An exploratory study examining the relationship between performance status and systemic inflammation frameworks and cytokine profiles in patients with advanced cancer.
The role of cytokines in the systemic inflammatory response (SIR) is now well established. This is in keeping with the role of the SIR in tumorigenesis, malignant spread, and the development of cachexia. However, the relationship between performance status/systemic inflammation frameworks and cytokine profiles is not clear. The aim of the present study was to examine the relationship between the Eastern cooperative oncology group performance status/modified Glasgow prognostic score (ECOG-PS/mGPS) and cooperative oncology group performance status/neutrophil platelet score (ECOG-PS/NPS) frameworks and their cytokine profile in patients with advanced cancer.This was a retrospective interrogation of data already collected as part of a recent clinical trial (NCT00676936). The relationship between the independent variables (ECOG-PS/mGPS and ECOG-PS/NPS frameworks), and dependent variables (cytokine levels) was examined using independent Mann-Whitney U and Kruskal Wallis tests where appropriate.Of the 40 patients included in final analysis the majority had evidence of an SIR assessed by mGPS (78%) or NPS (53%). All patients died on follow-up and the median survival was 91 days (4-933 days). With increasing ECOG-PS there was a higher median value of Interleukin 6 (IL-6, P = .016) and C-reactive protein (CRP, P < .01) and lower albumin (P < .01) and poorer survival (P < .001). With increasing mGPS there was a higher median value of IL-6 (P = .016), Macrophage migration inhibitory factor (MIF, P = .010), erythrocyte sedimentation rate (ESR, P < .01) and poorer survival (P < .01). With increasing NPS there was a higher median value of TGF-β (P < .001) and C-reactive protein (P = .020) and poor survival (P = .001). When those patients with an ECOG-PS 0/1 and mGPS0 were compared with those patients with an ECOG-PS 2 and mGPS2 there was a higher median value of IL-6 (P = .017) and poorer survival (P < .001). When those patients with an ECOG-PS 0/1 and NPS0 were compared with those patients with an ECOG-PS 2 and NPS1/2 there was a higher median value of IL-6 (P = .002), TGF-β (P < .001) and poorer survival (P < .01).In patients with advanced cancer IL-6 was associated with the ECOG-PS/mGPS and ECOG-PS/NPS frameworks and survival in patients with advanced cancer. Therefore, the present work provides supporting evidence that agents targeting IL-6 are worthy of further exploration.


Creating a learning environment for tomorrow's health care workforce.
The complexity of today's health care environment requires new teaching-learning strategies. Inova Health System's creative approach is highlighted through the development of the inova Learning Network.


[LEGAL BASIS FOR THE MOVEMENT OF MEDICINES ACROSS THE CUSTOMS BORDER OF THE EURASIAN ECONOMIC UNION BY LEGAL ENTITIES].
The issues of the movement of medicines across the customs border of the Eurasian Economic Union are timely and relevant, due to the increase in the turnover of medicines in the Russian Federation. The article deals with the issues of import and export through the customs border of the Eurasian Economic Union of both registered and unregistered medicines in the Russian Federation by legal entities. In addition, the authors investigated the regulatory and legal procedure for the movement of medicines across the customs border of the Eurasian Economic Union containing narcotic and psychotropic substances. Topical issues of falsification of medicines and criminal norms of the law on combating it are touched upon. The analysis carried out in the work allowed the authors to identify the existing problems of regulatory regulation of the issue under study and propose a solution.


The interactive Physical and Cognitive Exercise System (iPACES™): effects of a 3-month in-home pilot clinical trial for mild cognitive impairment and caregivers.
Alzheimer's and related dementias are on the rise, and older adults and their families are seeking accessible and effective ways to stave off or ameliorate mild cognitive impairment (MCI). This pilot clinical trial (ClinicalTrials.gov Identifier: 03069391) examined neuropsychological and neurobiological outcomes of interactive physical and mental exercise. Older adults (MCI and caregivers) were enrolled in a 3-month, in-home trial of a portable neuro-exergame (the interactive Physical and Cognitive Exercise System [iPACES™]), in which they pedaled and steered along a virtual bike path to complete a list of errands (Memory Lane™). Neuropsychological function and salivary biomarkers were measured at pre-, mid-, and posttrial. Ten older adults complied with the recommended use of iPACES (complete dose; ≥2×/wk, 67% of the 15 who also had pre- and postevaluation data). Statistical analyses compared change over time and also change among those with a complete dose vs inadequate dose. Correlations between change in neuropsychological and biomarker measures were also examined. Executive function and verbal memory increased after 3 months (p = 0.01; no significant change was found with an inadequate dose). Change in salivary biomarkers was moderately associated with increasing cognition (cortisol, r = 0.68; IGF-1, r = 0.37). Further research is needed, but these pilot data provide preliminary indications to suggest neuro-exergaming can impact cognitive function, perhaps via neurobiological mechanisms, and as such may provide an effective and practical way to promote healthy aging.


Observed, Executed, and Imagined Action Representations can be Decoded From Ventral and Dorsal Areas.
Previous functional magnetic resonance imaging (fMRI) research on action observation has emphasized the role of putative mirror neuron areas such as Broca's area, ventral premotor cortex, and the inferior parietal lobule. However, recent evidence suggests action observation involves many distributed cortical regions, including dorsal premotor and superior parietal cortex. How these different regions relate to traditional mirror neuron areas, and whether traditional mirror neuron areas play a special role in action representation, is unclear. Here we use multi-voxel pattern analysis (MVPA) to show that action representations, including observation, imagery, and execution of reaching movements: (1) are distributed across both dorsal (superior) and ventral (inferior) premotor and parietal areas; (2) can be decoded from areas that are jointly activated by observation, execution, and imagery of reaching movements, even in cases of equal-amplitude blood oxygen level-dependent (BOLD) responses; and (3) can be equally accurately classified from either posterior parietal or frontal (premotor and inferior frontal) regions. These results challenge the presumed dominance of traditional mirror neuron areas such as Broca's area in action observation and action representation more generally. Unlike traditional univariate fMRI analyses, MVPA was able to discriminate between imagined and observed movements from previously indistinguishable BOLD activations in commonly activated regions, suggesting finer-grained distributed patterns of activation.


Genetic parameters of IgM and IgG antibodies binding autoantigens in healthy chickens.
Levels of natural antibodies (NAb) binding keyhole limpet hemocyanin (KLH) in layers were shown to be heritable and to be potential indicative parameters for survival. A proportion of NAb are directed to self-molecules, or slightly changed self-molecules (neo-epitopes), labeled as natural autoantibodies (NAAb). It is unknown whether the levels of NAAb are heritable and genetically correlated. In this paper, we estimated genetic parameters in plasma of healthy layers for IgM and IgG antibodies binding ovalbumin (OVA), myosin (MYO), cardiolipin (CAR), lysozyme (LYS), and the model antigen keyhole limpet hemocyanin (KLH). A linear animal model was used to estimate (co)variance components, heritabilities, and correlations. The estimates of heritabilities ranged from 0.10 to 0.17 for IgM, and 0.02 to 0.11 for IgG, respectively. For both IgM and IgG, high genetic correlations were observed between levels of NAAb binding autoantigens and NAb binding KLH, except for IgG binding KLH and LYS, for which a low genetic correlation was found. Low to moderate phenotypic correlations were found between NAAb and NAb. In addition, significant maternal environmental effects of 0.03, 0.07, and 0.04 were observed for IgM binding OVA, LYS, and KLH, respectively. Results from this study indicated that NAAb or NAb levels in plasma were heritable and could provide tools to identify the health status of birds.


Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability.
The significance of low-level DNA microsatellite instability (MSI-L) is not well understood. K-ras mutation is associated with MSI-L colorectal cancer and with the silencing of the DNA repair gene O-6-methylguanine DNA methyltransferase (MGMT) by methylation of its promoter region. MGMT methylation was studied in sporadic colorectal cancers stratified as DNA microsatellite instability-high (n = 23), MSI-L (n = 44), and microsatellite-stable (n = 23). Methylation-specific PCR was used to detect MGMT-promoter hypermethylation in 3 of 23 (13%) microsatellite instability-high, in 28 of 44 (64%) MSI-L, and in 6 of 23 (26%) microsatellite-stable cancers (P = 0.0001). K-ras was mutated in 20 of 29 (69%) methylated MSI-L cancers and in 2 of 15 (13%) unmethylated MSI-L cancers (P = 0.001), indicating a relationship between MGMT-methylation and mutation of K-ras. Loss of nuclear expression of MGMT was demonstrated immunohistochemically in 23 of 31 (74%) cancers with methylated MGMT and in 10 of 49 (20%) cancers with nonmethylated MGMT (P < 0.0001). Loss of expression of MGMT was also demonstrated in 9 of 31 serrated polyps. Silencing of MGMT may predispose to mutation by overwhelming the DNA mismatch repair system and occurs with greatest frequency in MSI-L colorectal cancers.


Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases.
Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder of unknown etiology. Most patients present with lymph node involvement manifesting as adenopathy; however, RDD may arise primarily in a variety of extranodal sites, including bone. We report herein our experience with 15 cases of primary intraosseous RDD. The patients include 8 females and 7 males, who ranged in age from 3 to 56 (mean 27) years. The lesions arose in a variety of anatomical locations, including the tibia, femur, clavicle, skull, maxilla, calcaneus, phalanx, metacarpal, and sacrum. Radiographically, the lesions were lytic with well defined and usually sclerotic margins. Histologically, the lesions demonstrated the classic features of RDD and consisted of a mixed inflammatory infiltrate with numerous large histiocytes with abundant eosinophilic cytoplasm which exhibited emperipolesis. Some cases also contained numerous neutrophils. Immunohistochemical stains showed that the large histiocytes were S-100 positive. Follow-up information was available for 12 patients. Five patients eventually developed additional extraosseous manifestations, including testicular, lymph node, and subcutaneous lesions. One of these 5 also developed a new bony lesion within the sternum. One patient developed additional lesions within multiple bones of the hand and wrist, without extraosseous disease. One patient had stable bony lesions, whereas 5 remained disease free after treatment.


[Effect of vasopressin on the Na,K-ATPase activity in synaptic membranes of the brain of adult and old rats].
Vasopressin regulated in vitro the activity of Na+, K+-ATPase in synaptic membranes from rat brain cortex and brain stem. Low concentrations of the peptide activated the enzyme, high concentrations--inhibited. The effect was most distinct in brain stem. Age-dependent effects of vasopressin on the Na+, K+-ATPase activity were observed. Basal activity of the enzyme was not altered in synaptic membranes with ageing.


The crystal structure of phosphorylated MAPK13 reveals common structural features and differences in p38 MAPK family activation.
The p38 MAP kinases (p38 MAPKs) represent an important family centrally involved in mediating extracellular signaling. Recent studies indicate that family members such as MAPK13 (p38δ) display a selective cellular and tissue expression and are therefore involved in specific diseases. Detailed structural studies of all p38 MAPK family members are crucial for the design of specific inhibitors. In order to facilitate such ventures, the structure of MAPK13 was determined in both the inactive (unphosphorylated; MAPK13) and active (dual phosphorylated; MAPK13/pTpY) forms. Here, the first preparation, crystallization and structure determination of MAPK13/pTpY are presented and the structure is compared with the previously reported structure of MAPK13 in order to facilitate studies for structure-based drug design. A comprehensive analysis of inactive versus active structures for the p38 MAPK family is also presented. It is found that MAPK13 undergoes a larger interlobe configurational rearrangement upon activation compared with MAPK14. Surprisingly, the analysis of activated p38 MAPK structures (MAP12/pTpY, MAPK13/pTpY and MAPK14/pTpY) reveals that, despite a high degree of sequence similarity, different side chains are used to coordinate the phosphorylated residues. There are also differences in the rearrangement of the hinge region that occur in MAPK14 compared with MAPK13 which would affect inhibitor binding. A thorough examination of all of the active (phosphorylated) and inactive (unphosphorylated) p38 MAPK family member structures was performed to reveal a common structural basis of activation for the p38 MAP kinase family and to identify structural differences that may be exploited for developing family member-specific inhibitors.


Antigenic heterogeneity and molecular analysis of CopB of Moraxella (Branhamella) catarrhalis.
Outer membrane protein (OMP) CopB, an iron-repressible 81-kDa major OMP of Moraxella (Branhamella) catarrhalis has been a major focus of investigation. To assess CopB as a potential vaccine antigen, we elucidated the degree of antigenic and sequence heterogeneity in this protein among strains of M. catarrhalis. Two monoclonal antibodies, 1F5 and 2.9F, which bind to surface-exposed epitopes on CopB recognized 60 and 70% of the strains, respectively. The degree of sequence heterogeneity in CopB was assessed by cloning and sequencing the CopB gene from two different strains of M. catarrhalis and comparing with the published sequence. There was 92 to 96% homology between the sequences at the nucleotide level and 90 to 95% homology at the amino acid level. The variability in the protein sequence is confined mainly to three moderately variable regions. Restriction fragment length polymorphism (RFLP) analysis of the CopB genes obtained from 20 diverse strains by PCR was performed. Ninety percent of the potential restriction sites in the constant regions and 47% of the potential restriction sites in the variable regions were present in the 20 strains, indicating that the pattern of variable and constant areas in the CopB gene is a general pattern among strains of M. catarrhalis. We conclude that the CopB gene is largely conserved among strains of M. catarrhalis and contains discrete regions which show moderate heterogeneity among strains.


Occupation, work load and the size and shape of lumbar vertebral canals.
Measurements made from plain lumbar radiographs were used to compare the size and shape of the lumbar vertebral canals between various categories of occupation and work load among 77 men and 118 women with a history of low-back pain. The mean anteroposterior foraminal diameters proved to be wider in female farm workers than in other women, especially in the vertebra L3 (17.1 versus 15.4 mm). However, the men who did heavy manual work had smaller anteroposterior foraminal diameters than the men whose work involved less physical labor (difference at L5 9.4 versus 10.8 mm). Female farm workers were found to have shorter interarticular distances than females in other occupational groups. In the men who reported working in stooped postures or reported lifting and carrying heavy objects at work, the interarticular distances were wider than in men who had no such exposures.


[Effect of lipopolysaccharide toxin on lipid and protein composition of human serum low density lipoproteins].
Complexes of lipopolysaccharide (LPS) B of Salmonella typhimurium with human low density lipoproteins (LDL) formed during in vitro coincubation via spontaneous incorporation of LPS (complex LDL-LPS) or through the incorporation stimulated by the serum protein fraction (LPS/LDL complex) were studied. The LPS/LDL complex was shown to maximally bind 0.24 mg of LPS per 1 mg of LDL protein, whereas the LDL-LPS complex contained only 0.07 mg of LPS per 1 mg of LDL protein. The observed incorporation of LPS into LDL particles was not possibly associated with a transfer of lipids or proteins from high density lipoproteins to LDL. The insertion of LPS was probably accompanied by the expulsion of a small portion of phosphatidylcholine molecules from the outer monolayer of LDL into the aqueous medium and by an increase in the phosphatidylethanolamine concentration in LDL. Simultaneously, the level of esterified cholesterol in the LPS/LDL complex decreased, and the concentrations of free cholesterol and triacylglycerols showed a rise. The level of free fatty acids in the LPS/LDL complex increased more than twofold compared with intact LDL. The enhancement of LPS incorporation did not result in the insertion of any serum proteins into LDL, in which apoB-100 remained the major apolipoprotein (ca. 90%); apoB-100 fragments made up to 5-7%, whereas apoE and apoC contained altogether ca. 3-5%. It is suggested that the LPS/LDL complex obtained can bind to three types of cell receptors, i.e., apoB/E receptors, LPS receptors and scavenger receptors of macrophages (monocytes); the increased level of free fatty acids in the LPS/LDL complex may accelerate its subsequent catabolism.


Oncogenic mutations are associated with histological subtypes but do not have an independent prognostic value in lung adenocarcinoma.
Lung adenocarcinomas have diverse genetic and morphological backgrounds and are usually classified according to their distinct oncogenic mutations (or so-called driver mutations) and histological subtypes (the de novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS]). Although both these classifications are essential for personalized treatment, their integrated clinical effect remains unclear. Therefore, we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis. Analysis for oncogenic mutations included the direct sequencing of EGFR, KRAS, HER2, BRAF, PIK3CA, ALK, and RET for oncogenic mutations/rearrangements, and a rereview of the IASLC/ATS/ERS classification was undertaken. Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ, 20 minimally invasive adenocarcinomas, 901 invasive adenocarcinomas, 44 invasive mucinous adenocarcinomas, and three other variants. The invasive mucinous adenocarcinomas had a lower prevalence of EGFR mutations but a higher prevalence of KRAS, ALK, and HER2 mutations than invasive adenocarcinomas. Smoking, a solid predominant pattern, and a mucinous component were independently associated with fewer EGFR mutations. The ALK rearrangements were more frequently observed in tumors with a minor mucinous component, while the KRAS mutations were more prevalent in smokers. In addition, 503 patients with stage I-IIIA tumors were analyzed for overall survival (OS) and relapse-free survival. The stage and histological pattern were independent predictors of relapse-free survival, and the pathological stage was the only independent predictor for the OS. Although patients with the EGFR mutations had better OS than those without the mutations, no oncogenic mutation was an independent predictor of survival. Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification, which facilitates a morphology-based mutational analysis strategy. The combination of these two classifications might not increase the prognostic ability, but it provides essential information for personalized treatment.


Studies in the pathogenesis of experimental dysentery intoxication. Production of lesions by introduction of toxin into the cerebral ventricles.
The introduction of Shiga toxin into the ventricular system of the brain with major location in the third ventricle resulted in a response similar to that following the administration of the toxin either intravenously or by cross-circulation. The intravenous administration at the dosage level employed would have elicited no response. These observations lend support to the hypothesis that Shiga toxin activates some mechanisms in the central nervous system which are capable of producing visceral lesions. These mechanisms are those which control the vasomotor components of homeostasis. This hypothesis permits an explanation of the proximo-distal and intramural features of the lesion.


Partial purification and characterization of the components of the neutral ribonuclease II-inhibitor system of normal and distrophic mouse skeletal muscle.
The complexes between a proteinaceous inhibitor and neutral ribonuclease II (EC 3.127.5) purified from low ionic strength extracts of normal and dystrophic mouse muscle are essentially indistinguishable in (a) purification behavior, (b) apparent molecular weights of approximately 50 000, (c) thermal denaturation (50% loss of activity in 5 min at 73.5 degrees C), (d) isoelectric points (pH 4.8), and (e) procedures for reversible resolution into free inhibitor and free RNase II. The free RNase II species are also similar whether obtained by resolution of the purified complexes or by direct isolation of free enzyme from dystrophic muscle. All have apparent molecular weights of 11 500 compared with 13 700 for bovine pancreatic RNase A; all retain 80% of activity after 5 min at 95 degrees C. The active RNase II prepared directly from muscle, by resolution of inhibitor complexes or by organic mercurial treatment of the inhibitor complexes, all have identical pH-activity profiles in 200 mM KC1 with an optimum near pH 7.0. In comparison RNase A has an optimum pH near 7.5 and its activity decreases more rapidly as KC1 concentration is increased above 50 mM KC1. RNase II inhibitor obtained by resolution of the purified complexes or by direct isolation in the free form from normal muscle extracts has an apparent molecular weight of 42 000 and is very sensitive to heat; it loses all activity at 40 degrees C in 5 min. These studies (a) provide methods for obtaining useful amounts of the components of the neutral RNase II - inhibitor system from muscle, (b) provide the first method reported for the reversible resolution of RNase II - inhibitor complexes, (c) fail to show any distinct difference between corresponding components of the system from normal and dystrophic mice, (d) establish interesting differences between the apparently homologous enzymes, murine muscle neutral RNase II, and bovine pancreatic RNase A, and (e) provide a substantially lower molecular weight estimate for RNase II inhibitor from muscle than has been reported for the inhibitor from liver, kidney, and placenta.


Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption.
In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.


Inhibition of Human Cervical Cancer Cell Growth by Ethanolic Extract of Boerhaavia diffusa Linn. (Punarnava) Root.
In Indian traditional medicine, Boerhaavia diffusa (punarnava) roots have been widely used for the treatment of dyspepsia, jaundice, enlargement of spleen, abdominal pain and as an anti-stress agent. Pharmacological evaluation of the crude ethanolic extract of B. diffusa roots has been shown to possess antiproliferative and immunomodulatory properties. The extract of B. diffusa was studied for anti-proliferative effects on the growth of HeLa cells and for its effect on cell cycle. Bio-assays of extracts from B. diffusa root showed that a methanol : chloroform fraction (BDF 5) had an antiproliferative effect on HeLa cells. After 48 h of exposure, this fraction at a concentration of 200 μg mL(-1) significantly reduced cell proliferation with visible morphological changes in HeLa cells. Cell cycle analysis suggests that antiproliferative effect of BDF 5 could be due to inhibition of DNA synthesis in S-phase of cell cycle in HeLa cells, whereas no significant change in cell cycle was detected in control cells. The fraction BDF 5 caused cell death via apoptosis as evident from DNA fragmentation and caspase-9 activation. Thus the extract has potential to be evaluated in detail to assess the molecular mechanism-mediated anticancer activities of this plant.


[Quality indicators for ambulatory health education programme for overweight and obese children and adolescents].
In Germany, 9 to 12 % of all children between five and seven years of age have been shown to be overweight at school entry; 2.5 to 3.5 % of them are obese. Therapeutic intervention for obese children and adolescents is considered to be indicated especially in cases where an increased body mass index (BMI) is accompanied by a disease the effective treatment of which requires weight loss. Furthermore, the child and its family must be willing to actively change their habits. A multitude of health care providers have begun to offer multidisciplinary group programme for prevention and treatment of obesity to affected individuals and their families. The Medical Service of the Statutory Health Insurance (MDK) has therefore developed a list of quality and assessment criteria for such programme. A systematic search for information in international and national publications was performed using standard methodology of evidence-based medicine. Data were extracted and assessed according to pre-defined criteria taking into consideration previously published clinical guidelines and opinions of expert panels. Nearly all available studies were of low internal validity and mostly of poor methodological quality. Therefore, no binding recommendations for the design of health education programme for overweight and obese children and adolescents can be given. Potentially successful intervention should combine the following 4 modules: nutrition, physical activity, change of eating habits, physical activity habits and life style using methods of behavioural therapy, and involvement of parents. Such combinations may have the potential to reduce or stabilise the BMI at least during a defined period of time. In younger children, the beneficial effect will be more pronounced if the parents are actively involved. Up to now informative studies have not reliably shown that the effect of ambulatory health education programmes for overweight and obese children and adolescents and their parents may last for more than one or two years. Therefore, a controlled clinical trial determining the long-term effectiveness of such programme is imperative. The decision whether a defined programmes should be included in such a study could be taken on the basis of the quality indicators and assessment criteria described here.


Immunohistochemical analysis of human skeletal muscle AMP deaminase deficiency. Evidence of a correlation between the muscle HPRG content and the level of the residual AMP deaminase activity.
We have previously described that, in healthy human skeletal muscle, an anti-histidine-proline-rich-glycoprotein (HPRG) antibody selectively binds to type IIB fibers that are well known to contain the highest level of AMP deaminase (AMPD) activity, suggesting an association of the HPRG-like protein to the enzyme isoform M. The present paper reports an immunohistochemical study performed on human skeletal muscle biopsies from patients with AMPD deficiency and carried out utilizing both the anti-HPRG antibody and an anti-AMPD antibody specific for the isoform M. A correlation between the muscle content of the HPRG-like protein and the level of AMPD activity was demonstrated. In the specimens from patients with Acquired AMPD deficiency the HPRG-immunoreactivity was less intense than that shown by the control subjects and was related to the residual AMPD activity. The patients affected by Primary and Coincidental AMPD deficiency, which were characterized by an absence of enzyme activity and AMPD immunoreactivity, showed the lowest HPRG immunoreactivity that was clearly detectable by Western blot analysis, but not by immunohistochemistry. The interpretation of the significance of these observations suggests a physiological mutual dependence between skeletal muscle HPRG and AMPD polypeptides with regard to their stability.


Larvicidal potential of ethanolic extracts of dried fruits of three species of peppercorns against different instars of an indian strain of dengue fever mosquito, Aedes aegypti L. (Diptera: Culicidae).
Larvicidal bioassay was carried out in the laboratory to assess the potential of ethanolic extracts of dried fruits of three species of peppercorns: Long pepper, Piper longum L., Black pepper, Piper nigrum, and White pepper, Piper nigrum against the different instars of field-collected Indian strain of dengue fever mosquito (Aedes aegypti L.). The investigations established the larvicidal potential of all the varieties of pepper fruits against Ae. aegypti. Against early fourth instar, the ethanolic extracts of Black and White P. nigrum proved to be 30-40% less toxic than the extracts of P. longum, whereas against third instars, white pepper extracts exhibited 7% more efficacy than that of black pepper and 47% more toxicity than that of long pepper. The results also revealed that the extracts of all the three pepper species were 11-25 times more toxic against the third instar larvae as compared to the early fourth instars. The lethal concentration, 50% (LC(50)) values obtained with ethanolic extracts of P. longum, White P. nigrum and Black P. nigrum against early fourth instar larvae were 0.248, 0.356, and 0.405 ppm, respectively, and the lethal concentration, 90% (LC(90)) values were 0.605, 0.758, and 0.801 ppm, respectively. Whereas against third instar larvae, the LC(50) values recorded with three extracts were 0.022, 0.015, and 0.016 ppm and the LC(90) values recorded were 0.054, 0.034, and 0.046 ppm, respectively. The larvae treated with all the pepper species showed initial abnormal behavior in their motion followed by excitation, convulsions, and paralysis, leading to 100% kill indicating delayed larval toxicity and effects of the extracts on the neuromuscular system. Observations of morphological alterations on treated larvae under light microscopy revealed that most organs, except anal papillae, had a normal structural appearance as that of controls. The structural deformation in the form of shrinkage in the internal membrane exhibited by anal papillae suggests the anal papillae as the probable action sites of the pepper extracts. The potential of peppercorns as new types of larvicides for the control of mosquitoes are explored.


Attention-deficit/hyperactivity disorder in children and adolescents: rethinking diagnosis and treatment implications for complicated cases.
Children and adolescents who currently present for treatment frequently carry a principal diagnosis of attention-deficit/hyperactivity disorder in addition to other diagnoses. Many of these cases have long histories, are chronic, and are significantly complicated. Recognition of complicated cases requires rigorous diagnostic differentiation. Effective treatment and sustainable responses require individualized protocols that include integrated psychosocial and psychopharmacological interventions to minimize adverse reactions and enhance quality of life.


Favorable Outcome of Hurthle Cell Carcinoma of the Thyroid Treated With Total Thyroidectomy, Radioiodine, and Selective Use of External-Beam Radiotherapy.
There is controversy about the prognosis of Hurthle cell carcinoma of the thyroid. The purpose of this project is to report the outcome of a well-defined group of patients treated at a single institution in the modern era. Sixteen patients met the following inclusion criteria: Treatment with curative intent at our institution between January 1, 1997, and December 31, 2010. Primary treatment with total thyroidectomy with or without neck dissection. Age >18 years at the time of thyroidectomy. Confirmation by a pathologist of the diagnosis of a primary Hurthle cell carcinoma of the thyroid based on ≥75% Hurthle cells with extension through the tumor capsule. No areas of poorly differentiated (insular) or undifferentiated (anaplastic) carcinoma. Stage T1-3, NX-1b, M0. All patients received radioiodine immediately after thyroidectomy (remnant ablation, n=14) or as adjuvant for a recurrence (n=2). External-beam radiotherapy to the neck as adjuvant therapy after thyroidectomy was used in 2 patients and after resection of a neck recurrence in 1 patient. Five-year actuarial rates with a median 6 years of follow up on surviving patients were as follows:Overall and cancer-specific survival: 92% (1 death from Hurthle cell carcinoma). Relapse-free survival (no visible tumor and unstimulated thyroglobulin ≤1.0): 65%. Our experience suggests that the outcome of Hurthle cell carcinoma of the thyroid is favorable in adults with stage T1-3 NX-1b M0 disease who are managed with total thyroidectomy, radioiodine, and-in selected cases-external-beam radiotherapy. We do not have the ability to compare our results to other management strategies.


[Children and adolescents with chronic kidney disease in an educational-therapeutic environment: support for cultural nursing care].
This qualitative study was performed using an ethnographic approach, with the objective to understand how children and adolescents with chronic kidney disease experience their disease and treatment, and describe the educational-therapeutic care from the perspective of transcultural nursing. Participants were eleven subjects undergoing dialysis treatment. The study phases followed the observation-participation-reflection model, complemented by interviews. The analysis was guided by the four phases of the ethnonursing guide, revealing the following categories: living with kidney failure and changes in everyday life; and the hospital environment and educational-therapeutic activities, which show the discomforts and difficulties that impact several dimensions of life, somewhat compensated by the therapeutic environment and the opportunity for leisure. Culturally consistent care was understood as an intentional intervention constructed by the interaction between scientific knowledge and the valorization of the cultural knowledge of children and adolescents and their families.


Raman spectrum of a transfer RNA.
Raman spectrum of purified formylmethionine transfer RNA from Escherichia coli has been observed in its aqueous solution. In the 1800 to 200 cm(-l) range, about 30 Raman lines are found, each of which can be assigned to one of the constituent nucleotide residues. From the positions and intensities of the lines, information on the intramolecular environments of these base residues can be obtained.


Structural and regulatory elements of HCV NS5B polymerase--β-loop and C-terminal tail--are required for activity of allosteric thumb site II inhibitors.
Elucidation of the mechanism of action of the HCV NS5B polymerase thumb site II inhibitors has presented a challenge. Current opinion holds that these allosteric inhibitors stabilize the closed, inactive enzyme conformation, but how this inhibition is accomplished mechanistically is not well understood. Here, using a panel of NS5B proteins with mutations in key regulatory motifs of NS5B--the C-terminal tail and β-loop--in conjunction with a diverse set of NS5B allosteric inhibitors, we show that thumb site II inhibitors possess a distinct mechanism of action. A combination of enzyme activity studies and direct binding assays reveals that these inhibitors require both regulatory elements to maintain the polymerase inhibitory activity. Removal of either element has little impact on the binding affinity of thumb site II inhibitors, but significantly reduces their potency. NS5B in complex with a thumb site II inhibitor displays a characteristic melting profile that suggests stabilization not only of the thumb domain but also the whole polymerase. Successive truncations of the C-terminal tail and/or removal of the β-loop lead to progressive destabilization of the protein. Furthermore, the thermal unfolding transitions characteristic for thumb site II inhibitor-NS5B complex are absent in the inhibitor-bound constructs in which interactions between C-terminal tail and β-loop are abolished, pointing to the pivotal role of both regulatory elements in communication between domains. Taken together, a comprehensive picture of inhibition by compounds binding to thumb site II emerges: inhibitor binding provides stabilization of the entire polymerase in an inactive, closed conformation, propagated via coupled interactions between the C-terminal tail and β-loop.


Sustainable Protocol for the Reduction of Nitroarenes by Heterogeneous Au@SBA-15 with NaBH4 under Flow Conditions.
A gold-incorporated SBA-15 catalyst was prepared by a solvent-free ball-milling approach. The catalyst showed high reactivity and selectivity in the reduction of a variety of nitroarenes to anilines operating in absolute EtOH with NaBH4 as reducing agent. The catalyst was reused in batch conditions over five consecutive runs without any losses of activity or selectivity. Considering the high chemical stability and reusability of the catalytic system, a continuous-flow protocol was also investigated and defined to minimize the generation of waste and optimize the continuous reuse of the catalyst. Benefits of flow conditions were proven by turnover numbers that increased from 47.5 to 1902 and also by the minimization of both leaching (9.5 vs. 1 ppm) and E-factor values (8 vs. 23 in batch).


Validation of bioelectrical impedance analysis for assessing dry weight of dialysis patients in Pakistan.
Accurate dry weight estimation (DW) to achieve euvolemia is one of the key objectives of hemodialysis (HD). While conventionally DW is estimated by clinical examination, bioelectrical impedance analysis (BIA) has been proposed as an objective method to determine DW and has been tested extensively in the Western population. We aim to validate BIA for determining DW in a Pakistani population against the conventional clinician's method. This is a single-center validation study conducted at two outpatient HD units of Aga Khan Hospital, Karachi. One hundred and forty-eight DW readings of patients who were on maintenance HD were taken both by BIA technology and by clinical assessment. The clinician was blinded to readings obtained by BIA. Data analysis was carried out using the Statistical Package for Social Sciences (SPSS) version 19. Median age of patients was 63 years (range 12-89). Nearly 54.1% of the samples were female (n = 80). Spearman's correlation between the clinician's estimate and BIA-derived DW showed a correlation coefficient of 0.982, which was statistically significant (P <0.001). This association remained significant when stratified analysis was carried out by dividing the sample into subgroups according to age, gender, body mass index, and total body water content. Inter-rater reliability analysis using the kappa statistics showed almost perfect agreement between the two methods, κ = 0.929 (95% confidence interval, 0.878-0.980, P <0.001). BIA has been validated as a tool for DW assessment of HD patients in Pakistan in comparison to clinical method.


Regional and ethnic differences in stroke in the southeastern United States population.
The Stroke Belt in the United States lies in the Southeastern region where stroke mortality has been higher than in other geographic regions. The U.S. (African-American) black population has a higher stroke incidence and mortality rate than the US white population. This article reviews the English-language literature relating to observed regional and ethnic differences in stroke mortality, incidence, and risk factors. In addition, possible explanations for regional and ethnic differentials are explored. The significance of these regional and ethnic differences, and directions for future research, are examined.


Carbon footprint based on lifetime productivity for future cows selected for resilience to climate related disturbances.
Droughts, which can impact feed production, are projected to become more common under future climate conditions. In light of this, breeding cattle resilient to changes in feeding regimens is increasingly becoming an important topic. Body reserves can play a crucial role when the feed resources are limited. We simulated populations of dairy cows selected with 2 different breeding goals: one reflecting the current breeding goal and the other placing weight on minimum level of body reserves in early lactation and change in body reserves during lactation. We considered this latter as a breeding goal for resilience. We used the 2 dynamic simulation programs ADAM and AQAL to predict performance of the cows after selection. In AQAL, we modeled moderate and severe drought by decreasing feed quality and quantity offered to cows during one year. We compared cows selected with the 2 breeding goals under 3 environments: without disturbances related to climate and with moderate and severe drought. In the environments without disturbances and the moderate drought, the cows selected with the current breeding goal had higher life time lactation efficiency (energy invested in milk / energy acquired from feed) and lower carbon footprint per kg protein in milk and meat than cows selected for resilience. However, with severe drought, cows selected for resilience had higher life time lactation efficiency and lower carbon footprint per kg protein in milk and meat than those selected with the current breeding goal. This suggests that cows selected for high productive performance do not perform well under very limiting conditions, leading to increased climate impact. The importance of inclusion of body reserves as a resilience trait in dairy cattle breeding depends on the future environment in which the cows will be used.


Impact of comorbid depressive symptoms on nonverbal memory and visuospatial performance in obsessive-compulsive disorder.
Recent research has suggested that some executive dysfunctions in obsessive-compulsive disorder (OCD) represent an epiphenomenon of comorbid depressive symptoms. The present study investigated whether the impact of comorbid depressive symptoms on cognitive dysfunction in OCD extends to nonverbal memory impairment. A total of 32 OCD patients and 20 healthy controls took part in the study. Participants were administered a neurocognitive battery with a focus on nonverbal memory and visuospatial functions. While evidence was provided that neurocognitive processes necessitating visuospatial transformation and visuoconstruction are deficient in OCD patients regardless of comorbid depressive symptoms, nonverbal memory dysfunctions were only apparent for patients with elevated scores in the Hamilton Depression (HDRS) Rating Scale (total score > or = 8). Correlations with subscores of the HDRS revealed that core depressive symptoms are related to nonverbal memory deficits in OCD. Mental rotation, middle discrimination, and position discrimination were found to be unaffected in OCD. Y-BOCS scores, length of illness, onset of illness, number of hospital admissions, and checking compulsions were not associated with neurocognitive disturbances. Nonverbal memory is disturbed in only a subgroup of OCD patients displaying elevated HDRS scores (HDRS > or = 8). It is claimed but awaits further empirical testing that differences in depression profile across OCD studies have contributed to inconsistencies in prior investigations on neurocognitive functioning in OCD. Our results are questioning the hypothesis that nonverbal deficits are a causal factor for the development of checking compulsions.


Multicopy Targeted Integration for Accelerated Development of High-Producing Chinese Hamster Ovary Cells.
The ever-growing biopharmaceutical industry relies on the production of recombinant therapeutic proteins in Chinese hamster ovary (CHO) cells. The traditional timelines of CHO cell line development can be significantly shortened by the use of targeted gene integration (TI). However, broad use of TI has been limited due to the low specific productivity (qP) of TI-generated clones. Here, we show a 10-fold increase in the qP of therapeutic glycoproteins in CHO cells through the development and optimization of a multicopy TI method. We used a recombinase-mediated cassette exchange (RMCE) platform to investigate the effect of gene copy number, 5' and 3' gene regulatory elements, and landing pad features on qP. We evaluated the limitations of multicopy expression from a single genomic site as well as multiple genomic sites and found that a transcriptional bottleneck can appear with an increase in gene dosage. We created a dual-RMCE system for simultaneous multicopy TI in two genomic sites and generated isogenic high-producing clones with qP of 12-14 pg/cell/day and product titer close to 1 g/L in fed-batch. Our study provides an extensive characterization of the multicopy TI method and elucidates the relationship between gene copy number and protein expression in mammalian cells. Moreover, it demonstrates that TI-generated CHO cells are capable of producing therapeutic proteins at levels that can support their industrial manufacture.


PARP6 is a Regulator of Hippocampal Dendritic Morphogenesis.
Mono-ADP-ribosylation (MARylation) of mammalian proteins was first described as a post-translational modification catalyzed by bacterial toxins. It is now known that endogenous MARylation occurs in mammalian cells and is catalyzed by 11 members of the poly-ADP-ribose polymerase (PARP) family of proteins (17 in humans). The physiological roles of these PARPs remain largely unknown. Here we demonstrate that PARP6, a neuronally enriched PARP that catalyzes MARylation, regulates hippocampal dendrite morphogenesis, a process that is critical for proper neural circuit formation during development. Knockdown of PARP6 significantly decreased dendritic complexity in embryonic rat hippocampal neurons in culture and in vivo. Expression of wild-type PARP6 increased dendritic complexity; conversely, expression of a catalytically inactive PARP6 mutant, or a cysteine-rich domain deletion mutant that has significantly reduced catalytic activity, decreased dendritic complexity. The identification of PARP6 as a regulator of dendrite morphogenesis supports a role for MARylation in neurons during development.


Dynamic myocardial contractile parameters from left ventricular pressure-volume measurements.
A new dynamic model of left ventricular (LV) pressure-volume relationships in beating heart was developed by mathematically linking chamber pressure-volume dynamics with cardiac muscle force-length dynamics. The dynamic LV model accounted for >80% of the measured variation in pressure caused by small-amplitude volume perturbation in an otherwise isovolumically beating, isolated rat heart. The dynamic LV model produced good fits to pressure responses to volume perturbations, but there existed some systematic features in the residual errors of the fits. The issue was whether these residual errors would be damaging to an application where the dynamic LV model was used with LV pressure and volume measurements to estimate myocardial contractile parameters. Good agreement among myocardial parameters responsible for response magnitude was found between those derived by geometric transformations of parameters of the dynamic LV model estimated in beating heart and those found by direct measurement in constantly activated, isolated muscle fibers. Good agreement was also found among myocardial kinetic parameters estimated in each of the two preparations. Thus the small systematic residual errors from fitting the LV model to the dynamic pressure-volume measurements do not interfere with use of the dynamic LV model to estimate contractile parameters of myocardium. Dynamic contractile behavior of cardiac muscle can now be obtained from a beating heart by judicious application of the dynamic LV model to information-rich pressure and volume signals. This provides for the first time a bridge between the dynamics of cardiac muscle function and the dynamics of heart function and allows a beating heart to be used in studies where the relevance of myofilament contractile behavior to cardiovascular system function may be investigated.


Self-Identified Stage in Recovery and Substance-Use Behaviors among Pregnant and Postpartum Women and People with Opioid Use Disorder.
Opioid use among pregnant and postpartum women and people (PPWP) has significant health repercussions. This study explores how substance-use behaviors may vary by stage in recovery among PPWP with opioid use disorder (OUD). We recruited 29 PPWP with OUD. "High-risk" participants self-identified as "not being engaged in treatment" or "new or early in their recovery" (n = 11); "low-risk" participants self-identified as being "well-established" or "in long-term recovery" (n = 18). Participants were queried regarding sociodemographic, mental health, and drug-misuse factors; urine drug screens were collected at baseline. Univariate group comparisons between high-risk and low-risk PPWP were conducted. High-risk PPWP were more likely to self-identify as non-Hispanic African American and more likely to report current opioid use, other illicit drugs, and tobacco. High-risk PPWP had higher opioid cravings versus low-risk PPWP. High-risk PPWP were more likely to screen positive on urine tests for non-opioid drugs and on concurrent use of both non-opioid drugs and opioids versus low-risk participants. PPWP earlier in recovery are at higher-risk for opioid and other illicit drug misuse but are willing to disclose aspects of their recent use. PPWP early in recovery are an ideal population for interventions that can help facilitate recovery during the perinatal period and beyond.


[The dynamics of Phanerozoic marine animal diversity agrees with the hyperbolic growth model].
Generic diversity dynamics of the Phanerozoic marine animals is far better described by the hyperbolic model, widely used in demography and macrosociology, than by the exponential and logistic models from population dynamics traditionally employed for this purpose. Exponential and logistic models imply zero influence of interactions between taxa on the dynamics of diversity, with the exception of competing for unoccupied ecological space, whereas the hyperbolic model implies non-linear second-order positive feedback in the development of the biota. The hyperbolic human population growth is caused by positive feedback between population size and the rate of technological and cultural development (the more individuals, the more inventors, the more rapid progress, the more rapid growth of the Earth's bearing capacity; the smaller death-rate, the more accelerated growth-rate of the population). Probably there is also non-linear second-order positive feedback between diversity and community structure (the more genera, the higher alpha-diversity, which is defined as average number of genera per community, the more complicated and stable, "buffered" communities, the greater "taxonomic capacity of the environment" and average duration of the existence of genera; extinction rate dencreases, biodiversity growth-rate increases). The simplest mathematical model of biodiversity dynamics based on this assumption is confirmed by empirical data on alpha-diversity dynamics. Progressive complexification of marine communities during the Phanerozoic is also confirmed by the growing evennes of generic abundance distribution in paleocommunities.


Billroth I resection for peptic ulcer.
The Billroth I gastric resection, with and without vagotomy, was used in 20 selected cases of peptic ulcer. Vagotomy and pyloroplasty is considered the operation of first choice for duodenal ulcer. The cases for Billroth I resections were selected from cases not suitable for pyloroplasty. Operations for peptic ulcer which preserve the gastrointestinal continuity are considered to be physiologically superior. Vagotomy and pyloroplasty, and Billroth I gastric resection both qualify in this regard. The postoperative digestive symptoms after Billroth I gastric resection in the present series were minimal, which tends to confirm this theoretical superiority.


Patient, caregiver, and health care provider perspectives on barriers and facilitators to heart failure care in Kerala, India: A qualitative study.
Background: Deficits in quality of care for patients with heart failure (HF) contribute to high mortality in this population. This qualitative study aims to understand the barriers and facilitators to high-quality HF care in Kerala, India. Methods: Semi-structured, in-depth interviews were conducted with a purposive sample of health care providers (n=13), patients and caregivers (n=14). Additionally, focus group discussions (n=3) were conducted with patients and their caregivers. All interviews and focus group discussions were transcribed verbatim. Textual data were analysed using thematic analysis. Results: Patients' motivation to change their lifestyle behaviours after HF diagnosis and active follow-up calls from health care providers to check on patients' health status were important enablers of high-quality care. Health care providers' advice on substance use often motivated patients to stop smoking and consuming alcohol. Although patients expected support from their family members, the level of caregiver support for patients varied, with some patients receiving strong support from caregivers and others receiving minimal support. Emotional stress and lack of structured care plans for patients hindered patients' self-management of their condition. Further, high patient loads often limited the time health care providers had to provide advice on self-management options. Nevertheless, the availability of experienced nursing staff to support patients improved care within health care facilities. Finally, initiation of guideline-directed medical therapy was perceived as complex by health care providers due to multiple coexisting chronic conditions in HF patients. Conclusions: Structured plans for self-management of HF and more time for patients and health care providers to interact during clinical visits may enable better clinical handover with patients and family members, and thereby improve adherence to self-care options. Quality improvement interventions should also address the stress and emotional concerns of HF patients.


Immediate and delayed effects of invented writing intervention in preschool.
This study examined the effects of a 10 week invented writing program with five-year-old preschoolers (mean age 5.7 years) on their immediate post intervention literacy skills and also the facilitative effects of the intervention on the subsequent learning to read during the first 6 months of schooling. The study included 105 children (54 girls) from 12 preschools in Norway. The preschools were randomly assigned to the experimental group with the invented writing program, or the control group with the ordinary program offered to preschoolers. The classroom-based programs (40 sessions) were conducted by the children's regular teachers. The children's emergent literacy skills were evaluated using a pre-test, a post-test and a follow-up test 6 months later, and the data were analyzed using latent autoregressive models. The results showed that the invented writing group performed significantly better than the control group on the post-test for the measures of phoneme awareness (d = .54), spelling (d = .65) and word reading (d = .36). Additionally, indirect effects were observed on the delayed follow-up tests on phoneme awareness (d = .45), spelling (d = .48) and word reading (d = .26). In conclusion, we argue that invented writing appeared to smooth the progress of emergent literacy skills in preschool, including the subsequent reading development in school. Contextualized in a semi-consistent orthography and a preschool tradition that does not encourage the learning of written language skills, the findings add to our knowledge of how children learn to write and read.


Scientific Opinion related to a notification from Lyckeby Starch AB on barley starch to be used in the manufacturing of several foods as ingredient, of the food additive modified starch and of glucose syrups pursuant to Article 21(2) of Regulation (EU) No 1169/2011 - for permanent exemption from labelling.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on barley starch to be used in the manufacturing of several foods as ingredient, of the food additive modified starch and of glucose syrups pursuant to Article 21(2) of Regulation (EU) No 1169/2011, as notified by Lyckeby Starch AB. The applicant provided information on the manufacturing process and data on the content of total protein, gluten and allergenic proteins in barley starch. The applicant also performed IgE-binding in vitro tests, which were considered inconclusive by the Panel. No human intervention studies with barley starch or food products thereof were provided by the applicant, except for a DBPCFC with barley starch hydrolysate in cereal allergic individuals. The Panel notes that glucose syrups based on barley have been already exempted from allergen labelling as per Annex II of Regulation (EU) No 1169/2011 and that the current application is for the exemption from labelling of all foods manufactured from barley starch. In all the scenarios considered for the anticipated intake, the calculated total protein intake from barley starch was above the MED/MOED for wheat (expressed in mg of wheat protein) in adults (10 mg) and children (2 mg). The Panel concludes that the data available are insufficient to conclude on the likelihood of adverse allergic reactions in cereal-allergic individuals upon consumption of barley starch under the conditions of use proposed by the applicant, and that the consumption of foodstuffs produced from barley starch as starting (raw) material or foodstuffs containing barley starch as an ingredient is unlikely to cause an adverse reaction in individuals with coeliac disease who are not allergic to cereals, provided that the value of gluten for 'gluten-free' foods (20 mg/kg) is not exceeded.


Thrombendarterectomy in chronic pulmonary embolism. Reports of 3 cases.
Thrombendarterectomy of the pulmonary artery was performed in three cases of chronic pulmonary embolism with pulmonary hypertension and right heart failure. The indications for such tissue-preserving surgery are discussed against the background of the presented cases and of the literature. These indications are unilateral vascular obstruction with good run-off in combination with "moderate" pulmonary hypertension. Patients with peripheral vascular changes in both lungs and equilibrated pressures respond poorly to thrombendarterectomy and present high surgical risk. For such patients hope lies in future resources for combined heart-lung transplantation.


Association between IL-13 gene polymorphism and asthma in Han nationality in Hubei Chinese population.
In order to investigate whether Arg110Gln polymorphism in the coding region of the IL-13 gene is associated with asthma and total plasma IgE level in Han nationality in Hubei Chinese population, the allele frequency of 4257(g/a) site and Arg110Gln genotype of IL-13 was detected by using restriction fragment length polymorphism in Han nationality in Hubei Chinese population including 43 asthmatic children, 45 asthmatic adults, 31 control children and 46 control adults. Total plasma IgE was measured by Chemiluminescence assay. The results showed that the frequency of allele A at 4257 bp of IL-13 in children and adults was 0.39 and 0.32, respectively. The GlnGln form of Arg110Gln polymorphism of IL-13 gene was associated with susceptibility of asthma and elevated total plasma IgE in children (P=0.030 and 0.0009, respectively), but not with them in adults (P=0.219 and 0.174, respectively). Our results suggest that the Arg110Gln polymorphism of IL-13 gene is associated with susceptibility of asthma and elevated total plasma IgE in Chinese children of Han nationality in Hubei, but not with them in adults.


Protocol for developing a core outcome set for male infertility research: an international consensus development study.
We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform clinical practice for numerous reasons. These may include complex issues, such as variation in outcome measures and outcome reporting bias, as well as failure to consider the perspectives of men and their partners with lived experience of fertility problems. Previously, the Core Outcome Measure for Infertility Trials (COMMIT) initiative, an international consortium of researchers, healthcare professionals and people with fertility problems, has developed a core outcome set for general infertility research. Now, a bespoke core outcome set for male infertility is required to address the unique challenges pertinent to male infertility research. Stakeholders, including healthcare professionals, allied healthcare professionals, scientists, researchers and people with fertility problems, will be invited to participate. Formal consensus science methods will be used, including the modified Delphi method, modified Nominal Group Technique and the National Institutes of Health's consensus development conference. An international steering group, including the relevant stakeholders outlined above, has been established to guide the development of this core outcome set. Possible core outcomes will be identified by undertaking a systematic review of randomized controlled trials evaluating potential treatments for male factor infertility. These outcomes will be entered into a modified Delphi method. Repeated reflection and re-scoring should promote convergence towards consensus outcomes, which will be prioritized during a consensus development meeting to identify a final core outcome set. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. This work has been supported by the Urology Foundation small project award, 2021. C.L.R.B. is the recipient of a BMGF grant and received consultancy fees from Exscentia and Exceed sperm testing, paid to the University of Dundee and speaking fees or honoraria paid personally by Ferring, Copper Surgical and RBMO. S.B. received royalties from Cambridge University Press, Speaker honoraria for Obstetrical and Gynaecological Society of Singapore, Merk SMART Masterclass and Merk FERRING Forum, paid to the University of Aberdeen. Payment for leadership roles within NHS Grampian, previously paid to self, now paid to University of Aberdeen. An Honorarium is received as Editor in Chief of Human Reproduction Open. M.L.E. is an advisor to the companies Hannah and Ro. B.W.M. received an investigator grant from the NHMRC, No: GNT1176437 is a paid consultant for ObsEva and has received research funding from Ferring and Merck. R.R.H. received royalties from Elsevier for a book, consultancy fees from Glyciome, and presentation fees from GryNumber Health and Aytu Bioscience. Aytu Bioscience also funded MiOXYS systems and sensors. Attendance at Fertility 2020 and Roadshow South Africa by Ralf Henkel was funded by LogixX Pharma Ltd. R.R.H. is also Editor in Chief of Andrologia and has been an employee of LogixX Pharma Ltd. since 2020. M.S.K. is an associate editor with Human Reproduction Open. K.Mc.E. received an honoraria for lectures from Bayer and Pharmasure in 2019 and payment for an ESHRE grant review in 2019. His attendance at ESHRE 2019 and AUA 2019 was sponsored by Pharmasure and Bayer, respectively. The remaining authors declare no competing interests. Core Outcome Measures in Effectiveness Trials (COMET) initiative registration No: 1586. Available at www.comet-initiative.org/Studies/Details/1586. N/A. N/A.


Novel nitrated derivatives of 5,8-diazabenzo[c]phenanthrene and 9,14-diazadibenz[a,e]acephenanthrylene: new classes of potent mutagenic compounds.
We report the synthesis of 4-nitro-5,8-diazabenzo[c]phenanthrene (4-NDBP) and 11-nitro-9,14-diazadibenz[a,e]acephenanthrylene (11-NDDA) and the remarkable mutagenic activity of the latter. These two compounds and their non-nitrated parents, 5, 8-diazabenzo[c]phenanthrene (DBP) and 9,14-diazadibenz[a, e]acephenanthrylene (DDA), were screened in Ames plate incorporation assays against Escherichia coli WP2uvrA and Salmonella typhimurium TA98 both in the presence and absence of S9 liver fraction from Aroclor 1254-induced rats. None of the four compounds were cytotoxic up to the limits of their solubility and none showed mutagenic activity in E.coli WP2uvrA, which suggested that any such activity they may have had was not mediated via a base substitution mechanism. DBP and DDA also displayed a lack of activity in TA98 up to their precipitating doses (560 and 33.5 microg/plate, respectively). The two nitrated compounds, however, were genotoxic. 4-NDBP was active at a dose of 500 ng/plate, in the absence of S9, producing 80.0 +/- 28.0 prototrophic organisms (equivalent to 44 revertants/nmol) and at 0.5 ng/plate, in the presence of S9, giving 147 +/- 6.6 revertants (equivalent to 81 000/nmol) and allowed the description of this tetracycle as a potent mutagen. Much more striking was the activity of 11-NDDA: in the absence of S9 a dose of 8.0 ng produced 2000 revertants/nmol and, remarkably, in the presence of S9 80 pg produced the equivalent of 643 000 revertants/nmol. This makes the hexacyclic 11-NDDA the most potent mutagen to date, in the Ames procedures described here.


Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia.
Deleterious mutations in the glutamate receptor metabotropic 1 gene (GRM1) cause a recessive form of cerebellar ataxia, SCAR13. GRM1 and GRM5 code for the metabotropic glutamate type 1 (mGlu1) and type 5 (mGlu5) receptors, respectively. Their different expression profiles suggest they could have distinct functional roles. In a previous study, homozygous mice lacking mGlu1 receptors (Grm1crv4/crv4) and exhibiting ataxia presented cerebellar overexpression of mGlu5 receptors, that was proposed to contribute to the mouse phenotype. To test this hypothesis, we here crossed Grm1crv4 and Grm5ko mice to generate double mutants (Grm1crv4/crv4Grm5ko/ko) lacking both mGlu1 and mGlu5 receptors. Double mutants and control mice were analyzed for spontaneous behavior and for motor activity by rotarod and footprint analyses. In the same mice, the release of glutamate from cerebellar nerve endings (synaptosomes) elicited by 12mM KCl or by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was also evaluated. Motor coordination resulted improved in double mutants when compared to Grm1crv4/crv4 mice. Furthermore, in in vitro studies, glutamate release elicited by both KCl depolarization and activation of AMPA autoreceptors resulted reduced in Grm1crv4/crv4 mice compared to wild type mice, while it presented normal levels in double mutants. Moreover, we found that Grm1crv4/crv4 mice showed reduced expression of GluA2/3 AMPA receptor subunits in cerebellar synaptosomes, while it resulted restored to wild type level in double mutants. To conclude, blocking of mGlu5 receptor reduced the dysregulation of glutamate transmission and improved motor coordination in the Grm1crv4 mouse model of SCAR13, thus suggesting the possible usefulness of pharmacological therapies based on modulation of mGlu5 receptor activity for the treatment of this type of ataxia.


PREVALENCE OF AEROBIC VAGINITIS AFTER GYNECOLOGICAL SURGERIES AND ASSOCIATED ADVERSE PREGNANCY OUTCOME IN UKRAINE.
Aim: To determine prevalence of Aerobic Vaginitis (AV) after gynecologic surgery, risk factors and antimicrobial resistance of responsible pathogens, and adverse pregnancy outcomes in Ukraine. Materials and Methods: Multicenter retrospective cohort study was conducted from January 2020 to December 2022 in fifteen medical clinics from eight regions of Ukraine. Smears were analyzed using Donders' classification method and Dong's modified AV diagnosis for Gram stains. Definitions of HAIs were adapted from the CDC/NHSN. Antibiotic susceptibility testing of bacteria was determined by Kirby-Bauer disc diffusion test according to the protocol of the EUCAST. Results: Prevalence of AV among women's undergoing gynecologic surgery in Ukraine was 68.7%. Of the total AV cases, 70.3% were in non-pregnant and 29,7% in pregnant women. The most common pathogen of AV was Escherichia coli, followed by Enterococcus faecalis, Streptococcus agalactiae, Staphylococcus aureus, Enterococcus faecium, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Among the S. aureus strains, 11,6% of MRSA (Methicillin resistant S.aureus) were isolated whereas none of the CoNS were cefoxitin resistant. History of vaginal infection, history of post-operative infection and antibiotic use acted as an important risk factor of AV incidence rate. The presence of AV worsened pregnancy outcomes, by increasing the incidence of preterm birth, the premature rupture of membranes, miscarriage, neonatal jaundice, and neonatal infection. Conclusions: Aerobic Vaginitis after gynecological surgeries in Ukraine is a common medical problem in women that is associated with significant morbidity, adverse pregnancy outcome, and hence frequent medical visits.


One-Year Follow-up of the CAPO Kids Trial: Are Physical Benefits Maintained?
To determine the 12-month maintenance of a 9-month, thrice-weekly, 10-minute high-intensity exercise program, delivered in schools, on bone and other health-related performance variables in prepubertal children. All participants (N = 311) of the CAPO kids trial (testing times T1-T2) were contacted to undergo retesting (T3) of all original measures-including weight, standing and sitting height, calcaneal broadband ultrasound attenuation (Achilles, GE), and stiffness index (Achilles, GE)-waist circumference, resting heart rate, blood pressure, vertical jump, and aerobic capacity. Maturity was determined by estimating age of peak height velocity using sex-specific regression equations. A total of 240 children [12.3 (0.6) y old] were included in the current study (77% of initial follow-up sample at T2). Between the T2 and T3 time points, both exercise (EX) group and control (CON) group increased broadband ultrasound attenuation (EX: 5.6%, P ≤ .001; CON: 6.5%, P ≤ .001), stiffness index (EX: 7.3%, P ≤ .001; CON: 5.2%, P ≤ .001), vertical jump (EX: 5.9%, P ≤ .001; CON: 6.3%, P ≤ .001), estimated maximal oxygen consumption (EX: 13.3%, P ≤ .001; CON: 12.1%, P ≤ .001), and reduced waist circumference (EX: -5.2%, P ≤ .001; CON: -5.6%, P ≤ .001), with no between-group differences in the magnitude of those changes. No differences were detected in absolute values between groups at T3. Although the statistically significant differences observed between groups following the intervention were no longer significant 1 year after withdrawal of the intervention, the between-group similarities in growth trajectories of those parameters could suggest that some benefit of the intervention for bone health, waist circumference, and physical performance endured.


Gas chromatographic metabolic profiling: a sensitive tool for functional microbial ecology.
Microbial metabolomics, which consists of a non-targeted analysis of the metabolites released from ('exometabolome') or existing in ('endometabolome') a cell has mostly been used to study the metabolism of particular microbes. Metabolomes also represent a picture of microbial activity and we suggest that the exometabolome may also contain pertinent information for studying microbial interaction networks. Gas chromatography coupled to mass spectrometry is the most commonly used technique in metabolomics studies. It allows a wide range of metabolites to be detected but requires the derivatisation of compounds prior to detection. This type of non-targeted analysis can introduce biases to the detection and quantification of the different metabolites, particularly at the extraction and derivatisation steps. The aims of this study, therefore, were to quantify the sources of variability and to test the sensitivity of the GC metabolic profiling approach to small environmental changes such as shifts in temperature. The temperature sensitivity of metabolic profiles was compared with that of catabolic profiles obtained using Biolog microplates. Analytical variability was compared with biological variability by incubating bacterial strains isolated from soil with fructose at 20 degrees C and by replicating each step of the protocol (incubation, extraction and derivatisation). For both the endo- and the exometabolome, more than 70% of the total variability was of biological origin and principal components analysis clearly separated the strains along the first ordination axis. The endometabolome distinguished bacterial strains at the species level only, whereas separation was evident at the species and group level with the exometabolome. Temperature had a significant but differential effect on the metabolite production of the bacterial strains whilst their catabolic profiles remained relatively unaffected. The exometabolome was more sensitive to temperature shifts than the endometabolome, suggesting that this pool may be of interest for studies in environmental functional ecology.


Kinetic Measurements Reveal Enhanced Protein-Protein Interactions at Intercellular Junctions.
The binding properties of adhesion proteins are typically quantified from measurements with soluble fragments, under conditions that differ radically from the confined microenvironment of membrane bound proteins in adhesion zones. Using classical cadherin as a model adhesion protein, we tested the postulate that confinement within quasi two-dimensional intercellular gaps exposes weak protein interactions that are not detected in solution binding assays. Micropipette-based measurements of cadherin-mediated, cell-cell binding kinetics identified a unique kinetic signature that reflects both adhesive (trans) bonds between cadherins on opposing cells and lateral (cis) interactions between cadherins on the same cell. In solution, proposed lateral interactions were not detected, even at high cadherin concentrations. Mutations postulated to disrupt lateral cadherin association altered the kinetic signatures, but did not affect the adhesive (trans) binding affinity. Perturbed kinetics further coincided with altered cadherin distributions at junctions, wound healing dynamics, and paracellular permeability. Intercellular binding kinetics thus revealed cadherin interactions that occur within confined, intermembrane gaps but not in solution. Findings further demonstrate the impact of these revealed interactions on the organization and function of intercellular junctions.


Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.
Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. Public Health Research Foundation (Japan), Taiho Pharmaceutical.


Acute respiratory distress syndrome: diagnosis and management.
This review will attempt to put together the voluminous studies and concepts that have been published during the past 25 years following the description of the acute respiratory distress syndrome (ARDS) regarding diagnosis and management. The initial discussion will focus on how to clinically diagnose ARDS based recommendations. This also gives the current definition of acute lung injury and when to call it ARDS. The radiographic and hemodynamic characteristics are discussed including oxygenation parameters. The management outlines the conventional as well as new therapies intended to improve survival of this devastating disease.


Inferomedial Hip Center Decreases Failure Rates in Cementless Total Hip Arthroplasty for Crowe II and III Hip Dysplasia.
We sought to evaluate the outcomes of cementless acetabular components used in patients with Crowe II and III dysplasia, and to compare outcomes between cups placed within vs outside of an "anatomic" zone. Our specific aims were to (1) plot hip centers in these patients at our institution to characterize "anatomic" vs "nonanatomic" positions, (2) evaluate the association between hip center and radiographic loosening, (3) determine whether hip center was associated with acetabular component revision, and (4) compare patient-reported outcome scores between groups. We retrospectively reviewed 88 primary cementless total hip arthroplasties at a mean follow-up of 10 years (range 2-26 years). Patients were 85% female, with a mean age of 44 years (range 28-61 years) and a body mass index of 27 kg/m2 (range 19-42 kg/m2). Medical records and radiographs were reviewed, and a survey was conducted for all patients. Anatomic hip center was defined using the 4-zone system, wherein centers are "anatomic" if they are <1 cm superior and <1 cm lateral to the approximate femoral head center. Cox proportional analyses were used to compare outcomes between groups. Seventy hips (80%) had an anatomic hip center. Anatomic hips had a lower incidence of radiographic acetabular loosening (0% vs 17%, P = .007) and cup revision (0% vs 28%, P = .0002). There were no differences in Hip Disability and Osteoarthritis Outcome and Joint Replacement Scores (96.2 ± 5 vs 91.9 ± 12, P = .7). The incidence of aseptic loosening and cup revision were lower when hip center was <1 cm superior and 1 cm lateral to the approximate femoral head center.


Addressing self-criticism in depression using CBT-based emotion-focused chairwork: study protocol of a randomised controlled trial.
Self-criticism is a key feature in people diagnosed with depression, resulting in significant psychological distress. Despite the fact that cognitive-behavioural treatments are readily available, a significant number of patients report experiencing cognitive, but not emotional, change following therapy, resulting in the maintenance of psychological symptoms. Additionally, interventions targeting emotional experiencing, such as chairwork, are generally implemented within large-scale therapeutic treatments. Therefore, within the present study, we aim to evaluate the efficacy and safety of a short intervention using emotion-focused chairwork to target self-criticism in patients diagnosed with depression. The study is designed as a randomised controlled trial with two parallel arms. 62 patients diagnosed with depression will be randomised to the intervention group or the waiting-list control group receiving treatment as usual. The intervention comprises of three treatment sessions using the chairwork technique over the course of 3 weeks. Outcome assessments will take place 1 week before the first treatment session, as well as 1 week and 3 months after the last treatment session. The primary outcomes are self-criticism and self-compassion. Secondary outcomes assess depressive symptoms, emotion regulation and overall self-esteem. Statistical analysis will be performed using intention-to-treat analysis, as well as per-protocol analysis implementing linear-mixed models. The study was approved by the Ethics Committee of the State Chamber of Physicians in Baden-Wuerttemberg, Germany (approval number: F-2023-12). Scientific findings shall be published in peer-reviewed journals to inform prospective clinical studies focusing on the implementation of chairwork within clinical practice. German Clinical Trials Register (DRKS00031307; https://drks.de/search/de/trial/DRKS00031307).


124I-labeled engineered anti-CEA minibodies and diabodies allow high-contrast, antigen-specific small-animal PET imaging of xenografts in athymic mice.
Prolonged clearance kinetics have hampered the development of intact antibodies as imaging agents, despite their ability to effectively deliver radionuclides to tumor targets in vivo. Genetically engineered antibody fragments display rapid, high-level tumor uptake coupled with rapid clearance from the circulation in the athymic mouse/LS174T xenograft model. The anticarcinoembryonic antigen (CEA) T84.66 minibody (single-chain Fv fragment [scFv]-C(H)3 dimer, 80 kDa) and T84.66 diabody (noncovalent dimer of scFv, 55 kDa) exhibit pharmacokinetics favorable for radioimmunoimaging. The present work evaluated the minibody or diabody labeled with (124)I, for imaging tumor-bearing mice using a high-resolution small-animal PET system. Labeling was conducted with 0.2-0.3 mg of protein and 65-98 MBq (1.7-2.6 mCi) of (124)I using an iodination reagent. Radiolabeling efficiencies ranged from 33% to 88%, and immunoreactivity was 42% (diabody) or >90% (minibody). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA-positive) and C6 rat glioma (CEA-negative) xenografts. Mice were injected via the tail vein with 1.9-3.1 MBq (53-85 microCi) of (124)I-minibody or with 3.1 MBq (85 microCi) of (124)I-diabody and imaged at 4 and 18 h by PET. Some mice were also imaged using (18)F-FDG 2 d before imaging with (124)I-minibody. PET images using (124)I-labeled minibody or diabody showed specific localization to the CEA-positive xenografts and relatively low activity elsewhere in the mice, particularly by 18 h. Target-to-background ratios for the LS174T tumors versus soft tissues using (124)I-minibody were 3.05 at 4 h and 11.03 at 18 h. Similar values were obtained for the (124)I-diabody (3.95 at 4 h and 10.93 at 18 h). These results were confirmed by direct counting of tissues after the final imaging. Marked reduction of normal tissue activity, especially in the abdominal region, resulted in high-contrast images at 18 h for the (124)I-anti-CEA diabody. CEA-positive tumors as small as 11 mg (<3 mm in diameter) could be imaged, and (124)I-anti-CEA minibodies, compared with (18)F-FDG, demonstrated highly specific localization. (124)I labeling of engineered antibody fragments provides a promising new class of tumor-specific probes for PET imaging of tumors and metastases.


Impacts of Predischarge Diastolic Functional Recovery on Clinical Outcomes in Patients With Hypertensive Heart Failure.
Diastolic function is an independent predictor of death in heart failure (HF), but the effect of a change in diastolic function during hospitalization on clinical outcomes in patients with hypertensive HF (HHF) has been poorly studied. Therefore, the aim of this study was to investigate the effect of predischarge diastolic functional recovery (DFR) on future clinical outcomes in hospitalized patients with a first diagnosis of HHF.Methods and Results:A total of 175 hospitalized patients with HHF were divided into 2 groups according to the change in diastolic function on predischarge echocardiography in comparison with baseline echocardiography: DFR group (n=74, 54.2±17.1 years, 55 males) vs. no DFR group (n=101, 59.1±16.8 years, 72 males). During 66.5±37 months of clinical follow-up, major adverse cardiac events (MACE) occurred in 89 patients: 85 HF rehospitalizations, 4 deaths, no MI. The number of MACE were significantly higher in the no DFR group than in the DFR group (61.6% vs. 32.4%, P<0.001). Predischarge systolic functional recovery was not a predictor of MACE, but impaired DFR was an independent predictor of MACE (RR=2.952, P=0.010, confidence interval, 1.878-6.955). Impaired predischarge DFR, regardless of the type of HF or predischarge systolic functional recovery, is an independent predictor of future MACE in HHF. Changes in diastolic function should be carefully monitored and would be useful in risk stratification of HHF.


Thermal-Disrupting Interface Mitigates Intercellular Cohesion Loss for Accurate Topical Antibacterial Therapy.
Bacterial infections remain a leading threat to global health because of the misuse of antibiotics and the rise in drug-resistant pathogens. Although several strategies such as photothermal therapy and magneto-thermal therapy can suppress bacterial infections, excessive heat often damages host cells and lengthens the healing time. Here, a localized thermal managing strategy, thermal-disrupting interface induced mitigation (TRIM), is reported, to minimize intercellular cohesion loss for accurate antibacterial therapy. The TRIM dressing film is composed of alternative microscale arrangement of heat-responsive hydrogel regions and mechanical support regions, which enables the surface microtopography to have a significant effect on disrupting bacterial colonization upon infrared irradiation. The regulation of the interfacial contact to the attached skin confines the produced heat and minimizes the risk of skin damage during thermoablation. Quantitative mechanobiology studies demonstrate the TRIM dressing film with a critical dimension for surface features plays a critical role in maintaining intercellular cohesion of the epidermis during photothermal therapy. Finally, endowing wound dressing with the TRIM effect via in vivo studies in S. aureus infected mice demonstrates a promising strategy for mitigating the side effects of photothermal therapy against a wide spectrum of bacterial infections, promoting future biointerface design for antibacterial therapy.


Role of endoscopic ultrasound in pancreatic diseases: a systematic review.
Since its introduction, endoscopic ultrasonography (EUS) has been increasingly gaining more attention for diagnosing various gastrointestinal conditions. We aim to systematically review the literature and highlight the benefit of using EUS in different pancreatic diseases by primarily reviewing its importance in diagnosing, treating pancreatic pathologies, comparing its accuracy to other modalities and determining its limitations and complications. Using defined (MeSH) terms and keywords; two reviewers conducted a MEDLINE search through August 2014, in addition to manually searching relevant bibliographies cited in the included studies. All case reports, case series, letters, non-English and non-human articles were excluded. Total of (N.=2144) potentially relevant citations were identified and screened, of which (N.=525) fulfilled eligibility criteria and grouped into seven pancreatic disease categories: chronic pancreatitis (N.=72), acute pancreatitis (N.=75), autoimmune pancreatitis (N.=31), pancreatic cancer (N.=179), neuroendocrine pancreatic tumors (N.=48), pancreatic cysts (N.=111) and pancreatic divisum (N.=9). EUS sensitivity to diagnose chronic pancreatitis is greater than endoscopic retrograde cholangiopancreatography and CT, but using EUS-guided fine needle aspiration (EUS-FNA) is not diagnostic. In acute biliary pancreatitis, EUS is superior to CT and to magnetic resonance cholangiopancreatography (MRCP) for detection of microlithiasis. EUS-guided pseudocyst drainage is safe with a high success rate. Contrast-enhanced EUS is more valuable than EUS in autoimmune pancreatitis and EUS-FNA is not recommended. EUS is superior to MRCP and multiple detector CT in evaluating pancreatic divisum. Cystic carcinoembryonic antigen level obtained using EUS-FNA is the most accurate test to exclude malignant pancreatic cyst.


MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease.
The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.


Osmotically driven membrane process for the management of urban runoff in coastal regions.
An osmotic detention pond was proposed for the management of urban runoff in coastal regions. Forward osmosis was employed as a bridge to utilize natural osmotic energy from seawater for concentrating and reusing urban runoff water, and as a barrier to reject runoff-derived contaminants. The process was demonstrated by a lab scale testing using synthetic urban runoff (as the feed solution) and synthetic seawater (as the draw solution). The submerged forward osmosis process was conducted under neutral, acidic and natural organic matter fouling condition, respectively. Forward osmosis flux decline was mainly attributed to the dilution of seawater during a semi-batch process in lab scale testing. However, it is possible to minimize flux decrease by maintaining a constant salinity at the draw solution side. Various changes in urban runoff water quality, including acidic conditions (acid rain) and natural organic matter presence, did not show significant effects on the rejection of trace metals and phosphorus, but influenced salt leakage and the rejection of nitrate and total nitrogen. Rejection of trace metals varied from 98% to 100%, phosphorus varied from 97% to 100, nitrate varied from 52% to 94% and total nitrogen varied from 65% to 85% under different feed water conditions. The work described in this study contributes to an integrated system of urban runoff management, seawater desalination and possible power generation in coastal regions to achieve a sustainable solution to the water-energy nexus.


Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes.
For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.


Polyethylene wear, osteolysis and acetabular loosening with an HA-coated hip prosthesis. A follow-up of 94 consecutive arthroplasties.
We have followed up for a period of seven to nine years 100 consecutive arthroplasties of the hip in which an entirely HA-coated implant had been used. The clinical results were excellent and bony incorporation was extensive in all components. No stem became loose or subsided but five cups were revised because of loosening after 3.8 to 5.5 years, having functioned painlessly and shown radiological ingrowth. Revision procedures because of excessive polyethylene wear have been performed on 18 hips and are planned for six more. Two eroded metal backings with worn-through polyethylene were exchanged; six hips showed metallosis without polyethylene wear-through. There were two cases of granulomatous cysts in the groin and 66 hips had osteolysis located periarticularly, in the greater trochanter or in the acetabulum.