Clinical impact of broad-spectrum empirical antibiotic therapy in patients with healthcare-associated pneumonia: a multicenter interventional study.
Healthcare-associated pneumonia (HCAP) has been proposed as a new category of pneumonia distinct from community-acquired pneumonia (CAP). A multicenter observational study in 2008 finds that patients with HCAP have a mortality rate significantly higher than patients with CAP, and a worse outcome is associated at logistic regression analysis with a low adherence to empirical antibiotic therapy recommended by ATS/IDSA guidelines. We designed a prospective interventional study to establish whether administration of a broad-spectrum antibiotic therapy consistent with the 2005 ATS/IDSA guidelines has an effect on the clinical outcome of hospitalized patients with HCAP. All patients with HCAP prospectively admitted in 25 medical wards of 20 Italian hospitals during a 1-month period were included in the study. All patients were assigned to receive an empirical therapy including a fluoroquinolone plus an anti-MRSA agent plus either piperacillin-tazobactam or a carbapenem. Main measures for improvement were duration of antibiotic therapy, length of hospital stay, and in-hospital mortality rate. Patients were compared with a historical control group of 90 patients, and followed up to discharge or death. HCAP patients receiving a guideline-concordant therapy had a shorter duration of antibiotic therapy (median 15 vs. 12 days, p = 0.0002), a shorter duration of hospitalization (median 18 vs. 14 days, p = 0.02), and a lower mortality rate (17.8 vs. 7.1 %, p = 0.03). Our results suggest that an empirical broad-spectrum therapy is associated with improved outcome in patients with HCAP.


A mass and charge balanced metabolic model of Setaria viridis revealed mechanisms of proton balancing in C4 plants.
C4 photosynthesis is a key domain of plant research with outcomes ranging from crop quality improvement, biofuel production and efficient use of water and nutrients. A metabolic network model of C4 "lab organism" Setaria viridis with extensive gene-reaction associations can accelerate target identification for desired metabolic manipulations and thereafter in vivo validation. Moreover, metabolic reconstructions have also been shown to be a significant tool to investigate fundamental metabolic traits. A mass and charge balance genome-scale metabolic model of Setaria viridis was constructed, which was tested to be able to produce all major biomass components in phototrophic and heterotrophic conditions. Our model predicted an important role of the utilization of NH[Formula: see text] and NO[Formula: see text] ratio in balancing charges in plants. A multi-tissue extension of the model representing C4 photosynthesis was able to utilize NADP-ME subtype of C4 carbon fixation for the production of lignocellulosic biomass in stem, providing a tool for identifying gene associations for cellulose, hemi-cellulose and lignin biosynthesis that could be potential target for improved lignocellulosic biomass production. Besides metabolic engineering, our modeling results uncovered a previously unrecognized role of the 3-PGA/triosephosphate shuttle in proton balancing. A mass and charge balance model of Setaria viridis, a model C4 plant, provides the possibility of system-level investigation to identify metabolic characteristics based on stoichiometric constraints. This study demonstrated the use of metabolic modeling in identifying genes associated with the synthesis of particular biomass components, and elucidating new role of previously known metabolic processes.


Condensation of plasmid DNA with polylysine improves liposome-mediated gene transfer into established and primary muscle cells.
Cationic liposomes provide a means to introduce genes into cells both ex vivo and in vivo. In the past few years their use has been described in several tissues, e.g. lungs, liver, endothelium, brain. In this study we evaluated a commercially available poly-cationic liposome formulation in delivering a reporter gene into cultured myogenic cell lines from mouse and rat, and primary fetal human myoblasts. We also examined the effect of serum on liposome-mediated transfection and designed a new procedure to enhance transfection efficiency, based on the pre-condensation of plasmid DNA with polylysine. Polylysine pre-condensation was particularly effective when transfecting the cells in the presence of serum, a finding that could be significant for in vivo transfections.


Phyllocnistis podocarpa sp. nov. (Lepidoptera, Gracillariidae), a buddhist pine leaf-miner from Japan: taxonomy, DNA barcodes, damage and parasitoids.
Phyllocnistis podocarpa sp. nov., is described from mines in Podocarpus macrophyllus (Family Podocarpaceae). The host plant P. macrophyllus, also known as buddhist pine on the IUCN Red List, is a noticeable garden plant and thus of high economic value. Buddhist pine has been introduced to many other countries from its native habitat in southern Japan. Special attention has been paid for it during the overseas import in China. The morphology of the pupae of P. podocarpa, particularly the frontal process of the head and the spine clusters on terga, ones of the most useful diagnostic characters for species identification of Phyllocnistis on morphology, is demonstrated using SEM. Two parasitoid species of Eulophidae (Hymenoptera) are identified and illustrated. COI barcode sequences are provided along with a Neighbor Joining Tree covering related species for aiding identification.


Protein corona and nanoparticles: how can we investigate on?
Nanoparticles (NPs) represent one of the most promising tools for drug-targeting and drug-delivery. However, a deeper understanding of the complex dynamics that happen after their in vivo administration is required. Particularly, plasma proteins tend to associate to NPs, forming a new surface named the 'protein corona' (PC). This surface is the most exposed as the 'visible side' of NPs and therefore, can have a strong impact on NP biodistribution, targeting efficacy and also toxicity. The PC consists of two poorly delimited layers, known as 'hard corona' (HC) and 'soft corona' (SC), that are affected by the complexity of the environment and the formed protein-surface equilibrium during in vivo blood circulation. The HC corona is formed by proteins strongly associated to the NPs, while the SC is an outer layer consisting of loosely bound proteins. Several studies attempted to investigate the HC, which is easier to be isolated, but yielded poor reproducibility, due to varying experimental conditions. As a consequence, full mapping of the HC for different NPs is still lacking. Moreover, the current knowledge on the SC, which may play a major role in the 'first' interaction of NPs once in vivo, is very limited, mainly due to the difficulties in preserving it after purification. Therefore, multi-disciplinary approaches leading to the obtainment of a major number of information about the PC and its properties is strongly needed to fully understand its impact and to better support a more safety and conscious application of nanotechnology in medicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1467. doi: 10.1002/wnan.1467 For further resources related to this article, please visit the WIREs website.


Contributions of risk preference, time orientation and perceptions to breast cancer screening regularity.
Disparities in breast cancer screening are often explained by socioeconomic factors, although a growing body of papers show that risk preference, time orientation and perceptions may explain mammography use. The aim of this paper is to estimate the relative contribution of socioeconomic factors, risk preference, time orientation and perceptions to disparities in breast cancer screening regularity. These determinants are elicited in an experimental laboratory from 178 women aged between 50 and 75 years in France in 2013. The results reveal that risk aversion accounts for 30% of the variance in screening regularity, which is greater than that attributable to socioeconomic determinants (20%), perceptions (11.5%) or time orientation (2%). These results suggest that further investigation on the relationship between risk aversion and screening behaviors is needed to design more comprehensive public health interventions.


Practical and Broadly Applicable Catalytic Enantioselective Additions of Allyl-B(pin) Compounds to Ketones and α-Ketoesters.
A set of broadly applicable methods for efficient catalytic additions of easy-to-handle allyl-B(pin) (pin=pinacolato) compounds to ketones and acyclic α-ketoesters was developed. Accordingly, a large array of tertiary alcohols can be obtained in 60 to >98 % yield and up to 99:1 enantiomeric ratio. At the heart of this development is rational alteration of the structures of the small-molecule aminophenol-based catalysts. Notably, with ketones, increasing the size of a catalyst moiety (tBu to SiPh3 ) results in much higher enantioselectivity. With α-ketoesters, on the other hand, not only does the opposite hold true, since Me substitution leads to substantially higher enantioselectivity, but the sense of the selectivity is reversed as well.


First Report of Curtobacterium flaccumfaciens pv. flaccumfaciens Causing Bacterial Wilt and Blight on Sunflower in Russia.
In the summer of 2018, wilt and leaf spots were observed on sunflower (Helianthus annuus L.) plants in fields near Kursk (51.74°N, 36.02°E) in Russia. In the following years, incidence of this disease was 5 to 20% in the inspected fields. Marginal chlorosis on seedling leaves developed into wilt and necrosis about one week later (Fig. 1). Mature plants had leaves with blight and reduced height compared to symptomless plants. Pathogen isolation from seeds was done by the method of Tegli et al. (2002) with modifications. Bacteria from diseased plants were isolated by streaking inoculum from symptomatic tissues on nutrient dextrose agar (NDA) (Schaad et al. 1988). The plates were incubated at 30°C for 7 to 10 days. Isolates consistently formed slow-growing, yellow, circular, smooth colonies without soluble pigment. The isolated bacteria were aerobic, gram-positive, and rod-shaped. Eight strains, CF-20 to CF-26 from plants, and Curt1 and Curt3 from seeds, were identified by MALDI TOF MS analysis as Curtobacterium flaccumfaciens pv. flaccumfaciens or C. flaccumfaciens pv. poinsettiae. All strains had GENIII MicroPlate (BIOLOG) test results identical to C. flaccumfaciens pv. flaccumfaciens strain DSM20129T. Further analysis was done by specific PCR (Tegli et al. 2002) and 16S rDNA, gyrB, and atpD gene sequencing. For PCR amplification, DNA was extracted by the CitoSorb Kit (Syntol Co., Moscow). Primers 27F/1492R (16S rRNA) (Marchesi et al. 1998), 2F/6R (gyrB) (Richert et al. 2005), and aptD2F/aptD2R (Jacques et al. 2012) were used to amplify the target gene sequences. The PCR products were sequenced by Evrogen (Moscow). The 16S rRNA sequences (OL584192.1 to OL584199.1) were identical to that of C. flaccumfaciens pv. flaccumfaciens strain DSM20129T (AM410688.1; 1,477/1,477 bp). The phylogenetic tree of concatenated gyrB (560 bp) and atpD (716 bp) sequences (OL548915.1 to OL548922.1 and OL548923.1 to OL548930.1, respectively) clustered the strains from sunflower among C. flaccumfaciens pv. flaccumfaciens, C. flaccumfaciens pv. betae, and C. flaccumfaciens pv. oortii (Fig. 2) with high genetic similarity to other C. flaccumfaciens strains: 96.3 to 100% for atpD and 95 to 100% for gyrB. A pathogenicity test for each of the strains was performed by injecting 5 μl of a bacterial suspension (108 CFU/ml) grown for 72 h on NDA into the stems of five plantlets (four true leaf stage) of the sunflower cv. Tunka (Limagrain, France) and soybean cv. Kasatka (VIM, Russia). Strain DSM20129T was a positive control, while sterile water was a negative control. The plants were incubated at 24°C, 80% relative humidity, and 14-h light/day. Wilting and blight on sunflower (Fig. 3) and tan spots on soybean were observed in 15 to 20 days after inoculation for all sunflower strains and strain DSM20129T. The negative control plants were asymptomatic. The bacteria re-isolated from the inoculated plants exhibited the same morphological characteristics and 16S rDNA sequence as the original culture, thus fulfilling Koch's postulates. The presence of C. flaccumfaciens pv. flaccumfaciens in sunflower seeds indicated that the bacterium was transmitted via seed. Sunflower has been previously reported as a host for the pathogen (Harveson et al. 2015). The presence of C. flaccumfaciens pv. flaccumfaciens on beans in Russia was suggested from the disease symptoms (Nikitina and Korsakov 1978), but, to our knowledge, this is the first report of the pathogen affecting sunflower in Russia. Phytosanitary categorization placed C. flaccumfaciens pv. flaccumfaciens in the EPPO A2 list (EPPO 2011). Thus, sunflower seeds should be tested to protect pathogen-free areas from introduction of this pathogen.


A Systematic Literature Review of Asian American, Native Hawaiian, and Pacific Islander Youth Electronic Nicotine Delivery Systems (ENDS) Use.
Rates of electronic nicotine delivery systems (ENDS) use are exponentially increasing in youth and young adults within the United States, including Asian American, Native Hawaiian, and Pacific Islander (AANHPI) youth in Hawai'i. Disproportionately high ENDS use rates for AANHPI youth point to the need to understand the empirical literature in this area. A systematic literature review is a prerequisite for programs effectively curbing AANHPI youths' elevated use of ENDS. This systematic literature review examines empirical studies published between 2010-2020 on ENDS and their use as it applies to AANHPI youth. A total of 11 articles were identified using specific inclusionary and exclusionary criteria in a literature search. Studies described individual and interpersonal correlates to ENDS use. Notably, there were no published ENDS intervention studies detailed to AANHPI youth. Implications of these studies for prevention and social welfare interventions are discussed.


Comparative study of diagnostic accuracy between office-based closed needle biopsy and open incisional biopsy in patients with musculoskeletal sarcomas.
The biopsy is a simple but critical step in the diagnosis of the musculoskeletal lesions. Although the open incisional biopsy traditionally has been considered the gold standard with high diagnostic accuracy, an alternative, the closed needle biopsy (CNB), has been developed and widely used as it can be performed at an outpatient clinic under local anesthesia or in combination with the image guidance. In the present study, the authors purpose to study the diagnostic accuracy of CNB without real-time image-guidance at an outpatient clinic by comparing it with open incisional biopsy in musculoskeletal sarcoma patients. The authors retrospectively reviewed 200 biopsy cases of sarcoma patients since 2002-2011. There were 105 cases of open incisional biopsy 105 cases and 95 cases of CNB. The diagnostic accuracies of both mentioned methods were compared statistically in four aspects of histopathology: nature (benign or malignant), specific diagnosis, histological type and histological grade. The gold standard was afinal pathological diagnosis of the resected specimens receivedfrom definite surgery correlated with clinical findings and imnaging studies. The diagnostic accuracies of open incisional biopsy were 97.14% for nature, 89.52% for specific diagnosis, 89.52% for histological type, 88.57% for histological grade and the diagnostic accuracies of CNB were 96.84%, 89.47%, 88.42%, 86.32%, respectively. There was no significant statistical difference between the two methods in all histological aspects (p-value >0.05). The diagnostic yields of both methods were 98.13% for open incisional biopsy, 97.94% for CNB and there was no significant statistical difference (p-value >0.05). There were 6 cases (3%)for overall major errors, 3 cases (2.86%) firom open incisional biopsy and 3 cases (3.16%) from CNB. There were 18 cases (9%)for minor errors, 9 cases (8.57%) from open incisional biopsy and 9 cases (9.47%) from CNB. There was no biopsy related complication in either method. The office-based CNB diagnosis of musculoskeletal sarcoma can achieve an acceptably high diagnostic accuracy rate compared with open incisional biopsy.


[Diagnosis and treatment of urticaria and angioedema].
Current concepts on the diagnosis and treatment of urticaria and angioedema concerning allergic, non-allergic, idiopathic and symptomatic aetiology of this very complex disease were discussed. Much attention was paid to the necessity of multidrug therapy in which antihistamines play the most important role in chronic forms of the disease. The possibility of occurrence of life-threatening conditions was emphasised and the rules of their treatment and early prevention of intensification of symptoms typical of anaphylaxis.


Travel-associated diseases, Indian Ocean Islands, 1997-2010.
Data collected by the GeoSentinel Surveillance Network for 1,415 ill travelers returning from Indian Ocean islands during 1997-2010 were analyzed. Malaria (from Comoros and Madagascar), acute nonparasitic diarrhea, and parasitoses were the most frequently diagnosed infectious diseases. An increase in arboviral diseases reflected the 2005 outbreak of chikungunya fever.


Interleukin 2 induction of pore-forming protein gene expression in human peripheral blood CD8+ T cells.
Our studies have analyzed pore-forming protein (PFP) mRNA expression in resting and stimulated human peripheral blood CD3- large granular lymphocytes (LGL), CD3+ T cells, and their CD4+ or CD8+ subsets. Signals that stimulate T cells to develop cytotoxic activity (i.e., IL-2 or OKT-3 mAb) led to the induction of PFP mRNA in T cells. The data indicated that IL-2 directly increased PFP mRNA in the CD8+ subset of T cells, in the absence of new DNA or protein synthesis. Abrogation of IL-2-induced PFP mRNA expression and cytotoxic potential of T cells by the anti-p75 IL-2 receptor mAb suggested that low numbers of p75 IL-2 receptors on CD8+ T cells were capable of transducing signals responsible for these IL-2-induced effects. The induction of T cell PFP mRNA via CD3, using OKT-3 mAb, was less rapid but greater than that caused by IL-2; however, a combination of PMA and ionomycin, which bypasses crosslinking of the TCR/CD3 complex, could not mimic this increase in PFP mRNA levels in T cells. The role of second messenger systems in regulating PFP mRNA expression remains to be determined. In contrast, high constitutive PFP mRNA expression was observed in CD3- LGL and these mRNA levels could not be enhanced by stimulation with IL-2. The cytotoxic potential of peripheral blood T cells and LGL induced in response to IL-2 correlated with IL-2-induced PFP mRNA levels in these cells and was consistent with PFP being one of several important molecules involved in the effector function of cytotoxic lymphocytes.


The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35.
FK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506-FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap -FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.


Pharmacologic treatment of first-episode schizophrenia: a review of the literature.
To review the evidence base for the efficacy and tolerability of antipsychotic medication for the treatment of the first episode of schizophrenia. MEDLINE databases were searched for published articles in English over the last 25 years, from January 1986 to January 2011, on choice of antipsychotic treatment for the first episode of schizophrenia, with an emphasis on efficacy and tolerability of antipsychotic drugs in the acute phase of psychotic illness. The keywords antipsychotic drugs and schizophrenia were used in combination with drug treatment, pharmacologic treatment, efficacy, and tolerability in addition to atypical antipsychotics, first-generation antipsychotics, second-generation antipsychotics, first-episode psychosis, and acute psychotic episode. At present, there is no convincing evidence to guide clinicians in choosing a single first-line antipsychotic that is effective in treating the positive and negative symptoms of the first episode of schizophrenia. Even though second-generation antipsychotic drugs offer potential benefits in terms of less extrapyramidal side effects and some benefits in treating negative, affective, and cognitive symptoms, these drugs are not without their own side effects. With the introduction of a number of second-generation antipsychotic drugs there have been significant advances in antipsychotic drug treatment over the last decade. Despite these advances, there are still a number of limitations in continued use of some antipsychotic medications due to their efficacy and tolerability issues in the acute and early maintenance phases of psychosis. Active research in this area would provide more promising results of improved efficacy and tolerability of antipsychotic medication.


Risk Factors for Recurrent Abdominal Pain in Children with Nonorganic Acute Abdominal Pain.
The purpose of this study was to identify the risk factors for recurrent abdominal pain (RAP) in children who presented with nonorganic acute abdominal pain. A retrospective, single study was conducted on 2-15-year-old children diagnosed with nonorganic acute abdominal pain at the pediatric outpatient department of Vajira Hospital, Nawamindradhiraj University, between January 2015 and December 2019. The potential risk factors were analyzed using univariate and multivariate analyses. Of the 367 patients with nonorganic acute abdominal pain, 94 (25.6%) experienced RAP within three months. In this group with RAP, 76 patients (80.8%) were diagnosed with functional gastrointestinal disorders, including functional dyspepsia, irritable bowel syndrome, functional abdominal pain-not otherwise specified, and functional constipation. History of gastrointestinal infection (p=0.011), mental health problems (p=0.022), abdominal pain lasting ≥7 days (p<0.001), and change in stool frequency (p=0.001) were the independent risk factors associated with RAP in children with nonorganic acute abdominal pain; their odds ratios and 95% confidence intervals were 3.364 (1.314-8.162), 3.052 (1.172-7.949), 3.706 (1.847-7.435), and 2.649 (1.477-4.750), respectively. RAP is a common problem among children who first present with nonorganic acute abdominal pain. The identification of risk factors may provide proper management, especially follow-up plans for this group in the future.


Search results outliers among MEDLINE platforms.
Hypothetically, content in MEDLINE records is consistent across multiple platforms. Though platforms have different interfaces and requirements for query syntax, results should be similar when the syntax is controlled for across the platforms. The authors investigated how search result counts varied when searching records among five MEDLINE platforms. We created 29 sets of search queries targeting various metadata fields and operators. Within search sets, we adapted 5 distinct, compatible queries to search 5 MEDLINE platforms (PubMed, ProQuest, EBSCOhost, Web of Science, and Ovid), totaling 145 final queries. The 5 queries were designed to be logically and semantically equivalent and were modified only to match platform syntax requirements. We analyzed the result counts and compared PubMed's MEDLINE result counts to result counts from the other platforms. We identified outliers by measuring the result count deviations using modified z-scores centered around PubMed's MEDLINE results. Web of Science and ProQuest searches were the most likely to deviate from the equivalent PubMed searches. EBSCOhost and Ovid were less likely to deviate from PubMed searches. Ovid's results were the most consistent with PubMed's but appeared to apply an indexing algorithm that resulted in lower retrieval sets among equivalent searches in PubMed. Web of Science exhibited problems with exploding or not exploding Medical Subject Headings (MeSH) terms. Platform enhancements among interfaces affect record retrieval and challenge the expectation that MEDLINE platforms should, by default, be treated as MEDLINE. Substantial inconsistencies in search result counts, as demonstrated here, should raise concerns about the impact of platform-specific influences on search results.


Detection of prostate-specific antigen with a paired surface plasma wave biosensor.
In this study, we demonstrated that an amplitude-sensitive paired surface plasma wave biosensor (PSPWB) is capable of real-time detection of prostate-specific antigen (PSA) in diluted human serum without labeling. Experimentally, the detection limit of PSPWB was 8.4 x 10(-9) refractive index unit (RIU) and the PSPWB could measure PSA in a phosphate buffered saline solution from 10 fg/mL ( approximately 300 aM) to 100 pg/mL ( approximately 3 pM) successfully, with demonstration of a linear relationship between PSA concentrations and surface plasmon resonance (SPR) signals. Therefore, results were obtained over a wide dynamic range 5 orders of magnitude for analyte concentration. In addition, the PSPWB successfully detected PSA in diluted human serum as well. These experimental results indicate that the PSPWB is capable of detection with high sensitivity over a wide range by using SPR-based biosensors and has a capability of detecting biological analytes in clinical sample without complicated operating procedures.


Increased Circulating Endothelial Microparticles Associated with PAK4 Play a Key Role in Ventilation-Induced Lung Injury Process.
Inappropriate mechanical ventilation (MV) can result in ventilator-induced lung injury (VILI). Probing mechanisms of VILI and searching for effective methods are current areas of research focus on VILI. The present study aimed to probe into mechanisms of endothelial microparticles (EMPs) in VILI and the protective effects of Tetramethylpyrazine (TMP) against VILI. In this study, C57BL/6 and TLR4KO mouse MV models were used to explore the function of EMPs associated with p21 activated kinases-4 (PAK-4) in VILI. Both the C57BL/6 and TLR4 KO groups were subdivided into a mechanical ventilation (MV) group, a TMP + MV group, and a control group. After four hours of high tidal volume (20 ml/kg) MV, the degree of lung injury and the protective effects of TMP were assessed. VILI inhibited the cytoskeleton-regulating protein of PAK4 and was accompanied by an increased circulating EMP level. The intercellular junction protein of β-catenin was also decreased accompanied by a thickening alveolar wall, increased lung W/D values, and neutrophil infiltration. TMP alleviated VILI via decreasing circulating EMPs, stabilizing intercellular junctions, and alleviating neutrophil infiltration.


Kinetics of the reactions of O(3P) with CCl2=CH2, (Z)-CHCl=CHCl, and CCl2=CCl2: a temperature dependence study.
Absolute rate coefficients for the gas-phase reactions of ground-state oxygen atoms with CCl(2)=CH(2) (1), (Z)-CHCl=CHCl (2) and CCl(2)=CCl(2) (3) have been measured directly using the fast flow discharge technique. The experiments were carried out under pseudo-first-order conditions with [O((3)P)](0) << [chloroethene](0). The temperature dependences of the reactions of O((3)P) with CCl(2)=CH(2), (Z)-CHCl=CHCl and CCl(2)=CCl(2) were studied in the range 298-359 K. The kinetic data obtained were used to derive the following Arrhenius expressions (in units of cm(3) molecule(-1) s(-1)): k(1) = (1.82 +/- 1.29) x 10(-11) exp[-(12.63 +/- 0.97) x 10(3)/RT], k(2) = (1.56 +/- 0.92) x 10(-11) exp[-(16.68 +/- 1.54) x 10(3)/RT], k(3) = (4.63 +/- 1.38) x 10(-11) exp[-(19.59 +/- 3.21) x 10(3)/RT]. This is the first temperature dependence study of the reactions of O((3)P) atoms with (Z)-CHCl=CHCl and CCl(2)=CCl(2). All the rate coefficients display a positive temperature dependence and pressure independence, which points to the importance of the irreversibility of the addition mechanism for these reactions. The obtained rate coefficients are compared with previous studies carried out mainly at room temperature. The rates of addition of O atoms and OH radicals to the double bond of alkenes at 298 K are related by the expression: log k(OH) = 0.57278 log k(O(3P)) - 4.095. A correlation is presented between the reactivity of chloroethenes toward O atoms and the second-order perturbational term of the frontier molecular orbital theory which carries the contribution of the different atomic orbitals to the HOMO of the chloroethene. To a first approximation, this correlation allows room-temperature rate coefficients to be predicted within +/-25-30% of the measured values.


Greek dose reference levels in pediatric pelvis computed tomography examinations.
The fact that children do undergo computed tomography (CT) examinations similar to those for adults adults has been a research issue, especially since the former are exposed to greater risk levels (developing stochastic late effects, such as cancer) due to their increased radiosensitivity compared to the latter. In a previous research paper (), the values of dose levels were recorded, analyzed, and compared with the reference values for groups of 0, 1, 5 and 10 y-old children for the regions of head, chest, and abdomen. In this paper, the same age group has been considered for measuring dose levels of the pelvic region. Scanning the pelvic region has been one of the most important CT examination procedures, in which unfortunately part of the lower abdomen region is included without adapting any pediatric protocols. Furthermore, the study determines whether the adjustment of the scanning parameters results in any possible reduction in the radiation dose levels to which the patient is being exposed during the examination. The present work also includes the Greek reference levels for the pelvic CT examination for the 5- and 10-y-old children that have been used for comparison against the European ones.


Fiber diffraction study of spicules from marine sponges.
A synchrotron radiation fiber diffraction structural study of the axial filament of siliceous spicules from two species of marine sponges (the Demosponge Geodia cydonium and the Hexactinellid Scolymastra joubini) was carried out. The sharpness of the spots in the diffraction patterns indicated that the protein units in the filament of both samples were highly organized. A possible explanation is that the arrangement of the protein units is similar to that of the pores in highly ordered siliceous mesoporous materials. Nevertheless, the diffraction patterns are quite different for the two types of spicules. The pattern of G. cydonium is consistent with a regular 2D hexagonal lattice of protein units in the direction perpendicular to the spicule axis, with a repeating distance of 5.8 nm; the units are linked to form fibers along the axis. The pattern of S. joubini indicates the presence of two different 2D lattices in which the repeating protein units are inclined by +50 degrees and -50 degrees with respect to the elongation axis; the distance between the units increases to 8.4 nm. This 2D model is consistent with hexagonal packing of spirally oriented cylindrical protein units elongated along the filament axis.


[Ahern, historian of medicine].
Michel Joseph Ahern began the historical study of the medical profession in Quebec in 1910, with the publication of a series of biographies entitled Notes pour servir à l'histoire de la médecine dans le Bas-Canada depuis la fondation de Québec jusqu'au commencement du XIXe siècle in the Bulletin médical de Québec. After his death, his son George used his extant notes to continue the publication of these texts and a subsequent one-volume compilation with the same title. Despite several weaknesses, this work remains an indispensable source for researchers interested in the medical history of Quebec. Prepared in the context of several commemorations at the beginning of the 20th Century such as the 300th anniversary of the founding of Quebec City, Ahern's texts were tributes to the founders of medicine in Quebec, irrespective of their status; consequently, this work is not a pantheon of great names in medicine in the period. Doctor Ahern strove for historical integrity, and consulted archives, historians, and the learned men o f his time.


Preinfusion anxiety and laboratory-induced panic attacks in panic disorder patients.
Seventy panic disorder patients participated in a double-blind, placebo-controlled, randomized infusion study in which sodium lactate and isoproterenol were used to induce panic anxiety. Patients who panicked during lactate, isoproterenol, and placebo infusions generally had higher preinfusion anxiety scores. These findings held true irrespective of the order the infusions were given. Stepwise multiple regression analyses comparing panickers with nonpanickers as the criterion variable revealed that the items "afraid of going crazy," "feeling unsteady," and "feeling paralyzed" on the Panic Description Scale had the highest predicting values.


A Historical Perspective on Bacterial Persistence.
Bactericidal antibiotics quickly kill the majority of a bacterial population. However, a small fraction of cells typically survive through entering the so-called persister state. Persister cells are increasingly being viewed as a major cause of the recurrence of chronic infectious disease and could be an important factor in the emergence of antibiotic resistance. The phenomenon of persistence was first described in the 1940s, but remained poorly understood for decades afterwards. Only recently, a series of breakthrough discoveries has started to shed light on persister physiology and the molecular and genetic underpinnings of persister formation. We here provide an overview of the key studies that have paved the way for the current boom in persistence research, with a special focus on the technological and methodological advances that have enabled this progress.


Colonization of the axilla by Propionibacterium avidum in relation to age.
The prevalence of Propionibacterium avidum in the axillae of 248 individuals aged 5 to 18 years was studied. Both caucasoids and negroids, males (132) and females (116), were included. The frequency of recovery of the organism increased with age and was associated with the onset of puberty. The organism was recovered from only 2 of 40 females (5%) aged 5 to 10 years and from 1 of 22 males (4.5%), whereas 45% of females and 58% of males aged 15 to 16 years were colonized. Females tended to become colonized at an earlier age than males did. It appeared that negroids carried the organism more frequently than caucasoids, but the difference in prevalence was not statistically significant in matching age groups. It is suggested that the increase of hydration of the axilla with age and increase in substrate availability play an important part in the colonization process.


Synthetic mimetics of the endogenous gastrointestinal nanomineral: Silent constructs that trap macromolecules for intracellular delivery.
Amorphous magnesium-substituted calcium phosphate (AMCP) nanoparticles (75-150nm) form constitutively in large numbers in the mammalian gut. Collective evidence indicates that they trap and deliver luminal macromolecules to mucosal antigen presenting cells (APCs) and facilitate gut immune homeostasis. Here, we report on a synthetic mimetic of the endogenous AMCP and show that it has marked capacity to trap macromolecules during formation. Macromolecular capture into AMCP involved incorporation as shown by STEM tomography of the synthetic AMCP particle with 5nm ultra-fine iron (III) oxohydroxide. In vitro, organic cargo-loaded synthetic AMCP was taken up by APCs and tracked to lysosomal compartments. The AMCP itself did not regulate any gene, or modify any gene regulation by its cargo, based upon whole genome transcriptomic analyses. We conclude that synthetic AMCP can efficiently trap macromolecules and deliver them to APCs in a silent fashion, and may thus represent a new platform for antigen delivery.


The state of insulin resistance in patients with nonalcoholic fatty liver and the intervention with Gankangyin.
To explore the correlation of nonalcoholic fatty liver (NAFL) with insulin resistance and the intervention of it by Gankangyin(GKY). Ninety-six patients with NAFL were randomly assigned into the treated group and the control group. They were treated with GKY and Silymarin for 3 months respectively. Oral glucose tolerance test (OGTT) and insulin release test (IRT) were conducted and insulin sensitivity indexes were determined before and after treatment. And 32 healthy nonalcoholic persons were enrolled and used as the healthy control group. Before treatment, the levels of blood glucose and insulin at different time points in OGTT test, and the insulin resistance index (IRI) were significantly higher (P < 0.05 or P < 0.01) while insulin sensitivity index (ISI) and insulin active index (IAI) were lower (P < 0.05 or P < 0.01) in the NAFL patients than those in the healthy persons. After treatment, the above-mentioned raised criteria were significantly lowered (P < 0.05, P < 0.01) and the lowered criteria were significantly increased (P < 0.01) in the treated group, while in the control group all the criteria were insignificantly changed (P > 0.05). Evident insulin resistance exists in NAFL patients. GKY could increase the insulin sensitivity, thus improving the state of insulin resistance in NAFL patients.


Beta-globin transcripts carrying a single intron with three adjacent nucleotides of 5' exon are efficiently spliced in vitro irrespective of intron position or surrounding exon sequences.
To examine the role of exon sequences and intron position in the splicing of an mRNA precursor, we prepared series of sense or anti-sense transcripts of human beta-globin cDNA in which a cassette containing the beta-globin first intron was inserted into one of seven unusual positions. The intron cassette consisted of the intron alone (ml), the intron with three adjacent base pairs of the 5' exon (MI), or the intron with both 5' and 3' exon sequences. All these transcripts were examined in an in vitro splicing system with a HeLa cell nuclear extract. The sense transcripts carrying MI cassette were spliced efficiently and independently of the intron position, except when the 3' exon was too short. The anti-sense transcripts carrying MI cassette produced significantly less spliced products than did those of the sense transcripts. This was mostly because of the instability of the anti-sense transcripts, and the actual splicing efficiency was similar to that seen in the sense transcripts. Sense or anti-sense transcripts carrying ml cassette were spliced to various extents depending on the surrounding sequences. The results indicate that only three nucleotides of the 5' exon are required as specific exon sequences in the splicing of an mRNA precursor carrying a single intron, and that the intron position does not significantly affect the splicing efficiency in vitro.


Sanguinate's effect on pial arterioles in healthy rats and cerebral oxygen tension after controlled cortical impact.
Sanguinate, a polyethylene glycol-conjugated carboxyhemoglobin, was investigated for cerebral vasoactivity in healthy male Sprague-Dawley rats (Study 1) and for its ability to increase brain tissue oxygen pressure (PbtO2) after controlled cortical impact (CCI) - traumatic brain injury (TBI) (Study 2). In both studies ketamine-acepromazine anesthetized rats were ventilated with 40% O2. In Study 1, a cranial window was used to measure the diameters of medium - (50-100μm) and small-sized (<50μm) pial arterioles before and after four serial infusions of Sanguinate (8mL/kg/h, cumulative 16mL/kg IV), volume-matched Hextend, or normal saline. In Study 2, PbtO2 was measured using a phosphorescence quenching method before TBI, 15min after TBI (T15) and then every 10min thereafter for 155min. At T15, rats received either 8mL/kg IV Sanguinate (40mL/kg/h) or no treatment (saline, 4mL/kg/h). Results showed: 1) in healthy rats, percentage changes in pial arteriole diameter were the same among the groups, 2) in TBI rats, PbtO2 decreased from 36.5±3.9mmHg to 19.8±3.0mmHg at T15 in both groups after TBI and did not recover in either group for the rest of the study, and 3) MAP increased 16±4mmHg and 36±5mmHg after Sanguinate in healthy and TBI rats, respectively, while MAP was unchanged in control groups. In conclusion, Sanguinate did not cause vasoconstriction in the cerebral pial arterioles of healthy rats but it also did not acutely increase PbtO2 when administered after TBI. Sanguinate was associated with an increase in MAP in both studies.


Identification and characterisation of the Plasmodium vivax rhoptry-associated protein 2.
Plasmodium vivax is currently the most widespread of the four parasite species causing malaria in humans around the world. It causes more than 75 million clinical episodes per year, mainly on the Asian and American continents. Identifying new antigens to be further tested as anti-P. vivax vaccine candidates has been greatly hampered by the difficulty of maintaining this parasite cultured in vitro. Taking into account that one of the most promising vaccine candidates against Plasmodium falciparum is the rhoptry-associated protein 2, we have identified the P. falciparum rhoptry-associated protein 2 homologue in P. vivax in the present study. This protein has 400 residues, having an N-terminal 21 amino-acid stretch compatible with a signal peptide and, as occurs with its falciparum homologue, it lacks repeat sequences. The protein is expressed in asexual stage P. vivax parasites and polyclonal sera raised against this protein recognised a 46 kDa band in parasite lysate in a Western blot assay.


Assessment of right heart function in the athlete's heart.
It is known that the heart of an athlete has been physiologically adapted by prolonged training. There are a large number of echocardiographic studies which have focused on left ventricular wall thickness and dilatation, but there are few studies concerning right heart function in the athlete's heart. The aim of this study was to assess right heart function in elite athletes by conventional and new echocardiographic methods. The study population consisted of 36 elite highly-trained male athletes and 16 age-matched healthy sedentary controls. Right atrial, right ventricular, and inferior vena cava dimensions, and pulsed Doppler measurements of tricuspid inflow and right ventricular outflow were obtained, and systolic (preejection period, ejection time, preejection time/ejection time, QV peak, isovolumic contraction time) and diastolic (E peak, A peak, E/A ratio, decelaration time, isovolumic relexation time) function parameters were measured. The myocardial performance index was calculated as (isovolumetric contraction time + isovolumetric relaxation time)/ejection time. In addition, right ventricular systolic and diastolic functions were determined by Pulsed wave tissue Doppler imaging (S, E, and A velocities) at the lateral corners of the tricuspid annulus. The left ventricular mass index (P < 0.005), and right atrial (P < 0.001), right ventricular (P < 0.001), and inferior vena cava dimensions (P < 0.001) were significantly greater in athletes than in controls. Tricuspid E peak, A peak, E/A ratio, deceleration time, isovolumic relaxation time, preejection period, right ventricular ejection time, preejection time/ejection time, isovolumic contraction time, QV peak, and myocardial performance index were found to be similar in athletes and in controls (P > 0.05). Systolic, early diastolic, and late diastolic tissue Doppler imaging velocities were not significantly different in athletes and controls (P > 0.05). Left ventricular hypertrophy (LV mass index >134 g/m2) was found in 15 of the athletes. Right atrial dimension was greater in the athletes with left ventricular hypertrophy than in those without hypertrophy (P < 0.05). All right ventricular systolic and diastolic echocardiographic parameters were similar in athletes with and without left ventricular hypertrophy (P > 0.05). The results of this study indicate that right ventricular systolic and diastolic functions do not deteriorate in the athlete's heart despite significant chamber dilatation. They suggest that these changes are a normal physiologic adaptation to prolonged training.


[Tumors of cryptochid testis].
After comparing the statistics of Department of Urology of the Cochin Hospital (Paris) with international series, the author raises three questions: 1) is there a relation between the level of descent of the testicle and secondary development of carcinoma? 2(What is the incidence of orchidopexy on secondary development of carcinoma, and 3) is there a specific histology of tumors of the undescended testicle? After raising these questions, the author goes on to discuss the etiology of the tumors, and their treatment.


The role of surgery in low-grade gliomas: do timing and extent of resection matter?
Hugues Duffau is a Professor and Chairman of the Neurosurgery Department in the Montpellier University Medical Center and Head of the INSERM 1051 Team "plasticity of the central nervous system, human stem cells and glial tumors" at the Institute for Neurosciences of Montpellier (France). He is an expert in the awake cognitive neurosurgery of slow-growing brain tumors, such as low-grade gliomas, a routine which he has developed since 20 years. His fundamental approach is centered on the concepts of the brain connectomics and neuroplasticity, breaking with the traditional localizationist view of cerebral processing. For his innovative work in neurosurgery and neurosciences, he was awarded Doctor Honoris Causa several times, and he was the youngest recipient of the prestigious Herbert Olivecrona Award from the Karolinska Institute in Stockholm. He has written four textbooks and over 335 publications in international journals ranging from neurosurgery to fundamental neurosciences, including cognitive sciences and brain plasticity for a total of more than 20,800 citations and with an h-index of 77. He is a member of editorial boards of many journals (as brain and language, neurosurgery or neuro-oncology) and ad hoc reviewer for around 100 journals (over 900 reviews) including: New England Journal of Medicine, Lancet Oncology, Nature Medicine, Nature Reviews Neuroscience, Nature Reviews Neurology; Annals of Neurology, Brain, Cerebral Cortex, Trends in Cognitive Science, Current Biology, among others. He is a member of many societies: member of the French Academy of Medicine, member of the French Academy of Surgery, member of the World Academy of Neurological Surgery, member of the Young Neurosurgeons Award Committee of the World Federation of Neurosurgical Societies, member of the Scientific Committee of the European Association for Neuro-oncology, etc.


Development of a living membrane comprising a functional human renal proximal tubule cell monolayer on polyethersulfone polymeric membrane.
The need for improved renal replacement therapies has stimulated innovative research for the development of a cell-based renal assist device. A key requirement for such a device is the formation of a "living membrane", consisting of a tight kidney cell monolayer with preserved functional organic ion transporters on a suitable artificial membrane surface. In this work, we applied a unique conditionally immortalized proximal tubule epithelial cell (ciPTEC) line with an optimized coating strategy on polyethersulfone (PES) membranes to develop a living membrane with a functional proximal tubule epithelial cell layer. PES membranes were coated with combinations of 3,4-dihydroxy-l-phenylalanine and human collagen IV (Coll IV). The optimal coating time and concentrations were determined to achieve retention of vital blood components while preserving high water transport and optimal ciPTEC adhesion. The ciPTEC monolayers obtained were examined through immunocytochemistry to detect zona occludens 1 tight junction proteins. Reproducible monolayers were formed when using a combination of 2 mg ml(-1) 3,4-dihydroxy-l-phenylalanine (4 min coating, 1h dissolution) and 25 μg ml(-1) Coll IV (4 min coating). The successful transport of (14)C-creatinine through the developed living membrane system was used as an indication for organic cation transporter functionality. The addition of metformin or cimetidine significantly reduced the creatinine transepithelial flux, indicating active creatinine uptake in ciPTECs, most likely mediated by the organic cation transporter, OCT2 (SLC22A2). In conclusion, this study shows the successful development of a living membrane consisting of a reproducible ciPTEC monolayer on PES membranes, an important step towards the development of a bioartificial kidney.


Nonadditive functional interactions between ligand-binding sites of the multidrug efflux pump AdeB from Acinetobacter baumannii.
Multidrug efflux pumps of the resistance-nodulation-division superfamily of proteins are important contributors to various aspects of bacterial physiology and antibiotic resistance. Studies of the best-characterized model transporter AcrB from Escherichia coli suggested that these transporters operate by a functional rotation mechanism in which various substrates bind to at least two different binding sites. This study suggests that the mechanism of AdeB is distinct and that the binding sites in this transporter are functionally linked.


Significant Gene Biomarker Tyrosine Kinase Non-receptor 2 Mediated Cell Proliferation and Invasion in Colon Cancer.
Objective: This study aimed to investigate the expression and biological functions of TNK2 and miR-125a-3p in colon cancer. Materials and methods: The expression of TNK2 and miR-125a-3p in colon cancer tissues was analyzed using data deposited on public databases including UALCAN and ONCOMINE. We verified their expression in colon cancer cell lines by RT-qPCR and western blotting. By regulating the expression of TNK2 and miR-125a-3p in colon cancer cells, their functions and potential mechanisms were explored. Results: TNK2 was overexpressed in colon cancer cell lines, and it was found to directly bind to miR-125a-3p, which was downregulated in these cell lines. Their expression affected the proliferation and invasion of colon cancer cells. Additionally, colon cancer patients with lower TNK2 expression had better prognoses than those with higher TNK2 expression. Conclusion: Our results indicated that TNK2 and miR-125a-3p play critical roles in colon cancer, and could also serve as biomarkers for the diagnosis and prognosis of this malignant disease.


Pegylated Curcumin Derivative: Water-Soluble Conjugates with Antitumor and Antibacterial Activity.
During the past years, the synthesis of polymer prodrug structures, based on natural phytochemical compounds with a great range of valuable biological properties, has become a promising solution in cancer prevention, imaging, and detection. Curcumin (Curc) remains one of the most studied natural products, due to the impressive palette of biological properties and the possibility to be easily loaded in various micro- and nanostructures and chemically modified. In this study, pegylated curcumin derivatives were prepared by a direct esterification reaction between poly(ethylene glycol)diacid (PEG of 600 g/mol molar mass, PEG600) and Curc in the presence of N,N'-dicyclohexylcarbodiimide (PEG600-Curc). The successful reaction resulted in a water-soluble stable product that was characterized by infrared spectroscopy (Fourier transform infrared (FT-IR)) and proton (1H) and carbon (13C) NMR. The effect of the pH values of buffer solutions on PEG600-Curc spectral properties (absorption and photoluminescence) was investigated by UV-vis and fluorescence spectrophotometry. Based on the biological tests, it was confirmed that PEG600-Curc exhibits cytotoxic activity against Graffi cell lines, as a function of the Curc concentration in the conjugate and the incubation time. PEG600-Curc antibacterial activity was validated in microbiological tests against pathogenic microorganisms such as Staphylococcus aureus. Most importantly, despite the covalent attachment of Curc to PEG and the slight reduction in the therapeutic index of the conjugate, both the anticancer and antimicrobial activities remain the highest reported, thus opening the gate for further, more clinically oriented studies.


Computer Simulation Insight into the Adsorption and Diffusion of Polyelectrolytes on Oppositely Charged Surface.
In the present work, by means of computer simulation, we studied the adsorption and diffusion of polyelectrolyte macromolecules on oppositely charged surfaces. We considered the surface coverage and the charge of the adsorbed layer depending on the ionization degree of the macromolecules and the charge of the surface and carried out a computer experiment on the polymer diffusion within the adsorbed layers, taking into account its strong dependency on the surface coverage and the macromolecular ionization degree. The different regimes were distinguished that provided maximal mobility of the polymer chains along with a high number of charged groups in the layer, which could be beneficial for the development of the functional coatings. The results were compared with those of previous experiments on the adsorption of polyelectrolyte layers that may be applied as biocidal renewable coatings that can reversibly desorb from the surface.


Family history and the risk of sudden cardiac death as a manifestation of an acute coronary event.
Observational studies have suggested that a parental history of sudden death increases one's risk of dying suddenly. This study tested the hypothesis that a family history of sudden cardiac death (SCD) is a risk factor for SCD caused by an acute coronary event. A retrospective case-control study included (1) consecutive victims of SCD (n=138) whose deaths were verified to be due to an acute coronary event without a history of prior myocardial infarction at medicolegal autopsy, (2) consecutive patients surviving an acute myocardial infarction (AMI; n=254), and (3) healthy control subjects (n=470). Family history of AMI and SCD among the first-degree relatives was ascertained in each study group. The incidence of SCD in the 1223 first-degree relatives of SCD victims was higher (5.2%) than that in the 2326 relatives of AMI survivors (3.3%; odds ration [OR] 1.6, 95% confidence interval [CI] 1.2 to 2.2, P<0.01) or the 3748 relatives of controls (OR 2.2; 95% CI 1.6 to 3.0, P<0.001). The history of SCD in 2 or more first-degree relatives was also higher (10.9%) among SCD victims than among AMI survivors (3.5%; OR 3.3, 95% CI 1.4 to 7.8, P<0.01) or controls (1.1%; OR 11.3, 95% CI 4.0 to 31.8, P<0.001). The family history of AMI did not differ between the SCD and AMI groups. Male gender and current smoking were the only coronary risk factors that were more prevalent among SCD victims than among AMI survivors (P<0.001 for both). Subjects with a family history of SCD have an increased risk of dying suddenly during an acute coronary event.


Accurate measurement of nonlinear ellipse rotation using a phase-sensitive method.
We report on the accurate measurement of nonlinear ellipse rotation (NER) by means of a phase-sensitive method employing a dual-phase lock-in. The magnitudes and signs of pure refractive electronic nonlinearities of silica and BK7 were determined with this new method using 150 femtosecond (fs) laser pulses at 775 nm. Experimental and theoretical analyses of the NER signal were carried out and the results were compared to those obtained with the Z-scan technique.


Pediatric Celiac Disease: Follow-Up in the Spotlight.
The follow-up of celiac disease (CD) is challenging due to the scarcity of published data and the lack of standardized evidence-based protocols. The worldwide frequency and methods of CD follow-up appear to be heavily influenced by expert opinions of the individual physicians who assess children with CD. The aim of this review was to summarize the available studies on CD follow-up in children. We conducted a literature search with the use of PubMed, Medline, and Embase (from 1900 to 15 December 2016) for terms relevant to this review, including CD, follow-up, dietary adherence or dietary compliance, nutrition, comorbidities, complications, and quality of life. The aims of follow-up are as follows: to ensure strict adherence to a gluten-free diet, to ensure nutritional adequacy, to improve quality of life, and to prevent disease complications. For the correct evaluation of children with CD at follow-up, a clinical and biochemical evaluation is necessary on a regular basis. It is advisable to assess compliance, nutrition, comorbidities, or possible complications once a year at the referral center. Laboratory tests might be useful for a thorough evaluation of any patient with CD to rule out a micronutrient deficiency (full blood count, ferritin, folic acid, vitamin B-6, and vitamin B-12) and possible cardiovascular risk factors (glucose, LDL cholesterol, triglycerides). Biochemical evaluation is essential when there are clinical problems and should be customized on the basis of the specific clinical suspicion. Associated autoimmune thyroiditis should also be screened for yearly by measuring thyroid-stimulating hormone and thyroid autoantibody concentrations, regardless of symptoms, because hypothyroidism is often subtle and methods for early treatment are available and desirable. Although evidence-based recommendations for follow-up of pediatric patients with CD have not yet been established, we advise a yearly follow-up visit as the safest approach.


Interleukin-12 and interleukin-23 inhibition in psoriatic arthritis.
The cytokines interleukin (IL)-12 and interleukin (IL)-23 have been implicated variously in the pathogenesis of psoriasis and psoriatic arthritis (PsA). By corollary, the IL-12/23 inhibitor, Ustekinumab has been developed as an approved therapeutic for the skin and musculoskeletal syndrome of psoriasis / PsA. This review describes briefly the role of IL-12 and IL-23 in the pathophysiology of psoriatic arthritis and evaluates trial data that support its clinical use in psoriasis and different manifestations of psoriatic arthritis. The next steps towards targeting this pathway also are discussed.


Immunoglobulin V gene utilization in chronic lymphocytic leukemia and non-Hodgkin's B cell lymphomas.
Chronic lymphocytic leukemia (CLL) represents a malignancy of the CD5 B cell. Such CD5 B cells constitute a minor B cell subpopulation in normal adults that recently has been implicated as a source of IgM autoantibodies. NHL of follicular center cell origin, on the other hand, generally do not co-express CD5, and may be considered neoplasms of B cells from a lineage(s) or differentiation stage(s) distinct from that of the CD5 B cell. We examined antibody-expressing malignant B cells from patients with CLL for reactivity with each of several mouse monoclonal antibodies (mAb) specific for immunoglobulin (Ig) cross-reactive idiotypes (CRI) associated with human autoantibodies. Nearly 20% of all Ig-expressing CLL were recognized by a mAb specific for a rheumatoid factor (RF) heavy-chain associated CRI. Furthermore, approximately 20% of the kappa light chain expressing CLL reacted with 17.109, a mAb specific for a kappa-light-chain-associated CRI. In contrast, NHL that do not co-express the CD5 surface antigen apparently react with these anti-CRI mAbs at significantly lower frequencies. None of the forty CD5-negative NHL tested reacted with the mAb specific for the Ig heavy chain associated CRI. Moreover, only one of 30 kappa light chain expressing CD5-negative NHL tested reacted with 17.109. We examined the molecular basis for the high frequency expression of autoantibody-associated CRIs in CLL. Analyses of the Ig kappa light chain cDNA reveals remarkable conservation in the nucleic acid sequence of the kappa light chain variable region gene (Vk gene) expressed by 17.109-reactive leukemic cells from unrelated patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Cardiac sarcoidosis: a case report.
Cardiac involvement is found in approximately 5% of patients with sarcoidosis. The course of the disease is variable, ranging from benign arrhythmias to high-degree heart block or sudden death, and diagnosis is difficult. Endomyocardial biopsy can confirm the diagnosis but the diagnostic yield of the procedure is low because of the uneven distribution of the granulomatous process. Cardiac sarcoidosis should be presumed in patients with known sarcoidosis who develop arrhythmias, conduction disease, heart failure or ECG abnormalities. The authors present a case report and brief review of cardiac sarcoidosis.


Propylthiouracil hepatotoxicity: two pediatric cases and review of the literature.
We have observed isolated hepatotoxicity in two children treated with propylthiouracil (PTU) for hyperthyroidism. Neither patient had risk factors for or clinical evidence of preexisting liver disease. In one patient the drug was promptly discontinued when signs of liver disease were noted. This patient quickly recovered. The second patient continued to receive PTU for several days after developing symptoms. Her illness progressed to fulminant hepatic failure with encephalopathy, and she died. These are the third and fourth pediatric cases reported, and there have been 10 cases reported in adults in the English language literature. Thirteen of the 14 patients are female. The literature regarding all these patients is reviewed. Propylthiouracil may cause lethal hepatic damage. This drug should be discontinued immediately if signs or symptoms of hepatic injury are detected.


Breast composition and radiographic breast equivalence.
The composition of the female breast is an elusive variable in screen-film mammography that has a vital role in determining both the radiographic image quality and breast radiation dose. Despite the large volume of research in mammography only two studies known to the author define the chemical composition of the two major breast constituents, fibrous glandular tissue and adipose tissue. Unfortunately there is not complete agreement between these two studies. Upon this basis, a variety of breast phantom materials have been suggested and developed. This paper examines the radiographic equivalence of some of these materials dealing notably with formulations given by Hammerstein et al and ICRU Report 44, as well as BR12, water, and lucite. Radiographic equivalence was calculated using a computer simulation of mammographic spectra (after the example of Birch and Marshall and Tucker et al, and fitted to available FDA data) applied to attenuation data of phantom materials, in turn based on elemental linear attenuation coefficient data. A software algorithm was written that iteratively calculates the thickness of a nominated material required to match the attenuation of another material of particular thickness. The equivalence of 2-8 cm of lucite to various phantom materials was calculated for molybdenum target, molybdenum filter (Mo/Mo) x-ray beams from 25 to 35 kVp and for Mo/Rh and Rh/Rh beams from 27 to 35 kVp. It was found that for Mo/Mo beams the equivalent thickness of breast phantom material for certain thicknesses of lucite was largely independent of x-ray beam energy with the range of thickness equivalences being less than 3% at 8 cm of lucite and less than 0.5% at 2 cm of lucite. The RMI 156 breast phantom was found to be equivalent to 42 mm of Hammerstein et al. 50% glandular/50% adipose phantom material for Mo/Mo beams at 27 kVp, increasing to 43 mm for the range of Rh/Rh beams. While some questions remain on the accuracy of the present composition of breast constituents, it is clear that various breast compositions can be successfully simulated by using an appropriate thickness of lucite material. The use of lucite breast phantoms is then seen as an effective and reliable way of evaluating mammographic image quality and for calculating breast dose for varying required breast compositions.


Evaluation assays measuring platelet kinetics in bone marrow and peripheral blood. An overview.
Platelets play an important role in haemostasis and thrombosis. For an understanding of the pathophysiology and treatment of thrombocytopenia, it is not sufficient to measure only the platelet count. Platelet kinetic parameters, such as platelet survival and turnover, might be useful because many thrombocytopenia related disorders result from the interaction between production, utilization or destruction, and sequestration of platelets. Therefore, measuring platelet turnover with radiolabelled platelets could be a sensitive and qualitative tool for clinicians. However, the method does not enjoy widespread use because it has some serious drawbacks, such as the problems associated with the manipulation of blood and platelets, and the use of radioactivity. Recently, other useful assays for measuring platelet fluxes have been described in the literature, including plasma thrombopoietin and glycocalicin. In this review, these new tests will be described, compared with the classical method using radiolabelled platelets, and finally evaluated for their usefulness in clinical practice.


[Prevalence of the metabolic syndrome in ischaemic stroke population].
The metabolic syndrome (MetSyn), especially diabetes or dyslipidaemias, predisposes to cardiovascular disease or stroke development. We aimed to evaluate the prevalence of MetSyn in a non-selected population of acute ischaemic stroke (IS) patients using three definitions. We analyzed 763 IS patients (426 women, 337 men) consecutively admitted to a tertiary referral hospital specializing in acute stroke care (1.01.2003-30.09.2005). MetSyn was diagnosed in the presence of three from five disturbances (alimentary or simple obesity, increased blood pressure, increased triglycerides, low HDL cholesterol, fasting hyperglycaemia) according to definitions of: National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), International Diabetes Federation (IDF), American Heart Association - National Heart, Lung and Blood Institute (AHA-NHLBI). MetSyn was diagnosed according to criteria NCEP-ATP III, IDF, AHA-NHLBI in 54.3, 60.8 and 63.5% of IS patients, respectively, with significantly higher prevalence in women than in men in all age groups. Hypertension was the most frequent disturbance (93.7%). Alimentary or simple obesity and low HDL cholesterol level were significantly more frequent in women than in men (visceral obesity: NCEP-ATP III - 60.7 vs. 26.6%, IDF - 82 vs. 55.8%, AHA-NHLBI - 63.1 vs. 28.2%, respectively; low HDL cholesterol: 56.8 vs. 42%). Over half of acute ischaemic stroke patients have MetSyn, but in the female population MetSyn is 1.5 times more frequent than in men. It is necessary to pay a special attention to the population with MetSyn because of the high risk of ischaemic stroke.


Mitochondria and Their Role in Human Reproduction.
Genetic defects of the mitochondrial genome can be especially devastating to patients; moreover, attention on human mitochondrial disorders has grown remarkably in recent years. Mitochondrial DNA (mtDNA) is maternally inherited in most eukaryotes, with paternal mtDNA being eliminated from the embryo through a variety of mechanisms. Consequently, mtDNA mutations acquired in a woman's germline can impair fertility and/or lead to severe (and even fatal) diseases in her offspring. These issues are exacerbated as the age of the mother increases. In this review, we discuss the relationship between mitochondrial dysfunction, aging, and fertility, as well as current practices for screening and diagnosing mitochondrial defects in preimplantation embryos. We also discuss recent developments in the use of mitochondrial replacement therapy to prevent the transmission of maternally-inherited mitochondrial diseases.


The role of immunomodulatory medications in the treatment of COVID-19.
Given the role of inflammation in severe forms of COVID-19, glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) have been assessed as potential COVID-19 therapies. Randomized controlled trials (RCTs) have shown that glucocorticoids reduce mortality in severe COVID-19. RCTs of DMARDs have shown mixed results varying on intervention and inclusion criteria. DMARDs, including colchicine or biologic agents, may improve COVID-19 outcomes in specific patient populations. Glucocorticoids are an effective treatment for the management of severe COVID-19. Further studies are needed to better define the patient populations who could benefit from DMARD use, as well as provide guidance regarding the timing of these interventions.


Salivary gland function, development, and regeneration.
Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.


Oral retinoic acid as therapy for congenital ichthyosiform erythroderma.
Oral retinoic acid has been therapeutically beneficial for three patients with congenital ichthyosiform erythroderma and one with congenital bullous ichthyosifrom erythroderma. Response to therapy was slow but definite with suppression of scale formation, marked reduction of painful cracking of the underlying epidermis and disappearance of skin irritation. Side effects have not occurred. Therapy had to be maintained to prevent recurrence of symptoms.


Valedictory Editorial: The past six years.
Fifty years ago this month I graduated from the University of Liverpool. A few months earlier, along with three friends, I had driven overland to attend the International Dental Students Congress held that year in Israel. On the way we drove the spectacular road from Beirut up to Damascus, visited Petra in the Southern Jordanian desert, at that time devoid of tourists, viewed the Chagall windows in the synagogue on the Hadassah University Medical campus, and listened to the world cup final with a group of German students in a youth hostel overlooking the Mandelbaum Gate. Little did we know that within twelve months these beautiful countries and their kind people would be plunged into war and that this conflict and chaos would continue to haunt this region, almost unabated, for the next fifty years.


Ultraviolet A radiation (320-400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280-320 nm) or cis-urocanic acid.
T cell-mediated immune function, here measured as the contact hypersensitivity reaction, is readily suppressed by moderate exposure of mice to ultraviolet B (UVB) or solar-simulated radiation (SSUV), or by topical application of cis-urocanic acid. The effect of ultraviolet A (UVA) radiation on immune function has been unclear. Here we have demonstrated that when UVA radiation from a fluorescent tube source was rigorously filtered to remove contaminating UVB radiation, it was immunologically innocuous at physiologically relevant doses. Furthermore, we have found that mice exposed to UVA radiation, either immediately after, or up to 24 h before, immunosuppressive treatment with either UVB radiation, SSUV or cis-urocanic acid, became refractory to the immunosuppression and retained more normal contact hypersensitivity. A greater UVA exposure reversed the immunosuppression more effectively. The results suggest that there are immunologically significant interactions between UV wavebands, and that UVA exposure may induce a relatively long-lived immunoprotective photoproduct, as yet unidentified, that can inhibit the activity of epidermal cis-urocanic acid and thus provide protection from photoimmunosuppression.


CDK4/6 inhibitors: basics, pros, and major cons in breast cancer treatment with specific regard to cardiotoxicity - a narrative review.
Breast cancer is characterized by the uncontrolled proliferation of breast cells, with a high incidence reported in 2020 to have affected over 2 million women. In recent years, the conventional methods of treating breast cancer have involved radiotherapy and chemotherapy. However, the emergence of CDK4/6 inhibitors has shown potential as a promising cancer therapy. Cyclin-dependent kinases (CDK) inhibitors are a class of molecules that impede the formation of an active kinase complex, thereby hindering its activity and consequently halting the progression of the cell cycle. It was discovered that they have a significant impact on impeding the progression of the cancer. This is evident with the Food and Drug Administration's approval of drugs such as palbociclib, ribociclib, and abemaciclib for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies. In spite of enormous success in breast cancer treatment, certain obstacles have emerged, such as therapy resistance, side effects, and most of all, cardiotoxicity. Some of these drawbacks have been successfully overcome by dosage reduction, different combinations of the drugs, and the assessment of each patient's condition and suitability prior to treatment. Yet other drawbacks still require tenacious research, especially certain cases of cardiotoxicities. This article delves into the biological mechanisms of CDK4/6 in the cell cycle and cancer, as well as the clinical advantages and most common adverse events (AEs) associated with CDK4/6 inhibitors. The primary objective of this review is to provide a comprehensive analysis of cardiotoxic AEs and elucidate the underlying pathophysiological mechanisms responsible for the cardiotoxicity of CDK4/6 inhibitors.


Exposure to Diisocyanates and Their Corresponding Diamines in Seven Different Workplaces.
Biological monitoring to assess exposure to diisocyanates in the workplace is becoming increasingly widespread due to its relative ease of use and ability to look at all exposure routes. Currently, biological monitoring measures the corresponding isocyanate-derived diamine in urine, after hydrolysis. Because of this, any exposure to the diamines themselves released during the industrial process could confound the assessment of diisocyanate exposure. This paper reports an initial assessment of the extent of diamine formation and exposure during different processes involving diisocyanates including casting, grouting, core making, spray painting, foam blowing, and floor screeding. Air monitoring and glove analysis were conducted for both the relevant diisocyanate (measured as total NCO) and its corresponding diamine; urine samples were analysed (after hydrolysis) for the isocyanate-derived diamine. Processes that generated aerosols (as demonstrated by impinger analysis) such as spray painting and foam blowing were associated with the detection of diamines. Those processes that did not generate aerosols (casting, grouting, core making, and screeding) had no diamines detected, either in air or on gloves. In spray-painting tasks, diamines were a minor component (<15%) of the ambient concentration whereas in the foam blowing processes, where water is added to the process, diamine generation is more marked (up to eight times the airborne NCO concentration). Some non-aerosol processes gave rise to substantial diamine levels in urine (in exceedance of international guidance values, >5 µmol mol-1 creatinine) despite airborne levels being well within occupational exposure limits (20 µg m-3 total NCO in Great Britain); measurement data and statistical modelling indicated that skin absorption was the most likely exposure route. Foam blowing exposures were more complex, but urinary levels were greater than those expected from diisocyanate inhalation alone (measured as total NCO). This study provides evidence that biological monitoring for diisocyanates based on measuring the corresponding diamine in urine is valid, although any co-exposure to diamines themselves should be considered when interpreting results. It also demonstrates the potential for substantial skin absorption of diisocyanates in certain processes such as floor screeding and foam production.


Studies of the toxicological potential of capsinoids: IX. Teratology studies of dihydrocapsiate in rats and rabbits.
In order to determine the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS no. 205687-03-2), teratology studies were conducted in pregnant Sprague-Dawley rats (18 to 20 animals per group) and pregnant New Zealand white rabbits (20 to 21 animals per group). The test substance was administered by gavage for 11 days, from days 7 to 17 of gestation in rats, and for 13 days from days 6 to 18 of gestation in rabbits, at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. In the rat study, no deaths occurred in any group and there were no test substance-related changes or abnormalities in clinical signs, body weight, food consumption, or gross pathological findings. There were no test substance-related changes in the number of corpora lutea, number of implantations, index of implantations, index of embryofetal deaths, and number, sex ratio, or body weight of live fetuses at the end of the gestation period and there were no abnormalities in the placentae of live fetuses. There were no test substance-related abnormalities or variations in the external, skeletal, or visceral examinations of live fetuses. There were no abnormalities in ossification. En toto, it was concluded there were no teratogenic effects in the rat study. In the rabbit study, there were no test substance-related effects on clinical signs, body weight, food consumption, or necropsy findings in any group. There were neither test substance-related abortions nor test substance-related effects on the number of corpora lutea, number of implantations, or implantation index in any group. There were no test substance-related effects on the number of dead embryos/fetuses, the number, sex ratio, or body weight of live fetuses, or gross pathological finding of placentae. There were no test substance-related external abnormalities, or incidence of visceral or skeletal abnormalities or variations, and there were no test substance-related effects on the progress of ossification in any group. Based upon these data, the no observed adverse effect level (NOAEL) of dihydrocapsiate for general toxicity in dams, reproductive functions of dams, and embryofetal development was judged to be 1000 mg/kg/day both in rats and rabbits.


Resolving crossing fibres using constrained spherical deconvolution: validation using diffusion-weighted imaging phantom data.
Diffusion-weighted imaging can potentially be used to infer the connectivity of the human brain in vivo using fibre-tracking techniques, and is therefore of great interest to neuroscientists and clinicians. A key requirement for fibre tracking is the accurate estimation of white matter fibre orientations within each imaging voxel. The diffusion tensor model, which is widely used for this purpose, has been shown to be inadequate in crossing fibre regions. A number of approaches have recently been proposed to address this issue, based on high angular resolution diffusion-weighted imaging (HARDI) data. In this study, an experimental model of crossing fibres, consisting of water-filled plastic capillaries, is used to thoroughly assess three such techniques: constrained spherical deconvolution (CSD), super-resolved CSD (super-CSD) and Q-ball imaging (QBI). HARDI data were acquired over a range of crossing angles and b-values, from which fibre orientations were computed using each technique. All techniques were capable of resolving the two fibre populations down to a crossing angle of 45 degrees , and down to 30 degrees for super-CSD. A bias was observed in the fibre orientations estimated by QBI for crossing angles other than 90 degrees, consistent with previous simulation results. Finally, for a 45 degrees crossing, the minimum b-value required to resolve the fibre orientations was 4000 s/mm(2) for QBI, 2000 s/mm(2) for CSD, and 1000 s/mm(2) for super-CSD. The quality of estimation of fibre orientations may profoundly affect fibre tracking attempts, and the results presented provide important additional information regarding performance characteristics of well-known methods.


Determining an Upper Reference Value for the Urinary Fluoride-Creatinine Ratio in Healthy Children Younger than 7 Years.
The urinary fluoride/creatinine ratio (UF/Cr) in a spot urine sample could be a useful systemic F exposure monitoring tool. No reference value for UF/Cr currently exists, therefore this study aimed to establish an upper reference value for a UF/Cr, corresponding to excessive systemic F exposure, i.e., >0.07 mg F/kg body weight (b.w.)/day, in children. Subsidiary aims were to examine the relationship between (i) total daily F intake (TDFI) and 24-h urinary F excretion (DUFE); (ii) DUFE and UF/Cr, and (iii) TDFI and UF/Cr. Simultaneously collected TDFI, DUFE, and urinary creatinine (UCr) data in children <7 years were taken from UK studies conducted from 2002 to 2014 in order to calculate UF/Cr (mg/g) for each child. For the 158 children (mean age 5.8 years) included in the data analysis, mean TDFI and DUFE were 0.049 (SD 0.033) and 0.016 (SD 0.008) mg/kg b.w./day, respectively, and the mean UF/Cr was 1.21 (SD 0.61) mg/g. Significant (p < 0.001) positive linear correlations were found between TDFI and DUFE, DUFE and UF/Cr, and TDFI and UF/Cr. The estimated upper reference value for UF/Cr was 1.69 mg/g; this was significantly (p = 0.019) higher than the UF/Cr (1.29) associated with optimal F exposure (0.05-0.07 mg/kg b.w./day). In conclusion, the strong positive correlation between TDFI and UF/Cr confirms the strong association of these 2 F exposure variables and the value of a spot urine sample for prediction of TDFI (i.e., the most important risk factor in determining fluorosis occurrence and severity) in young children. Establishing an estimation of an upper reference value of 1.69 mg/g for UF/Cr in spot urine samples could simplify and facilitate their use as a valuable tool in large epidemiological studies.


Atomistic Molecular Simulations Suggest a Kinetic Model for Membrane Translocation by Arginine-Rich Peptides.
Arginine-rich cell penetrating peptides (ARCPPs) are known to quickly permeate cell membranes through a non-endocytotic pathway. Potential clinical applications of this facility have prompted enormous effort, both experimental and theoretical, to better understand how ARCPPs manage to overcome the prodigious thermodynamic cost of lipid bilayer permeation by these highly charged peptides. In this work we report the results of all-atom simulations, which suggest that a kinetic (rather than thermodynamic) mechanism may explain how ARCPPs are able to achieve this. Our simulations reveal that octaarginine significantly hinders the closing of membrane pores, either individually or via aggregation in the membrane pore, while octalysine (not an ARCPP) lacks this ability. Our proposed mechanism is an alternative to current attempts to explain pore-mediated translocation of ARCPPs. It asserts that ARCPPs need not lower the equilibrium thermodynamic cost of pore formation. Instead, they can achieve rapid bilayer translocation by instead slowing down the kinetics of naturally occurring thermal pores. Linking the pore lifetime to the characteristic time for peptide diffusion out of the pore, ARCPPs are able to cooperatively permeate the membrane pore.


What high-deductible plans look like: findings from a national survey of employers, 2005.
This paper documents the availability, enrollment, premiums, and cost sharing for high-deductible health plans that are offered with a health reimbursement arrangement (HRA) or are health savings account (HSA)-qualified plans. Almost 4 percent of employers that offer health benefits offer one of these arrangements in 2005, covering about 2.4 million workers. Deductibles, as expected, are relatively high, averaging dollar 1,870 for single coverage and dollar 3,686 for family coverage in high-deductible health plans with an HRA and dollar 1,901 for single coverage and dollar 4,070 for family coverage in HSA-qualified high-deductible health plans. One in three employers offering a high-deductible health plan that is HSA-qualified do not contribute to HSAs established by their workers.


Negative Regulation of Hepatic Inflammation by the Soluble Resistance-Related Calcium-Binding Protein via Signal Transducer and Activator of Transcription 3.
Host immune response is tightly controlled by negative regulators to avoid excessive immune reactions for homeostasis. Some pathogens may take advantage of host negative regulating system to evade host defense. Our previous report showed that foot-and-mouth disease virus (FMDV) VP1 inhibited TNF-α- and SeV-induced type I interferon response via interaction with cellular protein soluble resistance-related calcium-binding protein (sorcin). Conversely, TNF-α- or SeV-induced type I interferon response increased when sorcin knocked down, leading to inhibition of vesicular stomatitis virus replication. However, the exact role of sorcin in regulation of the immune response is still not clear. Here, we show that mice deficient of sorcin (sorcin-/-) display enhanced ConA-induced hepatitis. Importantly, splenocytes from sorcin-/- mice produced more IL-2, IL-4, IL-17, and IFN-γ than that of littermate controls (sorcin+/+) in response to anti-CD3/28 stimulation. Furthermore, our data indicate that sorcin interacts with signal transducer and activator of transcription 3 (STAT3) and enhances its phosphorylation and that STAT3 acts as an immediate downstream molecule of sorcin in the negative regulation of NF-κB signaling. Thus, sorcin, in association with STAT3, negatively regulates hepatic inflammation.


Comparison of serological tests for the detection of antibody to natural and experimental murine cytomegalovirus.
Three serological tests, i.e. complement fixation test, indirect immunofluorescent assay, and enzyme-linked immunosorbent assay (ELISA) were compared for sensitivity in the detection and titration of murine cytomegalovirus antibody. The three tests were compared using sera from experimentally inoculated and naturally infected mice bled at intervals from 3 to 140 days postinfection. In the acute infection, complement fixation and indirect immunofluorescent assay tests were of comparable sensitivity for early detection of antibody, whereas the ELISA was less sensitive. In persistent infection, higher titers were recorded with ELISA. Since murine cytomegalovirus has been shown to exert significant effects on the immune response of infected mice, this antigen should be included routinely in viral antibody screening programs.


Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription.
The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), whereas the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participates in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification. Immunostaining, quantitative PCR, and Western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to a low-level increase of p53 mRNA and protein in both pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNA-mediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification, and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.


Normal mode analysis of Pyrococcus furiosus rubredoxin via nuclear resonance vibrational spectroscopy (NRVS) and resonance raman spectroscopy.
We have used (57)Fe nuclear resonance vibrational spectroscopy (NRVS) to study the Fe(S(cys))(4) site in reduced and oxidized rubredoxin (Rd) from Pyrococcus furiosus (Pf). The oxidized form has also been investigated by resonance Raman spectroscopy. In the oxidized Rd NRVS, strong asymmetric Fe-S stretching modes are observed between 355 and 375 cm(-1); upon reduction these modes shift to 300-320 cm(-1). This is the first observation of Fe-S stretching modes in a reduced Rd. The peak in S-Fe-S bend mode intensity is at approximately 150 cm(-1) for the oxidized protein and only slightly lower in the reduced case. A third band occurs near 70 cm(-1) for both samples; this is assigned primarily as a collective motion of entire cysteine residues with respect to the central Fe. The (57)Fe partial vibrational density of states (PVDOS) were interpreted by normal mode analysis with optimization of Urey-Bradley force fields. The three main bands were qualitatively reproduced using a D(2)(d) Fe(SC)(4) model. A C(1) Fe(SCC)(4) model based on crystallographic coordinates was then used to simulate the splitting of the asymmetric stretching band into at least 3 components. Finally, a model employing complete cysteines and 2 additional neighboring atoms was used to reproduce the detailed structure of the PVDOS in the Fe-S stretch region. These results confirm the delocalization of the dynamic properties of the redox-active Fe site. Depending on the molecular model employed, the force constant K(Fe-S) for Fe-S stretching modes ranged from 1.24 to 1.32 mdyn/A. K(Fe-S) is clearly diminished in reduced Rd; values from approximately 0.89 to 1.00 mdyn/A were derived from different models. In contrast, in the final models the force constants for S-Fe-S bending motion, H(S-Fe-S), were 0.18 mdyn/A for oxidized Rd and 0.15 mdyn/A for reduced Rd. The NRVS technique demonstrates great promise for the observation and quantitative interpretation of the dynamical properties of Fe-S proteins.


Advancing Integrated Care through Psychiatric Workforce Development: A Systematic Review of Educational Interventions to Train Psychiatrists in Integrated Care.
Integrated or collaborative care is a well-evidenced and widely practiced approach to improve access to high-quality mental health care in primary care and other settings. Psychiatrists require preparation for this emerging type of practice, and such training is now mandatory for Canadian psychiatry residents. However, it is not known how best to mount such training, and in the absence of such knowledge, the quality of training across Canada has suffered. To guide integrated care education nationally, we conducted a systematic review of published and unpublished training programs. We searched journal databases and web-based 'grey' literature and contacted all North American psychiatry residency programs known to provide integrated care training. We included educational interventions targeting practicing psychiatrists or psychiatry residents as learners. We critically appraised literature using the Medical Education Research Study Quality Instrument (MERSQI). We described the goals, content, and format of training, as well as outcomes categorized according to Kirkpatrick level of impact. We included 9 published and 5 unpublished educational interventions. Studies were of low to moderate quality and reflected possible publication bias toward favourable outcomes. Programs commonly involved longitudinal clinical experiences for residents, mentoring networks for practicing physicians, or brief didactic experiences and were rarely oriented toward the most empirically supported models of integrated care. Implementation challenges were widespread. Similar to integrated care clinical interventions, integrated care training is important yet difficult to achieve. Educational initiatives could benefit from faculty development, quality improvement to synergistically improve care and training, and stronger evaluation. Systematic review registration number: PROSPERO 2014:CRD42014010295.


Implication of CYP24A1 splicing in breast cancer.
The expression of CYP27B1 or vitamin D 1α-hydroxylase (1α-OHase) and CYP24A1 in specific tissues may act as the central part between 25-hydroxyvitamin D [25(OH)D] serum levels and the anticancer effects of1α,25-dihydroxyvitamin D [1α,25(OH)2D3],alternative splicing of these enzymes may affect their biological functions. Here, we describe the expression of CYP24A1 and its splicing variants detected in breast cells and tissues. Manifestation of CYP24A1 mRNA was measured by RT-PCR followed by western blot analysis for protein expression. In MCF-7 cells, the expression of CYP24A1 protein was reduced by about 57% compared to MCF-10F cells. Western blot analysis revealed a signal band at 56 kDa, with additional bands detected at 42 and 44 kDa. The expression of CYP24A1 mRNA was reduced by about 58% in breast cancer tissues. We found only one signal in the benign tissues at 56 kDa in western blot, whereas in malignant tissue, an additional band was detected at 40kDa. Our results suggest that alternative splicing of CYP24A1 may lead to a catalytically dysfunctional enzyme.


Cloning and characterization of the human granulocyte chemotactic protein-2 gene.
We recently described a novel murine CXC chemokine, designated lipopolysaccharide-induced CXC chemokine (LIX). In an ongoing search for new human chemokines related to LIX, we cloned the gene for human granulocyte chemotactic protein-2 (GCP-2) as well as previously described CXC chemokine genes, including epithelial cell-derived neutrophil-activating peptide-78 (ENA-78). Both coding and noncoding portions of the GCP-2 gene have very high nucleotide similarity to ENA-78, except for the occurrence of a long interspersed DNA-1 sequence 5' of the GCP-2 gene. The GCP-2 gene encodes a propeptide of 114 amino acid residues. The predicted 77-residue mature peptide is identical with the GCP-2 protein previously isolated from MG-63 osteosarcoma cells, except for two additional residues at the carboxyl terminus. We confirmed expression of the gene by Northern analysis and by cloning a portion of the cDNA from reverse transcribed MG-63 cell RNA. Despite 85% identity of the first 270 nucleotides 5' of the transcription start sites, GCP-2 and ENA-78 show cell-specific differences in regulation. GCP-2 is induced in MG-63, but not A549 cells by TNF-alpha, IL-1beta, and LPS, while ENA-78 is expressed in both cell types. Analysis of nucleotide sequence relationships does not support the proposal, by others, that LIX is murine GCP-2. LIX is no more closely related to human GCP-2 than to human ENA-78 and is more distant from both human genes than is porcine alveolar macrophage chemotactic factor-II.