Muscarinic agonist-mediated heterologous desensitization in isolated ileum requires activation of both muscarinic M2 and M3 receptors.
We investigated the subtypes of the muscarinic receptor mediating short-term heterologous desensitization in the isolated ileum. Treatment of the ileum from C57BL/6 mice with acetylcholine (30 microM) for 20 min caused a subsequent decrease in contractile sensitivity to both prostaglandin F2alpha (PGF2alpha) and the muscarinic agonist, oxotremorine-M. This subsensitivity was characterized by 7- and 3-fold increases in the EC50 values of the agonists, respectively, with no significant effect on the maximal response. The subsensitivity to PGF2alpha was prevented in both M2 and M3 muscarinic receptor knockout mice. Similarly, the subsensitivity to oxotremorine-M was prevented in M2 knockout mice. Acetylcholine-mediated desensitization of histamine-induced contractions in the guinea pig ileum was inhibited by both M2- and M3-selective muscarinic antagonists with high potency, although careful analysis of the data suggested behavior more consistent with an M2 antagonistic profile. Modeling studies showed that the competitive antagonism of response contingent upon activation of two receptor subtypes should exhibit a pharmacological profile similar to that of the least sensitive signaling pathway. Our results demonstrate that muscarinic agonist-mediated short-term heterologous desensitization of intestinal smooth muscle is contingent upon activation of both M2 and M3 muscarinic receptors and that activation of either receptor by itself is insufficient to cause desensitization.


Imaging of chemiluminescent reactions in mesoscale silicon-glass microstructures.
Chemiluminescent reactions in mesoscale analytical structures (chips) containing micrometre-sized interconnecting channels and chambers (pL-nL total volume) were imaged. The chips were fabricated by bonding Pyrex glass to etched pieces of silicon using a high-temperature diffusive bonding technique. In initial experiments light emission from an enhanced chemiluminescent horseradish peroxidase reaction and from a peroxyoxalate reaction contained in straight channels (300 microns wide x 20 mu deep; volume 70.2 nL) and open chambers (812 microns wide, 400 microns deep, 5.2 mm long) linked by channels (100 microns wide, 20 microns deep) to an exit and entry port were studied using a specially modified microplate holder and an Amerlite microplate luminometer. Light emission from more complex structures (two chambers interconnected by a branching channel 100 microns wide, 20 microns deep) filled with a solution containing alkaline phosphatase, Emerald, and CSPD was imaged using a Photometrics Star 1 CCD camera. Detailed investigation of the detection and spatial resolution of the signal was performed on a Berthold Luminograph LB 980 using both the enhanced chemiluminescent horseradish peroxidase reaction and a peroxyoxalate reaction. We successfully resolved light emission from silicon structures with dimensions 100 microns wide and 20 microns deep. These simple silicon structures served as models for more complex designs that will be used for simultaneous multi-analyte assays in which an imaging system resolves and quantitates light emission from different locations on a silicon-glass analytical device.


Genome-Wide Enhancer Analysis Reveals the Role of AP-1 Transcription Factor in Head and Neck Squamous Cell Carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but its epigenomic features have not been determined. Here, we studied the chromatin landscape of active enhancers of HNSCC head tumor tissues by performing H3K27ac and H3K4me1 ChIP-Seq with a Tgfbr1/Pten double conditional knockout HNSCC mouse model. We identified 1,248 gain variant enhancer loci (VELs) and 2,188 lost VELs, as well as 153 gain variant super enhancer loci (VSELs) and 234 lost VSELs. Potentially involved transcription factors were predicted with motif analysis, and we identified AP-1 as one of the critical oncogenic transcription factors in HNSCC and many other types of cancer. Combining transcriptomic and epigenomic data, our analysis also showed that AP-1 and histone modifications coordinately regulate target gene expression in HNSCC. In conclusion, our study provides important epigenomic information for enhancer studies in HNSCC and reveals new mechanism for AP-1 regulating HNSCC.


The endocrine pancreas during pregnancy and lactation in the rat.
The percentage of endocrine tissue in the whole pancreas, the volume density of the insulin producing beta-cells, the non-fasting plasma glucose level and the plasma insulin level were studied in pregnant rats and in puerperal lactating and non-lactating rats. During pregnancy there was a progressive rise in the percentage of endocrine tissue, in the volume density of the beta-cells and in the insulin level in peripheral blood. Plasma glucose levels declined during pregnancy. A lower plasma glucose level, a lower plasma insulin level, a lower percentage of endocrine tissue and a lower volume density of the beta-cells was found in lactating compared to non-lactating rats.


Endoscopic features of primary upper gastrointestinal lymphoma.
Primary upper gastrointestinal lymphoma (PUGIL) is relatively common in the Middle East, and upper gastrointestinal (UGI) endoscopy is very useful for its diagnosis. Analysis of 33 patients with PUGIL revealed that ulceration, mainly superficial and/or multicentric, in 24 (73%) patients was the most frequent endoscopic feature. A granulonodular pattern was characteristic of duodenal involvement, but in contrast, infiltrative and polypoid patterns were more often seen in gastric lymphoma. Isolated involvement of the fundus was not seen in these patients. With a high index of suspicion and careful attention to mucosal details, the diagnosis of PUGIL may be made early by multiple biopsies during UGI endoscopy.


Remythologizing culture: Narrativity, justification, and the politics of personalization.
The thesis that the self is a story unfolding in prescriptive space is typically embraced by social constructionists as a radical alternative to naturalistic accounts of human development. Yet, the Tree of Knowledge (ToK) System proposed by Henriques (2003) implies that events at multiple levels of analysis (i.e., matter, life, mind, and culture) can be considered as conditions of possibility for the emergence of meaningful personal narratives. Thus, the ToK System represents an opportunity to recast the work of naturalists and social constructionists in a framework that is at once scientific and humanistic.


Treatment of tuberculosis with levofloxacin or moxifloxacin: report of 6 pediatric cases.
We report 6 pediatric cases of tuberculosis caused by Mycobacterium tuberculosis and treated them with levofloxacin or moxifloxacin in the mother-child unit of a university hospital in France between 2005 and 2011. We assess the clinical efficacy and safety of fluoroquinolones and the benefit-risk ratio for their use as second-line antituberculosis drugs in children and adolescents.


Human Paleoneurology and the Evolution of the Parietal Cortex.
Paleoneurology deals with the study of brain anatomy in fossil species, as inferred from the morphology of their endocranial features. When compared with other living and extinct hominids, Homo sapiens is characterized by larger parietal bones and, according to the paleoneurological evidence, also by larger parietal lobes. The dorsal elements of the posterior parietal cortex (superior parietal lobules, precuneus, and intraparietal sulcus) may be involved in these morphological changes. This parietal expansion was also associated with an increase in the corresponding vascular networks, and possibly with increased heat loads. Only H. sapiens has a specific early ontogenetic stage in which brain form achieves such globular appearance. In adult modern humans, the precuneus displays remarkable variation, being largely responsible for the longitudinal parietal size. The precuneus is also much more expanded in modern humans than in chimpanzees. Parietal expansion is not influenced by brain size in fossil hominids or living primates. Therefore, our larger parietal cortex must be interpreted as a derived feature. Spatial models suggest that the dorsal and anterior areas of the precuneus might be involved in these derived morphological variations. These areas are crucial for visuospatial integration, and are sensitive to both genetic and environmental influences. This article reviews almost 20 years of my collaborations on human parietal lobe evolution, integrating functional craniology, paleoneurology, and evolutionary neuroanatomy.


Micellar electrokinetic capillary chromatography fingerprints combined with multivariate statistical analyses to evaluate the quality consistency and predict the fingerprint-efficacy relationship of Salviae miltiorrhizae Radix et Rhizoma (Danshen).
Micellar electrokinetic capillary chromatography fingerprinting combined with quantification was successfully established and applied to evaluate the quality consistency of Danshen, which is a medicinal herb used to treat various diseases, especially coronary cerebrovascular diseases. A background electrolyte composed of 20 mmol/L sodium tetraborate, 90 mmol/L orthoboric acid, 25 mmol/L sodium phosphate monobasic dehydrate, and 65 mmol/L sodium dodecyl sulfate was used to separate compounds. To optimize micellar electrokinetic capillary chromatography conditions, a response surface strategy was set up for orthogonal experimental design. In fingerprint assessments, a systematic quantified fingerprint method was established for integrated quality assessment of Danshen samples from qualitative and quantitative perspectives, by which the quality of 30 samples was well differentiated. The principal component analysis coupled with quantitative determination of two components was applied to explain that the quality consistency of the medicinal herb was relatively good within one harvest season, but poor among harvest seasons for the Danshen samples. In addition, the fingerprint-efficacy relationship between the chemical fingerprints and antioxidant activities was investigated utilizing orthogonal projection to latent structures, which provided important medicinal efficacy information for quality control. This work offered an efficient, holistic, and powerful approach to evaluate the quality consistency of Danshen samples.


A passive acoustic monitoring method applied to observation and group size estimation of finless porpoises.
The present study aimed at determining the detection capabilities of an acoustic observation system to recognize porpoises under local riverine conditions and compare the results with sighting observations. Arrays of three to five acoustic data loggers were stationed across the main channel of the Tian-e-zhou Oxbow of China's Yangtze River at intervals of 100-150 m to record sonar signals of free-ranging finless porpoises (Neophocaena phocaenoides). Acoustic observations, concurrent with visual observations, were conducted at two occasions on 20-22 October 2003 and 17-19 October 2004. During a total of 42 h of observation, 316 finless porpoises were sighted and 7041 sonar signals were recorded by loggers. The acoustic data loggers recorded ultrasonic signals of porpoises clearly, and detected the presence of porpoises with a correct detection level of 77.6% and a false alarm level of 5.8% within an effective distance of 150 m. Results indicated that the stationed passive acoustic observation method was effective in detecting the presence of porpoises and showed potential in estimating the group size. A positive linear correlation between the number of recorded signals and the group size of sighted porpoises was indicated, although it is faced with some uncertainty and requires further investigation.


Estimation of allele-specific fitness effects across human protein-coding sequences and implications for disease.
A central challenge in human genomics is to understand the cellular, evolutionary, and clinical significance of genetic variants. Here, we introduce a unified population-genetic and machine-learning model, called Linear Allele-Specific Selection InferencE (LASSIE), for estimating the fitness effects of all observed and potential single-nucleotide variants, based on polymorphism data and predictive genomic features. We applied LASSIE to 51 high-coverage genome sequences annotated with 33 genomic features and constructed a map of allele-specific selection coefficients across all protein-coding sequences in the human genome. This map is generally consistent with previous inferences of the bulk distribution of fitness effects but reveals pervasive weak negative selection against synonymous mutations. In addition, the estimated selection coefficients are highly predictive of inherited pathogenic variants and cancer driver mutations, outperforming state-of-the-art variant prioritization methods. By contrasting our estimated model with ultrahigh coverage ExAC exome-sequencing data, we identified 1118 genes under unusually strong negative selection, which tend to be exclusively expressed in the central nervous system or associated with autism spectrum disorder, as well as 773 genes under unusually weak selection, which tend to be associated with metabolism. This combination of classical population genetic theory with modern machine-learning and large-scale genomic data is a powerful paradigm for the study of both human evolution and disease.


Wet Deposition of Globally Transportable Microplastics (<25 μm) Hovering over the Megacity of Beijing.
Microplastics of size <25 μm possess globally transportable features, but the impact of precipitation on their transport remains unclear. Here, microplastics were detected in all 10 studied rainfalls in Beijing, with <25 μm microplastics present in 8 rainfalls. Interestingly, microplastic abundance (7590-136,778 items·m-3) was tentatively linked to maximum rainfall intensity, with <25 μm microplastics making up 39.6 (±27.5)% of the total count. The composition of <25 μm microplastics differed from that of larger microplastics, although both mainly comprised polystyrene, polyethylene, and polypropylene. The microplastic communities differed among rainfalls, suggesting that atmospheric transport is a highly dynamic process. The first rainfall exhibited the highest microplastic abundance and community diversity after long-term exposure to dry atmospheric environment. The deposited microplastics were unstable and highly fragmented according to the conditional fragmentation model. The wet deposition rate of the microplastics was calculated as 2-463 μg·m-2 (146-8629 items·m-2) per rain, amounting to 25.44 tons per annum in Beijing. Although <25 μm microplastics represented a negligible proportion (0.00-1.24%) of the overall mass load of microplastics, their numerical abundance was high. Our results demonstrate that precipitation is an effective mechanism for removing airborne microplastics, which may enter urban soils and waters, exacerbate microplastic burdens in the environment, and cause potential risk for human health.


Application of polycaprolactone, chitosan, and collagen composite as a nanofibrous mat loaded with silver sulfadiazine and growth factors for wound dressing.
Fabrication of nanofibrous biomaterials composed of natural and synthetic materials that incorporated with antibiotic and growth factors with controlled release manner is an attractive topic in wound healing. The purpose of this study was to prepare optimal composite of materials as biomimetic nanofibrous mats for application in wound healing. The mat was prepared of polycaprolactone (PCL) in the bottom, chitosan/poly ethylene oxide (Cs/PEO) in the middle, and PCL/collagen (PCL/Coll) in the top layer. A panel of standard characterization tests of nanofibrous mat was performed and its compatibilities in strength and integration were confirmed. Middle layer was loaded with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), and silver sulfadiazine (SSD) was incorporated in the bottom layer as an anti-infection factor. Then, on the dorsum of rats, a 400-mm2 wound was created and surrounded by a silicone ring to control the usual tissue contractions. Nanofibrous mats with or without growth factors were applied as wound dressings and at day 14, the healing process was evaluated. At day 14, the treated group by designed mat showed faster epithelialization and angiogenesis. Silicone ring in the test group was desirable in wound closure compared to the control group. Reformation of skin tissue was manifested in a shorter time. This composite nanofibrous mat could be introduced as a dynamic and effective candidate for wound dressing.


Radioactivity near the sunken submarine "Kursk" in the Southern Barents Sea.
Radioactivity measurements were conducted on seawater, sediment, and biota samples collected in the vicinity of the Russian submarine "Kursk" in September, 2000, within 1 month of the vessel's sinking in the Barents Sea to determine whether leakage of radioactivity from the vessel's two nuclear reactors had occurred and to assess the impact on one of the most productive fishing areas in the world. Levels of radioactivity in surface sediments and biota are within the range of values previously measured in the Barents Sea and can be ascribed to inputs from global fallout, European nuclear fuel reprocessing facilities, and the Chernobyl accident. However, levels of 1291 in seawater in the Southern Barents Sea increased by 500% between 1992 and 2000, and the 129I/137Cs ratio increased by more than an order of magnitude during this time, owing to long-range transport of releases from reprocessing facilities at Sellafield (U.K.) and La Hague (France). Although these results indicate that, at the time of sampling, leakage from the Kursk had a negligible impact on the environment, they also show that regional background levels of artificial radioactivity are varying rapidly on annual timescales and that Europe's nuclear reprocessing facilities are the leading contributor of anthropogenic radioactivity to the region.


Initial experience with a new femoral artery closure device following percutaneous coronary intervention with glycoprotein IIb/IIIa inhibition.
The aim of the study was to determine the safety and efficacy of a novel femoral artery closure device (StarClose, Abbott Vascular Devices, Redwood City, CA) following percutaneous coronary intervention employing aspirin, heparin, and glycoprotein (GP) IIb/IIIa inhibition. A prospective nonrandomized single-center pilot study of the StarClose device included a subset of patients undergoing percutaneous coronary intervention utilizing GP IIb/IIIa inhibitors. Those that fulfilled the inclusion criteria (age < 80, no periprocedural haematoma, puncture above the superficial femoral and profunda femoralis artery bifurcation, no significant femoral artery disease) underwent closure of the femoral artery puncture site with a StarClose device immediately on completion of the procedure. Time to hemostasis (TTH), bleeding, mobilization, and short-term clinical follow-up data were collected, and an ultrasound scan of the femoral artery was performed 2 weeks later. Twenty-five patients were recruited, of whom 23 underwent percutaneous coronary intervention (PCI). Their mean age was 58 +/- 12 years, 84% were male, and 63% had unstable angina. All were on aspirin 100-150 mg daily and all PCI patients received i.v. heparin 4-10,000 units at commencement of the procedure and clopidogrel 600 mg on completion. Two patients were on a tirofiban infusion and 23 received a double bolus of eptifibatide, each 0.18 mg/kg, separated by 10 min. The procedural success was 100% and device success 23/25 (92%), with 1 failure due to technical error. The median device delivery time was 36 sec (range, 11-178) and median TTH 37 sec (range, 10-509 sec). There were no major adverse events. In 10 patients, a moderate amount of tract ooze required a short period of adjunctive manual compression. Follow-up ultrasound femoral artery scans revealed no compromise of the vessel lumen. Femoral artery closure with the device following coronary angiography and intervention using glycoprotein IIb/IIIa receptor inhibitors is safe and effective. A randomized trial of a larger number of patients is warranted.


Topical Cocaine Hydrochloride Nasal Solution: Anesthetic and Surgical Considerations.
Adequate surgical view during various types of nasal procedures is essential for surgical operations to be performed in a safe, efficient, and successful manner. Minimizing bleeding during surgery is an important way of increasing visualization that is commonly achieved by using a vasoconstrictive agent to control intraoperative hemorrhage. Many otolaryngologists choose to employ topical cocaine to minimize bleeding during surgery owing to its vasoconstrictive properties, while simultaneously benefitting from its dual local anesthetic effects. The relative benefit of topical cocaine for otolaryngologic procedures when compared to other topical analgesics and vasoconstrictors remains a topic of discussion due to the multiple potential cardiac and central nervous system side effects associated with cocaine administration. Furthermore, there is not a scientifically backed maximal safe dose published; instead, most of the guidelines for intranasal cocaine use are based on untested clinical practice. Despite this, the short latency, adequate duration of action, and inherent vasoconstrictive and decongestive capabilities make cocaine a valuable anesthetic agent for use in clinical procedures. As the relative benefit of using topical cocaine compared to the use of other vasoconstrictors and analgesics for nasal procedures remains undetermined in the current literature, this leaves the need for a comprehensive review of research that explores the risks and benefits of using topical cocaine in nasal procedures based on clinical trials that compare intranasal cocaine with various other analgesics and vasoconstrictors.


Structural similarity between lung surfactant protein D and conglutinin. Two distinct, C-type lectins containing collagen-like sequences.
Preparations of bovine lung surfactant D (SP-D) and conglutinin were examined by electron microscopy, gel-filtration and SDS/PAGE. SP-D is composed of non-covalently linked subunits, of 160 kDa, which each contain three, disulphide-linked, 44-kDa polypeptide chains. In the electron microscope a single 160-kDa subunit of SP-D appears as a 45.8 +/- 3-nm-long rod connected to a small globular 'head'. Particles were also seen which correspond to non-covalently linked dimers, trimers and tetramers of the 160-kDa monomer subunit of SP-D. The tetramer structure contains 12 polypeptide chains and is very similar to the electron microscopy images and model reported by Strang et al. [Strang, C. J., Slayter, US., Lachmann, P. J. and Davis, A. E. (1986) Biochem. J. 236, 3811-389] for bovine conglutinin in which four 160-kDa subunits are disulphide-linked to give a molecule of expected molecular mass of 528 kDa. This study confirmed the findings by Strang et al. in the above paper for intact conglutinin and also emphasised that the rod-like structures, of length 37.6 +/- 3.7 nm, seen in the conglutinin subunits were significantly shorter than those in SP-D despite the close similarity in amino acid sequence (79% identify) and chain length between the two proteins. In addition, a truncated form of conglutinin was found in the conglutinin preparations, due to limited proteolysis of the Arg-Ala bond at position 54 in the 44-kDa chains. These truncated conglutinin chains yield a subunit composed of three shortened, non-disulphide-linked, chains and this subunit appears as a monomer with a rod length of 34.2 +/- 2.8 nm in the electron microscope. On gel-filtration, a proportion of the SP-D preparation behaved, as expected, as a molecule with an apparent molecular mass of 600 kDa. The remainder of the SP-D preparation behaved as aggregated material with a molecular mass greater than 900 kDa which yielded no distinct structures in the electron microscope. Intact conglutinin was eluted at a position greater than 900 kDa but yet provided clear electron microscopy images of the tetramer structure described above.(ABSTRACT TRUNCATED AT 400 WORDS)


Parameters influencing the quality of colonoscopy in Belgium : a critical evaluation.
In relation to recent implementation of colorectal cancer screening programs at the regional level, quality assessment of colonoscopy gains more interest in Belgium. In order to evaluate quality indicators of colonoscopies in Belgium, we retrospectively analysed data about colonoscopies performed between 2002-2010. Coded data concerning number of medical procedures and polypectomy were provided by the Intermutualistic Agency (IMA). This database was used to calculate different quality indicators such as polyp detection rate (PDR), use of sedation, amount of procedures and time interval according to physician and center type. Considerable differences in polyp detection rate (PDR) exist between different physicians and centers. Mean PDR significantly correlated with the number of colonoscopies performed each year. A minimum of 106 colonoscopies per year was identified to maintain competence. Recuperation rate for polyps was low, and time intervals between colonoscopies were generally too short in comparison to European and international guidelines. In absence of a central colonoscopy registry in Belgium, our results were based on reimbursement data. Other quality parameters, although accuracy is questionable (eg. bowel cleansing and withdrawal time) are not systematically registered. Despite these difficulties, we were able to demonstrate that a minimum amount of 106 colonoscopies per year is necessary to maintain competence. The results from this large database can be used as a foundation to work out a quality colonoscopy bundle.


The amount of thiolic antioxidant ingestion needed to improve several immune functions is higher in aged than in adult mice.
With aging there is an increase of oxidative stress due to an imbalance between the oxidant production and the antioxidant levels in favor of the former. Since immune cell functions are specially linked to reactive oxygen species (ROS) generation, the oxidant/antioxidant balance is essential for these cells. Although low levels of antioxidants cause a decrease in immune function, very high levels of antioxidant compounds could show prooxidant effects. In the present work, we have studied the effect of diet supplementation, for 4 weeks, with two different doses of two thiolic antioxidants, namely thioproline (TP) and N-acetylcysteine (NAC), at 0.1% (w/w) and 0.3% (w/w, of each antioxidant) on the main immune system cells, i.e.: macrophages, lymphocytes and natural killer (NK) cells of adult (33+/-1 week old) and aged (75+/-1 week old) female Swiss mice. Two groups of animals, adult and aged mice, fed standard diet were used as controls. The results show that the ingestion of 0.1% doses of thiols improves, in the adult mice, several immune functions such as the chemotaxis capacity of both macrophages and lymphocytes, the phagocytosis of macrophages, the lymphoproliferative response to the mitogen Con A and the NK activity. Moreover, no change was observed in adherence capacity of immune cells, and superoxide production was decreased. By contrast, in aged mice the ingestion of these amounts of antioxidants did not change the immune functions studied with the exception of NK activity, which was stimulated. The ingestion of 0.3% of antioxidants by adult mice only increased some immune functions such as adherence and superoxide production, which are markers of oxidative stress. Other functions such as chemotaxis or lymphoproliferative response decreased. However, the ingestion of these very high amounts of thiols by aged animals increased the phagocytosis, the NK activity and specially the lymphoproliferative response to the mitogen, a function that is very depressed with aging.


Effect of selenium and grape seed extract on indomethacin-induced gastric ulcers in rats.
Indomethacin (IND) is a non-steroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the protective effect of selenium (SEL), grape seed extract (GSE), and both on IND-induced gastric mucosal ulcers in rats. Sprague-Dawley rats (200-250 g) were given SEL, GSE, and both by oral gavage for 28 days, and then gastric ulcers were induced by oral administration of 25 mg/kg IND. Malondialdehyde (MDA), non-enzymatic (reduced glutathione, GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants, prostaglandin E2 (PGE2) in gastric mucosa, and serum tumor necrosis factor alpha (TNF-α) were measured. Moreover, gastric ulcer index and preventive index were determined. Indomethacin increased the gastric ulcer index, MDA, TNF-α, and decreased PGE2 and non-enzymatic (GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants. Pretreatment with SEL, GSE, and both significantly decreased the gastric ulcer index, MDA, and TNF and increased antioxidants and PGE2. Histopathological observations confirm the gastric ulcer index and biochemical parameters. Selenium and GSE have a protective effect against IND-induced gastric ulcers through prevention of lipid peroxidation, increase of GSH, activation of radical scavenging enzymes, PGE2 generation, and anti-inflammatory activity. Co-administration of GSE and SEL is more effective than GSE or SEL alone.


Osimertinib Combined with Systemic Chemotherapy for EGFR Mutant, T790M-Negative, Non-Small Cell Lung Cancer Patients Who Develop Leptomeningeal Metastases with Extracranial Progression to Prior EGFR TKI.
Leptomeningeal metastasis (LM) is a rare but fatal clinical condition with a short survival time. The incidence of LM from epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) has increased due to the limited efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the central nervous system (CNS). Osimertinib is a third-generation, irreversible, CNS penetrant, oral EGFR TKI that demonstrates promising efficacy in CNS metastases regardless of T790M. Herein, we report four cases of T790M-negative EGFRm NSCLC patients treated with osimertinib combined with systemic chemotherapy, who progressed on prior EGFR TKI and developed LM with extracranial lesions. The combination treatment was well tolerated, and the mean overall survival from LM diagnosis was 14.7 months (95% confidence interval, 10.4 to 19.0). These results suggest that osimertinib combined with systemic chemotherapy would be a reasonable treatment option for T790M-negative EGFRm NSCLC patients who develop LM with extracranial progression to prior EGFR TKI. A further prospective study is warranted.


[Is protective therapy possible in occupational asthma? Role of immunotherapy].
Specific immunotherapy (ITS) can be a preventative measure for occupational allergy when allergens cannot be fully eliminated. Many allergens provoke IgE-mediated reactions, but when they are haptens and the physiopathology is complex, then the value of ITS is restricted. However, with common allergens whose density increases with occupation, such as house dust and house dust mites for domestic employees, pollens for florists and animal epithelia for breeders, then ITS is effective. On the other hand, when the allergen is specific for the job, of which there are two well documented examples in bakers asthma from wheat flour and laboratory worker's asthma to small laboratory animals there are disparate results. Overall, there is only a modest place for ITS in the treatment of professional asthma, because of the lack of purified, well-standardised extracts.


Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial.
In 14 patients with cirrhosis of the liver and portal-systemic shunts the effect of a branched-chain amino acid-enriched elemental diet on portal systemic encephalopathy, routine laboratory parameters and plasma amino acids was investigated. In addition to the standard therapy including protein restriction (40 g/day) the patients received 44 g of an amino acid-protein mixture containing 30% of branched-chain amino acids and placebo over 3 months in a crossover regimen. Plasma valine and leucine increased significantly, whereas all other amino acids, including the ratio (formula: see text), remained unchanged. The electroencephalogram, number connection test, clinical state and laboratory parameters were not influenced by therapy with branched-chain amino acids. Thus, orally administered branched-chain amino acids probably have no influence on hepatic encephalopathy but are an adequate source of nitrogen in patients with cirrhosis of the liver.


Effect of bilateral adrenalectomy on blood sugar level and plasma refill in a rat hemorrhagic shock model.
Recent studies suggest that the hyperglycemic response to hemorrhage and shock may play a role in promoting plasma refill via its hyperosmolar effect. This relationship was tested in a bilaterally adrenalectomized rat model. After a left carotid arterial cannulation, seven adrenalectomized rats and seven control rats with intact adrenal glands were bled periodically for periods of 15 min followed by 15 min of rest. The initial hemorrhage depleted 7.5% of the total blood volume (TBV) and subsequent hemorrhages 5% each. The study period extended up to 120 min to replicate a hemorrhage of 22.5% of TBV. Micromethod hematocrits (Hct) and blood sugar (BS) were monitored every 15 min and results were analyzed by use of a BMD-P statistical package on an AMDAHL 470 computer. A significant (p less than 0.05) increase in BS during shock was seen in the control rats, while the adrenalectomized animals did not demonstrate a significant hyperglycemic response. There was no significant difference in the plasma refill observed between the two groups. At 60 min, the Hct fell 3.6 +/- 1.7 and 4.6 +/- 0.6 percentage points for control and adrenalectomized animals, respectively, while at 120 min, a respective Hct drop of 7.5 +/- 1.6 and 5.4 +/- 1.1 percentage points was noted. This study indicates that the absence of the hyperglycemic response in the adrenalectomized rats had no effect on plasma refill when compared to the response of control rats with intact adrenals.


Acute hemodynamic effects of nilvadipine, a new calcium channel blocker, in patients with congestive heart failure.
The acute hemodynamic effects of nilvadipine, a newly synthesized calcium channel blocker, were studied in 12 patients with congestive heart failure. Hemodynamic measurements were made before and 15, 30, and 60 min after oral administration of 6 mg nilvadipine. Substantial reductions in systemic vascular resistance (-28.8 +/- 6.3%, p less than 0.01) and forearm vascular resistance (-52.0 +/- 6.2%, p less than 0.01) after nilvadipine administration were associated with increases in cardiac index (31.1 +/- 8.3%, p less than 0.01) and forearm blood flow (105.2 +/- 27.4%, p less than 0.01). Mean arterial and pulmonary arterial pressures were decreased by 12.2 +/- 3.0% (p less than 0.01) and 14.7 +/- 5.0% (p less than 0.05), respectively, after nilvadipine administration; however, heart rate remained unchanged. Decreases in mean arterial pressure correlated with the baseline arterial pressure (y = 0.58x - 41.6, r = 0.75, p less than 0.01). Pulmonary capillary wedge pressure decreased by 33.1 +/- 9.1% (p less than 0.01) after nilvadipine administration. However, right atrial pressure and the venous stiffness constant remained unchanged, and the venous pressure-volume curve was not shifted significantly. Therefore, the decrease in pulmonary capillary wedge pressure was attributed primarily to afterload reduction. Nilvadipine holds promise as a vasodilator for the therapy of congestive heart failure.


Repeatability of standardized tests of functional impairment and well-being in older people in a rehabilitation setting.
The aim of this study was to establish the repeatability of standardized tests of vision (Snellen chart testing), hearing (whispered voice test), communication (Frenchay aphasia screening test), loneliness (UCLA loneliness scale), morale (Philadelphia geriatric centre morale scale), and a multidimensional instrument (EASY-care) when used in a rehabilitation setting. The tests were administered by a research nurse to 50 older subjects attending a day rehabilitation unit, with repeat administration one or two weeks later by a nurse on the unit. Kappa statistics were used for level of agreement for categorized data and interclass correlation coefficient were used for data based on scores. Moderate repeatability for Snellen chart testing. whispered voice test; good to excellent for the FAST, UCLA loneliness scale and Philadelphia geriatric centre morale scale. Moderate to very good repeatability for all EASY-care items except communication, feeding, use of telephone and cognitive impairment, which had poor spread of data. Poor repeatability for commonly used tests of vision and hearing is worrying, whereas the positive results for the other tests will increase confidence in using them more in routine practice.


Post-traumatic vertigo.
The vestibular-like symptoms that commonly follow head injury are most often due to one of a number of specific pathologies affecting vestibular, CNS or cervical structures. These pathologies can be readily identified in the majority of cases by appropriate testing in the examining room, and in vestibular function or neurodiagnosic laboratories. Whereas vestibular suppressants have a roll, they often delay recovery and have been supplanted as the mainstay of treatment in most cases by vestibular rehabilitation techniques. Given the large number of patients requiring outpatient management following head injury, it is appropriate that most generalists and many subspecialists should be aware of the differential diagnosis, workup and treatment options for post-traumatic vertigo.


Results and complications after removal of tibial tuberosity advancement cage for treatment of surgical site infections: A retrospective study.
To describe the surgical technique and report the short-term results after removal of tibial tuberosity advancement (TTA) cages in dogs with surgical site infections (SSI). Retrospective clinical study. Seventeen client-owned dogs. Medical records of dogs treated for SSI by removal of a TTA cage between November 2012 and May 2015 were reviewed. Information collected included signalment, physical examination findings, affected stifle, cage size, date of SSI onset, time elapsed to implant removal, duration of procedure, culture results, any complications encountered, timing of follow-up recheck, and short-term results. Seventeen dogs (20 stifles) were included. Clinical signs related to SSI started at a mean of 403 days after TTA, and implants were removed 474 days (mean) after TTA. No intraoperative complications were reported. Postoperative complications occurred in 40% of dogs. Three dogs developed major complications, including a tibial tuberosity fracture. Eighty-five percent of owners reported complete resolution of clinical signs related to the SSI and were satisfied with the outcome. Surgical site infections were short- and long-term complications successfully treated by removal of the TTA cage in the majority of dogs in this study, although complications were common. Removal of the TTA cage can be considered as an adjunct to treat SSI but has the potential for postoperative complications.


Cloning of the gene for myxobacterial hemagglutinin and isolation and analysis of structural gene mutations.
Myxobacterial hemagglutinin (MBHA) is a major developmentally induced protein that accumulates during the period of cellular aggregation in the bacterium Myxococcus xanthus. It has been shown that this lectin is targeted to the cell surface and periplasmic space of developmental cells, suggesting that it may play a role in cell-cell recognition or agglutination. We have cloned the structural gene for MBHA by using synthetic deoxyoligonucleotides containing sequences deduced from the amino acid sequence of MBHA and have used the cloned gene to construct strains of M. xanthus that cannot synthesize MBHA. We found that although the MBHA-deficient strains are delayed in their developmental time course, they are otherwise able to aggregate and sporulate normally. Our results suggest that MBHA may function to increase the efficiency of fruiting-body formation but is not a critical component of cellular aggregation.


Reversible hydration and dehydration of polyanionic brushes bearing carboxylate, phosphate and sulfonate side groups: a comparative AFM study.
The present work reports on a systematic study of the swelling/collapse transition of three anionic polymer brushes bearing carboxylate, phosphate and sulfonate side groups via AFM measurement. Time scale of conformation change process can be approximately evaluated directly. All the three brushes in their sodium salt forms stretch away from the surface in pure water, as a result of charge repulsion and uptake of water. The collapse of weak brushes has two ways: normal charge screening and precipitation (strong ion pairing), depending on the types of cations that have different coordination capabilities with anionic groups. Alkali metal ions can make brushes shrink only at relatively high concentrations following a gradually increased charge screening mechanism. The brushes collapsed in this way can be restored by simply flushing with water. However, multivalent cations can irreversibly collapse brushes more easily even under very low concentrations (<10(-3) mol L(-1)). The brushes cannot be restored with simple water rinsing even for strong sulfonate containing brushes. In this case, recovery can be achieved by ion exchange in concentrated salt solution, which facilitates transit from strong ion pairing to less strong charge screening and then flushing with water. Alternatively, the multivalent ion can be extracted with chelating reagent of low concentration (10 mM EDTA). As the chelating agent doesn't affect the conformation of brushes, the brushes are one-step recovered directly, much more efficient than with high concentration electrolyte which usually requires extra water rinsing to remove excess salt inside brushes. The interaction between anions in the brushes and metal ions represents a model system to profoundly understand the mechanism of bio-mimic motions and how muscle works. In this regard, the present study provides useful information for the development of polyelectrolyte brushes based ion sensor and ion powered nanoactuators.


Effect of level of soluble fiber and n-6/n-3 fatty acid ratio on performance of rabbit does and their litters.
The aim of this work was to study whether the dietary supplementation with soluble fiber (SF) and the reduction of the n-6/n-3 fatty acid ratio or the combination of both influences the survival, body and milk composition, and reproductive performance of rabbit does during the first four parturitions. Four diets in a 2 × 2 factorial arrangement were used with two levels of SF (7.8 vs. 13.0, on dry matter [DM] basis; high soluble fiber [HSF] and low soluble fiber [LSF]) and two different n-6/n-3 fatty acid ratios (13.4/1 vs. 3.5/1). Nulliparous does (24/diet) were inseminated 11 d after parturition. Body chemical composition and energy content of rabbit does and their performance, litter growth, and milk production were measured between birth and weaning (25 d) along four parturitions, and milk composition and fecal digestibility were also recorded. The proportion of total removed does decreased in HSF respect to LSF groups (22.9 vs. 50.0%; P = 0.005), and it tended to decrease in LSF groups when the n-6/n-3 ratio increased and in HSF groups when the n-6/n-3 ratio decreased (P = 0.059). The increase of the level of SF reduced the digestible crude protein (CP)/digestible energy ratio (by 4%; P < 0.001) and improved the digestibility of all fibrous fractions (P < 0.001). The reduction of the n-6/n-3 ratio reduced the total dietary fiber digestibility in rabbit does fed LSF diets, but it had no effect in those fed HSF diets (P = 0.043). Treatments had no effect on average daily feed intake among parturitions (P = 0.16), but the digestible CP intake among parturitions was lower in HSF than in LSF groups (P = 0.003). Treatments had no effect on the total number of kits born, litter or average kit weight at birth, or litter size at weaning, fertility, feed efficiency, total milk production, and body chemical composition and energy content of rabbit does (P ≥ 0.29). The average weight of kits at weaning of LSF_Hn-6/n-3 and HSF_Ln-6/n-3 groups decreased by 6% compared with those from the other two groups (P = 0.030). The reduction of the dietary n-6/n-3 ratio increased the milk fat content by 12% with no effect on protein and DM content (P = 0.031). The proportion of milk odd fatty acids and saturated fatty acid increased in rabbit does fed the HSF diets compared with those fed LSF diets (P ≤ 0.037) with no effect of the n-6/n-3 fatty acid ratio. In conclusion, SF reduced the replacement rate of rabbit does with no effect of the n-6/n-3 ratio, while both dietary factors modified milk composition and fatty acid profile with minor influence on litter productivity.


Potential energy surface for interactions between two hydrogen molecules.
Nonrelativistic clamped-nuclei energies of interaction between two ground-state hydrogen molecules with intramolecular distances fixed at their average value in the lowest rovibrational state have been computed. The calculations applied the supermolecular coupled-cluster method with single, double, and noniterative triple excitations [CCSD(T)] and very large orbital basis sets-up to augmented quintuple zeta size supplemented with bond functions. The same basis sets were used in symmetry-adapted perturbation theory calculations performed mainly for larger separations to provide an independent check of the supermolecular approach. The contributions beyond CCSD(T) were computed using the full configuration interaction method and basis sets up to augmented triple zeta plus midbond size. All the calculations were followed by extrapolations to complete basis set limits. For two representative points, calculations were also performed using basis sets with the cardinal number increased by one or two. For the same two points, we have also solved the Schrodinger equation directly using four-electron explicitly correlated Gaussian (ECG) functions. These additional calculations allowed us to estimate the uncertainty in the interaction energies used to fit the potential to be about 0.15 K or 0.3% at the minimum of the potential well. This accuracy is about an order of magnitude better than that achieved by earlier potentials for this system. For a near-minimum T-shaped configuration with the center-of-mass distance R=6.4 bohrs, the ECG calculations give the interaction energy of -56.91+/-0.06 K, whereas the orbital calculations in the basis set used for all the points give -56.96+/-0.16 K. The computed points were fitted by an analytic four-dimensional potential function. The uncertainties in the fit relative to the ab initio energies are almost always smaller than the estimated uncertainty in the latter energies. The global minimum of the fit is -57.12 K for the T-shaped configuration at R=6.34 bohrs. The fit was applied to compute the second virial coefficient using a path-integral Monte Carlo approach. The achieved agreement with experiment is substantially better than in any previous work.


Influence of cholesterol on shape parameters of erythrocytes in hyperglycemic subjects.
We determined the morphological changes of erythrocytes in blood samples of diabetic patients with varying levels of hyperglycemia with normo- and hyper-cholesterol concentrations and compared them with cells of healthy subjects. The shape analysis was carried out by shape descriptors based on projected area, perimeter and form factor, as measured by the processing of erythrocyte images. Blood smears were collected from normal subjects and from glycemic subjects with normo- and hyper-cholesterol levels. After image processing techniques like edge enhancement, thresholding, filtering, contour extraction, and pattern analysis and recognition, the images were used for shape analysis. The shape parameters, which quantified the changes in erythrocytes in diabetic subjects with normal cholesterol level, showed significant deviation from the shape of normal cells. Cells of diabetic subjects with hyper-cholesterol level showed more deviation than cells with normal cholesterol. These changes lead to hyper aggregation and to a decrease in deformability of erythrocytes and hence increase microcirculatory complications.


UNESCO, genetics, and human rights.
In response to a mandate conferred on the International Bioethics Committee (IBC) of UNESCO in November 1993, the IBC has drafted a "universal declaration on the human genome and human rights," which will be considered by the General Conference of UNESCO in November 1997. This article discusses the development of the document and provides the text of the "revised preliminary draft" of the declaration.


Quantitative analysis of late gadolinium enhancement in hypertrophic cardiomyopathy.
Cardiovascular magnetic resonance (CMR) with the late gadolinium enhancement (LGE) technique allows the detection of myocardial fibrosis in Hypertrophic cardiomyopathy (HCM). The aim of this study was to compare different methods of automatic quantification of LGE in HCM patients. Forty HCM patients (mean age 48 y, 30 males) and 20 normal subjects (mean age 38 y, 16 males) underwent CMR, and we compared 3 methods of quantification of LGE: 1) in the SD2 method a region of interest (ROI) was placed within the normal myocardium and enhanced myocardium was considered as having signal intensity >2 SD above the mean of ROI; 2) in the SD6 method enhanced myocardium was defined with a cut-off of 6 SD above mean of ROI; 3) in the RC method a ROI was placed in the background of image, a Rayleigh curve was created using the SD of that ROI and used as ideal curve of distribution of signal intensity of a perfectly nulled myocardium. The maximal signal intensity found in the Rayleigh curve was used as cut-off for enhanced myocardium. Parametric images depicting non enhanced and enhanced myocardium was created using each method. Three investigators assigned a score to each method by the comparison of the original LGE image to the respective parametric map generated. Patients with HCM had lower concordance between the measured curve of distribution of signal intensity and the Rayleigh curve than controls (63.7 +/- 12.3% vs 92.2 +/- 2.3%, p < 0.0001).A cut off of concordance < 82.9% had a 97.1% sensitivity and 92.3% specificity to distinguish HCM from controls. The RC method had higher score than the other methods. The average extent of enhanced myocardium measured by SD6 and Rayleigh curve method was not significant different but SD6 method showed underestimation of enhancement in 12% and overestimation in 5% of patients with HCM. Quantification of fibrosis in LGE images with a cut-off derived from the Rayleigh curve is more accurate than using a fixed cut-off.


Intrinsic versus Extrinsic Cancer Risks: The Debate Continues.
Deciphering the relative contribution of intrinsic (e.g., genetic) and extrinsic (e.g., life style, environmental) risk factors in cancer development is crucial for strategizing cancer prevention. The recent publication by Wu and colleagues in Nature appears as an important contribution to the debate previously initiated by Tomasetti and Vogelstein in Science, who proposed that two-thirds of cancers can be attributed to random mutations and hence 'bad luck'. By contrast, Wu and colleagues, using four lines of evidence, suggest that cancer risk is dominated by extrinsic factors, and intrinsic risk factors only contribute marginally. The debate remains open, and an approach focusing on the evolutionary ecology of organs could provide crucial insights.


Non-enzymatic glycation and aggregation of camel immunoglobulins induce breast cancer cell proliferation.
Glycation of biomolecules results in the formation of advanced glycation end products (AGEs). Immunoglobulin G (IgG) has been implicated in the progression of various diseases, including diabetes and cancer. This study purified three IgG subclasses (IgG1, IgG2, and IgG3) from Camelus dromedarius colostrum using ammonium sulfate fractionation and chromatographic procedures. SDS-PAGE was performed to confirm the purity and molecular weight of the IgG subclasses. Several biochemical and biophysical techniques were employed to study the effect of glycation on camel IgG using methylglyoxal (MGO), a dicarbonyl sugar. Early glycation measurement showed an increase in the fructosamine content by ~four-fold in IgG2, ~two-fold in IgG3, and a slight rise in IgG1. AGEs were observed in all classes of IgGs with maximum hyperchromicity (96.6%) in IgG2. Furthermore, glycation-induced oxidation of IgGs led to an increase in carbonyl content and loss of -SH groups. Among subclass, IgG2 showed the highest (39.7%) increase in carbonyl content accompanied by 82.5% decrease in -SH groups. Far UV-CD analysis illustrated perturbation of β-sheet structure during glycation reaction with MGO. Moreover, glycation of IgG proceeds to various conformational states like aggregation and increased hydrophobicity. In addition, the cytotoxicity assay (MTT) illustrated the proliferation of breast cancer cells (MCF-7) with IgG2 treatment.


Photosynthetic leaf area modulates tiller bud outgrowth in sorghum.
Shoot branches or tillers develop from axillary buds. The dormancy versus outgrowth fates of buds depends on genetic, environmental and hormonal signals. Defoliation inhibits bud outgrowth indicating the role of leaf-derived metabolic factors such as sucrose in bud outgrowth. In this study, the sensitivity of bud outgrowth to selective defoliation was investigated. At 6 d after planting (6 DAP), the first two leaves of sorghum were fully expanded and the third was partially emerged. Therefore, the leaves were selectively defoliated at 6 DAP and the length of the bud in the first leaf axil was measured at 8 DAP. Bud outgrowth was inhibited by defoliation of only 2 cm from the tip of the second leaf blade. The expression of dormancy and sucrose-starvation marker genes was up-regulated and cell cycle and sucrose-inducible genes was down-regulated during the first 24 h post-defoliation of the second leaf. At 48 h, the expression of these genes was similar to controls as the defoliated plant recovers. Our results demonstrate that small changes in photosynthetic leaf area affect the propensity of tiller buds for outgrowth. Therefore, variation in leaf area and photosynthetic activity should be included when integrating sucrose into models of shoot branching.


Dendritic cell susceptibility to hepatitis C virus genotype 1 infection.
In vitro infection of human monocyte-derived dendritic cells was carried out to study their susceptibility to hepatitis C virus (HCV) infection. Immature dendritic cells and mature dendritic cells were incubated overnight at 37 degrees C with HCV-positive (genotype 1) serum samples; the presence of the viral genome associated with the production of its replicative intermediate was used as evidence of infection. In immature dendritic cells, HCV RNA was detectable from days 1-10 post-infection (p.i.), and de novo synthesis of negative-strand HCV RNA could be demonstrated by a strand-specific rTth reverse transcription-polymerase chain reaction at day 2. In mature dendritic cells, the positive-strand form was detectable from days 1-5 p.i., while the negative-strand HCV RNA appeared at days 1 and 2 p.i. Quasispecies present in the inoculum and 6 days p.i. were analyzed by sequencing hypervariable region 1 of the E2 protein. Only two of seven HVR variants present in the inoculum were found in HCV-infected immature dendritic cells. Another two HVR variants not found in the inoculum were recovered from infected immature dendritic cells, suggesting serum minor variants selection or virus evolution during in vitro replication. Analysis by single-strand conformation polymorphism assay of 5' untranslated region of HCV sequences showed that the patterns obtained from the inoculum and infected immature dendritic cells and mature dendritic cells differed slightly. These findings indicate that both immature dendritic cells and mature dendritic cells are susceptible to HCV genotype 1 infection, supporting at least HCV RNA replication. This model should be a valuable tool for the study of modulation of dendritic cell functions in HCV infection.


[Experimental study on carcinogenesis by human papillomavirus type 8 E7 gene].
Human papillomavirus (HPV) 5 and HPV8 are often detected in skin cancers developed in patients suffering from epidermodysplasia verruciformis, as well as in skin cancers developed in immunosuppressed patients. In the present study, in order to examine the transforming activity of the HPV8E7 gene, the HPV8E7 and HPV8E6/E7 genes were cloned into the expression vector (pcD2-Y), under the SV40 enhancer/promoter to construct pcD2-8E7 and pcD2-8E6/E7, respectively. The E7 and E6/E7 genes of genital high-risk HPV16 were also cloned into pcD2-Y to construct pcD2-16E7 and pcD2-16E6/E7, respectively. They were tested for their ability to collaboratively transform primary rat embryo fibroblasts (REFs) with activated H-ras gene. Transfection experiments of REFs having an activated H-ras gene revealed that pcD2-8E7, as well as pcD2-16E7 and pcD2-16E6/E7, induced transformation of cells in G418-resistant colonies at efficiencies of 11.9%, 43.0% and 53.0%, respectively. Transformed cell lines induced by activated H-ras gene and pcD2-8E7 or pcD2-16E7 were named 8RE and 16RE cell lines, respectively. Tumor induction in syngeneic newborn rats by injected the 8RE cells was higher than that of the 16RE cells. In cytological and histological examination, the 8RE cell lines and their induced tumors were different from the 16RE cell lines and their induced tumors. The 8RE cell lines showed the characteristic transformation with efficient growth ability on plastic and colony formation in 0.3% soft agar. These results support the hypothesis that the HPV8E7 gene plays an important role in the carcinogenesis of skin cancers.


SPONTANEOUS CLOSURE OF MACULAR HOLE IN A PATIENT WITH MACULAR TELANGIECTASIA TYPE 2.
To present a case of macular hole associated with macular telangiectasia Type 2 (Mac-Tel 2) which underwent spontaneous closure. A 58-year-old woman is admitted with complaints of blurred and distorted vision. Optical coherence tomography, fundus autofluorescence, and optical coherence tomography angiography were performed for diagnosis and follow-up. Optical coherence tomography revealed hyporeflective cavitations in both eyes, and full-thickness macular hole covered with internal limiting membrane drape in the left eye. Fundus autofluorescence showed loss of hypoautofluorescence in temporal parafoveal area in the right eye, and centrally in the left one. Vascular irregularities were detected in optical coherence tomography angiography images. The patient was diagnosed as Mac-Tel 2. During the follow-up, the macular hole underwent a process of spontaneous closure, starting as bridging at the level of external limiting membrane and outer nuclear layer followed by further repairment and organization of the outer plexiform layer, accompanied with visual gain. Spontaneous closure of macular hole in patients with Mac-Tel 2 is a rare entity. We hypothesize that extension or proliferation of Muller cells, which leads to reconstruction of normal foveal structure, is the main mechanism for this phenomenon.


Role of methyl-induced polarization in ion binding.
The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the effect of point substitutions on potassium (K-) channels illustrate quantitatively how methyl-induced polarization also contributes to biomolecular function. K- channels regulate transmembrane salt concentration gradients by transporting K(+) ions selectively. One of the K(+) binding sites in the channel's selectivity filter, the S4 site, also binds Ba(2+) ions, which blocks K(+) transport. This inhibitory property of Ba(2+) ions has been vital in understanding K-channel mechanism. In most K-channels, the S4 site is composed of four threonine amino acids. The K channels that carry serine instead of threonine are significantly less susceptible to Ba(2+) block and have reduced stabilities. We find that these differences can be explained by the lower polarizability of serine compared with threonine, because serine carries one less branched methyl group than threonine. A T→S substitution in the S4 site reduces its polarizability, which, in turn, reduces ion binding by several kilocalories per mole. Although the loss in binding affinity is high for Ba(2+), the loss in K(+) binding affinity is also significant thermodynamically, which reduces channel stability. These results highlight, in general, how biomolecular function can rely on the polarization induced by methyl groups, especially those that are proximal to charged moieties, including ions, titratable amino acids, sulfates, phosphates, and nucleotides.


Esophageal melanotic schwannoma presenting with superior vena caval obstruction.
A rare tumor with an unusual presentation can pose a diagnostic and management dilemma. In this paper, we will discuss the management of a 47-year-old lady with melanotic schwanoma of the esophagus who presented with superior vena caval obstruction. The initial histological diagnosis of esophageal metastatic malignant melanoma did not corroborate the clinical and operative findings. Further evaluation revealed positivity for HMB45, S-100 protein, and vimentin, and confirmed the diagnosis of melanotic schwannoma.


Time-distance vision transformers in lung cancer diagnosis from longitudinal computed tomography.
Features learned from single radiologic images are unable to provide information about whether and how much a lesion may be changing over time. Time-dependent features computed from repeated images can capture those changes and help identify malignant lesions by their temporal behavior. However, longitudinal medical imaging presents the unique challenge of sparse, irregular time intervals in data acquisition. While self-attention has been shown to be a versatile and efficient learning mechanism for time series and natural images, its potential for interpreting temporal distance between sparse, irregularly sampled spatial features has not been explored. In this work, we propose two interpretations of a time-distance vision transformer (ViT) by using (1) vector embeddings of continuous time and (2) a temporal emphasis model to scale self-attention weights. The two algorithms are evaluated based on benign versus malignant lung cancer discrimination of synthetic pulmonary nodules and lung screening computed tomography studies from the National Lung Screening Trial (NLST). Experiments evaluating the time-distance ViTs on synthetic nodules show a fundamental improvement in classifying irregularly sampled longitudinal images when compared to standard ViTs. In cross-validation on screening chest CTs from the NLST, our methods (0.785 and 0.786 AUC respectively) significantly outperform a cross-sectional approach (0.734 AUC) and match the discriminative performance of the leading longitudinal medical imaging algorithm (0.779 AUC) on benign versus malignant classification. This work represents the first self-attention-based framework for classifying longitudinal medical images. Our code is available at https://github.com/tom1193/time-distance-transformer.


Benefits of mass customized products: moderating role of product involvement and fashion innovativeness.
The objective of this study was to explore impacts and benefits of mass customized products on emotional product attachment, favorable attitudes toward a mass customization program, and the ongoing effect on loyalty intentions. This study further investigated how benefits, attachment, attitudes, and loyalty intentions differed as a function of involvement and fashion innovativeness. 290 female online shoppers in South Korea participated in an online survey. Results of this study revealed that perceived benefits positively influenced emotional product attachment and attitudes toward a mass customization program. In addition, attachment positively influenced attitudes, which in turn affected loyalty intentions. This study also found that benefits, attachment, attitudes, and loyalty intentions were all higher in highly involved consumers (high fashion innovators) than those in less involved consumers (low fashion innovators). This study concludes with theoretical and practical implications for mass customization programs.


Provision of Kidney Disease Education Service Is Associated with Improved Vascular Access Outcomes among US Incident Hemodialysis Patients.
Pre-ESKD Kidney Disease Education (KDE) has been shown to improve multiple CKD outcomes, but its effect on vascular access outcomes is not well studied. In 2010, Medicare launched KDE reimbursements policy for patients with advanced CKD. In this retrospective USRDS analysis, we identified all adult patients on incident hemodialysis with ≥6 months of pre-ESKD Medicare coverage during the first 5 years of CMS-KDE policy and divided them into CMS-KDE services recipients (KDE cohort) and nonrecipients (non-KDE cohort). The primary outcome was incident arteriovenous fistula (AVF) and the composite of incident AVF or arteriovenous graft (AVG) utilization. Secondary outcomes were central venous catheter (CVC) with maturing AVF/AVG and pure CVC utilizations. Step-wise multivariate analyses were performed in four progressive models (model 1, KDE alone; model 2, multivariate model encompassing model 1 with sociodemographics; model 3, model 2 with comorbidity and functional status; and model 4, model 3 with pre-ESKD nephrology care). Of the 211,990 qualifying patients on incident hemodialysis during the study period, 2887 (1%) received KDE services before dialysis initiation. The rates of incident AVF and composite AVF/AVG were more than double (30% and 35%, respectively, compared with 14% and 17%), and pure catheter use about a third lower (40% compared with 65%) in the KDE cohort compared with the non-KDE cohort. The maximally adjusted odds ratios in model 4 for study outcomes were incident AVF use, 1.78, 99% confidence interval, 1.55 to 2.05; incident AVF/AVG use, 1.78, 99% confidence interval, 1.56 to 2.03; incident CVC with maturing AVF/AVG, 1.69, 99% confidence interval, 1.44 to 1.97; and pure CVC without any AVF/AVG, 0.51, 99% confidence interval, 0.45 to 0.58. The benefits of the KDE service were maintained even after accounting for the presence, duration, and facility of ESKD care. The occurrence of pre-ESRD KDE service is associated with significantly improved incident vascular access outcomes. Targeted studies are needed to examine the effect of KDE on patient engagement and self-efficacy as a cause for improvement in vascular access outcomes.


Personality traits measured by the Swedish universities Scales of Personality: factor structure and position within the five-factor model in an Estonian sample.
The study aims to test the reliability and validity of the Estonian version of the Swedish universities Scales of Personality (SSP), and to characterize the position of the SSP-measured traits within the basic personality dimensions of the five-factor model. A total of 529 participants completed the Estonian version of the SSP. A subsample of 197 persons completed the SSP together with the Revised NEO Personality Inventory (NEO-PI-R). The internal consistency of the SSP scales was satisfactory. Principal component analysis yielded three factors representing neuroticism, aggression and disinhibition. The factor solution obtained in the Estonian sample was similar to the original SSP study in the Swedish normative sample. NEO-PI-R Neuroticism had highest correlations with SSP neuroticism factor scales. Extraversion had strongest relationship with adventure seeking and low detachment. Agreeableness correlated positively with SSP social desirability and negatively to aggression-irritability scales. Conscientiousness facet Deliberation correlated with Impulsiveness. The Estonian SSP showed acceptable reliability and validity, which confirms that SSP is applicable in different social and cultural background. The SSP measures traits that correspond to the major personality models. The SSP characterizes three broad dimensions of personality, namely neuroticism, disinhibition and aggression, which are useful in assessment of personality correlates of mental disorders.


The Domains of Human Nutrition: The Importance of Nutrition Education in Academia and Medical Schools.
Human nutrition encompasses an extremely broad range of medical, social, commercial, and ethical domains and thus represents a wide, interdisciplinary scientific and cultural discipline. The high prevalence of both disease-related malnutrition and overweight/obesity represents an important risk factor for disease burden and mortality worldwide. It is the opinion of Federation of the Italian Nutrition Societies (FeSIN) that these two sides of the same coin, with their sociocultural background, are related to a low "nutritional culture" secondary, at least in part, to an insufficient academic training for health-care professionals (HCPs). Therefore, FeSIN created a study group, composed of delegates of all the federated societies and representing the different HCPs involved in human nutrition, with the aim of identifying and defining the domains of human nutrition in the attempt to more clearly define the cultural identity of human nutrition in an academically and professionally oriented perspective and to report the conclusions in a position paper. Three main domains of human nutrition, namely, basic nutrition, applied nutrition, and clinical nutrition, were identified. FeSIN has examined the areas of knowledge pertinent to human nutrition. Thirty-two items were identified, attributed to one or more of the three domains and ranked considering their diverse importance for academic training in the different domains of human nutrition. Finally, the study group proposed the attribution of the different areas of knowledge to the degree courses where training in human nutrition is deemed necessary (e.g., schools of medicine, biology, nursing, etc.). It is conceivable that, in the near future, a better integration of the professionals involved in the field of human nutrition will eventually occur based on the progressive consolidation of knowledge, competence, and skills in the different areas and domains of this discipline.


Hospital costs associated with psychiatric comorbidities: a retrospective study.
Psychiatric comorbidities are relevant for the diagnostic and therapeutic regimes in somatic hospital care. The main aim of this study was to analyse the association between psychiatric comorbidities and hospital costs per inpatient episode. A further aim was to discuss and address the methodological challenges in the estimation of these outcomes based on retrospective data. The study included 338,162 inpatient episodes consecutively discharged between 2011 and 2014 at a German university hospital. We used detailed resource use data to calculate day-specific hospital costs. We adjusted analyses for sex, age, somatic comorbidities and main diagnoses. We addressed potential time-related bias in retrospective diagnosis data with sensitivity analyses. Psychiatric comorbidities were associated with an increase in hospital costs per episode of 40% and an increase of reimbursement per episode of 28%, representing marginal effects of 1344 € and 1004 €, respectively. After controlling for length of stay, sensitivity analyses provided a lower bound increase in daily costs and reimbursement of 207 € and 151 €, respectively. If differences in hospital costs between patient groups are not adequately accounted for in DRG-systems, perverse incentives are created that can reduce the efficiency of care. Therefore, we suggest intensifying the inclusion of psychiatric comorbidities in the German DRG system. Future research should investigate the appropriate inclusion of psychiatric comorbidities in other health care systems' payment schemes.


Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence.
The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.


In Situ Synthesized Particulates on a Zirconia Ceramic Surface and Their Effect on Bonding to Porcelain.
To explore the effect of in situ synthesized particulates on a zirconia surface on the bonding properties between zirconia and porcelain. Presintered yttrium-stabilized tetragonal zirconia (Y-TZP) was cut into slices and bars and polished with 1,200-grit silicon carbide abrasive paper. Samples were randomly divided into six groups (C, I1, I3, I5, I7, and I9) according to immersion time in hydrofluoric acid solution (0, 10, 30, 50, 70, and 90 seconds, respectively). Then, the samples were placed in calcium chloride solution for 90 seconds and dipped in sodium hydroxide solution at 80°C for 2 hours. After sintering, the surface topography and roughness were examined. After the porcelain was fired, the bonding interface was observed, and cross-sectional microhardness was measured. The shear bond strength of the zirconia to porcelain was evaluated, and failure modes were classified. A 3-point bending test was applied to confirm the effects of the treatment on the mechanical properties. The above data were statistically analyzed. Polycrystalline particulates were synthesized on the zirconia surface. The surface roughness values increased as the immersion time of the samples in hydrofluoric acid increased. The cross-sectional microhardness decreased gradually in the experimental groups. Group I7 showed an elevated bond strength (27.02 ± 2.44 MPa). Mainly mixed failure mode was obtained in the experimental groups. The Weibull characteristic strength for the experimental groups was higher than that of group C. The flexural strengths were not significantly different among the groups. In situ synthesized polycrystalline particulates on zirconia could effectively improve the bonding between zirconia ceramics and porcelain without significantly decreasing the mechanical properties.


[Research Progress in Norovirus Bioaccumulation in Shellfish].
Noroviruses (NoVs) are one of the most important foodborne viral pathogens worldwide. Shellfish are the most common carriers of NoVs as they can concentrate and accumulate large amounts of the virus through filter feeding from seawater. Shellfish may selectively accumulate NoVs with different genotypes, and this bioaccumulation may depend on the season and location. Our previous studies found various histo-blood group antigens (HBGAs) in shellfish tissues. While HBGAs might be the main reason that NoVs are accumulated in shellfish, the detailed mechanism behind NoV concentration and bioaccumulation in shellfish is not clear. Here we review current research into NoV bioaccumulation, tissue distribution, seasonal variation, and binding mechanism in shellfish. This paper may provide insight into controlling NoV transmission and decreasing the risks associated with shellfish consumption.


Effect of ganoderic acid D on colon cancer Warburg effect: Role of SIRT3/cyclophilin D.
Ganoderic acid D (GAD) is a highly oxygenated tetracyclic triterpenoid. This study aims to assess the effects of GAD on the energy metabolism of colon cancer through the regulation of SIRT3 expression and whether this effect is related to acetylated cyclophilin D. The results demonstrated that GAD inhibits the energy reprogramming of colon cancer cells including glucose uptake, lactate production, pyruvate and acetyl-coenzyme production in colon cancer cells. Meanwhile, GAD upregulated the protein expression of SIRT3. Furthermore, the interruption of SIRT3 expression significantly reversed all the effects of SIRT3 on the energy reprogramming of colon cancer. In addition, GAD induced the deacetylated cyclophilin D (CypD) by SIRT3, whereas SIRT3-shRNA inhibited its combining effect on CypD. The energy reprogramming effects of GAD on colon cancer seem to be mediated by SIRT3 upregulation via acetylated CypD inhibition.


The emerging role of Cardiovascular Magnetic Resonance in the evaluation of hypertensive heart disease.
Arterial hypertension is the commonest cause of cardiovascular death. It may lead to hypertensive heart disease (HHD), including heart failure (HF), ischemic heart disease (IHD) and left ventricular hypertrophy (LVH). According to the 2007 ESH/ESC guidelines, the recommended imaging technique is echocardiography (echo), when a more sensitive detection of LVH than that provided by ECG, is needed. Cardiovascular Magnetic Resonance (CMR), a non-invasive, non-radiating technique, offers the following advantages, beyond echo: a) more reliable and reproducible measurements of cardiac parameters such as volumes, ejection fraction and cardiac mass b) more accurate differentiation of LVH etiology by providing information about tissue characterisation c) more accurate evaluation of myocardial ischemia, specifically if small vessels disease is present d) technique of choice for diagnosis of renovascular, aortic tree/branches lesions and quantification of aortic valve regurgitation e) technique of choice for treatment evaluation in clinical trials. The superiority of CMR against echocardiography in terms of reproducibility, operator independency, unrestricted field of view and capability of tissue characterization makes the technique ideal for evaluation of heart, quantification of aortic valve regurgitation, aorta and aortic branches. CMR has a great potential in early diagnosis, risk stratification and treatment follow up of HHD. However, an international consensus about CMR in HHD, taking under consideration the cost-benefit ratio, expertise and availability, is still warranted.


Secondary structure of the ETS domain places murine Ets-1 in the superfamily of winged helix-turn-helix DNA-binding proteins.
The members of the ets gene family of transcription factors are characterized by a conserved 85-residue DNA-binding region, termed the ETS domain, that lacks sequence homology to structurally characterized DNA-binding motifs. The secondary structure of the ETS domain of murine Ets-1 was determined on the basis of NMR chemical shifts, NOE and J-coupling constraints, amide hydrogen exchange, circular dichroism, and FT-IR spectroscopy. The ETS domain is composed of three alpha-helices (H) and four beta-strands (S) arranged in the order H1-S1-S2-H2-H3-S3-S4. The four-stranded antiparallel beta-sheet is the scaffold for a putative helix-turn-helix DNA recognition motif formed by helices 2 and 3. The 25 residues extending beyond the ETS domain to the native C-terminus of the truncated Ets-1 also contain a helical segment. On the basis of the similarity of this topology with that of catabolite activator protein (CAP), heat shock factor (HSF), and hepatocyte nuclear factor (HNF-3 gamma), we propose that ets proteins are members of the superfamily of winged helix-turn-helix DNA-binding proteins.


Isolated oculomotor nerve palsy in a white-eyed patient with dural carotid-cavernous sinus fistulas: a case report.
The study reported a woman with dural carotid-cavernous sinus fistulas (CCFs) who presented with a unilateral white-eyed appearance, and painful oculomotor nerve palsy with pupillary involvement. After cerebral angiography, which revealed posterior drainage of the fistulas, the dural CCFs closed, the oculomotor nerve palsy subsided spontaneously and no recurrence occurred throughout the 2-year follow-up. Dural CCFs should be kept in mind when patients present with painful oculomotor nerve palsy. Moreover, cerebral angiography remains the standard diagnostic method and fistulas may close spontaneously following this procedure.


Estimating Gait Stability: Asymmetrical Loading Effects Measured Using Margin of Stability and Local Dynamic Stability.
Changes to intersegmental locomotor control patterns may affect body stability. Our study aimed to (a) characterize upper body dynamic stability in response to the unilateral addition of mass to the lower extremity and (b) evaluate the efficacy of 2 different stability measures commonly used in the literature to detect resulting symmetrical step pattern modifications across the weighted segments (spatial) and between epochs of the gait cycle (temporal). Young adults walked on a treadmill while unloaded or with weights applied unilaterally to their foot, shank, or thigh. Both margin of stability and local dynamic stability (LDS) estimates detected similar trends of distal segment weighting resulting in more unstable upper body movement compared to proximal weighting; however only LDS detected anteroposterior changes in upper body stability over time.


Mortality of midlife women with surgically verified endometriosis-a cohort study including 2.5 million person-years of observation.
Is all-cause and cause-specific mortality increased among women with surgically verified endometriosis? The all-cause and cause-specific mortality in midlife was lower throughout the follow-up among women with surgically verified endometriosis compared to the reference cohort. Endometriosis has been associated with an increased risk of comorbidities such as certain cancers and cardiovascular diseases. These diseases are also common causes of death; however, little is known about the mortality of women with endometriosis. A nationwide retrospective cohort study of women with surgically verified diagnosis of endometriosis was compared to the reference cohort in Finland (1987-2012). Follow-up ended at death or 31 December 2014. During the median follow-up of 17 years, 2.5 million person-years accumulated. Forty-nine thousand nine hundred and fifty-six women with at least one record of surgically verified diagnosis of endometriosis in the Finnish Hospital Discharge Register between 1987 and 2012 were compared to a reference cohort of 98 824 age- and municipality-matched women. The age (mean ± standard deviation) of the endometriosis cohort was 36.4 ± 9.0 and 53.6 ± 12.1 years at the beginning and at the end of the follow-up, respectively. By using the Poisson regression models the crude and adjusted all-cause and cause-specific mortality rate ratios (MRR) and 95% confidence intervals (CI) were assessed. Calendar time, age, time since the start of follow-up, educational level, and parity adjusted were considered in the multivariate analyses. A total of 1656 and 4291 deaths occurred in the endometriosis and reference cohorts, respectively. A lower all-cause mortality was observed for the endometriosis cohort (adjusted MRR, 0.73 [95% CI 0.69 to 0.77])-there were four deaths less per 1000 women over 10 years. A lower cause-specific mortality contributed to this: the adjusted MRR was 0.88 (95% CI 0.81 to 0.96) for any cancer and 0.55 (95% CI 0.47 to 0.65) for cardiovascular diseases, including 0.52 (95% CI 0.42 to 0.64) for ischemic heart disease and 0.60 (95% CI 0.47 to 0.76) for cerebrovascular disease. Mortality due to alcohol, accidents and violence, respiratory, and digestive disease-related causes was also decreased. These results are limited to women with endometriosis diagnosed by surgery. In addition, the study does not extend into the oldest age groups. The results might be explained by the characteristics and factors related to women's lifestyle, and/or increased medical attention and care received, rather than the disease itself. These reassuring data are valuable to women with endometriosis and to their health care providers. Nonetheless, more studies are needed to address the causality. This research was funded by the Hospital District of Helsinki and Uusimaa and The Finnish Medical Foundation. None of the authors report any competing interest in relation to the present work; all the authors have completed the disclosure form.


At the Crossroads Between Neurodegeneration and Cancer: A Review of Overlapping Biology and Its Implications.
A growing body of epidemiologic evidence suggests that neurodegenerative diseases occur less frequently in cancer survivors, and vice versa. While unusual, this inverse comorbidity is biologically plausible and could be explained, in part, by the evolutionary tradeoffs made by neurons and cycling cells to optimize the performance of their very different functions. The two cell types utilize the same proteins and pathways in different, and sometimes opposite, ways. However, cancer and neurodegeneration also share many pathophysiological features. In this review, we compare three overlapping aspects of neurodegeneration and cancer. First, we contrast the priorities and tradeoffs of dividing cells and neurons and how these manifest in disease. Second, we consider the hallmarks of biological aging that underlie both neurodegeneration and cancer. Finally, we utilize information from genetic databases to outline specific genes and pathways common to both diseases. We argue that a detailed understanding of the biologic and genetic relationships between cancer and neurodegeneration can guide future efforts in designing disease-modifying therapeutic interventions. Lastly, strategies that target aging may prevent or delay both conditions.


Myocardial infarction: nursing responsibilities in the first hour.
The aim of this article is to provide a comprehensive review of the physiological processes that occur during the first hour following a myocardial infarction (MI). It will identify the general principles and the physiological processes that occur in response to a MI, outlining the consequences of cellular hypoxia to the heart. The implications for clinical practice and how they link to the physiological processes are detailed. Understanding the physiological principles involved in a MI is important for identification and to ensure patient management is initiated. This, together with prompt diagnosis and interventions, will assist in reducing mortality within the first hour following a MI.


Bayesian meta-analysis using SAS PROC BGLIMM.
Meta-analysis is commonly used to compare two treatments. Network meta-analysis (NMA) is a powerful extension for comparing and contrasting multiple treatments simultaneously in a systematic review of multiple clinical trials. Although the practical utility of meta-analysis is apparent, it is not always straightforward to implement, especially for those interested in a Bayesian approach. This paper demonstrates that the recently-developed SAS procedure BGLIMM provides an intuitive and computationally efficient means for conducting Bayesian meta-analysis in SAS, using a worked example of a smoking cessation NMA data set. BGLIMM gives practitioners an effective and simple way to implement Bayesian meta-analysis (pairwise and network, either contrast-based or arm-based) without requiring significant background in coding or statistical modeling. Those familiar with generalized linear mixed models, and especially the SAS procedure GLIMMIX, will find this tutorial a useful introduction to Bayesian meta-analysis in SAS.


HYCONES II: a tool to build hybrid connectionist expert systems.
This paper describes HYCONES II--a tool to enable the construction of hybrid connectionist expert systems to solve classification problems. HYCONES II offers to the knowledge engineer a hybrid knowledge base that integrates frames with three different neural network models: the combinatorial neural model--CNM, the Fuzzy ARTMAP and the Semantic ART--SMART models. The latter is a new model, introduced by this paper, based on a combination of the two previous models. The validation section compares the performance of these three neural models to solve diagnostic problems in two medical domains. This paper also presents HYCONES II knowledge representation features, built in the symbolic component of its hybrid knowledge-base, to deal and represent fuzzy medical variables. Finally, the present status and future developments of the project are presented.


Synergistic Effect of Quercetin Magnetite Nanoparticles and Targeted Radiotherapy in Treatment of Breast Cancer.
Quercetin is a potent cancer therapeutic agent present in fruits and vegetables. The pharmaceutical uses of quercetin are limited due to many problems associated with low solubility, bioavailability, permeability, and instability. In addition, the high doses of quercetin show toxic effects in clinical and experimental studies. Therefore, a new strategy is warranted to overcome these problems without the use of toxic doses. The iron oxide nanoparticles can be used as a drug delivery system. This study aimed to prepare quercetin-conjugated magnetite nanoparticles (QMNPs) using biological simple nanoprecipitation and mediated by fungus Aspergillus oryzae. Also, we initiated in vitro and in vivo studies to determine whether QMNPs might sensitize breast cancer to radiotherapy treatment. The structural, morphological, and magnetic properties of the prepared nanoparticles were studied. The results indicated that QMNPs were spherical in shape and 40 nm in diameter. The in vitro studies showed that the incubation of MCF-7, HePG-2, and A459 cancer cells with QMNPs for 24 h effectively inhibited the growth of cancer cell lines in a concentration-dependent manner with IC50 values of 11, 77.5, and104 nmol/mL, respectively. The combination of QMNPs with irradiation (IR) potently blocked MCF-7 cancer cell proliferation and showed significant changes in the morphology of these cells as observed by bright-field inverted light microscopy. Focusing on the long-term toxicity of QMNPs (20 ml/kg), the assessment of hematological, hepatic, and renal markers indicated no toxic effect. Besides, QMNPs inhibited tumor growth and potently enhanced the lateral radiotherapy treatment in N-methyl-N-nitrosourea (MNU)-induced breast cancer in female white albino rats. These anticancer and radiosensitizing activities were ascribed to cytotoxicity, cell cycle arrest, immunomodulation, and efficiency through induction of apoptosis. In a conclusion, these observations suggest that the QMNPs combined with LRT could act as a potential targeted therapy in breast cancer.


Standardization of radiograph readings during bowel management week.
During "bowel management week," abdominal radiographs are used to monitor the amount and location of stool. A radiologist familiar with the treatment plan can provide an improved interpretation. The goal of this paper is to standardize the radiological reports during a bowel management week. We saw 744 patients during bowel management week from May 2016 until March 2023. Diagnosis included: anorectal malformation (397), idiopathic constipation (180), Hirschsprung disease (89), and spina bifida (78). Laxatives were the treatment for 51% of patients, and 49% received enemas. Characteristic radiographs were selected for each treatment group for a proposed reading standardization. When the stool is visualized, it is crucial to report its location. Having a contrast enema helps with the correct interpretation of the colonic anatomy. It is also essential to always compare the amount of stool with the radiograph from the previous day to determine if there is an increase or decrease in stool. Examples of radiographs are shown to guide the use of the preferred proposed terminology. Providing information regarding which treatment modality the patient is receiving and stating that a patient is on a bowel management week treatment is crucial for the radiologist to provide adequate interpretation. The radiologist must be familiar with the treatment goals and purpose of the daily radiograph.


Less frequent cardiac and extracardiac findings during 99mTc-methoxyisobutylisonitrile myocardial perfusion single-photon emission computed tomography with radiological correlates.
Myocardial perfusion single-photon emission computed tomography (SPECT) as a common imaging procedure in nuclear medicine laboratories may encompass findings in the heart or beyond it, in the thorax or abdomen, which may be related or unrelated to the symptoms of the patients. Sometimes, these findings may be discovered incidentally. In the present article, it is aimed to present some less frequent cardiac and extracardiac findings including radiolabeled emboli, transposition of great arteries, breast prosthesis, breast tissue uptake, pericardial effusion, hiatal hernia, hepatocellular carcinoma, ascites, aortic aneurysm, splenomegaly, and polycystic kidney disease during 99mTc-methoxyisobutylisonitrile myocardial perfusion SPECT with their radiological correlates.


White-rot fungus Phlebia floridensis ITM 12: Laccase production, oxidoreductase profile, and hydrogen-peroxide independent activity.
Phlebia genus is a relevant group of fungi with a crucial role in numerous ecosystems. In tropical and subtropical areas this genus allows the efficient degradation of lignin and carbon recovery; however, the majority of these fungal species remain undiscovered. The main purpose of this work was to determine the enzymatic activity of extracellular proteins of a novel Phlebia floridensis strain isolated in Yucatan Peninsula, Mexico. The results that are reported here demonstrate that the soluble protein extract of P. floridensis can degrade a broad spectrum of recalcitrant compounds. This induced protein extract is able to modify not only phenolic and nonphenolic compounds, but also anthroquinone dyes, even without the addition of exogenous hydrogen peroxide. Using liquid chromatography-mass spectrometry (LC-MS), we were able to identify a novel chloroperoxidase in enzymatic extract. As far as we know, this is the first report about the presence of this type of enzyme in the Phlebia genus.


Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells.
To gain an understanding of the molecular pathogenesis of thyroid cancer, we used DNA microarray to study the expression profiles of 10 different human thyroid carcinoma cell lines. These included papillary lines BHP 2-7, BHP 7-13, BHP 10-3, BHP 18-21, NPA 87, and TPC1; anaplastic lines ARO 81-1 and DRO 90-1; follicular line WRO 82-1; and medullary line HRO 85-1. Among the genes with increased expression in the cancer cell lines, a gene coding for nicotinamide N-methyltransferase (NNMT) was identified for being highly expressed only in the papillary cell lines. NNMT catalyzes N-methylation of nicotinamide and other structurally related compounds and is highly expressed in the human liver. The results were further confirmed by semiquantitative RT-PCR and Northern blot analysis. NNMT catalytic activities were determined in all of the cells described above and in additional cell lines. Significantly higher NNMT enzyme activities were detected in eight of 10 of the papillary lines and three of six of the follicular cell lines tested. Normal thyroid tissue, thyroid primary cultures, anaplastic cancer cells, and medullary cancer cells showed no or low enzyme activity. Immunohistochemical staining for NNMT of human thyroid specimens showed strong and abundant cytoplasmic reactions in the sections of papillary carcinomas, and weak or scanty reaction in the normal thyroid tissues. These results indicate that NNMT is a potential biomarker for papillary thyroid carcinoma.