GIL (185-325 g/d) was increased by 800 and 350 g respectively for each kg of glucose or casein infused. Casein infusion increased calculated amino acid absorption from 0.18 to 0.36 of ME, increased wool growth and increased calculated maternal N balance. Birth weight was unaffected by nutritional treatment and averaged 3.29 kg/lamb. When values from both experiments were combined, birth weight was related to GIL by a hyperbolic relation, with maximum predicted birth weight being 4.1 kg/lamb. It was postulated that this value was never attained in practice, due to uterine expansion being restricted by the low maternal body size. Marked decreases in birth weight occurred when GIL decreased below 173 g/d. It was calculated that ewes in all treatment groups were in negative energy balance, and that glucose supplied by the kale and unsupplemented ryegrass diets were respectively below and equal to calculated conceptus uptakes of glucose necessary to maintain growth of triplet fetuses. It was further calculated that amino acid requirements of triplet-bearing ewes in late pregnancy were likely to exceed substantially net absorption from digestion of fresh forage diets, and that maternal tissues go into negative N balance to ensure fetal growth, thus explaining the lack of response to abomasal casein infusion.


[Quantitative and qualitative determination of the bacterial colonization of the rat jejunum following long-term feeding with an elemental diet].
Elemental diets are increasingly used in the treatment of enteral diseases, but only limited studies have been hitherto carried out to clarify their actions on the intestinal flora. Therefore, the jejunal flora was assessed in rats fed an elemental diet or standard pellet food over a period of 60 days. In both sets of animals similar numbers of colony-forming bacteria per ml intestinal content of the aerobic and anaerobic flora were found. In addition, the individual genera did not exhibit significant differences in control and experimental animals. Thus, long-term feeding with an elemental diet does not influence the jejunal flora of rats.


Modified Zeiss beam splitter for operating microscope and television camera.
I have designed an asymmetrical 50/70 beam splitter that allows a television camera to be coupled directly to the Zeiss operating microscope. This device provides more light for the surgeon.


Crystallographic dissection of the thermal motion of protein-sugar complex.
The crystal structure of turkey egg lysozyme (TEL) complexed with di-N-acetylchitobiose (NAG2) was refined at 1.19 A resolution by the full-matrix least-squares method with anisotropic temperature factors, and its thermal motion was evaluated by the TLS method. The average ESDs of atomic parameters of nonhydrogen atoms were 0.030 A for coordinates and 0.025 A(2) for anisotropic temperature factors. The active site cleft of TEL binds the alpha-anomer of NAG2 in a nonproductive binding mode with its pyranose rings parallel to a beta-sheet. The TEL structure was compared with the re-refined 1.12 A structure of native TEL. The RMS difference for equivalent Calpha atoms was 0.103 A and a relatively large difference was observed in the region of residues 104-125 rather than in the beta-sheet region where NAG2 was bound. In contrast, the temperature factor of the beta-sheet region was significantly decreased by the NAG2 binding. The TLS model that describes the rigid body motion in translation, libration, and screw motion was adopted for the evaluation of the molecular motion of TEL and NAG2, and the TLS parameters were determined by the least-squares fit to U(ij). The contribution of the external motion of TEL was estimated to be 55.8% of the observed temperature factor for the native structure and 45.9% for the NAG2 complex. The internal motion of TEL represented with atomic thermal ellipsoids was very similar between the native and complex structures except the NAG2 binding region. In the structure of NAG2, the rigid body motion dominates the thermal motion. The center of rotation of NAG2, 4.45A far from the center of gravity, is on the nitrogen atom of the acetylamino group that is hydrogen bonded to the main-chain peptide groups of Asn49 and Ala107. The rigid body motion of NAG2 indicates that the acetylamino group is most strongly bound to the active site, and the recognition of this group is a crucial step of the substrate binding.


Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children.
Four Navajo children had a mutilating neuropathy with severe motor involvement. The disorder appears to be recessively inherited and is present from the earliest observable age. Manifestations include severe anesthesia, corneal ulceration, painless fractures, acral mutilation, and weakness. Mental function is normal. Sural nerves are practically devoid of myelinated fibers that show no evidence of regeneration. Unmyelinated axons show degenerative and regenerative morphologic and histometric features. Onion bulb formation is absent. We believe this neuropathy is a distinct clinical entity.


New platinum(II) complexes of beta-cyclodextrin diamine derivatives and their antitumor activity.
The new platinum(II) complexes of beta-cyclodextrin functionalized at the primary position with ethylenediamine or with propylenediamine were synthesized and characterized by mass spectrometry, electronic spectrophotometry, and multinuclear NMR spectroscopy. Platinum(II) complexation makes the cavity more asymmetric. These complexes were tested in vitro for their cytotoxic activity. The relevance of the low activity observed regarding the interaction between the cell and the cyclodextrin cavity is discussed.


Integrative analysis of biodiversity, ecosystem services, and ecological vulnerability can facilitate improved spatial representation of nature reserves.
Understanding how to identify priority conservation areas for biodiversity and ecosystem services (ESs) is crucial for nature reserve (NR) optimization and regional planning. This study reports a regional assessment in Qinghai Province of China, quantifying the biodiversity and the provision of four ESs (carbon sequestration-net primary productivity (NPP), water yield, soil retention, and sandstorm prevention). The representativeness-vulnerability framework was employed to identify priority conservation areas for biodiversity and ESs, and the conservation gaps of existing NRs. The results show that the biodiversity, ES supply, and vulnerability of biodiversity and ESs to human activities present spatial heterogeneity. Except for sandstorm prevention, the high-value areas of ESs are generally in eastern or southern Qinghai. NPP, water yield, soil retention, and biodiversity are positively correlated (p < 0.01). The ten NRs in Qinghai only protected 5.59 %, 5.01 %, 4.29 %, 0.65 %, and 4.49 % of the priority conservation area for biodiversity, NPP, water yield, sandstorm prevention, and soil retention, respectively. Overall, a total of 170,932 km2 of theoretically comprehensive priority conservation areas for both biodiversity and ESs have been identified, which were mostly distributed in eastern, southern, and southeastern Qinghai. The existing NRs has notable conservation gaps (161,956 km2 accounting for 94.75 % of the targeted conservation areas) for both biodiversity and ESs. This study illuminates a strategy for strengthening both biodiversity and ESs through NR optimization, which is also applicable to other regions.


Evaluation of Se-phenyl-thiazolidine-4-carboselenoate protective activity against oxidative and behavioral stress in the maniac model induced by ouabain in male rats.
This study investigates Se-phenyl-thiazolidine-4-carboselenoate (Se-PTC) protective activity against oxidative and behavioral stress in the model of mania induced by ouabain (OUA) in male rats. The compound used was Se-PTC (50mg/kg) and the positive control LiCl (45mg/kg) was administered for intragastric route (i.g.) 30min prior to administration of OUA (10-5M). OUA was dissolved in artificial cerebrospinal fluid (aCSF) and administered at the 5μl through an intracerebroventricular (i.c.v) cannula. The pretreatment with Se-PTC was effective in preventing the increase in locomotor activity induced by OUA, however the positive control LiCl is capable to block crossing augmentation induced by OUA. Na+/K+-ATPase activity was significantly reduced in OUA group and the Se-PTC to normalize Na+/K+-ATPase activity. Pretreatment with Se-PTC protect against the increase in catalase activity and thiobarbituric acid reactive species (TBARS) content in the brain caused by OUA. Therefore, Se-PTC is effective against OUA-induced hyperactivity and alterations in brain oxidative status of rats.


Radiofrequency ablation of benign symptomatic thyroid nodules: prospective safety and efficacy study.
Radiofrequency ablation (RFA) is a relatively novel procedure in the management of benign nodular goiter. This study was conducted to evaluate the safety and efficacy of ultrasound (US)-guided percutaneous RFA for benign symptomatic thyroid nodules as an alternative to surgery. The study involved patients for whom a fine needle aspiration biopsy had proved a diagnosis of benign nodular goiter and had nodule-related symptoms such as dysphagia, cosmetic problems, sensation of foreign body in the neck, hyperthyroidism due to autonomous nodules or fear of malignancy. Percutaneous RFA was performed as an outpatient procedure under local anesthesia. The primary outcome was an evaluation of the changes in symptom scores (0-10) for pain, dysphagia and foreign body sensation at the 1st, 3rd, and 6th months after the RFA procedure. Secondary outcomes were assessing volume changes in nodules, complication rates, and changes in thyroid function status. A total of 33 patients (24% female, 76% male) and a total of 65 nodules were included into the study. More than one nodule was treated in 63.6% of the patients. We found a statistically significant improvement from baseline to values at the 1st, 3rd, and 6th months, respectively, as follows: pain scores (2.9 ± 2.7, 2.3 ± 2.01, 1.8 ± 1.7, and 1.5 ± 1.2, p 0.005), dysphagia scores (3.9 ± 2.7, 2.6 ± 1.9; 1.7 ± 1.6, and 1.1 ± 0.3, p 0.032), and foreign body sensation scores 3.6 ± 3, 2.5 ± 2.2; 1.6 ± 1.5, and 1.1 ± 0.4, p 0.002).The mean pre-treatment nodule volume was 7.3 ± 8.3 mL. There was a statistically significant size reduction in the nodules at the 1st, 3rd, and 6th months after RFA (3.5 ± 3.8, 2.7 ± 3.4, and 1.2 ± 1.7 mL, p 0.002). The volume reduction was found to be 74% at 6th months following the RFA (p 0.005). 8 patients had autonomously functioning nodules in the pre-treatment period, 50% (n: 4) became euthyroid at the 6th month after RFA. There were no complaints other than pain (12%). RFA can be an alternative treatment modality in the management of benign symptomatic thyroid nodules. The results showed that it is a safe and effective procedure.


Field-deployable, rapid diagnostic testing of saliva for SARS-CoV-2.
To safely re-open economies and prevent future outbreaks, rapid, frequent, point-of-need, SARS-CoV-2 diagnostic testing is necessary. However, existing field-deployable COVID-19 testing methods require the use of uncomfortable swabs and trained providers in PPE, while saliva-based methods must be transported to high complexity laboratories for testing. Here, we report the development and clinical validation of High-Performance Loop-mediated isothermal Amplification (HP-LAMP), a rapid, saliva-based, SARS-CoV-2 test with a limit of detection of 1.4 copies of virus per µl of saliva and a sensitivity and specificity with clinical samples of > 96%, on par with traditional RT-PCR based methods using swabs, but can deliver results using only a single fluid transfer step and simple heat block. Testing of 120 patient samples in 40 pools comprised of 5 patient samples each with either all negative or a single positive patient sample was 100% accurate. Thus, HP-LAMP may enable rapid and accurate results in the field using saliva, without need of a high-complexity laboratory.


Olfactory test performance and its relationship with the perceived location of odors.
Odors are generally perceived as arising via the nose when sniffed and as part of an orally located flavor during ingestion. The perceived location of an odor may in part be an attentional phenomenon, with concurrent oral stimulation occurring at the expense of access to the olfactory channel. Two predictions were derived from this account: (a) tasks dependent on a capacity to attend to the olfactory channel--odor discrimination and naming--should be adversely affected by oral localization; and (b) tasks not dependent upon a capacity to attend--incidental learning/recognition memory--should not. Using a procedure to generate oral localization, in which odors were presented via the nose with concurrent oral stimulation (sucrose, a viscous fluid or water), greater reported oral localization was associated with poorer odor discrimination and naming, but not with recognition memory performance. These results support the notion that attentional processes contribute to oral localization of odors by reducing the capacity to attend to the olfactory channel.


Quantifying the value of older adult-specific clinical trials: Post-lumpectomy irradiation among older adults with early-stage breast cancer.
Although there is increasing interest in conducting cancer clinical trials in older adults, the benefit of such trials is unclear. We aimed to quantify the real-world clinical and economic effects of two phase 3 trials (CALGB 9343 and PRIME II) which showed that post-lumpectomy radiation therapy (RT) improves loco-regional recurrence but makes no improvement in overall survival among older women with early-stage breast cancer (ESBC). We developed a health-transition model to quantify the incremental clinical and economic outcomes between scenarios with vs. without older adult-specific trial results from a societal perspective between 2004 and 2018. The transition probabilities in the model were mainly derived from the 10-year results of CALGB 9343. The total number of the affected patient population in the US and the change in the probability of omitting post-lumpectomy RT due to the CALGB 9343 and PRIME II results were derived from a retrospective analysis of the SEER registry data for patients with ESBC. Sensitivity analyses were conducted to calculate the 95% credible interval (CR) of the incremental clinical and economic outcomes between the two scenarios. Between 2004 and 2018, 32,936 (95% CR: 31,512, 34,357) fewer patients received post-lumpectomy RT among those aged 70 years or older diagnosed with ESBC in the US and there was a decrease cost of $419 M USD (95% CR: -$238 M, -$689 M) in scenarios with vs. without older adult-specific trial results. The difference in projected life years (1083 years, 95% CI: -2542, 7985) and QALYs (866 years, 95% CI: -2561, 7780) were not significant. At a willingness-to-pay threshold of $100 k/QALY, the probability of older adult-specific trial results generating a positive net monetary benefit was 98%. The CALGB 9343 and PRIME II trial results were associated with a substantial cost-saving in the US society. Our results suggest that older adult-specific clinical trials that demonstrate no survival benefit of an intervention in older adults could be correlated with a significant monetary benefit. Further case studies are needed for different types of older adult-specific trials to understand the value of older adult-specific trials comprehensively.


Built environment from the ancient Bali: The Balinese heritage for sustainable water management.
Custom and tradition played essential roles in developing the built environment among the Balinese Hindu society for centuries. The wisdom in managing the environment has passed through generations, as demonstrated by some ancient remnants and Old Balinese inscriptions. We observed that glorifying the mountains in this society has long been a part of protecting the hydrologic cycle. This practice even started in the pre-Hindu era, as shown by sacred megalithic features adjacent to the natural reservoir, water spring, and mountainous forest. At some point, the behavior has successfully passed through times and even developed into a more complex socio-cultural system such as subak. Nevertheless, Balinese society is now facing the threat of hydrological disasters, primarily due to a rapid change in land use. Here, we describe the importance of revealing the value behind the ancient Balinese water-management system to gain people's resilience and sustainability. Multidimensional scaling (MDS) was used to measure the sustainability index and the leverage factors affecting water tradition in Bali. We reveal that the inheritance of the Balinese people's water management tradition is generally weak in each dimension. The socio-cultural dimension score is relatively high, with a sustainability score of 71.11%, which signifies that the society still trusts their culture of water resources management to protect nature. However, the economy and ecology dimensions' score low, with sustainability scores of 56.12 and 63.34%, respectively, indicating the need for improvement in economic matters through the policy strategy. Moreover, our study also suggests that the noble value of the cultural heritage related to the water management system needs to be revitalized and disseminated to the public. Hence, the implication is not limited to conserving the natural environment and cultural heritage. It also provides a reference for the current society regarding a built environment in harmony with sustainability principles.


MKL1 defines the H3K4Me3 landscape for NF-κB dependent inflammatory response.
Macrophage-dependent inflammatory response is considered a pivotal biological process that contributes to a host of diseases when aberrantly activated. The underlying epigenetic mechanism is not completely understood. We report here that MKL1 was both sufficient and necessary for p65-dependent pro-inflammatory transcriptional program in immortalized macrophages, in primary human and mouse macrophages, and in an animal model of systemic inflammation (endotoxic shock). Extensive chromatin immunoprecipitation (ChIP) profiling and ChIP-seq analyses revealed that MKL1 deficiency erased key histone modifications synonymous with transactivation on p65 target promoters. Specifically, MKL1 defined histone H3K4 trimethylation landscape for NF-κB dependent transcription. MKL1 recruited an H3K4 trimethyltransferase SET1 to the promoter regions of p65 target genes. There, our work has identified a novel modifier of p65-dependent pro-inflammatory transcription, which may serve as potential therapeutic targets in treating inflammation related diseases.


Ruptured jejunum following Heimlich maneuver.
The Heimlich maneuver, over time, has proved to be a useful resuscitative procedure in the management of cases with airway occlusion secondary to foreign body. Medical treatments, however, can have side effects, and this maneuver is no exception. A previously unreported complication is presented, that of jejunal rupture. The proper application of the maneuver minimizes the number of side effects; however, since they do occur, it is suggested that all persons subject to this maneuver be subsequently evaluated by a physician as soon after the incident as is practicable.


Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats.
Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20mg/kg body weight, p.o) and curcumin (100mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin.


Hidden Markov models and optimized sequence alignments.
We present a formulation of the Needleman-Wunsch type algorithm for sequence alignment in which the mutation matrix is allowed to vary under the control of a hidden Markov process. The fully trainable model is applied to two problems in bioinformatics: the recognition of related gene/protein names and the alignment and scoring of homologous proteins.


Reduction of absolute monocyte counts is associated with the severity of preterm necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is characterized by a rich infiltration of macrophages in the intestines, which is derived from monocytes in the blood. The authors aimed to explore the changing trend of absolute monocyte counts (AMC) over time in NEC infants and to verify whether the reduction of AMC correlates with the severity of NEC and whether it can be used to identify infants who need surgery. The authors collected the clinical data of 66 control and 222 NEC infants. The NEC infants were divided into medical NEC (M-NEC) and surgical NEC (S-NEC). The counting of monocyte and their percentage change were compared at the time of birth, before NEC (baseline), the onset of NEC and after NEC (recovery). In addition, the same comparison was made among stages 1, 2 and 3 of Bell's staging, respectively. The authors found that the AMC in NEC infants decreased sharply at the onset. Further comparison was made between 172 cases of M-NEC and 50 cases of S-NEC. It was discovered that the AMC reduced more in S-NEC infants at onset, but it increased more at recovery. In addition, the authors found that among stage 1,2 and 3, stage 3 had the lowest AMC and the largest percentage decrease at the onset. The AMC decreases sharply in NEC infants at onset, and the degree of decline is associated with the severity of NEC. AMC is expected to be a marker of NEC and provide a reference for clinicians in the diagnosis and treatment of NEC.


Response of poly-phosphate accumulating organisms to free nitrous acid inhibition under anoxic and aerobic conditions.
The response of free nitrous acid (FNA)-adapted poly-phosphate accumulating organisms (PAOs) to FNA inhibition under aerobic and anoxic conditions was studied. Anoxic P-uptake was 1-6 times more sensitive to the inhibition compared to aerobic P-uptake. The aerobic nitrite reduction rate increased with FNA concentration, accompanied by an equivalent decrease in the oxygen uptake rate, suggesting under high FNA concentration conditions, electrons were channeled to nitrite reduction from oxygen reduction. In contrast, the nitrite reduction rate decreased with increased FNA concentration under anoxic conditions. Anaerobic metabolism of PAO under both anoxic and aerobic conditions was observed at high FNA concentrations. Growth of PAOs decreased sharply with FNA concentration and stopped completely at FNA concentration of 10 μg HNO(2)-N/L. This study, for the first time, investigated the function of nitrite/FNA in an aerobic denitrifying phosphate removal process by evaluating electron as well as energy balances, and provides explanation for FNA inhibition mechanisms.


The link between increased Desulfovibrio and disease severity in Parkinson's disease.
Parkinson's disease (PD), a progressive and incurable neurodegenerative disease, has taken a huge economic toll and medical burden on our society. Increasing evidence has shown a strong link between PD and the gut microbiome, but studies on the relationship between the gut microbiome and the severity of PD are limited. In this study, 90 fecal samples were collected from newly diagnosed and untreated patients with PD (n = 47) and matched healthy control subjects (n = 43). The 16S rRNA amplicon and shotgun metagenomic sequencing was performed, aiming to uncover the connection between the gut microbiome and disease severity in PD. The results showed that Desulfovibrio was significantly increased in PD compared to healthy controls and positively correlated with disease severity. The increase in Desulfovibrio was mainly driven by enhanced homogeneous selection and weakened drift. Moreover, through metagenome-assembled genomes (MAGs) analysis, a Desulfovibrio MAG (MAG58) was obtained which was also positively correlated with disease severity. MAG58 possesses a complete assimilatory sulfate reduction pathway and a near-complete dissimilatory sulfate reduction pathway to produce hydrogen sulfide which may influence the development of PD. Based on these results, a potential pathogenic mechanism was presented to illustrate how the increased Desulfovibrio accelerates the development of PD by producing excessive hydrogen sulfide. The present study highlighted the vital role of Desulfovibrio in the development of PD, which may provide a new target for the diagnosis and treatment of PD. KEY POINTS: • The evidence for the link between increased Desulfovibrio and disease severity in PD • A Desulfovibrio MAG was obtained which was correlated with PD • A model was presented to illustrate how increased Desulfovibrio causes PD.


Parsing depression from fatigue in patients with cancer using the fatigue symptom inventory.
A central aim in the management of cancer-related fatigue (CRF) is to identify treatable causes, such as depression. However, CRF and depression symptoms overlap and frequently co-occur, complicating diagnostic assessment. As cancer-related symptoms have been associated with more functional impairment among patients who are depressed, this study tested the ratio of fatigue interference to fatigue severity as a method for identifying depression cases. Patients who reported that interference was greater than severity were expected to show higher rates of depression as measured by self-report instrument or structured interview. A secondary analysis was conducted using data from patients who were attending a hospital thoracic oncology clinic and who completed the Fatigue Symptom Inventory (FSI) and Hospital Anxiety and Depression Scale (Sample 1, n = 86). Analyses were then replicated in a sample of diverse cancer patients who completed the FSI and a structured clinical interview for depression on presentation to a CRF clinic at the same hospital (Sample 2, n = 39). Receiver operating curve analyses supported use of the FSI interference/severity ratio in distinguishing depression cases and noncases (area under the curve: Sample 1 = 0.84, 95% confidence interval [CI] 0.74-0.94; Sample 2 = 0.87, 95% CI 0.76-0.99). With sensitivity and specificity weighted equally, the optimal cutoff was ≥ 1.0 in Sample 1 (sensitivity = 62.5%, specificity = 91.4%) and Sample 2 (sensitivity = 90.9%, specificity=85.7%). A fatigue score pattern in which interference was greater than or equal to severity predicted depression in two patient samples. This ratio may be useful for brief initial screening of depression in the context of fatigue.


Digestive and nutritional consequences of pancreatic resections. The classical vs the pylorus-sparing procedure.
Digestive and nutritional alterations are a common occurrence after pancreatic resections. The authors report the results of a multiparametric evaluation performed in a group of 26 patients submitted to total or cephalic pancreatectomy. Patients were divided into two groups according to the surgical procedure; group A (n = 13) included gastroresected patients and group B (n = 13) included those submitted to pylorus-sparing pancreatic resection. Subclinical digestive and absorptive impairment has been found in 61.5% of group A patients; the nutritional status was clinically poor in four cases from the same group. Digestive alterations have also been found in 69.2% of group B cases, but nutritional status was always satisfactory in the whole group. The more positive results obtained with the pylorus-sparing technique encourage wider adoption of this procedure.


scd knockout activates β-oxidation of fatty acids via accumulating stearic acid (18:0) and induces anorexia in zebrafish.
Stearoyl-CoA desaturase (scd) is the rate-limiting enzyme for the biosynthesis of monounsaturated fatty acids (MUFA), and it plays a critical role in regulating hepatic lipogenesis and lipid oxidation. However, its role in teleosts remains unclear. In this study, we generated scd knockout zebrafish (scd-/-) to explore the role of Scd in regulating growth and metabolism in teleosts. The results showed that scd knockout reduces hepatic lipid deposition by down-regulating the expression of lipogenesis-related genes and up-regulating the expression of lipolysis-related genes. In addition, the knockout of scd suppressed food intake and reduced body weight. Further analysis confirmed that scd knockout suppressed the feeding behavior by decreasing expression of orexigenic peptide genes and increasing expression of anorexigenic peptide genes. The high-level stearic acid (18:0) feeding experiment results showed that the accumulation of 18:0 inhibited feeding behavior, reduced food intake, decreased body weight, and increased lipid β-oxidation, which was essentially consistent with the phenotypes of scd deficiency. Taken together, our results indicate that the knockout of scd inhibited the food intake through the accumulation of 18:0. This study preliminarily reveals the role of Scd in regulating food intake of teleosts, which provides theoretical basis for the functional study of Scd.


Effects of multiepisode case-based learning (CBL) on problem-solving ability and learning motivation of nursing students in an emergency care course.
Meeting the learning needs and developing the thinking skills of nursing students in caring for injured patients with complex, emergency, and unpredictable conditions is essential. The present study aimed to compare the effects of case-based learning (CBL) with multi-episode case studies and lecture-based learning (LBL) on the perceived problem-solving ability and learning motivation of undergraduate nursing students in an emergency care course. This study was conducted with a quasi-experimental, within-subjects, pretest-posttest design. Forty-three third-year undergraduate nursing students (as a single cohort) enrolled in the fall semester were selected using convenience sampling. The theoretical course of emergency nursing was taught to them using the LBL method (control group) during the first six weeks of the semester and then using the CBL method (intervention group) during the second six weeks of the semester through multi-episode cases in five steps. Outcomes including perceived problem-solving ability and learning motivation were measured using the Problem-Solving Inventory (PSI) and the Instructional Materials Motivation Scale (IMMS). There was a significant difference (P < 0.001) between the changes in the total mean score of perceived problem-solving ability and its subscales on the three measurement points, i.e. before lectures (pre-test), after lectures (mid-term test) and after CBL (final test). There was a significant difference between the LBL and CBL groups in terms of the students' total learning motivation score (t = 16.91, P = 0.000) and all its subscales after the CBL intervention. The study suggests that the CBL method applied through multi-episode cases is an effective approach to improving the perceived problem-solving ability and learning motivation of nursing students.


Acute Phlegmonous Esophagogastritis Causing Respiratory Distress.
Phlegmonous esophagogastritis is an extremely rare condition characterized by diffuse inflammation of the upper gastrointestinal tract, sparing the mucosa. Patients can present with an acute onset of symptoms, and computed tomography scans can show diffusely edematous wall with intramural low attenuation surrounded by ring enhancement. Here we report such a case of a man who presented with central chest pain and breathing difficulty. The patient developed respiratory distress due to compression of trachea by the edematous esophagus.


Keeping the clock running: The microbiome as a pivotal timekeeper.
Research of animal microbiomes is demonstrating that these host-microbe partnerships are on a profound circadian rhythm. Recently in Cell, Brooks et al. (2021) report that host rhythms drive behaviors of specific microbiome members, which orchestrate a coordination of the innate immune system with the circadian clock.


Ion-exchange high-performance liquid chromatographic studies on sulphydryl-catalysed structural alterations of bovine mercaptalbumin.
The N-A isomerization (the intramolecular SH/S-S exchange reaction) of bovine mercaptalbumin (BMA) in alkaline medium was studied by using ion-exchange high-performance liquid chromatography (HPLC) and moving-boundary electrophoresis. Results obtained by ion-exchange HPLC on the N-A isomerization of BMA were consistent with those by moving-boundary electrophoresis and showed at least two kinds of the A-form, A1 and A2, indicating that the N-A isomerization is a multi-step reaction. The rate of the N-A isomerization was strongly suppressed in [2H]water solution. The suppression by [2H]water might support the current view that intra- and intermolecular hydrophobic and/or hydrogen bonds are strengthened in [2H]water.


Classifying G-protein coupled receptors with bagging classification tree.
G-protein coupled receptors (GPCRs) play a key role in different biological processes, such as regulation of growth, death and metabolism of cells. They are major therapeutic targets of numerous prescribed drugs. However, the ligand specificity of many receptors is unknown and there is little structural information available. Bioinformatics may offer one approach to bridge the gap between sequence data and functional knowledge of a receptor. In this paper, we use a bagging classification tree algorithm to predict the type of the receptor based on its amino acid composition. The prediction is performed for GPCR at the sub-family and sub-sub-family level. In a cross-validation test, we achieved an overall predictive accuracy of 91.1% for GPCR sub-family classification, and 82.4% for sub-sub-family classification. These results demonstrate the applicability of this relative simple method and its potential for improving prediction accuracy.


A bovine papillomavirus type 1-encoded modulator function is dispensable for transient viral replication but is required for establishment of the stable plasmid state.
A bovine papillomavirus (BPV) type 1-encoded function (M) which is a negative regulator of viral plasmid replication has been described elsewhere (Berg et al. Cell, in press; Roberts and Weintraub, Cell, in press). We report here that expression of M, which is a repressor of transient BPV replication and is not required as a positive factor in these assays, is required for the establishment of the viral genome as a stable nuclear plasmid. This function is encoded in part by the 5' portion of the BPV E1 open reading frame, whereas the 3' part of this open reading frame encodes a positive replication function (R). The R function is required for early replication events. We used transient replication assays to define the phenotypes of mutants in both the R and M genes and complementation tests to show that R and M define two separate genes. We showed that R- and M- mutants could also complement each other in stable assays. In cotransfection experiments, M- mutants had a lethal effect on the growth of G418-resistant colonies, and in addition their morphological transformation efficiencies were reduced. The rare colonies which did appear contained the mutant DNA integrated into the cellular genome. R- mutants transformed with wild-type efficiency, and the mutant DNA was also found integrated. When cotransfected, R- and M- mutants could each be established as unrearranged plasmids.


Whole-body single-photon emission computed tomography using dual, large-field-of-view scintillation cameras.
A whole-body single-photon emission computed tomography system (SPECT) consisting of two large-field-of-view scintillation cameras mounted on a rotatable gantry, a minicomputer and a display station has been designed, constructed and evaluated. In its usual mode of operation, eleven contiguous transverse sections, each 12.5 or 25 mm thick, are reconstructed from projection data acquired during a single, continuous 360 degree rotation lasting from 2 to 22 min. A generalised filtered and weighted backprojection algorithm is used to reconstruct data obtained with conventional parallel-hole collimators in the case of body scanning, or with specially designed fan beam collimators in the case of centrally positioned organs. A simple, yet effective, correction is used to compensate for the effects of gamma ray attenuation within the patient. In addition to providing transverse section images, the system is capable of simultaneous acquisition of opposed conventional scintigrams, the reconstruction of longitudinal section images, and the acquisition of gated cardiac transverse sections. Resolutions in the reconstructed images are typically 15 mm for body scans and 11 mm for brain scans, with only slight variations in sensitivity and resolution within the image. Phantoms and clinical data demonstrate that the SPECT system generates high quality section images while maintaining most of the flexibility of normal scintillation cameras, with the added advantage of dual heads.


Monocyte deactivation in severe human sepsis or following cardiopulmonary bypass.
We investigated the specificity for gram-negative stimuli as well as the contribution of signal transduction pathways for leukocyte hyporesponsiveness in sepsis or following cardiopulmonary bypass (CPB). Whole blood of nine patients undergoing CPB and 25 patients with severe sepsis was stimulated ex vivo with LPS (E. coli O111:B4) or with Staphylococcus aureus Cowan strain I (SAC-I) lysate in the absence or presence of inhibitors of protein kinase C (PKC), protein-tyrosine kinase (PTK), or protein-tyrosine phosphatase (PTP). Both toxins stimulated a TNF-alpha response through PTK signaling. Although suppression of the cytokine response was similar for LPS and SAC-I after CPB, it was significantly more pronounced for SAC-I in sepsis. Inhibition of PTP failed to increase TNF-alpha upon LPS, whereas a moderate increase was observed with SAC-I. Impaired TNF-alpha responses occur in sepsis and after CPB. Although this has primarily been reported for gram-negative stimuli, our data suggest that this is even more pronounced for gram-positive stimuli in severe sepsis. Although PTK was the predominant signaling pathway, inhibition of PTP only partially restored the TNF-alpha response to SAC-I. Our results suggest that cellular mechanisms underlying monocyte deactivation are different in sepsis or following CPB and are discriminate for gram-positive and gram-negative toxins.


Actigraphy in patients with seasonal affective disorder and healthy control subjects treated with light therapy.
Abnormalities of the circadian rest-activity cycle are hypothesized to accompany the clinical picture of seasonal affective disorder (SAD). The purpose of this study was to investigate if bright light therapy (BLT) is able to reverse these disturbances. Seventeen SAD outpatients and 17 sex- and age-matched healthy control subjects were treated with BLT administered in the morning for 4 weeks. Activity levels were measured with wrist actigraphy. SAD patients had 33% lower total (p = .031) and 43% lower daylight activity (p = .006) in week 1 compared with control subjects. The relative amplitude of the sleep-wake cycle was attenuated by 6% in patients (p = .025); they were phase delayed by 55 minutes (p = .023) and had significantly lower sleep efficiency (p = .030). Total (p = .002) and daylight activity (p = .001) increased after 4 weeks of treatment in SAD patients. Moreover, BLT led to increase of relative amplitude (p = .005), advance of delayed rhythms (p = .036), and improved sleep efficiency (p = .011) in patients. Intradaily stability, measuring the strength of coupling of the rhythm to external zeitgebers, increased by 9% both in patients and healthy control subjects (p = .032). Treatment with BLT normalizes disturbed activity patterns and restores circadian rhythms in SAD patients. BLT might also stabilize the circadian rhythm in nondepressed individuals during the fall-winter season.


Surgical management of cirsoid aneurysms.
Cirsoid aneurysms (arteriovenous fistulas) of the scalp are rare lesions. They are infrequently encountered in neurosurgical practice. These lesions are difficult to manage because of their complex vascular anatomy, high shunt flow and cosmetic disfigurement. We report our experience in the surgical management of these lesions. We treated 11 patients with cirsoid aneurysms surgically. All except one patient were males who were in the second and third decades of life. History of trauma was present in 6 patients. In one patient, the lesion had been present since birth. Occipital and frontal regions were the sites commonly involved. Superficial temporal, occipital and posterior auricular arteries were the most frequent feeding arteries. The size ranged from 3 cms to 12 cms. Following investigations were done: CT, MRI, MRA, angiography and Doppler studies. Excision of the lesion was done in 8 patients and en bloc resection of the lesion with the scalp with reconstruction was done in the remaining three. One among the three patients who underwent en bloc resection had undergone prior surgery. None of the patients underwent preoperative endovascular treatment. One patient had undergone intralesional injection of sclerosing agents twice. Superficial scalp necrosis occurred in two patients but was treated successfully. All the patients except one had good cosmetic results and there was no recurrence during an average follow up of 18 months. Surgical excision with good cosmetic results is feasible in patients with cirsoid aneurysms.


[Acebutolol: experience with its use in ambulatory management of arterial hypertension].
32 patients (13 women and 19 men) with slight to severe hypertension were treated during an open medium term study with acebutolol, a beta-antagonist which is cardioselective and at the same time has an intrinsic sympatheticomimetic effect. The average daily dose of the drug was 743 mg. In about 69% of the cases results were excellent or good, in 21% fair and in the remaining 9% no improvement was observed. Average cardiac frequency was 93 beats per minute before treatment started and about 90 days later this had fallen to 70.6 beats per minute. Almost no side effects were observed.


Etanercept compared to intraarticular corticosteroid injection in rheumatoid arthritis: double-blind, randomized pilot study.
To compare etanercept (anti-tumor necrosis factor-α) with intraarticular (IA) corticosteroid injections to treat rheumatoid arthritis (RA). Patients with RA who had persistent monoarthritis received etanercept or IA corticosteroid injections. Efficacy was compared at Weeks 4 and 24. Thirty-four patients were included (8 dropped out). Mean age was 58.8 years. No difference between groups was found at Weeks 4 or 24, but both groups showed significant improvement at Weeks 4 and 24 compared to baseline. Etanercept and IA steroid injections resulted in significant improvement at Week 4 that persisted to Week 24. There was no significant difference in outcome between the groups.


[Effect of formaldehyde on energy metabolism in postnatal rat cortex neurons in culture].
The mechanism of the effect of formaldehyde on CNS which is much concerned to formaldehyde poisoning was studied. In the present study, incubation of postnatal rat cortex neurons in culture with formaldehyde at 1, 2, 4, 8 mg/L (medium) was carried out to evaluate the effect of formaldehyde on energy metabolism. The result of cytochemistry showed a significant down-regulation of cytochrome oxidase activity after consecutive formaldehyde treatment for 4 hours compared with the control (P < 0.01), the significant dosage-response relationship was also observed (R value is - 0.92, P < 0.01). The result demonstrates that excessive exposure of formaldehyde can decrease cytochrome oxidase activity in cortex neurons which indicates energy metabolism will be decreased and therefore normal physiology function would be damaged.


Worrying yourself sick? Association between pre-eclampsia onset and health-related worry in pregnancy.
Psychosocial stress may influence pregnancy health. We examined the relationship between worry about pregnancy health and pre-eclampsia. General stress, mental health, and self-reported pregnancy health worry were measured in a study of 10,037 U.S. nulliparous women. Logistic regression found a dose-response relationship between first trimester pregnancy-health worry and subsequent pre-eclampsia onset, controlling for health history (Beta = 0.40, SE = 0.09, P < 1 × 10-6). A machine learning regularized regression found a significant relationship between worry and pre-eclampsia onset, controlling for all other potential predictors of pre-eclampsia measured at baseline, suggesting that worry plays a unique role in pre-eclampsia risk.


In pursuit of a safe Canadian healthcare system.
This paper provides evidence that Canada's healthcare system is not as safe as it needs to be, and suggests ways to make it safer. Healthcare leaders must recognize that patient safety is indistinguishable from the delivery of high quality, affordable healthcare, and they must become more knowledgeable about the extent of the patient safety problem in Canada. The creation of a Patient Safety Board, modelled after Canada's Transportation Safety Board, will provide the authority healthcare leaders require to reduce medical errors. Without a national Patient Safety Board we cannot efficiently and effectively identify, quantify and address medical errors in Canada. This paper also urges healthcare leaders to recognize that a fundamental tool in improving patient safety is the electronic health record (EHR). Return on investment data for a national EHR strategy are presented. The author focuses on three EHR initiatives: outpatient electronic prescribing; in-patient computerized physician order entry; and home-based diabetes disease management. Potential net savings to Canada from these three EHR initiatives alone approach $2 billion annually. We must accelerate our EHR investment. Coordinated national EHR initiatives will cost less, save lives and prevent harm when compared to the status quo. These initiatives will also provide the foundation for transforming our healthcare system and will assist in building a better-educated, healthier and therefore more economically competitive nation.


Cellular and humoral immune responses to mycobacterial heat shock protein-65 and its human homologue in Takayasu's arteritis.
Expression of heat shock protein (HSP)-65 as well as infiltration of T-cells in arterial lesions and raised levels of circulating antibodies against mycobacterial HSP65 (mHSP65) led us to the concept that mHSP65 or its human homologue (hHSP60) might be involved in the etiopathogenesis of Takayasu's arteritis (TA). Therefore, we investigated mHSP65 and hHSP60 reactive peripheral blood T-cell subsets by BrdU incorporation assay and flow cytometry as well as investigating the different isotypes of anti-mHSP65 and hHSP60 antibodies by ELISA. Eighty-four percent (22/26) of the TA patients were observed to show T-cell proliferation to mHSP65 and hHSP60 whereas only 16% (3/18) healthy controls showed such proliferation (P <0.001). Both HSPs induced proliferation of exclusively CD4+ T-cells and not CD8+ T-cells. We also observed a significantly higher prevalence of only the IgG isotype reactive to mHSP65 and hHSP60 in TA as compared to HC (mHSP65: 92% TA versus 11% HC, P <0.0001 and hHSP60: 84% versus 22%, P <0.001). Our data show a significant correlation between mHSP65 and hHSP60 reactive T-cells (CD3+: r=0.901; CD4+: r=0.968) as well as anti-mHSP65 and anti-hHSP60 IgG antibodies (r=0.814) suggesting an infection induced autoimmunity in TA, possibly induced by molecular mimicry between mHSP65 and hHSP60 or other tissue specific antigens.


Hydrothermal synthetic mercaptopropionic acid stabled CdTe quantum dots as fluorescent probes for detection of Ag⁺.
Mercaptopropionic acid (MPA) capped CdTe quantum dots (QDs) with particle size 3 nm have been successfully synthesized in aqueous medium by hydrothermal synthesis method. And the effects of different metal ions on MPA capped CdTe QDs fluorescence were studied using fluorescence spectrometry. The results demonstrated that at the same concentration level, Ag(+) could strongly quench CdTe QDs fluorescence, and the other metal ions had little effect on CdTe QDs fluorescence except Cu(2+). On the basis of this fact, a rapid, simple, highly sensitive and selective method based on fluorescence quenching principle for Ag(+) detection in aqueous solution was proposed. Under optimal conditions, the quenched fluorescence intensity (F(0)-F) increased linearly with the concentration of Ag(+) ranging from 4 × 10(-7) to 32 × 10(-7)mol L(-1). The limit of detection for Ag(+) was 4.106 × 10(-8)mol L(-1). The obtained plot of F(0)/F versus [Ag(+)] was an upward curvature, concave towards the y-axis, rather than a straight line. The modified form of the Stern-Volmer equation was third order in Ag(+) concentration. According to the modified Stern-Volmer equation, it can be inferred that dynamic quenching and static quenching simultaneously occurred when Ag(+) interacted with MPA capped CdTe QDs. At the same time other factors might also influence the quenching process. Based on this study, hydrothermal synthesized MPA capped CdTe QDs with particle size 3 nm may be used as a novel fluorescence probe to quantificationally and selectively detect Ag(+).


Risk of septic spread during surgical management of digital flexor tendon sheath phlegmon: Exsanguination by mechanical compression versus simple elevation.
This study aimed to demonstrate that there was no risk of extension of infection in performing mechanical exsanguination before inflating the tourniquet for surgical treatment of digital flexor tendon sheath phlegmon. The series comprised 96 patients, with a mean age of 47 years (range, 18-87 years) and 37 women. Group I included 47 patients in whom exsanguination was performed with a Velpeau band before inflating the pneumatic tourniquet at the root of the limb. In Group II, which included 49 patients, the tourniquet was inflated after simple elevation of the limb. Six patients underwent revision surgery for recurrence or osteoarticular complications: 4 (8.5%) in Group I and 2 (4.1%) in Group II, the difference between two groups being non-significant (p = 0.6378). In conclusion, mechanical exsanguination before inflating the tourniquet did not incur risk of complications in surgical management of digital flexor tendon sheath phlegmon.


Rho Kinases in Embryonic Development and Stem Cell Research.
The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK's versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.


Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis.
Liver cirrhosis is associated with a high prevalence of pigmentary cholelithiasis. The major compound of pigment gallstones is unconjugated bilirubin (UCB) in the form of calcium bilirubinate salts or a black pigment polymer. Most of UCB in bile derives from enzymic or non-enzymic hydrolysis of mono- or diconjugated bilirubin. Changes in the relative ratios between these two bilirubin species have been associated with pigment gallstones. It has also been shown that UCB solubilization in bile depends on its interaction with bile salts. In order to clarify the factors predisposing cirrhotic patients to pigment stone formation, we measured UCB, monoconjugated bilirubin (MCB) and diconjugated bilirubin (DCB) in duodenal bile of 15 patients with cirrhosis, ten patients with chronic active hepatitis (CAH) and ten normal subjects, we also analyzed their relationships with lipids. In cirrhotic patients, the MCB concentration in bile was significantly (p less than 0.05) higher than in normal subjects and was correlated with the severity of the disease. Bile salts and lecithin concentrations were significantly lower in cirrhosis (p less than 0.005 vs. CAH or normals). Cirrhotic patients have a bile salts/UCB molar ratio which is one third that of CAH patients or normal subjects (p less than 0.01). No differences were found between CAH patients and controls in each of the parameters tested. In conclusion, we propose that the very low BS/UCB molar ratio and the very high biliary content in MCB represent two independent physico-chemical factors predisposing cirrhotic patients to pigmentary cholelithiasis.


Psychoanalytic therapy and narrative research interviewing: some reflections.
This article focuses on approaches to qualitative research interviewing that draw direct inspiration from psychoanalytic therapy. The reflective discussion piece provides a critical spotlight on this method to promote reflection and ethical application. To provide clarity regarding the meaning of psychoanalytically informed, psycho-social research and the interpretive nature of qualitative interviews and of therapy, and to reflect on nurse researchers' partiality for using quasi-dynamic interpretative comments and the sharing of formulations in interviews. The authors review relevant literature, and comment on the apprehension and uncertainty researchers may experience with this type of research approach. Researchers should consider how they conduct themselves as interviewers and what to share of the analysis of participants' accounts based on the specifics of the research, including their or their team's experience of conducting psychotherapy and their and participants' expectations about what may be therapeutic about interviews. Psychoanalytically informed research interviewing should be used in a reflective way by nurse researchers with attention paid to the limitations and possibilities of parallels between psychotherapeutic and research interview dialogue.


Blood pressure and muscle sympathetic nerve activity are associated with trait anxiety in humans.
Chronic anxiety is prevalent and associated with an increased risk of cardiovascular disease. Prior studies that have reported a relationship between muscle sympathetic nerve activity (MSNA) and anxiety have focused on participants with anxiety disorders and/or metabolic syndrome. The present study leverages a large cohort of healthy adults devoid of cardiometabolic disorders to examine the hypothesis that trait anxiety severity is positively associated with resting MSNA and blood pressure. Resting blood pressure (BP) (sphygmomanometer and finger plethysmography), MSNA (microneurography), and heart rate (HR; electrocardiogram) were collected in 88 healthy participants (52 males, 36 females, 25 ± 1 yr, 25 ± 1 kg/m2). Multiple linear regression was performed to assess the independent relationship between trait anxiety, MSNA, resting BP, and HR while controlling for age and sex. Trait anxiety was significantly correlated with systolic arterial pressure (SAP; r = 0.251, P = 0.018), diastolic arterial pressure (DAP; r = 0.291, P = 0.006), mean arterial pressure (MAP; r = 0.328, P = 0.002), MSNA burst frequency (BF; r = 0.237, P = 0.026), and MSNA burst incidence (BI; r = 0.225, P = 0.035). When controlling for the effects of age and sex, trait anxiety was independently associated with SAP (β = 0.206, P = 0.028), DAP (β = 0.317, P = 0.002), MAP (β = 0.325, P = 0.001), MSNA BF (β = 0.227, P = 0.030), and MSNA BI (β = 0.214, P = 0.038). Trait anxiety is associated with increased blood pressure and MSNA, demonstrating an important relationship between anxiety and autonomic blood pressure regulation.NEW & NOTEWORTHY Anxiety is associated with development of cardiovascular disease. Although the sympathetic nervous system is a likely mediator of this relationship, populations with chronic anxiety have shown little, if any, alteration in resting levels of directly recorded muscle sympathetic nerve activity (MSNA). The present study is the first to reveal an independent relationship between trait anxiety, resting blood pressure, and MSNA in a large cohort of healthy males and females devoid of cardiometabolic comorbidities.


Copy number variation in subjects with major depressive disorder who attempted suicide.
Suicide is one of the top ten leading causes of death in North America and represents a major public health burden, particularly for people with Major Depressive disorder (MD). Many studies have suggested that suicidal behavior runs in families, however, identification of genomic loci that drive this efffect remain to be identified. Using subjects collected as part of STAR D, we genotyped 189 subjects with MD with history of a suicide attempt and 1073 subjects with Major Depressive disorder that had never attempted suicide. Copy Number Variants (CNVs) were called in Birdsuite and analyzed in PLINK. We found a set of CNVs present in the suicide attempter group that were not present in in the non-attempter group including in SNTG2 and MACROD2 - two brain expressed genes previously linked to psychopathology; however, these results failed to reach genome-wide signifigance. These data suggest potential CNVs to be investigated further in relation to suicide attempts in MD using large sample sizes.


Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
Niacin reduces coronary heart disease morbidity and mortality when taken either alone or in combination with statins; however, the incremental impact of adding niacin to background statin therapy is unknown. This was a double-blind randomized placebo-controlled study of once-daily extended-release niacin (1000 mg) added to background statin therapy in 167 patients (mean age 67 years) with known coronary heart disease and low levels of high-density lipoprotein cholesterol (HDL-C; <45 mg/dL). The primary end point was the change in common carotid intima-media thickness (CIMT) after 1 year. Baseline CIMT (0.884+/-0.234 mm), low-density lipoprotein cholesterol (89+/-20 mg/dL), and HDL-C (40+/-7 mg/dL) were comparable in the placebo and niacin groups. Adherence to niacin exceeded 90%, and 149 patients (89.2%) completed the study. HDL-C increased 21% (39 to 47 mg/dL) in the niacin group. After 12 months, mean CIMT increased significantly in the placebo group (0.044+/-0.100 mm; P<0.001) and was unchanged in the niacin group (0.014+/-0.104 mm; P=0.23). Although the overall difference in IMT progression between the niacin and placebo groups was not statistically significant (P=0.08), niacin significantly reduced the rate of IMT progression in subjects without insulin resistance (P=0.026). Clinical cardiovascular events occurred in 3 patients treated with niacin (3.8%) and 7 patients treated with placebo (9.6%; P=0.20). The addition of extended-release niacin to statin therapy slowed the progression of atherosclerosis among individuals with known coronary heart disease and moderately low HDL-C.


X-ray- and TEM-induced mitotic recombination in Drosophila melanogaster: unequal and sister-strand recombination.
Twin mosaic spots of dark-apricot and light-apricot ommatidia were found in the eyes of wa/wa females, of wa males, of females homozygous for In(1)sc4, wa and of attached-X females homozygous for wa. The flies were raised from larvae which had been treated with 1630 R of X-rays at the age of 48-52 hours. An additional group of wa/wa females and wa males came from larvae that had been fed with triethylene melamine (TEM) at the age of 22-24 hours. The twin spots apparently were the result of induced unequal mitotic recombination, i.e. from unequal sister-strand recombination in the males and from unequal sister-strand recombination as well as, possibly, unequal recombination between homologous strands in the females. That is, a duplication resulted in waDp wa/wa dark-apricot ommatidia and the corresponding deficiency in an adjacent area of wa/Df wa light-apricot ommatidia. In an additional experiment sister-strand mitotic recombination in the ring-X chromosome of ring-X/rod-X females heterozygous for w and wco is believed to be the cause for X-ray induced single mosaic spots that show the phenotype of the rod-X marker.


CBA/N X-linked B-cell defect prevents NZB B-cell hyperactivity in F1 mice.
NZB mice and their F1 hybrids produce excessive polyclonal IgM and autoantibodies of both IgM and IgG classes. CBA/N mice and CBA/N-mothered F1 males fail to make antibody to many T-independent antigens and have low levels of serum IgM; further, these mice lack a population of splenic B cells characterized by a low-to-intermediate density of surface IgM. We have studied male CBA/N, NZB, CBA/N X NZB, NZB X CBA/N, and CBA/J mice; female CBA/N X NZB mice; and males of several control crosses of NZB and CBA/N mice. We have found that the CBA/N X-linked defect of T-independent immune response is completely expressed in CBA/N X NZB mice. In marked contrast to NZB mice and to NZB mice and to NZB F1 hybrids bearing at least one normal X chromosome, the CBA/N X NZB males failed to respond to two T-independent antigens, had small numbers of splenic IgM-producing cells, barely detectable splenic IgM production, and splenic B-cell surface-Ig patterns resembling those of CBA/N mice. These data suggest that the NZB B-cell abnormality resulting in excessive IgM production occurs almost exclusively in that population of B cells affected by the CBA/N X chromome-linked defect. Preliminary studies suggest that CBA/N X chromosome retards the spontaneous development of anti-erythrocyte autoantibodies in CBA/N X NZB males. Castration, known to accelerate autoimmune disease in certain NZB F1 males, appears to have no influence on the immune functions examined in this study.


The C-allele of tissue inhibitor of metalloproteinases 2 is associated with increased magnitude of QT dispersion prolongation in elderly Chinese - 4-year follow-up study.
Matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) trigger the signal cascade instigating cardiac remodeling and fibrosis, which lead to changes of repolarization variables. We investigate the influence of MMP9-1562 C/T and TIMP2-418 G/C gene polymorphisms on repolarization parameters including QT dispersion (QTd) and the peak and the end of the T wave interval (Tpe) in a prospective cohort. Of 1500 people screened, 106 elderly Chinese without organic heart disease were recruited and received electrocardiography at the baseline, second and 4th year follow-ups. The QTc (corrected QT), QTd, QTc dispersion (QTcd) and Tpe were manually calculated. Age was 72.7+/-4.1 y (range 62-81 y). QTd, QTcd and Tpe were significantly prolonged (all p <0.001 at the 2nd and 4th year). At the 4th year the magnitude of QTd prolongation but not Tpe was significantly higher in subjects carrying the TIMP2 C-allele than non C-allele carriers (p=0.033) as well as QTcd (p=0.010). This association was still significant in multivariate analyses (p=0.012 and p=0.003 for QTd and QTcd, respectively) but not in MMP9 genotype. The elderly Chinese with TIMP2 C-allele have higher magnitude of QTd and QTcd prolongation.


Preferred diffusion paths for copper electromigration by in situ transmission electron microscopy.
Ionic transport in the reverse direction of an electric field is caused by momentum transfer from free electrons to metal ions, i.e., electromigration (EM), which is a critical factor leading to copper (Cu) interconnect failure in integrated circuits under extreme operating conditions. We investigated Cu self-diffusion paths under electrical bias using in situ transmission electron microscopy (TEM). An electric current was applied to multigrain Cu lines in the TEM instrument for durations of up to the order of 104s to trace EM-induced Cu movement around voids and hillocks. Combining this approach with scanning nanobeam diffraction, we observed that high-angle grain boundaries exposed to the free surface are the most favored paths for Cu EM, rather than a specific orientation within the grain. On hillocks of accumulated Cu atoms, we directly observed grain growth, accompanied by the formation of Σ7 high-mobile and Σ3 twin coincidence site lattice boundaries for effective growth. This study provides insight into the EM mechanism to improve the reliability of metal interconnect design.


[Clinical experiences with polyurethane soft foam fillings for retinal surgery].
Polyurethane sponge was used for scleral buckling in 165 patients suffering from retinal detachment. This material showed good tissue compatibility and the therapeutic procedure was successful in 90% of the cases thus treated. In 10 patients polyurethane was used with success for cerclage. Postoperative complications observed were infection of the sponge in one patient and conjunctival dehiscence in two. Polyurethane sponge is less elastic than silicone sponge but has the same scleral buckling effect.


Defense Styles, Academic Procrastination, Psychological Wellbeing, and Approaches to Learning: A Person-Oriented Approach.
This study investigates the relationships among defense styles, academic procrastination, psychological well-being, and approaches to learning. The questionnaires Defense Style Questionnaire-88, Procrastination Assessment Scale Questionnaire, Flourishing Scale, and HowULearn are used to measure the aforementioned variables, respectively. Social science students (N = 628) take part in the study. A hierarchical cluster analysis is used for clustering students into homogeneous groups. Three groups of students are identified: "psychologically stable and adaptive" (n = 285), "immature and unstable at risk" (n = 134), and "defensively dissonant" (n = 209) students. A decision tree model is used with the grade point average (GPA) score as an outcome variable to further examine interactions between the three clusters and the years of study on GPA. "Psychologically stable and adaptive" students report the highest GPA. Our findings bridge mental health variables with learning shedding light on our understanding of the use of defense styles when it comes to learning.


Tolerance with low dose intravenous nitroglycerin therapy in acute myocardial infarction.
The question of vascular tolerance was examined in 154 patients with acute myocardial infarction (64 anterior, 90 inferior) who were treated with prolonged low dose intravenous nitroglycerin in a recent randomized placebo-controlled study. The dose of nitroglycerin was carefully titrated to decrease mean blood pressure by 10% in normotensive patients and 30% in hypertensive (blood pressure greater than 140/90 mm Hg) patients, but not less than 80 mm Hg. Tolerance was defined as the need to increase the dose to maintain this hemodynamic effect. It was labelled "true" if chest pain was absent and "apparent" if chest pain was present. Group analysis of dose, pain scores, hemodynamic, 2-dimensional echocardiographic and clinical parameters monitored serially before and after therapy indicated benefit with nitroglycerin over placebo despite equalizing of blood pressures after 10 hours. Reversal of blood pressures and volumes after discontinuing nitroglycerin suggested lack of significant tolerance. However, detailed individual analysis suggested significant hemodynamic tolerance in 37 patients (24%), both in the true tolerance (12%) and apparent tolerance (12%) subgroups. Tolerance appeared early, requiring the dose to be increased by 30 +/- 39 micrograms/min within 11 +/- 9 hours. The dose was greater (p less than 0.001) in the tolerance than in the no tolerance subgroup, both before (60 vs 27 micrograms/min) and after (90 vs 38 micrograms/min) 10 hours. Tolerance blunted the beneficial effect on infarct size, but positive effects on function, topography and complications persisted.


Treatment and Prognosis of Fibrolamellar Hepatocellular Carcinoma: a Systematic Review of the Recent Literature and Meta-analysis.
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare disease and current efforts are focused on the prognosis and on the development of efficient and specific treatments. This study aimed to review the latest evidence regarding FL-HCC treatment and prognosis. A systematic review of the literature over the past 10 years regarding FL-HCC, and meta-analysis of 1-, 3-, and 5-year overall survival (OS) comparing FL-HCC and conventional HCC were performed. Overall, 1567 articles were screened, of them 21 were selected for the systematic review, and 6 for meta-analysis. Twenty-one studies included a total of 2168 patients with FL-HCC, with a median age ranging from 11 to 56 years. The majority of patients underwent surgical resection or liver transplantation. After a median follow-up ranging from 24 to 58 months, 1-year OS was 67-100% and 5-year OS was 28-65%. A total of 743 patients with FL-HCC and 163,472 with conventional HCC were included in the meta-analysis. There was a significantly improved 1-, 3-, and 5-years OS in the FL-HCC group compared to the conventional HCC group, although high heterogeneity was found. When excluding population-based studies, and including 96 FL-HCC and 221 conventional HCC patients, the heterogeneity was low, and the meta-analysis showed a significantly longer 1-year OS in patients with FL-HCC than conventional HCC; however, there were no differences at 3- and 5-years OS. Surgical resection for FL-HCC is currently the only curative treatment available. FL-HCC is plagued by high-recurrence rates and poor long-term outcomes which may be related to the absence of specific treatment for advanced and recurrent disease.


Induction of Inhibitory Synaptic Plasticity Enhances Tonic Current by Increasing the Content of α5-Subunit Containing GABAA Receptors in Hippocampal Pyramidal Neurons.
It is known that besides synaptic inhibition, there is a persistent component of inhibitory drive mediated by tonic currents which is believed to mediate majority of the total inhibitory charge in hippocampal neurons. Tonic currents, depending on cell types, can be mediated by a variety of GABAA receptor (GABAAR) subtypes but in pyramidal neurons, α5-subunit containing receptors were found to be predominant. Importantly, α5-GABAARs were implicated in both inhibitory and excitatory synaptic plasticity as well as in a variety of cognitive tasks. In the present study, we asked whether the protocol that evokes NMDAR-dependent GABAergic inhibitory long-term potentiation (iLTP) also induces the plasticity of tonic inhibition in hippocampal pyramidal neurons. Our whole-cell patch-clamp recordings revealed that the induction of this type of iLTP is associated with a marked increase in tonic current. By using the specific inverse agonist of α5-containing GABAARs (L-655,709) we provide evidence that this plastic change in tonic current is correlated with an increased proportion of this type of GABAARs. On the contrary, the iLTP induction did not affect the tonic current potentiated by THIP, indicating that the pool of δ subunit-containing GABAARs receptors remains unaffected. We conclude that the α5-GABAARs-dependent plasticity of tonic inhibition is a novel dimension of the neuroplasticity of the inhibitory drive in the hippocampal principal neurons. Overall, α5-containing GABAARs emerge as key players in a variety of plasticity mechanisms operating over a large span of time and spatial scales.