Identification and isolation of glycoproteins that translocate to the cell surface from GLUT4-enriched vesicles in an insulin-dependent fashion.
It has previously been shown that in fat cells, the intracellular reservoir of the glucose transporter isoform GLUT4 consists of a membrane vesicle population highly enriched in this transporter (approximately 15% of the protein content) that has a relatively simple protein pattern as revealed by SDS-polyacrylamide gel electrophoresis and silver staining (Zorzano, A., Wilkinson, W., Kotliar, N., Thoidis, G., Wadzinski, B. E., Ruoho, A. E., and Pilch, P. F. (1989) J. Biol. Chem. 264, 12358-12363). Upon exposure of adipocytes to insulin, the cell-surface (plasma membrane) content of GLUT4 is dramatically enhanced, and this transporter appears to continually cycle from intracellular vesicles to the plasma membrane. To identify other proteins that may recycle in a similar fashion to GLUT4 and that may participate in the insulin-dependent alteration in the cellular location of GLUT4 and other membrane proteins, we performed immunoadsorption of GLUT4-enriched vesicles together with biotinylation of membranes using a cell-impermeant analog of biotin. We find that immunoadsorbed GLUT4-containing vesicles can be fractionated into Triton X-100-soluble and -insoluble fractions. The first includes three major glycoprotein components with molecular masses of 110, 160, and 230 kDa and a few minor polypeptides with lower molecular masses. A Triton X-100-resistant fraction consists of GLUT4 and an approximately 25-kDa protein. All three major Triton-soluble proteins (110, 160, and 230 kDa) isolated from the immunoimmobilized vesicles on wheat germ agglutinin-agarose are strongly biotinylated in an insulin-dependent fashion, i.e. they cycle to and from the cell surface in an apparently identical manner to GLUT4. Sequence analysis of two tryptic fragments from p160 reveals that it is a novel protein containing sequence with no homology to known proteins.


[Protective effect of the anterior lens capsule: corneal endothelial cell loss following intercapsular phacoemulsification compared with phacoemulsification with large open capsulotomy].
In an experimental study using rabbits, the intercapsular technique was performed in 20 eyes to make a small anterior capsulotomy. A large, "can opener" capsulotomy was performed in 20 eyes, and ten eyes (five non-operated animals) served as controls. Endothelial cell loss was determined by vital staining with Trypan blue and Alizarin red S. Average endothelial cell loss with the intercapsular technique was 1.2%; with the can opener technique the cell loss was 6.6%. This difference was statistically significant (p less than 0.01). The percentage in the control eyes was 0.05%. Positive relations between endothelial cell loss related to phacoemulsification time and/or the amount of irrigating fluid used existed for the can opener group only (p less than 0.01). These results demonstrate that the presence of an almost intact anterior lens capsule during removal of lens substance is protective to the corneal endothelium.


Liver kinase B1 overexpression controls mycobacterial infection in macrophages via FOXO1/Wnt5a signaling.
Mycobacterium tuberculosis (Mtb) is a primary cause of tuberculosis (TB), which has infected more than one-third of the world's population. Mtb survival and subsequent inflammation in macrophages are important components of TB. Liver kinase B1 (LKB1) has demonstrated anti-inflammation effects, but its function and underlying mechanism in mycobacteria-infected macrophages remains unknown. In the current study, we discovered that LKB1 was markedly decreased in Mtb-infected THP-1 and U937 macrophages. Moreover, LKB1 overexpression inhibited Mtb survival in macrophages. Mtb infection increased expression of nitric oxide, inducible nitric oxide synthase, and inflammation-related cytokines interleukin (IL)-6, tumor necrosis factor-α, and IL-1β, whereas pcDNA3-LKB1 transfection inhibited the release of these cytokines in THP-1 and U937 cells. Furthermore, LKB1 overexpression significantly decreased protein expression of Wnt5a, which is dependent on the elevation of forkhead box protein O1 (FOXO1). Generally, we show that interruption of FOXO1 or overexpression of Wnt5a can reverse the effects of LKB1 on mycobacterial intracellular survival, nitric oxide, inducible nitric oxide synthase expression, and inflammatory cytokine release. These findings indicate important roles for LKB1, FOXO1, and Wnt5a in controlling mycobacteria and cell inflammation.


Minimal access median sternotomy for aortic valve replacement in elderly patients.
We report our clinical experience with a approach for aortic valve replacement (AVR) via minimal access skin incision and complete median sternotomy. This approach was used in patients with higher age and multiple co-morbidities, facilitating an easy access with short bypass and cross clamp times. It was especially performed in patients asking for an excellent cosmetic result, who did not qualifying for minimally-invasive AVR via partial upper sternotomy. AVR via minimal-access median sternotomy, was performed in 58 patients between 01/2009 and 11/2011. Intra- and postoperative data including cross clamp time, cardiopulmonary bypass time, mortality, stroke, pacemaker implantation, re-operation for bleeding, ventilation time, ICU and hospital stay, wound infection, sternal dehiscence or fracture and 30 day mortality were collected. Mean patients age was 76.1 +/-9.4 years, 72% were female. Minimal-access AVR could be performed with a mean length of midline skin incision of 7.8 cm. Aortic cross-clamping time was 54.6 +/-6.3 min, cardiopulmonary bypass time 71.2+/-11.3 min and time of surgery 154.1 +/-26.8 min. Re-operation for bleeding had to be performed in 1 case (1.7%). There were no strokes or pacemaker implantations needed. Mean ventilation time was 4.5 h, ICU stay was 2 days and mean length of hospital stay was 6 days. 6 months follow up showed mortality of 0% and no sternal dehiscence or wound infection was observed. Minimal-access AVR via complete median sternotomy can be performed safely,in this elderly patient cohort without adding additional operative risk compared to conventional AVR. By avoidiance of large skin incisions this approach combines excellent cosmetic results with fast surgery time and excellent postoperative recovery.


Synthesis of Epitaxial MoS2/MoO2 Core-Shell Nanowires by Two-Step Chemical Vapor Deposition with Turbulent Flow and Their Physical Properties.
MoO2 nanowires (NWs), MoO2/MoS2 core-shell NWs, and MoS2 nanotubes (NTs) were synthesized by the turbulent flow chemical vapor deposition of MoO2 using MoO3, followed by sulfurization in the sulfur gas flow. The involvement of MoO x suboxide is suggested by density functional theory (DFT) calculations of the surface energies of MoO2. The thickness of the MoS2 layers can be controlled by precise tuning of sulfur vapor flow and temperatures. MoS2 had an armchair-type winding topology due to the epitaxial relation with the MoO2 NW surface. A single ∼ few-layer MoO2/MoS2 core-shell structure showed photoluminescence after the treatment with a superacid. The resistivities of an individual MoO2 NW and a MoS2 NT were measured, and they showed metallic and semiconducting resistivity-temperature relationships, respectively.


Thermophilic treatment by anaerobic granular sludge as an effective approach to accelerate the electron transfer and improve the reductive decolorization of azo dyes in bioreactors.
The effects of temperature, hydraulic retention time (HRT), and the redox mediator, anthraquinone-2,6-disulfonate (AQDS), on electron transfer and subsequent reductive decolorization of dyes from textile wastewater was assessed in mesophilic and thermophilic anaerobic bioreactors. The results clearly show that compared to mesophilic anaerobic treatment, thermophilic treatment at 55 degrees C is an effective approach for increasing the electron transfer capacity in bioreactors, and thus improving the decolorization rates. At an HRT of 2.5 h and in the absence of AQDS, the color removal was 5.3-fold higher at 55 degrees C compared to 30 degrees C. Furthermore, similar decolorizations were found at 55 degrees C between the AQDS-free and AQDS-supplemented reactors, whereas a significant difference (up to 3.6-fold) on dye reduction occurred at 30 degrees C.


Pseudoxanthoma elasticum: is the left internal mammary artery a suitable conduit for coronary artery bypass grafting?
Coronary artery revascularization remains a feasible and beneficial treatment for coronary artery disease in patients with pseudoxanthoma elasticum. Careful angiographic evaluation of the left internal mammary artery and coronary arteries is required in patients with pseudoxanthoma elasticum with suspected coronary artery disease. A nonstenosed left internal mammary artery at angiography may be used as a conduit for coronary artery revascularization; however, both the effect of harvest and anastomosis on the disease process in the left internal mammary artery and the long-term patency of left internal mammary artery grafts remain unknown.


Enhanced memory for central visual and auditory elements experienced during a stressful episode.
Acute psychosocial stress has been shown to benefit memory for central visual elements of a stressful episode. Here, we aimed at investigating whether this effect is accompanied by improved visual memory for the committee members in a modified version of the Trier Social Stress Test (TSST). Specifically, we tested participants´ recognition memory for accessories located on the bodies of the committee members, as well as their faces. Moreover, we investigated how stress influences memories for the content of the verbal interactions. That is, we studied how well participants remembered factual information associated with the main stress source, like name, age, and position of the committee members, as well as how accurately they could recite the exact wording of phrases used by them. In a counterbalanced 2 × 2 design, 77 men and women took part either in a stressful or non-stressful version of the TSST. While stressed participants better remembered personal information about the committee members than non-stressed participants, no differences in memory for the correct wording of phrases could be observed. Furthermore, in line with our hypothesis, stressed participants better remembered central, but not peripheral visual stimuli, compared to non-stressed participants, while, contrary to our expectations, stress did neither affect memory for objects located on the bodies of the committee members nor their faces. Our results are in line with the theory of enhanced memory binding under stress and extend previous results regarding improved memory for central visual elements encoded under stress to auditory learning material associated with the stressor.


Hydroxycamptothecin induces apoptosis and inhibits tumor growth in colon cancer by the downregulation of survivin and XIAP expression.
10-Hydroxycamptothecin (10-HCPT), isolated from a Chinese tree Camptotheca acuminate, inhibits the activity of topoisomerase I and has a broad spectrum of anticancer activity in vitro and in vivo. It has been shown that HCPT is more active and less toxic than conventional camptothecins and can induce cancer cell apoptosis. However, the mechanisms of HCPT-induced apoptosis in colon cancer cells remain unclear. In this study, we investigated the effects of HCPT on apoptosis of colon cancer and underlying mechanism. Cell proliferation was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, and apoptosis was measured using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Expression of genes was detected using real-time reverse transcription-polymerase chain reaction (real time-PCR) and Western blot. Tumor growth in vivo was evaluated using a nude mouse xenograft model. HCPT could significantly inhibit cell proliferation and induce apoptosis in colon cancer SW1116 and Colo 205 cells in dose- and time-dependent manners. HCPT treatment activated the activities of caspase 3, 7, 8 and 9, downregulated the expression of survivin, survivinΔEx3, survivin-3B and XIAP, and upregulated expression of surviving 2B. Moreover, the combination of HCPT and 5-fluorouracial (5-FU) synergistically induced apoptosis and downregulated the expression of survivin and XIAP. Knockdown of survivin and XIAP by siRNA sensitized colon cancer to HCTP-induced apoptosis. Furthermore, HCPT treatment significantly inhibited SW1116 xenograft tumor growth. Our results elucidate new mechanisms of HCPT antitumor by the downregulation of survivin and XIAP expression. The combination of HCPT with 5-FU or IAP inhibitors may be a potential strategy for colon cancer treatment.


Caenorhabditis elegans algn-2 Is Critical for Longevity Conferred by Enhanced Nonsense-Mediated mRNA Decay.
Nonsense-mediated mRNA decay (NMD) is a biological surveillance mechanism that eliminates mRNA transcripts with premature termination codons. In Caenorhabditis elegans, NMD contributes to longevity by enhancing RNA quality. Here, we aimed at identifying NMD-modulating factors that are crucial for longevity in C. elegans by performing genetic screens. We showed that knocking down each of algn-2/asparagine-linked glycosylation protein, zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule increased the transcript levels of NMD targets. Among these, algn-2 exhibited an age-dependent decrease in its expression and was required for maintaining normal lifespan and for longevity caused by various genetic interventions. We further demonstrated that upregulation of ALGN-2 by inhibition of daf-2/insulin/IGF-1 receptor contributed to longevity in an NMD-dependent manner. Thus, algn-2, a positive regulator of NMD, plays a crucial role in longevity in C. elegans, likely by enhancing RNA surveillance. Our study will help understand how NMD-mediated mRNA quality control extends animal lifespan.


Alterations to functional analysis methodology to clarify the functions of low rate, high intensity problem behavior.
Current research provides few suggestions for modifications to functional analysis procedures to accommodate low rate, high intensity problem behavior. This study examined the results of the extended duration functional analysis procedures of Kahng, Abt, and Schonbachler (2001) with six children admitted to an inpatient hospital for the treatment of severe problem behavior. Results of initial functional analyses (Iwata, Dorsey, Slifer, Bauman, & Richman, 1982/1994) were inconclusive for all children because of low levels of responding. The altered functional analyses, which changed multiple variables including the duration of the functional analysis (i.e., 6 or 7 hrs), yielded clear behavioral functions for all six participants. These results add additional support for the utility of an altered analysis of low rate, high intensity problem behavior when standard functional analyses do not yield differentiated results.


Effects of oral prophylaxis including tongue cleaning on halitosis and gingival inflammation in gingivitis patients-a randomized controlled clinical trial.
The objective of this study was to assess the effect of oral prophylaxis including tongue scraping on level of halitosis, clinical periodontal parameters and local cytokine response in gingivitis patients. In this randomized controlled clinical trial, 36 gingivitis patients were randomly assigned into two subgroups after scaling and polishing. Group 1 received oral hygiene instructions including the use of tongue scraper; group 2 received oral hygiene instructions alone without tongue cleaning. Levels of volatile sulfur compounds (VSC), organoleptic and tongue coating scores, clinical periodontal parameters and gingival crevicular fluid (GCF) samples were collected at baseline and 7 days after oral prophylaxis. GCF samples were analyzed using multiplexing analysis for the simultaneous measurements of cytokines. The Chi-square, Mann-Whitney U, Wilcoxon, and Student's paired and unpaired t tests were used for statistical analysis. Statistically significant reductions were found in terms of clinical periodontal parameters in both groups. However, significant improvements in VSC levels, organoleptic and tongue coating scores were observed just in tongue scraping group. Moreover, the GCF levels of IL-1β and IL-8 significantly decreased after the treatment in group 1 according to the baseline values. The present study indicated that oral prophylaxis including tongue scraping was effective in improving intra-oral halitosis and pro-inflammatory cytokine response in GCF in gingivitis patients. The results suggest that tongue scraping can be taken into consideration in order to manage gingival inflammation as well as VSC levels in gingivitis patients but further clinical studies are required to judge the clinical relevance.


HBsAg Level as Predictor of Liver Fibrosis in HBeAg Positive Patients With Chronic Hepatitis B Virus Infection.
Preliminary data suggests lower serum hepatitis B surface antigen level is associated with more severe liver fibrosis in HBeAg positive patients. We evaluated the association of HBsAg level with biochemical, virological, and histological features in asymptomatic patients with chronic HBV infection. HBsAg levels were measured at baseline in 481 asymptomatic, treatment naive patients with chronic HBV infection. Subjects were followed-up prospectively (median, 12; range, 8-36 months). Phases of HBV infection were defined after regular monitoring of HBV-DNA and transaminases. Liver histology was scored using the METAVIR system. HBeAg positive (n, 126) patients were significantly younger than HBeAg negative (n, 355), median age 26 vs 30 years; P < 0.01. HBV genotype could be determined in 350 patients, 240 (68.57%) had genotype D and 100 (28.57%) had genotype A. HBsAg level had modest correlation with serum HBV DNA(r = 0.6 vs 0.4 in eAg positive & negative respectively). HBeAg + ve patients with fibrosis score ≥ F2 showed significantly lower median serum HBsAg levels and serum HBV DNA levels compared with patients with F0-F1 score (median, range; 4.51, 2.99-6.10 vs 5.06, 4.13-5.89, P < 0.01) and (8.39, 3.85-10.60, P < 0.01) respectively. Significant inverse correlation of HBsAg level was found with liver fibrosis in eAg positive group (r = -0.76; P < 0.001). HBsAg level cut off value 4.7 log10 IU/ml predicted moderate to advance fibrosis (F ≥ 2) with 92% sensitivity, 85% specificity & 91% negative predictive value. Lower HBsAg level might reflect the status of advanced liver fibrosis in HBeAg positive chronic hepatitis B subjects.


Development and application of a radioimmunoassay for methotrexate.
An antiserum to methotrexate has been produced in a sheep against a conjugate of ovalbumin and methotrexate (MTX) prepared using a water-soluble carbodiimide. The antibodies produced were specific for substances containing the 2,4-diamino pteridine structure. Naturally occurring folates did not interfere with the assay. A radioimmunoassay has been developed using this antiserum, which can be used to measure MTX concentrations of less than 1 ng/ml in biological samples without prior extraction. The concentrations of MTX in the blood and urine of patients following a single i.v. bolus injection and following oral administration of the drug have been measured. The published radioimmunoassays for MTX have been compared.


Use of rsfMRI-fALFF for the detection of changes in brain activity in patients with normal-tension glaucoma.
We know little about the changes of brain activity in patients with normal-tension glaucoma (NTG). To investigate the altered spontaneous brain activity in patients with NTG through the resting state functional magnetic resonance imaging-fractional amplitude of low-frequency fluctuation (rsfMRI-fALFF) technique, and to explore the relationship with optical coherence tomography (OCT) and field of vision. Twenty patients with NTG and 20 healthy controls (HCs) (matched for sex, age, and level of education) were enrolled. Spontaneous cerebral activity variations were investigated using the rsfMRI-fALFF technique in all individuals. The average fALFF values of patients with NTG and HCs were compared. Compared with HCs, patients with NTG had significantly lower fALFF values in the right angular gyrus and precuneus; however, higher fALFF values in the brain regions were not observed. The values showed statistically significant negative correlation with those of the retinal nerve fiber layer (right angular gyrus: r = -0.607, P = 0.010; right precuneus: r = -0.504, P = 0.020). There was no significant correlation between the fALFF value and cup-disc ratio (right angular gyrus: r = 0.158, P = 0.494; right precuneus: r = -0.087, P = 0.706), mean deviation (right angular gyrus: r = 0.096, P = 0.468; right precuneus: r = 0.026, P = 0.845), and pattern SD value (right angular gyrus: r = 0.064, P = 0.626; right precuneus: r = -0.145, P = 0.268). Abnormal spontaneous activities were detected in numerous brain regions of patients with NTG, which may provide useful information for understanding the dysfunction in NTG. These activity changes in brain regions may be used as effective clinical indicators for NTG.


PSA-NCAM-negative neural crest cells emerging during neural induction of pluripotent stem cells cause mesodermal tumors and unwanted grafts.
Tumorigenic potential of human pluripotent stem cells (hPSCs) is an important issue in clinical applications. Despite many efforts, PSC-derived neural precursor cells (NPCs) have repeatedly induced tumors in animal models even though pluripotent cells were not detected. We found that polysialic acid-neural cell adhesion molecule (PSA-NCAM)(-) cells among the early NPCs caused tumors, whereas PSA-NCAM(+) cells were nontumorigenic. Molecular profiling, global gene analysis, and multilineage differentiation of PSA-NCAM(-) cells confirm that they are multipotent neural crest stem cells (NCSCs) that could differentiate into both ectodermal and mesodermal lineages. Transplantation of PSA-NCAM(-) cells in a gradient manner mixed with PSA-NCAM(+) cells proportionally increased mesodermal tumor formation and unwanted grafts such as PERIPHERIN(+) cells or pigmented cells in the rat brain. Therefore, we suggest that NCSCs are a critical target for tumor prevention in hPSC-derived NPCs, and removal of PSA-NCAM(-) cells eliminates the tumorigenic potential originating from NCSCs after transplantation.


Imaging Genetic Heterogeneity in Glioblastoma and Other Glial Tumors: Review of Current Methods and Future Directions.
The purpose of this review is to summarize advances in the molecular analysis of gliomas, the role genetics plays in MRI features, and how machine-learning approaches can be used to survey the tumoral environment. The genetic profile of gliomas influences the course of treatment and clinical outcomes. Though biopsy is the reference standard for determining tumor genetics, it can suffer diagnostic delays due to surgical planning and pathologic assessment. Radiogenomics may allow rapid, low-risk characterization of genetic heterogeneity.


Retraction notice to "Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer" [Cancer Lett. 242 (2) (2006) 222–230]. Makoto Suzuki, Hisayuki Shigematsu, Narayan Shivapurkar, Jyotsna Reddy, Kuniharu Miyajima, Takao Takahashi, Adi F. Gazdar, Eugene P. Frenke.
Available online <2nd December 2008>. This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the first author, who accepts responsibility. Following an internal review at the UT Southwestern Medical Center in Dallas, evidence has been found of improper manipulation and duplication of Figure 1 in this article.


The Promise of Smartphone Applications in the Remote Monitoring of Postsurgical Wounds: A Literature Review.
To review the clinical and scientific literature on remote monitoring and management of postsurgical wounds using smartphone applications (apps). MEDLINE, PubMed, EMBASE, and Cochrane libraries were searched for relevant articles on patients who received surgery and were monitored postdischarge via an app. Articles were selected with the terms "mobile phones," "smartphones," "wounds," "monitor," and "patient preference." The authors found 276 review articles related to telemedicine in wound care. Investigators reviewed the titles and abstracts of the search results and selected 83 articles that were relevant to the remote monitoring of wounds using smartphone apps. The topics explored in selected literature included smartphone app importance to telemedicine, benefits (medical and financial), app examples, and challenges in the context of wound monitoring and management. The authors identified several challenges and limitations that future studies in the field need to address. Remote monitoring and management of wounds using smartphone apps is a valuable technique to enhance the quality of and access to healthcare. However, although some patients may prefer this technology, some lack technological competence, limiting telemedicine's applicability. In addition, issues remain with the reliable interpretation of data collected through apps.


Diagnostic and therapeutic yields of early capsule endoscopy and device-assisted enteroscopy in the setting of overt GI bleeding: a systematic review with meta-analysis.
Small-bowel capsule endoscopy (SBCE) and device-assisted enteroscopy (DAE) are essential in obscure GI bleeding (OGIB) management. However, the best timing for such procedures remains unknown. This meta-analysis aimed to compare, for the first time, diagnostic and therapeutic yields, detection of active bleeding and vascular lesions, recurrent bleeding, and mortality of "early" versus "nonearly" SBCE and DAE. MEDLINE, ScienceDirect, and Cochrane Central Register of Controlled Trials were searched to identify studies comparing early versus nonearly SBCE and DAE. Random-effects meta-analysis was performed; reporting quality was assessed. From 1974 records, 39 were included (4825 patients). Time intervals for the early approach varied, within 14 days in SBCE and 72 hours in DAE. The pooled diagnostic and therapeutic yields of early DAE were superior to those of SBCE (7.97% and 20.89%, respectively; P < .05). The odds for active bleeding (odds ratio [OR], 5.09; I2 = 53%), positive diagnosis (OR, 3.99; I2 = 45%), and therapeutic intervention (OR, 3.86; I2 = 67%) were higher in the early group for SBCE and DAE (P < .01). Subgroup effects in diagnostic yield were only identified for the early group sample size. Our study failed to identify differences when studies were classified according to time intervals for early DAE (I2 < 5%), but the analysis was limited because of a lack of data availability. Lower recurrent bleeding in early SBCE and DAE was observed (OR, .40; P < .01; I2 = 0%). The role of small-bowel studies in the early evaluation of OGIB is unquestionable, impacting diagnosis, therapeutic intervention, and prognosis. Comparative studies are still needed to identify optimal timing.


Complementation of vaccinia virus lacking the double-stranded RNA-binding protein gene E3L by human cytomegalovirus.
The cellular response to viral infection often includes activation of pathways that shut off protein synthesis and thereby inhibit viral replication. In order to enable efficient replication, many viruses carry genes such as the E3L gene of vaccinia virus that counteract these host antiviral pathways. Vaccinia virus from which the E3L gene has been deleted (VVDeltaE3L) is highly sensitive to interferon and exhibits a restricted host range, replicating very inefficiently in many cell types, including human fibroblast and U373MG cells. To determine whether human cytomegalovirus (CMV) has a mechanism for preventing translational shutoff, we evaluated the ability of CMV to complement the deficiencies in replication and protein synthesis associated with VVDeltaE3L. CMV, but not UV-inactivated CMV, rescued VVDeltaE3L late gene expression and replication. Thus, complementation of the VVDeltaE3L defect appears to depend on de novo CMV gene expression and is not likely a result of CMV binding to the cell receptor or of a virion structural protein. CMV rescued VVDeltaE3L late gene expression even in the presence of ganciclovir, indicating that CMV late gene expression is not required for complementation of VVDeltaE3L. The striking decrease in overall translation after infection with VVDeltaE3L was prevented by prior infection with CMV. Finally, CMV blocked both the induction of eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation and activation of RNase L by VVDeltaE3L. These results suggest that CMV has one or more immediate-early or early genes that ensure maintenance of a high protein synthetic capacity during infection by preventing activation of the PKR/eIF2alpha phosphorylation and 2-5A oligoadenylate synthetase/RNase L pathways.


[Indications and techniques for intubation of the lacrimal ducts].
There are several well established methods to correct congenital and acquired lacrimal canalicular stenosis. The primary goal of all these surgical methods is the reopening and recanalization of a functional lacrimal pathway. Intubation by bicanalicular or monocanalicular silicone tubes has been established as a means of enhancing the redevelopment of a smooth epithelial surface and keeping the recanalized tear ducts continuously open. The use after endocanalicular surgery is mostly undisputed and unequivocally advocated after trauma but the use after either endonasal or transcutaneous dacryocystorhinostomy is still controversial as there is no clear evidence that it produces superior results. There are several systems available to place monocanalicular or bicanalicular silicone tubes. The decision to place an intubation depends mainly on the level and the type of stenosis.


Resveratrol in the treatment of neuroblastoma: a review.
Resveratrol, polyphenol naturally occurring in grapes or nuts, has anti-cancer properties in the treatment of neuroblastoma - the most common childhood solid tumor. It affects cancer cells by increasing apoptosis, inducing cell necrosis and reducing tumor mass. Mechanism of action - (1) converting procaspases, mainly procaspases three and nine into active forms - caspases, (2) blocking kinases, and also (3) leading the cell to the S-cell cycle, where it is most effective while increasing the concentration of cyclin E and lowering the concentration of p21 protein. In vitro, as well as, rodent animal models studies are available and show promising results. Therapeutic doses, currently within 10-100 μmol/L, are also being tested, as well as other forms of resveratrol, such as its trans-4,4'-dihydroxystilbene analog and polyphenol lipoconjugates. In our review, we presented the known molecular mechanisms of polyphenol anti-tumor activity against neuroblastoma and discussed the studies confirming its effectiveness.


Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid.
Ursodeoxycholic acid (UDCA) is clinically beneficial in chronic cholestatic liver disease, but the underlying mechanisms are unclear. It has been suggested that intrahepatic retention of endogenous hydrophobic bile acids contributes to cholestasis and that the hydrophilic bile acid UDCA reduces this retention; the aim of our study was to test these hypotheses. Twelve patients with primary biliary cirrhosis (PBC) and 5 with primary sclerosing cholangitis (PSC) were studied before and during UDCA (10 mg.kg-1.day-1) and compared with 11 healthy controls. Following intravenous 75Se labeled homocholic acid taurine (75SeHCAT) in the fasting state, abdominal gamma camera imaging was performed for 90 minutes. Initial hepatic uptake, transit time, net, and absolute excretory rates for 75SeHCAT were measured. Mean initial hepatic uptake was not different between patients and controls (17.2% and 19.9% dose/minute, not significant). However, net and absolute excretory rates were significantly reduced in patients (1.4% vs. 3.7% dose/minute, P < 0.0001; and 2.35% vs. 3.96% dose/minute, P < 0.02, respectively), and hepatic transit time was prolonged (18.7 minutes vs. 11.6 minutes, P < 0.002). UDCA improved net and absolute hepatic excretory rates and transit time (1.43% to 1.96% dose/minute, P < 0.001; 2.35% to 3.15% dose/minute, P < 0.005 and 18.7 to 14.7 minutes, P < 0.001, respectively). However, UDCA did not alter initial hepatic uptake. In PBC and PSC, there is a defect in hepatic bile acid excretion but not in uptake, implying bile acid retention. This retention is reduced by UDCA.


Epidemiology and outcome of patients with postoperative abdominal fistula.
to present the epidemiological profile, incidence and outcome of patients who developing postoperative abdominal fistula. This observational, cross-sectional, prospective study evaluated patients undergoing abdominal surgery. We studied the epidemiological profile, the incidence of postoperative fistulas and their characteristics, the outcome of this complication and the predictors of mortality. The sample consisted of 1,148 patients. The incidence of fistula was 5.5%. There was predominance of biliary fistula (26%), followed by colonic fistulas (22%) and stomach (15%). The average time to onset of fistula was 6.3 days. For closure, the average was 25.6 days. The mortality rate of patients with fistula was 25.4%. Predictors of mortality in patients who developed fistula were age over 60 years, presence of comorbidities, fistula closure time more than 19 days, no spontaneous closure of the fistula, malnutrition, sepsis and need for admission to the Intensive Care Unit. abdominal postoperative fistulas are still relatively frequent and associated with significant morbidity and mortality. apresentar o perfil epidemiológico, incidência e desfecho em pacientes que evoluíram com fístula abdominal pós-operatória. trata-se de um estudo prospectivo transversal observacional que avaliou pacientes submetidos à cirurgia abdominal. Foram estudados o perfil epidemiológico, a incidência das fístulas pós-operatórias e suas características, desfecho desta complicaçãoe fatores preditivos de mortalidade. a amostra constou de 1148 pacientes. A incidência de fístula foi 5,5%. Houve predominância de fístulas biliares (26%), seguidas de fístulas colônicas (22%) e gástricas (15%). O tempo médio para o surgimento da fístula foi 6,3 dias. Para o fechamento, a média foi 25,6 dias. A taxa de mortalidade dos pacientes com fístula foi 25,4%. Os fatores preditivos de mortalidade nos casos que desenvolveram fístula foram idade maior do que 60 anos, presença de comorbidades, tempo de fechamento da fístula superior a 19 dias, não fechamento espontâneo da fístula, desnutrição, sepse e necessidade de admissão em Unidade de Terapia Intensiva. as fístulas pós-operatórias abdominais ainda são relativamente frequentes e associadas à morbidade e mortalidade significativas.


Effectiveness of arm supports during typing for adults with neurological disorders.
Four computer-typing accommodations were evaluated to determine if arm supports would enhance typing performance and/or comfort of adults with neurological disorders. Each of 12 adults (6 females and 6 males) participated in 7-min typing tasks under the following conditions: 1) without arm support, 2) Ergo Rest arm support, 3) custom arm support in fixed mode, and 4) custom arm support with movable mode. The objective dependent variables were speed, errors, and type of errors. The subjective dependent measures were reported body part discomfort, and arm support ratings. The data were found to be nonparametric in nature. Therefore, nonparametric techniques were employed to analyze the data. Only one of the objective dependent measures were statistically significant; Type of error (additional key). This result may be attributed to the wide range of disability manifestations among participants. Subjective dependent measures were found to be statistically significant, leading to the conclusion that typing with an arm support was more comfortable and easier than without an arm support.


Phorbol ester and diacylglycerol induce protein phosphorylation at tyrosine.
The phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) is an efficient tumour promoter in vivo. In vitro, TPA activates the phospholipid- and Ca2+-dependent protein kinase, kinase C. This activation is believed to reflect the structural similarity between TPA and diacylglycerol, the endogenous protein kinase C activator which is produced in vivo by hydrolysis of phosphatidylinositol (reviewed in ref. 3). Protein kinase C phosphorylates protein substrates at serine and threonine residues in vitro. The effects of TPA on cultured fibroblasts--including enhanced hexose uptake, disruption of actin stress fibres and growth stimulation--are very similar to those induced by certain retrovirus transforming proteins and by peptide growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and multiplication-stimulating activity (MSA). These transforming proteins and mitogenic agents seem to act by inducing tyrosine-specific protein phosphorylation. Such observations suggested that some of the effects of TPA in vivo may be mediated by protein phosphorylation at tyrosine residues. A 42,000-molecular weight (42 K) polypeptide was previously shown to be phosphorylated at tyrosine in cells transformed by avian sarcoma viruses and in cells stimulated by EGF, PDGF or MSA (J. Cooper, personal communication and refs 11 and 12; this polypeptide was originally designated 43 K or spot n in ref. 10). We show here that this polypeptide also becomes phosphorylated at tyrosine in cells treated with TPA. Furthermore, exogenously added diacylglycerol likewise stimulates the phosphorylation of this protein at tyrosine.


Phosphorylation and Pin1 binding to the LIC1 subunit selectively regulate mitotic dynein functions.
The dynein motor performs multiple functions in mitosis by engaging with a wide cargo spectrum. One way to regulate dynein's cargo-binding selectivity is through the C-terminal domain (CTD) of its light intermediate chain 1 subunit (LIC1), which binds directly with cargo adaptors. Here we show that mitotic phosphorylation of LIC1-CTD at its three cdk1 sites is required for proper mitotic progression, for dynein loading onto prometaphase kinetochores, and for spindle assembly checkpoint inactivation in human cells. Mitotic LIC1-CTD phosphorylation also engages the prolyl isomerase Pin1 predominantly to Hook2-dynein-Nde1-Lis1 complexes, but not to dynein-spindly-dynactin complexes. LIC1-CTD dephosphorylation abrogates dynein-Pin1 binding, promotes prophase centrosome-nuclear envelope detachment, and impairs metaphase chromosome congression and mitotic Golgi fragmentation, without affecting interphase membrane transport. Phosphomutation of a conserved LIC1-CTD SP site in zebrafish leads to early developmental defects. Our work reveals that LIC1-CTD phosphorylation differentially regulates distinct mitotic dynein pools and suggests the evolutionary conservation of this phosphoregulation.


Modular motor learning.
An interesting theory of sensorimotor control has been recently extended and simulated. The simulation can learn to control an arm in several mutually exclusive 'contexts', situations where the arm carries one of four objects with different mechanical properties. It provides a good theoretical framework for testing biological motor systems.


Evaluation of normal-appearing white matter with perfusion and diffusion MRI in patients with treated glioblastoma.
We tried to reveal how the normal appearing white matter (NAWM) was affected in patients with glioblastoma treated with chemo-radiotherapy (CRT) in the period following the treatment, by multiparametric MRI. 43 multiparametric MRI examinations of 17 patients with glioblastoma treated with CRT were examined. A total of six different series or maps were analyzed in the examinations: Apparent Diffusion Coefficient (ADC) and Fractional Anisotropy (FA) maps, Gradient Echo (GRE) sequence, Dynamic susceptibility contrast (DSC) and Arterial spin labeling (ASL) perfusion sequences. Each sequence in each examination was examined in detail with 14 Region of Interest (ROI) measurements. The obtained values were proportioned to the contralateral NAWM values and the results were recorded as normalized values. Time dependent changes of normalized values were statistically analyzed. The most prominent changes in follow-up imaging occurred in the perilesional region. In perilesional NAWM, we found a decrease in normalized FA (nFA), rCBV (nrCBV), rCBF (nrCBF), ASL (nASL)values (p < 0.005) in the first 3 months after treatment, followed by a plateau and an increase approaching pretreatment values, although it did not reach. Similar but milder findings were present in other NAWM areas. In perilesional NAWM, nrCBV values were found to be positively high correlated with nrCBF and nASL, and negatively high correlated with nADC values (r: 0.963, 0.736, - 0.973, respectively). We also found high correlations between the mean values of nrCBV, nrCBF, nASL in other NAWM areas (r: 0.891, 0.864, respectively). We showed that both DSC and ASL perfusion values decreased correlatively in the first 3 months and showed a plateau after 1 year in patients with glioblastoma treated with CRT, unlike the literature. Although it was not as evident as perfusion MRI, it was observed that the ADC values also showed a plateau pattern following the increase in the first 3 months. Further studies are needed to explain late pathophysiological changes. Because of the high correlation, our results support ASL perfusion instead of contrast enhanced perfusion methods.


[Prevalence of urinary tract infection in infants with high fever in the emergency department].
There is no current data on the prevalence of urinary tract infection (UTI) in infants and toddlers with high fever. We conducted this study to assess the point prevalence of UTI in children aged less than 2 years presenting with high fever to the emergency department. We conducted a prospective, multicentre, observational study including febrile children aged less than 2 years in whom urinalysis was performed to rule out UTI over a 1-year period in seven paediatric emergency departments in Spain. Boys younger than 1 year and girls younger than 2 years of age were eligible for the study if they had a rectal temperature greater than 39°C, were not taking antibiotics, and there was no identifiable source of fever. The diagnosis of UTI was based on the presence of leukocyturia and positive urine culture results. We included a total of 1675 patients. Two hundred sixty infants (15.5%; 95% CI, 13.8-17.3) received a diagnosis of UTI. The point prevalence of UTI was 32.9% (95% CI, 26.6-39.9) in febrile boys aged less than 6 months and 19.3% (95% CI, 16.1-22.9) in febrile girls aged less than 12 months. The point prevalence of UTI was 13% (95% CI, 10.8-15.6) in children with a duration of fever of less than 24hours, compared to 17.5% (95% CI, 15.2-20.1) in those with a longer duration of fever (p = 0.014). The point prevalence of UTI in infants and toddlers with fever without source greater than 39°C was higher in our study compared to previous studies of UTI prevalence, especially in male infants aged less than 6 months and female infants aged less than 12 months. Our findings suggest that clinicians need to carefully assess for UTI in infants with unexplained fever greater than 39°C.


Endovascular management of severe lower gastrointestinal bleeding from angiodysplasia in the cecum: A case report.
Gastrointestinal angiodysplasias (GIADs) are rare disorder but can cause noticeable issue clinically. Their clinical characteristics can range from being an asymptomatic incidental finding to causing life-threatening bleeding. Many modalities are applied for treating bleeding GIADs include endoscopic therapies, angiography with embolization, surgical resection, and pharmacologic therapy. However, since patients with GIADs are often aged and have many comorbidities, endoscopic therapies may not be the best initial option. Angiography is suitable method for hemodynamically unstable patients with active bleeding, patients with an unknown active bleeding source, and patients who are poor surgical candidates. Angiography not only diagnose the bleeding point but also provide therapeutic endovascular intervention at the same time. We report a case of endovascular management of severe lower gastrointestinal bleeding from a GIAD in the cecum using a mixture of n-butyl cyanoacrylate and lipiodol to embolize the bleeding source. Clinical symptoms improved without prominent complications.


Comparison of taurocholate accumulation in cultured hepatocytes of pig, rat and man.
Intracellular accumulation at 37 degrees C of 50 microM [14C]taurocholic acid by hepatocytes of pig and rat, cultured for 24 hours, and by human hepatocytes, cultured for 12 hours, reached equilibrium after an incubation time of 1 to 2 hours. Maximum capacity to accumulate taurocholate intracellularly was assessed in 3-hour incubations with increasing extracellular taurocholate concentrations. Accumulation capacity of pig and rat hepatocytes was saturated at 100 microM, while uptake by human hepatocytes slightly increased even further above this concentration. At extracellular concentrations of 100 to 500 microM, hepatocytes of these three species concentrated taurocholic acid intracellularly to between 13 and 17 nmol per mg cell protein, corresponding to an intracellular concentration which was 10-70 times higher than the added extracellular concentration. With proceeding culture age, accumulation capacity of rat and human hepatocytes declined steeply (-80% and -60%, respectively between the first and second culture day). In contrast, in cultured pig hepatocytes, this capacity was only 40% lower on the third day compared to the first day of culture. It is concluded that in cultured pig hepatocytes, the capacity to accumulate bile acids is retained for a longer time than in cultured rat and human hepatocytes.


Secretion of recombinant pediocin PA-1 by Bifidobacterium longum, using the signal sequence for bifidobacterial alpha-amylase.
A recombinant DNA, encoding the chimeric protein of the signal sequence for bifidobacterial alpha-amylase mature pediocin PA-1, was introduced into Bifidobacterium longum MG1. Biologically active pediocin PA-1 was successfully secreted from the strain and showed bactericidal activity against Listeria monocytogenes and the same molecular mass as native pediocin PA-1.


Investigation of spatial resolution improvement by use of a mouth-insert detector in the helmet PET scanner.
The dominant factor limiting the intrinsic spatial resolution of a positron emission tomography (PET) system is the size of the crystal elements in the detector. To increase sensitivity and achieve high spatial resolution, it is essential to use advanced depth-of-interaction (DOI) detectors and arrange them close to the subject. The DOI detectors help maintain high spatial resolution by mitigating the parallax error caused by the thickness of the scintillator near the peripheral regions of the field-of-view. As an optimal geometry for a brain PET scanner, with high sensitivity and spatial resolution, we proposed and developed the helmet-chin PET scanner using 54 four-layered DOI detectors consisting of a 16 × 16 × 4 array of GSOZ scintillator crystals with dimensions of 2.8 × 2.8 × 7.5 mm3. All the detectors used in the helmet-chin PET scanner had the same spatial resolution. In this study, we conducted a feasibility study of a new add-on detector arrangement for the helmet PET scanner by replacing the chin detector with a segmented crystal cube, having high spatial resolution in all directions, which can be placed inside the mouth. The crystal cube (which we have named the mouth-insert detector) has an array of 20 × 20 × 20 LYSO crystal segments with dimensions of 1 × 1 × 1 mm3. Thus, the scanner is formed by the combination of the helmet and mouth-insert detectors, and is referred to as the helmet-mouth-insert PET scanner. The results show that the helmet-mouth-insert PET scanner has comparable sensitivity and improved spatial resolution near the center of the hemisphere, compared to the helmet-chin PET scanner.


Synthesis and characterization of aramid composites reinforced with silanized graphene platelets.
The synthesis and characterization of aramid composites reinforced with graphene platelets are reported. Hydroxy-functionalised graphene platelets were modified with two sol-gel binders (aminopropyl- or aminophenyl-trialkoxysilanes) and then chemically linked with aramid chains. The effect of the two sol-gel binders on the physiochemical and mechanical properties was evaluated. Chemical changes during the sol-gel reaction and subsequent amidation process in the nano-composite preparation were evaluated by the XPS and FTIR analyses. Thin films of these composites with different proportions of graphene were prepared. Morphology of the hybrids prepared was studied by the SEM technique. Properties of the composite films were studied by dynamical mechanical thermal (DMT) analysis to measure their glass transition temperature (T g) and storage modulus. These properties have been compared with previously reported values using pristine graphene (Gr) as a filler. The increase in thermal mechanical properties on addition of silanized graphene (SiGr) showed a large shift in the T g and more increase in storage modulus by chemically binding SiGr sheets on the aramid chains. Aminophenyl-trialkoxysilane was found to give better results due to the presence of phenyl groups which were more rigid than propyl groups present in aminopropyl-trialkoxysilane. The effect of chemical bonding and the possible π-π secondary bond interactions between the matrix and graphene platelets on the properties of the resulting hybrids are discussed.


Effects of age on neurocognitive measures of children ages 5 to 12: a cross-sectional study on 800 children from the United States.
The standardization of the NEPSY-A Developmental Neuropsychological Assessment (Korkman, Kirk, & Kemp, 1998) provided an opportunity to study the effects of age across the age range 5 to 12 years. Test scores of 800 children on 20 subtests of NEPSY were analyzed. These measures are based on traditions of neuropsychological assessment and are thought to reflect attention and executive functions, language, sensorimotor functions, visuospatial functions, and memory and learning. The effects of age were very significant on all measures, confirming the developmental sensitivity of the NEPSY. The effects of age were more significant in the 5- to 8-year age range than in the 9- to 12-year range. Only performance on tasks of fluency and memory span for sentences showed significant age effects in the 10- to 12-year age range. This suggests that neurocognitive development is rapid in the 5- to 8-year age range and more moderate in the 9- to 12-year age range.


[Axial displacement of IOL and visual impairment].
After a cataract surgery procedure with vitreous loss a vitreous strand remained in the wound. An unusual visual impairment was observed. A shift in refraction depending on the pupillary diameter was observed. In miosis the refraction was estimated to +1.0 sph, in mydriasis -1.0 sph/ -0.5 cyl, respectively. We presumed that the vitreous strand between the iris and the intraocular lens caused an axial displacement of the IOL during the change from miosis to mydriasis and v.v. Therefore the vitreous strand was surgically eliminated. After surgery the refractive changes by pupillary actions were overcome. In a computer simulation (ray tracing), the amount of axial displacement of the IOL was estimated to 1.5 mm. This paper reminds of considering other reasons for loss of VA than CME, e.g. axial displacement of IOL. An adequate method of examination is the measurement of refraction in miosis and mydriasis.


What Should Be the Cut Point for Classification Criteria of Studies in Gout? A Conjoint Analysis.
To determine the acceptable level of positive predictive value (PPV) and negative predictive value (NPV) for classification criteria for gout, given the type of study. We conducted an international web-based survey with 91 general practitioners and rheumatologists experienced in gout. Conjoint analysis was used as the framework for designing and analyzing pairs of 2 profiles, each describing a study type, a PPV, and an NPV. There were 5 study types presented: a phase III randomized controlled trial (RCT) of a nonsteroidal antiinflammatory drug versus prednisone for acute gout flares, a phase III RCT of a biologic agent for acute gout flares, a phase II RCT of a novel uricosuric drug of unknown efficacy and limited toxicity data, a case-control, genome-wide association study of gout, and a cohort study examining long-term outcomes of gout. PPV and NPV both had 5 levels ranging from 60-99%. The panelists in majority were male (65%) rheumatologists (93%) with an average of 19 years of practice, seeing 5 to 60 gout patients monthly. PPV was most highly weighted in decision making: the relative importance was 59% for PPV, 29% for NPV, and 13% for study type. The preferred PPV was 90% or 80%, with an accompanying NPV of 70% or 80%, dependent on study type. Preferred PPVs and NPVs range between 70% and 90% and differ by study type. A single cut point can be a reasonable approach for all study types if a PPV of 90% and NPV of 80% is approximated.


A structural domain of the covalent polymer globin chains of artemia. Interpretation of amino acid sequence data.
Artemia is unusual in having extracellular hemoglobins of Mr 260,000 comprising two globin chains (Mr 130,000), each of which is a polymer of eight covalently linked domains of about Mr 16,000. The amino acid sequence of one of these domains (E1) has been determined. It has 147 residues and Mr of 17,574 including heme. Sequence alignment revealed 19.0% identity with sperm whale myoglobin, whereas other vertebrate and invertebrate globins had between 13 and 24% identity. However, a much higher percentage of residues has a similar side chain character, suggesting that the domain E1 is very similar to other globins in showing the myoglobin fold. Template model building based on the known three-dimensional structure of myoglobin further supports this conclusion. Conversely, the differences between E1 and other globins are believed to reflect differences in the packing of the domains, first in a covalent polymeric subunit containing eight hemes and subsequently by association of two of these subunits as dimers. These findings provide further evidence for the versatility of the myoglobin fold.


Next-generation sequencing identifies potential novel therapeutic targets in Chinese HGSOC patients.
Targeted therapy, especially the use of poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors (PARPis), has improved the outcome of patients with ovarian cancer. However, most high-grade serous ovarian cancer (HGSOC) patients have wild-type BRCA1/2, and it is necessary to disclose more potential novel targets for other available targeted drugs. So, detection of genetic alterations beyond BRCA1/2 is critical to screen HGSOC patients for personalized therapy. In this study, a broad, hybrid capture-based next-generation sequencing (NGS) assay was used to identify actionable genetic alterations from HGSOC cancer tissues. Sixty-eight patients with HGSOC were enrolled, including 6 International Federation of Gynecology and Obstetrics (FIGO) stage I, 15 stage II, 37 stage III and 10 stage IV patients. All patients signed informed consent forms. Potentially actionable genetic alterations, including base substitutions, indels, copy number alterations, and gene fusions, were identified using targeted NGS. In our study, 14.7% (10/68) of the tumors harbored actionable genetic alterations in patients with BRCA1. A total of 25.0% (17/68) of patients without BRCA1 mutations harbored other actionable genetic alterations, such as homologous recombination repair (HRR) pathway-related genes (ATM, CDK12, FANCA, and FANCD2), PI3K/AKT/mTOR pathway genes (NF1, FBXW7, PIK3CA, PTEN, TSC1, and TSC2), and some other genes (ARID1A, FGFR1, KRAS, and NRAS). Furthermore, some patients harboring ARID1A or NF1 actionable genetic alterations showed good clinical efficacy to immune checkpoint inhibitors (ICIs) and everolimus, respectively. Our research indicates that 39.7% (27/68) of patients with HGSOC harbored at least one actionable genetic alteration. 25.0% (17/68) of patients had somatic mutations or copy number variations beyond BRCA1 mutations and might be treated with off-label therapy or to be allocated into clinical trial. NGS assays of HGSOC patients are necessary to screen actionable genetic alterations to guide personalized and precise treatment.


Effectiveness of Risk Minimization Measures for Fentanyl Buccal Tablet (FENTORA) in Canada: A Mixed-Methods Evaluation Using Surveys, Medical Chart Records and Web Surveillance.
Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015. The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use. The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern. KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use. The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice.


[Anatomic correction of transposition of the great arteries: a model of surgical "cure" in pediatric cardiology?].
Transposition of the great arteries (TGA) is a common congenital heart malformation, involving inversion of the two great vessels (aorta and pulmonary artery). Without surgical treatment, TGA is not compatible with life. The prognosis of this malformation has been dramatically changed by the development of neonatal cardiac surgery. "Anatomic" repair was introduced in the 1980s, with the goal of providing near-normal cardiac anatomy. It is carried out in neonates with isolated TGA (so-called simple TGA), as well as in those with associated anomalies (ventricular septal defect, aortic coarctation). Since January 1987, 1020 neonates have undergone anatomic repair of TGA in the pediatric cardiac surgery department of Groupe Hospitalier Laennec-Necker-Enfants Malades in Paris. The overall mortality rate was 4.8% (49 patients), and all deaths occurred within the first postoperative year. Among the 966 survivors who could be monitored (mean follow-up 6.2 years), 52 children (5.4%) underwent reoperation, with no additional mortality. Nearly all the survivors have normal cardiac function and quality of life. Despite significant mortality (albeit currently low) anda low risk of reoperation, the mid-term results of anatomic repair of TGA are excellent and represent a surgical "cure" in most cases. Very-long-term outcome remains to be determined.


Metabolic and endocrine studies in a case of lipoatrophic diabetes.
A 20-yr-old female with congenital lipoatrophic diabetes was studied, with the following findings: (1) Serum insulin levels increased after both oral glucose and intravenous arginine administration; there was no growth hormone response to the latter. (2) The infusion of insulin (0.1 units and 0.5 units/kg) during the fed state and following at 110-hr fast produced only minimal changes of various fuels measured, with the exception of a decrease in the branched-chain amino acids. (3) There was a minimal production of ketones during the 110-hr fast. (4) Matabolic expenditure was markedly increased during the postabsorptive state (65-75 kcal/hr/sg m); it fell into the normal range during the 110-hr fast (31-35 kcal/hr/sq m). (5) Following meals, the patient experienced complaints ranging from cold and shivering to feeling hot with gross diaphoresis. These findings were associated with intermittent lability of her skin temperature, which varied 1 degree - 2 degrees F during a 3-hr period. (6) Progressive increases in doses of regular insulin before each meal resulted in up to a total of 9000 units/day being required before normal blood glucose levels were achieved. (7) A 2-wk therapeutic trial of pimozide provided no significant changes in a variety of hormones and fuels in the basal state or following insulin perturbations. (8) A variety of pituitary hormones and pituitary target organ hormones were studied in both the hypothyroid (Hashimoto's thyroiditis) and euthyroid state (following thyroid replacement). All the hormone responses were normal except that growth hormone did not rise during the slow wave sleep in either thyroid state.


The fortuitous diagnosis of cholera in a two-year-old girl.
We are reporting the fortuitous diagnosis of a case of cholera and the unusual failure of the commercial bacteriologic media that led to the unexpected isolation of Vibrio cholerae. The case demonstrates the need for communication between the medical staff and laboratory personnel when an uncommon disease, such as cholera, is suspected. This case also alerts the clinician to the possibility of multiple enteric pathogens coinfecting a traveller.


Differences between unipolar depression and bipolar II depression in women.
Bipolar disorder II (BPII) and unipolar depression (UD) are both characterized by episodes of major depression (MDE), however DSM-IV criteria for MDE are identical, regardless of diagnosis. As a result, misdiagnosis of BP II and UD is common, leading to inappropriate treatment. Because women are twice as likely as men to experience MDE, differentiating UD from BP II in the context of depression is especially important for women. We examined symptoms and clinical features of MDE in women with UD and BPII to compare presentations of the two disorders in women. We compared characteristics of depressed women meeting DSM-IV criteria for BPII (n=48) or UD (n=48), matched on age. Feelings of worthlessness occurred in 98% of participants with UD versus 85% with BPII (p=0.03). Participants with UD experienced either insomnia or hypersomnia, but participants with BPII were more likely to experience both simultaneously (p=0.04). Those with UD were significantly less likely to have >5 prior mood episodes compared to those with BP II (12% versus 61%; p<0.0001) and had a later age of onset (p=0.003). Small sample size and exclusion criteria (i.e., comorbid substance abuse) may limit generalizability of findings. Among a sample of women, number of prior episodes, feelings of worthlessness, age of onset, and sleep patterns distinguished between UD and BP II depressive episodes. A better understanding of differential presentation of BP II versus UD depression in women may help guide clinicians to more accurate diagnoses and, ultimately, better treatment.


Reproductive success and foraging of the crab spider Misumena vatia.
Reproductive success and growth rate data were collected for individually marked crab spiders Misumena vatia (Clerck) in 1980, 1981, and 1982. All measures of reproductive success were found to be quite variable between individuals within years, but did not differ between years. Reproductive effort (mass of clutch/prereproductive mass of female) was the least variable measurement and was not correlated with female weight at reproduction. Clutch weight and number of eggs per clutch were highly correlated with female reproductive weight. Egg weight was not correlated with the number of eggs per clutch. Hatching success did not vary with clutch size and averaged 94.5%. Growth rates of spiders were highly variable, indicating large variation in feeding rate. In 1981 and 1982, approximately 20% of female spiders were unable to capture enough prey to grow and reproduce. Primary prey species differed in weight and in their contribution to spider egg production. Spiders attacked a larger percentage of bumblebees but captured a larger percentage of honeybees. There was no simple relationship between diet choice and reproductive success. Spiders which selected suboptimal umbels to forage on some or all of the time, however, had significantly lower reproductive success than spiders choosing the best umbels.


Various 30 and 69 bp deletion variants of the Epstein-Barr virus LMP1 may arise by homologous recombination in nasopharyngeal carcinoma of Tunisian patients.
Nasopharyngeal carcinoma (NPC) occurs with a striking geographic distribution, it is endemic in certain areas of Southeast Asia and North Africa. NPC is tightly linked to Epstein-Barr virus (EBV), however, only a small subset of EBV genes are expressed, among them the latent membrane protein 1 (LMP1). LMP1 is considered as the main EBV oncoprotein and its 30 bp deleted-variant has been reported to be more prevalent in biopsies of NPC. We have assessed the 30 bp deletion and the XhoI polymorphisms of the BNLF1 gene in 30 peripheral bloods of NPC patients and 62 nasopharyngeal biopsies, 42 being confirmed as undifferentiated nasopharyngeal carcinoma and 20 are normal nasopharyngeal epithelium cells. Our results show that 100% of individuals retained the XhoI restriction site. A rare NPC variant, having a 69 bp deletion in the C-terminus region of the BNLF1 gene, covering the 30 bp deletion, was found in two NPC biopsies. The deleted 30 and 69 bp deleted-variants are significantly (p = 0.006) more frequent in NPC (71.42%) than in control biopsies (52%). In peripheral blood of NPC patients, the deleted-variants (47%) are also lower than in tumor tissues (p = 0.0004), suggesting that the deletion could be associated with a risk of tumor genesis. Direct repeats, located at the extremities of the 30 and 69 bp deletions, should be involved in this process. We propose that other deletions could be found since another similar direct repeat is present at the vicinity of the former ones.


In-vivo analysis of thoracic mechanical response under belt loading: the role of body mass index in thorax stiffness.
Thoracic injuries are a major cause of mortality in frontal collisions, especially for elderly and obese people. Car occupant individual characteristics like BMI are known to influence human vulnerability in crashes. In the present study, thoracic mechanical response of volunteers quantified by optical method was linked to individual characteristics. 13 relaxed volunteers of different anthropometries, genders and age were submitted to non-injurious sled tests (4 g, 8 km/h) with a sled buck representing the environment of a front passenger restrained by a 3-point belt. A resulting shoulder belt force was computed using the external and internal shoulder belt loads and considering shoulder belt geometry. The mid sternal deflection was calculated as the distance variation between markers placed at mid-sternum and the 7th vertebra spinous process of the subject. Force-deflection curves were constructed using resulting shoulder belt force and midsternal deflection. Average maximum chest compression was 7.9±2.3% and no significant difference was observed between overweight subjects (BMI≥25 kg/m²) and normal subject (BMI<25 kg/m²). The overweight subjects exhibited significantly greater resultant belt forces than normal subjects (715±132 N vs. 527±111 N, p<0.05), higher effective stiffness (30.9±10.6N/mm vs. 19.6±8.9 N/mm, p<0.05) and lower dynamic stiffness (42.7±8.71 N/mm vs. 61.7±15.5 N/mm, p<0.05).


Evidence-based guidelines for cataract surgery: guidelines based on data in the European Registry of Quality Outcomes for Cataract and Refractive Surgery database.
In March 2008, the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO) commenced. This 3-year project was cofunded by the European Union (EU) and the European Society of Cataract & Refractive Surgeons (ESCRS). The ESCRS became the lead partner in the project with 11 national societies as associated partners. The aims of the project were to improve treatment and standards of care for cataract and refractive surgery and to develop evidence-based guidelines for cataract and refractive surgery across Europe. Surgeons from all participating societies contributed to the database, which contained data on 820,000 cataract surgeries in November 2011. The present guidelines are based on data entered from January 1, 2009, to August 28, 2011 (523,921 cataract extractions). The guidelines include only those steps in the cataract surgery process that can be analyzed by the database.


Relevance of thrombophilia and impact of office hysteroscopy on recurrent in vitro fertilization failures: a case series.
The study evaluated the validity of office hysteroscopy (OH) in 51 infertile women and whether congenital or acquired thrombophilia is more prevalent in women with recurrent IVF failures.


Intraoperative retrograde mesenteric angioplasty for acute occlusive mesenteric ischaemia: a case series.
Acute mesenteric ischaemia secondary to atherosclerotic disease of the superior mesenteric artery is a surgical emergency associated with a poor prognosis, and requires prompt diagnosis and early revascularisation in order to improve outcome. The traditional management of surgical resection of necrotic bowel plus mesenteric revascularisation by surgical bypass is associated with significant morbidity and mortality. We describe the use of a combined surgical and endovascular approach, using intraoperative retrograde superior mesenteric angioplasty at the time of laparotomy. Four patients have been treated by this combined technique with three surviving, although one subsequently required an open surgical revascularisation procedure.


Solution NMR and CD spectroscopy of an intrinsically disordered, peripheral membrane protein: evaluation of aqueous and membrane-mimetic solvent conditions for studying the conformational adaptability of the 18.5 kDa isoform of myelin basic protein (MBP).
The stability and secondary structure propensity of recombinant murine 18.5 kDa myelin basic protein (rmMBP, 176 residues) was assessed using circular dichroic and nuclear magnetic resonance spectroscopy (1H-15N HSQC experiments) to determine the optimal sample conditions for further NMR studies (i.e., resonance assignments and protein-protein interactions). Six solvent conditions were selected based on their ability to stabilise the protein, and their tractability to currently standard solution NMR methodology. Selected solvent conditions were further characterised as functions of concentration, temperature, and pH. The results of these trials indicated that 30% TFE-d2 in H2O (v/v), pH 6.5 at 300 K, and 100 mM KCl, pH 6.5 at 277 K were the best conditions to use for future solution NMR studies of MBP. Micelles of DPC were found to be inappropriate for backbone resonance assignments of rmMBP in this instance.


CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade.
Tumor-infiltrating cells play an important role in tumor immunology, and tumor-infiltrating lymphocytes (TILs) are critical in antitumor reaction related to immune checkpoint inhibition targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). In nude mice, which are immune deficient because they lack T cells, and inbred A/J mice, which are syngeneic to neuroblastoma cells (Neuro-2a) and have normal T cell function, we investigated the importance of T lymphocytes in immune checkpoint inhibition in mouse neuroblastoma and analyzed the immune cells in the tumor microenvironment. Then, we subcutaneously injected mouse Neuro-2ainto nude mice and A/J mice, administered anti-PD-1 and anti-PD-L1 antibodies by intraperitoneal injection, and evaluated tumor growth. At 16 d after Neuro-2a cells injection, mice were euthanized, tumors and spleens were harvested, and immune cells were analyzed by flow cytometry. The antibodies suppressed tumor growth in A/J but not in nude mice. The co-administration of antibodies did not affect regulatory T cells (culster of differentiation [CD]4+CD25+FoxP3+ cells) or activated CD4+ lymphocytes (expressing CD69). No changes in activated CD8+ lymphocytes (expressing CD69) were observed in spleen tissue. However, increased infiltration of activated CD8+ TILs was seen in tumors weighing less than 300 mg, and the amount of activated CD8+ TILs was negatively correlated with tumor weight. Our study confirms that lymphocytes are essential for the antitumor immune reaction induced by blocking PD-1/PD-L1 and raises the possibility that promoting the infiltration of activated CD8+ TIL into tumors may be an effective treatment for neuroblastoma.


CT scanning for papilloma of choroid plexus.
A case of choroid plexus papilloma is presented which was extensively investigated. The location of the pedicle of this tumor was not demonstrated by conventional CT, ventriculography of ventriculoscopy. Coronal CT sections, however, clearly showed the pedicle and its location. Dilatation of the cisterns and sulci suggested that there was overproduction of cerebrospinal fluid.


An additive selection of markers to improve diagnostic accuracy based on a discriminatory measure.
The estimation of the area under the receiver operating characteristic (ROC) curve (AUC) often relies on the assumption that the truly positive population tends to have higher marker results than the truly negative population. The authors propose a discriminatory measure to relax such an assumption and apply the measure to identify the appropriate set of markers for combination. The proposed measure is based on the maximum of the AUC and 1-AUC. The existing methods are applied to estimate the measure. The subset of markers is selected using a combination method that maximizes a function of the proposed discriminatory score with the number of markers as a penalty in the function. The properties of the estimators for the proposed measure were studied through large-scale simulation studies. The application was illustrated through a real example to identify the set of markers to combine. Simulation results showed excellent small-sample performance of the estimators for the proposed measure. The application in the example yielded a reasonable subset of markers for combination.


Tracing the Flow of Perceptual Features in an Algorithmic Brain Network.
The model of the brain as an information processing machine is a profound hypothesis in which neuroscience, psychology and theory of computation are now deeply rooted. Modern neuroscience aims to model the brain as a network of densely interconnected functional nodes. However, to model the dynamic information processing mechanisms of perception and cognition, it is imperative to understand brain networks at an algorithmic level--i.e. as the information flow that network nodes code and communicate. Here, using innovative methods (Directed Feature Information), we reconstructed examples of possible algorithmic brain networks that code and communicate the specific features underlying two distinct perceptions of the same ambiguous picture. In each observer, we identified a network architecture comprising one occipito-temporal hub where the features underlying both perceptual decisions dynamically converge. Our focus on detailed information flow represents an important step towards a new brain algorithmics to model the mechanisms of perception and cognition.


Five cases of Plasmodium vivax malaria treated with artemisinin derivatives: the advantages of a unified approach to treatment.
In endemic countries with a high level of chloroquine resistance, Plasmodium vivax malaria is associated with high morbidity and mortality. In these areas, the dihydroartemisinin-piperaquine combination resulted in clinical response, a more rapid clearance of parasitaemia, compared to chloroquine therapies, and reduction of recrudescence or reinfection. We describe five cases of Plasmodium vivax malaria in returning travelers treated with dihydroartemisinin-piperaquine. All patients showed the early parasite clearance and no side effects. Our preliminary results suggest that the dihydroartemisinin-piperaquine combination is effective and safe even in imported cases. A unified treatment policy using the artemisinin combination therapy should be adopted even in non-endemic countries and larger studies are underway to support this strategy.


Automatic identification method of bridge structure damage area based on digital image.
It is of great scientific and practical value to use effective technical means to monitor and warn the structural damage of bridges in real time and for a long time. Traditional image recognition network models are often limited by the lack of on-site images. In order to solve the problem of automatic recognition and parameter acquisition in digital images of bridge structures in the absence of data information, this paper proposes an automatic identification method for bridge structure damage areas based on digital images, which effectively achieves contour carving and quantitative characterization of bridge structure damage areas. Firstly, the digital image features of the bridge structure damage area are defined. By making full use of the feature that the pixel value of the damaged area is obviously different from that of the surrounding image, an image pre-processing method of the structure damaged area that can effectively improve the quality of the field shot image is proposed. Then, an improved Ostu method is proposed to organically fuse the global and local threshold features of the image to achieve the damaged area contour carving of the bridge structure surface image. The scale of damage area, the proportion of damage area and the calculation rule of damage area orientation are constructed. The key inspection and characteristic parameter diagnosis of bridge structure damage area are realized. Finally, test and analysis are carried out in combination with an actual project case. The results show that the method proposed in this paper is feasible and stable, which can improve the damage area measurement accuracy of the current bridge structure. The method can provide more data support for the detection and maintenance of the bridge structure.


Treatment Outcomes in Patients With Symptomatic Lymphoceles Following Radical Prostatectomy Depend Upon Size and Presence of Infection.
To guide treatment decisions for symptomatic lymphoceles after radical prostatectomy. We examined our experience to create a treatment algorithm. We evaluated all patients that underwent radical prostatectomy at our institution from 2003 to 2012. Presenting signs, management and treatment outcomes were evaluated. Of the 8081 patients who underwent radical prostatectomy from 2003 to 2012, we identified 123 (1.5%) patients who developed a symptomatic lymphocele, 70 sterile and 53 infected. Percutaneous aspiration was performed in 26 of 123 (21%) patients, of those, 100% recurred. A drain was placed in 86 of 123 (70%) patients for a median of 13 vs 33 days for the infected and sterile lymphocele groups, respectively (P <.001). The median duration of drainage for sterile lymphoceles was 15 vs 58 days for lymphoceles <10 cm vs ≥10 cm (P <.001). Percutaneous drainage was successful in 93% and 86% of patients with infected and sterile lymphoceles, respectively. Laparoscopic unroofing was performed in 18 sterile lymphocele patients (15%) with a success rate of 94%. Aspiration of symptomatic lymphoceles should be reserved for diagnostic purposes due to a high risk of recurrence. Infected lymphoceles are optimally treated with drain placement and antibiotics, and have excellent resolution rates. While sterile lymphoceles <10 cm can be successfully managed with drain placement, if drainage and sclerotherapy fail, laparoscopic unroofing should be considered. For patients with sterile lymphoceles ≥10 cm there should be a shared decision-making process to weigh the risk of a protracted course if a drain is utilized vs upfront laparoscopic unroofing.


Cooperation of synthetic insulin-like growth factor I/somatomedin C and 1,25-dihydroxyvitamin D3 on regulation of function in clonal osteoblastic cells.
We investigated the effects of insulin-like growth factor I/somatomedin C (IGF-I/SM-C), and the interaction of IGF-I and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on mouse clonal osteoblasts, MC3T3-E1. IGF-I stimulated [3H]thymidine incorporation into the DNA of the cells at concentrations of 1.3-130 X 10(-9) M. The alkaline phosphatase (ALP) activity in cultures was also raised by the hormone at the same concentrations. The optimal dose of IGF-I was 13 X 10(-9) M. Co-addition of IGF-I (1.3-130 X 10(-9) M) and 1,25(OH)2D3 (10(-11) to 10(-10) M) to the culture of MC3T3-E1 cells caused a synergistic increase in ALP activity. 25(OH)D3 and 24,25(OH)2D3 showed a similar effect with IGF-I at 1000-2000 times higher concentrations than 1,25(OH)2D3. [3H]Proline incorporation into collagenase digestible protein (CDP) in media was stimulated dose-dependently by IGF-I up to 2.2-fold over the control levels at 130 X 10(-9) M. Addition of 1,25(OH)2D3 (5 X 10(-11) M) and IGF-I further elevated the proline incorporation into CDP. However, the increment in CDP synthesis, induced by the two hormones was less than the increment in ALP activity. Thus, we conclude (1) that IGF-I stimulates both cell replication and differentiated functions in cultured murine osteoblasts and (2) that IGF-I and 1,25(OH)2D3 have the synergistic effect on ALP activity and the additive effect on collagen synthesis in MC3T3-E1 cells.


Off-Pump Tricuspid Annuloplasty through a Direct Transatrial Approach: Early Results.
Severe tricuspid regurgitation constitutes a growing disease burden. Conventional surgery for tricuspid valve disease has an increased risk while several interventional procedures are currently under clinical investigation, yet do not offer comprehensive solutions. We investigated a novel surgical approach for off-pump beating-heart tricuspid annuloplasty in circulating blood through a single port in the right atrium. Early feasibility results in preclinical porcine in vivo studies encourage further development of this approach, combining the proven concept of surgical annuloplasty with the benefits of minimally invasive off-pump procedures in a hybrid setting.


Analysing a Chinese Regional Integrated Healthcare Organisation Reform Failure using a Complex Adaptive System Approach.
China's organised health system has remained outdated for decades. Current health systems in many less market-oriented countries still adhere to traditional administrative-based directives and linear planning. Furthermore, they neglect the responsiveness and feedback of institutions and professionals, which often results in reform failure in integrated care. Complex adaptive system theory (CAS) provides a new perspective and methodology for analysing the health system and policy implementation. We observed the typical case of Qianjiang's Integrated Health Organization Reform (IHO) for 2 years to analyse integrated care reforms using CAS theory. Via questionnaires and interviews, we observed 32 medical institutions and 344 professionals. We compared their cooperative behaviours from both organisational and inter-professional levels between 2013 and 2015, and further investigated potential reasons for why medical institutions and professionals did not form an effective IHO. We discovered how interested parties in the policy implementation process influenced reform outcome, and by theoretical induction, proposed a new semi-organised system and corresponding policy analysis flowchart that potentially suits the actual realisation of CAS. The reform did not achieve its desired effect. The Qianjiang IHO was loosely integrated rather than closely integrated, and the cooperation levels between organisations and professionals were low. This disappointing result was due to low mutual trust among IHO members, with the main contributing factors being insufficient financial incentives and the lack of a common vision. The traditional organised health system is old-fashioned. Rather than being completely organised or adaptive, the health system is currently more similar to a semi-organised system. Medical institutions and professionals operate in a middle ground between complete adherence to administrative orders from state-run health systems and completely adapting to the market. Thus, decision-making, implementation and analysis of health policies should also be updated according to this current standing. The simplest way to manage this new system is to abandon linear top-down orders and patiently wait for an explicit picture of IHO mechanisms to be revealed after complete and spontaneous negotiation between IHO allies is reached. In the meantime, bottom-up feedback from members should be paid attention to, and common benefits and fluid information flow should be prioritised in building a successful IHO.


Diagnostic performance of 18F-labeled PSMA PET/CT in patients with biochemical recurrence of prostate cancer: a systematic review and meta-analysis.
After initial treatment of prostate cancer, increases in prostate-specific antigen (PSA) levels commonly signify potential relapse or metastasis. 18F-labeled prostate-specific membrane antigen (PSMA) is considered a promising treatment due to its favorable physical properties. To investigate the diagnostic value of 18F-PSMA PET/CT for the recurrence and/or metastasis of biochemical recurrence of prostate cancer (BRPca). A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library databases. Combined sensitivity and specificity values for the use of 18F-PSMA PET/CT in patients with BRPca were obtained. The quality of the studies was tested using the Diagnostic Accuracy Research Quality Assessment tool. Meta-analysis was performed using STATA 15 software, and heterogeneity was subsequently tested. A total of 16 studies (1162 patients) were enrolled and had significant heterogeneity. The pooled sensitivity, specificity, and AUC values for 18F-PSMA PET/CT in the diagnosis of prostate recurrence and/or metastasis were 0.93 (0.89-0.95), 0.94 (0.85-0.98), and 0.96 (0,94-0.98), respectively. Meta-regression analyses showed that the sources of heterogeneity did not relate to ligands, study designs, or participants. The pooled sensitivity and specificity values of 18F-DCFPyL PET/CT were 0.90 (0.85-0.94) and 0.89 (0.85-0.93), respectively. The pooled sensitivity and specificity values of 18F-PSMA-1007 PET/CT were 0.89 (0.85-0.93) and 0.93 (0.70-0.99), respectively. The per-patient pooled sensitivity and specificity values were 0.92 (0.86-0.96) and 0.83 (0.41-0.97), respectively. The per-lesion pooled sensitivity and specificity values were 0.91 (0.86-0.94) and 0.91 (0.86-0.94), respectively. According to our meta-analysis, 18F-PSMA PET/CT has the potential to be critical for the diagnosis of recurrence and/or metastasis in patients with BRPca.


Multiple host shifts between distantly related plants, Juglandaceae and Ericaceae, in the leaf-mining moth Acrocercops leucophaea complex (Lepidoptera: Gracillariidae).
Insect herbivores such as gall formers and leaf miners are often highly specialized and adapted to their respective natal host plants. Due to the specialization and adaptation, it is presumed that host shifts readily occur among closely related plant species. Leaf-mining moths, the Acrocercops leucophaea complex, consist of three species, A. leucophaea, A. defigurata, and A. transecta. Larvae of all the species of the complex feed on Juglandaceae plants, but A. leucophaea and A. transecta are also associated with an Ericaceae plant, which is quite distantly related to Juglandaceae. Such a host utilization as in this species complex is very rare among phytophagous insects. In the present study, we estimate the history of host shifts by reconstructing the phylogeny of the A. leucophaea complex using molecular data (partial sequence of mitochondrial COI, 12S rDNA, and ND5). Parsimony and maximum likelihood analyses indicated that the common ancestor of the A. leucophaea complex used Juglandaceae only, and that the association with Ericaceae has evolved in A. leucophaea and A. transecta independently. Parametric bootstrap analysis also supported multiple origins of the association with Ericaceae in this complex. These results imply that there are ecological and biochemical factors that promote host shifting between Juglandaceae and Ericaceae despite the two families being not closely related.


Interaction of the integrin beta1 cytoplasmic domain with ICAP-1 protein.
In a yeast two-hybrid screen, a protein named ICAP-1 (beta1 integrin cytoplasmic domain associated protein) associated with the integrin beta1 cytoplasmic tail but not with tails from three other integrin beta subunits (beta2, beta3, and beta5) or from seven different alpha subunits. Likewise in human cells, ICAP-1 associated specifically with the beta1 but not beta2, beta3, or beta5 tails. The carboxyl-terminal 14 amino acids of beta1 were critical for ICAP-1 interaction. ICAP-1 is a ubiquitously expressed protein of 27 and 31 kDa, with the smaller form being preferentially solubilized by Triton X-100. Phosphorylation of both 27- and 31-kDa forms was constitutive but was increased by 1.5-2-fold upon cell spreading on fibronectin, compared with poly-L-lysine. Also, ICAP-1 contributes to beta1 integrin-dependent migration because (i) ICAP-1 transfection markedly increased chemotactic migration of COS7 cells through fibronectin-coated but not vitronectin-coated porous filters, and (ii) support of beta1-dependent cell migration (in Chinese hamster ovary cells transfected with various wild type and mutant beta1 forms) correlated with ICAP-1 association. In summary, ICAP-1 (i) associates specifically with beta1 integrins, (ii) is phosphorylated upon beta1 integrin-mediated adhesion, and (iii) may regulate beta1-dependent cell migration.


Evaluation of a systematic postal screening and treatment service for genital Chlamydia trachomatis, with remote clinic access via the internet: a cross-sectional study, East of England.
England's National Chlamydia Screening Programme provides opportunistic testing for all 15-24-year-olds in healthcare and non-healthcare settings. The authors undertook an evaluation of a population service-based postal chlamydia screening and treatment service, with registration and access to the service via the internet, in order to target screening interventions more effectively in future. Individuals aged between 18 and 24 years, within the North East Essex Primary Care Trust, were identified for chlamydia screening by the service between 1 December 2008 and 31 January 2009. Associations between test uptake and positivity, and individuals' personal characteristics, were examined. The efficacy of partner notification was estimated, and the costs of screening were compared with the national average. Uptake of chlamydia screening was 11.5%, with lower response rates among men, individuals older than 20 years and those living in more deprived areas. The chlamydia positivity was 4.4% and higher in those reporting multiple sexual partners, individuals older than 20 years and those living in more deprived areas. The proportion of partners notified per index case was 0.17. The service contributed to 3431 of the overall 11,209 annual chlamydia screens of the Primary Care Trust in 2008-2009, at a cost of £ 78 per screening test completed and £ 1764 per case detected. Our evaluation shows that this service model can contribute substantially to the overall coverage of chlamydia screening tests. However, the costs of service provision per case detected and treated, using this model, were high compared to the National Chlamydia Screening Programme.


[Nephrolithiasis].
The development of efficacious techniques for stone elimination, and in particular of extracorporeal lithotripsy, slackened, in the last two decades, the pharmacological research on nephrolithiasis, with the result that the currently available efficacious drugs are very few. Instead, the recent elucidation of some relevant etiopathogenetic aspects, with special reference to the quantitative and qualitative changes of specific urinary inhibitors of crystallization, could open new therapeutic avenues for many lithiasic forms, now considered idiopathic.


Collagen Type III and VI Remodeling Biomarkers Are Associated with Kidney Fibrosis in Lupus Nephritis.
Lupus nephritis (LN) occurs in <40% of patients with SLE. Reliable biomarkers of kidney damage are needed to identify patients with SLE at risk of developing LN to improve screening, treat the disease earlier, and halt progression to kidney failure. Novel biomarkers of extracellular matrix remodeling were evaluated as markers of kidney fibrosis and disease activity in patients with LN. Biomarkers of the interstitial collagen type III (PRO-C3) and type VI (PRO-C6) formation and of collagen type III (C3M) degradation were evaluated in the serum and urine of 40 patients with LN, 20 patients with SLE but without LN, 20 healthy controls, and ten biopsy controls (histologic kidney inflammation/damage without SLE). Their association with histologic markers of interstitial fibrosis and tubular atrophy, with inflammatory cell infiltration and with disease activity and chronicity in the patients with LN was assessed. Despite PRO-C3 (serum) and PRO-C6 (serum and urine) being significantly elevated in patients with LN compared with healthy controls, the markers did not differentiate patients with LN from those with SLE. C3M (urine) levels were not different in LN compared with the other groups. C3M (urine) strongly correlated and PRO-C6 (serum and urine) inversely correlated with kidney function (eGFR). The biomarkers of interstitial collagen turnover PRO-C6 (serum) and C3M (urine) correlated with histologic markers of interstitial fibrosis, tubular atrophy, and monocyte infiltration. Noninvasive collagen turnover biomarkers are promising tools to identify patients with SLE with kidney histologic modifications.


Scientism as a Social Response to the Problem of Suicide.
As one component of a broader social and normative response to the problem of suicide, scientism served to minimize sociopolitical and religious conflict around the issue. As such, it embodied, and continues to embody, a number of interests and values, as well as serving important social functions. It is thus comparable with other normative frameworks and can be appraised, from an ethical perspective, in light of these values, interests, and functions. This work examines the key values, interests, and functions of scientism in suicidology and argues that although scientism has had some social benefit, it primarily serves to maintain political and professional interests and has damaging implications for suicide research and prevention.


Parenting During Residency: Providing Support for Dr Mom and Dr Dad.
Parenting during family medicine residency is increasingly common. Relatively little is known about how the competing demands of work and family life affect residents. We conducted an exploratory qualitative study of parenting family medicine residents at one program in the Midwest utilizing focus groups to understand residents' perceptions of the positive and negative characteristics of their roles as physicians and parents. We used consensus coding to identify themes in the data and then developed a model to illustrate the relationships among the identified themes. Competing demands on their time require parenting family medicine residents to often make difficult choices, which result in both positive and negative outcomes for residents, their families, and their residency experience. Parenting family medicine residents experience numerous conflicts in their concurrent roles of learner, physician, and parent. Parenting-friendly residency training programs would likely offer valuable support for these individuals during this stressful life period.


Chemiluminescence of neutrophils from patients with Behçet's disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora.
Zymosan-induced chemiluminescence was investigated in whole blood and in neutrophils: in both, the peak count was frequently elevated in Behçet's disease, and was significantly higher than in healthy controls; similarly the peak time was shorter. There were more uncommon serotypes of Streptococcus sanguis in the oral flora of patients with Behçet's disease. Common serotypes were present in the flora of healthy controls, but not in patients with the disease. The percentage of Strep. sanguis in the oral flora was significantly correlated with the level of chemiluminescence response. Thus infection with uncommon serotypes of Strep. sanguis may play a role in the aetiology of Behçet's disease.