NIR-II-Responsive CeO2-x@HA Nanotheranostics for Photoacoustic Imaging-Guided Sonodynamic-Enhanced Synergistic Phototherapy.
The therapeutic effect of photothermal therapy (PTT) and photodynamic therapy (PDT) is severely limited because of the shallow tissue penetration depth of the first near-infrared (NIR-I) light. Multifunctional nanotheranostics irradiated by the second near-infrared (NIR-II) light have received wide interest with respect to deeper tissue penetration, and sonodynamic therapy (SDT) synergistic phototherapy can achieve the complete elimination of tumors. Herein, we successfully constructed a single NIR-II light-induced nanotheranostic using cerium oxide (CeO2-x) with abundant oxygen vacancies for photoacoustic imaging-guided SDT-enhanced phototherapy for the first time. CeO2-x with surface crystalline disorder showed extensive NIR-II region absorption and an outstanding photothermal conversion ability. In addition, the CeO2-x layer with numerous oxygen defects can promote the separation of holes and electrons by ultrasound irradiation, which can remarkably enhance the efficacy of phototherapy to achieve high-efficiency tumor ablation. CeO2-x was surface modified with hyaluronic acid (HA) to prepare CeO2-x@HA to allow active tumor targeting efficiency. Both cell and animal experiments confirmed that all-in-one CeO2-x@HA exhibited a high therapeutic efficacy of SDT-enhanced PDT/PTT under 1064 nm laser irradiation, which achieved complete tumor eradication without systemic toxicity. This study significantly broadened the application of NIR-II-responsive CeO2-x for photoacoustic imaging-mediated SDT-enhanced phototherapy to the highly efficient and precise elimination of tumors.


Long non-coding RNAs as prognostic biomarkers in papillary renal cell carcinoma.
The aim of the present study was to identify long non-coding RNA (lncRNA)-based prognostic biomarkers in papillary renal cell carcinoma (pRCC). lncRNA expression data and corresponding clinical data from patients with pRCC were obtained from The Cancer Genome Atlas. R software and packages were used for data analysis. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were performed to identify key lncRNAs, which were then used to construct a prognostic model using multivariate Cox regression analysis. Patients were divided into high- and low-risk groups, and Kaplan-Meier (KM) survival curves and time-dependent receiver operating characteristic (ROC) curves were plotted. The C-index was calculated to estimate the model's prognostic power. The hazard ratio (HR), 95% confidence interval (CI), and statistical significance of each key lncRNA were also calculated by multivariate Cox regression. Based on the result of the multivariate Cox regression analysis, KM survival plots were plotted for each significantly associated lncRNA. The subcellular locations of the prognostic biomarkers were predicted using lncRNAMap and lncLocator. A total of 17 lncRNA signatures were identified as key lncRNAs. Overall survival rate was significantly higher in the low-risk group compared with the high-risk group. The areas under the ROC curve were 0.93 (3-year ROC) and 0.902 (5-year ROC), and the C-index was 0.915. A forest plot was used to illustrate the HR and 95% CI of key lncRNAs. KM survival analysis revealed the prognostic significance of two protective biomarkers, AC024022.1 and GAS6-AS1, and three adverse biomarkers, AC087379.2, AL352984.1, and AL499627.1. It was predicted that AC024022.1 and AC087379.2 may be located in the cytoplasm and GAS6-AS1 may be located in the cytosol. The present study may contribute to the management of pRCC and serve as a foundation for further investigations into the underlying mechanism of tumorigenesis and progression of pRCC.


Sensory Restoration of the Facial Region.
Normal sensitivity of the face is very important for preserving its integrity and function as an efferent source of information for the brain. The trigeminal nerve, which is the largest cranial nerve, conducts most of facial sensory function through its 3 branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). The trigeminal nerve may be damaged by a variety of etiologies including inflammatory disorders, brain tumor resection, trauma, iatrogenic injury, or congenital anomalies. Temporary or permanent damage can lead to numbness, lip-biting injury, corneal anesthesia, and, in the worst scenario, even blindness. Different age groups, mechanisms of the injury, and the time between injury and repair can affect the final result of the nerve repair. Unlike the well-understood facial nerve palsy, so far there is no universal approach to restore the facial sensory function. This article serves to thoroughly review the basic anatomy of trigeminal nerve, diagnosis of sensory nerve dysfunction, and attempts to establish a protocol for treatment and rehabilitation of affected patients.


[Dysplasia of the epithelium of the gastric mucosa].
A review of the literature on the spread, location, morphology, and fate of dysplasia of the gastric mucosa epithelium is presented. Dysplastic conditions of the gastric mucosa epithelium is presented. Dysplastic conditions of the gastric mucosa are noted to occur in all pre-cancer changes of the mucous membrane and to indicate a higher risk of adenocarcinoma development. The degree of this risk in relation to the severity of dysplasia has not yet been established, however. Only severe dysplasia has been found to be topographically associated with gastric carcinoma. Different classifications of dysplasias are presented. On the basis of the data from the literature and their own experience the authors recommend to use classification of dysplasia proposed in 1975 by Grundmann.


Remote control of induced dopaminergic neurons in parkinsonian rats.
Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.


Relation between diet composition and coronary heart disease risk factors.
The aim was to evaluate dietary intakes and their correlation to some risk factors for coronary heart disease. The study was a population based survey with random sample selection stratified by age and sex. 352 adults living in a small town in Northern Italy took part in the study. Response rate was 46% among females and 48% among males. Refusal to take part was mainly due to the large number of tests involved. Diets were high in protein (animal/vegetable ratio 1.7 in women and 1.4 in men) and in fat and low in carbohydrates. The hypercholesterolaemic and atherogenic potential of the diet, evaluated by the cholesterol/saturated fat index, was high in about 50% of the population. The thiamin and riboflavin intakes were lower than the Italian recommended allowances in more than 60% of the people tested, whereas the vitamin A intake was more than adequate in about 70%. A positive association was found in the younger groups (men and women 20-39 years old) between some nutrient components (energy, alcohol, total and saturated fats) and some blood lipids. In the older people blood lipids were correlated with body mass index. The overall data indicate that a correlation exists between dietary intake and some risk factors for coronary heart disease; dietary intervention, at least in young adults, is suggested.


Fetal growth restriction: How reliable is information available to patients on Google? A systematic review.
To review systematically the quality, readability and credibility of English language webpages offering patient information on fetal growth restriction. A systematic review of patient information was undertaken on Google with location services and browser history disabled. Websites from the first page were included providing they gave at least 300 words of health information on fetal growth restriction aimed at patients. Validated assessment of readability, credibility and quality were undertaken. An accuracy assessment was performed based on international guidance. Characteristics were tabulated. Thirty-one websites including 30 different texts were included. No pages had a reading age of 11 years or less, none were credible, and only one was of high quality. Median accuracy rating was 9/24. Patients cannot rely on Google as a source of information on fetal growth restriction. As well as being difficult to read, information tends to be low quality, low accuracy and not credible. Healthcare professionals must consider how to enable access to high-quality patient information and give time for discussion of information patients have found: failure to do so may disenfranchise patients.


Concentration and motility of spermatozoa and testosterone level of kacang goat after seminal vesicle extract administration.
This study aimed to determine the effect of seminal vesicle extract administration to increase the concentration and motility of spermatozoa and testosterone level of kacang goat. The experiment was arranged using a randomly completely block design (RCBD). Three kacang goats were used and each goat received three treatments namely P0 (2 mL of 0.9% NaCl), P1 (1.5 mL Capriglandin, PGF2α), and P2 (2 mL of seminal vesicle extract, EVS). Semen and blood were collected two days post-treatment to measure the concentration and motility of spermatozoa and testosterone level. Testosterone levels were measured with enzyme-linked immunosorbent assay (ELISA). Duration between treatments was one week after semen collection. The result showed that the average spermatozoa concentration (x106) in P0; P1; and P2 respectively were 2,763.0±395.0; 2,060.00±678.2; and 2,387.0±442.7 (P>0.05), while the spermatozoa motility score in P0; P1; and P2 respectively were 3.7±1.1, 3.4±0.5, and 3.4±0.5 (P>0.05). The mean testosterone levels in P0, P1, and P2 respectively were 10.27±5.42, 18.51±19.46, and 29.57±12.96 ng/mL (P<0.05). It can be concluded that administration of EVS did not increase concentration and motility of spermatozoa but increased the level of testosterone in kacang goat.


Comparison of the secretory response of the nasal mucosa to methacholine and histamine.
To better understand the secretory response of the nasal mucosa, we must be able to accurately measure its physiological response. To this end, we developed a localized challenge technique using paper disks to stimulate the mucosa on one side and measure secretions from both sides to study both direct and reflex responses. Both methacholine and histamine induced a dose-dependent increase in secretion weights on the challenge side, whereas only histamine induced a contralateral reflex. Repeated stimulation with histamine, but not methacholine, resulted in tachyphylaxis. Pretreatment with atropine resulted in inhibition of the contralateral secretory response to histamine and the ipsilateral response to methacholine with only partial inhibition of the ipsilateral histamine response. Terfenadine pretreatment resulted in the complete inhibition of both the ipsilateral and contralateral responses to histamine with no effect on methacholine-induced secretions. Ipsilaterally applied lidocaine had no effect on the histamine response but, when applied contralaterally, partially inhibited that response. Topical diphenhydramine applied ipsilaterally led to significant inhibition of the ipsilateral and contralateral secretory responses to histamine but had no effect when applied contralaterally. We conclude that methacholine and histamine have different effects on the nasal mucosa. We speculate that methacholine stimulates glands directly, whereas histamine includes both direct and neurogenic stimulation.


Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.


Degree of Language Experience Modulates Visual Attention to Visible Speech and Iconic Gestures During Clear and Degraded Speech Comprehension.
Visual information conveyed by iconic hand gestures and visible speech can enhance speech comprehension under adverse listening conditions for both native and non-native listeners. However, how a listener allocates visual attention to these articulators during speech comprehension is unknown. We used eye-tracking to investigate whether and how native and highly proficient non-native listeners of Dutch allocated overt eye gaze to visible speech and gestures during clear and degraded speech comprehension. Participants watched video clips of an actress uttering a clear or degraded (6-band noise-vocoded) action verb while performing a gesture or not, and were asked to indicate the word they heard in a cued-recall task. Gestural enhancement was the largest (i.e., a relative reduction in reaction time cost) when speech was degraded for all listeners, but it was stronger for native listeners. Both native and non-native listeners mostly gazed at the face during comprehension, but non-native listeners gazed more often at gestures than native listeners. However, only native but not non-native listeners' gaze allocation to gestures predicted gestural benefit during degraded speech comprehension. We conclude that non-native listeners might gaze at gesture more as it might be more challenging for non-native listeners to resolve the degraded auditory cues and couple those cues to phonological information that is conveyed by visible speech. This diminished phonological knowledge might hinder the use of semantic information that is conveyed by gestures for non-native compared to native listeners. Our results demonstrate that the degree of language experience impacts overt visual attention to visual articulators, resulting in different visual benefits for native versus non-native listeners.


Process control analysis of IMRT QA: implications for clinical trials.
The purpose of this study is two-fold: first is to investigate the process of IMRT QA using control charts and second is to compare control chart limits to limits calculated using the standard deviation (sigma). Head and neck and prostate IMRT QA cases from seven institutions in both academic and community settings are considered. The percent difference between the point dose measurement in phantom and the corresponding result from the treatment planning system (TPS) is used for analysis. The average of the percent difference calculations defines the accuracy of the process and is called the process target. This represents the degree to which the process meets the clinical goal of 0% difference between the measurements and TPS. IMRT QA process ability defines the ability of the process to meet clinical specifications (e.g. 5% difference between the measurement and TPS). The process ability is defined in two ways: (1) the half-width of the control chart limits, and (2) the half-width of +/-3sigma limits. Process performance is characterized as being in one of four possible states that describes the stability of the process and its ability to meet clinical specifications. For the head and neck cases, the average process target across institutions was 0.3% (range: -1.5% to 2.9%). The average process ability using control chart limits was 7.2% (range: 5.3% to 9.8%) compared to 6.7% (range: 5.3% to 8.2%) using standard deviation limits. For the prostate cases, the average process target across the institutions was 0.2% (range: -1.8% to 1.4%). The average process ability using control chart limits was 4.4% (range: 1.3% to 9.4%) compared to 5.3% (range: 2.3% to 9.8%) using standard deviation limits. Using the standard deviation to characterize IMRT QA process performance resulted in processes being preferentially placed in one of the four states. This is in contrast to using control charts for process characterization where the IMRT QA processes were spread over three of the four states with none of the processes in the ideal state. Control charts may be used for IMRT QA in clinical trials to categorize process performance, minimize protocol variation and guide process improvements. For the duration of an institution's participation in a protocol, updated control charts can be periodically sent to the protocol QA center to document continued process performance to protocol specifications.


Bulgecin A: a novel inhibitor of binuclear metallo-beta-lactamases.
Bulgecin A, a sulphonated N-acetyl-D-glucosamine unit linked to a 4-hydroxy-5-hydroxymethylproline ring by a beta-glycosidic linkage, is a novel type of inhibitor for binuclear metallo-beta-lactamases. Using steady-state kinetic analysis with nitrocefin as the beta-lactam substrate, bulgecin A competitively inhibited the metallo-beta-lactamase BceII from Bacillus cereus in its two-zinc form, but failed to inhibit when the enzyme was in the single-zinc form. The competitive inhibition was restored by restoring the second zinc ion. The single-zinc metallo-beta-lactamase from Aeromonas veronii bv. sobria, ImiS, was not inhibited by bulgecin A. The tetrameric L1 metallo-beta-lactamase from Stenotrophomonas maltophilia was subject to partial non-competitive inhibition, which is consistent with a kinetic model in which the enzyme bound to inhibitor retains catalytic activity. Docking experiments support the conclusion that bulgecin A co-ordinates to the zinc II site in metallo-beta-lactamases via the terminal sulphonate group on the sugar moiety.


DDT residues and declining reproduction in the Bermuda petrel.
Residues of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] averaging 6.44 parts per million in eggs and chicks of the carnivorous Bermuda petrel indicate widespread contamination of an oceanic food chain that is remote from applications of DDT. Reproduction by the petrel has declined during the last 10 years at the annual rate of 3.25 percent; if the decline continues, reproduction will fail completely by 1978. Concentrations of residues are similar to those in certain terrestrial carnivorous birds whose productivity is also declining. Various considerations implicate contamination by insecticides as a probable major cause of the decline.


Effects of recombinant human granulocyte colony-stimulating factor (CSF), human granulocyte macrophage-CSF, and gibbon interleukin-3 on hematopoiesis in human long-term bone marrow culture.
We have studied the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF), hG macrophage-CSF (hGM-CSF), and gibbon interleukin-3 (gIL-3) on cell proliferation and differentiation in human long-term bone marrow culture (LTBMC). hG-CSF induced a maximal increase of 2.3-fold in both total nonadherent cells and GM cluster-forming cells, but only an increase of 1.7-fold in GM-colony-forming cell (GM-CFC) numbers, influencing mainly neutrophil differentiation. Cultures treated with hGM-CSF demonstrated a peak of 12.8-, 21- and 3.2-fold elevations in total nonadherent cells, cluster, and GM-CFC, respectively, and influenced differentiation of neutrophils, monocytes, eosinophils, and lymphocytes. Cultures treated with gIL-3 demonstrated the largest expansion in the GM-CFC population, reaching a maximum of 5.3-fold in relation to that of unstimulated controls. IL-3 treatment also increased the numbers of GM clusters and mature cells (including all myeloid cells and lymphocytes) 7.8- and 4.8-fold, respectively. Similar quantitative and qualitative changes were induced by G-CSF, GM-CSF, and IL-3 in LTBMCs of patients in remission after treatment for acute lymphoblastic leukemia or Hodgkin's lymphoma. Overall, the expansion of GM progenitor cells in cultures treated with growth factors was larger in the adherent cell layer than in the nonadherent cell fraction. In addition, hGM-CSF, gIL-3, and hG-CSF to a less extent, increased the cycling rates of GM-CFC progenitors located in the adherent layer. These results indicate that hG-CSF is a much less potent stimulus of hematopoiesis in LTBMC than the other CSFs assayed, and that the increases in cell production after treatment with G-CSF, GM-CSF, or IL-3 may be achieved by primary expansion of different cell populations within the hierarchy of the hematopoietic system. The effects of the growth factors were transient and the longevity of hematopoiesis in the cultures was not altered, suggesting that treatment with IL-3, GM-CSF, or G-CSF had not compromised the ability of primitive cells to give rise to mature cells. This indicates that the stromal microenvironment in LTBMC can override potential differentiation-inducing activities of the CSFs.


Differences in MSU-induced superoxide responses by neutrophils from gout subjects compared to healthy controls and a role for environmental inflammatory cytokines and hyperuricemia in neutrophil function and survival.
To determine whether monosodium urate (MSU) crystal-induced superoxide production is greater for neutrophils from patients with gout compared to asymptomatic hyperuricemic and healthy controls, and whether neutrophil functions are altered by an MSU crystal-induced inflammatory environment. Neutrophils were purified from the whole blood of study participants, restimulated with 500 mg MSU crystals ex vivo, and superoxide production measured using the colorimetric dye WST-1. Purified neutrophils were exposed to conditioned media from MSU crystal-activated blood monocyte cultures with and without neutralizing antibodies for interleukin 1ss (IL-1ss), IL-8 (CXCL8), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Neutrophil superoxide production was measured and neutrophil apoptosis and IL-8 production were determined by flow cytometry. Serum samples were collected from participants and analyzed by Lincoplex bead array for IL-1ss, IL-8, IL-6, and TNF-alpha. Neutrophils from gout and asymptomatic hyperuricemic subjects produced higher levels of MSU crystal-induced superoxide, and a weak trend toward elevated serum cytokines was observed compared to healthy controls. A correlation between serum uric acid and elevated neutrophil superoxide production was also observed. Neutrophils exposed to media from MSU crystal-activated monocytes exhibited enhanced superoxide production to MSU-crystal stimulation, increased IL-8 production, and extended cell survival that was predominantly dependent on IL-8, TNF-alpha and IL-6, respectively. Neutrophils from gout and asymptomatic hyperuricemic individuals are primed for enhanced MSU crystal-induced superoxide production that may be driven by a subclinical inflammatory cytokine environment combined with hyperuricemia. This inflammatory environment likely contributes to elevated neutrophil IL-8 production and survival in the absence of direct crystal stimulation. Asymptomatic hyperuricemia is not associated with suppressed neutrophil function.


Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.
Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.


Novel use patterns of Salvia divinorum: unobtrusive observation using YouTube™.
ETHNOPHARMACOLOGICAL RELEVANCE AND AIMS: The traditional use of the Hallucinogenic sage, Salvia divinorum has been of ethnopharmalogical interest for some time. This plant, endemic to Oaxaca Mexico and traditionally used by the Mazatec, is now utilized worldwide for its psychoactive effects. This use demonstrates a novel use pattern which is distinctly different from Mazatec use. This study offers a new methodology to study emerging global plant use and assesses the users' experience with it. The aim of this research was to develop a new methodology to collect and analyze archived data on the World Wide Web, specifically videos which depict Salvia divinorum use. The basis of the methodology for this project was unobtrusive observation which allows the researcher to observe without influencing the event which is being observed. Qualitative, ethnographic data was used in conjunction with quantitative meta data collected by a customized web crawler programed to archive YouTube™ data. Using this methodology enabled us to understand reported uses and the users' experiences as expressed on the World Wide Web. The main result of this research was the documentation of a distinct, novel use pattern of Salvia divinorum which has developed outside of Oaxaca; a use pattern which differs in a number of ways from traditional, Mazatec use. The majority of the YouTube™ videos analyzed were found to present indications of a positive Salvia divinorum experience. This result highlighted the contradiction between ethnographic data and what is reported by the media. Finally the representation of Salvia divinorum on YouTube™ (and by inference the WWW as a whole) is a growing phenomena. While anthropological and more specifically medico-anthropological research has, for many years, embraced the dynamics of cultures, until recently, ethnopharmalogical research has generally focused on 'traditional' plant use, failing to capture the dynamic elements of plant/human interaction and framing research in the past or as decontextualized largely descriptive reports. Global migration and urban environments formed a basis for looking at the interplay of continuity and change. Such cultural dynamics are exacerbated by the opportunities which the WWW offers.


Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals.
In traditional molecular mechanics force fields, intramolecular non-bonded interactions are modelled as intermolecular interactions, and the form of the torsion potential is based on the conformational profiles of small organic molecules. We investigate how a separate model for the intramolecular forces in pharmaceuticals could be more realistic by analysing the low barrier to rotation of the phenyl ring in the fenamates (substituted N-phenyl-aminobenzoic acids), that results in a wide range of observed angles in the numerous fenamate crystal structures. Although the conformational energy changes by significantly less than 10 kJ mol(-1) for a complete rotation of the phenyl ring for fenamic acid, the barrier is only small because of small correlated changes in the other bond and torsion angles. The maxima for conformations where the two aromatic rings approach coplanarity arise from steric repulsion, but the maxima when the two rings are approximately perpendicular arise from a combination of an electronic effect and intramolecular dispersion. Representing the ab initio conformational energy profiles as a cosine series alone is ineffective; however, combining a cos 2ξ term to represent the electronic barrier with an intramolecular atom-atom exp-6 term for all atom pairs separated by three or more bonds (1-4 interactions) provides a very effective representation. Thus we propose a new, physically motivated, generic analytical model of conformational energy, which could be combined with an intermolecular model to form more accurate force-fields for modelling the condensed phases of pharmaceutical-like organic molecules.


[Detection of clostridia toxin markers in different types of the course of acute intestinal infections].
The purpose of the investigation was to study the detection rates of markers and the level of C. diffcile A and B toxins and C. perfringens type A enterotoxin in patients with acute intestinal infections (AII). Two hundred and seventy-three patients with AII of varying etiology were followed up. According to the clinical syndrome, the patients were divided into 3 groups: (1) patients with the gastroenteritic (GE) type; (2) those with the gastroenterocolitic (GEC) type; (3) those with enterocolitic (EC) type. The circulation of markers of C. difficile A and B toxins and C. perfringens type A enterotoxin was studied, by employing the immunological test systems in the coagglutination test using the plates. The higher levels of antigens of all toxins were identified in the acute period of the disease in the GE and EC types than in the GEC type. There was a short increase in the levels of antigens of the test toxins in the GEC type and a gradual decrease in the GE and EC types. By discharge from hospital, the markers of toxins (more commonly of C. diffcile A) were preserved in 16.4% of the patients mainly in the GEC type.


The cooperative effect of Lewis pairs in the Friedel-Crafts hydroxyalkylation reaction: a simple and effective route for the synthesis of (±)-carbinoxamine.
An efficient C-C bond formation strategy between aromatic/heteroaromatic π-nucleophiles and Lewis acid activated aldehydes is described. This aromatic electrophilic substitution reaction of arenes or heteroarenes is facilitated by Lewis acid AlBr3. Aromatic rings with electron donating substituents are excellent nucleophilic counterparts in this reaction, generating carbinols in excellent yields (61-94%). The formation of triarylmethanes is also witnessed in the case of certain reactive aldehydes and aromatic π-nucleophiles through reactive carbocation formation. The formation of triarylmethane is reduced to a greater extent via retardation of the second π-nucleophile addition through a Lewis base, for example, pyridine, coordination with an aluminium alkoxide intermediate. Various aliphatic aldehydes also underwent Friedel-Crafts type hydroxyalkylation and generated the expected carbinols in moderate yields (41-53%) in the presence of AlBr3. This protocol has been successfully applied to the synthesize of the (±)-carbinoxamine, a therapeutically important histamine H1 antagonist, in a one-pot manner.


Are Lymphocytes and Eosinophils Associated with the COVID-19 Severity: A Large, Retrospective Study.
Coronavirus disease 2019 is an ongoing disease with high morbidity and mortality. We aimed to investigate the relationship between demographics, lymphocytes, eosinophils, and the coronavirus disease 2019 severity at hospital admission. A retrospective, observational cross-sectional study was carried out with 5828 coronavirus disease 2019 patients between March 11, 2020, and November 30, 2020. Patients were divided into 3 groups according to where they were followed up as an indicator of disease severity, namely outpatients, inpatients, and critically ill patients. The patients' demographics and hemogram values on admission were recorded. The predictive accuracies of lymphocyte count, lymphocyte percentage, eosinophil count, and eosinophil percentage for predicting severity were determined using receiver operating characteristic curves. Logistic regression analysis was used to predict intensive care unit demand according to lymphocyte and eosinophil values. Of the 5828 coronavirus disease 2019 patients, 4050 were followed up as outpatients, 1581 were hospitalized in a ward, and 197 were hospitalized in the intensive care unit. Lymphocyte count and lymphocyte percentage were significantly different between the groups, but the difference for eosinophil count and eosinophil percentage was not significant as it was for lymphocytes. Cutoff values for lymphocyte count (1.0 × 109 /L), lymphocyte percentage (22%), eosinophil count (0.052 × 109 /L), and eosinophil percentage (0.08%) were found to indicate a high risk for intensive care unit admission. Coronavirus disease 2019 patients >55 years of age, with a lymphocyte count <1.0 × 109 /L, a lymphocyte percentage <22%, and an eosinophil percentage <0.08% had a 2-fold higher risk of requiring intensive care unit management. Lymphocyte counts and percentages are quick and reliable biomarkers for predicting coronavirus disease 2019 severity and may guide physicians for proper management earlier.


Dietary naringenin increases hepatic peroxisome proliferators-activated receptor α protein expression and decreases plasma triglyceride and adiposity in rats.
Naringenin, a flavonoid present in grapefruit, has recently been shown to exert hypolipidemic and hypocholesterolemic effects, which has a particular importance for protecting against chronic diseases. However, the lipid-lowering potential of naringenin at the concentrations in the dietary range and its underlying mechanisms have yet to be fully elucidated. The aim of the present study was (1) to investigate the effects of dietary naringenin on plasma and hepatic triglyceride and cholesterol levels and on adipose deposition in rat and (2) to determine the contribution of hepatic peroxisome proliferators-activated receptor α (PPARα) expression to fatty acid oxidation. Male Long-Evans hooded rats were fed a diet supplemented with naringenin (0.003, 0.006, and 0.012%) for 6 weeks. We analyzed plasma and hepatic lipid contents and determined the protein expression of PPARα, carnitine-palmitoyl transferase 1L (CPT-1), and uncoupling protein 2 (UCP2), all of which are critical genes for fatty acid oxidation. Naringenin supplementation caused a significant reduction in the amount of total triglyceride and cholesterol in plasma and liver. In addition, naringenin supplementation lowered adiposity and triglyceride contents in parametrial adipose tissue. Naringenin-fed animals showed a significant increase in PPARα protein expression in the liver. Furthermore, expression of CPT-1 and UCP2, both of which are known to be regulated by PPARα, was markedly enhanced by naringenin treatment. Our results indicate that the activation of PPARα transcription factor and upregulation of its fatty acid oxidation target genes by dietary naringenin may contribute to the hypolipidemic and anti-adiposity effects in vivo.


Sodium chloride and water transport in the renal distal tubule of the rainbow trout.
Isolated segments of the renal tubules from the freshwater trout, Salmo gairdneri, were perfused in vitro to characterize ion and water transport. The distal tubule showed a transepithelial voltage (Vt) positive in the lumen (+17.8 +/- 1.4 mV). Furosemide added to the lumen and Na cyanide and ouabain added to the bath reduced the lumen-positive Vt of the distal tubule. Removal of either Cl- or Na+ from both perfusate and bathing medium abolished the lumen-positive Vt. When the distal tubule was perfused and bathed with isosmotic solution, net water flux (Jv) was nearly zero. Jv and hydraulic conductivity remained low when the osmolality of the bathing fluid was increased with raffinose. Neurohypophysial hormones added to the bath showed no effect. Chloride efflux (lumen to bath, 171.1 +/- 17.1 peq x mm-1. min-1) was significantly higher than chloride influx (bath to lumen, 105.6 +/- 12.3 peq x mm-1 x min-1), suggesting that net chloride reabsorption exists. These results suggest that in the freshwater trout, which lack the loop of Henle, the distal tubule acts as a diluting segment. The presence of sodium, in addition to chloride, is required to generate the lumen-positive Vt in the distal tubule.


Bioaccessibility of polyphenols and antioxidant capacity of fresh or minimally processed modern or traditional lettuce (Lactuca sativa L.) varieties.
Modern city lifestyle is characterized by an increased demand for fresh or minimally processed foods. Lettuce (Lactuca sativa L.), mainly iceberg lettuce, is the main vegetable used during the manufacture of fresh-cut salads. The current study evaluated the phenolic content and antioxidant activity of ten fresh and minimally processed lettuce varieties. The phenolic content of selected lettuce samples varied significantly among varieties. Although a higher phenolic content was observed in modern lettuce varieties, when compared to the traditional ones (except for the landrace Francès 219/855), the antioxidant capacity of modern and traditional lettuce varieties was similar. Minimal processing followed by storage for a 7-day period led to an increased phenolic content in varieties Rutilaï RZ, Abago RZ, Maravilla LS044, Francès 219/855, Negre borratger 386/935, and D'hivern LS008, supporting the hypothesis that wounding can induce the accumulation of phenolic compounds in lettuce leaves. For example, the total phenolic content of Francès 219/855 after processing and storage increased from 8.3 to 11.3 mg/100 g (p < 0.05). Accumulation of phenolic compounds after minimal processing was not observed in all the studied samples, suggesting that this effect could be matrix-dependant. The amount of bioaccessible polyphenols was higher after minimal processing and storage. Indeed, the amount of bioaccessible polyphenols after a simulated gastrointestinal digestion of fresh or minimally processed Pelikan lettuce was calculated as 32.6 or 43.3 mg/100 g respectively (p < 0.05), suggesting that the increased amount of polyphenols caused by processing and storage can also lead to a higher amount of bioaccessible phenolic compounds.


The role of statins in stroke.
Although evidence from epidemiological studies examining a relationship between cholesterol level and stroke is less than definitive, there is a compelling evidence from the clinical therapy trials primarily designed to examine the coronary benefits of statins that statin therapy also causes a reduction in the risk of stroke. Even though a stroke does not have the same exact pathophysiology as a heart attack, specific trials in stroke patients confirm advantages and risks of statin therapy in this kind of population. In primary prevention, statins are effective both when low-density lipoprotein (LDL) is raised and when hs-CRP is elevated. In secondary prevention, an absolute reduction of recurrent stroke can be obtained with statins, with a number needed to treat at 5 years of 45.


Nocturnal sleep-wake parameters of adolescents at home following cancer chemotherapy.
The purpose of this descriptive, longitudinal study was to describe objective nocturnal sleep-wake parameters of adolescents at home after receiving chemotherapy in the hospital or outpatient clinic and explore differences in sleep variables by age, gender, and corticosteroid use. We collected 7 days of wrist actigraphy and sleep diary data from 48 adolescents (10-19 years) who were receiving cancer chemotherapy for a primary or secondary cancer or a relapse. The actigraphic sleep variables included rest interval (i.e., time in bed), sleep onset, sleep offset, sleep duration, total sleep time (TST), wake after sleep onset (WASO), and %WASO. Of the 48 adolescents, 38 had at least five nights of scored actigraphy and were included in analyses. Older (13-18 years) adolescents went to bed later and had fewer minutes of TST than younger adolescents (10-12 years). Exploratory analyses revealed no differences between adolescents who were taking oral corticosteroids (i.e., prednisone, dexamethasone) and those who were not or between males and females. These adolescents had sleep durations that met or exceeded the recommended sleep duration for their age groups but experienced significant WASO. Further research is needed to estimate sleep needs of adolescents during chemotherapy and determine factors that contribute to nocturnal wake-time so that targeted interventions can be designed to improve sleep quality.


[Stanols--a new perspective in treatment of hypercholesterolemia?].
Since the unfavorable impact of hypercholesterolemia on the cardiovascular system has been proven, effective, inexpensive and easy to use cholesterol-lowering treatment options have been looked for. In the 1990s as the effect of a few decades of research, stanols have been introduced as new cholesterol-lowering agents. Stanols are derivates of plant sterols, which act through inhibition of intestinal cholesterol absorption. Their incorporation into normal diet fats has led to a significant reduction of both total and LDL cholesterol in investigated subjects, also in those on cholesterol-lowering diet or taking cholesterol-lowering drugs. When the dose considered optimal, i.e. 2-3 g/d, was used, the average reduction was 10% for total and 14% for LDL cholesterol. So far no adverse effects of stanols and no influence on the taste of food have been observed. The possible role of stanols in primary and secondary prevention of cardiovascular diseases still remains to be verified. It seems, however, that stanols have a potential to become a significant element in the treatment of hypercholesterolemia and in preventing its consequences.


Comparison of methods for analyzing left-censored occupational exposure data.
The National Institute for Environmental Health Sciences (NIEHS) is conducting an epidemiologic study (GuLF STUDY) to investigate the health of the workers and volunteers who participated from April to December of 2010 in the response and cleanup of the oil release after the Deepwater Horizon explosion in the Gulf of Mexico. The exposure assessment component of the study involves analyzing thousands of personal monitoring measurements that were collected during this effort. A substantial portion of these data has values reported by the analytic laboratories to be below the limits of detection (LOD). A simulation study was conducted to evaluate three established methods for analyzing data with censored observations to estimate the arithmetic mean (AM), geometric mean (GM), geometric standard deviation (GSD), and the 95th percentile (X0.95) of the exposure distribution: the maximum likelihood (ML) estimation, the β-substitution, and the Kaplan-Meier (K-M) methods. Each method was challenged with computer-generated exposure datasets drawn from lognormal and mixed lognormal distributions with sample sizes (N) varying from 5 to 100, GSDs ranging from 2 to 5, and censoring levels ranging from 10 to 90%, with single and multiple LODs. Using relative bias and relative root mean squared error (rMSE) as the evaluation metrics, the β-substitution method generally performed as well or better than the ML and K-M methods in most simulated lognormal and mixed lognormal distribution conditions. The ML method was suitable for large sample sizes (N ≥ 30) up to 80% censoring for lognormal distributions with small variability (GSD = 2-3). The K-M method generally provided accurate estimates of the AM when the censoring was <50% for lognormal and mixed distributions. The accuracy and precision of all methods decreased under high variability (GSD = 4 and 5) and small to moderate sample sizes (N < 20) but the β-substitution was still the best of the three methods. When using the ML method, practitioners are cautioned to be aware of different ways of estimating the AM as they could lead to biased interpretation. A limitation of the β-substitution method is the absence of a confidence interval for the estimate. More research is needed to develop methods that could improve the estimation accuracy for small sample sizes and high percent censored data and also provide uncertainty intervals.


The creatine kinase reaction: a simple reaction with functional complexity.
The classical role of PCr is seen as a reservoir of high-energy phosphates defending cellular ATP levels under anaerobic conditions, high rates of energy transfer or rapid fluctuations in energy requirement. Although the high concentration of PCr in glycolytic fast-twitch fibers supports the role of PCr as a buffer of ATP, the primary importance of the creatine kinase (CK) reaction may in fact be to counteract large increases in ADP, which could otherwise inhibit cellular ATPase-mediated systems. A primary role for CK in the maintenance of ADP homeostasis may explain why, in many conditions, there is an inverse relationship between PCr and muscle contractility but not between ATP and muscle contractility. The high rate of ATP hydrolysis during muscle contraction combined with restricted diffusion of ADP suggests that ADP concentration increases transiently during the contraction phase (ADP spikes) and that these are synchronized with the contraction. The presence of CK, structurally bound in close vicinity to the sites of ATP utilization, will reduce the amplitude and duration of the ADP spikes through PCr-mediated phosphotransfer. When PCr is reduced, the efficiency of CK as an ATP buffer will be reduced and the changes in ADP will become more prominent. The presence of ADP spikes is supported by the finding that other processes known to be activated by ADP (i.e. AMP deamination and glycolysis) are stimulated during exercise but not during anoxia, despite the same low global energy state. Breakdown of PCr is driven by increases in ADP above that depicted by the CK equilibrium and the current method to calculate ADPfree from the CK reaction in a contracting muscle is therefore questionable.


An evaluation of the use of Telehealth within palliative care settings across Scotland.
There is a lack of evidence-based research in the use of Telehealth within palliative care in the UK, particularly in Scotland. The aim of this project was to evaluate the current use of Telehealth applications within palliative care across Scotland, and how these and future applications are perceived by patients, carers and professionals. This paper reports on the qualitative findings from focus groups with patients and carers in three geographical areas in Scotland, and individual interviews with key stakeholders from across Scotland, who currently work within areas of high and low Telehealth activity. The key findings indicated that Telehealth initiatives are welcomed by patients and carers but that these should be an adjunct to clinical care rather than an alternative. The stakeholder interviews revealed several notable differences between those working within areas of high and low Telehealth activity. Principally, areas of high Telehealth activity appear to be driven by national and local policy and seem to benefit from a greater level of investment in Telehealth equipment and facilities than in the more central, and hence accessible, parts of Scotland.


Daily activity budgets reveal a quasi-flightless stage during non-breeding in Hawaiian albatrosses.
Animals adjust activity budgets as competing demands for limited time and energy shift across life history phases. For far-ranging migrants and especially pelagic seabirds, activity during breeding and migration are generally well studied but the "overwinter" phase of non-breeding has received less attention. Yet this is a critical time for recovery from breeding, plumage replacement and gaining energy stores for return migration and the next breeding attempt. We aimed to identify patterns in daily activity budgets (i.e. time in flight, floating on the water's surface and active foraging) and associated spatial distributions during overwinter for the laysan Phoebastria immutabilis and black-footed P. nigripes albatrosses using state-space models and generalized additive mixed-effects models (GAMMs). We applied these models to time-series of positional and immersion-state data from small light- and conductivity-based data loggers. During overwinter, both species exhibited a consistent 'quasi-flightless' stage beginning c. 30 days after initiating migration and lasting c. 40 days, characterized by frequent long bouts of floating, very little sustained flight, and infrequent active foraging. Minimal daily movements were made within localized areas during this time; individual laysan albatross concentrated into the northwest corner of the Pacific while black-footed albatross spread widely across the North Pacific Ocean basin. Activity gradually shifted toward increased time in flight and active foraging, less time floating, and greater daily travel distances until colony return c. 155 days after initial departure. Our results demonstrate that these species make parallel adjustments to activity budgets at a daily time-scale within the overwinter phase of non-breeding despite different at-sea distributions and phenologies. The 'quasi-flightless' stage likely reflects compromised flight from active wing moult while the subsequent increase in activity may occur as priorities shift toward mass gain for breeding. The novel application of a GAMM-based approach used in this study offers the possibility of identifying population-level patterns in shifting activity budgets over extended periods while allowing for individual-level variation in the timing of events. The information gained can also help to elucidate the whereabouts of areas important at different times across life history phases for far-ranging migrants.


Predicting cross-protection against foot-and-mouth disease virus strains by serology after vaccination.
Serology is widely used to predict whether vaccinated individuals and populations will be protected against infectious diseases, including foot-and-mouth disease (FMD), which affects cloven-hoofed animals. Neutralising antibody titres to FMD challenge viruses correlate to protection against FMD, for vaccinated cattle that are infected with the same strain as in the vaccine (homologous protection). Similar relationships exist for cross-strain protection between different vaccine and challenge viruses, although much less data are available for these heterologous studies. Poor inter-laboratory reproducibility of the virus neutralisation test (VNT) also hampers comparisons between studies. Therefore, day-of-challenge sera (n = 180) were assembled from 13 previous FMD cross-protection experiments for serotypes O (n = 2), A (n = 10), and SAT 2 (n = 1). These were tested by VNT against the challenge viruses at the FMD FAO World Reference Laboratory (WRLFMD) and the titres were compared to challenge outcomes (protected or not). This dataset was combined with equivalent serology and protection data for 61 sera from four cross-protection experiments carried out at WRLFMD for serotypes O (n = 2), A (n = 1), and Asia 1 (n = 1). VNT results and protection outcomes were also analysed for a serotype O cross-protection experiment involving 39 cattle, where the sera were not available for retesting at WRLFMD. Three categories of association between heterologous neutralising antibody titre and heterologous protection were found (Group 1-3). The log10 reciprocal titres associated on average with 75% protection (with 95% credible limits) were: Group 1: 2.46 (2.11-2.97); Group 2: 1.67 (1.49-1.92); Group 3: 1.17 (1.06-1.30). Further cross-protection data are needed to understand the factors that underpin this variability and to develop more robust antibody thresholds. Establishing cut-off serological titres that can be used to score the adequacy of vaccine-induced immunity will facilitate the monitoring and thereby the performance of FMD vaccination in the field.


Leaky-mode resonant reflectors with extreme bandwidths.
We present ultrawide flat-band reflectors enabled with multilevel resonant leaky-mode structures. The reflectors are designed using particle swarm optimization. We show that three-level silicon-on-insulator structures provide bandwidths of approximately 840 nm for TE polarization and approximately 835 nm for TM polarization, across which reflectance is greater than 99% and 97.5%, respectively. For the germanium-on-insulator system, the 99% TE and TM bandwidths are approximately 1100 nm and approximately 1050 nm. The results indicate the potential of multilevel resonant leaky-mode elements in electromagnetics and photonics.


Organocatalytic kinetic resolution cascade reactions: new mechanistic and stereochemical manifold in diphenyl prolinol silyl ether catalysis.
A new cascade reaction involving an iminium-catalyzed intramolecular oxa-Michael addition followed by an enamine-catalyzed intermolecular Michael addition is reported herein. This cascade reaction generates enantiopure, highly functionalized tetrahydropyrans and tetrahydrofurans in a one-pot reaction and in up to 89 % combined yield and up to 99 % ee. This cascade reaction is catalyzed by diaryl prolinol silyl ethers, which are a privileged class of catalysts. The stereochemical outcome of these cascade reactions is unprecedented. Computational studies indicate that this stereochemical outcome arises from nonclassical hydrogen-bonding interactions between the electrophile and the substrate, and from entropic considerations of preorganization. The unprecedented configurations of the cascade products, combined with the computational models, reveal for the first time that asymmetric induction by diaryl prolinol silyl ether catalysts is not always exclusively reagent controlled. The stereochemical outcome also arises from a kinetic resolution or dynamic kinetic resolution of the β-stereocenter through an enamine-catalyzed intermolecular reaction. This unprecedented organocascade reaction mechanism may be adaptable to diaryl prolinol silyl ether-catalyzed cascade reactions, in which both the iminium- and enamine-catalyzed steps are intermolecular, an underdeveloped type of cascade reaction.


Role of bacteria in bioaccumulation of mercury in the oyster Crassostrea virginica.
An investigation of mercury-resistant bacteria was undertaken to determine their role in the accumulation of mercury in a simplified food chain. Oysters (Crassostrea virginica) were maintained in a closed system, sealed aquarium with stirred, aerated water containing 10 mug of 203-HgCl2 per liter. Uptake of 203-Hg by oysters held under control conditions was compared with that of 203-Hg uptake by oysters under similar conditions except that mercury-accumulating and mercury-metabolizing species of Pseudomonas, isolated from Chesapeake Bay, were added to the experimental oysters. After incubation for 4 days, the major portion ofthe 203-Hg in the water column was found to be associated with the microparticulate fraction, corresponding to a rise in total viable count. Mercury accumulation in the oysters was significantly higher in the gill and visceral tissue than other tissue. Mercury concentrations were 200 times greater in tissue fractions of oysters dosed with mercury-metabolizing bacteria compared with the oysters held under control conditions without mercury-metabolizing bacteria.


The solid phase extraction of some metal ions using palladium nanoparticles attached to silica gel chemically bonded by silica-bonded N-propylmorpholine as new sorbent prior to their determination by flame atomic absorption spectroscopy.
In this research at first palladium nanoparticle attached to a new chemically bonded silica gel has been synthesized and has been characterized with different techniques such as X-ray diffraction (XRD), fourier transform infrared (FT-IR), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Then, this new sorbent (chemically modified silica gel with N-propylmorpholine (PNP-SBNPM)) was efficiently used for preconcentration of some metal ions in various food samples. The influence of effective variables including mass of sorbent, flow rate, pH of sample solutions and condition of eluent such as volume, type and concentration on the recoveries of understudy metal ions were investigated. Following the optimization of variables, the interfering effects of some foreign ions on the preconcentration and determination of the investigated metal ions described. At optimum values of variables, all investigated metal ions were efficiently recovered with efficiency more than 95%, relative standard deviation (RSD) between 2.4 and 2.8, and detection limit in the range of 1.4-2.7 ng mL⁻¹. The present method is simple and rapidly applicable for the determination of the understudied metal ions (ng mL⁻¹) in different natural food samples.


Metachronous cancer of gallbladder and pancreas with pancreatobiliary maljunction.
Pancreaticobiliary maljunction is a congenital anomaly in which the junction between the pancreatic duct and the common bile duct is located outside the sphincter of Oddi. It is well known that pancreaticobiliary maljunction is frequently associated with carcinoma of thebiliary tract. We report a case of metachronous cancer of the gallbladder and pancreas associated with pancreaticobiliary maljunction and cystic dilatation of common bile duct in a 68-year-old Tunisian woman who underwent a cholecystectomy for acute cholecystitis. The pancreatic tumor was an adenosquamous carcinoma. Pancreaticobiliary maljunction allows for pancreatobiliary or biliopancreatic reflux which may induce biliary tract carcinoma. Few cases of multifocal cancer associated with this anomaly have been reported. The association with pancreatic carcinoma remains rare. Close attention should be given to both the biliary tract system and pancreas during the long-term follow-up of patients with pancreaticobiliary maljunction, especially after they have undergone a choledochojejunostomy.


[Identification of the area of influence of the public basic health care delivery to the elderly population in Viçosa-MG].
This study aimed to describe the demographic and epidemiological characteristics of the elderly population, identify the area of influence of basic care in relation to the area of residence of the elderly and the rate of service use, as well as to map the demand according to the geographic location of the Basic Care Unit. The sample comprised 6,964 male and female subjects aged 60 years or more, who sought any of the outpatient public health services between May 2003 and April 2004. From this total, 64.1% were women and 35.9% men. The results show that cardiovascular diseases account for the greater part of medical consultations in the health system, with a mean of 3,576 consultations per year per elderly. Geographic mapping showed the demand for medical consultations in determinate basic care units to be related with the medical specialty available at these units. These results allow identifying the neighborhoods with the highest concentrations of specific diseases, indicating the need for insertion/redistribution of professionals between the basic care units in order to improve the quality of life of the elderly.


Application of cell-based biological bioassays for health risk assessment of PM2.5 exposure in three megacities, China.
The determination of PM2.5-induced biological response is essential for understanding the adverse health risk associated with PM2.5 exposure. In this study, we conducted cell-based bioassays to measure the toxic effects of PM2.5 exposure, including cytotoxicity, oxidative stress, genotoxicity and inflammatory response. The concentration-response relationship was analyzed by benchmark dose (BMD) modeling and the BMDL10 was used to estimate the biological potency of PM2.5 exposure. PM2.5 samples were collected from three typical megacities of China (Beijing, BJ; Wuhan, WH; Guangzhou, GZ) in typical seasons (winter and summer). The total PM, water-soluble fractions (WSF), and organic extracts (OE) were prepared and subjected to examination of toxic effects. The biological potencies for cytotoxicity, oxidative stress and genotoxicity were generally higher in winter samples, while the inflammatory potency of PM2.5 was higher in summer samples. The relative health risk (RHR) was determined by integration of the biological potencies and the cumulative exposure level, and the ranks of RHR were BJ-W > WH-W > BJ-S > WH-S > GZ-W > GZ-S. Notably, we note that different PM2.5 compositions were associated with distinct biological effects, and the health effects distribution of PM2.5 varied in regions and seasons. These findings demonstrate that the approach of integrated cell-based bioassays could be used for the evaluation of health effects of PM2.5 exposure.


Apoptosis in human polymorphonuclear leukocytes: searching for a genetic roadmap.
Polymorphonuclear leukocytes (PMNs or neutrophils) are essential components of the innate immune system in humans and function primarily to eliminate invading microorganisms. Neutrophil influx to sites of infection is desirable because it also initiates an inflammatory response. Paradoxically, PMNs are also intimately associated with inflammatory disease. As part of normal neutrophil turnover in humans and to limit inflammatory potential, PMNs undergo programmed cell death, or apoptosis. Several host factors, including cytokines and growth factors, are capable of extending neutrophil survival and, thus, capacity to fight infection. On the other hand, phagocytosis of bacterial pathogens generally accelerates PMN apoptosis. Due in part to the extensive complexity of programmed cell death, relatively little is known about the signaling pathways that govern these processes in PMNs. Recently, microarray strategies have been employed to gain an understanding of these processes in activated PMNs, and new evidence indicates that gene transcription is important in the regulation of neutrophil apoptosis and, thus, inflammation. A series of provocative discoveries led to the hypothesis that neutrophil programmed cell death is the result of an apoptosis-differentiation program, a final stage of transcriptionally regulated PMN maturation or hematopoietic differentiation. Further characterization of the apoptosis-differentiation program and associated biochemical pathways in mature PMNs will likely yield important insights into the resolution of inflammation and infection.


Could Bet v 1 affect sensitization molecular pattern in children?
Allergy is characterized by allergen-specific IgE production. Molecular-based allergy diagnostic allows to define the precise sensitization profile. Bet v 1 is the major allergen of the PR-10 family. It has been reported that pan-allergens could affect the sensitization panel in adults. This study aimed to evaluate the impact of Bet v 1 sensitization on clinical presentation in a sample of children with Bet v 1-sensitization; oral allergy syndrome (OAS) or anaphylaxis (ANA) were considered. Serum IgE molecular components were assessed by ISAC method. Sera and clinical data from 132 children, 91 males (68.94%) and 41 females (31.06%), mean age 9.08 years (3.45 years), were analyzed. Bet v 1-sensitized children were frequently, but not exclusively, sensitized to other molecules belonging to PR-10 family. However, there was no significant difference concerning IgE levels between children with or without food allergy and between children with OAS and ANA, but hazelnut only for generic food allergy. The present study demonstrates that Bet v 1 sensitization may affect the sensitization pattern in children living in Genoa, a Mediterranean city located in a birch-free area, but it is unable to discriminate patients from a clinical point of view. So, ISAC test should be integrated with more precise IgE assay.


The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy.
Obliterative bronchiolitis is the most significant long-term complication of lung and heart-lung transplantation characterized by the rapid development of obstructive airway disease. It is thought to be a manifestation of chronic rejection and has been treated, with limited success, with augmentation of immunosuppression. Early detection of obliterative bronchiolitis and prompt initiation of therapy may result in an improved outcome. The role of transbronchial biopsy has been reported in the diagnosis of acute rejection and infection but not for obliterative bronchiolitis. To study this problem we retrospectively reviewed the transbronchial biopsy results of patients with advanced clinical obliterative bronchiolitis, as defined physiologically. Between January 1, 1988, and December 31, 1991, 46 "sets" of adequate transbronchial biopsy specimens were obtained from 16 patients (15 heart-lung recipients and one double lung recipient). Seven sets of transbronchial biopsy specimens (15.2%) showed obliterative bronchiolitis by pathologic study. In four patients with severe clinical obliterative bronchiolitis, only one transbronchial biopsy specimen of seven (14.3%) showed obliterative bronchiolitis. The pathologic diagnosis of obliterative bronchiolitis was confirmed in three of these patients at the time of autopsy or retransplantation. Twelve patients were still alive at the end of the study period, and all experienced further deterioration of lung function typical for obliterative bronchiolitis. We conclude that the sensitivity of transbronchial biopsy for obliterative bronchiolitis is poor. Possible explanations for these results are explored.


The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.
In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely. A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules. In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin. Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve. Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 gene editing showed that the promyelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5. This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known promyelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.


Structural characterization of type II dockerin module from the cellulosome of Clostridium thermocellum: calcium-induced effects on conformation and target recognition.
The assembly of a functional cellulose-degrading complex termed the cellulosome involves two specific calcium-dependent cohesin-dockerin interactions: type I and type II. Extensive structural and mutagenesis studies have been performed on the type I modules and their interaction in an attempt to identify the underlying molecular determinants responsible for this specificity. However, very little structural information exists for the type II interaction. We have performed a variety of biophysical studies on the type II dockerin-X-module modular pair (DocX), which comprises the C-terminal region of cellulosomal scaffoldin subunit from Clostridium thermocellum, to determine the effect of calcium on its structure and interaction with type II cohesin. Our results indicate that calcium binding to type II dockerin occurs with an apparent dissociation constant (K(d)) of 7 microM, induces stable secondary and tertiary structure, and leads to the exposure of a hydrophobic surface. Calcium binding also results in the homodimerization of DocX. Analytical ultracentrifugation experiments indicate that the DocX homodimer has an elongated shape and a K(d) of approximately 40 microM. However, addition of the SdbA type II cohesin binding partner led to the dissociation of the DocX homodimer and to the formation of a 1:1 heterodimer. We propose that the exposed hydrophobic surface forms, at least in part, the type II cohesin-binding site, which in the absence of cohesin results in the dimerization of DocX.


A novel array chip to monitor in situ composite degradation using electrochemical impedance spectroscopy.
This paper presents a novel array-chip technology used to monitor the physical properties of dental composites in situ. The DECAY chip (Degradation via Electrochemical Array) leverages microfabrication techniques to construct a uniform array of recessed wells that may be filled with dental restorative materials (e.g. composite or amalgam) and analyzed electrochemically in solution. The array enables the uniform preparation of multiple specimens and reference controls on a common substrate, all of which may be simultaneously evaluated. The DECAY-chip presented here consists of a 3 × 3 array of 100 μm deep wells, and is used to monitor the degradation of a common dental composite as a function of time. The data correlate changes in the measured dielectric properties to surface and bulk changes as the composite is exposed to an ethanol:DI mixture (75% ethanol). A model for the system is presented, as are future plans to simplify the methodology for rapid materials screening and in vitro analyses. This in situdiagnostic chip will enable evaluation of composite specimens, tested under a wide range of simulated oral environments. It may also serve as a screening platform for new composite formulations and aid in the study of materials degradation and failure mechanisms.


[Metastatic bone disease. Strategies for imaging].
Skeletal metastases represent the most common malignant bone tumor. They occur mainly in adults and even more frequently in the elderly. The most common metastases in men are from prostate cancer (60%) and in women from breast cancer (70%). Other primitive tumors responsible for bone metastases are: lung, kidney, thyroid, alimentary tract, bladder, and skin. The spine and pelvis are the most common metastatic sites, due to the presence of red (haematopoietic active) bone marrow in a high amount. As a general rule, the radiographic pattern was lytic type; other aspects were osteosclerotic, mixed, lytic vs mixed and osteosclerotic vs lytic patterns. The main symptom is pain, although many bone metastases are asymptomatic. The most severe consequences are pathologic fractures and cord compression. Clinical evaluation of patients with skeletal metastases needs multimodal diagnostic imaging, able to detect lesions, to assess their extension and localization, and eventually drive the biopsy (for histo-morphological diagnosis). These techniques give different performances in terms of sensitivity and specificity; but none of the modalities alone seems to be adequate to yield a reliable diagnostic outcome. Therefore multidisciplinary cooperation is required to optimize the screening, clinical management and follow-up of the patients. In other terms, what is the efficacy of these new diagnostic tests compared to the "older" diagnostic tests? Frequently the new procedures do not replace the older one, but it is added to the diagnostic workup, thereby increasing costs without impacting the "patient's condition". The aim of the present work is to propose an "algorithm" for the detection and diagnosis of skeletal metastases, which may be applied differently in symptomatic and asymptomatic oncologic patients. Bone scintigraphy remains the first choice technique in the evaluation of asymptomatic patients, in whom skeletal metastases are supposed. Although it has a high sensitivity, scintigraphy is unspecific. So that a negative scan response has to be re-evaluated with other methods: if clinical status remains "negative", the diagnostic route can stop. On the contrary, in patients with "positive" scan or with local symptoms and pain, the screening of metastatic lesions must be accomplished by a combination of radiography and CT: the result may be negative (for low sensitivity of conventional radiology), not conclusive (in this case bone biopsy is necessary) or symptoms are not due to metastatic lesions (i.e., osteoarthritis). CT represents an excellent mean of defining the extent of any metastatic lesions, especially those located at sites difficult to evaluate (vertebral column and pelvis). Before bone biopsy is carried out, MRI must be performed, because it is the only technique that makes it possible to distinguish between bone marrow components. It has been used most extensively in the evaluation of spine metastases. The limitation of MRI is the unspecificity of its findings, which may lead to an equivocal diagnosis, and because only part of the skeleton can be studied.


A 2.6 A structure of a serpin polymer and implications for conformational disease.
The function of the serpins as proteinase inhibitors depends on their ability to insert the cleaved reactive centre loop as the fourth strand in the main A beta-sheet of the molecule upon proteolytic attack at the reactive centre, P1-P1'. This mechanism is vulnerable to mutations which result in inappropriate intra- or intermolecular loop insertion in the absence of cleavage. Intermolecular loop insertion is known as serpin polymerisation and results in a variety of diseases, most notably liver cirrhosis resulting from mutations of the prototypical serpin alpha1-antitrypsin. We present here the 2.6 A structure of a polymer of alpha1-antitrypsin cleaved six residues N-terminal to the reactive centre, P7-P6 (Phe352-Leu353). After self insertion of P14 to P7, intermolecular linkage is affected by insertion of the P6-P3 residues of one molecule into the partially occupied beta-sheet A of another. This results in an infinite, linear polymer which propagates in the crystal along a 2-fold screw axis. These findings provide a framework for understanding the uncleaved alpha1-antitrypsin polymer and fibrillar and amyloid deposition of proteins seen in other conformational diseases, with the ordered array of polymers in the crystal resulting from slow accretion of the cleaved serpin over the period of a year.


Adaptive risk-based targeted surveillance for foreign animal diseases at the wildlife-livestock interface.
Animal disease surveillance is an important component of the national veterinary infrastructure to protect animal agriculture and facilitates identification of foreign animal disease (FAD) introduction. Once introduced, pathogens shared among domestic and wild animals are especially challenging to manage due to the complex ecology of spillover and spillback. Thus, early identification of FAD in wildlife is critical to minimize outbreak severity and potential impacts on animal agriculture as well as potential impacts on wildlife and biodiversity. As a result, national surveillance and monitoring programs that include wildlife are becoming increasingly common. Designing surveillance systems in wildlife or, more importantly, at the interface of wildlife and domestic animals, is especially challenging because of the frequent lack of ecological and epidemiological data for wildlife species and technical challenges associated with a lack of non-invasive methodologies. To meet the increasing need for targeted FAD surveillance and to address gaps in existing wildlife surveillance systems, we developed an adaptive risk-based targeted surveillance approach that accounts for risks in source and recipient host populations. The approach is flexible, accounts for changing disease risks through time, can be scaled from local to national extents and permits the inclusion of quantitative data or when information is limited to expert opinion. We apply this adaptive risk-based surveillance framework to prioritize areas for surveillance in wild pigs in the United States with the objective of early detection of three diseases: classical swine fever, African swine fever and foot-and-mouth disease. We discuss our surveillance framework, its application to wild pigs and discuss the utility of this framework for surveillance of other host species and diseases.


[Resection of a Huge Gastrointestinal Stromal Tumor of the Stomach Following Neoadjuvant Chemotherapy with Imatinib].
We report a case of a huge gastric gastrointestinal stromal tumor(GIST)that was safely resected followingpreoperative imatinib therapy. A 72-year-old woman was hospitalized with severe abdominal distension. Computed tomography revealed a 27×17 cm tumor in the left upper abdominal cavity. The patient was diagnosed with high risk GIST by EUS-FNA. We initiated preoperative adjuvant chemotherapy with imatinib to achieve a reduction of operative risks and functional preservation. After 6 months of chemotherapy, CT showed a reduction in the tumor size and the patient underwent partial gastrectomy and partial resection of the diaphragm. Histologically, most of the tumor cells were replaced by hyalinized collagen and viable cells were scattered only around the blood vessels. Neoadjuvant chemotherapy with imatinib has the potential to become an important therapeutic option for the treatment of huge GISTs.


Nutrition Status and Health-Related Quality of Life Among Outpatients With Advanced Head and Neck Cancer.
This pilot study evaluated nutrition status and health-related quality of life (HRQOL) outcomes among outpatients with head and neck cancer (HNC). Data were collected from 19 patients (18 males, 1 female) during 3 time points: once before chemoradiotherapy (CRT) initiation and 1 and 3 months after CRT. Nutrition status was evaluated using the Scored Patient-Generated Subjective Global Assessment (PG-SGA). Malnutrition was defined as PG-SGA stage B (moderate/suspected malnutrition) or stage C (severely malnourished). HRQOL was assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its HNC-specific module (QLQ-H&N35). We found that well-nourished patients reported having fewer issues with pain, fatigue, appetite loss, chewing, sticky saliva, coughing, and social eating than those categorized as malnourished (P < .05). The association between the global quality-of-life score and PG-SGA score was statistically significant but weak in strength (r = -0.37, P = .012). Although PG-SGA identified 70% as either moderately or severely malnourished before treatment initiation, the mean body mass index was in the overweight category (29 ± 5 kg/m2 ). Compared with pretreatment, patients reported more severe problems with chewing, swallowing, sticky saliva, dry mouth, speech, social eating, and taste and smell sensations at 1-month follow-up, although issues with dry mouth persisted 3 months post treatment (P = .003). In conclusion, malnourished patients reported having worse HRQOL symptoms compared with well-nourished patients. Routine nutrition and psychosocial assessment through PG-SGA and EORTC tools might help identify patients in need of nutrition and psychosocial care.


Challenges in operationalizing the DSM-IV clinical significance criterion.
An explicit clinical significance (CS) criterion was added to many DSM-IV diagnoses in an attempt to more closely approximate the clinical diagnostic process and reduce the proportion of false positives in epidemiological studies. The American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP) offered a unique opportunity to examine the success of this effort. To determine the impact of distress, impairment, and help-seeking reported in a lay structured interview on concordance with a clinical reappraisal. Further, to test the efficacy of 5 operationalizations of CS on the concordance and prevalence of DSM-IV lifetime disorders. Completed between 1997 and 2000, a cross-sectional probability sample survey with clinical reappraisal of approximately 10% of participants. General community. A population-based sample of 3084 members of 2 American Indian tribal groups, who were between the ages of 15 and 54 years and resided on or near their home reservations, were randomly sampled from the tribal rolls and participated in structured psychiatric interviews. Clinical reappraisals were conducted with approximately 10% of the lay-interview participants. The response rate for the lay interview was 75%, and for the clinical reappraisal it was 72%. The AI-SUPERPFP Composite International Diagnostic Interview (CIDI), a culturally adapted version of the CIDI, University of Michigan version. Adapted to assess DSM-IV diagnoses, questions assessing the CS criterion were inserted in all diagnostic modules. The Structured Clinical Interview for DSM-III-R (SCID) was used in the clinical reappraisal. Most participants who qualified as having AI-SUPERPFP CIDI lifetime disorders reported at least moderate levels of distress or impairment. Evidence of increased concordance between the CIDI and the SCID was lacking when more restrictive operationalizations of CS were used; indeed, the CIDI was very likely to underdiagnose disorders compared with the SCID (false negatives). Concomitantly, the CS operationalizations affected prevalence rates dramatically. The CS criterion, at least as operationalized to date, demonstrates little effectiveness in increasing the validity of diagnoses using lay-administered structured interviews.


T cells engrafted with a UniCAR 28/z outperform UniCAR BB/z-transduced T cells in the face of regulatory T cell-mediated immunosuppression.
Adoptive transfer of chimeric antigen receptor (CAR)-equipped T cells have demonstrated astonishing clinical efficacy in hematological malignancies recently culminating in the approval of two CAR T cell products. Despite this tremendous success, CAR T cell approaches have still achieved only moderate efficacy against solid tumors. As a major obstacle, engineered conventional T cells (Tconvs) face an anti-inflammatory, hostile tumor microenvironment often infiltrated by highly suppressive regulatory T cells (Tregs). Thus, potent CAR T cell treatment of solid tumors requires efficient activation of Tconvs via their engrafted CAR to overcome Treg-mediated immunosuppression. In that regard, selecting an optimal intracellular signaling domain might represent a crucial step to achieve best clinical efficiency. To shed light on this issue and to investigate responsiveness to Treg inhibition, we engrafted Tconvs with switchable universal CARs (UniCARs) harboring intracellularly the CD3ζ domain alone or in combination with costimulatory CD28 or 4-1BB. Our studies reveal that UniCAR ζ-, and UniCAR BB/ζ-engineered Tconvs are strongly impaired by activated Tregs, whereas UniCARs providing CD28 costimulation overcome Treg-mediated suppression both in vitro and in vivo. Compared to UniCAR ζ- and UniCAR BB/ζ-modified cells, UniCAR 28/ζ-armed Tconvs secrete significantly higher amounts of Th1-related cytokines and, furthermore, levels of these cytokines are elevated even upon exposure to Tregs. Thus, in contrast to 4-1BB costimulation, CD28 signaling in UniCAR-transduced Tconvs seems to foster a pro-inflammatory milieu, which contributes to enhanced resistance to Treg suppression. Overall, our results may have significant implications for CAR T cell-based immunotherapies of solid tumors strongly invaded by Tregs.


Preparation, identification, activity prediction, and protective effects on IR-HepG2 cells of five novel DPP-IV inhibitory peptides from protein hydrolysate of skipjack tuna dark muscles.
To produce peptides with high dipeptidyl peptidase IV (DPP-IV) inhibitory activity, neutrase was selected from five proteases (trypsin, neutrase, pepsin, alcalase and flavor protease) with the highest degree of hydrolysis (DH) (18.23 ± 1.08%) and DPP-IV inhibitory rate (53.35 ± 4.02%) to produce protein hydrolysate (NPH) from the dark muscles of skipjack tuna (Katsuwonus pelamis). Then, NPH-1 was isolated from NPH by gel permeation chromatography and found to possess the highest DPP-IV inhibitory rate (65.12 ± 7.94% at 0.5 mg ml-1) in the separated components (including NPH-1, NPH-2, NPH-3 and NPH-4). Subsequently, the available prediction models of tripeptides and tetrapeptides with the DPP-IV inhibitory rate were established using an artificial neural network (ANN). The RMSE (0.56 and 0.33 for the model established through collected tripeptides and tetrapeptides, respectively) and R2 (0.95 and 0.99 for the model established through collected tripeptides and tetrapeptides, respectively) of the ANN model's parameters were within acceptable limits, indicating that this model is available. Next, the ANN model was applied to predict tripeptides and tetrapeptides from the hydrolysate of skipjack tuna dark muscles, and five peptides (Ala-Pro-Pro (APP), Pro-Pro-Pro (PPP), Asp-Pro-Leu-Leu (DPLL), Glu-Ala-Val-Pro (EAVP) and Glu-Ala-Iie-Pro (EAIP)) possessing a noticeable DPP-IV inhibitory rate (with DPP-IV IC50 values of 42.46 ± 5.02, 37.71 ± 9.17, 58.85 ± 14.42, 49.94 ± 6.69 and 57.15 ± 6.13 μM, respectively) were screened from the protein hydrolysate. The above five peptides were proved to effectively promote glucose consumption in the insulin resistant-HepG2 (IR-HepG2) cell model considering that the glucose consumption rates of APP, PPP, DPLL, EAVP and EAIP treatment groups are all more than twice that of the dexamethasone group. Accordingly, mechanistic studies showed that these peptides interacted with PI3K/AKT and AMPK signaling pathways and promoted the phosphorylation of PI3K p110, AKT and AMPK (the protein expressions of PI3K p110, p-AKT and p-AMPK in APP, PPP, DPLL, EAVP and EAIP treatment groups are 1.64-2.22 fold compared with that in the dexamethasone group), thereby enhancing glucose uptake and further alleviating insulin resistance. These findings demonstrated that skipjack tuna dark muscle is a potential DPP-IV inhibitory peptide source, and five DPP-IV inhibitory peptides from its hydrolysate may exert potent anti-diabetic activity. In comparison, PPP may be the most potential active ingredient for healthy food against type 2 diabetes mellitus in the five screened peptides considering synthetically the DPP-IV inhibitory rate, bioavailability and synthesis cost.


Professional Benefits of a Web-based Journal Club for Critical Care Residents and Their Mentors.
Objective. To identify the perceptions and benefits of participation in a web-based journal club by the critical care pharmacy residents who presented and their mentors. Methods. Former and current resident presenters and their mentors were invited to complete one of three electronic surveys created to assess their perceptions of their experiences with a web-based journal club sponsored by the Clinical Pharmacy and Pharmacology (CPP) Section of the Society of Critical Care Medicine (SCCM). Descriptive statistics were used to analyze the data gathered. Results. Thirty-eight (41%) former residents, 23 (72%) recent or current residents, and 32 (58%) presentation mentors responded to the survey. Residents in both groups indicated that participation was a beneficial educational and professional experience. Residents who more recently presented an online journal club reported improved confidence in critically evaluating research, determining clinical applications of published literature, developing evidence-based recommendations, and educating trainees on evidence-based medicine. Mentors believed their residents' journal club participation influenced their future involvement in both the SCCM and the CPP Section and were extremely likely to recommend their future residents participate in the web-based journal club. Conclusion. Participation in a web-based journal club provided professional benefits to participants and their mentors that extended beyond the presentation itself. Interaction with the organization through this experience may have encouraged these individuals to maintain their professional involvement in the organization after the web-based journal club experience was completed. Other professional organizations may benefit from implementation of a similar web-based journal club.


[Gray-scale histogram analysis in thyroid sonography. Critique of visual evaluation of echogenicity].
Three hundred and eighteen grey scale histograms of thyroid glands in 121 patients have been analysed. The arithmetic average grey scale value (GWMi) and the most commonly appearing grey value (GWMa) were determined electronically. The normal range of GWMi was 24 +/- 4.6 (x +/- s) grey scale units (GWE), for GWMa it was 26 +/- 5.6 GWe (x +/- s). Macrofollicular thyroid adenomas (8 cases) and thyroids with diffuse autonomy (12 cases) differed with a GWMi of 21 +/- 3.8 and 23 +/- GEW (x +/- s) respectively and a GWMa of 23 +/- 3.9 and 25 +/- 4.8 GWE and were within the normal range (p greater than 0.05). Microfollicular thyroid adenomas (12 cases), immunological thyroid lesions (25 cases) and parathyroid adenomas (6 cases) had reduced GWMi (6 +/- 3.1 and 8 +/- 1.8 GWE respectively) and GWMa (5 +/- 3 and 7 +/- 2 GWE, p less than 0.005). Thyroid carcinomas (9 cases) and lymph node metastases (8 cases) were also significantly below normal, with a GWMi of 11 +/- 2.3 and 11 +/- 3.4 respectively (p less than 0.05). Analysis of grey scale histograms makes it possible to evaluate changes in the thyroid without reference to surrounding tissues.


Adapting to an invasive species: toxic cane toads induce morphological change in Australian snakes.
The arrival of invasive species can devastate natural ecosystems, but the long-term effects of invasion are less clear. If native organisms can adapt to the presence of the invader, the severity of impact will decline with time. In Australia, invasive cane toads (Bufo marinus) are highly toxic to most snakes that attempt to eat them. Because snakes are gape-limited predators with strong negative allometry for head size, maximum relative prey mass (and thus, the probability of eating a toad large enough to be fatal) decreases with an increase in snake body size. Thus, the arrival of toads should exert selection on snake morphology, favoring an increase in mean body size and a decrease in relative head size. We tested these predictions with data from specimens of four species of Australian snakes, collected over >80 years. Geographic information system layers provided data on the duration of toad exposure for each snake population, as well as environmental variables (latitude, precipitation, and temperature). As predicted, two toad-vulnerable species (Pseudechis porphyriacus and Dendrelaphis punctulatus) showed a steady reduction in gape size and a steady increase in body length with time since exposure to toads. In contrast, two species at low risk from toads (Hemiaspis signata and Tropidonophis mairii) showed no consistent change in these morphological traits as a function of the duration of toad exposure. These results provide strong evidence of adaptive changes in native predators as a result of the invasion of toxic prey.


Recognizing acetabular version in the radiographic presentation of hip dysplasia.
Attention to the radiographic shadow of the walls of the acetabulum seen on the anteroposterior projection of a well-centered radiograph of the pelvis is important to identify the orientation of the opening of the acetabulum. This is referred to as the acetabular version. The opening of the mouth of the acetabulum may be oriented anteriorly, which is referred to as anteverted; posteriorly, or retroverted; or when the shadow of the lips of the anterior and posterior walls terminate together on the lateral edge of the acetabular rim, neutral version. The radiographs of 153 patients with developmental hip dysplasia presenting with hip pain were reviewed to determine the frequency of retroversion of the acetabulum. In this group of patients, retroversion of the hip socket was surprisingly common, one in three hip sockets, and generally was associated with smaller values of the lateral center edge measurement. The observation is important, because it must be taken into account when planning a corrective osteotomy of the acetabulum so the abnormal horizontal orientation of socket is corrected along with the usual anterior and lateral insufficiency.


Schisandrin B Alleviates Renal Tubular Cell Epithelial-Mesenchymal Transition and Mitochondrial Dysfunction by Kielin/Chordin-like Protein Upregulation via Akt Pathway Inactivation and Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase Pathway Activation in Diabetic Kidney Disease.
Diabetic kidney disease is a common complication of diabetes and remains the primary cause of end-stage kidney disease in the general population. Schisandrin B (Sch B) is an active ingredient in Schisandra chinensis. Our study illustrates that Sch B can mitigate renal tubular cell (RTC) epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction in db/db mice, accompanied by the downregulation of TGF-β1 and the upregulation of PGC-1α. Similarly, Sch B demonstrated a protective effect by reducing the expression of TGF-β1, α-SMA, fibronectin, and Col I, meanwhile enhancing the expression of E-cadherin in human RTCs (HK2 cells) stimulated with high glucose. Moreover, under high glucose conditions, Sch B effectively increased mitochondrial membrane potential, lowered ROS production, and increased the ATP content in HK2 cells, accompanied by the upregulation of PGC-1α, TFAM, MFN1, and MFN2. Mechanistically, the RNA-seq results showed a significant increase in KCP mRNA levels in HK2 cells treated with Sch B in a high glucose culture. The influence of Sch B on KCP mRNA levels was confirmed by real-time PCR in high glucose-treated HK2 cells. Depletion of the KCP gene reversed the impact of Sch B on TGF-β1 and PGC-1α in HK2 cells with high glucose level exposure, whereas overexpression of the KCP gene blocked EMT and mitochondrial dysfunction. Furthermore, the PI3K/Akt pathway was inhibited and the AMPK pathway was activated in HK2 cells exposed to a high concentration of glucose after the Sch B treatment. Treatment with the PI3K/Akt pathway agonist insulin and the AMPK pathway antagonist compound C attenuated the Sch B-induced KCP expression in HK2 cells exposed to a high level of glucose. Finally, molecular autodock experiments illustrated that Sch B could bind to Akt and AMPK. In summary, our findings suggested that Sch B could alleviate RTC EMT and mitochondrial dysfunction by upregulating KCP via inhibiting the Akt pathway and activating the AMPK pathway in DKD.