Cell Lineage-Guided Microanalytical Mass Spectrometry Reveals Increased Energy Metabolism and Reactive Oxygen Species in the Vertebrate Organizer.
Molecular understanding of the vertebrate Organizer, a tissue center critical for inductive signaling during gastrulation, has so far been limited to transcripts and some proteins due to limitations in detection and sensitivity. The Spemann-Mangold Organizer (SMO) in the South African Clawed Frog ( X. laevis ), a popular model of development, has long been discovered to induce the patterning of the central nervous system. Molecular screens on the tissue have identified several genes, such as goosecoid, chordin, and noggin, with independent ability to establish a body axis. A comprehensive study of proteins and metabolites produced in the SMO and their functional roles has been lacking. Here, we pioneer a deep discovery proteomic and targeted metabolomic screen of the SMO in comparison to the rest of the embryo using liquid chromatography high-resolution mass spectrometry (HRMS). Quantification of ∼4,600 proteins and a panel of metabolites documented differential expression for ∼450 proteins and multiple intermediates of energy metabolism in the SMO. Upregulation of oxidative phosphorylation (OXPHOS) and redox regulatory proteins gave rise to elevated oxidative stress and an accumulation of reactive oxygen species in the Organizer. Imaging experiments corroborated these findings, discovering enrichment of hydrogen peroxide in the SMO tissue. Chemical perturbation of the redox gradient affected mesoderm involution during early tissue movements of gastrulation. HRMS expands the bioanalytical toolbox of cell and developmental biology, providing previously unavailable information on molecular classes to challenge and refine our classical understanding of the Organizer and its function during early patterning of the embryo.


The impact of food assistance on weight gain and disease progression among HIV-infected individuals accessing AIDS care and treatment services in Uganda.
The evidence evaluating the benefits of programmatic nutrition interventions to HIV-infected individuals in developing countries, where there is a large overlap between HIV prevalence and malnutrition, is limited. This study evaluates the impact of food assistance (FA) on change in weight and disease progression as measured by WHO staging. We utilize program data from The AIDS Support Organization (TASO) in Uganda to compare outcomes among FA recipients to a control group, using propensity score matching (PSM) methods among 14,481 HIV-infected TASO clients. FA resulted in a significant mean weight gain of 0.36 kg over one year period. This impact was conditional on anti-retroviral therapy (ART) receipt and disease stage at baseline. FA resulted in mean weight gain of 0.36 kg among individuals not receiving ART compared to their matched controls. HIV-infected individuals receiving FA with baseline WHO stage II and III had a significant weight gain (0.26 kg and 0.2 kg respectively) compared to their matched controls. Individuals with the most advanced disease at baseline (WHO stage IV) had the highest weight gain of 1.9 kg. The impact on disease progression was minimal. Individuals receiving FA were 2 percentage points less likely to progress by one or more WHO stage compared to their matched controls. There were no significant impacts on either outcome among individuals receiving ART. Given the widespread overlap of HIV and malnutrition in sub-Saharan Africa, FA programs have the potential to improve weight and delay disease progression, especially among HIV-infected individuals not yet on ART. Additional well designed prospective studies evaluating the impact of FA are urgently needed.


[Effect of proteolytic enzymes on cyclic nucleotide levels and DNA synthesis in lymphocytes].
It is shown that the treatment of mouse spleen lymphocytes with the optimum mitogenic concentrations of thrombin and plasmin increases the intracellular amount of cGMP, the intracellular level of cAMP remaining the same. An increase of the intracellular level of cGMP and enhancement of the DNA synthesis in lymphocytes, on the one hand and the absence of these metabolic changes with the use of inactivated proteases, on the other, indicate that thrombin- and plasmin-induced proliferation of lymphocytes at the initial stages of cell activation is, probably, realized by the cGMP-dependent mechanisms.


Isolation and characterization of an RIP (ribosome-inactivating protein)-like protein from tobacco with dual enzymatic activity.
Ribosome-inactivating proteins (RIPs) are N-glycosidases that remove a specific adenine from the sarcin/ricin loop of the large rRNA, thus arresting protein synthesis at the translocation step. In the present study, a protein termed tobacco RIP (TRIP) was isolated from tobacco (Nicotiana tabacum) leaves and purified using ion exchange and gel filtration chromatography in combination with yeast ribosome depurination assays. TRIP has a molecular mass of 26 kD as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and showed strong N-glycosidase activity as manifested by the depurination of yeast rRNA. Purified TRIP showed immunoreactivity with antibodies of RIPs from Mirabilis expansa. TRIP released fewer amounts of adenine residues from ribosomal (Artemia sp. and rat ribosomes) and non-ribosomal substrates (herring sperm DNA, rRNA, and tRNA) compared with other RIPs. TRIP inhibited translation in wheat (Triticum aestivum) germ more efficiently than in rabbit reticulocytes, showing an IC50 at 30 ng in the former system. Antimicrobial assays using highly purified TRIP (50 microg mL(-1)) conducted against various fungi and bacterial pathogens showed the strongest inhibitory activity against Trichoderma reesei and Pseudomonas solancearum. A 15-amino acid internal polypeptide sequence of TRIP was identical with the internal sequences of the iron-superoxide dismutase (Fe-SOD) from wild tobacco (Nicotiana plumbaginifolia), Arabidopsis, and potato (Solanum tuberosum). Purified TRIP showed SOD activity, and Escherichia coli Fe-SOD was observed to have RIP activity too. Thus, TRIP may be considered a dual activity enzyme showing RIP-like activity and Fe-SOD characteristics.


Returns to integrated pest management research and outreach for soybean aphid.
Soybean aphid, Aphis glycines Matsumura, is a major invasive pest that has caused substantial yield loss and increased insecticide use in the United States since its discovery in 2000. Using the economic surplus approach, we estimate the economic benefits of U.S. research and outreach for integrated pest management (IPM) of soybean aphid. We calculate ex ante net benefits from adoption of an IPM economic threshold (ET). The ET triggers insecticide application only if the value of predicted yield damage from pest scouting is expected to exceed the cost of pest control. Our research finds that gradual adoption of an ET for soybean aphid management will generate a projected economic net benefit of $1.3 billion, for an internal rate of return of 124%, over the 15 yr since soybean aphid IPM research began in 2003. Lower and upper bound sensitivity analysis brackets the estimated net benefit to U.S. consumers and soybean, Glycine max (L.) Merr., growers in the range of $0.6 to $2.6 billion in 2005 dollars. If a 10% rate of return is attributed to IPM applied research and outreach on soybean aphid, that would leave nearly $800 million to compensate prior activities that contribute to the development and adoption of IPM.


Two-axis tracking using translation stages for a lens-to-channel waveguide solar concentrator.
A two-axis tracking scheme designed for <250x concentration realized by a single-axis mechanical tracker and a translation stage is discussed. The translation stage is used for adjusting positions for seasonal sun movement. It has two-dimensional x-y tracking instead of horizontal movement x-only. This tracking method is compatible with planar waveguide solar concentrators. A prototype system with 50x concentration shows >75% optical efficiency throughout the year in simulation and >65% efficiency experimentally. This efficiency can be further improved by the use of anti-reflection layers and a larger waveguide refractive index.


Expression and serum immunoreactivity of developmentally restricted differentiation antigens in epithelial ovarian cancer.
Cancer-embryo antigens or developmentally restricted differentiation antigens (DRDAGs), such as PLAC1 (CT92) and developmental pluripotency associated-2 (DPPA2/CT100), are expressed in pluripotent embryonic cells. They are also recognized as cancer-testis antigens (CT) which are proteins normally expressed only in the human germ line but that are also present in a significant subset of malignant tumors. These antigens may prove to be markers of 'repopulating' cells with stem cell-like characteristics and could be critical targets for immunotherapy in epithelial ovarian cancer (EOC). Our objective was to define the frequency of expression and immunogenicity of PLAC1 and DPPA2 in EOC and correlate expression with clinical outcome. One-step reverse transcriptase PCR was performed on 101 EOC samples and a panel of normal tissues. Expression of PLAC1 and DPPA2 in the EOC specimens was 21/101 (21%) and 31/101 (31%) respectively. In normal tissues, PLAC1 expression was restricted to the placenta while DPPA2 expression was restricted to the placenta and testis. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were also performed on a subset of specimens. Humoral immunity was demonstrable in 2/12 serum samples from patients whose tumors expressed DPPA2. There was no demonstrable antibody response to PLAC1 in patients with PLAC1 positive tumors. The presence of PLAC1 and DPPA2 did not have a statistically significant effect on recurrence-free and overall survival. The tissue-restricted expression of PLAC1 and DPPA2, their expression in a significant proportion of EOC patients, and their potential to represent markers of stem cells make DRDAGs attractive targets for antigen-specific immunotherapy in EOC.


[Amelanotic acral melanoma originating from the foot: a clinical case.]
We will present the case of a 75-year-old woman diagnosed with an amelanotic acral melanoma originating from the left foot relapsed to the lung and to muscular and subcutaneous tissues less than one year after the surgical treatment (pT4bN3c, AJCC 8th ed.) of the primary lesion. Treated with first-line encorafenib + binimetinib, the patient reported a complete response lasting 37 months and followed by a partial response, still ongoing after 19 months, to anti-PD-1 antibody second line therapy.


Identification of novel serum biomarkers for gastric cancer by magnetic bead.
Early diagnosis and early treatment is known to improve prognosis for gastric cancer. Magnetic affinity beads can be used to extract peptides from un-fractionated serum samples. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can detect the presence and the molecular mass of peptides. MALDI-TOF-MS mass spectra of peptides and proteins were generated after WCX CLINPROT bead fractionation of 62 gastric cancer serum samples. The discovery set consisted of 44 samples while the validation set was 18 serum samples. The spectra were analyzed statistically using flexAnalysisTM and Clin-ProtTM bioinformatic software. The six most significant peaks were selected out by ClinProTool software and utilized to train a Supervised Neural Network to identify gastric cancer sera from control sera. The sensitivity and specificity of the model when tested on the validation set were 100% and 75%, respectively. A set of 6 peptides that can be used to distinguish serum from gastric cancer patients with good sensitivity and specificity were identified, and these peptides may be useful biomarkers to distinguish cancer individuals who may benefit from radiologic or endoscopic examination.


Sensing and avoiding sick conspecifics requires Gαi2+ vomeronasal neurons.
Rodents utilize chemical cues to recognize and avoid other conspecifics infected with pathogens. Infection with pathogens and acute inflammation alter the repertoire and signature of olfactory stimuli emitted by a sick individual. These cues are recognized by healthy conspecifics via the vomeronasal or accessory olfactory system, triggering an innate form of avoidance behavior. However, the molecular identity of the sensory neurons and the higher neural circuits involved in the detection of sick conspecifics remain poorly understood. We employed mice that are in an acute state of inflammation induced by systemic administration of lipopolysaccharide (LPS). Through conditional knockout of the G-protein Gαi2 and deletion of other key sensory transduction molecules (Trpc2 and a cluster of 16 vomeronasal type 1 receptors), in combination with behavioral testing, subcellular Ca2+ imaging, and pS6 and c-Fos neuronal activity mapping in freely behaving mice, we show that the Gαi2+ vomeronasal subsystem is required for the detection and avoidance of LPS-treated mice. The active components underlying this avoidance are contained in urine whereas feces extract and two selected bile acids, although detected in a Gαi2-dependent manner, failed to evoke avoidance behavior. Our analyses of dendritic Ca2+ responses in vomeronasal sensory neurons provide insight into the discrimination capabilities of these neurons for urine fractions from LPS-treated mice, and how this discrimination depends on Gαi2. We observed Gαi2-dependent stimulation of multiple brain areas including medial amygdala, ventromedial hypothalamus, and periaqueductal grey. We also identified the lateral habenula, a brain region implicated in negative reward prediction in aversive learning, as a previously unknown target involved in these tasks. Our physiological and behavioral analyses indicate that the sensing and avoidance of LPS-treated sick conspecifics depend on the Gαi2 vomeronasal subsystem. Our observations point to a central role of brain circuits downstream of the olfactory periphery and in the lateral habenula in the detection and avoidance of sick conspecifics, providing new insights into the neural substrates and circuit logic of the sensing of inflammation in mice.


Expanded medical home model works for children in foster care.
The Illinois Child Welfare Department implemented a statewide health care system to ensure that children in foster care obtain quality health care by providing each child with a medical home. This study demonstrates that the Medical Home model works for children in foster care providing better health outcomes in higher immunization rates.These children used the health care system more effectively and cost-effective as reflected in the higher utilization rates of primary care and well-child visits and lower utilization of emergency room care for children with chronic conditions.


[Myocardial oxygen supply in hemodilution in patients with healthy hearts and heart surgery patients].
Infusion of colloid solutions for intentional isovolemic hemodilution can help to save homologous blood in surgical patients. In addition, hemodilution improves blood fluidity which leads to an increased organ blood flow and better tissue oxygenation. A major limiting factor for the degree of dilutional anemia induced by hemodilution is the oxygen supply of the myocardium since unimpaired heart function is of utmost importance. The basic mechanism that compensates for the reduction of hemoglobin-concentration (fall of oxygen capacity) of the diluted blood is a rise in cardiac output and coronary blood flow which maintains or even enhances systemic and coronary oxygen transport capacity (hemoglobin-concentration x saturation x cardiac output or coronary blood flow). In normovolemic patients with unimpaired cardiac function there is no problem in this respect and clinical experience has shown that even high degrees of dilutional anemia are well tolerated. Patients with heart disease, however, may have a limited ability to increase cardiac output and coronary blood flow. Therefore, in these cases the risks of intentional hemodilution can exceed its benefits and a careful evaluation of risks is mandatory for every individual patient. In the following, we review knowledge from the literature and our own experimental and clinical data to explain the influence of dilutional anemia on the physiology and pathophysiology of myocardial oxygen supply.


Bacterial liver abscess in children.
From November 1987, 136 children with bacterial liver abscess were encountered. There were 97 males and 39 females and the age ranged from 1-15 years (mean = 8.42 years). The clinical signs and symptoms of liver abscess were confirmed by radiography, ultrasonography, percutaneous transhepatic drainage (PTHD) and radioisotope scanning. 103 children had solitary abscess and the remaining 33 children, multiple abscesses. Of the children with multiple abscesses, 23 had abscesses confined to one lobe of the liver and 10 had involvement of both lobes of the liver. 86 children had culture of liver abscesses done and only 63 (73.2%) yielded positive culture. Staphylococcus aureus and Escherichia coli were the commonest organisms cultured from liver abscesses. 72 cases had drainage of liver abscesses, one of them ended up with hepatic artery ligation. A further 15 cases treated by PTHD survived. Of the remaining 49 cases who had antibiotic therapy, 2 died of septicemia, giving a mortality rate of 1.47%. 36.3% of children with liver abscesses responded to antibiotic therapy. The indication and method for surgical management are discussed. Percutaneous transhepatic drainage (PTHD) of liver abscesses, under the guidance of ultrasonography is found to be safe and effective.


Spondylodiscitis, nephrology department's experience.
Spondylodiscitis is an infection of the vertebral body and adjacent intervertebral discs, whose most common means of spreading is the haematogenous route. It is a rare disease but its overall incidence is increasing, mainly due to increased bacteraemia in patients with intravascular devices, such as that used in patients on renal replacement therapy with haemodialysis. Its diagnosis is difficult due to non-specific symptoms and as such, for early and accurate diagnosis, MRI is necessary. The early empirical antibiotic treatment and the multidisciplinary approach may improve the prognosis of this potentially serious infection. We report a series of cases diagnosed with spondylodiscitis in our Nephrology Unit.


The work of a rural practice.
Study of the work load in the month of November over some years in a single handed rural practice has revealed several interesting trends, one being the way in which the work is gradually increasing. A more detailed study of the work over 12 months has demonstrated how fallacious impressions about one's work can be--the work being spread over a very much larger proportion of the patients than had been originally suspected.


Evaluating optical coherence tomography for surgical margin assessment of canine mammary tumours.
Optical coherence tomography (OCT) uses near-infrared light waves to generate real-time, high-resolution images on the microscopic scale similar to low power histopathology. Previous studies have demonstrated the use of OCT for real-time surgical margin assessment for human breast cancer. The use of OCT for canine mammary tumours (CMT) could allow intra-operative visualisation of residual tumour at the surgical margins. The purpose of this study was to assess OCT imaging for the detection of incomplete tumour resection following CMT surgery. We hypothesized that the OCT images would have comparable features to histopathological images of tissues at the surgical margins of CMT resections along with a high sensitivity of OCT detection of incomplete surgical excision of CMT. Thirty surgical specimens were obtained from nineteen client-owned dogs undergoing surgical resection of CMT. OCT image appearance and characteristics of adipose tissue, skin, mammary tissue and mammary tumour at the surgical margins were distinct and different. The OCT images of normal and abnormal tissues at the surgical margins were utilized to develop a dataset of OCT images for observer evaluation. The sensitivity and specificity for ex vivo images were 83.3% and 82.0% (observer 1) and 70.0% and 67.9% (observer 2). The sensitivity and specificity for in vivo images were 70.0% and 89.3% (observer 1) and 76.7% and 67.9% (observer 2). These results indicate a potential use of OCT for surgical margin assessment for CMT to optimize surgical intervention and clinical outcomes. Improved training and experience of observers may improve sensitivity and specificity.


Measured versus predicted vertical displacement of the sacrum during gait as a tool to measure biomechanical gait performance.
The vertical displacement of the sacrum during walking is proposed as an estimation of the overall biomechanical performance of walking, independent of cardiopulmonary factors. Vertical sacral displacement during walking was measured using an optoelectronic motion analysis system in 10 normal volunteers at variable speeds. Oxygen consumption was simultaneously measured. The actual vertical displacement of the sacrum, when correlated with body weight, reliably predicted oxygen consumption (r2 = 0.91). The relationship between vertical sacral displacement and oxygen consumption persisted when controlling for the variables, velocity, square of velocity, cadence or stride length, each known to co-vary with cardiopulmonary performance. A mathematic model designed to predict the vertical displacement of the sacrum, based on sacral height and average stride length, was tested. The actual vertical sacral displacement correlated with predicted displacement (r = 0.94). Unilateral immobilization of each subject's knee resulted in a greater average vertical sacral displacement during gait than predicted. Comparing measured with predicted vertical sacral displacement may provide a clinically useful and specific overall assessment of biomechanical gait performance.


Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet.
Hypertensive patients have reduced lymphocyte beta-adrenergic responsiveness which is corrected by a low sodium (Na) diet. To determine if this represents a more generalized abnormality in beta adrenoceptor response, we studied beta adrenergic-mediated vasodilation in hand veins of borderline hypertensive subjects and controls. Subjects received a 5-d diet containing high Na/low potassium (K), high Na/high K, or low Na/high K. Venous distension, as evaluated by a linear variable differential transformer, was measured in relation to infusion of phenylephrine followed by isoproterenol and nitroglycerin. On both the high Na/high K and high Na/low K diets, hypertensive subjects had significantly decreased isoproterenol-mediated vasodilation (47% decrease, P less than 0.01 and 36% decrease, P less than 0.01, respectively). On the low Na/high K diet, isoproterenol-mediated vasodilation in hypertensive subjects increased 41% (P less than 0.01) to a level not different from controls. Nitroglycerin-mediated vasodilation was not different in normotensive and hypertensive subjects, nor was it altered with Na intake. Phenylephrine-mediated vasoconstriction did not differ between normotensive and hypertensive groups. Venous beta-adrenergic response correlated with lymphocyte beta adrenoceptor density in normotensive (r = 0.53, P less than 0.005) but not hypertensive subjects. This study demonstrates that beta-adrenergic responsiveness is selectively reduced in peripheral veins of borderline hypertensive subjects, and this is corrected by a low Na diet. In view of our previous findings of reduced lymphocyte beta-adrenergic responsiveness in borderline hypertension, these studies suggest a generalized defect of beta adrenoceptor responsiveness in human hypertension. Further, dietary Na may play an important role in regulating this abnormality.


Electrochemical optical waveguide lightmode spectroscopy (EC-OWLS): a pilot study using evanescent-field optical sensing under voltage control to monitor polycationic polymer adsorption onto indium tin oxide (ITO)-coated waveguide chips.
A new technique has been developed that combines evanescent-field optical sensing with electrochemical control of surface adsorption processes. This new technique, termed "electrochemical optical waveguide lightmode spectroscopy" (EC-OWLS), proved efficient in monitoring molecular surface adsorption and layer thickness changes of an adsorbed polymer layer examined in situ as a function of potential applied to a waveguide in a pilot study. For optical sensing, a layer of indium tin oxide (ITO) served as both a high-refractive-index waveguide and a conductive electrode. In addition, an electrochemical flow-through fluid cell was provided, which incorporated working, reference, and counter electrodes, and was compatible with the constraints of optical sensing. Poly(L-lysine)-grafted-poly(ethylene glycol) (PLL-g-PEG) served as a model, polycation adsorbate. Adsorption of PLL-g-PEG from aqueous buffer solution increased from 125 to 475 ng/cm(2 )along a sigmoidal path as a function of increasing potential between 0 and 1.5 V versus the Ag reference electrode. Upon buffer rinse, adsorption was partially reversible when a potential of >/=0.93 V was maintained on the ITO waveguide. However, reducing the applied potential back to 0 V before rinsing resulted in irreversible polymer adsorption. PLL-g-PEG modified with biotin demonstrated similar adsorption characteristics, but subsequent streptavidin binding was independent of biotin concentration. Applying positive potentials resulted in increased adsorbed mass, presumably due to polymer chain extension and reorganization in the molecular adlayer.


Endoscopic resection and histological evaluation of colorectal polyps: Is it a definitive treatment?
Primary aim of the present study was the evaluation of efficacy and safety of endoscopic polypectomy in a tertiary advanced endoscopic laboratory in Northwestern Greece. Additional aim was to estimate the effectiveness of endoscopic treatment of colorectal polyps and record the clinical course. One hundred and fifty consecutive patients (97 men) with colorectal polyps of size larger than 0.5 cm were included. The size, topography, shape and presence of pedicle were recorded for every polyp. Concerning the size, polyps were divided into: <1 cm, between 1-2 cm, >2 cm. The rectum and sigmoid were the most common sites of detection (76.6%). Endoscopic resection was successful and the complication rate was very low (2.6%). The majority of the removed polyps were neoplastic (87.1%). Most neoplastic polyps were tubulovillous adenomas (50.8%). Low-grade dysplasia was detected in most of the polyps (82.9%), but highgrade dysplasia or invasive carcinoma was also detected in some patients. In total, 10 patients underwent surgical resection. Regular follow-up did not reveal significant residual polyps or recurrence of the lesions. Endoscopic polypectomy is effective and safe and leads to complete resection of neoplastic polyps in the majority of cases.


Quantitative Proteomics Reveals Antibiotics Resistance Function of Outer Membrane Proteins in Aeromonas hydrophila.
Outer membrane proteins (OMPs) play essential roles in antibiotic resistance, particularly in Gram-negative bacteria; however, they still have many unidentified functions regarding their behavior in response to antibiotic stress. In the current work, quantitative tandem mass tag labeling-based mass spectrometry was used to compare the outer membrane related proteins between an oxytetracycline-resistant (OXY-R) and its original control stain (OXY-O) in Aeromonas hydrophila. Consequently, a total of 261 commonly altered proteins in two biological repeats were identified including 29 proteins that increased and 28 that decreased. Gene ontology analysis showed that the expression of transport proteins was significantly reduced, and translation-related proteins were downregulated in the OXY-R strain. After using western blotting to validate selected altered proteins, eight OMP-related genes were knocked out and their roles in antibiotic resistance were further evaluated. The survival assays showed that some mutants such as ΔAHA_4281, ΔAHA_2766, ΔAHA_2282, ΔAHA_1181, and ΔAHA_1280 affected the susceptibility of A. hydrophila to antimicrobials. Moreover, the minimum inhibitory concentration assay showed that these candidate mutants also respond differently to other types of antibiotics. Our results reveal several novel outer membrane related proteins of A. hydrophila that play important roles in antibiotic resistance, and as such, may be helpful for screening studies to identify novel drug targets.


Augmentation of natural cytotoxicity by chronic low-dose ionizing radiation in murine natural killer cells primed by IL-2.
The possible beneficial effects of chronic low-dose irradiation (LDR) and its mechanism of action in a variety of pathophysiological processes such as cancer are a subject of intense investigation. While animal studies involving long-term exposure to LDR have yielded encouraging results, the influence of LDR at the cellular level has been less well defined. We reasoned that since natural killer (NK) cells constitute an early responder to exogenous stress, NK cells may reveal sentinel alterations in function upon exposure to LDR. When purified NK cells received LDR at 4.2 mGy/h for a total of 0.2 Gy in vitro, no significant difference in cell viability was observed. Likewise, no functional changes were detected in LDR-exposed NK cells, demonstrating that LDR alone was insufficient to generate changes at the cellular level. Nonetheless, significant augmentation of cytotoxic, but not proliferative, function was detected when NK cells were stimulated with low-dose IL-2 prior to irradiation. This enhancement of NK cytotoxicity was not due to alterations in NK-activating receptors, NK1.1, NKG2D, CD69 and 2B4, or changes in the rate of early or late apoptosis. Therefore, LDR, in the presence of suboptimal cytokine levels, can facilitate anti-tumor cytotoxicity of NK cells without influencing cellular proliferation or apoptosis. Whether these results translate to in vivo consequences remains to be seen; however, our data provide initial evidence that exposure to LDR can lead to subtle immune-enhancing effects on NK cells and may explain, in part, the functional basis underlying, diverse beneficial effects seen in the animals chronically exposed to LDR.


Angiographic Analysis of Vascular Integrity After Percutaneous Closure Using Prostar XL Device During Transcatheter Aortic Valve Implantation.
Percutaneous closure devices are commonly used to achieve hemostasis during endovascular procedures including transcatheter aortic valve implantation (TAVI). The aim of our study was to investigate the quality of the percutaneous femoral arterial closure by Prostar XL device using a systematic peroperative angiographic control at the end of TAVI procedure. Two hundred seventeen consecutive patients (mean age: 84 [6.5]; 112 women and 105 men) undergoing TAVI with percutaneous transfemoral access were prospectively registered in our center. Preoperative computed tomography scan was performed, and mean femoral vessel diameter was 7.9 (0.9) mm. At the end of TAVI intervention, the hemostasis was systematically achieved using the percutaneous closure device Prostar XL, without selection of patients based on anatomical criteria. An angiography with front and oblique views was performed to evaluate the quality and the safety of the closure device. Success of the percutaneous closure was defined as the absence of hemorrhage and the restitution of the arterial anatomy. Complications related to the percutaneous closure were classified as stenosis, dissection at the puncture site, suture failure, misplacement, or persistent bleeding. Twenty-three (10.6%) patients had complications related to arterial percutaneous closure-14 (60.8%) stenosis, 6 (26.1%) persistent bleeding, and 1 (4.3%) dissection. These lesions were accessible to endovascular treatment via a crossover procedure. One (4.3%) suture failure and 1 (4.3%) misplacement of the device, with a puncture site created above the femoral arch, were reported. The patient developed a retroperitoneal hematoma postoperatively and required transfusion of 2 units of red blood cells associated with a cutdown to remove hematoma and to repair the common femoral artery. Angiography after arterial percutaneous closure using Prostar XL device during TAVI allows detection and endovascular treatment of vascular complications and is associated with low rate of conversion to open surgery.


A deficiency of the small GTPase rab8 inhibits membrane traffic in developing neurons.
One of the major activities of developing neurons is the transport of new membrane to the growing axon. Candidates for playing a key role in the regulation of this intense traffic are the small GTP-binding proteins of the rab family. We have used hippocampal neurons in culture and analyzed membrane traffic activity after suppressing the expression of the small GTP-binding protein rab8. Inhibition of protein expression was accomplished by using sequence-specific antisense oligonucleotides. While rab8 depletion resulted in the blockage of morphological maturation in 95% of the neurons, suppression of expression of another rab protein, rab3a, had no effect, and all neurons developed normal axons and dendrites. The impairment of neuronal maturation by rab8 antisense treatment was due to inhibition of membrane traffic. Thus, by using video-enhanced differential interference contrast microscopy, we observed in the rab8-depleted cells a dramatic reduction in the number of vesicles undergoing anterograde transport. Moreover, by incubating antisense-treated neurons with Bodipy-labeled ceramide, a fluorescent marker for newly formed exocytic vesicles, we observed fluorescence labeling restricted to the Golgi apparatus, whereas in control cells labeling was found also in the neurites. These results show the role of the small GTPase rab8 in membrane traffic during neuronal process outgrowth.


Vibrio gigantis sp. nov., isolated from the haemolymph of cultured oysters (Crassostrea gigas).
Polyphasic analysis of four new Vibrio isolates originating from the haemolymph of diseased cultured oysters is described. The new isolates were closely related to Vibrio splendidus, having 98 % 16S rRNA gene sequence similarity. Phylogenetic analysis based on DNA gyrase subunit B (gyrB), RNA polymerase sigma70 factor (rpoD), replication origin-binding protein (rctB) and transmembrane regulatory protein (toxR) genes, fluorescent amplified fragment length polymorphism and DNA-DNA hybridization experiments clearly showed that the new isolates form a tight genomic group that is different from the currently known Vibrio species. It is proposed that these new isolates should be accommodated in a novel species, Vibrio gigantis sp. nov. Phenotypic features that differentiate V. gigantis from other known Vibrio species include arginine dihydrolase, gelatinase and beta-galactosidase activities, NO(2) production, growth at 35 degrees C, and utilization of sucrose, melibiose, amygdalin, glycerol, galactose, starch and glycogen. The type strain is LGP 13T (=LMG 22741T=CIP 108656T).


Primary intramedullary primitive neuroectodermal tumor (PNET)--case report and review of the literature.
Spinal primitive neuroectodermal tumors (PNET) are very rare tumors, and intramedullary localization is even less common. Indeed, amongst the 23 cases of the spinal PNET described in the literature, only eight cases had an intramedullary localization. Following the WHO 2000 classification, PNETs have been considered embryonal tumors composed of undifferentiated neuroepithelial cells with a capacity of differentiation into different cellular lines, such as astrocytic, ependymal, melanotic and muscular. They have been considered to arise from a neoplastic transformation of primitive neuroepithelial cells, thereby making their presence possible in any part of the central nervous system. The optimal treatment for these malignant tumors is not yet clear, although, over the years, radiotherapy has been considered the best treatment for spinal PNETs. The described case is that of a 38-year-old man with a primary intra-extramedullary PNET, treated by laminectomy, open biopsy and chemotherapy. The patient, 18 months after the onset of his symptomatology, died without cerebral tumor involvement.


Intraoperative ventilation: incidence and risk factors for receiving large tidal volumes during general anesthesia.
There is a growing concern of the potential injurious role of ventilatory over-distention in patients without lung injury. No formal guidelines exist for intraoperative ventilation settings, but the use of tidal volumes (VT) under 10 mL/kg predicted body weight (PBW) has been recommended in healthy patients. We explored the incidence and risk factors for receiving large tidal volumes (VT > 10 mL/kg PBW). We performed a cross-sectional analysis of our prospectively collected perioperative electronic database for current intraoperative ventilation practices and risk factors for receiving large tidal volumes (VT > 10 mL/kg PBW). We included all adults undergoing prolonged (≥ 4 h) elective abdominal surgery and collected demographic, preoperative (comorbidities), intraoperative (i.e. ventilatory settings, fluid administration) and postoperative (outcomes) information. We compared patients receiving exhaled tidal volumes > 10 mL/kg PBW with those that received 8-10 or < 8 mL/kg PBW with univariate and logistic regression analyses. Ventilatory settings were non-uniform in the 429 adults included in the analysis. 17.5% of all patients received VT > 10 mL/kg PBW. 34.0% of all obese patients (body mass index, BMI, ≥ 30), 51% of all patients with a height < 165 cm, and 34.6% of all female patients received VT > 10 mL/kg PBW. Ventilation with VT > 10 mL/kg PBW is still common, although poor correlation with PBW suggests it may be unintentional. BMI ≥ 30, female gender and height < 165 cm may predispose to receive large tidal volumes during general anesthesia. Further awareness of patients' height and PBW is needed to improve intraoperative ventilation practices. The impact on clinical outcome needs confirmation.


Implementing a working together model for Aboriginal patients with acute coronary syndrome: an Aboriginal Hospital Liaison Officer and a specialist cardiac nurse working together to improve hospital care.
Acute coronary syndrome (ACS) contributes to the disparity in life expectancy between Aboriginal and non-Aboriginal Australians. Improving hospital care for Aboriginal patients has been identified as a means of addressing this disparity. This project developed and implemented a working together model of care, comprising an Aboriginal Hospital Liaison Officer and a specialist cardiac nurse, providing care coordination specifically directed at improving attendance at cardiac rehabilitation services for Aboriginal Australians in a large metropolitan hospital in Melbourne. A quality improvement framework using a retrospective case notes audit evaluated Aboriginal patients' admissions to hospital and identified low attendance rates at cardiac rehabilitation services. A working together model of care coordination by an Aboriginal Hospital Liaison Officer and a specialist cardiac nurse was implemented to improve cardiac rehabilitation attendance in Aboriginal patients admitted with ACS to the cardiac wards of the hospital. A retrospective medical records audit showed that there were 68 Aboriginal patients admitted to the cardiac wards with ACS from 1 July 2008 to 30 June 2011. A referral to cardiac rehabilitation was recorded for 42% of these. During the implementation of the model of care, 13 of 15 patients (86%) received a referral to cardiac rehabilitation and eight of the 13 (62%) attended. Implementation of the working together model demonstrated improved referral to and attendance at cardiac rehabilitation services, thereby, has potential to prevent complications and mortality. WHAT IS KNOWN ABOUT THE TOPIC?: Aboriginal Australians experience disparities in access to recommended care for acute coronary syndrome. This may contribute to the life expectancy gap between Aboriginal and non-Aboriginal Australians. WHAT DOES THIS PAPER ADD?: This paper describes a model of care involving an Aboriginal Hospital Liaisons Officer and a specialist cardiac nurse working together to improve hospital care and attendance at cardiac rehabilitation services for Aboriginal Australians with acute coronary syndrome. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS?: The working together model of care could be implemented across mainstream health services where Aboriginal people attend for specialist care.


Evolving judgments of terror risks: foresight, hindsight, and emotion.
The authors examined the evolution of cognitive and emotional responses to terror risks for a nationally representative sample of Americans between late 2001 and late 2002. Respondents' risk judgments changed in ways consistent with their reported personal experiences. However, they did not recognize these changes, producing hindsight bias in memories for their judgments. An intensive debiasing procedure failed to restore a foresightful perspective. A fear-inducing manipulation increased risk estimates, whereas an anger-inducing manipulation reduced them-both in predictions (as previously observed) and in memories and judgments of past risks. Thus, priming emotions shaped not only perceptions of an abstract future but also perceptions of a concrete past. These results suggest how psychological research can help to ensure an informed public.


[Periodontal regeneration: the use of polypeptide growth factors].
Polypeptide growth factors are a class of potent natural biologic mediators which regulate many of the activities of wound healing including cell proliferation, migration and metabolism. Periodontal regeneration is thought to require the migration and proliferation of periodontal ligament cells on the root surface. In fact, repopulation of the detached root surface by cells from periodontal ligament (PDL) is a prerequisite for new attachment formation. Many studies suggested that Polypeptide Growth Factors (PGF) such as Insulin-like Growth Factor I (IGF-I), Platelet Derived Growth Factor (PDGF), Transforming Growth Factor B (TGF-B), Epidermal Growth Factor (EGF), are important mediators of cellular events in wound healing. Studies in vitro analysed the mitogenic effects determined on periodontal ligament cells by growth factors using (3H) Thymidine incorporation during DNA synthesis. The results suggested that recombinant human PDGF and IGF-I stimulate the proliferation of PDL fibroblastic cells and the combination of these growth factors showed a synergistic effect revealing the highest mitogenic effect among all individual growth factors as well as any combination of the growth factors tested. Furthermore these studies demonstrated that rh-PDGF and IGF-I stimulate chemotaxis of PDL fibroblastic cells, and supported a role for TGF-B as a regulator of the mitogenic response to PDGF in these cells. Other studies in vivo showed periodontal tissues regeneration introducing mixtures of recombinant human platelet derived growth factor and insulin-like growth factor into lesions of experimentally induced periodontitis in beagle dogs and monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)


Hemoglobin Riyadh-beta 0-thalassemia in an Indian family.
An Indian (Asian) patient with compound heterozygosity for Hb Riyadh and beta 0-thalassemia is described. Hb Riyadh forms about 95% of the hemoglobin present. The clinico-pathological picture is identical to that of simple beta-thalassemia trait confirming the harmless nature of the substitution beta 120(GH3) Lys leads to Asn.


Heavy episodic drinking among Kenyan female sex workers is associated with unsafe sex, sexual violence and sexually transmitted infections.
This study examined patterns of alcohol use and its association with unsafe sex and related sequelae among female sex workers in Mombasa, Kenya. A community-based cross-sectional study was conducted using snowball sampling. Binge drinkers (> or =5 alcoholic drinks on > or =1 occasion in the previous month) were compared with non-binge drinkers. Of 719 participants, 22.4% were lifetime-alcohol abstainers, 44.7% non-binge and 33.0% binge drinkers. Compared with non-binge drinkers, binge drinkers were more likely to report unprotected sex (adjusted odds ratio (AOR)=1.59, 95% confidence interval [CI]=1.00-2.53; P=0.047) and sexual violence (AOR=1.85, 95% CI=1.27-2.71; P=0.001) and to have either syphilis, Neisseria gonorrhoeae or Trichomonas vaginalis infection (AOR=1.56, 95% CI=1.00-2.41; P=0.048). HIV prevalence was higher among women having ever drunk (39.9%) than lifetime abstainers (23.2%; P<0.001), but was not associated with drinking patterns. Interventions are needed to assist female sex workers adopt safer drinking patterns. Investigation is needed for the effectiveness of such interventions in reducing unprotected sex, sexual violence and sexually transmitted infections.


A general MOF-intermediated synthesis of hollow CoFe-based trimetallic phosphides composed of ultrathin nanosheets for boosting water oxidation electrocatalysis.
Engineering an electrode material for boosting reaction kinetics is highly desired for the oxygen evolution reaction (OER) in the anodic half reaction, and is still a grand challenge for energy conversion technologies. By taking inspiration from the catalytic properties of transition metal phosphides (TMPs) and metal-organic frameworks (MOFs), we herein propose a general MOF-intermediated synthesis of a series of hollow CoFeM (M = Bi, Ni, Mn, Cu, Ce, and Zn) trimetallic phosphides composed of ultrathin nanosheets as advanced electrocatalysts for the OER. A dramatic improvement of electrocatalytic performance toward the OER is observed for hollow CoFeM trimetallic phosphides compared to bimetallic CoFe phosphides. Remarkably, composition-optimized CoFeBiP hollow microspheres could deliver superior electrocatalytic performance, achieving a current density of 10 mA cm-2 with an overpotential of only 273 mV. Mechanistic investigations reveal that the Bi and P doping effectively optimizes the electronic structure of Co and Fe by charge redistribution, which significantly lowers the adsorption energy of oxygen intermediates. Moreover, the hollow microsphere structures composed of ultrathin nanosheets also enable them to provide rich surface active sites to boost the electrocatalytic OER.


Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses.
Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.


Isolation of circulating tumor cells to diagnose melanoma and evaluate the efficacy of surgical resection using melanoma-specific microsystem.
Melanoma is one of the most aggressive skin cancers due to its potential to metastasize widely in the body. The risk of metastasis is increased with later detection and increased thickness of the primary lesion, thus early identification and surgical removal is critical for higher survival rates for patients. However, even with appropriate treatment, some patients will develop recurrence which may be difficult to identify until advanced or causing symptoms. Recent advances in liquid biopsy have proposed less-invasive alternatives for cancer diagnosis and monitoring using minimal/zero invasion at sample collection, and circulating tumor cells(CTCs) have been considered a promising blood-based surrogate marker of primary tumors. However, previous CTC technologies relying on epithelial-cell adhesion molecules have limited to epithelial cells, thus hampering use of CTCs for non-epithelial cancers such as melanoma. Here, we used the Melanoma-specific OncoBean platform(MelanoBean) conjugated with melanoma specific antibodies(MCAM and MCSP). The device was used in comprehensive studies for diagnosing melanoma and evaluating surgery efficacy based on change in the number and characteristics of CTCs and CTC-clusters pre- and post-surgical treatment. Our study demonstrated that melanoma patients(n=45) at all stages(I-IV) have a noticeable number of MCTCs as well as MCTC-clusters compared to healthy donors(n=9)(P=0.0011), and surgical treatment leads to a significant decrease in the number of CTCs(P<0.0001). The CTCs recovered from the device underwent molecular profiling for melanoma-associated genes expression using multiplexed qRT-PCR, demonstrating the ability to monitor molecular signature through treatment. The presented MelanoBean and the comprehensive approach will empower prognostic value of CTCs in melanoma in much larger cohort studies.


A functionalized metal-organic framework decorated with O- groups showing excellent performance for lead(ii) removal from aqueous solution.
Heavy metal ions are highly toxic and widely spread as environmental pollutants. New strategies are being developed to efficiently remove these toxic ions. Herein, we use the intrinsic advantages of metal-organic frameworks (MOFs) and develop a porous Zn(ii)-based MOF decorated with O- groups for the removal of Pb2+. Benefiting from its multiple porosity, sufficient adsorption sites and strong affinity, the activated MOF material exhibits an ultrahigh Pb2+ uptake capacity (616.64 mg g-1), surpassing all those of reported MOF adsorbents. Moreover, it can selectively capture Pb2+ with high efficiency (>99.27%) against background ions. Even in the presence of a high concentration of competitive ions, such as Ca2+ or Mg2+, effective removal (>99.21%) can also be achieved in a short time. The excellent removal performance demonstrates the strong electrostatic attraction and coordination interaction between the highly accessible O- groups and Pb2+. The possible adsorption mechanism was systematically verified by zeta potential, FT-IR and XPS studies. Our work reveals the enormous potential of functionalized MOFs as an appealing platform to construct sorbent materials.


Human immune response to an iron-repressible outer membrane protein of Bacteroides fragilis.
Under conditions of iron starvation, Bacteroides fragilis expresses various iron-repressible outer membrane proteins (IROMPs). A 44-kDa protein appears to be one of the major outer membrane proteins (OMPs) in B. fragilis under iron stress and plays a role in heme uptake by this bacterium. To determine whether the 44-kDa IROMP of B. fragilis is expressed in vivo and whether this protein is immunogenic, we used Western immunoblotting to examine serum samples from patients with an infection caused by Bacteroides species. All the serum samples from patients and from normal controls showed reactivity with several proteins of B. fragilis. Only serum samples from patients infected with B. fragilis showed immunoreactivity with the 44-kDa protein. We also used a rat infection model to study the immune response against this protein during the process of an intra-abdominal infection in these animals. During the first 8 days of infection a gradual increase of antibodies to the 44-kDa protein in the rat was detected. These results suggest that the 44-kDa IROMP is expressed in vivo, since it induces an antibody response in patients and animals. We also analyzed 85 strains of the B. fragilis group for the presence of proteins antigenically related to the B. fragilis 44-kDa protein. The data indicate that this protein was conserved in B. fragilis strains and was absent in the other bacterial strains tested.


An analysis of carotid artery stenting procedures performed in New York and Florida (2005-2006): procedure indication, stroke rate, and mortality rate are equivalent for vascular surgeons and non-vascular surgeons.
Carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CEA) for the treatment of carotid artery stenosis. Unlike CEA, CAS is performed by a wide variety of specialists including vascular surgeons (VS), interventional cardiologists (IC), and interventional radiologists (IR). This study compares the indications, in-patient mortality rate, and in-patient stroke rate for patients undergoing CAS, according to operator specialty. The State In-patient Databases from New York and Florida, made available by the Healthcare Cost and Utilization Project, were reviewed by International Classification of Disease (ICD)-9-CM codes to identify all patients treated with CAS for the years 2005 and 2006. This cohort was then stratified according to operator specialty defined by procedures performed by each operator over the years surveyed. Primary endpoints were in-patient death and stroke. Propensity score matching adjusting for indication, demographics, and comorbidities was employed to evaluate the influence of operator type on outcomes. During the study period, 4001 CAS procedures were performed. All primary analyses compared VS (n = 1350) to non-VS (n = 2651). Patient characteristics were similar, except VS treated fewer patients with CAD (44.2% vs 50.9%, P < .001) and valvular disease (6.3% vs 8.6%, P = .01) and more patients with chronic lung disease (19.4% vs 15.9%, P = .01). Each group performed an equal proportion of CAS for symptomatic disease (8.1% vs 9.0%, P = .32). Univariate analysis revealed no difference in mortality (0.9% vs 0.5%, P = .13) or stroke (1.3% vs 1.5%, P = .73). Propensity score matched analysis also demonstrated no difference in mortality (0.7% vs 0.4%, P = .48) or stroke (1.1% vs 1.7%, P = .27). Subgroup analysis comparing VS, IC, and IR showed no significant difference in mortality or stroke, but demonstrated that of the three specialties, IC treated the smallest proportion of symptomatic patients. The proportion of CAS performed by VS differed significantly by state (New York 46%, Florida 19%, P < .01). Despite a paucity of level 1 evidence for CAS in asymptomatic patients and current Centers for Medicare and Medicaid Services (CMS) policy limiting reimbursement for CAS to only high-risk symptomatic patients, VS and non-VS are treating primarily asymptomatic patients. Perioperative rates of stroke and death are equivalent between VS, IC, and IR. Regional variation of operator type is substantial, and despite similar outcomes, <50% of CAS is performed by VS.


Renal net acid and electrolyte excretion in an experimental model of hypochloremic metabolic alkalosis in sheep.
Renal electrolyte and net acid excretion were characterized during generation and maintenance of hypochloremic metabolic alkalosis in a ruminant model. Two phases of renal response with regard to sodium and net acid excretion were documented. An initial decrease in net acid excretion was attributable to increase in bicarbonate excretion with associated increase in sodium excretion. As the metabolic disturbance became more advanced, a second phase of renal excretion was observed in which sodium and bicarbonate excretion were markedly decreased, leading to increase in net acid excretion and development of aciduria. Throughout the metabolic disturbance, chloride excretion was markedly decreased; potassium excretion also decreased. These changes were accompanied by increase in plasma renin and aldosterone concentrations. There was apparent failure to concentrate the urine optimally during the course of the metabolic disturbance, despite increasing plasma concentration of antidiuretic hormone.


Supratentorial cortical ependymoma in a 21-month-old boy.
Two-thirds of ependymomas arise in the infratentorial or intraventricles, whereas one-third are located supratentorially. But supratentorial "cortical" ependymomas are very rare. We report a case of a cortical ependymoma in a 21-month-old boy. The patient presented with simple partial seizures. This tumor was located in the postcentral gyrus and he had gross total excision. Microscopy and immunohistochemistry showed grade II differentiation ependymoma.


Statistical validation based on parametric receiver operating characteristic analysis of continuous classification data.
The accuracy of diagnostic test and imaging segmentation is important in clinical practice because it has a direct impact on therapeutic planning. Statistical validations of classification accuracy was conducted based on parametric receiver operating characteristic analysis, illustrated on three radiologic examples, Two parametric models were developed for diagnostic or imaging data. Example 1: A semi-automated fractional segmentation algorithm was applied to magnetic resonance imaging of nine cases of brain tumors. The tumor and background pixel data were assumed to have bi-beta distributions. Fractional segmentation was validated against an estimated composite pixel-wise gold standard based on multi-reader manual segmentations. Example 2: The predictive value of 100 cases of spiral computed tomography of ureteral stone sizes, distributed as bi-normal after a non-linear transformation, under two treatment options received. Example 3: One hundred eighty cases had prostate-specific antigen levels measured in a prospective clinical trial. Radical prostatectomy was performed in all to provide a binary gold standard of local and advanced cancer stages. Prostate-specific antigen level was transformed and modeled by bi-normal distributions. In all examples, areas under the receiver operating characteristic curves were computed. RESULTS. The areas under the receiver operating characteristic curves were: Example 1: Fractional segmentation of magnetic resonance imaging of brain tumors: meningiomas (0.924-0.984); astrocytomas (0.786-0.986); and other low-grade gliomas (0.896-0.983). Example 3: Ureteral stone size for treatment planning (0.813). Example 2: Prostate-specific antigen for staging prostate cancer (0.768). All clinical examples yielded fair to excellent accuracy. The validation metric area under the receiver operating characteristic curves may be generalized to evaluating the performances of several continuous classifiers related to imaging.


Evidence of oxidative injury of the spinal cord in 2 horses with equine degenerative myeloencephalopathy.
The cervical spinal cords of 2 horses with equine degenerative myeloencephalopathy (EDM) were evaluated for evidence of oxidative damage to the central nervous system (CNS) using immunohistochemical staining for 3-nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE). Neurons of the CNS from horses with EDM had positive immunohistochemical staining, whereas control samples did not, thus supporting the theory that oxidative damage is a potential underlying factor in horses with EDM. In addition, serum vitamin E concentration was low in both EDM-affected horses, and vitamin E concentration was also deficient in the cerebrospinal fluid in 1 EDM horse, further supporting the association between low vitamin E concentrations and oxidative damage to the CNS. Continued research is necessary to further define the pathophysiologic mechanisms of EDM.


Comparative efficacy of beta-irradiation and mitomycin-C in primary and recurrent pterygium.
To determine the efficacy and safety of mitomycin-C as adjunctive treatment and to compare this drug with beta irradiation with strontium-90 after surgical excision of primary and recurrent pterygia. The study group consisted of 193 patients with primary and recurrent pterygia who underwent surgical excision with the bare sclera technique. They were divided into two groups according to the type of adjunctive treatment. In group I, 130 patients (141 eyes, 67.8%) were treated with beta irradiation with Sr-90 doses of 1000-7000 cGy. In group II 63 patients (67 eyes, 32.2%) received topical mitomycin-C at a concentration of 0.02% four times daily for one week postoperatively. Recurrence rates, complications and efficacy of these treatments were compared with the chi-square of Fisher's exact test. The recurrence rates were 6.4% in group I after a mean postoperative follow-up of 89 months and 17.9% in group II after a mean follow-up of 14.9 months. Recurrence, rates and complications were higher in group II and the difference was significant (p<0.05, p<0.001). Life-table analysis showed a success rate of 93.6% for Sr-90 and 81.9% for the mitomycin-C, the difference being significant (p<0.005). Beta irradiation with Sr-90 after surgical excision was more effective than topical mitomycin-C in patients with primary and recurrent pterygium in terms of recurrence rates, and safer in terms of complications.


The association between types of eating behaviour and dispositional mindfulness in adults with diabetes. Results from Diabetes MILES. The Netherlands.
Although healthy food choices are important in the management of diabetes, making dietary adaptations is often challenging. Previous research has shown that people with type 2 diabetes are less likely to benefit from dietary advice if they tend to eat in response to emotions or external cues. Since high levels of dispositional mindfulness have been associated with greater awareness of healthy dietary practices in students and in the general population, it is relevant to study the association between dispositional mindfulness and eating behaviour in people with type 1 or 2 diabetes. We analysed data from Diabetes MILES - The Netherlands, a national observational survey in which 634 adults with type 1 or 2 diabetes completed the Dutch Eating Behaviour Questionnaire (to assess restrained, external and emotional eating behaviour) and the Five Facet Mindfulness Questionnaire-Short Form (to assess dispositional mindfulness), in addition to other psychosocial measures. After controlling for potential confounders, including demographics, clinical variables and emotional distress, hierarchical linear regression analyses showed that higher levels of dispositional mindfulness were associated with eating behaviours that were more restrained (β = 0.10) and less external (β = -0.11) and emotional (β = -0.20). The mindfulness subscale 'acting with awareness' was the strongest predictor of both external and emotional eating behaviour, whereas for emotional eating, 'describing' and 'being non-judgemental' were also predictive. These findings suggest that there is an association between dispositional mindfulness and eating behaviour in adults with type 1 or 2 diabetes. Since mindfulness interventions increase levels of dispositional mindfulness, future studies could examine if these interventions are also effective in helping people with diabetes to reduce emotional or external eating behaviour, and to improve the quality of their diet.


Association of inflammatory disease and long-term outcomes among young adults with myocardial infarction: the Mass General Brigham YOUNG-MI Registry.
Autoimmune systemic inflammatory diseases (SIDs) are associated with an increased risk of cardiovascular (CV) disease, particularly myocardial infarction (MI). However, there are limited data on the prevalence and effects of SID among adults who experience an MI at a young age. We sought to determine the prevalence and prognostic implications of SID among adults who experienced an MI at a young age. The YOUNG-MI registry is a retrospective cohort study from two large academic centres, which includes patients who experienced a first MI at 50 years of age or younger. SID was ascertained through physician review of the electronic medical record (EMR). Incidence of death was ascertained through the EMR and national databases. The cohort consisted of 2097 individuals, with 53 (2.5%) possessing a diagnosis of SID. Patients with SID were more likely to be female (36% vs. 19%, P = 0.004) and have hypertension (62% vs. 46%, P = 0.025). Over a median follow-up of 11.2 years, patients with SID experienced an higher risk of all-cause mortality compared with either the full cohort of non-SID patients [hazard ratio (HR) = 1.95, 95% confidence interval (CI) (1.07-3.57), P = 0.030], or a matched cohort based on age, gender, and CV risk factors [HR = 2.68, 95% CI (1.18-6.07), P = 0.018]. Among patients who experienced a first MI at a young age, 2.5% had evidence of SID, and these individuals had higher rates of long-term all-cause mortality. Our findings suggest that the presence of SID is associated with worse long-term survival after premature MI.


[Determinants of dengue transmission in Veracruz: an ecological approach to its control].
To assess the ecological, social, and demographic factors associated with the transmission of dengue virus infection in Veracruz, Mexico, and to identify risk areas to target control measures. This ecological study included data for 1,249 localities within the 11 Health Jurisdictions of the State of Veracruz, Mexico, for the 1995-1998 period. The following data were collected for each locality: total number of cases per year, population by sex, number of households, provision of public services, altitude, latitude, longitude, and deprivation index. Dengue transmission was registered in 17% of the localities in the State; 70% of the cases were concentrated in only 6% of the localities. Recurrent localities were urban centers with adequate availability of public services and low deprivation indices. Dengue transmission was detected in rural areas, but it was not common. The average number of cases differed according to the size of the locality and the number of years dengue was reported. A population threshold to maintain transmission was found. Recurrent localities concentrating 70% of dengue fever cases were identified, as well as the ecological and demographic factors associated with dengue transmission. The risk stratification approach to dengue transmission may improve control and prevention of this disease in high-risk areas.


Body mass index and waist circumference in early adulthood are associated with thoracolumbar spine shape at age 60-64: The Medical Research Council National Survey of Health and Development.
This study investigated associations between measures of adiposity from age 36 and spine shape at 60-64 years. Thoracolumbar spine shape was characterised using statistical shape modelling on lateral dual-energy x-ray absorptiometry images of the spine from 1529 participants of the MRC National Survey of Health and Development, acquired at age 60-64. Associations of spine shape modes with: 1) contemporaneous measures of total and central adiposity (body mass index (BMI), waist circumference (WC)) and body composition (android:gynoid fat mass ratio and lean and fat mass indices, calculated as whole body (excluding the head) lean or fat mass (kg) divided by height2 (m)2); 2) changes in total and central adiposity between age 36 and 60-64 and 3) age at onset of overweight, were tested using linear regression models. Four modes described 79% of the total variance in spine shape. In men, greater lean mass index was associated with a larger lordosis whereas greater fat mass index was associated with straighter spines. Greater current BMI was associated with a more uneven curvature in men and with larger anterior-posterior (a-p) vertebral diameters in both sexes. Greater WC and fat mass index were also associated with a-p diameter in both sexes. There was no clear evidence that gains in BMI and WC during earlier stages of adulthood were associated with spine shape but younger onset of overweight was associated with a more uneven spine and greater a-p diameter. In conclusion, sagittal spine shapes had different associations with total and central adiposity; earlier onset of overweight and prior measures of WC were particularly important.


Strategies Aimed at Preventing Chronic Post-surgical Pain: Comprehensive Perioperative Pain Management after Total Joint Replacement Surgery.
Chronic post-surgical pain (CPSP) is a frequent outcome of musculoskeletal surgery. Physiotherapists often treat patients with pain before and after musculoskeletal surgery. The purposes of this paper are (1) to raise awareness of the nature, mechanisms, and significance of CPSP; and (2) to highlight the necessity for an inter-professional team to understand and address its complexity. Using total joint replacement surgeries as a model, we provide a review of pain mechanisms and pain management strategies. By understanding the mechanisms by which pain alters the body's normal physiological responses to surgery, clinicians selectively target pain in post-surgical patients through the use of multi-modal management strategies. Clinicians should not assume that patients receiving multiple medications have a problem with pain. Rather, the modern-day approach is to manage pain using preventive strategies, with the aims of reducing the intensity of acute postoperative pain and minimizing the development of CPSP. The roles of biological, surgical, psychosocial, and patient-related risk factors in the transition to pain chronicity require further investigation if we are to better understand their relationships with pain. Measuring pain intensity and analgesic use is not sufficient. Proper evaluation and management of risk factors for CPSP require inter-professional teams to characterize a patient's experience of postoperative pain and to examine pain arising during functional activities.


Pentacam Accuracy in Discriminating Keratoconus From Normal Corneas: A Diagnostic Evaluation Study.
This study aims to determine the diagnostic ability of Pentacam indices for keratoconus and identifying the best index for differentiating diseased from normal cases. In this study, 150 keratoconus patients and 150 refractive surgery candidates with a definitive diagnosis of normal healthy corneas were enrolled. Initially, the placido disk topography imaging was performed. The keratoconus and normal corneas were defined based on placido disk topographic data from Rabinowitz-McDonnell. After complete eye examinations for all participants, they underwent Pentacam imaging, and corneal surface topographic indices were extracted. Multiple logistic regression was used to determine the best indices for differentiating diseased from healthy corneas, and the receiver operating curve was calculated to determine the diagnostic capability of each index. Among the studied indices, the keratoconus index (KI), index of vertical asymmetry (IVA), thinnest point (TP), and maximum keratometry (Kmax) were found capable of detecting keratoconus. Among these, IVA was the best index, with an area under curve (AUC) of 95.24%. The best cutoff point for IVA was 0.20 μm, and its sensitivity and specificity were 87.50% and 96.30%, respectively. Comparison of the AUC of different indices showed that only TP and IVA significantly differed (P=0.002). The combination of KI, IVA, Kmax, and TP indices leads to correct detection in 78% of cases. Measuring corneal topographic indices using Pentacam can be helpful in the diagnosis of keratoconus. According to the results of this study, IVA is the best diagnostic index for keratoconus. However, it is recommended to use a combination of Pentacam indices for more accurate differentiation of keratoconus from normal cases.


Initial clinical experience with a partly autonomous robotic surgical instrument server.
The authors believe it would be useful to have surgical robots capable of some degree of autonomous action in cooperation with the human members of a surgical team. They believe that a starting point for such development would be a system for delivering and retrieving instruments during a surgical procedure. The described robot delivers instruments to the surgeon and retrieves the instruments when they are no longer being used. Voice recognition software takes in requests from the surgeon. A mechanical arm with a gripper is used to handle the instruments. Machine-vision cameras locate the instruments after the surgeon puts them down. Artificial intelligence software makes decisions about the best response to the surgeon's requests. A robot was successfully used in surgery for the first time June 16, 2005. The operation involved excision of a benign lipoma. The procedure lasted 31 min, during which time the robot performed 16 instrument deliveries and 13 instrument returns with no significant errors. The average time between verbal request and delivery of an instrument was 12.4 s. The described robot is capable of delivering instruments to a surgeon at command and can retrieve them independently using machine vision. This robot, termed a "surgical instrument server," represents a new class of information-processing machines that will relieve the operating room team of repetitive tasks and allow the members to focus more attention on the patient.


Study of the antioxidant and anti-pancreatic cancer activities of Anchusa strigosa aqueous extracts obtained by maceration and ultrasonic extraction techniques.
Pancreatic cancer is a highly aggressive malignancy and a leading cause of cancer-related deaths worldwide. Moreover, the incidence and mortality rates for pancreatic cancer are projected to keep increasing. A major challenge in the treatment of pancreatic cancer is the lack of effective screening approaches, which contributes to its poor prognosis, indicating the need for new treatment regimens and alternative therapies, such as herbal medicine. The medicinal plant A. strigosa, which is widely distributed in the Eastern Mediterranean region, is a short prickly plant from the Boraginaceae family that has been widely used in traditional medicine for treating various diseases. Nevertheless, its effect on human pancreatic cancer remains poorly investigated. In the present study, we screened the phytochemical content of Anchusa strigosa aqueous extracts obtained by maceration and ultrasound-assisted methods (ASM and ASU, respectively) and evaluated their antioxidant effects. We also investigated their anticancer effects and possible underlying mechanisms. The results show that both extracts were rich in bioactive molecules, with slight differences in their composition. Both extracts exhibited remarkable antioxidant potential and potent radical-scavenging activity in vitro. Additionally, non-cytotoxic concentrations of both extracts attenuated cell proliferation in a time- and concentration-dependent manner, which was associated with a decrease in the proliferation marker Ki67 and an induction of the intrinsic apoptotic pathway. Furthermore, the extracts increased the aggregation of pancreatic cancer cells and reduced their migratory potential, with a concomitant downregulation of integrin β1. Finally, we showed that the ASM extract caused a significant decrease in the levels of COX-2, an enzyme that has been linked to inflammation, carcinogenesis, tumor progression, and metastasis. Taken together, our findings provide evidence that A. strigosa extracts, particularly the extract obtained using the maceration method, have a potential anticancer effect and may represent a new resource for the design of novel drugs against pancreatic cancer.


Early selectivity for vocal and musical sounds: electrophysiological evidence from an adaptation paradigm.
There is growing interest in characterizing the neural basis of music perception and, in particular, assessing how similar, or not, it is to that of speech. To further explore this question, we employed an EEG adaptation paradigm in which we compared responses to short sounds belonging to the same category, either speech (pseudo-sentences) or music (piano or violin), depending on whether they were immediately preceded by a same- or different-category sound. We observed a larger reduction in the N100 component magnitude in response to musical sounds when they were preceded by music (either the same or different instrument) than by speech. In contrast, the N100 amplitude was not affected by the preceding stimulus category in the case of speech. For P200 component, we observed a diminution of amplitude when speech sounds were preceded speech, compared to music. No such decrease was found when we compared the responses to music sounds. These differences in the processing of speech and music are consistent with the proposal that some degree of category selectivity for these two classes of complex stimuli already occurs at early stages of auditory processing, possibly subserved by partly separated neuronal populations.


Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.
We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.


Aesthetic and incentive salience of cute infant faces: studies of observer sex, oral contraception and menstrual cycle.
Infant cuteness can influence adult-infant interaction and has been shown to activate reward centres in the brain. In a previous study, we found men and women to be differentially sensitive to small differences in infant facial cuteness, with reproductive hormone status as the potential underlying cause. It is unclear, however, whether reproductive hormone status impacts on the aesthetic and incentive salience of infant faces. To address this question, we conducted two interlinked studies. We used static images of the same smiling and neutral-looking infant faces in both a rating task, in which participants had to rate the cuteness of infant faces (aesthetic salience - 'liking'), and a key-press task, in which participants could prolong or shorten viewing time of infant faces by rapid alternating key-presses (incentive salience - 'wanting'). In a first study, we compared the performance of men, women who are taking oral contraceptives, and regularly cycling women. In this study, we found a significant correlation between cuteness ratings within and between groups, which implies that participants had the same concept of cuteness. Cuteness ratings and effort to look at faces was linked regardless of sex and reproductive hormone status, in that cute faces were looked at for longer than less cute faces. A happy facial expression contributed only marginally to the incentive salience of the face. To explore the potential impact of reproductive hormone status in more detail, we followed a subset of regularly cycling women during the menstrual, follicular and luteal phases of their cycle. The aesthetic and incentive salience of infant faces did not change across the menstrual cycle. Our findings suggest that reproductive hormone status does not modulate the aesthetic and incentive value of infant faces.


Direct effect of cortistatin on GH release from cultured pituitary cells in the rat.
Cortistatin (CST) is a 17-amino acid neuropeptide expressed mainly in the cortex and hippocampus. It is also found in the peripheral tissues such as the stomach, kidney, pancreas and the immune system. Two forms of cortistatin CST-17, CST-29 bind with high affinity all somatostatin (SS) receptor subtypes. It has been reported that a receptor called MrgX(2) is able to selectively bind both CST-17 and CST-14 rather than SS. In human tissues CST-17 and CST-29, rather than SS, also bind ghrelin receptor GHS-r1a. In in vivo experiments CST inhibited GH and insulin secretion. The aim of this study was to evaluate the effect of cortistatin on GH release in in vitro experiments. CST-14 and SS-14 in doses of 1nMol, 10nMol, and 100nMol were added after 48 hrs of pituitary cell culture, and the medium was collected 30, 60, 120, 240 min thereafter. rGH was measured with RIA kits provided by Linco. CST-14 stimulated GH release from cultured pituitary cells in a dose dependent manner. The maximum effect of CST-14 was observed after 60 min of incubation. However, SS-14 in doses of 10 nMol and 100 nMol inhibited GH release. A direct stimulating effect of Cortistatin-14 on GH release from cultured pituitary cells was found.


The long-term renal and cardiovascular consequences of prematurity.
Infants born prematurely at <37 weeks' gestation account for over 80% of infants weighing <2,500 g at birth-low birth weight (LBW) infants. This designation remains the surrogate marker for developmental origins of adult disease. Landmark studies spanning four decades have shown that individuals born with a LBW are more likely to develop cardiovascular and renal disease in later life, which is believed to be related to 'developmental programming' of such adult disease during vulnerable periods of growth in utero and in the early postnatal period. There has long been ambiguity regarding the distinction between infants with intrauterine growth restriction and preterm infants since both show a low nephron endowment that is associated with subsequent hypertension and chronic kidney disease. Knowledge is growing specific to the preterm infant and the developmental associations of being born preterm with the interruption of normal organogenesis relative to the vascular tree and kidney. Both systems develop by branching morphogenesis and interruptions lead to considerable deficits in their structure and function. These developmental aberrations can lead to endothelial dysfunction, hypertension, proteinuria and metabolic abnormalities that persist throughout life. This Review will examine the effect of preterm birth on the development of cardiovascular and kidney disease in later life and will also discuss potential early interventions to alter the progression of disease.


New approaches to peptide synthesis with the help of trypsin.
Picolyl esters of amino acids are suitable inverse substrates for trypsin. These esters can be used for peptide synthesis catalyzed by trypsin. Study of hydrolysis of non-specific substrates for trypsin permits to conclude, that hydrogen band in P'2 subsite is very important for their reactivity. Carboxamido methyl esters (CAM-esters) are the most suitable substrates for trypsin catalyzed peptide synthesis. Using CAM-esters and trypsin several di-,tri- and tetra-peptides were synthesized with good yields.


Associations of Japanese food intake with survival of stomach and colorectal cancer: A prospective patient cohort study.
Dietary factors may affect the prognosis of digestive tract cancer, but evidence has been sparse. We investigated the association between pretreatment intake of 6 Japanese foods (including soy food, miso [soybean paste] soup and seaweed) and the risk of death among patients with histologically confirmed major digestive tract cancers (stomach, 1931; colon, 793; rectum, 510) diagnosed during 1997-2013 at a single institution in Japan. Pretreatment dietary intake was assessed using a food frequency questionnaire, and the patients were followed until December 2016. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among the patients with stomach cancer, frequent intake of soy food was inversely associated with the risk of all-cause (Ptrend for four frequency groups = 0.01; HR = 0.72, 95% CI: 0.50-1.04 for highest vs lowest group) and stomach cancer (Ptrend = 0.03; HR = 0.63, 95% CI: 0.40-0.99) death. A similar inverse association was also found for intake of miso soup. In contrast, frequent seaweed intake was inversely associated with the risk of all-cause death among the patients with colon cancer (Ptrend = 0.03). Rectal cancer patients who had frequently consumed seaweed tended to have a lower risk of rectal cancer death (Ptrend = 0.02). These findings indicate that pretreatment intake of Japanese foods such as soybean products and seaweed may have favorable effects on patient survival of stomach and colorectal cancer, although this needs to be confirmed by further research.


Hyperpolarization-activated chloride currents in Xenopus oocytes.
During hyperpolarizing pulses, defolliculated Xenopus oocytes have time- and voltage-dependent inward chloride currents. The currents vary greatly in amplitude from batch to batch; activate slowly and, in general, do not decay; have a selectivity sequence of I- > NO3- > Br- > Cl- > propionate > acetate; are insensitive to Ca2+ and pH; are blocked by Ba2+ and some chloride channel blockers; and have a gating valence of approximately 1.3 charges. In contrast to hyperpolarization-activated chloride currents induced after expression of phospholemman (Palmer, C. J., B. T. Scott, and L. R. Jones. 1991. Journal of Biological Chemistry. 266:11126; Moorman, J. R., C. J. Palmer, J. E. John, J. E. Durieux, and L. R. Jones. 1992. 267:14551), these endogenous currents are smaller; have a different pharmacologic profile; have a lower threshold for activation and lower voltage-sensitivity of activation; have different activation kinetics; and are insensitive to pH. Nonetheless, the endogenous and expressed current share striking similarities. Recordings of macroscopic oocyte currents may be inadequate to determine whether phospholemman is itself an ion channel and not a channel-modulating molecule.


The mouse digit tip: from wound healing to regeneration.
A challenge to the study of regeneration is determining at what point the processes of wound healing and regeneration diverge. The mouse displays level-specific regeneration responses. An amputation through the distal third of the terminal phalanx will prompt a regeneration response and result in a new digit tip that mimics the morphology of the lost digit tip. Conversely, an amputation through the distal third of the intermediate phalanx initiates a wound healing and scarring response. The mouse, therefore, provides a model for studying the transition between wound healing and regeneration in the same animal. This chapter details the methods used in the study of mammalian digit regeneration, including a method to introduce exogenous protein into the mouse digit amputation model via microcarrier beads and methods for analysis of bone regeneration.


In situ naphthalene bioactivation and nasal airflow cause region-specific injury patterns in the nasal mucosa of rats exposed to naphthalene by inhalation.
Despite the fact that naphthalene (NA), a volatile, ubiquitous air pollutant, was recently identified as a probable human carcinogen, little is known about nasal cytotoxicity from inhaled NA. To define and compare acute nasal injury from inhalation and systemic NA exposures, male Sprague-Dawley rats were exposed to filtered air; 3.4 or 23.8 ppm NA by inhalation for 4 h; or to 0, 25, 50, 100, or 200 mg/kg NA via intraperitoneal injection. Severe cellular injury occurred exclusively in the olfactory mucosa 24 h postinhalation exposure to 3.4 ppm NA for 4 h. This level is significantly below both the current Occupational Safety and Health Administration standard (10 ppm; 8 h) for NA and the lowest observed adverse effect level (10 ppm; 2 years) for the incidence of rat olfactory neoplasms. Injury within the olfactory mucosa from inhaled NA was confined to the medial meatus, whereas systemic NA generated severe injury throughout the olfactory region. The pattern of nasal injury from inhaled NA in this study is consistent with previous studies of nasal airflow simulation within the olfactory region. The nonolfactory mucosa on the nasal septum, a high airflow region, metabolized naphthalene slowly, whereas the olfactory regions of the nasal septum and ethmoturbinates metabolized this substrate at high rates. This study concludes that 1) the incidence of acute nasal injury from systemic and inhaled NA correlates with the rates of regional microsomal NA metabolism and that 2) the nasal airflow pattern determines the pattern of olfactory mucosal injury from inhaled NA.


Indices to assess patients with systemic lupus erythematosus in clinical trials, long-term observational studies, and clinical care.
This review summarises most currently used indices to assess and monitor patients with systemic lupus erythematosus (SLE) in clinical trials, long-term observational studies, and clinical care. Six SLE disease activity indices include the British Isles Lupus Assessment Group Index (BILAG), European Consensus Lupus Activity Measurement (ECLAM), Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Lupus Activity Index (LAI), and Systemic Lupus Erythematosus Activity Questionnaire (SLAQ). Three SLE responder indices include Responder Index for Lupus Erythematosus (RIFLE), SLE Responder Index (SRI), and BILAG Based Combined Lupus Assessment (BICLA). Three SLE damage indices include the Systemic Lupus International Collaborating Clinics/American College of Rheumatology-Damage Index (SLICC/ACE-DI), Lupus Damage Index Questionnaire (LDIQ), and Brief Index of Lupus Damage (BILD). The SLAQ, LDIQ and the BILD are patient self-report questionnaires, which appear to give similar information to physician-completed indices, but are pragmatically more easily completed as patients do almost all the work. Additional self-report indices which have been used to assess and monitor patients with in SLE include a generic general health short form 36 (SF36), a SLE-specific Lupus Patient Reported Outcome (LupusPRO), and a generic rheumatology index, Routine Assessment of Patient Index Data 3 (RAPID3). These activity, response, damage and patient self-report indices have been validated at different levels with no consensus about what it is the most appropriate for every setting. Sensitive and feasible assessment of SLE in clinical trials, observational studies, and busy clinical settings remains a challenge to the rheumatology community.


Structural organizations of yeast RNase P and RNase MRP holoenzymes as revealed by UV-crosslinking studies of RNA-protein interactions.
Eukaryotic ribonuclease (RNase) P and RNase MRP are closely related ribonucleoprotein complexes involved in the metabolism of various RNA molecules including tRNA, rRNA, and some mRNAs. While evolutionarily related to bacterial RNase P, eukaryotic enzymes of the RNase P/MRP family are much more complex. Saccharomyces cerevisiae RNase P consists of a catalytic RNA component and nine essential proteins; yeast RNase MRP has an RNA component resembling that in RNase P and 10 essential proteins, most of which are shared with RNase P. The structural organizations of eukaryotic RNases P/MRP are not clear. Here we present the results of RNA-protein UV crosslinking studies performed on RNase P and RNase MRP holoenzymes isolated from yeast. The results indicate locations of specific protein-binding sites in the RNA components of RNase P and RNase MRP and shed light on the structural organizations of these large ribonucleoprotein complexes.


Scopolamine induced learning failures in man.
Two experiments were performed to determine the locus of the amnestic effects of scopolamine in man. The first experiment involved 24 volunteers receiving one of three doses of scopolamine (5, 8 or 10 microng/kg) or a placebo, intravenously. The subjects were tested for retention of material learned prior to administration of the drug, acquisition of new information, and retention of material learned while under the influence of the drug. Results indicated that scopolamine has its primary effect on the acquisition of new material and less of an effect on the retrieval of information already learned. The second experiment was designed to refine and expand upon the results of the first and involved 18 volunteers receiving eith 5 or 10 microng/kg of scopolamine or a placebo, intravenously. The subjects were given four trials to learn a list of verbal materials, and their recall for that material was measured at various intervals up to 24 h. These results confirmed those of the first experiment in that the predominant influence of the drug was to impair the acquisition of new information. Implications of these results for memory mechanisms are discussed.


Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications.
Abnormal regulation of DNA methylation and its readers has been associated with a wide range of cellular dysfunction. Disruption of the normal function of DNA methylation readers contributes to cancer progression, neurodevelopmental disorders, autoimmune disease and other pathologies. One reader of DNA methylation known to be especially important is MeCP2. It acts a bridge and connects DNA methylation with histone modifications and regulates many gene targets contributing to various diseases; however, much remains unknown about how it contributes to cancer malignancy. We and others previously described novel MeCP2 post-translational regulation. We set out to test the hypothesis that MeCP2 would regulate novel genes linked with tumorigenesis and that MeCP2 is subject to additional post-translational regulation not previously identified. Herein we report novel genes bound and regulated by MeCP2 through MeCP2 ChIP-seq and RNA-seq analyses in two breast cancer cell lines representing different breast cancer subtypes. Through genomics analyses, we localize MeCP2 to novel gene targets and further define the full range of gene targets within breast cancer cell lines. We also further examine the scope of clinical and pre-clinical lysine deacetylase inhibitors (KDACi) that regulate MeCP2 post-translationally. Through proteomics analyses, we identify many additional novel acetylation sites, nine of which are mutated in Rett Syndrome. Our study provides important new insight into downstream targets of MeCP2 and provide the first comprehensive map of novel sites of acetylation associated with both pre-clinical and FDA-approved KDACi used in the clinic. This report examines a critical reader of DNA methylation and has important implications for understanding MeCP2 regulation in cancer models and identifying novel molecular targets associated with epigenetic therapies.


Effects of miR-125a-5p on Cell Proliferation,Apoptosis and Cell Cycle of Pancreatic Cancer Cells.
Objective To investigate the effects of miR-125a-5p on cell proliferation,apoptosis and cell cycle of pancreatic cancer cells.Methods The expression level of miR-125a-5p in pancreatic cancer was determined using quantitative real-time polymerase chain reaction analysis in 4 pairs of pancreatic cancer tissues and matched adjacent normal tissues samples. The expression of miR-125a-5p was downregulated in pancreatic cancer cell lines by transfection with miR-125a-5p inhibitor. Cell counting kit-8 assays was conducted to detect the growth ability of pancreatic cancer cell lines. Flow cytometry was applied to detect the cell cycle and apopotosis. Soft agar colony formation test was employed to assess the role of miR-125a-5p in process of malignant transformation.Results MiR-125a-5p was significantly highly expressed in pancreatic ductal adenocarcinoma tissues than adjacent normal tissues(P<0.05). After the expression level of miR-125a-5p in Panc-1 and MIA PaCa-2 was downregulated,the growth ability was suppressed(P<0.05),early apopotosis rate was promoted by 13.6% and 11.0% respectively(P<0.05),the amount of colony formation was reduced by 27.3% and 27.8%,respectively(P<0.05),and the percentage of S stage of Panc-1 was reduced by 11.8% (P<0.05).Conclusions The expression of miR-125a-5p is high in pancreatic ductal adenocarcinoma tissues. After the expression level of miR-125a-5p is downregulated,the growth ability,colony formation,and cell cycle of Panc-1 and MIA PaCa-2 are suppressed,and the early apopotosis rate will be promoted. Therefore,miR-125a-5p may play an oncogenic role in pancreatic ductal adenocarcinoma.