Is derived vectorcardiography a potential screening tool for pulmonary hypertension?
Patients with atrial septal defects and pulmonary hypertension would benefit from early identification and treatment of pulmonary hypertension prior to closure. Noninvasive screening tools for pulmonary hypertension are inadequate. Electrocardiography, though readily available, has so far been of limited screening utility in patients with pulmonary hypertension. We hypothesize that derived vectorcardiographic parameters will aid in identifying increased right ventricular afterload and thus provide an additional screening tool for pulmonary hypertension in patients with secundum atrial septal defects. Establish whether vectorcardiography can be used to screen for pulmonary hypertension. A retrospective review of patients with secundum atrial septal defects (ASD) who underwent cardiac catheterization at the University of Minnesota from 2012 to 2020 was performed. We excluded patients with other congenital heart diagnoses, insufficient hemodynamic data, or lacking sinus rhythm electrocardiogram at time of cardiac catheterization. Parameters analyzed included: Sokolow-Lion right ventricular hypertrophy criteria, PR duration, QRS duration, corrected QT intervals, QRS and T wave frontal plane axes, rSR', R' amplitude, as well as vectorcardiographic parameters (Kors regression-related method), the QRS vector magnitude, T wave vector magnitude, and the spatial QRS-T angle. These were compared to measures of pulmonary hypertension obtained at cardiac catheterization. The spatial QRS-T angle significantly differentiated ASD patients with pulmonary hypertension (median 104 degrees, interquartile range 55-137 degrees) from ASD patients without pulmonary hypertension (median 37 degrees, interquartile range 21-63 degrees, p-value of 0.002). At a cut-off of 124 degrees, the positive and negative predictive values for identification of pulmonary hypertension were 36.4% and 96.4%, respectively, with an odds ratio of 13.4 (95% confidence interval of 2.9 to 63.7). The positive predictive value was significantly improved when combined with echocardiographic data to screen for pulmonary hypertension. The spatial QRS-T angle is associated with pulmonary hypertension in patients with secundum atrial septal defects.


Spectra of weighted scale-free networks.
Much information about the structure and dynamics of a network is encoded in the eigenvalues of its transition matrix. In this paper, we present a first study on the transition matrix of a family of weight driven networks, whose degree, strength, and edge weight obey power-law distributions, as observed in diverse real networks. We analytically obtain all the eigenvalues, as well as their multiplicities. We then apply the obtained eigenvalues to derive a closed-form expression for the random target access time for biased random walks occurring on the studied weighted networks. Moreover, using the connection between the eigenvalues of the transition matrix of a network and its weighted spanning trees, we validate the obtained eigenvalues and their multiplicities. We show that the power-law weight distribution has a strong effect on the behavior of random walks.


Induction of the adaptive response of Escherichia coli to alkylation damage by the environmental mutagen, methyl chloride.
Methyl chloride (MeCl) is an abundant environmental mutagen and carcinogen and may be one of several environmental alkylating agents against which the protection of an adaptive response is required in microorganisms. Both MeCl and methyl iodide (MeI), at micromolar concentrations, induced the adaptive response to alkylation damage in Escherichia coli. This response is regulated by the Ada protein which is converted into a transcriptional activator by self-methylation on repair of methylphosphotriesters in methylated DNA. However, using high amounts of Ada protein, activation of Ada occurred in vitro following direct protein methylation by both MeI (in agreement with previously published data) and MeCl. Activation was enhanced when methyl halide treatments were performed in the presence of DNA. An unadapted E. coli cell contains only 2 to 4 molecules of Ada protein, and presents an extremely small target of 2 to 4 specific cysteine residues per cell for activation of Ada by direct protein methylation in vivo. Thus, it is proposed that induction of the adaptive response in vivo initially occurs via efficient repair by the Ada protein of a low number of methylphosphotriesters in DNA. When the cellular Ada protein level has substantially increased, a greater probability of direct methylation and activation of Ada at cysteine-69 by MeCl may sustain and further increase induction of the adaptive response.


Interaction of erythrocyte protein 4.1 with phospholipids. A monolayer and liposome study.
We have studied the interaction of purified human erythrocyte protein 4.1 with phospholipid membranes by monitoring both the increase in surface pressure of monolayers at the air/water interface and the change in permeability in liposomes to fluorescent molecules, in the presence of protein 4.1. Protein 4.1 penetrated into monolayers of brain phosphatidylserine (PS) and egg phosphatidylcholine (PC), even above surface pressures of 30 mN/m. Protein 4.1 increased the permeability of negatively charged PS, but not PC, liposomes, measured as the increase in fluorescence when encapsulated 1-aminonaphthalene-3,6,8-trisulfonic acid (ANTS) and p-xylenebispyridinium bromide (DPX) or carboxyfluorescein were released into the medium. The interaction of protein 4.1 with PS large unilamellar vesicles (LUV) was increased as the pH and the ionic strength were lowered, and decreased as the Ca2+ or Mg2+ concentrations and ionic strength were raised. In order to study the relevance of these measurements to the erythrocyte, we prepared LUV of synthetic lipid mixtures characteristic of both the inner and the outer membrane leaflets. Protein 4.1 increased the permeability of inner, but not outer, leaflet LUV at both pH 6.0 and 7.4. These observations suggest that negatively charged phospholipid domains around the protein 4.1 high-affinity protein-binding site(s) may contribute to the anchoring of protein 4.1 to the cytoplasmic surface of the red cell membrane.


Microgeographic variation in the diets of garter snakes.
Diets of the terrestrial garter snake (Thamnophis elegans) and the common garter snake (T. sirtalis) were studied at 22 sites in an area of about 250 km2 in northern California, during the summers of 1978-80. Overall, T. sirtalis consumed mostly amphibian and T. elegans ate an equal mixture of amphibians, fish, and leeches. However, this was more an effect of differential distribution of the two species among sites than of habitat partitioning within sites. Site was 5 times better as a predictor of diet than was species of snake. The relative frequency of T. sirtalis at the sites was correlated with the number of amphibian species.


Prevalence of "complicated" stress urinary incontinence in female patients: can urodynamics provide more information in such patients?
The role of urodynamic investigation has been recently questioned on the basis of data from a selected population of patients with stress urinary incontinence defined as uncomplicated. The aim of this study was to determine the proportion of patients who underwent urodynamic investigation in our centre in whom the stress urinary incontinence could be defined as uncomplicated. The secondary aim was to assess the number of women in whom the urodynamic investigation added information to the preurodynamic assessment. This was a retrospective single-centre study. The data from female patients who underwent urodynamic evaluation prior to surgery for stress urinary incontinence between 2008 and 2012 were considered. Patients were categorized as presenting with uncomplicated or complicated stress urinary incontinence according to the definitions used in the ValUE trial. Urodynamic observations were then compared with preurodynamic data. Data from 244 female patients were considered. Due to incomplete data, 33 of these patients were excluded from the evaluation. Only 47 patients (22.3 %) were considered to have uncomplicated stress urinary incontinence according to the definition used in the ValUE trial. The remaining 164 patients (77.7 %) were considered to have complicated stress urinary incontinence. Urodynamic observations differed from the preurodynamic data in 134 of 211 patients (63.5 %). A diagnosis of voiding dysfunction was obtained in 25.6 % of patients. The majority of our patients had complicated stress urinary incontinence. In a relevant percentage of these patients, a urodynamic test added some new information, including a diagnosis of voiding dysfunction. The role of urodynamic investigation needs to be explored in this patient group.


Telemonitoring in Chronic Pain Management Using Smartphone Apps: A Randomized Controlled Trial Comparing Usual Assessment against App-Based Monitoring with and without Clinical Alarms.
The usefulness of mHealth in helping to target face-to-face interventions for chronic pain more effectively remains unclear. In the present study, we aim to test whether the Pain Monitor mobile phone application (app) is well accepted by clinicians, and can help improve existent medical treatments for patients with chronic musculoskeletal pain. Regarding this last goal, we compared three treatment conditions, namely usual treatment, usual treatment with an app without alarms and usual treatment with an app with alarms. All treatments lasted one month. The three treatments were compared for all outcomes, i.e., pain severity and interference, fatigue, depressed mood, anxiety and anger. In this randomized controlled trial, the usual monitoring method (i.e., onsite; n = 44) was compared with daily ecological momentary assessment using the Pain Monitor app-both with (n = 43) and without alarms (n = 45). Alarms were sent to the clinicians in the presence of pre-established undesired clinical events and could be used to make treatment adjustments throughout the one-month study. With the exception of anger, clinically significant changes (CSC; 30% improvement) were greater in the app + alarm condition across outcomes (e.g., 43.6% of patients experienced a CSC in depressed mood in the app + alarm condition, which occurred in less than 29% of patients in the other groups). The clinicians were willing to use the app, especially the version with alarms. The use of apps may have some benefits in individual health care, especially when using alarms to tailor treatments.


Oocyte Quality, In Vitro Fertilization and Embryo Development of Alpaca Oocytes Collected by Ultrasound-Guided Follicular Aspiration or from Slaughterhouse Ovaries.
The morphological quality and the in vitro developmental competence of cumulus-oocyte complexes (COCs) collected from in vivo or slaughtered alpacas was compared. COCs were recovered from ovarian follicles using: (i) manual aspiration in ovaries of alpacas (n = 15) sacrificed at a local slaughterhouse, or (ii) transrectal ultrasound-guided follicular aspiration (or ovum-pick-up, OPU) in live alpacas (n = 13) 4 days after the administration of an ovarian superstimulation protocol (200 UI eCG). COCs recovered from both groups were morphologically evaluated and graded. Grade I to III COCs were in vitro matured for 26 h and in vitro fertilized afterwards for 20 h using fresh alpaca epididymal spermatozoa. Presumptive zygotes from both groups were in vitro cultured for 7 days. The proportion of COCs recovered over the total number of follicles punctured was similar between groups, but the mean number of COCs collected from individual ovaries was greater (p < 0.05) in slaughterhouse ovaries. A significantly higher (p < 0.05) percentage of low-quality COCs (grades III and IV) and a lower (p < 0.05) percentage of grade I COCs was obtained using OPU. The number of blastocysts, regarding cleavage and COCs collected, was higher (p < 0.007 and p < 0.0002 respectively) for COCs collected by OPU; however, the total number of blastocysts per female did not differ between groups. We can conclude that the recovery rate and morphological quality of COCs was significantly higher when follicles were manually aspirated from slaughterhouse alpaca ovaries; however, a statistically higher developmental potential was observed in oocytes collected by OPU from live alpaca donors.


Pathology protocol increases lymph node yield in neck dissection for oral cavity squamous cell carcinoma.
Lymph node yield (LNY) is a proposed quality indicator in neck dissection for oral cavity squamous cell carcinoma (OCSCC). Retrospective series including 190 patients with OCSCC undergoing neck dissection between 2016 and 2018. A change in pathologic grossing protocol was initiated during the study period to assess residual adipose tissue. A generalized linear model was used to assess the impact of multiple variables on LNY. Mean LNY was 28.59 (SD = 17.65). The protocol identified a mean of 10.32 lymph nodes per case. Multivariable analysis identified associations between LNY and use of the pathology protocol (P = .02), number of dissected lymph node levels (P < .001), presence of pathologic lymph nodes (P = .002), body mass index (P = .02), prior neck surgery (P = .001), and prior neck radiation (P = .001). Assessment of residual adipose tissue within neck dissection specimens improves accuracy of LNY. LNY in neck dissection is influenced by multiple factors including methods of pathologic assessment.


Adverse effects during the treatment with pegylated interferon and ribavirin in children with chronic hepatitis C.
Administration of pegylated interferon-alpha (IFN-alpha) and ribavirin in adults with chronic hepatitis C (CHC) is a recommended therapeutic standard. Nevertheless, this therapeutic regimen rises numerous controversies. The aim of this study was to analyze adverse effects during the treatment with pegylated IFN-alpha and ribavirin in children with CHC. Study group comprised 30 children with CHC, age 8-19 years (mean 13,6 years), 9 girls and 21 boys. All patients were administered two medication therapy with pegylated IFN-alpha-2b in the dose of 1.5 microg/kg of body weight 1x/week subcutaneously and daily oral ribavirin 15 mg/kg of bodyweight for 48 weeks. Blood samples were taken at baseline and every 4 weeks during the whole treatment and 24 weeks of follow-up period. Panel of test included: cellular blood count and smear, ALT activity, bilirubin level. Patients complaints were noticed during every visit. Thyroid hormones and antibodies were checked every 3 months. Children were divided into group A that responded to treatment and group B-nonresponders. Abnormalities in laboratory tests (white blood cells, neutrophils, haemoglobin) were observed mainly during first weeks of treatment. Mean bilirubin level and platelets were normal. Mean ALT normalized during the treatment. After 12-16 weeks of the therapy somatic adverse effects decreased significantly. Administration of pegylated IFN-alpha and ribavirin in children with CHC is related to characteristic adverse effects. Periodical dose reduction was necessary. Although side effects and subjective patient complaints were present, children attended school without difficulties. Constant monitoring is required during the whole treatment.


[Computed tomography with variable levels of energy of x-ray radiation].
Method of computer tomography with variable radiant energy is described. It permits to compensate the distortions in computer-tomographic sections in case of change in tube operating conditions and in visualization of information about tissue composition within the sectional limits. The developed method increases the efficacy of computer tomography.


Enhanced Competition at the Nano-Bio Interface Enables Comprehensive Characterization of Protein Corona Dynamics and Deep Coverage of Proteomes.
Introducing engineered nanoparticles (NPs) into a biofluid such as blood plasma leads to the formation of a selective and reproducible protein corona at the particle-protein interface, driven by the relationship between protein-NP affinity and protein abundance. This enables scalable systems that leverage protein-nano interactions to overcome current limitations of deep plasma proteomics in large cohorts. Here the importance of the protein to NP-surface ratio (P/NP) is demonstrated and protein corona formation dynamics are modeled, which determine the competition between proteins for binding. Tuning the P/NP ratio significantly modulates the protein corona composition, enhancing depth and precision of a fully automated NP-based deep proteomic workflow (Proteograph). By increasing the binding competition on engineered NPs, 1.2-1.7× more proteins with 1% false discovery rate are identified on the surface of each NP, and up to 3× more proteins compared to a standard plasma proteomics workflow. Moreover, the data suggest P/NP plays a significant role in determining the in vivo fate of nanomaterials in biomedical applications. Together, the study showcases the importance of P/NP as a key design element for biomaterials and nanomedicine in vivo and as a powerful tuning strategy for accurate, large-scale NP-based deep proteomic studies.


William A Silverman lecture.
This is the text of the William A Silverman lecture given by Dr David K Stevenson at the Pediatric Academic Societies Annual Meeting in Washington, DC, May 4-7, 2013.


The reconstruction of complex networks with community structure.
Link prediction is a fundamental problem with applications in many fields ranging from biology to computer science. In the literature, most effort has been devoted to estimate the likelihood of the existence of a link between two nodes, based on observed links and nodes' attributes in a network. In this paper, we apply several representative link prediction methods to reconstruct the network, namely to add the missing links with high likelihood of existence back to the network. We find that all these existing methods fail to identify the links connecting different communities, resulting in a poor reproduction of the topological and dynamical properties of the true network. To solve this problem, we propose a community-based link prediction method. We find that our method has high prediction accuracy and is very effective in reconstructing the inter-community links.


Lymph transport before and after regional lymphadenectomy as demonstrated with 99Tcm. Preliminary experiences.
The lymphatic transport of a radioactive tracer injected intralymphatically on the dorsum of the foot was determined before and after surgery in 3 patients with vulvar carcinoma. The centrally recorded activity curves showed different time courses before and after inguinal lymphadenectomy, suggesting that the lymphatic transport is short-circuited via lymphovenous anastomoses after lymphadenectomy. Thus, non-radical surgery for primary carcinoma combined with lymphadenectomy will increase the risk of haematogenous spread.


Von Willebrand factor and the thrombophilia of severe COVID-19: in situ evidence from autopsies.
COVID-19 is accompanied by a hypercoagulable state and characterized by microvascular and macrovascular thrombotic complications. In plasma samples from patients with COVID-19, von Willebrand factor (VWF) levels are highly elevated and predictive of adverse outcomes, especially mortality. Yet, VWF is usually not included in routine coagulation analyses, and histologic evidence of its involvement in thrombus formation is lacking. To determine whether VWF, an acute-phase protein, is a bystander, ie, a biomarker of endothelial dysfunction, or a causal factor in the pathogenesis of COVID-19. We compared autopsy samples from 28 patients with lethal COVID-19 to those from matched controls and systematically assessed for VWF and platelets by immunohistochemistry. The control group comprised 24 lungs, 23 lymph nodes, and 9 hearts and did not differ significantly from the COVID-19 group in age, sex, body mass index (BMI), blood group, or anticoagulant use. In lungs, assessed for platelets by immunohistochemistry for CD42b, microthrombi were more frequent in patients with COVID-19 (10/28 [36%] vs 2/24 [8%]; P = .02). A completely normal pattern of VWF was rare in both groups. Accentuated endothelial staining was found in controls, while VWF-rich thrombi were only found in patients with COVID-19 (11/28 [39%] vs 0/24 [0%], respectively; P < .01), as were NETosis thrombi enriched with VWF (7/28 [25%] vs 0/24 [0%], respectively; P < .01). Forty-six percent of the patients with COVID-19 had VWF-rich thrombi, NETosis thrombi, or both. Trends were also seen in pulmonary draining lymph nodes (7/20 [35%] vs 4/24 [17%]; P = .147), where the overall presence of VWF was very high. We provide in situ evidence of VWF-rich thrombi, likely attributable to COVID-19, and suggest that VWF may be a therapeutic target in severe COVID-19.


Bilateral subepidermal calcified nodules of the eyelid.
A subepidermal calcified nodule (SCN) is an uncommon benign lesion, which usually develops in early childhood and is typically solitary. A rare form of this lesion has been reported in the eyelid. We report here a case of a 12-year-old girl with bilateral nodules of the right upper eyelid and a left lower eyelid simulating epidermal cyst. The histopathologic examination of the excised nodule confirmed the diagnosis. To our knowledge, this may be the first bilateral case of eyelid SCN reported in the literature.


Catalan ethnoflora: a meta-analytic approach to life forms and geographic territories.
Catalonia (in the north east of the Iberian Peninsula) is among the most prospected territories in Europe, from the ethnobotanical point of view. The aim of the present paper is to undertake a global analysis in the area considered, including plants, plant life forms, and ethnobotanical data within a physiographic and geographic framework. Data from 21 ethnobotanical prospection areas in Catalonia were collected, analyzed, and compared, with the focus on plant life forms and geographic divisions. A total of 824 taxa constitute the Catalan ethnoflora, and 316 of them are shared by the six physiographic zones recognized in Catalonia. When three major geographic areas are considered (Pyrenean, inland, and littoral), 394 taxa have been reported in only one out of the three areas. Concerning life forms, phanerophytes and chamaephytes together, i.e., those taxa present all through the year, are the most cited (37.12%). This first study constitutes a new approach to ethnobotanical data analysis. The results show the particular importance of plants with a large distribution area and plants with available biomass throughout the year. Apart from this, other kind of plants, e.g., those present in only one territory, are of interest for its originality and sometimes for the local significance.


Trans-generational effect of neurotoxicity and related stress response in Caenorhabditis elegans exposed to tetrabromobisphenol A.
Tetrabromobisphenol A (TBBPA), one of the most common brominated flame retardants, has been associated with immunotoxicity, neurotoxicity, and reproductive toxicity. However, little attention has been focused on understanding the trans-generational effects of TBBPA. The present study used the Caenorhabditis elegans (C. elegans) animal model to evaluate the trans-generational effects of neurotoxicity induced by environmentally relevant concentrations of TBBPA (0, 0.1, 1, 10, 100, and 1000 µg/L). Multiple indicators including physiological effects (body length, brood size, head thrashes, body bends, and crawling trajectory), degree of neuronal damage (dopamine, GABAergic, and glutamatergic neurons), oxidative stress-related biochemical indicators (superoxide dismutase [SOD] activity, catalase [CAT] enzyme, malondialdehyde [MDA] production, and reactive oxygen species [ROS] accumulation), and stress-related gene expressions have been evaluated in the exposed parental C. elegans generation (G1) and their progeny (G2) under TBBPA-free conditions. The results showed that TBBPA exposure induced adverse effects on physiological endpoints, among which body bends and head thrashes were the most sensitive ones, detected above 1 µg/L in G1 and 100 µg/L in G2 nematodes, respectively. After contaminant exposure, the three neurons revealed damage related to neurobehavioral endpoints, with no hereditary effects in the progeny. The oxidative stress-related biochemical endpoints demonstrated that when the exposure concentrations were above 1 µg/L in maternal worms, impairment can be detected in both generations, but the progeny recovered at low toxicity concentration (1-100 µg/L). The integrated target gene expression profiles were clearly altered in G1 and G2 worms at concentrations between 1 and 1000 µg/L, and a more significant difference existed in two generations of nematodes at low levels (1-10 µg/L) of TBBPA. Studing trans-generational neurotoxicity and the underlying mechanism can generate a precise evaluation of the environmental risk of TBBPA.


A steroid-cell tumor of the ovary resulting in massive androgen excess early in the gonadol steroidogenic pathway.
We describe the case of a 35-year-old woman with an ovarian steroid-cell tumor secreting markedly elevated levels of testosterone (28.3 nmol/l), dehydroepiandrosterone sulfate (19.7 mumol/l), androstenedione (>34.7 nmol/l) and 17-hydroxyprogesterone (100.5 nmol/l) into plasma. We could find no report within the literature of androgens at the levels described in this patient. Herein we review the literature and discuss the possible endocrine etiology of the excess androgens observed in this case. We also discuss the differential diagnosis, investigation and interpretation of androgens of adrenal and ovarian origin.


Focus groups to support the industrial/product designer: a review based on current literature and designers' feedback.
Focus groups are widely used within human factors, social sciences and market research. Whilst user-research methods may be familiar to other disciplines, conventional design training has not, until recently, incorporated such activities. With the increased awareness for the necessity to elicit user needs beyond the functional, design research is becoming more established. However, there is a significant gap in training material for design research. This paper will review the scope of application of focus group techniques, with particular emphasis on the suitability of focus groups for use by industrial/product designers, based on the current literature and designer feedback from two case studies.


A polyoxometalate-based Pd(II)-coordinated ionic solid catalyst for heterogeneous aerobic oxidation of benzene to biphenyl.
An ionic solid catalyst by pairing Keggin polyoxometalate-anions with Pd(II)-coordinated nitrile-tethered ionic liquid cations was synthesized, characterized, and tested for aerobic oxidation of benzene to biphenyl. A unique heterogeneous intramolecular electron transfer mechanism is proposed to understand its high activity.


Effect of transient elevation of glucose on contractile properties in non-diabetic rat cardiac muscle.
In non-diabetic patients with severe disease, such as acute myocardial infarction or acute heart failure, admission blood glucose level is associated with their short-term and long-term mortality. We examined whether transient elevation of glucose affects contractile properties in non-diabetic hearts. Force, intracellular Ca2+ ([Ca2+]i), and sarcomere length were measured in trabeculae from rat hearts. To assess contractile properties, maximum velocity of contraction (Max dF/dt) and minimum velocity of relaxation (Min dF/dt) were calculated. The ratio of phosphorylated troponin I (P-TnI) to troponin I (TnI) was measured. One hour after elevation of glucose from 150 to 400 mg/dL, developed force, Max dF/dt, and Min dF/dt were reduced without changes in [Ca2+]i transients at 2.5 Hz stimulation and 2.0 mM [Ca2+]o, while developed force and [Ca2+]i transients showed no changes at 0.5 Hz stimulation and 0.7 mM [Ca2+]o. In the presence of 1 μM KN-93, a Ca2+/calmodulin-dependent protein kinaseII (CaMKII) inhibitor, or 50 μM diazo-5-oxonorleucine, a L-glutamine-D-fructose-6-phosphate amidotransferase inhibitor, the reduction of contractile properties after elevation of glucose was suppressed. Furthermore, 1 h after elevation of glucose to 400 mg/dL at 2.0 mM [Ca2+]o, the ratio of P-TnI to TnI was increased. These results suggest that in non-diabetic hearts under higher Ca2+-load, transient elevation of glucose for 1 h reduces contractile properties probably by activating CaMKII through O-GlcNAcylation. Thus, in the patients with severe disease, transient elevation of blood glucose, such as due to stress, may worsen cardiac function and thereby affect their mortality without known diabetes.


Honeycomb-like 3D ordered macroporous SiOx/C nanoarchitectures with carbon coating for high-performance lithium storage.
SiOx anodes are garnering significant interest in lithium-ion batteries (LIBs) due to theirs low voltage plateau and high capacity. However, critical drawbacks, including high expansion rate and low electronic conductivity, severely limit their practical applications. While 0D, 1D, and 2D scale nanostructures have been proven to mitigate these issues, these materials tend to accumulate after prolonged cycling, leading to adverse effects on the mass transfer processes within the electrode. Herein, we have developed a honeycomb-like SiOx/C nanoarchitecture with carbon coating based on a 3D ordered macroporous (3DOM) structure. The 3D interconnected pore windows facilitate the diffusion and transport of lithium ions (Li+) in the electrolyte, and the extremely thin walls (<15 nm) provide a shorter transport path for Li+ in the solid. The carbon cladding buffers volume expansion and enhances electronic conductivity. The as-prepared anode demonstrates a high reversible capacity of 1068 mAh/g and an initial coulombic efficiency of 70.7 %. It maintains a capacity of 644 mAh/g (capacity retention of 84.63 %) even at a high current of 1.0 A/g after 700 cycles. The unique honeycomb-like structure offers enormous insights into the study of energy storage in 3D materials.


Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia.
The synovial sarcoma X breakpoint 2 (SSX2) belongs to a multigene family of cancer-testis antigens and can be found overexpressed in multiple malignancies. Its restricted expression in immune-privileged normal tissues suggest that SSX2 may be a relevant target antigen for chimeric antigen receptor (CAR) therapy. We have developed a T cell receptor (TCR)-like antibody (Fab/3) that binds SSX2 peptide 41-49 (KASEKIFYV) in the context of HLA-A∗-0201. The sequence of Fab/3 was utilized to engineer a CAR with the CD3 zeta intra-cellular domain along with either a CD28 or 4-1BB costimulatory endodomain. Human T cells from HLA-A2+ donors were transduced to mediate anti-tumor activity against acute myeloid leukemia (AML) tumor cells. Upon challenge with HLA-A2+/SSX2+ AML tumor cells, CAR-expressing T cells released interferon-γ and eliminated the tumor cells in a long-term co-culture assay. Using the HLA-A2+ T2 cell line, we demonstrated a strong specificity of the single-chain variable fragment (scFv) for SSX2 p41-49 and the closely related SSX3 p41-49, with no response against the others SSX-homologous peptides or unrelated homologous peptides. Since SSX3 has not been observed in tumor cells and expression cannot be induced by pharmacological intervention, SSX241-49 represents an attractive target for CAR-based cellular therapy to treat multiple types of cancer.


Retention prediction and hydrophobicity estimation of weak acidic compounds by reversed-phase liquid chromatography using acetic and perchloric acids as ion suppressors.
Simple acids are usually applied to suppress the ionization of weakly ionizable acidic analytes in reversed-phase liquid chromatography. The purpose of this study is to investigate the retention behavior of various weak acidic compounds (monoprotic, diprotic, triprotic, and tetraprotic acids) using acetic or perchloric acid as ion suppressor in a binary hydroorganic mobile phase. The apparent n-octanol-water partition coefficient (K(ow)") was proposed to calibrate the n-octanol-water partition coefficient (K(ow)) of weak acidic compound. LogK(ow)" was found to have a better linear correlation with logk(w), the logarithm of the retention factor obtained by extrapolating to neat aqueous fraction of the mobile phase, for all weakly ionizable acidic compounds. This straightforward relationship offers a potential medium for direct measurement of K(ow) data of weak acidic analytes and can be used to predict retention behavior of these compounds in the ion suppression reversed-phase liquid chromatographic mode.


Impact of 9-Minute Withdrawal Time on the Adenoma Detection Rate: A Multicenter Randomized Controlled Trial.
Although current quality indicators of colonoscopy recommend 6 minutes as the minimum standard for withdrawal time (WT), the impact of a WT longer than 6 minutes on neoplasia detection is unclear. A multicenter randomized controlled trial involving 1027 patients was conducted from January 2018 to July 2019. Participants were randomly divided into a 9-minute (n = 514) and 6-minute (n = 513) WT group, and a timer was used to adjust the withdrawal speed. The primary outcome was the adenoma detection rate (ADR). Intention-to-treat analysis showed a significantly higher ADR in the 9-minute versus 6-minute WT group (36.6% vs. 27.1%, P = .001). Prolonging WT from 6 to 9 minutes significantly increased ADR of the proximal colon (21.4% vs. 11.9%, P < .001) as well as of the less experienced colonoscopists (36.8% vs. 23.5%, P = .001). Improvements were also observed in the polyp detection rate (58.0% vs. 47.8%, P < .001), and mean number of polyps and adenomas detected per colonoscopy (1.1 vs. 0.9, P = .002; 0.5 vs. 0.4, P = .008, respectively). The higher ADRs in 9-minute WT were also confirmed by the per-protocol (PP) analysis and subgroup analyses, with an increased rate of sessile serrated lesion detection in the 9-minute WT by PP analysis (4.0% vs. 1.3%, P = .04). Multivariate logistic regression demonstrated that the 9-minute WT was independently associated with increased ADR (P = .005). Prolonging WT from 6 to 9 minutes significantly improved ADR, especially in the proximal colon and for less experienced colonoscopists. A 9-minute WT benchmark should be considered as one of the quality indicators of colonoscopy. ClinicalTrials.gov (identifier, NCT03399045).


Transtraumatic Epidural Electrostimulation of the Spinal Cord in a Pig Model.
The effect of transtraumatic epidural electrostimulation (TEES) above (T5) and below (L2) spinal cord injury in the lower thoracic region (T8-T9) in combination with treadmill exercise in pigs was evaluated using electrophysiological examination methods and behavioral tests. Two weeks after spinal cord injury, motor evoked potentials of m. soleus were recorded during electrostimulation at the level of T5 and L2 segments, which indicated activation of spinal cord structures above and below the focus of injury. After 6 weeks of TEES in combination with physical training, restoration of the characteristics of M-response and H-reflex of the soleus muscle in response to stimulation of the sciatic nerve, improvement of joint mobility, and appearance of voluntary motor activity in the hindlimbs were observed. Neuromodulation with TEES had been proven to be an effective way to stimulate posttraumatic spinal cord regeneration and can be used in the development of a neurorehabilitation protocol for patients with spinal cord injury.


Mental health status and related influencing factors in patients with COVID-19.
The outbreak of the Corona Virus Disease 2019 (COVID-2019) has resulted in a significant number of diagnosed patients requiring treatment in designated hospitals. However, limited evidence exists regarding the prevalence of mental health problems and associated psychological factors in COVID-19 patients. This study investigated the prevalence rates of anxiety, depression, and insomnia among COVID-19 patients, as well as explored the associations between these mental health problems and psychological factors. A cross-sectional study was conducted among 387 COVID-19 patients in a designated shelter hospital. Online measures were used to assess anxiety, depression, insomnia, social support, coping styles, and emotional regulation. Data were analyzed to determine the prevalence rates of mental health problems and examine the associations between these problems and the psychological factors. The results revealed high prevalence rates of anxiety (21.80%), depression (49.0%), and insomnia (63.70%) among COVID-19 patients. Objective social support scores and positive coping style scores were significantly associated with lower levels of anxiety, depression, and insomnia, respectively. Conversely, high negative coping style scores, higher education level, and self-perceived illness severity, were significantly related to higher levels of anxiety, depression, or insomnia symptoms. Emotional regulation scores did not show a significant association with any of the examined mental health problems. These findings have implications for guiding psychological interventions tailored to COVID-19 patients in future outbreaks. By targeting social support and promoting adaptive coping strategies, psychological interventions can address the psychological distress experienced by COVID-19 patients.


Amyloidosis mimics achalasia's effect on lower esophageal sphincter.
Esophageal involvement in systemic amyloidosis is common. Manometric studies have been few in number and have revealed a variety of findings compatible with deposition of amyloid in myopathic as well as neuropathic patterns. This report describes a patient with primary amyloid whose esophageal dysfunction was limited to the lower esophageal sphincter, with both a hypertensive sphincter and impaired relaxation after swallows. Pharmacologic testing confirmed a mild abnormality of the inhibitory pathway to the LES with an intact excitatory pathway and sphincter muscle. This case suggests that amyloidosis, like idiopathic achalasia and carcinoma of the lower esophagus, can produce dysphagia by selective impairment of the inhibitory neural pathway to the lower esophageal sphincter.


Increasing the effect of annonacin using nanodiamonds to inhibit breast cancer cells growth in rats (Rattus norvegicus)-Induced breast cancer.
Annonaceous acetogenins have been reported to have anti-cancer properties but low viability. In this study, we aimed to investigate the potency of nanodiamonds to be employed as a carrier of annonacin to help increase its viability and inhibit the growth of breast cancer cells. The annonacin was coupled with nanodiamond and characterized using UV-Vis spectrophotometer, FTIR, SEM, and PSA, and determined their stability and drug release. A cell growth inhibition assay and cell migration assay was performed using the breast cancer MCF7 and T747D cell lines, and in vivo analysis was performed in rats (Rattus norvegicus). MCF7 and T747D cells were treated with 12.5 μg/mL annonacin coupled with nanodiamonds for 24 and 48 h and further analyzed by MTT, cell migration, and reactive oxygen species (ROS) assays. Twenty-five female rats were divided into five groups. Breast cancer was induced using two intraperitoneal doses of N-nitroso-N-methylurea (NMU) (50 and 30 mg/kg body weight). Annonacin coupled with nanodiamonds was administered by intraperitoneal injection (17.5 mg/kg body weight) for 5 weeks, one injection per 3 days. Administration of annonacin coupled with nanodiamonds significantly reduced MCF7 cell growth and reactive oxygen species (ROS) levels. The in vivo study showed that administration of annonacin coupled with nanodiamonds significantly reduced PI3KCA levels and increased p53 expression, reduced cancer antigen-15-3 (CA-15-3) levels in serum, increased caspase-3 expression, reduced Ki-67 levels, and reduced the thickness of the mammary ductal epithelium. Collectively, this study demonstrated the effectiveness of nanodiamonds as a carrier of annonacin to inhibit breast cancer cell growth through inhibition of the PI3K/Akt signaling pathway.


Ten-year outcomes of the first 'one-stop haematuria clinic' in an Australian public hospital.
Urgent assessment of haematuria is critical to exclude malignancy. The utilization of haematuria clinics in Australia remains in its infancy. It is hoped that the streamlined investigative service will achieve earlier diagnosis of urological malignancy and subsequently decrease morbidity and mortality. We report the 10-year prospectively collected outcomes from Australia's first dedicated one-stop haematuria clinic (OSHC). Since its commencement in May 2008 through to July 2018, all consecutive patients assessed in the OSHC were included in the analysis. Data collected included demographics, presentation, wait times, investigation, assessment, initial treatment, referral and histopathology. A total of 3008 patients were seen in the OSHC with non-visible haematuria (1024, 34%) and visible haematuria (1984, 66%). Three hundred and twenty-seven (10.9%) patients were diagnosed with urothelial malignancy. In all, 306 (10.2%) patients had lower tract disease and 21 (0.7%) had upper tract disease. Urothelial cases were compiled of 123 (37.6%) Ta LG, 39 (11.9%) Ta HG, 21 (6.4%) Tis, 67 (20.5%) T1 and 77 (23.6%) T2-4. Urothelial malignancy was diagnosed more often in males (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.35-2.25), older patients elder than 60 years (OR 1.97, 95% CI 1.47-2.64) and patients with visible haematuria (OR 5.42, 95% CI 3.73-7.86). In all, 53.4% of patients were discharged after a single visit to the OSHC. The OSHC has served as an effective tool for rapid, streamlined assessment of patients presenting with haematuria. This model of care has been subsequently adopted by numerous public centres across Australia. Current funding structures present a barrier to this excellent approach for rapid access diagnostics.


Quantitative high-resolution gas chromatography and mass spectrometry of toxaphene residues in fish samples.
This report describes an analytical method which permits the determination of ppb (1 microgram/kg) level of toxaphene in fish tissues. Interferences both from biogenic and from xenobiotic substances are reduced even with low-resolution mass spectrometry. The methodology has a low susceptibility to false positive determinations, which could result from the presence of a wide variety of co-contaminants. The method is based on the measurement of a signal representative of the toxaphene residue (m/z 158.9) relative to a known amount of an internal standard 37Cl-labelled compound. A modular approach to toxaphene enrichment has permitted a moderately simple procedure, significantly reducing analytical time requirements and the number of sample manipulations, and making the procedure amenable to automation. The reliability and accuracy of the procedure are demonstrated by the results of intra- and interlaboratory studies. The methodology has been validated and the presented data indicate that the detection limit is 1 microgra/kg of total toxaphene. Toxaphene recovery from fish at concentration levels between 0.1 and 10 micrograms/g is 84 +/- 12%.


Osseous metaplasia in ovarian papillary serous cystadenocarcinoma.
The finding of osseous metaplasia within an ovarian papillary serous cystadenocarcinoma is very rare. A review of the medical literature reveals only two previously published cases where mature bone was found in an ovarian serous cystadenocarcinoma. This report presents an additional case of this unusual phenomenon whose clinical significance remains uncertain.


Sediment-associated bacterial community and predictive functionalities are influenced by choice of 16S ribosomal RNA hypervariable region(s): An amplicon-based diversity study.
Meta-omics approaches such as high-throughput sequencing of 16S hypervariable region(s) [HVR(s)] is extensively applied for profiling microbial community. Several studies have deciphered the influence of HVR(s) on bacterial diversity; most of these were devoted to human body habitats. Extent to which targeted HVR(s) influences the diversity estimates of environmental samples is rather unclear. Here, we evaluated the performance of five widely used universal primer pairs spanning V1-V3, V3-V4, V4, V5-V6 and V7-V9 HVRs to characterize bacterial diversity and predictive functionality of complex marine sediments. Obtained results revealed that the HVR(s) V4 and V5-V6 represented the higher species richness than others while, V1-V3 and V7-V9 were unsuccessful to detect Bacteroidetes and Planctomycetes. Further, PICRUSt analysis showed that the selected HVR(s) also had significant impact on the predictive functional profile. Conclusively, this study proved that HVR selection has a profound effect on overall results and thus should be selected with utmost caution.


Biochemical and toxicological effects of short-term, intermittent xylene inhalation exposure and combined ethanol intake.
Intermittent inhalation of 300 ppm of xylene vapour 6 h daily for 2 weeks caused a marked accumulation of the solvent in the perirenal fat. Simultaneous ethanol ingestion reduced the solvent load significantly although the perirenal xylene concentration increased in both test groups between the first and second week of exposure. Xylene inhalation enhanced hepatic and renal ethoxycoumarin 0-deethylase activity about 1.5-fold. The combination of inhaled xylene and peroral ethanol showed a markedly potentiated effect on microsomal ethoxycoumarin 0-deethylase activity especially in the kidneys. The enhanced monooxygenase activity was compatible with the decreased body solvent burden. Therefore, simultaneous ethanol intake might significantly modify the toxicological hazard in xylene exposure. Slightly increased proteolysis was detected in brain of animals in the xylene-ethanol experiment after the second week. Brain RNA content decreased after 2 weeks of exposure in the ethanol consuming animals. Xylene inhalation enhanced cerebral DT-diaphorase activity in both groups after 2 weeks of exposure. Ethanol intake also potentiated the behavioural effects caused by the solvent inhalation.


Mechanism of conformational coupling in SecA: Key role of hydrogen-bonding networks and water interactions.
SecA uses the energy yielded by the binding and hydrolysis of adenosine triphosphate (ATP) to push secretory pre-proteins across the plasma membrane in bacteria. Hydrolysis of ATP occurs at the nucleotide-binding site, which contains the conserved carboxylate groups of the DEAD-box helicases. Although crystal structures provide valuable snapshots of SecA along its reaction cycle, the mechanism that ensures conformational coupling between the nucleotide-binding site and the other domains of SecA remains unclear. The observation that SecA contains numerous hydrogen-bonding groups raises important questions about the role of hydrogen-bonding networks and hydrogen-bond dynamics in long-distance conformational couplings. To address these questions, we explored the molecular dynamics of SecA from three different organisms, with and without bound nucleotide, in water. By computing two-dimensional hydrogen-bonding maps we identify networks of hydrogen bonds that connect the nucleotide-binding site to remote regions of the protein, and sites in the protein that respond to specific perturbations. We find that the nucleotide-binding site of ADP-bound SecA has a preferred geometry whereby the first two carboxylates of the DEAD motif bridge via hydrogen-bonding water. Simulations of a mutant with perturbed ATP hydrolysis highlight the water-bridged geometry as a key structural element of the reaction path.


An economic evaluation of the 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of mild-to-moderate hypertension in Greece.
In the 2003 European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines, it is concluded that the major classes of antihypertensive agents are suitable for the initiation and maintenance of antihypertensive therapy. The aim of this study was to compare the cost-effectiveness of each one of the major antihypertensive agents as monotherapy in the management of mild-to-moderate hypertension in Greece, when following the 2003 ESH-ESC guidelines. We performed a cost-effectiveness analysis based on numbers needed to treat. A decision analysis model was developed to compare chlorthalidone, propranolol, amlodipine, enalapril and losartan. Clinical inputs were derived from a meta-analysis and randomized controlled trials and cost data from public sources. The evaluation of the cost of managing hypertension includes the cost of drug therapy, monitoring, treating side effects, poor compliance and switching. All costs were calculated from a public insurance system perspective, in 2004 Euros. Future costs and clinical benefits were discounted at 5%. The time frame was 5 years. Extensive sensitivity analyses were also performed. The cost (in Euros) of uncomplicated hypertension treatment for 5 years was 485.87, 567.66, 851.44, 607.45, and 1279.88 for chlorthalidone, propranolol, amlodipine, enalapril, and losartan, respectively. The estimated total cost (in Euros) to prevent one death was 60230.71, 70369.96, 105596.72, 75301.40, and 158659.35, respectively. In mild-to-moderate uncomplicated hypertension chlorthalidone is the most cost-effective agent. If it was the drug of choice to initiate treatment of uncomplicated hypertension, it would probably save the public insurance system organizations a great amount of expenses for benefit of the insured patients.


Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice.
Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-kappaB and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression.


Acinar distribution of glutathione-dependent detoxifying enzymes. Low glutathione peroxidase activity in perivenous hepatocytes.
The acinar distribution of glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G-6-PDH) was examined by analyzing periportal (p.p.) and perivenous (p.v.) rat hepatocytes selectively isolated by the digitonin-collagenase perfusion. The cytosolic GST activity was higher in p.v. cells, but the microsomal GST and cytosolic GR were found to be evenly distributed in the acinus. In contrast, the activity of both the Se-dependent GPx and the microsomal (Se-independent) GPx, as well as G-6-PDH, was much lower in the p.v. than in the p.p. cells. The heterogeneous distribution of GST, GPx and G-6-PDH was confirmed by analyzing liver perfusion effluents collected after ante- or retrograde digitonin infusion. The relatively low activities of GPx and G-6-PDH in the p.v. cells could partly explain the susceptibility of this region to chemical injury.


Dermatoses of pregnancy: Nomenclature, misnomers, and myths.
The most recent reclassification of dermatoses of pregnancy includes polymorphic eruption of pregnancy, atopic eruption of pregnancy, and pemphigoid gestationis; intrahepatic cholestasis of pregnancy, strictly not a dermatosis, was included in specific dermatoses of pregnancy for working purposes. Another dermatosis, pustular psoriasis of pregnancy, could be included for similar reasons. The nomenclature of these pregnancy-specific eruptions has been revised several times, generating potential confusion among practitioners. Clouding the picture further are misnomers that have been used to describe dermatoses of pregnancy. In addition, several cutaneous conditions that are associated with, but not specific to, pregnancy, have been misunderstood, which has resulted in certain myths among patients and physicians. In this contribution, we describe how the nomenclature of each dermatosis of pregnancy has evolved to fit the current classification scheme. We then identify several misnomers that have generated confusion within the scheme. Finally, we debunk several myths that have developed around cutaneous conditions outside of this scheme, in both mother and newborn.


Stroke survivor and informal caregiver perceptions of poststroke depressive symptoms.
Poststroke depression is common but remains underdiagnosed and undertreated. One explanation for this is that depressive symptoms go unrecognized by stroke survivors and their family caregivers and thus go unreported to the stroke survivor's healthcare provider. Forty-four stroke survivor-informal caregiver dyads were interviewed using a depression knowledge scale, the Center for Epidemiologic Studies Depression Scale, and an adapted version of the Revised Illness Perception Questionnaire to determine their lay knowledge of depressive symptoms, recognition of poststroke depressive symptoms, and perception of the recognized symptoms. Caregivers and stroke survivors had moderate knowledge of depressive symptoms but had some misconceptions. The most commonly recognized poststroke depressive symptoms by stroke survivors were "feeling like everything was an effort," "restless sleep," "difficulty concentrating," and "talking less than usual." Caregivers identified that the stroke survivor was "feeling like everything was an effort," had "restless sleep," "felt sad," and "felt depressed." Three quarters of stroke survivors with high levels of depressive symptoms identified the cluster of symptoms as potentially being depression. Neuroscience nurses are in the unique position to educate stroke survivors and their caregivers about poststroke depressive symptoms, treatment options, and the importance of discussing depressive symptoms with their healthcare provider.


No effect of diltiazem on the hepatic clearance of indocyanine green in the rats.
In order to investigate the effect of the pretreatment with various doses of diltiazem (DTZ) on the pharmacokinetics of indocyanine green (ICG) at steady state, especially the hepatic blood clearance due to the change of hepatic blood flow, the following experiments were carried out with ICG, a hepatic function test marker, not metabolized in liver and only excreted in bile. The intravenous bolus injection (3,780 micrograms/kg) and the constant-rate infusion (10,100 micrograms/kg/hr) of ICG into the left femoral vein were made in order to check the steady-state plasma concentration (Css of 10 micrograms/ml) of ICG at 20, 25 and 30 min. Following a 90-min washout period, the intravenous bolus injection (108, 430, 860 and 1,720 micrograms/kg) and the constant-rate infusion (108, 433, 866 and 1,730 micrograms/kg/hr) of DTZ into the right femoral vein were made and the achievement of the steady-state plasma levels (Css of 50, 200, 400 and 800 ng/ml) of DTZ were conformed at 60, 70 and 80 min. During the steady state of DTZ, the intravenous bolus injection (3,780 micrograms/kg) and the constant-rate infusion (10,200 micrograms/kg/hr) of ICG into the left femoral vein were made and also the steady-state plasma concentration of ICG was checked at 20, 25 and 30 min. The plasma concentrations of DTZ and ICG were determined using a high performance liquid chromatographic technique. At the steady state, the hepatic blood clearance of ICG was obtained from the plasma concentration and blood-to-plasma concentration ratio (RB) of ICG. The pretreatment with various doses of DTZ did not influence the plasma concentrations, RB and plasma free fraction (fp) of ICG. So the hepatic blood clearance of ICG was independent of concentration of DTZ. The hepatic blood clearance of ICG could be affected by both hepatic blood flow and hepatic intrinsic clearance. But there was no change of the hepatic blood clearance of ICG between the control and the DTZ-pretreated rats in this study. So it may be suggested that DTZ does not influence hepatic blood flow.


Fatal Familial Insomnia: Clinical Aspects and Molecular Alterations.
Fatal familiar insomnia (FFI) is an autosomal dominant inherited prion disease caused by D178N mutation in the prion protein gene (PRNP D178N) accompanied by the presence of a methionine at the codon 129 polymorphic site on the mutated allele. FFI is characterized by severe sleep disorder, dysautonomia, motor signs and abnormal behaviour together with primary atrophy of selected thalamic nuclei and inferior olives, and expansion to other brain regions with disease progression. This article reviews recent research on the clinical and molecular aspects of the disease. New clinical and biomarker tools have been implemented in order to assist in the diagnosis of the disease. In addition, the generation of mouse models, the availability of 'omics' data in brain tissue and the use of new seeding techniques shed light on the molecular events in FFI pathogenesis. Biochemical studies in human samples also reveal that neuropathological alterations in vulnerable brain regions underlie severe impairment in key cellular processes such as mitochondrial and protein synthesis machinery. Although the development of a therapy is still a major challenge, recent findings represent a step toward understanding of the clinical and molecular aspects of FFI.


Assessing caffeine intake in the United Kingdom diet.
Caffeine occurs naturally in the leaves and seeds of many plants and is artificially added to some beverages. Consumption of caffeine has been linked to both positive and adverse health outcomes. We incorporated estimates of caffeine content (mg/100g or ml) of foods and drinks, taken from the published literature, to provide a preliminary estimate of caffeine intake for the UK population, based on data collected in the National Diet and Nutrition Survey 2008-10. Among consumers mean total caffeine intakes of adult men 19+ y were significantly greater than intakes by boys 4-10y and 11-18y (p<0.05), with the same age-related differences seen for females. 4.1% of men 19+ y and 3.8% of women 19+ y had caffeine intakes in excess of 300mg/d. The addition of caffeine to UK food composition databases will allow more detailed study of the health effects of caffeine consumption.


The potential beneficial role of Ginkgetin in doxorubicin-induced hepatotoxicity: Elucidating the underlying claim.
Doxorubicin (DOX) is a widely used chemotherapeutic agent for various tumors treatment; apart from its chemotherapeutic activity, the traditional usage of DOX has been limited by its adverse effects on multiple organs, mainly hepatotoxicity. The molecular mechanisms underlying DOX hepatotoxicity are mainly due to the production of reactive oxygen species (ROS) inducing oxidative stress, diminishing antioxidant enzymes, apoptosis, inflammation, and mitochondrial dysfunction. Thus, there is an urgent need to develop a therapy that minimizes DOX hepatotoxicity and widens its use in various types of cancers without fear of its serious hepatotoxicity. Ginkgetin (GINK), a natural biflavonoid, exhibits diverse actions, including promising free radical scavenging, antioxidant, and anti-inflammatory activities. So, this study's objectives were to determine whether GINK could mitigate DOX's hepatotoxic effects and look into a putative hepatoprotective molecular pathway. Mice were divided into five groups: Normal control, control GINK 100, Untreated DOX group, and DOX groups treated with GINK (50 and 100 mg/kg) intraperitoneally daily for four days before DOX administration and an additional three days afterward. GINK 100 pretreatment showed marked protection from DOX hepatotoxicity and also attenuation of histopathological structural alterations. These outcomes were corroborated biochemically by a considerable decrease in alanine aminotransferases, aspartate aminotransferase, and alkaline phosphatase levels. GINK significantly augmented silent information regulator 1 and nuclear translocation of NF-E2-related factor 2 and repressed the expression and protein levels of forkhead box protein O1, inducible nitric oxide synthase, and P53 relative to DOX group. GINK alleviated oxidative stress and induced significant anti-inflammatory effects via suppression of interleukin-6, nuclear factor Kabba B, and iNOS respectively. This study is the first to investigate GINK's potentially beneficial effects in acute DOX hepatotoxicity, possibly exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects by modulation of Sirt1/FOXO-1/NF-κB Signal.


Lennox-Gastaut syndrome and epilepsy with myoclonic-astatic seizures.
Among nonsymptomatic epilepsies exhibiting several types of generalized seizures in children two syndromes were progressively identified: epilepsy with myoclonic-astatic seizures (MAE) and nonsymptomatic Lennox-Gastaut syndrome (LGS). Various approaches based on etiology, electroclinical semiology, and mathematical analysis have progressively helped to distinguish these two conditions. Both conditions preferentially affect boys. The course is stereotyped in MAE, characterized by progressive worsening of epilepsy, usual pharmacoresistance at onset and tonic-clonic seizures, myoclonus and frequent episodes of myoclonic status epilepticus. EEG shows 3Hz spike wave bursts characteristic of idiopathic generalized epilepsy together with slowing of the tracing. In LGS, major seizures are mainly atypical absences and tonic seizures with 0.5-2Hz slow spike-waves and eventually focal anomalies. Prognosis in both syndromes ranges from recovery without sequelae to pharmacoresistant epilepsy that has improved over the past 2 decades with the new generation antiepileptic compounds. Iatrogenic factors may contribute to the poor prognosis, mainly in MAE. Pathophysiology remains speculative for both syndromes: although both share factors of brain maturation, MAE is probably mainly related to genetic predisposition whereas LGS results from some unidentified cortical brain malformation. In unfavorable cases, there may therefore be a continuum between both syndromes. They need to be distinguished from other epilepsy syndromes and inborn errors of metabolism that begin in the same age range: atypical idiopathic benign epilepsy, frontal lobe epilepsy with secondary bisynchrony, ring chromosome 20, ceroid lipofuscinosis, and nonsymptomatic late-onset spasms.


Regulating local molecular polarization of triazine-PDI based polymer for high-efficient photocatalytic coupling of benzylamine.
Designing a robust built-in electric field (BF) is a charming strategy for enhancing the separation and transportation of charges via introducing large π-conjugated molecules. However, it has flexible or semiflexible geometries, which significantly disorder the crystalline and deteriorated the built-in electric field. Here, a straightforward tactic for creating a cyano-functionalized smaller D (benzene) - A (triazine) units in PDI- triazine based polymer (PDIMB) to enhance intrinsic molecule dipole has been proposed. The density functional theory (DFT) calculation revealed that the modification of smaller D-A groups destroyed the π-localization of charges, which enhanced the molecular dipole and the BF for promoting the exciton dissociation and charge transfer. Moreover, it not only exposed number of active sites, but also enhanced the interfacial molecular interacting. Therefore, PDIMB-2 exhibits high activity (24.5 mmol g-1 h-1) and selectivity (>99%) for the photooxidation of benzylamine to N-benzylidenebenzylamine under mild conditions. Our work offers a potential and simple synthetic option for enhancing the built-in electric field of polymer.


A historical review of placebo-controlled, relapse prevention trials in schizophrenia: The loss of clinical equipoise.
Recent ethical critiques have proposed that placebo-controlled, relapse prevention trials in schizophrenia are no longer justifiable and are therefore unethical. This review provides an historical perspective on the justifications for these trials and how arguments evolved over several decades. We identified 87 placebo-controlled, relapse prevention trials published over the last seventy years and examined the purpose for each trial. We found that first-generation trials had compelling justifications, yet these arguments changed considerably over time. Second-generation trials offered comparatively weaker-and sometimes no-justifications for their conduct. Without clear and compelling justifications for a given trial, it is not ethical to continue using this study design.


Correlations of disease severity and age with hematology parameter variations in patients with COVID-19 pre- and post-treatment.
For better understanding of the pathological changes of COVID-19, benefiting clinical management of the disease and the preparation for future waves of similar pandemics. Hematology parameters from a total of 52 cases of COVID-19 admitted for treatment in a designated hospital were retrospectively analyzed. Data were analyzed by SPSS statistical software. Pre-treatment T-cell subsets, total lymphocytes, red blood cell distribution width (RDW), eosinophils, and basophils were significantly lower than that of post-treatment, while the inflammatory indexes neutrophils, neutrophil to lymphocyte ratio (NLR), and C-reactive protein (CRP) levels, as well as red blood cell (RBC) and hemoglobin, were significantly reduced after treatment. The T-cell subsets, total lymphocytes, and basophils in severely and critically ill patients were significantly lower than those in moderately ill patients. Neutrophils, NLR, eosinophils, procalcitonin (PCT), and CRP was significantly higher in severely and critically ill patients than in moderately ill patients. CD3+, CD8+, total lymphocytes, platelets, and basophils in patients older than 50 were lower than that of those younger than 50, while neutrophils, NLR, CRP, and RDW in patients older than 50 were higher than that of younger than 50. There was a positive correlation among prothrombin time (PT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in severely and critically ill patients. T-cell subsets, lymphocyte count, RDW, neutrophils, eosinophils, NLR, CRP, PT, ALT, and AST are important indicators in the management especially for severely and critically ill patients with COVID-19.


Platinum Group Element distribution in water and marine biota from two impacted estuarine environments (Douro and Ave estuaries, Portugal).
Platinum Group Elements (PGEs) are contaminants of emerging environmental concern considering their continuous increasing use and subsequent release in the environment. While recent field studies provided PGE levels in seawater, scarce knowledge still exists regarding PGE contamination in marine organisms, especially for rhodium (Rh). Water, macroalgae and mussels were sampled along two representative urbanized estuarine systems and adjacent coastal areas (Douro and Ave estuaries, Portugal). Rhodium and platinum (Pt) concentrations were quantified through both stripping voltammetry and mass spectrometry in collected samples. Spatial mapping of PGE contamination was, to a certain extent, correlated with proxies of urban effluents. The use of Pt/Rh ratios reflected the dominant influence of PGE traffic emissions along the Douro and inputs from various sources (including industries) on the Ave Estuary. Macroalgae and mussels PGE concentrations reflected urban pressure, amplifying environmental signals, and supporting their relevant use as bioindicators of PGE contamination in estuarine/coastal systems.


An isobolographic analysis of the anti-nociceptive effect of geraniin in combination with morphine or diclofenac.
Geraniin, a dehydroellagitannin, is a major component of the aqueous extract of the aerial parts of Phyllanthus muellerianus (Kuntze) Exell. (Euphorbiaceae). Several Phyllanthus species are traditionally used for painful disorders. The anti-nociceptive effects of the aqueous extract of the aerial parts of P. muellerianus and of geraniin have been scientifically established. The aim of the paper is to determine whether a combination of geraniin and diclofenac or geraniin and morphine leads to better anti-nociceptive effects. The nature of the interactions of morphine and diclofenac with geraniin was evaluated by undertaking the isobolographic analysis. Mice were treated with geraniin (3-30 mg/kg), morphine (1-10 mg/kg), and diclofenac (10-100 mg/kg) to obtain the ED50 values of the agents in the formalin test. Dose-response curves were then obtained and analyzed after the co-administration of geraniin with morphine or diclofenac in fixed ratio (1:1) combinations based on specific fractions (1/2, 1/4, and 1/8) of their respective ED50 values for the formalin test. Geraniin was less potent than morphine but more potent than diclofenac in the formalin-induced nociception. The isobolographic analysis of geraniin/morphine (G/M) and geraniin/diclofenac combinations (G/D) at different fractions revealed the potentiation of their anti-nociceptive effects. The degrees of potentiation, which were calculated as interaction indices, showed synergism for both combinations in both phase I (G/M: 0.040, G/D: 0.017) and phase II (G/M: 0.004, G/D: 0.002) of the formalin test. The present study demonstrates synergism for the co-administration of geraniin with both morphine and diclofenac.


Tunable physical and mechanical properties of gelatin hydrogel after transglutaminase crosslinking on two gelatin types.
The crosslinking and related gel properties of 3 wt% gelatin (type-A and type-B) catalyzed by microbial transglutaminase (MTG, dose of 0-20 U/g gelatin) have been investigated. A MTG-depended increase in the molecular weight and mean diameter of both gelatins was observed, where type-A presented a higher crosslinking efficiency than type-B due to more acyl donors of the former. As MTG concentration increased, the surface hydrophobicity and thermal stability of type-A gelatin increased. Textural profile analysis (TPA) of type-A gelatin hydrogel showed a decrease in hardness and slight increase in springiness, while type-B gelatin gel was not affected generally. Rheological measurements confirmed the melting point of type-A gelatin hydrogel continually increased until the disappearance of gel thermo-reversibility at higher MTG levels (≥12 U/g gelatin), while type-B gelatin hydrogel always showed a sol-gel transition, suggesting that the gel performance was depended on the dominance of whether physical crosslinking or chemical crosslinking. Scanning electron microscope (SEM) results showed that the network structure of the type-A gelatin became more irregular as MTG increasing which indicated that introducing additional covalent cross-links within or between gelatin chains had a profound influence on gel's network structure, closely associated with the gel properties mentioned above. In summary, the superiority of type-A in MTG-crosslinking efficiency than type-B, can be used to modulate the physical and mechanical properties of gelatin hydrogel, governing by the combing of weak physical crosslinking and strong covalent crosslinking, which will be suitable for numerous industrial applications.


Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload.
Many patients with hepatic iron overload do not have identifiable mutations and often present with metabolic disorders and hepatic steatosis. Since the pathophysiology of Dysmetabolic Hepatic Iron Overload (DHIO) is still obscure, the aim of this study was to evaluate, in these patients, possible alterations in iron-related molecule expression. Iron-related gene mRNA levels were determined by quantitative-PCR in liver biopsies of subjects with NAFLD without iron overload and patients with HFE-hemochromatosis, beta-thalassemia major and DHIO. Urinary hepcidin was measured by immunoblotting. No alterations in mRNA expression of either iron transporters or exporters were found in DHIO. mRNA and urinary hepcidin levels normalized for the amount of iron overload showed a significantly lower ratio than in controls, although not as low as in hemochromatosis or beta-thalassemia. Differently from what observed in hemochromatosis, hepcidin mRNA did not correlate with urinary hepcidin. Patients with DHIO show appropriate regulation of mRNAs encoding proteins involved in iron uptake and efflux but dysregulation of hepcidin production. The relatively elevated urinary hepcidin can explain the iron phenotype in DHIO (more macrophage iron retention and low/normal transferrin saturation).


A novel device for elimination of cancer cells from blood specimens.
Circulating tumor cells (CTCs) are derivatives of solid cancerous lesions that detach from the tumor mass and enter the blood circulation. CTCs are considered to be the precursors of metastasis in several cancer types. They are present in the blood of cancer patients as single cells or clusters, with the latter being associated with a higher metastatic potential. Methods to eliminate CTCs from the bloodstream are currently lacking. Here, we took advantage of the lower shear stress-resistance of cancer cells compared to blood cells, and developed a device that can eliminate cancer cells without blood damage. The device consists of an axial pump and a coupled rotating throttle, controllable to prevent local blood flow impairment, yet maintaining a constant shear performance. When processing cancer cells through our device, we observe cancer cell-cluster disruption and viability reduction of single cancer cells, without noticeable effects on human blood cells. When injecting cancer cell-containing samples into tumor-free recipient mice, processed samples fail to generate metastasis. Together, our data show that a selective disruption of cancer cells is possible while preserving blood cells, paving the way towards the development of novel, implantable tools for CTC disruption and metastasis prevention.


Free-field sensitivity level of audiometric earphones to be used for speech audiometer calibration.
Speech audiometric test results strongly depend on the frequency response of the equipment used for speech transmission. For the comparison of data measured with different kinds of acoustic transducers, e.g. earphones and loudspeakers, a common reference basis for the specification of the frequency response of speech audiometers is therefore needed. The most obvious basis is the free sound field. In order to provide data for earphone specification in terms of the equivalent free-field response, which are to be included in an IEC standard on speech audiometers under preparation, comprehensive loudness comparison measurements with free progressive sound waves were performed on various audiometric earphones. When these data are used, calibration and testing of speech audiometers are as simple as in the case of puretone audiometers.


Effects of captopril on arterial and venous pressure, renal function, and humoral factors in severe chronic congestive heart failure.
The effects of captopril in several humoral factors were studied to elucidate the role of the renin-angiotensin (RA) system in arterial and venous pressures and renal function in patients with severe chronic congestive heart failure. A single oral dose of captopril in 20 subjects reduced mean arterial blood pressure from 77 to 67 mm Hg; this decrease correlated with baseline plasma renin activity (PRA). The increase in PRA and the decrease in plasma aldosterone levels after captopril were much greater in subjects with higher PRA. Plasma norepinephrine (NE) levels decreased, while those of epinephrine did not change. Peripheral venous pressure declined from 107 to 77 mm H2O; this decrease correlated with the change in NE levels. During 7-day captopril therapy, urine volume and sodium excretion increased (1145 to 1136 ml/day and 76 to 94 mEq/day) in 11 subjects in whom renal function was followed. Renal plasma flow (RPF) rose from 237 to 364 ml/min, while glomerular filtration rate did not change; the filtration fraction decreased from 32% to 23%. Simultaneous infusion of aprotinin in six of the subjects did not affect the captopril-induced increase in RPF, despite the suppression of plasma bradykinin levels. These results suggest that captopril reduces arterial blood pressure in patients with high PRA through inhibition of the RA system and dilates veins by attenuation of sympathetic nervous activity. Increased RPF and urinary sodium excretion induced by captopril might result from inhibition of the RA system; the kallikrein-kinin system or bradykinin-mediated prostaglandins do not appear to play a major role.


Inhibition of chemokine expression in rat inflamed paws by systemic use of the antihyperalgesic oxidized ATP.
We previously showed that local use of periodate oxidized ATP (oATP, a selective inhibitor of P2X7 receptors for ATP) in rat paw treated with Freund's adjuvant induced a significant reduction of hyperalgesia Herein we investigate the role of oATP, in the rat paws inflamed by carrageenan, which mimics acute inflammation in humans. Local, oral or intravenous administration of a single dose of oATP significantly reduced thermal hyperalgesia in hind paws of rats for 24 hours, and such effect was greater than that induced by diclofenac or indomethacin. Following oATP treatment, the expression of the pro-inflammatory chemokines interferon-gamma-inducible protein-10 (IP-10), mon ocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) within the inflamed tissues markedly decreased on vessels and infiltrated cells. In parallel, the immunohistochemical findings showed an impairment, with respect to the untreated rats, in P2X7 expression, mainly on nerves and vessels close to the site of inflammation. Finally, oATP treatment significantly reduced the presence of infiltrating inflammatory macrophages in the paw tissue. Taken together these results clearly show that oATP reduces carrageenan-induced inflammation in rats.


The correlation between ART and OCRA methods used for posture assessment of repetitive tasks.
Repetitive tasks are among the causes of musculoskeletal disorders. Assessment of repetitivetasks is performed through various methods with different scores and significance given to risk factors considered in these methods. Knowing the strengths and weaknesses of each method can contribute to modifying the methods and improving the correlation between them. This study aimed to investigate the correlation between ART and OCRA methods in a career with repetitive movements. After hierarchical task analysis in a vegetable grower job with repetitive movements, the subtasks were assessed by an assessor who mastered both ART and OCRA methods. The final score of each method was checked using the Pearson correlation coefficient in SPSS 18, after testing the normality of data. Moderate risk levels were reported for 16 out of the 14 sub-tasks analyzed using both methods. In the ART method, 3 sub-tasks and in the OCRA method, 2 sub-tasks had high-risk levels. The Pearson correlation coefficient was 0.842 indicating a moderate correlation between the two posture assessment methods. The findings of the study showed an acceptable correlation and compatibility between the two methods considering the risk levels.


Comparison of dry- and wet-heat induced changes in physicochemical properties of whey protein in absence or presence of inulin.
Changes in whey protein (10%, w/v) induced by dry-heating (60 °C for 5 days at a relative humidity of 63%), wet-heating (85 °C for 30 min) or the two-combined heating in absence or presence of inulin (8%, w/v) were studied. Mixture of whey protein and inulin showed significantly higher absorbance at 290 nm than whey protein alone in all heating conditions while only dry-heated samples showed significantly increased absorbance value at 420 nm (p < 0.05). Whey protein after heating showed significantly lower zeta potential and inulin decreased the value of all heated samples further (p < 0.05) except for samples after dry-heating. Heating decreased the free sulfhydryl group content of whey protein samples while presence of inulin decreased further (p < 0.05). Dry-heating decreased while wet-heating increased the surface hydrophobicity of whey protein. Inulin had no effect on the surface hydrophobicity of heated whey protein under dry-heating but decreased under wet-heating.


A brief guideline for studies of phase-separated biomolecular condensates.
Cells are exquisitely compartmentalized to achieve precise spatiotemporal regulation of myriad processes and pathways. Phase separation offers one way to achieve territorial organization in the cellular context, via the creation of membrane-less organelles (MLOs). MLOs formed through phase separation are associated with numerous critical biological functions. Although hundreds of publications on related topics are produced each year, robust criteria for the determination of biologically meaningful phase separation are yet to be well established. Here we present some principles and propose a few guidelines for phase-separation studies in biology. Specifically, we provide an in-depth experiment pipeline for phase-separation studies, including mechanisms of the molecular driving forces, ways to correlate in vivo and in vitro observations, and strategies to relate the phase-separation phenomenon to biological functions. We also intend to contribute to streamlining the aforementioned diagnostic criteria by further stressing a few common caveats in the field.


U1 snRNP telescripting regulates a size-function-stratified human genome.
U1 snRNP (U1) functions in splicing introns and telescripting, which suppresses premature cleavage and polyadenylation (PCPA). Using U1 inhibition in human cells, we show that U1 telescripting is selectively required for sustaining long-distance transcription elongation in introns of large genes (median 39 kb). Evidence of widespread PCPA in the same locations in normal tissues reveals that large genes incur natural transcription attrition. Underscoring the importance of U1 telescripting as a gene-size-based mRNA-regulation mechanism, small genes were not sensitive to PCPA, and the spliced-mRNA productivity of ∼1,000 small genes (median 6.8 kb) increased upon U1 inhibition. Notably, these small, upregulated genes were enriched in functions related to acute stimuli and cell-survival response, whereas genes subject to PCPA were enriched in cell-cycle progression and developmental functions. This gene size-function polarization increased in metazoan evolution by enormous intron expansion. We propose that telescripting adds an overarching layer of regulation to size-function-stratified genomes, leveraged by selective intron expansion to rapidly shift gene expression priorities.


All-Epiphyseal Anterior Cruciate Ligament Repair Using Suture Ring Device in the Skeletally Immature Patient.
Anterior cruciate ligament (ACL) tears in pediatric patients pose distinct challenges in management, especially in patients with open distal femoral and proximal tibial physes. There are a variety of contemporary reconstruction techniques that attempt to address these challenges. However, with the resurgence of ACL repair in the adult population, it has become apparent that the pediatric patient may also benefit from primary ACL repair rather than reconstruction. ACL repair is a procedure performed to treat ACL tears that avoids the donor-site morbidity seen with ACL reconstruction using autograft. We describe a surgical technique involving FiberRing sutures (Arthrex, Naples, FL) and TightRope-internal brace fixation (Arthrex) for ACL repair with all-epiphyseal fixation in the pediatric patient. The FiberRing is a knotless, tensionable suture device that can be used to stitch the torn ACL and coupled with the TightRope and internal brace to fix the ACL.


Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.
p21CIP1/WAF1 is a CDK inhibitor regulated by the tumor suppressor p53 and is hypothesized to mediate G1 arrest. p53 has been suggested to derive anti-oncogenic properties from this relationship. To test these notions, we created mice lacking p21CIP1/WAF1. They develop normally and (unlike p53-/- mice) have not developed spontaneous malignancies during 7 months of observation. Nonetheless, p21-/- embryonic fibroblasts are significantly deficient in their ability to arrest in G1 in response to DNA damage and nucleotide pool perturbation. p21-/- cells also exhibit a significant growth alteration in vitro, achieving a saturation density as high as that observed in p53-/- cells. In contrast, other aspects of p53 function, such as thymocytic apoptosis and the mitotic spindle checkpoint, appear normal. These results establish the role of p21CIP1/WAF1 in the G1 checkpoint, but suggest that the anti-apoptotic and the anti-oncogenic effects of p53 are more complex.


Meta-analysis of short- and long-term outcomes after pure laparoscopic versus open liver surgery in hepatocellular carcinoma patients.
The advantages of laparoscopy are widely known. Nevertheless, its legitimacy in liver surgery is often questioned because of the uncertain value associated with minimally invasive methods. Our main goal was to compare the outcomes of pure laparoscopic (LLR) and open liver resection (OLR) in patients with hepatocellular carcinoma. We searched EMBASE, MEDLINE, Web of Science, and The Cochrane Library databases to find eligible studies. The most recent search was performed on December 1, 2017. Studies were regarded as suitable if they reported morbidity in patients undergoing LLR versus OLR. Extracted data were pooled and subsequently used in a meta-analysis with a random-effects model. Clinical applicability of results was evaluated using predictive intervals. Review was reported following the PRISMA guidelines. From 2085 articles, forty-three studies (N = 5100 patients) were included in the meta-analysis. Our findings showed that LLR had lower overall morbidity than OLR (15.59% vs. 29.88%, p < 0.001). Moreover, major morbidity was reduced in the LLR group (3.78% vs. 8.69%, p < 0.001). There were no differences between groups in terms of mortality (1.58% vs. 2.96%, p = 0.05) and both 3- and 5-year overall survival (68.97% vs. 68.12%, p = 0.41) and disease-free survival (46.57% vs. 44.84%, p = 0.46). The meta-analysis showed that LLR is beneficial in terms of overall morbidity and non-procedure-specific complications. That being said, these results are based on non-randomized trials. For these reasons, we are calling for randomization in upcoming studies. Systematic review registration: PROSPERO registration number CRD42018084576.


Oxymetholone treatment in myelofibrosis.
In order to study the effect of oxymetholone therapy in advanced myelofibrosis, 11 patients (4 females, 7 males) were given, 3--5 mg per kg body weight, long-term oxymetholone treatment in a prospective multicenter study. Five cases had previously had a diagnosis of polycythemia vera. All patients had anemia initially, 4 leukocytopenia and 10 thrombocytopenia in addition. Hepato-splenomegaly was present in all cases but in varying degree. Five patients required regular blood transfusions before treatment. In 9 of the 15 courses given, there was normalization of the peripheral blood or substantial improvement (better than 3 g hemoglobin/dl or 50 X 10(9) platelets/1) after androgens. Significant effects were noted both on hemoglobin values and platelet counts. The need for blood transfusions ceased completely in all 5 cases. When oxymetholone treatment was reduced or interrupted 4 patients relapsed; 2 of them responded to a renewed course. The red cell counts returned to previous polycythemic values in one patient and another died from acute leukemia. The results of this study suggest that androgens might be of value in advanced cases of myelofibrosis with transfusion-requiring anemia or severe thrombocytopenia.


Characterization of c-myc 3' to 5' mRNA decay activities in an in vitro system.
The levels of mRNA and protein encoded by the c-myc protooncogene set the balance between proliferation and differentiation of mammalian cells. Thus, it is essential for the cell to tightly control c-myc expression. Indeed, cells utilize many mechanisms to control c-myc expression, including transcription, RNA processing, translation, and protein stability. We have focused on turnover of c-myc mRNA as a key modulator of the timing and level of c-myc expression. c-myc mRNA is labile in cells, and its half-life is controlled by multiple instability elements located within both the coding region and the 3'-untranslated region (3'-UTR). Much work has focused on the protein factors that bind the instability elements, yet little is known about the enzymatic activities that effect the degradation of c-myc mRNA. Here I have utilized a novel cell-free mRNA decay system to characterize the c-myc mRNA decay machinery. This machinery consists of 3' to 5' mRNA decay activities that are Mg2+-dependent, require neither exogenous ATP/GTP nor an ATP-regenerating system, and act independently of a 7mG(5')ppp(5')G cap structure to deadenylate an exogenous mRNA substrate in a c-myc 3'-UTR-dependent fashion. Following deadenylation, nucleolytic decay of the 3'-UTR occurs generating 3' decay intermediates via a ribonucleolytic activity that can assemble on the c-myc 3'-UTR in a poly(A)-independent manner.


Battle of the axes: simulation-based assessment of fine needle aspiration biopsies for thyroid nodules.
Ultrasound-guided fine-needle aspiration biopsies (UGFNA) play a crucial role in the diagnosis of thyroid nodules. There are two techniques for performing an UGFNA: short-axis technique and long-axis technique. There is sparsity in the literature regarding the differences between these two techniques. To compare the efficiency between long-axis and short-axis thyroid UGFNA techniques in trainees. Our secondary outcomes were to define the comfort level and learning curves of trainees. A longitudinal prospective cohort study, completed from December 2018 to November 2019, using the Blue Phantom Thyroid Model© for UGFNA. Face and construct validity of the model were verified. Residents completed UGFNA on an assigned nodule using both long-axis and short-axis techniques, the order of which was sequentially allocated. The rate and time to successful biopsy were obtained for both techniques. Biopsy attempts were repeated to establish learning curves. Single-center study. Fourteen Otolaryngology-Head & Neck Surgery residents at the University of Toronto. Biopsy success and efficiency for novice learners completing UGFNA on a simulated thyroid model using long-axis and short-axis techniques. A trend towards higher odds of successful biopsy using the long-axis technique with no difference in procedure duration was observed (OR = 2.2, p = 0.095, CI = 0.87-5.39). Learning curve graphs appeared heterogenous according to trainee level. Trainees found the long-axis technique easier to perform (10/14, 71%), and the simulator valuable for learning (12/14, 86%). Thyroid UGFNA using the long-axis technique may have an increased success rate and is generally favored by trainees for being easier to perform. Thyroid simulators have the potential to increase learner comfort and efficiency with UGFNA.


Computerized tomography enterography and its role in small-bowel imaging.
Computerized tomography enterography is being adopted rapidly by many institutions as the primary technique used to image the small bowel. The purpose of this article is to summarize how the examination is performed, and to specify appropriate indications and alternatives, performance characteristics, and anticipated future developments.


A comparison of the effects of different substrata on chondrocyte morphology and the synthesis of collagen types IX and X.
Embryonic chick sternal chondrocytes were cultured either within three dimensional gels of type I collagen, type II collagen or agar, or as monolayers on plastic dishes coated with air-dried films of these matrix macromolecules. It was observed that cell shape and cell growth varied markedly between the different culture conditions. Flattened monolayers of cells on plastic or films of type I or type II collagen, proliferated more rapidly and reached a higher final cell density per culture than the more rounded cells found in the cultures on agar films or within three-dimensional gels. Biosynthetic studies demonstrated that in addition to the synthesis of type II collagen, all the cultures were producing collagen types IX and X. Chondrocytes cultured on plastic or films of the different matrix macromolecules all showed a similar expression of types IX and X collagen, independent of whether they displayed a flattened or round cell morphology. In contrast, marked variations in the proportions of the minor collagens, particularly type X collagen, were observed when the cells were cultured within three-dimensional gels. The data suggest that direct interaction of the cell surface with matrix constituents displaying a particular spatial array could be an important aspect in the control of type IX and X collagen expression by chondrocytes.


Intra-subject variability in human bone marrow stromal cell (BMSC) replicative senescence: molecular changes associated with BMSC senescence.
The outcomes of clinical trials using bone marrow stromal cell (BMSC) are variable; the degree of the expansion of BMSCs during clinical manufacturing may contribute to this variability since cell expansion is limited by senescence. Human BMSCs from aspirates of healthy subjects were subcultured serially until cell growth stopped. Phenotype and functional measurements of BMSCs from two subjects including senescence-associated beta-galactosidase staining and colony formation efficiency changed from an early to a senescence pattern at passage 6 or 7. Transcriptome analysis of 10 early and 15 late passage BMSC samples from 5 subjects revealed 2122 differentially expressed genes, which were associated with immune response, development, and cell proliferation pathways. Analysis of 57 serial BMSC samples from 7 donors revealed that the change from an early to senescent profile was variable among subjects and occurred prior to changes in phenotypes. BMSC age expressed as a percentage of maximum population doublings (PDs) was a good indicator for an early or senescence transcription signature but this measure of BMSC life span can only be calculated after expanding BMSCs to senescence. In order to find a more useful surrogate measure of BMSC age, we used a computational biology approach to identify a set of genes whose expression at each passage would predict elapsed age of BMSCs. A total of 155 genes were highly correlated with BMSC age. A least angle regression algorithm identified a set of 24 BMSC age-predictive genes. In conclusion, the onset of senescence-associated molecular changes was variable and preceded changes in other indicators of BMSC quality and senescence. The 24 BMSC age predictive genes will be useful in assessing the quality of clinical BMSC products.


Vasoactive intestinal polypeptide regulation of rabbit renal adenylate cyclase activity in vitro.
1. The effect of vasoactive intestinal polypeptide (VIP) upon adenylate cyclase activity was determined in purified cortical basolateral membranes and in glomeruli and tubular elements obtained from rabbit kidney. 2. In purified basolateral membranes prepared from cortex, 1 microM-VIP consistently stimulated adenylate cyclase activity above basal levels (1.55 +/- 0.09-fold (mean +/- S.E. of mean), n = 10 animals). Half-maximal stimulation was observed at 17 +/- 11 nM-VIP (S.D., n = 9). 3. Related peptides, e.g. secretin, glucagon, gastric inhibitory peptide, human pancreatic growth hormone releasing factor, and peptide having N-terminal histidine and C-terminal isoleucine amide (PHI), were without effect or gave lower stimulations of adenylate cyclase activity when tested at 1 microM. 4. Significant VIP degradation was observed under the assay conditions used but this did not substantially alter the response or selectivity to VIP. 5. In separate preparations of isolated glomeruli and proximal tubules addition of 1 microM-VIP resulted in a 3.3 +/- 1.1-fold (S.D., n = 3) and 2.2 +/- 1.0-fold (S.D., n = 3) stimulation (respectively) of adenylate cyclase activity. 6. In isolated medullary tubule suspensions, isolated by collagenase-hyaluronidase digestion of outer (red) medulla, and in thick ascending-limb-enriched preparations prepared by Percoll density gradient fractionation, 1 microM-VIP significantly increased adenylate cyclase activity by 2.4 +/- 0.6-fold (S.D., n = 3) and 2.1 +/- 0.7-fold (S.D., n = 3) respectively. 7. A possible role for VIP in the regulation of renal function in the rabbit is discussed in relation to the occurrence of VIP stimulation of adenylate cyclase activity in several renal cellular elements.