Identification of genomic regions for grain yield and yield stability and their epistatic interactions.
The task of identifying genomic regions conferring yield stability is challenging in any crop and requires large experimental data sets in conjunction with complex analytical approaches. We report findings of a first attempt to identify genomic regions with stable expression and their individual epistatic interactions for grain yield and yield stability in a large elite panel of wheat under multiple environments via a genome wide association mapping (GWAM) approach. Seven hundred and twenty lines were genotyped using genotyping-by-sequencing technology and phenotyped for grain yield and phenological traits. High gene diversity (0.250) and a moderate genetic structure (five groups) in the panel provided an excellent base for GWAM. The mixed linear model and multi-locus mixed model analyses identified key genomic regions on chromosomes 2B, 3A, 4A, 5B, 7A and 7B. Further, significant epistatic interactions were observed among loci with and without main effects that contributed to additional variation of up to 10%. Simple stepwise regression provided the most significant main effect and epistatic markers resulting in up to 20% variation for yield stability and up to 17% gain in yield with the best allelic combination.


Identification of Hepatic Dendritic Cells in Liver Biopsies Showing Steatosis in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Associated with Obesity.
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the term used for hepatic steatosis in patients who are overweight or obese, have type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation. The prevalence of MAFLD among morbidly obese subjects is 65-93%. Hepatic dendritic cells (hDCs) are antigen-presenting cells that induce T cell-mediated immunity. MAFLD pathogenesis involves numerous immune cell-mediated inflammatory processes, while the particular role of hDCs is yet to be well defined. This study aimed to identify hDCs in liver biopsies from 128 patients with MAFLD associated with obesity. MATERIAL AND METHODS In this cross-sectional study, 128 liver biopsies from 128 patients with MAFLD (diagnosed as presence of hepatic steatosis, plus T2DM, metabolic dysregulation or overweight/obesity) were collected and assessed for CD11c⁺ immunoreactivity degree (CD11c as dendritic cell biomarker), through antigen retrieval, reaction with CD11c antibodies (primary), and marking with diaminobenzidine chromogen. RESULTS Among the 128 patients with MAFLD, 64 (50%) had MAFLD and fibrosis and 72 (56.2%) positively expressed hDCs (CD11c⁺). Among morbidly obese patients, 49 (64.5%) positively expressed hDCs (CD11c⁺) in liver tissue; from patients with obesity grade I- grade II (GI-II), 18 (54.5%) positively expressed hDCs (CD11c⁺) in liver tissue; and from non-obese patients with MAFLD, 5 (26.3%) positively expressed hDCs (CD11c⁺) in liver tissue. CONCLUSIONS hDC expression increases significantly in morbidly obese patients with MAFLD compared with non-obese patients, independent of the degree of fibrosis, suggesting the role of adaptive changes within hDCs in the perpetuation of inflammatory insults in chronic liver diseases.


Continuous hypoxia attenuates paraquat-induced cytotoxicity in the human A549 lung carcinoma cell line.
Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride; PQ), an effective and widely used herbicide, was commercially introduced in 1962. It is reduced by the electron donor NADPH, and then reduced PQ transfers the electrons to molecular oxygen, resulting in the production of reactive oxygen species (ROS), which are related to cellular toxicity. However, the influence of continuous hypoxia on PQ-induced ROS production has not fully been investigated. We evaluated in vitro the protective effect of continuous hypoxia on PQ-induced cytotoxicity in the human carcinogenic alveolar basal epithelial cell line (A549 cells) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and live and dead assay, and by measuring lactate dehydrogenase (LDH) release. To elucidate the mechanism underlying this effect, we monitored the immunofluorescence of intracellular ROS and measured malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Continuous hypoxia protected the A549 cells from PQ-induced cytotoxicity. Continuous hypoxia for a period of 24 h significantly reduced intracellular ROS, decreased MDA concentration in the supernatant, and normalized SOD and GPx activities. Continuous hypoxia attenuated PQ-induced cell toxicity in A549 cells. This protective effect might be attributable to the suppression of PQ-induced ROS generation.


Water-Air Interface to Mimic In Vitro Tumoral Cell Migration in Complex Micro-Environments.
The long-known role of cell migration in physiological and pathological contexts still requires extensive research to be fully understood, mainly because of the intricate interaction between moving cells and their surroundings. While conventional assays fail to capture this complexity, recently developed 3D platforms better reproduce the cellular micro-environment, although often requiring expensive and time-consuming imaging approaches. To overcome these limitations, we developed a novel approach based on 2D micro-patterned substrates, compatible with conventional microscopy analysis and engineered to create micro-gaps with a length of 150 µm and a lateral size increasing from 2 to 8 µm, where a curved water-air interface is created on which cells can adhere, grow, and migrate. The resulting hydrophilic/hydrophobic interfaces, variable surface curvatures, spatial confinements, and size values mimic the complex micro-environment typical of the extracellular matrix in which aggressive cancer cells proliferate and migrate. The new approach was tested with two breast cancer cell lines with different invasive properties. We observed that invasive cells (MDA-MB-231) can align along the pattern and modify both their morphology and their migration rate according to the size of the water meniscus, while non-invasive cells (MCF-7) are only slightly respondent to the surrounding micro-environment. Moreover, the selected pattern highlighted a significative matrix deposition process connected to cell migration. Although requiring further optimizations, this approach represents a promising tool to investigate cell migration in complex environments.


The properties of Msh2-Msh6 ATP binding mutants suggest a signal amplification mechanism in DNA mismatch repair.
DNA mismatch repair (MMR) corrects mispaired DNA bases and small insertion/deletion loops generated by DNA replication errors. After binding a mispair, the eukaryotic mispair recognition complex Msh2-Msh6 binds ATP in both of its nucleotide-binding sites, which induces a conformational change resulting in the formation of an Msh2-Msh6 sliding clamp that releases from the mispair and slides freely along the DNA. However, the roles that Msh2-Msh6 sliding clamps play in MMR remain poorly understood. Here, using Saccharomyces cerevisiae, we created Msh2 and Msh6 Walker A nucleotide-binding site mutants that have defects in ATP binding in one or both nucleotide-binding sites of the Msh2-Msh6 heterodimer. We found that these mutations cause a complete MMR defect in vivo The mutant Msh2-Msh6 complexes exhibited normal mispair recognition and were proficient at recruiting the MMR endonuclease Mlh1-Pms1 to mispaired DNA. At physiological (2.5 mm) ATP concentration, the mutant complexes displayed modest partial defects in supporting MMR in reconstituted Mlh1-Pms1-independent and Mlh1-Pms1-dependent MMR reactions in vitro and in activation of the Mlh1-Pms1 endonuclease and showed a more severe defect at low (0.1 mm) ATP concentration. In contrast, five of the mutants were completely defective and one was mostly defective for sliding clamp formation at high and low ATP concentrations. These findings suggest that mispair-dependent sliding clamp formation triggers binding of additional Msh2-Msh6 complexes and that further recruitment of additional downstream MMR proteins is required for signal amplification of mispair binding during MMR.


[Patient engagement in health care. New perspectives in oncology].
During the last decade, an increasing number of studies has been focused on patient engagement programs through which patients can be effective and informed managers of their health and health care. Based on our recent review, studies examining the nature of patient participation in service planning have found that most activities are limited to various forms of consultation, rather than the interactive partnerships advocated for treatment decision-making. Despite this clear evidence, many people want to play an active role in their own healthcare. They want to know how to protect and improve their health when they are well; and when they are ill, they want information about treatment options and likely outcomes. Consistent with these considerations, this paper intends to underline the importance to engage patients, to describe some different interventions to make patient effective informed; and, finally, to show some pilot projects from around the world, with a special focus on cancer care service of Ontario.


Metagenomic Next-Generation Sequencing to Investigate Infectious Endophthalmitis of Brucella: A Case Report.
Brucellosis is a systemic disease that exists prevalently in clinical manifestations. The symptoms present in organs such as the eyes (in ocular brucellosis) can lead to misdiagnosis or even failure to diagnose. Metagenomic Next-Generation Sequencing (mNGS), a high-throughput sequencing approach, could be applied for the detection of microorganisms. A 57-year-old female with acute right-eye vision loss, treated with clindamycin and dexamethasone sodium phosphate for 1.5 months, was difficult to diagnose using regular methods. mNGS was utilized for the aqueous fluid from the patient, and Brucella melitensis was identified. The inflammation was treated with 3 months of antibiotherapy. However, even with specific medicine and surgery, the vision remained poor because severe ocular conditions last for a long time. It suggests that brucella should still be a probable pathogen in endophthalmitis despite its low incidence in non-epidemic areas. Moreover, mNGS can achieve early diagnosis and timely treatment for difficult-to-diagnose ocular infections.


Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats' hearts.
Ischaemic heart disease is the main cause of mortality in the world. After myocardial infarction (MI) cardiomyocytes apoptosis and ventricular remodelling have occurred. Apelin is a peptide that has been shown to exert cardioprotective effects. The aim of this study was to investigate the anti-apoptotic and anti-remodelling effects of [Pyr¹]apelin-13 in the rat model of post-MI. Thirty-six male Wistar rats were randomly divided into three groups: (1) sham, (2) MI, and (3) MI treated with [Pyr¹] apelin-13 (MI+Apel). MI animals were subjected to 30-min ligation of the left anterior descending coronary artery (LAD) and 14 days of reperfusion. Twenty-four hours after LAD ligation, [Pyr¹]apelin-13 (10 nmol/kg/day, i.p.) was administered for five consecutive days. Hypertrophic parameters, left ventricular (LV) remodelling, and gene expression of Apel, apelin receptor (Apelr), Bax, caspase-3 (Casp-3), and Bcl-2 by real-time polymerase chain reaction and cardiomyocytes apoptosis by TUNEL immunostaining were assessed on day 14 post-MI. Post-infarct treatment with [Pyr¹]apelin-13 improved myocardial hypertrophic and LV remodelling parameters and led to a significant increase in the expression of Apel, Apelr, and Bcl-2, and a decrease in the expression of Bax and Casp-3. Furthermore, treatment with [Pyr¹]apelin-13 decreased cardiomyocyte apoptosis. [Pyr¹]apelin-13 has anti-hypertrophic, anti-remodelling, and anti-apoptotic effects via overexpression of Apel, Apelr, and Bcl-2 and reduces gene expression of Bax and Casp-3 in the infarcted myocardium, which can in turn lead to repair myocardium.


On the structure of Ce-containing silicophosphate glasses: a core-shell molecular dynamics investigation.
Classical molecular dynamics simulations have been used to investigate the local and medium range structure of Ce-containing silicophosphate glasses widely used in optical and photonic devices because of their enhanced UV absorption and radiation damage resistance properties. New Ce(3+)-O and Ce(4+)-O parameters for a force-field based on the core-shell model were developed by fitting on the crystalline structures of Ce-containing crystal phases, and used to get insights into the structure of five silicophosphate glasses with increasing Ce2O3 and P2O5 content. An excellent agreement between experimental and computational data was found for the local environment around cerium ions and network former cations. The Ce(3+)-O bond lengths are generally longer than Ce(4+)-O, which shows higher coordination numbers. Both P and Si are four-fold coordinated; their allocation in the network is not uniform: the increasing Ce content leads to the formation of silica-rich domains and phosphate-rich domains, which entrap Ce cations increasing their solubility in the glass. We found that both the Q(n) distributions of phosphorous and Ce clustering depend on the Ce/P ratio in the glass. In particular, Ce clustering begins for Ce/P ratios between 0.17 and 0.29 in the glass series investigated.


Cobalamin-binding capacity of haptocorrin and transcobalamin: age-correlated reference intervals and values from patients.
Unsaturated cobalamin-binding capacity in plasma (P-UBBC) is determined by use of a silica gel (QUSO G32) to separate haptocorrin (P-ApoHC) and transcobalamin (P-ApoTC). The method is sensitive and precise: detection limit 13 pmol/L, interassay coefficients of variation 3% for P-UBBC (mean = 1080 pmol/L), 4% for P-ApoTC (mean = 700 pmol/L) (n = 30). Values for P-UBBC, P-ApoHC, P-ApoTC, and P-TBBC (P-UBBC plus P-cobalamin) determined in a population study of 228 individuals, ages 21-87 years, did not differ by sex. These values increased with age, whereas the cobalamin saturation (P-cobalamin as percentage of P-TBBC) decreased with age. However, these changes were statistically significant but marginal and thus not clinically important. We therefore suggest using combined reference intervals (central 95 percentiles) for all age groups: 500-1200 pmol/L for P-UBBC, 90-275 pmol/L for P-ApoHC, 400-930 pmol/L for P-ApoTC, 850-1600 pmol/L for P-TBBC, and 20-50% for cobalamin saturation. Results for 277 inpatients show high P-ApoHC in myeloproliferative disorders or acute nonlymphatic leukemia, whereas P-ApoTC concentrations are high in some patients with lymphoproliferative disorders or autoimmune diseases.


Serial passage of the etiologic agent of epizootic bovine abortion in immunodeficient mice.
Molecular studies have provided convincing evidence that a unique deltaproteobacterium is the causative agent of epizootic bovine abortion (EBA). Bovine fetuses, infected following dam exposure, are the only identified susceptible mammalian host. The inability to cultivate the bacterial agent of EBA (aoEBA) in vitro, associated with the substantial cost of bovine experimentation, drove efforts to identify an alternative laboratory animal host. Mice with severe combined immunodeficiency (SCID) were chosen as a potential host after immunocompetent mice proved resistant to infection. SCID mice inoculated with aoEBA-infected bovine fetal thymus homogenates began to show clinical signs at 2 months and became increasingly cachectic over the next 1-2 months. Following a 2nd passage (P2) through SCID mice, three susceptible pregnant heifers were inoculated with P2 murine tissue homogenates. All three fetuses presented with lesions indistinguishable from naturally occurring EBA, confirming successful passage of the bacterial pathogen in SCID mice. All murine (P1 and P2) and bovine fetal tissues contained aoEBA as determined by PCR; 16S bacterial ribosomal nucleotide sequences were identical in all murine and fetal bovine tissues examined. Bacteria in fetal bovine tissues were determined to be heavily opsonized, based upon microscopic evaluation of tissues stained with either FITC-conjugated anti-bovine IgG or biotin-conjugated anti-bovine IgG in conjunction with avidin-FITC. Unlike the near-term bovine fetus, the absence of an antibody response in infected SCID mice permits harvest of unopsonized bacteria for development of serologic assays.


Recognition of different Toxoplasma antigens by IgM and IgG antibodies in mothers and their congenitally infected newborns.
The protein-blotting technique was used to determine the antigens of Toxoplasma gondii that were recognized by IgG and IgM antibodies in sera of congenitally infected newborns and their mothers. Patterns of IgG and IgM blots with sera from newborns revealed antigen-antibody reactions (bands) that were not present in the respective blots obtained with sera from their mothers. This was true for 50% of 24 congenitally infected newborns. In contrast, such a difference was noted in only one (5%) of 21 newborns who were not congenitally infected but whose mothers had serological evidence of acute infection with T. gondii acquired during gestation. Our results suggest that the protein-blotting method or an adaptation may be valuable for study of the immune response of the mother, fetus, and newborn to various antigens of infectious organisms and for diagnosis of congenital infections in the newborn.


Use of Rapid Reduced Electric Field Switching to Enhance Compound Specificity for Proton Transfer Reaction-Mass Spectrometry.
The high sensitivity of proton transfer reaction-mass spectrometry (PTR-MS) makes it a suitable analytical tool for detecting trace compounds. Its specificity is primarily determined by the accuracy of identifying the m/ z of the product ions specific to a particular compound. However, specificity can be enhanced by changing the product ions (concentrations and types) through modifying the reduced electric field. For current PTR-MS systems, this is not possible for trace compounds that would only be present in the reaction chamber of a PTR-MS for a short time (seconds). For such circumstances, it is necessary to change the reduce electric field swiftly if specificity enhancements are to be achieved. In this paper we demonstrate such a novel approach, which permits any compound that may only be present in the drift tube for seconds to be thoroughly investigated. Specifically, we have developed hardware and software which permits the reaction region's voltages to be rapidly switched at a frequency of 0.1-5 Hz. We show how this technique can be used to provide a higher confidence in the identification of compounds than is possible by keeping to one reduced electric field value through illustrating the detection of explosives. Although demonstrated for homeland security applications, this new technique has applications in other analytical areas and disciplines where rapid changes in a compound's concentration can occur, for example, in the Earth's atmosphere, plant emissions and in breath. Importantly, this adaptation provides a method for improved selectivity without expensive instrumental changes or the need for high mass resolution instruments.


Association between spinal immobilization and survival at discharge for on-scene blunt traumatic cardiac arrest: A nationwide retrospective cohort study.
Spinal immobilization has been indicated for all blunt trauma patients suspected of having cervical spine injury. However, for traumatic cardiac arrest (TCA) patients, rapid transportation without compromising potentially reversible causes is necessary. Our objective was to investigate the temporal trend of spinal immobilization for TCA patients and to examine the association between spinal immobilization and survival. We conducted a retrospective cohort study using the Japan Trauma Data Bank 2004-2015 registry data. Our study population consisted of adult blunt TCA patients encountered at the scene of a trauma. The primary outcome was the survival proportion at hospital discharge, and the secondary outcome was the proportion achieving return of spontaneous circulation (ROSC). We examined the association between spinal immobilization and these outcomes using a logistic regression model based on imputed data sets with the multiple imputation method to account for missing data. Among 4313 patients who met the inclusion criteria, 3307 (76.7%) were immobilized. The proportion of patients that underwent spinal immobilization gradually decreased from 82.7% in 2004-2006 to 74.0% in 2013-2015. 1.0% of immobilized and 0.9% of non-immobilized patients had severe cervical spine injury. Spinal immobilization was significantly associated with lower survival at discharge (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.42 to 0.98) and ROSC by admission (OR, 0.48; 95%CI, 0.27 to 0.87). There was no significant sub-group difference of the association between spinal immobilization and survival at discharge by patients with or without cervical spine injury (p for interaction 0.73). Spinal immobilization is widely used even for blunt TCA patients, even though it is associated with a lower rate of survival at discharge and ROSC by admission. According to these results, we suggest that spinal immobilization should not be routinely recommended for all blunt TCA patients.


Current Choices and Management of Treatment in Persons with Severe Hemophilia A without Inhibitors: A Mini-Delphi Consensus.
Regular treatment to prevent bleeding and consequent joint deterioration (prophylaxis) is the standard of care for persons with severe hemophilia A, traditionally based on intravenous infusions of the deficient clotting FVIII concentrates (CFCs). In recent years, extended half-life (EHL) CFCs and the non-replacement agent emicizumab, subcutaneously administered, have reduced the treatment burden. To compare and integrate the opinions on the different therapies available, eight hemophilia specialists were involved in drafting items of interest and relative statements through the Estimate-Talk-Estimate (ETE) method ("mini-Delphi"), in this way reaching consensus. Eighteen items were identified, then harmonized to 10, and a statement was generated for each. These statements highlight the importance of personalized prophylaxis regimens. CFCs, particularly EHL products, seem more suitable for this, despite the challenging intravenous (i.v.) administration. Limited real-world experience, particularly in some clinical settings, and the lack of evidence on long-term safety and efficacy of non-replacement agents, require careful individual risk/benefit assessment and multidisciplinary data collection. The increased treatment options extend the opportunities of personalized prophylaxis, the mainstay of modern management of hemophilia. Close, long-term clinical and laboratory follow-up of patients using newer therapeutic approaches by specialized hemophilia treatment centers is needed.


[Study of dynamics and left ventricular function using radioisotopic technics in the heart cavities].
The imaging of the cardiac cavities with appropriate tracer materials (99 m Technetium or 113 m Indium), the recording of intracardiac dilution curves by radionuclide angiography and dynamic studies by gamma cinecardiography give global and regional parameters of left ventricular function which are reliable and reproducible: an index of cardiac output, intracardiac circulation times and ventricular volumes. The assessment of left ventricular contraction and global and regional ejection fractions is facilitated by coupling the gamma camera and the electrocardiogramme and computer analysis of the results. "First passage" recordings may be used to differentiate the right from the left heart chambers. "Equilibrium" studies give detailed information at rest, under stress (or leg-raising) and under pacing and/or trinitrin. Average and maximal rates of contraction derived from the ejection fraction and left ventricular contraction times are indices comparable to the rate of fibre shortening. The calculation or regional parameters point by point such as the ejection fraction, contraction time and ejection volume gives a more accurate and sensitive estimation of left ventricular function than the global left ventricular indices. They are many practical applications in cardiology especially in coronary artery disease: monitoring the changes in the acute phase of myocardial infarction, the selection of patients for aorto-coronary bypass surgery and their pre- and post-operative controls. These non-invasive, easy and reliable cardiac studies justify the development of laboratories of nuclear cardiology within departments of cardiac physiological investigation.


Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy.
Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion-channel genes being implicated, including those encoding the GABA(A) receptor. Here, we evaluated the frequency of additional mutations in the GABA(A) receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25-bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABA(A) receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals.


In vivo study on biocompatibility and bonding strength of hydroxyapatite-20vol%Ti composite with bone tissues in the rabbit.
Biocompatibility and bonding strength of hydroxyapatite-20vol%Ti composite fabricated by hot-pressing technique with bone tissues in the rabbit were investigated by in vivo studies in comparison with those of Ti metal and dense HA ceramic. Although fibrous tissues formed at the interface between the composite and bone tissues at 3 weeks in vivo, bonding strength of the composite increases faster than that of dense HA after 4 weeks. At 3 months in vivo, bonding strength of the composite is higher than that of dense HA and exceeds 6.5 MPa. Moreover, as compared with the visible bonding interfaces between dense HA and new bones, the bonding interfaces for the composite cannot already be distinguished and the composite was osseointegrated fully with bone tissues into one bony body. The shear fracture of bonding strength test for the composite occurred in new bone zones near the interface, which indicates that bonding strength of the composite could even exceed the shear strength of new bones after 3 months in vivo. In conclusion, HA-Ti composite has better osteoconduction and osseointegration abilities than Ti metal and dense HA ceramic after 3 months in vivo and is a promising biomaterial for hard tissue replacement.


Development of a therapeutic hypothermia protocol: implementation for postcardiac arrest STEMI patients.
Therapeutic hypothermia (TH) reduces neurologic injury and mortality in out-of-hospital cardiac arrest survivors. Myocardial infarction (MI) is one of the main causes of cardiac arrest and primary percutaneous coronary intervention (PCI) is recommended as initial treatment for patients who present with acute ST-segment elevated MI (STEMI). Cape Fear Valley Medical Center (CFVMC) was the only designated PCI center in the state of North Carolina without a TH protocol. The purpose of this quality improvement initiative was to develop and implement a TH protocol for postcardiac arrest STEMI patients at CFVMC. The existing STEMI process was adapted to include the use of TH for STEMI patients who presented from out-of-hospital cardiac arrest. Steps to development of the protocol included creation of TH STEMI flow map, reallocation of nursing staff, exploration of cooling methods and equipment options, development of a evidence-based physician order set, creation of nursing documentation process and competency assessment, organization of educational sessions, and approval through multiple hospital committees. The development of a postarrest STEMI TH protocol involved multiple disciplines and required approval from several committees. Lack of physician and nursing knowledge of the protocol proved to be the greatest challenge. The TH protocol is a step forward in implementing evidence-based practice and improving the quality of postresuscitation care provided to postcardiac arrest STEMI patients.


Glycosidation-anomerisation reactions of 6,1-anhydroglucopyranuronic acid and anomerisation of beta-D-glucopyranosiduronic acids promoted by SnCl(4).
The reaction of silylated nucleophiles with 6,1-anhydroglucopyranuronic acid (glucuronic acid 6,1-lactones) catalysed by tin(IV) chloride provides 1,2-trans or 1,2-cis (deoxy)glycosides in a manner dependent on the donor structure. The alpha-glycoside was obtained for reactions of the donor with the 2-acyl group and 2-deoxydonors, whereas the 2-deoxy-2-iodo donor gave the beta-glycoside. Experimental evidence shows that when 1,2-cis-glycoside formation occurs, the anomerisation of initially formed 1,2-trans-glycosides catalysed by SnCl(4) is possible. The anomerisation of beta-D-glucopyranosiduronic acids was found to be faster, in some cases, than anomerisation of related beta-D-glucopyranosiduronic acid esters and beta-D-glucopyranoside derivatives and the rates are dependent on the structure of the aglycon. Moreover, the rates of anomerisation of beta-D-glucopyranuronic acid derivatives can be qualitatively correlated with rates of hydrolysis of beta-D-glucopyranosiduronic acids. Mechanistic possibilities for the reactions are considered.


Arthroscopic treatment for femoroacetabular impingement syndrome (FAIS) in adolescents-5-year follow-up.
To report the minimum 5-year outcome after hip arthroscopy with labral repair in adolescents. From 2011 to 2014, 29 consecutive patients with a mean age 16.3 years (range 12.7-19.8 years) underwent hip arthroscopy treatment for femoroacetabular impingement syndrome. Patient-related outcome measures (PROMs) including modified Harris Hip Score (mHHS), Visual Analog Scale (VAS) for pain and Copenhagen Hip and Groin Outcome Score (HAGOS) were used preoperatively and at follow-up (FU). Percentage of patients achieving minimum clinically important difference (MCID) and substantial clinical benefit (SCB) for mHHS and HAGOS were determined. Mean FU was 6.7 years (range 5-9.6 years), and a 100% FU was accomplished. Significant improvements were seen for all PROMs at FU in patients not having a periacetabular osteotomy (PAO) with VAS pain score improving from mean 62 to 9, mHHS from 58 to 94 and HAGOS improved in all subgroups. For mHHS, SCB changes were achieved by 76% and MCID by 76% of the patients. Percentage of patients achieving MCID for HAGOS subgroups were 81% for pain, 67% for symptoms, 76% for physical function in daily living, 76% for physical function in sport and recreation, 81% for participation in physical activities and 81% for hip-related quality of life. Two patients had revision hip arthroscopy. PAO was later performed in three patients. The risk of further surgery with center edge (CE) bony edge (CEB) <30° was 42% and 0% with CEB ≥30°. Adolescents having hip arthroscopy with labral repair and resection of cam and pincer morphology achieve significant improvements at mean 6.7 years of FU. CEB < 30° increases the risk of further surgery.


Justification of Wife Beating in Adolescents: Associated Beliefs and Behaviors.
Socioeconomically disadvantaged adolescents who are exposed to social norms related to violence against women are more likely to experience or be perpetrators of intimate partner violence. This study evaluated factors hypothesized to be associated with acceptance of wife beating among 240 male and female adolescents aged 10-16 years participating in a World Vision program in Armenia. Acceptance of wife beating was associated with relational victimization, perceived social support, and parent and community boundaries and expectations, but was not associated with overt victimization or aggression. These findings highlight several areas that may be important for violence prevention research.


The Woman in Red: Examining the Effect of Ovulatory Cycle on Women's Perceptions of and Behaviors Toward Other Women.
Previous research has shown that during her monthly peak fertile window, a woman competes with other women for a suitable mate. Drawing upon research on ovulation and socially constructed meanings of the color red, we examine how a woman's fertility status and red clothing worn by a target woman change perceptions of the target, as well as behaviors toward the target. Following previous research on the ovulatory status and color red effects, we rely on both hormonal and self-reported fertility data. Across six studies, our research fails to provide support for the prediction that an ovulating woman is less likely to trust another woman wearing red compared with a nonovulating woman.


Aviation model cognitive risk factors applied to medical malpractice cases.
Aviation accidents have been reduced substantially by training pilots to avoid high-risk behaviors caused by cognitive errors. To determine whether similar cognitive cause factors or errors are involved in medical malpractice cases, and to evaluate the reliability of identifying such factors, physicians reviewed state and federal malpractice cases in a legal database. Reviewing physicians evaluated 30 cases meeting inclusion criteria from state and federal malpractice cases for the year 2004 in the 8th US Circuit Court of Appeals region, using criteria for cognitive factors derived from aviation. The cases were categorized into three classes based on the degree of agreement between the reviewers. The results as to prevalence of the factors and reliability of identifying the factors were then analyzed statistically. Fifty-nine percent of the cases met criteria for strong and good correlation with the factors. Cognitive factors involving IMSAFE (illness, medications, stress, alcohol, physiogical (f), and emotional) and medical team management/leadership can be reliably identified. Other factors, such as hazardous attitudes and loss of situational awareness, were identified with minimal reliability. The aeronautical cognitive causative approach can be translated into a medical approach to reliably identify cognitive causes of errors in a significant proportion of medical malpractice cases from a legal database.


Association between 9p21 genomic markers and heart disease: a meta-analysis.
Associations between chromosome 9p21 single-nucleotide polymorphisms (SNPs) and heart disease have been reported and replicated. If testing improves risk assessments using traditional factors, it may provide opportunities to improve public health. To perform a targeted systematic review of published literature for effect size, heterogeneity, publication bias, and strength of evidence and to consider whether testing might provide clinical utility. Electronic search via HuGE Navigator through January 2009 and review of reference lists from included articles. English-language articles that tested for 9p21 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an odds ratio (OR). Articles were excluded if reporting only intermediate outcomes (eg, atherosclerosis) or if all participants had existing disease. Twenty-five articles were initially identified and 16 were included. A follow-up search identified 6 additional articles. Independent extraction was performed by 2 reviewers and consensus was reached. Credibility of evidence was assessed using published Venice criteria. Forty-seven distinct data sets from the 22 articles were analyzed, including 35 872 cases and 95 837 controls. The summary OR for heart disease among individuals with 2 vs 1 at-risk alleles was 1.25 (95% confidence interval [CI], 1.21-1.29), with low to moderate heterogeneity. Age at disease diagnosis was a significant covariate, with ORs of 1.35 (95% CI, 1.30-1.40) for age 55 years or younger and 1.21 (95% CI, 1.16-1.25) for age 75 years or younger. For a 65-year-old man, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 13.2% vs 11%. For a 40-year-old woman, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 2.4% vs 2.0%. Nearly identical but inverse results were found when comparing 1 vs 0 at-risk alleles. Three studies showed net reclassification indexes ranging from -0.1% to 4.8%. We found a statistically significant association between 9p21 SNPs and heart disease that varied by age at disease onset, but the magnitude of the association was small.


Recurrent atrial myxoma.
We have chosen this case of sporadic atrial myxoma for our presentation because it had a particular evolution, with recurrence at 8 years after surgical excision (echocardiography was performed every year) and a particular diagnostic means - at echocardiographic follow-up, the patient being asymptomatic. This presentation, together with a review of literature included in the article, emphasizes the importance of a careful postoperative follow-up of the patients and the existence of some particular aspects of the evolution and symptomatology of recurrent atrial myxoma.


Construction of Infrared-Light-Responsive Photoinduced Carriers Driver for Enhanced Photocatalytic Hydrogen Evolution.
Infrared light, more than 50% of the solar light energy, is long-termly ignored in the photocatalysis field due to its low photon energy. Herein, infrared-light-responsive photoinduced carriers driver is first constructed taking advantage of pyroelectric effect for enhancing photocatalytic hydrogen evolution. In order to give full play to its role, the photocatalytic reaction is localized on the surface and interface of the composite based on a new semi-immersion type heat collected photocatalytic microfiber system. The system is consisted of distinctive pyroelectric substrate poly(vinylidene fluoride-co-hexafluropropylene (PVDF-HFP), typical photothermal material carbon nanotube (CNT), and representative photocatalyst CdS. The transient photocurrent, electrochemical impedance spectroscopy, time-resolved photoluminescence and pyroelectric potential characterizations indicate that the infrared-light-responsive carriers driver significantly promotes the photogenerated charge separation, accelerates carrier migration, and prolongs carrier lifetime. The photocatalytic hydrogen evolution efficiency is remarkably improved more than five times with the highest average apparent quantum yield of 16.9%. It may open up new horizons to photocatalytic technology for the more efficient use of infrared light.


Analysis of the CHK2 gene in lymphoid malignancies.
The CHK2 gene encodes a protein kinase that is important for the regulation of cell cycle arrest after DNA damage. CHK2 acts downstream of ataxia teleangiecstasia mutated (ATM), modulates the function of p53 and may help mediate cell cycle arrest at G2/M by phosphorylation of Cdc25C. Recently, the human homolog of the checkpoint kinase Cds1 (CHK2) has been suggested to be a tumor suppressor gene. Heterozygous germline mutations have been reported in Li-Fraumeni syndrome (LFS), a highly penetrant familial cancer phenotype, and in sporadic colon cancer. LFS is associated with the development of lymphoid malignancies, especially childhood ALL. Therefore, we analyzed the DNA from 143 lymphoid malignancies to determine whether they had mutations of the CHK2 gene. The 14 exons of CHK2 were studied by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and sequencing of aberrantly migrating bands. One missense mutation changing serine to phenylalanine (codon 428) in an evolutionarily highly conserved domain was found in a non-Hodgkin's aggressive lymphoma. Another point mutation in the non-coding region was identified in one of adult T-cell leukemias (ATL) samples. This result suggests that mutation of the CHK2 gene may rarely be involved in the development of selected lymphomas.


A Scanning Spherical Mirror Interferometer for the Analysis of CO(2) Laser Radiation.
A theoretical and experimental investigation was performed on a scanning spherical mirror interferometer designed for the spectral analysis of CO(2) laser radiation. It is shown that this instrument can be applied to study laser modes and also to measure with high precision the wavenumber difference of two lines spaced several reciprocal centimeters apart. As calculated and observed, the error in determining wavenumber differences for the instrument used is below about +/-0.05 cm(-1) and it is shown that a much more accurate instrument can be constructed. An attempt to use a mode-degenerate (confocal) resonator with central coupling holes was unsuccessful.


Study of the X-Ray Diagnosis of Unstable Pelvic Fracture Displacements in Three-Dimensional Space and its Application in Closed Reduction.
ABSTRACTS Objective: To study the method of X-ray diagnosis of unstable pelvic fractures displaced in three-dimensional (3D) space and its clinical application in closed reduction. Five models of hemipelvic displacement were made in an adult pelvic specimen. Anteroposterior radiographs of the pelvis were analyzed in PACS. The method of X-ray diagnosis was applied in closed reductions. From February 2012 to June 2016, 23 patients (15 men, 8 women; mean age, 43.4 years) with unstable pelvic fractures were included. All patients were treated by closed reduction and percutaneous cannulate screw fixation of the pelvic ring. According to Tile's classification, the patients were classified into type B1 in 7 cases, B2 in 3, B3 in 3, C1 in 5, C2 in 3, and C3 in 2. The operation time and intraoperative blood loss were recorded. Postoperative images were evaluated by Matta radiographic standards. Five models of displacement were made successfully. The X-ray features of the models were analyzed. For clinical patients, the average operation time was 44.8 min (range, 20-90 min) and the average intraoperative blood loss was 35.7 (range, 20-100) mL. According to the Matta standards, 7 cases were excellent, 12 cases were good, and 4 were fair. The displacements in 3D space of unstable pelvic fractures can be diagnosed rapidly by X-ray analysis to guide closed reduction, with a satisfactory clinical outcome.


Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG).
The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.


Restricting restriction.
Systems biology is a new, fashionable and well-funded discipline, which to quote from a recent review aims to 'examine the structure and dynamics of cellular and organismal function, rather than the characteristics of isolated parts of a cell or organism em leader ' (Kitano, H. (2002) Science 295:1662-1664). Systems biology will do this by profiting from the vast amounts of biological information that are available in the genomics era and make extensive use of computer modelling. But: 'many breakthroughs in experimental devices, advanced software and analytical methods are required before the achievements of system biology can live up to their much-touted potential'. This edition of Molecular Microbiology contains a paper that is the product of traditional experimental biology but which could serve as a test case for systems biology. The paper shows how bacteria integrate such disparate subsystems as DNA restriction, homologous recombination and regulated proteolysis to protect their chromosomes from degradation. When systems biology can predict this level of choreography, it will be a mature discipline.


beta-estradiol suppresses T cell-mediated delayed-type hypersensitivity through suppression of antigen-presenting cell function and Th1 induction.
Although an immunomodulatory role for estrogens has long been demonstrated by experimental and clinical observations, the mechanism by which estrogens exert their effect on T cells has not been clearly defined. In this study we analyzed the effects of beta-estradiol (E2), at its contraceptive dose, on the delayed-type hypersensitivity (DTH) to purified protein derivatives (PPD) and associated immune response in female mice. E2 treatment decreased PPD-specific DTH response, which coincided with a decrease in the leukocytes numbers in the draining lymph nodes (DLN) and spleen compared with control mice. E2 treatment also suppressed the in vitro PPD-specific proliferative response of DLN and spleen cells from PPD-primed mice. The analysis of production and gene expression of cytokines by DLN cells demonstrated that E2 treatment suppressed IL-2 and IFN-gamma production in response to PPD in vitro. In contrast, IL-4 and IL-10 gene expression by DLN cells of E2-treated mice, taken 24 h after in vivo restimulation of mice with PPD, was enhanced. Furthermore, we found that spleen APC from E2-treated mice failed to induce optimum proliferation of the PPD-primed T cells in response to PPD in vitro. The impaired APC function by E2 was not due to induction of suppressor cell activity because addition of the normal spleen APC to APC from E2-treated mice restored the proliferative response of the PPD-primed T cells in response to PPD. Our results suggest that the E2-mediated inhibition of DTH reaction is due to a combination of the down regulation of APC function and deviation of the immune response from Th1-type to Th2-type.


Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets.
Osteopontin (Opn) is important for T helper type 1 (T(H)1) immunity and autoimmunity. However, the role of this cytokine in T(H)2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse T(H)2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of T(H)2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and T(H)2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established T(H)2 responses and protected mice from allergic disease. These effects on T(H)2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.


[Cervical smears: towards an optimal screening for cervical cancer].
THE INTEREST OF CERVICO-UTERINE CYTOLOGY: Cytology is the most appropriate means of screening for cancers and pre-cancerous states of the cervix. It permits the prevention of invasive cancers by identifying the precursor lesions, which exist more than 10 years before the invasion, and their effective excision or destruction. The absence of screening represents the greatest risk factor for invasive cancer and explains its higher frequency in developing countries. The Bethesda system is a language shared by cytologists and clinicians for spotting situations at risk Histology is essential before any therapeutic decision. It is provided by biopsies during colposcopy or by diagnostic coning in ambiguous situations. The cytological diagnosis of a low grade lesion and atypia of undetermined significance sometimes corresponds, histologically, to a high grade lesion. ENHANCING THE RESULTS OF SCREENING: The invasive cervical cancers still observed in France can be attributed to the lack of screening, lack of management and cytological false negatives. Conditions for optimising screening are wide coverage of women, good quality smears, competent cytologists and the appropriate follow-up of abnormal smears.


History of sexual and physical abuse in women with dyspareunia: association with pain, psychosocial adjustment, and sexual functioning.
Dyspareunia is a women's sexual health problem that still often goes undiagnosed despite its high prevalence and its detrimental impact on sexual, relationship, and psychological adjustment. Although sexual and physical abuse may constitute risk factors for the development of dyspareunia, the effects of past abuse on current pain and associated sexual and psychosocial impairments have never been examined. Thus, the aim of this study is to determine the relation between a history of sexual and physical abuse and a series of pain, psychological, dyadic, and sexual functioning variables in a sample of women with dyspareunia. A hundred and fifty-one women took part in the study via health professional referrals and advertisements in local newspapers. Each participant underwent a standardized gynecological examination and a structured interview in order to confirm the diagnosis of dyspareunia. They also completed self-report questionnaires investigating past sexual and physical abuse, in addition to current pain, psychosocial adjustment, and sexual functioning. Dependent measures included: (i) The Brief Symptom Inventory; (ii) the Sexual History Form; and (iii) the Locke-Wallace Marital Adjustment Scale. Pain was assessed via the McGill Pain Questionnaire and a visual analogue scale. Results revealed that a history of sexual abuse involving penetration was associated with poorer psychological adjustment and sexual functioning. Additionally, findings showed that women who perceived a link between their dyspareunia and their past sexual abuse reported worse sexual functioning than those who did not. Finally, the experience of sexual abuse was not associated with pain intensity and physical abuse was not associated with any of the outcome measures. Findings suggest that the presence of a sexual abuse history in women with dyspareunia is associated with increased psychological distress and sexual impairment, although there is no relation between a history of physical abuse and these outcomes.


Exceptional dinosaur fossils reveal early origin of avian-style digestion.
Birds have a highly specialized and efficient digestive system, but when this system originated remains uncertain. Here we report six gastric pellets attributable to the recently discovered 160-million-year-old troodontid dinosaur Anchiornis, which is among the key taxa for understanding the transition to birds. The gastric pellets contain lightly acid-etched lizard bones or fish scales, and some are associated with Anchiornis skeletons or even situated within the oesophagus. Anchiornis is the earliest and most basal theropod known to have produced gastric pellets. In combination with other lines of evidence, the pellets suggest that a digestive system resembling that of modern birds was already present in basal members of the Paraves, a clade including troodontids, dromaeosaurids, and birds, and that the evolution of modern avian digestion may have been related to the appearance of aerial locomotion in this lineage.


Stakeholder engagement in research on quality of life and palliative care for brain tumors: a qualitative analysis of #BTSM and #HPM tweet chats.
Research is needed to inform palliative care models that address the full spectrum of quality of life (QoL) needs for brain tumor patients and care partners. Stakeholder engagement in research can inform research priorities; engagement via social media can complement stakeholder panels. The purpose of this paper is to describe the use of Twitter to complement in-person stakeholder engagement, and report emergent themes from qualitative analysis of tweet chats on QoL needs and palliative care opportunities for brain tumor patients. The Brain Cancer Quality of Life Collaborative engaged brain tumor (#BTSM) and palliative medicine (#HPM) stakeholder communities via Twitter using tweet chats. The #BTSM chat focused on defining and communicating about QoL among brain tumor patients. The #HPM chat discussed communication about palliative care for those facing neurological conditions. Qualitative content analysis was used to identify tweet chat themes. Analysis showed QoL for brain tumor patients and care partners includes psychosocial, physical, and cognitive concerns. Distressing concerns included behavioral changes, grief over loss of identity, changes in relationships, depression, and anxiety. Patients appreciated when providers discussed QoL early in treatment, and emphasized the need for care partner support. Communication about QoL and palliative care rely on relationships to meet evolving patient needs. In addition to providing neurological and symptom management, specialized palliative care for brain tumor patients may address unmet patient and care partner psychosocial and informational needs. Stakeholder engagement using Twitter proved useful for informing research priorities and understanding stakeholder perspectives on QoL and palliative care.


Effects of Shot Peening and Cavitation Peening on Properties of Surface Layer of Metallic Materials-A Short Review.
Shot peening is a dynamically developing surface treatment used to improve the surface properties modified by tool, impact, microblasting, or shot action. This paper reviews the basic information regarding shot peening methods. The peening processes and effects of the shot peening and cavitation peening treatments on the surface layer properties of metallic components are analysed. Moreover, the effects of peening on the operational performance of metallic materials are summarized. Shot peening is generally applied to reduce the surface roughness, increase the hardness, and densify the surface layer microstructure, which leads to work hardening effects. In addition, the residual compressive stresses introduced into the material have a beneficial effect on the performance of the surface layer. Therefore, peening can be beneficial for metallic structures prone to fatigue, corrosion, and wear. Recently, cavitation peening has been increasingly developed. This review paper suggests that most research on cavitation peening omits the treatment of additively manufactured metallic materials. Furthermore, no published studies combine shot peening and cavitation peening in one hybrid process, which could synthesize the benefits of both peening processes. Moreover, there is a need to investigate the effects of peening, especially cavitation peening and hybrid peening, on the anti-wear and corrosion performance of additively manufactured metallic materials. Therefore, the literature gap leading to the scope of future work is also included.


Microwave-assisted and continuous flow multistep synthesis of 4-(pyrazol-1-yl)carboxanilides.
A series of 4-(pyrazol-1-yl)carboxanilides active as inhibitors of canonical transient receptor potential channels were synthesized in an efficient three-step protocol using controlled microwave heating. The general synthetic strategy involves condensation of 4-nitrophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by reduction of the nitro group to the amine, which is then amidated with carboxylic acids. Compared to the conventional protocol a dramatic reduction in overall processing time from ~2 days to a few minutes was achieved, accompanied by significantly improved product yields. In addition, the first two steps in the synthetic pathway were also performed under continuous flow conditions providing similar isolated product yields. As an alternative to the three-step protocol, a novel two-step route to the desired 4-(pyrazol-1-yl)carboxanilides was devised involving condensation of 4-bromophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by Pd-catalyzed Buchwald-Hartwig amidation with carboxylic acid amides.


[Choice of a central analgesic for anesthesia with spontaneous respiration].
The ventilatory effects of tramadol (T) and nefopam (N) are evaluated in anesthetized patients with enflurane in a closed circuit breathing system and compared with the effects of pentazocine (P). The following parameters tidal volume (VT), minute ventilation (V), CO2 (capnometry) occlusion pressure (OP), ventilatory response to hypercarbia are recorded after 30 minutes of anaesthesia, before and after repeated injections of the analgesics, P: 15 mg, N: 40 mg, T: 100 mg are injected I.V., and analgesics administration is repeated at 30 minutes interval, so that the patients receive a total P dose of 30 mg, a total N dose of 60 mg and a total T dose of 200 mg. The administration of 15 mg of P induces a change in VT (-24%), ventilatory frequency (-40%), OP (-18) OP only returns to basal values after a second dose. The ventilatory response to hypercarbie is indeed satisfying (increase of 61% in V). After N and T, ventilatory frequency is not disturbed. V increases of 16% and 11% respectively after the first injection, and of 31% and 2% after the second injection. OP increases by 39% and 56% respectively after the first injection and gets better over time with nefopam (+ 58%), 30 mg of P. 20 mg of N and 100 mg of T are equivalent for analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)


Ion transport in goby intestine: cellular mechanism of urotensin II stimulation.
The Na- and Cl-absorbing goby posterior intestinal epithelium is composed predominantly of mitochondria-rich, tall columnar cells. Glass intracellular microelectrode recording technique was applied to absorptive cells of this relatively leaky epithelium to measure apical cell membrane potential difference (psi mc) and apical membrane fractional resistance. As determined by ion-substitution studies, absorptive cells are characterized by a large, Ba2+-inhibitable apical K conductance, which is a major factor determining psi mc and smaller Cl and Na conductances. Inhibition of the apical Na-Cl-coupled influx directly by furosemide or indirectly by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine produced hyperpolarization of psi mc, consistent with the greater apical membrane conductance to Cl than Na. The urophysial neurosecretory peptide urotensin II, which stimulates Na-Cl-coupled absorption, markedly depolarized psi mc in posterior intestinal tissues from 5% seawater-adapted gobies. This response is consistent with a stimulatory effect of urotensin II at the apical membrane carrier rather than at the basolateral Na-K-ATPase. Urotensin II is without effect on psi mc in tissues from seawater-adapted fish and somatostatin, a natural analogue of urotensin II, is without effect on tissues from fish adapted to either salinity. This specificity parallels that determined using radiotracer fluxes.


The Shape of Water Stream Induces Differences in P300 and Alpha Oscillation.
Touching is a fundamental human behavior used to evaluate objects in the external world. Many previous studies have used tactile stimulation to conduct psychological and psychophysiological experiments. However, most of these studies used solid material, not water stream, as an experimental stimulus. To investigate water perception, or to easily control the temperature of an experimental stimulus, it is important to be able to control the water stimulus. In this study, we investigated the usability of water as an experimental stimulus for electroencephalography (EEG) experiments and report the basic EEG response to water stimulus. We developed a tactile stimulation device using a water stream to study EEG responses, with the ability to control the stimulus onset timing. As stimuli, we selected two types of water stream, normal and soft, based on a psychological experiment to confirm a difference of subjective feeling induced by these water streams. We conducted a typical oddball task using the two different water streams and recorded EEG waveforms from 64 electrodes while participants touched the water streams. We calculated P300 at the Pz electrode, alpha asymmetry at the frontal electrodes, and alpha suppression at the parietal area. As a result, we observed typical P300 differentiation based on the stimulus proportion (target 20% and standard 80%). We observed a weaker alpha suppression when participants touched the soft water stream compared to the normal shower. These results demonstrate the usability of water stream in psychophysiological studies and suggested that alpha suppression could be a candidate to evaluate comfort of water stream.


IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection.
Mounting effective T cell responses is critical for eliciting long-lasting immunity following viral infection and vaccination. A multitude of inhibitory and stimulatory factors are induced following infection, and it is the compilation of these signals that quantitatively and qualitatively program the ensuing effector and memory T cell response. In response to lymphocytic choriomeningitis virus (LCMV) infection, the immunosuppressive cytokine IL-10 is rapidly up-regulated; however, how IL-10 is regulating what is often considered an "optimal" immune response is unclear. We demonstrate that IL-10 directly inhibits effector and memory CD4 T cell responses following an acutely resolved viral infection. Blockade of IL-10 enhanced the magnitude and the functional capacity of effector CD4 T cells that translated into increased and more effective memory responses. On the other hand, lack of IL-10 signaling did not impact memory CD8 T cell development. We propose that blockade of IL-10 may be an effective adjuvant to specifically enhance CD4 T cell immunity and protection following vaccination.


[Scedosporium apiospermum disseminated infection in a single lung transplant recipient].
Scedosporium spp. are filamentous fungi, and the 2 most important species are Scedosporium prolificans and Scedosporium apiospermum. S. apiospermum accounts for approximately 25% of non-Aspergillus filamentous fungi infections in organ transplant recipients. Scedosporium can colonize the sinuses and airways of lung recipients with underlying pulmonary diseases, such as bronchiectasis or cystic fibrosis before transplant, and develop invasive disease after lung transplantation. In fact, invasive diseases caused by S. apiospermum have been reported only rarely, in single lung transplant recipients and cystic fibrosis transplant patients. The treatment of scedosporiasis is complicated due to the difficulty in early diagnosis together with inherent resistance to amphotericin B. A case of disseminated S. apiospermum infection after single lung transplant in a patient with pulmonary fibrosis is reported. Leg mycetoma was the initial sign of this disseminated infection. In this case report, current treatment options are discussed, and a review of the literature of previously published cases of lung transplants is made. One conclusion based on this case is the risk of emergent molds related to antifungal prophylaxis. In addition, colonization by Scedosporium in transplant recipients should not be ignored, and target prophylaxis or suppressive therapy should be considered in all those cases with residual lesions in native lung or chronic rejection in transplanted lungs.


Hepatitis B virus genotypes in chronic liver disease patients from New Delhi, India.
To study the Hepatitis B virus (HBV) genotypes and their effect on the progression and outcome in patients with chronic liver diseases from New Delhi, India. Sera from 100 HBV-related chronic liver disease (CLDB) cases were tested for HBV genotype using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Type-specific primers-based PCR (TSP-PCR) targeting to the surface (S) gene encoding hepatitis B surface antigen. Only genotypes A and D were present and genotype D was dominant. Genotype D was present in all CLDB patient categories. The genotype distribution for the 100 patients with CLDB was as follows: genotype A, 16/100 (16%) (7/40- 17% chronic hepatitis B (CHB); 8/47, 17%, HBV-related cirrhosis (CRB); 1/13, 7.6%, HBV-related hepatocellular carcinoma (HCCB); genotype D- 84/100 (84%) (32/40- 80% CHB; 38/47- 81%, CRB; 11/13, 85%, HCCB); genotype A+D, 3/100 (3%) (1/40- 3% CHB; 1/47- 2%, CRB; 1/13, 7.6%, HCCB); C, 0; B, 0; E, 0; F, 0; G 0, H 0; (P<0.01, genotype D vs A). Only HBV genotypes A and D were present in patients with CLDB from New Delhi, India. Compared with genotype D, genotype A patients had no significant clinical or biochemical differences (P>0.05). Mixed infection with genotype A and D were seen in 3% of the cases. Genotype D was the dominant genotype prevalent in all patient categories.


The role of retinoblastoma protein in apoptosis.
The retinoblastoma gene and its protein product (Rb) have been studied intensively for their role in development, oncogenesis, cell growth, differentiation and cell cycle regulation. In addition, Rb appears to be a key factor in protecting cells from apoptosis. It is likely that Rb plays an essential role in cell survival by regulating the activity of multiple apoptotic mediators. Rb expression as a nuclear phosphoprotein is essential for normal cell cycle function. Clearly, any damage to the cell cycle or to DNA integrity is a potent trigger of apoptosis and Rb involvement. The E2F transcription factor is a critical component in the Rb-dependent apoptotic pathway(s), and can act either in concert or independently of the p53 tumour suppressor. Until recently, it was suggested that Rb, E2F and p53 modulate the apoptotic threshold by acting upstream of certain death proteases involved in programmed cell death. However, Rb activity can also be regulated downstream by the interleukin-converting enzyme-like (ICE-like) proteases, which abolish Rb activity by cleavage of aspartate-enriched regions within its C-terminus. Finally, Bcl-2, which inhibits multiple-factorial-induced apoptosis, does so, in part, by modulating the phosphorylation state of Rb. Taken together, Rb acts not only as a tumour suppressor protein which controls cell cycle function, but also determines the final destiny of a cell through apoptosis.


A day in the life of an urban emergency department.
The annual number of patient visits to emergency departments (EDs) continues to increase. Patients seen in the ED for nonemergent conditions potentially increase the cost of health care and lead to overcrowding in EDs. To gain insights into the factors leading to nonemergent use of hospital EDs. During a 24-hour period, we interviewed 67 patients in an urban ED. A total of 232 patients were seen in the ED and the hospital provided all claims data. None. Elicit and record patient-stated reasons for seeking care in the ED. Interview results showed that 90% of patients had a primary care clinic although 23% of those clinics were not affiliated with the hospital. Of the 67 interviewed patients, 72% reported they came to the ED because their condition was an emergency, 79% had spoken to someone prior to going to the ED, but only 30% consulted medical personnel. Patients did not go to the ED because they lacked a primary care clinic. Most patients did not discuss their condition with medical personnel prior to going to the ED. Informing patients of clinic and hospital affiliations may improve continuity of care and access to electronic health records.


[Obstructive anuria: unilateral cutaneous ureterostomy with remission of contralateral ureter obstruction].
We experienced 1 case of obstructive anuria. This patient had received radiotherapy for uterine cancer. We performed unilateral cutaneous ureterostomy. Excretion of urine from the contralateral kidney occurred from the 17th postoperative day indicating improvement in renal functions. The possible mechanism for improvement of functions of the contralateral kidney is considered to be release of unilateral obstruction resulting in improvement in edema of tissues around kidney and ureter and remission of intravesical ureter obstruction caused by inflammation as a sequela of radiotherapy through improvement in inflammation.


Long-acting somatostatin analogues in the treatment of unresectable/metastatic neuroendocrine tumors.
Neuroendocrine tumors (NETs) are a relatively rare and heterogeneous group of neoplasms with an annual incidence of ~35 cases per 100,000 people in the United States. The updated World Health Organization (WHO) classification system of gastroenteropancreatic (GEP)-NETs categorizes these tumors according to site of origin, clinical syndrome, and degree of differentiation. Well-differentiated NETs arising from the gastrointestinal tract or lungs (formerly known as carcinoid tumors) are often indolent and slow-growing. In contrast, poorly differentiated neuroendocrine carcinomas (NECs) are aggressive and have a poor prognosis. Due to their insidious onset, most NETs are diagnosed at an advanced stage and a curative approach is not possible. In these patients, medical therapy is limited to disease control, including relief of symptoms that arise from overproduction of peptide hormones by the tumors. Somatostatin analogues (SSAs) have remained the mainstay of symptoms control. In addition to symptoms control, clinical data also support an anti-proliferative effect of SSAs in patients with well- to moderately differentiated NETs. Long-acting SSAs have greatly facilitated their use. This review will focus on two long-acting SSAs, octreotide LAR and lanreotide, and their use in the clinical setting. Information necessary to assess their relative merits is summarized. We conclude these two therapies are interchangeable making value a very important consideration in their use.


Recovery Improvement for Large-Area Tungsten Diselenide Gas Sensors.
Semiconducting two-dimensional transition-metal dichalcogenides are considered promising gas-sensing materials because of their large surface-to-volume ratio, excellent electrical conductivity, and susceptible surfaces. However, enhancement of the recovery performance has not yet been intensively explored. In this study, a large-area uniform WSe2 is synthesized for use in a high-performance semiconductor gas sensor. At room temperature, the WSe2 gas sensor shows a significantly high response (4140%) to NO2 compared to the use of NH3, CO2, and acetone. This paper demonstrates improved recovery of the WSe2 gas sensor's NO2-sensing performance by utilizing external thermal energy. In addition, a novel strategy for improving the recovery of the WSe2 gas sensor is realized by reacting NH3 and adsorbed NO2 on the surface of WSe2: the NO2 molecules are spontaneously desorbed, and the recovery time is dramatically decreased (85 min → 43 s). It is expected that the fast recovery of the WSe2 gas sensor achieved here will be used to develop an environmental monitoring system platform.


Involuntary autobiographical memories and their relation to other forms of spontaneous thoughts.
Involuntary autobiographical memories are memories of personal events that come to mind spontaneously-that is, with no conscious initiation of the retrieval process. Such spontaneously arising memories were long ignored in cognitive psychology, which generally has focused on controlled and strategic forms of remembering, studied in laboratory settings. Recent evidence shows that involuntary memories of past events are highly frequent in daily life, and that they represent a context-sensitive, and associative way of recollecting past events that involves little executive control. They operate by constraints that favour recent events and events with a distinct feature overlap to the current situation, which optimizes the probability of functional relevance to the ongoing situation. In addition to adults, they are documented in young children and great apes and may be an ontogenetic and evolutionary forerunner of strategic retrieval of past events. Findings suggest that intrusive involuntary memories observed clinically after traumatic events should be viewed as a dysfunctional subclass of otherwise functional involuntary autobiographical memories. Because of their highly constrained, situation-dependent and automatic nature, involuntary autobiographical memories form a distinct category of spontaneous thought that cannot be equated with mind wandering. This article is part of the theme issue 'Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation'.


Nursing care of bulimia with cognitive behavioural therapy.
Eating disorders, bulimia in particular, are increasingly being encountered in clinical practice. Nurses are ideally placed to identify and respond to these problems. The development of the nursing care of bulimia within a cognitive behavioural model is described.


Advanced Composites Based on Sea Buckthorn Carotenoids for Mayonnaise Enrichment.
This study aimed at the extraction and encapsulation of the carotenoids from sea buckthorn fruits and obtaining value-added mayonnaise. First, the carotenoids from sea buckthorn fruits were extracted using ultrasound-assisted extraction. Then, they were microencapsulated through complex coacervation and freeze-drying techniques using different wall material combinations. Two powders were obtained and analyzed in terms of encapsulation efficiency, total carotenoid content, antioxidant activity, stability of phytochemicals and color, morphological structure, and in vitro digestibility. All results pointed out that the carotenoid molecules were successfully encapsulated within the mixture of alginate, agar, and chitosan, with a 61.17 ± 0.89% encapsulation efficiency. To probe the functionality, the powder was added into mayonnaise in 2.5% and 5% amounts. The obtained mayonnaise samples were characterized in terms of phytochemical and antioxidant activity properties with their storage stability and texture, color, and sensory characteristics. A significant increase of total carotenoid content and antioxidant activity compared to the control sample was observed. The addition of powder also led to improved texture by increasing the firmness and adhesion. In addition, the sensory evaluation indicated an improved color and overall acceptability of the value-added mayonnaise. Thus, sea buckthorn extracts may be considered as valuable ingredients for the development of added-value food products.


Attentional bias to emotional stimuli is altered during moderate- but not high-intensity exercise.
Little is known regarding how attention to emotional stimuli is affected during simultaneously performed exercise. Attentional biases to emotional face stimuli were assessed in 34 college students (17 women) using the dot-probe task during counterbalanced conditions of moderate- (heart rate at 45% peak oxygen consumption) and high-intensity exercise (heart rate at 80% peak oxygen consumption) compared with seated rest. The dot-probe task consisted of 1 emotional face (pleasant or unpleasant) paired with a neutral face for 1,000 ms; 256 trials (128 trials for each valence) were presented during each condition. Each condition lasted approximately 10 min. Participants were instructed to perform each trial of the dot-probe task as quickly and accurately as possible during the exercise and rest conditions. During moderate-intensity exercise, participants exhibited significantly greater attentional bias scores to pleasant compared with unpleasant faces (p < .01), whereas attentional bias scores to emotional faces did not differ at rest or during high-intensity exercise (p > .05). In addition, the attentional bias to unpleasant faces was significantly reduced during moderate-intensity exercise compared with that during rest (p < .05). These results provide behavioral evidence that during exercise at a moderate intensity, there is a shift in attention allocation toward pleasant emotional stimuli and away from unpleasant emotional stimuli. Future work is needed to determine whether acute exercise may be an effective treatment approach to reduce negative bias or enhance positive bias in individuals diagnosed with mood or anxiety disorders, or whether attentional bias during exercise predicts adherence to exercise.


Clinical and histologic evaluation of the use of mandibular tori as donor site for mandibular block autografts: report of three cases.
The present paper reports on three patients who underwent localized alveolar ridge augmentation using block autografts harvested from the mandibular tori. Autogenous particulate bone graft was placed at the periphery of the block. Resorbable collagen membrane was placed above the graft material. Implant placement surgery followed at 6 to 16 months after bone grafting. During implant surgery, a biopsy was taken from the block autograft. Clinical evaluation revealed incorporation of the graft material at the recipient site. No donor site complication was noted. Histologic evaluation suggested that the block autograft was vital and in an active remodeling phase at the time of implant placement. Impressions were made intraorally before and 6 months after bone grafting. Laboratory measurements revealed 13% resorption at 6 months after bone grafting while 0.53 mL of ridge augmentation was achieved 6 months after bone grafting. Linear tomographs indicated 4.33 mm of lateral alveolar ridge augmentation. This report suggests that block autografts harvested from the mandibular tori may have the potential to maintain their vitality after bone grafting, while they may demonstrate resorption rates similar to those of autografts harvested from other intraoral donor sites.


Angiogenic activity in the sera of patients with post-kidney transplant erythrocytosis.
Post-kidney transplant erythrocytosis (PTE) is one of the hematological complications in the renal transplant patients. While its pathogenesis still remains to be elucidated completely, a number of therapies are available for the management of PTE. The aim of this prospective study was to investigate whether angiogenesis may be involved in the pathogenesis of post-transplant erythrocytosis by comparing its level with those of different classes of erythrocytosis [polycythemia vera (PV), idiopathic erythrocytosis and secondary erythrocytosis]. The angiogenic activity was evaluated by the assessment of the serum vascular endothelial growth factor (VEGF) levels, as one of circulating angiogenic factor, using a standardized enzyme-linked immunosorbent assay commercial kit in 13 PTE (2 F/11 M), in 75 untreated erythrocytosis non-transplant patients and in 21 healthy subjects controls. The results indicated that VEGF was overproduced in advanced and untreated PV patients and to a lesser degree in idiopathic erythrocytosis thus confirming an increased angiogenic activity. However, there is no evidence of increased angiogenesis in PTE and in secondary erythrocytosis. The absence of angiogenesis in PTE and its presence in PV is another argument that the pathogenesis of these two entities is different.


Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency.
Common variable immunodeficiency (CVID) is a disorder characterized by antibody deficiency. A significant fraction of the patients suffer from immune dysregulation, which leads to increased morbidity and mortality. The pathogenesis of this condition is poorly understood. Our aim was to find out whether the plasma protein signature in CVID is associated with clinical characteristics and lymphocyte aberrations. A highly sensitive proximity extension assay was used for targeted profiling of 145 plasma proteins in 29 patients with CVID. Phenotyping of peripheral lymphocytes was done by flow cytometry. The findings were correlated with the burden of immune dysregulation. Unsupervised clustering of plasma protein profiles identified 2 distinct groups of patients with CVID that differed significantly in terms of the degree of complications due to immune dysregulation and in terms of the frequency of activated B- and T-cell subpopulations. Pathway analysis identified IFN-γ and IL-1β as the top enriched upstream regulators associated with higher grade of immune dysregulation. In addition, CVID was found to be associated with increased plasma levels of the B-cell-attracting chemokine CXCL13. Clustering based on plasma protein profiles delineated a subgroup of patients with CVID with activated T cells and clinical complications due to immune dysregulation. Thus, data indicate that CVID-associated immune dysregulation is a TH1-mediated inflammatory process driven by the IFN-γ pathway.


Equilibrium shapes of erythrocytes in rouleau formation.
A well known physiological property of erythrocytes is that they can aggregate and form a rouleau. We present a theoretical analysis of erythrocyte shapes in a long rouleau composed of cells with identical sizes. The study is based on the area difference elasticity model of lipid membranes, and takes into consideration the adhesion of curved axisymmetric membranes. The analysis predicts that the erythrocytes in the rouleau can have either a discoid or a cup-like shape. These shapes are analogous to the discoid and stomatocyte shapes of free erythrocytes. The transitions between the discoid and cup-like shapes in the rouleau are characterized. The occurrence of these transitions depends on three model parameters: the cell relative volume, the preferred difference between the areas of the membrane bilayer leaflets, and the strength of the adhesion between the membranes. The cup-like shapes are favored at small relative volumes and small preferred area differences, and the discoid shapes are favored at large values of these parameters. Increased adhesion strength enlarges the contact area between the cells, flattens the cells, and consequently promotes the discoid shapes.


Relationships between in-role performance and individual values, commitment, and organizational citizenship behavior among Israeli teachers.
This study examines the relationship between (1) individual values, (2) organizational and occupational commitment, and (3) organizational citizenship behavior (OCB) and in-role performance in a sample of 192 teachers employed in 10 secular Jewish schools (response rate of 64%). The results showed that individual values were related to all commitment forms examined here, but contrary to expectations, there was no clear distinction between values that represent conservation and self-transcendence and values that represent openness to change and self-enhancement in terms of their relationship either to commitment or to behavioral outcomes. Likewise, there was no clear distinction between the three dimensions of commitment (affective, continuance, and normative) or two commitment foci (organizational and occupational) in terms of their relationships to different values. Unsurprisingly, the findings showed a strong effect of commitment on OCB and in-role performance. The findings show that both individual values and commitment are concepts that can increase our understanding of employees' behavior in the workplace. We conclude by emphasizing the need for further research on the relationship between values, commitment, and performance and by suggesting some directions for such research.


Evidence for pleiotropic signaling at the mouse beta3-adrenoceptor revealed by SR59230A [3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate].
This study examines the action of the beta(3)-adrenoceptor antagonist SR59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] at cloned mouse beta(3)-adrenoceptors expressed in Chinese hamster ovary cells (CHO-K1-beta(3)) or endogenously expressed in 3T3-F442A adipocytes or ileum. SR59230A displayed partial agonist properties compared with the beta(3)-adrenoceptor agonist CL316243 [(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate] in CHO-K1-beta(3) with the intrinsic activity increasing with the level of receptor expression. Functional affinity values for SR59230A at each level of receptor expression were in agreement with pK(I) values determined by binding. In cytosensor microphysiometer studies, SR59230A was a full agonist for increases in extracellular acidification rates (ECARs) at all levels of receptor expression, and antagonist actions were measurable only in medium- or low-expressing cells. In 3T3-F442A adipocytes, SR59230A antagonized CL316243-mediated increases of cAMP and had no agonist actions. However, in the cytosensor micro-physiometer, SR59230A (acting via beta(3)-adrenoceptors) was an agonist with an intrinsic activity greater than CL316243. In mouse ileum, SR59230A relaxed smooth muscle, although concentration-response curves were biphasic. Relaxant effects were produced by concentrations that did not affect cAMP levels. Differences in tissue responses to SR59230A were not caused by major differences in expression of Galphas. ECAR responses were not affected by pretreatment of cells with pertussis toxin, indicating that signaling did not involve Gi. Therefore, SR59230A displays agonist and antagonist actions at the mouse beta(3)-adrenoceptor. Because SR59230A only antagonized accumulation of cAMP in 3T3-F442A adipocytes yet in the same cells was an agonist for ECAR, cAMP-independent signaling pathways must mediate part of the agonist actions in the microphysiometer.


Antibiotic use.
Over the past decade, the number of people with cutaneous abscesses who present to emergency departments, walk-in centres or minor injury units has increased.


Regulation of mTORC1 signaling by pH.
Acidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is activated by various growth-stimulating signals and inactivated by starvation conditions. Whether mTORC1 can also respond to changes in extracellular or cytoplasmic pH and play a role in limiting anabolic processes in acidic conditions is not known. We examined the effects of acidifying the extracellular medium from pH 7.4 to 6.4 on human breast carcinoma MCF-7 cells and immortalized mouse embryo fibroblasts. Decreasing the extracellular pH caused intracellular acidification and rapid, graded and reversible inhibition of mTORC1, assessed by measuring the phosphorylation of the mTORC1 substrate S6K. Fibroblasts deleted of the tuberous sclerosis complex TSC2 gene, a major negative regulator of mTORC1, were unable to inhibit mTORC1 in acidic extracellular conditions, showing that the TSC1-TSC2 complex is required for this response. Examination of the major upstream pathways converging on the TSC1-TSC2 complex showed that Akt signaling was unaffected by pH but that the Raf/MEK/ERK pathway was inhibited. Inhibition of MEK with drugs caused only modest mTORC1 inhibition, implying that other unidentified pathways also play major roles. This study reveals a novel role for the TSC1/TSC2 complex and mTORC1 in sensing variations in ambient pH. As a common feature of low tissue perfusion, low glucose availability and high energy expenditure, acidic pH may serve as a signal for mTORC1 to downregulate energy-consuming anabolic processes such as protein synthesis as an adaptive response to metabolically stressful conditions.


Handling and reporting of nephrectomy specimens for adult renal tumours: a survey by the European Network of Uropathology.
To collect information on current practices of European pathologists for the handling and reporting of nephrectomy specimens with renal tumours. A questionnaire was circulated to the members of the European Network of Uropathology, which consists of 343 pathologists in 15 European countries. Replies were received from 48% of members. These replies indicated that nephrectomy specimens are most often received in formalin. Lymph nodes are found in less than 5% of nephrectomy specimens. All respondents give an objective measure of tumour size, most commonly in three diameters. The most common method to search for capsule penetration is to slice tissue outside the tumour perpendicularly into the tumour. The most common sampling algorithm from tumours greater than 2 cm is one section for every centimetre of maximum tumour diameter. Most respondents use the 2004 WHO renal tumour classification although only slightly over half consider small papillary tumours malignant if the diameter is greater than 5 mm. The Fuhrman grading system is widely used. Almost all use immunohistochemistry for histological typing in some cases, while only 7% always use it. The most utilised special stains are CK7 (95%), CD10 (93%), vimentin (86%), HMB45 (68%), c-kit (61%) and Hale's colloidal iron (52%). Only 18% use other ancillary techniques for diagnosis in difficult cases. While most pathologists appear to follow published guidelines for reporting renal carcinoma, there is still a need for the development of consensus and further standardisation of practice for contentious areas of specimen handling and reporting.


Management of anaphylaxis in children: a survey of parents and school personnel in Qatar.
Allergies are a growing health concern with a significant impact on quality of life and healthcare costs. It is critical to develop an appropriate care plan to deal with children's allergies. This study aimed to assess and compare the knowledge and perception of families and school personnel caring for children with history of anaphylaxis who were prescribed the epinephrine autoinjector (EpiPen). The study also examined the underlying reasons for any observed knowledge gaps. A cross-sectional study of 128 families and 50 corresponding school personnel caring for children at risk of anaphylaxis who had been prescribed the EpiPen was conducted. The primary outcome was to identify any knowledge deficiency within family and school personnel and the reasons behind knowledge gaps. Of the 128 screened schools, 30 (23%) were not informed by parents about their pupils' risk of anaphylaxis. Importantly, 113 (88%) of families and 42 (84%) of schools were unable to recognise the symptoms of anaphylaxis. Also, 67 (52%) of families and 22 (44%) of schools were not aware that a child should ideally have two EpiPen in case of a severe allergic reaction. The EpiPen had been used by 18 (14%) families and 5 (6%) schools. Communication among families and school personnel regarding anaphylaxis was suboptimal. Both parents and school personnel lacked key information in allergy management. Managing a child at risk of anaphylaxis requires effective communication among healthcare professionals, families and schools. There is an urgent need to improve knowledge of anaphylaxis and its management among families and school caregivers.


Effect of dissolved oxygen concentration on iron efficiency: Removal of three chloroacetic acids.
The monochloroacetic, dichloroacetic and trichloroacetic acid (MCAA, DCAA and TCAA) removed by metallic iron under controlled dissolved oxygen conditions (0, 0.75, 1.52, 2.59, 3.47 or 7.09 mg/L DO) was investigated in well-mixed batch systems. The removal of CAAs increased first and then decreased with increasing DO concentration. Compared with anoxic condition, the reduction of MCAA and DCAA was substantially enhanced in the presence of O2, while TCAA reduction was significantly inhibited above 2.59 mg/L. The 1.52 mg/L DO was optimum for the formation of final product, acetic acid. Chlorine mass balances were 69-102%, and carbon mass balances were 92-105%. With sufficient mass transfer from bulk to the particle surface, the degradation of CAAs was limited by their reduction or migration rate within iron particles, which were dependent on the change of reducing agents and corrosion coatings. Under anoxic conditions, the reduction of CAAs was mainly inhibited by the available reducing agents in the conductive layer. Under low oxic conditions, the increasing reducing agents and thin lepidocrocite layer were favorable for CAA dechlorination. Under high oxic conditions, the redundant oxygen competing for reducing agents and significant lepidocrocite growth became the major restricting factors. Various CAA removal mechanisms could be potentially applied to explaining the effect of DO concentration on iron efficiency for contaminant reduction in water and wastewater treatment.


Catalysis in Enzymatic Decarboxylations: Comparison of Selected Cofactor-dependent and Cofactor-independent Examples.
This review is focused on three types of enzymes decarboxylating very different substrates: (1) Thiamin diphosphate (ThDP)-dependent enzymes reacting with 2-oxo acids; (2) Pyridoxal phosphate (PLP)-dependent enzymes reacting with α-amino acids; and (3) An enzyme with no known co-factors, orotidine 5'-monophosphate decarboxylase (OMPDC). While the first two classes have been much studied for many years, during the past decade studies of both classes have revealed novel mechanistic insight challenging accepted understanding. The enzyme OMPDC has posed a challenge to the enzymologist attempting to explain a 1017-fold rate acceleration in the absence of cofactors or even metal ions. A comparison of the available evidence on the three types of decarboxylases underlines some common features and more differences. The field of decarboxylases remains an interesting and challenging one for the mechanistic enzymologist notwithstanding the large amount of information already available.


Pilot study of a 4-week Pain Coping Strategies (PCS) programme for the chronic pain patient.
A 4-week Pain Coping Strategies (PCS) programme has been developed for chronic pain patients who may still be undergoing medical interventions but who would benefit from learning pain management skills. The long-term negative behaviours associated with chronic pain may be prevented by introducing pain management strategies at an earlier stage. The PCS programme combines all the fundamental aspects of the traditional Pain Management Programme including exercise, relaxation, pacing, medication review, pain pathways, posture and challenging negative thoughts. The study compared 31 patients' mood, functional status and physical ability pre and 6 weeks post the programme using the Hospital Anxiety and Depression Scale (HAD), Canadian Occupational Performance Measure (COPM) and a series of physical tests. A paired samples t-test showed a significant improvement in levels of depression and anxiety, functional status and physical ability. The results reveal that an early intervention programme may be effective for chronic pain patients by promoting self-management and teaching positive coping strategies. The current study has found promising results for a brief early intervention for chronic pain, regardless of completion of medical interventions.


Overcoming multidrug resistance in human cancer cells by natural compounds.
Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC) transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (-)-epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized.


Kisspeptin: a novel role in the regulation of reproductive function.
Kisspeptin appears to have a pivotal role in the regulation of reproductive function and may have a therapeutic role in the treatment of disorders of reproduction. In this review we summarise the evidence regarding kisspeptin and its function in the hypothalamic pituitary gonadal axis and also examine future therapeutic applications.