Heat-attributable deaths between 1992 and 2009 in Seoul, South Korea.
Climate change may significantly affect human health. The possible effects of high ambient temperature must be better understood, particularly in terms of certain diseases' sensitivity to heat (as reflected in relative risks [RR]) and the consequent disease burden (number or fraction of cases attributable to high temperatures), in order to manage the threat. This study investigated the number of deaths attributable to abnormally high ambient temperatures in Seoul, South Korea, for a wide range of diseases. The relationship between mortality and daily maximum temperature using a generalized linear model was analyzed. The threshold temperature was defined as the 90th percentile of maximum daily temperatures. Deaths were classified according to ICD-10 codes, and for each disease, the RR and attributable fractions were determined. Using these fractions, the total number of deaths attributable to daily maximum temperatures above the threshold value, from 1992 to 2009, was calculated. Data analyses were conducted in 2012-2013. Heat-attributable deaths accounted for 3,177 of the 271,633 deaths from all causes. Neurological (RR 1.07; 95% CI, 1.04-1.11) and mental and behavioral disorders (RR 1.04; 95% CI, 1.01-1.07) had relatively high increases in the RR of mortality. The most heat-sensitive diseases (those with the highest RRs) were not the diseases that caused the largest number of deaths attributable to high temperatures. This study estimated RRs and deaths attributable to high ambient temperature for a wide variety of diseases. Prevention-related policies must account for both particular vulnerabilities (heat-sensitive diseases with high RRs) and the major causes of the heat mortality burden (common conditions less sensitive to high temperatures).


Markup of temporal information in electronic health records.
Temporal information plays a critical role in the understanding of clinical narrative (i.e., free text). We developed a representation for marking up temporal information in a narrative, consisting of five elements: 1) reference point, 2) direction, 3) number, 4) time unit, and 5) pattern. We identified 254 temporal expressions from 50 discharge summaries and represented them using our scheme. The overall inter-rater reliability among raters applying the representation model was 75 percent agreement. The model can contribute to temporal reasoning in computer systems for decision support, data mining, and process and outcomes analyses by providing structured temporal information.


Tuning spin wave modes in yttrium iron garnet films with stray fields.
The nanopatterning of Yttrium Iron Garnets (YIGs) has proven to be a non-trivial problem even with advances in modern lithography techniques due to non-compatibility with a conventional complementary metal oxide semiconductor platform. In an attempt to circumvent this problem, we demonstrate a simple and reliable method to indirectly pattern YIG films on a Gadolinium Gallium Garnet (GGG) substrate. We fabricated exchange-coupled arrays of Py dots onto the underlying YIG films using nanostencil lithography. The stray fields generated from the Py dots were used to transfer patterned magnetic information to the underlying YIG films. The static and dynamic properties of the fabricated hybrid YIG/Py dot structure and reference YIG film were characterized using the focused magneto-optic Kerr effect and by broadband ferromagnetic resonance spectroscopy. For the reference YIG film, as expected, a single field-dependent resonance mode with a narrow linewidth was observed in contrast to the splitting into three distinct resonance modes for the YIG/Py dot structure as predicted by micromagnetic simulations. We have thus shown that it is possible to utilize stray field effects from easily patternable magnetic materials for the development of future YIG-based magnonic devices.


Incidence of hypersensitivity and anaphylaxis with sugammadex.
To evaluate the incidence of hypersensitivity and anaphylaxis after administration of sugammadex. Retrospective analysis. Sugammadex clinical development program and post-marketing experience. Surgical patients and healthy volunteers who received sugammadex or placebo/comparator with anesthesia and/or neuromuscular blockade (NMB). Sugammadex administered as 2.0 mg/kg at reappearance of the second twitch, 4.0 mg/kg at 1-2 post-tetanic count, or 16.0 mg/kg at 3 min after rocuronium 1.2 mg/kg. Three analytical methods were used: 1) automated MedDRA queries; 2) searches of adverse events (AEs) consistent with treatment-related hypersensitivity reactions as diagnosed by the investigator; and 3) a retrospective adjudication of AEs suggestive of hypersensitivity by a blinded, independent adjudication committee (AC). In addition, a search of all post-marketing reports of events of hypersensitivity was performed, and events were retrospectively adjudicated by an independent AC. Anaphylaxis was determined according to Sampson Criterion 1. The pooled dataset included 3519 unique subjects who received sugammadex and 544 who received placebo. The automated MedDRA query method showed no apparent increase in hypersensitivity or anaphylaxis with sugammadex as compared to placebo or neostigmine. Similarly, there was a low overall incidence of AEs of treatment-related hypersensitivity (<1%), with no differences between sugammadex and placebo or neostigmine. Finally, the retrospective adjudication of AEs suggestive of hypersensitivity showed a low incidence of hypersensitivity (0.56% and 0.21% for sugammadex 2 mg/kg and 4 mg/kg, respectively), with an incidence similar to subjects who received placebo (0.55%). There were no confirmed cases of anaphylaxis in the pooled studies. During post-marketing use, spontaneous reports of anaphylaxis occurred with approximately 0.01% of sugammadex doses. Subjects who received sugammadex with general anesthesia and/or NMB had a low overall incidence of hypersensitivity, with no apparent increase in hypersensitivity or anaphylaxis with sugammadex as compared to placebo or neostigmine.


Quantitative Interrogation of the Human Kinome Perturbed by Two BRAF Inhibitors.
Oncogenic BRAF mutations contribute to the development of a number of cancers, and small-molecule BRAF inhibitors have been approved by the Food and Drug Administration (FDA) for anticancer therapy. In this study, we employed two targeted quantitative proteomics approaches for monitoring separately the alterations in protein expression and ATP binding affinities of kinases in cultured human melanoma cells elicited by two FDA-approved small-molecule BRAF inhibitors, dabrafenib and vemurafenib. Our results showed that treatment with the two inhibitors led to markedly different reprograming of the human kinome. Furthermore, we confirmed that vemurafenib could compromise the ATP binding capacity of MAP2K5 in vitro and inhibit its kinase activity in cells. Together, our targeted quantitative proteomic methods revealed profound changes in expression levels of kinase proteins in cultured melanoma cells upon treatment with clinically used BRAF inhibitors and led to the discovery of novel putative target kinases for these inhibitors.


Bifid intrathoracic rib: a case report and classification of intrathoracic ribs.
Bifid intrathoracic rib is a very rare anomaly of the ribs that is characterized by an osseous prominence of a rib into the thoracic cavity. We report a 21-year-old woman with bifid intrathoracic rib arising from the anterior-lateral portion of a depressed 4th rib, based on findings from chest radiography and computed tomography (CT). This is only the second reported case of this type of intrathoracic rib worldwide. We discuss differential diagnoses for this case and suggest a classification of intrathoracic rib from the perspective of morphology and developmental biology.


Prolonged and fluctuating giant T-wave inversion after electroconvulsive therapy.
A 76-year-old woman was scheduled to receive 8 treatments of electroconvulsive therapy (ECT) for severe depression. Although she experienced no adverse consequences in the first 2 treatments, giant T-wave inversion ensued from the third treatment despite no change in anesthesia or technical parameters of ECT. T-wave inversion appeared to have almost disappeared 8 days after the third ECT, but reappeared at 3 weeks after treatment during severe pain from gallbladder stone. T-wave inversion lasted for 4 months with gradual attenuation. Exaggerated sympathetic stimulation associated with ECT as physical and emotional stressors might have played a role in the appearance of T-wave inversion similar to catecholamine-induced cardiomyopathy. Furthermore, reappearance of T-wave inversion may have been involved in additive effects of pain from gallbladder stone on vulnerability due to a catecholamine-induced cardiomyopathy-like condition.


Epac1 agonist decreased inflammatory proteins in retinal endothelial cells, and loss of Epac1 increased inflammatory proteins in the retinal vasculature of mice.
Increased inflammatory mediator levels are reported in diabetic retinopathy. We previously reported that β-adrenergic receptor agonists reduced inflammatory mediators in the diabetic retina; however, these agents cannot be given systemically. Here, we investigated whether Epac1 is key to the protective effects of β-adrenergic receptor agonists. We cultured primary human retinal endothelial cells (RECs) in normal (5 mM) or high (25 mM) glucose and treated them with an Epac1-specific agonist. Additionally, we generated Epac1 conditional vascular endothelial cell knockout mice by breeding Epac1 floxed mice with Cdh5 Cre mice to investigate the role of Epac1 in the retinal levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa beta (NFκB), and inhibitor of kappa beta (IκB). Confocal microscopy was performed to localize Epac1 in the mouse retina. Data showed that high glucose increased the TNF-α and IL-1β levels in the RECs, which were reduced cells treated with the Epac1 agonist. The loss of Epac1 in the retinas of the conditional knockout mice resulted in statistically significantly increased levels of TNF-α and IL-1β, as well as NFκB. These data indicate that Epac1 may be protective to the retina through inhibition of key inflammatory mediators.


Dopamine stimulation of the septum enhances exercise efficiency during complicated treadmill running in mice.
We aimed to identify the neurotransmitters and brain regions involved in exercise efficiency in mice during continuous complicated exercises. Male C57BL/6J mice practiced treadmill running with intermittent obstacles on a treadmill for 8 days. Oxygen uptake (VO2) during treadmill running was measured as exercise efficiency. After obstacle exercise training, the VO2 measured during treadmill running with obstacles decreased significantly. Obstacle exercise-induced c-Fos expressions and dopamine turnover (DOPAC/dopamine) in the septum after obstacle exercise training were significantly higher than that before training. The dopamine turnover was correlated with exercise efficiency on the 3rd day after exercise training. Furthermore, the training effect on exercise efficiency was significantly decreased by injection of dopamine receptor antagonists into the septum and was associated with decreased c-Fos expressions in the septum and hippocampus of the mice. These results suggest that dopaminergic function in the septum is involved in exercise efficiency during continuous complicated exercises.


Creatinine reduction ratio: a useful marker to identify medium and high-risk renal transplants.
Delayed graft function (DGF) has a major impact on long-term renal transplant survival. However, it is a diagnosis made retrospectively with little opportunity to modify treatment protocols. A classification based on creatinine reduction ratio between days 1 and 2 (CRR2) suggests that patients with CRR2 less than or equal to 30% (nondialysis requiring DGF [ND-DGF]) have similar outcomes to those with dialysis-requiring delayed graft function (D-DGF). We retrospectively applied this definition in our cohort of patients to examine outcomes. We studied the association between CRR2 and graft outcomes in all 367 patients transplanted between 1996 and 2004 at our center. Patients were divided into the following three groups: IGF (immediate graft function; CRR2 >30%), D-DGF, and ND-DGF. Mean follow-up was 4.2 years. IGF accounted for 36% of patients, D-DGF for 22%, and ND-DGF for 42%. CRR2 was inversely correlated with serum creatinine on days 7, 30, 90, and 365 (r ranging from -0.65 to -0.22, P<0.001). Graft survival at 5 years was 98% (IGF), 74% (D-DGF), and 89% (ND-DGF). There was a significant difference in graft survival between IGF and D-DGF (P<0.001) and IGF and ND-DGF (P=0.005). In a multivariate analysis adjusting for recipient age and sex, donor age and sex, and human leukocyte antigen mismatch, graft failure was 2.4 times more likely to occur in patients with D-DGF than those with ND-DGF(P=0.02). Our study shows CRR2 influences long-term graft outcomes. Unlike the original description, patients with ND-DGF carry an intermediate risk and perhaps should be considered on day 2 for alternative treatment protocols.


Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis.
Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis.


[Nuclear spin tomography of the male pelvis. Methods, anatomy and initial clinical results].
A pilot study of MRI was carried out on three normal male volunteers and 15 patients with tumours in the prostate or bladder. One advantage of the method is the ability to obtain images in three planes, without moving the patient. It is therefore possible for the first time to demonstrate lesions in the base of the bladder in their cranio-caudal extent. Tissue contrast of MRI, using long sequences with suitable proton or T2-weighted images is better than with CT and provides more accurate diagnosis. Even non-expansive tumours within the gland can be differentiated from normal glandular tissue. It has been noted that carcinoma of the prostate in the T2-mode provides an increased signal, whereas tumours of the bladder look dark. Up to a point, tissue characterisation may be possible.


Successful prophylaxis of intracranial hemorrhage in infants with severe congenital factor VII deficiency.
During the period 1984-1992, 2 severe cases (1 male, 1 female) of congenital F VII deficiency with intracranial hemorrhage (ICH) were referred to the Department of Pediatrics, Siriraj Hospital Bangkok, Thailand at the ages of 1 and 3 months old. They both responded very well to fresh frozen plasma (FFP) transfusion therapy. Subsequently, both had repeated episodes of ICH (repeated ICH) 5 and 6 times, despite the 10-14 days of replacement therapy for each episode and eventually died at the ages of 11 and 13 months. Since September 1996, another 2 severe cases (2 females) of congenital F VII deficiency who had ICH within their first month of life were referred to us. In order to prevent repeated ICH, we started a prophylactic regime after the second episode of ICH, by giving FFP 10 ml/kg twice a week. The average duration of follow up was 21 months (at 8 and 34 months). All of them (aged 14, and 38 months old) are doing well at this time and free from repeated ICH. From this observation, if there is FFP available, this regime is an effective way to prevent repeated ICH in infants with severe congenital Factor VII deficiency.


Optimal efficiency of self-assembling light-harvesting arrays.
Using a classical master equation that describes energy transfer over a given lattice, we explore how energy transfer efficiency along with the photon capturing ability depends on network connectivity, on transfer rates, and on volume fractions-the numbers and relative ratio of fluorescence chromophore components, e.g., donor (D), acceptor (A), and bridge (B) chromophores. For a one-dimensional AD array, the exact analytical expression (derived in Appendix A) for efficiency shows a steep increase with a D-to-A transfer rate when a spontaneous decay is sufficiently slow. This result implies that the introduction of B chromophores can be a useful method for improving efficiency for a two-component AD system with inefficient D-to-A transfer and slow spontaneous decay. Analysis of this one-dimensional system can be extended to higher-dimensional systems with chromophores arranged in structures such as a helical or stacked-disk rod, which models the self-assembling monomers of the tobacco mosaic virus coat protein. For the stacked-disk rod, we observe the following: (1) With spacings between sites fixed, a staggered conformation is more efficient than an eclipsed conformation. (2) For a given ratio of A and D chromophores, the uniform distribution of acceptors that minimizes the mean first passage time to acceptors is a key point to designing the optimal network for a donor-acceptor system with a relatively small D-to-A transfer rate. (3) For a three-component ABD system with a large B-to-A transfer rate, a key design strategy is to increase the number of the pathways in accordance with the directional energy flow from D to B to A chromophores. These conclusions are consistent with the experimental findings reported by Francis, Fleming, and their co-workers and suggest that synthetic architectures of self-assembling supermolecules and the distributions of AD or ABD chromophore components can be optimized for efficient light-harvesting energy transfer.


Distribution of uncrossed and crossed retinofugal axons in the cat optic nerve and their relationship to patterns of fasciculation.
The course of optic axons that take different routes at the chiasm have been traced through horizontally sectioned optic nerves in the cat, after unilateral injections of horseradish peroxide into the optic tract. Behind the eye and for most of the course of the nerve, nearly all of the axons that remain uncrossed at the chiasm are located in a retinotopically appropriate position, in the lateral aspect of the nerve. However, in the most caudal segment of the nerve an increasing proportion of these axons are located in regions that are retinotopically inappropriate. Just before the nerve joins the chiasm, uncrossed axons can be found across the full medio-lateral extent of the nerve, although there is still a relative increase in their density laterally. Labeled axons that cross at the chiasm course in a relatively parallel manner along the greater proportion of the nerve. However, in the caudal segment of the nerve their relative positions change and they appear to course in an irregular manner. This occurs where the uncrossed projection becomes increasingly more widespread. Axons in the optic nerve are grouped into fascicules. This pattern of organization also changes in the caudal region of the nerve. Although clear fascicular patterns are present along the greater part of the nerve, they become progressively less distinct caudally. The change in the pattern of fasciculation occurs over the same region of the nerve as the relative changes in axon trajectory and distribution. These results demonstrate that irrespective of chiasmatic route, optic axons in the cat are reorganized in the caudal segment of the nerve.(ABSTRACT TRUNCATED AT 250 WORDS)


Photochemical Synthesis of Nepetanudone.
Nepetanudone and nepetaparnone have been suspected of being the products of a photochemical dimerization of nepetapyrone. Both are natural products found in a variety of Nepeta species. The synthesis of (±)-nepetapyrone and subsequent photochemical experiments are described. (±)-Nepetanudone was produced upon irradiation of (±)-nepetapyrone, while (±)-nepetaparnone, a diastereomer of nepetanudone, was not observed.


Elevated circulating lipocalin-2 levels independently predict incident cardiovascular events in men in a population-based cohort.
Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of cardiovascular diseases (CVD). Lipocalin-2 (LCN2), mainly released from adipocytes, has been shown to be positively associated with CVD in cross-sectional studies. We aimed to evaluate the association of LCN2 with CVD involving a population-based cohort recruited from the Shanghai Diabetes Study. Serum LCN2 levels were measured using ELISA. Independent predictors of CVD development were identified using Cox proportion hazards regression. The predictive performances of the various models were assessed by Kaplan-Meier analysis. At baseline, circulating LCN2 was significantly associated with a cluster of traditional cardiovascular risk factors. Baseline LCN2 levels in male subjects who developed CVD events during follow-up were significantly higher than those who did not develop CVD events (P=0.012). However, such difference was not significant in female subjects. LCN2 was a predictor of CVD in men, which remained statistically significant after adjustment for traditional cardiovascular risk factors (hazard ratio, 1.038 [95% confidence interval, 1.017-1.060]). LCN2 remained significantly associated with incident CVD even after adjustment for renal function, adiponectin, and high-sensitivity C-reactive protein levels. Kaplan-Meier analysis suggested combination of LCN2 and high-sensitivity C-reactive protein might improve the prediction of CVD events in male subjects. Elevated circulating LCN2 level is an independent predictor of CVD events in men in a population-based cohort and adds to the prognostic value of high-sensitivity C-reactive protein, which is currently the most extensively studied biomarker of CVD. Measurement of serum LCN2 might be useful for early detection and intervention of CVD.


SARS-CoV-2 gamma variant and chronic arterial insufficiency due to late arterial thrombosis.
The current evidence suggests a state of hypercoagulability as one of the sequelae of hyperinflammation. Thus, it is an important pathogenic mechanism that contributes to increase the mortality caused by COVID-19. The aim of the present study is to report chronic arterial insufficiency after post-thrombosis in the same arteries 32 days later, as a sequel after severe acute respiratory syndrome coronavirus 2 P.1. After the 2nd day of discharge, she had a lot of pain in her left and limiting leg and was referred to the vascular service. The patient was evaluated by vascular surgery who underwent a clinical diagnosis of Rutherford II.A arterial thrombosis and underwent arteriography of the limb that revealed thrombosis of the anterior, posterior, and fibular arteries in the middle third and the plantar arch was not contrasted. She underwent emergency embolectomy with selective isolation of the tibial arteries, but with success after the procedure only for the posterior tibial artery. Anticoagulation was maintained and 100 mg aspirin was associated.


Water quality management planning zone development by introducing a GIS tool in Kathmandu valley, Nepal.
This research was conducted to identify the critical pollution (BOD, TN, TP) areas and to develop the priority mitigation zone for the Bagmati River pollution in the Kathmandu valley, Nepal. A GIS tool was used to define and identify the critical pollution areas and sources. Pollution source information such as population, livestock, industry and land use were collected on the basis of the individual village boundary. The industrial, land use and living pollution were aggregated by the GIS overlay analysis capability to obtain the combined pollution load within the watershed. Priority areas for the mitigation of the pollution were defined considering the pollution loading rate, distance of stream from pollution source, and political, religious, and touristic values of the area. This research noticed that Kathmandu, Lalitpur and Bhaktapur municipalities are the major polluting areas and living beings are the major factors of Bagmati River pollution. Delivery ratio for the watershed was found to vary from 40-69% for BOD and nitrogen but the delivery of phosphorus was exceptionally high (92% at Gaurighat and 77% at Chovar) due to cremation activity of the Hindu religion on the riverbanks. Thus, the priority areas for the mitigation of the carbonaceous and nutrient source pollution were identified. At present the land use and industry impaired a very low contribution compared to the huge pollution load from the municipalities to the river system.


The Ran-GTP gradient spatially regulates XCTK2 in the spindle.
Ran is a small GTP binding protein that was originally identified as a regulator of nucleocytoplasmic transport [1] and subsequently found to be important for spindle formation [2-5]. In mitosis, a gradient of Ran-GTP emanates from chromatin and diminishes toward spindle poles [6]. Ran-GTP promotes spindle self-organization through the release of importin-bound spindle assembly factors (SAFs), which stimulate microtubule (MT) nucleation and organization and regulate MT dynamics [7-9]. Although many SAFs are non-motile MT-associated proteins, such as NuMA, TPX2, and HURP [7, 10-12], Ran also controls motor proteins, including Kid and HSET/XCTK2 [13, 14]. The Kinesin-14 XCKT2 is important for spindle assembly and pole organization [15-20], and Ran-GTP is proposed to promote XCKT2 MT crosslinking activity by releasing importin α/β from a bipartite nuclear localization signal (NLS) located in the tail domain [14]. Here, we show that the Ran-GTP gradient spatially regulates XCTK2 within the spindle. A flattened Ran-GTP gradient blocked the ability of excess XCTK2 to stimulate bipolar spindle assembly and resulted in XCTK2-mediated bundling of free MTs. These effects required the XCTK2 tail, which promoted the motility of XCTK2 within the spindle independent of the Ran-GTP gradient. In addition, the turnover kinetics of XCTK2 were spatially controlled: they were faster near the poles relative to the chromatin, but not with a mutant XCTK2 that cannot bind to importin α/β. Our results support a model in which the Ran-GTP gradient spatially coordinates motor localization with motility to ensure efficient spindle formation.


Measurement of migration of soft tissue by modified Roentgen stereophotogrammetric analysis (RSA): validation of a new technique to monitor rotator cuff tears.
The purpose of this study was to develop a technique to use Roentgen stereophotogrammetric analysis (RSA) to measure migration of soft-tissue structures after rotator cuff repair. RSA stereo films were obtained; images were analysed using a semi-automatic software program allowing 3D viewing of results. RSA imaging experiments were performed to validate the technique, using a glass phantom with implanted RSA beads and an animal model with steel sutures as RSA markers which were moved known distances. Repeated measurements allowed assessment of inter- and intra-observer variability at a maximum of 1.06 mm. RSA analysis of the phantom showed a variation up to 0.22 mm for static and 0.28 mm for dynamic studies. The ovine tissue specimen demonstrated that using steel sutures as RSA markers in soft tissue is feasible, although less accurate than when measuring bone motion. This novel application of RSA to measure soft tissue migration is practicable and can be extended to in vivo studies.


Laser chorioretinal venous anastomosis for progressive nonischemic central retinal vein occlusion.
The use of high or medium-intensity lasers to create an anastomotic connection between a retinal vein and a choroidal vein for the treatment of nonischemic central retinal vein occlusion (CRVO) has shown encouraging results. We established communication between an obstructed retinal vein and the choroid using a modified laser application in the eye of a 17-year-old boy with progressive nonischemic CRVO with macular edema and achieved excellent anatomic and visual results. The macular edema totally resolved and visual acuity significantly improved from 6/60 to 6/6.


Policing the ball: a new potassium channel subunit determines inactivation rate.
Inactivation of potassium currents during maintained firing results in a progressive increase in action potential width and neuronal excitability. In Kv1.1 channels, inactivation has attributed to a beta subunit that blocks the pore of the channel shortly after channel opening. In this issue of Neuron, Shulte and colleagues have identified a novel channel subunit whose interaction with Kv1.1 and the beta subunit prevents such inactivation. Mutations in this subunit lead to temporal lobe epilepsy.


Saksenaea dorisiae sp. nov., a New Opportunistic Pathogenic Fungus from Europe.
A new species, Saksenaea dorisiae (Mucoromycotina, Mucorales), isolated from a water sample originating from a private well in Manastirica, Petrovac, in the Republic of Serbia (Europe), is described and illustrated. The new taxon is well supported by multilocus phylogenetic analysis that included the internal transcribed spacer (ITS) region, domains D1 and D2 of the 28S rRNA gene (LSU), and translation elongation factor-1α gene (tef-1α), and it is resolved in a clade with S. oblongispora and S. trapezispora. This fungus is characterized by its moderately slow growth at 15 and 37°C, sparse rhizoids, conical-shaped sporangia, and short-cylindrical sporangiospores. Saksenaea dorisiae is a member of the opportunistic pathogenic genus often involved in severe human and animal mucormycoses encountered in tropical and subtropical regions. Despite its sensitivity to several conventional antifungals (terbinafine and ciclopirox), the fungus can potentially evoke clinically challenging infections. This is the first novel taxon of the genus Saksenaea described from the moderately continental climate area of Europe.


Factors affecting the effectiveness and success of retrograde holmium laser endopyelotomy as the primary treatment of ureteropelvic junction obstruction in adults.
To evaluate the factors affecting the effectiveness, safety, and success of retrograde holmium:yttrium-aluminum-garnet laser endopyelotomy as the primary treatment of ureteropelvic junction obstruction in adults. Adult patients who underwent retrograde holmium:yttrium-aluminum-garnet laser endopyelotomy as the primary treatment of ureteropelvic junction obstruction between January 2012 and June 2016 at our clinic were retrospectively analyzed. Success was defined as the relief of symptoms and the resolution of obstruction, as assessed via radiography. Factors affecting success were analyzed, such as the clinical characteristics, procedural outcomes, complications, and the type of ureteroscopy used in the procedure. Procedural success was achieved in 29 (74.4%) out of 39 patients, with a mean age of 38.3 ± 12.3 years during a median follow-up duration of 44 (33-65) months. Failure occurred at a median of 4.5 (3-22) months. It was detected that the presence of primary obstruction, ipsilateral kidney function being >30% of normal, and the length of obstruction being <1 cm positively affected procedural success (p = 0.009, p = 0.011, and p = 0.019, respectively). In the postoperative period, two Grade I and four Grade II complications were observed according to the Clavien-Dindo classification. There was a difference only in the operation time between semirigid (24) and flexible ureteroscopes (15), with the operation time being shorter with the use of a semirigid ureteroscope than with the use of a flexible uteroscope (p < 0.001). Retrograde holmium:yttrium-aluminum-garnet laser endopyelotomy is a minimally invasive method that can be used effectively and safely as the primary treatment of patients with ureteropelvic obstruction, when long-term results are also taken into consideration. The decision of performing laser endopyelotomy should be made after a detailed evaluation of the characteristics of the patient as well as of the obstruction.


Autoimmune liver disease.
To review studies that improve the diagnosis and treatment of autoimmune hepatitis and presage new drug and molecular site-specific interventions. Autoimmune hepatitis can present as acute or chronic hepatitis and as allograft dysfunction after liver transplantation. Elderly patients have an indolent but aggressive disease that responds well to corticosteroid therapy, and human leukocyte antigen DR4 characterizes this population. Geographic and ethnic factors influence clinical phenotype and behavior, and defects in T-regulatory cells may enhance cell-mediated cytotoxicity. Treatment response is the best index of prognosis, and normalization of serum aminotransferase abnormalities prevents disease progression. Mycophenolate mofetil, budesonide, rapamycin, and 6-thioguanine have been effective in small clinical experiences. De-novo autoimmune hepatitis can occur in adults and children after liver transplantation, and rapamycin may be an effective treatment. Autoimmune hepatitis has a global distribution and diverse clinical manifestations. Phenotypes are affected by regional and ethnic factors which may provide clues to the etiologic agents. Defects in counter-regulatory functions enhance cell-mediated cytotoxicity, and interventions that promise site-specific actions affecting immunocyte differentiation and proliferation are now feasible. Autoimmune hepatitis must be considered in all patients with acute and chronic hepatitis and in all cases of allograft dysfunction after liver transplantation.


New treatment guidelines on Cushing's disease.
It is important to treat patients with Cushing's disease as rapidly as possible to limit its long-term mortality and morbidity. Selective transphenoidal pituitary adenomectomy remains the treatment of choice but, unfortunately, the rate of cure at long-term follow-up is suboptimal and recurrences are high, even in the hands of expert neurosurgeons. Treatment options for persistent or relapsed disease include repeat trasphenoidal pituitary surgery, radiotherapy or bilateral adrenalectomy. Medical treatment, a second-line treatment option, may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs. Cabergoline and pasireotide (SOM230), two pituitary tumor-directed drugs, are the most exciting news in the human pharmacological approach. However, the use of these drugs in clinical practice and their real impact in the management of patients is yet to be determined. The treatment of patients with Cushing's disease is complex and requires a multidisciplinary and individualized approach to patient management using cost-benefit analyses.


Assessment of V600E mutation of BRAF gene and rate of cell proliferation using fine-needle aspirates from metastatic melanomas.
metastatic melanomas are incurable by systemic treatment and it is therefore of the highest concern to develop new therapeutic regimens. RAF kinases play a key role in the RAS-RAF-MAPK signalling pathway which mediates cellular response to growth signals. An inhibitor of the RAS-RAF-MAPK cascade, sorafenib, has shown promising therapeutic results in treatment of several types of metastatic tumours. It can be hypothesized that metastatic melanomas with activating BRAF mutation may respond to RAF kinase-blocking therapy. The objective of the study was to analyze if the activating BRAF V600E mutation is present in metastatic melanomas. Fine-needle aspirates from 44 metastatic melanomas were studied. The V600E mutation in exon 15 of the BRAF gene was selected for genotyping. A Taq-Man MGB biallelic discrimination system was used. Immunocytochemical assessment of the Ki-67 antigen was used to analyze the growth fraction of cells. Nearly 39% of metastatic melanomas had BRAF V600E mutation. Tumours with BRAF V600E mutation had a tendency to have a more aggressive clinical course. The growth fraction showed correlation with tumour progression. This study indicates that the V600E mutation is present in metastatic melanomas and occurs more often in sites without chronic sun exposure. Mutated tumours may have a more aggressive clinical course since such melanomas metastasize at an earlier stage. Determination of the BRAF mutation and the growth fraction of melanomas may add a prognostic value. A fraction of melanoma cases possess an activating BRAF mutation and may benefit from RAF-kinase inhibitor treatment. Future studies are needed to confirm this hypothesis.


The Spoilage of UHT-Treated Chocolate Milk by Thermoduric Bacteria.
The sporadic occurrence of swollen packs of chocolate milk at a local milk processing plant is the main reason for this investigation and to identify and characterize the spoilage agents. Of the 62 packs of chocolate milk collected, 15 became swollen within 24 h. All of these had high viable bacterial counts on plate count agar, whereas those that did not swell were free from bacterial contamination. There were two bacterial types found either individually or together in the swollen packs. Both isolates were confirmed as spoilers because when they were inoculated into intact packs, spoilage occurred within 48 h and the inoculant organisms were re-isolated from these packs. In addition, the onset of swelling was more rapid with increasing inoculum rate. Both isolates showed versatility in their ability to grow over fairly wide pH and temperature ranges both aerobically and anaerobically. Although they showed no evidence of sporulating, both isolates identified as Enterobacter sp. and Micrococcus sp. showed fairly high temperature tolerance but low H2O2 tolerance. The temperature-tolerant gram-negative rod which was identified as an Enterobacter sp. could have implications for the acceptable levels of heat treatment to be used in milk preservation in Trinidad.


Properties of recombinant endo-β-1,6-glucanase from Trichoderma harzianum and its application in the pustulan hydrolysis.
The gene encoding Trichoderma harzianum fungus pustulanase (ThBGL1.6, GH5 family, endo-β-1,6-glucanase, EC 22.214.171.124) was cloned and heterologously expressed by the highly productive Penicillium verruculosum fungus. The recombinant ThBGL1.6 was purified and its properties were studied. The ThBGL1.6 had an observed molecular mass of 46 kDa (SDS-PAGE data) and displayed maximum of the enzyme activity at pH 5.0 and 50 °C. At 45 °C, the ThBGL1.6 was stable for at least 3 h. The Km was 1.0 g/L with pustulan as the substrate. Reaction product analysis by HPLC clearly indicated that ThBGL1.6 has an endo-hydrolytic mode of action against pustulan as specific substrate. It was also identified that gentiobiose is the main reaction product at studying of long-term pustulan hydrolysis.


Caring through relation and dialogue: a nursing perspective for patient education.
Nursing's recognition of the importance of patient education is evident in nursing's history and in the work of early nurse theorists. However, to date, there has been no clear articulation of a nursing framework specific to this essential aspect of clinical care. A nursing perspective for patient education based on a conceptualization of caring is presented. This perspective includes explication of philosophic views for nursing and patient education. A middle-range theory for patient education is generated from this philosophic premise.


Prognostic significance of peripheral blood-derived neutrophil/lymphocyte ratio in patients with digestive cancer.
Accumulating studies reported the clinical value of derived neutrophil/lymphocyte ratio (dNLR) regarding the prediction of survival outcomes in digestive cancers, however, the prognostic significances of dNLR in these cancers were inconsistent. This study was carried out to clarify the relationship between circulating dNLR and prognosis in gastrointestinal (GI) cancers. Eligible publications were collected and extracted by searching Pubmed, Embase, Web of Science, and Google Scholar up to November 21, 2018. The prognostic impact of dNLR in subjects with GI cancers was assessed with the overall hazard ratios (HRs). A total of 26 studies with up to 13,945 participants were recruited. Our findings showed that peripheral blood dNLR before treatment could be a useful prognostic predictor in digestive cancers, an elevated dNLR indicated a shorter overall survival (OS) in GI tumors (HR, 1.44; 95% confidence interval [CI], 1.36-1.51). Furthermore, its significant prognostic value for OS was also confirmed in subgroup analyses stratified by disease type, publication year, type of research, detection method, geographic location, cut-off value, treatment, analysis type, follow-up time and disease stage. In addition, high dNLR was significantly associated with worse cancer-specific survival (HR, 1.25; 95% CI, 1.04-1.47) and inferior event-free survival (HR, 1.22; 95% CI, 1.11-1.33) in patients with digestive cancers. Our study showed elevated peripheral blood dNLR may indicate unfavorable outcomes in digestive cancer.


The Comparison between Endoscopic Submucosal Dissection and Surgery in Gastric Cancer: A Systematic Review and Meta-Analysis.
There are two treatment modalities for early gastric cancer (EGC)-surgery and endoscopic submucosal dissection (ESD). We aimed to compare the safety and efficacy of ESD with surgery. The article was performed by searching PubMed databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) calculated and P value. 13 studies were identified. The incidence of perforation in two groups was different [OR = 6.18 (95% CI: 1.37-27.98), P = 0.02]. The prevalences of synchronous and metachronous cancer in the ESD group were higher than those in the surgery group [OR = 8.52 (95% CI: 1.99-36.56), P = 0.004 and OR = 7.15 (95% CI: 2.95-17.32), P < 0.0001]. The recurrence and complete resection rates were different [OR = 6.93 (95% CI: 2.83-16.96), P < 0.0001 and OR = 0.32 (95% CI: 0.20-0.52), P < 0.00001]. Compared with the surgery group, the hospital stay was shorter [IV = -7.15 (95% CI: -9.08-5.22), P < 0.00001], the adverse event rate was lower, and the quality of life (QOL) was better in the ESD group. The difference of bleeding was not found. ESD appears to be preferable for EGC, due to a lower rate of adverse events, shorter hospital stay, cheaper cost, and higher QOL.


Milano-Torino Staging and Long-Term Survival in Chinese Patients with Amyotrophic Lateral Sclerosis.
(1) Background: The aim of this longitudinal study was to evaluate the association between disease progression according to the Milano-Torino staging (MITOS) system and long-term survival in Chinese patients with amyotrophic lateral sclerosis (ALS). We also examined factors affecting MITOS progression. (2) Methods: Patients were enrolled and underwent follow-up at 6, 12, 18, and 24 months, and their demographic and clinical data, including the Milano-Torino stage, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and neuropsychiatric data, were evaluated. The sensitivity and specificity of predicting survival outcomes based on MITOS progression and ALSFRS-R score decline from baseline to 6 months were compared. The associations between MITOS progression from baseline to 6 months and survival outcome at 12, 18 and 24 months were examined, and factors associated with disease progression were evaluated with subgroup analyses. (3) Results: Among the 100 patients included, 74% were in stage 0 at baseline, and approximately 95% progressed to a higher stage of the MITOS system at 24 months. MITOS progression from baseline to 6 months and ALSFRS-R decline showed comparable value for predicting survival at 12, 18, and 24 months. MITOS progression from baseline to 6 months is strongly associated with death outcomes. Older age at onset and increased depression and anxiety scores may be related to disease progression. (4) Conclusions: MITOS progression during the early disease course could serve as a prognostic marker of long-term survival and may have utility in clinical trials. Age at onset and diagnosis and neuropsychiatric factors might be associated with disease progression.


Development of a nanodrug-delivery system camouflaged by erythrocyte membranes for the chemo/phototherapy of cancer.
Aim: Development of a new drug-delivery system using a compound derived from Pronephrium penangianum (J5) for the treatment of cervical cancer. Materials & methods: The delivery system was developed using Prussian blue nanoparticles, camouflaged by red blood cell membrane and with folic acid surface modifications. Results: Our results showed the successful development of a nanodrug-delivery system, which increases the half-life and immune evasion ability of the drug. The mechanism of this system was through suppressing B-cell lymphoma 2 and increasing B-cell lymphoma 2-associated X protein and the cleaved caspase level. An in vivo study also confirmed good antitumor activity without any side effects to normal tissue. Conclusion: This drug-delivery system provides a good alternative for the treatment of cervical cancer using J5.


Solid pseudopapillary tumor of the pancreas with concomitant pancreas divisum. A case report.
Solid pseudopapillary tumor of the pancreas is a rare neoplasm which affects young women. On the other hand, pancreas divisum is an anomaly which develops at 7 weeks of gestation. Here, we report a case of a solid pseudopapillary tumor of the pancreas with concomitant pancreas divisum. A 26-year-old woman was diagnosed as having a pancreatic tumor with solid and cystic components in the pancreatic head. Pancreatograms obtained by ERCP and MRCP showed no communication between the ventral and dorsal pancreatic ducts, indicating that pancreas divisum was present. Microscopically, the resected tumor had solid and cystic components. Immunohistochemical study demonstrated that the tumor cells were positive for alpha-1-antitrypsine, vimentin and progesterone receptors but negative for estrogen receptors, NSE, insulin or glucagon. The tumor was diagnosed as a solid pseudopapillary tumor of the pancreas. Although more than 700 cases of solid pseudopapillary tumors of the pancreas have been reported in the English literature, a search of PubMed turned up no reports of concomitant solid pseudopapillary tumor and pancreas divisum. Solid pseudopapillary tumors of the pancreas with concomitant pancreas divisum are extremely rare.


The stabilizing effect of moisture on the solid-state degradation of gabapentin.
Gabapentin is known to undergo intramolecular cyclization to form a lactam (gaba-L) with concomitant loss of water. Gabapentin was milled in a planetary mill for 15-60 min. Unmilled and milled gabapentin were stored at 50°C with relative humidity ranged between 5% and 90%. The unmilled and milled samples were assayed for gabapentin and gaba-L by reversed phase-high-performance liquid chromatography and also subjected to powder X-ray diffraction, solid-state nuclear magnetic resonance and surface area analyses. The rates of lactamization in the milled gabapentin samples correlated to increased surface area, milling duration, and in-process lactam levels. This effect of milling could not be explained solely by the increase in surface area with increased milling time but was more likely due to increased regions of crystal disorder caused by the mechanical and thermal milling stresses. The lactamization rate of milled gabapentin samples was greatest in the presence of the lowest humidity conditions and dramatically decreased with increasing humidity. In particular, milled gabapentin appeared to be much more stable at humidity levels greater than 31% RH. This finding could not be attributed to the possibility of lactam hydrolysis at high humidity but rather to a competitive annealing process wherein milling-induced crystal defects were lost upon exposure to atmospheric moisture thereby stabilizing the milling-damaged drug substance.


Ethnicity and falls in older men: low rate of falls in Italian-born men in Australia.
past research suggests that fall rates in older persons may differ by ethnicity. The aim of this study was to compare the incidence of falls between older male Italian-born immigrants and their Australian-born counterparts. this study analysed data from 335 Italian-born and 848 Australian-born men aged 70 years and over participating in the Concord Health and Ageing in Men Project (CHAMP). Prospective falls data were collected by 4 monthly phone calls (mean follow-up time: 26.7 months). Negative binomial regression compared falls incidence rate ratios (IRR) between the two groups of men. there were 37 (11%) Italian-born men and 185 (22%) Australian-born men who had two or more falls during follow-up (P < 0.001). Negative binomial analysis demonstrated that Italian-born men had half the incidence rate of falls compared with Australian-born men (IRR = 0.51, 95% CI = 0.38-0.67). After adjustment for falls risk factors, Italian-born men remained significantly less likely to fall with a 43% lower fall rate (IRR = 0.57, 95% CI = 0.39-0.85). older male Italian-born immigrants are less likely to fall than their Australian-born counterparts. Differences in fall rates between the two groups are not explained by established falls risk factors.


A framework for assessing patient crossover and health information exchange value.
To evaluate the benefit of a health information exchange (HIE) between hospitals, we examine the rate of crossover among neurosurgical inpatients treated at Emory University Hospital (EUH) and Grady Memorial Hospital (GMH) in Atlanta, Georgia. To inform decisions regarding investment in HIE, we develop a methodology analyzing crossover behavior for application to larger more general patient populations. Using neurosurgery inpatient visit data from EUH and GMH, unique patients who visited both hospitals were identified through classification by name and age at time of visit. The frequency of flow patterns, including time between visits, and the statistical significance of crossover rates for patients with particular diagnoses were determined. The time between visits, flow patterns, and proportion of patients exhibiting crossover behavior were calculated for the total population studied as well as subpopulations. 5.25% of patients having multiple visits over the study period visited the neurosurgical departments at both hospitals. 77% of crossover patients visited the level 1 trauma center (GMH) before visiting EUH. The true patient crossover may be under-estimated because the study population only consists of neurosurgical inpatients at EUH and GMH. We demonstrate that detailed analysis of crossover behavior provides a deeper understanding of the potential value of HIE.


Myomectomy during early pregnancy.
Abdominal pain during early pregnancy may be caused by leiomyoma of the uterus. Inconsistency of uterine size and gestational dates in a pregnant patient with acute abdominal pain may be the first sign of leiomyoma. This 31-year-old primigravida presented with progressively worsening lower abdominal pain at 12 weeks gestational age. Ultrasonography and magnetic resonance imaging demonstrated a large fundal heterogeneous mass and an intrauterine gestation compatible with her menstrual dates. Exploratory surgery and myomectomy confirmed a large leiomyoma showing benign degenerative changes. The operative procedure was successful, and the pregnancy progressed normally. An elective cesarean section was performed at 37 weeks gestation after confirming fetal maturity by amniocentesis and serial ultrasonography. Abdominal pain in a pregnant patient with leiomyoma uteri may be attributable to degenerative changes in the myoma. Surgical intervention during pregnancy is occasionally necessary in uncommon cases of intractable pain.


[E-health--challenge for health care system].
E-health and systems related to the electronic patient record (EPR) are seen as important factors in the development of the health care System. In 2004 European Commission had adopted e-Health Action Plan, which indicated the development directions of European e-Health. In Poland, the main development trends and Government course of actions in this regard, are contained in the document Computerization plan "e-Health Poland" 2009-2015. The European Commission defines e-Health as an application of tools and services, information and communication technologies in healthcare. EPR is a collection of patient data that are stored in a certain place and it is possible to access them. E-health and EPR are closely related to the concept of interoperability. Denmark is one of the countries in which the information services and information technology in healthcare is mostly used. The introduction of ERP involves a lot of positive effects. Using the ERP, stored data can be optimally used by both physicians and patients. However, also risks associated with data security need to be considered. Furthermore, the Polish law defines in great detail the issues associated with creating, storing and sharing medical records (1). According to the Act from 17 February 2005, concerning the computerization of public service activities, it possible to keep medical documentation in electronically form.


Long-term exposure to nonylphenol affects insulin signaling in the liver of adult male rats.
In the present study, we sought to investigate the long-term effects of nonylphenol (NP) on insulin signaling and glucose metabolism in liver. Furthermore, reactive oxygen species (ROS) in liver was evaluated as it is known to induce insulin resistance. Rats were administered NP by oral gavage at the doses of 15, 150 and 1500 μg/ kg body weight per day for 45 days. Hydrogen peroxide (H(2)O(2)) generation and lipid peroxidation were increased, and the activities of antioxidant enzymes were decreased in the liver of NP-treated rats. NP increased the plasma glucose and insulin levels and altered the enzymes of carbohydrate metabolism. Decrease in the protein levels of insulin signaling molecules insulin receptor (IR), IR substrate (IRS)-1, IRS-2 and phosphatidylinositol-3-kinase were observed with parallel increase in H(2)O(2) levels in the liver of NP-treated rats. These results suggest that NP downregulates insulin signaling in liver, which could be due to ROS production and oxidative damage.


[Prevention of mumps in preschool institutions using a live mumps vaccine made from strain L-3].
The effectiveness of the emergency vaccinal prophylaxis of epidemic parotitis was studied in 19 children's day-care centers. As revealed in this study, the immunological effectiveness of vaccination did not depend on the age of vaccinees, but sharply decreased if live parotitis vaccine contained less than 10,000 HADU50 per immunization dose. After a single administration of the vaccine 91.1 +/- 0.98% of children were found to produce mumps antibodies. The immunization of children with live parotitis vaccine prepared from strain l-3 immediately after the first case of parotitis had been registered proved to be a highly effective measure. The coefficient of epidemiological effectiveness was 96.4%.


Forging Marxist psychology in China's Cold War geopolitics, 1949-1965.
This article investigates the history of psychology in China from 1949 to 1965, with a focus on the geopolitics involving Western, Soviet, and Chinese schools of psychology. In the early 1950s, the Chinese Communist Party (CCP) pressured psychologists to replace existing Western approaches with Pavlov's Soviet-sanctioned psychological theory. The shaky marriage of Pavlovian theory with Marxism, coupled with domestic and international political shifts, paved the way for two leftist criticisms of psychology, one in 1958 and the another before the Cultural Revolution in 1966. Both criticisms demanded that psychologists conceptualize mental phenomena as sociopolitically contingent and replace experimentation with class analysis. The clash between two views of human nature-the natural-biological view, which emphasized intrapersonal mental processes, and the revolutionary view, which highlighted individual connections to the sociopolitical milieu-stemmed from the Cold War ideological division, shifting Sino-Soviet relations, the CCP's conflicting commitments, and the power dynamic between the CCP and psychologists. Both critical movements were self-undermined by their violent enactment and failed to generate a fully developed Marxist psychology. In tracing these historical events, this article explores two questions. First, inspired by postcolonial historiography of psychology, it excavates Chinese Marxist critiques to rethink Western natural-scientific psychology regarding its disciplinary identity, subject matter, research methods, and social commitments. Second, by situating various schools of psychology in China's revolution, it argues that whereas natural scientific approaches of the West served scientific modernization, Chinese revolutionaries' sociopolitical approach to psychological research was tethered to class struggle. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Carcinogenesis of the ethmoidal adenocarcinoma due to wood dust].
To recognize the mechanisms and the different oncogenic pathways of ethmoid adenocarcinoma (EADC) in woodworkers. A systematic review of the literature and evaluation according to scientific evidences. Wood dust less than 10 microm settles on the external aspects of the ethmoid sinus that is the middle turbinate, the middle meatus and the olfactory cleft. The risk of developing an EADC is important from the first year. It is impossible to know what determines the latency period. Usually, this period exceeds 30 years and only 10% of patients are younger than 50 years of age. Chromosomal instability of the respiratory mucosa appears to be one of the major phases in the oncogenic process. Certain biomolecular and genetic factors are shared with the adenocarcinoma of the colon but they are not activated with the same importance and in the same context suggesting two distinct mechanisms of evolution. The local anatomo-clinical setting in the nasal cavity and carcinogenic substances in the wood dust play a key specific role in the development of EADC. No oncoproteins or immunohistochemistry features were identified in the process suggesting a cascade of genetic or molecular series of events.


Atypical glomus tumour of the wrist: a case report.
Wrist glomus tumours are extremely rare. We report a case of an unusually large wrist glomus tumour with atypical presentation. Magnetic resonance imaging (MRI) findings correlated well to those previously described for digital glomus tumours. This rare differential should be considered when evaluating lesions around the wrist.


Repeat posterior lamellar grafting for recalcitrant lower eyelid retraction is effective.
To review one surgeon's (J.H.O.) experience with repeat retractor release and posterior lamellar grafting in patients with residual lower eyelid retraction. To quantify the amount of eyelid elevation expected from each procedure. Retrospective chart review of patients with repeat posterior lamellar grafting between 1992 and 2010. Patients were grouped into thyroid associated orbitopathy (TAO) and other causes. Hard palate mucosa or free tarsoconjunctiva grafts were used. Preoperative and postoperative inferior scleral show, lagophthalmos, superficial punctate keratopathy, and patient symptoms were recorded. Outcome measures were changes in scleral show and lagophthalmos with each procedure. Combined results were examined.Results in patients with TAO were analysed separately and compared with other etiologies. In this series, a single procedure is expected to reduce scleral show by a mean of 1.63 mm (76%) and lagophthalmos by a mean of 0.48 mm (55%). A second procedure can further reduce residual scleral show by a mean of 0.71 mm (80%) and residual lagophthalmos by a mean of 0.43 mm (76%). Patients with TAO were more likely to have larger measurements of preoperative scleral show (1.40 mm versus 0.46 mm, p < 0.001). Patients with other etiologies were more likely to have larger measurements of preoperative lagophthalmos (1.25 mm versus 0.47 mm, p = 0.004). This is the first study to evaluate outcomes of recalcitrant lower lid retraction requiring repeat posterior lamellar grafting. Mean reductions in scleral show and lagophthalmos can be used as a guide in the preoperative evaluation and counseling of patients with lower lid retraction.


Expression profile of epidermal differentiation complex genes in normal and anal cancer cells.
Anal cancer originates from a peculiar histological region and provides a useful model for investigating alterations in proliferation and/or differentiation of neoplastic keratinocytes. Epidermal differentiation complex (EDC) genes, which form one of the major gene clusters in the human genome, are involved in the terminal differentiation of epithelial cells and in many instances have been implicated in epithelial tumours. We constructed a DNA macroarray capable of characterising the expression profiles of the entire EDC gene complex in normal mucosa and anal cancer biopsies of seven unrelated patients. Brain tissue and cultured keratinocytes were used as controls. All anal cancer samples showed expression profiles in which none of the EDC genes was silent, as evaluated by phosphor-imager analysis. Variance analysis showed significantly lower expression of SPRR2 with respect to SPRR1 or SPRR3, and significantly higher expression of S100A8 than of other S100A subfamily members. At hierarchical clustering analysis, the four basaloid anal cancer cases conglomerated in the top five positions. The macroarray method used by us provides the first demonstration of the expression profile of the EDC gene family in anal cancer, and is capable of producing significant information on the subgrouping of epithelial tumours such as anal cancer.


Size-controlled growth of colloidal gold nanoplates and their high-purity acquisition.
A facile while flexible approach to size-controllable high-purity colloidal gold nanoplates has been presented. By adjusting the quantity of seeds and I(-) through a seed-mediated, cetyltrimethylammonium bromide (CTABr)-assisted synthetic system, the edge length of the gold nanoplates can be adjusted from 140 to 30 nm without changing their thickness or crystal structure. By simply increasing the ion concentration of the reaction solution, the as-prepared gold nanoplates can be deposited due to the different electrostatic aggregation effects between nanoplates and spherical nanoparticles. Effective storage methods to keep the structural and optical stability of these gold nanoplates are also proposed.


Effect of Nd:YAG Laser Irradiation on the Number of Open Dentinal Tubules and Their Diameter with and without Smear of Graphite: An in Vitro Study.
Dentin hypersensitivity (DH) is characterized by tooth pain arising from exposure of dental roots. In this study the efficiency of neodymium yttrium-aluminum-garnet (Nd:YAG) laser in association with graphite on dentinal surface changes as the alternative to the treatment of DH was evaluated. Sixteen noncarious human third molars were collected and sectioned into 5 parts from cementoenamel junction (CEJ) to the furcation area. The prepared samples were randomly assigned into five groups (Gs) of each 16: Control (G1), treated by Nd:YAG laser at 0.5 W (G2), irradiation of Nd:YAG with a 0.25 W output power(G3), smeared with graphite and then using Nd:YAG laser at output powers of 0.5 W (G4) and 0.25 W (G5). For all groups the parameters were 15 Hz, 60 s, at two stages and with a right angle irradiation. The number and diameter of dentinal tubules (DT) were compared and analyzed by SPSS software, One way ANOVA and Post hoc LSD tests. The number of open dentinal tubules varied significantly between all groups except among G1 with G3 and G2 with G5. Multiple comparison tests also exhibited significant differences regarding the diameter of tubules between the groups two by two except among G2 with G5. Nd:YAG laser used at 0.25 W and 0.5 W with application of graphite smear was able to reduce the number and diameter of dentinal tubules.


Extraperitoneal urine leak after renal transplantation: the role of radionuclide imaging and the value of accompanying SPECT/CT - a case report.
The differentiation of the nature of a fluid collection as a complication of kidney transplantation is important for management and treatment planning. Early and delayed radionuclide renography can play an important role in the evaluation of a urine leak. However, it is sometimes limited in the evaluation of the exact location and extent of a urine leak. A 71-year-old male who had sudden anuria, scrotal swelling and elevated creatinine level after cadaveric renal transplantation performed Tc-99 m MAG3 renography to evaluate the renal function, followed by an ultrasound which was unremarkable. An extensive urine leak was evident on the planar images. However, an exact location of the urine leak was unknown. Accompanying SPECT/CT images confirmed a urine leak extending from the lower aspect of the transplant kidney to the floor of the pelvic cavity, presacral region and the scrotum via right inguinal canal as well as to the right abdominal wall. Renal scintigraphy is very useful to detect a urine leak after renal transplantation. However, planar imaging is sometimes limited in evaluating the anatomical location and extent of a urine leak accurately. In that case accompanying SPECT/CT images are very helpful and valuable to evaluate the anatomical relationships exactly.


Low-Pressure Plasma-Processed Ruthenium/Nickel Foam Electrocatalysts for Hydrogen Evolution Reaction.
In this paper, low-pressure 95%Ar-5%H2, pure Ar, and 95%Ar-5%O2 plasmas were used for post-treatment of ruthenium (Ru) deposited on nickel foam (NF) (Ru/NF). Ru/NF was then tested as a catalyst for a hydrogen evolution reaction. Significant improvement in electrocatalytic activity with the lowest overpotential and Tafel slope was observed in an alkaline electrolyte (1 M KOH) with 95%Ar-5%O2 plasma processing on Ru/NF. Linear scanning electrical impedance spectroscopy (EIS) and cyclic voltammetry (CV) also indicate the lowest interfacial impedance and largest electrical double layer capacitance. Experimental results with 0.1 M phosphate buffered saline (PBS) and 0.5 M H2SO4 electrolytes were also demonstrated and compared.


Expression of the mau genes involved in methylamine metabolism in Paracoccus denitrificans is under control of a LysR-type transcriptional activator.
Expression of methylamine dehydrogenase in Paracoccus denitrificans and its concomitant ability to grow on methylamine is regulated by a substrate-induction mechanism as well as by a catabolite-repression-like mechanism. Methylamine dehydrogenase is synthesized in cells growing on either methylamine or ethylamine, but not during growth on succinate, methanol or choline as sole sources of carbon and energy. The synthesis of methylamine dehydrogenase is repressed when succinate is added to the growth medium in addition to methylamine. Repression is not observed when the growth medium contains methylamine and either choline or methanol. Induction of the mau genes encoding methylamine dehydrogenase is under control of the mauR gene. This regulatory gene is located directly in front of, but with the transcription direction opposite to that of, the structural genes in the mau cluster. The mauR gene encodes a LysR-type transcriptional activator. Inactivation of the gene results in loss of the ability to synthesize methylamine dehydrogenase and amicyanin, and loss of the ability to grow on methylamine. The mutation is completely restored when the mauR gene is supplied in trans. The first gene of the cluster of mau genes that is under control of MauR is mauF, which encodes a putative membrane-embedded protein. Inactivation of the gene results in the inability of cells to grow on methylamine. Downstream from mauF and in the same transcription direction, mauB is located. This gene encodes the large subunit of methylamine dehydrogenase.


Transtactin: a universal transmembrane delivery system for Strep-tag II-fused cargos.
The delivery of molecules into cells poses a critical problem that has to be solved for the development of diagnostic tools and therapeutic agents acting on intracellular targets. Cargos which by themselves cannot penetrate cellular membranes due to their biophysical properties can achieve cell membrane permeability by fusion to protein transduction domains (PTDs). Here, we engineered a universal delivery system based on PTD-fused Strep-Tactin, which we named Transtactin. Biochemical characterization of Transtactin variants bearing different PTDs indicated high thermal stabilities and robust secondary structures. Internalization studies demonstrated that Transtactins facilitated simple and safe transport of Strep-tag II-linked small molecules, peptides and multicomponent complexes, or biotinylated proteins into cultured human cells. Transtactin-introduced cargos were functionally active, as shown for horseradish peroxidase serving as a model protein. Our results demonstrate that Transtactin provides a universal and efficient delivery system for Strep-tag II-fused cargos.


Financial Costs of Emergency Department Presentations for Australian Patients With Heart Disease in the Last 3 Years of Life.
This study described emergency department (ED) resource use patterns and associated costs among patients with heart disease in their last 3 years of life in a high-income country. This study used linked data from ED and death registry databases in Australia. A random sample of 1000 patients who died due to any cause in 2017, and who had been living with heart disease for at least the prior 10-years were included. The outcomes of interest were number of ED presentations over each of the last 3 years prior to death and relative cost contributions of ED-related items. The number of patients needing ED care and number of ED presentations per patient increased as patients were closer to death, with 85% experiencing at least one ED presentation in their last year of life. Mean per patient ED presentation cost increased with each year closer to death. Costs related to labor, pathology, patient travel, and goods and services contributed more than 85% of the total cost in each of the 3 years. The increase in cost burden as patients neared death was attributable to more frequent ED presentations per person rather than more expensive ED presentations. The scope of this study was limited to ED presentations, and may not be representative of heart-disease-related end-of-life care more broadly.


Synthesis, cytotoxicity and human telomerase inhibition activities of a series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione homologues.
A series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione tetracyclic analogues with different side chain were prepared using an various synthetic route via acylation, cyclization, condensation, and intramolecular heterocyclization. Tetracyclic system containing alkyl and aryl, aromatic and heterocyclic, linear and cyclic, polar and apolar, and basic and acids residues were incorporated. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and in vitro cytotoxicity against NCI's 60 cell line human tumor screen. Compounds 4, 11, 12, 14, 15, 16, 17, 19, 20, 23, 25, and 26 were selected by the NCI for one dose screening program and further studies on 4, 23 and 25 where the curves cross these lines represent the interpolated values to cause 50% growth inhibition (GI(50)), total growth inhibition (TGI) and 50% cell killing (LC(50)), respectively. Further studies did not reveal any compound that showed potent and significant on telomerase inhibitory activity and hTERT repressing ability. Comparative testing of these compounds in the NCI's screen revealed varying levels of potency and differential cytotoxicity, apparently related to the unsaturation levels in and substitution patterns on the core ring system. It appeared that addition of a fourth planar aromatic system to a tricyclic chromophore might enhances potent cytotoxic agents, at a level equivalent to a second side chain in one of the tricyclic series. Although the exact mechanism of how this pharmacophore contributes to its activity is still unclear, however, the group in the extended arm of the tetracyclic system might contribute to proper binding to the residues within the grove of G-quadruplex structure.


Egg incubation and collection of painted turtle embryos.
This protocol describes how to incubate painted turtle eggs and collect embryos for gene expression analysis. The same basic protocol can be used to incubate eggs and collect embryos from other turtle species by modifying the incubation temperature to suit the particular developmental needs of each species.


[Serodiagnosis of Campylobacter pylori].
The colonization of gastric mucosa with Campylobacter pylori can be detected by serological methods. ELISA and immunoblot methods are currently being employed for detection of antibodies against Campylobacter pylori. In general, both tests will differentiate between Campylobacter pylori positive and Campylobacter pylori negative patients. However, 5-10% of persons with negative cultures for Campylobacter pylori have positive serological tests, but only very few patients with Campylobacter pylori associated with chronic gastritis have negative serological tests. This is true for tests detecting IgG and IgA antibodies. Tests for IgM antibodies have not been found to be useful. Immunoblot analyses have shown that detection of antibodies against a 100-120 KD antigen has a high specificity for Campylobacter pylori infection. In a small study we evaluated the possible use of serological testing for follow-up studies on patients after Campylobacter pylori therapy. We found that patients who became Campylobacter pylori negative after therapy showed a significant decline of serum IgG titers against Campylobacter pylori.


Genetic diversity in the US ex situ populations of the endangered Puerto Rican Boa, Chilabothrus inornatus.
The Puerto Rican Boa (Chilabothrus inornatus) was placed on the US Endangered Species List in 1970. Progress has been made since to clarify the recovery status of this species, though the design of a new recovery plan must include information regarding genetic variation within and among populations of this species. While measures of genetic diversity in wild populations of this species are finally becoming available, relative genetic diversity represented in ex situ populations is unknown, which hampers efforts to develop an ex situ species management plan. Here, we provide an analysis of genetic diversity in US public and private collections (zoos and breeders) using mitochondrial sequence data and five highly polymorphic nuclear microsatellite loci. We analyzed 50 boas from the US ex situ population and determined overall genetic diversity and relatedness among these individuals. We then compared these data to mitochondrial and microsatellite data obtained from 176 individuals from wild populations across the native range of the species. We found little inbreeding and a large amount of retained genetic diversity in the US ex situ population of C. inornatus relative to wild populations. Genetic diversity in the ex situ population is similar to that found in wild populations. Ours is only the second explicit attempt to characterize genetic diversity at the molecular level in ex situ populations of boid snakes. We anticipate that these results will inform current breeding strategies as well as offer additional information that will facilitate the continuation of ex situ conservation breeding or management in boas.


Carcinoma of the breast in three siblings.
Reported are three siblings, a sister and 2 brothers, who had breast cancer. The paternal grandmother of the proband was known to have had breast cancer. It is our belief that this report supports further the genetic etiology of certain breast cancers. The study examines the literature with regard to genetically transmitted female breast cancer and also implies a genetic etiology of male breast cancer. Of special interest is the fact that the female sibling had bilateral breast cancer during her premenopausal years and that one of the two brothers also developed his lesion at an early age, 41 years.


A regioselectivity switch in Pd-catalyzed hydroallylation of alkynes.
By exploiting the reactivity of a vinyl-Pd species, we control the regioselectivity in hydroallylation of alkynes under Pd-hydride catalysis. A monophosphine ligand and carboxylic acid combination promotes 1,5-dienes through a pathway involving isomerization of alkynes to allenes. In contrast, a bisphosphine ligand and copper cocatalyst favor 1,4-dienes via a mechanism that involves transmetalation. Our study highlights how to access different isomers by diverting a common organometallic intermediate.


Organ and tissue transplantation: past, present and future.
Organ and tissue transplantation are now clinical treatment options for irreversible failure of many organs and systems. Living related donors or cadaver donors are used in kidney transplantation and it is a well-established procedure with defined results. Cardiac graft results match those obtained for recipients of unrelated kidney grafts from cadavers. Combined heart and lung grafts have been successfully used to treat cor pulmonale. Liver transplantation is technically demanding, and suffers from the absence of effective liver-support systems, but can achieve lifesaving short-term and long-term survival in selected patients. Pancreatic transplantation offers great potential, but long-term results both of isolated islet-cell transplantation and of organ grafts have been disappointing. Lung transplantation as an isolated procedure has had very little success. Bone-marrow transplantation is now the method of choice of treatment of aplastic anaemia, and is occasionally successful in management of malignancies. Transplantation of skin, bone, cartilage, endocrine, and vascular tissues has a variety of important clinical applications. Corneal transplantation has the longest successful history of all allografts.


Characterization of the interaction between liposomal formulations and Pseudomonas aeruginosa.
The interactions between three liposomal formulations and Pseudomonas aeruginosa cells were evaluated by a lipid mixing assay and electron paramagnetic resonance (EPR) spectroscopy. The effect of the bacteria on the liposomal phase characteristics, the release of the liposomes' content, and the uptake rate of gentamicin by bacteria were monitored as a function of time, using EPR spectroscopy. The [16-DSA uptake](Total) from DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) liposomes reached 93 +/- 12% over a 3-hour assay period, of which 9% crossed the bacterial inner membrane. A small amount of 16-DSA uptake from DPPC/Chol (cholesterol) vesicles was found throughout the 3-hour period of time. Although DPPC/DMPG (dimyristoylphosphatidylglycerol) vesicles showed a smaller value of [16-DSA uptake](Total) with respect to that of DPPC vesicles, they appeared to be effective in disrupting the bacterial membrane, resulting in a greater accumulation of 16-DSA inside the inner membrane. Exposure to bacteria caused the DPPC/Chol, DPPC, and DPPC/DMPG formulations to release 4.6 +/- 1.5, 17.6 +/- 1.2, and 34 +/- 3.7% of their content, respectively. Time-dependent fluid regions were developed within the vesicles when mixed with bacteria, and their growth over time depended on liposomal formulations. Incubation of gentamicin with bacteria for 3 hours resulted in 87 +/- 3% of the drug crossing the bacterial inner membrane. In conclusion, interaction between the liposome drug carriers and the bacterial cells result in vesicle fusion, disruption of the bacterial membrane, release of the liposomal content in the close vicinity of the bacteria cells, and the subsequent intracellular uptake of the released liposomal content.


A combined analysis of the Frost Multidimensional Perfectionism Scale (FMPS), Child and Adolescent Perfectionism Scale (CAPS), and Almost Perfect Scale-Revised (APS-R): Different perfectionist profiles in adolescent high school students.
To investigate differences and similarities in the dimensional constructs of the Frost Multidimensional Perfectionism Scale (FMPS; Frost, Marten, Lahart, & Rosenblate, 1990), Child and Adolescent Perfectionism Scale (CAPS; Flett, Hewitt, Boucher, Davidson, & Munro, 2000), and Almost Perfect Scale-Revised (APS-R; Slaney, Rice, Mobley, Trippi, & Ashby, 2001), 938 high school students completed the 3 perfectionism questionnaires, as well as the Depression Anxiety Stress Scales (DASS; Lovibond & Lovibond, 1995). Preliminary analyses revealed commonly observed factor structures for each perfectionism questionnaire. Exploratory factor analysis of item responses from the questionnaires (combined) yielded a 4-factor solution (factors were labeled High Personal Standards, Concerns, Doubts and Discrepancy, Externally Motivated Perfectionism, and Organization and Order). A latent class analysis of individuals' mean ratings on each of the 4 factors yielded a 6-class solution. Three of the 6 classes represented perfectionist subgroups (labeled adaptive perfectionist, externally motivated maladaptive perfectionist, and mixed maladaptive perfectionist), and 3 represented nonperfectionist subgroups (labeled nonperfectionist A, nonperfectionist B, and order and organization nonperfectionist). Each of the 6 subgroups was meaningfully associated with the DASS. Findings showed that 3 out of 10 students were classified as maladaptive perfectionists, and maladaptive perfectionists were more prevalent than adaptive perfectionists. In sum, it is evident that combined ratings from the FMPS, CAPS, and APS-R offer a meaningful characterization of perfectionism.


Dealing with HIV-related stigma: a qualitative study of women outpatients from the Chris Hani Baragwanath Hospital.
HIV-related stigma is widely regarded as a key impediment to effective prevention and care. The purpose of this study was to explore HIV-infected women outpatients' experiences of stigma and the coping strategies that they devised to deal with it. Six HIV-infected women receiving antiretroviral treatment from the Nthabiseng Clinic of the Chris Hani Baragwanath Hospital participated in this qualitative study. HIV-related stigma was experienced by all the participants and was narrated as a sense of loss that gave rise to feelings of fear and shame. To cope with this, the women isolated themselves, became secretive about their health, disclosed strategically, and enlisted support. The elements of stigma and the coping strategies employed as uncovered in this study suggest a basis from which interventions aimed at assisting HIV-infected people to deal with stigma can be planned.


Head circumference catch-up growth among preterm very low birth weight infants: effect on neurodevelopmental outcome.
The purpose of this study was to determine whether head circumference (HC) catch-up is associated with improved neurocognitive development. A retrospective cohort study was conducted in 179 preterm very low birth weight (VLBW) (BW≤1500 g) infants. The infants were born in 2000-2002 and were followed to the age of 5.5 years. The association between HC catch-up and neurodevelopmental outcome was assessed and perinatal risk factors, infant characteristics and nutritional practices associated with HC catch-up were determined. HC catch-up occurred in 59 (34%) infants and was positively correlated with neurodevelopmental outcome. The likelihood of HC catch-up increased with increasing birth weight and gestational age. HC catch-up occurred more often with breast milk feeding during hospitalization and with supplemental formula feeding at discharge, but decreased in prevalence with longer duration of breastfeeding after discharge. HC catch-up was more likely to occur in first-born infants and in families with high socioeconomic status. Most HC catch-up occurred between birth and three months corrected age. Among preterm-VLBW infants, there is a close relation between HC growth and neurodevelopmental outcome. Efforts to improve neurocognitive outcomes should focus on factors associated with HC catch-up.


Do FIGO stage IA and small (≤2 cm) IB1 cervical adenocarcinomas have a good prognosis and warrant less radical surgery?
There is a controversy regarding the optimal management of small cervical adenocarcinomas, and more radical surgery is often undertaken compared to similar size squamous carcinomas. We wished to determine the risk of parametrial involvement and metastatic disease and the outcome in International Federation of Gynecology and Obstetrics (FIGO) stage IA and small (≤2 cm) stage IB1 cervical adenocarcinomas. All women with a diagnosis of International Federation of Gynecology and Obstetrics stages IA1, IA2, or IB1 cervical adenocarcinoma with a maximum tumor size of 2 cm were identified between 1999 and 2010 in Northern Ireland. A single pathologist reviewed all pathology prospectively at a cancer center tumor board. A total of 74 women were identified (mean age, 39 years; range, 25-72 years). In total, 36 women had stage IA1, 9 women had stage IA2, and 29 women had stage IB1 cervical adenocarcinomas. Surgical treatment ranged from local excision (cone or large loop excision of transformation zone) to radical hysterectomy and pelvic lymph node dissection; adjuvant therapy was not administered in any case. No parametrial involvement was seen in the 36 women who underwent parametrial resection. No lymph node metastasis was identified in the 45 women who underwent pelvic lymph node dissection. Lymphovascular space invasion was identified in 6 cases. No tumor recurrence or metastasis was noted during a mean follow-up of 35 months. The optimal management of women with IA or small IB1 cervical adenocarcinoma is controversial, and radical surgery is often undertaken. Our data suggest that there is an extremely low risk of parametrial and lymph node involvement with tumors 2 cm or smaller and a low recurrence rate. Less radical surgery may be warranted for small cervical adenocarcinomas, and this should be addressed by future studies.


Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER).
The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure-activity relationship (SAR) studies of small-molecule ERα degraders based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in the discovery of highly potent and effective PROTAC ER degraders, as exemplified by ERD-308 (32). ERD-308 achieves DC50 (concentration causing 50% of protein degradation) values of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines, respectively, and induces >95% of ER degradation at concentrations as low as 5 nM in both cell lines. Significantly, ERD-308 induces more complete ER degradation than fulvestrant, the only approved selective ER degrader (SERD), and is more effective in inhibition of cell proliferation than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may lead to a new therapy for advanced ER+ breast cancer.


Ingrowth and formation of bone in defects in an uncemented fiber-metal total hip-replacement model in dogs.
An osseous defect was created in the acetabulum and femur of twenty dogs, and then a fiber-metal total hip prosthesis was inserted. A comparison was made between the effects of leaving the defects unfilled, filling the defects with an autogenous bone graft, and filling them with a 50:50 mixture of autogenous bone graft and a biphasic ceramic composed of hydroxyapatite and tricalcium phosphate. The characteristics of formation of bone within the sites of the defects and the extent of the ingrowth of bone into the underlying porous surface were analyzed. At six and twelve weeks after implantation, the dogs in the control group (unfilled defects) had the least amount of bone in the sites of the defects. In the dogs that had had an autogenous bone graft and those in which the defects had been filled with a mixture of autogenous bone graft and biphasic ceramic, there were excellent osteoconductive properties in the filling of the sites of the defects with new bone. A comparison was made between the amount of bone that formed in the osseous defects and the amount that formed in the spaces of the porous-surfaced fiber-metal components of the prostheses, directly underlying and adjacent to the defects. At six weeks, the greatest amount of ingrowth of bone into the spaces of the underlying titanium fiber-metal acetabular components was seen in the control group (22 per cent of the porous surface), followed by the group in which the defects had been filled with a mixture of autogenous bone graft and biphasic ceramic (19 per cent). The defects that had been filled only with autogenous bone graft had poor ingrowth of bone into the porous surface (4 per cent) and predominantly fibrous ingrowth. At twelve weeks, these defects again showed the least amount of ingrowth of bone (15 per cent) compared with the defects in the control group (24 per cent) and those that had been filled with a mixture of autogenous bone graft and biphasic ceramic (24 per cent). No statistically significant differences were found in the amount of ingrowth of bone into the defects that had been created in the femur in the three groups of dogs at either six or twelve weeks. However, the trends appeared to correlate with the data for the acetabular defects.


Early treatment with a combination of two potent neutralizing antibodies improves clinical outcomes and reduces virus replication and lung inflammation in SARS-CoV-2 infected macaques.
There is an urgent need for effective therapeutic interventions against SARS-CoV-2, including new variants that continue to arise. Neutralizing monoclonal antibodies have shown promise in clinical studies. We investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, C135-LS and C144-LS that carry half-life extension mutations, in the rhesus macaque model of COVID-19. Twelve young adult macaques (three groups of four animals) were inoculated intranasally and intra-tracheally with a high dose of SARS-CoV-2 and 24 hours later, treated intravenously with a high (40 mg/kg) or low (12 mg/kg) dose of the C135-LS and C144-LS antibody combination, or a control monoclonal antibody. Animals were monitored for 7 days. Compared to the control animals, animals treated with either dose of the anti-SARS-CoV-2 antibodies showed similarly improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. In conclusion, this study provides proof-of-concept in support of further clinical development of these monoclonal antibodies against COVID-19 during early infection.


Ultrasound-responsive thrombus treatment with zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator.
This study is undertaken to design zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator (t-PA) for thrombolytic therapy where the t-PA activity can be recovered in the blood circulation upon ultrasound irradiation. Various molecular weights of gelatin were complexed with t-PA by their simply mixing in aqueous solution. Then, zinc acetate, calcium acetate or magnesium acetate was added to form nano-sized gelatin-t-PA complexes. The complexes had the apparent molecular size of about 100 nm. When zinc ions were added to the gelatin-t-PA complexes, the t-PA activity was suppressed most strongly to 57% of the original, free t-PA activity. Upon ultrasound exposure in vitro, the t-PA activity was fully recovered. A cell culture experiment with L929 fibroblasts demonstrated no cytotoxicity of complexes at the concentration used for the in vivo experiment. The half-life of t-PA in the blood circulation prolonged by the complexation with gelatin and zinc ions. The zinc-stabilized t-PA-gelatin complex is a promising t-PA delivery system which can manipulate the thrombolytic activity by the local ultrasound irradiation.


Sulfonic Acid Functionalization of Different Zeolites and Their Use as Catalysts in the Microwave-Assisted Etherification of Glycerol with tert-Butyl Alcohol.
The etherification of glycerol with tert-butyl alcohol in the liquid phase, over different sulfonic acid functionalized zeolites, has been studied. The reaction was carried out using microwaves as a way of heating, measured at autogenous pressure and without any solvent. Dealuminated HY and HZSM-5 zeolites by acid treatment were functionalized with two different organosilica precursors: 3-mercaptopropyltrimethoxysilane (M), which incorporates thiol groups, and 2-(4-chlorosulfonylphenyl)ethyltrimethoxysilane (C), which incorporates the sulfonic acid groups directly. The thiol groups were oxidized into sulfonic groups employing hydrogen peroxide. The textural and structural properties of the solids were studied by XRD and N₂ adsorption-desorption isotherms, whereas the incorporation of the organosilica in the zeolites was studied by TGA and XPS. The novelty functionalization of M gave rise to solids with the highest acidity, and exhibited the highest yields with more substituted ethers (Yh-GTBE = 13%), at 75 °C and 15 min of reaction time. In addition to the acidity, the textural properties of the zeolites played an important role in their activity; HY, with the largest size of the channels, were more active than the HZSM-5.


Can the presence of KRAS mutations guide the type of liver resection during simultaneous resection of colorectal liver metastasis?
It is generally accepted that non-anatomical resection (NAR) in colorectal liver metastasis (CRLM) has comparable safety and efficacy compared to anatomical resection (AR); however, there are reports that AR may have better outcomes in KRAS mutated CRLM. This study aimed to determine the effects of KRAS mutations and surgical techniques on survival outcomes in CRLM patients. Two hundred fifty patients who underwent hepatic resection of CRLM with known KRAS mutational status between 2007 and 2018 were analyzed. A total of 94 KRAS mutated CRLM and 156 KRAS wild-type CRLM were subdivided by surgical approach and compared for short- and long-term outcomes. In both KRAS wild-type and mutated type, there was no difference in estimated blood loss, postoperative complications, and 30-day mortality. There was no difference in disease-free survival (DFS) between AR and NAR in both groups (p = 0.326, p = 0.954, respectively). Finally, there was no difference in intrahepatic DFS between AR and NAR groups in both the KRAS groups (p = 0.165, p = 0.516, respectively). The presence of KRAS mutation may not be a significant factor when deciding the approach in simultaneous resection of CRLM.


Frequency-segmented power amplification using multi-band radio frequency amplifiers to produce a high-voltage pulse.
A method of frequency-segmented power amplification using multiband radio frequency (RF) amplifiers was proposed to generate stable and arbitrary high-voltage pulses. The concept behind this method is that an arbitrary pulse with a specified duration and sharp edges can be reconstructed using only several frequencies, and most of the power is concentrated on the fundamental frequency. The high-voltage pulse can, therefore, be obtained by amplifying each segmented frequency and then combining it with the RF power combiners. To correct the frequency-dependent group delays and gain of the amplifier circuit and to perform fine-tuning of the pulse structure, a seed pulse is divided into several lines that have bandpass filters, variable delay lines, variable power attenuators, and main RF amplifiers. A prototype pulse amplifier was designed and fabricated based on this method to generate rectangular pulses for the electron beam chopper of an x-ray free-electron laser injector. Flat and stable pulses with a 2 ns width of 0.2 kV height, peak-to-peak flat top of 0.8%, and route-mean-squared peak jitter of less than 0.2% were successively generated in both single- and multi-bunch structures. In the future, this type of pulse generator will play an important role in accelerators that require complicated and precise beam handling at high repetition rates of kHz or MHz.


Bronchial artery embolisation for the management of haemoptysis in patients with pulmonary tuberculosis.
To evaluate immediate and long-term outcomes of bronchial artery embolisation (BAE) for the treatment of haemoptysis in patients with pulmonary tuberculosis (TB), and to clarify factors that influence recurrence. Of 398 patients with haemoptysis who underwent BAE between January 2004 and June 2009, 169 were retrospectively reviewed. All of the patients had either a history of pulmonary TB or a current diagnosis of TB. Follow-up ranged from 1 day to 66 months. Haemoptysis was stopped or markedly decreased, with subsequent clinical improvement, in 163 patients (96.4%); in 50 patients symptoms recurred during the follow-up period. Disease activity, aortography and mycetoma showed a statistically significant correlation with recurrence rate. Cumulative non-recurrence rates were 76.1% for 12 months and 51.4% for 40 months. The median non-recurrence time was 41.2 months. Disease activity and mycetoma showed a statistically significant correlation with early recurrence. Only one major complication was observed. BAE is a safe and effective treatment option for the control of haemoptysis in TB patients. Disease activity and mycetoma both correlate with higher recurrence rate and early time of recurrence.