Circulating miRNAs as Biomarkers of Acute Muscle Damage in Rats.
Skeletal muscle damage is an often-occurring event. Diagnosis using the classic blood marker creatine kinase sometimes yields unsatisfactory results due to great interindividual variability. Therefore, the identification of reliable biomarkers is important. Our aim was to detect and characterize circulating miRNAs in plasma in response to acute notexin-induced muscle damage in rats. Real-time quantitative RT-PCR profiling led to the identification of miRNAs that were highly increased in plasma in response to notexin injection into several muscles, namely miR-1-3p, -133a-3p, -133b-3p, -206-3p, -208b-3p, and -499-5p, as well as miR-378a-3p and miR-434-3p. Peak values of miRNAs appeared 12 hours after injury, and were contained both in the vesicular and nonvesicular fractions of plasma. Receiver operating characteristic curve analysis showed that circulating miRNAs could accurately discriminate between damaged and nondamaged tissues. Furthermore, we tested the robustness of expression profiles in slow- and fast-type fibers. Upon inducing damage in slow- or fast-type muscle, we found that the damaged-muscle phenotype had a very limited impact on the miRNA response. Similarly, the circulating miRNAs selected were not affected by hemolysis or platelets, two pre-analytical factors known to affect plasma miRNA profiles. Taken together, our results show that circulating muscle-specific miRNAs, miR-378a-3p and miR-434-3p, are robust and promising biomarkers of acute muscle damage in rats.


Prognostic Impact of Organomegaly in Mastocytosis: An Analysis of the European Competence Network on Mastocytosis.
Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression.


Weakly associated TFPB anions are superior to PF6 anions when preparing (pseudo)rotaxanes from crown ethers and secondary dialkylammonium ions.
Making the right choice: Tetrakis(3,5-trifluoromethylphenyl)borate (TFPB) counter anions can facilitate the threading of dibenzylammonium (DBA(+)) ions through macrocycles in cases where the corresponding PF(6)(-) salts fail to exhibit complexation.


Ultrasound guided lateral quadratus lumborum block enhanced recovery in patients undergoing laparoscopic colorectal surgery.
This study aimed to evaluate the effects of lateral quadratus lumborum block (QLB) on postoperative pain and recovery in patients undergoing laparoscopic colorectal surgery. Patients between 18 and 70 years old, diagnosed with colon or rectal cancer, with American Society of Anesthesiologists (ASA) physical status I or II, and scheduled for laparoscopic colorectal surgery were recruited. Patients were excluded if they were allergic to local anesthetics and unable to complete the procedure of puncture or follow-up evaluation. All included patients were randomly allocated to either QLB or Sham group. The primary outcome was perioperative cumulative sufentanil consumption. There were no significant differences between the groups in anesthetic time, operation time, dosage of propofol, and remifentanil (P > 0.05). Patients in the QLB group had significantly less sufentanil consumption both intraoperatively and postoperatively, compared with the Sham group (P < 0.05). Postoperative VAS pain scores on coughing in the QLB group at 2 h, 6 h, 12 h, 24 h time points and VAS pain score at rest 2 h, 6 h after surgery were significantly lower than in the Sham group (P < 0.05). Compared with the Sham group, time to first ambulation and anal flatus after surgery in the QLB group were significantly shorter (P < 0.05). Significant differences of postoperative rescue analgesic usage and QoR-15 score at 48 h were found between the two groups (P < 0.05). Ultrasound-guided lateral QLB significantly reduced perioperative opioid consumption, alleviated postoperative pain, shortened the time to first ambulation and anal flatus, and enhanced postoperative recovery of the patients undergoing laparoscopic colorectal surgery.


Respiratory muscle strength, exercise capacity and physical activity in patients with primary ciliary dyskinesia: A cross-sectional study.
The pathophysiological mechanisms of primary ciliary dyskinesia (PCD) may affect many functions, including respiratory, physical, and health status. This study aimed to compare respiratory muscle strength, inspiratory muscle endurance, muscle strength, exercise capacity, physical activity levels, and quality of life in PCD patients and controls. Twenty-seven patients and 28 controls were included. Respiratory muscle strength (maximal inspiratory (MIP) and maximal expiratory (MEP) pressures), inspiratory muscle endurance (incremental threshold loading test), muscle strength (quadriceps femoris, shoulder abductor, elbow flexor, handgrip), exercise capacity (6-min walk test (6MWT)), physical activity and quality of life (QOL-PCD) were evaluated. MIP, inspiratory muscle endurance, quadriceps femoris, and handgrip muscle strength, 6MWT distance, total energy expenditure; childrens' (6-12 years) and their parents' physical function, upper, lower respiratory, and hearing symptoms and treatment burden QOL-PCD subscales scores were significantly lower in patients compared with controls (p < 0.05). The 66.7% of patients did not meet the optimal number of steps. MEP, shoulder abductor, and elbow flexor muscle strength, active energy expenditure, physical activity duration, average metabolic equivalents, number of steps, lying time, and sleep duration; childrens' and their parents' other subscales and adolescents' all QOL-PCD subscales scores were similar between groups (p > 0.05). Inspiratory muscle strength and endurance, lower extremity and total muscle strength, exercise capacity, total energy expenditure, and childrens' quality of life are impaired compared to healthy controls. Decreased physical activity level is prevalent in these patients. Effects of pulmonary rehabilitation on these impaired outcomes for PCD patients should be investigated. Clinicaltrials.gov: NCT03370029; December 12, 2017.


Mining Clinical Data for Novel Posttraumatic Stress Disorder Medications.
Despite the prevalence and negative impact of posttraumatic stress disorder (PTSD), there are few medications approved by the U.S. Food and Drug Administration for treatment, and approved medications do not work well enough. We leveraged large-scale electronic health record data to identify existing medications that may be repurposed as PTSD treatments. We constructed a mechanistic tree of all Food and Drug Administration-approved medications and used the tree-based scan statistic to identify medications associated with greater than expected levels of clinically meaningful improvement in PTSD symptoms using electronic health record data from the U.S. Department of Veterans Affairs. Our cohort included patients with a diagnosis of PTSD who had repeated symptom measurements using the PTSD Checklist over a 20-year period (N = 168,941). We calculated observed numbers based on patients taking each drug or mechanistically related class of drugs and the expected numbers based on the tree as a whole. Medications typically used to treat PTSD, such as the Food and Drug Administration-approved agent sertraline, were associated with improvement in PTSD symptoms, but the effects were small. Several, but not all, direct-acting antivirals used in the treatment of hepatitis C virus demonstrated a strong association with PTSD improvement. The finding was robust to a sensitivity analysis excluding patients who received established PTSD treatments, including trauma-focused psychotherapy, concurrent with hepatitis treatment. Our exploratory approach both demonstrated findings that are consistent with what is known about pharmacotherapy for PTSD and uncovered a novel class of medications that may improve PTSD symptoms.


Superior Capsule Reconstruction Using Acellular Dermal Allograft Secured at 45° of Glenohumeral Abduction Improves the Superior Stability of the Glenohumeral Joint in Irreparable Massive Posterosuperior Rotator Cuff Tears.
The purpose of the current study was to create a dynamic cadaveric shoulder model to determine the effect of graft fixation angle on shoulder biomechanics following SCR and to assess which commonly used fixation angle (30° vs 45° of abduction) results in superior glenohumeral biomechanics. Twelve fresh-frozen cadaveric shoulders were evaluated using a dynamic shoulder testing system. Humeral head translation, subacromial and glenohumeral contact pressures were compared among 4 conditions: 1) Intact, 2) Irreparable supra- and infraspinatus tendon tear, 3) SCR using acellular dermal allograft (ADA) fixation at 30° of abduction, and 4) SCR with ADA fixation at 45° of abduction. SCR at both 30° (0.287 mm, CI: -0.480 - 1.05 mm; P < .0001) and 45° (0.528 mm, CI: -0.239-1.305 mm; P = .0006) significantly decreased superior translation compared to the irreparably torn state. No significant changes in subacromial peak contact pressure were observed between any states. The average glenohumeral contact pressure increased significantly following creation of an irreparable RCT (373 kPa, CI: 304-443 vs 283 kPa, CI 214-352; P = .0147). The SCR performed at 45° (295 kPa, CI: 226-365, P = .0394) of abduction significantly decreased the average glenohumeral contact pressure compared to the RCT state. There was no statistically significant difference between the average glenohumeral contact pressure of the intact state and SCR at 30° and 45°. SCR improved the superior stability of the glenohumeral joint when the graft was secured at 30° or 45° of glenohumeral abduction. Fixation at 45° of glenohumeral abduction provided more stability than did fixation at 30°. Grafts attached at 45° of glenohumeral abduction biomechanically restore the glenohumeral stability after SCR using ADA better than fixation at 30° of glenohumeral abduction.


Placozoa and the evolution of Metazoa and intrasomatic cell differentiation.
The multicellular Metazoa evolved from single-celled organisms (Protozoa) and usually - but not necessarily - consist of more cells than Protozoa. In all cases, and thus by definition, Metazoa possess more than one somatic cell type, i.e. they show-in sharp contrast to protists-intrasomatic differentiation. Placozoa have the lowest degree of intrasomatic variation; the number of somatic cell types according to text books is four (but see also Jakob W, Sagasser S, Dellaporta S, Holland P, Kuhn K, and Schierwater B. The Trox-2 Hox/ParaHox gene of Trichoplax (Placozoa) marks an epithelial boundary. Dev Genes Evol 2004;214:170-5). For this and several other reasons Placozoa have been regarded by many as the most basal metazoan phylum. Thus, the morphologically most simply organized metazoan animal, the placozoan Trichoplax adhaerens, resembles a unique model system for cell differentiation studies and also an intriguing model for a prominent "urmetazoon" hypotheses-the placula hypothesis. A basal position of Placozoa would provide answers to several key issues of metazoan-specific inventions (including for example different lines of somatic cell differentiation leading to organ development and axis formation) and would determine a root for unraveling their evolution. However, the phylogenetic relationships at the base of Metazoa are controversial and a basal position of Placozoa is not generally accepted (e.g. Schierwater B, DeSalle R. Can we ever identify the Urmetazoan? Integr Comp Biol 2007;47:670-76; DeSalle R, Schierwater B. An even "newer" animal phylogeny. Bioessays 2008;30:1043-47). Here we review and discuss (i) long-standing morphological evidence for the simple placozoan bauplan resembling an ancestral metazoan stage, (ii) some rapidly changing alternative hypotheses derived from molecular analyses, (iii) the surprising idea that triploblasts (Bilateria) and diploblasts may be sister groups, and (iv) the presence of genes involved in cell differentiation and signaling pathways in the placozoan genome.


Estimating leaf SPAD values of freeze-damaged winter wheat using continuous wavelet analysis.
Freeze injury, one of the most destructive agricultural disasters caused by climate, has a significant impact on the growth and production of winter wheat. Chlorophyll content is an important indicator of a plant's growth status. In this study, we analyzed the hyperspectral reflectance of normal and freeze-stressed leaves of winter wheat using a spectro-radiometer in a laboratory. The response of the chlorophyll spectra of plants under freeze stress was analyzed to predict the severity of freeze injury. A continuous wavelet transform (CWT) was conducted in conjunction with a correlation analysis, which generated a correlation scalogram that summarized the correlation between the chlorophyll content (SPAD value) and wavelet power at different wavelengths and decomposition scales. A linear regression model was established to relate the SPAD values and wavelet power coefficients. The results indicated that the most sensitive wavelet feature (region E: 553 nm, scale 5, R(2) = 0.8332) was located near the strong pigment absorption bands, and the model based on this feature could estimate the SPAD value with a high coefficient of determination (R(2) = 0.7444, RMSE = 7.359). The data revealed that the chlorophyll content of leaves under different low temperatures treatments could be accurately estimated using CWT. Also, this emerging spectral analytical approach can be applied to other complex datasets, including a broad range of species, and may be adapted to estimate basic leaf biochemical elements, such as nitrogen, cellulose, and lignin.


Hormonal and histologic findings in human cryopreserved ovarian autografts.
This is the first report showing a hormonal and histologic discrepancy in cryopreserved human ovarian tissue 11 months after orthotopic autotransplantation. The presence of antral follicles was observed although the hormonal values had returned to castrated levels.


Association of Baseline Patient-reported Health-related Quality of Life Metrics with Outcome in Localised Prostate Cancer.
Although health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. This was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b-T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. Overall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003-1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.023). In a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity.


A mutagen precursor in Chinese cabbage, indole-3-acetonitrile, which becomes mutagenic on nitrite treatment.
After treatment with nitrite, Chinese cabbage showed direct-acting mutagenicity on Salmonella typhimurium TA100 inducing 3100 revertants per g. One of the mutagen precursors that became mutagenic after nitrite treatment was isolated, and identified as indole-3-acetonitrile. After treatment with nitrite, 1 mg of indole-3-acetonitrile induced 17 400 revertants of TA100 and 21 000 revertants of TA98 without S9 mix.


Random mutagenesis of a plasmid-borne glycosidase gene and phenotypic selection of mutants in Escherichia coli.
The bglA gene from Bacillus polymyxa encodes a beta-glucosidase able to hydrolyze p-nitrophenyl-beta-D-glucopyranoside (PNPG), and 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal), chromogenic substrates for beta-glucosidases and beta-galactosidases respectively. A plasmid carrying the blgA gene inserted in vector pUC18 was mutagenized in vitro with hydroxylamine, and subsequently used to transform E. coli selecting for the ampicillin resistance conferred by the cloning vector. The transformants were screened on petri dishes for mutations causing inability to hydrolyze either one of the two substrates, and for mutations increasing resistance of the enzyme to thermal inactivation. The isolation of several mutants with such characteristics suggests that the simple procedure used here can be applied to generate modifications of enzymatic properties that fit specific industrial requirements.


Engaging a Nursing Workforce in Evidence-Based Practice: Introduction of a Nursing Clinical Effectiveness Committee.
This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787.


Cardiopulmonary Bypass Strategy to Facilitate Transfusion-Free Congenital Heart Surgery in Neonates and Infants.
Priming the cardiopulmonary bypass (CPB) circuit without the addition of homologous blood constitutes the basis of blood-saving strategies in open-heart surgery. For low-weight patients, in particular neonates and infants, this implies avoidance of excessive hemodilution during extracorporeal circulation. The circuit has to be miniaturized and tubing must be cut as short as possible to reduce the priming volume to prevent unacceptable hemodilution with initiating CPB. During perfusion, measures should be taken to prevent blood loss from the primary circuit to avoid replacement by additional volume. Favorable factors such as mild hypothermia/normothermia and high heparin concentrations during extracorporeal circulation promote earlier hemostasis after coming off bypass.Lower mortality score, first chest entry, higher hemoglobin concentration before going on bypass, and shorter CPB duration support transfusion-free CPB procedure. Reduced postoperative morbidity and mortality were observed when CPB was performed without blood transfusion. In our experience, this can be achieved in at least 70% of CPBs, even in low-weight patients.Bloodless CPB circuit priming should become a widespread reality, even in neonates and young infants, in any open-heart procedure.


[Determination of the thyroglobulin content in malignant and benign thyroid gland tumors as well as in thyrotoxic strumas using an immunological method].
A decreased content of the organospecific antigen (thyroglobulin) was found in the tissues of 70% of thyroid gland cancers and in about 50% of thyroid benign tumours and thyrotoxic goiters studied. These data testify to the fact that the antigenic simplification is not an obligatory and specific process for the malignant transformation of thyroid tissue. Among the neoplasms with decreased thyroglobulin content there were found tumours built up both of "A" and "C" cellular types, thus indicating the dual nature of the antigenic simplification of the thyroid tumours.


A non-classical view on calcium oxalate precipitation and the role of citrate.
Although calcium oxalates are relevant biominerals, their formation mechanisms remain largely unresolved. Here, we investigate the early stages of calcium oxalate formation in pure and citrate-bearing solutions. Citrate is used as a well-known oxalate precipitation inhibitor; moreover, it resembles the functional domains of the biomolecules that modulate biomineralization. Our data suggest that calcium oxalate forms after Ca2+ and C2O42- association into polynuclear stable complexes that aggregate into larger assemblies, from which amorphous calcium oxalate nucleates. Previous work has explained citrate inhibitory effects according to classical theories. Here we show that citrate interacts with all early stage CaC2O4 species (polynuclear stable complexes and amorphous precursors), inhibiting calcium oxalate nucleation by colloidal stabilization of polynuclear stable complexes and amorphous calcium oxalate. The control that citrate exerts on calcium oxalate biomineralization may thus begin earlier than previously thought. These insights provide information regarding the mechanisms governing biomineralization, including pathological processes (e.g., kidney stone formation).The formation mechanism of abundant calcium oxalate biomaterials is unresolved. Here the authors show the early stages of calcium oxalate formation in pure and citrate-bearing solutions by using a titration set-up in conjunction with solution quenching, transmission electron microscopy and analytical ultracentrifugation.


Phoenixin-14: detection and novel physiological implications in cardiac modulation and cardioprotection.
Phoenixin-14 (PNX) is a newly identified peptide co-expressed in the hypothalamus with the anorexic and cardioactive Nesfatin-1. Like Nesfatin-1, PNX is able to cross the blood-brain barrier and this suggests a role in peripheral modulation. Preliminary mass spectrography data indicate that, in addition to the hypothalamus, PNX is present in the mammalian heart. This study aimed to quantify PNX expression in the rat heart, and to evaluate whether the peptide influences the myocardial function under basal condition and in the presence of ischemia/reperfusion (I/R). By ELISA the presence of PNX was detected in both hypothalamus and heart. In plasma of normal, but not of obese rats, the peptide concentrations increased after meal. Exposure of the isolated and Langendorff perfused rat heart to exogenous PNX induces a reduction of contractility and relaxation, without effects on coronary pressure and heart rate. As revealed by immunoblotting, these effects were accompanied by an increase of Erk1/2, Akt and eNOS phosphorylation. PNX (EC50 dose), administered after ischemia, induced post-conditioning-like cardioprotection. This was revealed by a smaller infarct size and a better systolic recovery with respect to those detected on hearts exposed to I/R alone. The peptide also activates the cardioprotective RISK and SAFE cascades and inhibits apoptosis. These effects were also observed in the heart of obese rats. Our data provide a first evidence on the peripheral activity of PNX and on its direct cardiomodulatory and cardioprotective role under both normal conditions and in the presence of metabolic disorders.


Lactate: Where Are We Now?
There is a tight relationship between lactate levels (and its changes over time) with morbidity and mortality and the presence of tissue hypoxia/hypoperfusion in both models of shock and clinical studies. These findings have placed lactate in the center of guiding resuscitation in patients with increased lactate levels. However, given the complex metabolism and clearance of lactate, especially in sepsis, the actual use of lactate is more complex than suggested by some guidelines. By using other markers of tissue hypoperfusion together with lactate levels provides a more solid framework to guide the initial hours of resuscitation.


Sister Joseph's nodule in non-Hodgkin's lymphoma.
Sister Joseph's nodule is traditionally regarded as a sign of poor prognosis in untreatable malignancy. We describe a patient with a metastatic umbilical nodule in non-Hodgkin's lymphoma who had a good outcome. The possible mechanisms of tumour spread to the umbilicus and reasons for its rarity in lymphoma are discussed. The need for histological confirmation to exclude treatable disease is emphasized.


Kinetic and immunohistochemical characteristics of mitogen-induced cutaneous hypersensitivity in chickens selected for antibody responsiveness.
Mitogen-induced cutaneous hypersensitivity was evaluated in chickens selected for high and low antibody responses to SRBC, and in a random bred control line. Wing web swelling responses were found after subcutaneous administration of phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), and Escherichia coli lipopolysaccharide (LPS), respectively, in all three lines. All mitogens induced significant acute 4 h wing web swelling responses, followed by a significant (classical) late 24 h wing web swelling response. The 4 h responses were significantly lower in the L line, whereas a tendency for lower responses at 24 h in the L line was found as well. Immunohistochemical evaluation of the early and late wing web swelling responses revealed extravascular localisation of leukocytes at 24 h after sensitization with mitogens, which consisted of CD4+ cells, CD8+ cells, TCR-1+ cells, and heterophils, but no B cells, whereas the 4 h swelling response was primarily characterized by oedema. Cutaneous hypersensitivity either initiated by T-cell mitogens as well as B-cell mitogens may depend for an important part on the rapid induction of local homing of lymphocytes towards the sensitizing agent, which may be mediated by an acute local expression of molecules with chemo-attractive capacities. Interpretation of cellular immunity responses in vivo such as delayed-type hypersensitivity should therefore incorporate oedema-initiating characteristics of sensitizing agents. The relationship between the magnitude of cutaneous hypersensitivity to mitogens and selection for antibody responsiveness is discussed.


Optical changes of human dentin after non-vital bleaching and effect of Er,Cr:YSGG laser on micro-shear bond strength of a self-etch and an etch-and-rinse adhesive system.
The aim was to evaluate the optical changes of bleached human dentin and the efficacy of Er,Cr:YSGG laser on micro-shear bond strength (μSBS) of two adhesive systems for immediate and delayed applications. Seventy-two human dentin specimens (1 mm) were obtained. Colour measurements of 30 specimens (control and bleaching groups) were made at baseline, after bleaching and a 7-day delay. Differences at colour (ΔE00), translucency (ΔTP00) and whiteness (ΔWID) were calculated by recorded data. Forty-two specimens were used to compare μSBS of a self-etch (Clearfil SE Bond [SE]) and an etch-and-rinse (Prime&Bond NT [PBNT]) adhesive to bleached dentin. Additional to a negative group, six groups were contemplated for each adhesive, considering the time of composite application (immediate, delayed) and whether additional surface treatment by laser (1 W, 2 W) or not. Colour and μSBS data were statistically analysed. For optical analysis, only ΔE00 and ΔWID calculated for the difference between baseline and bleaching were found significantly different for control and bleaching groups. Whiteness of bleached specimens was remarkably decreased after a 7-day delay. Despite immediate applications of SE showing lower μSBS than negative control, delayed applications showed no significant differences except that of the 2 W laser etching. For PBNT, laser etching increased μSBS for both of the immediate and delayed applications, and no significant difference was observed from negative control. Related with the preferred adhesive system, Er,Cr:YSGG laser etching can be an alternative for optimal bond strength of immediate restorations, but the clinicians should always keep in mind that perceived colour and whiteness will change by the passing time which can affect the shade match.


[Popular appeal of physical grooming and warning against unhealthy cosmetics at the end of the 18th century].
The instruction to preservation of health especially the popularization of the personal hygiene are demanded a serious place from the medicine in the Age of Englightment. In reference to the salubrious influence of the bath and the warning against the use of unhealthy, metallic make-ups the purposive efforts of the physicians are illustrated.


Clinicopathological features of primary splenic follicular lymphoma.
Follicular lymphoma (FL) is a low-grade lymphoma that is usually characterized by generalized lymphadenopathy. Extranodal invasion by FL generally involves the bone marrow, skin, and duodenum; splenic infiltration often occurs in the advanced stages. However, primary splenic FL is very rare. Hence, few studies have been performed on splenic FL, and its clinicopathological features have not been established. This study aimed to investigate the clinicopathological features of primary splenic FL, as compared to nodal FL. We analyzed 17 patients diagnosed with primary splenic FL and 153 control patients with systemic FL. Hepatitis C virus (HCV)-positive status was significantly more common in patients with splenic FL than in the control patients (p = 0.02). Ann Arbor stage III or IV (p = 0.0003) and high-risk FLIPI (Follicular Lymphoma International Prognostic Index) (p = 0.03) were significantly less common in patients with splenic FL than in the control patients; however, the overall and progression-free survival curves were not significantly different between the groups. Among the 17 patients with splenic FL, the progression-free survival was significantly worse in patients who underwent splenectomy without receiving postoperative chemotherapy than in those who did (p = 0.03). These results suggest that primary splenic FL should be considered different from systemic FL; accordingly, its management should also be conducted differently.


Combined PET/MRI: one step further in multimodality imaging.
Given the need for sophisticated in vivo detection techniques to better characterize the cellular and subcellular processes in animals and humans, molecular imaging has become an important discipline. Techniques in molecular imaging have developed from stand alone modalities to multimodality methods. Among these, the combination of positron emission tomography (PET) and computed tomography (CT) is a successful imaging method and has become an important tool in clinical practice. Technological approaches that combine magnetic resonance imaging (MRI) with diffuse optical tomography (DOT), fluorescence tomography (FT) and PET have now been introduced. PET/MRI and the resulting combination of molecular, morphological and functional information will pave the way for a better understanding of physiological and disease mechanisms in preclinical and clinical settings.


A theoretical model for the Fåhræus effect in medium-large microvessels.
This paper presents a mathematical model capable to reproduce a celebrated phenomenon in blood microcirculation known as Fåhræus effect, since its discovery by Robin Fåhræus (1929). This consists in a decaying of the relative hematocrit in small vessels as the vessel diameter decreases. The key point of the model is a formula, direct consequence of the basic principles of fluid dynamics, that links the relative hematocrit to the reservoir hematocrit and the vessel diameter, which confirms the observed behavior. To test the model we selected, among the few experiments carried on since then, those performed by Barbee and Cokelet (1971). The agreement is remarkable. An extended comparison is also carried out with a celebrated empirical formula proposed by Pries et al. (1992) to describe the same phenomenon.


Adolescent Cannabis Misuse Scale: Longitudinal Associations with Substance Use, Mental Health, and Social Determinants of Health in Early Adulthood.
Some patterns of cannabis use may presage risk for long-term negative effects. We examined associations between a novel adolescent cannabis misuse scale and early-adult life course outcomes. We performed a secondary data analysis of a cohort of Los Angeles, CA high school students from grade 9 through age 21. Participants reported baseline individual demographic and family characteristics at grade 9, adolescent cannabis misuse (8-items) and alcohol misuse (12-items) at grade 10, and outcomes at age 21. We used multivariable regression to model the associations of cannabis misuse scale score with problem substance use (defined as any of: 30-day illegal drug use, 30-day use of another's prescription to get high, hazardous drinking) and several secondary outcomes (behavioral, mental health, academic, social determinants of health), adjusting for covariates. Parallel analyses were conducted for alcohol misuse. The 1,148 participants (86% retention) were 47% male, 90% Latinx, 87% US born, and 40% native English speakers. Approximately 11.4% and 15.9% of participants reported at least one item on the cannabis and alcohol misuse scales, respectively. At age 21, approximately 6.7% of participants reported problem substance use, which was associated with both Cannabis and Alcohol Misuse Scales (OR 1.31, 95%CI[1.16, 1.49] and OR 1.33, 95%CI[1.18, 1.49], respectively). Both scales were similarly associated with outcomes in all four categories. The Adolescent Cannabis Misuse Scale is a promising tool for identifying early patterns of substance use that predict future negative outcomes and enabling early intervention at a critical period in youth development.


Preparation and biocompatibility of novel UV-curable chitosan derivatives.
UV-curable chitosans (UVCC-7-10) were synthesized using less-toxic agents. The UVCC-7 was completely cured by UV spot irradiation for 4 s. The UVCC-7 was implanted into murine subcutaneous tissues, and the response to the implantation was observed by histological examination at 7 days after implantation. In the histological findings, the implant was surrounded by thin fibrous granulating tissue with no inflammatory cellular infiltration. Fibroblasts infiltrate between the cured implant. The novel synthesized UVCC-7 showed good biocompatibility.


M and N proteins of SARS coronavirus induce apoptosis in HPF cells.
SARS-associated coronavirus (SARS-CoV) induced cell apoptosis and its structural proteins may play a role in this process. To determine whether the structural proteins M and N of SARS-CoV induce apoptosis. We investigated human pulmonary fibroblast (HPF) cells, were transfected with plasmids containing the M or N gene, by TdT-mediated dUTP nick end labeling (TUNEL), Hoechst 33342 staining for nuclei, and observation of morphology. We found that in the absence of serum about 16.34% of cells transfected by pcDNA3.1-M and 21.72% of N-transfected cells showed typical apoptotic characteristics, significantly different from mock-transfected cells (only 6.23%, p<0.01). Furthermore, the cells that were co-transfected with M and N proteins showed more obvious phenomena of cell death (about 36.03%). There was a statistical significance between M-transfected cells and co-transfected cells (p<0.01), and a remarkable difference between N-transfected cells and co-transfected cells (p<0.01). The results show that M and N proteins of SARS-CoV can induce apoptosis of HPF cells. Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells.


Antioxidant and Anti-Inflammatory Activity of Ethanol Extract Stem of Etlingera rubroloba A.D. Poulsen.
Background and Objective: Etlingera rubroloba A.D. Poulsen (E. rubroloba) is a plant endemic to South-East Sulawesi which is used empirically by local people as a pain reliever for joints and to increase endurance after typhoid fever. This study aimed to determine the antioxidant and anti-inflammatory activity of the ethanol extract stem of E. rubroloba. Materials and Methods: The stem of the ethanol extract of E. rubroloba with evaluated for antioxidants using the FRAP method and anti-inflammatory activity with the parameter level of Tumor Necrosis Factor-Alpha (TNF-α) in vivo by using 6 groups of rats, namely the normal, the negative (Na-CMC 0.5%), the positive control (Diclofenac sodium) and the ethanol extract group at doses of 200, 300 and 400 mg kg1 b.wt. Results: The results of this study indicated that the antioxidant activity value of the IC50 ethanol extract was 12.720±0.12 μg mL1 and ascorbic acid (vitamin C) as a standard control was 3.14±0.12 μg mL1. The TNF- α normal group (7.83 pg mL1), negative control (250.92 pg mL1), positive control (123.66 pg mL1), treatment group dose 200 (192.20 pg mL1), 300 (97, 95 pg mL1) and 400 mg kg1 b.wt. (28.78 pg mL1). Conclusion: This study concluded that the ethanol extract of the stem of E. rubroloba has a very strong antioxidant activity and is an anti-inflammatory which is the best in reducing levels of TNF-α at a dose of 400 mg kg1 b.wt.


Evaluation of plasma LC3B+extracellular vesicles as a potential novel diagnostic marker for hepatocellular carcinoma.
Circulating extracellular vesicles (EVs) are recognized as a promising source of cancer biomarkers. We previously reported that tumor cell-released autophagosomes, a new subgroup of EVs expressing the mature autophagosome-specific marker LC3B (LC3B+ EVs), are critical modulators of host anti-tumor immunity. This study aimed to assess the level of plasma LC3B+ EVs and the correlation with clinical outcomes in liver cancer patients. The plasma and ascites samples were obtained from patients with liver cancer, non-malignant liver disease, and healthy controls. EVs were isolated by differential centrifugation and characterized using flow cytometry, nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of plasma LC3B+ EVs or HSP90α+LC3B+ EVs from liver cancer patients. The relationship between the expression levels of HSP90AA1 or MAP1LC3B and survival were analyzed using patient data from the TCGA database. The correlation between HSP90α in LC3B+ EVs and PD-1highCD8+ exhausted T cells from the ascites and peripheral blood of liver cancer patients was also evaluated. The EVs preparation from liver cancer patients contained LC3B+ EVs expressing epithelial tumor cell adhesion molecules (EpCAM), indicating that these LC3B+ EVs originated from epithelial tumor cells. The levels of plasma LC3B+ EVs and HSP90α+LC3B+ EVs in liver cancer patients were significantly higher than in non-malignant liver disease patients and healthy controls. The expression of HSP90α in plasma LC3B+ EVs (AUC 0.9595, sensitivity 86.00%, specificity 96.67%) accurately differentiated liver cancer patients from non-liver cancer controls. Additionally, a significant decrease in the levels of plasma LC3B+ EVs and HSP90α+LC3B+ EVs was found post-surgery in each patient, and high expression of HSP90AA1 or MAP1LC3B in the tumor tissue correlated with significantly worse survival compared to those with low expression. We also observed that the level of LC3B+ EVs and HSP90α+LC3B+ EVs positively correlated with the PD-1highCD8+ exhausted T cells in liver cancer patients. Human CD8+ T cells treated with purified LC3B+ EVs in vitro exhibited a dose-dependent increase in the percentage of PD-1+CD8+ T cells, whereas the production of IFN-γ was decreased. We demonstrated that isolation and detection of plasma LC3B+ EVs carrying bioactive molecules is an effective diagnostic marker of liver cancer, and may also be used as a potential marker for immune monitoring and predicting prognosis clinically.


The impact of abdominal complications on the outcome after thoracic transplantation--a single center experience.
Abdominal complications after thoracic transplantation (Tx) are potentially associated with an increased risk of mortality. We recently reported about the severe outcome after bowel perforation in patients following lung transplantation (LuTx). The aim of the present study was to likewise identify the risk factors with an impact on patient survival following heart transplantation (HTx). A retrospective analysis for the frequency and outcome of abdominal interventions following HTx was performed in 342 patients, and these data thereafter compared to a re-evaluated pool of 1,074 patients following LuTx. All patients were transplanted at Hanover Medical School, Germany, between January 2000 and October 2011. The incidence for abdominal surgery was comparable between patients following HTx (n = 33; 9.6 %) and LuTx (n = 90; 8.4 %). Elective operations were more frequently performed in patients after HTx (8.5 vs. 5.1 %). In contrast, the incidence of emergency interventions was higher after LuTx (5.3 %) than that following HTx (2.3 %). Herewith associated was the mortality observed in these transplant recipients (15.3 and 9.9 % for LuTx and HTx, respectively). Leading diagnosis for emergency surgery was bowel perforation (n = 18, regarding all cases). In 11 of these patients, perforation occurred within the first 6 months after Tx and eight of them died in the course of this complication (one patient after HTx and seven patients after LuTx). Abdominal complications after HTx are less frequently than after LuTx but equally correlate with a high mortality rate. In finding or even reasonable suspicion of an acute abdomen after thoracic Tx, a broad practice for extended diagnostics and a low barrier for an early explorative laparotomy thus are recommended.


Do long radiology workdays affect nodule detection in dynamic CT interpretation?
A previous study demonstrated decreased diagnostic accuracy for finding fractures and decreased ability to focus on skeletal radiographs after a long working day. Skeletal radiographic examinations commonly have images that are displayed statically. The aim of this study was to investigate whether diagnostic accuracy for detecting pulmonary nodules on CT of the chest displayed dynamically would be similarly affected by fatigue. Twenty-two radiologists and 22 residents were given 2 tests searching CT chest sequences for a solitary pulmonary nodule before and after a day of clinical reading. To measure search time, 10 lung CT sequences, each containing 20 consecutive sections and a single nodule, were inspected using free search and navigation. To measure diagnostic accuracy, 100 CT sequences, each with 20 sections and half with nodules, were displayed at preset scrolling speed and duration. Accuracy was measured using receiver operating characteristic curve analysis. Visual strain was measured via dark vergence, an indicator of the ability to keep the eyes focused on the display. Diagnostic accuracy was reduced after a day of clinical reading (P = .0246), but search time was not affected (P > .05). After a day of reading, dark vergence was significantly larger and more variable (P = .0098), reflecting higher levels of visual strain, and subjective ratings of fatigue were also higher. After their usual workday, radiologists experience increased fatigue and decreased diagnostic accuracy for detecting pulmonary nodules on CT. Effects of fatigue may be mitigated by active interaction with the display.


Fabrication of magnetic microsphere-confined graphene for the preconcentration of some phthalate esters from environmental water and soybean milk samples followed by their determination by HPLC.
In this study, a magnetic microsphere-confined graphene (Fe3O4@SiO2-G) was prepared as a novel adsorbent for the preconcentration of some phthalate esters in environmental water and soybean milk samples prior to high performance liquid chromatography analysis. The properties and morphology of the Fe3O4@SiO2-G were characterized by transmission electron microscopy and X-ray diffraction. This novel graphene-based magnetic nanocomposite showed great adsorptive ability toward the analytes. The method, which takes the advantages of both the high adsorption capacity of G and easy phase separation of the magnetic adsorbent from the sample solution, could avoid the time-consuming experimental procedures related to the traditional solid phase extraction. Various experimental parameters that could affect the extraction efficiencies, such as the amount of Fe3O4@SiO2-G, the extraction time, the pH of sample solution and the desorption conditions, were investigated. Under the optimum conditions, the limits of detection (S/N=3) of the method for the compounds were between 0.07 and 0.10 ng mL(-1) in water samples, and between 0.15 and 0.30 ng mL(-1) in soybean milk samples. The relative standard deviations (RSDs) varied from 2.7% to 6.1% (n=5). The recoveries of the method were in the range between 87.2% and 109.0% for environmental water and soybean milk samples. The method is suitable to determine the five phthalate esters (diallyl phthalate, di-n-propyl-phthalate, benzyl butyl phthalate, dicyclohexyl-phthalate and diethyl-hexyl-phthalate) in environmental water and soybean milk samples.


The prognostic value of the changes in the mode of ventricular tachycardia induction noted during therapy with a marked reduction of ventricular ectopic activity.
The prognostic significance of changes in the mode of induction of ventricular tachycardia (VT) noted during therapy was studied in 49 patients with sustained VT or ventricular fibrillation. Before treatment, all patients had inducible sustained VT by programmed stimulation (one to three extrastimuli) and frequent (greater than or equal to 30/hr) ventricular premature complexes (VPCs). On the discharge regimen, VT was no longer inducible by programmed stimulation in 22 patients (group 1). Twenty-seven patients (group 2) with persistent induction of VT despite extensive serial drug testings were discharged on a regimen that resulted in a marked reduction of VPCs on Holter monitoring (greater than or equal to 50% reduction of VPCs, greater than or equal to 90% reduction of couplets, and abolition of nonsustained VT). The modes of induction at baseline and on the discharge regimen were compared in each patient in group 2. Induction of VT was more difficult, requiring more aggressive stimulation protocol in 5 of 27 patients, unchanged in 14 patients, and easier in 8 patients. The duration of follow-up was 20 +/- 13 months (mean +/- SD). Arrhythmia-free survival rates at 6, 12, 18, and 24 months were 95%, 89%, 82%, and 73% in group 1, 92%, 84%, 75%, and 75% in group 2, 93%, 83%, 77%, and 69% in 27 patients with noninducibility or harder induction, and 95%, 90%, 79%, and 79% in 22 patients with the same or easier induction, respectively. The differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)


Single nucleotide polymorphism and haplotype association of the interleukin-8 gene with nasopharyngeal carcinoma.
The cytokine interleukin-8 (IL-8) may play a role in the pathogenesis of nasopharyngeal carcinoma (NPC) through the modulation of tumor immune response or enhanced angiogenesis. Polymorphism of IL-8 gene, which may affect the production level of cytokine, has been inversely associated with a number of cancers. To test this hypothesis, we investigated the relationship of IL-8 gene polymorphisms and NPC in a Chinese population. We analyzed single nucleotide polymorphisms (SNPs) of IL-8 gene -845 T/C, -738 T/A, -353 A/T, -251 A/T and +678 T/C in 280 patients with NPC and 290 age and sex matched controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction-sequence specific primers method (PCR-SSP). There were significant differences in the genotype and allele distribution of -251 A/T polymorphism of the IL-8 gene among cases and controls. The -251 AA and AT genotypes were associated with a significantly increased risk of NPC as compared with the -251 TT genotypes (OR=1.820, 95% CI, 1.120-2.959, P=0.015 and OR=1.590, 95% CI, 1.104-2.290, P=0.013, respectively). Haplotype analysis revealed that the homozygosity of the AAT haplotype (defined by SNPs at positions -353, -251 and +678) of IL-8 gene conveys the highest risk for NPC compared with the homozygosity for the TTC haplotype (OR=1.396; 95% CI, 1.064-1.831; P=0.016). The -251 A/T polymorphism of IL-8 and its haplotype are associated with NPC in a Chinese population. Our data suggests that IL-8 gene may play a role in the development of NPC.


[Aneurysm of the membranous ventricular septum with ventricular septal defect, mitral and tricuspid insufficiency].
A seventy-year-old man was admitted at our hospital because of dyspnea. Echocardiogram and left ventriculogram showed an aneurysm formation of the membranous ventricular septum and small left-to-right shunt through ventricular septum defect and also severe mitral and tricuspid insufficiency. Operation was performed after medical therapy for congestive heart failure. During operation, mitral leaflets showed no organic lesions nor prolapse, but the annulus was dilated. The cause of mitral insufficiency, we thought, might be congenital, and the annulus dilatation was caused of mitral insufficiency, we thought, might be congenital, and the annulus dilatation was caused to produce tricuspid insufficiency secondary. The ventricular septal communication became small (diameter; 5 mm) and was associated with aneurysm formation of the remaining portion of the membranous septum. And the aneurysm, protruding to the septal leaflet of tricuspid valves, enhanced tricuspid insufficiency. It was reported by many authors that the aneurysm formation was related to spontaneous closure of ventricular septal defect. Patients with small ventricular septal defect, without any symptoms, must be followed intensively, or they might get cardiac complications, such as arrhythmia, right ventricular outflow obstruction, tricuspid insufficiency, and so on.


Changes in general and central fatness are associated with hepatocellular carcinoma: A Korean nationwide longitudinal study.
We investigated the impact of short-term changes in general and central fatness on the risk of hepatocellular carcinoma (HCC) in a large, population-based cohort. We screened 7 221 479 subjects who underwent health examinations provided by the National Health Insurance Service of South Korea in 2009 and 2011. In total, 6 789 472 subjects were included in the final analysis. General fatness was defined as a body mass index (BMI) ≥25 kg/m2 , and central fatness was defined as a waist circumference (WC) ≥90 cm in men and ≥85 cm in women. Subjects were classified according to the change in body fatness between 2009 and 2011, as follows: (a) persistent no fatness as no fatness in both 2009 and 2011, (b) reversed fatness as fatness in 2009, but no fatness in 2011, (c) incident fatness as no fatness in 2009, but fatness in 2011 or (d) persistent fatness as fatness in both 2009 and 2011. During a median 6.4-year follow-up, we documented 9952 HCC cases. Compared to subjects with a persistent no general fatness, the risk of HCC significantly increased in those with incident (adjusted hazard ratio [aHR] = 1.10, 95% confidence interval [CI] = 1.01-1.20) and persistent (aHR = 1.28, 95% CI = 1.23-1.34) general fatness. Compared to subjects with persistent no central fatness, those with incident and persistent central fatness showed a significantly increased risk of HCC (aHR = 1.19, 95% CI = 1.11-1.27 and aHR = 1.33, 95% CI = 1.26-1.40, respectively). Taken together, these findings indicate the importance of strategies for preventing and reversing body fatness to reduce the incidence of HCC.


Accumulation of type A trichothecenes in maize, wheat and rice by Fusarium sporotrichioides isolates under diverse culture conditions.
Toxigenic isolates of Fusarium sporotrichioides were tested for the production of type A trichothecenes (T-2 toxin, HT-2 toxin, diacetoxyscirpenol and neosolaniol) when grown on three substrates (maize, rice and wheat) under various conditions of temperature and water activity in the laboratory for 3 weeks. Trichothecenes were determined by high-performance liquid chromatography with fluorescence detection, after derivatisation with coumarin-3-carbonyl chloride. This is the first time this analytical method has been applied to an extensive study of trichothecene accumulation. With minor exceptions, greater trichothecene production occurred when samples were incubated at 20 degrees C and moistened with 35% water (water activity 0.990) although incubation conditions affected the substrates studied in different ways. No correlation between the different pairs of trichothecenes was found except for neosolaniol and diacetoxyscirpenol (r=0.56). Principal component analysis results show that the data points can be grouped in three rough clusters related to cereal type, which points out that the composition of these cereals can influence the production of type A trichothecenes.


Cortical beta oscillations reflect the contextual gating of visual action feedback.
In sensorimotor integration, the brain needs to decide how its predictions should accommodate novel evidence by 'gating' sensory data depending on the current context. Here, we examined the oscillatory correlates of this process by recording magnetoencephalography (MEG) data during a new task requiring action under intersensory conflict. We used virtual reality to decouple visual (virtual) and proprioceptive (real) hand postures during a task in which the phase of grasping movements tracked a target (in either modality). Thus, we rendered visual information either task-relevant or a (to-be-ignored) distractor. Under visuo-proprioceptive incongruence, occipital beta power decreased (relative to congruence) when vision was task-relevant but increased when it had to be ignored. Dynamic causal modeling (DCM) revealed that this interaction was best explained by diametrical, task-dependent changes in visual gain. These results suggest a crucial role for beta oscillations in the contextual gating (i.e., gain or precision control) of visual vs proprioceptive action feedback, depending on current behavioral demands.


The micronutrient zinc inhibits EAEC strain 042 adherence, biofilm formation, virulence gene expression, and epithelial cytokine responses benefiting the infected host.
Enteroaggregative Escherichia coli (EAEC) is a major pathogen worldwide, associated with diarrheal disease in both children and adults, suggesting the need for new preventive and therapeutic treatments. We investigated the role of the micronutrient zinc in the pathogenesis of an E. coli strain associated with human disease. A variety of bacterial characteristics-growth in vitro, biofilm formation, adherence to IEC-6 epithelial cells, gene expression of putative EAEC virulence factors as well as EAEC-induced cytokine expression by HCT-8 cells-were quantified. At concentrations (≤ 0.05 mM) that did not alter EAEC growth (strain 042) but that are physiologic in serum, zinc markedly decreased the organism's ability to form biofilm (P<0.001), adhere to IEC-6 epithelial cells (P<0.01), and express putative EAEC virulence factors (aggR, aap, aatA, virK) (P<0.03). After exposure of the organism to zinc, the effect on virulence factor generation was prolonged (> 3 h). Further, EAEC-induced IL-8 mRNA and protein secretion by HCT-8 epithelial cells were significantly reduced by 0.05 mM zinc (P<0.03). Using an in vivo murine model of diet-induced zinc-deficiency, oral zinc supplementation (0.4 µg/mouse daily) administered after EAEC challenge (10 (10) CFU/mouse) significantly abrogated growth shortfalls (by>90%; P<0.01); furthermore, stool shedding was reduced (days 9-11) but tissue burden of organisms in the intestine was unchanged. These findings suggest several potential mechanisms whereby physiological levels of zinc alter pathogenetic events in the bacterium (reducing biofilm formation, adherence to epithelium, virulence factor expression) as well as the bacterium's effect on the epithelium (cytokine response to exposure to EAEC) to alter EAEC pathogenesis in vitro and in vivo. These effects may help explain and extend the benefits of zinc in childhood diarrhea and malnutrition.


Imaging features of hepatic sinusoidal obstruction syndrome or veno-occlusive disease in children.
Hepatic sinusoidal obstruction syndrome, also known as veno-occlusive disease, can occur as a complication of myeloablative chemotherapy, as a result of low-intensity chemotherapy-related liver toxicity or radiotherapy of the liver. Symptoms of sinusoidal obstruction syndrome can range from asymptomatic to liver dysfunction or severe disease with life-threatening acute multi-organ failure. Imaging features can suggest or support this clinical diagnosis. Familiarity with the imaging spectrum of sinusoidal obstruction syndrome is therefore important for both radiologists and clinical oncologists. Here, multi-modality radiologic appearances of sinusoidal obstruction syndrome in pediatric patients are illustrated, including outcome after follow-up.


The Annual Gynecologic Examination Updated for the 21st Century.
The concept of an annual gynecologic screening visit to identify disease at an early stage has long been an established component of women's health care. Women and their health care providers have historically accepted the schedule of an annual gynecologic examination with cervical cancer screening and a pelvic examination. Recently, researchers questioned the value of the annual breast and pelvic examinations in asymptomatic women and re-established the intervals for Pap test screening with the addition of human papillomavirus co-testing to establish cervical cancer risk. The updated well woman examination is now an opportunity to engage women in health education, screening for chronic disease risks, and health care concerns such as depression and violence.


Assessing heat tolerance through productive vs physiological indicators. Data from dairy sheep under on-farm conditions.
The search for criteria that allow the quantification of the level of thermotolerance of an animal is a major challenge in animal production. Different criteria have been proposed to date, mainly the use of routine milk recording and weather information or the collection of physiological measures related with heat stress. This study aimed at quantifying the association between indicators of heat tolerance derived from productive and physiological traits. For this purpose, two physiological traits, rectal temperature (RT) and respiratory rate (RR), and nine productive traits (milk yield, fat, protein and lactose yields and contents, casein and urea contents) were measured from June to September of 2018 in three flocks of Manchega sheep. A total of 462 lactating ewes participated in the study. Air temperature (Ta), relative humidity (RH) and associated temperature and humidity index (THI) were recorded inside the barn and also obtained from the closest weather station from the national meteorological network, and used to produce several measurements of heat load on animals. Based on the results of fits for quadratic and cubic regressions on the alternative heat load measures, the cubic regression on Ta and THI obtained inside the barn at time of recording yielded the best fit for physiological and productive parameters. The use of weather information taken from the official weather station closest to the farm also produced similar estimates and could be considered as a good alternative when on-farm meteorological data are not available. Two-trait random regression models that involved individual intercept and slope of response to heat load were used to obtain correlations between basal levels and heat tolerance within and across traits. Estimated correlations showed that animals with smaller vs larger basal levels of RT and RR tend to be more vs less heat tolerant (correlations up to 0.46) and that slopes of increase for RR and RT under heat stress were highly correlated (0.82). Estimated correlations between tolerance criteria from production vs physiology were up to -0.5 (between milk yield and RT), indicating that animals that show less increase in body temperature also tend to show a smaller decrease in production under heat stress. However, because of the non-unity correlation between the two types of indicators of heat tolerance, both sources of information, productive and physiological ought to be taken into account to ensure the long-term sustainability of selection programmes aiming at improving productive levels when heat stress is a concerning issue.


Relation between conduit vessel stiffness (assessed by tonometry) and endothelial function (assessed by flow-mediated dilatation) in patients with and without coronary heart disease.
Endothelial dysfunction and large artery stiffness occur in patients with risk factors for coronary artery disease (CAD) and in those with established CAD. We evaluated the relation between endothelial function and conduit vessel distensibility in normal subjects, in patients with documented stable CAD, and in patients demonstrating only risk factors but no overt atherosclerosis. Endothelium-dependent dilatation was evaluated by way of flow-mediated dilatation of the brachial artery using high-resolution ultrasound. Large artery stiffness was assessed using tonometry. After adjusting for age and intergroup differences, percent flow-mediated dilatation showed statistically significant correlations with several measures of stiffness, including central pulse pressure (r = -0.457, p = 0.019), central systolic pressure (r = -0.442, p = 0.024), peripheral pulse pressure (r = -0.393, p = 0.039), peripheral systolic pressure (r = -0.398, p = 0.036), and proximal aortic compliance (r = 0.390, p = 0.049). Measures of arterial stiffness correlate significantly with those of endothelial function. An increase in large conduit vessel stiffness may represent either a cause or consequence of endothelial dysfunction and may explain why elevated pulse pressure is a new cardiovascular risk factor.


Monosynaptic and disynaptic activation of pyriform cortex neurons by synchronous lateral olfactory tract volleys in the rabbit.
To elucidate the organization of synaptic inputs to pyriform cortex neurons, intracellular and extracellular responses of single units were analyzed in urethane-anesthetized rabbits. The lateral olfactory tract (LOT) or the olfactory bulb (OB) was electrically stimulated. Intracellular recordings revealed two types of cells (type I and type II cells), according to the types of EPSP evoked by the LOT or OB shock. The EPSP in the type I cells had shorter latencies (0.0 to 0.9 ms) from the onset of the component 2 (C2) wave of the field potential (which signals the onset of the synaptic depolarization of the apical dendrites of the pyramidal cells in the PC), and that in the type II cells had longer latencies (1.0 to 6.0 ms). A conditioning LOT or OB shock did not suppress the testing EPSP in the type I cells, whereas the conditioning stimulation greatly suppressed the testing EPSP in most of the type II cells. Extracellular recordings from units responding synaptically to the LOT or OB shock revealed a group of units which had short latencies (0.7 to 1.9 ms) of spike discharges. Those units, which were likely to be the same cells as the type I cells, are believed to mediate excitatory synaptic inputs to the type II cells. On the basis of these results, we concluded that type I cells are monosynaptically activated by LOT volleys, whereas type II cells are activated di- or polysynaptically by way of a relay from type I cells. The type I cells were recorded in both the superficial and the deep parts of the pyriform cortex, although they were recorded more frequently in the superficial part. On the other hand, most of the type II cells were recorded in the deep part of the PC. These results support and extend the previous model, in which the monosynaptically activated superficial pyramidal cells give rise to excitatory inputs to other pyramidal cells and neurons in deep layers.


Leaf litter processing and energy flow through macroinvertebrates in a woodland pond (Switzerland).
Energy generated by leaf litter processing and its flow through the associated macroinvertebrate community was quantified in a pond near Geneva (Switzerland). Annual density, biomass, and production on oak (Quercus robur) leaf litter were assessed for all macroinvertebrate taxa with emphasis on predators. Empirical energetic relations provided an energy budget for the macroinvertebrate community. On 1 m2 of pond bottom, the processing of 5641 kJ of oak leaf litter resulted in 8.5% of leachate (6 days), and after 1 year 32% of material remained; the other 59.5% was biologically (animal or microbial) converted, including 11.2% processed by shredders. The mean annual density of associated macroinvertebrates was 51374 individuals, mean biomass was 3.53 g (dry mass) and production was about 1451 kJ (or 65 g). Predator production was 170 kJ/m2, non-chironomid primary consumer production was 101 kJ/m2 (including 57 kJ from shredders) and chironomid primary consumer production was estimated at 1180 kJ/m2. Predators contributed to a high proportion of total biomass (39%) but to a smaller amount of production (12%) or density (6%). In this two-stepped food-chain mainly based on detritus, the transfer coefficient between first level (detritus + primary producers) and third level (secondary consumers) was high (2-2.5%) and indicated efficient conversion of energy. This high efficiency was partly related to the reutilization of fine particulate organic matter by the collectors. The production estimate measured on leaf litter was compared with two other predominant substrates (Typha latifolia stems and Chara sp.), and exhibited the highest value. This study shows how leaf litter can constitute a direct source for high secondary production and be an efficient energy source in freshwater ecosystems. It is also demonstrated that a woodland pond can support a high macroinvertebrate production as compared with other freshwater ecosystems.


Rapid maxillary expansion outcomes in treatment of obstructive sleep apnea in children.
The objectives of this study were to confirm the efficacy of rapid maxillary expansion in children with moderate adenotonsillar hypertrophy in a larger sample and to evaluate retrospectively its long-term benefits in a group of children who underwent orthodontic treatment 10 years ago. After general clinical examination and overnight polysomnography, all eligible children underwent cephalometric evaluation and started 12 months of therapy with rapid maxillary expansion. A new polysomnography was performed at the end of treatment (T1). Fourteen children underwent clinical evaluation and Brouilette questionnaire, 10 years after the end of treatment (T2). Forty patients were eligible for recruitment. At T1, 34/40 (85%) patients showed a decrease of apnea-hypopnea index (AHI) greater than 20% (ΔAHI 67.45% ± 25.73%) and were defined responders. Only 6/40 (15%) showed a decrease <20% of AHI at T1 and were defined as non-responders (ΔAHI -53.47% ± 61.57%). Moreover, 57.5% of patients presented residual OSA (AHI > 1 ev/h) after treatment. Disease duration was significantly lower (2.5 ± 1.4 years vs 4.8 ± 1.9 years, p <0.005) and age at disease onset was higher in responder patients compared to non-responders (3.8 ± 1.5 years vs 2.3 ± 1.9 years, p <0.05). Cephalometric variables showed an increase of cranial base angle in non-responder patients (p <0.05). Fourteen children (mean age 17.0 ± 1.9 years) who ended orthodontic treatment 10 years previously showed improvement of Brouilette score. Starting an orthodontic treatment as early as symptoms appear is important in order to increase the efficacy of treatment. An integrated therapy is needed.


Gremlin: a complex molecule regulating wound healing and fibrosis.
Gremlin-1 is part of the TGF-β superfamily and is a BMP antagonist that blocks BMP signalling to precisely control BMP gradients. Gremlin-1 is primarily involved in organogenesis and limb patterning however, has recently been described as being involved in fibrotic diseases. Initially described as a key factor involved in diabetic kidney fibrosis due to being induced by high glucose, it has now been described as being associated with lung, liver, eye, and skin fibrosis. This suggests that it is a key conserved molecule mediating fibrotic events irrespective of organ. It appears that Gremlin-1 may have effects mediated by BMP-dependent and independent pathways. The aim of this review is to evaluate the role of Gremlin-1 in fibrosis, its mechanisms and if this can be targeted therapeutically in fibrotic diseases, which currently have very limited treatment options and are highly prevalent.


Consolidation therapy of arsenic trioxide alternated with chemotherapy achieves remarkable efficacy in newly diagnosed acute promyelocytic leukemia.
Currently, all-trans retinoic acid (ATRA) combined with daunorubicin and ATRA combined with arsenic trioxide (ATO) therapies are considered the standard induction therapy regimens for adult patients newly diagnosed with acute promyelocytic leukemia (APL). However, there is no consensus concerning the optimal consolidation and maintenance therapies after induction therapy. In this study, we explored a new therapeutic strategy for APL that may be simple, effective, and safe. The patients in our study were divided into high white blood cell (WBC) group and low WBC group according to the numeration of leukocytes at the first visit. The low WBC group received ATRA and ATO until complete remission (CR), and the high WBC group received anthracycline, ATRA, and ATO until CR. After achieving hematologic CR, ATO was alternated with chemotherapy for consolidation therapy. Three cycles were completed in the 1st year with no maintenance therapy. The patients were followed for a median of 5 years after their initial treatment. After induction therapy, the rate of CR for the 18 patients was 100%. The rate of negativity for the PML/RARα fusion gene following induction therapy was 100%. There was no mortality during the treatment. Both the 5-year event-free survival rate and 5-year overall survival rate were 100%. No relapses occurred during the follow-up period. This study proposes a novel treatment for APL that is efficient, well-tolerated, and very simple to perform.


Comparing prophylactic use of cefazolin for SSI in cesarean section: a systematic review and meta-analysis.
To summarize the available evidence to explore the effect of different prophylactic cefazolin regimens on postoperative surgical site infection after cesarean section. We searched WOS, Pubmed, and EMBASE Database also traced citations in the reference sections of the retrieved studies. English search words: Cesarean section, Surgical site infection, Cefazolin. The majority of the literature are randomized controlled trials comparing varied regimens of cefazolin. A total of 11 randomized controlled trials and 4 non-randomized controlled trials involving 16,328 pregnant women were eligible. There was no statistically significant difference in the risk of SSI after cesarean section when cefazolin was given at a high dose compared with cefazolin at a low dose (OR 0.77, 95% CI 0.57-1.04, I2 = 0.0%). The risk of SSI after cesarean section was reduced by prophylactic use of cefazolin before skin incision compared with that after the umbilical cord clamping (OR 0.48, 95% CI 0.29-0.82, I2 = 53.4%). Because of the extreme heterogeneity of the combined drug use, no meta-analysis results were provided. The consequences of cefazolin combined with other antibiotics (either orally or intravenously) vary widely. For pregnant women with different risk factors, cefazolin alone or the type, dose and drug route of cefazolin combined with additional antibiotics need to be further studied and explored. All in all, this article illustrates a better use of cefazolin for the control of Surgical incision site infection in the cesarean section. For pregnant women with cesarean section without high-risk factors of infection, the use of cefazolin is effective, but for pregnant women with different high-risk factors, the specific use of prophylactic antibiotics needs to be further explored.


An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis.
Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2(+) cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically in concert with a cascade of MLL2-associating epigenetic regulators to dampen sensitivity of the cancer cells to lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy.


Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone, monoamines, and blood Pb in rats.
The level of lead (Pb) exposure in children has decreased dramatically since restrictions on its use were implemented. However, even with restrictions, children are exposed to Pb and still present with cognitive and behavioral deficits. One prominent aspect of the exposome of these children is that many come from low social economic status (SES) conditions, and low SES is associated with stress. In order to compare the combined effects of early stress and Pb, Sprague-Dawley rats were exposed to vehicle or Pb either alone or in combination with maternal separation stress during brain development (i.e., postnatal day (P)4-P11, P19, or P28). Maternally separated/isolated pups had lower body and thymus weights during exposure and had increased levels of blood Pb compared with vehicle controls. Isolation, but not Pb, affected the response to an acute stressor (standing in shallow water) when assessed on P19 and P29, but not earlier on P11. Interactions of Pb and isolation were found on monoamines in the neostriatum, hippocampus, and hypothalamus on turnover but not on levels, and most changes were on dopamine turnover. Isolation had greater short-term effects than Pb. Interactions were dependent on age, sex, and acute stress.


Induction of feeding by 7-chlorokynurenic acid, a strychnine-insensitive glycine binding site antagonist.
Two experiments examined the involvement of the strychnine-insensitive glycine binding site (SIGBS) of the N-methyl-D-aspartate (NMDA) receptor/channel complex in feeding behavior. The first experiment demonstrated that the SIGBS antagonist, 7-chlorokynurenic acid (7CK), dose-dependently increased food intake in rats without producing significant locomotor deficits or stereotypies. The second experiment showed that D-serine, a SIGBS agonist, dose-dependently antagonized 7CK induced feeding, such that at the highest dose of D-serine used 7CK induced feeding was completely abolished, demonstrating that the effects of 7CK are specific to an action at the SIGBS.


Delayed symptomatic hyponatremia in transsphenoidal surgery: Systematic review and meta-analysis of its incidence and prevention with water restriction.
Delayed symptomatic hyponatremia (DSH) is an unpredictable postoperative complication after transsphenoidal pituitary surgery. Universal postoperative sodium screening and water restriction are two strategies to detect or prevent the development of DSH. We performed a meta-analysis of studies characterizing the rate of DSH using sodium screening and water restriction protocols. Literature search was done using MEDLINE/PUBMED, EMBASE, and Cochrane databases. Inclusion criteria are (1) development of DSH after endoscopic or microscopic transsphenoidal, sellar surgery, and (2) reporting of a standardized postoperative sodium screening protocol for monitoring or prevention of DSH. A total of 23 publications fulfilled the inclusion criteria resulted in a total of 5870 patients. Two meta-analyses were conducted. Of the 19 studies (N = 4488 patients) examining rate of DSH after sodium screening, DSH rates ranged from 0% to 19.7%. In the first meta-analysis, using a random-effect estimate of the combined proportions, the overall rate of DSH was 5.60% (4.0%-7.1%, I2 = 96.54%, T2 = 0.0007). In the second meta-analysis, a fixed-effect model of four studies consisted of 1382 patients. Eight hundred fifty-two patients were included prior to and 530 were included after water restriction protocol. Meta-analysis showed an odds ratio (OR) of 5.02 (95% CI: 2.16-11.65) favoring water restriction. This meta-analysis summarized rates of DSH with sodium screening protocol to be 5.60% (4.0%-7.1%) and showed a decreased risk of DSH after implementation of a water restriction protocol. The results are limited due to few studies examining fluid restriction (N = 4) and heterogeneity in water restriction protocols. No adverse events were seen with fluid restriction protocol. Prospective and multicenter studies should be conducted to further investigate the utility of water restriction following transsphenoidal pituitary surgery.


Efficacy and safety of levetiracetam in pediatric epilepsy.
To evaluate the efficacy and tolerability of Levetiracetam (LEV) as an adjunctive therapy in pediatric patients with different generalized epilepsies. Chart review of 22 consecutive children age 4-19 years who were treated with LEV for at least 1 year was observed retrospectively. The mean dose rang of LEV was from 250 to 2000 mg. Data were collected on epilepsy type, seizure frequency, concomitant antiepileptic drug and adverse effect. Of the 22 patient reviewed, 13 (59%) were boys and 9 (41%) were girls. Predominant seizure types were generalized tonic-clonic seizures 13 (59%) and tonic seizure 6 (27%). Other seizure types included myoclonic seizures 2 (9%) and focal seizure 3 (5%). The results showed 10 (45%) had become free of seizure for almost 7 months to 1 year. Eight of these 10 patients (80%) had normalized EEG. Seizure frequency was reduced in 9 (41%) patients and 3 (14%) patients still had seizure. No side effects were reported related to LEV treated patients except for 1 patient. Our results confirm that LEV may be an effective adjunctive therapy in treatment of childhood epilepsy, especially tonic-clonic seizure, with possible no evident side effect.


Grading Evidence to Support Legislative and Budget Proposals-Veterans Health Administration's Key to Implementing the Evidence Act.
The Foundations for Evidence-Based Policymaking Act of 2018 requires cabinet-level agencies to use evidence to justify and support budget and policy making. As investigators from the Quality Enhancement Research Initiative (QUERI) program, we were tasked with assisting Veterans Health Administration (VHA) leadership with the implementation of the Evidence-Based Policymaking Act of 2018. Through meetings with stakeholders, we identified a gap in the review process for legislative and budget proposals; no systematic process existed to evaluate the supporting evidence base for proposals. Here, we describe the development, refinement, and use of a checklist to assess the strength of evidence included in VHA legislative and budget proposals for changes to care delivery; clinical, research, and administrative operations; and staffing and workforce issues. The evidence assessment checklist is now part of the regular review process for VHA legislative and budget proposals. It is also being adapted for use elsewhere within the Department of Veterans Affairs. The checklist has provided a framework for briefings and training on best practices for using evidence to guide policy and budget decisions. Including evidence reviews in the legislative and budget proposal prioritization process may be an effective institutional arrangement to promote the use of evidence to inform high-level health policy decisions and to build a "culture of evidence" within the government.


[Socially significant associations of age(ing) and body: social gerontologically founded theories].
The body is more than a biological basic condition; it is provided with social meanings and used for constructing, defining and describing age(ing) in different contexts. The social significance of the body can, for example, be seen by the fact that it is a bearer of age attributes, serves as a display surface and a knowledge bearer for the "normal" and "natural" aging process. Formal and informal chronological age limits are used to describe, divide etc. ageing, without expatiating that certain interpretations of physical attributes are the basis of this construction. In the scientific discourse and in everyday understanding, dichotomous views on the aging body "old means ill" and "successfully old means active" prevail. After a social constructivism and phenomenology discussion, about these socially significant connections of aging and body they are discussed exemplarily based on two interviews. It excerpts that the body-related significance of ageing turns out to be considerably more differentiated in everyday understanding. Therefore, a first intermediate conclusion for research and practice concerning the social significance of the body in the gerontological field has to be reached.


Low aromatase activity and gene expression in human fetal testes.
Because of previous indications that estradiol (E2) plays a role in the regulation of testicular testosterone (T) production in some species, the production of E2 and aromatase gene expression in human fetal testes were investigated. Testicular minces from 14 fetuses (fetal age 15-23 weeks) were incubated with and without 200 ng/ml highly purified hCG, and the production of E2 and T was measured by RIA. Basal T production was high at 15-18 weeks of gestation and decreased thereafter. Estradiol production was low in all testes. Aromatase mRNA (P-450 arom messenger ribonucleic acid) was not detectable in fetal testicular tissues when studied by Northern and dot blot techniques. Placenta and fetal liver expressed aromatase mRNA, but fetal ovary contained only miniscule amounts. HCG significantly stimulated the production of both T and E2 in the testes of older fetuses (19-23 weeks), but the testicular E2 production of the youngest fetuses (15-18 weeks) did not increase significantly after hCG stimulation. These results indicate that aromatase activity and gene expression are very low in human fetal testes. These findings suggest that E2 may not play a major role in testicular T production in the human fetus.


Leukocyte-endothelial interactions in environmental hypoxia.
Hypoxia induced by reducing inspired PO2 (PIO2) to 70 Torr, promotes a rapid microvascular response characterized by increased leukocyte rolling and adherence to the venular endothelium, leukocyte emigration to the perivascular space and increased vascular permeability. This appears to be a generalized response since it is observed in venules of the mesentery, cremaster muscle and pial microcirculations. After three weeks of acclimatization to hypoxia (barometric pressure 380 Torr, PIO2 70 Torr), the initial microvascular response resolves and exposure to even lower PIO2 (50 Torr) fails to elicit a microvascular response. The initial response is accompanied by a reversible increase in the generation of reactive oxygen species (ROS) and is blocked by antioxidants and by interventions that increase the tissue levels of nitric oxide (NO). In contrast to ischemia/reperfusion, ROS levels increase during hypoxia and return towards pre-hypoxic values after return to normoxia. Acclimatization involves upregulation of inducible NO synthase (iNOS): inhibition of iNOS using two different antagonists results in increased leukocyte-endothelial interactions and increased ROS generation. The results suggest that hypoxia initially leads to an alteration of the ROS/NO balance which is eventually restored during the acclimatization process. This phenomenon may have relevance to the microcirculatory alterations associated with hypoxic exposure, including acute mountain sickness and high altitude pulmonary and cerebral edema.


Quality control of mRNA decoding on the bacterial ribosome.
The ribosome is a major player in providing accurate gene expression in the cell. The fidelity of substrate selection is tightly controlled throughout the translation process, including the initiation, elongation, and termination phases. Although each phase of translation involves different players, that is, translation factors and tRNAs, the general principles of selection appear surprisingly similar for very different substrates. At essentially every step of translation, differences in complex stabilities as well as induced fit are sources of selectivity. A view starts to emerge of how the ribosome uses local and global conformational switches to govern induced-fit mechanisms that ensure fidelity. This review describes the mechanisms of tRNA and mRNA selection at all phases of protein synthesis in bacteria.


Strength and power assessment. Issues, controversies and challenges.
Athletic strength and power refer to the forces or torques generated during sporting activity. Their assessment can be used for strength diagnosis or talent identification, to monitor the effects of training interventions and to estimate the relative significance of strength and power to particular athletic pursuits. However, strength and power assessment is a difficult task. Reasons for this include: the fledgling status of research within the area, our limited understanding of the mechanisms underpinning strength and power performance and development, and limitations associated with various forms of dynamometry. This article describes a frame work for the collection of data which may ultimately lead to recommendations for the assessment of strength and power in sporting contexts. Such a framework will be evolutionary and depends upon synergistic improvements in our understanding of: the physiological mechanisms underpinning strength and power development; the effect that various training regimens have upon the development of strength and power; and factors influencing the validity and reliability of dynamometry. Currently, isometric, isoinertial and isokinetic dynamometry are employed in assessment. Each form has its supporters and detractors. Basically, proponents and critics of isokinetic and isometric dynamometry emphasis their apparently high internal and apparently low external [corrected] validity respectively. While the converse applies for isoinertial dynamometry. It appears that all 3 modalities can have acceptable reliability, however this should be established rather than assumed, as the reliability of each can be threatened by a number of considerations (e.g. instruction for isometric tasks, the impact of weight used during weighted jumping tasks, and the effects of gravity and feedback on isokinetic performance). While reliability is a seminal issue in assessment, it is not the only critical issue. Specifically, there has been little research into the correlation between strength and power measures and athletic performance. This work is central to the use of such indices in talent identification. To date, this work has generally been limited to heterogeneous rather than homogeneous groups. More work is required in this area. Furthermore, not all modes of assessment are sensitive or similarly sensitive to various training interventions. This suggests that these modalities are measuring different neuromuscular qualities. How these qualities relate to performance requires more work, and will determine the contexts in which various strength and power assessment modalities and protocols are used.(ABSTRACT TRUNCATED AT 400 WORDS)


Left hepatic trisectionectomy for hepatobiliary malignancy: results and an appraisal of its current role.
To analyze results of 70 patients undergoing left hepatic trisectionectomy and to clarify its current role. Left hepatic trisectionectomy remains a complicated hepatectomy, and few reports have described the long-term results of the procedure. Short-term and long-term outcomes of 70 consecutive patients who underwent left hepatic trisectionectomy from January 1993 to February 2004 were analyzed. Of the 70 patients, 36 had colorectal liver metastasis, 24 had cholangiocarcinoma, 4 had hepatocellular carcinoma, and the remaining 6 had other tumors. Overall morbidity, 30-day and 90-day mortality rates were 46%, 7%, and 9%, respectively. Multivariate analysis disclosed that preoperative jaundice and intraoperative blood transfusion were positive independent predictors for postoperative morbidity; however, there were no independent predictors for postoperative mortality. Postoperative morbidity (87% versus 35%, P < 0.001) and mortality (20% versus 5%, P = 0.108) were observed more frequently in patients with preoperative obstructive jaundice than in those without jaundice. Each survival according to tumor type was acceptable compared with reported survivals. Survival for patients with colorectal liver metastasis undergoing left hepatic trisectionectomy with concomitant partial resection of the remnant liver was similar to those without this concomitant procedure. This concomitant procedure was not associated with postoperative morbidity and mortality. Left hepatic trisectionectomy remains a challenging procedure. Preoperative obstructive jaundice considerably increases perioperative risk. Concomitant partial resection of the remaining liver appears to be safe and offers the potential for cure in patients with colorectal metastasis affecting all liver segments.


Glycoproteins expression on platelet membrane in inherited macrothrombocytopenias.
Inherited giant platelet disorders (IGPD) are a heterogeneous group of rare diseases characterized by thrombocytopenia, large platelets and variable bleeding symptoms. Glycoprotein (GP) expression on platelet surface in these conditions is poorly characterized. We have investigated the expression of constitutively expressed platelet membrane GP and the response to TRAP activation in a group of patients with different forms of inherited macrothrombocytopenias. Two patients diagnosed Epstein syndrome (ES), two with Bernard-Soulier syndrome (BSS) and eight with Mediterranean macrothrombocytopenia (MM) were studied using flow cytometry combined to monoclonal antibodies (MoAbs). Mean platelet volume was also measured. In general, there was an increase in the binding of MoAbs directed against platelet membrane GPs in the patients studied (except, obviously, in BSS patients). The observed increase ranged between 0.9 and 3.36 times the value of the control for GPIbalpha, between 1.36 and 7.2 times for GPIIb-IIIa and 0.94 and 8.07 times for GPIV. However, when the observed value was divided by the measured platelet volume, the estimated density was similar to controls in the case of GPIbalpha but were increased for GPIIb-IIIa and GPIV. TRAP activation provoked significant increments in the number of copies of GPIIb-IIIa complexes present on platelet surface in controls (91%), MM patients (49%), but almost no changes in BSS platelets (6%). In the group of macrothrombocytopenia studied, an increase in the expression of platelet membrane GP was observed, although a wide variability exists even in patients with the same disorder.


[A case report of advanced gastric cancer remarkably responding to mitomycin C, aclacinomycin A, SF-SP and lentinan combination therapy].
A 63-year-old female diagnosed as inoperable gastric cancer was treated with combination immunochemotherapy of Mitomycin C, Aclacinomycin A, SF-SP and Lentinan. In this case, the tumor directly invaded the pancreas and the peritoneal dissemination, metastasis to the para-aortic lymph nodes and Virchow's metastasis were identified. As the result of this therapy, the primary tumor was remarkably reduced in size. The subjective symptoms and the metastasis of the para-aortic lymph nodes and Virchow's metastasis disappeared. The side effect was only mild thrombocytopenia.


Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.
Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired resistance remains an important problem. Genomic profiling has demonstrated that ERBB2+ve breast cancers are distinguished from ER+ve and 'triple-negative' breast cancers by harbouring not only the ERBB2 amplification on 17q12, but also a number of co-amplified genes on 17q12 and amplification events on other chromosomes. Some of these genes may have important roles in influencing clinical outcome, and could represent genetic dependencies in ERBB2+ve cancers and therefore potential therapeutic targets. Here, we describe an integrated genomic, gene expression and functional analysis to determine whether the genes present within amplicons are critical for the survival of ERBB2+ve breast tumour cells. We show that only a fraction of the ERBB2-amplified breast tumour lines are truly addicted to the ERBB2 oncogene at the mRNA level and display a heterogeneous set of additional genetic dependencies. These include an addiction to the transcription factor gene TFAP2C when it is amplified and overexpressed, suggesting that TFAP2C represents a genetic dependency in some ERBB2+ve breast cancer cells.


Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824.
Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F(420) deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F(420) and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data.


Induction by chemically modified actin derivatives of antibody specificity. A relation between modified sites and antibody interactions with monomeric and filamentous actins.
A comparison of specific antibodies induced by unfolded actins modified either by oxidation or by arylation of lysine residues was reported. We have focused our work on binding properties with filamentous actin and located its preferential antigenic sites for the anti-arylated-actin antibodies in the C-part of the molecule. An interference of anti-oxidized actin antibodies upon actin polymerisation has also been reported.