Effective natural interferon-alpha therapy in recombinant interferon-alpha-resistant patients with hairy cell leukemia.
To explore the relationship between anti-interferon-alpha (anti-IFN-alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment, we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy, 10 patients developed rIFN-alpha-2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL, while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN-induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore, these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU, three times a week. All eight patients responded to treatment with nIFN-alpha, achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.


Changes in sleep and the prevalence of probable insomnia in undergraduate university students over the course of the COVID-19 pandemic: findings from the U-Flourish cohort study.
Sleep problems associated with poor mental health and academic outcomes may have been exacerbated by the COVID-19 pandemic. To describe sleep in undergraduate students during the COVID-19 pandemic. This longitudinal analysis included data from 9523 students over 4 years (2018-2022), associated with different pandemic phases. Students completed a biannual survey assessing risk factors, mental health symptoms and lifestyle, using validated measures. Sleep was assessed with the Sleep Condition Indicator (SCI-8). Propensity weights and multivariable log-binomial regressions were used to compare sleep in four successive first-year cohorts. Linear mixed-effects models were used to examine changes in sleep over academic semesters and years. There was an overall decrease in average SCI-8 scores, indicating worsening sleep across academic years (average change -0.42 per year; P-trend < 0.001), and an increase in probable insomnia at university entry (range 18.1-29.7%; P-trend < 0.001) before and up to the peak of the pandemic. Sleep improved somewhat in autumn 2021, when restrictions loosened. Students commonly reported daytime sleep problems, including mood, energy, relationships (36-48%) and concentration, productivity, and daytime sleepiness (54-66%). There was a consistent pattern of worsening sleep over the academic year. Probable insomnia was associated with increased cannabis use and passive screen time, and reduced recreation and exercise. Sleep difficulties are common and persistent in students, were amplified by the pandemic and worsen over the academic year. Given the importance of sleep for well-being and academic success, a preventive focus on sleep hygiene, healthy lifestyle and low-intensity sleep interventions seems justified.


Relationship between Diet, Microbiota, and Healthy Aging.
Due to medical advances and lifestyle changes, population life expectancy has increased. For this reason, it is important to achieve healthy aging by reducing the risk factors causing damage and pathologies associated with age. Through nutrition, one of the pillars of health, we are able to modify these factors through modulation of the intestinal microbiota. The Mediterranean and Oriental diets are proof of this, as well as the components present in them, such as fiber and polyphenols. These generate beneficial effects on the body thanks, in part, to their interaction with intestinal bacteria. Likewise, the low consumption of products with high fat content favors the state of the microbiota, contributing to the maintenance of good health.


Transthyretin deposition promotes progression of osteoarthritis.
Deposition of amyloid is a common aging-associated phenomenon in several aging-related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is its major risk factor. Transthyretin (TTR) is an amyloidogenic protein that is deposited in aging and OA-affected human cartilage and promotes inflammatory and catabolic responses in cultured chondrocytes. Here, we investigated the role of TTR in vivo using transgenic mice overexpressing wild-type human TTR (hTTR-TG). Although TTR protein was detected in cartilage in hTTR-TG mice, the TTR transgene was highly overexpressed in liver, but not in chondrocytes. OA was surgically induced by destabilizing the medial meniscus (DMM) in hTTR-TG mice, wild-type mice of the same strain (WT), and mice lacking endogenous Ttr genes. In the DMM model, both cartilage and synovitis histological scores were significantly increased in hTTR-TG mice. Further, spontaneous degradation and OA-like changes in cartilage and synovium developed in 18-month-old hTTR mice. Expression of cartilage catabolic (Adamts4, Mmp13) and inflammatory genes (Nos2, Il6) was significantly elevated in cartilage from 6-month-old hTTR-TG mice compared with WT mice as was the level of phospho-NF-κB p65. Intra-articular injection of aggregated TTR in WT mice increased synovitis and significantly increased expression of inflammatory genes in synovium. These findings are the first to show that TTR deposition increases disease severity in the murine DMM and aging model of OA.


[The processes of cell renewal in H. pylori-associated chronic atrophic gastritis].
To evaluate the expression of Ki-67 protein in stomach mucosa in H. pylori-associated chronic atrophic gastritis according to the stage of atrophy. The immunohistochemical and histological study of gastric mucosal biopsies from dyspeptic patients was performed. The new international system of gastric musocal atrophy staging (OLGA) was used. The rates of cellular proliferation increase along the rising of the stage of stomach mucosal atrophy in Hpylori-associated chronic atrophic gastritis. In H. pylori-associated chronic atrophic gastritis, the acceleration of the cellular renewal was revealed, proportional to a stage of gastric mucosal atrophy that implies the increase of risk of development of precancerous changes.


Dissection of the role of CD3gamma chains in profound but reversible T-cell receptor down-regulation.
T-lymphocyte activity in the immune system is regulated by the quantity of surface membrane T-cell antigen receptors (TCR). The amount of surface-bound TCR is dependent on the rate of [1] biosynthesis, assembly and intracellular transport of the individual chains composing the TCR/CD3 complex and [2] the internalization and recycling of the receptors. The TCR-ligand interaction augments receptor internalization. In the present paper, we have studied short- and long-term down-regulation of TCR/CD3 complexes with monoclonal anti-TCR/CD3 antibodies, and attempted to determine which component(s) of the TCR/CD3 complex are responsible for these two phenomena. Our data indicate that short- and long-term down-regulation is mediated by different mechanisms, and that the extracellular and/or transmembrane regions of CD3gamma molecules appear to play an important role in chronic TCR/CD3 down-regulation and subsequent deficient re-expression. These results may have important implications for the understanding of induction of T-cell tolerance or anergy.


Littorina littorea: An Indicator of Norse Settlement in North America?
It is suggested that the originally European species Littorina littorea was introduced to North Ameriea by Norse settlers about A.D. 1000. Its subfossil distribution might be used in tracing the extent of Norse travel in this region. Recent archeological finds match very well with the historical records of the Norse exploration and settlements. This activity seems to have been concentrated in Nova Scotia and Newfoundland.


Structural and Spectroscopic Characterization of Rhenium Complexes Containing Neutral, Monoanionic, and Dianionic Ligands of 2,2'-Bipyridines and 2,2':6,2″-Terpyridines: An Experimental and Density Functional Theory (DFT)-Computational Study.
The molecular and electronic structures of the members of the following electron transfer series have been determined by single crystal X-ray crystallography, temperature dependent magnetic susceptibility measurements, and UV-vis-NIR and electron paramagnetic resonance spectroscopy and verified by density functional theory calculations (DFT B3LYP): [Re((Me)bpy)3](n), [Re(tpy)2](n), [Re(Tp)(bpy)Cl](n) (n = 2+, 1+, 0, 1-), and [Re(bpy)(CO)3](1+,0,1-) ((Me)bpy = 4, 4'-dimethyl-2,2'-bipyridine; Tp(-) = tris-pyrazolylborate, tpy = 2, 2':6, 2″-terpyridine). For each series we show that the average Cpy-Cpy bond length and the average C-Nchel bond distance vary in a linear fashion with the charge n of the N,N'-coordinated (bpy)(n) and N,N',N″-coordinated (tpy)(n) ligand. Consequently, the difference Δ between these two bond lengths varies also linearly with n. Δ is shown to be a useful single marker for the oxidation level of these two heterocyclic ligands (neutral, π-radical anion, and dianion). In addition, we have synthesized and structurally as well as spectroscopically characterized the following complexes: [((cy)DAB(•))Re(IV)Cl3(PPh3)](0) 1, [Re(III)(tpy(•))Cl(PPh3)2]Cl 2, [Re(III)(tpy(0))2Cl](OTf)2·2Et2O 8. There are no structurally significant (experimentally detectable) π-back-bond effects of the neutral bpy(0) or tpy(0) ligands irrespective of the d(N) configuration (N = 0-7) of the central Re atom.


Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir.
Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability >25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens.


Chronic vulvar ulceration in an immunocompetent woman due to acyclovir-resistant, thymidine kinase-deficient herpes simplex virus.
A 34-year-old healthy woman presented with a 15-month history of persistent, nonhealing vulvar ulcerations due to herpes simplex virus (HSV) type 2. Extensive dermatologic workup and serial skin biopsies failed to reveal an underlying vulvar dermatosis or autoimmune bullous disorder. Virologic studies revealed resistance to acyclovir in vitro due to deficiency in thymidine kinase activity. Serum antibody to human immunodeficiency virus was negative on two occasions, separated by 1 year. Immunologic evaluation showed normal HSV-specific proliferative and CD8 cytotoxic T lymphocyte responses as well as normal NK cell function. Vulvar lesions failed to heal in association with trials of topical trifluorothymidine and oral valacyclovir but resolved completely with the application of 1% foscarnet cream. No recurrence of HSV has been observed in 24 months of follow-up to date.


Glutathione system in young spontaneously hypertensive rats.
Glutathione (GSH) forms a part of the antioxidant system that plays a vital role in preventing oxidative stress, and an imbalance in the oxidant/antioxidant system has been linked to the pathogenesis of hypertension. The aim of this study was to investigate the status of the GSH system in the kidney of spontaneously hypertensive rats (SHR). Components of the GSH system, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), and total GSH content, were measured in the kidneys of 4, 6, 8, 12, and 16 weeks old SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure of SHR was significantly higher from the age of 6 weeks onwards compared with age-matched WKY rats. GPx activity in the SHR was significantly lower from the age of 8 weeks onwards when compared to that in age-matched WKY rats. No significant differences were evident in the GPx-1 protein abundance, and its relative mRNA levels, GR, GST activity, and total GSH content between SHR and age-matched WKY rats. The lower GPx activity suggests of an impairment of the GSH system in the SHR, which might be due to an abnormality in its protein rather than non-availability of a cofactor. Its role in the development of hypertension in SHR however remains unclear.


Prevalence of antibacterial resistant bacterial contaminants from mobile phones of hospital inpatients.
Mobile phones contaminated with bacteria may act as fomites. Antibiotic resistant bacterial contamination of mobile phones of inpatients was studied. One hundred and six samples were collected from mobile phones of patients admitted in various hospitals in Jazan province of Saudi Arabia. Eighty-nine (83.9%) out of 106 mobile phones were found to be contaminated with bacteria. Fifty-two (49.0%) coagulase-negative Staphylococcus, 12 (11.3%) Staphylococcus aureus, 7 (6.6%) Enterobacter cloacae, 3 (2.83%) Pseudomonas stutzeri, 3 (2.83%) Sphingomonas paucimobilis, 2 (1.8%) Enterococcus faecalis and 10 (9.4%) aerobic spore bearers were isolated. All the isolated bacteria were found to be resistant to various antibiotics. Hence, regular disinfection of mobile phones of hospital inpatients is advised.


Effect of transdermal magnesium cream on serum and urinary magnesium levels in humans: A pilot study.
Oral magnesium supplementation is commonly used to support a low magnesium diet. This investigation set out to determine whether magnesium in a cream could be absorbed transdermally in humans to improve magnesium status. In this single blind, parallel designed pilot study, n = 25 participants (aged 34.3+/-14.8y, height 171.5+/-11cm, weight 75.9 +/-14 Kg) were randomly assigned to either a 56mg/day magnesium cream or placebo cream group for two weeks. Magnesium serum and 24hour urinary excretion were measured at baseline and at 14 days intervention. Food diaries were recorded for 8 days during this period. Mg test and placebo groups' serum and urinary Mg did not differ at baseline. After the Mg2+ cream intervention there was a clinically relevant increase in serum magnesium (0.82 to 0.89 mmol/l,p = 0.29) that was not seen in the placebo group (0.77 to 0.79 mmol/L), but was only statistically significant (p = 0.02)) in a subgroup of non-athletes. Magnesium urinary excretion increased from baseline slightly in the Mg2+ group but with no statistical significance (p = 0.48). The Mg2+ group showed an 8.54% increase in serum Mg2+ and a 9.1% increase in urinary Mg2+ while these figures for the placebo group were smaller, i.e. +2.6% for serum Mg2+ and -32% for urinary Mg2+. In the placebo group, both serum and urine concentrations showed no statistically significant change after the application of the placebo cream. No previous studies have looked at transdermal absorbency of Mg2+ in human subjects. In this pilot study, transdermal delivery of 56 mg Mg/day (a low dose compared with commercial transdermal Mg2+ products available) showed a larger percentage rise in both serum and urinary markers from pre to post intervention compared with subjects using the placebo cream, but statistical significance was achieved only for serum Mg2+ in a subgroup of non-athletes. Future studies should look at higher dosage of magnesium cream for longer durations. ISRCTN registry ID No. ISRTN15136969.


Finite curved creases in infinite isometric sheets.
Geometric stress focusing, e.g., in a crumpled sheet, creates pointlike vertices that terminate in a characteristic local crescent shape. The observed scaling of the size of this crescent is an open question in the stress focusing of elastic thin sheets. According to experiments and simulations, this size depends on the outer dimension of the sheet, but intuition and rudimentary energy balance indicate it should only depend on the sheet thickness. We address this discrepancy by modeling the observed crescent with a more geometric approach, where we treat the crescent as a curved crease in an isometric sheet. Although curved creases have already been studied extensively, the crescent in a crumpled sheet has its own unique features: the material crescent terminates within the material, and the material extent is indefinitely larger than the extent of the crescent. These features together with the general constraints of isometry lead to constraints linking the surface profile to the crease-line geometry. We construct several examples obeying these constraints, showing finite curved creases are fully realizable. This approach has some particular advantages over previous analyses, as we are able to describe the entire material without having to exclude the region around the sharp crescent. Finally, we deduce testable relations between the crease and the surrounding sheet and discuss some of the implications of our approach with regards to the scaling of the crescent size.


Inhibition of interleukin-6 trans-signaling prevents inflammation and endothelial barrier disruption in retinal endothelial cells.
Vascular inflammation plays a critical role in the pathogenesis of diabetic retinopathy. Recently, Interleukin-6 (IL-6) trans-signaling via soluble IL-6 receptor (sIL-6R) has emerged as a prominent regulator of inflammation in endothelial cells. This study was designed to test the hypothesis that selective inhibition of the IL-6 trans-signaling pathway will attenuate inflammation and subsequent barrier disruption in retinal endothelial cells. Human retinal endothelial cells (HRECs) were exposed to IL-6 and sIL-6R to induce IL-6 trans-signaling and the commercially available compound sgp130Fc (soluble gp-130 fused chimera) was used to selectively inhibit IL-6 trans-signaling. IL-6 trans-signaling activation caused a significant increase in STAT3 phosphorylation, expression of adhesion molecules, ROS production and apoptosis in HRECs whereas a significant decrease in mitochondrial membrane potential and NO production was observed in IL-6 trans-signaling activated cells. These changes were not observed in cells pre-treated with sgp130Fc. IL-6 trans-signaling activation was sufficient to cause barrier disruption in endothelial monolayers and pre-treatment of HRECs with sgp130Fc, maintained endothelial barrier function similar to that of untreated cells. Thus, in conclusion, these results indicate that IL-6 trans-signaling is an important mediator of inflammation, apoptosis and barrier disruptive effects in the retinal endothelial cells and inhibition of the IL-6 trans-signaling pathway using sgp130-Fc attenuates vascular inflammation and endothelial barrier disruption.


Enhancing Endocannabinoid Control of Stress with Cannabidiol.
The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.


Selection and characterization of Chinese hamster ovary cell mutants resistant to melphalan (L-phenylalanine mustard).
Melphalan (Alkeran) is an alkylating agent commonly used in the treatment of multiple myeloma and other neoplasia. We have isolated melphalan-resistant (MelR) Chinese hamster ovary cells in vitro. Stably resistant clones were observed with a frequency of about 10(-7) after a single drug exposure. Two clones, MelR1 and MelR6, were studied in detail, and their phenotypes were compared to a colchicine-resistant membrane permeability mutant (CHRC5) isolated previously by Ling and Thompson (J. Cell Physiol., 83: 103-116, 1974), which was cross-resistant to melphalan. The MelR cones were cross-resistant to the nitrogen mustard class of alkylating agents, such as melphalan, nitrogen mustard, and chlorambucil, but not to alkylating agents, such as methanesulfonic acid:ethyl ester or mitomycin C. The MelR clones differed from CHRC5 in their lack of cross-resistance to puromycin and Adriamycin. Studies with [14C]melphalan showed CHRC5, but not the MelR clones, to be defective in drug accumulation into whole cells. The mechanism of melphalan resistance in CHRC5 is attributed to reduced drug accumulation due to a plasma membrane alteration. In the MelR clones, investigation of drug distribution into cell subfractions revealed reduced accumulation into the nucleus compared to the parental cell line. We therefore propose that the mechanism of resistance in the MelR cells results from a nuclear alteration(s) specific to a subclass of alkylating agents.


Exact Extremal Statistics in the Classical 1D Coulomb Gas.
We consider a one-dimensional classical Coulomb gas of N-like charges in a harmonic potential-also known as the one-dimensional one-component plasma. We compute, analytically, the probability distribution of the position x_{max} of the rightmost charge in the limit of large N. We show that the typical fluctuations of x_{max} around its mean are described by a nontrivial scaling function, with asymmetric tails. This distribution is different from the Tracy-Widom distribution of x_{max} for Dyson's log gas. We also compute the large deviation functions of x_{max} explicitly and show that the system exhibits a third-order phase transition, as in the log gas. Our theoretical predictions are verified numerically.


Subunit Vaccines Against Emerging Pathogenic Human Coronaviruses.
Seven coronaviruses (CoVs) have been isolated from humans so far. Among them, three emerging pathogenic CoVs, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and a newly identified CoV (2019-nCoV), once caused or continue to cause severe infections in humans, posing significant threats to global public health. SARS-CoV infection in humans (with about 10% case fatality rate) was first reported from China in 2002, while MERS-CoV infection in humans (with about 34.4% case fatality rate) was first reported from Saudi Arabia in June 2012. 2019-nCoV was first reported from China in December 2019, and is currently infecting more than 70000 people (with about 2.7% case fatality rate). Both SARS-CoV and MERS-CoV are zoonotic viruses, using bats as their natural reservoirs, and then transmitting through intermediate hosts, leading to human infections. Nevertheless, the intermediate host for 2019-nCoV is still under investigation and the vaccines against this new CoV have not been available. Although a variety of vaccines have been developed against infections of SARS-CoV and MERS-CoV, none of them has been approved for use in humans. In this review, we have described the structure and function of key proteins of emerging human CoVs, overviewed the current vaccine types to be developed against SARS-CoV and MERS-CoV, and summarized recent advances in subunit vaccines against these two pathogenic human CoVs. These subunit vaccines are introduced on the basis of full-length spike (S) protein, receptor-binding domain (RBD), non-RBD S protein fragments, and non-S structural proteins, and the potential factors affecting these subunit vaccines are also illustrated. Overall, this review will be helpful for rapid design and development of vaccines against the new 2019-nCoV and any future CoVs with pandemic potential. This review was written for the topic of Antivirals for Emerging Viruses: Vaccines and Therapeutics in the Virology section of Frontiers in Microbiology.


Hemithyroidectomy: a meta-analysis of postoperative need for hormone replacement and complications.
We sought to determine certain factors predicting postoperative need for hormone replacement therapy (HRT) after hemithyroidectomy. A PubMed search was conducted to identify articles with separate cohorts for total and hemithyroidectomy. Outcomes of interest included hypothyroidism and complications. Of 50,445 patients, 15,412 (30.6%) underwent hemithyroidectomy. The reported incidence rate of postoperative hypothyroidism was 10.9-48.8%. The pooled mean preoperative thyroid-stimulating hormone (TSH) level was 1.06 µIU/l (0.83-1.29) higher in hypothyroid patients. A preoperative TSH level >2.5 µIU/l was associated with a relative risk (RR, 95% CI) of 3.16 (2.03-4.90) for postoperative hypothyroidism. There was a significant pooled RR of 3.52 (2.55-4.86) for thyroid antibodies and 3.30 (2.49-4.36) for thyroiditis on pathology for postoperative HRT. The pooled RR for postoperative complications was 10.67 (5.75-19.31) for temporary hypocalcemia, 3.17 (1.72-5.83) for permanent hypocalcemia, 1.69 (1.30-2.20) for temporary injury to the recurrent laryngeal nerve (RLN), 1.85 (1.28-2.69) for permanent RLN injury and 2.58 (1.69-3.93) for hemorrhage in patients who underwent total thyroidectomy compared to hemithyroidectomy. Higher preoperative TSH levels, presence of anti-thyroid antibodies and thyroiditis predict postoperative need for HRT. It is imperative to counsel patients with these findings regarding their higher risk of developing postoperative hypothyroidism and need for HRT after hemithyroidectomy.


An apparent preferential antagonism by practolol of the positive inotropic responses of guinea-pig isolated atria to isoprenaline.
The positive inotropic response of guinea-pig isolated atria to isoprenaline was antagonized to a greater extent than the positive chronotropic response, when measured at 38 degrees C as the reduction of the responses to a single concentration of isoprenaline. This method avoided increasing the the concentration of agonist in the presence of practolol and any difference in the proportion metabolized affecting the blockade. This observation was substantiated from the vertical displacement of dose-response curves from four concentrations of isoprenaline added sequentially. No difference between the antagonism of rate and tension was obtained when the antagonism was measured as the horizontal displacement of complete dose-response curves constructed sequentially or cumulatively. The resultant pA2 values from cumulative dose-response curves were identical, indicating that the beta-adrenoceptors subserving these responses are the same. The rate and tension curves were not, however, superimposable; rate lay to the left. By lowering the bath temperature to 30 degrees C they were brought together and the selective antagonism was no longer observed. This phenomenon was therefore attributed to the separation of rate and tension curves at 38 degrees C, the selected concentration of isoprenaline occupying different positions on these curves.


Relationship between CMV and graft rejection after heart transplantation.
This study, which included 153 heart transplant patients, was designed to determine whether the cytomegalovirus (CMV) status of both donor and recipient may influence graft rejection. The follow-up was 1 year and they all received the same triple-drug immunosuppressive regimen with induction (antilymphocyte serum). There was no difference in the total rejection rate, but an increase in repeated rejection rate was shown in transplant recipients with hearts from CMV seropositive donors (P < 0.05). These data strongly suggest the impact of CMV in enhancement but not in induction of rejection. To prevent iterative rejection in the CMV seropositive donor group, antiviral therapy could be proposed during enhancement of antirejection therapy.


Soybeans transformed with a fungal phytase gene improve phosphorus availability for broilers.
Male broilers (n = 416) were used to compare the efficacy of providing dietary phytase either as a commercial supplement or as a recombinant protein in transformed soybean. From 7 to 21 d of age, broilers were fed a basal diet containing 0.20% nonphytate P (nP) with additional supplementation by fungal phytase as Natuphos or as raw transformed soybeans expressing recombinant phytase at 400, 800, or 1,200 U/kg. For comparison, broilers were also fed the basal diet containing 0.08, 0.16, or 0.24 added nP. The basal diet was fed as the negative control. Diets were consumed ad libitum as a mash. All excreta were collected from each pen from 18 through 20 d of age, and the birds were killed at 21 d of age. Supplementing the basal diet with nP linearly increased body weight gain, feed efficiency, feed intake, toe ash weight and percentage, and tibia shear force and energy. Phosphorus digestibility decreased linearly as nP level increased, but P excretion increased. Dietary phytase linearly increased growth rate, feed intake, toe ash weight and percentage, tibia shear force and energy, and P digestibility, whereas excretion was decreased. Except for P digestibility, there was no difference in efficacy of responses for performance, bone mineralization, and P excretion between the two sources of phytase. It appears from this study that phytase can improve growth performance of broilers fed low nP diets when provided either as a commercial supplement or in the form of transformed seeds.


Nitrous oxide emission from full-scale municipal aerobic granular sludge.
The nitrous oxides emission was measured over 7 months in the full-scale aerobic granular sludge plant in Dinxperlo, the Netherlands. Nitrous oxide concentrations were measured in the bulk liquid and the off-gas of the Nereda® reactor. Combined with the batch wise operation of the reactor, this gave a high information density and a better insight into N2O emission in general. The average emission factor was 0.33% based on the total nitrogen concentration in the influent. The yearly average emission factor was estimated to be between 0.25% and 0.30%. The average emission factor is comparable to continuous activated sludge plants, using flocculent sludge, and it is low compared to other sequencing batch systems. The variability in the emission factor increased when the reactor temperature was below 14 °C, showing higher emission factors during the winter period. A change in the process control in the winter period reduced the variability, reducing the emission factors to a level comparable to the summer period. Different process control might be necessary at high and low temperatures to obtain a consistently low nitrous oxide emission. Rainy weather conditions lowered the emission factor, also in the dry weather flow batches following the rainy weather batches. This was attributed to the first flush from the sewer at the start of rainy weather conditions, resulting in a temporarily increased sludge loading.


Light and myopic refraction in children.
Studies over many years, carried out in different climatic zones of the country, were focussed on the investigation of the role of light in the prophylaxis of development of near-sightedness. It has been found that not only the accommodation reflex but also the pupillary reflex play a role in the enhancement of the optic power of the eye. A scheme of interaction of the mentioned reflexes depending on the level of visible radiation was presented. Provision of optimum illumination is one of the basic conditions for the prevention of eye fatigue and development of myopia.


Antibiotic activity of telithromycin and comparators against bacterial pathogens isolated from 3,043 patients with acute exacerbation of chronic bronchitis.
Antimicrobial therapy is considered an important component in the medical management of most patients with acute exacerbation of chronic bronchitis (AECB). The three predominant bacterial species isolated are nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Staphylococcus aureus is also frequently isolated while atypical bacteria are thought to cause up to 10% of exacerbations. Antibacterial resistance is increasing worldwide and little surveillance data exist concerning pathogens isolated from patients with AECB. This study examines the prevalence of antibacterial resistance in isolates obtained from patients with clinically diagnosed AECB. A total of 3043 isolates were obtained from 85 centres in 29 countries, between 1999-2003, and were tested against the new ketolide telithromycin and a panel of commonly used antibiotics. Of the S. pneumoniae isolates, 99.9% were susceptible to telithromycin, but only 71% were susceptible to erythromycin and 75.3% to penicillin. Of the H. influenzae isolates, 99.6% were susceptible to telithromycin. 11.7% of these isolates produced beta-lactamase. Almost 10% of S. pneumoniae were multidrug-resistant; 99.0% of these isolates were susceptible to telithromycin. Telithromycin also demonstrated good in vitro activity against M. catarrhalis (MIC90 = 0.12 mg/L) and was the most active compound against methicillin-susceptible S. aureus (98.9% susceptible). Telithromycin demonstrated similar or better activity against the bacterial species investigated than the other agents, with the most complete coverage overall. These species are the predominant causative bacterial pathogens in AECB and thus the spectrum of activity of telithromycin makes it a potential alternative for the empirical treatment of AECB.


Developing a Logarithmic Chinese Reading Acuity Chart.
An individual's reading ability cannot be reliably predicted from his/her letter acuity, contrast sensitivity, and visual field extent. We developed a set of Chinese reading acuity charts (C-READ) to assess the reading ability of Chinese readers, based on the collective wisdom of previously published reading acuity charts, especially the MNRead and the Radner Reading Charts. The C-READ consists of three charts. Each consists sixteen 12-character simplified Chinese sentences crafted from first- to third-grade textbooks. One hundred eighteen native Chinese-speaking college students (aged 22.1 ± 2.1 years) with normal or corrected to normal near vision (-0.26 ± 0.05 logMAR) were included in the study to develop the C-READ charts, to test the homogeneity of the three charts, and to validate the C-READ against the text paragraphs from the International Reading Speed Texts (IReST) with corrected and uncorrected near vision. The reading acuity, critical print size, and maximum reading speed for young normal native Chinese-speaking readers were 0.16 ± 0.05 logMAR, 0.24 ± 0.06 logMAR, and 273.44 ± 34.37 characters per minute (mean ± SD), respectively. The reliability test revealed no significant differences among the three C-READ charts and no significant test order effect in the three reading parameters. Regression analyses showed that the IReST reading speed could be reliably predicted by the C-READ maximum reading speed under the corrected near-vision condition (adjusted R = 0.72) and by C-READ maximum reading speed and critical print size under the uncorrected near-vision condition (adjusted R = 0.69). The three C-READ charts are very comparable to each other, and there is no significant order effect. Reading test results can accurately predict continuous text reading performance quantified by the IReST reading speed over a wide range of refractive errors. The C-READ is a reliable and valid clinical instrument for quantifying reading performance in simplified Chinese readers.


Current natural therapies in the treatment against glioblastoma.
Glioblastoma (GBM) is the most common and aggressive brain tumor, which causes the highest number of deaths worldwide. It is a highly vascularized tumor, infiltrative, and its tumorigenic capacity is exacerbated. All these hallmarks are therapeutic targets in GBM treatment, including surgical removal followed by radiotherapy and chemotherapy. Current therapies have not been sufficient for the effective patient's management, so the classic therapies have had to expand and incorporate new alternative treatments, including natural compounds. This review summarizes natural products and their physiological effects in in vitro and in vivo models of GBM, specifically by modulating signaling pathways involved in angiogenesis, cell migration/invasion, cell viability, apoptosis, and chemoresistance. The most important aspects of natural products and their derivatives were described in relation to its antitumoral effects. As a final result, it can be obtained that within the compounds with more evidence that supports or suggests its clinical use are the cannabinoids, terpenes, and curcumin, because many have been shown to have a significant effect in decreasing the progress of GBM through known mechanisms, such as chemo-sensitization or decrease migration and cell invasion. Natural compounds emerge as promising therapies to attack the progress of GBM.


Fabrication of all-solid photonic bandgap fiber coupler.
We report the fabrication of a tunable all-solid photonic bandgap fiber coupler based on the side-polishing technique. This device is believed to be the first demonstration of a photonic bandgap fiber coupler to eliminate the contamination of the open air holes. By adjusting the length of the interaction section, the tunable coupling ratio as much as 92.5% at 1550 nm is achieved. The investigation of the spectrum properties shows that the coupler has excellent tunability properties, for which the coupling ratio can be smoothly and continuously controlled.


Identification of novel Ras-cooperating oncogenes in Drosophila melanogaster: a RhoGEF/Rho-family/JNK pathway is a central driver of tumorigenesis.
We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (Ras(ACT)) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with Ras(ACT) in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance Ras(ACT)-driven hyperplasia. Ras(ACT)-cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wild-type cells, only Rac1, an activated allele of Rho1 (Rho1(ACT)), RhoGEF2, and pbl cooperated with Ras(ACT), resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with Ras(ACT) upregulated Jun kinase (JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with Ras(ACT), while in the clonal setting, JNK upregulation was sufficient for Ras(ACT)-mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of Ras(V12)-expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER2(+) human breast cancers (where human epidermal growth factor 2 is overexpressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with Ras(ACT) in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/Rho-family/JNK pathway in cooperative tumorigenesis with Ras(ACT).


Reconsidering cochlear implants: the lessons of Martha's Vineyard.
I distinguish and assess three separate arguments utilized by the opponents of cochlear implants: that treating deafness as a medical condition is inappropriate since it is not a disability; that so treating it sends a message to the Deaf that they are of lesser worth; and that the use of such implants would signal the end of Deaf culture. I give some qualified support to the first and second claim, but find that the principal weight of the argument must be borne by the third argument: that use of the cochlear implants is impermissible because Deaf culture is intrinsically valuable. I show that this claim is, in practice, incompatible with the claim that deafness is not a disability: that the significant disadvantages suffered by the hearing impaired can only be corrected by measures that would end Deaf culture. Since the potential recipients of cochlear implants are, in the main, the prelingually deaf children of hearing parents, the burden of banning the implants would be borne by people who are not members of Deaf culture, and who owe that culture nothing over and above what we all owe cultures in general. I conclude that we cannot ask the parents of these children to sacrifice the interests of their children for the sake of Deaf culture.


Serology and ultrasound for diagnosis of choledocholithiasis.
Magnetic resonance cholangiopancreatography (MRCP) is not a routine investigation to exclude choledocholithiasis unless there is clinical or biochemical suspicion of common bile duct (CBD) stones. This study attempted to determine which radiological or serological parameters best predicted CBD stones. All patients undergoing MRCP from 2005 to 2011 were selected. Patients with pancreatitis were excluded. Liver function tests (LFTs) at admission and prior to MRCP were recorded, as was abdominal ultrasonography and MRCP results. Parameters measured routinely on LFTs included alkaline phosphatase (ALP), alanine transaminase (ALT) and bilirubin. Receiver operating characteristic curve area analysis (area under the curve [AUC]) and chi-squared analysis were undertaken. Overall, 195 patients were identified, 71 of whom had CBD stones on MRCP. Raised ALP levels on admission demonstrated a correlation with CBD stones (AUC: 0.619, odds ratio [OR]: 3.16, p=0.06). At ultrasonography, a dilated CBD (OR: 3.76, p<0.001) and intrahepatic duct dilation (OR: 5.56, p<0.001) were highly significant predictors. However, only 37% of patients had a dilated CBD on ultrasonography. Ongoing elevation of LFT parameters, particularly ALP (AUC: 0.707, OR: 4.64, p<0.001) and ALT (AUC: 0.646, OR: 5.40, p<0.001), displayed a significant correlation with CBD stones. Ongoing (even if minor) elevations of liver function test parameters should prompt the need to exclude CBD stones even in the presence of a normal CBD diameter on ultrasonography.


Historicity of nursing graduate studies in Brazil: an analysis of the Sociology of the Professions.
to analyze the scientific productions about the history of graduate studies in Brazilian nursing in the light of Eliot Freidson's Sociology of the Professions. an integrative review, carried out in the databases indexed in Virtual Health Library. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations were followed. Thematic content analysis and Eliot Freidson's concepts were adopted. two categories emerged: "Institutionalization of graduate courses in Brazilian nursing", highlighting the historical process of professionalization in nursing through transition from empirical to professional care, subsidized by the monopoly of the construction of one's own knowledge; "The scientific production of graduate nursing in Brazil", showing the strengthening of a new generation of nurse researchers, given the greater scientificity in teaching due to implementation of graduate studies. the analyzes present the historicity of graduate studies' institutionalization, supporting the understanding of professionalization outlines of Brazilian nursing.


Verifying causes of death in Thailand: rationale and methods for empirical investigation.
Cause-specific mortality statistics by age and sex are primary evidence for epidemiological research and health policy. Annual mortality statistics from vital registration systems in Thailand are of limited utility because about 40% of deaths are registered with unknown or nonspecific causes. This paper reports the rationale, methods, and broad results from a comprehensive study to verify registered causes in Thailand. A nationally representative sample of 11,984 deaths was selected using a multistage stratified cluster sampling approach, distributed across 28 districts located in nine provinces of Thailand. Registered causes were verified through medical record review for deaths in hospitals and standard verbal autopsy procedures for deaths outside hospitals, the results of which were used to measure validity and reliability of registration data. Study findings were used to develop descriptive estimates of cause-specific mortality by age and sex in Thailand. Causes of death were verified for a total of 9,644 deaths in the study sample, comprised of 3,316 deaths in hospitals and 6,328 deaths outside hospitals. Field studies yielded specific diagnoses in almost all deaths in the sample originally assigned an ill-defined cause of death at registration. Study findings suggest that the leading causes of death in Thailand among males are stroke (9.4%); transport accidents (8.1%); HIV/AIDS (7.9%); ischemic heart diseases (6.4%); and chronic obstructive lung diseases (5.7%). Among females, the leading causes are stroke (11.3%); diabetes (8%); ischemic heart disease (7.5%); HIV/AIDS (5.7%); and renal diseases (4%). Empirical investigation of registered causes of death in the study sample yielded adequate information to enable estimation of cause-specific mortality patterns in Thailand. These findings will inform burden of disease estimation and economic evaluation of health policy choices in the country. The development and implementation of research methods in this study will contribute to improvements in the quality of annual mortality statistics in Thailand. Similar research is recommended for other countries where the quality of mortality statistics is poor.


Nicotine induces TIPE2 upregulation and Stat3 phosphorylation contributes to cholinergic anti-inflammatory effect.
Cholinergic anti-inflammatory pathway has therapeutic effect on inflammation-associated diseases. However, the exact mechanism of nicotine-mediated anti-inflammatory effect is still unclear. TIPE2, a new member of tumor necrosis factor-α-induced protein-8 family, is a negative regulator of immune homeostasis. However, the roles of TIPE2 in cholinergic anti-inflammatory effect are still uncertain. Here, we demonstrated that nicotine exerts its anti-inflammatory effect by TIPE2 upregulation and phosphorylated stat3 mediated the inhibition of NF-κB activation, which was supported by the following evidence: firstly, both nicotine and TIPE2 inhibit pro-inflammatory cytokine release via NF-κB inactivation. Secondly, nicotine upregulates TIPE2 expression via α7 nicotinic acetylcholine receptor. Moreover, the enhancement of stat3 phosphorylation and decrease of LPS-induced p65 translocation were achieved by nicotine treatment. Importantly, nicotine treatment augments the interaction of phosphorylated stat3 and p65, indicating that the inhibitory effect of nicotine on NF-κB activation was mediated with protein-protein interactions. Hence, this study revealed that TIPE2 upregulation and stat3 phosphorylation contribute to nicotine-mediated anti-inflammation effect, indicating that TIPE2 and stat3 might be potential molecules for dealing with inflammation-associated diseases.


Description of hospitalized cases of influenza A(H1N1)pdm09 infection on the basis of the national hospitalized-case surveillance, 2009-2010, Japan.
This study reports the epidemiological characteristics of hospitalized cases of influenza A(H1N1)pdm09 infection analyzed on the basis of surveillance data collected from July 24, 2009, the date on which the hospital-based surveillance of influenza cases was implemented in Japan, to September 5, 2010. During the study period, 13,581 confirmed cases were reported. Among those cases with information regarding the reason for hospitalization, 39% were admitted to hospitals for non-therapeutic purposes such as medical observation and laboratory testing. The overall hospitalization rate was 5.8 cases per 100,000 population when cases hospitalized for non-therapeutic purposes were excluded. While those aged under 20 years accounted for over 85% of hospitalized cases, the largest proportion of fatal cases was observed in those aged over 65 years. The overall case fatality rate for all hospitalized cases was 1.5%. The year-round surveillance for hospitalized influenza-like illness cases was launched in 2011, and it was expected that this surveillance system could add value by monitoring changes in the epidemiological characteristics of hospitalized cases of seasonal influenza.


Think, blink or sleep on it? The impact of modes of thought on complex decision making.
This paper examines controversial claims about the merit of "unconscious thought" for making complex decisions. In four experiments, participants were presented with complex decisions and were asked to choose the best option immediately, after a period of conscious deliberation, or after a period of distraction (said to encourage "unconscious thought processes"). In all experiments the majority of participants chose the option predicted by their own subjective attribute weighting scores, regardless of the mode of thought employed. There was little evidence for the superiority of choices made "unconsciously", but some evidence that conscious deliberation can lead to better choices. The final experiment suggested that the task is best conceptualized as one involving "online judgement" rather than one in which decisions are made after periods of deliberation or distraction. The results suggest that we should be cautious in accepting the advice to "stop thinking" about complex decisions.


Placenta Praevia: A Retrospective Review of Experience at Olabisi Onabanjo University Teaching Hospital, Sagamu.
Placenta praevia is the most common cause of antepartum haemorrhage. It is a potentially life threatening condition associated with morbidity and mortality. There is no study on the pattern and management of placenta praevia in Sagamu. To determine the risk factors, pattern of presentation and management outcome of pregnancies complicated by placenta praevia. This was a five-year retrospective study Setting: Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State, Nigeria. Relevant information was retrieved from the case notes of all patients who presented with placenta praevia from 1st January, 2013 to 31st December, 2017. The data were analyzed by using SPSS version 21. Out of the 5124 deliveries, there were 47 cases of placenta praevia giving a prevalence of 0.92%. Twenty-one subjects (50%) were within 31-40 years age group. The modal parity was 1. Twenty women (47.6%) had parity of 1-2. Thirty subjects (71.4%) were unbooked. Painless vaginal bleeding was the commonest mode of presentation in 30(73.8%) women while Type III was the commonest grade 15(35.7%). Nineteen subjects (45.2%) had no identifiable risk factors. Postpartum haemorrage was the most common complication (23.8%). There was no maternal death while the perinatal mortality was 13.5%. There was no significant association between booking status, type of placenta praevia, mode of delivery, blood loss at delivery, and the one minute APGAR score. The prevalence of placenta praevia in Olabisi Onabanjo University Teaching Hospital is comparable with other tertiary facilities in Nigeria. Upgrading comprehensive emergency obstetric services, improving neonatal services and a multidisciplinary approach to management of all cases will ensure good outcome for the mother and baby.


Experiences of doctors and nurses implementing nurse-delivered cardiovascular prevention in primary care: a qualitative study.
This paper reports on a study of the experiences of general practitioners and practice nurses implementing nurse-delivered cardiovascular prevention to high risk patients in primary care. Difficulties may arise when innovations are introduced into routine daily practice. Whether or not implementation is successful is determined by different factors related to caregivers, patients, type of innovation and context. A qualitative study nested in a randomized trial (2006-2008) to evaluate the effectiveness of nurse-delivered cardiovascular prevention. Six primary health care centres in the Netherlands (25 general practitioners, 6 practice nurses) participated in the trial. Interviews were held on two occasions: at 3 and at 18 months after commencement of consultation. The first occasion was a group interview with six practice nurses. The second consisted of semi-structured interviews with one general practitioner and one practice nurse from each centre. Main barriers to the implementation included: lack of knowledge about the guideline, attitudes towards treatment targets, lack of communication, insufficient coaching by doctors, content of life style advice. At the start of the consultation project, practice nurses expressed concern of losing nursing tasks. Other barriers were related to patients (lack of motivation), the guideline (target population) and organizational issues (insufficient patient recording and computer systems). Both general practitioners and practice nurses were positive about nurse-delivered cardiovascular prevention in primary care. Nurses could play an important role in successive removal of barriers to implementation of cardiovascular prevention. Mutual confidence between care providers in the healthcare team is necessary.


A social representation is not a quiet thing: exploring the critical potential of social representations theory.
Following Moscovici (1972), this paper addresses the questions: What is the aim of research within a social representations perspective? Is it to support or to criticize the social order? Is it to consolidate or transform it? After a brief overview of social representations theory, I argue that while the theory appears to have the conceptual tools to begin this critical task, there are serious criticisms and points of underdevelopment that need addressing. In order for social representations theory to develop into a rigorously critical theory there are three controversial issues that require clarification. These are (a) the relationship between psychological processes and social practices, (b) the reification and legitimization of different knowledge systems, and (c) agency and resistance in the co-construction of self-identity. After discussing each issue in turn, with illustrations from research on racializing representations, I conclude the paper with a discussion of the role of representations in the ideological construction and contestation of reality.


EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients.
To determine whether EGFR tyrosine kinase domain mutations are early events in the pathogenesis of lung adenocarcinomas, we tested for the presence of EGFR mutations in histologically normal bronchial and bronchiolar epithelia from lung adenocarcinomas bearing the common EGFR mutations. DNA was extracted from microdissected tissue obtained from 21 tumors with known EGFR mutations, 16 tumors without mutation, and 90 sites of normal bronchial and bronchiolar epithelium from the same surgical specimens. With the use of PCR and direct DNA sequencing, EGFR mutations identical to the tumors were detected in the normal respiratory epithelium in 9 of 21 (43%) patients with EGFR mutant adenocarcinomas but none in patients without mutation in the tumors. The finding of mutations being more frequent in normal epithelium within tumor (43%) than in adjacent sites (24%) suggests a localized field effect phenomenon. Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target.


George E. Brown memorial lecture. Local modulation of adrenergic neurotransmission.
The cardiovascular reflexes, by regulating the traffic in the sympathetic nerves, govern the amount of norepinephrine released from the nerve endings. However, the final adjustments in the amount of neurotransmitter available to activate the beta 1 receptors in the heart and the alpha receptors in the blood vessels take place at the sympathetic neuroeffector junction. Thus, a decrease in pH, hyperosmolarity, moderate increases in the concentration of K+ ion, adenosine and adenine nucleotides depress the release of norepinephrine at any given level of sympathetic nerve activity. These metabolic changes, which occur in active tissues, and in particular in adenosine, have been proposed as mediators of the accompanying local hyperemia. In addition, they apparently facilitate this local dilatation by disconnecting the blood vessels in the active tissues from sympathetic control. Acetylcholine, histamine and 5-hydroxytryptamine are present in and around certain blood vessels and can activate specific receptors on the prejunctional fibers and cause vasodilatation by reducing the output of neutrotransmitter. Some of the norepinephrine released into the synaptic cleft may depress its continued release by activating prejunctional alpha receptors. In contrast, angiotensin II, by a local action on the nerve endings, can augment the release of transmitter. Decreases in local temperature reduce transmitter release but augment the affinity of the postjunctional alpha receptors for norepinephrine. The role of these local events at the neuroeffector junction, their physiologic significance and potential clinical importance are discussed in this review.


Terminal Lucidity in a Pediatric Oncology Clinic.
The sporadic occurrence of unusually enhanced mental clarity before death has been documented over time and cultures, and reported in patients with and without neurodegenerative diseases, psychiatric disorders, and other neurocognitive deficits, as well as those with nonterminal and terminal conditions. Using a purposive sampling method via existing professional networks, clinical presentations of terminal lucidity in pediatric populations, as witnessed by pediatric oncologists and medical personnel, were solicited. We document clinical presentations suggestive of terminal lucidity in children, which were compiled by their attending physician at two large tertiary pediatric hospitals. Unanticipated and unexplained changes in mental clarity, verbal communication, and/or physical capability in the days and hours before the death of the pediatric patients were observed. Each patient's medical condition should not have allowed for such changes. The phenomenon known as terminal lucidity provides a conceptual framework for these deviations, although more systematic documentation and clinical research is required before definitive conclusions can be drawn.


Lexical Acquisition Through Category Matching: 12-Month-Old Infants Associate Words to Visual Categories.
Although it is widely recognized that human infants build a sizeable conceptual repertoire before mastering language, it remains a matter of debate whether and to what extent early conceptual and category knowledge contributes to language development. We addressed this question by investigating whether 12-month-olds used preverbal categories to discover the meanings of new words. We showed that one group of infants ( n = 18) readily extended novel labels to previously unseen exemplars of preverbal visual categories after only a single labeling episode, but two other groups struggled to do so when taught labels for unfamiliar categories (those who had been previously exposed, n = 18, or not exposed, n = 18, to category tokens). These results suggest that infants expect labels to denote categories of objects and are equipped with learning mechanisms responsible for matching prelinguistic knowledge structures with linguistic inputs. This ability is consistent with the idea that our conceptual machinery provides building blocks for vocabulary and language acquisition.


[Profile of bipolar disorder outpatients: a cross-sectional study in the Madrid Community].
The purpose of this cross-sectional study is to obtain a sociodemographic, clinical, psychosocial functioning and therapeutic profile of bipolar outpatients in the Madrid Community. A total of 115 outpatients were consecutively recruited by 10 psychiatrists. Mean time between initial symptoms and an accurate bipolar diagnosis was of 7.6 years. A depressive episode was the onset of the illness in most patients independently of clinical subtype. Syndromal or subsyndromal symptoms were present in 47% of the patient population, dominating the depressive polarity (33.1%). A subjectively reduced perception of quality of life was associated to the presence of depressive symptoms and a worse clinical outcome last year. More than half of the patients (58.2%) were overweight or obese. Lithium was the most frequently used mood stabilizer (71.3%), whereas 41% of the patients were taking at least three psychotropic drugs. Results of this study widely confirm previous data on bipolar disorder. Reduction in quality of life of bipolar patients associated to depressive symptoms must be highlighted. It is necessary to optimize treatments in bipolar disorder in order to improve prognosis.


Altered immune responsiveness associated with experimental syphilis in the rabbit: elevated IgM and depressed IgG responses to sheep erythrocytes.
Generalized suppression of immunoglobulin G (IgG) synthesis detectable by depressed responses to heterologous antigens may be a mechanism by which certain parasites evade host defenses and establish chronic infections. To determine if such a mechanism occurs in syphilis, rabbits were infected with Treponema pallidum, and at weekly intervals thereafter these rabbits and uninfected controls were sensitized with SRBC. Seven days later the number of antibody-forming cells present in the spleen was determined by the Jerne plaque technique. After a transient suppression in the 1st week, IgM-PFC were elevated from up to 7 weeks after infection. The IgG response to SRBC was depressed early in infection and continued to decline to less than one-tenth of control levels over the next few weeks persisting throughout overt infection and returning to normal by the end of 2 months. IgG-PFC, and 2-ME-resistant hemagglutinins and hemolysins were also significantly depressed in infected rabbits after two immunizing doses of SRBC. These results suggest that the depressed IgG response caused by syphilitic infection may enable treponemes to evade host immunity by interfering with immunoregulatory mechanisms.


Incidental Identification of Osteoid Osteoma of Skull Bone on 68 Ga-PSMA PET/CT.
An osteoid osteoma (OO) is a benign bone neoplasm, characterized by significant nocturnal pain that usually responds to nonsteroidal anti-inflammatory drugs. It occurs most commonly in the lower extremities and vertebrae. Here, we present a case of carcinoma prostate, who was referred to our department for 68 Ga-PSMA PET/CT scan, and we incidentally found out PSMA-avid OO involving frontal bone of skull, which is a rare finding. To the best of our knowledge, this is the second case in which high PSMA uptake is found in the OO, suggesting a possible PSMA expression related to osteoblastic activity.


Frontal Lobe Circuitry in Posttraumatic Stress Disorder.
Symptoms of posttraumatic stress disorder include hyperarousal, avoidance of trauma-related stimuli, re-experiencing of trauma, and mood changes. This review focuses on the frontal cortical areas that form crucial links in circuitry pertinent to posttraumatic stress disorder symptomatology: (1) the conditioned fear extinction circuit, (2) the salience circuit, and (3) the mood circuit. These frontal areas include the ventromedial prefrontal cortex (conditioned fear extinction), the dorsal anterior cingulate and insular cortices (salience), and the lateral orbitofrontal and subgenual cingulate cortices (mood). Frontal lobe structural abnormalities in posttraumatic stress disorder, including volumetric reductions in the cingulate cortices, impact all three circuits. Functional analyses of frontal cortices in posttraumatic stress disorder show abnormal activation in all three according to task demand and emotional valence. Network analyses reveal altered amygdalo-frontal connectivity and failure to suppress the default mode network during cognitive engagement. Spine shape alterations also have been detected in the medial orbito-frontal cortex in posttraumatic stress disorder postmortem brains, suggesting reduced synaptic plasticity. Importantly, frontal lobe abnormalities in posttraumatic stress disorder extend beyond emotion-related circuits to include the lateral prefrontal cortices that mediate executive functions. In conclusion, widespread frontal lobe dysfunction in posttraumatic stress disorder provides a neurobiologic basis for the core symptomatology of the disorder, as well as for executive function impairment.


In vivo biocompatibility evaluation of a new resilient, hard-carbon, thin-film coating for ventricular assist devices.
The purpose of this study was to evaluate in vivo the biocompatibility of BioMedFlex (BMF), a new resilient, hard-carbon, thin-film coating, as a blood journal bearing material in Cleveland Heart's (Charlotte, NC, USA) continuous-flow right and left ventricular assist devices (RVADs and LVADs). BMF was applied to RVAD rotating assemblies or both rotating and stator assemblies in three chronic bovine studies. In one case, an LVAD with a BMF-coated stator was also implanted. Cases 1 and 3 were electively terminated at 18 and 29 days, respectively, with average measured pump flows of 4.9 L/min (RVAD) in Case 1 and 5.7 L/min (RVAD) plus 5.7 L/min (LVAD) in Case 3. Case 2 was terminated prematurely after 9 days because of sepsis. The sepsis, combined with running the pump at minimum speed (2000 rpm), presented a worst-case biocompatibility challenge. Postexplant evaluation of the blood-contacting journal bearing surfaces showed no biologic deposition in any of the four pumps. Thrombus inside the RVAD inlet cannula in Case 3 is believed to be the origin of a nonadherent thrombus wrapped around one of the primary impeller blades. In conclusion, we demonstrated that BMF coatings can provide good biocompatibility in the journal bearing for ventricular assist devices.


On the origin of schizophrenia: Testing evolutionary theories in the post-genomic era.
Considering the relatively high heritability of schizophrenia and the fact that it significantly reduces the reproductive fitness of affected individuals, it is not clear how the disorder is still maintained in human populations at a disproportionally high prevalence. Many theories propose that the disorder is a result of a trade-off between costs and benefits of the evolution of exclusively human adaptations. There have also been suggestions that schizophrenia risk alleles are accompanied with increase in fitness of affected persons or their relatives in both past and current social contexts. The discoveries of novel schizophrenia-related genes and the advancements in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids) have finally made certain evolutionary theories testable. In this paper, we review the current understanding of the genetics of schizophrenia, the basic principles of evolution that complement our understanding of the subject, and the latest genetic studies that examine long-standing evolutionary theories of schizophrenia using novel methodologies and data. We find that the origin of schizophrenia is complex and likely governed by different evolutionary mechanisms that are not mutually exclusive. Furthermore, the most recent evidence implies that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but has been a mildly deleterious by-product of specific patterns of the evolution of the human brain. In other words, novel findings do not support previous hypotheses stating that schizophrenia risk genes have an evolutionary advantage.


Molecular-based tumour subtypes of canine mammary carcinomas assessed by immunohistochemistry.
Human breast cancer is classified by gene expression profile into subtypes consisting of two hormone (oestrogen and/or progesterone) receptor-positive types (luminal-like A and luminal-like B) and three hormone receptor-negative types [human epidermal growth factor receptor 2-expressing, basal-like, and unclassified ("normal-like")]. Immunohistochemical surrogate panels are also proposed to potentially identify the molecular-based groups. The present study aimed to apply an immunohistochemical panel (anti-ER, -PR, -ERB-B2, -CK 5/6 and -CK14) in a series of canine malignant mammary tumours to verify the molecular-based classification, its correlation with invasion and grade, and its use as a prognostic aid in veterinary practice. Thirty-five tumours with luminal pattern (ER+ and PR+) were subgrouped into 13 A type and 22 B type, if ERB-B2 positive or negative. Most luminal-like A and basal-like tumours were grade 1 carcinomas, while the percentage of luminal B tumours was higher in grades 2 and 3 (Pearson Chi-square P = 0.009). No difference in the percentage of molecular subtypes was found between simple and complex/mixed carcinomas (Pearson Chi-square P = 0.47). No significant results were obtained by survival analysis, even if basal-like tumours had a more favourable prognosis than luminal-like lesions. The panel of antibodies identified only three tumour groups (luminal-like A and B, and basal-like) in the dog. Even though canine mammary tumours may be a model of human breast cancer, the existence of the same carcinoma molecular subtypes in women awaits confirmation. Canine mammary carcinomas show high molecular heterogeneity, which would benefit from a classification based on molecular differences. Stage and grade showed independent associations with survival in the multivariate regression, while molecular subtype grouping and histological type did not show associations. This suggests that caution should be used when applying this classification to the dog, in which invasion and grade supply the most important prognostic information.


Danger points, complications and medico-legal aspects in endoscopic sinus surgery.
Endoscopic endonasal sinus surgery represents the overall accepted type of surgical treatment for chronic rhinosinusitis. Notwithstanding raised and still evolving quality standards, surgeons performing routine endoscopic interventions are faced with minor complications in 5% and major complications in 0.5-1%. A comprehensive review on all minor and major complications of endoscopic surgery of the paranasal sinuses and also on the anterior skull base is presented listing the actual scientific literature. The pathogenesis, signs and symptoms of each complication are reviewed and therapeutic regimens are discussed in detail relating to actual publication references. Potential medico-legal aspects are explicated and recent algorithms of avoidance are mentioned taking into account options in surgical training and education.


[Phthalic acid esters (PAEs) pollution in farmland soils: a review].
The environmental pollution and food safety problems caused by phthalic acid esters (PAEs) have been attracted 'extensive attention around the world. As a large PAEs producer and consumer, China is facing severe PAEs environmental pollution problems. This paper reviewed the present pollution status of six PAEs classified by the U.S. Environmental Protection Agency as the priority pollutants in China farmland soils, analyzed the sources of these six PAEs in this country, and discussed the absorption and accumulation characteristics of the PAEs in different crops as well as the bio-toxic effects of PAEs pollutants. The PAEs concentrations in China farmland soils are significantly higher those in the farmland soils of the United States and European countries. The main sources of PAEs in China farmland soils are atmospheric deposition, agricultural films, sewage sludge application, and wastewater irrigation. There exist significant differences in the characteristics of PAEs absorption, accumulation, and distribution among different crops. PAEs not only have negative effects on soil quality, crop growth, and crop physiological and biochemical properties, but also possess bio-accumulative characteristics. The weaknesses in current researches were pointed out, and the suggestions for the further researches were given, e. g., to expand the scope of PAEs pollution survey, to explore the toxic mechanisms of PAEs on crops, and to develop the techniques for in situ remediation of PAEs-polluted soils.


Research on the effect and mechanism of the CXCR-4-overexpressing BMSCs combined with SDF-1α for the cure of acute SCI in rats.
To evaluate the effect and mechanism of bone marrow stem cells (BMSCs) modified with CXCR-4 gene combined with stromal derived factor-1α (SDF-1α) in the treatment of acute spinal cord injury (SCI) in rats. CXCR-4 gene was transfected by a virus. Spinal cord injury rats were randomly divided into four groups: control group, SDF-1α group, CXCR-4/BMSC group and combined group. The motor function was evaluated with Blood Brain Barrier (BBB) score and the RNA expression of CXCR-4 were measured by PCR. Apoptosis of spinal cord was measured by TUNEL kit (Hu Bei, China). The protein level of Bcl-2 and Bax were measured by Western-blot. The BBB scores, mRNA CXCR-4 expression, and apoptosis rate were compared between four groups at 1d, 3d, 7d, 14d, 21d after the operation. The exercise ability in combined group restored in early and late periods of SCI. The apoptosis rates in the combined group are less than other three groups; the difference was statistically significant (p < 0.05). Bcl-2 in combined group is higher than the other 3 groups and Bax is less than the other 3 groups, the difference is statistically significant (p < 0.05). The neurological function of rats with a spinal cord can be improved by BMSCs modified with CXCR-4 combined with SDF-1α. The main mechanism may improve the expression of SDF-1α and decrease the apoptosis of the spinal cord.


ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.
We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC). We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046. Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39-0.54]; ceritinib 0.52 [0.42-0.64]; alectinib 300 BID 0.16 [0.08-0.33]; alectinib 600 BID 0.23 [0.17-0.30]; brigatinib 0.23 [0.15-0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17-0.70]; alectinib v. ceritinib 0.30 [0.14-0.64]; brigatinib v. crizotinib 0.49 [0.33-0.73]; brigatinib v. ceritinib 0.43 [0.27-0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39-0.83]) and crizotinib (0.68 [0.48-0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56-2.79]) and alectinib (1.60 [1.00-2.58]) but not ceritinib (1.25 [0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants. Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.


Age and the severity of carpal tunnel syndrome.
Several studies have shown an increased incidence of Carpal Tunnel Syndrome (CTS) with increasing age, as well as a longer Median sensory latency in older CTS patients. In this study, data was analyzed from 19 patients with bilaterally normal UE EMG/NCS and no symptoms of CTS (38 hands), as well as 18 patients with unilateral CTS and 21 with bilateral CTS (60 hands) to determine the effect of age on the severity of nerve conduction abnormalities associated with CTS. Most of these parameters showed increasing severity with age. Median motor latency rises sharply with age (r = .41, p = .001), and amplitude falls (r = .34, p = .008). Median sensory rises significantly with age in CTS patients (r = .42, p = .001) and amplitude falls (r = .29, p = .022). Furthermore, the (Median-Ulnar) motor and sensory latency differences both rise with age (r = .40, p = .001, and r = .35, p = .004 respectively). This is crucial, for an increase in Median motor or sensory latency with age could represent a similar degree of pathologic slowing superimposed on normally slower conduction with age. However, the sharp rise in the (Median-Ulnar) latency differences (from 2.2 msecs at age 40 to 3.8 msecs at age 70 for motor, and 1.6 msecs to 2.5 msecs for sensory) shows that the compression is more severe with age.


Physiological basis of starvation resistance in Drosophila leontia: analysis of sexual dimorphism.
Geographically varying starvation stress has often been considered as a natural selector that constrains between-population differences for starvation resistance (SR) in Drosophila species. On the Indian subcontinent, a dozen Drosophila species have shown clinal variations in SR across latitude, but the evolved physiological basis of such contrasting adaptations is largely unknown. In the present study, I untangled the physiological basis of sex-specific as well as between-population divergence for SR in D. leontia, collected across a latitudinal transect of the Indian subcontinent (11°45'-31°19'N). Secondly, I tested the assumptions that hardening to starvation stress facilitates an increased survival under subsequent lethal levels of starvation, and such plastic effects differ between the sexes. I observed several interesting results. In contrast to a steeper cline of starvation-related traits with latitude in females, a shallower gradient was observed for males. Females stored higher (~1.3-fold) dry-mass-specific levels of body lipids and glycogen contents, and utilized these both of these energy resources under starvation stress, whereas the starved males metabolized only body lipids as a source of energy. Conversely, the rate of body lipid utilization and threshold need were considerably higher in females as compared with males. Between-population differences were significant for storage levels of energy reserves only, but not for other avenues (rate of metabolite utilization and threshold need) of SR for both sexes. These findings indicate that multiple pathways shape the physiological basis of sexual dimorphism for SR in D. leontia. Further, single or multiple bouts of starvation hardening conferred an increased longevity (~4-9 h; P<0.001) under subsequent lethal levels of starvation stress for females only, and such plastic responses were consistent with a decrease in rate of metabolite utilization. Nevertheless, between-population effects were non-significant for absolute hardening capacity (AHC=KSR-C). Altogether, these findings suggest that similar evolutionary constraints have resulted in divergent genetic as well as plastic responses to evolve adaptations under starvation stress, and account for the observed sexual dimorphism for basal SR in D. leontia.


Experiences with audio feedback in a veterinary curriculum.
On a national scale in the United Kingdom, student surveys have served to highlight areas within higher education that are not achieving high student satisfaction. Of particular concern to the veterinary and medical disciplines are the persistently poor levels of student satisfaction with academic feedback compared to students in other subjects. In this study we describe experiences with audio feedback trials in a veterinary curriculum. Students received audio feedback on either an in-course laboratory practical report or on an in-course multiple-choice test. Shortly after receiving their feedback, students were surveyed using an electronic questionnaire. In both courses, more students strongly agreed that audio feedback was helpful compared to either text-based (course A) or whole-class (course B) feedback. When asked to reflect on the helpfulness of various types of feedback they had received, audio feedback was rated less helpful than individual discussion with a member of staff (course A and course B), more helpful than peer discussion or automated feedback (course A and course B), and more helpful than written comments or whole-class review sessions (course B). From a faculty perspective, in course A, use of audio feedback was more efficient than handwritten feedback. In course B, the additional time commitment required was approximately 5 hours. Major themes in the qualitative data included the personal and individual nature of the feedback, quantity of feedback, improvement in students' insight into the process of marking, and the capacity of audio feedback to encourage and motivate.


Isolation of an inducible amidase from Pseudomonas acidovorans AE1.
A bacterial strain, AEI, which hydrolysed acetanilide, was isolated from soil and identified as Pseudomonas acidovorans. Numerous amides, esters and enzyme inhibitors were tested as amidase inducers. Phenacetin was chosen as inducer for the large scale cultivation of these organisms because it was less toxic to the bacteria than acetanilide. The induction increased the enzymic activity 250-fold. In comparison, the type culture strain of P. acidovorans, ATTCCI5668, had no amidase activity which could be induced by phenacetin. Optimal growth conditions were established with respect to the concentration of carbon source and inducer so that about 10% of the extractable bacterial protein consisted of the amidase. The organisms were lysed with lysozyme in the presence of EDTA and the enzyme was isolated mainly by column chromatography procedures. A preparation form 60 g (wet wt) bacteria yielded about 100 mg highly purified amidase with a specific activity of 137 mugmol substrate hydrolysed/min/mg protien. In addition to acetanilide, the purified enzyme hydrolysed several other amides and esters. As standard substrate, p-nitroacetanilide was chosen.


Deep learning based multimodal urban air quality prediction and traffic analytics.
Urban activities, particularly vehicle traffic, are contributing significantly to environmental pollution with detrimental effects on public health. The ability to anticipate air quality in advance is critical for public authorities and the general public to plan and manage these activities, which ultimately help in minimizing the adverse impact on the environment and public health effectively. Thanks to recent advancements in Artificial Intelligence and sensor technology, forecasting air quality is possible through the consideration of various environmental factors. This paper presents our novel solution for air quality prediction and its correlation with different environmental factors and urban activities, such as traffic density. To this aim, we propose a multi-modal framework by integrating real-time data from different environmental sensors and traffic density extracted from Closed Circuit Television footage. The framework effectively addresses data inconsistencies arising from sensor and camera malfunctions within a streaming dataset. The dataset exhibits real-world complexities, including abrupt camera or station activations/deactivations, noise interference, and outliers. The proposed system tackles the challenge of predicting air quality at locations having no sensors or experiencing sensor failures by training a joint model on the data obtained from nearby stations/sensors using a Particle Swarm Optimization (PSO)-based merit fusion of the sensor data. The proposed methodology is evaluated using various variants of the LSTM model including Bi-directional LSTM, CNN-LSTM, and Convolutions LSTM (ConvLSTM) obtaining an improvement of 48%, 67%, and 173% for short-term, medium-term, and long-term periods, respectively, over the ARIMA model.


Wearable and Implantable Soft Bioelectronics Using Two-Dimensional Materials.
Soft bioelectronics intended for application to wearable and implantable biomedical devices have attracted great attention from material scientists, device engineers, and clinicians because of their extremely soft mechanical properties that match with a variety of human organs and tissues, including the brain, heart, skin, eye, muscles, and neurons, as well as their wide diversity in device designs and biomedical functions that can be finely tuned for each specific case of applications. These unique features of the soft bioelectronics have allowed minimal mechanical and biological damage to organs and tissues integrated with bioelectronic devices and reduced side effects including inflammation, skin irritation, and immune responses even after long-term biointegration. These favorable properties for biointegration have enabled long-term monitoring of key biomedical indicators with high signal-to-noise ratio, reliable diagnosis of the patient's health status, and in situ feedback therapy with high treatment efficacy optimized for the requirements of each specific disease model. These advantageous device functions and performances could be maximized by adopting novel high-quality soft nanomaterials, particularly ultrathin two-dimensional (2D) materials, for soft bioelectronics. Two-dimensional materials are emerging material candidates for the channels and electrodes in electronic devices (semiconductors and conductors, respectively). They can also be applied to various biosensors and therapeutic actuators in soft bioelectronics. The ultrathin vertically layered nanostructure, whose layer number can be controlled in the synthesis step, and the horizontally continuous planar molecular structure, which can be found over a large area, have conferred unique mechanical, electrical, and optical properties upon the 2D materials. The atomically thin nanostructure allows mechanical softness and flexibility and high optical transparency of the device, while the large-area continuous thin film structure allows efficient carrier transport within the 2D plane. In addition, the quantum confinement effect in the atomically thin 2D layers introduces interesting optoelectronic properties and superb photodetecting capabilities. When fabricated as soft bioelectronic devices, these interesting and useful material features of the 2D materials enable unconventional device functions in biological and optical sensing, as well as superb performance in electrical and biochemical therapeutic actuations. In this Account, we first summarize the distinctive characteristics of the 2D materials in terms of the mechanical, optical, chemical, electrical, and biomedical aspects and then present application examples of the 2D materials to soft bioelectronic devices based on each aforementioned unique material properties. Among various kinds of 2D materials, we particularly focus on graphene and MoS2. The advantageous material features of graphene and MoS2 include ultrathin thickness, facile functionalization, large surface-to-volume ratio, biocompatibility, superior photoabsorption, and high transparency, which allow the development of high-performance multifunctional soft bioelectronics, such as a wearable glucose patch, a highly sensitive humidity sensor, an ultrathin tactile sensor, a soft neural probe, a soft retinal prosthesis, a smart endoscope, and a cell culture platform. A brief comparison of their characteristics and performances is also provided. Finally, this Account concludes with a future outlook on next-generation soft bioelectronics based on 2D materials.


Metal-free synthesis of aryl esters from carboxylic acids and diaryliodonium salts.
An efficient arylation of carboxylic acids with diaryliodonium salts has been developed, giving aryl esters in high yields within short reaction times for both aromatic and aliphatic substrates. The transition-metal-free conditions are compatible with a range of functional groups, and good chemoselectivity is observed with unsymmetric diaryliodonium salts. Furthermore, steric hindrance in the ortho positions is well tolerated both in the carboxylic acid and in the diaryliodonium salt, yielding aryl esters that cannot be obtained via other esterification protocols.


Production of the signalling molecule, autoinducer-2, by Neisseria meningitidis: lack of evidence for a concerted transcriptional response.
Neisseria meningitidis is a Gram-negative bacterium which is an important causative agent of septicaemia and meningitis. LuxS has been shown to be involved in the biosynthesis of a quorum sensing molecule, autoinducer-2 (AI-2), known to play a role in virulence in Escherichia coli, as well as other bacteria. Evidence that serogroup B of N. meningitidis produces AI-2, along with the observation that a luxS mutant of this strain had attenuated virulence in an infant rat model of bacteraemia, led to further investigation of the role of this quorum sensing molecule in N. meningitidis. In this study, it is demonstrated that AI-2 is not involved in regulating growth of meningococci, either in culture or in contact with epithelial cells. Furthermore, transcriptional profiling using DNA microarrays shows an absence of the concerted regulation seen in other bacteria. Taken together, these data suggest that in N. meningitidis, AI-2 may be a metabolic by-product and not a cell-to-cell signalling molecule.


Unusual case of digestive hemorrhage: celiac axis-portal vein arteriovenous fistula.
A case of intractable upper gastrointestinal-hemorrhage was reported in a patient with portal hypertension caused by an arterioportal fistula (APF), namely, celiac axis-portal vein arteriovenous fistula. Portal hypertension caused by extrahepatic-APFs is extremely rare. Trauma, malignancy, and hereditary causes are the common etiology of APFs; but were absent in our patient. Our patient represents an unusual case of unexplained APF who presented with portal hypertension and was successfully managed through endovascular aortic repair.


Polybrominated diphenyl ethers and persistent organochlorines in Japanese human adipose tissues.
The present study determined concentrations of polybrominated diphenyl ethers (PBDEs) and persistent organochlorines (OCs) in Japanese human adipose tissues collected during 2003-2004. Concentrations of PBDEs in adipose tissues were 1-2 orders of magnitude lower than those of OCs. However, observed PBDE congener levels in this study were relatively higher than those in Japanese human adipose tissues collected during 2000 reported previously, while OC levels were comparable to those in specimens collected during 1999 reported by our group. In addition, no age-dependent accumulation of PBDEs was observed, while OC levels except chlordane compounds increased with age. These results indicate recent human exposure to PBDEs in Japan. Among PBDE congeners accumulated in Japanese adipose tissues, BDE-153 was dominant, but this trend was different from those in human milk (BDE-47) and blood (BDE-209) reported previously in Japan, implying the congener-specific kinetics in human bodies. The significant positive correlations between PBDEs and OCs were observed in Japanese adipose tissues, indicating the similar exposure route of these contaminants for Japanese citizens, probably via fish intake.


Salt sensitivity of blood pressure: developmental and sex-related effects.
Epidemiologic studies have shown convincingly that drastically reducing salt intake in the community is accompanied by blood pressure reductions that are comparable to those achieved by antihypertensive medication. Moreover, many subjects with hypertension are salt sensitive. This implies that, in these subjects, blood pressure is more responsive to changes in salt intake than in subjects with normal blood pressure. The presence of conventional risk factors associated with the metabolic syndrome correlates with salt sensitivity. However, women appear to be more salt sensitive than men. Sparse data indicate that the salt sensitivity of blood pressure is greater in subjects with low birth weight. Experimental studies in rats have also shown that hypertensive offspring of dams maintained on low-protein diets throughout or in late pregnancy are more salt sensitive. This is accompanied by increased expression of the thick ascending limb Na-K-2Cl symporter (NKCC2). Perinatal interventions aimed at persistently lowering blood pressure in genetically hypertensive rats have consistently proven to be very effective and are often accompanied by a wave of natriuresis exclusively at 4 wk of age. In sum, in addition to conventional metabolic risk factors for cardiovascular disease, low birth weight and possibly its sequels such as catch-up growth should be viewed as modifiable risk factors for salt sensitivity of blood pressure. Female sex may also be a nonmodifiable risk factor for salt sensitivity. Experimental data indicate that NKCC2 may well be an important determinant of salt sensitivity in acquired (developmental) hypertension.


Resection of rectal metastasis after previous radical surgery for pancreatic cancer: Case report and literature review.
Pancreatic ductal adenocarcinoma (PDAC) is the main type of pancreatic cancer with a poor prognosis. Rectal metastasis after radical resection of PDAC is comparatively rare, and the understanding of such cases is currently not unified. This study presents the entire process of diagnosis and treatment of a patient with PDAC metastasized to the rectal. We propose the viewpoint of exploring potential biomarkers or establishing effective predictive models to assist in the clinical decision-making of such cases. We present the case of a 71-year-old man with slight abdominal distension and dull pain. He underwent surgical treatment for a malignant tumor of the pancreatic body, which was discovered through computed tomography and magnetic resonance imaging examinations. Nine months after the pancreatectomy, a rectal mass was identified by digital rectal examination and diagnosed as a malignant lesion through a puncture biopsy. After a multidisciplinary joint consultation, the patient underwent radical surgery. It was later confirmed as rectal adenocarcinoma based on postoperative pathological results. The pathological result after pancreatic surgery was PDAC, which had invaded the peripheral nerves and abdominal arteries. A diagnosis of rectal metastasis was determined ultimately by combining with the medical history and immunohistochemical staining results. Treatment of the PDAC included laparoscopic resection of the body and tail of the pancreas combined with splenectomy, and postoperative systemic chemotherapy. In addition, treatment of the rectal metastasis included laparoscopic radical resection and postoperative systemic chemotherapy. The patient's current living condition was good. As a rare metastatic site of PDAC, rectal metastasis should be avoided because of misdiagnosis and missed diagnosis. Surgical resection is still an effective treatment strategy for localized pancreatic tumors and isolated metastases. Furthermore, the mining of potential biomarkers or the establishment of predictive models for pancreatic cancer and its metastases may contribute to better clinical decision-making in the future.