Biological effects of polycyclic aromatic hydrocarbons (PAH) and their first metabolic products in in vivo exposed Atlantic cod (Gadus morhua).
The monitoring of the presence of polycyclic aromatic hydrocarbons (PAH) in the aquatic environment is a worldwide activity since some of these compounds are well-established carcinogens and mutagens. Contaminants in this class are in fact regarded as priority hazardous substances for environmental pollution (Water Framework Directive 2000/60/EC). In this study, Atlantic cod (Gadus morhua) was selected to assess in vivo effects of two PAH and their first metabolic products, namely, the corresponding trans-dihydrodiols, using biological markers. Fish were exposed for 1 wk to a single PAH (naphthalene or chrysene) and its synthetic metabolites ((1R,2R)-1,2-dihydronaphthalene-1,2-diol and (1R,2R)-1,2-dihydrochrysene-1,2-diol) by intraperitoneal injection in a continuous seawater flow system. After exposure, PAH metabolism including PAH metabolites in bile and ethoxyresorufin O-deethylase (EROD) activity, oxidative stress glutathione S-transferases (GST) and catalase (CAT) activities, and genotoxicity such as DNA adducts were evaluated, as well as general health conditions including condition index (CI), hepatosomatic index (HSI), and gonadosomatic index (GSI). PAH metabolite values were low and not significantly different when measured with the fixed-wavelength fluorescence screening method, while the gas chromatography-mass spectroscopy (GC-MS) method showed an apparent dose response in fish exposed to naphthalene. DNA adduct levels ≥0.16 × 10(-8) relative adduct level (RAL) were detected. It should be noted that 0.16 × 10(-8) RAL is considered the maximal acceptable background level for this species. The other biomarkers activities of catalase, GST, and EROD did not display a particular compound- or dose-related response. The GSI values were significantly lower in some chrysene- and in both naphthalene- and naphthalene diol-exposed groups compared to control.


Edge Delamination of Monolayer Transition Metal Dichalcogenides.
Delamination of thin films from the supportive substrates is a critical issue within the thin film industry. The emergent two-dimensional, atomic layered materials, including transition metal dichalcogenides, are highly flexible; thus buckles and wrinkles can be easily generated and play vital roles in the corresponding physical properties. Here we introduce one kind of patterned buckling behavior caused by the delamination from a substrate initiated at the edges of the chemical vapor deposition synthesized monolayer transition metal dichalcogenides, led by thermal expansion mismatch. The atomic force microscopy and optical characterizations clearly showed the puckered structures associated with the strain, whereas the transmission electron microscopy revealed the special sawtooth-shaped edges, which break the geometrical symmetry for the buckling behavior of hexagonal samples. The condition of the edge delamination is in accordance with the fracture behavior of thin film interfaces. This edge delamination and buckling process is universal for most ultrathin two-dimensional materials, which requires more attention in various future applications.


The deposition of suberin lamellae determines the magnitude of cytosolic Ca2+ elevations in root endodermal cells subjected to cooling.
A transient increase in cytosolic Ca2+ concentration ([Ca2+]cyt) is thought to be a prerequisite for an appropriate physiological response to both chilling and salt stress. The [Ca2+]cyt is raised by Ca2+ influx to the cytosol from the apoplast and/or intracellular stores. It has been speculated that different signals mobilise Ca2+ from different stores, but little is known about the origin(s) of the Ca2+ entering the cytosol in response to specific environmental challenges. We have utilised the developmentally regulated suberisation of endodermal cells, which is thought to prevent Ca2+ influx from the apoplast, to ascertain whether Ca2+ influx is required to increase [Ca2+]cyt in response to chilling or salt stress. Perturbations in [Ca2+]cyt were studied in transgenic Arabidopsis thaliana, expressing aequorin fused to a modified yellow fluorescent protein solely in root endodermal cells, during slow cooling of plants from 20 to 0.5 degrees C over 5 min and in response to an acute salt stress (0.333 m NaCl). Only in endodermal cells in the apical 4 mm of the Arabidopsis root did [Ca2+]cyt increase significantly during cooling, and the magnitude of the [Ca2+]cyt elevation elicited by cooling was inversely related to the extent of suberisation of the endodermal cell layer. No [Ca2+]cyt elevations were elicited by cooling in suberised endodermal cells. This is consistent with the hypothesis that suberin lamellae isolate the endodermal cell protoplast from the apoplast and, thereby, prevent Ca2+ influx. By contrast, acute salt stress increased [Ca2+]cyt in endodermal cells throughout the root. These results suggest that [Ca2+]cyt elevations, upon slow cooling, depend absolutely on Ca2+ influx across the plasma membrane, but [Ca2+]cyt elevations in response to acute salt stress do not. They also suggest that Ca2+ release from intracellular stores contributes significantly to increasing [Ca2+]cyt upon acute salt stress.


Diagnosing gestational diabetes mellitus: implications of recent changes in diagnostic criteria and role of glycated haemoglobin (HbA1c).
Gestational diabetes mellitus (GDM; approximately 5% of pregnancies) represents the most important risk factor for development of later-onset diabetes mellitus. We examined concordance between GDM diagnosis defined using the original 1999 World Health Organization (WHO) criteria and the more recent 2013 WHO criteria and 2015 National Institute for Health and Care Excellence (NICE) criteria. We studied two groups: a case-control group of 257 GDM positive and 266 GDM negative cases, and an incident cohort 699 GDM positive and 6,231 GDM negative cases. In the incident cohort, GDM prevalence was 3.7% (WHO 1999 criteria), 11.4% (NICE 2015 criteria) and 13.7% (WHO 2013 criteria). Our results showed that a significant number of additional cases are detected using the more recent NICE and WHO criteria than the original 1999 WHO criteria, but these additional cases represent an intermediate group with 'moderate' dysglycaemia (abnormal blood glucose levels). Our results also show that use of these newer criteria misses a similar group of intermediate cases that were defined as GDM by the 1999 WHO criteria and that glycated haemoglobin in isolation is unlikely to replace the oral glucose tolerance test in GDM diagnosis.


Application of Glaser-Hay Diyne Coupling To Constrain Nα-Amino Acid Amides via a N-N Bridge.
We present the application of a Glaser-Hay diyne coupling for the synthesis of conformationally constrained Nα-amino acid amides with different diyne ring sizes. Twelve-membered rings were the smallest rings that could be prepared by this approach. We observed the formation of triethylammonium adducts in the cases of smaller (10- and 11-membered) rings. Calculation of the conformational barriers for the cyclization reactions of various ring sizes demonstrated that the formation of amino acid-derived smaller rings by this reaction is thermodynamically unfavorable.


Diagnostic accuracy of neutrophil counts in histopathological tissue analysis in periprosthetic joint infection using the ICM, IDSA, and EBJIS criteria.
Histology is an established tool in diagnosing periprosthetic joint infections (PJIs). Different thresholds, using various infection definitions and histopathological criteria, have been described. This study determined the performance of different thresholds of polymorphonuclear neutrophils (≥ 5 PMN/HPF, ≥ 10 PMN/HPF, ≥ 23 PMN/10 HPF) , when using the European Bone and Joint Infection Society (EBJIS), Infectious Diseases Society of America (IDSA), and the International Consensus Meeting (ICM) 2018 criteria for PJI. A total of 119 patients undergoing revision total hip (rTHA) or knee arthroplasty (rTKA) were included. Permanent histology sections of periprosthetic tissue were evaluated under high power (400× magnification) and neutrophils were counted per HPF. The mean neutrophil count in ten HPFs was calculated (PMN/HPF). Based on receiver operating characteristic (ROC) curve analysis and the z-test, thresholds were compared. Using the EBJIS criteria, a cut-off of ≥ five PMN/HPF showed a sensitivity of 93% (95% confidence interval (CI) 81 to 98) and specificity of 84% (95% CI 74 to 91). The optimal threshold when applying the IDSA and ICM criteria was ≥ ten PMN/HPF with sensitivities of 94% (95% CI 79 to 99) and 90% (95% CI 76 to 97), and specificities of 86% (95% CI 77 to 92) and 92% (95% CI 84 to 97), respectively. In rTKA, a better performance of histopathological analysis was observed in comparison with rTHA when using the IDSA criteria (p < 0.001). With high accuracy, histopathological analysis can be supported as a confirmatory criterion in diagnosing periprosthetic joint infections. A threshold of ≥ five PMN/HPF can be recommended to distinguish between septic and aseptic loosening, with an increased possibility of detecting more infections caused by low-virulence organisms. However, neutrophil counts between one and five should be considered suggestive of infection and interpreted carefully in conjunction with other diagnostic test methods. Cite this article: Bone Joint Res 2021;10(8):536-547.


Increased stathmin correlates with advanced stage and poor survival of non-small cell lung cancer.
Previous studies show that overexpression of stathmin involved in the malignant biological behavior of lung cancer. This investigation is to disclose the expression status of stathmin in non-small cell lung cancer (NSCLC) and its clinical value for the diagnosis and prognosis to lung cancer. The expression of stathmin in cells and tissues of NSCLC was examined using immunohistochemistry (IHC), in-situ hybridization (ISH), and Western blot. The correlation between stathmin expression and survival of lung cancer patients was evaluated by a Kaplan-Meier method and the multiple regression analysis. NSCLC tissues and cells showed an overexpression of stathmin compared with normal lung tissues and cells (p< 0.05). And the expression level of stathmin was significantly associated with lung adenocarcinoma (LAC) (p< 0.05), lymphatic invasion (p< 0.05) and advanced stages of NSCLC (p< 0.05). Moreover, overexpression of stathmin predicted a reduced survival (p<0.05). Increased stathmin correlated with pathologic grade, lymphatic invasion, advanced stage and poor survival of NSCLC, which indicated that stathmin could serve as a potential biomarker of NSCLC.


LC-MS/MS profiling of a mastic leaf phenol enriched extract and its effects on H2O2 and Aβ(25-35) oxidative injury in SK-B-NE(C)-2 cells.
The development of polyphenol neuroprotective nutraceuticals useful for functional foods could be a valuable strategy for counteracting oxidative stress relative diseases as Alzheimer's Disease (AD). Oxidative stress is one of the AD earliest event and seems to play a central role in Aβ generation, neuroinflammation, and neuronal apoptosis. In order to counteract AD neurodegeneration, the inhibition of the vicious cycle of Aβ generation and oxidation is an attractive therapeutic strategy, and antiamyloidogenic and antioxidant plant drugs could represent an alternative and valid approach. In this context, an alcoholic extract (Pl-M) from deterpenated Pistacia lentiscus L. leaves was investigated for its phenol composition through LC-ESI-MS/MS analysis. Besides the identified metabolites, ten compounds were reported for the first time as constituents of Pistacia lentiscus leaves. Through DPPH, ABTS, and ORAC methods, the antioxidant potential of the extract was initially investigated. In order to evaluate the preparation of a safe and no toxic extract, MTT, SRB, and LDH assays toward SH-5YSY, and SK-N-BE(2)-C human neuronal cell lines, as well as on C6 mouse glial cell line, were performed. Evaluating the protective effects from oxidant injury in SK-N-BE(2)-C cells cotreated with the plant complex and H2O2, or Aβ(25-35) fragment, it was observed that Pl-M extract exerted a significant cytoprotective response in both the oxidized cell systems. In particular, Pl-M extract was able to reduce by nearly 50% the Aβ(25-35) induced toxicity at 25.0 μg/mL dose level, whereas it counteracted almost completely the cytotoxic action at 100.0 μg/mL. Data obtained allow us to hypothesize the use of Pistacia lentiscus leaves, a broadly available and renewable source, as an alternative strategy for the enrichment of food matrices with polyphenol bioactives. The present study put the basis for bioavailability and preclinical studies, able to define Pl-M extract safety and efficacy.


The role of computational models of the immune system in designing vaccination strategies.
Mathematical and computational models are designed to improve our understanding of biological phenomena, to confirm/reject hypotheses, and to find points of intervention by altering the behavior of the studied systems. Here we describe the role of mathematical/computational models of the immune system. In particular, we analyze some examples of how mathematical modeling can contribute to finding optimal vaccination strategies. Indeed, computational modeling offers an intriguing opportunity from the theoretical point of view, and it will be of interest for clinically oriented investigators who wish to find optimal therapeutic strategies and for pharmaceutical industries that want to produce effective and successful drugs.


Paradoxical intention for insomnia: A systematic review and meta-analysis.
Paradoxical intention (PI) has been considered an evidence-based treatment for insomnia since the 1990s, but it has not been evaluated with modern review techniques such as meta-analysis. The present study aimed to conduct the first systematic review and meta-analysis of studies that explore the effectiveness of PI for insomnia on insomnia symptomatology and theory-derived processes. A systematic review and meta-analysis was conducted by searching for eligible articles or dissertations in six online bibliographic databases. Randomised controlled trials and experimental studies comparing PI for insomnia to active and passive comparators and assessing insomnia symptoms as outcomes were included. A random effects model was estimated to determine the standardised mean difference Hedge's g at post-treatment. Test for heterogeneity was performed, fail-safe N was calculated, and study quality was assessed. The study was pre-registered at International Prospective Register of Systematic Reviews (PROSPERO, CRD42019137357). A total of 10 trials were identified. Compared to passive comparators, PI led to large improvements in key insomnia symptoms. Relative to active comparators, the improvements were smaller, but still moderate for several central outcomes. Compared to passive comparators, PI resulted in great reductions in sleep-related performance anxiety, one of several proposed mechanisms of change for PI. PI for insomnia resulted in marked clinical improvements, large relative to passive comparators and moderate compared to active comparators. However, methodologically stronger studies are needed before more firm conclusions can be drawn.


Down-regulation of class I HLA antigens and of the Epstein-Barr virus-encoded latent membrane protein in Burkitt lymphoma lines.
Epstein-Barr virus (EBV)-carrying Burkitt lymphoma (BL) cells are relatively or completely resistant to the lytic effect of major histocompatibility complex class I HLA antigen-restricted cytotoxic T lymphocytes (CTLs) generated by stimulating lymphocytes of EBV-seropositive donors with the autologous EBV-transformed lymphoblastoid cell line (LCL). We previously found that EBV-negative and EBV-carrying BL lines derived from HLA-A11-positive donors were not only resistant to lysis by the HLA-A11-restricted CTL generated by stimulation with the autologous LCL, but also to HLA-A11-specific CTL derived from lymphocytes of an EBV-seronegative donor stimulated with an allogeneic LCL. Using the same and additional cell lines, we now show that the CTL resistance of the BL lines is probably due to a selective down-regulation of HLA-A11. We also show that the EBV-encoded latent membrane protein is expressed at a lower level in the EBV-carrying BL lines than in EBV-transformed LCLs. Only one of eight in vitro EBV-converted BL lines that shifted to a more LCL-like growth pattern expressed LMP at a high level. This line also reexpressed the HLA-A11 antigen that was undetectable in its EBV-negative progenitor. Our findings suggest that the typical BL cell phenotype is associated with low expression of both proteins.


Spinning and translational motion of Sb nanoislands manipulated on MoS2.
Antimony nanoislands grown on a MoS2 surface in ultra-high vacuum have been manipulated by atomic force microscopy (AFM) in ambient conditions. The island profiles have been digitized and provided as an input to a collisional algorithm based on classical mechanics. Assuming that the islands are rigid and static friction is high enough to prevent further motion after the passage of the probing tip, the direction of motion and the angle of rotation of the islands have been reproduced numerically. For a given spacing between the scan lines, the angle of deflection with respect to the fast scan direction and the angular speed of the islands are expected to vary with the friction between islands and substrate. From a comparison between model and experiment a shear strength in the order of 0.2 MPa is estimated.


Electron scattering from gas-phase glycine molecules.
Low-energy electron collisions with gas-phase glycine molecules have been studied using the fixed-nuclei R-matrix method based on state-averaged complete-active-space self-consistent-field orbitals. A total of 40 electronic states of neutral glycine, including 3s and 3p Rydberg excited states, are included in the R-matrix model. A large peak is observed in the A(") partial elastic cross section around 3.4 eV, which originates from the pi( *) shape resonance. In addition, many sharp narrow peaks coming from core excited resonances are seen in the elastic and inelastic cross sections at energies above 5 eV. Although the effect of the Rydberg orbitals on the elastic cross section is insignificant, these orbitals are crucial to represent core excited resonances in the inelastic cross sections. In previous experiments on dissociative electron attachment to gas-phase glycine, noticeable product ion peaks have been observed at electron collision energies around 1-2 and 5-10 eV. The resonance positions obtained in our calculations are generally close to these experimental results.


Isolation and characterization of a herpesvirus from leukemic guinea pigs.
A guinea pig herpesvirus (GPHV) has consistently been isolated from leukemic lymphoblasts of strain-2 guinea pigs. GPHV is serologically related to the guinea pig herpes-like virus isolated by Hsiung and Kaplow. The virions of GPHV consist of an icosahedral capsid containing a dense nucleoprotein core enclosed in a double-layered membrane. The average diameters of GPHV virion and capsid were 166 and 101 nm, respectively. Studies on the morphogenesis of GPHV revealed that, as in other herpesvirus infections, only the naked capsids with or without the nucleoprotein core were found in the infected cell nuclei; it was also learned that the virion acquired its envelope by budding from the nuclear membrane of the infected cells. However, GPHV-infected cell nuclei also contained dense fibrous rods, resembling nucleo-protein core outside the capsids, and tubules resembling viral core protein. The capsids were often embedded in dense granular antigen. GPHV deoxyribonucleic acid (DNA) has a density of 1.716 g/ml in cesium chloride compared to herpes simplex virus DNA (rho = 1.728 g/ml) and cellular DNA (rho = 1.700 g/ml).


Crystalline ice growth on PT(111): observation of a hydrophobic water monolayer.
The growth of crystalline water films on Pt(111) is investigated using rare gas physisorption. The water monolayer wets Pt(111) at all temperatures investigated (20-155 K). At low temperatures (T< or =120 K), additional water layers kinetically wet the monolayer surface. However, crystalline ice films grown at higher temperatures (T > 135 K) do not wet the water monolayer. These results are consistent with recent theory and experiments suggesting that the molecules in the water monolayer form a surface with no dangling OH bonds or lone pair electrons, giving rise to a hydrophobic water monolayer on Pt(111).


Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors.
Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of thesein vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice. Previous results showed that diet restriction (DR) had minimal or no effect on the lifespan of Rb1+/- mice, suggesting that the beneficial response to DR is dependent on pRb1. Since long-term eRapa treatment may at least partially mimic chronic DR in lifespan extension, we predicted that it would have a minimal effect in Rb1+/- mice. Beginning at 9 weeks of age until death, we fed Rb1+/- mice a diet without or with eRapa at 14 mg/kg food, which results in an approximate dose of 2.24 mg/kg body weight per day, and yielded rapamycin blood levels of about 4 ng/ml. Surprisingly, we found that eRapa dramatically extended life span of both female and male Rb1+/- mice, and slowed the appearance and growth of pituitary and decreased the incidence of thyroid tumors commonly observed in these mice. In this model, eRapa appears to act differently than DR, suggesting diverse mechanisms of action on survival and anti-tumor effects. In particular the beneficial effects of rapamycin did not depend on the dose of Rb1.


Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment.
Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed.


[The intraoperative visualization of the bile ducts by the use of fluorescent substances. A feasibility study].
Iatrogenic bile duct injury during cholecystectomy is the most serious complication of this surgical procedure. Initial reports suggest that this complication is particularly problematic during laparoscopic cholecystectomy. Proper identification of biliary anatomy in the subhepatic region is the only way to avoid this severe complication. The potential benefit from a simple, reliable method for intraoperative delineation of biliary anatomy is self-evident. In this experimental work the Authors-study the possibility and the feasibility of intraoperative biliary tree imaging with two fluorescent molecules (rolitetracyclin and fluorescin).


Denosumab-associated hypocalcaemia: incidence, severity and patient characteristics in a tertiary hospital setting.
Denosumab-associated hypocalcaemia (DAH) has been reported in patients with osteoporosis or metastatic bone disease and is associated with stages 4 and 5 chronic kidney disease (CKD, estimated glomerular filtration rate <30 mL/min/1.73m2 ). Other risk factors for hypocalcaemia have not been fully elucidated. We aimed to investigate the incidence of hypocalcaemia amongst patients receiving denosumab and to identify clinical features associated with this adverse event. Retrospective cohort study between June 2013 and June 2014 of patients administered denosumab (60/120 mg) at a tertiary hospital in Melbourne, Australia, to identify the incidence of an albumin-adjusted serum calcium concentration <2.10 mmol/L or ionized calcium <1.13 mmol/L within 6 months of treatment. Univariable and multivariable logistic regression analyses were performed to identify clinical features associated with DAH. One hundred and fifty-five patients were administered denosumab (100 osteoporosis, 55 bone metastases). Twenty-two patients (14% [95%CI 9.1-20.7]) developed hypocalcaemia: 55% were men, and 55% had osteoporosis. Eighty-six per cent had a 25-hydroxyvitamin D concentration >50 nmol/L, and 91% were on calcium/colecalciferol supplementation. Stages 4 and 5 CKD (adjusted odd ratio [aOR] 4.71, 95%CI 1.61-13.79, p = 0.005) and male sex (aOR 4.30, 95%CI 1.69-10.96, p = 0.002) were associated with DAH. No patients were documented as having hypocalcaemic symptoms. One patient received intravenous calcium gluconate treatment. The incidence of denosumab-associated hypocalcaemia was 14% (95%CI 9.1-20.7) within 6 months of treatment despite widespread use of appropriate calcium/colecalciferol supplementation. Stages 4 and 5 CKD and male sex were associated with subsequent hypocalcaemia. Copyright © 2016 John Wiley & Sons, Ltd.


Prevalence of Anoplocephala perfoliata and lesions of Draschia megastoma in Thoroughbreds in Kentucky at necropsy.
A total of 396 Thoroughbreds (86 males, 293 females, and 17 geldings) in Kentucky, 1 to 30 years of age, were examined at necropsy for presence of Anoplocephala perfoliata (2 female horses were not examined) in the cecum for lesions of Draschia megastoma in the stomach, during the 1-year period of Mar 1, 1982 through Feb 28, 1983. Prevalence of A perfoliata was 53% and of lesions of D megastoma was 63%. All lesions of D megastoma were partially or entirely in the glandular region of the stomach. Distances of the midpoint of these lesions from the margo plicatus varied from 0 to 290 mm. The center of about 88% of the lesions was within 50 mm of the margo plicatus . Measurements of the size of the lesions, exclusive of masses, indicated that about 95% were less than or equal to 50 mm in diameter. There appeared to be a higher infection rate of lesions of D megastoma in younger horses (81% in 1 to 7 year olds) than in older horses (41% in 8 to 30 year olds) with a few exceptions.


A Feasibility Analysis of Land-Based SINS/GNSS Gravimetry for Groundwater Resource Detection in Taiwan.
The integration of the Strapdown Inertial Navigation System and Global Navigation Satellite System (SINS/GNSS) has been implemented for land-based gravimetry and has been proven to perform well in estimating gravity. Based on the mGal-level gravimetry results, this research aims to construct and develop a land-based SINS/GNSS gravimetry device containing a navigation-grade Inertial Measurement Unit. This research also presents a feasibility analysis for groundwater resource detection. A preliminary comparison of the kinematic velocities and accelerations using multi-combination of GNSS data including Global Positioning System, Global Navigation Satellite System, and BeiDou Navigation Satellite System, indicates that three-system observations performed better than two-system data in the computation. A comparison of gravity derived from SINS/GNSS and measured using a relative gravimeter also shows that both agree reasonably well with a mean difference of 2.30 mGal. The mean difference between repeat measurements of gravity disturbance using SINS/GNSS is 2.46 mGal with a standard deviation of 1.32 mGal. The gravity variation because of the groundwater at Pingtung Plain, Taiwan could reach 2.72 mGal. Hence, the developed land-based SINS/GNSS gravimetry can sufficiently and effectively detect groundwater resources.


Virulence properties and attaching-effacing activity of Escherichia coli O45 from swine postweaning diarrhea.
Escherichia coli O45 isolates associated with swine postweaning diarrhea in Québec were characterized with respect to virulence determinants genetically and investigated for their attaching and effacing (A/E) activities by experimental inoculation of gnotobiotic piglets and by the HEp-2 cell adherence assay. All of 32 isolates tested were negative for enterotoxigenic and verotoxigenic E. coli virulence determinants, heat-labile enterotoxin (LT), heat-stable enterotoxins (STap, STb), verotoxins (VT1, VT2), and F4 (K88), F5 (K99), F6 (987P), and F41, except one STb-positive and two F4-positive isolates. A total of 25 isolates hybridized with an EaeA probe, and 11 hybridized with an enteropathogenic E. coli adherence factor (EAF) probe. None of 32 isolates hybridized with a bundle-forming pilus (BFP) probe. The EAF, EaeA, and BFP factors have been associated with human enteropathogenic E. coli strains. A total of 10 of 12 eaeA-positive porcine O45 isolates induced A/E lesions characterized by intimate adherence of bacteria to the intestinal epithelial cell membrane with effacement of the microvilli, similar to those of human attaching-effacing E. coli. However, A/E lesions were not observed in the piglets inoculated with any one of three eaeA-negative O45 isolates. All E. coli O45 isolates were non-adherent to HEp-2 cells. Thus, we have demonstrated the production of typical A/E lesions by nonenterotoxigenic E. coli O45 isolates from swine postweaning diarrhea. The results indicate the significance of the eaeA gene in A/E activities of these isolates and suggest that EAF and BFP are not involved in O45 E. coli infection of weaning piglets.


Renal failure due to primary amyloidosis: a case report and literature review.
Primary amyloidosis, also known as AL amyloidosis, is commonly caused by clonal expansion of plasma cells in the bone marrow, thereby segregating light chains of clonal immunoglobulin that settle in tissues in the form of insoluble amyloid fibrils. The aim of this study was to report a case of primary amyloidosis with renal failure, diagnosed in Hospital São João, Porto, Portugal, focusing on the diagnostic difficulties and presenting a literature review. A 68-year-old Caucasian man was admitted to the Internal Medicine Department of the hospital with a condition of anasarca and nephrotic syndrome. After performing a renal biopsy that tested positive using Congo red and immunohistochemistry, lambda light chain amyloidosis was diagnosed. This evolved into terminal renal disease, which led to hemodialysis and several episodes of urinary and catheter infections. He was started on chemotherapy, consisting of bortezomib 0.7 mg/m(2) and dexamethasone 40 mg in six cycles. This led to clinical improvement, stabilization of the illness and good tolerance of the treatment. Amyloidosis is a rare entity that is difficult to diagnose. This is because of the unspecific early clinical manifestations of the disease. The hypothesis of amyloidosis is only considered when specific organ failure occurs. This case consisted of primary amyloidosis with involvement of the kidneys as an initial presentation of the disease and its difficulties were shown, going from the clinical approach to the final diagnosis.


Sliding-Scale Insulin Use in Long-Term Care: An Updated Perspective.
Diabetes affects approximately 26% of individuals oldeR THAN 65 years of age in the United States and up to 33% of patients in long-term care facilities. The most commonly prescribed insulin therapy for patients in long-term care is sliding-scale insulin (SSI): the use of finger-stick blood glucose testing to assess the need for insulin administration based on current blood glucose levels. SSI has been on the Beers Criteria of Potentially Inappropriate Medications since 2012. However, its sole use for long-term treatment is specifically not recommended by the American Diabetes Association and other stakeholders in diabetes management. This review discusses recent updates to several published guidelines, including Centers for Medicare & Medicaid Services, the Beers criteria, the American Medical Directors Association, and the American Diabetes Association regarding the use of SSI-only insulin regimens for elderly patients in long-term care.


Triumfetta cordifolia Gum as a Promising Bio-Ingredient to Stabilize Emulsions with Potentials in Cosmetics.
The cosmetics industry is searching for efficient and sustainable substances capable of stabilizing emulsions or colloidal dispersions that are thermodynamically unstable because of their high surface energy. Therefore, surfactants are commonly used to stabilize the water/oil interface. However, the presence of a surfactant is not always sufficient to obtain stable emulsions on the one hand, and conventional surfactants are often subject to such controversies as their petroleum origin and environmental concerns on the other hand. As a consequence, among other challenges, it is obvious that research related to new-natural, biodegradable, biocompatible, available, competitive-surfactants are nowadays more intensive. This study aims to valorize a natural gum from Triumfetta cordifolia (T. cordifolia) as a sustainable emulsifier and stabilizer for oil-in-water (O/W) emulsions, and to evaluate how the nature of the fatty phase could affect this potential. To this end, O/W emulsions were prepared at room temperature using three different oils varying in composition, using a rotor-stator mixer. Resulting mixtures were characterized using optical microscopy, laser granulometry, rheology, pH and stability monitoring over time. The results demonstrated good potential for the gum as an emulsifying agent. T. cordifolia gum appears efficient even at very low concentrations (0.2% w/w) for the preparation and stabilization of the different O/W emulsions. The best results were observed for cocoglyceride oil due to its stronger effect of lowering interfacial tension (IFT) thus acting as a co-emulsifier. Therefore, overall results showed that T. cordifolia gum is undoubtedly a highly promising new bio-sourced and environmentally friendly emulsifier/stabilizer for many applications including cosmetics.


Role of the bHLH transcription factor TCF21 in development and tumorigenesis.
Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.


Combination immune therapies to enhance anti-tumor responses by NK cells.
Natural killer (NK) cells are critical innate immune lymphocytes capable of destroying virally infected or cancerous cells through targeted cytotoxicity and further assisting in the immune response by releasing inflammatory cytokines. NK cells are thought to contribute to the process of tumor killing by certain therapeutic monoclonal antibodies (mAb) by directing antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIA (CD16). Numerous therapeutic mAb have been developed that target distinct cancer-specific cell markers and may direct NK cell-mediated ADCC. Recent therapeutic approaches have combined some of these cancer-specific mAb with additional strategies to optimize NK cell cytotoxicity. These include agonistic mAb targeting NK cell activating receptors and mAbs blocking NK cell inhibitory receptors to enhance NK cell functions. Furthermore, several drugs that can potentiate NK cell cytotoxicity through other mechanisms are being used in combination with therapeutic mAb. In this review, we examine the mechanisms employed by several promising agents used in combination therapies that enhance natural or Ab-dependent cytotoxicity of cancer cells by NK cells, with a focus on treatments for leukemia and multiple myeloma.


Search for a progesterone-binding protein in secretory granules of the ovine corpus luteum.
The hypothesis that electron-dense granules present in the corpus luteum contain progesterone in a protein-bound form was examined using differential and sucrose gradient centrifugation. Ovine luteal tissue was fractionated by differential centrifugation at 1,000 X g (P1 pellet), 10,000 X g (P2), and 82,000 X g (P3; supernatant S3). Samples of P2, P3, and S3 were further fractionated o 20-40% (P2 and P3) or 5-25% (S3) sucrose gradients and examined for progesterone-binding activity by measuring the progesterone content and/or the specific binding of [3H]progesterone of sucrose gradient samples. In addition, saturation binding assays were performed with steroid-free samples of P2 and S3. Saturable binding of progesterone was not found in P2, the fraction containing electron-dense granules. In S3, two progesterone-binding proteins with sedimentation rates of 3.2S and 8.6S and an affinity of 7.1 X 10(5) M-1 for progesterone were detected. The sedimentation behavior of these proteins was distinct from that of ovine plasma transcortin, a 4S protein. The view that a binding protein is released into the interstitial fluid during the exocytosis of granules was examined by measuring the progesterone-binding activity of protein released by slices of corpus luteum in vitro. No binding activity was found. The results of this investigation do not support the hypothesis that putative progesterone-secreting granules observed in luteal tissue contain a binding protein


Improved Visualization of Gastrointestinal Slow Wave Propagation Using a Novel Wavefront-Orientation Interpolation Technique.
High-resolution mapping of gastrointestinal (GI) slow waves is a valuable technique for research and clinical applications. Interpretation of high-resolution GI mapping data relies on animations of slow wave propagation, but current methods remain as rudimentary, pixelated electrode activation animations. This study aimed to develop improved methods of visualizing high-resolution slow wave recordings that increases ease of interpretation. The novel method of "wavefront-orientation" interpolation was created to account for the planar movement of the slow wave wavefront, negate any need for distance calculations, remain robust in atypical wavefronts (i.e., dysrhythmias), and produce an appropriate interpolation boundary. The wavefront-orientation method determines the orthogonal wavefront direction and calculates interpolated values as the mean slow wave activation-time (AT) of the pair of linearly adjacent electrodes along that direction. Stairstep upsampling increased smoothness and clarity. Animation accuracy of 17 human high-resolution slow wave recordings (64-256 electrodes) was verified by visual comparison to the prior method showing a clear improvement in wave smoothness that enabled more accurate interpretation of propagation, as confirmed by an assessment of clinical applicability performed by eight GI clinicians. Quantitatively, the new method produced accurate interpolation values compared to experimental data (mean difference 0.02 ± 0.05 s) and was accurate when applied solely to dysrhythmic data (0.02 ± 0.06 s), both within the error in manual AT marking (mean 0.2 s). Mean interpolation processing time was 6.0 s per wave. These novel methods provide a validated visualization platform that will improve analysis of high-resolution GI mapping in research and clinical translation.


Epigenetic regulation of cell adhesion-mediated drug resistance acquisition in multiple myeloma.
Elucidation of the epigenetic mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification for cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance in multiple myeloma. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inactivating phosphorylation of EZH2, leading to sustained expression of anti-apoptotic genes including IGF1, BCL2 and HIF1A. Inhibition of the IGF-1R/PI3K/Akt pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. To our knowledge, this is the first demonstration of an epigenetic mechanism underlying CAM-DR and provides a rationale for the inclusion of kinase inhibitors counteracting EZH2 phosphorylation in combination chemotherapy aimed at increasing the therapeutic index.


IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo.
Myeloid cells, such as macrophages and microglia, play a crucial role in neuroinflammation and have been recently identified as a novel therapeutic target, especially for chronic forms. The general aim would be to change the phenotype of myeloid cells from pro- to anti-inflammatory, favoring their tissue-trophic and regenerative functions. Myeloid cells, however, display a number of functional phenotypes, not immediately identifiable as pro- or anti-inflammatory, and associated to ambiguous markers. We employed in vitro assays to study macrophage polarization/differentiation in the presence of classical polarizing stimuli such as IFNγ (pro-inflammatory) and IL4 (anti-inflammatory). We induced neuroinflammation in mice by immunization with a myelin antigen and treated diseased mice with intracisternal delivery of an IL4-expressing lentiviral vector. We analyzed clinical, pathological, and immunological outcomes with a focus on myeloid cells. We found that IL6, usually considered a pro-inflammatory cytokine, was released in vitro by macrophages treated with the anti-inflammatory cytokine IL4. We show the existence of macrophages expressing IL6 along with classical anti-inflammatory markers such as CD206 and demonstrate that these cells are immunosuppressive in vitro. In neuroinflamed mice, we show that IL4 delivery in the central nervous system (CNS) is associated with clinical and pathological protection from disease, associated with increased IL6 expression in infiltrating macrophages. IL6 is known to mediate both pro- and anti-inflammatory effects, having two distinct ways to induce cell-signaling: either through the membrane bound receptor (anti-inflammatory) or through trans-signaling (pro-inflammatory). We show here that IL6-expressing macrophages are associated to protection from neuroinflammation, suggesting that IL6 anti-inflammatory properties prevail in the CNS, and calling for a general reconsideration of IL6 in macrophage polarization.


[Chapter 4. The embryo, object of researches : a look at patents].
Although research on human biological material has long been the subject of much controversy, the question of the embryo is an extremely delicate subject.Concerns are strong about the possibilities of conducting research on embryonic matter, and the difficulties in defining the legal rules applicable to the embryo are also found in research and intellectual property. The field of patentability depends on the notion retained about the embryo because of a principle prohibiting the use of human embryos for industrial or commercial purposes.This study is devoted to the evolution of the concept on a European scale, particularly via the decisions made by the CJEU : by adopting an evolutionary notion of the embryo according to scientific progress, the field of patentability extends and offers new perspectives in research.


Surgical considerations in managing the remaining breast during postmastectomy breast reconstruction.
The age and general condition of the patient, size and shape of the remaining breast, various risk factors such as the histologic type of carcinoma, and family history are all critical in governing the definitive management of the remaining breast during postmastectomy breast reconstruction. The philosophy, timing, and method of dealing with the remaining breast must be discussed carefully with the patient. The psychological, social, and physical status of the patient must be addressed, with special emphasis in regard to her future and the degree of risk involved.


Equianalgesic dosing of opioids.
The concept of opioid equianalgesia, limitations in current dose conversion systems, equianalgesic dose tables, and computer assisted dose conversions are discussed. Conversions for methadone, fentanyl and hydromorphone are described.


Does a "stoplight!" improve processing a stoplight? Cross-modal influences of time-compressed spoken denotations on automotive icon classification.
Findings from three experiments support the conclusion that semantic auditory primes facilitate processing of complex warning icons in the automotive context. In Experiment 1, we used a cross-modal icon identification task with auditory primes and visual icons as targets, presented in a high perceptual load context. Responses were faster for congruent priming in comparison to neutral or incongruent priming. This effect also emerged for different levels of time-compression of auditory primes. In Experiment 2, participants took part in a driving simulation with target icons on a gantry road sign. Participants had to categorize the color of the icons. Again, compressed auditory primes facilitated responses in cases of congruency (compared with incongruent and neutral primes). This result was replicated in Experiment 3 with more complex responses (i.e., braking, switching lanes). Our results suggest semantic object-based auditory-visual interactions, which rapidly increase the denoted target object's salience. (PsycINFO Database Record


Recent surprises in protein targeting to mitochondria and plastids.
The functions of mitochondria and chloroplasts rely on thousands of proteins, mostly imported from the cytosol through specialized import channels. Neither the detailed import mechanisms nor the identities of all targeted proteins are known. Recent surprises include unexpected results concerning import receptors, unexpectedly frequent dual-targeting of proteins, and the discovery of novel routes of protein trafficking. Such findings make it more difficult to predict which proteins really are targeted to organelles. By combining experimental and bioinformatics data, we estimate the size of the mitochondrial and plastid proteomes to be approximately 2000 and 2700 proteins, respectively. Advances in cell and organelle fractionation coupled with modern proteomics techniques are probably the best route to understanding organellar protein composition.


Bladder Agenesis: A Systematic Review.
Bladder agenesis is a rare congenital deformity characterized by the absence of the bladder. It is primarily observed in postmortem dissections of stillbirths rather than live births. The condition is often associated with other congenital anomalies, leading to the hypothesis that most affected fetuses do not survive to term. However, the exact cause and specific associated anomalies remain unclear and poorly described in the literature. The limited mention of bladder agenesis in textbooks and literature underscores the importance of creating a comprehensive source for future research in this field. Therefore, our objective is to collect and analyze data on bladder agenesis, focusing on associated anomalies and potential causes, to enhance our understanding of the condition. We conducted a thorough review of reports collected from three databases, Google Scholar, PubMed, and Science Direct, last searched on July 30, 2023, starting with 327 reports. Excluding duplicates and records written in languages other than English, veterinary studies, irrelevant reports, or stillbirths. Inclusion criteria were the following: cases must have proven bladder agenesis, not hypoplasia, and must have most of the information, including the age of diagnosis, presenting symptoms, gender, associated anomalies, and management or outcome of the patient. A quality assessment was conducted according to the Joanna Briggs Institute checklist for case reports. A total of 65 case reports from 56 articles were included in the review. Through our manual analysis, we documented a wild array of malformations associated with bladder agenesis. Among the reports reviewed, 93% exhibited urinary system malformations beside bladder agenesis, 77% were found to have reproductive malformations, 44% had gastrointestinal anomalies, 38% showed musculoskeletal malformations, 28% had cardiac malformations, and another 28% had vascular anomalies. The overall mortality rate was 38%, with a higher rate of 74% for males compared to 20% for females. By collating and analyzing those case reports, we aim to contribute to a better understanding of bladder agenesis and its associated anomalies, facilitating further investigations and advancements in the field.


Profile of microvascular disease in type 2 diabetes in a tertiary health care hospital in India.
Diabetes mellitus (DM) is a metabolic disorder complicated by microvascular and macrovascular diseases. The clinical profile of these complications has not been adequately studied in many tertiary health care centers in India. The authors studied the clinical profile of microvascular diabetes complications [peripheral sensory neuropathy (PSN), diabetic retinopathy (DR), nephropathy] in patients attending a tertiary care hospital in India. In this cross-sectional study, patients (n = 1529) with type 2 diabetes mellitus (T2DM) were studied for the presence of complications. PSN was diagnosed when the vibration perception threshold of big toe was >25 V. Retinopathy was diagnosed using direct ophthalmoscopy (presence of microaneurysms, exudates, and hemorrhages), and nephropathy with microalbuminuria (≥30 mg/l albumin in a spot urine sample) or low creatinine clearance (<90 ml/min) using Cockcroft-Gault formula. PSN was present in 37% (565/1529), nephropathy in 20% (297/1529), and retinopathy in 17% (256/1529) of the study population. Microvascular complications are seen in 48% (734/1529) patients of the study population. Increasing age (P < 0.001), long duration of diabetes (P < 0.001), and higher HbA1c (P = 0.036) were the common risk factors for all complications. Hypertriglyceridemia (P = 0.016) and low body weight (P = 0.039) predisposed to retinopathy over other microangiopathies. Overall, nephropathy was associated strongly with retinopathy (P = 0.015). The data showed that neuropathy was the most common microangiopathy and coexisted with other complications in many patients. Old age, long duration of disease, and poor glycemic control are the common risk factors for microvascular complications.


Impact of PBP4 Alterations on β-Lactam Resistance and Ceftobiprole Non-Susceptibility Among Enterococcus faecalis Clinical Isolates.
Penicillin-resistance among Enterococcus faecalis clinical isolates has been recently associated with overexpression or aminoacidic substitutions in low-affinity PBP4. Ceftobiprole (BPR), a new-generation cephalosporin, is a therapeutic option against E. faecalis. Here, we present evidence that pbp4 gene sequence alterations may influence the expression level of the gene and ceftobiprole binding to PBP4 in E. faecalis clinical isolates showing remarkable MDR-phenotypes, and how this could interfere with BPR in vitro antibacterial and bactericidal activity. Seven E. faecalis strains from bloodstream infections were analyzed for their antibiotic and β-lactam resistance. BPR bactericidal activity was assessed by time-kill analysis; pbp4 genes were sequenced and pbp4 relative expression levels of transcription were performed by RT-qPCR. Five penicillin-resistant ampicillin-susceptible (PRAS) isolates were detected, 4 of which were also BPR non-susceptible (BPR-NS). In the time-kill experiments, BPR exposure resulted in a potent bactericidal activity (3-5 log10 reduction) at the different concentrations tested. pbp4 gene sequence analysis revealed some mutations that may account for the changes in PBP4 affinity and MIC increase in the 4 BPR-NS strains (MICs 4-16 mg/L): the deletion of an adenine (delA) in the promoter region in all PRAS/BPR-NS strains; 12 different amino acid substitutions, 7 of which were next to the PBP catalytic-sites. The most significant were: T418A, located 6 amino acids (aa) upstream of the catalytic-serine included in the 424STFK427motif I; L475Q, 7 aa upstream of the 482SDN484motif II; V606A and the novel Y605H, 13/14 aa upstream of the 619KTGT622motif III. Taken together, our data showed that elevated BPR MICs were attributable to increased transcription of pbp4 - associated with a single upstream adenine deletion and PBP4 alterations in the catalytic-site motifs - which might interfere with the formation of the BPR/PBP4 complex. pbp4 molecular alterations may account for the changes in PBP4 affinity and MIC increase, without affecting BPR cidal activity. Indeed, our in vitro dynamic analysis by time-kill assays showed that BPR exerted a bactericidal activity against E. faecalis clinical isolates, despite their MDR phenotypes.


Effect of BCG immunotherapy on N-nitroso-N-methylurea-induced carcinogenesis of guinea pig colon.
A total of 480 guinea pigs each received twice weekly intrarectal instillations of 1 mg N-nitroso-N-methylurea (NMU) during 14-35 weeks (total dose NMU, 28-70 mg) to induce colon neoplasms. At 24, 28, or 35 weeks after the start of NMU instillation, the distal colon was exposed by a ventral laparotomy and suspected neoplastic lesions were treated by one of four methods: A, intratumoral instillation of an emulsion of killed BCG cell walls attached to oil droplets; B, intratumoral instillation of a control emulsion of killed BCG cell walls in an aqueous phase rather than lipid phase; C, surgical excision of the colon lesion with formation of a ventral diverting colostomy; or D, sham operation (no treatment). All guinea pigs were allowed to recover from surgery and were then observed for a period of 1 year for the study of the effects of these treatments on NMU-induced colon neoplasms. Colon neoplasms were produced in 76% of all sham-operated control guinea pigs, and the frequency of such neoplasms was dependent on the total dose of NMU. Most neoplasms were adenocarcinomas with invasion of the bowel wall but only approximately 5% of them metastasized. Treatment with BCG failed to alter the course of NMU-induced colon carcinogenesis, as determined by the frequency of colon neoplasia, the number, the gross, or microscopic characteristics of colon neoplasms, or the rate of survival.


Lipid advanced glycosylation: pathway for lipid oxidation in vivo.
To address potential mechanisms for oxidative modification of lipids in vivo, we investigated the possibility that phospholipids react directly with glucose to form advanced glycosylation end products (AGEs) that then initiate lipid oxidation. Phospholipid-linked AGEs formed readily in vitro, mimicking the absorbance, fluorescence, and immunochemical properties of AGEs that result from advanced glycosylation of proteins. Oxidation of unsaturated fatty acid residues, as assessed by reactive aldehyde formation, occurred at a rate that paralleled the rate of lipid advanced glycosylation. Aminoguanidine, an agent that prevents protein advanced glycosylation, inhibited both lipid advanced glycosylation and oxidative modification. Incubation of low density lipoprotein (LDL) with glucose produced AGE moieties that were attached to both the lipid and the apoprotein components. Oxidized LDL formed concomitantly with AGE-modified LDL. Of significance, AGE ELISA analysis of LDL specimens isolated from diabetic individuals revealed increased levels of both apoprotein- and lipid-linked AGEs when compared to specimens obtained from normal, nondiabetic controls. Circulating levels of oxidized LDL were elevated in diabetic patients and correlated significantly with lipid AGE levels. These data support the concept that AGE oxidation plays an important and perhaps primary role in initiating lipid oxidation in vivo.


Clinical presentation of Graves' ophthalmopathy.
The eye findings of Graves' ophthalmopathy were prospectively recorded in 90 consecutive untreated patients (66 females, 24 males; mean age 44.5 years) according to the 1977 NOSPECS classification. Soft-tissue involvement was observed in 90%, proptosis greater than or equal to 23 mm in 30%, eye muscle involvement in 60%, corneal involvement in 9% and sight loss in 34%. No differences in the distribution of eye changes between right and left eye were found. Values for proptosis (mean +/- SD, 20.2 +/- 3.6 mm) had a near-normal distribution. Orbital computed tomography (CT) scanning (performed in 80 cases) demonstrated enlargement of inferior rectus in 60%, medial rectus in 50%, superior rectus in 40% and lateral rectus in 22%. Unilateral eye disease was present in 13 patients (14%); in 4 of these patients the CT scan showed eye muscle enlargement also in the fellow eye and in 2 patients bilateral eye disease subsequently developed. The distribution of age, sex and NOSPECS classes in patients with unilateral eye disease was similar to that in patients with bilateral eye disease, but the interval between the onset of thyroid and eye disease was much shorter in cases of unilateral than in cases of bilateral eye disease. Patients without clinically evident thyroid disease (n = 20, 22%) were not different from patients with thyroid disease in age, sex or ophthalmological presentation. The various data suggest: (1) the 1977 NOSPECS classification under-represents significant proptosis in 12% of cases; (2) the age and sex distribution of patients with Graves' ophthalmopathy is similar to that of cases with thyroidal Graves' disease, and (3) unilateral Graves' ophthalmopathy may represent an early stage of the disease, that as a rule already is or develops shortly afterwards into a bilateral disease.


Prescriber responsibility, predictors for initiation, and 20-year trends in use of non-aspirin non-steroidal anti-inflammatory drugs in patients with cardiovascular contraindications: a nationwide cohort study.
To examine whether prescription patterns complied with recommendations not to use non-steroidal anti-inflammatory drugs (NSAIDs) in patients with cardiovascular contraindications. Moreover, we examined predictors for initiation and prescriber responsibility. We used Danish medical databases to identify all patients with first-time cardiovascular disease during 1996-2017 (n = 628 834). We assessed standardized prevalence proportions, predictors from logistic regression, and prescriber identifiers. One-year prevalence of NSAID initiation increased 3.4% from 1996 (19.4%) to 2001 (22.7%) and declined by 2.7% thereafter until 2017 (13.5%). Trends were independent of age, sex, and disease subtype, although larger annual declines occurred for heart failure (3.9%) and ischaemic heart disease (3.5%) since 2002. One-year prevalence remained highest among patients with venous thromboembolism (16.6%) and angina (13.8%), and lowest for ST-segment elevation myocardial infarction (7.0%) and heart failure (8.8%). Initiators were predominantly prescribed ibuprofen (59%), diclofenac (23%), and etodolac (6%). Diclofenac and coxib use declined, while ibuprofen and naproxen use increased. Median prescribed pill dose of ibuprofen declined after 2008 from moderate/high (600 mg) to low (400 mg). Treatment duration declined for all NSAIDs, except celecoxib. Rheumatic, obesity, and pain-related conditions predicted NSAID initiation. General practitioners issued 86-91% of all NSAID prescriptions, followed by hospital prescribers (7.3-12%). Initiation of NSAIDs in patients with cardiovascular disease declined since 2002. Shorter treatment duration, declining COX-2 inhibition, and increasing use of naproxen and low-dose ibuprofen suggest adherence to guidelines when NSAIDs cannot be avoided. Still, NSAID use remained prevalent despite cardiovascular contraindications, warranting awareness of appropriateness of use among general practitioners in particular.


Beta and alpha electroencephalographic activity changes after acute exercise.
Exercise has been widely related to changes in cortical activation and enhanced brain functioning. Quantitative electroencephalography (qEEG) is frequently used to investigate normal and pathological conditions in the brain cortex. Therefore, the aim of the present study was to observe absolute power alterations in beta and alpha frequency bands after a maximal effort exercise. Ten healthy young volunteers were submitted to an eight-minute resting EEG (eyes closed) followed by a maximal exercise test using a mechanical cycle ergometer. Immediately after the exercise, another identical eight-minute EEG was recorded. Log transformation and paired student's t-test compared the pre and post exercise values (p<0.05). Results indicated a significant absolute power increase in beta after exercise at frontal (Fp1, F3 and F4) and central (C4) areas, which might be related to increased cortical activation.


Diagnosis and Treatment of Pseudo-Class III Malocclusion.
Pseudo-Class III malocclusion is characterized by the presence of an anterior crossbite due to a forward functional displacement of the mandible; in most cases, the maxillary incisors present some degree of retroclination, and the mandibular incisors are proclined. Various types of appliances have been described in the literature for the early treatment of pseudo-Class III malocclusion. The objectives of this paper are to demonstrate the importance of making the differential diagnosis between a skeletal and a pseudo-Class III malocclusion and to describe the correction of an anterior crossbite. The association of maxillary expansion and a 2 × 4 appliance can successfully be used to correct anterior crossbites.


Bandlike motion and mobility saturation in organic molecular semiconductors.
We analyze a model that accounts for the inherently large thermal lattice fluctuations associated with the weak van der Waals intermolecular bonding in crystalline organic semiconductors. In these materials the charge mobility generally exhibits a "metalliclike" power-law behavior, with no sign of thermally activated hopping characteristic of carrier self-localization, despite apparent mean free paths comparable to or lower than the intermolecular spacing. Our results show that such a puzzling transport regime can be understood from the simultaneous presence of band carriers and incoherent states that are dynamically localized by the thermal lattice disorder.


Different morphologic aspects and clinical features in massive hepatic amyloidosis.
4 cases of massive hepatic amyloidosis are reported with special reference to their clinical profiles and histologic features. On the basis of these data, two different clinical and histologic courses of the disease can be distinguished. 2 patients showed marked hepatomegaly without cholestasis, whereas in the other 2 the clinical picture was characterized by much less pronounced hepatomegaly, but by severe and progressive intrahepatic cholestasis. The time course of the disease seems to be different in the two forms, the cholestatic form being more rapidly fatal than the other.


Clinicopathologic features and long-term results of alpha-fetoprotein-producing gastric cancer.
During a 10-yr-period, 24 cases of alpha-fetoprotein-producing gastric cancer were experienced in our department. The mean age was 62.5 yr, and the sex ratio of males to females was 3:1. Borrmann II and III types of gastric cancer were predominant (83.3%). The prognosis was dismal. Most of the patients, including three radically operated cases of early gastric cancer, died from liver metastasis within 2 yr. The 1-, 3-, and 6-yr survival rates were 37.5%, 8.3%, and 8.3%, respectively, for all cases and 75.0%, 25.0%, and 25.0% for radically operated cases. The incidences of synchronous and metachronous liver metastasis were 31.8% and 40.9%, significantly higher than the incidences of AFP-negative gastric cancer (p less than 0.91). Despite radical gastrectomy, metachronous liver metastasis occurred in 75.0% of the cases. Two radical hepatic resections, including extended right lobectomy, were performed in one patient with early gastric cancer who had repeated metachronous liver metastasis. However, the tumor recurred immediately. Apparently, radical gastrectomy or hepatic resection alone may not suffice for this particular type of cancer. The methods of treatment and follow-up considered should be different from that for other types of gastric cancer.


Differentiation of retinal ganglion cells from induced pluripotent stem cells: a review.
Glaucoma is a common optic neuropathy that is characterized by the progressive degeneration of axons and the loss of retinal ganglion cells (RGCs). Glaucoma is one of the leading causes of irreversible blindness worldwide. Current glaucoma treatments only slow the progression of RGCs loss. Induced pluripotent stem cells (iPSCs) are capable of differentiating into all three germ layer cell lineages. iPSCs can be patient-specific, making iPSC-derived RGCs a promising candidate for cell replacement. In this review, we focus on discussing the detailed approaches used to differentiate iPSCs into RGCs.


Dietary DHA during development affects depression-like behaviors and biomarkers that emerge after puberty in adolescent rats.
DHA is an important omega-3 PUFA that confers neurodevelopmental benefits. Sufficient omega-3 PUFA intake has been associated with improved mood-associated measures in adult humans and rodents, but it is unknown whether DHA specifically influences these benefits. Furthermore, the extent to which development and puberty interact with the maternal diet and the offspring diet to affect mood-related behaviors in adolescence is poorly understood. We sought to address these questions by 1) feeding pregnant rats with diets sufficient or deficient in DHA during gestation and lactation; 2) weaning their male offspring to diets that were sufficient or deficient in DHA; and 3) assessing depression-related behaviors (forced swim test), plasma biomarkers [brain-derived neurotrophic factor (BDNF), serotonin, and melatonin], and brain biomarkers (BDNF) in the offspring before and after puberty. No dietary effects were detected when the offspring were evaluated before puberty. In contrast, after puberty depressive-like behavior and its associated biomarkers were worse in DHA-deficient offspring compared with animals with sufficient levels of DHA. The findings reported here suggest that maintaining sufficient DHA levels throughout development (both pre- and postweaning) may increase resiliency to emotional stressors and decrease susceptibility to mood disorders that commonly arise during adolescence.


SOFTDOCK: understanding of molecular recognition through a systematic docking study.
Molecular recognition and docking are essential to the biological functions of proteins. SOFTDOCK was one of the first molecular docking methods developed for protein-protein docking. Its ability to represent the molecular surface with different shapes and properties and to dock a variety of molecular complexes with certain conformational changes was demonstrated in a previous study. In the present work, we studied the effects of the docking parameters through statistical analysis. Seventy one typical binary complexes of different categories in PDB were also systematically docked for a test; 57 of them produced correct solutions with one set of docking parameters whereas the other 14 complexes required adjustment of the docking parameters, by decreasing the softness of the recognition and hence the background noise. We found that these 14 complexes had special structural features. Our results suggest that a variety of mechanisms may be involved in molecular recognition rather than the shape complementarity only, which is very helpful in developing more powerful methods for predicting molecular recognition.


Hydraulic responses to environmental perturbations in Tsuga canadensis and Betula lenta.
Eastern hemlock (Tsuga canadensis (L). Carr.) is a late-successional species found across the northeastern United States of America that is currently threatened by the exotic pest, hemlock woolly adelgid (Adelges tsugae Annand). Because whole-tree physiological characteristics may scale to influence ecosystem processes, we considered whole-tree hydraulic controls in eastern hemlock and the replacement species black birch (Betula lenta L.). Through a series of misting perturbations, whole-tree resistances (R), capacitances (C) and time constants (tau) were determined from time series sap flux data in eastern hemlock and black birch. Black birch trees responded more rapidly to environmental perturbations than eastern hemlock. Utilizing the step function after applied treatments, whole-tree tau ranged between 9.4 and 24.8 min in eastern hemlock trees compared with 5.9 to 10.5 min in black birch. Species was not a significant predictor of R or C when controlling for tree size. In both species, R decreased with sapwood area and C increased. Our tau results indicate that the loss and replacement of eastern hemlock by black birch will decrease the lag between transpiration and absorption of water from the soil and potentially alter the diurnal pattern of carbon and water uptake.


Why hasn't eliminating acute rejection improved graft survival?
Although patients with end-stage renal disease can be maintained with dialysis therapy, the superiority of patient survival with renal transplantation makes transplantation the preferred method of renal replacement. Potent immunosuppressive therapies, particularly calcineurin inhibitors, have greatly reduced the incidence of acute rejection. However, long-term allograft survival remains limited. We discuss the impact of acute rejection on long-term allograft survival and discuss other factors leading to late allograft loss, including calcineurin inhibitor toxicity, chronic allograft nephropathy, and BK virus nephropathy, as well as donor and recipient factors associated with long-term allograft loss.


Theory for nanoscale curvature induced enhanced inactivation kinetics of SARS-CoV-2.
We develop a novel theory for the nanomorphology dependent outer sphere heterogeneous electron transfer (ET) rate constant () based on an energy level alignment approach. is modelled through the activation free energy, which is a product of the water monolayer covered metal work function (WF) and the fractional electronic charge exchanged at the transition state (attained through the alignment of the metal Fermi and HOMO/LUMO energy levels of the electroactive species). The theory shows that is an exponentially increasing and decreasing function of the mean curvature in concave and convex nanomorphologies, respectively, for electroactive species or proteins involving their HOMO energy. For the specific spike protein of SARS-CoV-2, we have estimated the half lifetime (t1/2) and degree of inactivation as a function of the metal WF, nanostructure mean curvature, spike protein HOMO energy, and the environmental temperature (T). By varying the metal from Ag to Au, t1/2 is reduced from 7 h to 4 min, respectively. The reduction in the copper nanoparticle size from 50 to 5 nm increases the degree of inactivation from 60 to 99.6% (with a reduction factor of 10 in t1/2). Similarly, the increase in T from 10 °C to 65 °C causes a 100 times lowering of the t1/2 and t99.9% of SARS-CoV-2 on Cu metal. The theory predicts that involving the HOMO energy level of a protein follows the surface nanostructure shape dependent order as follows: spherical nanoparticle > cylindrical nanorod > cylindrical nanopore > spherical nanocavity, while the opposite trend is observed in the case of the LUMO energy level participation. Finally, the theory shows agreement with the reported experimental data of the degree of inactivation of SARS-CoV-2 on Ag and Cu nanoparticles.


Upward trend in the rate of detection of new cases of leprosy in the State of Bahia, Brazil.
The worldwide fall in the rate of detection of new cases of leprosy has been partly attributed to the introduction of multidrug therapy and other improvements in control programs. However, the rate of detection of new cases has not decreased in Brazil. An analysis was made of the temporal distribution of 18,872 newly reported leprosy cases in Bahia, Brazil, from 1974 to 1997. Population denominators for the annual detection rate were obtained from population estimates based on the national census. Trends were presented by sex, date of birth, date of diagnosis, date of release, clinical form and by residence in areas which had notified cases in the 5 years prior to the rise in detection rate. There was a marked increase in the new case detection rate (NCDR) in the State of Bahia, from 0.19 to 1.43 cases per 10,000 inhabitants during the study period, an increment of nearly 7% to 8% per year. This increase was also observed in people aged 14 years and younger. During this period tuberculoid and indeterminate forms have become predominant among women and younger people. The average age of male cases has shifted toward younger ages. We interpret this pattern to mean that the increase in NCDR reflects a real increase in incidence of leprosy, whether or not accompanied by improved detection.


[Complicated colonic diverticulosis. Changes in treatment and results over 22 years].
The aim of this study was to analyse the clinical course, surgical strategy and results in patients with complicated colonic diverticular disease. We retrospectively compared two groups of patients who underwent surgery for complicated colonic diverticulosis from 1970 to 1984 (Group A, n = 94, mean age 60 years, 49 males, 45 females) and from 1985 to 1992 (Group B, n = 76, mean age 63.5, 32 males, 44 females). Patients in the two groups were comparable; only the rate of peritonitis (20 vs 8%) was different (p < 0.05). The most frequent operations in Group A were colostomy-drainage (43%) and Hartman's procedure (26%) in emergency situations and resection with immediate anastomosis (63%) or resection-anastomosis with diverting stomy (19%) in elective cases. In Group B, surgical strategy led to a different pattern of operations, 4 and 56% in emergency, and 94 and 2% in elective surgery, respectively. Overall mortality was 11%, with 17% and 4% in Groups A and B respectively (p < 0.01). This major drop in mortality was particularly important in emergency cases (31 vs 4%; p < 0.02). Morbidity in emergency surgery fell from 21 to 4% (P < 0.0006). Interrupting the use of colostomy-drainage was a major factor in reducing mortality followed by a sharp fall in mortality after Hartmann's procedure (28.5 vs 0%). The marked improvement in results between the two groups was mainly due to preferring resections of pathological colonic segments over colostomy-drainage.


Propagation of human candidate calicivirus in cell culture.
Evidence is presented for the first time that a human candidate calicivirus (HCV) replicates in human embryo kidney cells when trypsin is incorporated in the culture medium. The virus multiplies in the presence of actinomycin D and radiolabelling experiments with [3H]uridine indicate that it has an RNA genome. These observations provide further support for the view that HCV should be tentatively classified as a member of the Caliciviridae .


Phenotype-genotype correlation in eight Polish patients with inherited Factor XIII deficiency: identification of three novel mutations.
Inherited factor XIII (FXIII) deficiency is known as one of the most rare blood coagulation disorder in humans. In the present study, phenotype and genotype of eight FXIII deficient Polish patients from five unrelated families were compared. The patients presented with a severe phenotype demonstrated by a high incidence of intracerebral haemorrhages (seven of eight patients), haemarthrosis (six patients) and bleeding due to trauma (five patients). Introduction of regular substitution with FXIII concentrate prevented spontaneous bleeding in seven patients. In all patients, mutations within the F13A gene have been identified revealing four missense mutations (Arg77Cys, Arg260Cys, Ala378Pro, Gly420Ser), one nonsense mutation (Arg661X), one splice site mutation (IVS5-1 G>A) and one small deletion (c.499-512del). One homozygous large deletion involving exon 15 was detected by failure of PCR product. The corresponding mutations resulted in severely reduced FXIII activity and FXIII A-subunit antigen concentration, while FXIII B-subunit antigen remained normal or mildly decreased. Structural analysis demonstrated that the novel Ala378Pro mutation may cause a disruption of the FXIII catalytic triad leading to a non-functional protein which presumably undergoes premature degradation. In conclusion, the severe phenotype with high incidence of intracranial bleeding and haemarthrosis was in accordance with laboratory findings on FXIII and with severe molecular defects of the F13A gene.


Diversity of color vision: not all Australian marsupials are trichromatic.
Color vision in marsupials has recently emerged as a particularly interesting case among mammals. It appears that there are both dichromats and trichromats among closely related species. In contrast to primates, marsupials seem to have evolved a different type of trichromacy that is not linked to the X-chromosome. Based on microspectrophotometry and retinal whole-mount immunohistochemistry, four trichromatic marsupial species have been described: quokka, quenda, honey possum, and fat-tailed dunnart. It has, however, been impossible to identify the photopigment of the third cone type, and genetically, all evidence so far suggests that all marsupials are dichromatic. The tammar wallaby is the only Australian marsupial to date for which there is no evidence of a third cone type. To clarify whether the wallaby is indeed a dichromat or trichromatic like other Australian marsupials, we analyzed the number of cone types in the "dichromatic" wallaby and the "trichromatic" dunnart. Employing identical immunohistochemical protocols, we confirmed that the wallaby has only two cone types, whereas 20-25% of cones remained unlabeled by S- and LM-opsin antibodies in the dunnart retina. In addition, we found no evidence to support the hypothesis that the rod photopigment (rod opsin) is expressed in cones which would have explained the absence of a third cone opsin gene. Our study is the first comprehensive and quantitative account of color vision in Australian marsupials where we now know that an unexpected diversity of different color vision systems appears to have evolved.


Core-shell structures of silica-organic pigment nanohybrids visualized by electron spectroscopic imaging.
Energy-filtering electron transmission spectroscopy observation has been achieved to elucidate the nanostructures of powdery nanohybrids, which were produced by the dry mechanical milling of organic pigments and silica nanoparticles. The hybrids possess core-shell structures, irrespective of the levels of aggregation of primary particles, whereas hollow sites of aggregates of primary silica particles were filled with the pigment, leading to the locally concentrated distribution of the pigment to reduce the surface areas of the hybrids. The results imply that nanohybridization is referred to as the buildup method, although mechanical tools and procedures are quite the same as those for the conventional breakdown method.


BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort.
BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. Rapidly evolving human BRCA generates oncogenic variants causing high cancer risk. BRCA variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift. Taiwanese population of 23.8 million is an admixture of multiple ethnic origins; Taiwan's subtropical and tropical climate and geographically islandic location provide a unique natural environment. Therefore, Taiwanese population provides a unique model to study human BRCA variation. Through collecting, standardizing, annotating, and classifying publicly available BRCA variants derived from Taiwanese general population and the cancer cohort, we identified 335 BRCA variants, of which 164 were from 1,517 non-cancer individuals, 126 from 2,665 cancer individuals, and 45 from both types of individuals. We compared the variant data with those from other ethnic populations such as mainland Chinese, Macau Chinese, Japanese, Korean, Indian, and non-Asians. We observed that the sharing rates with other Asian ethnic populations were correlated with its genetic relationship. Over 60% of the 335 Taiwanese BRCA variants were VUS, unclassified variants, or novel variants, reflecting the ethnic-specific features of Taiwanese BRCA variation. While it remains challenging to classify these variants, our structural and in silico analyses predicted their enrichment of BRCA deleterious variants. We further determined the 3.8% prevalence of BRCA pathogenic variants in the Taiwanese breast cancer cohort, and determined 0.53% prevalence of the BRCA pathogenic variants in Taiwanese general population, with the estimated 126,140 BRCA pathogenic variant carriers. We identified BRCA2 c.5164_5165delAG at BRCA2 BRC6 motif as a potential founder mutation in Taiwanese population. Our study on BRCA variation in Taiwanese and other East Asian populations demonstrates that ethnic specificity is a common phenomenon for BRCA variation in East Asian population; the data generated from the study provide a reference for clinical applications in BRCA-related cancer in Taiwanese population.


Spontaneous endogenous microbubbles in a child with Berlin heart ventricular assist device.
We report the case of an 11-year-old boy with familial dilated cardiomyopathy on biventricular assist devices (Berlin Heart EXCOR) who was found to have spontaneous endogenous microbubbles in the left ventricular (LV) cavity on routine echocardiogram. Although no major sequelae resulted from the presence of these microbubbles, it did however lead to several noninvasive investigations. To our knowledge, this is a novel observation of spontaneous endogenous microbubbles in a patient with a Berlin Heart. The unknown clinical significance of this phenomenon highlights the need for further studies.


A literature review of randomized controlled trials of the organization of care at the end of life.
We searched nine electronic databases for randomized controlled trials (RCTs) about care at the end of life and found 23 RCTs. We assessed their quality using the criteria of the Cochrane Collaboration. The RCTs researched three themes: (a) the effect of providing palliative care through dedicated community teams on quality of life, on the management of symptoms, on satisfaction with care, on the duration of the palliative period, and on place of death; (b) the effects of specific palliative care interventions-advanced planning of care for the end of life, patient-held records, providing quality-of-life data to patients and physicians, grief education for relatives, palliative care education for nurses, and palliative care for patients with dementia; and (c) the costs of palliative compared to conventional care. We identify difficulties in conducting research on palliative care and solutions and discuss future possible research themes.


Direct arylation and heterogeneous catalysis; ever the twain shall meet.
The formation of aryl-aryl bonds and heteroaryl analogues is one of the most important C-C bond forming processes in organic chemistry. Recently, a methodology termed Direct Arylation (DA) has emerged as an attractive alternative to traditional cross-coupling reactions (Suzuki-Miyaura, Stille, Negishi, etc.). A parallel focus of the pharmaceutical and other chemical industries has been on the use heterogeneous catalysis as a favourable substitute for its homogeneous counterpart in cross-coupling reactions. Only very recently has heterogeneous catalysis been proposed and applied, to DA reactions. In this perspective, we consider the terms 'heterogeneous' and 'homogeneous' and the problems associated with their delineation in transition-metal catalysed reactions. We highlight the reports at the interface of DA and heterogeneous catalysis and we comment briefly on the methods used which attempt to classify reaction types as homo- or heterogeneous. In future work we recommend an emphasis be placed on kinetic methods which provide an excellent platform for analysis. In addition two analytical techniques are described which if developed to run in situ with DA reactions would illuminate our understanding of the catalysis. Overall, we provide an entry point, and bring together the mature, yet poorly-understood, subject of heterogeneous catalysis with the rapidly expanding area of DA, with a view towards the acceleration of catalyst design and the understanding of catalyst behaviour.


Characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire in patients with advanced lung cancer.
Lung cancer is one of the greatest threats to human health, and is initially detected and attacked by the immune system through tumor-reactive T cells. The aim of this study was to determine the basic characteristics and clinical significance of the peripheral blood T-cell receptor (TCR) repertoire in patients with advanced lung cancer. To comprehensively profile the TCR repertoire, high-throughput sequencing was used to identify hypervariable rearrangements of complementarity determining region 3 (CDR3) of the TCR β chain in peripheral blood samples from 64 advanced lung cancer patients and 31 healthy controls. We found that the TCR repertoire differed substantially between lung cancer patients and healthy controls in terms of CDR3 clonotype, diversity, V/J segment usage, and sequence. Specifically, baseline diversity correlated with several clinical characteristics, and high diversity reflected a better immune status. Dynamic detection of the TCR repertoire during anticancer treatment was useful for prognosis. Both increased diversity and high overlap rate between the pre- and post-treatment TCR repertoires indicated clinical benefit. Combination of the diversity and overlap rate was used to categorize patients into immune improved or immune worsened groups and demonstrated enhanced prognostic significance. In conclusion, TCR repertoire analysis served as a useful indicator of disease development and prognosis in advanced lung cancer and may be utilized to direct future immunotherapy.


Uncertainty of decibel levels.
The mean sound exposure level from a source is routinely estimated by the mean of the observed sound exposures from repeated measurements. A formula for the standard uncertainty based on the Guide to the expression of Uncertainty in Measurement (GUM) is derived. An alternative formula is derived for the case where the GUM method fails. The formulas are applied on several examples, and compared with a Monte Carlo calculation of the standard uncertainty. The recommended formula can be seen simply as a convenient translation of the uncertainty on an energy scale into the decibel level scale, but with a theoretical foundation.


Haemodynamic Preservation In Caesarean Sections By Low Dose 0.5% Hyperbaric Bupivacaine.
Spinal anaesthesia is technique of choice for caesarean sections and hyperbaric bupivacaine is a recommended drug for this popular block. Although safe but few complications are haemodynamic changes, postdural puncture headache, cauda equina syndrome and radiculopathy. However, hypotension remains the common side effect which is believed to occur in 95% of patients resulting in reduction of uteroplacental perfusion causing foetal acid-base abnormalities. Various doses regimes are in safe anaesthesia practice for providing regional anaesthesia for such patients with least detrimental effects on foetal outcome. This study was carried out to find the effective dose of 0.5 % hyperbaric bupivacaine in caesarean section patients by comparing two different doses. After enrolling two hundred patients of C section (Caesarean section) for this study, 90 patients were selected to compare the effects of 0.5% hyperbaric bupivacaine. Group A (n=45) received 10 mg of drug while group B (n=45) received 12 mg for spinal anaesthesia. Onset of block, sensory and motor level, haemodynamic changes, surgery time, maternal satisfaction, Apgar score and incidence of complications were compared in two groups. Blood pressure decreases were less in Group A (p-0.074) but not statistically significant. Phenylephrine for hypotension was given to 17% vs 5% in group B. Maternal satisfaction was found to be better in group B 33 vs 17 but was statistically significant (p 0.034). 2% patients had bradycardia in group A which was treated by atropine. No complications were reported in either group. Doses of hyperbaric bupivacaine for spinal anaesthesia in caesarean sections must be at least 12 mg because it produces excellent anaesthesia and maternal satisfaction without complications.


DNA sequencing and expression of the formyl coenzyme A transferase gene, frc, from Oxalobacter formigenes.
Oxalic acid, a highly toxic by-product of metabolism, is catabolized by a limited number of bacterial species utilizing an activation-decarboxylation reaction which yields formate and CO2. frc, the gene encoding formyl coenzyme A transferase, an enzyme which transfers a coenzyme A moiety to activate oxalic acid, was cloned from the bacterium Oxalobacter formigenes. DNA sequencing revealed a single open reading frame of 1,284 bp capable of encoding a 428-amino-acid protein. A presumed promoter region and a rho-independent termination sequence suggest that this gene is part of a monocistronic operon. A PCR fragment containing the open reading frame, when overexpressed in Escherichia coli, produced a product exhibiting enzymatic activity similar to the purified native enzyme. With this, the two genes necessary for bacterial catabolism of oxalate, frc and oxc, have now been cloned, sequenced, and expressed.


Evidence of skeletal treponematosis from the medieval burial ground of St. Mary Spital, London, and implications for the origins of the disease in Europe.
Treponematosis is a syndrome of chronic infectious diseases. There has been much debate on its origins and spread, particularly with regard to venereal syphilis, an unsightly and debilitating disease in preantibiotic populations. The osteological analysis of 5,387 individuals excavated by Museum of London Archaeology from the medieval burial ground of St. Mary Spital in London (dated c 1120-1539) provided an unprecedented opportunity to investigate the nature and prevalence of disease over a period of time. Twenty-five individuals were found with suspected treponematosis, originating from all but the earliest period of the burial ground. Descriptions of affected individuals from each period, together with supporting images, are provided. In this work, particular emphasis was given to the distribution of lesions on the skeleton and the variation in patterns by sex and over time. Little change was observed in the distribution of bony change between individuals dated to pre- and post-Columbian periods. However, a dramatic rise in the prevalence of the disease in the final period (c 1400-1539) may reflect documentary reports of a European epidemic from the late 15th century.


Stress resets ancestral heritable small RNA responses.
Transgenerational inheritance of small RNAs challenges basic concepts of heredity. In Caenorhabditis elegans nematodes, small RNAs are transmitted across generations to establish a transgenerational memory trace of ancestral environments and distinguish self-genes from non-self-elements. Carryover of aberrant heritable small RNA responses was shown to be maladaptive and to lead to sterility. Here, we show that various types of stress (starvation, high temperatures, and high osmolarity) induce resetting of ancestral small RNA responses and a genome-wide reduction in heritable small RNA levels. We found that mutants that are defective in various stress pathways exhibit irregular RNAi inheritance dynamics even in the absence of stress. Moreover, we discovered that resetting of ancestral RNAi responses is specifically orchestrated by factors that function in the p38 MAPK pathway and the transcription factor SKN-1/Nrf2. Stress-dependent termination of small RNA inheritance could protect from run-on of environment-irrelevant heritable gene regulation.


The usefulness of pulsed tissue Doppler for the clinical assessment of right ventricular function.
Standard Doppler echocardiographic evaluation of the right ventricular (RV) function has several limitations because of a difficult technical approach. The purpose of the present review was to investigate, even in the light of such problems, the usefulness of pulsed tissue Doppler (TD) during the assessment of RV transverse and longitudinal function on the basis of the regional velocities and time intervals. TD-derived (systolic and diastolic) velocities of the RV free wall and of the lateral tricuspid annulus have been used to establish reference values in healthy subjects and in different cardiac diseases. Some studies have shown the usefulness of myocardial systolic velocities for the detection of RV systolic failure at rest and of right coronary artery stenosis during stress. The myocardial early diastolic velocities, combined to Doppler standard tricuspid inflow measurements, represent reliable indexes of right chamber hemodynamics, the ratio between the Doppler tricuspid E velocity and the TD-derived early diastolic velocity of the lateral tricuspid annulus being positively related to the mean right atrial pressure after heart transplantation. Even the assessment of RV regional time intervals may have clinical implications. In particular, the relaxation time of the lateral tricuspid annulus, very short or even absent in healthy subjects increases progressively with the pulmonary systolic artery pressure and its length is strongly influenced also by the increasing RV wall thickness in septal hypertrophic cardiomyopathy and in hypertensive left ventricular hypertrophy. The interaction between the two ventricles is identified by assessing the TD velocities of the RV tricuspid annulus which are often associated with the corresponding velocities of the mitral annulus in different pathologies. On the grounds of these studies, the clinical use of pulsed TD merits consideration. Longitudinal follow-up of TD RV patterns will be useful to evaluate the progression from early RV wall dysfunction until the development of global RV failure and the possible beneficial effect of cardiac drugs on RV function as determined by TD evaluation.


Validation of the Apraxia Screen TULIA (AST) in Schizophrenia.
Deficits in social interaction and community functioning, including impaired use, performance, and perception of hand gestures, are key features in schizophrenia. A well-established tool to assess gesture deficits is the test of upper limb apraxia (TULIA). However, given its time-consuming application based on video analyses, research has proposed the bedside apraxia screen of TULIA (AST). This study aims to test the validity and reliability of the AST to detect gesture abnormalities at bedside in a sample of 27 patients diagnosed with schizophrenia, schizotypal disorder, acute and transient psychotic disorders, or schizoaffective disorder. Patients completed the 48-item TULIA and the 12-item AST. Two different raters assessed the AST: one at bedside (online) and the other based on the video recordings. The total AST scores demonstrated a high parallel reliability, moderate inter-rater reliability on a single-item level, and good construct validities. The psychometric properties of the AST suggest it can well be used for the clinical assessment of gesture deficits in schizophrenia. However, when detailed information is required, the AST rated from video or conducting the full TULIA is recommended. The findings call for refining the selection of the TULIA items for a psychosis-AST bedside test to increase specificity.