Risk factors for postoperative pancreatic fistula in patients with insulinomas: analysis of 292 consecutive cases.
Pancreatic fistula (PF) remains the most challenging complication in pancreatic surgery, yet few published studies have focused on the risk factors for postoperative PF in patients undergoing surgery for insulinomas. From January 1990 to February 2010, a total of 292 patients with insulinomas underwent surgery at Peking Union Medical College Hospital. Demographic data, intraoperative procedures, and postoperative data were collected. Particular attention was paid to variables associated with PF as defined by the International Study Group of Pancreatic Fistula (ISGPF). Univariate and multivariate analyses were used to identify possible risk factors for PF. PF was found in 132 (45.2%) patients, of whom 90 were classified into ISGPF grade A, 33 grade B, and 9 grade C. Multivariate analysis showed that male patients (OR=2.56; P=0.007) and operative time >180 minutes (OR=3.756; P<0.0001) were independent risk factors for clinical PF. Pancreatic resection with stapler was a protective factor for both total PF (OR=0.022; P=0.010) and clinical PF (OR=0.097; P=0.007). Male gender and operative time >180 minutes were independent risk factors for clinical PF, while pancreatic resection with a stapler was a protective factor. Whether body mass index (BMI) and other variables during operation are risk factors of PF needs further study.


[The scientific revolutions in medicine in XVII-XIX centuries: disclaimer of Galenism and initiation of natural-scientific foundations of medicine. Report 5. The development of new conceptions about the structure and mechanisms of functioning of nervous system].
The article deals with the history of study of anatomy and physiology of central and peripheral nervous system in the course of scientific revolution in medicine.


Dynamic chest radiography for pulmonary vascular diseases: clinical applications and correlation with other imaging modalities.
Dynamic chest radiography (DCR) is a novel functional radiographic imaging technique that can be used to visualize pulmonary perfusion without using contrast media. Although it has many advantages and clinical utility, most radiologists are unfamiliar with this technique because of its novelty. This review aims to (1) explain the basic principles of lung perfusion assessment using DCR, (2) discuss the advantages of DCR over other imaging modalities, and (3) review multiple specific clinical applications of DCR for pulmonary vascular diseases and compare them with other imaging modalities.


Risk factors for the development of osteoporosis after spinal cord injury. A 12-month follow-up study.
Spinal cord injury (SCI) has been associated with a marked bone loss after injury and a consequent increased risk of osteoporosis. The evaluation of bone mineral density shortly after SCI is a simple and effective method for predicting the development of osteoporosis during the first year after SCI. Spinal cord injury (SCI) has been associated with a marked bone loss after injury and a consequent increased risk of osteoporosis and fractures. The aim of this study was to analyze the factors associated with osteoporosis development short-term after SCI. We included patients with complete recent SCI (<6 months) evaluating bone turnover markers (P1NP, bone ALP, and sCTx), 25-OH-vitamin D (25OHD) levels, and lumbar and femoral BMD (Lunar, Prodigy) at baseline, 6 and 12 months after SCI. The risk factors for osteoporosis analyzed included the following: age, gender, BMI, toxic habits, bone turnover markers, 25OHD levels, lumbar and femoral BMD, level, severity and type of SCI, and days-since-injury. Osteoporosis was defined according to WHO criteria. Thirty-five patients aged 35 ± 16 years were included, and 52 % developed osteoporosis during the 12-month follow-up. These latter patients had lower BMD values at femur and lumbar spine and higher bone turnover markers at baseline. On multivariate analysis, the principal factors related to osteoporosis development were as follows: total femur BMD <1 g/cm(2) (RR, 3.61; 95 % CI 1.30-10.06, p = 0.002) and lumbar BMD <1.2 g/cm(2) at baseline (0.97 probability of osteoporosis with both parameters under these values). Increased risk for osteoporosis was also associated with increased baseline values of bone ALP (>14 ng/mL) (RR 2.40; 95 % CI 1.10-5.23, p = 0.041) and P1NP (>140 ng/mL) (RR 3.08; 95 % CI 1.10-8.57, p = 0.017). The evaluation of BMD at the lumbar spine and femur short-term after SCI is a simple, effective method for predicting the development of osteoporosis during the first year after SCI. Our results also indicate the need to evaluate and treat these patients shortly after injury.


The discovery of novel β-secretase inhibitors: pharmacophore modeling, virtual screening, and docking studies.
This article describes the identification of two small molecular inhibitors for β-secretase by integrating virtual screening with fluorescence resonance energy transfer bioassay. A ligand-based pharmacophore model was developed, and the sequential virtual screening of ZINC database was performed using the acquired pharmacophore model and molecular docking. Biological evaluation of 10 virtual hits led to the identification of two novel inhibitors with IC(50) values of 4.76 and 0.31 μm, respectively. These two moderate inhibitors could represent new potentials for the development of anti-Alzheimer's disease agents.


Phosphorylation: a molecular switch in opioid tolerance.
Protein phosphorylation is a key posttranslational modification mechanism controlling the conformation and activity of many proteins. Increasing evidence has implicated an essential role of phosphorylation by several major protein kinases in promoting and maintaining opioid tolerance. We review some of the most recent studies on protein kinase C (PKC), cyclic AMP dependent protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase G (PKG), and G protein receptor kinase (GRK). These kinases act as the molecular switches to modulate opioid tolerance. Pharmacological interventions at one or more of the protein kinases and phosphatases may provide valuable strategies to improve opioid analgesia by attenuating tolerance to these drugs.


Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations.
The objective of this report was to evaluate ocular and systemic outcomes after primary transpupillary thermotherapy for choroidal melanoma and to identify the limitations of this treatment method. Noncomparative interventional case series. The participants included 256 patients with newly diagnosed choroidal melanoma. The outcome measures included local tumor recurrence and visual acuity. Before treatment, the mean tumor base was 7.1 mm, and mean tumor thickness was 2.7 mm. Overlying subretinal fluid was present in 215 cases (84%) and orange pigment on the tumor surface in 200 cases (78%). All tumors showed either photographic documentation of growth (114 cases; 45%) or substantial risk factors for growth (142 cases; 55%). After a mean of three treatment sessions, complete tumor control without recurrence was found in 232 cases (91%) and recurrence in 24 cases (9%). The mean time to recurrence was 22 months, and the mean recurrent tumor size was 3.8 mm base and 2.4 mm thick. Of the recurrent tumors, additional thermotherapy was successful in controlling 13 (5%), plaque radiotherapy in 8 (3%), and enucleation in 3 (1%). Using multivariable analysis, the risk factors for tumor recurrence included increasing number of thermotherapy sessions (reflecting less responsive tumor) (P = 0.0001) and optic disc overhung by tumor (P = 0.03). Kaplan Meier estimates revealed that 4% showed recurrence at 1 year, 12% at 2 years, and 22% at 3 years follow-up. When analyzing those 214 patients without multivariable risk factors for recurrence, Kaplan Meier estimates for recurrence were 2% at 1 year, 8% at 2 years, and 10% at 3 years. The visual acuity after treatment was 20/20 to 20/40 in 128 cases (50%), 20/50 to 20/100 in 47 (18%), and 20/200 or worse in 81 (32%). Using multivariable analysis, the most statistically significant factors at initial visit that were predictive of poor visual acuity (20/200 or worse) after treatment included documented tumor growth before treatment (P = 0.0001), mushroom tumor configuration (P = 0.002), initial symptom of blurred vision (P = 0.008), poor initial visual acuity (P = 0.005), superior quadrant tumor location (P = 0.03), underlying diabetes mellitus (P = 0.04), and optic disc overhung by tumor (P = 0.04). Tumor-related mortality occurred in two patients (1%), one of whom showed complete tumor regression to thermotherapy and the other with diffuse choroidal melanoma and local tumor margin recurrence. Transpupillary thermotherapy is an effective treatment for certain small choroidal melanomas. Appropriate tumor selection is critical to successful treatment. Patients with tumors abutting or overhanging the optic disc or those requiring more than three sessions for tumor control are more likely to develop ultimate tumor recurrence. Transpupillary thermotherapy can cause damaging effects to the retina, leading to visual loss shortly after treatment.


Pfannenstiel incision for incarcerated inguinal hernia in neonates.
The authors report on 2 neonates with irreducible inguinal hernia in whom a Pfannenstiel skin incision followed by lower abdominal midline fasciotomy were used to open the abdomen during emergency operation. By using this approach, the inguinal canal could also be opened and the hernia sac ligated. Bowel resection followed by anastomosis in one case and appendectomy in the other case could be performed safely intraabdominally because of the better exposure provided by using our approach compared with an inguinal incision alone. A Pfannenstiel incision followed by a midline fasciotomy decreases the risks associated with surgical intervention by enhancing exposure and contributing to good outcome by improving wound cosmesis.


Outcome of microvascular decompression for hemifacial spasm associated with the vertebral artery.
We retrospectively compared the outcome of microvascular decompression (MVD) for hemifacial spasm (HFS) associated with the vertebral artery (VA) with that of MVD for HFS unrelated to the VA. Between April 2008 and April 2015, 22 patients with VA-associated HFS underwent MVD at our institution. The median follow-up period was 28 months (range, 12-90 months). Results were classified as excellent in 19 patients (86 %), good in one (5 %), fair in one (5 %), and poor in one (5 %). Immediate complications developed in five patients (23 %), and one of these complications (5 %) was permanent. The surgical outcome of MVD for VA-associated HFS was similar to that of MVD for HFS unrelated to the VA; however, the incidence of complications was significantly more frequent in patients whose VA compressed the more proximal portion of the facial nerve root exit zone from the caudal side at the pontomedullary sulcus. We conclude that preoperative evaluation of VA compression patterns is important to predict the difficulty of the planned MVD procedure.


Two new species of the leafhopper genus Mitjaevia Dworakowska from China (Hemiptera, Cicadellidae, Typhlocybinae).
The leafhopper genus Mitjaevia Dworakowska,1970 includes 19 species worldwide, nine species are known in China and is widely distributed in Palaearctic and Oriental Regions. Two new species from Guizhou Province, China are described within the genus Mitjaevia Dworakowska, 1970 (Hemiptera: Cicadellidae: Typhlocybinae). A key to the species of the genus is provided and the female valvulae are described and figured.


Long-term exercise training as a modulator of mammary cancer vascularization.
Breast cancer remains a leading cause of death by cancer worldwide. It is commonly accepted that angiogenesis and the expression of angiogenic factors such as vascular endothelial growth factor-A (VEGF-A) is associated with the increased risk of metastasis and poor patient outcome. This work aimed to evaluate the effects of long-term exercise training on the growth and vascularization of mammary tumors in a rat model. Fifty female Sprague-Dawley rats were divided into four groups: two N-methyl-N-nitrosourea (MNU)-exposed groups (exercised and sedentary) and two control groups (exercised and sedentary). MNU was administered once, intraperitoneally at 7 weeks-old. Animals were then exercised on a treadmill for 35 weeks. Mammary tumors were evaluated using thermography, ultrasonography [Power Doppler (PDI), B Flow and contrast-enhanced ultrasound (CEUS)], and immunohistochemistry (VEGF-A). Both, MNU sedentary and exercised groups showed 100% of tumor incidence, but exercised animals showed less tumors with an increased latency period. Exercise training also enhanced VEGF-A immunoexpression and vascularization (microvessel density, MVD) (p<0.05), and reduced histological aggressiveness. Ultrasound and thermal imaging analysis confirmed the enhanced vascularization of tumors on exercised animals. Long-term exercise training increased VEGF-A expression, leading to enhanced tumor vascularization and reduced tumor burden, multiplicity and histological aggressiveness.


Higher COPD Assessment Test Score Associated With Greater Exacerbations Risk: A Post Hoc Analysis of the IMPACT Trial.
In the InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI and UMEC/VI in patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis tested the relationship between baseline health status, risk of future exacerbations, and efficacy outcomes. IMPACT was a Phase 3, double-blind, 52-week trial in patients with symptomatic COPD (COPD Assessment Test [CAT] score ≥10) and ≥1 moderate/severe exacerbation in the prior year randomized 2:2:1 to FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Annual rate of on-treatment moderate/severe exacerbations, lung function, and safety were analyzed by continuous baseline CAT score. Moderate/severe exacerbation rates increased with increasing baseline CAT scores in FF/UMEC/VI and UMEC/VI arms. There was a very small increase in on-treatment pneumonia rates at higher baseline CAT scores across all treatment arms. FF/UMEC/VI reduced moderate/severe exacerbation rates versus UMEC/VI (i.e., the inhaled corticosteroid effect) consistently across the range of CAT scores. The reduction with FF/UMEC/VI versus FF/VI (i.e., the long-acting muscarinic antagonist effect) was greatest at lower CAT scores and appeared lesser at higher CAT scores. Improvements in lung function were observed with FF/UMEC/VI versus FF/VI and UMEC/VI, regardless of baseline CAT score. The CAT score was predictive of exacerbation risk. Worse baseline health status was associated with higher moderate/severe exacerbation and pneumonia rates. Irrespective of baseline CAT score, FF/UMEC/VI improved lung function, and reduced the annual moderate/severe exacerbation rates versus dual therapy. Results indicate an overall favorable benefit-risk profile of triple versus dual therapy, irrespective of CAT score. Clinical Trial Registration:GSK (CTT116855/NCT02164513).


Exposure of medical personnel to radiation during radionuclide therapy practices.
Radioisotopes that emit beta radiation are used for the treatment of hepatocellular carcinoma, of arthritic patients (radiosynovectomy) and treatment of bone metastases with, respectively, I-labelled lipiodol, colloidal citrate of Y or and Sm-labelled EDTMP. Radiation energy of these radioisotopes that emit beta or beta and gamma radiation (from 300 to 2000 keV) leads to an increase in radiation dose received by nuclear medicine staff. In this paper we focused on clinical and laboratory staff exposure during these types of metabolic radiation therapies. Cylindrical LiF thermoluminescence dosimeters were used to measure radiation-related whole-body doses (WBDs) and finger doses of the clinical staff. Exposure of the two radiopharmacists and three nurses taking part in I-labelled lipiodol, Y-colloid and Sm-EDTMP therapies, for 12 months in succession, were 146 microSv and 750 microSv, respectively, considering WBD, and 14.6 mSv and 6.5 mSv, respectively, considering finger doses. Extrapolated annual exposures (six radiosynovectomies per year) for the rheumatologists were estimated to be 21 microSv (WBD) and 13.2 mSv (finger dose). Extrapolated annual WBDs and finger doses (25 I-labelled lipiodol treatments per year) for radiologists were estimated to 165 microSv and 3.8 microSv, respectively. Fortunately, these doses were always lower than the limits reported in the European Directive EURATOM 96/29 05/13/1996 (WBD <20 mSv.year; finger dose: 500 mSv.year) but have to be added to those relative to other metabolic radiotherapies such as radioiodine treatments and new metabolic radiotherapies (Y-conjugated peptides or antibodies). Nevertheless, the global exposure of medical staff involved in all these clinical practices justifies dosimetry studies to validate protocols and radiation protection devices for each institution.


Mentors' competence in mentoring nursing students in clinical practice: Detecting profiles to enhance mentoring practices.
To describe the mentoring competence of clinical practice nurse mentors and identify different mentor profiles. Cross-sectional research design, secondary analysis. An international, cross-sectional study design was performed in five European countries. A total of 1 604 mentors from 33 healthcare organizations participated in the study between 2016-2019. The Mentors' Competence Instrument (MCI), which includes seven sub-dimensions and 44 items, was used to collect data. K-means cluster and binary regression analyses were performed to detect mentor profiles and determine how various factors affect competence, respectively. The K-means cluster analysis identified three distinct profiles: A (n = 926); B (n = 566); and C (n = 85). The profiles showed significantly different values (p < .001) across all seven areas of mentoring competence. In comparison with the other profiles, nurses in profile A were older, had more work experience and were more probably to have completed mentoring-specific training.


Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons.
There has been a worldwide proliferation of synthetic cannabinoids that have become marketed as legal alternatives to cannabis (marijuana). Unfortunately, there is a dearth of information about the pharmacological effects of many of these emerging synthetic cannabinoids (ESCs), which presents a challenge for regulatory authorities that need to take such scientific evidence into consideration in order to regulate ECSs as controlled substances. We aimed to characterize the pharmacological properties of ten ESCs using two cell based assays that enabled the determination of potency and efficacy relative to a panel of well-characterized cannabinoids. Agonist-mediated inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live HEK293T cells transfected with human cannabinoid receptor 1 gene (CNR1) and pGloSensor-22F. Pharmacological analysis of this data indicated that all of the ESCs tested were full agonists, with the following rank order of potency: Win 55212-2≈5F-PB-22≈AB-PINACA≈EAM-2201≈MAM-2201>JWH-250≈ PB-22>AKB48 N-(5FP)>AKB-48≈STS-135>XLR-11. Assessment of agonist-stimulated depression of Ca(2+) transients was also used to confirm the efficacy of five ESCs (XLR-11, JWH-250, AB-PINACA, 5F-PB-22, and MAM-2201) in cultured primary hippocampal neurons. This work aims to help inform decisions made by regulatory agencies concerned with the profusion of these poorly characterized recreational drugs.


Streptomycin interferes with conformational coupling between codon recognition and GTPase activation on the ribosome.
Aminoacyl-tRNAs (aa-tRNAs) are selected by the ribosome through a kinetically controlled induced fit mechanism. Cognate codon recognition induces a conformational change in the decoding center and a domain closure of the 30S subunit. We studied how these global structural rearrangements are related to tRNA discrimination by using streptomycin to restrict the conformational flexibility of the 30S subunit. The antibiotic stabilized aa-tRNA on the ribosome both with a cognate and with a near-cognate codon in the A site. Streptomycin altered the rates of GTP hydrolysis by elongation factor Tu (EF-Tu) on cognate and near-cognate codons, resulting in almost identical rates of GTP hydrolysis and virtually complete loss of selectivity. These results indicate that movements within the 30S subunit at the streptomycin-binding site are essential for the coupling between base pair recognition and GTP hydrolysis, thus modulating the fidelity of aa-tRNA selection.


Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin.
Smooth muscle cells (SMCs) modulate their phenotype between proliferative and differentiated states in response to physiological and pathological cues. Insulin-like growth factor-I stimulates differentiation of SMCs by activating phosphoinositide-3-kinase (PI3K)-Akt signaling. Foxo forkhead transcription factors act as downstream targets of Akt and are inactivated through phosphorylation by Akt. We show that Foxo4 represses SMC differentiation by interacting with and inhibiting the activity of myocardin, a transcriptional coactivator of smooth muscle genes. PI3K/Akt signaling promotes SMC differentiation, at least in part, by stimulating nuclear export of Foxo4, thereby releasing myocardin from its inhibitory influence. Accordingly, reduction of Foxo4 expression in SMCs by siRNA enhances myocardin activity and SMC differentiation. We conclude that signal-dependent interaction of Foxo4 with myocardin couples extracellular signals with the transcriptional program for SMC differentiation.


Complete Genome Sequence of Strain YCSC6, a Marine Bacterium Isolated from Saturated Saltpan with Activity Against Uronema marinum.
Salinivibrio proteolyticus strain YCSC6 was isolated from a saturated saltpan and demonstrated to have strong insecticidal activity against turbot's pathogenic ciliate-Uronema marinum. In this study, we sequenced its complete genome. Results showed that it consists of two circular chromosomes: 2.49 Mbps and 0.74 Mbps, respectively. It encodes 3429 protein-coding sequences. Biosynthetic gene clusters predicted to synthesize bacteriocins and antimicrobial peptides were discovered, which might be the key factors to lyse and kill U. marinum. The complete genome sequence of strain YCSC6 provides insights into the fundamental genetic potential for elucidating its insecticidal mechanism against U. marinum.


Utilization of various sterols by lecithin-cholesterol acyltransferase as acyl acceptors.
Highly purified lecithin-cholesterol acyltransferase of human plasma was used to study the utilization of various sterols as the acyl acceptor. The esterification of sterols was facilitated by the presence of a 3beta-hydroxyl group and the trans configuration of the A/B rings, as was evident from the lack of acceptor activity of all 3 alpha-hydroxy sterols tested and coprostanol. Cholesterol analogs in which the side chain is modified, such as campesterol, beta-sitosterol, desmosterol and stigmasterol, were less effective than cholesterol as acyl acceptors. However, androstan-3 beta-ol, which completely lacks the side chain, was found to be more active than cholesterol. The transfer of the acyl group to all effective sterols required the presence of the cofactor peptide apolipoprotein A-I.


Application of Ozone against the Larvae of Plodia interpunctella (Hübner) and Its Impacts on the Organoleptic Properties of Walnuts.
One of the most important products grown in Iran is walnut (Juglans regia L.), but it can be threatened by storage pests such as insects. Ozonation is an environmentally friendly method for killing pest insects; accordingly, ozone efficacy in the control of a pest species of walnut, Indian meal moth (Plodia interpunctella (Hübner)), was assessed in this research. The selected walnut samples were infested with larvae of Indian meal moth and then subjected to various combinations of ozone concentration (3, 4.5, and 6 ppm) and exposure time (20, 30, 40, and 50 min). After exposure to the treatment combinations, larval mortality rates and changes to the sensory properties (color, taste, smell, crispness, stiffness, and overall acceptability), indicating consumer preference, of the walnuts were evaluated. Our results revealed enhanced mortality rates of P. interpunctella with an increase in both ozone concentration and exposure time: 99% mortality was recorded at the concentration and exposure time of 6 ppm and 50 min, respectively. Sensory assessments of the samples showed that ozone treatments had no significant impacts on the color, taste, crispness, stiffness, and overall acceptability of the product. Also, few changes were recorded for its smell, which could be improved over time after being exposed to the air. We conclude that application of higher ozone concentrations might provide acceptable levels of insect pest control for stored walnuts with no associated reduced trade-off for their quality attributes.


The crystal structure of the emerging human-infecting hepatitis E virus E2s protein.
Hepatitis E virus (HEV) is a non-enveloped, globular particle that is responsible for acute hepatitis. HEV is classified into the Hepeviridae family and can be divided into four species (A-D). All HEV variants that infect humans are reported to belong to species A (HEV-A), except species C (HEV-C), which was reported to infect humans in December 2018. We determined the crystal structure of the HEV-C E2s domain at 1.8 Å resolution. It contains a classical 12-stranded β-sandwich motif and forms dimers by hydrogen bonding, though the amino acid residues that form hydrogen bonds are quite different from the residues of HEV-A. The HEV-C E2s domain shares the common groove region with other structurally related viruses, and some subtle differences in this region may be related to host adoption or antibody binding. Antibody binding experiments and structural analysis revealed that HEV-C E2s is able to bind to the previously reported broad-spectrum antibody 8G12 but not bind to the antibody 8C11. Meanwhile, the structure analysis shows that HEV-C E2s does not have the key sites for binding to host cells as displayed by HEV-A (Genotype 1) E2s. These structural and biological findings present important implications for understanding the molecular mechanisms of host recognition and entry of HEV-C, as well as provide clues to the development of therapeutic antibodies and vaccines against HEV-C infection.


Serpin=serine protease-like complexes within neurofilament conglomerates of motoneurons in amyotrophic lateral sclerosis.
Neurofilamentous conglomerates (NfCg), as axonal spheroids or conglomerates in motoneurons, are the histopathologic hallmarks for early stages of amyotrophic lateral sclerosis (ALS). We hypothesize that NfCg may be formed by post-translational modifications of altered Nf proteins that include: (1) hyperphosphorylation, (2) glycosylation (or glycoxidation), (3) nitration, (4) ubiquitination and/or (5) crosslinking by the Ca++-dependent transglutaminase (TGase). These, as well as other changes, are predicted to be initiated or accentuated by oxidative damage. The damaged Nf proteins then activate cascades of intracellular protein degradation which include ATP-dependent ubiquitin/proteasome proteolysis. Other proteolytic systems, either Ca++-dependent or independent, may also be activated, such as serine and cysteine protease systems. These enzymes, either lysosomal or non-lysosomal may also participate in the degradation of damaged Nf proteins being balanced by their cognate inhibitors. Protein complexes formed by these protease=inhibitor systems, along with damaged Nf proteins, may accumulate within the cell bodies as neuronal inclusions, since a number of intracellular inclusions are found in motor neurons in ALS. In the current study, we investigated the involvement of serine proteases and their serpins in NfCg formation. Pairs of three serine proteases (trypsin, chymotrypsin and thrombin) and their cognate serpins (alpha1-anti-trypsin, alpha1-anti-chymotrypsin, and protease nexin I) were probed in motoneurons with their antibodies for both NfCg and inclusions. Positive immunoreactivities for all serine proteases and their cognate serpins support the contention that the imbalance of serine proteases and internalized serpins may have a role in formation of NfCg and inclusions, and hence, the pathogenesis of ALS.


Mutation in TTI2 reveals a role for triple T complex in human brain development.
Tel2-interacting proteins 1 and 2 (TTI1 and TTI2) physically interact with telomere maintenance 2 (TEL2) to form a conserved trimeric complex called the Triple T complex. This complex is a master regulator of phosphoinositide-3-kinase-related protein kinase (PIKKs) abundance and DNA damage response signaling. Using a combination of autozygosity mapping and high-throughput sequencing in a large consanguineous multiplex family, we found that a missense c.1307T>A/p.I436N mutation in TTI2 causes a human autosomal recessive condition characterized by severe cognitive impairment, microcephaly, behavioral troubles, short stature, skeletal anomalies, and facial dysmorphic features. Immunoblotting experiment showed decreased amount of all Triple T complex components in the patient skin fibroblasts. Consistently, a drastically reduced steady-state level of all PIKKs tested was also observed in the patient cells. Combined with previous observations, these findings emphasises the role of the TTI2 gene in the etiology of intellectual disability and further support the role of PIKK signaling in brain development and functioning.


Structural and thermodynamic responses of mutations at a Ca2+ binding site engineered into human lysozyme.
Structural determinants of Ca2+ binding sites within proteins typically comprise several acidic residues in appropriate juxtaposition. Three residues (Ala-83, Gln-86, and Ala-92) in human lysozyme are characteristically mutated to Lys, Asp, and Asp, respectively, in natural Ca2+ binding lysozymes and alpha-lactalbumins. The effects of these mutations on the stability and Ca2+ binding properties of human lysozyme were investigated using calorimetry and were interpreted with crystal structures. The double mutant, in which Glu-86 and Ala-92 were replaced with Asp, clearly showed Ca2+ binding affinity, whereas neither point mutant showed Ca2+ affinity, indicating that both residues are essential. The further mutation of Ala-83 --> Lys did not affect the Ca2+ binding of the double mutant. The point mutations Ala-83 --> Lys and Glu-86 --> Asp did not affect the stability, whereas the mutation Ala-92 --> Asp was about 1.3 kcal/mol less stable. Structural analyses showed that both Asp-86 and Lys-83 were exposed to solvent. Side chains of Asp-86 and Asp-91 were rotated in opposite directions about chi1 angle, as if to reduce the electrostatic repulsion. The charged amino acids at the Ca2+ binding site did not significantly affect stability of the protein, possibly because of the local conformational change of the side chains.


The interaction of RNA polymerase II with the adenovirus-2 major late promoter is precluded by phosphorylation of the C-terminal domain of subunit IIa.
Mammalian RNA polymerase II contains at the C terminus of its largest subunit an unusual domain consisting of 52 tandem repeats of the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. The phosphorylation of this domain is thought to play an important role in the transition of RNA polymerase II from a preinitiation complex to an elongating complex. The unphosphorylated form of RNA polymerase II is designated IIA, whereas the phosphorylated form is designated IIO. In an effort to determine the consequence of C-terminal domain phosphorylation on complex formation, 32P-labeled RNA polymerases IIA and IIO were prepared and examined for their ability to form a stable preinitiation complex on the adenovirus-2 major late promoter in the presence of a reconstituted HeLa cell transcription extract. Preinitiation complexes were formed in the absence of ATP and purified from free RNA polymerase II by chromatography on Sepharose CL-4B. The state of phosphorylation of the largest subunit was monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the transcriptional activity was determined by assaying specific transcript formation upon the addition of nucleotides and a competing DNA template. RNA polymerase IIA was recovered in transcriptionally active complexes in reactions in which the input enzyme was RNA polymerase IIA. In reactions with RNA polymerase IIO as the input enzyme, no IIO was recovered in excluded fractions that normally contain preinitiation complex. In reactions with equimolar amounts of RNA polymerases IIO and IIA, purified preinitiation complexes contained almost exclusively RNA polymerase HA. These results support the idea that RNA polymerase II containing an unphosphorylated C-terminal domain preferentially associates with the adenovirus-2 major late promoter. The state of phosphorylation of the C-terminal domain can, therefore, directly influence preinitiation complex formation. We also report here the presence of an activity in HeLa cell extracts that catalyzes dephosphorylation of the C-terminal domain, thereby converting RNA polymerase IIO to IIA. This C-terminal domain phosphatase is specific in that it does not catalyze the dephosphorylation of a serine residue phosphorylated by casein kinase II. The presence of a C-terminal domain phosphatase in in vitro transcription reactions containing RNA polymerase IIO results in the formation of RNA polymerase IIA. This RNA polymerase IIA associates preferentially with preinitiation complexes.


Manipulation of tissue fatty acid profile by intravenous lipids in dogs.
This study was undertaken to determine the effects on the fatty acid (FA) composition of various dog tissues of 4 different lipid emulsions (a 100% long-chain triacylglycerol (LCT) derived from soya bean oil emulsion, a mixed 50% medium-chain triacylglycerol (MCT)/50% LCT emulsion as well as both these emulsions supplemented with 10% fish oil (FO) triacylglycerols), when daily infused over 15 days as a substantial component of total parenteral nutrition. Lipids represented 55% of the non-protein energy. Blood samples as well as biopsies from liver, muscle and adipose tissue were taken 15 days before, and again immediately after TPN. In addition, the spleen was also removed immediately after TPN. Tissue FA composition was analysed by gas liquid chromatography of each lipid component after separation by thin layer chromatography. No differences in either safety or tolerance were detected between the different TPN preparations. In particular, infusion over 2 weeks of fat emulsions containing 10% fish oil was tolerated as well as conventional LCT and MCT/LCT emulsions. Relative linoleate content of tissue triacylglycerol (TG) was markedly increased in animals that received the LCT emulsions (e.g. from 22.6 +/- 2.5% to 32.2 +/- 0.6% in the liver), this effect being markedly reduced with MCT/LCT preparations. n-3FA were slightly incorporated into liver TG (from 0.0 +/- 0.0% to 2.3 +/- 0.7% and 1.2 +/- 0.4% for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) respectively, with LCT + FO), but remained undetectable in extrahepatic tissue TG. Of interest, medium chain FA were found in tissue TG after infusion of the mixed MCT/LCT emulsions. As expected, changes of tissue phospholipid (PL) composition involved only long-chain FA. Infusion of soya bean oil emulsion was associated with an increased content of linoleate in liver PL (from 13.6 +/- 0.4% to 17.7 +/- 0.4%), but not in other tissues. MCT/LCT did not markedly affect PL/FA pattern in any tissue. Supplementation with fish oil was associated with an efficient incorporation of n-3FA into tissue PL, particularly in the liver (from 0.4 +/- 0.1% to 2.5 +/- 0.3% for EPA and from 3.9 +/- 0.8% to 9.1 +/- 0.4% for DHA, with the LCT + FO emulsion).


Cophylogeny and disparate rates of evolution in sympatric lineages of chewing lice on pocket gophers.
Although molecular-based phylogenetic studies of hosts and parasites are increasingly common in the literature, no study to date has examined two congeneric lineages of parasites that live in sympatry on the same lineage of hosts. This study examines phylogenetic relationships among chewing lice (Phthiraptera: Trichodectidae) of the Geomydoecus coronadoi and Geomydoecus mexicanus species complexes and compares these to phylogenetic patterns in their hosts (pocket gophers of the rodent family Geomyidae). Sympatry of congeneric lice provides a natural experiment to test the hypothesis that closely related lineages of parasites will respond similarly to the same host. Sequence data from the mitochondrial COI and the nuclear EF-1alpha genes confirm that the two louse complexes are reciprocally monophyletic and that individual clades within each species complex parasitize a different species of pocket gopher. Phylogenetic comparisons reveal that both louse complexes show a significant pattern of cophylogeny with their hosts. Comparisons of rates of nucleotide substitution at 4-fold degenerate sites in the COI gene indicate that both groups of lice have significantly higher basal mutation rates than their hosts. The two groups of lice have similar basal rates of mutation, but lice of the G. coronadoi complex show significantly elevated rates of nucleotide substitution at all sites. These rate differences are hypothesized to result from population-level phenomena, such as effective population size, founder effects, and drift, that influence rates of nucleotide substitution.


Elderly patients with hypercholesterolaemia: a double-blind study of the efficacy, safety and tolerability of fluvastatin.
Coronary heart disease is a major cause of morbidity and mortality in the elderly, a rapidly growing section of the population. Elderly patients have been excluded from most preventative risk factor trials. We evaluated fluvastatin, a fully synthetic hydroxymethyl glutaryl coenzyme A reductase inhibitor, in white patients older than 60 years, in seven hospital centres. After an 8-week cholesterol-decreasing diet phase, patients were allocated to groups to receive fluvastatin 40 mg daily (n = 33) or placebo (n = 36) given for 12 weeks. All patients had low-density lipoprotein cholesterol concentrations > or = 4.1 mmol/l 1 week before they were allocated to a treatment at random. After receiving randomised treatment for 12 weeks, 50 patients then received fluvastatin 40 mg daily on an open basis for a further 12 weeks. Mean +/- SD age was 70.7 +/- 5.2 years for fluvastatin patients and 68.3 +/- 5.6 years for placebo. Mean +/- SD percentage changes in lipid concentrations from randomisation to the end of 12 weeks were calculated (n = 63) by intent-to-treat analysis. Total cholesterol decreased by 21.64 +/- 8.7% in the fluvastatin group and by 2.91 +/- 7.25% in the placebo group (P < 0.01); high-density lipoprotein cholesterol increased by 4.98 +/- 10.84% in the fluvastatin group and decreased by 0.05 +/- 8.68% in the placebo group (P = 0.05); low-density lipoprotein cholesterol decreased by 27.14 +/- 8.45% in the fluvastatin group and by 2.16 +/- 9.68% in the placebo group (P < 0.01); very-low-density lipoprotein cholesterol decreased by 30.70 +/- 30.65% in the fluvastatin group and by 9.80 +/- 28.6% in the placebo group (P < 0.01); triglyceride decreased by 18.13 +/- 17.35% in the fluvastatin group and by 2.97 +/- 21.85% in the placebo group (P < 0.01). There were no statistically significant differences between treatment groups for any other biochemical or haematological parameters. Adverse events were mainly mild, diminishing with continued treatment, and no event was serious by standard criteria. Patient-assessed tolerability after randomised treatment was 'very good' for 18 fluvastatin patients and for 26 placebo patients (P = 0.79). Seven patients withdrew from the 12-week follow-up (four from the fluvastatin group and three from the placebo group). We conclude that fluvastatin decreases lipid concentrations effectively and safely in elderly patients, producing clinically significant decreases in total cholesterol, low-density lipoprotein cholesterol, triglyceride and, especially, very-low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol moderately.


Activated electric arc furnace slag as an effective and reusable Fenton-like catalyst for the photodegradation of methylene blue and acid blue 29.
In this work, an activated electric arc furnace slag (A-EAFS) was investigated as an effective Fenton catalyst for the photodegradation of methylene blue (MB) and acid blue 29 (AB29). Fourier transform infrared spectroscopy and UV-visible absorption analyses indicated that A-EAFS offers additional Fe3O4 because of the changes in the iron oxide phase and the favorable response to visible light. It has been found that the highest degradation efficiency can reach up to 94% for MB under optimal conditions of 1 g L-1 of A-EAFS, 20 mM H2O2, and pH 3. The optimal conditions for AB29 were 0.1 g L-1 A-EAFS, 4 mM H2O2, and pH 3 to reach 98% degradation efficiency. Visible light enhanced the degradation of both dyes. In addition, A-EAFS, could be easily separated magnetically, exhibited good chemical stability after seven successive photodegradation cycles.


WDR5 facilitates recruitment of N-MYC to conserved WDR5 gene targets in neuroblastoma cell lines.
Collectively, the MYC family of oncoprotein transcription factors is overexpressed in more than half of all malignancies. The ability of MYC proteins to access chromatin is fundamental to their role in promoting oncogenic gene expression programs in cancer and this function depends on MYC-cofactor interactions. One such cofactor is the chromatin regulator WDR5, which in models of Burkitt lymphoma facilitates recruitment of the c-MYC protein to chromatin at genes associated with protein synthesis, allowing for tumor progression and maintenance. However, beyond Burkitt lymphoma, it is unknown whether these observations extend to other cancers or MYC family members, and whether WDR5 can be deemed as a "universal" MYC recruiter. Here, we focus on N-MYC amplified neuroblastoma to determine the extent of colocalization between N-MYC and WDR5 on chromatin while also demonstrating that like c-MYC, WDR5 can facilitate the recruitment of N-MYC to conserved WDR5-bound genes. We conclude based on this analysis that N-MYC and WDR5 colocalize invariantly across cell lines at predicted sites of facilitated recruitment associated with protein synthesis genes. Surprisingly, we also identify N-MYC-WDR5 cobound genes that are associated with DNA repair and cell cycle processes. Dissection of chromatin binding characteristics for N-MYC and WDR5 at all cobound genes reveals that sites of facilitated recruitment are inherently different than most N-MYC-WDR5 cobound sites. Our data reveals that WDR5 acts as a universal MYC recruiter at a small cohort of previously identified genes and highlights novel biological functions that may be coregulated by N-MYC and WDR5 to sustain the neuroblastoma state.


Altered sialidase expression in human myeloid cells undergoing apoptosis and differentiation.
To gain insight into sialic acid biology and sialidase/neuraminidase (NEU) expression in mature human neutrophil (PMN)s, we studied NEU activity and expression in PMNs and the HL60 promyelocytic leukemic cell line, and changes that might occur in PMNs undergoing apoptosis and HL60 cells during their differentiation into PMN-like cells. Mature human PMNs contained NEU activity and expressed NEU2, but not NEU1, the NEU1 chaperone, protective protein/cathepsin A(PPCA), NEU3, and NEU4 proteins. In proapoptotic PMNs, NEU2 protein expression increased > 30.0-fold. Granulocyte colony-stimulating factor protected against NEU2 protein upregulation, PMN surface desialylation and apoptosis. In response to 3 distinct differentiating agents, dimethylformamide, dimethylsulfoxide, and retinoic acid, total NEU activity in differentiated HL60 (dHL60) cells was dramatically reduced compared to that of nondifferentiated cells. With differentiation, NEU1 protein levels decreased > 85%, PPCA and NEU2 proteins increased > 12.0-fold, and 3.0-fold, respectively, NEU3 remained unchanged, and NEU4 increased 1.7-fold by day 3, and then returned to baseline. In dHL60 cells, lectin blotting revealed decreased α2,3-linked and increased α2,6-linked sialylation. dHL60 cells displayed increased adhesion to and migration across human bone marrow-derived endothelium and increased bacterial phagocytosis. Therefore, myeloid apoptosis and differentiation provoke changes in NEU catalytic activity and protein expression, surface sialylation, and functional responsiveness.


Biocompatible Fe3O4@SiO2-NH2 nanocomposite as a green nanofiller embedded in PES-nanofiltration membrane matrix for salts, heavy metal ion and dye removal: Long-term operation and reusability tests.
High purity amorphous silica (95.55%) was simply extracted from rice husk and used as a shell for Fe3O4 magnetic nanoparticles. The obtained eco-friendly nanomaterial was functionalized by (3-Aminopropyl)trimethoxysilane and characterized by SEM, FT-IR, XRD, VSM, TEM and zeta potential analyses. The synthesized Fe3O4@SiO2-NH2 nanocomposite was embedded into the polyethersulfone membranes with different concentrations via phase inversion method. The effects of Fe3O4@SiO2-NH2 on various properties of the prepared nanofiltration membranes including membrane morphology, hydrophilicity, porosity, and mechanical stability were investigated using SEM image, water contact angle test, porosity measurement and mechanical property analysis, respectively. The performance of Fe3O4@SiO2-NH2 nanocomposite modified membranes was evaluated by measuring the pure water flux, salts rejection, Cd(II) ions removal, MR dye retention, and antifouling property. The results showed that the pure water flux was significantly increased in Fe3O4@SiO2-NH2 modified membranes due to the presence of hydrophilic functional groups on the Fe3O4@SiO2-NH2 surface. In addition, the significant enhancement in efficiency of modified membranes for removal of Cd(II) ions and MR dye was observed due to the adsorption properties of Fe3O4@SiO2-NH2 nanocomposite. Among the modified membranes with different concentrations of Fe3O4@SiO2-NH2, the 0.5 wt% concentration of nanocomposite showed the highest efficiency for the removal of Cd(II) ions (93%) and MR dye (97%). Membrane reusability study indicated a slightly decrease (≈7%) in Cd(II) ions removal after five continuous cycles. Membrane long-term filtration study showed a little reduction in permeate flux with unchanged MR dye retention during long-term filtration, which confirmed the stability of modified membrane.


[Characteristics of spinal stress in modeling scoliotic deformity and the methods of its correction].
Having studied the dynamics of stresses in models of scoliotic models of different types of surgical correction the authors have determined the optimal methods of treatment depending on the kind of deformation.


Pelvic arteriovenous malformations: gadolinium-enhanced three-dimensional MR angiography findings.
Pelvic arteriovenous malformations (PAV-Ms) are rare disorders traditionally diagnosed by conventional angiography. Breath-hold three-dimensional gadolinium-enhanced MR angiography (3D-Gd-MRA) is a state-of-the-art alternative for vascular imaging. We describe the 3D-Gd-MRA findings in two patients with PAVMs. The 3D-Gd-MRA approach provides a noninvasive and versatile method for evaluation of PAVMs that enables both angiographic assessment of the malformations and evaluation of visceral involvement, which can preclude surgical intervention.


Characterization and crystallization of core streptavidin.
We have characterized a streptavidin product that had been reduced to a minimal size that still retained full biotin-binding activity. This core streptavidin is proteolyzed at both ends at points that correspond closely with the termini of hen egg white avidin. Core streptavidin is more soluble than is the parent molecule. We have grown three different types of crystals of core streptavidin. The symmetry properties of these crystals prove that the molecule is a tetramer organized in tetrahedral (D2) point symmetry. The crystallographic response to the interaction of biotin with core streptavidin indicates that some conformational change accompanies ligand binding. We are attempting to determine the three-dimensional structure of streptavidin and its complex with selenobiotin from these crystals of core streptavidin.


Revealing metabolite biomarkers for acupuncture treatment by linear programming based feature selection.
Acupuncture has been practiced in China for thousands of years as part of the Traditional Chinese Medicine (TCM) and has gradually accepted in western countries as an alternative or complementary treatment. However, the underlying mechanism of acupuncture, especially whether there exists any difference between varies acupoints, remains largely unknown, which hinders its widespread use. In this study, we develop a novel Linear Programming based Feature Selection method (LPFS) to understand the mechanism of acupuncture effect, at molecular level, by revealing the metabolite biomarkers for acupuncture treatment. Specifically, we generate and investigate the high-throughput metabolic profiles of acupuncture treatment at several acupoints in human. To select the subsets of metabolites that best characterize the acupuncture effect for each meridian point, an optimization model is proposed to identify biomarkers from high-dimensional metabolic data from case and control samples. Importantly, we use nearest centroid as the prototype to simultaneously minimize the number of selected features and the leave-one-out cross validation error of classifier. We compared the performance of LPFS to several state-of-the-art methods, such as SVM recursive feature elimination (SVM-RFE) and sparse multinomial logistic regression approach (SMLR). We find that our LPFS method tends to reveal a small set of metabolites with small standard deviation and large shifts, which exactly serves our requirement for good biomarker. Biologically, several metabolite biomarkers for acupuncture treatment are revealed and serve as the candidates for further mechanism investigation. Also biomakers derived from five meridian points, Zusanli (ST36), Liangmen (ST21), Juliao (ST3), Yanglingquan (GB34), and Weizhong (BL40), are compared for their similarity and difference, which provide evidence for the specificity of acupoints. Our result demonstrates that metabolic profiling might be a promising method to investigate the molecular mechanism of acupuncture. Comparing with other existing methods, LPFS shows better performance to select a small set of key molecules. In addition, LPFS is a general methodology and can be applied to other high-dimensional data analysis, for example cancer genomics.


A case report of an excellent response to interferon- α in a patient with functional metastasized neuroendocrine tumor refractory to other treatments.
Interferon alpha (IFNα) has been used for a long time in patients with functionally active neuroendocrine tumors (NET). However, due to the unfavorable toxicity profile of interferon, the perceived limited efficacy as well as the development of novel substances, IFNα is only used sparingly in the treatment of NET to date. We describe the case of a 63-year-old male patient with highly differentiated, functional NET of the ileum and synchronous liver metastasis. After failure of classical therapies including dose-intensified somatostatin analog treatment and palliative primary tumor resection, a therapy with pegylated IFNα2a (135 μg/wk) was initiated. Following this treatment, the patient fully recovered from signs of hypersecretion and demonstrated an impressive tumor response. Thirty months after initiating IFNα, the patient is still free of clinical symptoms and shows a sustained tumor response. Notably, no relevant side effects were observed. Our case report supports the use of IFNα in patients with functional NET refractory to classical treatments.


Mean corpuscular volume levels and all-cause and liver cancer mortality.
An elevated mean corpuscular volume (MCV) is associated with aging, nutrition, alcohol abuse and more, and it is known as a survival predictor in chronically ill patients. The aim of this study was to investigate the association between MCV levels and mortality from all-causes, cancer and site-specific cancer in a non-anemic healthy population. A total of 36,260 participants aged 40 years or older who underwent routine check-ups at Seoul National University Hospital Health Promotion Center between 1995 and 2008 were followed-up for mortality until December 31, 2008, retrospectively. During an average follow-up of 8.0 years, 1107 deaths including 547 cancer deaths were observed. The adjusted hazard ratios (aHRs) of the subjects with the highest quartile of MCV ≥95.8 fL in men and MCV ≥94.2 fL in women for all-cause and cancer mortality were 1.44 [95% confidence interval (CI), 1.15-1.80] and 1.51 (95% CI, 1.10-2.07) for men and 1.55 (95% CI, 1.08-2.22) and 1.25 (95% CI, 0.74-2.11) for women, respectively, compared with those in the reference group (90.5 fL≤MC <93.0 fL in men and 89.2 fL≤MCV<91.6 fL in women). Elevated MCV level was related to an increased risk of liver cancer mortality in men (aHR, 3.55; 95% CI, 1.75-7.21). This study suggests that the elevated MCV level in non-anemic cancer-free individuals was associated with increased all-cause mortality in both men and women, and with cancer mortality, in particular liver cancer mortality in men. Future prospective studies are required to consolidate our findings.


Near infra-red spectroscopy and arterial oxygen extraction at altitude.
The ratio of oxygenated to total haemoglobin (Hb), or rSO2, obtained by near infrared spectroscopy (NIRS), includes both arterial and venous blood of the region examined. The relationship of arterial oxygen extraction, E, and saturation, SaO2, to rSO2 can be expressed, for normally functioning tissue, as E = 1.39 (1 - rSO2/SaO2). Cerebral E, at rest, is constant at lower altitudes but is reduced at 5000 m. This corresponds to constant values of E for SaO2 values above 90% (approximately). E declines linearly for lower SaO2 values, either including measurement at high altitude or at sea level with a reduced inspiratory oxygen concentration. In addition to measurements of brain NIRS resting oxygen extraction of liver, muscle and kidney have also been calculated from NIRS measurements made, on normal inspired air, at sea level and after acute ascent to 2400 m and 5050 m. At 5050 m E was reduced for all four regions but at 2400 m was the same as at sea level for brain, liver and muscle; for the kidney E was elevated at 2400 m. Cerebral oxygen extraction was calculated for rest and the full range of exercise. It was constant at sea level for the lower levels of exercise and, if the calculated extraction value assumptions still hold at lower SaO2 values, reduced for the higher work rates at intermediate altitudes. The present study confirms constancy of oxygen extraction and hence the ratio of oxygen delivery to oxygen consumption (1/E), within physiological limits, and appears to show where those limits lay and, to some extent, show how matters change beyond ordinary physiological limits.


Longitudinal evaluation of cartilage composition of matrix-associated autologous chondrocyte transplants with 3-T delayed gadolinium-enhanced MRI of cartilage.
The purposes of this study were to use delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to evaluate the zonal distribution of glycosaminoglycans (GAGs) in normal cartilage and repair tissue and to use 3-T MRI to monitor the GAG content in matrix-associated autologous chondrocyte transplants. Fifteen patients who underwent matrix-associated autologous chondrocyte transplantation in the knee joint underwent MRI at baseline and 3-T follow-up MRI 1 year later. Total and zonal changes in longitudinal relaxivity (deltaR1) and relative deltaR1 were calculated for repair tissue and normal hyaline cartilage and compared by use of analysis of variance. There was a significant difference between the mean deltaR1 of repair tissue and that of reference cartilage at baseline and follow-up (p < 0.001). There was a significant increase in deltaR1 value and a decrease in GAG content from the deep layer to the superficial layer in the reference cartilage and almost no variation and significantly higher values for the repair tissue at both examinations. At 1-year follow-up imaging, there was a 22.7% decrease in deltaR1 value in the deep zone of the transplant. T1 mapping with dGEMRIC at 3 T shows the zonal structure of normal hyaline cartilage, highly reduced zonal variations in repair tissue, and a tendency toward an increase in global and zonal GAG content 1 year after transplantation.


Profiling Chromatin Landscape at High Resolution and Throughput with 2C-ChIP.
Chromatin immunoprecipitation (ChIP) is used to probe the presence of proteins and/or their posttranslational modifications on genomic DNA. This method is often used alongside chromosome conformation capture approaches to obtain a better-rounded view of the functional relationship between chromatin architecture and its landscape. Since the inception of ChIP, its protocol has been modified to improve speed, sensitivity, and specificity. Combining ChIP with deep sequencing has recently improved its throughput and made genome-wide profiling possible. However, genome-wide analysis is not always the best option, particularly when many samples are required to study a given genomic region or when quantitative data is desired. We recently developed carbon copy-ChIP (2C-ChIP), a new form of the high-throughput ChIP analysis method ideally suited for these types of studies. 2C-ChIP applies ligation-mediated amplification (LMA) followed by deep sequencing to quantitatively detect specified genomic regions in ChIP samples. Here, we describe the generation of 2C-ChIP libraries and computational processing of the resulting sequencing data.


Does a positive bias relate to social behavior in children with ADHD?
This study examines whether positively biased self-perceptions relate to social behaviors in children with attention-deficit/hyperactivity disorder (ADHD) as compared to control children. The social behaviors of children with ADHD (n=87) were examined relative to control children (CTL; n=38) during a laboratory-based dyadic social interaction task. Children with ADHD were subgrouped into those with a positive illusory bias (PIB) in their self-perceptions (ADHD + PIB) versus those without such a bias (ADHD - PIB). Using a behavioral coding system adapted for this study, ADHD + PIB, ADHD - PIB, and CTL participants were compared on objectively coded social behaviors occurring within the context of the social interaction task. Whereas both ADHD groups displayed more disruptive behavior than controls, only the ADHD + PIB group displayed less prosocial behavior and less effortful behavior. This study breaks new ground by examining positively biased self-perceptions as they relate to social behavior in children with ADHD and provides promising new insight into the social problems experienced by these children.


From handmaiden to right hand--the infancy of nursing.
AFTER THE AMERICAN CIVIL WAR was over, women once again faced prejudice that kept them out of the nursing profession, but they were not willing to accept this fate. NURSING PIONEERS, such as Linda Richards and Lillian Wald, persisted in their quest for training and oversaw the establishment of a number of training programs for nurses in the United States. THESE WOMEN, recognizing the importance of organization to their fledgling profession, then turned their attention to continuity in training programs and licensure.


Self-check with plaque disclosing solution improves oral hygiene in schoolchildren living in a children's home.
The effectiveness of an oral hygiene program for children living in a children's home has been reported. However, to the best of our knowledge, no studies have evaluated the possible effects of self-checking of oral health among children residing in a children's home. The objective of this study was to examine if self-checking using plaque disclosing solution improves oral hygiene in schoolchildren living in a children's home. We enrolled nine schoolchildren (six girls) without untreated decayed teeth living in a children's home in Japan. This preliminary study was designed as a 5-month program comprising group and individual instructions and self-checking using plaque disclosing solution. Paired t-test and Wilcoxon signed-rank test were used for statistical analysis to evaluate the change of Plaque Control Record (PCR) and Patient Hygiene Performance (PHP). The mean PCR significantly decreased to 38.7% after 3 months of self-checking using disclosing solution compared with that before self-checking (i.e., at 1 month) (60.7%) (P < 0.01). PHP score significantly decreased to 1.4 at 4 months compared with that at baseline (2.8) and at 1 month (2.7) (P = 0.012 and P = 0.018). Improvement of oral hygiene status was evaluated according to the ratio of PCR at 4 months to that at 1 month. The average improvement ratio was 0.4 ± 0.35 (range: 0.0-1.0). Significant correlation was not found between improvement rate and school grade (r = 0.63, P = 0.070). Our results suggest that self-checking with disclosing solution may be effective in improving oral hygiene among schoolchildren at a children's home.


Aspirin and heparin to improve live birth rate in IVF for unexplained implantation failure?
The data concerning use of aspirin and/or heparin in IVF failure patients is reviewed. A number of methodological and biological problems are identified. A strategy to achieve reliable conclusions is explained.


A tetrahedral coordination of Zinc during transmembrane transport by P-type Zn(2+)-ATPases.
Zn(2+) is an essential transition metal required in trace amounts by all living organisms. However, metal excess is cytotoxic and leads to cell damage. Cells rely on transmembrane transporters, with the assistance of other proteins, to establish and maintain Zn(2+) homeostasis. Metal coordination during transport is key to specific transport and unidirectional translocation without the backward release of free metal. The coordination details of Zn(2+) at the transmembrane metal binding site responsible for transport have now been established. Escherichia coli ZntA is a well-characterized Zn(2+)-ATPase responsible for intracellular Zn(2+) efflux. A truncated form of the protein lacking regulatory metal sites and retaining the transport site was constructed. Metrical parameters of the metal-ligand coordination geometry for the zinc bound isolated form were characterized using x-ray absorption spectroscopy (XAS). Our data support a nearest neighbor ligand environment of (O/N)(2)S(2) that is compatible with the proposed invariant metal coordinating residues present in the transmembrane region. This ligand identification and the calculated bond lengths support a tetrahedral coordination geometry for Zn(2+) bound to the TM-MBS of P-type ATPase transporters.


Recent advances in fluorescent probes for dual-detecting ONOO- and analytes.
Although peroxynitrite (ONOO-) plays an essential role in cellular redox homeostasis, its excess ONOO- will affect the normal physiological function of cells. Therefore, real-time monitoring of changes in local ONOO- will contribute to further revealing the biological functions. Reliable and accurate detection of biogenic ONOO- will definitely benefit for disentangling its complex functions in living systems. In the past few years, more fluorescent probes have been developed to help understand and reveal cellular ONOO- changes. However, there has been no comprehensive and critical review of multifunctional fluorescent probes for cellular ONOO- and other analytes. To highlight the recent advances, this review first summarized the recent progress of multifunctional fluorescent probes since 2018, focusing on molecular structures, response mechanisms, optical properties, and biological imaging in the detection and imaging of cellular ONOO- and analytes. We classified and discussed in detail the limitations of existing multifunctional probes, and proposed new ideas to overcome these limitations. Finally, the challenges and future development trends of ONOO- fluorescence probes were discussed. We hoped this review will provide new research directions for developing of multifunctional fluorescent probes and contribute to the early diagnosis and treatment of diseases.


Crocidolite asbestos inhibits pentose phosphate oxidative pathway and glucose 6-phosphate dehydrogenase activity in human lung epithelial cells.
The cytotoxicity of asbestos has been related to its ability to increase the production of reactive oxygen species (ROS), via the iron-catalyzed reduction of oxygen and/or the activation of NADPH oxidase. The pentose phosphate pathway (PPP) is generally activated by the cell exposure to oxidant molecules. Contrary to our expectations, asbestos (crocidolite) fibers caused a dose- and time-dependent inhibition of PPP and decreased its activation by an oxidative stress in human lung epithelial cells A549. In parallel, the intracellular activity of the PPP rate-limiting enzyme, glucose 6-phosphate dehydrogenase (G6PD), was significantly diminished by crocidolite exposure. This inhibition was selective, as the activity of other PPP and glycolysis enzymes was not modified, and was not attributable to a decreased expression of G6PD. On the opposite, the incubation with glass fibers MMVF10 did not modify PPP and G6PD activity. PPP and G6PD inhibition did not correlate with the increased nitric oxide (NO) production elicited by crocidolite in A549 cells. Experiments with the purified enzyme suggest that crocidolite inhibits G6PD by directly interacting with the protein. We propose here a new mechanism of asbestos-evoked oxidative stress, wherein fibers increase the intracellular ROS levels also by inhibiting the main antioxidant pathway of the cell.


[Postoperative Quality Assurance After Cataract Surgery Via the Internet].
Numerous surgeries in the field of ophthalmology take place on an outpatient basis or only as part of a short inpatient stay. The quality requirements are very high. Postoperative quality controls often can't be done by surgeons themselves because the postoperative aftercare is usually no longer carried out at the surgical centre but by the referring ophthalmologists. To optimize our operative quality assurance, the eye center of the University Hospital Freiburg has developed an internet-based quality assurance procedure in cooperation with the Augennetz Südbaden (ANSB), in which numerous established ophthalmologists from the region network. There is comprehensive reporting on cataract surgeries. The results of the follow-up examinations are reported in a structured manner via secure internet masks from the doctors' practices, taking into account data protection regulations. Feedback always takes place after 3 months and, thus, at a point in time at which the final surgical result can usually be assessed. Since the establishment of the quality register in November 2009, a total of 8043 records of cataract operations have been reported until the end of 2018. This sample comprises 20.2% of all cataract operations performed at the eye center of the University Hospital Freiburg during the same period. Mean follow-up was 76 days. During cataract surgery, the target refraction was missed by less than 1 dioptre in 90% of all operated eyes. Keratoplasty was identified as a risk factor for missing the target refraction. The internet-based quality assurance of the eye center of the University Hospital Freiburg enables continuous monitoring of the operation quality over a longer period of time. In patients that underwent keratoplasty, the biometry should be critically questioned preoperatively.


Melanin inspired microcapsules delivering immune metabolites for hepatic fibrosis management.
Patients with hepatic fibrosis (HF) have a high risk of developing liver cirrhosis and hepatocellular carcinoma, and there is an urgent need for preventive strategies to block this process. Previous studies have found that disordered inflammation and oxidative damage play important roles in HF progression, suggesting two attractive therapeutic targets. Herein, a new kind of bioinspired microcapsules with a core-shell structure is generated using microfluidics. Polydopamine nanoparticles (PDANPs), a synthetic analogue of natural melanin, are embedded in the polymer shell to provide antioxidative properties for these microcapsules. The aqueous core is used to encapsulate ketone body β-hydroxybutyrate (BHB), an energy metabolite recently known to have regulating effects of cellular signals involved in chronic inflammation. In a HF mouse model, the BHB-encapsulated PDANPs-embedded microcapsules (BHB-PDA-MCs) can not only decrease the severity of inflammatory response, but also the level of oxidative stress. As a result, this combinational strategy is demonstrated to prevent the activation of hepatic stellate cells, the accumulation of extracellular matrix, and the damage of hepatic lobules. These findings indicate that BHB-PDA-MCs can be a promising drug delivery system and have a synergistic effect on HF management.


Liquid chromatographic-tandem mass spectrometric method for the quantitation of sildenafil in human plasma.
A method to determine sildenafil in human plasma involving liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed. Sildenafil and the internal standard (I.S.), diazepam, are extracted from human plasma with ether-dichloromethane (3:2, v/v) at basic pH and analyzed by reversed-phase high-performance liquid chromatography (HPLC) using methanol-10mM ammonium acetate pH 7.0 (85:15, v/v) as the mobile phase. Detection by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring mode was linear over the concentration range 0.125-40.0 ng/ml. Intra- and inter-day precision of the assay at four concentrations within this range were 2.5-8.0%. The method was used to evaluate plasma concentration-time profiles in healthy volunteers given an oral dose of 20mg sildenafil as a combination tablet also containing apomorphine.


Gender Disparities in Industry Payments to Urologists.
To analyze and compare industry payments to urologists in the Open Payments Database by gender. We hypothesized that industry payments might be greater to male vs women urologists. The Open Payments Database was analyzed from 2013-2017 and gender determined for all urologists receiving payments in the following categories: (1) research (made in connection to a research program or protocol), (2) ownership (ownership or investment interests held by the physician or immediate family member), and (3) general. Payment form and amount was collected and average payment per category, by gender, was calculated. A total of 12,161 urologists received industry payments from 2013-2017, of which 90% were male. Over the study period, there was a greater proportional increase in female urologists participating in industry payments: 46.8% for female urologists, vs 12.3% for male urologists (P <.01). Male urologists earned twice as much as women in all categories except for Ownership. Average payment (USD) per urologist was $3,106 vs $1338, $34, 494 vs $16,020, and $39,062 vs $252,710 for General, Research, and Ownership, respectively. Although the number of female urologists receiving industry payment increased during the study period, the average payment amount increased by 14.6% for women, compared to 107.8% for men (P <.01). Analysis of the Open Payments Database shows that on average women urologists earned half as much as men in their industry reported payments.


The relaxation dynamics of a confined glassy simple liquid.
We use molecular-dynamics computer simulations to study the relaxation dynamics of a confined simple liquid. Two types of confining walls are considered: A rough wall and a smooth wall. The simulation is set up in such a way that the static properties of the confined system are identical to the ones of the bulk. Nevertheless, we find that upon cooling the relaxation dynamics of the confined systems differ strongly from the one of the bulk. In particular, we find that close to the rough/smooth wall this dynamics is slowed down/accelerated by orders of magnitude. Using these results we are able to extract a dynamical length scale of the system and we show that this length shows an Arrhenius dependence.


Novel viruses detected in bats in the Republic of Korea.
Bats are natural reservoirs for potential zoonotic viruses. In this study, next-generation sequencing was performed to obtain entire genome sequences of picornavirus from a picornavirus-positive bat feces sample (16BF77) and to explore novel viruses in a pooled bat sample (16BP) from samples collected in South Korea, 2016. Fourteen mammalian viral sequences were identified from 16BF77 and 29 from 16BP, and verified by RT-PCR. The most abundant virus in 16BF77 was picornavirus. Highly variable picornavirus sequences encoding 3Dpol were classified into genera Kobuvirus, Shanbavirus, and an unassigned group within the family Picornaviridae. Amino acid differences between these partial 3Dpol sequences were ≥ 65.7%. Results showed that one bat was co-infected by picornaviruses of more than two genera. Retrovirus, coronavirus, and rotavirus A sequences also were found in the BP sample. The retrovirus and coronavirus genomes were identified in nine and eight bats, respectively. Korean bat retroviruses and coronavirus demonstrated strong genetic relationships with a Chinese bat retrovirus (RfRV) and coronavirus (HKU5-1), respectively. A co-infection was identified in one bat with a retrovirus and a coronavirus. Our results indicate that Korean bats were multiply infected by several mammal viruses.


Effects of body mass index or dosage on gastrointestinal disorders associated with extended-release metformin in type 2 diabetes: Sub-analysis of a Phase IV open-label trial in Chinese patients.
To determine whether gastrointestinal (GI) tolerability of metformin monotherapy varies according to baseline BMI or at doses >1500mg/day in patients newly diagnosed with type 2 diabetes. We performed a sub-analysis of the safety population from a prospective, multicenter, Phase IV open-label study in which 371 Chinese patients with type 2 diabetes received extended-release metformin monotherapy for 16 weeks. The incidence, severity and duration of GI adverse events (AEs) were compared between normal-weight (BMI<25kg/m(2), n=155) and overweight/obese (BMI≥25kg/m(2), n=216) patients. The primary objective was to determine whether baseline BMI affect the incidence, severity and duration of GI AEs, using Fisher's exact test and Student's t-test. Secondary objectives were to compare these factors according to final metformin dose (≤1500mg/day versus 2000mg/day). The proportion of patients who reported ≥1 GI AE did not differ significantly between BMI groups (25.2% of the normal-weight group versus 21.3% of the overweight/obese group; p=0.3840). Patients who reported GI AEs in the two BMI groups experienced similar GI AE severity (p=0.5410), mean duration (p=0.3572) and duration distribution (p=0.1347). There was no significant difference in GI AE severity and duration between metformin dosage groups (≤1500mg/day versus 2000mg/day). Newly-diagnosed Chinese type 2 diabetes patients of normal weight are no more likely than overweight/obese patients to suffer from increased incidence rates, severity or duration of GI AEs when treated with first-line extended-release metformin monotherapy. Doses of 2000mg/day did not increase the severity or duration of GI AEs.


Effect of Aplidin in acute lymphoblastic leukaemia cells.
The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G(1) and a G(2) M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (>88%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.


Allene oxide synthase from Arabidopsis thaliana (CYP74A1) exhibits dual specificity that is regulated by monomer-micelle association.
We investigate the effects of detergent on the kinetics and oligomeric state of allene oxide synthase (AOS) from Arabidopsis thaliana (CYP74A1). We show that detergent-free CYP74A1 is monomeric and highly water soluble with dual specificity, but has relatively low activity. Detergent micelles promote a 48-fold increase in k(cat)/K(m) (to 5.9 x 10(7)M(-1)s(-1)) with concomitant changes in the spin state equilibrium of the haem-iron due to the binding of a single detergent micelle to the protein monomer, which is atypical of P450 enzymes. This mechanism is shown to be an important determinant of the substrate specificity of CYP74A1. CYP74A1 may be suited for structural resolution of the first plant cytochrome P450 and its 9-AOS activity and behaviour in vitro has implications for its role in planta.


Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1.
In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up. Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only). Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed. With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.


Facilitating a safe and caring atmosphere in everyday life in forensic mental health wards - a qualitative study.
To explore healthcare professionals' experiences with facilitating a safe and caring atmosphere in patients' everyday lives in forensic mental health wards. This qualitative study employed interviews with 16 healthcare professionals working shifts in two forensic mental healthcare wards in Norway. Data were analysed using phenomenological hermeneutic analysis. The findings are presented in terms of two themes. The first theme is "Creating a calming atmosphere" and includes the subthemes "Creating caring surroundings with safety, comfort and trust" and "Balancing everyday life activities". The second theme is "Facilitating risk assessments and care" and includes the subthemes "Acting as a team", "Becoming aware of the meaning in signs" and "Becoming aware of vulnerability and the window of tolerance". Involvement in patients' history and lived lives is important both for understanding general social behaviour as well as for assessing signs, symptoms, and changes in patients' conditions; furthermore, it provides valuable information that allows healthcare professionals to become aware of the underlying meanings in signs, which can facilitate examinations and treatment. Acting as a team is essential to solve issues in a calm and safe way when signs of violence occur. In addition, our participants highlighted the need to be aware of individual patients' vulnerability and windows of tolerance to obtain a deeper understanding of patients' lived lives as a whole in the context of providing therapy and care to patients.


A taxonomy of occupational and organisational stressors and protectors of mental health reported by veterinary professionals in Australasia.
To develop a taxonomy of positive and negative occupational and organisational factors reported that impact the mental health of veterinary professionals. Veterinary professionals working in Australasia were surveyed between February and June of 2021. The survey comprised two questions related to participants' perceptions of the positive and negative aspects of their job role that impact their mental health and wellbeing. Reflexive thematic analysis was employed to analyse the responses and generate two taxonomies of occupational and organisation stressors and protectors reported by participants. Fifty-three responses from veterinary professionals were analysed. The final stressor taxonomy generated contained 9 overarching themes and 36 subthemes. The most common of these were negative work conditions, challenging relationships with clients, and adverse events and patient outcomes. The taxonomy of protectors contained 11 overarching themes and 32 subthemes, with the most common including fulfillment and satisfaction, positive work conditions, and relationships with colleagues. This study is the first to examine both positive and negative factors in the veterinary industry reported by veterinary professionals in Australasia. The results highlighted stressors that can be addressed on both an individual and organisational level to promote the mental and health well-being of professionals working in the animal care industry.


Antarctic ice mass variations from 1979 to 2017 driven by anomalous precipitation accumulation.
Antarctic ice mass balance is determined by precipitation and ice discharge, and understanding their relative contributions to contemporary Antarctic ice mass change is important to project future ice mass loss and resulting sea level rise. There has been evidence that anomalous precipitation affects Antarctic ice mass loss estimates, and thus the precipitation contribution should be understood and considered in future projections. In this study, we revisit changes in Antarctic ice mass over recent decades and examine precipitation contributions over this period. We show that accumulated (time-integrated) precipitation explains most inter-annual anomalies of Antarctic ice mass change during the GRACE period (2003-2017). From 1979 to 2017, accumulated Antarctic precipitation contributes to significant ice mass loss acceleration in the Pacific sector and deceleration in the Atlantic-Indian Sectors, forming a bi-polar spatial pattern. Principal component analysis reveals that such a bi-polar pattern is likely modulated by the Southern Annular Mode (SAM). We also find that recent ice mass loss acceleration in 2007 is related to a variation in precipitation accumulation. Overall ice discharge has accelerated at a steady rate since 1992, but has not seen a recent abrupt increase.


[Thoracic surgery in tuberculosis and non-tuberculous mycobacterial diseases].
Tuberculosis and non-tuberculous mycobacteria are common indications of pleural and mediastinal surgery on a diagnostic intend. However, parenchymatous resection on a curative intend has been proven to benefit to patients with multiresistant tuberculosis in adjunction with prolonged antibiotic treatment. Furthermore, tuberculosis sequelae, i.e. destroyed lung, Aspergillus-infected cavitary tuberculosis, and related hemoptysis are eradicated by a surgical management after careful medical preparation. Finally, surgical resection of localized Mycobacterium avium and M. xenopii infections is associated with a high rate of sputum conversion and a low morbidity.


Sources of variation in the analysis of trichothecenes in cereals by gas chromatography-mass spectrometry.
The sources of variation In the analysis of trichothecenes in cereals by gas chromatography mass spectrometry (GC-MS) were studied and Identified. Ways to decrease some of the variations identified are presented and discussed. The method Is validated for deoxynivalenol, nivalenol, 3-acetyldeoxynivalenol, fusarenon-X, diacetoxyscirpenol, HT-2 toxin and T-2 toxin. The general variability in the performance of the GC-MS apparatus itself, as well as derivatisation, matrix effect, injection and quantification were identified to be the sources of variation. The use of internal standards was studied in order to decrease the variation due to problems with derivatisation and the overall sample preparation. Two derivatisation reagents were compared, one of which was found to be more effective for decreasing this variation. The calibrants prepared in the cereal extract reduced the variation due to the matrix effect and thus improved the quantification. "Constant Standards" were introduced in order to detect and decrease the variation caused by injection and the apparatus itself. The validation study proved that this analytical method for trichothecenes was adequately reliable and sensitive. The relative standard deviation varied between 3-9% and the recovery between 46-90% for the different trichothecenes determined. The limit of detection for a range of trichothecenes varied from 5 μg/kg to 15 μg/kg.


[Exploration of a third degree atrioventricular block by standard echocardiography, tissue Doppler imaging, and treatment with a cardiac pacemaker in a German wire-haired pointer].
A nine-year-old intact male Drathaar was evaluated for syncope and extreme weakness, and was found to have a third degree atrioventricular (AV) block. As there were no biochemic, serologic, organic (thoracic radiographs, abdominal echography, standard and tissue Doppler echocardiographies) and histologic (interventricular septum biopsy) anomalies, the dog was treated with a permanently implanted cardiac pacemaker.


Characterization of a novel picornavirus prevalent in experimental rabbits (Oryctolagus cuniculus).
Here, using viral metagenomic method a novel picornavirus (named UJS-2019picorna, GenBank accession number OP821762) was discovered in fecal and blood samples of experimental rabbits (Oryctolagus cuniculus). The complete genome size of UJS-2019picorna is 7832 bp excluding the poly(A)-tail, with GC content of 44.00% and a nucleotide composition of 28.0% A, 28.0% U, 21.5% G, and 22.5% C. The viral genome has a typical picornavirus organization pattern from the 5'-3' direction: VPg-5' UTR-(L)-P1, (VP4-VP2-VP3-VP1)-P2, (2 A-2B-2C)-P3, (3 A-3B-3C-3D)-3' UTR-poly(A). The P1 region of UJS-2019picorna is related to Erbovirus with amino acid identity of 37.31%, while the P2 and P3 regions are the closest to Bopivirus with amino acid identity of 35.66%-39.53%. According to the Picornaviridae Study Group guidelines, UJS-2019picorna should be presumed to be a new genus belonging to the Picornaviridae family. Epidemiologic study revealed that this novel picornavirus was prevalent in a cohort of experimental rabbits, with prevalence rate of 23.68% (9/38) in feces and 18.4% (7/38) in blood samples. Further work is required to elucidate whether this virus is pathogenic to rabbits and whether it has influence on studies using rabbits as experimental animal.


Interdental papilla loss: treatment by hyaluronic acid gel injection: a case series.
The purpose of this prospective clinical trial was to examine the clinical and patient outcomes following esthetic reconstruction of interdental papilla loss in anterior teeth, using an injectable, non-animal-based, hyaluronic acid gel. Ten systemically healthy adults, with at least one anterior site with class I or II interdental papilla loss, were recruited. Following local anesthesia, ∼0.2 ml of hyaluronic acid gel was injected directly into the base of the papilla. The injection was repeated twice 21 days later. Patients were seen monthly for follow-up. Lost papilla surface area was calculated from digital clinical photographs taken at baseline and at 4 and 6 months postoperatively. Differences in lost papilla surface area between baseline and postoperative time points were statistically analyzed. Participants completed questionnaires (satisfaction surveys). Seventeen sites (13 maxillary, 4 mandibular) were treated in 9 females who completed the study. The lost inderdental papilla area at baseline and at the 4- and 6-month postoperative visits was 1.2 ± 1.8 mm(2) (mean ± SD), 0.6 ± 0.9 mm(2), and 0.7 ± 0.7 mm(2), respectively. Differences between baseline and postoperative visits were statistically significant (p < 0.0001). Two thirds of the patients would choose to undergo the procedure again. Use of hyaluronic acid gel to treat interdental papilla loss resulted in significant improvement at 6 months. Patients expressed satisfaction with the obtained improvement and dissatisfaction with the associated procedure discomfort. Treatment of interdental papilla loss (black triangle) by hyaluronic acid gel injection appears a promising modality to address this esthetic patient concern.


Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas.
We investigated the protein expression of three glioma-associated antigens (GAAs) in pediatric brain stem glioma (BSG) and non-brain stem glioma (NBSG) cases with a view to their possible use in immunotherapy. Expression of EphA2, IL-13Ralpha2 and Survivin were studied by immunohistochemistry on paraffin-embedded tissues using a series of 15 BSG cases and 12 NBSG cases. Thirteen of 15 BSGs and all 12 NBSGs expressed at least one of GAAs; and 7 BSGs and 9 NBSGs expressed at least two of these GAAs at higher levels than non-neoplastic brain. There was no association between the tumor grade and levels of GAA expression. Although many cases demonstrated diffuse expression of GAAs throughout specimens, partial or patchy expression was noted in a small number of cases, suggesting a need for targeting multiple GAAs in immunotherapy. These results suggest that EphA2, IL-13Ralpha2 and Survivin are suitable targets for developing vaccine strategies for pediatric glioma.


Nanosecond fluorometry of the single tryptophan in cytochrome P-450e (P450IIB2).
Properties of the single tryptophan residue in rat liver microsomal phenobarbital-inducible cytochrome P-450e (P450IIB2) were studied by the nanosecond time-resolved fluorometry. The tryptophan fluorescence decay time was found to be 3.6 ns and it was not affected by the addition of substrate (perhydrophenanthrene). This result strongly indicates that the tryptophan residue is not a part of the substrate-binding site.


MRI quality control: six imagers studied using eleven unified image quality parameters.
Quality control of the magnetic resonance imagers of different vendors in the clinical environment is non-harmonised, and comparing the performance is difficult. The purpose of this study was to develop and apply a harmonised long-term quality control protocol for the six imagers in our organisation in order to assure that they fulfil the same basic image quality requirements. The same Eurospin phantom set and identical imaging parameters were used with each imager. Values of 11 comparable parameters describing the image quality were measured. Automatic image analysis software was developed to objectively analyse the images. The results proved that the imagers were operating at a performance level adequate for clinical imaging. Some deficiencies were detected in image uniformity and geometry. The automated analysis of the Eurospin phantom images was successful. The measurements were successfully repeated after 2 weeks on one imager and after half a year on all imagers. As an objective way of examining the image quality, this kind of comparable and objective quality control of different imagers is considered as an essential step towards harmonisation of the clinical MRI studies through a large hospital organisation.


Characterization of a porcine glucosephosphate isomerase-processed pseudogene at chromosome 1q1.6-1.7.
A porcine glucosephosphate isomerase-processed pseudogene has been isolated and sequenced. The pseudogene has several base substitutions as well as an insertion and deletions, and is 83% homologous to the corresponding cDNA. It contains an intervening sequence of 565 bp, is truncated at the 3' end, and is flanked by direct repeats of seven nucleotides. Fluorescent in situ hybridization to porcine metaphase chromosomes localized the processed pseudogene to Chromosome (Chr) 1q1.6-1.7. A (GT)14(AT)15 microsatellite was detected close to the processed pseudogene.


Effects of thyroliberin, triiodothyronine and cyclic guanosine 3'5'-monophosphate on the volume of nuclei of thyrotropic cells in rat anterior pituitary in vitro.
Influence of TRH, T3 and cGMP on the volume of thyrotropic cells nuclei in rat pituitary in vitro has been examined. A significant increase of the volume of thyrotropic cells nuclei in the culture exposed to TRH, in another one exposed to cGMP and in the third one exposed to both TRH and cGMP together have been observed. The mean volume of cells nuclei within the group exposed to T3 was significantly lower, when compared to the control. T3 inhibited the TRH-induced increase of the volume of thyrotrophs nuclei. The obtained results suggest that the role of cGMP and T3 in the regulation of the thyrotropic cell function are independent and rather opposed. Since TRH increases the level of cAMP in the anterior pituitary, additive effect of TRH and exogenous cGMP support the assumption that both the cyclic nucleotides within the thyrotropic cell act in the same direction.


Integrative Analysis Revealing Human Adipose-Specific Genes and Consolidating Obesity Loci.
Identification of adipose-specific genes has contributed to an understanding of mechanisms underlying adipocyte development and obesity. Herein, our analyses of the recent Genotype-Tissue Expression (GTEx) database revealed 38 adipose-specific/enhanced protein coding genes, among which 3 genes were novel adipose-specific, and 414 highly differentially expressed genes (DEGs) between subcutaneous and omental adipose depots. By integrative analyses of genome-wide association studies (GWASs), 14 adipose-specific/enhanced genes and 60 DEGs were found to be associated with obesity-related traits and diseases, consolidating evidence for contribution of these genes to the regional fat distribution and obesity phenotypes. In addition, expression of HOXC cluster was up-regulated in subcutaneous adipose tissue, and the majority of the HOXB cluster was expressed highly in omental adipose tissue, indicating differential expression patterns of HOX clusters in adipose depots. Our findings on the distinct gene expression profiles in adipose tissue and their relation to obesity provide an important foundation for future functional biological studies and therapeutic targets in obesity and associated diseases.