Scleral infolding combined with vitrectomy and gas tamponade for retinal detachment with macular holes in highly myopic eyes.
To describe the effectiveness of a surgical procedure, scleral infolding combined with vitrectomy and gas tamponade, for retinal detachment caused by macular holes in highly myopic eyes. In a pilot study, scleral infolding was performed in 5 patients with macular holes, who were selected from 10 consecutive highly myopic patients with retinal detachment caused by macular holes (8 patients) or extramacular posterior-pole holes (2 patients), treated during 1 year at Okayama University Hospital. The patients were all women, 48-77 years of age (mean = 63.4 years), who had been followed-up for 1-2 years. Selection criteria for scleral infolding were either second surgeries for reopening of macular holes (2 patients) or residual retinal detachment around macular holes after complete fluid-air exchange with drainage of subretinal fluid at the initial surgery (3 patients). Following vitrectomy and complete epiretinal membrane removal in the posterior pole, the sclera was shortened by infolding on the temporal side. Three mattress sutures with 5-0 Dacron in each quadrant, 6 sutures in total, were placed at a 7-mm anteroposterior interval with posterior sutures located as deep as possible, near vortex veins. Fluid-gas exchange was then done, with or without endophotocoagulation applied around macular holes. After scleral infolding, macular holes were closed, and the retina was totally attached in all 5 patients. The final visual acuity ranged from 20/2000 to 20/70. Scleral infolding is a simple and effective procedure for treating retinal detachment with macular holes in highly myopic eyes and could be used as an optional procedure of reoperation for a failed initial vitrectomy.


Reliability of the thyromental height test for prediction of difficult visualisation of the larynx: A prospective external validation.
Thyromental height (TMH) has been reported to be useful for prediction of difficult visualisation of the larynx (DVL), defined as Cormack--Lehane (C&L) grade III or IV. The aim of this study was to compare the diagnostic accuracy of the TMH test for DVL with that of other clinically used tests in Japanese patients. Six hundred and nine surgical patients undergoing endotracheal intubation under general anaesthesia were enrolled in this prospective observational study. TMH, thyromental distance (TMD), and Samsoon and Young's modified Mallampati (MMT) tests were performed in all patients. The C&L grades for the laryngoscopic view with and without external backward, upward, rightward pressure (BURP) were determined by designated airway assessors. The cutoff value for the TMH test was calculated using receiver-operating characteristic (ROC) curve analysis. The sensitivity, specificity, positive predictive value, accuracy, positive likelihood ratio, and area under the ROC curve (AUROC) for each predictive test were calculated and compared. ROC curve analysis indicated that 54 mm is the optimal cutoff value for the TMH test. However, both this value and the conventional cutoff value of 50 mm, which has been reported as having good diagnostic accuracy in the literature, had poor diagnostic accuracy. The AUROC for the TMH test was 0.631 without BURP and 0.592 with BURP; these values were not superior to those for the TMD test or MMT. The TMH test is not a good predictor of DVL in Japanese patients.


Anaerobic respiration of Escherichia coli in the mouse intestine.
The intestine is inhabited by a large microbial community consisting primarily of anaerobes and, to a lesser extent, facultative anaerobes, such as Escherichia coli, which we have shown requires aerobic respiration to compete successfully in the mouse intestine (S. A. Jones et al., Infect. Immun. 75:4891-4899, 2007). If facultative anaerobes efficiently lower oxygen availability in the intestine, then their sustained growth must also depend on anaerobic metabolism. In support of this idea, mutants lacking nitrate reductase or fumarate reductase have extreme colonization defects. Here, we further explore the role of anaerobic respiration in colonization using the streptomycin-treated mouse model. We found that respiratory electron flow is primarily via the naphthoquinones, which pass electrons to cytochrome bd oxidase and the anaerobic terminal reductases. We found that E. coli uses nitrate and fumarate in the intestine, but not nitrite, dimethyl sulfoxide, or trimethylamine N-oxide. Competitive colonizations revealed that cytochrome bd oxidase is more advantageous than nitrate reductase or fumarate reductase. Strains lacking nitrate reductase outcompeted fumarate reductase mutants once the nitrate concentration in cecal mucus reached submillimolar levels, indicating that fumarate is the more important anaerobic electron acceptor in the intestine because nitrate is limiting. Since nitrate is highest in the absence of E. coli, we conclude that E. coli is the only bacterium in the streptomycin-treated mouse large intestine that respires nitrate. Lastly, we demonstrated that a mutant lacking the NarXL regulator (activator of the NarG system), but not a mutant lacking the NarP-NarQ regulator, has a colonization defect, consistent with the advantage provided by NarG. The emerging picture is one in which gene regulation is tuned to balance expression of the terminal reductases that E. coli uses to maximize its competitiveness and achieve the highest possible population in the intestine.


Assuring access to data for chemical evaluations.
A database for studies used for U.S. Environmental Protection Agency (EPA) pesticide and chemical reviews would be an excellent resource for increasing transparency and improving systematic assessments of pesticides and chemicals. There is increased demand for disclosure of raw data from studies used by the U.S. EPA in these reviews. Because the Information Quality Act (IQA) of 2001 provides an avenue for request of raw data, we reviewed all IQA requests to the U.S. EPA in 2002-2012 and the U.S. EPA's responses. We identified other mechanisms to access such data: public access databases, the Freedom of Information Act (FOIA), and reanalysis by a third party. Only two IQA requests to the U.S. EPA were for raw data. Both of these were fulfilled under FOIA, not the IQA. Barriers to the U.S. EPA's proactive collection of all such data include costs to the U.S. EPA and researchers, significant time burdens for researchers, and major regulatory delays. The U.S. EPA regulatory authority in this area is weak, especially for research conducted in the past, not funded by the U.S. government, and/or conducted abroad. The U.S. EPA is also constrained by industry confidential business information (CBI) claims for regulatory testing data under U.S. chemical and pesticide laws. The National Institutes of Health Clinical Trials database systematically collects statistical data about clinical trials but not raw data; this database may be a model for data from studies of chemicals and pesticides. A database that registers studies and obtains systematic sets of parameters and results would be more feasible than a system that attempts to make all raw data available proactively. Such a proposal would not obviate rights under the IQA to obtain raw data at a later point.


Whole genome sequencing of NDM-1-producing serotype K1 ST23 hypervirulent Klebsiella pneumoniae in China.
The emergence and spread of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is causing worldwide concern, whereas NDM-producing hvKP is still rare. Here we report the complete genome sequence characteristics of an NDM-1-producing ST23 type clinical hvKP in PR China. Capsular polysaccharide serotyping was performed by PCR. The complete genome sequence of isolate 3214 was obtained using both the Illumina Hiseq platform and Pacbio RS platform. Multilocus sequence type was identified by submitting the genome sequence to mlst 2.0 and the antimicrobial resistance genes and plasmid replicons were identified using ResFinder and PlasmidFinder, respectively. Transferability of the blaNDM-1-bearing plasmid was determined by conjugation experiment, S1 pulsed-field gel electrophoresis and Southern hybridization. Isolate 3214 was classified to ST23 and belonged to the K1 capsular serotype. The isolate's total genome size was 6 171 644 bp with a G+C content of 56.39 %, consisting of a 5 448 209 bp chromosome and seven plasmids. The resistome included 18 types of antibiotic resistance genes. Fourteen resistance genes including blaNDM-1 and blaCTX-M-14 were located on plasmids and five also including blaCTX-M-14 were in the chromosome. Plasmid pNDM_3214 carrying blaNDM-1 harboured six types of resistance genes surrounded by insertion sequences and was conjugative. The worldwide pLVPK-like virulence plasmid harbouring rmpA2 and rmpA was also found in this isolate. This study provides basic information of phenotypic and genomic features of ST23 CR-hvKP isolate 3214. Our data highlights the potential risk of spread of NDM-1-producing ST23 hvKP.


Management of Endometrial Hyperplasia With a Levonorgestrel-Releasing Intrauterine System: A Korean Gynecologic-Oncology Group Study.
The aim of the study was to evaluate the efficacy of the levonorgestrel intrauterine system (LNG-IUS) for treatment of endometrial hyperplasia (EH). A prospective multicenter study was conducted from November 2010 to March 2014. Patients with histologically confirmed EH were treated with LNG-IUS. At 3, 6, and 9 months after LNG-IUS insertion, follow-up endometrial aspiration biopsies with the LNG-IUS in the uterus were undertaken. At the 12th month of follow-up, endometrial tissues were obtained via 2 methods: endometrial aspiration biopsy with the LNG-IUS in the uterus, followed by dilatation and curettage (D&C) after LNG-IUS removal. The primary outcome was the regression rate at 12 months after LNG-IUS insertion, and the secondary outcome was the consistency of the results between the endometrial aspiration biopsy and the D&C. The study population comprised 75 patients, including 37 with simple hyperplasia without atypia; 3 with atypical simple hyperplasia; 23 with complex hyperplasia without atypia, and 12 with atypical complex hyperplasia. Of these patients treated with the LNG-IUS, 38 (50.7%) were followed up at 12 months after LNG-IUS insertion. The complete regression rate at 12 months was 94.7% (36/38): 100% (6/6) of patients with atypical EH and 93.7% (30/32) with EH without atypia. In all of the cases (100%, 36/36), patients achieved complete regression within 3 months of LNG-IUS insertion. A comparison of the pathologic results from endometrial aspiration biopsy and D&C was carried out for 15 patients. In the histologic results by endometrial aspiration biopsy, 14 patients were diagnosed as "normal endometrium" and 1 as "insufficient tissue for pathologic evaluation." Among the 14 cases of normal endometrium by endometrial aspiration biopsy, 1 was diagnosed as "residual EH" by D&C, and the 1 case with insufficient tissue was diagnosed as normal endometrium by D&C. Levonorgestrel intrauterine system is an effective and favorable method for treatment of EH.


Radiation dose reduction in pediatric cardiac computed tomography: experience from a tertiary medical center.
Cardiac CT angiography (cCTA) has become an established method for the assessment of congenital heart disease. However, the potential harmful effects of ionizing radiation must be considered, particularly in younger, more radiosensitive patients. In this study, we sought to assess the temporal change in radiation doses from pediatric cCTA during an 8-year period at a tertiary medical center. This retrospective study included all patients ≤18 years old who were referred to electrocardiography (ECG)-gated cCTA for the assessment of congenital heart disease or inflammatory disease (Kawasaki disease) from November 2004 to September 2012. During the study period, 95 patients were scanned using 3 different scanner models-64-slice multidetector CT (64-MDCT) and first- (64-DSCT) and second-generation (128-DSCT) dual-source CT-and 3 scan protocols-retrospective ECG-gated helical scanning (RG), prospective ECG-triggered axial scanning (PT), or prospective ECG-triggered high-pitch helical scanning (HPH). Effective dose (ED) was calculated with the dose length product method with a conversion factor (k) adjusted for age. ED was then compared among scan protocols. Image quality was extracted from clinical cCTA reports when available. Overall, 94 % of scans were diagnostic (80 % for 64-slice MDCT, 93 % for 64-slice DSCT, and 97 % for 128-slice DSCT).With 128-DSCT, median ED (1.0 [range 0.6-2.0] mSv) decreased by 85.8 % and 66.8 % compared with 64-MDCT (6.8 [range 2.9-13.6] mSv) and 64-DSCT (2.9 [range 0.9-4.1] mSv), respectively. With HPH, median ED (0.9 [range 0.6-1.8] mSv) decreased by 59.4 % and 85.4 % compared with PT (2.2 [range 0.9-3.4] mSv) and RG (6.1 [range 2.5-10.6] mSv). cCTA can now be obtained at very low radiation doses in pediatric patients using the latest dual-source CT technology in combination with prospective ECG-triggered HPH acquisition.


Effect of energetic constraints on distribution and winter survival of weasel males.
1. The absolute energy needs of small animals are generally lower than those of larger animals. This should drive higher mortality of larger animals, when the environmental conditions deteriorate. However, demonstration of the effect of energy constraints on survivals proved difficult, because the range of body mass within species is generally too small to produce enough variation for studying such an effect. An opportunity for an intraspecific study comes from weasels inhabiting the Białowieża Forest (north-eastern Poland), which are characterized by a threefold variation in body mass. 2. We assumed that in summer larger weasel males are favoured by sexual selection, because they are more successful when competing for mates. We then tested whether they suffer higher mortality in winter, because they have difficulty finding sufficient food to satisfy their energy needs and/or because the additional foraging time would result in increased exposure to predation. 3. We measured daily energy expenditures (DEE) of overwintering weasel males using the doubly labelled water (DLW) technique. We constructed an energetic model predicting how individuals of different size are able to balance their energy budgets feeding on large and small prey while minimizing time spent hunting, thereby reducing their own exposure to predation. 4. The range of body mass in overwintering weasels predicted by our model corresponded very well with the distribution of prey body mass in three different habitats within our study area. Larger individuals were able to compensate for higher food requirements by using habitats with larger prey species than those available to smaller male weasels. This effectively offset the expected negative association between body mass and winter survival predicted from considerations of energy balance. 5. Our results show how energetic constraints affect body mass and spatial segregation of a species at the intra-specific level not only across large geographical ranges, but also within a relatively small area.


Control of luteinizing hormone and testosterone secretion in a flexibly breeding male passerine, the Rufous-winged Sparrow, Aimophila carpalis.
Rufous-winged Sparrows, Aimophila carpalis, reside in the Sonoran desert and although testicular development is initiated in the spring under the influence of increasing day length, breeding occurs opportunistically in summer in association with heavy rainfall or "monsoon". The aim of this study in free-living male Rufous-winged Sparrows was to establish the relationship between concentrations of plasma luteinizing hormone (LH) and testosterone (T), and breeding associated with heavy rainfall, and to investigate whether breeding is mediated by changes in pituitary gland sensitivity to gonadotropin releasing hormone-I (GnRH) and the recently discovered avian gonadotropin-inhibitory hormone (GnIH). Concentrations of plasma LH and T were relatively low until mid-summer, but increased rapidly and transiently immediately prior to the monsoon which occurred after the summer solstice, when day lengths were decreasing. At this time the birds came into full breeding condition. An injection of chicken GnRH (10 ng) increased plasma LH within 2 min when given before or during the monsoon. An injection of GnIH (1 microg) did not affect plasma LH within 2 min during the monsoon and did not decrease GnRH-elicited LH secretion before or during the monsoon. No experimental treatment affected plasma T concentrations. The data suggest in male Rufous-winged Sparrows that the seasonal increase in plasma LH associated with summer monsoon results from increased stimulation of the pituitary gland by GnRH, rather than from a change in the responsiveness of the gland to GnRH, and that GnIH does not play an acute role in this mechanism. However, a possible chronic role for GnIH in the seasonal control of LH synthesis and secretion through an inhibitory effect on the hypothalamic GnRH system remains to be investigated.


Cloning of the neutral protease gene of Bacillus subtilis and the use of the cloned gene to create an in vitro-derived deletion mutation.
The neutral protease gene of Bacillus subtilis has been cloned, and its nucleotide sequence has been determined. The cloned gene was used to create an in vitro-derived deletion mutation, which was used to replace the wild-type copy of the gene. This deletion, in combination with a deletion of the alkaline protease gene, completely abolished protease production. The loss of the proteases had no detectable effect on growth, morphology, or sporulation.


Iatrogenic insertion of impression mould into middle ear and mastoid and its retrieval after 9 years: a case report.
The magnitude of hearing loss in Pakistan is enormous. One in twelve children of Pakistan suffers from some form of hearing impairment. Many of them are unable to afford surgical procedures and resort to the use of cheap hearing aids fitted by untrained individuals or people lacking the required expertise. This predisposes the patients to significant complications during a process that is otherwise considered safe.We report the case of a child, where the process of making the mould for a hearing aid led to the perforation of the tympanic membrane and pouring of mould material into the middle ear, necessitating surgical intervention. During initial surgery it was thought that all mould had been removed from the middle ear but 9 years later this child underwent cochlear implantation at the same center and remaining part of ear mould was discovered from mastoid cavity.


Analysis of MreB interactors in Chlamydia reveals a RodZ homolog but fails to detect an interaction with MraY.
Chlamydia is an obligate intracellular bacterial pathogen that has significantly reduced its genome in adapting to the intracellular environment. One class of genes for which the bacterium has few annotated examples is cell division, and Chlamydia lacks FtsZ, a central coordinator of the division apparatus. We have previously implicated MreB as a potential substitute for FtsZ in Chlamydia (Ouellette et al., 2012). Thus, to identify new chlamydial cell division components, we searched for proteins that interacted with MreB. We performed a small-scale screen using a Gateway® compatible version of the Bacterial Adenylate Cyclase Two Hybrid (BACTH) system, BACTHGW, to detect proteins interacting with chlamydial MreB and identified a RodZ (YfgA) homolog. The chlamydial RodZ aligns well with the cytoplasmic domain of E. coli RodZ but lacks the periplasmic domain that is dispensable for rod cell shape maintenance in E. coli. The expression pattern of yfgA/rodZ was similar to that of mreB and ftsI, suggesting that these genes may operate in a common functional pathway. The chlamydial RodZ correctly localized to the membrane of E. coli but was unable to complement an E. coli rodZ mutant strain, likely because of the inability of chlamydial RodZ to interact with the native E. coli MreB. Finally, we also tested whether chlamydial MreB could interact with MraY, as suggested by Gaballah et al. (2011). However, we did not detect an interaction between these proteins even when using an implementation of the BACTH system to allow native orientation of the N- and C-termini of MraY in the periplasm. Thus, further work will be needed to establish this proposed interaction. In sum, we have added to the repertoire of potential cell division proteins of Chlamydia.


NRG1-ErbB signalling promotes microglia activation contributing to incision-induced mechanical allodynia.
Spinal microglia activation is one of the pathologic mechanisms involved in post-operative pain, which results from surgical injuries in skin, fascia, muscle and small nerves innervating these tissues. Recent research has shown that neuregulin-1 (NRG1) and its receptor erythroblastosis oncogene B (ErbB) family mediate microglia proliferation and chemotaxis contributing to the development of neuropathic pain. However, it is unclear whether NRG1-ErbB signalling contributes to incision-induced mechanical allodynia. Expressions of NRG1, ErbB2 and activation of microglia in spinal cord following paw plantar incision in an incision-induced mechanical allodynia model were detected with real-time PCR, Western blot and immunofluorescence staining. Altered mechanical pain and spinal microglia activation were observed by pharmacologically blocking of NRG1-ErbB signalling or down-regulation of NRG1 types I and II via small interfering RNA (siRNA) intervention. NRG1-ErbB signalling mediated incision-induced microglia activation and mechanical allodynia. Expressions of types I and II NRG1 in L5 dorsal root ganglion at RNA level and in spinal cord at protein level were dramatically increased after paw incision. Pharmacologically blocking of NRG1-ErbB signalling by ErbB inhibitor and down-regulation, the expression of NRG1 types I and II via siRNA suppressed incision-induced microglia activation and alleviated mechanical allodynia. Incision-induced NRG1 expression mediated activation of dorsal horn microglia and contributed to the development of mechanical allodynia. Specifically targeting NRG1-ErbB signalling may therefore provide a new therapeutic intervention for relieving incision-induced mechanical allodynia.


Clentiazem reduces infarct size in rabbit middle cerebral artery occlusion.
We assessed the value of pretreatment with clentiazem (8-chlorodiltiazem), a diltiazem derivative with cerebroselective properties, on the consequences of surgical occlusion of the middle cerebral artery via a transorbital approach in 38 rabbits. Nineteen rabbits received 1.7 (n = 5), 5 (n = 8), or 15 (n = 6) mg/kg clentiazem orally four times a day for 24 hours before and 48 hours after occlusion. Upon sacrifice, a segment of the right middle cerebral artery distal to the occlusion and a corresponding segment from the nonoccluded left middle cerebral artery were mounted on myographs for in vitro study of their reactivity to histamine, acetylcholine, serotonin, norepinephrine, and electrical stimulation of intramural sympathetic nerves. Morphometric measurements of 2,3,5-triphenyltetrazolium chloride-stained brain slices permitted us to estimate infarct volume. Pretreatment with 1.7, 5, and 15 mg/kg clentiazem significantly reduced infarct volume (p less than 0.05, p less than 0.01, and p less than 0.01, respectively). Mean infarct volume of the 15 mg/kg-treated group was only 4% that of the untreated group. There were no postoperative deaths in any treated group compared with a death rate of 36% in the untreated group. Mean values for vascular smooth muscle contractility to histamine and relaxation to acetylcholine were significantly enhanced in vessels from treated rabbits. These studies indicate that pretreatment with clentiazem offers cerebral protection and significantly reduces infarct volume as well as arterial wall damage beyond the occlusion.


Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase.
In eukaryotic cells, newly synthesized histone H4 is acetylated at lysines 5 and 12, a transient modification erased by deacetylases shortly after deposition of histones into chromosomes. Genetic studies in Saccharomyces cerevisiae revealed that acetylation of newly synthesized histones H3 and H4 is likely to be important for maintaining cell viability; the precise biochemical function of this acetylation is not known, however. The identification of enzymes mediating site-specific acetylation of H4 at Lys5 and Lys12 may help explain the function of the acetylation of newly synthesized histones. A cDNA encoding the catalytic subunit of the human Hat1 acetyltransferase was cloned and, using specific antibodies, the Hat1 holoenzyme was purified from human 293 cells. The human enzyme acetylates soluble but not nucleosomal H4 at Lys5 and Lys12 and acetylates histone H2A at Lys5. Unexpectedly, we found Hat1 in the nucleus of S-phase cells. Like its yeast counterpart, the human holoenzyme consists of two subunits: a catalytic subunit, Hat1, and a subunit that binds core histones, p46, which greatly stimulates the acetyltransferase activity of Hat1. Both p46 and the highly related p48 polypeptide (the small subunit of human chromatin assembly factor 1; CAF-1) bind directly to helix 1 of histone H4, a region that is not accessible when H4 is in chromatin. We suggest that p46 and p48 are core-histone-binding subunits that target chromatin assembly factors, chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA.


Fluorescence correlation spectroscopy study of the complexation of DNA hybrids, IgG antibody, and a chimeric protein of IgG-binding ZZ domains fused with a carbohydrate binding module.
Fluorescence correlation spectroscopy (FCS) was used to characterize the molecular interactions between the four components of a DNA recognition system. A fluorescent DNA probe was used to assess: (i) the hybridization with a complementary biotin-labeled target, (ii) the complexation of the resulting hybrid and an anti-biotin antibody, and (iii) the binding of the latter complex to a ZZ-CBM fusion protein that combines small synthetic IgG Fc-binding Z domains with a carbohydrate binding module (CBM). These binding interactions were monitored by exposing the fluorescent DNA probe to different amounts and combinations of the other molecules in solution. Through the analysis of FCS autocorrelation curves, an association constant (Ka) of 2.9 × 107 M-1 was estimated for DNA·DNA hybridization, and the presence of (non-) complementary target DNA in solution could be discriminated. The specific capture of biotinylated DNA hybrids by anti-biotin IgG was verified, with an apparent Ka of 2.5 × 106 M-1. The increment in the diffusion time measured when the DNA·DNA:antibody complexes were in contact with the ZZ-CBM fusion protein suggested that the binding occurs at a stoichiometric ratio of DNA/antibody complex to fusion larger than 1 : 1. The FCS-derived information obtained is useful to gain insight into molecular interactions involved in diagnostic assays.


Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme.
Biotin-dependent multifunctional enzymes carry out metabolically important carboxyl group transfer reactions and are potential targets for the treatment of obesity and type 2 diabetes. These enzymes use a tethered biotin cofactor to carry an activated carboxyl group between distantly spaced active sites. The mechanism of this transfer has remained poorly understood. Here we report the complete structure of pyruvate carboxylase at 2.0 angstroms resolution, which shows its domain arrangement. The structure, when combined with mutagenic analysis, shows that intermediate transfer occurs between active sites on separate polypeptide chains. In addition, domain rearrangements associated with activator binding decrease the distance between active-site pairs, providing a mechanism for allosteric activation. This description provides insight into the function of biotin-dependent enzymes and presents a new paradigm for multifunctional enzyme catalysis.


Postoperative Complications, In-Hospital Mortality and 5-Year Survival After Surgical Resection for Patients with a Pancreatic Neuroendocrine Tumor: A Systematic Review.
Studies on postoperative complications and survival in patients with pancreatic neuroendocrine tumors (pNET) are sparse and randomized controlled trials are not available. We reviewed all studies on postoperative complications and survival after resection of pNET. A systematic search was performed in the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE from 2000-2013. Inclusion criteria were studies of resected pNET, which described postoperative complications separately for each surgical procedure and/or 5-year survival after resection. Prospective and retrospective studies were pooled separately and overall pooled if heterogeneity was below 75%. The random-effect model was used. Overall, 2643 studies were identified and after full-text analysis 62 studies were included. Pancreatic fistula (PF) rate of the prospective studies after tumor enucleation was 45%; PF-rates after distal pancreatectomy, pancreatoduodenectomy, or central pancreatectomy were, respectively, 14-14-58%. Delayed gastric emptying rates were, respectively, 5-5-18-16%. Postoperative hemorrhage rates were, respectively, 6-1-7-4%. In-hospital mortality rates were, respectively, 3-4-6-4%. The 5-year overall survival (OS) and disease-specific survival (DSS) of resected pNET without synchronous resected liver metastases were, respectively, 85-93%. Heterogeneity between included studies on 5-year OS in patients with synchronous resected liver metastases was too high to pool all studies. The 5-year DSS in patients with liver metastases was 80%. Morbidity after pancreatic resection for pNET was mainly caused by PF. Liver resection in patients with liver metastases seems to have a positive effect on DSS. To reduce heterogeneity, ISGPS criteria and uniform patient groups should be used in the analysis of postoperative outcome and survival.


Comparative analysis of vascular bulldog clamps used in robot-assisted partial nephrectomy.
During robot-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN), clamping of the vascular pedicle before excision of the tumor is the key to minimize blood loss and maintain adequate visualization. Multiple options for hilar control exist, including recently introduced robot-specific bulldog vascular clamps. The relative efficacy of these new clamps has not been assessed. We conducted a comparative analysis of robotic and laparoscopic vascular clamps focusing on clamp force and flow across a clamped model vessel. We compared 10 different vascular clamps used in RAPN and LPN: The Klein robotic; Klein laparoscopic short, medium straight, medium curved, and long; Aesculap short straight, short curved, long straight and long curved; and a laparoscopic Satinsky clamp. Force testing was performed at 1 cm and 2 cm distances from the fulcrum and at the tip. To simulate a clamped vessel, a quarter inch Penrose was clamped and the proximal end attached to a pressure flow monitor. Flow across the tubing at various pressures and leak point pressure (LPP) were recorded. Comparative analysis was conducted using descriptive statistics and t tests. The Klein robotic clamp exerted significantly less clamp force along the length of the clamp compared with the laparoscopic placed Klein, Aesculap, and Satinsky clamps (P<0.001). In our vascular model, the Klein robotic clamp had a LPP of 8.3 mm Hg vs 36.3 mm Hg (Klein lap) and >170 mm Hg (Aesculap) (P<0.001). At all pressures, the robotic clamp allowed more flow compared with laparoscopic clamps. Robotic vascular bulldog clamps produce significantly less clamping force than laparoscopic bulldog or Satinksy clamps and thus allow more flow across the clamped segment. This difference appears to be intrinsic to the clamp itself. This may translate into poorer hemostasis intraoperatively.


Safety of the Combination of PERC and YEARS Rules in Patients With Low Clinical Probability of Pulmonary Embolism: A Retrospective Analysis of Two Large European Cohorts.
This study aimed to determine the failure rate of a combination of the PERC and the YEARS rules for the diagnosis of pulmonary embolism (PE) in the emergency department (ED). We performed a retrospective analysis of two European cohorts of emergency patients with low gestalt clinical probability of PE (PROPER and PERCEPIC). All patients we included were managed using a conventional strategy (D-dimer test, followed, if positive, by computed tomographic pulmonary angiogram (CTPA). We tested a diagnostic strategy that combined PERC and YEARS to rule out PE. The primary endpoint was a thromboembolic event diagnosed in the ED or at 3-months follow-up. Secondary endpoints included a thromboembolic event at baseline in the ED and a CTPA in the ED. Ninety-five percent confidence intervals (CIs) of proportions were calculated with the use of Wilson's continuity correction. We analyzed 1,951 patients (mean ± SD age = 47 ± 18 years, 56% women) with an overall proportion of patients with PE of 3.5%. Both PERC and YEARS strategies were associated with 11 missed PE in the ED: failure rate 0.57 (95% CI = 0.32-1.02). At 3-month follow-up, the overall failure rate was 0.83% (95% CI = 0.51-1.35). Among the 503 patients who underwent a CTPA (26%), the use of the PERC-YEARS combination would have ruled out PE without CTPA in 249 patients (50% [95%CI = 45%-54%], absolute reduction 13% (95% CI = 11%-14%]). The combination of PERC then YEARS was associated with a low risk of PE diagnostic failure and would have resulted in a relative reduction of almost half of CTPA.


TNFA -308G>A in two international population-based cohorts and risk of asthma.
Genetic association studies have related the tumour necrosis factor-alpha gene (TNFA) guanine to adenine substitution of nucleotide -308 (-308G>A) polymorphism to increased risk of asthma, but results are inconsistent. The aim of the present study was to test whether two single-nucleotide polymorphisms, of TNFA and of the lymphotoxin-alpha gene (LTA), are associated with asthma, bronchial hyperresponsiveness and atopy in adults, by combining the results of two large population-based multicentric studies and conducting a meta-analysis of previously published studies. The European Community Respiratory Health Survey (ECRHS) and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) used comparable protocols, including questionnaires for respiratory symptoms and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped at TNFA -308 and LTA 252. Logistic regression employing fixed and random effects models and nonparametric techniques were used. The prevalence of asthma was 6%. The TNFA -308G>A polymorphism was associated with increased asthma prevalence and with bronchial hyperresponsiveness. No consistent association was found for atopy. The LTA 252A>G polymorphism was not associated with any of the outcomes. A meta-analysis of 17 studies showed an increased asthma risk for the TNFA -308 adenine allele. The tumour necrosis factor-alpha gene nucleotide -308 polymorphism is associated with a moderately increased risk of asthma and bronchial hyperresponsiveness, but not with atopy. These results are supported by a meta-analysis of previously published studies.


Expression of the heat shock protein HSP27 in human ovarian cancer.
The relationship of the heat shock protein HSP27 in ovarian cancer to several biological and clinical parameters was investigated in a series of primary tumors and cell lines. Analysis of 72 primary tumors (54 malignant, 5 borderline, and 13 benign neoplasms) indicated that malignant tumors expressed higher HSP27 concentrations than benign tumors (median values, 0.56 versus 0.25 ng/microgram cytosolic protein; P = 0.032). Tumors from patients with advanced stage (stages II, III, or IV) disease contained significantly higher HSP27 concentrations than tumors from stage I patients (P = 0.018), and an HSP27 content >2.0 ng/microgram cytosolic protein was associated with reduced survival (P = 0.03). Tumors that had demonstrated progressive growth after chemotherapy had a significantly higher HSP27 content than tumors that were static or responsive (P = 0.022). These data indicate that HSP27 is associated with more aggressive malignant ovarian disease and with inherent resistance to chemotherapy. Concentrations of HSP27 were also correlated with indicators of estrogen sensitivity. Therefore, the HSP27 concentration correlated with the estrogen receptor (all tumors, P = 0.0014; malignant tumors only, P = 0.047) but not with the progesterone receptor concentration. Analysis of ovarian cancer cell lines in vitro and in vivo indicated that the HSP27 content was higher in cell lines that were estrogen receptor rich and whose growth was modulated by estrogen as compared with those that were not. Additionally, two estrogen receptor-rich ovarian carcinoma lines demonstrated a small but significant decrease in HSP27 levels in response to 17beta-estradiol in culture. These results suggest that HSP27 may help identify tumors responsive to estrogens.


Clonal alteration of breast cancer receptors between primary ductal carcinoma in situ (DCIS) and corresponding local events.
Emerging data propose biomarker alteration due to clonal selection between the primary invasive breast cancer and corresponding metastases. In addition, impact on survival has been demonstrated. The present study investigates the relationship between the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between primary ductal carcinoma in situ (DCIS) and intra-individually matched ipsilateral event. The cohort includes 1504 patients, diagnosed with a primary DCIS between 1986 and 2004. Of the 274 patients who developed a local relapse, 135 developed a new in situ carcinoma and 139 an invasive cancer up to 31st December 2011. ER and PR were identified by immunohistochemistry (IHC) and HER2 by silver-enhanced in situ hybridisation (SISH) as well as IHC. ER (n=112), PR (n=113) and HER2 (n=114) status from both the primary DCIS and the corresponding relapse were assessed and were demonstrated to be discordant in 15.1%, 29.2% and 10.5% respectively. The receptor conversion was both from negative to positive and from positive to negative with no general pattern being seen in spite of sub-dividing into in situ relapse and invasive relapse. However, primary DCIS was HER2 positive in 40.3% whereas in situ and invasive relapses were HER2 positive in 42.9% and 34.5% respectively. Receptor conversion for ER, PR and HER2 status occurred between primary DCIS and corresponding local relapse in 10-30%. This study could not confirm that HER2 overexpression in primary DCIS had any impact on tumour progression to invasive cancer which has been proposed.


Lenalidomide for the Treatment of Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated with Deletion 5q Cytogenetic Abnormality: An Evidence Review of the NICE Submission from Celgene.
The National Institute for Health and Care Excellence (NICE) invited the manufacturer of lenalidomide (Celgene) to submit evidence of the clinical and cost effectiveness of the drug for treating adults with myelodysplastic syndromes (MDS) associated with deletion 5q cytogenetic abnormality, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and the NICE's subsequent decisions. The ERG reviewed the evidence for clinical and cost effectiveness of the technology, as submitted by the manufacturer to the NICE. The ERG searched for relevant additional evidence and validated the manufacturer's decision analytic model to examine the robustness of the cost-effectiveness results. Clinical effectiveness was obtained from a three-arm, European, randomized, phase III trial among red blood cell (RBC) transfusion-dependent patients with low-/intermediate-1-risk del5q31 MDS. The primary endpoint was RBC independence for ≥26 weeks, and was reached by a higher proportion of patients in the lenalidomide 10 and 5 mg groups compared with placebo (56.1 and 42.6 vs 5.9 %, respectively; both p < 0.001). The option of dose adjustments after 16 weeks due to dose-limiting toxicities or lack of response made long-term effectiveness estimates unreliable, e.g. overall survival (OS). The de novo model of the manufacturer included a Markov state-transition cost-utility model implemented in Microsoft Excel. The base-case incremental cost-effectiveness ratio (ICER) of the manufacturer was £56,965. The ERG assessment indicated that the modeling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. In response to the appraisal documentation, the company revised the economic model, which increased the ICER to £68,125 per quality-adjusted life-year. The NICE Appraisal Committee (AC) did not recommend lenalidomide as a cost-effective treatment. Subsequently, the manufacturer submitted a Patient Access Scheme (PAS) that provided lenalidomide free of charge for patients who remained on treatment after 26 cycles. This PAS improved the ICER to £25,300, although the AC considered the proportion of patients who received treatment beyond 26 cycles, and hence the ICER, to be uncertain. Nevertheless, the AC accepted a commitment from the manufacturer to publish, once available, data on the proportion of patients eligible for the PAS, and believed this provided reassurance that lenalidomide was a cost-effective treatment for low- or intermediate-1-risk MDS patients.


Avoiding Pitfalls and Realising Opportunities: Reflecting on Issues of Sampling and Recruitment for Online Focus Groups.
The increasing prominence of the Internet in everyday life has prompted methodological innovations in qualitative research, particularly the adaptation of established methods of data collection for use online. The alternative online context brings with it both opportunities and challenges. To date the literature on online focus groups has focused mainly on the suitability of the method for qualitative data collection, and the development of approaches to facilitation that maximise interaction. By reflecting on our experiences of designing and attempting to recruit participants to online focus groups for two exploratory research projects, we aim to contribute some novel reflections around the less articulated issues of sampling and recruitment for online focus groups. In particular, we highlight potentially problematic issues around offline recruitment for an online method of data collection; the potential of using social media for recruitment; and the uncertainties around offering incentives in online recruitment, issues which have received little attention in the growing literature around online focus groups. More broadly, we recommend continued examination of online social practices and the social media environment to develop appropriate and timely online recruitment strategies and suggest further areas for future research and innovation.


The distribution of PAX-2 immunoreactivity in the prostate gland, seminal vesicle, and ejaculatory duct: comparison with prostatic adenocarcinoma and discussion of prostatic zonal embryogenesis.
PAX-2 is a homeogene strongly expressed during development of the genitourinary tract, including the kidney and both wolffian- and müllerian-derived tissues. Expression of PAX-2 by immunohistochemistry has been studied mainly in renal epithelial neoplasms with little attention to the lower male genitourinary tract. We studied PAX-2 expression in epithelium of normal seminal vesicle, normal ejaculatory duct, normal prostatic secretory epithelium, and prostatic adenocarcinoma to define its immunoreactivity pattern throughout the prostate gland and to evaluate its potential diagnostic role in the discrimination of seminal vesicle/ejaculatory duct epithelium from prostatic adenocarcinoma. In addition, given that PAX-2 is highly expressed in tissues of wolffian duct embryologic origin, we also sought to confirm the divergent embryogenesis of the central zone, seminal vesicle, and ejaculatory duct from other regions of the prostate. Prostatectomy specimens from 12 patients were reviewed to identify blocks containing seminal vesicle, ejaculatory duct, periurethral glands, benign prostatic glands, and prostatic acinar adenocarcinoma. A total of 35 blocks from the 12 patients were evaluated. In addition, 2 tissue microarrays representing 15 additional seminal vesicles and 45 prostatic adenocarcinomas, 7 whole sections from prostatic adenocarcinomas of the central zone, and 5 core needle biopsies of seminal vesicle were also evaluated with anti-PAX-2 antibody. In the 12 radical prostatectomy whole sections, nuclear reactivity for PAX-2 was identified in 12 (100%) of 12 of the seminal vesicle epithelium, 9 (90%) of 10 of the ejaculatory duct epithelium, 0 of 12 of the prostatic adenocarcinoma, and 0 of 6 of the high-grade prostatic intraepithelial neoplasia. All 20 total additional seminal vesicles were positive for PAX-2 in the tissue microarray and biopsies; and all 52 additional prostatic adenocarcinomas were negative, including 7 of central zone origin. The staining intensity and percentage of immunoreactive cells in seminal vesicle were both 3+ in all cases. Although the ejaculatory ducts also showed diffuse staining, their staining intensity was less (2+) than that in the seminal vesicles, particularly in the ejaculatory ducts in the periurethral area (1-2+intensity). The smaller glands surrounding the main seminal vesicle duct also showed less intense staining than the luminal cells of the main duct. Of the 19 total cases with evaluable central zone glands, 2 (10.5%) had focal nuclear reactivity in normal, benign prostatic secretory cells. All other benign prostatic secretory epithelia from the peripheral and transition zones were negative for PAX-2. In conclusion, nuclear PAX-2 immunoreactivity is typical in epithelium of the seminal vesicle and ejaculatory duct; but the intensity of staining is less in the ejaculatory duct. No reactivity for PAX-2 was seen in prostatic adenocarcinoma or high-grade prostatic intraepithelial neoplasia. PAX-2 has diagnostic utility as a positive immunohistochemical marker of seminal vesicle and ejaculatory duct epithelium. In addition, these data add further support to the proposed embryogenesis of the prostatic central zone, seminal vesicle, and ejaculatory ducts from the wolffian system.


Assessment of virally vectored autoimmunity as a biocontrol strategy for cane toads.
The cane toad, Bufo (Chaunus) marinus, is one of the most notorious vertebrate pests introduced into Australia over the last 200 years and, so far, efforts to identify a naturally occurring B. marinus-specific pathogen for use as a biological control agent have been unsuccessful. We explored an alternative approach that entailed genetically modifying a pathogen with broad host specificity so that it no longer caused disease, but carried a gene to disrupt the cane toad life cycle in a species specific manner. The adult beta globin gene was selected as the model gene for proof of concept of autoimmunity as a biocontrol method for cane toads. A previous report showed injection of bullfrog tadpoles with adult beta globin resulted in an alteration in the form of beta globin expressed in metamorphs as well as reduced survival. In B. marinus we established for the first time that the switch from tadpole to adult globin exists. The effect of injecting B. marinus tadpoles with purified recombinant adult globin protein was then assessed using behavioural (swim speed in tadpoles and jump length in metamorphs), developmental (time to metamorphosis, weight and length at various developmental stages, protein profile of adult globin) and genetic (adult globin mRNA levels) measures. However, we were unable to detect any differences between treated and control animals. Further, globin delivery using Bohle iridovirus, an Australian ranavirus isolate belonging to the Iridovirus family, did not reduce the survival of metamorphs or alter the form of beta globin expressed in metamorphs. While we were able to show for the first time that the switch from tadpole to adult globin does occur in B. marinus, we were not able to induce autoimmunity and disrupt metamorphosis. The short development time of B. marinus tadpoles may preclude this approach.


Reversible folding of Ada protein (O6-methylguanine-DNA methyltransferase) of Escherichia coli.
The multifunctional 39 kDa Escherichia coli Ada protein (O6-methylguanine-DNA methyltransferase) (EC 22.214.171.124), product of the ada gene, is a monomeric globular polypeptide with two distinct alkylacceptor activities located in two domains. The two domains are of nearly equal size and are connected by a hinge region. The Ada protein accepts stoichiometrically the alkyl group from O6-alkylguanine in DNA at the Cys-321 residue and from alkyl phosphotriester at the Cys-69 residue. This protein functions in DNA repair by direct dealkylation of mutagenic O6-alkylguanine. The protein methylated at Cys-69 becomes a transcriptional activator of the genes in the ada regulon, including its own. Each of the two domains functions independently as an alkyl acceptor. The purified homogeneous protein is unstable at 37 degrees C and spontaneously loses about 30% of its secondary structure in less than 30 min concomitant with a complete loss of activity. However, sedimentation equilibrium studies indicated that the inactive protein remains in the monomeric form without aggregation. Furthermore, electrospray mass spectroscopic analysis indicated the absence of oxidation of the inactive protein. This temperature-dependent inactivation of the Ada protein is inhibited by DNA. In the presence of increasing concentrations of urea or guanidine, the protein gradually loses more than 80% of its structure. The two alkyl acceptor activities appear to be differentially sensitive to unfolding and the phosphotriester methyltransferase activity is resistant to 7 M urea. The partial or complete unfolding induced by urea or guanidine is completely reversed within seconds by removal of the denaturant. The heat-coagulated protein can also be restored to full activity by cycling it through treatment with 8 M urea or 6 M guanidine. These results suggest that the nascent or unfolded Ada polypeptide folds to a metastable form which is active and that the thermodynamically stable structure is partially unfolded and inactive.


Integrated microinterferometric sensor for in-plane displacement measurement.
We present an integrated sensor based on a grating interferometer (GI) for in-plane displacement measurement in microregions of large engineering structures. The system concept and design, based on a monolithic version of Czarnek's GI, is discussed in detail. The technology chain of the GI measurement head (MH), including the master fabrication and further replication by means of hot embossing, is described. The numerical analyses of the MH by means of geometric ray tracing and scalar wave propagation are provided. They allow us to determine geometrical tolerance values as well as refractive index homogeneity and nonflatness of MH working surfaces, which provide proper beam guiding. Finally the demonstrative measurement performed with a model of the sensor is presented.


Sexually abstinent African American adolescent females' descriptions of abstinence.
To describe sexual abstinence from the perspective of abstinent African American female adolescents. Descriptive qualitative. Data were collected from 14 sexually abstinent, African American adolescent girls during two semi-structured interviews. Data were collected using the life history method and were analyzed in the style of narrative analysis. This analysis indicated four themes in descriptions of abstinence: limited information, categorization of sexual behaviors, activities that lead to intercourse, and abstinence as a self-determined choice. For most participants, "having sex" referred to heterosexual vaginal intercourse and being abstinent meant that one chose to refrain from intercourse. The participants' limited definition of abstinence might lead them to unknowingly put themselves at risk by engaging in other forms of genital sexual activities. They may think that they are protected because they believe that they are practicing abstinence.


Yoga reduces inflammatory signaling in fatigued breast cancer survivors: a randomized controlled trial.
Yoga is a popular mind-body therapy that has demonstrated beneficial effects on psychological, behavioral, and functional outcomes. However, few studies have investigated effects on inflammatory processes. This study tested the hypothesis that an Iyengar yoga intervention specifically designed for fatigued breast cancer survivors would lead to decreases in inflammation-related gene expression and circulating markers of proinflammatory cytokine activity. Breast cancer survivors with persistent cancer-related fatigue were randomized to a 12-week Iyengar yoga intervention (n=16) or a 12-week health education control condition (n=15). Blood samples were collected at baseline, post-intervention, and at a 3-month follow-up for genome-wide transcriptional profiling and bioinformatic analyses. Plasma inflammatory markers and salivary cortisol were also assessed. In promoter-based bioinformatics analyses, the yoga group showed reduced activity of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB), increased activity of the anti-inflammatory glucocorticoid receptor, and reduced activity of cAMP response element-binding protein (CREB) family transcription factors relative to controls (all ps<.05). There was also a significant intervention effect on the soluble tumor necrosis factor receptor type II (sTNF-RII), a marker of TNF activity; plasma levels of sTNF-RII remained stable in the yoga group, whereas levels of this marker increased in the health education group (p=.028). A similar, non-significant trend was observed for the interleukin 1 receptor antagonist (p=.16). No significant changes in C reactive protein (CRP), interleukin 6 (IL-6), or diurnal cortisol measures were observed. A 12-week restorative Iyengar yoga intervention reduced inflammation-related gene expression in breast cancer survivors with persistent fatigue. These findings suggest that a targeted yoga program may have beneficial effects on inflammatory activity in this patient population, with potential relevance for behavioral and physical health.


Role of the pulsed dye laser in the management of ulcerated capillary haemangiomas.
A complication of capillary haemangiomas is ulceration, which may arise after trauma and/or infection. Until recently, conservative management was the rule. However, the recent advent of the pulsed dye laser has revolutionised the treatment of vascular birthmarks and provided a new tool for the management of capillary haemangiomas. Thirteen cases of ulcerated capillary haemangiomas referred to our department were reviewed; five were treated conservatively and eight were treated with the laser. Those treated with the laser had all failed conservative management and healed completely within one to four weeks. Remarkably rapid alleviation of pain was achieved. For those haemangiomas around the mouth and perineum, laser treatment enabled early restoration of normal feeding, micturition, and defaecation. It is therefore recommended that if ulcerated capillary haemangiomas do not improve after a short period of optimal conservative treatment, laser treatment should be considered.


Inequitable Gender Norms From Early Adolescence to Young Adulthood in Uganda: Tool Validation and Differences Across Age Groups.
We aimed to describe and compare gender norms among 10- to 14-year-olds versus 15- to 24-year-olds and to conduct a rigorous evaluation of the GEM Scale's performance among these two age groups. We conducted a two-stage cluster-sampled survey among 387 females and 583 males, aged 10-24 years, in rural and urban communities near Kampala, Uganda. We applied, assessed, and adapted the GEM Scale (Pulerwitz and Barker, 2008), which measures views toward gender norms in four domains. We describe levels of support for (in)equitable norms, by gender and age, and associations with key health outcomes (partner violence). Confirmatory factor analysis and multi-group measurement invariance analysis were used to assess scale performance. All participants reported high levels of support for inequitable gender norms; 10- to 14-year-olds were less gender equitable than their older counterparts. For example, 74% of 10- to 14-year-olds and 67% of 15- to 24-year-olds agreed that "a woman should tolerate violence to keep her family together." Comparing responses from males and females indicated similar support for gender inequity. Analyses confirmed a one-factor model, good scale fit for both age groups, and that several items from the scale could be dropped for this sample. The ideal list of items for each age group differed somewhat but covered all four scale domains in either case. An 18-item adapted scale was used to compare mean GEM Scale scores between the two age groups; responses were significantly associated with early sexual debut and partner violence. Young people internalize gender norms about sexual and intimate relationships, and violence, at early ages. Programs to address negative health outcomes should explicitly address inequitable gender norms and more consistently expand to reach younger age groups. In this first application of the GEM Scale among 10- to 14-year-olds, we confirm that it is a valid measure in this setting.


Climate change impact on neotropical social wasps.
Establishing a direct link between climate change and fluctuations in animal populations through long-term monitoring is difficult given the paucity of baseline data. We hypothesized that social wasps are sensitive to climatic variations, and thus studied the impact of ENSO events on social wasp populations in French Guiana. We noted that during the 2000 La Niña year there was a 77.1% decrease in their nest abundance along ca. 5 km of forest edges, and that 70.5% of the species were no longer present. Two simultaneous 13-year surveys (1997-2009) confirmed the decrease in social wasps during La Niña years (2000 and 2006), while an increase occurred during the 2009 El Niño year. A 30-year weather survey showed that these phenomena corresponded to particularly high levels of rainfall, and that temperature, humidity and global solar radiation were correlated with rainfall. Using the Self-Organizing Map algorithm, we show that heavy rainfall during an entire rainy season has a negative impact on social wasps. Strong contrasts in rainfall between the dry season and the short rainy season exacerbate this effect. Social wasp populations never recovered to their pre-2000 levels. This is probably because these conditions occurred over four years; heavy rainfall during the major rainy seasons during four other years also had a detrimental effect. On the contrary, low levels of rainfall during the major rainy season in 2009 spurred an increase in social wasp populations. We conclude that recent climatic changes have likely resulted in fewer social wasp colonies because they have lowered the wasps' resistance to parasitoids and pathogens. These results imply that Neotropical social wasps can be regarded as bio-indicators because they highlight the impact of climatic changes not yet perceptible in plants and other animals.


Controlling the transverse localization of THz waves in an InSb based disordered waveguide array using temperature.
We propose that the transverse localization in a semiconductor-based disordered waveguide array can be made controllable in the terahertz (THz) regime by changing the ambient temperature. The standard scalar Helmholtz equation is used to describe THz wave propagation through the waveguide array. It is assumed that the waveguides are fabricated from the indium-antimonide (InSb) semiconductor, while the spacing between them is a dielectric. Disorder is introduced in the system by the random refractive index of the spacing medium. Our results demonstrate that the transverse width of the output intensity increases when increasing the temperature. This effect is attributed to the temperature-dependent electric permittivity of the used semiconductor. Then, the waveguides are composed of a dielectric and the spacing between them is filled with the InSb semiconductor. For this case, to introduce disorder, we assumed that the refractive indices of the waveguides are randomized. It is found that the output intensity becomes more localized with increasing temperature. However, further increasing the temperature leads to the delocalization of output intensity. The effect of spacing between adjacent waveguides on the threshold degree of disorder has also been investigated.


Chiral Spin Mode on the Surface of a Topological Insulator.
Using polarization-resolved resonant Raman spectroscopy, we explore collective spin excitations of the chiral surface states in a three dimensional topological insulator, Bi_{2}Se_{3}. We observe a sharp peak at 150 meV in the pseudovector A_{2} symmetry channel of the Raman spectra. By comparing the data with calculations, we identify this peak as the transverse collective spin mode of surface Dirac fermions. This mode, unlike a Dirac plasmon or a surface plasmon in the charge sector of excitations, is analogous to a spin wave in a partially polarized Fermi liquid, with spin-orbit coupling playing the role of an effective magnetic field.


Light absorption in hybrid silicon-on-insulator/quantum dot waveguides.
We analyze the absorption coefficient of planarized silicon-on-insulator waveguides coated by close packed mono- and multilayers of colloidal PbS/CdS quantum dots (QDs). Experimental data clearly show the influence of the QDs on the waveguide absorbance around 1500 nm, where we find that QDs absorb stronger in thicker layers. To simulate the absorption coefficient of QD functionalized waveguides, the QD layer is replaced by an effective medium with a dielectric function determined by dipolar coupling between neighbouring QDs. Using the host dielectric constant εh as an adjustable parameter, excellent agreement with the experimental results is obtained. In this way, the increase in absorption cross section with layer thickness can be traced back to an increasing εh. We argue that this reflects the decreasing influence of the surroundings on the εh, which therefore evolves from an extrinsic property for monolayers to a more intrinsic film property for multilayers.


Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis.
Ataxia-telangiectasia mutated (ATM) kinase orchestrates nuclear DNA damage responses but is proposed to be involved in other important and clinically relevant functions. Here, we provide evidence for what we believe are 2 novel and intertwined roles for ATM: the regulation of ribonucleotide reductase (RR), the rate-limiting enzyme in the de novo synthesis of deoxyribonucleoside triphosphates, and control of mitochondrial homeostasis. Ataxia-telangiectasia (A-T) patient fibroblasts, wild-type fibroblasts treated with the ATM inhibitor KU-55933, and cells in which RR is inhibited pharmacologically or by RNA interference (RNAi) each lead to mitochondrial DNA (mtDNA) depletion under normal growth conditions. Disruption of ATM signaling in primary A-T fibroblasts also leads to global dysregulation of the R1, R2, and p53R2 subunits of RR, abrogation of RR-dependent upregulation of mtDNA in response to ionizing radiation, high mitochondrial transcription factor A (mtTFA)/mtDNA ratios, and increased resistance to inhibitors of mitochondrial respiration and translation. Finally, there are reduced expression of the R1 subunit of RR and tissue-specific alterations of mtDNA copy number in ATM null mouse tissues, the latter being recapitulated in tissues from human A-T patients. Based on these results, we propose that disruption of RR and mitochondrial homeostasis contributes to the complex pathology of A-T and that RR genes are candidate disease loci in mtDNA-depletion syndromes.


2,500 living donor kidney transplants: a single-center experience.
To review a single center's experience and outcome with living donor transplants. Outcome after living donor transplants is better than after cadaver donor transplants. Since the inception of the authors' program, they have performed 2,540 living donor transplants. For the most recent cohort of recipients, improvements in patient care and immunosuppressive protocols have improved outcome. In this review, the authors analyzed outcome in relation to protocol. The authors studied patient and graft survival by decade. For those transplanted in the 1990s, the impact of immunosuppressive protocol, donor source, diabetes, and preemptive transplantation was analyzed. The incidence of rejection, posttransplant steroid-related complications, and return to work was determined. Finally, multivariate analysis was used to study risk factors for worse 1-year graft survival and, for those with graft function at 1 year, to study risk factors for worse long-term survival. For each decade since 1960, outcome has improved after living donor transplants. Compared with patients transplanted in the 1960s, those transplanted in the 1990s have better 8-year actuarial patient and graft survival rates. Death with function and chronic rejection have continued to be a major cause of graft loss, whereas acute rejection has become a rare cause of graft loss. Cardiovascular deaths have become a more predominant cause of patient death; infection has decreased. Donor source (e.g., ideally HLA-identical sibling) continues to be important. For living donor transplants, rejection and graft survival rates are related to donor source. The authors show that patients who had preemptive transplants or less than 1 year of dialysis have better 5-year graft survival and more frequently return to full-time employment. Readmission and complications remain problems; of patients transplanted in the 1990s, only 36% never required readmission. Similarly, steroid-related complications remain common. The authors' multivariate analysis shows that the major risk factor for worse 1-year graft survival was delayed graft function. For recipients with 1-year graft survival, risk factors for worse long-term outcome were pretransplant smoking, pretransplant peripheral vascular disease, pretransplant dialysis for more than 1 year, one or more acute rejection episodes, and donor age older than 55. These data show that the outcome of living donor transplants has continued to improve. However, for living donors, donor source affects outcome. The authors also identify other major risk factors affecting both short- and long-term outcome.


[Can staging and profiling ensure that the costs of quality care are adequately reimbursed?].
The current system for financing effective mental health can improve or reduce the quality of care provided. The system of financing includes reimbursing the care-provider, a risk-adjustment system for the health insurer and personal payments by the patient. Care-providers, patients and health insurers are worried that the current system is detrimental to quality care. To find out whether the financing system can be improved by the introduction of a system which weighs the costs according to the intensity of the care provided and which is based on staging and profiling. We performed a critical evaluation of the current financing system and we explored how staging and profiling could help to keep complex care affordable. The current model for financing mental health care does not involve staging and profiling. Reimbursement is based on diagnoses and on the number of minutes of care provided, no differentiation being made between the levels of expertise required. As a result it can become financially unattractive to administer the best possible treatment to patients with the greatest needs. Staging and profiling have the potential to create the best possible relationship between the level of care needed by the patient and the treatment costs incurred, because the factors that led to the previous imbalance have been removed. Staging and profiling can be introduced gradually at roughly the same pace as the national system of risk-adjustment is being introduced for health insurers.


A comprehensive conceptual framework for road safety strategies.
Road safety strategies (generally called Strategic Highway Safety Plans in the USA) provide essential guidance for actions to improve road safety, but often lack a conceptual framework that is comprehensive, systems theory based, and underpinned by evidence from research and practice. This paper aims to incorporate all components, policy tools by which they are changed, and the general interactions between them. A framework of nine mutually interacting components that contribute to crashes and ten generic policy tools which can be applied to reduce the outcomes of these crashes was developed and used to assess 58 road safety strategies from 22 countries across 15 years. The work identifies the policy tools that are most and least widely applied to components, highlighting the potential for improvements to any individual road safety strategy, and the potential strengths and weaknesses of road safety strategies in general. The framework also provides guidance for the development of new road safety strategies, identifying potential consequences of policy tool based measures with regard to exposure and risk, useful for both mobility and safety objectives.


Myc potentiates apoptosis by stimulating Bax activity at the mitochondria.
The ability of the c-Myc oncoprotein to potentiate apoptosis has been well documented; however, the mechanism of action remains ill defined. We have previously identified spatially distinct apoptotic pathways within the same cell that are differentially inhibited by Bcl-2 targeted to either the mitochondria (Bcl-acta) or the endoplasmic reticulum (Bcl-cb5). We show here that in Rat1 cells expressing an exogenous c-myc allele, distinct apoptotic pathways can be inhibited by Bcl-2 or Bcl-acta yet be distinguished by their sensitivity to Bcl-cb5 as either susceptible (serum withdrawal, taxol, and ceramide) or refractory (etoposide and doxorubicin). Myc expression and apoptosis were universally associated with Bcl-acta and not Bcl-cb5, suggesting that Myc acts downstream at a point common to these distinct apoptotic signaling cascades. Analysis of Rat1 c-myc null cells shows these same death stimuli induce apoptosis with characteristic features of nuclear condensation, membrane blebbing, poly (ADP-ribose) polymerase cleavage, and DNA fragmentation; however, this Myc-independent apoptosis is not inhibited by Bcl-2. During apoptosis, Bax translocation to the mitochondria occurs in the presence or absence of Myc expression. Moreover, Bax mRNA and protein expression remain unchanged in the presence or absence of Myc. However, in the absence of Myc, Bax is not activated and cytochrome c is not released into the cytoplasm. Reintroduction of Myc into the c-myc null cells restores Bax activation, cytochrome c release, and inhibition of apoptosis by Bcl-2. These results demonstrate a role for Myc in the regulation of Bax activation during apoptosis. Moreover, apoptosis that can be triggered in the absence of Myc provides evidence that signaling pathways exist which circumvent Bax activation and cytochrome c release to trigger caspase activation. Thus, Myc increases the cellular competence to die by enhancing disparate apoptotic signals at a common mitochondrial amplification step involving Bax activation and cytochrome c release.


The impact of the COVID-19 pandemic on Sexually Transmitted Infections surveillance data: incidence drop or artefact?
Before the COVID-19 pandemic, Sexually transmitted infections (STIs) were increasing in Europe, and Spain and Catalonia were not an exception. Catalonia has been one of the regions with the highest number of COVID-19 confirmed cases in Spain. The objective of this study was to estimate the magnitude of the decline, due to the COVID-19 pandemic, in the number of STI confirmed cases in Catalonia during the lockdown and de-escalation phases. Interrupted time series analysis was performed to estimate the magnitude of decline in the number of STI reported confirmed cases - chlamydia, gonorrhoea, syphilis, and lymphogranuloma venereum- in Catalonia since lockdown with historical data, from March 13th to August 1st 2020, comparing the observed with the expected values. We found that since the start of COVID-19 pandemic the number of STI reported cases was 51% less than expected, reaching an average of 56% during lockdown (50% and 45% during de-escalation and new normality) with a maximum decrease of 72% for chlamydia and minimum of 22% for syphilis. Our results indicate that fewer STIs were reported in females, people living in more deprived areas, people with no previous STI episodes during the last three years, and in the HIV negative. The STI notification sharp decline was maintained almost five months after lockdown started, well into the new normality. This fact can hardly be explained without significant underdiagnosis and underreporting. There is an urgent need to strengthen STI/HIV diagnostic programs and services, as well as surveillance, as the pandemic could be concealing the real size of the already described re-emergence of STIs in most of the European countries.


[Spouse violence: experiences expressed in male narratives].
Aiming the research of violence experiences in conjugal relation, this descriptive study, of qualitative and quantitative approach, aimed to identify conjugal violence in male discourse. Population was composed of 50 men residing in Calafate community, San Martin, a quarter in Salvador/Ba. In order to collect data, one utilized the interview with semi-structured formulary. Sample was characterized by men between 20 and 40 years old (74%) cohabiting. Concerning to conjugal violence, we found an 80% index. Relating to the forms of violence, we've distinguished emotional and physical violence.


Inflammation and coagulation following minimally invasive extracorporeal circulation technologies.
Minimally invasive extracorporeal perfusion technologies are based on the use of a minimally invasive extracorporeal circulation (MiECC) system. This includes a closed CPB circuit; biologically inert blood contact surfaces; reduced priming volume; a centrifugal pump; a membrane oxygenator; a heat exchanger; a cardioplegia system; a venous bubble trap/venous air removing device; and a shed blood management system. Some of these items, alone or in combination, are able to modify the blood activation usually elicited by cardiopulmonary bypass (CPB). The hemostatic system activation is less activated and lower degrees of thrombin generation and platelet activation have been found in numerous studies. Additionally, the reduced level of hemodilution plays an important role in preserving clot firmness after CPB with MiECC. These biochemical changes are reflected by a blood loss containment, a reduced need for allogeneic blood transfusions, and, in some studies, by a lower thromboembolic complications rate. The activation of the inflammatory cascade is in turn limited by MiECC, both directly (through a blunting of the contact-phase activation) and indirectly (through a limited thrombin generation, platelet activation, and consequent lower release of pro-inflammatory cytokines). The clinical consequences of this are mainly demonstrated by a lower rate of postoperative atrial fibrillation; other inflammation-derived outcomes appear favorably affected by MiECC (lung function, acute kidney injury) but the multi-factorial nature of these complications makes difficult to clearly attribute this pattern to a lower degree of inflammation. Overall, the existing body of evidence is in favor of MiECC with respect to standard CPB.


Corticosteroids operate as a switch between memory systems.
Stress and corticosteroid hormones are known to affect learning and memory processes. In this study, we examined whether stress and corticosteroids are capable of facilitating the switch between multiple memory systems in mice. For this purpose, we designed a task that allowed measurement of nucleus caudate-based stimulus-response and hippocampus-based spatial learning strategies. Naive mice used spatial strategies to locate an exit hole on a circular hole board at a fixed location flagged by a proximal stimulus. When the mice were either stressed or administered corticosterone before the task, 30-50% of the mice switched to a stimulus-response strategy. This switch between learning strategies was accompanied by a rescue of performance, whereas performance declined in the stressed mice that kept using the spatial strategy. Pretreatment with a mineralocorticoid receptor antagonist prevented the switch toward the stimulus-response strategy but led to deterioration of hippocampus-dependent performance. These findings (i) show that corticosteroids promote the transition from spatial to stimulus-response memory systems, (ii) provide evidence that the mineralocorticoid receptor underlies this corticosteroid-mediated switch, and (iii) suggest that a stress-induced switch from hippocampus-based to nucleus caudate-based memory systems can rescue performance.


Can environmental constraints determine random patterns of plant species co-occurrence?
Plant community ecologists use the null model approach to infer assembly processes from observed patterns of species co-occurrence. In about a third of published studies, the null hypothesis of random assembly cannot be rejected. When this occurs, plant ecologists interpret that the observed random pattern is not environmentally constrained - but probably generated by stochastic processes. The null model approach (using the C-score and the discrepancy index) was used to test for random assembly under two simulation algorithms. Logistic regression, distance-based redundancy analysis, and constrained ordination were used to test for environmental determinism (species segregation along environmental gradients or turnover and species aggregation). This article introduces an environmentally determined community of alpine hydrophytes that presents itself as randomly assembled. The pathway through which the random pattern arises in this community is suggested to be as follows: Two simultaneous environmental processes, one leading to species aggregation and the other leading to species segregation, concurrently generate the observed pattern, which results to be neither aggregated nor segregated - but random. A simulation study supports this suggestion. Although apparently simple, the null model approach seems to assume that a single ecological factor prevails or that if several factors decisively influence the community, then they all exert their influence in the same direction, generating either aggregation or segregation. As these assumptions are unlikely to hold in most cases and assembly processes cannot be inferred from random patterns, we would like to propose plant ecologists to investigate specifically the ecological processes responsible for observed random patterns, instead of trying to infer processes from patterns.


Bifidobacterium infantis 35624 protects against salmonella-induced reductions in digestive enzyme activity in mice by attenuation of the host inflammatory response.
Salmonella-induced damage to the small intestine may decrease the villi-associated enzyme activity, causing malabsorption of nutrients and diarrhea, and thus contribute to the symptoms of infection. The objective of this study was to determine the mechanism by which different doses and durations of Salmonella infection and lipopolysaccharide (LPS) affect brush border enzyme activity in the mouse, and to determine if the probiotic Bifidobacterium longum subspecies infantis 35624 could attenuate the intestinal damage. BALB/c mice were challenged with Salmonella enterica serovar Typhimurium UK1 at various doses (10(2)-10(8) colony-forming unit (CFU)) and durations (10(6) CFU for 1-6 days). Mice were also treated with B. longum subsp. infantis 35624 for 2 weeks before and during a 6-day S. Typhimurium challenge (10(6) CFU), or before injection of LPS. The small intestine was assessed for morphological changes, mRNA expression of cytokines, and activity of the brush border enzymes sucrase-isomaltase, maltase, and alkaline phosphatase. S. Typhimurium infection significantly reduced the activity of all brush border enzymes in a dose- and time-dependent manner (P<0.05). This also occurred following injection of LPS. Pre-treatment with B. longum subsp. infantis 35624 prevented weight loss, protected brush border enzyme activity, reduced the small intestinal damage, and inhibited the increase in interleukin (IL)-10 and IL-8 expression due to Salmonella challenge. Salmonella infection reduces the small intestinal brush border enzyme activity in mice, with the level of reduction and associated weight loss increasing with dose and duration of infection. B. longum subsp. infantis 35624 treatment attenuated the effect of Salmonella infection on brush border enzyme activity and weight loss, which may be due to modulation of the host immune response.


Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy.
Open laparotomy has traditionally been required to stage hepatobiliary and pancreatic (HBP) cancers accurately. For unresectable patients, costs and morbidity have been high. Today, laparoscopy alone or combined with laparoscopic ultrasonography (LUS) is being examined for its value in defining the extent of malignancy. We have analyzed the effect of routine implementation of this new staging technique in our HBP center. Staging laparoscopy (SL) with LUS was performed in 50 consecutive patients with HBP malignancies. All patients were considered to have resectable tumors as determined by traditional preoperative staging modalities. Primary tumors were located in the liver (n = 7), biliary tract (n = 11), or pancreas (n = 32). An average of 2.7 preoperative studies per patient were performed prior to SL-LUS. Staging laparoscopy with laparoscopic ultrasonography predicted resectable tumors in 28 patients (56%). At laparotomy, 26 of 28 were actually resectable: the false-negative rate was 4%. Staging laparoscopy with laparoscopic ultrasonography indicated unresectability in 22 patients (44%). Staging laparoscopy alone demonstrated previously unrecognized occult metastases in 11 patients (22%). In 11 other patients (22%) in whom SL alone was negative, LUS established unresectability from vascular invasion (n = 5), lymph node metastases (n = 5), or intraparenchymal hepatic tumor (n = 1). All cases of unresectability due to vascular invasion were validated by laparotomy. Five of six lymph node or hepatic metastases were proved histologically by LUS-guided needle biopsy rather than laparotomy. Unnecessary laparotomy can be safely avoided by SL-LUS in many patients with HPB malignancies, reducing costs and morbidity.


Novel receptor site involved in enhancement of stimulus-induced acetylcholine, dopamine, and serotonin release.
The cognitive enhancer DuP 996 [3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one] and its structural analogs enhance the K(+)-stimulated release of acetylcholine, dopamine, and serotonin in brain slices, without effect on basal release. A novel receptor site labeled by [3H]DuP 996 has been identified. The [3H]DuP 996 binding site has a Kd of 19 nM and a Bmax of 102 fmol/mg of protein. Binding to this site is specific, saturable, reversible, and time, pH, and temperature dependent. Specific binding is decreased by treatment with trypsin and not affected by phospholipase C. Specific binding is inhibited by Ca2+ and increased by Mn2+ but not affected by Na+, K+, or Mg2+. The [3H]DuP 996 binding sites are heterogeneously distributed in brain, with striatum and hypothalamus having highest density and cerebellum lowest. The [3H]DuP 996 binding site does not belong to any known class of receptor site, because [3H]DuP 996 binding could not be displaced by a broad variety of standard pharmacological agents and neuropeptides. Physiological significance of this binding site is suggested by the excellent correlation between the binding affinity for this site and the potency to enhance K(+)-stimulated release of acetylcholine for a series of DuP 996 analogs. Ligands for this receptor site may have therapeutic potential for the treatment of cognitive deficits and neurodegenerative diseases.


Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.
Since Helicobacter pylori was first cultivated from human gastric biopsy specimens in 1982, it has become apparent that many related species can often be found colonizing the mucosal surfaces of humans and other animals. These other Helicobacter species can be broadly grouped according to whether they colonize the gastric or enterohepatic niche. Gastric Helicobacter species are widely distributed in mammalian hosts and are often nearly universally prevalent. In many cases they cause an inflammatory response resembling that seen with H. pylori in humans. Although usually not pathogenic in their natural host, these organisms serve as models of human disease. Enterohepatic Helicobacter species are an equally diverse group of organisms that have been identified in the intestinal tract and the liver of humans, other mammals, and birds. In many cases they have been linked with inflammation or malignant transformation in immunocompetent hosts and with more severe clinical disease in immunocompromised humans and animals. The purpose of this review is to describe these other Helicobacter species, characterize their role in the pathogenesis of gastrointestinal and enterohepatic disease, and discuss their implications for our understanding of H. pylori infection in humans.


Anxiogenic effects of chronic exposure to nandrolone decanoate (ND) at supraphysiological dose in rats: a brief report.
Nandrolone decanoate (ND) is frequently used anabolic androgenic steroid (AAS) among the athletes. Despite the health risks, there is significant increase in prevalence of AAS abuse. The aim of this study was to investigate the effects of chronic exposure to ND at supraphysiological dose (to mimic the doses for human AAS abusers) on anxiety levels in adult rats. We performed several behavioral tests (open field test, elevated plus maze test, beam-walking test, evoked beam-walking test and tail suspension test) for estimation of anxiety in rats. Adult rats received 20 mg/kg intraperitoneal injection of ND weekly for four weeks. Behavioral test were performed on the seventh day after the last dose of ND. Anxiogenic-like pattern of behavior was clearly observed in several behavioral tests, such as open field test (decrease of total distance moved and cumulative duration of moving, decrease of an average velocity of the animals, decrease of frequency and total time in centre zone); elevated plus maze (decreased total time spent in open arms and the number of entries in open arms of the elevated plus maze); evoked beam-walking test (decreased time to cross the beam) and tail suspension test (increased latency to first immobility and decreased total duration of immobility). Results of this study show that four-week treatment with the supraphysiological dose of ND produced anxiogenic effects in sedentary male rats. Our results show that rats after chronic treatment with a supraphysiological dose of ND exhibited anxiety-like behavior.


Health-related quality of life of preschool caregivers in Hong Kong.
The aim of this study was to explore the health-related quality of life (HRQOL) of preschool caregivers in Hong Kong with a view to informing policy-makers about health promotion within this population. The following research questions were addressed: (i) What was the HRQOL of young children's caregivers in Hong Kong? (ii) Were there differences between these caregivers' health and the general Hong Kong population's health? (iii) What demographic factors were related to these caregivers' quality of life? Mixed methods research, including quantitative and qualitative tools, was utilized. Data from a study consisted of a survey of 834 preschool caregivers along with 3 in-depth interviews with employees of kindergarten-cum-childcare centres from different socio-economic groups within the city of Hong Kong. An HRQOL questionnaire (the SF-36 v. 1), together with demographic characteristics and illness/disease incidence data, were collected. The results suggested that the Hong Kong preschool caregivers had a substantially poorer HRQOL than Hong Kong's general population. The analysis found that young caregivers and caregivers with young families had a significantly lower HRQOL than more senior caregivers. They tended to feel tired, lacked energy and failed to perform vigorous activities. Significant differences were also found according to the caregivers' socio-economic status. Health and education policy-makers should note that young children's caregivers are in a serious state of ill health. Further health education and promotion efforts should target this population.


The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children.
TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure. The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131). TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002). We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.


LGI proteins in the nervous system.
The development and function of the vertebrate nervous system depend on specific interactions between different cell types. Two examples of such interactions are synaptic transmission and myelination. LGI1-4 (leucine-rich glioma inactivated proteins) play important roles in these processes. They are secreted proteins consisting of an LRR (leucine-rich repeat) domain and a so-called epilepsy-associated or EPTP (epitempin) domain. Both domains are thought to function in protein-protein interactions. The first LGI gene to be identified, LGI1, was found at a chromosomal translocation breakpoint in a glioma cell line. It was subsequently found mutated in ADLTE (autosomal dominant lateral temporal (lobe) epilepsy) also referred to as ADPEAF (autosomal dominant partial epilepsy with auditory features). LGI1 protein appears to act at synapses and antibodies against LGI1 may cause the autoimmune disorder limbic encephalitis. A similar function in synaptic remodelling has been suggested for LGI2, which is mutated in canine Benign Familial Juvenile Epilepsy. LGI4 is required for proliferation of glia in the peripheral nervous system and binds to a neuronal receptor, ADAM22, to foster ensheathment and myelination of axons by Schwann cells. Thus, LGI proteins play crucial roles in nervous system development and function and their study is highly important, both to understand their biological functions and for their therapeutic potential. Here, we review our current knowledge about this important family of proteins, and the progress made towards understanding their functions.


Antiretroviral-associated Hepatotoxicity.
The use of highly active antiretroviral therapy has dramatically reduced HIV-associated morbidity and mortality. As a result, patients are often being treated longer and with more complex medical regimens than ever before, increasing the risk for drug interactions and toxicities. In particular, hepatotoxicity caused by antiretroviral use has become an increasingly appreciated potential complication of drug treatment. All classes of antiretrovirals have been reported to induce liver enzyme abnormalities. However, certain antiretrovirals appear much more likely to be associated with drug-induced hepatotoxicity. The risk of antiretroviral-related hepatotoxicity may be associated with patient-specific risk factors, including pre-existing viral hepatitis, baseline elevated liver function test results, female gender, and substance abuse. In addition, complex drug-drug interactions may potentate the risk of antiretroviral-associated hepatotoxicity. Coinfection with hepatitis B or hepatitis C appears to increase the risk of antiretroviral-related hepatotoxicity.


A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma.
The efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial. Chemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m(2) on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m(2) every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS). A total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631-0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738-1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm. nab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile.


Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8+ T cells.
An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8+ T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re-engagement of T lymphocytes into the effector program. IFN-I appears involved in this remodeling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses.