Effects of endothelial basement membrane on neutrophil adhesion and migration.
The influence of the sub-endothelial basement membrane (BM) on the adhesion and migration of leukocytes is not well-defined. We therefore investigated the behaviour of human neutrophils on purified BM proteins and on BM deposited by short- or long-term cultures of endothelial cells (EC). The adhesion, but not migration velocities, of neutrophils activated with interleukin-8 was dependent on the coating concentrations of purified collagen, laminin or fibronectin. In contrast, adhesion was similar on matrices deposited by 3-day or 20-day cultures of EC, but neutrophils migrated more slowly on the distinct BM that formed over 20 days. In addition, while adhesion on all surfaces was greatly reduced when neutrophils were treated with antibody against beta(2)-integrins, antibody against beta(1)-integrins only inhibited adhesion to the 20-day BM. Thus, the native BM has distinct effects on integrin usage and migration by neutrophils, which are not reproduced by purified proteins or matrix deposited early during endothelial culture.


Control of Sarcoptes scabiei var. suis with ivermectin: influence on scratching behaviour of fattening pigs and occurrence of dermatitis at slaughter.
The behaviour of fattening pigs, the occurrence of erythematous papular dermatitis in pigs at slaughter and the effects of treatment for mange with ivermectin at the start of the fattening period were evaluated at ten farms. At each farm, trial pigs were randomly allotted to a control or a treated group. At the start of the trial, the control group was injected intramuscularly with 5 mg kg-1 levamisole, and the treated group was injected subcutaneously with 300 micrograms kg-1 ivermectin. Skin scrapings, taken from each pig before medication at the start of the trial, and at slaughter, were examined for presence of sarcoptic mites. Pig behaviour was monitored at 2 week intervals from Week 5 to Week 13 of the trial. Carcasses of trial pigs were inspected for dermatitis at slaughter. Low to moderate Sarcoptes scabiei var. suis infestations were demonstrated at the start of the trial on five farms (S+ farms). At slaughter, the mean percentage of Sarcoptes-positive pigs per pen on S+ farms was 34.8% (range 11-60%) for the control group as compared with 0.5% (range 0-2.7%) for the ivermectin-treated group (P < 0.01). No S. scabiei was recovered from any pig at any time from the five other farms (mange-free (S-) farms). The low initial levels of mange in the controls at S+ farms resulted in a consistently high scratching index. Ivermectin treatment resulted in a significantly (P < 0.01) lower prevalence of scratching, comparable with the prevalence observed at S- farms. High prevalences of generalized dermatitis at slaughter were observed in control pigs from all S+ farms. Ivermectin treatment resulted in much lower prevalences, reflected in a significantly (P < 0.01) lower grand mean dermatitis index per pen for this group as compared with the controls. The majority of pigs from both treatment groups at all S- farms were free of papular lesions. These results indicate that low levels of sarcoptic mange at the start of fattening, left untreated, will result in a high prevalence of scratching during the fattening period and high prevalences of Sarcoptes and dermatitis at slaughter. Treatment with ivermectin at the start of fattening results in behaviour and dermatitis prevalences similar to those observed in mange-free herds.


Substrate specificity and reaction mechanism of purified alkane hydroxylase from the hydrocarbonoclastic bacterium Alcanivorax borkumensis (AbAlkB).
An alkane hydroxylase from the marine organism Alcanivorax borkumensis (AbAlkB) was purified. The purified protein retained high activity in an assay with purified rubredoxin (AlkG), purified maize ferredoxin reductase, NADPH, and selected substrates. The reaction mechanism of the purified protein was probed using the radical clock substrates bicyclo[4.1.0]heptane (norcarane), bicyclo[3.1.0]hexane (bicyclohexane), methylphenylcyclopropane and deuterated and non-deuterated cyclohexane. The distribution of products from the radical clock substrates supports the hypothesis that purified AbAlkB hydroxylates substrates by forming a substrate radical. Experiments with deuterated cyclohexane indicate that the rate-determining step has a significant CH bond breaking character. The products formed from a number of differently shaped and sized substrates were characterized to determine the active site constraints of this AlkB. AbAlkB can catalyze the hydroxylation of a large number of aromatic compounds and linear and cyclic alkanes. It does not catalyze the hydroxylation of alkanes with a chain length longer than 15 carbons, nor does it hydroxylate sterically hindered C-H bonds.


Neuronal acetylcholine receptor channels from insects: a comparative electrophysiological study.
The channel properties of nicotinic acetylcholine receptor subtypes in the nervous system of insects (Locusta migratoria) have been characterized. Single channel measurements were performed using patch-clamp techniques as well as planar lipid bilayer reconstitution approaches. In reconstitution experiments using receptor-preparations isolated from neuronal membranes by alpha-toxin affinity chromatography, a ligand-gated channel type was found, which showed a high conductance and a short mean lifetime. Patch-clamp experiments on synapse-free somata of isolated nerve cells revealed an acetylcholine-gated channel type with a lower conductance but a longer lifetime. The two different agonist-activated channel types are supposed to represent synaptic and extrasynaptic acetylcholine receptors.


Salt priming induces low-temperature tolerance in sugar beet via xanthine metabolism.
To understand the physiological mechanisms involved in xanthine metabolism during salt priming for improving low-temperature tolerance, salt priming (SP), xanthine dehydrogenase inhibitor (XOI), exogenous allantoin (EA), and back-supplemented EA (XOI + EA) treatments were given and the low-temperature tolerance of sugar beet was tested. Under low-temperature stress, salt priming promoted the growth of sugar beet leaves and increased the maximum quantum efficiency of PS II (Fv/Fm). However, during salt priming, either XOI or EA treatment alone increased the content of reactive oxygen species (ROS), such as superoxide anion and hydrogen peroxide, in the leaves under low-temperature stress. XOI treatment increased allantoinase activity with its gene (BvallB) expression under low-temperature stress. Compared to the XOI treatment, the EA treatment alone and the XOI + EA treatment increased the activities of antioxidant enzymes. At low temperatures, the sucrose content and the activity of key carbohydrate enzymes (AGPase, Cylnv, and FK) were significantly reduced by XOI compared to the changes under salt priming. XOI also stimulated the expression of protein phosphatase 2C and sucrose non-fermenting1-related protein kinase (BvSNRK2). The results of a correlation network analysis showed that BvallB was positively correlated with malondialdehyde, D-Fructose-6-phosphate, and D-Glucose-6-phosphate, and negatively correlated with BvPOX42, BvSNRK2, dehydroascorbate reductase, and catalase. These results suggested that salt-induced xanthine metabolism modulated ROS metabolism, photosynthetic carbon assimilation, and carbohydrate metabolism, thus enhancing low-temperature tolerance in sugar beet. Additionally, xanthine and allantoin were found to play key roles in plant stress resistance.


Neighborhood design and active aging.
This qualitative analysis of focus groups describes how neighborhood design encourages active aging. Nine focus groups were conducted in 2002 and 2003 with residents (N=60) aged 55 and over living in Portland, OR, USA. Content analysis revealed that local shopping and services, traffic and pedestrian infrastructure, neighborhood attractiveness, and public transportation influence activity among older adults. This information will be useful for making policy recommendations relating to land use planning and transportation, to assist in senior-friendly developments and neighborhood improvements, and to design effective senior health interventions with an emphasis on neighborhood design influences.


Traumatic thermal injuries of the middle ear.
Eleven cases of thermal otic injury are reviewed. The final outcome of therapy, whether medical or surgical is poor--only two of 11 patients were restored to normal. The possible pathogenesis of failure is discussed. Most cases could have been prevented by wearing ear plugs.


Deoxynivalenol, zearalenone, ochratoxin A: Quality of feed cereals.
In order to determine the distribution of mycotoxin contamination in Bavaria, Germany, and to control the quality of feed cereals the three toxins, deoxynivalenol (DON), ochratoxin A (OTA), and zearalenone (ZEA) from 5 different cereals out of 5 districts were analysed. Our investigation demonstrates that all data are near the discussed guide values thus the quality of cereals was not affected seriously in 1999. Calculating the medians for the 5 districts separately it was possible to establish a rough grid revealing a more detailed view on the mycotoxin situation in Bavaria.


Sensitized luminescence of trivalent lanthanide complexes Eu3+/quinaldinic acid and Eu3+/1,4-dihydro-oxo-chinoline-3-carboxilic acid.
Studies of the luminescence of Eu(3+)/quinaldinic acid sodium [Eu(QA)(3)] and Eu(3+)/1,4-dihydro-4-oxo-quinoline-carboxylic acid sodium [Eu/(DOQCA)(3)], both in solid form and in aqueous solution, are presented in room temperature. The energy transfer to the emitting levels of the lanthanide ions are discussed on the basis of the emission spectra and lifetime data of (5)D(0) and (5)D(1) levels of Eu(3+). In the aquated Eu/(QA)(3) complex, the most intense spectral band belongs to the (5)D(0) --> (7)F(1) transition (592 nm) and not to (5)D(0) --> (7)F(2) (616 nm), which otherwise occurs usually. In the cases of the Eu/(DOQCA)(3) complex the hypersensitive transition (5)D(0) --> (7)F(2) is the most intense as so far was reported for various Eu(3+) chelates.


An application of the density standard and scaled-pixel-counting protocol to assess the radiodensity of equine incisor teeth affected by resorption and hypercementosis: preliminary advancement in dental radiography.
Equine Odontoclastic Tooth Resorption and Hypercementosis (EOTRH) syndrome is a dental disease where the radiographic signs may be quantified using radiographic texture features. This study aimed to implement the scaled-pixel-counting protocol to quantify and compare the image structure of teeth and the density standard in order to improve the identification of the radiographic signs of tooth resorption and hypercementosis using the EOTRH syndrome model. A detailed examination of the oral cavity was performed in 80 horses and maxillary incisor teeth were evaluated radiographically, including an assessment of the density standard. On each of the radiographs, pixel brightness (PB) was extracted for each of the ten steps of the density standard (S1-S10). Then, each evaluated incisor tooth was assigned to one of 0-3 EOTRH grade-related groups and annotated using region of interest (ROI). For each ROI, the number of pixels (NP) from each range was calculated. The linear relation between an original X-ray beam attenuation and PB was confirmed for the density standard. The NP values increased with the number of steps of the density standard as well as with EOTRH degrees. Similar accuracy of the EOTRH grade differentiation was noted for data pairs EOTRH 0-3 and EOTRH 0-1, allowing for the differentiation of both late and early radiographic signs of EOTRH. The scaled-pixel-counting protocol based on the use of density standard has been successfully implemented for the differentiation of radiographic signs of EOTRH degrees.


Cellular degeneration and synaptogenesis in the developing retina of the rat.
We have investigated the time course and magnitude of cellular degeneration in the ganglion cell layer and the presumptive amacrine and bipolar regions of the inner nuclear layer during the development of the retina in the rat. Pyknotic profiles are present in the ganglion cell layer during the first 2 postnatal weeks, reaching peak numbers during the first 4 postnatal days (corresponding to the time of greatest loss of ganglion cells and their axons: Potts et al., '82; Lam et al., '82; Perry et al., '83). Two observations suggest that the majority of pyknotic profiles present in the ganglion cell layer during the second postnatal week are not ganglion cells. First, following injection of kainic acid into one superior colliculus, degenerating ganglion cells in the contralateral retina are cleared within 24-48 hours. Therefore, since most ganglion cell and axon loss occurs within the first postnatal week, few of the pyknotic profiles present in the second week are likely to be ganglion cells. Second, the time course of cellular degeneration in the ganglion cell layer during the second postnatal week follows a very similar pattern to that seen in the presumptive amacrine sublayer of the inner nuclear layer. Such a correspondence suggests that two phases of cell death occur in the ganglion cell layer: during the first postnatal week the majority of dying cells are ganglion cells, and in the second, most cell death is due to a loss of displaced amacrine cells. In the inner nuclear layer pyknotic profiles are most numerous in the presumptive amacrine region on postnatal days 6 and 7, and in the presumptive bipolar region on day 10. Synaptogenesis in the inner plexiform layer occurs later but reflects the order of cell death. Thus, conventional (presumed amacrine) synapses were first observed on day 11 and synaptic ribbons (indicative of bipolar synapses) on day 13. These observations suggest that amacrine and bipolar cells initiate synapses only after their numbers have stabilized.


Computerized dietary assessments compare well with interviewer administered diet histories for patients with type 2 diabetes mellitus in the primary healthcare setting.
To test repeatability and relative validity of a computerized and interviewer administered assessment. Using a context-based case-control trial, 41 adults with type 2 diabetes mellitus were randomized into four groups to complete dietary assessments (computerized or interviewer administered) at 0, 2 and 8 weeks and food records at 0 and 2 weeks. Repeatability of reported energy, total fat, saturated, polyunsaturated and monounsaturated fatty acids between the computerized and interviewer administered methods were assessed using repeated measures ANOVA. Paired t-tests and Pearson's correlations determined relative validity of the assessments. Thirty-one patients completed all visits. Statistically significant differences were found between computerized and interviewer administered data for total fat (p=0.048) and saturated fatty acids (p=0.019) between 0 and 2 weeks. Computerized assessments correlated better with food records (r=0.16-0.52) compared with interviewer administered assessments (r=-0.02 to 0.51). Computerized assessments saw a learning effect with repeated use indicating that users were becoming more familiar with the website with repeated use. Relative validity suggests that the website may capture more foods though this requires further investigation. By allowing patients to self-report their intakes on a computer, dietitians will have the ability to spend increased time with their patients counseling them toward change.


Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases.
HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y1221/1222) and pHER3(Y1222) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin.


NaOH cell maceration/scanning electron microscopic studies on the connective tissue core in the incisive portion of the mouse hard palate.
NaOH cell-maceration method was applied to the oral surface of the mouse hard palate to demonstrate the three-dimensional architecture of the connective tissue core (CTC) in the incisive portion. The CTC of the incisive papilla was inverted T-shaped, and was partially fused to that of the first antemolar ruga. Between the CTC of the incisive papilla and that of the first antemolar ruga, the incisive foramen opened in the shaped of crescent hiatus. Further, the round depressions, corresponding to the site of the taste buds, were situated exclusively in the anteromedial margin of the incisive foramen and in the oral aspect of the CTC of the incisive papilla close to the foramen. Such topographical relationship between the taste buds and the incisive foramen seems to be correlated to the discriminatory function of the taste buds. In the lateral sides of the incisive papilla, the connective tissue layer formed the conspicuous serrated ridges. It is suggested that the serrated ridges are interdigitated with the furrows in the basal surface of the epithelium, and act to prevent the epithelium from slipping during mastication.


Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia.
We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.


Down-regulation of norepinephrine sensitivity after induction of long-term neuronal plasticity (kindling) in the rat dentate gyrus.
Actions of norepinephrine (NE) in the dentate gyrus were examined before and after kindling-induced epilepsy, neuronal plasticity produced by daily high-frequency stimulation. NE, acting on beta 1-receptors, depolarized granule cells, increased input resistance, firing and influx of Ca2+ in response to repetitive stimulation, and elicited long-lasting potentiation of synaptic potentials. In addition, NE acting via alpha 1-receptors, attenuated Ca2+-dependent regenerative potentials. After kindling-induced plasticity, there were marked reductions in all these effects of NE on granule cells, changes likely to influence kindling-induced seizures, protecting against further enhancement of excitability once plasticity is in place.


Spectroscopic, single crystal X-ray, Hirshfeld, in vitro and in silico biological evaluation of a new series of potent thiazole nucleus integrated with pyrazoline scaffolds.
In the present study, the spectroscopic characterization of a new series of substituted thiazole linked pyrazoline scaffolds 4a-l was performed. The formation of 4a-l from the intermediate 3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2 and substituted 2-bromo-1-phenylethanone 3a-l was evidenced through the changes in FTIR, 1H NMR, 13C NMR, LCMS data. The X-ray diffraction studies revealed that compound 2 and 4g crystallized in monoclinic crystal system with P21/n space group. Compound 4j crystallized in triclinic system, P1̄ space group with Z=4. The percentage of intermolecular contacts and distribution of electrostatic potential of molecular crystal structures was resolved by Hirshfeld surface analysis with 2D finger plots and electrostatic potential map. The newly synthesized derivatives were screened for their in vitro antioxidant and antimicrobial activity. The single crystal studies revealed that, for compounds 2, 4g and 4j the isopropyl phenyl ring is positioned at near right angle with the other rings. Due to the lack of planarity of bulkier group substituted to phenyl ring (ring B), all the synthesized molecules showed weak to moderate radical scavenging capacity owing to the destabilization of the radical formed during oxidation. Also, on performing molecular docking studies to explore the interactions of ligand with the target pyrimidine nucleoside hydrolase YbeK with bound ribose complex (PNH, PDB ID-3GHW), disclosed that active compounds emerged for in vitro studies also bound to PNH more efficiently. The compounds with polar group substitution interacted through hydrogen bonding while other molecules with non-covalent interactions.


Ni-catalyzed mild hydrogenolysis and oxidations of C-O bonds via carbonate redox tags.
Oxygenated molecules are omnipresent in natural as well as artificial settings making the redox transformation of the present C-O bonds a central tool for their processing. However, the required (super)stoichiometric redox agents which traditionally include highly reactive and hazardous reagents pose multiple practical challenges including process safety hazards or special waste management requirements. Here, we report a mild Ni-catalyzed fragmentation strategy based on carbonate redox tags for redox transformations of oxygenated hydrocarbons in the absence of any external redox equivalents or other additives. The purely catalytic process enables the hydrogenolysis of strong C(sp2)-O bonds including that of enol carbonates as well as the catalytic oxidation of C-O bonds under mild conditions down to room temperature. Additionally, we investigated the underlying mechanism and showcased the benefits of carbonate redox tags in multiple applications. More broadly, the work herein demonstrates the potential of redox tags for organic synthesis.


Prostate cancer screening and prevention: "realities and hope".
Case finding and population screening for early prostate cancer are extensively debated issues. The increasing incidence and mortality of prostate cancer, although largely in older patients, suggests that some type of preventive measures should be undertaken to reverse this trend. The basic requirements for initiation of a population screening program were established by Wilson and Jungner in 1968. Based on available data, the following requirements are considered to be realities in this article: the importance of the health problem, the effectiveness of available treatment, the availability of the facilities, the identification of latent stages of the disease, the existence of effective screening methodology, and the acceptability of screening by the population to be screened. For choice of treatment and the stage of the tumor at the time of diagnosis, the data analysis is positive but caution is advised. Errors of commission and omission do occur in daily practice. The answers to the remaining four requirements are less clear. There is hope--but no certainty--that we are able to predict the natural history of the disease, that early treatment does reduce mortality, that treatment strategies avoid overlap, and that the cost of population screening has been appropriately calculated. The lack of a positive answer to these questions leads us to advise against general screening but to support definitively a randomized screening trial to provide answers in the next decade.


Efficacy of short-course colchicine treatment in hospitalized patients with moderate to severe COVID-19 pneumonia and hyperinflammation: a randomized clinical trial.
Some patients with COVID-19 pneumonia develop an associated cytokine storm syndrome that aggravates the pulmonary disease. These patients may benefit of anti-inflammatory treatment. The role of colchicine in hospitalized patients with COVID-19 pneumonia and established hyperinflammation remains unexplored. In a prospective, randomized controlled, observer-blinded endpoint, investigator-initiated trial, 240 hospitalized patients with COVID-19 pneumonia and established hyperinflammation were randomly allocated to receive oral colchicine or not. The primary efficacy outcome measure was a composite of non-invasive mechanical ventilation (CPAP or BiPAP), admission to the intensive care unit, invasive mechanical ventilation requirement or death. The composite primary outcome occurred in 19.3% of the total study population. The composite primary outcome was similar in the two arms (17% in colchicine group vs. 20.8% in the control group; p = 0.533) and the same applied to each of its individual components. Most patients received steroids (98%) and heparin (99%), with similar doses in both groups. In this trial, including adult patients with COVID-19 pneumonia and associated hyperinflammation, no clinical benefit was observed with short-course colchicine treatment beyond standard care regarding the combined outcome measurement of CPAP/BiPAP use, ICU admission, invasive mechanical ventilation or death (Funded by the Community of Madrid, EudraCT Number: 2020-001841-38; 26/04/2020).


Fast and accurate non-sequential protein structure alignment using a new asymmetric linear sum assignment heuristic.
The three dimensional tertiary structure of a protein at near atomic level resolution provides insight alluding to its function and evolution. As protein structure decides its functionality, similarity in structure usually implies similarity in function. As such, structure alignment techniques are often useful in the classifications of protein function. Given the rapidly growing rate of new, experimentally determined structures being made available from repositories such as the Protein Data Bank, fast and accurate computational structure comparison tools are required. This paper presents SPalignNS, a non-sequential protein structure alignment tool using a novel asymmetrical greedy search technique. The performance of SPalignNS was evaluated against existing sequential and non-sequential structure alignment methods by performing trials with commonly used datasets. These benchmark datasets used to gauge alignment accuracy include (i) 9538 pairwise alignments implied by the HOMSTRAD database of homologous proteins; (ii) a subset of 64 difficult alignments from set (i) that have low structure similarity; (iii) 199 pairwise alignments of proteins with similar structure but different topology; and (iv) a subset of 20 pairwise alignments from the RIPC set. SPalignNS is shown to achieve greater alignment accuracy (lower or comparable root-mean squared distance with increased structure overlap coverage) for all datasets, and the highest agreement with reference alignments from the challenging dataset (iv) above, when compared with both sequentially constrained alignments and other non-sequential alignments. SPalignNS was implemented in C++. The source code, binary executable, and a web server version is freely available at: http://sparks-lab.org email@example.com.


[Effectiveness of peri-articular infiltration with local anesthetic and adjuvants for post-surgical pain control in total knee replacement].
Total knee arthroplasty (TKA) is one of the most successful orthopedic treatments, however, it has been associated with severe postsurgical pain in 30-60% of patients. We propose that infiltration of the articular capsule of the knee during surgery will decrease postsurgical pain. Experimental, randomized, double-blind study in patients undergoing unilateral TKA between April 2018 and January 2019. Patients were divided into two groups, the first infiltration with placebo and the second with anesthetic solution and adjuvants (fentanyl, epinephrine and ketorolac). Pain was measured with the visual analog scale (VAS) at 4, 6, 8, 12, 18, 24, 36 and 48 hours postsurgical, as well as the consumption of opioid analgesics and antiemetics. 20 patients in each group, with a follow-up of 4 weeks. There were no significant differences in demographic characteristics between the two groups. Better control of postsurgical pain was observed in the group that received infiltration with anesthetic and adjuvant, as well as a decrease in the consumption of opioid analgesics and antiemetics. There was no difference in bleeding or in the incidence of infections between the two groups. Peri-capsular infiltration is a safe and effective method, as part of multimodal analgesia in total knee arthroplasty, as it decreases postsurgical pain, opioid and antiemetic use and does not increase postsurgical bleeding.


Characterization of T cell-expressed chimeric receptors with antibody-type specificity for the CD4 binding site of HIV-1 gp120.
Chimeric T cell receptors (cTCR) with an antibody specificity have been proposed in several models as a combination of antibody and cellular immunotherapy without MHC restriction. Such a tool could be of a limited use in HIV infection because of the great variability of the virus. The human single-chain antibody (ScFv-b12) derives from the b12 antibody directed to the CD4 binding site of gp120, a potent neutralizer of different HIV-1 strains, including a large panel of primary isolates. A single-chain fragment variable (ScFv) bearing the VH Pro-->Glu mutation that improves b12 affinity 54-fold, called ScFv-b12E, was also constructed. The ScFv were linked to the signal-transducing y chain of the Fc(gamma)RIII, with or without spacer region, and expressed in the murine MD45 T cell line. The different cTCR formats behave similarly in terms of ScFv surface expression, but differ according to their activation threshold. T cell transfectants can be stimulated with immobilized gp120 derived from all HIV strains tested. BHK cells infected with Semliki forest virus (SFV) carrying an HIV-1 envelope gene (SFV-env) derived from either HIV-1 laboratory strains (LAI, MN12, HXB2) or field isolates (BX08, CHAR or 133) were used as targets for the transfectants. All gp120-expressing cells induced cTCR-specific activation. The latter result is contrasting with the lack of specific recognition of SFV-CHAR- or 133-infected cells by the native b12 antibody, as measured by cytofluorometric analysis. Finally, HeLa cells (which constitutively express the coreceptor CXCR4) are able to bind HIV-1 gp160 when transfected with the chimeric receptor ScFv-b12-gamma, but, importantly, do not become infected by the virus. Our results therefore suggest that cTCR with b12 specificity can confer to T cells broad anti-HIV reactivity without making them susceptible to HIV infection.


Cecal Tumorigenesis in Aryl Hydrocarbon Receptor-Deficient Mice Depends on Cecum-Specific Mitogen-Activated Protein Kinase Pathway Activation and Inflammation.
The aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/β-catenin pathway activation. However, whether β-catenin degradation is AhR dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histologic characteristics of the tumors and cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Of the 28 Ahr-/- mice, 10 developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr-/- mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, whereas only IL-6 production increased in Ahr-/- peritoneal macrophages after lipopolysaccharide + ATP stimulation. Neither Myc (alias c-myc) up-regulation nor β-catenin nuclear translocation was observed, unlike previously reported. Interestingly, enhanced phosphorylation of extracellular signal-regulated kinase, Src, and epidermal growth factor receptor and Amphiregulin up-regulation at Ahr-/- lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphologic similarity to Ahr-/- cecal lesions. Our results suggest novel mechanisms underlying Ahr-/- cecal tumorigenesis, depending primarily on cecum-specific mitogen-activated protein kinase pathway activation and inflammation.


Screening history of women with cervical cancer: a 6-year study in Aarhus, Denmark.
To identify possible weaknesses in cervical screening in Aarhus County, 10 years after the programme was introduced, screening histories were examined. A major problem for the screening programme was that 31% of women were never screened and 61% under-screened, the latter group being significantly dominated by older women and high-stage tumours.


Objective follow-up after laparoscopic repair of large type III hiatal hernia. Assessment of safety and durability.
Symptomatic results of laparoscopic repair of large type III hiatal hernias, with/without prosthetic mesh, are often excellent; however, a high recurrence rate is detected when objective radiological/endoscopic follow-up is performed. The use of mesh may reduce the incidence of postoperative hernia recurrence or wrap migration in the chest. We retrospectively studied 54 patients (10 men, 44 women; median: age 64.5 years) with a diagnosis of large type III hiatal hernia (>1/3 stomach in the chest on x-ray) who underwent laparoscopic repair at our department from January 1992 to June 2005. Complications, recurrences, and symptomatic and objective (radiological/endoscopic) long-term outcome were evaluated. Nineteen patients had laparoscopic Nissen/Toupet fundoplication with simple suture; in 35 patients a double mesh was added. The median radiological/endoscopic follow-up was 64 months (interquartile range (IQR): 6-104) for the non-mesh group and 33 (IQR:12-61) for the mesh group (p = 0.26). Recurrences occurred in 11/54 (20%) patients: 8/19 (42.1%) without mesh and 3/35 (8.6%) with mesh (p = 0.01). The 3 recurrences in the mesh group all occurred < or =12 months postoperatively; 4/8 recurrences in the non-mesh group occurred > or =5 years after operation. On multivariate logistic regression analysis, only mesh absence significantly predicted hernia recurrence or wrap migration. Laparoscopic repair of large type III hiatal hernias is safe and effective. Short-term symptomatic results are excellent, but mid-term objective radiological/endoscopic evaluation reveals a high recurrence rate. Possible reasons for failure of a laparoscopic hiatal repair are tension or poor muscle tissue characteristics in the hiatus. The use of a mesh, either by reducing tension or reinforcing muscle at the hiatus, might be associated with a lower recurrence rate. Longer-term follow-up will be needed before definitive conclusions can be drawn, however.


The Circular RNA-miRNA Axis: A Special RNA Signature Regulatory Transcriptome as a Potential Biomarker for OSCC.
Oral squamous cell carcinoma (OSCC) is a highly recurrent form of cancer arising from the oral epithelium, which is the result of mutational change due to etiological factors such as tobacco, smoking, chewing of areca nuts, and alcohol consumption. OSCC occurrence has been observed to be prevalent in different regions of Pacific countries and in most Asian countries. Despite the accessibility of the oral cavity, OSCC is diagnosed at an extremely late stage of pathogenic tumor node metastasis pTNM (III-IV), resulting in a poor prognosis for the individual. Therefore, it is important to make definitive, early, and efficient diagnoses. Owing to the development of omic-natured studies, the presence of proteins, transcribed elements, metabolic products, and even microflora detected in saliva helps us to select biomarkers, which is an especially exciting potential because of the availability and the non-invasive nature of sample collection. Since the discovery of circular RNA (circRNA) by Sanger sequencing, it has been reported to play a pivotal role in several human diseases, including cancer. circRNA functions as a microRNA (miRNA) sponge in the regulation of mRNA expression, forming the circRNA-miRNA regulatory axis. In the case of OSCC, overexpression of different circRNAs exhibits both tumor-progressive and tumor-suppressive effects.


Long term cortical thickness changes after a first episode of non- affective psychosis: The 10 year follow-up of the PAFIP cohort.
Cortical thickness has been widely studied in individuals with schizophrenia and, in particular, first-episode psychosis. Abnormalities have been described, although there is, to date, a lack of consensus regarding changes across time and correlations with clinical and functional outcomes of the illness. One hundred and twenty-three first-episode psychosis patients and 74 healthy volunteers were subjected to magnetic resonance imaging scans and clinical and functional assessments by different scales at four consecutive visits during a 10 year follow-up period. Linear mixed effects models were applied to our data to compute cortical thickness changes over time in (1) schizophrenia patients versus healthy controls and (2) in patients with good versus poor functional outcome. The associations between cortical thickness percentage changes and clinical and functional status at 10 years were also assessed. The patients presented a thinner cortex than the controls at baseline (b's = -0.06; q ≤ 0.00023) with non-significant coefficients for the interaction term (follow-up time x group) (b's = -0.001; q ≥ 0.681). Poor functioning patients presented statistically significant coefficients for the interaction term (follow-up time x functionality) (left: b = -0.005, q = 0.019; right: b = -0.005, q = 0.022). In contrast, no correlations were found between cortical thickness measurements and clinical variables at 10 years. Overall, there were widespread thickness anomalies in first-episode psychosis patients across cortical regions that remained stable across time. Progressive thickness changes were related to patient functional outcomes, with progressive and steeper cortical thinning in patients with worse functional outcomes and a stabilization in those with better outcomes.


Determination of imidacloprid and its metabolite 6-chloronicotinic acid in greenhouse air by application of micellar electrokinetic capillary chromatography with solid-phase extraction.
A method is described for the analysis of the insecticide imidacloprid [1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine] and its metabolite 6-chloronicotinic acid by micellar electrokinetic chromatography with diode-array detection at 270 and 227 nm, respectively. The best results were obtained using sodium dodecyl sulphate at a concentration of 60 mM and a running buffer of NH4Cl/NH3 at 15 mM (pH 8.5). The selection of instrumental parameters such as voltage at 30 kV with an injection time of 20 s gave the best resolution with an analysis time of less than 6 min. The method yields similar sensitivity for the parent compound and for the metabolite, with detection limits of 0.71 and 1.18 microg/ml for imidacloprid and 6-chloronicotinic acid, respectively. The sampling and analysis of these two pesticides in greenhouse air was carried out using personal samplers connected to XAD-2 cartridges as sampling media, investigating the dissipation of analytes in a 24-h period after their application.


Multidisciplinary study to monitor consequences of pollution on intertidal benthic ecosystems (Hauts de France, English Channel, France): Comparison with natural areas.
The intertidal areas of the Hauts-de-France (English Channel - France) stand out for the occurrence of fragile ecosystems that are exposed to natural and human-induced stress. Over the last two centuries, the northern part of this region has experienced a strong human pressure, with the settlement of numerous activities (i.e., metallurgic factories, harbors, embankments). On the contrary, the southern part includes mostly natural areas. The whole region is influenced by a macrotidal regime. A multidisciplinary approach based on sedimentological (grain-size), geochemical (trace metals, biomarkers) and biological (foraminifera) proxies was used to unravel the contrasting environmental conditions in the Hauts-de-France. Three foraminiferal-types communities, which reflect different ecological characteristics at regional scale, were identified: 1) estuarine macrotidal assemblages (Haynesina germanica associated to Elphidiidae) in low impacted estuaries; 2) industrial-perturbed assemblages (H. germanica and Cribroelphidium excavatum) in harbor areas; and 3) infaunal-dominant assemblages (Bolivina variabilis and B. pseudoplicata) in embankment areas. The outcomes of this study show that a multiproxy procedure needs to be adopted for properly characterizing intertidal ecosystems, where human impacts and natural stresses overlap and are hard to disentangle.


Neural Correlates of Disturbed Emotion Processing in Borderline Personality Disorder: A Multimodal Meta-Analysis.
Disturbances in the processing and regulation of emotions are core symptoms of borderline personality disorder (BPD). To further elucidate neural underpinnings of BPD, the present meta-analysis summarizes functional neuroimaging findings of emotion processing tasks, as well as structural neuroimaging findings, and investigates multimodally affected brain regions. Combined coordinate- and image-based meta-analyses were calculated using anisotropic effect size signed differential mapping. Nineteen functional neuroimaging studies investigating the processing of negative compared with neutral stimuli in a total of 281 patients with BPD and 293 healthy control subjects (HC) were included. In addition, 10 studies investigating gray matter abnormalities in 263 patients with BPD and 278 HC were analyzed. Compared with HC, BPD patients showed relatively increased activation of the left amygdala and posterior cingulate cortex, along with blunted responses of the bilateral dorsolateral prefrontal cortex, during the processing of negative emotional stimuli. The multimodal analysis identified the left amygdala to be characterized by a combination of functional hyperactivity and smaller gray matter volume compared with HC. Hyperresponsivity of the amygdala was moderated by medication status of the patient samples. Medication-free samples were characterized by limbic hyperactivity, whereas no such group differences were found in patients currently taking psychotropic medication. Results strengthen the assumption that dysfunctional dorsolateral prefrontal and limbic brain regions are a hallmark feature of BPD and therefore are consistent with the conceptualization of BPD as an emotion dysregulation disorder.


Mitogen-activated protein kinase signaling.
The mechanism by which cells respond to extracellular stimuli involves a series of signal transduction events across the cell membrane and through the cytoplasm to the nucleus. Mitogen-activated protein (MAP) kinases are important mediators of signal transduction and play a key role in the regulation of many cellular processes, such as cell growth and proliferation, differentiation, and apoptosis. In mammalian cells, three major groups of MAP kinases have been identified: extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAP kinase. It is well documented that ERK is typically stimulated by growth-related signals, whereas the JNK and p38 MAP kinase cascades are activated by various stress stimuli. Studies have indicated that MAP kinases are expressed abundantly in the central nervous system (CNS) and that ERK is involved in long-lasting neuronal plasticity, including long-term potentiation and memory consolidation. While the role of ERK in neuronal plasticity and behavioral adaptation is beginning to emerge, the role of MAP kinase signal transduction cascades in major psychiatric disorders, including schizophrenia, is not well understood. This review outlines the intermediates of this signaling cascade and downstream transcription factor targets and recent evidence implicating MAP kinases to important biological functions in the CNS. Evidence from human post-mortem studies, as well as from the phencyclidine model of schizophrenia, that different MAP kinase cascades may be involved in the pathogenesis of schizophrenia, and potentially in other psychiatric disorders, is presented. Knowledge of MAP kinase signaling will aid greatly in our ability t o understand causal changes in disease process and may lead to new therapeutic approaches in controlling or treating schizophrenia.


Good response to pulmonary arterial hypertension-targeted therapy in 2 pulmonary veno-occlusive disease patients: A case report.
Pulmonary veno-occlusive disease (PVOD) is a kind of rare and fatal pulmonary arterial hypertension (PAH). Different from other subtypes of PAH, PVOD patients have a very poor prognosis because of the progressive nature of pulmonary vascular involvement and fatal pulmonary edema induced by PAH-targeted drugs. Lung transplantation is the only choice for these patients. We reported 2 cases of PVOD which was misdiagnosed as idiopathic pulmonary arterial hypertension initially due to the lack of typical findings of PVOD. Right heart catheterization was done. The results showed severe PAH with mean pulmonary artery pressure at 76 mmHg and 68 mmHg. The diagnosis of idiopathic pulmonary arterial hypertension was corrected by eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) mutation screening. Biallelic mutations (c.1387delT (p. Arg463fs); c.989-990 delAA (p. Lys330fs)) were detected by next-generation sequencing for whole exome from blood sample. The presence of biallelic EIF2AK4 mutation was sufficient to confirm the diagnosis of PVOD. The 2 patients had good response to PAH-targeted therapy (Ambrisentan 10 mg once a day and tadalafil 20 mg once a day) in the following 1 year. Because the patients had a good response to targeted drugs, the treatment of the 2 cases was unchanged. Over 1-year period, they still have a good response to PAH-targeted drugs. There was no sign of pulmonary edema. All these results may indicate that PVOD is not so rare and typical findings of PVOD are lacking in some patients. EIF2AK4 mutation screening by next-generation sequencing maybe useful to differentiate PVOD from other PAH subtypes. PVOD is a heterogeneity population and different patients have different characteristics including response to PAH-targeted therapy. How to pick off this portion of patients timely is the core issue. Further study is necessary to answer this question.


Hypodiploidy and serum immunoglobulin concentrations in the elderly.
Chromosome analyses and Ig level determinations were carried out on seventeen aged men and women, 83--100 years of age. In men, significant correlations were found between hypodiploidy and IgA (gamma = 0.95) and between monosomy C and IgG (gamma = 0.79) while in women, monosomy G and IgG were significantly correlated (gamma = 0.73). The emergence of significant correlations between chromosome loss and Ig levels in this study provides support for a relationship between age-associated chromosomal changes in T cells and the immunologic response of B cells.


A major gene model of adult height is suggested in Chinese.
Adult height (stature), as a complex quantitative trait, has been studied in different populations. However, few genetic studies on height were performed on the Chinese, the largest population in the world. In this study, familial correlation and segregation analyses were carried out for adult height in a Chinese sample composed of 385 nuclear families with a total of 1,169 informative individuals. The results suggest that a major gene with a recessive effect accounts for about 17.2% of the total adult height variation in the Chinese. Significant familial residual effects are found. The heritability (+/-SE) of height is estimated to be 0.647 (+/-0.122). This study, for the first time, provides evidence for the high degree of genetic determination of adult height in the Chinese population and furnishes a valuable reference for further mapping and identification of adult height genes in the Chinese.


The prediction of pregnancy failure by measurement of pregnancy-associated plasma protein A (PAPP-A) following in vitro fertilization and embryo transfer.
Circulating PAPP-A was measured serially in five patients following successful IVF-ET. PAPP-A concentrations were consistently normal in all three patients in whom pregnancies progressed normally to term. Depressed levels of PAPP-A were observed in one patient who miscarried spontaneously at 17 weeks' gestation despite ultrasound evidence of normal fetal development. Circulating PAPP-A was not detected in the fifth patient, whose tubal pregnancy ruptured at 8 weeks. These data are discussed in relation to surveillance of pregnancies following IVF-ET.


Magnitude of residual internal anatomy motion on heavy charged particle dose distribution in respiratory gated lung therapy.
To assess the variation in carbon beam dose distribution due to residual motion in lung cancer patients undergoing respiratory-gated radiotherapy. A total of 11 lung cancer patients underwent four-dimensional computed tomography with a 256-multislice computed tomography scanner under free-breathing conditions. A compensating bolus was designed to cover the treatment beam for all planning target volumes during a 30% duty cycle centered on exhalation (gating window). This bolus was applied to the four-dimensional computed tomography data for one respiratory cycle, and then the carbon beam dose distribution was calculated. A water equivalent pathlength variation of <5 mm was observed in the gating window, but this increased to </=20 mm on inhalation. As a result, beam overshoot/undershoot occurred around inhalation, which increased the excessive dosing to normal tissues and the organs at risk. The dose for >95% volume irradiation is dependent on the respiratory phase but not the gating window. However, the dose for >95% volume irradiation correlated well with the tumor displacement distance. More than 90% of the dose for >95% volume irradiation could be delivered in the gating window with <4-mm tumor displacement resulting from exhalation. The results of our study have shown that even when the treatment beam delivery occurs outside the gating window, the prescribed dose to the target is not affected in patients with a tumor displacement of <4 mm. Thus, respiratory gating is not required in radiotherapy for patients with <4-mm tumor displacement in a respiratory cycle.


Effects of biodegradable hydrogel spacer injection on contralateral submandibular gland sparing in radiotherapy for head and neck cancers.
Xerostomia is the most common late toxicity after head and neck radiation. We demonstrate injection of a hydrogel spacer anteriorly displacing the submandibular gland. This procedure enables reduced dose to the displaced submandibular gland in cadaveric models of oropharynx cancer treated with IMRT, with potential implications in reducing xerostomia risk.


Reduced alpha-Gal A enzyme activity in Fabry fibroblast cells and Fabry mice tissues induced by serum from antibody positive patients with Fabry disease.
Fabry disease is a progressive, life-threatening lysosomal storage disorder which is characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. Studies have demonstrated that both enzyme preparations currently available for treatment of Fabry disease (i.e., agalsidase beta and agalsidase alpha) elicit immune responses in the majority of patients which negatively influences the reduction of urinary globotriaosylceramide concentration. In the current study, agalsidase beta antibodies were found to be associated with inhibition of alpha-Gal A enzyme activity in cultured Fabry fibroblast and tissues from Fabry mice. However, the negative effect of antibody formation could be overcome by increasing the dose of enzyme administered to mice. In conclusion, antibody titers and the dose of enzyme influenced alpha-Gal A enzyme activities in vivo. Further studies are required to investigate to what extend antibody formation impacts on therapeutic responses in antibody positive Fabry patients receiving enzyme replacement therapy and if negative effects can be overcome by adjusting the dose of enzyme.


Based on network pharmacology method to discovered the targets and therapeutic mechanism of Paederia scandens against nonalcoholic fatty liver disease in chicken.
The aim of the study is to determine the target of Paeteria scandens in nonalcoholic fatty liver disease (NAFLD). The Chinese herbal medicine pharmacology data and analysis platform were used to search and screen for the effective components of the Paeteria scandens compounds and to analyze the possible therapeutic targets based on network topology. In addition, various known disease target databases were enrolled, the therapeutic target proteins in NAFLD were screened, and a protein-protein interaction network was constructed. Enrichment analysis was performed on key nodes. Finally, the inhibitory effect of Paeteria scandens on NAFLD was verified by experiments. We identified 33 major candidate targets of Paeteria scandens and successfully constructed a "drug-compound-target-disease" network. Abovementioned targets revealed by gene enrichment analysis have played a significant role in the cell cycle, apoptosis, and related signal pathways. We demonstrated that Paeteria scandens downregulated serum triglyceride and lipopolysaccharides levels in NAFLD chickens by feeding with a high-capacity diet and endotoxin of Salmonella enteritidis was given by gavage. Paeteria scandens may regulate the hepatic cell cycle and apoptosis through the Salmonella infection pathway, Toll-like receptor signaling pathway, and apoptosis pathway. For NAFLD, Paeteria scandens may be a promising, long-lasting treatment strategy.


The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease.
Humans have relatively low plasma ascorbate levels and high serum uric acid levels compared to most mammals due to the presence of genetic mutations in l-gulonolactone oxidase and uricase, respectively. We review the major hypotheses for why these mutations may have occurred. In particular, we suggest that both mutations may have provided a survival advantage to early primates by helping maintain blood pressure during periods of dietary change and environmental stress. We further propose that these mutations have the inadvertent disadvantage of increasing our risk for hypertension and cardiovascular disease in today's society characterized by Western diet and increasing physical inactivity. Finally, we suggest that a "planetary biology" approach in which genetic changes are analyzed in relation to their biological action and historical context may provide the ideal approach towards understanding the biology of the past, present and future.


Evaluation of engraftment of ex vivo expanded cord blood cells in humans.
Cord blood transplants (CBT) result in high rates of engraftment in patients transplanted because of inherited diseases even across marked HLA disparities, mostly in children, with less severe manifestations of GVHD than BM and PBSC transplants. Evaluation of engraftment potential of CBT based on early progenitor content is difficult due to their inaccurate quantification. Instead, post-thaw nucleated cell counts (Pt-NCC) are commonly used for this purpose. We have analyzed engraftment as a function of pre-freeze nucleated cell counts (Pf-NCC) in patients receiving CBT because of inherited diseases. We have observed median times to engraftment of 26 days or less, shortest times ranging 8 to 13 days, late engraftment or graft failures tending to be associated with age >15 years and infusions of <3.7 x 10(7)/Pf-NCC/kg. These data may be appropriate references to evaluate engraftment of CBT performed with previously ex vivo expanded cells. CBT performed with units of which one aliquot has been previously culture-expanded have resulted in times to engraftment similar to the ones observed in the above-mentioned analysis. In these trials it is not possible to trace the actual origin of the early engrafting cells because the pre-cultured cells lack differentiating markers. To better evaluate the engraftment dynamics of culture-expanded CB cells in humans, we have used a model of simultaneously transplanting cells from two different donors to the same patient. Preliminary results of patients that have simultaneously received one uncultured CB unit and culture-expanded purified CB CD34+ cells obtained from a second one show no significant contribution of cultured cells to early engraftment, and no prohibitive unfavorable immunological problems have been observed.


Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis?
It has recently been suggested that prolonged protein restriction preceding dialysis may induce protein malnutrition and thus confer a poor prognosis during dialysis. We examined the records of all patients who were prescribed a very low protein diet (0.3 g/kg ideal body weight) plus supplemental essential amino acids and/or ketoacids for 6 to 72 months (median 26 months) preceding renal replacement, numbering 43. Hypoalbuminemia immediately preceding dialysis was present in only two patients. Final serum albumin averaged 4.1 +/- 0.4 (SD) g/dl. Final transferrin was subnormal in eight patients, but had been subnormal in six of these, without attendant hypoalbuminemia, for one to four years. Mean final transferrin was 241 +/- 56 mg/dl. Final serum cholesterol was below 150 mg/dl in six subjects, all of whom had normal levels of albumin (mean 4.0 +/- 0.2 g/dl) and a normal mean value for transferrin (211 +/- 22 mg/dl). In five patients who exhibited subnormal albumin and transferrin and high cholesterol concentrations at the beginning of dietary therapy, albumin and transferrin levels rose to normal or nearly normal, and hypercholesterolemia receded during the ensuing four months. Thus this predialysis dietary regimen, rather than causing protein malnutrition, prevents it; when protein malnutrition is present, this regimen corrects it.


Hypoglycemic and antioxidant effect of Juniperus procera extract on rats with streptozotocin-induced diabetes.
Juniperus procera, a coniferous tree in the cypress family, is one of the famous medicinal plants traditionally used in the southern area of the Arabian peninsula. This study examined the anti-hyperglycemic action of Juniperus procera extract (JPE) on diabetic rats. Sixty male rats were divided into 6 equal groups: control, control treated with JPE (200 mg/kg), diabetic, diabetic treated with insulin (1 U/kg), diabetic treated with JPE (200 mg/kg), and diabetic treated with both insulin and JPE. Blood and tissue samples were collected for serum chemistry, gene expression, and immunohistochemistry analyses, the results of which revealed hyperglycemia and inflammation following diabetes induction. Administration of JPE alone or with insulin reduced the hyperglycemia reported in diabetic rats by 25 %. The immunohistochemical examination of pancreatic tissues demonstrated a moderate restoration of insulin and NF-κB expression in pancreatic and hepatic tissues. Significant recovery was observed for glutathione-S-transferase (GST), superoxide dismutase (SOD), and glutathione peroxidase (GPx) mRNA expression in the livers of rats treated with JPE. Administration of JPE led to similar amelioration of the mRNA expression of pyruvate kinase (PK) and phosphoenol pyruvate carboxy kinase (PEPCK) in the livers of diabetic rats. In addition, diabetic rats treated with insulin, JPE, or a combination of these agents demonstrated an improvement in the mRNA expression of IRS-1 and IRS-2 in hepatic and pancreatic tissues, reaching levels approaching normal. Our findings led us to conclude that JPE has a powerful anti-inflammatory effect accompanied by a moderate hypoglycemic effect that occurs via different mechanisms.


Anti-Ulcerogenic and Cytoprotective Effects of Saharian (Sidr) Honey from Algeria.
This study aimed at investigating the gastro-protective effects of Algerian Sahara (Sidr) honey from Apis mellifera intermissa against HCl/Ethanol-induced gastric ulcers in rats. Total phenolic content, antioxidant activity and phenolic compounds were determined. Then, three groups of rats (control, HCl/ Ethanol-induced ulcer, and orally administered honey) were used for the determination of gastro-protective effect of Sidr honey. Total phenolic content, total flavonoid content, and DPPH activity of the honey sample were determined as 47.35±3.35 mg GAE/ 100 g, 2.13±0.17 mg QE/ 100 g, and 229.24±0.02 mg/mL, respectively. Oral pretreatment of rats with honey (1.2 g/Kg body weight orally at an interval of 2 days) protected gastric mucosa against HCl/Ethanol-induced damage by decreasing ulcer score, the volume and acidity of gastric juice and increasing pH. These results were confirmed by the histological assessment, which demonstrated a significant gastro-protective activity of Saharian (Sidr) honey against HCl/Ethanol-induced stomach ulcer. Plasma tumor necrosis factor-α, IL-6 and PGE2 were also measured. Sahara honey significantly decreased the plasma TNF-α, PGE2, and IL-6 concentrations.


The common cold.
The common cold continues to be the major cause of absences from school and work. A better understanding of the epidemiology and the natural history should lead to less anxiety about this disease. Although there is still much misinformation among the public, the time should soon come when better-informed patients with this disease will make fewer visits to the physician and will not expect unnecessary and worthless treatment.


Can a reflective rubric be applied consistently with raters globally? A study across three countries.
Reflection is a powerful tool for assisting students to develop the skills to make better informed decisions. As a pharmacy competency standard, reliable and fair assessment strategies are required to measure reflective skills and support students in developing their reflective capacity. The aim of this research was to explore whether we can extend the applicability of a previously tested rubric to a range of educational settings, to account for diversity of pharmacy educators and curricula internationally. Four raters from three countries applied a reflective rubric to assess a sample (n = 43) of reflective accounts, representing 41% of a cohort of 105 second-year undergraduate pharmacy students. The interrater reliability (IRR) was measured utilizing the intra-class correlation coefficient (ICC), using a two-way random effects model with absolute agreement, to determine the level of agreement between the raters' absolute scores. Generalizability Theory analysis was used to estimate generalizability of raters and stages. Results indicated agreement of raters for (i) each of the seven stages of reflection and (ii) overall score for the reflective account, with moderate to substantial agreement (ICC = 0.55-0.69, p < 0.001); and high agreement for all raters for the overall score (ICC = 0.96, p < 0.001), respectively. The G-Study estimated a relative error coefficient of 0.78. This additional analysis further confirms the reliability and applicability of the rubric to a range of rater academic backgrounds.


Health benefits of seafood; is it just the fatty acids?
There is a considerable body of literature suggesting a wide range of health benefits associated with diets high in seafood. However, the demand for seafood across the world now exceeds that available from capture fisheries. This has created a rapidly increasing market for aquaculture products, the nutrient composition of which is dependent on feed composition. The use of fishmeal in this food chain does little to counteract the environmental impact of fisheries and so the on-going development of alternative sources is to be welcomed. Nevertheless, an in-depth understanding as to which nutrients in seafood provide benefit is required to permit the production of foods of maximal health benefit to humans. This paper reviews our current knowledge of the beneficial nutrient composition of seafood, in particular omega-3 fatty acids, selenium, taurine, vitamins D and B12, in the context of the development of environmentally sustainable aquaculture.


Metabolic profiling reveals therapeutic effects of Herba Cistanches in an animal model of hydrocortisone-induced 'kidney-deficiency syndrome'.
Herba Cistanches (Roucongrong) is effective in treating Shenxu Zheng ('kidney-deficiency syndrome'). However, the mechanisms and systemic metabolic responses to the herbal intervention are unclear. Using GC-MS-based metabolic profiling, we investigated the metabolic responses to Herba Cistanches intervention in a rat model of the hydrocortisone-induced 'kidney-deficiency syndrome'. The metabolic profiles of the rats after hydrocortisone injection deviated from the pre-dose metabolic state at different time points, ranging from day 1 to day 10, whereas the metabolic profiles of the rats treated with both hydrocortisone and water extract of Herba Cistanches returned to the pre-dose state on day 10. The intervention of Herba Cistanches caused a systemic recovery from the hydrocortisone-induced metabolic perturbation in rats. This study also demonstrates that metabolic profiling is useful in studying therapeutic mechanisms of herbal medicines.


Intestinal plasticity and metabolism as regulators of organismal energy homeostasis.
The small intestine displays marked anatomical and functional plasticity that includes adaptive alterations in adult gut morphology, enteroendocrine cell profile and their hormone secretion, as well as nutrient utilization and storage. In this Perspective, we examine how shifts in dietary and environmental conditions bring about changes in gut size, and describe how the intestine adapts to changes in internal state, bowel resection and gastric bypass surgery. We highlight the critical importance of these intestinal remodelling processes in maintaining energy balance of the organism, and in protecting the metabolism of other organs. The intestinal resizing is supported by changes in the microbiota composition, and by activation of carbohydrate and fatty acid metabolism, which govern the intestinal stem cell proliferation, intestinal cell fate, as well as survivability of differentiated epithelial cells. The discovery that intestinal remodelling is part of the normal physiological adaptation to various triggers, and the potential for harnessing the reversible gut plasticity, in our view, holds extraordinary promise for developing therapeutic approaches against metabolic and inflammatory diseases.


A stable, selective electrode for recording single motor-unit potentials in humans.
A new application of electrode technology has enabled recording of single motor-unit potentials in human first dorsal interosseus muscle with more versatility than has been traditionally associated with this paradigm. The design, manufacture, and application are detailed for an electrode which has been used to discriminate potentials during efforts up to maximal voluntary contraction. The electrode comprises a branched, bipolar configuration which is positioned subcutaneously over the belly of the muscle. This extramuscular location maximizes stability and, with appropriate orientation of the electrode relative to the architecture of the muscle, ensures adequate selectivity of single motor-unit potentials.


Predicting the rising incidence and mortality of endometrial cancers among women aged 65-74 years in Catalonia.
Endometrial cancer is currently one of the most common gynecological cancers. Reported incidence rates vary in Spain depending on the region. We estimated what the incidence and mortality of endometrial cancers in Catalonia will be by 2030 and compared the predictions with data from 2010. Bayesian autoregressive age-period-cohort models were employed to predict incidence and mortality rates for 2015-2030. The incidence of endometrial cancer for women younger than 65 years was predicted to be lower in 2030 than in 2010, whereas it was predicted to be higher for women aged 65-74 years. Moreover, mortality rates for women aged ≥65 in 2030 are likely to exceed the rates in 2010. Five-year relative survival for all ages was slightly higher in the period 2005-2009 (79.3 %, 95 %CI: 75.8 %-82.9 %) compared with those in 1995-1999 (76.0 %, 95 %CI: 72.1 %-80.2 %). This plausible new scenario might be useful to plan new clinical and preventive strategies in the near future.


Attitudinal versus ecological approaches to the characterization of institutional treatment environments.
The relational and discriminative properties of attitudinal and ecological measures of environments were examined within the context of a state hospital for mentally retarted clients. Three hypotheses were advanced, and the results gave substantial support for one of these and partial support for a second: (a) that the correlations between attitudinal and ecological measures should not differ significantly from zero, and (b) that differences among hospital treatment programs and living units should be reflected in ecological but not in attitudinal measures. However, the results did not provide clear confirmation for a third hypothesis: that differences among staff demographic characteristics and employment history should be reflected in attitudinal but not in ecological measures. It was suggested that these background variables may not be appropriate measures of personality-linked attributes.


Validation of a frailty index in older cancer patients with solid tumours.
Frailty is an indicator of physiological reserve in older people. In non-cancer settings, frailty indices are reliable predictors of adverse health outcomes. The aims of this study were to 1) derive and validate a frailty index (FI) from comprehensive geriatric assessment (CGA) data obtained in the solid tumour chemotherapy setting, and 2) to explore whether the FI-CGA could predict chemotherapy decisions and survival in older cancer patients with solid tumours. Prospective cohort study of a consecutive series sample of 175 cancer patients aged 65 and older with solid tumours. A frailty index was calculated using an accumulated deficits model, coding items from the comprehensive geriatric assessment tool administered prior to chemotherapy decision-making. The domains of physical and cognitive functioning, nutrition, mood, basic and instrumental activities of daily living, and comorbidities were incorporated as deficits into the model. The FI-CGA had a right-skewed distribution, with median (interquartile range) of 0.27 (0.21-0.39). The 99% limit to deficit accumulation was below the theoretical maximum of 1.0, at 0.75. The FI-CGA was significantly related (p < 0.001) to vulnerability as assessed by the Vulnerable Elders Survey-13 and to medical oncologists' assessments of fitness or vulnerability to treatment. Baseline frailty as determined by the FI-CGA was also associated with treatment decisions (Treatment Terminated, Treatment Completed, No Planned Treatment) (p < 0.001), with the No Planned Treatment group significantly frailer than the other two groups. The FI-CGA is a potentially useful adjunct to cancer clinical decision-making that could predict chemotherapy outcomes in older patients with solid tumours.


Predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae causing infection among intensive care unit patients with prior colonization.
We investigated the predictive factors for extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) causing infections among intensive care unit patients with prior documented ESBL-PE colonization. Using multivariate analysis, referral from medical ward, nursing home or rehabilitation center [Odds ratio (OR), 2.5; 95 % confidence interval (CI), [1.3-5.0]; p = 0.007], previous fluoroquinolone treatment (OR, 3.4; CI, [1.1-10.5]; p = 0.003), extracorporeal membrane oxygenation (OR, 4.6; CI, [1.3-15.9]; p = 0.02), and absence of prior positive ESBL-PE rectal swab culture (OR, 5.0; CI, [1.6-10.0]; p = 0.0009) were risk factors for ESBL-PE infection. Easily identifiable factors may help with targeting carbapenem prescriptions.


Changes in the lateral diffusion of fluorescent lipid analogues in the surface membrane of adult male Schistosoma mansoni.
The effect of serotonin on the fluidity of the tegumental membranes of adult male Schistosoma mansoni was assessed by the fluorescence recovery after photobleaching technique. It was demonstrated that the translational diffusion of 5-N'-octadecanoyl aminofluorescein is reduced by a mechanism involving G-protein coupled activation of adenylate cyclase and lowering of intracellular calcium concentration. Furthermore, the lateral diffusion coefficient and the mobile fraction appear to be controlled by calcium and cAMP dependent pathways respectively. No change in the diffusion of the fluorescent phospholipid N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-phosphatidyl choline was observed, suggesting the two probes used here partition into two different domains that are under independent control. An increase in the amount of protein associating with a membrane cytoskeleton is also demonstrated.


68Ga-DOTANOC PET/CT Detects a Rare Case of Metastatic Neuroendocrine Neoplasm of the Gallbladder.
Gallbladder neuroendocrine neoplasms (NENs) are rare tumors of the biliary system. These neoplasms express somatostatin receptors, and hence radiolabeled somatostatin analog 68Ga-DOTANOC is used as a PET radiotracer in detection and staging. Gallbladder NEN cannot be differentiated from an adenocarcinoma of the gallbladder based on clinical symptoms or routine radiological imaging such as ultrasound or CT. These are either diagnosed postcholecystectomy or after biopsy from primary or metastatic sites. We present a rare case of gallbladder NEN detected on 68Ga-DOTANOC PET/CT.


Bone-implant-contact and new bone formation around implants placed in FDB blocks compared to placement at the adjunction of particulate FDB.
The efficacy of human freeze-dried bone (h-FDB) as particulate vs block forms as a proper onlay augmented bone graft material to accommodate implants is undetermined. To evaluate osseointegration and new bone formation at implants placed in FDB blocks (BL group) and those at the adjunction of particulate FDB (PR group). Twelve pairs of h-FDB blocks were stabilized bilaterally to the calvaria of 12 rabbits. Twenty-four SLA implants were placed at the remodeled grafted blocks, 4 months later. A circumferential gap was created around one implant in each pair and packed with particulate h-FDB. Section biopsies were obtained at 2-month post implant placement (6 months post-block grafting). Bone-to-implant contact (BIC) and bone-area fraction (BAF) were histomorphometrically calculated. The mean BIC was 34.4% and 33.5% for the BL and PR groups, respectively. The mean BAF was 23.9% and 26.4% for the corresponding groups, respectively. Osseointegration and newly formed bone were evident mostly between the threaded portions of the implants in proximity to the host rabbit calvaria compared to its cervical neck. The particulate and the cancellous block h-FDB forms yielded similar BIC and BAF outcome. Full revascularization/revitalization is questioned.


Gestational and early life influences on infant body composition at 1 year.
Excess weight gain during both pre- and postnatal life increases risk for obesity in later life. Although a number of gestational and early life contributors to this effect have been identified, there is a dearth of research to examine whether gestational factors and weight gain velocity in infancy exert independent effects on subsequent body composition and fat distribution. To test the hypothesis that birth weight, as a proxy of prenatal weight gain, and rate of weight gain before 6 months would be associated with total and truncal adiposity at 12 months of age. Healthy, term infants (N = 47) were enrolled in the study and rate of weight gain (g/day) was assessed at 0-3 months, 3-6 months, and 6-12 months. Total and regional body composition were measured by dual-energy X-ray absorptiometry (DXA) at 12 months. Stepwise linear regression modeling indicated that lean mass at 12 months, after adjusting for child length, was predicted by rate of weight gain during each discrete period of infancy (P < 0.05), and by maternal pre-pregnancy BMI (P < 0.05). Total fat mass at 12 months was predicted by rate of weight gain during each discrete period (P < 0.01), and by older maternal age at delivery (P < 0.05). Trunk fat mass at 12 months, after adjusting for leg fat mass, was predicted by rate of weight gain from 0-3 months and 3-6 months (P < 0.05). Results suggest that growth during early infancy may be a critical predictor of subsequent body composition and truncal fat distribution.


Searching glycolate oxidase inhibitors based on QSAR, molecular docking, and molecular dynamic simulation approaches.
Primary hyperoxaluria type 1 (PHT1) treatment is mainly focused on inhibiting the enzyme glycolate oxidase, which plays a pivotal role in the production of glyoxylate, which undergoes oxidation to produce oxalate. When the renal secretion capacity exceeds, calcium oxalate forms stones that accumulate in the kidneys. In this respect, detailed QSAR analysis, molecular docking, and dynamics simulations of a series of inhibitors containing glycolic, glyoxylic, and salicylic acid groups have been performed employing different regression machine learning techniques. Three robust models with less than 9 descriptors-based on a tenfold cross (Q2 CV) and external (Q2 EXT) validation-were found i.e., MLR1 (Q2 CV = 0.893, Q2 EXT = 0.897), RF1 (Q2 CV = 0.889, Q2 EXT = 0.907), and IBK1 (Q2 CV = 0.891, Q2 EXT = 0.907). An ensemble model was built by averaging the predicted pIC50 of the three models, obtaining a Q2 EXT = 0.933. Physicochemical properties such as charge, electronegativity, hardness, softness, van der Waals volume, and polarizability were considered as attributes to build the models. To get more insight into the potential biological activity of the compouds studied herein, docking and dynamic analysis were carried out, finding the hydrophobic and polar residues show important interactions with the ligands. A screening of the DrugBank database V.5.1.7 was performed, leading to the proposal of seven commercial drugs within the applicability domain of the models, that can be suggested as possible PHT1 treatment.


Pulmonary tumor colony formation following i.v. inoculation of six human colorectal carcinoma xenografts in young gnotobiotic athymic mice.
The lung colonizing potential of 6 xenografted human colorectal adenocarcinomas following tail vein inoculation of tumor cell suspensions into gnotobiotic 3-4-week-old congenitally athymic mice was investigated. One of the lines, CRCo2, was of particular interest, as apparently distinctive lung colonizing phenotypes, large (greater than 2.5 mm diameter) and small (less than 1 mm diameter) colonies were identified, and variant lines with greater, equal, or lesser ability to grow in the lungs relative to the sc tumor of origin were observed. Another line, CRCo1, was also able to grow well in the lungs following tail vein inoculation, but subsequent cycles of lung tumor recovery and reinoculation i.v. did not result in an enhancement of the tumor's lung colonizing ability relative to the initial i.v. inoculation of the sc carried tumor. Scattered lung colonies were observed following i.v. inoculation of sc carried xenografts in three of the four other lines, but we could not consistently recover lung colonies with these tumors. The data are in accord with the clinical observation that pulmonary metastasis is not a high frequency event in human colorectal carcinoma, illustrating the selective nature and experimental utility of this model of metastasis. Further, there were indications of the inefficient and/or random nature of the metastatic process in some of the tumors, while in others, evidence for both effectively higher and lower metastatic variants were found, as might be predicted in heterogeneous tumor cell populations.


Interaction between the C5a receptor and Gi in both the membrane-bound and detergent-solubilized states.
C5a elicits a variety of responses from the polymorphonuclear leukocyte all of which utilize G proteins as transducing elements. In the present study, we report the consequences of the interaction between the C5a receptor and the G proteins and describe a system which may allow identification of the transducing proteins. C5a binding to polymorphonuclear leukocyte membranes is inhibited by pertussis, but not cholera, toxin and by a variety of guanine nucleotides. In the absence of nucleotide, we observed a single class of sites with a Kd of 17 pM. The presence of guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) did not alter this affinity but did result in a concentration-dependent decrease in the number of binding sites. Surprisingly, we did not observe the concomitant appearance of a low affinity state implying that, if such a state exists, its affinity is below our limit of detection (5 nM). The receptor and G protein retained their functional interaction following solubilization of the membrane in digitonin. In the absence of nucleotide, we observed a single class of sites with a Kd of 28 pM. Addition of GTP gamma S suppressed binding, and, as was found in membranes, this inhibition is due almost entirely to a decrease in the number of sites. Again we failed to detect the appearance of a lower affinity state. Gel filtration studies of the detergent-solubilized receptor and receptor-C5a complexes indicate that the receptor is precoupled to G protein in the absence of ligand (C5a).


Predictive equations for estimating resting energy expenditure in women with overweight and obesity at three postpartum stages.
The objective was to investigate which predictive equations provide the best estimates of resting energy expenditure (REE) in postpartum women with overweight and obesity. Lactating women with overweight or obesity underwent REE measurement by indirect calorimetry, and fat-free mass (FFM) was assessed by dual-energy X-ray absorptiometry at three postpartum stages. Predictive equations based on body weight and FFM were obtained from the literature. Performance of the predictive equations were analysed as the percentage of women whose REE was accurately predicted, defined as a predicted REE within ±10 % of measured REE. REE data were available for women at 10 weeks (n 71), 24 weeks (n 64) and 15 months (n 57) postpartum. Thirty-six predictive equations (twenty-five weight-based and eleven FFM-based) were validated. REE was accurately predicted in ≥80 % of women at all postpartum visits by six predictive equations (two weight-based and four FFM-based). The weight-based equation with the highest performance was that of Henry (weight, height, age 30-60 years) (HenryWH30-60), with an overall mean of 83 % accurate predictions. The HenryWH30-60 equation was highly suitable for predicting REE at all postpartum visits (irrespective of the women's actual age), and the performance was sustained across changes in weight and lactation status. No FFM-based equation was remarkably superior to HenryWH30-60 for the total postpartum period.


Specification of hemocyte subpopulations based on immune-related activities and the production of the agglutinin MkC1qDC in the bivalve Modiolus kurilensis.
Bivalves, such as Modiolus are used as indicator organisms to monitor the state of the marine environment. Even though hemocytes are known to play a key role in the adaptive and protective mechanisms of bivalves, these cells are poorly studied in horse-mussel Modiolus kurilensis. In this paper, we present classification of horse-mussel hemocytes based on their immune functions, including the production of specific immune-related molecules, as well as their morphological composition after isolation by density gradient centrifugation. An effective fractionation protocol was adapted to separate four hemocyte subpopulations with distinct morphofunctional profiles. First subpopulation consisted of small under-differentiated hemoblasts (2.20 ± 0.85%) with a bromodeoxyuridine positive nucleus, and did not show any immune reactivity. Second was represented by agranulocytes (24.11 ± 2.40%), with evenly filled cytoplasm containing a well-developed protein-synthesizing apparatus, polysomes, smooth endoplasmic reticulum and mitochondria, and positively stained for myeloperoxidase, acidic proteins, glycogen and neutral polysaccharides. Third subpopulation consisted of eosinophilic granulocytes (62.64 ± 9.32%) that contained the largest number of lysosomes, peroxisomes and vesicles with contents of different density, and showed the highest phosphatase, reactive oxygen species (ROS) and phagocytic activities. Lastly, fourth group, basophilic granulocytes (14.21 ± 0.34%), are main producers of lectin-like protein MkC1qDC, recently discovered in M. kurilensis and characterized by pronounced antibacterial and anticancer activity. These cells characterized by intracytoplasmic of the MkC1qDC localization, forming granule-like bodies visualized with specific antibody. Both granulocytes and agranulocytes showed phagocytic activity and ROS production, and these reactions were more pronounced for eosinophilic granulocytes, suggesting that this group is the key element of the cell-mediated immune response of M. kurilensis. Our results support a concept of bivalve's hemocyte specification with distinct phenotypes.


Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF-18.
In Caenorhabditis elegans, the insulin/IGF-1 DAF-2 receptor controls entry into dauer and longevity. DAF-2 signaling cascade includes the PI3 kinase homolog AGE-1 and the FOXO transcription factor DAF-16. The DAF-2 pathway is downregulated by DAF-18 which is encoded by the ortholog of the human tumor suppressor gene PTEN. We have previously shown that, like PTEN, DAF-18 antagonizes the activity of PI3 kinase/AGE-1. To further explore the role of DAF-18 in the regulation of the insulin pathway, we investigated which tissue(s) DAF-18 functions in to regulate dauer formation and lifespan. Our data show that complete dauer formation requires daf-18 expression in several tissues and that the remodeling of dauer tissues depends on both cell autonomous and cell nonautonomous daf-18 function(s). Conversely, daf-18 expression increases adult lifespan in all individual tissues tested. Furthermore, we show that the role of DAF-18 in dauer and lifespan control depends on DAF-16 activation, which is regulated by both cell autonomous and cell nonautonomous DAF-18 function(s) and in a tissue-specific manner. Overall, our data strongly suggest that several tissues act as signaling centers to mediate DAF-18 function and that DAF-18 could act outside the canonical DAF-2/DAF-16 pathway to regulate dauer and lifespan.


Stem cells as a potential therapy in managing various disorders of metabolic syndrome: a systematic review.
Recent explorations on mesenchymal stem/stromal cells (MSC) have reported a promising future for cell-based therapies. MSCs are widely sourced from various tissues and express unique properties of regenerative potential and immunomodulation. Currently, there is a growing interest in utilizing MSC for treatment of chronic diseases to overcome the drawbacks of chemical drugs. Metabolic Syndrome (MetS) is described as a cluster of metabolic abnormalities categorized as abdominal obesity, dyslipidaemia, hypertension, hypertriglyceridemia, and hyperglycaemia. Patients diagnosed with MetS have a high predisposition for developing cardiovascular complications, diabetes, non-alcoholic fatty liver diseases, bone loss, cancer, and mortality. Hence, research on MSC as therapy for MetS and related diseases, is greatly valued and are advantaged by the low immunogenicity with high regenerative capacity. However, there are many obstacles to be addressed such as the safety, efficacy, and consistency of different MSC sources. Additionally, factors such as effective dose level and delivery method are equally important to achieve uniform therapeutic outcomes. This systematic review discusses the potential roles of MSC in managing the multiple clusters of MetS. Research articles during the past 20 years were systematically searched and filtered to update the progress in the field of MSC therapy in managing various components of MetS. The different sources of MSC, dosage, method of delivery and outcome measures for the stem cell therapies were compiled from the systematically selected research articles. It can be concluded from the review of the selected articles that MSCs can improve the various disorders of MetS such as abdominal obesity, hyperglycaemia, hypertriglyceridemia and hypertension, and represent a promising alternative to conventional therapy of the MetS cluster.


Accumulated incidence of falls in people hospitalised with cancer and related factors.
To study the accumulated incidence of falls of people hospitalised with cancer and analyse the related intrinsic and extrinsic factors. A prospective study of people hospitalised with cancer at the Catalan Institute of Oncology. Intrinsic factors and extrinsic factors related to the fall have been studied. The data were gathered from the clinical history and a specific adverse events notification programme and patients were followed during hospitalisation. A total of 117 of 6090 patients admitted during the period of study were included, with an accumulated incidence of falls of 0.019. Mean age 63.4 years (SD 11.5) and 65.5% men. Patients with lung cancer accounted for 25.6% of the total number of falls, followed by haematological cancer at 24.8%. Most falls were without consequences (71.8%). The data reveal that people hospitalised with cancer are at greater risk of falling, even though the accumulated incidence observed in the present study is low.


Continuous efficient removal and inactivation mechanism of E. coli by bismuth-doped SnO2/C electrocatalytic membrane.
The Bi-SnO2/C electrocatalytic membrane was fabricated via a simple electrochemical reduction and hydrothermal method. Under the action of electric field, the Sn2+ and Bi3+ were firstly adsorbed and reduced to metallic Sn and Bi on the carbon membrane surface by cathodic reduction reaction, and the Bi-SnO2/C membrane was obtained subsequently through hydrothermal oxidation process. Confirmed by SEM, TEM, XRD, and XPS characterizations, the nano-Bi-SnO2 is homogeneously distributed on the membrane surface and is firmly attached to the carbon membrane via C-O-Sn chemical bond. Through CV, LSV, and EIS electrochemical analysis, the Bi-SnO2/C membrane possesses the higher electrocatalytic activity and stability than carbon membrane. Therefore, the Bi-SnO2/C membrane could continuously efficiently remove and inactivate Escherichia coli in water through flow-through mode. As a result, the sterilization efficiency can reach more than 99.99% under the conditions of cell voltage 4 V, flow rate 1.4 mL/min, and E. coli initial concentration 1.0 × 104 CFU/mL, owing to the synergistic effect of the membrane separation and electrocatalytic oxidation. Moreover, it was found that the oxidation groups of ⋅OH radicals generated by Bi-SnO2/C membrane play the crucial role for bactericidal performance. This work presents a low-cost, highly active, and stable electrocatalytic membrane towards continuous bacterial inactivation, which exhibits promising potential in water disinfection and is beneficial for practical large-scale applications.


Hospitality Invites Sociability, Which Builds Cohesion: a Model for the Role of Main Streets in Population Mental Health.
The aim of this study was to investigate the contribution of main streets to community social cohesion, a factor important to health. Prior work suggests that casual contact in public space, which we call "sociability," facilitates more sustained social bonds in the community. We appropriate the term "hospitality" to describe a main street's propensity to support a density of such social interactions. Hospitality is a result of the integrity and complex contents of the main street and surrounding area. We examine this using a typology we term "box-circle-line" to represent the streetscape (the box), the local neighborhood (the circle), and the relationship to the regional network of streets (the line). Through field visits to 50 main streets in New Jersey and elsewhere, and a systematic qualitative investigation of main streets in a densely interconnected urban region (Essex County, New Jersey), we observed significant variation in main street hospitality, which generally correlated closely with sociability. Physical elements such as street wall, neighborhood elements such as connectivity, inter-community elements such as access and perceived welcome, and socio-political elements such as investment and racial discrimination were identified as relevant to main street hospitality. We describe the box-circle-line as a theoretical model for main street hospitality that links these various factors and provides a viable framework for further research into main street hospitality, particularly with regard to geographic health disparities.


Synthesis and anti-proliferative activity of novel azazerumbone conjugates with chalcones.
The conjugation of azazerumbone ((3E,7E,11E)-5,5,8,12-tetramethylazacyclododeca-3,7,11-trien-2-one (7)) and 2,4-dihydroxychalcones was carried out for the preparation of novel target compounds 9a-g with 1-ethylene-4-methylene-1,2,3-triazole linker and 10a-f with propylene linker between amide nitrogen of azazerumbone and 4-hydroxy group of chalcone. The anti-proliferative activity of these compounds against the LU-1, Hep-G2, MCF-7 and SW480 human cancer cell lines were significantly improved compared to those of azazerumbone or zerumbone. The anti-proliferative activities of (3E,7E,11E)-1-((1-(2-(3-hydroxy-4-((E)-3-(3-methoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-5,5,8,12-tetramethyl azacyclododeca-3,7,11-trien-2-one (9b) and (3E,7E,11E)-1-(3-(4-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)phenoxy)propyl)-5,5,8,12-tetramethylazacyclododeca-3,7,11-trien-2-one (10d) are nearly comparable to those of ellipticine.


Differential expression of myosin heavy chain isoforms between abductor and adductor muscles in the human larynx.
This study examines the differential expression of myosin heavy chain (MyHC) components in human laryngeal muscle groups. A battery of monospecific monoclonal antibodies in Western blots was used to determine expression of IIX, extraocular-specific (EOM), and IIB MyHCs for the thyroarytenoid (TA), vocalis (VOC), lateral cricoarytenoid (LCA), cricothyroid (CT), and posterior cricoarytenoid (PCA) muscles obtained from fresh cadaver specimens. Fast IIX MyHC was only expressed in the TA, VOC, and LCA muscles. Fast IIA and slow MyHCs were expressed in all laryngeal muscles including the CT and PCA. The CT with mixed phonatory and respiratory function and the PCA with respiratory function did not express IIX MyHC. The 2 MyHC isoforms associated with the highest speeds of contraction in rat laryngeal muscle, namely, the EOM MyHC and IIB MyHC, were not detected in human laryngeal muscles. Novel MyHC bands were not detected in SDS-PAGE gels or Western blots using a broad specificity MyHC antibody. The profile of MyHC expression in human laryngeal muscles differs from that observed in human extraocular and masticator muscles, and other mammalian species. Our data demonstrate that IIX MyHC expression is associated primarily with muscles affecting glottic closure and is absent in CT and PCA. A higher percentage of IIX MyHC is expected to impart a high speed of shortening to the TA and LCA muscles. The absence of IIX MyHC in muscles with respiratory (PCA) and mixed respiratory/phonatory function (CT) further supports the inference that the physiologic difference between laryngeal muscles is reflected in the molecular composition of contractile protein.