An examination of deoxyadenosine 5'(alpha-thio)triphosphate as a ligand to define P2Y receptors and its selectivity as a low potency partial agonist of the P2Y1 receptor.
1. The functional activity of deoxyadenosine 5'(alpha-thio)triphosphate (dATP alpha S) was assessed at the cloned human P2Y1 receptor stably expressed in 1321N1 human astrocytoma cells and transiently expressed in Cos-7 cells. 2. Cells expressing the receptor responded to adenine nucleotides with an increase in [3H]-inositol phosphate accumulation. Half-maximal responses were obtained at approximately 30 nM for 2-methylthioadenosine-5'-triphosphate (2MeSATP), 300 nM for dATP alpha S, and 1000 nM for adenosine 5'-triphosphate (ATP). dATP alpha S produced a maximal response that was only 37 +/- 4% of that produced by ATP or 2MeSATP. dATP alpha S also competitively antagonized the phospholipase C response to 2MeSATP with a KB of 644 +/- 14 nM. Thus dATP alpha S acts as a low potency partial agonist at P2Y1 receptors. 3. The selectivity of dATP alpha S for P2Y1 receptors was determined by examining its capacity to activate P2Y2, P2Y4 and P2Y6 receptors also stably expressed in 1321N1 cells. Although dATP alpha S was a partial agonist at P2Y1 receptors it was a full agonist at P2Y2 receptors, albeit with a potency that was two orders of magnitude lower than at P2Y1 receptors. No agonist or antagonist activity was observed at P2Y4 and P2Y6 receptors. 4. Although [35S]-dATP alpha S bound to a relatively high density (ca 10 pmol mg-1 protein) of binding sites in membranes from 1321N1 or Cos-7 cells expressing the P2Y1 receptor, no difference in the total density of sites was observed between membranes from wild-type, empty vector-transfected, or P2Y1 receptor-expressing cells. Moreover, adenine nucleotide analogues inhibited [35S]-dATP alpha S binding with an order of potency that differed markedly from that for the accumulation of inositol phosphates in intact transfected P2Y1 receptor-expressing cells. Saturation binding experiments demonstrated multiple affinity states for [35S]-dATP alpha S binding in wild-type Cos-7 cell membranes. These data from 1321N1 and Cos-7 cells suggest that cellular membranes exhibit a large number of high affinity binding sites for [35S]-dATP alpha S that are not related to P2Y receptor subtypes.


Development of primary culture of ovine fetal hepatocytes for studies of amino acid metabolism and insulinlike growth factors.
We report the development and characterization of a system of primary culture of ovine fetal hepatocytes to aid in the understanding of the cellular regulation of fetal growth and metabolism with emphasis on amino acid metabolism and insulinlike growth factor gene expression and to allow comparison to in vivo studies. Hepatocytes were isolated from late gestation fetal lambs by in situ perfusion and collagenase digestion utilizing occlusion of the ductus venosus to limit intrahepatic shunting. Hepatocytes were cultured in media modified to mimic fetal concentrations of glucose, lactate, and amino acids. Ovine fetal hepatocytes in primary culture maintain the pattern of fetal amino acid production and utilization seen across the fetal liver in vivo. Specifically, there is a net production of serine and a net utilization of glycine. Cultured ovine fetal hepatocytes specifically increase tritiated thymidine incorporation in response to insulin and insulinlike growth factor II (IGF-II). IGF-II mRNA abundance is high and IGF-I mRNA is low in cultured ovine fetal hepatocytes as in the fetal sheep liver in vivo. These data demonstrate the successful isolation of ovine fetal hepatocytes that retain some of the characteristics of the ovine fetal liver while maintained in short-term culture.


Agmatine potentiates morphine-induced conditioned place preference in mice: modulation by alpha2-adrenoceptors.
The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective alpha2-agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the alpha2-adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective alpha2-antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve alpha2-adrenergic receptors.


Desorption of cobalt-laden algal biosorbent.
Following an effective accumulation of cobalt by nonliving algal biomass of Ascophyllum nodosum, the desorption release of the metal from the biosorbent was examined using H(2)SO(4), HCl, NH(4)OH, KHCO(3), EDTA, KSCN, KCl, and CaCl(2) solutions. The solution of CaCl(2) (0.05M) in HCl appeared to be the best eluant capable of desorbing more than 96% of the sequestered cobalt at the optimum pH 2-3. The optimum solid-to-liquid ratio was more than 10 with the cobalt reuptake capacity of the biosorbent undiminished. The effect of temperature on the elution process and the elution rate was not significant up to 60 degrees C. The infrared (IR) spectra of the native and the eluted biomass did not show significant differences. The electron micrographs of the algal biomass taken after washing it with the CaCl(2) (0.1M) eluant solution indicated no damage to the cells and cell walls, while strong acid, alkaline, and KSCN treatment resulted in some changes in the cellular structure. The kinetics of the cobalt stripping process was quite rapid. The required contact time for the complete metal removal from the biomass was shorter than 2 h, even for the highest levels of cobalt initially deposited on the biomass.


The effects of the sperm motility activators 2-deoxyadenosine and pentoxifylline used for sperm micro-injection on mouse and human embryo development.
The sperm motility stimulants 2-deoxyadenosine (DOA) and pentoxifylline (PTF), used to improve the success of insemination and sperm micro-injection for low motility sperm samples, were studied for their effects on the developmental capacity of mouse and human oocytes. When human oocytes were micro-injected with spermatozoa in 3 mM DOA 80% of them became blocked at the 1-cell pronuclear stage. However, when spermatozoa in 3 mM PTF were used for micro-injection or when spermatozoa were washed to remove DOA before micro-injection only a few oocytes (9-10%) were blocked. Pregnancies occurred in five of 14 patients into whom cleaving embryos from all three treatments had been transferred, indicating that once cleavage was initiated, development of embryos occurred at expected rates. Exposure of mouse oocytes to DOA for a short period during insemination (4-6 h) or a longer period during the pronuclear cell cycle (18-20 h) significantly reduced cleavage beyond the 2-cell stage, resulting in a dramatic reduction in blastocyst formation. PTF did not significantly reduce mouse embryo development. Similar results were obtained for oocytes inseminated in vitro or micro-injected with a spermatozoon into the perivitelline space. Neither DOA nor PTF increased fertilization of mouse oocytes. PTF reduced fertilization, particularly in cumulus-enclosed oocytes and oocytes micro-injected with spermatozoa in PTF. We conclude that DOA is a potent inhibitor of embryo development and oocytes should not be exposed to DOA. Exposure of oocytes to PTF had little effect on their subsequent development but treatment of cauda epididymal mouse spermatozoa can reduce their fertilizing capacity.


Test of the Singh-Anderson model of transparency.
A new model of achromatic transparency has been recently proposed by Singh and Anderson as an alternative to the model proposed long ago by Metelli. The study reported here compared these models using achromatic stimuli consisting of a transparent disk on a background formed by two adjoining rectangles, with the common border of the rectangles dividing the disk in half. Let a and b denote the luminances of the left and right parts of the background, respectively, and let p and q denote the luminances of the left and right parts of the disk, respectively. The value of b was varied for fixed values of a, p, and q. For these values the Singh-Anderson model predicts that the perceived extent of transparency T of the disk is constant with b, while Metelli's model predicts that T decreases as b increases. Participants rated T. The results confirm the prediction of Metelli's model. It is also shown that the Singh-Anderson model is invalid in principle in that, unlike Metelli's model, it fails to capture the principle of independence of the effects of a, b, p, and q on T.


Interplay of collective excitations in quantum-well intersubband resonances.
Intersubband resonances in a semiconductor quantum well (QW) display fascinating features involving various collective excitations such as Fermi-edge singularity (FES) and intersubband plasmon (ISP). Using a density matrix approach, we treated many-body effects such as depolarization, vertex correction, and self-energy consistently for a two-subband system. We found a systematic change in resonance spectra from FES- to ISP-dominated features, as QW width or electron density is varied. Such an interplay between FES and ISP significantly changes both line shape and peak position of the absorption spectrum. We found that a cancellation of FES and ISP undresses the resonant responses and recovers the single-particle features of absorption for semiconductors with a strong nonparabolicity such as InAs, leading to a dramatic broadening of the absorption spectrum.


Compression bandaging for venous leg ulcers.
Effective compression heals leg ulcers and prevents their recurrence. Incorrect bandaging and poor technique are often features of leg ulcer management. A number of bandage systems are currently in use. Multi-layer systems appear to be more effective than single-layer systems.


Serum hyaluronate in the assessment of liver endothelial cell function after orthotopic liver transplantation in the rat.
This study was designed to evaluate the use of serum hyaluronate as a marker of liver endothelial cell function after liver transplantation. We performed orthotopic liver transplantation in both isogeneic and allogeneic rejector models. After transplantation, hepatocyte function was assessed on the basis of serum ALT and total bilirubin levels, and liver endothelial cell function was judged on the basis of serum hyaluronate levels. Significant increase of hyaluronate in the rejector model, compared with the isogeneic model, was seen before any significant results could be obtained from conventional liver function tests. The impaired metabolism of hyaluronate in the rejector model was observed after intravenous injection of trace amounts of radioactive material. Serial studies demonstrate that the endothelial cell is a more susceptible target for the immune response than the hepatocyte. Serum hyaluronate concentration may be a better indicator in the early assessment of graft function. We also examined serum hyaluronate levels to evaluate cold ischemia-reperfusion injury to the liver endothelial cells in the isogeneic model. At 2 hr after reperfusion, hyaluronate levels in the 6-hr cold ischemia (nonviable allograft) group were significantly higher than in the 1-hr and 3-hr cold ischemia (viable allograft) groups. However, there was little difference between the viable allograft groups. After an intravenous injection of 1 mg/kg hyaluronate, the hyaluronate elimination rate in the 3-hr group was distinctly slower than that in the 1-hr group. These data indicate that the hyaluronate elimination rate may be a more sensitive marker of liver endothelial cell function in viable liver after a short period of ischemia.


Mesoporous Si-Cu nanocomposite anode for a lithium ion battery produced by magnesiothermic reduction and electroless deposition.
Copper deposited mesoporous silicon was fabricated by magnesiothermic reduction and electroless deposition and its electrochemical properties as an anode for lithium ion batteries were investigated. The 300-400 nm sized mesoporous Si particles were synthesized by magnesiothermic reduction of SiO2 nanospheres prepared by the Stöber method. The mesopores of Si particles were effectively decorated with Cu using Sn sensitization/Pd activation and subsequent Cu electroless deposition. The homogeneous distribution of Cu inside the mesoporous Si particles was confirmed by high resolution transmission electron microscopy images and energy dispersive spectroscopy mapping on the cross-sectional specimen prepared by a focused ion beam. The mesoporous Si-Cu nanocomposite exhibited high initial Coulombic efficiency, long cycle stability, and high rate capability, delivering a high capacity of 1569 mAh g-1 after 200 cycles at the current density of 1000 mA g-1. The improved electrochemical performance in a mesoporous Si-Cu nanocomposite was attributed to the high electrical conductivity, high Li+ ion mobility, and structural stability to restrict the aggregation and pulverization of active materials.


Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis.
Radium 223 (Ra-223) was approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) patients with bone-only disease, following demonstration of significant improvement in overall survival (OS). To date, there are no validated prognostic factors useful in predicting outcome of mCRPC patients treated with Ra-223. Our retrospective study aims to evaluate the prognostic role of treatment discontinuation due to adverse events in mCRPC patients treated with Ra-223, and to identify which factors correlate with the toxicity onset. We performed a retrospective analysis of all consecutive mCRPC patients treated with Ra-223 from September 2013 to December 2019 at our institute. Patients were divided in 2 groups according to the reason of Ra-223 therapy discontinuation: toxicity versus other causes. Outcome measures were progression-free survival (PFS) and OS. In the overall population (75 patients) median PFS and OS were 5.46 months and 11.15 months respectively. Patients who discontinued treatment due to toxicity had a lower median PFS (3.49 vs 5.89 months, HR: 1.88, 95% CI: 1.14-3.12, p = 0.014) and OS (8.59 vs 14.7 months HR: 3.33, 95% CI: 1.85-6.01, p < 0.001) than patients who discontinued therapy due to other causes. The risk of Ra-223 discontinuation due to toxicity correlates with the number of previous treatments (p = 0.002), previous chemotherapy treatment (p = 0.039), baseline LDH (p = 0.012), Hb (p = 0.021) and platelet-to-lymphocyte ratio (p = 0.024). Discontinuation due to toxicity is associated with worse outcomes in mCRPC patients treated with Ra-223. To reduce the risk of developing toxicities that may compromise treatment efficacy, Ra-223 should be used early in mCRPC patients.


Error Sensitivity to Environmental Noise in Quantum Circuits for Chemical State Preparation.
Calculating molecular energies is likely to be one of the first useful applications to achieve quantum supremacy, performing faster on a quantum than a classical computer. However, if future quantum devices are to produce accurate calculations, errors due to environmental noise and algorithmic approximations need to be characterized and reduced. In this study, we use the high performance qHiPSTER software to investigate the effects of environmental noise on the preparation of quantum chemistry states. We simulated 18 16-qubit quantum circuits under environmental noise, each corresponding to a unitary coupled cluster state preparation of a different molecule or molecular configuration. Additionally, we analyze the nature of simple gate errors in noise-free circuits of up to 40 qubits. We find that, in most cases, the Jordan-Wigner (JW) encoding produces smaller errors under a noisy environment as compared to the Bravyi-Kitaev (BK) encoding. For the JW encoding, pure dephasing noise is shown to produce substantially smaller errors than pure relaxation noise of the same magnitude. We report error trends in both molecular energy and electron particle number within a unitary coupled cluster state preparation scheme, against changes in nuclear charge, bond length, number of electrons, noise types, and noise magnitude. These trends may prove to be useful in making algorithmic and hardware-related choices for quantum simulation of molecular energies.


The C-terminal domains of the gingipain K polyprotein are necessary for assembly of the active enzyme and expression of associated activities.
The Porphyromonas gingivalis lysine-specific cysteine protease (gingipain K, Kgp) is expressed as a large precursor protein consisting of a leader sequence, a pro-fragment, a catalytic domain with a C-terminal IgG-like subdomain (IgSF) and a large haemagglutinin/adhesion (HA) domain. In order to directly study the role of these non-catalytic domains in pro-Kgp processing and maturation in P. gingivalis, the wild-type form of the gene was replaced with deletion variants encoding C-terminally truncated proteins, including KgpDeltaHA3/4 (Delta1292-1732 aa), KgpDeltaHA2-4 (Delta1157-1732 aa), KgpDeltaHA1-4 (Delta738-1732 aa), KgpDeltaC-term/HA (Delta681-1732 aa) and KgpDeltaIg/C-term/HA (602-1732 aa). Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that all truncated variants of the kgp gene were transcribed in P. gingivalis. Despite high levels of kgpDeltaC-term/HA and kgpDeltaIg/C-term/HA transcripts, no Kgp-specific antigen was detected in cultures of these mutants as determined by Western blot analysis with monoclonal antibodies specific for the Kgp catalytic domain. Furthermore, only barely measurable amounts of Kgp-specific activity were detected in these two mutants. The remaining mutants expressed significant Kgp activity, however, at lower levels when compared with the parental strain. The decreased activity most probably resulted from altered folding and/or hindered secretion of the protein. The kgp gene truncation was also demonstrated to alter the distribution of the gingipain protein between membrane-associated and -secreted forms. While both gingipain K activity and the protein were cell membrane-associated in the parental strain, the mutants released significant amounts of both protein and activity into the media. Taken together, these results suggest that the C-terminal HA domains of Kgp are not only essential for full expression of gingipain activity, but also for proper processing of the multiprotein complex assembly on the P. gingivalis outer membrane. Moreover, our results indicate that the immunoglobulin-like subdomain is indispensable for proper folding and expression of the gingipains.


Compassionate faces: Evidence for distinctive facial expressions associated with specific prosocial motivations.
Compassion is a complex cognitive, emotional and behavioural process that has important real-world consequences for the self and others. Considering this, it is important to understand how compassion is communicated. The current research investigated the expression and perception of compassion via the face. We generated exemplar images of two compassionate facial expressions induced from two mental imagery tasks with different compassionate motivations (Study 1). Our kind- and empathic compassion faces were perceived differently and the empathic-compassion expression was perceived as best depicting the general definition of compassion (Study 2). Our two composite faces differed in their perceived happiness, kindness, sadness, fear and concern, which speak to their underling motivation and emotional resonance. Finally, both faces were accurately discriminated when presented along a compassion continuum (Study 3). Our results demonstrate two perceptually and functionally distinct facial expressions of compassion, with potentially different consequences for the suffering of others.


Metal-Phenolic Network-Facilitated "Foe-to-Friend" Conversion of Melittin for Cancer Immunotherapy with Boosted Abscopal Effect.
As a naturally occurring cytolytic peptide, melittin (Mel) has strong cytolytic activity and is a potent therapeutic peptide for cancer therapy. However, the serious hemolytic activity of Mel largely impedes its clinical applications. In this work, based on the strong interactions between proteins/peptides and polyphenols, we develop a tannic acid-Fe3+ metal-phenolic network (MPN)-based strategy that can convert Mel from foe to friend via shielding its positive charges and reducing its hemolytic activity. Besides, an immune adjuvant resiquimod (R848) is also introduced for immunostimulation, affording the final Mel- and R848-coloaded nanodrug. The Mel-caused membrane disruption can induce immunogenic cell death for immunostimulation, R848 can act as an immune adjuvant to further facilitate the immunostimulatory effect, and the tannic acid-Fe3+ MPN-mediated Fenton reaction can produce reactive oxygen species for cancer treatment. Further experiments reveal that the nanodrug can effectively cause immunogenic cell death of tumor cells and arouse robust intratumoral and systemic antitumor immunostimulation. In the bilateral tumor-bearing mouse models, the nanodrug considerably destroys the primary tumor and also boosts the abscopal effect to ablate the distant tumor. Collectively, the MPN-facilitated "foe-to-friend" strategy may promote the practical applications of Mel and foster the development of cancer immunotherapeutics.


[Clinical course and features in acute stage of Kawasaki disease].
Kawasaki disease is diagnosed as a syndrome by definitive 6 principle signs and suspi cious clinical course. Health professionals are requested to know a common knowledge for those characteristics. In Japanese diagnostic guideline, fever is regarded as one of six prin ciple signs because some cases with five principle signs other than fever also developed coronary artery aneurysm. Japanese diagnostic guideline describes that duration of fever do not need 5 days or longer, if the fever resolved before the 5th day by early treatment such as intravenous immunoglobulin. Guideline warns that some incomplete cases also develop coronary artery complications.


Impact of Frailty on Inpatient Outcomes of Acute Traumatic Spinal Cord Injury: Evidence From US National Inpatient Sample.
Spinal cord injury (SCI) is any spinal cord injury or affliction that results in temporary or permanent impairment of motor or sensory function. This study determined the prevalence of frailty and its impact on in-hospital outcomes of patients admitted with acute traumatic SCI (TSCI). This retrospective study extracted data of adults 18 to 85 years with acute TSCI from the US Nationwide Inpatient Sample (NIS) 2016 to 2018. Frailty status were assessed by the 11-factor modified Frailty Index (mFI-11) through claim codes. Patients with an mFI ≥3 were classified as frail. Associations between study variables and in-hospital mortality, discharge status, prolonged length of stay, severe infection, and hospital costs were determined by univariate and multivariable regression analyses. A total of 52,263 TSCI patients were identified, where 12,203 (23.3%) patients were frail. After adjusting for relevant confounders, frailty was independently associated with increased risk for in-hospital mortality [adjusted odds ratio (aOR) = 1.25, 95% CI:1.04-1.49], unfavorable discharge (aOR =1.15, 95% CI: 1.09-1.22), prolonged length of stay (aOR =1.32, 95% CI: 1.24-1.40), and severe infection (aOR =2.52, 95% CI: 2.24-2.83), but not hospital cost. Stratified analyses revealed frailty was associated with higher unfavorable discharge and severe infection regardless of age, Charlson Comorbidity Index, and injury level. In acute TSCI, frailty is independently associated with increased risk for adverse inpatient outcomes in terms of in-hospital mortality, prolonged hospital stays, unfavorable discharge, and particularly severe infection.


Erythromelanosis follicularis faciei et colli: report of involvement in two female patients.
Erythromelanosis follicularis faciei is a rare disease characterized by reddish brown pigmentation and follicular papules localized on certain areas such as the face and neck. Young men are usually affected, but young women or children may be affected. Bilateral distribution is usual, but it may occur unilaterally. Histopathologically, hyperkeratosis, increased melanization and dilatation of the hair follicle are characteristic. Two female patients with typical localizations and clinical findings of the disease are reported here.


Incidence and predictors of 30-day hospital readmissions for liver cirrhosis: insights from the United States National Readmissions Database.
Cirrhosis is associated with substantial inpatient morbidity and mortality. This study aimed to determine the trends in 30-day hospital readmission rates among patients with cirrhosis and identify factors associated with these readmissions. We conducted a retrospective analysis of data retrieved from the Nationwide Readmissions Database to determine trends in 30-day readmission for patients discharged with a diagnosis of cirrhosis in 2010 through 2014. Multivariate logistic regression analysis was used to identify predictors of readmission. Among 303,346 patients identified from the database, the 30-day readmission rate for patients with a discharge diagnosis of cirrhosis was 31.4% (n=95,298). The trends in the readmission rates remained steady during the study period. On multivariate analysis, female sex, age 45 years or older, esophagogastroduodenoscopy (EGD) during admission, and disposition to a short-term care facility or skilled nursing facility protected against readmissions. In contrast, coverage by Medicaid insurance, admission during a weekend, nonalcoholic cause of cirrhosis, and history of hepatic encephalopathy and ascites were associated with readmission. We found an exceptionally high 30-day readmission rate in patients with cirrhosis, although it remained stable during the study period. This study identified some modifiable factors such as disposition to a short-term care facility or skilled nursing facility and patients' attendance of alcohol rehabilitation facilities that could decrease the likelihood of readmission and could inform local and national healthcare policymakers.


3D Direct Printing of Silicone Meniscus Implant Using a Novel Heat-Cured Extrusion-Based Printer.
The first successful direct 3D printing, or additive manufacturing (AM), of heat-cured silicone meniscal implants, using biocompatible and bio-implantable silicone resins is reported. Silicone implants have conventionally been manufactured by indirect silicone casting and molding methods which are expensive and time-consuming. A novel custom-made heat-curing extrusion-based silicone 3D printer which is capable of directly 3D printing medical silicone implants is introduced. The rheological study of silicone resins and the optimization of critical process parameters are described in detail. The surface and cross-sectional morphologies of the printed silicone meniscus implant were also included. A time-lapsed simulation study of the heated silicone resin within the nozzle using computational fluid dynamics (CFD) was done and the results obtained closely resembled real time 3D printing. Solidworks one-convection model simulation, when compared to the on-off model, more closely correlated with the actual probed temperature. Finally, comparative mechanical study between 3D printed and heat-molded meniscus is conducted. The novel 3D printing process opens up the opportunities for rapid 3D printing of various customizable medical silicone implants and devices for patients and fills the current gap in the additive manufacturing industry.


Short-chain fatty acids in the normal human feces.
The short-chain fatty acids ( SCFAs ) have been studied in the feces of 20 healthy subjects--10 methane excretors and 10 non-methane excretors. The analytical procedure included homogenization of fecal samples followed by vacuum distillation and subsequent gas chromatography. This method for analysis of fecal SCFAs showed recoveries of the individual acids from 90% to 109% and coefficients of variation for the inter-assay reproducibility from 6.0% to 19.7%, highest for those acids present in the smallest concentrations. There was no difference in the concentrations or relative compositions of SCFAs between methane-excreting subjects and non-methane-excreting subjects. The concentrations of SCFAs , given as mmol/kg feces (wet weight), were (median and range): total, 76.8 (27.9-187.7); acetic acid, 37.4 (12.8-103.4); propionic acid, 12.5 (4.5-27.8); i-butyric acid, 2.2 (0.7-3.8); n-butyric acid, 12.4 (4.0-53.0); i-valeric acid, 3.2 (0.8-5.9); n-valeric acid, 2.4 (0.6-3.8) and n-caproic acid, 0.5 (0.0-3.6). The study shows that the SCFAs are quantitatively the most important anions in the feces of healthy subjects. The pronounced individual variations in the concentrations of SCFAs are real biological variations and cannot be explained by methodological variations.


Blood cells in thyroid cancer patients: a possible influence of apoptosis.
The side effects of radioactive iodine (131-I) treatment of differentiated thyroid cancer (DTC) patients include reduction of peripheral blood cell counts. The aim of this study was to analyze some potential changes in blood cell counts of DTC patients after 131-I therapy, especially CD3-positive, CD19-positive, and CD56-positive peripheral blood lymphocytes (PBL), as well as the possible role of apoptosis in selected lymphocyte populations. The study group included 24 thyroid cancer patients and 24 control subjects. Peripheral blood samples from patients and controls were analyzed using 5-color flow cytometry. Apoptotic cells were detected using an Annexin V-FITC/7-AAD kit. There was a statistically significant decrease of all blood cells after the 131-I therapy. The CD19+ B lymphocyte population was the most affected (5.82 ± 3.21% before therapy vs. 3.93 ± 2.60% after therapy, p = 0.008). This decrease was correlated with the degree of apoptosis of peripheral blood lymphocytes (Spearman's r = 0.563, p =0.013). We concluded that 131-I therapy of DTC patients led to a decrease of all peripheral blood cells, especially CD19+ B lymphocytes. This directly correlated with apoptosis of PBLs, indicating that radiation damage to B cells leads to subsequent elimination by apoptosis.


ATP binding to nucleotide binding domain (NBD)1 of the ClpB chaperone induces motion of the long coiled-coil, stabilizes the hexamer, and activates NBD2.
The molecular chaperone ClpB can rescue the heat-damaged proteins from an aggregated state in cooperation with other chaperones. It has two nucleotide binding domains (NBD1 and NBD2) and forms a hexamer ring in a manner dependent on ATP binding to NBD1. In the crystal structure of ClpB with both NBDs filled by nucleotides, the linker between two NBDs forms an 85-A-long coiled-coil that extends on the outside of the hexamer and leans to NBD1. To probe the possible motion of the coiled-coil, we tested the accessibility of a labeling reagent, fluorescence change of a labeled dye, and cross-linking between the coiled-coil and NBD1 by using the mutants with defective NBD1 or NBD2. The results suggest that the coiled-coil is more or less parallel to the main body of ClpB in the absence of nucleotide and that ATP binding to NBD1 brings it to the leaning position as seen in the crystal structure. This motion results in stabilization of the hexamer form of ClpB and promotion of ATP hydrolysis at NBD2.


Postoperative serious adverse events in a teaching hospital: a prospective study.
To assess the incidence and nature of postoperative serious adverse events (SAEs) among inpatients having surgery in a tertiary hospital, and to determine which subgroups of patients might be at greatest risk. Prospective observational study from 1 December 1998 - 31 March 1999. Tertiary teaching hospital in Melbourne, Victoria. 1,125 subjects having inpatient surgery during the study period. Inhospital mortality, length of hospital stay, and SAEs (myocardial infarction, pulmonary embolism, acute pulmonary oedema, unscheduled tracheostomy, respiratory failure, cardiac arrest, stroke, severe sepsis, acute renal failure, and emergency admission to intensive care unit [ICU]). There were 414 SAEs in 190 of the 1,125 patients (16.9%); 80 patients died (7.1%). The most common adverse events were emergency admission to ICU (95), respiratory failure (52) and readmission to ICU (37). In patients without SAEs, mean duration of hospital stay was 18.4 days (95% Cl, 15.4-21.4), while in those with SAEs it was 38.5 days (95% CI, 35.3-41.7) (P < 0.0001). SAEs, including deaths, were more common after unscheduled surgery and in patients over 75 years of age. The combination of these two factors carried a 20% mortality. There were no differences in the incidence of SAEs among the major surgical specialties. SAEs are common and result in high mortality, especially in older surgical inpatients and those having unscheduled surgery. These findings raise important issues of optimal perioperative management in tertiary hospitals.


A Novel Head-Fixed Assay for Social Touch in Mice Uncovers Aversive Responses in Two Autism Models.
Social touch, an important aspect of social interaction and communication, is essential to kinship across animal species. How animals experience and respond to social touch has not been thoroughly investigated, in part because of the lack of appropriate assays. Previous studies that examined social touch in freely moving rodents lacked the necessary temporal and spatial control over individual touch interactions. We designed a novel head-fixed assay for social touch in mice, in which the experimenter has complete control to elicit highly stereotyped bouts of social touch between two animals. The user determines the number, duration, context, and type of social touch interactions, while monitoring an array of complex behavioral responses with high resolution cameras. We focused on social touch to the face because of its high translational relevance to humans. We validated this assay in two different models of autism spectrum disorder (ASD), the Fmr1 knock-out (KO) model of Fragile X syndrome (FXS) and maternal immune activation (MIA) mice. We observed higher rates of avoidance running, hyperarousal, and aversive facial expressions (AFEs) to social touch than to object touch, in both ASD models compared with controls. Fmr1 KO mice showed more AFEs to mice of the same sex but whether they were stranger or familiar mice mattered less. Because this new social touch assay for head-fixed mice can be used to record neural activity during repeated bouts of social touch it could be used to uncover underlying circuit differences.SIGNIFICANCE STATEMENT Social touch is important for communication in animals and humans. However, it has not been extensively studied and current assays to measure animals' responses to social touch have limitations. We present a novel head-fixed assay to quantify how mice respond to social facial touch with another mouse. We validated this assay in autism mouse models since autistic individuals exhibit differences in social interaction and touch sensitivity. We find that mouse models of autism exhibit more avoidance, hyperarousal, and aversive facial expressions (AFEs) to social touch compared with controls. Thus, this novel assay can be used to investigate behavioral responses to social touch and the underlying brain mechanisms in rodent models of neurodevelopmental conditions, and to evaluate therapeutic responses in preclinical studies.


Effects of naringin on the pharmacokinetics of intravenous paclitaxel in rats.
It was reported that paclitaxel is an inhibitor of hepatic P-glycoprotein (P-gp) and hepatic microsomal cytochrome P450 (CYP) 3A1/2, and that naringin is an inhibitor of biliary P-gp and CYP3A1/2 in rats. The purpose of this study was to report the effects of oral naringin on the pharmacokinetics of intravenous paclitaxel in rats. Oral naringin (3.3 and 10 mg/kg) was pretreated 30 min before intravenous (3 mg/kg) administration of paclitaxel. After intravenous administration of paclitaxel, the AUC was significantly greater (40.8% and 49.1% for naringin doses of 3.3 and 10 mg/kg, respectively), and Cl was significantly slower (29.0% and 33.0% decrease, respectively) than controls. The significantly greater AUC could be due mainly to an inhibition of metabolism of paclitaxel via CYP3A1/2 by oral naringin. The inhibition of hepatic P-gp by oral naringin could also contribute to the significantly greater AUC of intravenous paclitaxel by oral naringin.


1-(4-Bromo-phen-yl)-2-ethyl-sulfinyl-2-(phenyl-selan-yl)ethanone monohydrate.
In the title hydrate, C(16)H(15)BrO(2)SSe·H(2)O, the sulfinyl O atom lies on the opposite side of the mol-ecule to the Se and carbonyl O atoms. The benzene rings form a dihedral angle of 51.66 (17)° and are splayed with respect to each other. The observed conformation allows the water mol-ecules to bridge sulfinyl O atoms via O-H⋯O hydrogen bonds, generating a linear supra-molecular chain along the b axis; the chain is further stabilized by C-H⋯O contacts. The chains are held in place in the crystal structure by C⋯H⋯π and C-Br⋯π inter-actions.


mir-637 inhibits the proliferation of cholangiocarcinoma cell QBC939 through interfering CTSB expression.
To investigate the role of mir-637 on the proliferation, migration and apoptosis in human cholangiocarcinoma (CCA) cell line QBC939, and the impact of mir-637 on Cathepsin B (CTSB) expression. Expression of mir-637 and CTSB in CCA tissues and adjacent non-tumor tissues were measured by Real-time PCR. CTSB expression in human CCA cell lines was detected with or without mir-637 exogenous overexpression through fluorescent quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method. The efficiency of lentivirus-mir-637 vector infection, and the effect of mir-637 on the proliferation, migration ability, apoptosis and cell cycle of CCA cell were detected, respectively. The possibility of mir-637 targeting CTSB was also tested by bioinformatics method, correlation analysis and molecular biology method. Decreased mir-637 and increased CTSB expression were observed in CCA tissue compared with adjacent non-tumor tissues. CTSB expression in mir-637 exogenously overexpressed QBC939 cells decreased compared with negative control. Mir-637 overexpression caused significant decrease of proliferation and migration ability of QBC939 cell. In addition, mir-637 overexpression induced that the cell cycle was blocked in G0/G1 phase, and cell apoptosis rate increased significantly. mir-637 and CTSB play an important role in the proliferation and migration of CCA cells. Mir-637 could inhibit CTSB expression significantly, which in-turn down-regulates the proliferation, migration and invasion ability of QBC939 cell, and promotes apoptosis in QBC939 cell line.


Efficacy of Target Drug Delivery and Dead Space Reduction Using Antibiotic-loaded Bone Cement for the Treatment of Complex Spinal Infection.
A retrospective study. We have treated complex cases of surgical site infection (SSI) successfully using antibiotic-loaded bone cement to avoid the need for implant removal. In the present study, we describe a new treatment option for SSI. Although there are several treatment options for SSI after spinal surgery involving instrumentation, several types of problems may arise and are difficult to cure. Eleven patients with SSI after undergoing spinal surgery involving instrumentation were studied. All had been refractory to conventional treatments, including intravenous antibiotic administration and conventional debridement and irrigation. Antibiotic-loaded bone cement was placed on and around the instrumentation to cover them and to occupy the surrounding dead space. Two general types of antibiotics were loaded into the polymethylmethacrylate bone cement. The recipes for the mixture were changed depending on the bacterial cultures. Sensitive antibiotics were administered generally for 2-6 weeks until the C-reactive protein level was normalized. All patients were treated successfully using antibiotic-loaded bone cement. Only 1 patient needed a repeat of this procedure to treat an infection. Antibiotic-loaded bone cement was placed in situ in all patients during the follow-up period and there were no significant adverse events. Antibiotic-loaded bone cement treatment reduces the dead space and achieves the targeted drug delivery simultaneously. Treatment using antibiotic-loaded bone cement is an effective treatment option for complex spinal SSI.


Prognostic Implications of Physical Activity on Mortality from Ischaemic Heart Disease: Longitudinal Cohort Study Data.
The prevalence of physical inactivity has been rising in many countries in recent years, adding to the burden of non-communicable diseases and affecting overall health worldwide. The aim of this study was to determine the comprehensive assessment of the prognostic value of physical activity in leisure time on mortality from ischemic heart disease (IHD) by gender separately for those respondents who were diagnosed with IHD and for those who were not diagnosed with IHD in their baseline health survey. In the baseline survey (2006-2008), 7100 men and women ages 45-72 were examined within the framework of the international study Health, Alcohol, and Psychosocial Factors in Eastern Europe (HAPIEE). A total of 6770 participants were available for statistical analysis (after excluding 330 respondents due to missing information on study variables). Physical activity was determined by leisure-time physical activities (hours/week). All participants in the baseline survey were followed up for IHD mortality events until 31 December 2018. Using multivariate Cox regression analysis, it was found that moderate and higher levels of physical activity significantly reduced the risk of IHD mortality (HR = 0.54, p = 0.016 and HR = 0.60, p = 0.031, respectively) in men who were not diagnosed with IHD at baseline compared with physically inactive subjects. It was found that among men and women who were diagnosed with IHD at baseline, physical activity reduced the risk of mortality from IHD compared with those who were physically inactive (HR = 0.54, p = 0.021 and HR = 0.41, p = 0.025, respectively). Using mediation analysis, it was found that physical activity directly predicted statistically lower IHD mortality (p < 0.05) in men and women. High physical activity was a significant factor that directly predicted statistically lower IHD mortality in men, regardless of whether subjects had IHD at baseline or not. However, only moderate physical activity was a significant factor that directly predicted statistically lower IHD mortality in the women group with IHD at baseline.


The role of nutrition in the adaptation of the small intestine after massive resection.
The demonstration that weight gain, growth, and development can be achieved by supplying all essential nutrients exclusively by vein prompted the laboratory evaluation of this parenteral feeding technique in animals that had undergone enterectomy. This study was undertaken to determine the role of nutrition and anabolism in compensation of the small intestine after massive intestinal resection. Three or 4 littermate beagle puppies from 10 litters, obtained 8 weeks after weaning and weighing 2 to 3 kg, underwent enterectomy at 10 weeks of age. In the standardized operation, 90% or 95% of the small intestine was removed, as measured from the tail of the pancreas to the ileocecal junction. After enterectomy, the dogs were divided into 2 groups, 1 group being fed exclusively with a kennel diet and the other offered the orally administered diet, whereas all the required nutrients were by vein. After 1 month of continuous infusion, the puppies were weaned from the IV-administered nutrient solution and maintained solely on the standard, orally administered diet. Thirty-four puppies were evaluated for up to 1 year with their control littermates with no resection. Normal growth and development occurred in all puppies after enterectomy during the total IV administration of nutrition. After the parenteral feeding, the dogs with a 90% resection achieved near normal weight gain in contrast to the orally fed dogs with enterectomy that grew to only one-half normal size. In the 95% resected group, 5 of 6 dogs survived more than 4 months after parenteral feedings, whereas only 1 of 5 lived more than 1 month while receiving oral feedings alone. At 1 year, the intestine from the parenterally fed dogs that had undergone enterectomy demonstrated increased mucosal cellularity, marked villus hypertrophy, and increased intestinal weight gain per unit length when compared with the orally fed dogs that had undergone resection and the control littermates. By providing all essential nutrients by vein for 30 days, significant improvement in survival, growth, and nutrition was noted in puppies after massive intestinal resection.


Clear cell carcinoma of the ovary: potential pathogenic mechanisms (Review).
Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer-related mortality. Clear cell EOC (cEOC) has a number of clinical features distinguishing it from other EOC because of frequent concurrence of endometriosis and highly chemoresistant nature resulting in a poor prognosis. Recent biochemical studies based on genome-wide expression analysis technology have noted specific expression of a transcription factor, hepatocyte nuclear factor-1beta (HNF-1beta), in cEOC and genetic alteration may be involved in oxidative stress. We describe the HNF-1beta-dependent pathophysiology of cEOC and discuss its role in oxidative stress-induced carcinogenesis. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2009, combining the keywords, genome-wide, microarray, epithelial ovarian cancer, clear cell carcinoma, oxidative stress, and detoxification, with specific expression profiles of genes. The catalog of cEOC-specificity might be a manifestation of six essential alterations in cell physiology: oxidative stress and detoxification, proteases, signal transduction, adhesion, transcription, and metabolism. Among 54 genes highly upregulated in cEOC, 47 genes (87.0%) were associated with the redox-related genes. Several important cEOC-related genes overlap with those known to be regulated by HNF-1beta. Twenty-two (40.7%) of the 54 genes predominantly identified in cEOC were involved in downstream targets of HNF-1beta. The HNF-1beta-dependent pathway might provide new insights into regulation of glycogen synthesis, detoxification and resistance to anticancer agents. This review summarizes recent advances in the understanding of oxidative stress and antioxidant mechanisms in pathogenesis of cEOC. A redox-sensitive subset of cEOC genes linked to oxidative and detoxification pathways was identified and associated with HNF-1beta-specific downstream targets.


Fluorescent probes based on acridine derivatives and their application in dynamic monitoring of cell polarity variation.
Polarity and viscosity, as important microenvironment parameters, play an essential role in cell metabolism. Therefore, 9-acridine carboxaldehyde reacted with cyano compounds to obtain polarity-sensitive probes 1a-b and viscosity-sensitive probes 1c-d. Among them, with the increase in solvent polarity, the maximum emission wavelength of acridine-dicyanoisophorone-based probe 1a red-shifted from 553 nm to 594 nm, the fluorescence quantum yield increased from 0.5% to 35.6%, and the fluorescence intensity enhanced 38 fold. The acridine-cyanofuranone based probe 1b also has a polarity response similar to 1a. Nevertheless, when the solution viscosity increased from 0.89 cP (100% water) to 856 cP (1% water), the fluorescence intensity of the acridine-tricyanodihydrofuran based probe 1c at 430 nm enhanced 5.6 times. The acridine-cyanobenzothiazole based probe 1d also had a viscosity response similar to 1c. In addition, probes 1a-b were used for further HeLa cell imaging experiments due to their good photostability and the results suggested that probe 1a could locate lipid droplets and probes 1b-c could stain lysosomes. Moreover, probes 1a-b could dynamically monitor the changes in intracellular polarity.


Annexin A2-modulated proliferation of pulmonary arterial smooth muscle cells depends on caveolae and caveolin-1 in hepatopulmonary syndrome.
We have established that annexin A2 (ANXA2) is an important factor in the experimental hepatopulmonary syndrome (HPS) serum-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the detailed mechanism remains unclear. ANXA2 translocated to the caveolin-enriched microdomains (caveolae) in PASMCs upon HPS serum stimulation. The disruption of caveolae by Methyl-β-cyclodextrin (MβCD) alleviated the caveolae recruitment of ANXA2 and the ANXA2-mediated activation of ERK1/2 and NF-κB, so that ANXA2-modulated PASMC proliferation was suppressed. The over-expression of Cav-1 resulted in the relocation of ANXA2 from caveolae and negatively regulated ERK1/2 and NF-κB activation, which inhibited the ANXA2-modulated PASMC proliferative behavior. These data indicate that caveolae function as a signaling platform for ANXA2-induced proliferative behavior and Cav-1 participates upstream of ANXA2 in the activation of ERK1/2 and NF-κB.


Diagnosis of Neonatal Sepsis: The Role of Inflammatory Markers.
This is a narrative review on the role of biomarkers in the diagnosis of neonatal sepsis. We describe the difficulties to obtain standardized definitions in neonatal sepsis and discuss the limitations of published evidence of cut-off values and their sensitivities and specificities. Maternal risk factors influence the results of inflammatory markers as do gestational age, the time of sampling, the use of either cord blood or neonatal peripheral blood, and some non-infectious causes. Current evidence suggests that the use of promising diagnostic markers such as CD11b, CD64, IL-6, IL-8, PCT, and CRP, either alone or in combination, might enable clinicians discontinuing antibiotics confidently within 24-48 h. However, none of the current diagnostic markers is sensitive and specific enough to support the decision of withholding antibiotic treatment without considering clinical findings. It therefore seems to be justified that antibiotics are often initiated in ill term and especially preterm infants. Early markers like IL-6 and later markers like CRP are helpful in the diagnosis of neonatal sepsis considering the clinical aspect of the neonate, the gestational age, maternal risk factors and the time (age of the neonate regarding early-onset sepsis) of blood sampling.


Gold Nanorods Conjugated Porous Silicon Nanoparticles Encapsulated in Calcium Alginate Nano Hydrogels Using Microemulsion Templates.
Porous silicon nanoparticles (PSiNPs) and gold nanorods (AuNRs) can be used as biocompatible nanocarriers for delivery of therapeutics but undesired leakage makes them inefficient. By encapsulating the PSiNPs and AuNRs in a hydrogel shell, we create a biocompatible functional nanocarrier that enables sustained release of therapeutics. Here, we report the fabrication of AuNRs-conjugated PSi nanoparticles (AuNRsPSiNPs) through two-step chemical reaction for high-capacity loading of hydrophobic and hydrophilic therapeutics with photothermal property. Furthermore, using water-in-oil microemulsion templates, we encapsulate the AuNRsPSiNPs within a calcium alginate hydrogel nanoshell, creating a versatile biocompatible nanocarrier to codeliver therapeutics for biomedical applications. We find that the functionalized nanohydrogel effectively controls the release rate of the therapeutics while maintaining a high loading efficiency and tunable loading ratios. Notably, combinations of therapeutics coloaded in the functionalized nanohydrogels significantly enhance inhibition of multidrug resistance through synergism and promote faster cancer cell death when combined with photothermal therapy. Moreover, the AuNRs can mediate the conversion of near-infrared laser radiation into heat, increasing the release of therapeutics as well as thermally inducing cell damage to promote faster cancer cell death. Our AuNRsPSiNPs functionalized calcium alginate nanohydrogel holds great promise for photothermal combination therapy and other advanced biomedical applications.


The nature of nurture: Effects of parental genotypes.
Sequence variants in the parental genomes that are not transmitted to a child (the proband) are often ignored in genetic studies. Here we show that nontransmitted alleles can affect a child through their impacts on the parents and other relatives, a phenomenon we call "genetic nurture." Using results from a meta-analysis of educational attainment, we find that the polygenic score computed for the nontransmitted alleles of 21,637 probands with at least one parent genotyped has an estimated effect on the educational attainment of the proband that is 29.9% (P = 1.6 × 10-14) of that of the transmitted polygenic score. Genetic nurturing effects of this polygenic score extend to other traits. Paternal and maternal polygenic scores have similar effects on educational attainment, but mothers contribute more than fathers to nutrition- and heath-related traits.


Synthesis of Poly-γ-S-2-methylbutyl-l-glutamate and Poly-γ-S-2-methylbutyl-d-glutamate and Their Use as Enantiodiscriminating Alignment Media in NMR Spectroscopy.
Lyotropic liquid crystalline (LLC) phases of polyglutamic acid derivatives, such as poly-γ-benzyl-l-glutamate, are suitable alignment media for organic structure elucidation by NMR spectroscopy. Their helical structure is responsible for enantiodiscrimination. As part of our ongoing investigations concerning the alignment mechanism(s) of these systems, we considered whether an additional chiral center in the side chain could improve enantiodiscrimination relative to the helical polymer with an achiral side chain. Therefore, the diastereoisomers poly-γ-S-2-methylbutyl-l-glutamate (PSMBLG) and poly-γ-S-2-methylbutyl-d-glutamate (PSMBDG) were synthesized. These two polymers were tested for their liquid crystallinity and suitability as alignment media. The spatial structure of the solutes (-)-curcumol and isopinocampheol (IPC) were validated by the residual dipolar coupling data obtained. Additionally, enantiodiscrimination of IPC was observed in the new alignment media and compared with the enantiodiscrimination of IPC in other homopolypeptides.


Blistering eruption in a Latino migrant farmworker.
Skin rashes are among the most common problems seen by those providing health care to agricultural workers. We present a case report of a migrant farmworker patient with a painful, blistering eruption of the axilla and adjacent skin developing after an insect bite. The possibility of infection was not initially considered, and teledermatology was helpful in making the diagnosis of bullous impetigo. This was important because initial culture confirmation was not obtained and antibiotic treatment had not been initiated. After the consultation, the impetigo was treated by empiric antibiotic coverage. The environmental conditions of migrant farmworkers raise special issues for infectious skin diseases like bullous impetigo. Crowded living conditions, lack of proper sanitary facilities, and poor accessibility to health care increase the risk of occurrence and spread of this disease. With the recent emergence of multi-drug-resistant organisms such as methicillin-resistant Staphylococcus aureus in community settings, this case report should serve to reinforce the need to recognize the possibility of infection and to obtain culture specimens at the initial visit to better treat and control this infectious skin condition.


Overview of thyroid physiology: an essential for understanding familial euthyroid multinodular goiter.
Nontoxic goiter is a diffuse or nodular enlargement of the thyroid gland that does not result from an inflammatory or neoplastic process and is not associated with abnormal thyroid function. Familial forms of goiter in areas not known to feature iodine deficiency are much less common. However, not all individuals in the same iodine deficiency region develop goiter and iodine supplementation does not prevent goiter development in all treated individuals. The etiology of euthyroid goiter is still incompletely understood. It is assumed that the development of goiter depends on various interactions between genetic and environmental factors. We present an overview on the thyroid physiology, which is important for a better understanding of Familial Euthyroid Multinodular Goiter.


Electronic and geometric structure of the 3d-transition metal monocarbonyls MCO, M=Sc, Ti, V, and Cr.
The electronic and geometric structure of the 3d-transition metal monocarbonyls MCO, M=Sc, Ti, V, and Cr was investigated through coupled cluster (CC) and multireference variational methods (MRCI) combined with large basis sets. For the ground and a few low-lying excited states complete potential energy profiles were constructed at the CC-level of theory. The M-CO dissociation energies of the ground states X 4Sigma-,X 5Delta,X 6Sigma+, and X 7A' are calculated to be 36, 27, 18, and 2 kcal/mol for ScCO, TiCO, VCO, and CrCO, with respect to Sc(4F),Ti(5F),V(6D),Cr(7S)+CO(X 1Sigma+). The bonding is rather complicated and could be attributed mainly to pi-conjugation effects between the M and CO pi-electrons, along with weak sigma-charge transfer from CO to M atoms. Almost in all cases the metal atoms appear to be slightly positively charged, at least according to the direction of the dipole moment vectors and the MRCI population densities.


Targeting NUPR1 for Cancer Treatment: A Risky Endeavor.
NUPR1 is a transcription factor that has attracted great attention because of its various roles in cancer. Several studies were carried out to determine its molecular targets and mechanism of action to develop novel therapies against cancer. Here, we shed light on the role of NUPR1 in different types of cancer. NUPR1 regulates a complex network of pathways that may be affected by its silencing, which can cause varying effects. Its role in some types of cancer has been reported but remains incompletely understood, whereas its roles in other types of cancers have not been reported yet. Therefore, targeting NUPR1 for cancer treatment remains challenging and risky.


Relationship between reversibility score on corresponding left ventricular segments and fractional flow reserve in coronary artery disease.
The objective of this study was to find the correlation between the severity of perfusion abnormality detected by scintigraphy and the FFR value, as well as the localization of a particular coronary lesion. On the basis of FFR values and the corresponding left ventricular segments, we proposed a combined index to aim for better correlation with myocardial ischemia than the FFR parameter alone. Twenty-eight patients (male: 22, female: 6, age 62±7.62) having FFR measurements and myocardial perfusion SPECT studies were enrolled in our retrospective analysis. FFR measurements on 36 vessels (20 LAD, 6 LCx, 10 RCA) with intermediate stenosis (40%-60%) were compared to the Tc-99m SestaMIBI myocardial perfusion SPECT studies. SPECT studies were performed before the invasive procedure in all cases. We introduced a new ischemic index, the left ventricular ischemic index (LVIi), by combining FFR values with the number of corresponding myocardial segments (N) [LVIi=N x (1-FFR)]. This index correlated with the regional myocardial perfusion defects identified on the scintigrams. A perfusion reversibility score of 2 or above was considered indicative of active ischemia (regional difference score: rDSc). For the statistical analysis, we used linear regression analysis and receiver operating characteristic (ROC) curve analysis to compare the different parameters. A close linear relationship was found between the LVIi and rDSc values (p<0.001) with linear regression analysis. When analyzing all FFR values independently of the localization of the lesions, they also correlated significantly to the rDSc, but this relation was not as close. LVIi predicted active ischemia (≥2 rDSc) on myocardial scintigraphy with 78% sensitivity and 94% specificity when the cutoff value was set to 0.96. FFR alone predicted ischemia on scintigraphy with 72% sensitivity and 94% specificity at the best 0.8 cut-off value. The area under the ROC curve was significantly higher for LVIi than FFR (0.94 vs. 0.87; p<0.05). The scintigraphic data indicate that an LVIi >0.96 implies a clinically relevant stenotic lesion. In our opinion, FFR values, weighted with the corresponding left ventricular segments, should be taken into consideration for the best clinical decision-making.


The effect of indomethacin and aspirin on alkaline phosphatase secretion and [3H]thymidine incorporation by human osteoblasts.
Since it has been suggested that long-term treatment with indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) may result in destructive changes in the hip joint, we have examined the effect of indomethacin and aspirin on the secretory and mitotic activity of human osteoblasts in culture. Both indomethacin and aspirin inhibited the secretion of alkaline phosphatase and the uptake of [3H]thymidine by osteoblasts in a dose-dependent fashion at therapeutic concentrations. Both drugs also inhibited insulin- and 1,25-dihydroxycholecalciferol-stimulated alkaline phosphatase production and [3H]thymidine uptake by human osteoblasts. It is concluded that indomethacin and aspirin, and possibly other NSAIDs, may have an inhibitory effect on osteoblast function.


Testing causal mechanisms of nonsyndromic craniosynostosis using path analysis of cranial contents in rabbits with uncorrected craniosynostosis.
Various causal mechanisms of familial nonsyndromic craniosynostosis have been presented. One hypothesis suggests that overproduction of bone at the suture is the primary origin of craniosynostosis, which affects brain and cranial growth secondarily through altered intracranial pressure (Primary Suture Fusion Model). Other hypotheses suggest that decreased cranial base growth or abnormal brain growth are the primary cause of craniosynostosis (Cranial Base, Brain Parenchyma Models, respectively). This study was designed to investigate which model best describes neurocranial changes associated with craniosynostosis in a rabbit model through multivariate path analysis. Serial magnetic resonance imaging scans and intracranial pressure measurements were obtained at 10, 25, and 42 days of age from 18 rabbits: six controls, six with delayed-onset synostosis, and six with early-onset synostosis. Five variables were collected from each rabbit: calvarial thickness at the affected suture, cranial base length, brain volume, cerebrospinal fluid volume, and intracranial pressure. This data set was used to test causal pathway relationships generated by the proposed models. Goodness of fit was measured by experimental group for each model. Primary Suture Fusion Model best explained the variables in both delayed-onset and early-onset synostotic rabbits (Goodness of fit = 93%, 97%, respectively). Cranial Base Model (Goodness of fit = 94%) best explained the data in control rabbits. Results suggest that the primary site of craniosynostosis in craniosynostotic rabbits is most likely the synostosed suture. Other cranial vault anomalies are most likely secondary compensatory changes. Results of the present study may provide insight regarding the causal pathway of craniosynostosis.


Lidocaine removal during resin hemoperfusion for phenobarbital intoxication.
A deeply comatose patient with severe phenobarbital intoxication was hemoperfused with an Amerlite XAD-4 column. She was receiving lidocaine for ventricular ectopy. The rate of lidocaine infusion had to be increased to control ventricular arrhythmias during hemoperfusion. Plasma clearance for lidocaine by the column was 122 ml/min at initiation and 75 ml/min at 2 h. These findings suggest that an increment in lidocaine infusion may be needed during resin hemoperfusion in patients receiving this drug because of its removal by the column.


Candidate of metastasis 1 regulates in vitro growth and invasion of bladder cancer cells.
COM1 (candidate of metastasis 1) has been recently shown to influence the metastatic ability of cancer cells and disease progression of certain solid tumours. The role of COM1 in bladder cancer remains unknown. In the present study, we examined the expression of the COM1 protein in human bladder tissues, and also its effect on growth, adhesion, migration and invasion of human bladder cancer cells, in vitro. The expression of COM1 in human bladder tissues and bladder cancer cell lines was assessed at both the mRNA and protein levels using RT-PCR and immunohistochemistry, respectively. COM1 staining was compared with tumour staging. Mammalian COM1 expression construct and anti-COM1 ribozyme transgenes were used to generate sublines of human bladder cancer cells with differential expression of COM1. The effect of COM1 on cellular functions was examined in bladder cancer cells with which COM1 was overexpressed or knocked down using a variety of in vitro assays. In normal bladder tissues, stronger staining of COM1 was seen in the cytoplasm of normal urothelial cells. In contrast, the staining was notably weak or absent in cancer cells of tumour tissues and invasive tumours had significantly low levels of staining compared with non-invasive tumours (p=0.012). Knockdown of COM1 in bladder cancer cell lines resulted in an increase in cellular growth and invasion, while overexpression of COM1 suppressed invasiveness and growth of these cells. Further investigation revealed an increased apoptosis and upregulated p21 in bladder cancer cells when COM1 was overexpressed. COM1 is expressed at low levels in human bladder cancer and in particular in invasive bladder tumours. COM1 levels are inversely correlated with the invasiveness and growth of bladder cancer cells in vitro. Induced apoptosis and upregulation of p21 are indicated in the mechanism of COM1 inhibiting bladder cancer cell growth. It suggests that COM1 is a potential tumour suppressor in human bladder cancer.


Population and evolutionary dynamics of Helitron transposable elements in Arabidopsis thaliana.
Helitrons, a recently discovered superfamily of DNA transposons that capture host gene fragments, constitute up to 2% of the Arabidopsis thaliana genome. In this study, we identified 565 insertions of a family of nonautonomous Helitrons, known as Basho elements. We aligned subsets of these elements, estimated their phylogenetic relationships, and used branch lengths to yield insight into the age of each Basho insertion. The age distribution suggests that 87% of Bashos inserted within 5 Myr, subsequent to the divergence between A. thaliana and its sister species Arabidopsis lyrata. We screened 278 of these insertions for their presence or absence in a sample of 47 A. thaliana accessions. With both phylogenetic and population frequency data, we investigated the effects of gene density, recombination rate, and element length on Basho persistence. Our analyses suggested that longer Basho copies are less likely to persist in the genome, consistent with selection against the deleterious effects of ectopic recombination between Basho elements. Furthermore, we determined that 39% of Basho elements contain fragments of expressed protein-coding genes, but all of these fragments were explained by only 5 gene-capture events. Overall, the picture of A. thaliana Helitron evolution is one of rapid expansion, relatively few gene-capture events, and weak selection correlated with element length.


COVID-19 safety guidelines for school eye health screening programs.
COVID-19 pandemic has significantly impacted every sphere of life. Health care workers, including eye care professionals, are at a higher risk of contracting infection directly or indirectly. To mitigate the risk of cross-infection among these front-line workers, it is vital to follow appropriate safety protocols. On the other hand, childhood eye conditions lead to permanent vision loss unless these are identified and treated early. School eye health programs are the best option to reach a large childhood population for early detection and treatment of vision-threatening eye conditions. While several clinical safety guidelines have been developed for ophthalmic practice, no such guidelines are available for carrying out school eye health programs. This article aims to set out COVID-19 safety guidelines for conducting school eye health programs in India.


The Use of MDHAQ/RAPID3 in Different Rheumatic Diseases A Review of the Literature.
Composite indices are frequently used for most rheumatic diseases because of the absence of a single "gold standard" measure applicable to all individual patients with a specific diagnosis. Some of the most commonly used composite indices in rheumatology are too complex and time-consuming for usual clinical care. Nowadays, there is an increasing focus on patient-centered care, and the use of patient-reported outcome measures (PROMs) might offer a patient-friendly, time and cost efficient strategy to monitor chronic diseases. Although initially developed for rheumatoid arthritis (RA), a multidimensional health assessment questionnaire (MDHAQ), which only includes PROMs, has been found informative in many rheumatic diseases. Assessment of a patient with any rheumatic disease requires information beyond what is found on a patient questionnaire, including a careful history and physical examination, as well as relevant laboratory tests and imaging studies, to formulate an optimal treatment plan for each individual patient. Nonetheless, documentation of patient clinical status and change in status may be best accomplished through patient questionnaires. This review summarizes all the evidence relevant to the use of MDHAQ in other rheumatic diseases apart from RA.


Antimicrobial Activity of Mast Cells: Role and Relevance of Extracellular DNA Traps.
Mast cells (MCs) have been shown to release their nuclear DNA and subsequently form mast cell extracellular traps (MCETs) comparable to neutrophil extracellular traps, which are able to entrap and kill various microbes. The formation of extracellular traps is associated with the disruption of the nuclear membrane, which leads to mixing of nuclear compounds with granule components and causes the death of the cell, a process called ETosis. The question arises why do MCs release MCETs although they are very well known as multifunctional long-living sentinel cells? MCs are known to play a role during allergic reactions and certain parasitic infections. Nonetheless, they are also critical components of the early host innate immune response to bacterial and fungal pathogens: MCs contribute to the initiation of the early immune response by recruiting effector cells including neutrophils and macrophages by locally releasing inflammatory mediators, such as TNF-α. Moreover, various studies demonstrate that MCs are able to eliminate microbes through intracellular as well as extracellular antimicrobial mechanisms, including MCET formation similar to that of professional phagocytes. Recent literature leads to the suggestion that MCET formation is not the result of a passive release of DNA and granule proteins during cellular disintegration, but rather an active and controlled process in response to specific stimulation, which contributes to the innate host defense. This review will discuss the different known aspects of the antimicrobial activities of MCs with a special focus on MCETs, and their role and relevance during infection and inflammation.


[Quality of care at a regional emergency medical system].
The Emergency Medical System (EMS) in the district of Florence is based upon the activity of 13 Emergency Mobile Unit (EMU). The activity of such a huge system is difficult to evaluate: we have concentrated our attention upon the diagnostic process assuming that "correct diagnosis = correct treatment = benefit for the patient". Then we compared diagnoses set on EMU to diagnoses made in hospitals, giving to each comparison a score from 1 to 5. In terms of quality the services of the EMS in Florence seem to be effective, since in 72% of cases the Hospital Emergency Department has confirmed the diagnoses achieved under emergency conditions, and in 12% only there has been remarkable difference. Comparing the diagnoses made on EMU to that at the hospital discharge, in two thirds of cases there is excellent correlation.


Short Segment Spinal Instrumentation in Early-onset Scoliosis Patients Treated With Magnetically Controlled Growing Rods: Surgical Technique and Mid - Short-term Outcomes.
A prospective, a single-institution, nonrandomized study. The aim of this study was to evaluate the safety and effectivity of short-segment instrumentation in early-onset scoliosis (EOS) patients treated by magnetic-controlled growing rods (MCGRs). Despite the common use of conventional growing rods and the recent popularity of MCGR in the treatment of progressive EOS, distal instrumented vertebra and number of the spanned levels are not standardized. Patients with progressive EOS, characterized by the major thoracic curve and nonstructural compensatory curve, were a candidate to be treated by dual MCGR short segment spinal instrumentation spanning the major thoracic curve; such patients are followed up for a minimum period of 30 months. Radiological data were collected and analyzed in terms of Cobb angle of both primary and secondary curve, kyphosis angle, T1-T12, and T1-S1 distances, and T1-T12/T1-S1 ratio in preoperative, postoperative, and last follow-up. Sixteen patients with different diagnoses of EOS, mean age at the operation was 7 years and 10 months (5 years and 6 months-9 years and 10 months), and mean period of follow-up was 37 (30-54) months. The Cobb angle of both major and compensatory curve are corrected by the mean value of 62° (44-85), 35° (22-45) preoperatively to 29° (12-49), 14° (9-24) postoperatively, and maintained at 28° (10-47), 10° (2-20) in the last follow-up, respectively. The T1-T12/T1-S1 ratio was 0.58 preoperatively, 0.6 postoperatively, and 0.62 at the last follow-up. The average yearly T1-T12 and T1-S1 length increase were calculated as 7 and 9 mm/year, respectively. Selective fusion principals are applicable to EOS, in that short segment instrumentation with MGCR in thoracic curve EOS patients is an effective technique in correction of both structural and compensatory curve, and in maintaining the correction during subsequent nonsurgical spinal distraction. 4.


Value of computed tomography in planning medical and surgical treatment of chronic osteomyelitis.
The contributions of computed tomographic (CT) images to the planning of medical and surgical treatment of osteomyelitis were assessed in seven patients. The scans helped medical therapy in two cases by guiding nonsurgical percutaneous biopsy of infected tissue, permitting prompt institution of proper antibiotics. The scans indicated the need for surgery and provided vital information on disease extent that helped plan the appropriate operation in five patients. Sequestra, medullary involvement, and the extent of sinus tracts that could not be seen on conventional imaging tests were detectable on CT. It is concluded that CT plays an important role in proper choices of both medical and surgical treatment in patients with osteomyelitis.


Bleeding patients on extracorporeal membrane oxygenation have reduced platelet aggregation and plasma fibrinogen: a longitudinal observational study.
This study investigated changes in coagulation and associations with occurrence of bleeding and thrombosis during extracorporeal membrane oxygenation (ECMO) therapy. The study included 100 adult ECMO-patients. Standard coagulation parameters, platelet aggregation and thromboelastometry (ROTEM®) were compared with healthy controls. Data on bleeding and thrombosis were collected until recovery or death. Mortality data were collected 30 days after weaning from ECMO. During ECMO therapy, 53 patients experienced at least one moderate or major bleed. Among these, 42 (79%) patients experienced the first bleeding on day 1 or 2. Platelet aggregation and ROTEM® revealed a hypocoagulable state in ECMO patients when compared with healthy controls. Patients bleeding on day 1 or 2, had lower platelet count (p = 0.04), poorer platelet aggregation and lower levels of fibrinogen (p < 0.01) than patients not bleeding on day 1 or 2. Further, ROTEM® clot propagation was reduced in bleeding patients (p < 0.001). Mortality was higher among bleeding patients than patients not bleeding on day 1 or 2 (67% versus 34%, p < 0.01). Congruity existed between ROTEM® measurements and standard coagulation assays, but plasma fibrinogen had a stronger association with bleeding than ROTEM® measurements. The present study does not support ROTEM® analysis as a routine part of coagulation monitoring during ECMO therapy.


Recurrence and 5-FU sensitivity of stage III/Dukes' C colorectal cancer with occult neoplastic cells in lymph node sinuses.
In 72 patients without occult neoplastic cells (ONCs) in their lymph node sinuses, the 5-year relapse-free survival (RFS) rate and overall survival (OS) rate were 71.3% and 69.2%, respectively. In 33 patients with ONCs, the 5-year RFS rate and OS rate were 33.9% and 31.3%, respectively. There was a marked difference of survival between the two groups (p=0.0001 and p=0.0003). The metastatic lymph nodes of the 33 ONC-positive patients had high and low levels of thymidilate synthase (TS) expression in 38.1% (8/21) and 61.9% (13/21) of the recurrence group (n=21), respectively, while high and low levels of dihydropyrimidine dehydrogenase (DPD) expression were found in 38.1% (8/21) and 61.9% (13/21), respectively. In the non-recurrence group (n=12), high and low levels of TS or DPD expression were detected in 58.3% (7/12) and 41.7% (5/12) versus 16.7% (2/12) and 83.3% (10/12), respectively. Patients with high TS and low DPD expression accounted for 9.5% (2/21) of the recurrence group and 50.0% (6/12) of the non-recurrence group (p<0.01). These results suggest that ONCs are clearly associated with the 5-year RFS and OS rates. Unlike the non-recurrence group, the recurrence group of ONC-positive patients with Dukes' C colorectal cancer is unlikely to respond well to treatment with 5-FU plus LV and require combination chemotherapy based on CPT-11 and/or L-OHP.


Exciton energy transfer-based quantum dot fluorescence sensing array: "chemical noses" for discrimination of different nucleobases.
A novel exciton energy transfer-based fluorescence sensing array for the discrimination of different nucleobases was developed through target nucleobase-triggered self-assembly of quantum dots (QDs). Four QD nanoprobes with different ligand receptors, including mercaptoethylamine, N-acetyl-l-cysteine, 2-dimethyl-aminethanethiol, and thioglycolic acid, were created to detect and identify nucleobase targets. These QDs served as both selective recognition scaffolds and signal transduction elements for a biomolecule target. The extent of particle assembly, induced by the analyte-triggered self-assembly of QDs, led to an exciton energy transfer effect between interparticles that gave a readily detectable fluorescence quenching and distinct fluorescence response patterns. These patterns are characteristic for each nucleobase and can be quantitatively differentiated by linear discriminate analysis. Furthermore, a fingerprint-based barcode was established to conveniently discriminate the nucleobases. This pattern sensing was successfully used to identify nucleobase samples at unknown concentrations and five rare bases. In this "chemical noses" strategy, the robust characteristics of QD nanoprobes, coupled with the diversity of surface functionality that can be readily obtained using nanoparticles, provides a simple and label-free biosensing approach that shows great promise for biomedical applications.


Frontiers of change: the reasons behind land-use change in the Mekong Basin.
Land-use change processes are commonly understood as simplified cause-effect relationships, which, in turn, support many environment-development policies. This paper uses wide-ranging evidence from a number of global case studies to challenge some of the prevailing "myths" around land-use change in the Mekong Basin and supports the conclusion that the simple explanations found in population growth, poverty, and infrastructure studies rarely provide an adequate understanding of land-use change.


Delayed and Unreported Drug-Susceptibility Testing Results in the US National Tuberculosis Surveillance System, 1993-2014.
Drug-susceptibility testing (DST) of Mycobacterium tuberculosis is necessary for identifying drug-resistant tuberculosis, administering effective treatment regimens, and preventing the spread of drug-resistant tuberculosis. DST is recommended for all culture-confirmed cases of tuberculosis. We examined trends in delayed and unreported DST results in the Centers for Disease Control and Prevention's National Tuberculosis Surveillance System. We analyzed culture-confirmed tuberculosis cases reported to the National Tuberculosis Surveillance System during 1993-2014 for annual trends in initial DST reporting for first-line antituberculosis drugs and trends in on-time, delayed, and unreported results. We defined on-time reporting as DST results received during the same calendar year in which the patient's case was reported or ≤4 months after the calendar year ended and delayed reporting as DST results received after the calendar year. We compared cases with on-time, delayed, and unreported DST results by patient and tuberculosis program characteristics. The proportion of cases with reported results for all first-line antituberculosis drugs increased during 1993-2011. Reporting of pyrazinamide results was lower than reporting of other drugs. However, during 2000-2012, of 134 787 tuberculosis cases reported to the National Tuberculosis Surveillance System, reporting was on time for 125 855 (93.4%) cases, delayed for 5332 (4.0%) cases, and unreported for 3600 (2.7%) cases. Despite increases in the proportion of cases with on-time DST results, delayed and unreported results persisted. Carefully assessing causes for delayed and unreported DST results should lead to more timely reporting of drug-resistant tuberculosis.


Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.
Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability.


A spinal microglia population involved in remitting and relapsing neuropathic pain.
Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury. Nerve-injured mice with spinal CD11c+ microglial depletion failed to recover spontaneously from this hypersensitivity. CD11c+ microglia expressed insulin-like growth factor-1 (IGF1), and interference with IGF1 signaling recapitulated the impairment in pain recovery. In pain-recovered mice, the depletion of CD11c+ microglia or the interruption of IGF1 signaling resulted in a relapse in pain hypersensitivity. Our findings reveal a mechanism for the remission and recurrence of neuropathic pain, providing potential targets for therapeutic strategies.


Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis.
Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we synthesize the literature on the association of ADT for the treatment of prostate cancer with dementia risk. We conducted a systematic review of articles reporting the outcome of dementia among individuals with prostate cancer in those exposed to ADT versus a lesser-exposed comparison group (for example, ADT versus no-ADT; continuous versus intermittent ADT) using PubMed (1966-present), Web of Science (1945-present), Embase (1966-present) and PsycINFO (1806-present). The search was undertaken on 4 December 2016 by two authors. We meta-analyzed studies reporting an effect estimate and controlling for confounding. Random- or fixed-effects meta-analytic models were used in the presence or absence of heterogeneity per the I2 statistic, respectively. Small study effects were evaluated using Egger and Begg's tests. Nine studies were included in the systematic review. Seven studies reported an adjusted effect estimate for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, which included 50 541 individuals, showed an increased risk of dementia among ADT users (hazard ratio (HR), 1.47; 95% confidence interval (CI), 1.08-2.00; P=0.02). We separately meta-analyzed studies reporting all-cause dementia (HR, 1.46; 95% CI, 1.05-2.02; P<0.001) and Alzheimer's disease (HR, 1.25; 95% CI, 0.99-1.57; P=0.06). There was no evidence of bias from small study effects (Egger, P=0.19; Begg, P=1.00). The currently available combined evidence suggests that ADT in the treatment of prostate cancer may be associated with an increased dementia risk. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively.


A pragmatic comparison of noise burst and electric shock unconditioned stimuli for fear conditioning research with many trials.
Several methods that are promising for studying the neurophysiology of fear conditioning (e.g., EEG, MEG) require a high number of trials to achieve an adequate signal-to-noise ratio. While electric shock and white noise burst are among the most commonly used unconditioned stimuli (US) in conventional fear conditioning studies with few trials, it is unknown whether these stimuli are equally well suited for paradigms with many trials. Here, N = 32 participants underwent a 260-trial differential fear conditioning and extinction paradigm with a 240-trial recall test 24 h later and neutral faces as conditioned stimuli. In a between-subjects design, either white noise bursts (n = 16) or electric shocks (n = 16) served as US, and intensities were determined using the most common procedure for each US (i.e., a fixed 95 dB noise burst and a work-up procedure for electric shocks, respectively). In addition to differing US types, groups also differed in closely linked US-associated characteristics (e.g., calibration methods, stimulus intensities, timing). Subjective ratings (arousal/valence), skin conductance, and evoked heart period changes (i.e., fear bradycardia) indicated more reliable, extinction-resistant, and stable conditioning in the white noise burst versus electric shock group. In fear conditioning experiments where many trials are presented, white noise burst should serve as US.


The structure of a thirty-six kilobase region of the human chromosome including the fibroblast interferon gene IFN-beta.
The isolation of a human genomic cosmid hybrid containing the interferon beta gene has recently been reported (Gross et al., 1981). This hybrid was mapped using single and double digests and cross-hybridisation with the sub-cloned EcoRI and BgIII fragments. Purified fragments and subclones were used as hybridisation probes against chromosomal "Southern" blots to show that at least half of the region has been cloned without alteration. This cannot at present be confirmed for the rest of the region due to the presence of highly repetitive DNA on these cloned fragments. Sequencing data on the 5'-end of the fibroblast IFN-beta gene shows a high density of direct and inverted repeats. The IFN-beta mRNA coding region contains no intron, although the possibility of other transcription starts is not ruled out. The cloned region shows no similarities to known genomic clones containing IFN-alpha genes.


Chikungunya myeloradiculopathy: a rare complication.
Chikungunya, an alpha virus belonging to the family of Togaviridae is transmitted to humans by the bite of Aedes aegypti mosquito and presents with fever, headache, rash, and severe arthralgia. Chikungunya virus is not known to be neurotropic, but cases of meningoencephalitis have been reported during outbreaks. The clinical, laboratory and neuroimaging findings of a 56-year-old man who initially developed Chikungunya fever with arthralagia and later on lead to Chikungunya myeloradiculopathy, a relatively unknown and rare complication of the infection has been presented.


Intravenous Patient-controlled Analgesia Versus Thoracic Epidural Analgesia After Open Liver Surgery: A Prospective, Randomized, Controlled, Noninferiority Trial.
We conducted a randomized, controlled, noninferiority trial to investigate if intravenous, multimodal, patient-controlled analgesia (IV-PCA) could be noninferior to multimodal thoracic epidural analgesia (TEA) in patients undergoing open liver surgery. The increasing use of minimally invasive techniques and fast track protocols have questioned the position of epidural analgesia as the optimal method of pain management after abdominal surgery. Patients operated with open liver resection between February 2012 and February 2016 were randomly assigned to receive either IV-PCA enhanced with ketorolac/diclofenac (IV-PCA, n = 66) or TEA (n = 77) within an enhanced recovery after surgery protocol. Noninferiority would be declared if the mean pain score on the numeric rating scale (NRS) for postoperative days (PODs) 0 to 5 in the IV-PCA group was no worse than the mean pain score in the TEA group by a margin of <1 point on an 11-point scale (0-10). The primary endpoint, mean NRS pain score was 1.7 in the IV-PCA group and 1.6 in the TEA group, establishing noninferiority. Pain scores were lower in the TEA group on PODs 0 and 1, but higher or equal on PODs 2 and 5. Postoperative hospital stay was significantly shorter for patients in the IV-PCA group (74 vs 104 h, P < 0.001). The total opioid consumption during the first 3 days was significantly lower in the IV-PCA group. IV-PCA was noninferior to TEA for the treatment of postoperative pain in patients undergoing open liver resection.


Evolutionary ecology of facultative paedomorphosis in newts and salamanders.
Facultative paedomorphosis is an environmentally induced polymorphism that results in the coexistence of mature, gilled, and fully aquatic paedomorphic adults and transformed, terrestrial, metamorphic adults in the same population. This polymorphism has been of interest to scientists for decades because it occurs in a large number of caudate amphibian taxa as well as in a large diversity of habitats. Numerous experimental and observational studies have been conducted to explain the proximate and ultimate factors affecting these heterochronic variants in natural populations. The production of each alternative phenotype is based on a genotypexenvironment interaction and research suggests that differences in the environment can produce paedomorphs through several ontogenetic pathways. No single advantage accounts for the maintenance of this polymorphism. Rather, the interplay of different costs and benefits explains the success of the polyphenism across variable environments. Facultative paedomorphosis allows individuals to cope with habitat variation, to take advantage of environmental heterogeneity in the presence of open niches, and to increase their fitness. This process is expected to constitute a first step towards speciation events, and is also an example of biodiversity at the intraspecific level. The facultative paedomorphosis system is thus ripe for future studies encompassing ecology, evolution, behaviour, endocrinology, physiology, and conservation biology. Few other systems have been broad enough to provide varied research opportunities on topics as diverse as phenotypic plasticity, speciation, mating behaviour, and hormonal regulation of morphology. Further research on facultative paedomorphosis will provide needed insight into these and other important questions facing biologists.


Asymmetric dimethylarginine in normotensive pregnant women with isolated fetal intrauterine growth restriction: a comparison with preeclamptic women with and without intrauterine growth restriction.
The aim of this study was to evaluate maternal asymmetric dimethylarginine (ADMA) levels in pregnancies complicated by isolated fetal intrauterine growth restriction (IUGR), in preeclamptic pregnancies with and without IUGR, and in healthy normotensive pregnant women with proper weight fetuses. The study was carried out on 54 normotensive pregnant patients with pregnancy complicated by IUGR, 35 patients with IUGR in the course of preeclampsia, 29 preeclamptic patients with appropriate-for-gestational-age weight infants and 54 healthy normotensive pregnant patients. The ADMA concentrations were evaluated using an ELISA assay. The preeclamptic women and normotensive patients with pregnancy complicated by isolated IUGR revealed higher levels of maternal serum ADMA. The mean values of maternal serum ADMA were 0.5730 ± 0.1769 μmol/l in the P group, 0.5727 ± 0.1756 μmol/l in the PI group, 0.6129 ± 0.1517 μmol/l in the IUGR group, and 0.5017 ± 0.1116 μmol/l in the control group. The levels of ADMA were additionally higher in the patients with HELLP syndrome and in patients with pregnancy complicated by eclampsia. It seems that ADMA is an active agent not only in preeclamptic patients, but also in normotensive pregnant women with isolated fetal IUGR and could be a marker of severity of preeclampsia.


Detecting Changes in Suicide Content Manifested in Social Media Following Celebrity Suicides.
The Werther effect describes the increased rate of completed or attempted suicides following the depiction of an individual's suicide in the media, typically a celebrity. We present findings on the prevalence of this effect in an online platform: r/SuicideWatch on Reddit. We examine both the posting activity and post content after the death of ten high-profile suicides. Posting activity increases following reports of celebrity suicides, and post content exhibits considerable changes that indicate increased suicidal ideation. Specifically, we observe that post-celebrity suicide content is more likely to be inward focused, manifest decreased social concerns, and laden with greater anxiety, anger, and negative emotion. Topic model analysis further reveals content in this period to switch to a more derogatory tone that bears evidence of self-harm and suicidal tendencies. We discuss the implications of our findings in enabling better community support to psychologically vulnerable populations, and the potential of building suicide prevention interventions following high-profile suicides.