A Single-Arm, Prospective, Phase II Study of Cisplatin Plus Weekly Docetaxel as First-Line Therapy in Patients with Metastatic or Recurrent Salivary Gland Cancer.
Salivary gland cancers (SGCs) are relatively rare but comprise various histologic subtypes, which complicates design of prospective trials. Systemic chemotherapy plays a limited role in treatment of SGCs, but cisplatin and docetaxel showed efficacy in a previous preclinical study. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of cisplatin plus weekly docetaxel in patients with metastatic or recurrent SGC. We included patients with histologically confirmed SGCs of the following subtypes: mucoepidermoid carcinoma, adenocarcinoma, ductal carcinoma, or adenoid cystic carcinoma. Patients had no prior systemic chemotherapy for metastatic or recurrent tumors and at least one measurable lesion. Patients were treated with docetaxel 35 mg/m2 (D1, 8) and cisplatin 70 mg/m2 (D1) every 21 days. Forty-one patients were enrolled between April 2014 and October 2020. The median age was 58 years (range, 32 to 73 years). The most common histologic subtype was adenoid cystic carcinoma (63.4%), followed by ductal carcinoma (24.4%). The most common metastatic site was the lung (75.6%). The median treatment cycle was 5.5 (range, 3 to 8), and the objective response rate was 46.3%, with three complete responses. The median duration of response was 6.8 months (interquartile range, 4.0 to 10.2). The progression-free survival and overall survival were 9.4 months (95% confidence interval [CI], 8.4 to 10.5) and 28.2 months (95% CI, 22.7 to 33.6), respectively. There were no treatment-related deaths. The most common grade 3/4 adverse events were neutropenia (4.9%) and fatigue (4.9%). Cisplatin plus weekly docetaxel is effective and tolerable with manageable toxicity as first-line therapy in patients with metastatic or recurrent SGC.


Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus.
Regulated intramembrane proteolysis (Rip) is an ancient and widespread process by which cells transmit information from one compartment (the endoplasmic reticulum) to another (the nucleus). Two separate cleavages that are carried out by two separate proteases are required for Rip. The first protease cleaves its protein substrate within an extracytoplasmic domain; the second cleaves it within a membrane-spanning domain, releasing a functionally active fragment of the target protein. In eukaryotes, examples of Rip can be divided into two classes, according to the proteases that are involved and the orientation of the substrates with the membrane. Class 1 Rip involves type 1 transmembrane proteins and requires presenilin for cleavage within a membrane-spanning domain. In Class 2 Rip, the highly hydrophobic metalloprotease, site-2 protease, is required for cleavage within a membrane-spanning domain and substrates are type 2 transmembrane proteins. Both classes of Rip are implicated in diseases that are important in modern societies, such as hyperlipidaemias (via the sterol regulatory element binding protein pathway) and Alzheimer's disease (via processing of the amyloid precursor protein.)


[Clinical and expert opinion aspects of vertebrobasilar insufficiency].
As many as 103 patients with vertebral basilar failure (VBF) underwent clinical expert examination. The patients' age ranged from 34 to 58 years. Bearing in mind the clinicopathogenetic characteristics, the patients were distributed into 3 groups. Group I (n = 32) included patients with the irritable vertebral artery syndrome, group II (n = 54) was made up of patients with mixed spondylogenous atherosclerotic chronic VBF, and group III (n = 17) of patients with sequelae of strokes in the vertebral basilar basin. Indications for patients' referral to the medical expert commission for evaluation of working capacity were elaborated and the clinical and socio-occupational criteria for the loss of patients' work fitness were established. A table describing stages of the development of VBF of spondylogenous atherosclerotic genesis was devised.


A chemical probe inhibitor targeting STAT1 restricts cancer stem cell traits and angiogenesis in colorectal cancer.
Colorectal cancer (CRC) is a worldwide cancer with rising annual incidence. New medications for patients with CRC are still needed. Recently, fluorescent chemical probes have been developed for cancer imaging and therapy. Signal transducer and activator of transcription 1 (STAT1) has complex functions in tumorigenesis and its role in CRC still needs further investigation. RNA sequencing datasets in the NCBI GEO repository were analyzed to investigate the expression of STAT1 in patients with CRC. Xenograft mouse models, tail vein injection mouse models, and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were generated to study the roles of STAT1 in CRC. A ligand-based high-throughput virtual screening approach combined with SWEETLEAD chemical database analysis was used to discover new STAT1 inhibitors. A newly designed and synthesized fluorescently labeled 4',5,7-trihydroxyisoflavone (THIF) probe (BODIPY-THIF) elucidated the mechanistic actions of STAT1 and THIF in vitro and in vivo. Colonosphere formation assay and chick chorioallantoic membrane assay were used to evaluate stemness and angiogenesis, respectively. Upregulation of STAT1 was observed in patients with CRC and in mouse models of AOM/DSS-induced CRC and metastatic CRC. Knockout of STAT1 in CRC cells reduced tumor growth in vivo. We then combined a high-throughput virtual screening approach and analysis of the SWEETLEAD chemical database and found that THIF, a flavonoid abundant in soybeans, was a novel STAT1 inhibitor. THIF inhibited STAT1 phosphorylation and might bind to the STAT1 SH2 domain, leading to blockade of STAT1-STAT1 dimerization. The results of in vitro and in vivo binding studies of THIF and STAT1 were validated. The pharmacological treatment with BODIPY-THIF or ablation of STAT1 via a CRISPR/Cas9-based strategy abolished stemness and angiogenesis in CRC. Oral administration of BODIPY-THIF attenuated colitis symptoms and tumor growth in the mouse model of AOM/DSS-induced CRC. This study demonstrates that STAT1 plays an oncogenic role in CRC. BODIPY-THIF is a new chemical probe inhibitor of STAT1 that reduces stemness and angiogenesis in CRC. BODIPY-THIF can be a potential tool for CRC therapy as well as cancer cell imaging.


Glial Fatty Acid-Binding Protein 7 (FABP7) Regulates Neuronal Leptin Sensitivity in the Hypothalamic Arcuate Nucleus.
The hypothalamus is involved in the regulation of food intake and energy homeostasis. The arcuate nucleus (ARC) and median eminence (ME) are the primary hypothalamic sites that sense leptin and nutrients in the blood, thereby mediating food intake. Recently, studies demonstrating a role for non-neuronal cell types, including astrocytes and tanycytes, in these regulatory processes have begun to emerge. However, the molecular mechanisms involved in these activities remain largely unknown. In this study, we examined in detail the localization of fatty acid-binding protein 7 (FABP7) in the hypothalamic ARC and sought to determine its role in the hypothalamus. We performed a phenotypic analysis of diet-induced FABP7 knockout (KO) obese mice and of FABP7 KO mice treated with a single leptin injection. Immunohistochemistry revealed that FABP7+ cells are NG2+ or GFAP+ in the ARC and ME. In mice fed a high-fat diet, weight gain and food intake were lower in FABP7 KO mice than in wild-type (WT) mice. FABP7 KO mice also had lower food intake and weight gain after a single injection of leptin, and we consistently confirmed that the number of pSTAT3+ cells in the ARC indicated that the leptin-induced activation of neurons was significantly more frequent in FABP7 KO mice than in WT mice. In FABP7 KO mice-derived primary astrocyte cultures, the level of ERK phosphorylation was lower after leptin treatment. Collectively, these results indicate that in hypothalamic astrocytes, FABP7 might be involved in sensing neuronal leptin via glia-mediated mechanisms and plays a pivotal role in controlling systemic energy homeostasis.


Pericardial multicystic proliferation.
We report the case of an intrapericardial lesion with the pathological features of a multilocular cyst, found on the adventitia of an aortic aneurysm in a 62-yr-old man. Microscopically, it consisted of numerous cavities lined by flattened or cuboidal cells with the immunocytochemical and electron microscopical features of mesothelium, sometimes forming a hyperplastic pattern. Numerous nerve bundles and collections of inflammatory cells were present in the stroma. These features were consistent with a reactive lesion.


Part and whole perceptual-motor practice of a polyrhythm.
An experiment is reported that investigated the effectiveness of receiving the perceptual experience of a bimanual, 2:3 polyrhythm during motor practice of the unimanual parts of the polyrhythm. Thirty-six participants were randomly assigned to one of three practice groups: One group practiced both parts of the 2:3 polyrhythm coincident with both pacing metronome tones (whole practice). Another group practiced each rhythm separately, hearing only the pacing tone for the corresponding rhythm (part practice). A third group also practiced each rhythm separately but heard pacing tones for both rhythms during practice (part/whole practice). Each group performed 25, 40 s learning trials for each rhythm; 900 ms intervals for the left hand, and 600 ms intervals for the right hand (a 2:3 polyrhythm). Transfer tests consisted of continuation tapping of the component rhythms, both unimanually and bimanually. Polyrhythmic structure, but not absolute timing stability, was facilitated when training was conducted in the presence of the whole perceptual experience of the task, even when part of the task was practiced unimanually.


Correlates of video games playing among adolescents in an Islamic country.
No study has ever explored the prevalence and correlates of video game playing among children in the Islamic Republic of Iran. This study describes patterns and correlates of excessive video game use in a random sample of middle-school students in Iran. Specifically, we examine the relationship between video game playing and psychological well-being, aggressive behaviors, and adolescents' perceived threat of video-computer game playing. This cross-sectional study was performed with a random sample of 444 adolescents recruited from eight middle schools. A self-administered, anonymous questionnaire covered socio-demographics, video gaming behaviors, mental health status, self-reported aggressive behaviors, and perceived side effects of video game playing. Overall, participants spent an average of 6.3 hours per week playing video games. Moreover, 47% of participants reported that they had played one or more intensely violent games. Non-gamers reported suffering poorer mental health compared to excessive gamers. Both non-gamers and excessive gamers overall reported suffering poorer mental health compared to low or moderate players. Participants who initiated gaming at younger ages were more likely to score poorer in mental health measures. Participants' self-reported aggressive behaviors were associated with length of gaming. Boys, but not girls, who reported playing video games excessively showed more aggressive behaviors. A multiple binary logistic regression shows that when controlling for other variables, older students, those who perceived less serious side effects of video gaming, and those who have personal computers, were more likely to report that they had played video games excessively. Our data show a curvilinear relationship between video game playing and mental health outcomes, with "moderate" gamers faring best and "excessive" gamers showing mild increases in problematic behaviors. Interestingly, "non-gamers" clearly show the worst outcomes. Therefore, both children and parents of non-game players should be updated about the positive impact of moderate video gaming. Educational interventions should also be designed to educate adolescents and their parents of the possible harmful impact of excessive video game playing on their health and psychosocial functioning.


An analysis of the differences in the acute hospitalization charges following minimally invasive versus open posterior lumbar interbody fusion.
Minimally invasive spine (MIS) procedures are increasingly being recognized as equivalent to open procedures with regard to clinical and radiographic outcomes. These techniques are also believed to result in less pain and disability in the immediate postoperative period. There are, however, little data to assess whether these procedures produce their intended result and even fewer objective data to demonstrate that they are cost effective when compared with open surgery. The authors performed a retrospective analysis of hospital charges for 1- and 2-level MIS and open posterior interbody fusion for lumbar spondylotic disease, disc degeneration, and spondylolisthesis treated at a single academic medical center. Patients presenting with bilateral neurological symptoms were treated with open surgery, and those with unilateral symptoms were treated with MIS. Overall hospital charges and surgical episode-related charges, length of stay (LOS), and discharge status were obtained from the hospital finance department and adjusted for multi-/single-level surgeries. During a 14-month period, 74 patients (mean age 55 years) were treated. The series included 59 single-level operations (75% MIS and 25% open), and 15 2-level surgeries (53% MIS and 47% open). The demographic profile, including age and Charlson Comorbidity Index, were similar between the 4 groups. The mean LOS for patients undergoing single-level surgery was 3.9 and 4.8 days in the MIS and open cases, respectively (p = 0.017). For those undergoing 2-level surgery, the mean LOS was 5.1 for MIS versus 7.1 for open surgery (p = 0.259). With respect to hospital charges, single-level MIS procedures were associated with an average of $70,159 compared with $78,444 for open surgery (p = 0.027). For 2-level surgery, mean charges totalled $87,454 for MIS versus $108,843 for open surgery (p = 0.071). For single-level surgeries, 5 and 20% of patients undergoing MIS and open surgery, respectively, were discharged to inpatient rehabilitation. For 2-level surgeries, the rates were 13 and 29%, respectively. While hospital setting, treatment population, patient selection, and physician expectation play major roles in determining hospital charges and LOS, this pilot study at an academic teaching hospital shows trends for quicker discharge, reduced hospital charges, and lower transfer rates to inpatient rehabilitation with MIS. However, larger multicenter studies are necessary to validate these findings and their relevance across diverse US practice environments.


Preserving quantum states using inverting pulses: a super-Zeno effect.
We construct an algorithm for suppressing the transitions of a quantum mechanical system, initially prepared in a subspace P of the full Hilbert space of the system, to outside this subspace by subjecting it to a sequence of unequally spaced short-duration pulses. Each pulse multiplies the amplitude of the vectors in the subspace by -1. The number of pulses required by the algorithm to limit the leakage probability to epsilon in time increases as T exp[square root log(T(2)/epsilon)], compared to T(2)epsilon(-1) in the standard quantum Zeno effect.


Representational untangling by the firing rate nonlinearity in V1 simple cells.
An important computational goal of the visual system is 'representational untangling' (RU): representing increasingly complex features of visual scenes in an easily decodable format. RU is typically assumed to be achieved in high-level visual cortices via several stages of cortical processing. Here we show, using a canonical population coding model, that RU of low-level orientation information is already performed at the first cortical stage of visual processing, but not before that, by a fundamental cellular-level property: the thresholded firing rate nonlinearity of simple cells in the primary visual cortex (V1). We identified specific, experimentally measurable parameters that determined the optimal firing threshold for RU and found that the thresholds of V1 simple cells extracted from in vivo recordings in awake behaving mice were near optimal. These results suggest that information re-formatting, rather than maximisation, may already be a relevant computational goal for the early visual system.


Potential involvement of the 18 kDa translocator protein and reactive oxygen species in apoptosis of THP-1 macrophages induced by sonodynamic therapy.
Sonodynamic therapy (SDT) with exogenous protoporphyrin IX (PpIX) or endogenous PpIX derived from 5-aminolevulinic acid (ALA) has been carried out to produce apoptotic effects on macrophages, indicating a potential treatment methodology for atherosclerosis. Our previous studies have found that mitochondria damage by reactive oxygen species (ROS) plays a major role in the SDT-induced apoptosis. This study aimed at investigating the potential involvement of the mitochondrial 18 kDa translocator protein (TSPO) and ROS in the pro-apoptotic effects of SDT on THP-1 macrophages. THP-1 macrophages were divided into control and SDT groups, and went through pretreatment of the specific TSPO ligand PK11195 and ROS scavengers N-Acetyl Cysteine (NAC), then compared with groups without pretreatment. Application of PK11195 reduced intracellular accumulation of endogenous PpIX. PK11195 and NAC reduced the generation of intracellular ROS and oxidation of cardiolipin induced by SDT, respectively. PK11195 and NAC also reduced SDT-induced mitochondrial membrane potential (ΔΨm) loss, the translocation of cytochrome c and cell apoptosis. PpIX accumulation, ROS generation and cell apoptosis were also attenuated by siTSPO. Our findings indicate the pivotal role of TSPO and ROS in SDT-induced cardiolipin oxidation, ΔΨm collapse, cytochrome c translocation and apoptosis in THP-1 macrophages.


Laser-induced breakdown spectroscopy of bulk aqueous solutions at oceanic pressures: evaluation of key measurement parameters.
The development of in situ chemical sensors is critical for present-day expeditionary oceanography and the new mode of ocean observing systems that we are entering. New sensors take a significant amount of time to develop; therefore, validation of techniques in the laboratory for use in the ocean environment is necessary. Laser-induced breakdown spectroscopy (LIBS) is a promising in situ technique for oceanography. Laboratory investigations on the feasibility of using LIBS to detect analytes in bulk liquids at oceanic pressures were carried out. LIBS was successfully used to detect dissolved Na, Mn, Ca, K, and Li at pressures up to 2.76 x 10(7) Pa. The effects of pressure, laser-pulse energy, interpulse delay, gate delay, temperature, and NaCl concentration on the LIBS signal were examined. An optimal range of laser-pulse energies was found to exist for analyte detection in bulk aqueous solutions at both low and high pressures. No pressure effect was seen on the emission intensity for Ca and Na, and an increase in emission intensity with increased pressure was seen for Mn. Using the dual-pulse technique for several analytes, a very short interpulse delay resulted in the greatest emission intensity. The presence of NaCl enhanced the emission intensity for Ca, but had no effect on peak intensity of Mn or K. Overall, increased pressure, the addition of NaCl to a solution, and temperature did not inhibit detection of analytes in solution and sometimes even enhanced the ability to detect the analytes. The results suggest that LIBS is a viable chemical sensing method for in situ analyte detection in high-pressure environments such as the deep ocean.


Diagnosis of bowel obstruction on plain abdominal radiographs: significance of air-fluid levels at different heights in the same loop of bowel.
Differential air-fluid levels are two distinct air-fluid interfaces on horizontal-beam abdominal radiographs that are at different heights but within the same loop of bowel. Differential air-fluid levels have been considered by many to be strong evidence of mechanical bowel obstruction, but others have found this sign unreliable for differentiating mechanical from adynamic obstructions. Neither opinion is supported by evidence from large series of patients. Accordingly, we determined the efficacy of differential air-fluid levels for distinguishing mechanical from adynamic bowel obstruction. We identified patients who had a total of 62 episodes of proved mechanical bowel obstruction and 38 episodes of adynamic obstruction through a computer search of medical records and radiographic files. On horizontal-beam abdominal radiographs of these patients, the presence and height of intestinal differential air-fluid levels were determined by the consensus of two experienced radiologists. These data were then statistically analyzed to determine the usefulness of differential air-fluid levels for distinguishing between mechanical and adynamic bowel obstructions. Plain films showed differential air-fluid levels in 32 (52%) of the 62 episodes of mechanical obstructions compared with 11 (29%) of the 38 adynamic obstructions, giving a sensitivity for mechanical obstruction of 0.52 and a specificity of 0.71. As the minimum significant height of differential air-fluid levels increased, specificity increased and sensitivity decreased. The positive predictive value also increased as differential air-fluid level heights increased, reaching a level of 0.86 or greater at 20 mm. The presence of differential air-fluid levels is an insensitive method of determining if a bowel obstruction is mechanical, because only a small proportion of mechanical obstructions have differential air-fluid levels. In our population of patients, however, a differential air-fluid level of 20 mm or greater was moderately suggestive that a bowel obstruction was mechanical in nature.


[Inhibition of CD96 enhances interferon-γ secretion by natural killer cells to alleviate lung injury in mice with pulmonary Chlamydia muridarum infection].
To assess the effect of neutralizing CD96 on natural killer (NK) cell functions in mice with pulmonary Chlamydia muridarum infection and explore the possible mechanism. Male BALB/c mice were randomly divided into infection group (Cm group), anti-CD96 treatment group (anti-CD96 group) and control group (n=5). In the former two groups, C. muridarum was inoculated via intranasal administration to establish mouse models of pulmonary C. muridarum infection, and the mice in the control group received intranasal administration of the inhalation buffer. In anti-CD96 group, the mice were injected with anti-CD96 antibody intraperitoneally at the dose of 250 μg every 3 days after the infection; the mice in Cm group received intraperitoneal injections of saline. The body weight of the mice was recorded daily. The mice were sacrificed 5 days after C. muridarum infection, and CD96 expression was detected by quantitative real-time PCR and Western blotting. HE staining and pathological scores were used to evaluate pneumonia of the mice. The inclusion body forming units (IFUs) were detected in the lung tissue homogenates to assess lung tissue chlamydia load. Flow cytometry and ELISA were used to assess the capacity of the lung NK cells to produce interferon-γ (IFN-γ) and regulate macrophages and Th1 cells. C. muridarum infection inhibited CD96 expression in NK cells of the mice. Compared with those in Cm group, the mice in antiCD96 mice showed significantly milder lung inflammation (P < 0.05) and reduced chlamydia load in the lung tissue (P < 0.05). Neutralizing CD96 with anti-CD96 significantly enhanced IFN-γ secretion by the NK cells (P < 0.05) and augmented the immunoregulatory effect of the NK cells shown by enhanced responses of the lung macrophages (P < 0.05) and Th1 cells (P < 0.05). Inhibition of CD96 alleviates pneumonia in C. muridarum-infected mice possibly by enhancing IFN-γ secretion by NK cells and augmenting the immunoregulatory effect of the NK cells on innate and adaptive immunity.


Stenotrophomonas maltophilia Infections in Pediatric Patients - Experience at a European Center for Pediatric Hematology and Oncology.
Stenotrophomonas maltophilia is an important nosocomial pathogen in immunocom-promised individuals and characterized by intrinsic resistance to broad-spectrum antibacterial agents. Limited data exists on its clinical relevance in immunocompromised pediatric patients, particularly those with hematological or oncological disorders. In a retrospective single center cohort study in pediatric patients receiving care at a large european pediatric hematology and oncology department, ten cases of invasive S.maltophilia infections (blood stream infections (BSI), 4; BSI and pneumonia, 3, or soft tissue infection, 2; and pneumonia, 1) were identified between 2010 and 2020. Seven patients had lymphoblastic leukemia and/or were post allogeneic hematopoietic cell transplantation. Invasive S.maltophilia infections occurred in a setting of indwelling central venous catheters, granulocytopenia, defective mucocutaneous barriers, treatment with broad-spectrum antibacterial agents, and admission to the intensive care unit. Whole genome sequencing based typing revealed no genetic relationship among four individual S.maltophilia isolates. The case fatality rate and mortality at 100 days post diagnosis were 40 and 50%, respectively, and three patients died from pulmonary hemorrhage. Invasive S.maltophilia infections are an emerging cause of infectious morbidity in patients receiving care at departments of pediatric hematology and oncology and carry a high case fatality rate.


The centrosomal kinase Plk1 localizes to the transition zone of primary cilia and induces phosphorylation of nephrocystin-1.
Polo-like kinase (Plk1) plays a central role in regulating the cell cycle. Plk1-mediated phosphorylation is essential for centrosome maturation, and for numerous mitotic events. Although Plk1 localizes to multiple subcellular sites, a major site of action is the centrosomes, which supports mitotic functions in control of bipolar spindle formation. In G0 or G1 untransformed cells, the centriolar core of the centrosome differentiates into the basal body of the primary cilium. Primary cilia are antenna-like sensory organelles dynamically regulated during the cell cycle. Whether Plk1 has a role in ciliary biology has never been studied. Nephrocystin-1 (NPHP1) is a ciliary protein; loss of NPHP1 in humans causes nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. We here demonstrate that Plk1 colocalizes with nephrocystin-1 to the transition zone of primary cilia in epithelial cells. Plk1 co-immunoprecipitates with NPHP1, suggesting it is part of the nephrocystin protein complex. We identified a candidate Plk1 phosphorylation motif (D/E-X-S/T-φ-X-D/E) in nephrocystin-1, and demonstrated in vitro that Plk1 phosphorylates the nephrocystin N-terminus, which includes the specific PLK1 phosphorylation motif. Further, induced disassembly of primary cilia rapidly evoked Plk1 kinase activity, while small molecule inhibition of Plk1 activity or RNAi-mediated downregulation of Plk1 limited the first and second phase of ciliary disassembly. These data identify Plk1 as a novel transition zone signaling protein, suggest a function of Plk1 in cilia dynamics, and link Plk1 to the pathogenesis of NPH and potentially other cystic kidney diseases.


Mental health and mental illness in the workplace: diagnostic and treatment issues.
Mental health, mental illness and stress-related disability are especially ill-defined, complex and controversial issues when considered in the context of the workplace. A multi-determined disorder such as major depressive disorder (MDD) does not fit a simple cause and effect model, but is similar to other complex occupational illnesses such as low back pain. Currently, a knowledge gap exists between mental health professionals and employers regarding symptom-based models of illness and function-based models of work performance. As a result, psychiatric disorders affecting workers are under-identified and under-treated and likely result in unmitigated impairment and disability. The authors examine several conceptual models for workplace mental illness across medical and psychological disciplines and propose a unifying construct. The utility of the existing screening methods for common workplace illnesses and their potential application are reviewed. The challenges of diagnosis and effective treatment of workplace mental illness are highlighted within an "occupational mental health system" with suggestions for future research directions.


Characteristics of the Molecular Weight of Polyhexamethylene Guanidine (PHMG) Used as a Household Humidifier Disinfectant.
(1) Background: Household humidifier disinfectant (HD) brands containing polyhexamethylene guanidine (PHMG) have been found to cause the most HD-associated lung injuries (HDLIs) in the Republic of Korea. Nevertheless, no study has attempted to characterize the potential association of the health effects, including HDLI, with the physicochemical properties of PHMG dissolved in different HD brands. This study aimed to characterize the molecular weight (MW) distribution, the number-average molecular weight (Mn), the weight-average molecular weight (Mw), and the structural types of PHMG used in HD products. (2) Methods: Quantitative measurements were made using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The Mn, Mw, and MW distributions were compared among various HD products. (3) Results: The mean Mn and Mw were 542.4 g/mol (range: 403.0-692.2 g/mol) and 560.7 g/mol (range: 424.0-714.70 g/mol), respectively. The degree of PHMG oligomerization ranged from 3 to 7. The MW distribution of PHMG indicated oligomeric compounds regardless of the HD brands. (4) Conclusions: Based on the molecular weight distribution, the average molecular weight of PHMG, and the degree of polymerization, the PHMG collected from HDLI victims could be regarded as an oligomer. PHMG, as used in household humidifiers, should not be exempted from toxic chemical registration as a polymer. Further study is necessary to examine the association of PHMG oligomeric compounds and respiratory health effects, including HDLI.


Selected behaviors that increase risk for HIV infection among high school students--United States, 1990.
From January 1987 through December 1991, the cumulative number of acquired immunodeficiency syndrome (AIDS) cases among adolescents aged 13-19 years in the United States increased from 127 to 789, and in 1989, AIDS became the sixth leading cause of death for persons aged 15-24 years. Because the median incubation period between infection with human immunodeficiency virus (HIV) and onset of AIDS is nearly 10 years, many 20-29-year-olds with AIDS may have been infected during adolescence. Surveillance of selected sexual and injecting-drug-use (IDU) behaviors among adolescents can provide critical information about the risk for HIV infection among this group. This article presents self-reported data from 1990 about HIV-risk behaviors among U.S. high school students and describes strategies to reduce HIV infection among adolescents.


[Teaching of nursing in Rio Grande do Sul in the 1950].
The purpose of this research was to analyze how the undergraduate teaching of nursing in Rio Grande do Sul has constructed its knowledge, since the first course, as of the decade of 1950s. The survey has involved teaching nurses who have lived such period of our history, and the discourse analysis has been utilized for the documental analysis. The information data indicate, among them, the most integrated curriculum that seeks articulating theory/practice without fragmenting the knowledge and the teaching-learning relationship, wherein professors and students are subjects of such procedure.


Cloning and partial characterization of regulated promoters from Lactococcus lactis Tn917-lacZ integrants with the new promoter probe vector, pAK80.
Transposon Tn917-LTV1 was used to produce a collection of Lactococcus lactis strains with fusion of a promoterless lacZ gene to chromosomal loci. Screening 2,500 Tn917-LTV1 integrants revealed 222 that express beta-galactosidase on plates at 30 degrees C. Pulsed-field gel electrophoresis revealed Tn917-LTV1 insertions in at least 13 loci in 15 strains analyzed. Integrants in which beta-galactosidase expression was regulated by temperature or pH and/or arginine concentration were isolated. In most cases, the regulation observed on plates was reproducible in liquid medium. One integrant, PA170, produces beta-galactosidase at pH 5.2 but not at pH 7.0, produces more beta-galactosidase at 15 degrees C than at 30 degrees C, and has increased beta-galactosidase activity in the stationary phase. DNA fragments potentially carrying promoters from selected Lactococcus lactis integrants were cloned in Escherichia coli. A new promoter probe vector, pAK80, containing promoterless beta-galactosidase genes from Leuconostoc mesenteroides subsp. cremoris and the Lactococcus lactis subsp. lactis biovar diacetylactis citrate plasmid replication region was constructed, and the lactococcal fragments were inserted. Plasmid pAK80 was capable of detecting and discriminating even weak promoters in Lactococcus lactis. When inserted in pAK80, the promoter cloned from PA170 displayed a regulated expression of beta-galactosidase analogous to the regulation observed in PA170.


Passive and active DNA methylation and the interplay with genetic variation in gene regulation.
DNA methylation is an essential epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not fully understood. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression. DOI:http://dx.doi.org/10.7554/eLife.00523.001.


[Headache in Behçet's disease: case-control study and literature review].
To evaluate the prevalence of headache and its different patterns in patients with Behçet's disease (BD) with and without neurological involvement and to investigate clinical correlations. Patients fulfilling the International Study Group criteria for Behçet disease (ISGc) were studied. Patients were invited to fill a "headache questionnaire", which consisted of two sections: the first one included demographic and anamnestic data, family history for both headache and BD, disease duration and clinical manifestations of BD; the second section included items about headache, investigated accordingly to International Headache Society diagnostic criteria (IHS, 2004). Clinical history and current comorbidities-medications were collected. Each patient underwent a neurological examination to assess neurological involvement (Neuro-BD) and, if necessary, instrumental investigations. One hundred-fifty healthy subjects matched for age and gender were used as control group for comparison. Of the 55 patients diagnosed as BD (ISG criteria) 41 patients adhered and were enrolled into the study. Headache occurred in 29 of BD patients (70,7%) and in 13 of Neuro-BD patients (92,8%). Migraine without aura did prove the most frequent type of headache in BD patients (with and without neurological involvement) and there were no differences in the frequency of the different pattern of headache between BD patients and controls. Headache is a frequent manifestation in BD and primary headache like migraine emerged as the most frequent type of headache. A careful search for headache should be included in the diagnostic work-up of BD since this manifestation may be related to the underlying disease.


Disrupted corticosterone pulsatile patterns attenuate responsiveness to glucocorticoid signaling in rat brain.
Chronically elevated circulating glucocorticoid levels are although to enhance vulnerability to psychopathology. Here we hypothesized that such sustained glucocorticoid levels, disturbing corticosterone pulsatility, attenuate glucocorticoid receptor signaling and target gene responsiveness to an acute challenge in the rat brain. Rats were implanted with vehicle or 40 or 100% corticosterone pellets known to flatten ultradian and circadian rhythmicity while maintaining daily average levels or mimic pathological conditions. Additionally, recovery from constant exposure was studied in groups that had the pellet removed 24 h prior to the challenge. Molecular markers for receptor responsiveness (receptor levels, nuclear translocation, promoter occupancy, and target gene expression) to an acute challenge mimicking the stress response (3 mg/kg ip) were studied in the hippocampal area. Implantation of 40 and 100% corticosterone pellets dose-dependently down-regulated glucocorticoid receptor and attenuated mineralocorticoid receptor and glucocorticoid receptor translocation to the acute challenge. Interestingly, whereas target gene Gilz expression to the challenge was already attenuated by tonic daily average levels (40%), Sgk-1 was affected only after constant high corticosterone exposure (100%), indicating altered receptor responsiveness due to treatment. Washout of 100% corticosterone recovered all molecular markers (partial), whereas removal of the 40% corticosterone pellet still attenuated responsiveness to the challenge. We propose that corticosteroid pulsatility is crucial in maintaining normal responsiveness to glucocorticoids. Whereas the results with 100% corticosterone are likely attributed to receptor saturation, subtle changes in the pattern of exposure (40%) induces changes at least as severe for glucocorticoid signaling as overt hypercorticism, suggesting an underlying mechanism sensitive to the pattern of hormone exposure.


[Identification of the enterobacteria isolated from patients by using the Enterotube test system].
The Enterotube test system intended for the accelerated identification of enterobacteria was used to study 319 strains isolated from patients with suppurative complications after surgical operations and traumatic lesions. The test system was found to allow a reliable identification of Enterobacteriaceae having characteristic biochemical properties. It was also found that the kit intended for 10 tests could prove insufficient for the identification of atypical bacteria. The Enterotube test system made it possible to differentiate 95% of enterobacterial strains; in the identification of bacteria by their genus and species and results obtained with the use of the Enterotube test system and common biochemical methods were found to be identical (in 96.4% of tests).


Systematic review of guidelines for managing physical health during treatment for substance use disorders: Implications for the alcohol and other drug workforce.
Substance use disorders are associated with significant physical health comorbidities, necessitating an integrated treatment response. However, service fragmentation can preclude the management of physical health problems during addiction treatment. The aim of this systematic review was to synthesise the recommendations made by clinical practice guidelines for addressing the physical health of people attending alcohol and other drug (AOD) treatment. An iterative search strategy of grey literature sources was conducted from September 2020 to February 2021 to identify clinical practice guidelines. Content pertaining to physical health care during AOD treatment was extracted. Quality of guidelines were appraised using the Appraisal of Guidelines Research and Evaluation II (AGREE-II) tool. Thirty-three guidelines were included for review. Fourteen guidelines were considered high quality based on AGREE-II scores. Neurological conditions (90.9%) and hepatitis (81.8%) were the most frequent health problems addressed. Most guidelines recommended establishing referral pathways to address physical health comorbidities (90.9%). Guidance on facilitating these referral pathways was less common (42.4%). Guidelines were inconsistent in their recommendations related to oral health, tobacco use, physical activity, nutrition and the use of standardised assessment tools. Greater consistency and specificity in the recommendations made for integrating physical health care within addiction treatment is needed. Ensuring that recommendations are applicable to the AOD workforce and to treatment services limited by funding and resource constraints should enhance implementation. Future guideline development groups should consider increased consultation with the AOD workforce and inclusion of clinical tools and decision aids to facilitate referral pathways.


[Hyperbaric oxygen treatment for macular edema after retinal vein occlusion--fluorescein angiographic findings and visual prognosis].
It has been reported that hyperbaric oxygen treatment improves visual function in patients with chronic macular edema associated with retinal vein occlusion. This study was designed to investigate relationship between visual prognosis and characteristics of macular edema. From fluorescein angiography performed prior to the therapy, areas of capillary closure and fluorescein leakages were quantitatively evaluated within 1 disc diameter from the fovea. In 27 eyes for which good angiograms were available, 19 eyes were classified as having mild ischemia 1 (area of capillary closure < 25%) and 8 eyes were classified as having severe ischemia (closure area < or = 25%). Of the 27 eyes, 14 showed visual improvement after the therapy. While only one eyes (13%) had visual improvement in the severe ischemic group, 11 eyes (58%) showed visual improvement in the mild ischemic group. The degree of fluorescein leakage before the therapy had no effect on visual outcome. The degree of macular ischemia was found to be a more significant factor influencing visual prognosis after the treatment than the degree of macular edema.


Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial.
No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Randomized, double-blind, placebo-controlled trial. Medical intensive care units of 4 medical centers. Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO2 to fraction of inspired oxygen (FIO2), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO2 to FIO2 (mean [SEM], 262 [19] vs 148 [35]; P<.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P=.03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.


Chemotherapy for squamous cell carcinoma of the head and neck: an overview.
Chemotherapy is being utilized to treat patients with recurrent tumors and advanced squamous cell carcinoma of the head and neck. Current treatment modalities utilized include intra-arterial chemotherapy, simultaneous and sequential chemotherapy and radiation therapy, and neoadjuvant chemotherapy. Each of these modes of treatment, as well as pharmacology of squamous cell-active chemotherapeutic agents, will be addressed in this review.


Global, regional, and national trends in incidence of depression among women, 1990-2019: An analysis of the global burden of disease study.
Depression is a common mental disorder and more women are affected by depression than men. In this study, we aimed to analyze the trends in the incidence of depression among women from 1990 to 2019 and their associations with sociodemographic and universal health coverage indices based on data from the Global Burden of Disease study 2019. It was observed that while the incidence rate of depression among women decreased by an average of 0.35% per year at the global level, the incidence rate increased at the regional level for the high sociodemographic index region by an average of 0.39% per year from 1990 to 2019. And the global downward trend in incidence rate from 1990 to 2019 was contributed by the downward trend from 2000 to 2009. In Spearman correlation analyzes at the level of country/territory, a negative correlation between the estimated annual percentage change in the incidence rate and the universal health coverage index was found (ρ=-0.15).


A Community-Based, Technology-Supported Health Service for Detecting and Preventing Frailty among Older Adults: A Participatory Design Development Process.
Frailty is a multifaceted condition that affects many older adults and marks decline on areas such as cognition, physical condition, and nutritional status. Frail individuals are at increased risk for the development of disability, dementia, and falls. There are hardly any health services that enable the identification of prefrail individuals and that focus on prevention of further functional decline. In this paper, we discuss the development of a community-based, technology-supported health service for detecting prefrailty and preventing frailty and further functional decline via participatory design with a wide range of stakeholders. The result is an innovative service model in which an online platform supports the integration of traditional services with novel, Information Communication Technology supported tools. This service is capable of supporting the different phases of screening and offers training services, by also integrating them with community-based services. The service model can be used as a basis for developing similar services within a wide range of healthcare systems. We present the service model, the general functioning of the technology platform, and the different ways in which screening for and prevention of frailty has been localized. Finally, we reflect on the added value of participatory design for creating such health services.


[Preoperative sanation of the bronchi].
Among 255 patients with suppurative pulmonary diseases, aerosol therapy was performed preoperatively in 80 patients, complex sanation of bronchi--in 140, including 30--in association with visual sounding of segmental bronchi and intrapulmonary suppurative foci. As a result of complex sanation of bronchi, as compared with patients in whom no sanation was performed, or it was limited only by aerosol therapy, there was noted a reliable decrease in the number of postoperative pleural empyemas and bronchial fistulas, as well as an increase in the number of patients discharged with a recovery from 74.3% and 78.7% to 90%.


Could this be measles?
Infection with the measles virus causes an unpleasant disease with many potentially serious complications. It is predominantly a childhood illness but can affect any age. Measles is extraordinarily contagious, but immunisation with measles containing vaccine provides comprehensive protection. An international programme of universal immunisation from the mid-1980s has been very effective; measles was declared eliminated in the USA nearly two decades ago and became a rarity in other countries with high rates of vaccine uptake. Until recently, this was a forgotten disease in high-income countries, but paediatricians, emergency and primary care physicians worldwide are now encountering measles with increased frequency. Attributed to international travel and pockets of vaccine hesitancy locally, new outbreaks of measles have been recorded in many regions thought to have been free of the disease. Because it was previously so uncommon, measles presents a diagnostic challenge and an unrecognised case may cause infection to spread among communities. The present article presents a case of confirmed measles infection and discusses the epidemiology, clinical features, investigation, management and prevention of measles.


Marked variability in the radiographic features of cartilage-hair hypoplasia: case report and review of the literature.
Cartilage-hair hypoplasia (CHH) is a rare recessive metaphyseal chondrodysplasia characterized by severe short stature, ectodermal dysplasia, anemia in childhood, immune deficiency, susceptibility to malignancy, and normal intelligence. Short, thick long bones, metaphyseal flaring and irregularities, and globular epiphyses at the knees and ankles are the typical radiographic findings. The diagnosis is primarily made on the basis of clinical features, although mutations in the RMRP gene have recently been described in affected individuals, facilitating confirmation of the clinical diagnosis in atypical patients. We present a patient with two RMRP mutations whose stature and ectodermal features supported the diagnosis of CHH, but whose radiographic findings and other extraskeletal findings did not. We propose that the most consistent and reliable features of CHH are short stature of prenatal onset and ectodermal dysplasia, and suggest that the diagnosis of CHH be considered and mutation analysis pursued even when typical radiographic findings are absent.


[Inhibiting action of glycomacropeptide on stomach secretion induced by various humoral stimulants].
Tests staged on dogs demonstrated the action of GMP to differ depending upon the nature of the gastric secretion stimulant actually used. The inhibition of the gastric juice secretion occurring against the background of multiple introduction of histamine or gastrin tetrapeptide amide was quite spectacular: the secretion dropped down to zero and the action was more prolonged than following administration of pentagastrin with which the secretion was not inhibited to such a sharp degree and the effect of GMP was less protracted. The mechanism of the GMP action of the gastric secretion and the causes of described differences require further investigations.


Enhanced memory ability: Insights from synaesthesia.
People with synaesthesia show an enhanced memory relative to demographically matched controls. The most obvious explanation for this is that the 'extra' perceptual experiences lead to richer encoding and retrieval opportunities of stimuli which induce synaesthesia (typically verbal stimuli). Although there is some evidence for this, it is unlikely to be the whole explanation. For instance, not all stimuli which trigger synaesthesia are better remembered (e.g., digit span) and some stimuli which do not trigger synaesthesia are better remembered. In fact, synaesthetes tend to have better visual memory than verbal memory. We suggest that enhanced memory in synaesthesia is linked to wider changes in cognitive systems at the interface of perception and memory and link this to recent findings in the neuroscience of memory.


Cost effectiveness of a new strategy to identify HNPCC patients.
Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives. To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years. The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals. Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of 3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became 2184 per life year gained. Sensitivity analysis showed these findings to be robust. MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.


[New possibilities resulting from oocyte banking].
Oocyte cryopreservation solves the legal and ethical problems associated with the cryopreservation of embryos in patients undergoing in vitro fertilization procedures. Furthermore, it may also offer the possibility of extending the reproductive capability of young women with malignant diseases in cases where the treatment may compromise the ovarian reserve. Moreover, it may also offer alternatives for infertile patients who are subject to ovarian hyper-stimulation syndrome or premature ovarian faiLure or who require oocyte donation. The creation of banks for cryopreserved oocytes avoids the need for cycle synchronization or the formation of an over-supply of embryos destined for cryopreservation. If a Large number of oocytes is obtained it could possibly enable women and couples the opportunity to postpone childbirth according to their wishes. This paper reviews the revolution obtained by oocyte vitrification, reports on ethical issues and discusses the pros and cons of oocyte banking and its potential effects on society.


5,14-Diaryldiindeno[2,1- f:1',2' -j]picene: A New Stable [7]Helicene with a Partial Biradical Character.
5,14-Diaryldiindeno[2,1- f:1',2' -j]picene (DDP, 1), a thermally and chemically stable helical arene, can be prepared from 1,4-bis[2-(arylethynyl)phenyl]benzene in four synthetic steps. Its helical backbone, which incorporates an o-quinodimethane moiety, was verified by X-ray crystallography, and this structural feature results in a very high barrier to racemization (exceeding 50 kcal/mol). DDP possesses versatile and promising properties, including a small HOMO-LUMO energy gap (1.31 eV for the dimesityl-substituted derivative 1ab), an electron spin resonance (ESR)-active character, a small triplet-singlet energy gap (4.75 kcal/mol), broad photoabsorption covering the ultraviolet, visible, and near-infrared (NIR) regions, two-photon absorption in the NIR range, and respectable ambipolar charge-transport behavior in a solution-processed organic field-effect transistor.


Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes--focus on pancreatitis and pancreas cancer.
The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide , is a widely used drug for the treatment of type 2 diabetes. Liraglutide is one of several incretin-based agents that have been suggested to be associated with pancreatitis and pancreas cancer. The suspicion accelerated after publication of an autopsy study claiming increased incidences of several pathological changes in pancreata from patients with diabetes treated with incretin-based drugs. The aim of the present review is to give an overview of the pharmacology of liraglutide and provide a review of adverse reactions associated with liraglutide with a focus on the risk of pancreatitis and pancreas cancer. When comprehensively reviewing the available literature, no clear and significant associations between liraglutide and pancreatitis and/or pancreas cancer seem evident. However, a recently published analysis suggests a trend toward a slightly elevated risk of pancreatitis with GLP-1 receptor agonists (including liraglutide), which may become statistical significant as more data become available. Well-established side effects are of gastrointestinal origin, typical mild-to-moderate and of transient character. The risk of hypoglycemia associated with liraglutide treatment is low.


Usefulness of the pancreas as a prime target for histopathological diagnosis of Tilapia parvovirus (TiPV) infection in Nile tilapia, Oreochromis niloticus.
Tilapia parvovirus (TiPV) is an emerging virus reportedly associated with disease and mortality in farmed tilapia. Although previous descriptions of histopathological changes are available, the lesions reported in these are not pathognomonic. Here, we report Cowdry type A inclusion bodies (CAIB) in the pancreas as a diagnostic histopathological feature found in adult Nile tilapia naturally infected with TiPV. This type of inclusion body has been well-known as a histopathological landmark for the diagnosis of other parvoviral infections in shrimp and terrestrial species. Interestingly, this lesion could be exclusively observed in pancreatic acinar cells, both in the hepatopancreas and pancreatic tissue along the intestine. In situ hybridization (ISH) using a TiPV-specific probe revealed the intranuclear presence of TiPV DNA in multiple tissues, including the liver, pancreas, kidney, spleen, gills and the membrane of oocytes in the ovary. These findings suggest that although TiPV can replicate in several tissue types, CAIB manifest exclusively in pancreatic tissues. In addition to TiPV, most diseased fish were co-infected with Streptococcus agalactiae, and presented with multifocal granulomas secondary to this bacterial infection. Partial genome amplification of TiPV was successful and revealed high nucleotide identity (>99%) to previously reported isolates. In summary, this study highlights the usefulness of pancreatic tissue as a prime target for histopathological diagnosis of TiPV in diseased Nile tilapia. This pattern may be critical when determining the presence of TiPV infection in new geographic areas, where ancillary testing may not be available. TiPV pathogenesis in this landmark organ warrants further investigation.


Development of myenteric cholinergic neurons in ChAT-Cre;R26R-YFP mice.
Cholinergic neurons are the major excitatory neurons of the enteric nervous system (ENS), and include intrinsic sensory neurons, interneurons, and excitatory motor neurons. Cholinergic neurons have been detected in the embryonic ENS; however, the development of these neurons has been difficult to study as they are difficult to detect prior to birth using conventional immunohistochemistry. In this study we used ChAT-Cre;R26R-YFP mice to examine the development of cholinergic neurons in the gut of embryonic and postnatal mice. Cholinergic (YFP+) neurons were first detected at embryonic day (E)11.5, and the proportion of cholinergic neurons gradually increased during pre- and postnatal development. At birth, myenteric cholinergic neurons comprised less than half of their adult proportions in the small intestine (25% of myenteric neurons were YFP+ at P0 compared to 62% in adults). The earliest cholinergic neurons appear to mainly project anally. Projections into the presumptive circular muscle were first observed at E14.5. A subpopulation of cholinergic neurons coexpress calbindin through embryonic and postnatal development, but only a small proportion coexpressed neuronal nitric oxide synthase. Our study shows that cholinergic neurons in the ENS develop over a protracted period of time.


Taking apart what brings us together: The role of action prediction, perspective-taking, and theory of mind in joint action.
The ability to act together with others to achieve common goals is crucial in life, yet there is no full consensus on the underlying cognitive skills. While influential theoretical accounts suggest that interaction requires sophisticated insights into others' minds, alternative views propose that high-level social skills might not be necessary because interactions are grounded on sensorimotor predictive mechanisms. At present, empirical evidence is insufficient to decide between the two. This study addressed this issue and explored the association between performance at joint action tasks and cognitive abilities in three domains-action prediction, perspective-taking, and theory of mind-in healthy adults (N = 58). We found that, while perspective-taking played a role in reading the behaviour of others independently of the social context, action prediction abilities specifically influenced the agents' performance in an interactive task but not in a control (social but non-interactive) task. In our study, performance at a theory of mind test did not play any role, as confirmed by Bayesian analyses. The results suggest that, in adults, sensorimotor predictive mechanisms might play a significant and specific role in supporting interpersonal coordination during motor interactions. We discuss the implications of our findings for the contrasting theoretical views described earlier and propose a way they might be partly reconciled.


[Allergic conjunctivitis in children].
Allergic conjunctivitis is a group of diseases that are frequent in childhood, associated to several allergic diseases affecting the ocular surface. It is related to type 1 hypersensitivity reactions. Two acute disorders: seasonal allergic conjunctivitis and perennial allergic conjunctivitis, exist, as do three chronic diseases: vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis. The ocular surface inflammation causes itching, tearing, lid and conjunctival edema-redness, and photophobia during the acute phase and can lead to a classic late-phase response (associated to eosinophilia and neutrophilia) in a subset of individuals. As in the case of several chronic allergic diseases, it can remodel the ocular surface tissue. This allergic disease is very frequent. Vernal keratoconjunctivitis could produce corneal lesions and visual illness; however, atopic keratoconjunctivitis does not permanently affect the vision. The aim of this review is to provide a current overview for a better understanding of the symptoms associated to this disease, to describe its classification, recent advances in its physiopathology and its treatment.


Quantitative western blotting using [gamma-33P]ATP and the ultrasensitive bio-imaging analyzer.
This report describes a method for simultaneous quantitative determination of antigens from protein blots based on the highly sensitive "contact-copy" procedure, applying the phosphorylation reaction as a general detection principle. Using ultrasensitive bio-imaging analyzer systems permits us to quickly and easily quantify single bands directly from the picture screen and to achieve a high-resolution printing of the image (pictography). By applying a new kanamycin loading procedure it is possible to use phosphocellulose paper P81 as a substrate matrix. Replacing 32P with 33P as a detection isotope leads to an improvement of the sensitivity, resolution, and safety. The method is applied to analyze the proteins dystrophin, myosin, vinculin, and desmin from human tissue lysates. The high sensitivity of the procedure (detection limit approximately 1 pg dystrophin) permits determination of the quantity of dystrophin in very small tissue biopsy samples, which is of special interest for Duchenne/Becker muscular dystrophy diagnosis.


Initial management of Parkinson's disease.
Parkinson's disease is one of the most common neurodegenerative disorders seen in the United States and United Kingdom. The disease is characterised by two processes-cellular degeneration and the resulting biochemical deficiency of dopamine. Although these processes are inter-related, they are approached separately in the clinical setting. Currently, no proven neuroprotective or disease modifying treatment is available for Parkinson's disease. Several agents can be used to treat the motor symptoms associated with dopamine deficiency, and it is important to choose wisely when starting treatment. Drugs can have mild, moderate, or high potency, and the patient's goals, comorbidities, and the short and long term implications of choosing a specific agent should be taken into account when selecting the appropriate agent. Non-motor symptoms, such as depression, fatigue, and disorders of sleep and wakefulness, also need to be evaluated and treated. Research is under way to deliver dopaminergic therapy more effectively, but studies aimed at slowing or stopping disease progression have not shown promise.


Coral community response to bleaching on a highly disturbed reef.
While many studies of coral bleaching report on broad, regional scale responses, fewer examine variation in susceptibility among coral taxa and changes in community structure, before, during and after bleaching on individual reefs. Here we report in detail on the response to bleaching by a coral community on a highly disturbed reef site south of mainland Singapore before, during and after a major thermal anomaly in 2010. To estimate the capacity for resistance to thermal stress, we report on: a) overall bleaching severity during and after the event, b) differences in bleaching susceptibility among taxa during the event, and c) changes in coral community structure one year before and after bleaching. Approximately two thirds of colonies bleached, however, post-bleaching recovery was quite rapid and, importantly, coral taxa that are usually highly susceptible were relatively unaffected. Although total coral cover declined, there was no significant change in coral taxonomic community structure before and after bleaching. Several factors may have contributed to the overall high resistance of corals at this site including Symbiodinium affiliation, turbidity and heterotrophy. Our results suggest that, despite experiencing chronic anthropogenic disturbances, turbid shallow reef communities may be remarkably resilient to acute thermal stress.


Using a knowledge translation framework to implement asthma clinical practice guidelines in primary care.
Quality problem International guidelines establish evidence-based standards for asthma care; however, recommendations are often not implemented and many patients do not meet control targets. Initial assessment Regional pilot data demonstrated a knowledge-to-practice gap. Choice of solutions We engineered health system change in a multi-step approach described by the Canadian Institutes of Health Research knowledge translation framework. Implementation Knowledge translation occurred at multiple levels: patient, practice and local health system. A regional administrative infrastructure and inter-disciplinary care teams were developed. The key project deliverable was a guideline-based interdisciplinary asthma management program. Six community organizations, 33 primary care physicians and 519 patients participated. The program operating cost was $290/patient. Evaluation Six guideline-based care elements were implemented, including spirometry measurement, asthma controller therapy, a written self-management action plan and general asthma education, including the inhaler device technique, role of medications and environmental control strategies in 93, 95, 86, 100, 97 and 87% of patients, respectively. Of the total patients 66% were adults, 61% were female, the mean age was 35.7 (SD = ± 24.2) years. At baseline 42% had two or more symptoms beyond acceptable limits vs. 17% (P< 0.001) post-intervention; 71% reported urgent/emergent healthcare visits at baseline (2.94 visits/year) vs. 45% (1.45 visits/year) (P< 0.001); 39% reported absenteeism (5.0 days/year) vs. 19% (3.0 days/year) (P< 0.001). The mean follow-up interval was 22 (SD = ± 7) months. Lessons learned A knowledge-translation framework can guide multi-level organizational change, facilitate asthma guideline implementation, and improve health outcomes in community primary care practices. Program costs are similar to those of diabetes programs. Program savings offset costs in a ratio of 2.1:1.


[Induction of ovulation, with pulsatile GnRH by subcutaneous route in amenorrhea of hypothalamic origin].
Twelve patients affected by secondary amenorrhea of hypothalamic origin, resistant to Clomiphene Citrate treatment, were treated for 2 consecutive cycles with subcutaneous pulsatile administration (s.c.) of Gn-RH by computerized portable pump (Ziklomat-Ferring) at a dose of 20 mcg every 60-90 minutes for a total of 20 cycles. On the average 85% of ovulatory cycles and 30% of pregnancies per cycle were obtained with this therapy. The number of ovulatory cycles and pregnancies obtained in the second cycle of treatment were in percentage higher, with respect to the first cycle of treatment. Only one subject, not responsive to both cycles of s.c. administration, underwent an intravenous therapy with positive results.


AIDS-related lymphoma: resolution with antiretroviral therapy alone.
Patients with HIV are at increased risk of malignancy, particularly lymphoma, which is the most common malignancy leading to death. With the advent of highly active antiretroviral therapy (HAART), patients live longer but have a longer duration of antigenic stimulation, increasing the prevalence of AIDS-related lymphoma (ARL) in the population living with HIV. Highly active antiretroviral therapy plays a direct role in preserving the immune system, helping to decrease the incidence of ARL. We present a case of a female patient with HIV (CD4 count of 576 cells/mm3) diagnosed with a stage Ill-B non-Hodgkin lymphoma in 2009 while off HAART. She was subsequently started on HAART, leading to full resolution of her lymphoma without any chemotherapeutic intervention. She was last seen in the clinic in December 2013 without any evidence of recurrence of her lymphoma. To our knowledge, this is the first case report of a stage III-B non-Hodgkin<in lymphoma in an HIV-infected patient, which resolved with only HAART.


Effects of diets containing grape seed, linseed, or both on milk production traits, liver and kidney activities, and immunity of lactating dairy ewes.
This study aimed to evaluate the effects of the dietary inclusion of grape seed, alone or in combination with linseed, on milk production traits, immune response, and liver and kidney metabolic activity of lactating ewes. Twenty-four Sarda dairy ewes were randomly assigned to 4 dietary treatments consisting of a control diet (CON), a diet containing 300 g/d per head of grape seed (GS), a diet containing 220 g/d per head of extruded linseed (LIN), and a diet containing a mix of 300 g/d per head of grape seed and 220 g/d per head of extruded linseed (MIX). The study lasted 10 wk, with 2 wk of adaptation period and 8 wk of experimental period. Milk yield was measured and samples were collected weekly and analyzed for fat, protein, casein, lactose, pH, milk urea nitrogen, and somatic cell count. Blood samples were collected every 2 wk by jugular vein puncture and analyzed for hematological parameters, for albumin, alkaline phosphatase, bilirubin, creatinine, gamma glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, protein, blood urea nitrogen, and for anti-albumin IgG, IL-6, and lymphocyte T-helper (CD4(+)) and lymphocyte T-cytotoxic (CD8(+)) cells. On d 0, 45, and 60 of the trial, lymphocyte response to phytohemagglutinin was determined in vivo on each animal by measuring skin-fold thickness (SFT) at the site of phytohemagglutinin injection. Humoral response to chicken egg albumin was stimulated by a subcutaneous injection with albumin. Dietary treatments did not affect milk yield and composition. Milk urea nitrogen and lactose were affected by diet × period. Diets did not influence hematological, kidney, and liver parameters, except for blood urea nitrogen, which decreased in LIN and increased in MIX compared with CON and GS. Dietary treatments did not alter CD4(+), CD8(+), and CD4(+)-to-CD8(+) ratio. The SFT was reduced in GS and MIX and increased in LIN compared with CON. The IgG and IL-6 were affected by diet × period. The reduction in IgG on d 60 and SFT in ewes fed GS suggests an immunomodulatory effect of this residue. The limited variation in milk and hematological and metabolic parameters suggests that GS and LIN can be included, alone or in combination, in the diet of dairy ewes without adverse effects on milk production and health status.


Plasma 7beta-hydroxycholesterol as a possible predictor of lung cancer risk.
Epidemiological data suggests a role of dietary cholesterol in the etiology of lung cancer without having a clear biological hypothesis. Although smoking as the outstanding risk factor for lung cancer may enhance lipid peroxidation reactions, this study was planned to assess smoking-independent associations between the extent of cholesterol oxidation and the risk for lung cancer. In the frame of a nested case-control study in European Prospective Investigation on Cancer-Heidelberg, six cholesterol oxidation products (COPs) were determined in plasma samples of 20 incident lung cancer patients obtained 1.9 +/- 0.6 years before diagnosis and in 40 matched (including smoking habits) controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression. Among all COP compounds tested, plasma 7beta-hydroxycholesterol was associated with lung cancer risk. The high crude risk estimate (OR approximately equals 5) became significant after adjustment for sports activity (OR = 6.83, CI = 1.08-43.01, 3rd versus 1st tertile). For the independent effect of 7beta-hydroxycholesterol, i.e., adjusted for other COP compounds, an OR of 8.08 (CI = 1.12-58.54, 3rd versus 1st tertile) was calculated (P = 0.04 for trend). Lung cancer risk adjusted for sports activity significantly increased by 26% (CI = 1.050-1.506, P = 0.01) per unit (1 nmol/mmol plasma cholesterol) of 7beta-hydroxycholesterol. No dietary factor had a significant effect in the regression model, but the dietary intake of meat, eggs, animal fat, cholesterol, and fruits (inversely) correlated with plasma COP concentrations. In this small study, plasma 7beta-hydroxycholesterol appeared to be a smoking-independent predictor of lung cancer risk and might therefore be used as a biomarker. Because of the rather high-risk estimate, research on possible intrinsic biological effects of this compound should be encouraged.


Zygosity and umbilical cord length.
Differences in cord length between weight-concordant pairs were studied in 43 monochorionic, 59 same-sex dichorionic and 42 different-sex dichorionic sets of twins and comparisons were made between groups. Of obvious and curious note was the narrow range of cord length differences between twins in monochorionic pairs (range, 0-5 cm; mean, 2.1 +/- 1.6 cm). Same-sex and different-sex dichorionic groups had significantly wider ranges of cord length differences than the monochorionic group (range, 0-34 cm; means, 7.7 +/- 6.4 and 11.0 +/- 6.1 cm, respectively). In the same-sex dichorionic group no pair whose cord lengths differ by > 5 cm has yet been found to be identical. Discordant monochorionic twins had greater differences in cord length. All other factors being equal, the remarkably similar cord lengths of concordant identical twins strongly supports the hypothesis that a genetic component influences cord length.


Electron paramagnetic resonance of the tungsten derivative of rat liver sulfite oxidase.
Sulfite oxidase purified from livers of tungsten-treated rats has been used for EPR studies of tungsten substituted at the molybdenum site of the enzyme in a fraction of the molecules. The EPR signal of W(V) in sulfite oxidase is quite similar to that of Mo(V) in its line shape and in its sensitivity to the presence of anions such as phosphate and fluoride. Hyperfine interaction with a dissociable proton is also observed in both signals. The pH-dependent alteration in line shape exhibited by the Mo(V) EPR signal of the rat liver enzyme. Incomplete reduction of the tungsten center at pH 9 is indicated by attenuated signal intensity at this pH. The W(V) signal has g values lower than those of the Mo(V) signal, has a much broader resonance envelope, and is much less readily saturated by increasing microwave power. Kinetic studies on the reduction of the heme and tungsten centers of sulfite oxidase have shown that reduction of de-molybdo forms of sulfite oxidase by sulfite is catalyzed by the residual traces of native molybdenum-containing molecules. Reduction is accomplished by electron transfer involving intermolecular heme-heme interaction. The W(V) signal is generated only after all the heme centers are reduced. The rate and extent of heme reduction at pH 9 are the same as at pH 7. Studies on the reoxidation of W(V) and reduced heme by O2 and by cytochrome c suggest that the cytochrome b5 of sulfite oxidase is the site of electron transfer to cytochrome c, whereas oxidase activity is the property of the molybdenum center. It appears that the tungsten center in sulfite oxidase is incapable of oxidizing sulfite.


[Ultrastructural changes in female germ cells during the meiotic prophase in the rat: a special study of membranes after cryofracture].
Ultrastructural changes in the nuclear and cytoplasmic elements in the germ cells of female rats were followed before meiotic prophase (15.50 days post-coïtum and 17.25 days post-coïtum) and during it (17.75 days post-coïtum to birth). We observed: modifications in the nuclear envelope which was thick during the oogonial stage, becoming thinner when the chromosomes entered preleptotene stage. The thinning of the envelope was due to the disappearance of the chromatin material lining it; variations in the number and distribution of germ cell nuclear pores according to stage; the pores were first scattered in small clusters of 6 to 8 over the entire nuclear membrane. From the preleptotene to zygotene stage, these clusters enriched in pores to form large areas. Finally, in the pachytene and diplotene stages, clusters of more than 100 pores were seen; nucleolar fragmentation from the preleptotene stage, followed by the formation of a new active nucleole in the diplotene; polarization of the mitochondria in the oldest oogonia just before the beginning of meiotic prophase. This polarization disappeared after the onset of the meiotic processes, then appeared again near the developing Golgi apparatus at the end of the pachytene stage; the formation of large gap junctions and numerous bands of tight junctions between the somatic cells; these formations contrasted with small gap junctions, and the tight junctions became scarce just before the meiotic process began. These observations, as well as those concerning nuclear pore distribution were made using the cryofracture technique.


Kinetic properties of the Bacillus licheniformis penicillin-binding proteins.
In the analysis of the interactions between beta-lactam antibiotics and their target enzymes, it is often difficult to estimate the kinetic properties of the molecules which react rapidly with their targets and in consequence behave as the most efficient antibiotics. The combined utilization of fluorescein-labelled penicillins and of a new competition method has allowed an accurate determination of the high second-order rate constants characterizing the acylation of Bacillus licheniformis penicillin-binding protein 1 (PBP1) by penicillins and cephalosporins. Strategies were devised for measuring high acylation rates while avoiding titration effects. The method was also suitable for measuring the PBP kinetic parameters in intact cells. These results also confirmed that PBP1 is probably the main target of most beta-lactam antibiotics. Cephalexin, however, reacted faster with PBP3.


Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts.
An updated definition of early allograft dysfunction (EAD) was recently validated in a multicenter study of 300 deceased donor liver transplant recipients. This analysis did not differentiate between donation after brain death (DBD) and donation after cardiac death (DCD) allograft recipients. We reviewed our prospectively entered database for all DBD (n=377) and DCD (n=38) liver transplantations between January 1, 2006 and October 30, 2011. The incidence of EAD as well as its ability to predict graft failure and survival was compared between DBD and DCD groups. EAD was a valid predictor of both graft and patient survival at six months in DBD allograft recipients, but in DCD allograft recipients there was no significant difference in the rate of graft failure in those with EAD (11.5%) compared with those without EAD (16.7%) (P=0.664) or in the rate of death in recipients with EAD (3.8%) compared with those without EAD (8.3%) (P=0.565). The graft failure rate in the first 6 months in those with international normalized ratio ≥1.6 on day 7 who received a DCD allograft was 37.5% compared with 6.7% for those with international normalized ratio <1.6 on day 7 (P=0.022). The recently validated definition of EAD is a valid predictor of patient and graft survival in recipients of DBD allografts. On initial assessment, it does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts, however a study with a larger sample size of DCD allografts is needed to confirm these findings. The high ALT/AST levels in most recipients of DCD livers as well as the predisposition to biliary complications and early cholestasis make these parameters as poor predictors of graft failure. An alternative definition of EAD that gives greater weight to the INR on day 7 may be more relevant in this population.


Clementine observations of the aristarchus region of the moon.
Multispectral and topographic data acquired by the Clementine spacecraft provide information on the composition and geologic history of the Aristarchus region of the moon. Altimetry profiles show the Aristarchus plateau dipping about 1 degrees to the north-northwest and rising about 2 kilometers above the surrounding lavas of Oceanus Procellarum to the south. Dark, reddish pyroclastic glass covers the plateau to average depths of 10 to 30 meters, as determined from the estimated excavation depths of 100- to 1000-meter-diameter craters that have exposed materials below the pyroclastics. These craters and the walls of sinuous rilles also show that mare basalts underlie the pyroclastics across much of the plateau. Near-infrared images of Aristarchus crater reveal olivine-rich materials and two kilometer-sized outcrops of anorthosite in the central peaks. The anorthosite could be either a derivative of local magnesium-suite magmatism or a remnant of the ferroan anorthosite crust that formed over the primordial magma ocean.


The 25-kDa FK506-binding protein is localized in the nucleus and associates with casein kinase II and nucleolin.
FK506-binding proteins (FKBPs) have been identified as the cellular receptors of the immunosuppressive drugs FK506 and rapamycin. Recently, we cloned a 25-kDa FKBP family member (FKBP25) and found that FKBP25 contains a nuclear localization sequence and several potential casein kinase II phosphorylation sites. It has been previously shown that phosphorylation of proteins by casein kinase II can enhance their nuclear localization. Here we demonstrate that FKBP25 is localized to the nucleus and that a glutathione S-transferase fusion protein of FKBP25 (GST-FKBP25) can be phosphorylated by casein kinase II. Also a stable FKBP25/casein kinase II complex was formed when the GST-FKBP25 fusion protein was incubated either with purified casein kinase II or with cell lysates. Furthermore, when GST-FKBP25 was incubated with nuclear lysates, nucleolin, a major nuclear substrate of casein kinase II, was found associated with the GST-FKBP25/casein kinase II complex. Casein kinase II phosphorylation of several cytosolic and nuclear substrates, including nucleolin, appears to be important for the regulation of cell growth. The interaction of FKBP25 with casein kinase II may regulate these functions.


Immunohistochemical analysis of human growth hormone-releasing hormone gene expression in transgenic mice.
The tissue-specific expression of a fusion gene encoding the mouse metallothionein-1 promoter and the coding region of the human GH-releasing hormone (hGRH) gene was studied in transgenic mice by immunohistochemistry using an anti-hGRH serum that does not recognize endogenous mouse GRH. hGRH immunoreactivity (GRH-IR) was detected in specific cells of the pituitary, pancreas, kidney, duodenum, lung, testis, ovary, adrenal, heart, and brain. In the pituitary, using double immunofluorescent staining, GRH-IR was found in some, but not all, somatotrophs, gonadotrophs, thyrotrophs, and mammotrophs. GRH-IR was found in both pancreatic exocrine cells and endocrine islets. Within the islet, GRH-IR was colocalized in A and D cells with glucagon and somatostatin, respectively. Immunopositive cells in other tissues were localized in kidney proximal convoluted tubules, duodenal submucosal glands of Brunner, the smooth muscles of pulmonary arterioles, testicular Leydig cells, oocytes, adrenal medullary chromaffin cells, and cardiac atria. In the brain, GRH-IR was seen in the external layer of the median eminence and in perikarya and fibers of the hypothalamic arcuate nucleus, the parvocellular region of the paraventricular nucleus, the supraoptic nucleus, and the amygdala. Somatostatin-immunoreactive cell bodies and fibers in transgenic and control mouse hypothalamus were not appreciably different. In summary, hGRH expression in transgenic mice occurs in a cell-specific manner in the hypothalamus as well as in numerous other tissues, many of which have secretory functions.


The maximum lactate clearance: a new concept to approach the endurance level of an athlete.
The purpose of this study is to present a mathematical model based on physiological observations which describes the evolution of the blood lactate concentration ([LA-]) versus the oxygen uptake (VO2) during a continuous graded exercise test. This model is based on several assumptions: 1) [LA-] reflects the balance between the rates of appearance and disappearance of the lactate in the blood compartment; 2) VO2 measured at the end of each step, is a linear function of the power output and thus of the time; 3) the appearance rate of lactate into the blood is an exponential function of VO2; 4) the rate of disappearance is a saturable process which can be modelized by Michaelis-Menten kinetics; 5) the volume of distribution of lactate in the blood compartment is a constant during exercise. The parameters used in this model correspond to the integration of several biochemical and physiological phenomenons. The originality of this approach is to express the rate of lactate appearance and disappearance versus VO2 rather than time. Whatever the general pattern of the data, the fitted curve gives always very good results. Especially, the theoretical curve fits the decrease in [LA-] usually observed during the first steps of such an exercise. From the computed parameters the evolution of lactate clearance during a continuous graded exercise test may be modelized. A strong relationship exists between the level of endurance training and the maximum lactate clearance (Clmax) reached during the exercise test. The VO2 for Clmax is an indicator of the shift of the relationship [LA-]-VO2. Then, we propose to use the maximum lactate clearance which is individually determined, to characterize the endurance level of an athlete.


Antiemetic study design: desirable objectives, stratifications and analyses.
Once the optimal dose and safety of an antiemetic has been established a randomised double blind parallel subjects design is recommended for phase III studies. Randomisation distributes the unknown prognostic variables so that their effects can be allowed for in tests for statistical significance. Stratification can equally distribute the known prognostic factors e.g. prior exposure to chemotherapy, strength of the emetic stimulus, age, sex and prior alcohol consumption. A cross-over design is often proposed because less patients would be required to achieve the same power as a parallel subjects study. The major problem with this design is in being able to estimate and allow for carry over effects or treatment period interactions which can interact with each other and the direct treatment effect. The study must be large enough to detect a statistically significant difference of clinical importance. Interim analyses should be preplanned and early termination should require a difference between the arms with a more significant P value than 0.05. Simple evaluation of efficacy could include quantitation of objective parameters and use of simple ordinal scales to record more subjective phenomena. In a parallel subjects design patients must assess their overall tolerance of therapy which balances the antiemetic's efficacy and toxicity.


First Report of Powdery Mildew Caused by Erysiphe betae on Swiss Chard in China.
Swiss chard (Beta vulgaris L. subsp. cicla) is a widely planted vegetable in China. From May to June 2013, an outbreak of powdery mildew on Swiss chard cultivar Fangzheng was observed in the commercial fields in Zhoukou city of Henan Province, located in central China. More than 80% of the plants exhibited symptoms of the disease. At the beginning of infection, circular, white, dust-like colonies of powdery mildew occurred mainly on adaxial surfaces of leaves. As the disease progressed, white mycelia covered the foliar parts of plant. No cleistothecia were found on or in collected samples. Upon microscopic evaluation, conidiophores were unbranched with the length of 63 to 126 and width of 7 to 10 μm (n = 50), produced conidia singly, and composed of a cylindrical foot cell followed by one to three short cells. Conidia were colorless, hyaline, ovoid, measured 29 to 40 × 12 to 18 μm (n = 100), lacked fibrosin bodies, and produced germ tubes on the ends of the conidia. The fungus was identified as Erysiphe betae according to the morphological features (1). To verify the identity, the internal transcribed spacer (ITS) region was amplified with the universal primers ITS1 and ITS4 (2) and sequenced. The ITS sequence obtained was assigned as Accession No. KF268348 in GenBank, which showed 100% homogeneity with two ITS sequences of E. betae isolates from UK (DQ164432 and DQ164436). Koch's postulates were conducted by inoculating 15 healthy 5-week-old plants (cv. Fangzheng) with detached infected leaves, which grew in a growth chamber under 22/16°C (day/night), 50% relative humidity, 120 μmol/m2/s light and a 16-h photoperiod. Fifteen non-inoculated plants grew in another growth chamber with the same conditions as control. Symptoms consistent with the infected field plants were observed on the inoculated plants, while no symptoms were found on the control plants. Microscopic observation revealed that the pathogen growing on the inoculated plants was consistent with the morphology of the original fungus. To our knowledge, this is the first report of E. betae infection on Swiss chard in China (3). References: (1) S. Francis. Mol. Plant Pathol. 3:119, 2002. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, CA, 1990. (3) R. Y. Zheng et al. Page 63 in: Flora Fungorum Sinicorum, Vol. 1, Erysiphales. Science Press, Beijing, 1987.


Regulation of integrin activity and signalling.
The ability of cells to attach to each other and to the extracellular matrix is of pivotal significance for the formation of functional organs and for the distribution of cells in the body. Several molecular families of proteins are involved in adhesion, and recent work has substantially improved our understanding of their structures and functions. Also, these molecules are now being targeted in the fight against disease. However, less is known about how their activity is regulated. It is apparent that among the different classes of adhesion molecules, the integrin family of adhesion receptors is unique in the sense that they constitute a large group of widely distributed receptors, they are unusually complex and most importantly their activities are strictly regulated from the inside of the cell. The activity regulation is achieved by a complex interplay of cytoskeletal proteins, protein kinases, phosphatases, small G proteins and adaptor proteins. Obviously, we are only in the beginning of our understanding of how the integrins function, but already now fascinating details have become apparent. Here, we describe recent progress in the field, concentrating mainly on mechanistical and structural studies of integrin regulation. Due to the large number of articles dealing with integrins, we focus on what we think are the most exciting and rewarding directions of contemporary research on cell adhesion and integrins.


Ecology theory disentangles microbial dichotomies.
Microbes are often discussed in terms of dichotomies such as copiotrophic/oligotrophic and fast/slow-growing microbes, defined using the characterisation of microbial growth in isolated cultures. The dichotomies are usually qualitative and/or study-specific, sometimes precluding clear-cut results interpretation. We can unravel microbial dichotomies as life history strategies by combining ecology theory with Monod curves, a laboratory mathematical tool of bacterial physiology that relates the specific growth rate of a microbe with the concentration of a limiting nutrient. Fitting of Monod curves provides quantities that directly correspond to key parameters in ecological theories addressing species coexistence and diversity, such as r/K selection theory, resource competition and community structure theory and the CSR triangle of life strategies. The resulting model allows us to reconcile the copiotrophic/oligotrophic and fast/slow-growing dichotomies as different subsamples of a life history strategy triangle that also includes r/K strategists. We also used the number of known carbon sources together with community structure theory to partially explain the diversity of heterotrophic microbes observed in metagenomics experiments. In sum, we propose a theoretical framework for the study of natural microbial communities that unifies several existing proposals. Its application would require the integration of metagenomics, metametabolomics, Monod curves and carbon source data.


Increases in circulating levels of monocyte-platelet and neutrophil-platelet complexes following hip arthroplasty.
Platelets and leucocytes are important effector cells of the haemostatic and inflammatory responses to tissue injury. To investigate the effects of surgical trauma on platelet activation (assessed by measuring levels of P-selectin and beta-thromboglobulin), leucocyte activation (CD11b expression) and leucocyte-platelet interactions (leucocyte-platelet complexes), 30 patients undergoing primary hip arthroplasty were studied before and at the end of surgery, and on days 1 and 10 post-operatively, using a whole-blood flow cytometry assay. The inflammatory response was followed by measurement of the levels of C-reactive protein and interleukin-6 in plasma, and the activation of coagulation was monitored by determination of prothrombin fragment 1+2 levels. On day 1 post-operatively a significantly increased expression of CD11b on monocytes was noted, but no direct correlation was found between monocyte activation and interleukin-6 production or C-reactive protein at this time point. The percentage of monocyte-platelet and neutrophil-platelet complexes was markedly increased on day 10 post-operatively compared with pre-operative levels, and levels of these complexes were significantly positively correlated with beta-thromboglobulin levels. Activation of coagulation (prothrombin fragment 1+2) on day 10 post-operatively was positively correlated with the extent of surgical trauma (duration of surgery, amount of blood loss) and with the increase in platelet activation (beta-thromboglobulin). In conclusion, hip arthroplasty induces platelet and coagulation activation, and also an inflammatory response that is maintained for more than 10 days post-operatively. This indicates an interaction between the immune and the haemostatic systems in the post-operative phase after hip arthroplasty.