Assimilation of water and dietary ions by the gastrointestinal tract during digestion in seawater-acclimated rainbow trout.
Recent studies focusing on the consequences of feeding for ion and water balance in freshwater fish have revealed the need for similar comparative studies in seawater fish. A detailed time course sampling of gastrointestinal (GI) tract contents following the ingestion of a single meal of a commercial diet revealed the assimilation of both water and dietary ions (Na(+), Cl(-), K(+), Ca(2+), Mg(2+)) along the GI tract of seawater-acclimated rainbow trout (Oncorhynchus mykiss) which had been fasted for 1 week. Consumption of the meal did not change the drinking rate. There was a large secretion of fluid into the anterior intestine and caecae (presumably bile and/or pancreatic secretions). As a result, net assimilation (63%) of the ingested water along the GI tract was lower than generally reported for fasted trout. Mg(2+) was neither secreted into nor absorbed from the GI tract on a net basis. Only K(+) (93% assimilated) and Ca(2+) (43% assimilated) were absorbed in amounts in excess of those provided by ingested seawater, suggesting that dietary sources of K(+) and Ca(2+) may be important to seawater teleosts. The oesophagus-stomach served as a major site of absorption for Na(+), Cl(-), K(+), Ca(2+), and Mg(2+), and the anterior intestine and caecae as a major site of net secretion for all of these ions, except Cl(-). Despite large absorptive fluxes of these ions, the ionic composition of the plasma was maintained during the digestion of the meal. The results of the present study were compared with previous work on freshwater-acclimated rainbow trout, highlighting some important differences, but also several similarities on the assimilation of water and ions along the gastrointestinal tract during digestion. This study highlights the complicated array of ion and water transport that occurs in the intestine during digestion while revealing the importance of dietary K(+) and Ca(2+) to seawater-acclimated rainbow trout. Additionally, this study reveals that digestion in seawater-acclimated rainbow trout appears to compromise intestinal water absorption.


Alamethicin channels in a membrane: molecular dynamics simulations.
Alamethicin (Alm) is a 20 residue peptide which forms a kinked alpha-helix in membrane and membrane-mimetic environments. Ion channels formed by intramembraneous aggregates of Alm are thought to be formed by bundles of approximately parallel Alm helices surrounding a central bilayer pore. Different channel conductance levels correspond to different numbers of helices per bundle, ranging from N = 5 to N > 8. Calculation of the predicted pKA values of the ring of Glu18 sidechains at the C-terminal mouth of the pore suggests that at neutral pH most or all of these sidechains will remain protonated. Nanosecond molecular dynamics (MD) simulations of N = 5, 6, 7 and 8 bundles of Alm helices in a POPC bilayer have been run, corresponding to a total simulation time of 4 ns. These simulations explore the stability and conformational dynamics of these helix bundle channels when embedded in a full phospholipid bilayer in an aqueous environment. The structural and dynamic properties of water in these model channels are examined. As in earlier in vacuo simulations (J. Breed, R. Sankararamakrishnan, I. D. Kerr and M. S. P. Sansom, Biophys. J., 1996, 70, 1643) the dipole moments of water molecules within the pores are aligned antiparallel to the helix dipoles. This helps to contribute to the stability of the helix bundles.


Promotion of responsible drinking in hotels.
This study reports on an intervention programme to promote responsible drinking in hotels. The licensees of eight hotels agreed to participate in a trial of measures designed to assist patrons to avoid drink-driving, and seven other hotels were used as controls. The interventions acceptable to licensees comprised commercial-quality promotional material with the theme "0.05 Know Your Limits", and a breath analysis machine and poster on its use. Patrons leaving the hotels on Thursday, Friday and Saturday nights were interviewed and breath-tested. Although the intervention material had been seen by one-third of patrons in the intervention hotels, there was no significant difference between them and control hotel patrons in either median BAC or the proportion who were going to drive with BAC over the legal limit. There was poor compliance by hotels with the intervention procedures, indicating that a major impediment to the implementation and evaluation of programmes to promote responsible drinking is a lack of motivation by many licensees, despite support by some licensees and the Australian Hotels Association.


High Diagnostic Accuracy of Nitrite Test Paired with Urine Sediment can Reduce Unnecessary Antibiotic Therapy.
Urinary tract infections (UTIs) are common bacterial infections dominated by lower UTI in women (LUTIW). Symptoms only are insufficient for diagnosis and accordingly, near patient diagnostic tests confidently confirming significant bacteriuria are desirable. The nitrite test (NIT) has low sensitivity, while bacterial and leukocyte counts disjunctively paired in urine sediment microscopy (SED) have high sensitivity. Similar symptomatic cure rates are found post antibiotic vs. placebo therapy in patients with negative cultures. Consequently, prescription on symptoms only implies unnecessary antibiotic therapy. to evaluate the diagnostic outcomes of NIT, SED and NIT disjunctively paired with SED (NIT+SED) vs. urine culture, with special focus on bladder incubation time (BIT), and to assess if NIT+SED can reduce unnecessary antibiotic therapy. A diagnostic, primary care, multicentre study including 1070 women with symptoms suggestive of lower UTI. Significant bacteriuria was found in 77%. The BIT highly influenced the diagnostic outcomes and the optimal duration was ≥4h with sensitivity of 66, 90 and 95% for NIT, SED and NIT+SED, respectively. SED performed only in NIT negative specimens could reduce unnecessary antibiotics by 10% vs. prescription on symptoms only. The number needed to test with SED to reduce one unnecessary antibiotic course was five patients at BIT ≥4h and six patients at ≤3h or overall. The BIT highly influences the diagnostic outcomes with the highest accuracy of NIT+SED. Diagnosis of LUTIW with NIT+SED can reduce unnecessary antibiotic therapy and subsequently decrease antimicrobial resistance. The Swedish Medical Product Agency 1995 03 01:151:01783/94.


Loss of foundation species increases population growth of exotic forbs in sagebrush steppe.
The invasion and spread of exotic plants following land disturbance threatens semiarid ecosystems. In sagebrush steppe, soil water is scarce and is partitioned between deep-rooted perennial shrubs and shallower-rooted native forbs and grasses. Disturbances commonly remove shrubs, leaving grass-dominated communities, and may allow for the exploitation of water resources by the many species of invasive, tap-rooted forbs that are increasingly successful in this habitat. We hypothesized that exotic forb populations would benefit from increased soil water made available by removal of sagebrush, a foundation species capable of deep-rooting, in semiarid shrub-steppe ecosystems. To test this hypothesis, we used periodic matrix models to examine effects of experimental manipulations of soil water on population growth of two exotic forb species, Tragopogon dubius and Lactuca serriola, in sagebrush steppe of southern Idaho, USA. We used elasticity analyses to examine which stages in the life cycle of T. dubius and L. serriola had the largest relative influence on population growth. We studied the demography of T. dubius and L. serriola in three treatments: (1) control, in which vegetation was not disturbed, (2) shrubs removed, or (3) shrubs removed but winter-spring recharge of deep-soil water blocked by rainout shelters. The short-term population growth rate (Lambda) of T. dubius in the shrub-removal treatment was more than double that of T. dubius in either sheltered or control treatments, both of which had limited soil water. All L. serriola individuals that emerged in undisturbed sagebrush plots died, whereas Lambda of L. serriola was high (Lambda > 2.5) in all shrub-removal plots, whether they had rainout shelters or not. Population growth of both forbs in all treatments was most responsive to flowering and seed production, which are life stages that should be particularly reliant on deep-soil water, as well as seedling establishment, which is important to most plant populations, especially during invasion. These data indicate the importance of native species, in this case the dominant shrub, in influencing soil resources and restricting population growth of exotic plants. These results argue that management of invasive plants should focus not only on removal of nonnatives, but also on reestablishment of important native species.


Effect of temperature and moisture contents on dielectric properties at 2.45 GHz of fruit and vegetable processing by-products.
Microwave heating is a part of several food processing unit-operations, while also emerging as a processing technology for by-products. Process efficiency depends on dielectric properties; however, data of these by-products are scarce in literature. The present study is focused on the effect of temperature and moisture content (M) on the dielectric constant (ε') and loss (ε'') of carrot waste, apple pomace, pineapple peel and spent coffee grounds at 2.45 GHz. Results on ε' showed moisture-dependent temperature effect with an inflection point at M = 50.3%. The ε'' increased with increasing M up to 60% and decreased at higher moisture levels. Results at different temperatures were significantly affected by the composition of the studied materials and thus the calculated power penetration depth. Although fresh food dielectric properties are available in literature, the data is not always suitable to estimate food waste properties as processing may cause compositional changes. The obtained results support microwave process optimization in the field of food-waste valorization.


Real-time analysis of the assembly of ligand, receptor, and G protein by quantitative fluorescence flow cytometry.
We describe a general approach for the quantitative analysis of the interaction among fluorescent peptide ligands (L), receptors (R), and G proteins (G) using fluorescence flow cytometry. The scheme depends upon the use of commercially available fluorescent microbeads as standards to calibrate the concentration of fluorescent peptides in solution and the receptor number on cells in suspension. We have characterized a family of fluoresceinated formyl peptides and analyzed both steady-state and dynamic aspects of ligand formyl peptide-receptor interactions in digitonin-permeabilized human neutrophils. Detailed receptor-binding studies were performed with the pentapeptide N-formyl-Met-Leu-Phe-Phe-Lys-fluorescein. Equilibrium studies showed that GTP [S] caused a loss of binding affinity of approximately two orders of magnitude, from approximately 0.04 nM (LRG) to approximately 3 nM (LR), respectively. Kinetic studies revealed that this change in affinity was principally due to an increase in the dissociation rate constants from approximately 1 x 10(-3) s-1 (LRG) to approximately 1 x 10(-1) s-1 (LR). In contrast, the association rate constants in the presence and absence of guanine nucleotide (approximately 3 x 10(7) s-1 M-1) were statistically indistinguishable and close to the diffusion limit. In the presence of guanine nucleotide (LR), the kinetic data were adequately fit by a single-step reversible-binding model. In the absence of guanine nucleotides, not all receptors have rapid access to G to form the LRG ternary complex. Mathematically, those R that have rapid access to G are either precoupled to R or the association of G with R is fast compared to the association of L with R. The physiological consequences of coupling heterogeneity are discussed.


Differentiation of local tumor recurrence from radiation-induced changes after stereotactic radiosurgery for treatment of brain metastasis: case report and review of the literature.
Structural follow-up magnetic resonance imaging (MRI) after stereotactic radiosurgery (SRS) for brain metastases frequently displays local changes in the area of applied irradiation, which are often difficult to interpret (e.g., local tumor recurrence, radiation-induced changes). The use of stereotactic biopsy for histological assessment of these changes has a high diagnostic accuracy and can be considered as method of choice. In order to solve this relevant clinical problem non-invasively, advanced MRI techniques and amino acid positron-emission-tomography (PET) are increasingly used. We report the long-term follow-up of a patient who had been treated with linear accelerator based SRS for cerebral metastases of a lung cancer. Fifty-eight months after SRS, the differentiation of local recurrent brain metastasis from radiation-induced changes using structural MRI was difficult. For further differentiation, perfusion-weighted MRI (PWI), proton magnetic resonance spectroscopy (MRS), and (11)C-methyl-L-methionine (MET) PET was performed. Due to artifacts and technical limitations, PWI MRI and MRS findings were not conclusive. In contrast, MET PET findings were suggestive for radiation-induced changes. Finally, a stereotactic biopsy for histological assessment of these changes demonstrated clearly a radiation-induced necrosis and the absence of vital tumor. The use of stereotactic biopsy for histological assessment of indistinguishable lesions on structural MRI after SRS for treatment of brain metastasis represents a highly reliable method to differentiate local tumor recurrence from radiation-induced changes. In this field, results of studies with both advanced MRI techniques and amino acid PET suggest encouraging results. However, artifacts and technical limitations (e.g., lesion size) are still a problem and comparative studies are needed to investigate the relationship, diagnostic performance, and complementary character of advanced MRI techniques and amino acid PET.


Cervical screening rates for women vaccinated against human papillomavirus.
To compare cervical screening rates for women vaccinated with a quadrivalent human papillomavirus (HPV) vaccine with those for unvaccinated women, to address concerns that vaccinated women may not be participating in cervical screening. Cross-sectional analysis of linked data from the Victorian Cervical Cytology Registry and the National HPV Vaccination Program Register for 20-29-year-old women in Victoria, Australia, for the period 1 January 2009 to 31 December 2011. Screening participation rates for vaccinated and unvaccinated women. Participation in cervical screening during the 2-year period 2010-2011 was significantly lower in 20-24-year-old vaccinated women compared with unvaccinated women of the same age (37.6% v 47.7%, a 10.1 percentage point difference [95% CI, 9.7-10.6]; P < 0.001) and significantly lower in 25-29-year-old vaccinated women compared with unvaccinated women of the same age (45.2% v 58.7%, a 13.5 percentage point difference [95% CI, 13.1%-13.9%]; P < 0.001). Similar results were observed for participation during the 3-year period 2009-2011. Despite education messages provided to young women, our results suggest that vaccinated women are being screened at lower rates than unvaccinated women in Australia. While some degree of undermatching of women in the study may have occurred, this cannot wholly explain our findings. Effective implementation of Individual Healthcare Identifiers to health records, including registry records, is needed to prevent potential undermatching of individuals in future linkage studies. In the meantime, efforts to increase participation in cervical screening by vaccinated women are needed.


The influence of 5-HTT and COMT genotypes on verbal fluency in ecstasy users.
Deficits in verbal fluency associated with ecstasy use have been well established; however, the mechanisms underlying this impairment have yet to be elucidated. In this study we investigated for the first time whether there was a disproportionate impairment in two cognitive subcomponents of verbal fluency: clustering (ability to generate words within the same subcategory) and switching (ability to change the subcategory). We also investigated a possible association between ecstasy use and verbal fluency in subjects genotyped for 5-HTT (5-HTTLPR and 5-HTTVNTR) and COMT (val(108/158)met, rs165599 and rs2097603) polymorphisms, in order to find a potential implication of genetic factors. Ecstasy polydrug users (n = 30) and non-ecstasy users (n = 41) were evaluated in both semantic and phonemic fluency. Results showed that ecstasy users had poorer semantic (but not phonemic) fluency performance than controls. Detailed analysis of clustering and switching performance revealed that this impairment was associated with poorer clustering mechanisms. Clustering was also modulated by the COMT rs165599 polymorphism independently of the group. A specific effect of the 5-HTTLPR polymorphism on switching performance was also found, with ss carriers performing significantly worse than ls and ll carriers, suggesting a serotonin modulation of frontal-executive flexibility. Based on the impaired clustering and switching strategies observed in ecstasy users, it might be proposed that both semantic knowledge and retrieval are impaired in this population. The verbal fluency deficit in ecstasy users may be attributable to a disruption of frontal-striatal circuits directly related with the serotonin function as well as a depletion of lexical-semantic stores mediated by temporal structures.


Annoyance and performance of three environmentally intolerant groups during experimental challenge with chemical odors.
This study investigated exposure- and subject-related determinants of annoyance and performance during the chemical odor provocation of healthy persons with self-reported environmental annoyance. Persons with self-reported annoyance attributed to (i) chemicals or smells (smell-annoyed, SA, N=29), (ii) electrical equipment (electrically annoyed, EA, N= 16), and (iii) both smells and electricity (generally annoyed, GA, N=39) were, together with referents (N=54), challenged with n-butyl acetate in an exposure chamber at levels far below the threshold values for neurotoxic effects and trigeminal irritation. A sequence of three air concentrations, 0.37, 1.5, and 6 ppm (1.8, 7.1, and 28 mg/m3) was used, counterbalanced within groups, together with intermittent periods of room air between each exposure level. The response measures comprised ratings of annoyance and smell intensity and reaction-time tests. Only the GA group showed clearly elevated ratings of smell annoyance, mucous membrane irritation, and fatigue, as well as longer reaction times, compared with the referents, in response to the challenge. No group difference was found for the smell-intensity ratings. During intermittent periods without exposure, only the GA group maintained higher ratings for mucous membrane irritation and fatigue. Reaction time and all the rating dimensions showed a positive relationship with momentary n-butyl acetate concentration, while cumulative exposure had a more limited impact on the ratings and reaction time. A suggestion effect by the chamber environment before exposure could not be demonstrated. The results suggest that self-reported annoyance generalized to both electrical equipment and smells is a better predictor of chemical intolerance than self-reported annoyance to smells only.


Iron porphyrins with different imidazole ligands. A theoretical comparative study.
A theoretical comparative study of a series of five- and six-coordinate iron porphyrins, FeP(L) and FeP(L)(O(2)), has been carried out using DFT methods, where P = porphine and L = imidazole (Im), 1-methylimidazole (1-MeIm), 2-methylimidazole (2-MeIm), 1,2-dimethylimidazole (1,2-Me(2)Im), 4-ethylimidazole (4-EtIm), or histidine (His). Two ligated "picket-fence" iron porphyrins, FeTpivPP(2-MeIm) and FeTpivPP(2-MeIm)(O(2)), were also included in the study for comparison. A number of density functionals were employed in the computations to obtain reliable results. The performance of functionals and basis set effects were investigated in detail on FeP, FeP(Im), and FeP(Im)(O(2)), for which certain experimental information is available and there are some previous calculations in the literature for comparison. Many subtle distinctions in the effects of the different imidazole ligands on the structures and energetics of the deoxy- and oxy iron porphyrins are revealed. While FeP(2-MeIm) is identified to be high spin (S = 2), the ground state of FeP(1-MeIm) may be an admixture of a high-spin (S = 2) and an intermediate-spin (S = 1) state. The ground state of FeP(L)(O(2)) may be different with different L. A weaker Fe-L bond more likely leads to an open-shell singlet ground state for the oxy complex. The 2-methyl group in 2-MeIm, which increases steric contact between the ligand and the porphyrinato skeleton, weakens the Fe-O(2) bond, and thus iron porphyrins with 2-MeIm mimic T-state (low affinity) hemoglobin. The calculated FeP(2-MeIm)-O(2) bonding energy is comparable to the FeTpivPP(2-MeIm)-O(2) one, in agreement with the fact that the picket-fence iron porphyrin binds O(2) with affinity similar to that of myoglobin but different from the result obtained by the CPMD scheme. Im and 4-EtIm closely resemble His, the biologically axial base, and so future computations on hemoprotein models can be simplified safely by using Im.


Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues?
Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project. We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children. The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest). Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.


Effect of N-acetylcysteine and L-NAME on aluminium phosphide induced cardiovascular toxicity in rats.
To investigate the protective effects of N-acetylcysteine (NAC) and Nomega-Nitro-L-arginine methyl ester (L-NAME) on aluminium phosphide (AlP) poisoning induced hemodynamic changes, myocardial oxygen free radical injury and on survival time in rats. AlP (12.5 mg/kg) was administered intragastrically under urethane anaesthesia. The effect of pre- and post-treatment with NAC and L-NAME alone and in combination was studied on haemodynamic parameters [blood pressure (BP), heart rate (HR), and electrocardiogram (ECG)] and biochemical parameters (malonyldialdehyde, catalase, and glutathione peroxidase). AlP caused significant hypotension, tachycardia, ECG abnormalities, and finally marked bradycardia. The mean survival time was (90 +/- 10) min. There was significant increase in myocardial malonyldialdehyde (MDA), and decrease in catalase and glutathione peroxidase (GSH Px) levels. NAC infusion (6.25 mg . kg-1 . min-1, iv for 30 min) caused insignificant hemodynamic and biochemical changes. Pre- and post-treatment of NAC with AlP significantly increased the survival time, stabilized BP, HR, and ECG, decreased MDA and increased GSH Px levels compared to AlP group. L-NAME infusion (1 mg . kg-1 . min-1, iv for 60 min) as such caused significant rise in BP but precipitated ECG abnormalities. Pre- and post-treatment of L-NAME with AlP neither improved the survival time nor the biochemical parameters despite significant rise in BP. Co-administration of both the drugs with AlP worsened the hemodynamic and biochemical parameters with reduction in the survival time as compared to AlP. NAC increased the survival time by reducing myocardial oxidative injury whereas L-NAME showed no such protective effects in rats exposed to AlP.


Nitric oxide modulates superoxide release and peroxynitrite formation in human blood vessels.
Nitric oxide and superoxide have important roles as vascular signaling molecules. Nitric oxide (NO) reacts rapidly with superoxide, producing peroxynitrite. The relative balance between these radicals has important implications for vascular pathophysiology in hypertension and other vascular disease states. However, the relationships between superoxide, NO, and peroxynitrite formation in human blood vessels remain unclear. Accordingly, we systematically measured NO, superoxide, and peroxynitrite production from human internal mammary arteries, radial arteries, and saphenous veins from 78 patients undergoing coronary bypass surgery. Basal superoxide release was detected in all vessels at similar levels. However, endothelial removal or nitric oxide synthase inhibition increased mean superoxide release, with a corresponding reduction in peroxynitrite formation. Conversely, NO donors and superoxide scavengers both reduced superoxide release, whereas only NO donors increased peroxynitrite formation. These changes were much larger in arteries that in veins, but there were striking correlations between superoxide production, NO bioavailability, and peroxynitrite formation between the vessel types. Our findings provide direct evidence for coordinated vascular signaling mediated by interactions between NO, superoxide, and peroxynitrite and have important implications for studies of the functional effects of these radicals in human blood vessels.


Precipitating antigen-antibody systems are required for the formation of subepithelial electron-dense immune deposits in rat glomeruli.
This study was conducted to determine whether multivalent, precipitating antigens are required for formation of subepithelial electron-dense immune deposits in glomeruli. 2-nitro-4-azidophenyl (NAP) was conjugated with variable density to human serum albumin (HSA) to yield nonprecipitating (NAP3.1 X HSA and NAP11.4 X HSA) and precipitating (NAP19.7 X HSA) antigens with antibodies to the hapten. These antigen preparations were cationized with ethylene diamine to enhance deposition in renal glomeruli due to interaction with the fixed negative charges in the glomerular capillary wall. Following injection into the left renal artery of rats these antigens alone persisted in the glomeruli for a relatively short time by immunofluorescence microscopy. When antibodies to NAP were injected intravenously after the antigen injection, the nonprecipitating antigens and antibodies were detectable in the glomeruli by immunofluorescence microscopy up to 8 h, comparable to antigen alone. Electron-dense deposits were not formed in these glomeruli. In contrast, when the precipitating antigen was injected and followed by antibodies to the hapten, antigen and antibody were detected by immunofluorescence microscopy through 96 h. In these specimens electron-dense deposits were present from 40 min through 96 h and after 24 h the deposits were present only in the subepithelial area. The same results were obtained when the nonprecipitating hapten-carrier conjugates were followed with antibodies to the carrier molecule. These data indicate that the persistence of immune deposits by immunofluorescence microscopy and the formation of electron-dense deposits in the subepithelial area require a precipitating antigen-antibody system.


Metabolic shifts in residual breast cancer drive tumor recurrence.
Tumor recurrence is the leading cause of breast cancer-related death. Recurrences are largely driven by cancer cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease. Here, using mouse models that faithfully recapitulate human disease together with organoid cultures, we have demonstrated that residual cells acquire a transcriptionally distinct state from normal epithelium and primary tumors. Gene expression changes and functional characterization revealed altered lipid metabolism and elevated ROS as hallmarks of the cells that survive tumor regression. These residual cells exhibited increased oxidative DNA damage, potentiating the acquisition of somatic mutations during hormonal-induced expansion of the mammary cell population. Inhibition of either cellular fatty acid synthesis or fatty acid transport into mitochondria reduced cellular ROS levels and DNA damage, linking these features to lipid metabolism. Direct perturbation of these hallmarks in vivo, either by scavenging ROS or by halting the cyclic mammary cell population expansion, attenuated tumor recurrence. Finally, these observations were mirrored in transcriptomic and histological signatures of residual cancer cells from neoadjuvant-treated breast cancer patients. These results highlight the potential of lipid metabolism and ROS as therapeutic targets for reducing tumor recurrence in breast cancer patients.


Guidelines for prevention of hospital acquired infections.
These guidelines, written for clinicians, contains evidence-based recommendations for the prevention of hospital acquired infections Hospital acquired infections are a major cause of mortality and morbidity and provide challenge to clinicians. Measures of infection control include identifying patients at risk of nosocomial infections, observing hand hygiene, following standard precautions to reduce transmission and strategies to reduce VAP, CR-BSI, CAUTI. Environmental factors and architectural lay out also need to be emphasized upon. Infection prevention in special subsets of patients - burns patients, include identifying sources of organism, identification of organisms, isolation if required, antibiotic prophylaxis to be used selectively, early removal of necrotic tissue, prevention of tetanus, early nutrition and surveillance. Immunodeficient and Transplant recipients are at a higher risk of opportunistic infections. The post tranplant timetable is divided into three time periods for determining risk of infections. Room ventilation, cleaning and decontamination, protective clothing with care regarding food requires special consideration. Monitoring and Surveillance are prioritized depending upon the needs. Designated infection control teams should supervise the process and help in collection and compilation of data. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, de-escalation, optimizing dosing, active use of information technology among other measure. The recommendations in these guidelines are intended to support, and not replace, good clinical judgment. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments.


Elasticity-dependent self-assembly of micro-templated chromonic liquid crystal films.
We explore micropatterned director structures of aqueous lyotropic chromonic liquid crystal (LCLC) films created on square-lattice cylindrical-micropost substrates. The structures are manipulated by modulating the LCLC mesophases and their elastic properties via concentration through drying. Nematic LCLC films exhibit preferred bistable alignment along the diagonals of the micropost lattice. Columnar LCLC films, dried from nematics, form two distinct director and defect configurations: a diagonally aligned director pattern with local squares of defects, and an off-diagonal configuration with zig-zag defects. The formation of these states appears to be tied to the relative splay and bend free energy costs of the initial nematic films. The observed nematic and columnar configurations are understood numerically using a Landau-de Gennes free energy model. Among other attributes, the work provide first examples of quasi-2D micropatterning of LC films in the columnar phase and lyotropic LC films in general, and it demonstrates alignment and configuration switching of typically difficult-to-align LCLC films via bulk elastic properties.


microRNA-10b Is Overexpressed and Critical for Cell Survival and Proliferation in Medulloblastoma.
This study demonstrates the effects of miRNA-10b on medulloblastoma proliferation through transcriptional induction of the anti-apoptotic protein BCL2. Using a cancer specific miRNA-array, high expression of miRNA-10b in medulloblastoma cell lines compared to a normal cerebellar control was shown, and this was confirmed with real time PCR (RT-PCR). Two medulloblastoma cell lines (DAOY and UW228) were transiently transfected with control miRNA, miRNA-10b inhibitor or miRNA-10b mimic and subjected to RT-PCR, MTT, apoptosis, clonogenic assay and western blot analysis. Transfection of miRNA-10b inhibitor induced a significant down-regulation of miRNA-10b expression, inhibited proliferation, and induced apoptosis, while miRNA-10b mimic exerted an opposite effect. Inhibition of miRNA-10b abrogated the colony-forming capability of medulloblastoma cells, and markedly down-regulated the expression of BCL2. Down-regulation of BCL2 by antisense oligonucleotides or siRNA also significantly down-regulated miRNA-10b, suggesting that BCL2 is a major mediator of the effects of miRNA-10b. ABT-737 and ABT-199, potent inhibitors of BCL2, downregulated the expression of miRNA-10b and increased apoptosis. Analysis of miRNA-10b levels in 13 primary medulloblastoma samples revealed that the 2 patients with the highest levels of miRNA-10b had multiple recurrences (4.5) and died within 8 years of diagnosis, compared with the 11 patients with low levels of miRNA-10b who had a mean of 1.2 recurrences and nearly 40% long-term survival. The data presented here indicate that miRNA-10b may act as an oncomir in medulloblastoma tumorigenesis, and reveal a previously unreported mechanism with Bcl-2 as a mediator of the effects of miRNA-10b upon medulloblastoma cell survival.


Nanoscale hydration dynamics of DNA-lipid blend dry films: DNA-size dependency.
In this study, nanoscale hydration dynamics of DNA-lipid blend dry films are investigated via small angle X-ray diffraction. Compared to the hydration of lipid films, fragmented short DNA strands and counterions in stacked lipid layers dramatically accelerate both the relaxation of the lamellar distance to a metastable interval and the subsequent peeling-off process of lipid bilayers. Moreover, genome-sized long DNA and counterions accelerate the relaxation process, but suppress the peeling-off process and simultaneously induce a damped-oscillation of the lamellar interval; this is probably due to the viscoelastic properties of the entangled long DNA dissolved in hydrated water between the stacked lipid bilayers. This study's findings can pave the way for producing cell-sized liposomes, which efficiently encapsulate any arbitrary sized DNA through natural swelling.


Real-world incidence and prevalence of systemic lupus erythematosus in Alberta, Canada.
Systemic lupus erythematosus (SLE) is rather uncommon than rare. The purpose of this study was to estimate the incidence and prevalence of SLE in the population of Alberta, Canada, using administrative health data. Multiple population-based data sources, including the Alberta Health Care Insurance Plan Central Stakeholder Registry (AHCIP CSR), Fee-For-Service, and Hospital Discharge Abstract Database were used. Age- and sex-specific incidence and prevalence rates, and 95% confidence intervals (CI), were computed using the AHCIP CSR mid-year population estimates as the denominator, for the period of 2000-2015. The overall incidence of SLE for all age groups was 4.43 (95% CI 3.65, 5.04) per 100,000 population. The overall incidence in male and female of all age groups was 1.26 (95% CI 0.72, 1.76) and 7.69 (95% CI 6.22, 8.81) per 100,000 population, respectively. A prevalence of 47.99 per 100,000 (male = 13.5, female = 83.2) of SLE was observed for the year 2000 and has increased to 90 (male = 25.5, female = 156.7) per 100,000 population in 2015. Over the 16-year period, the incidence of SLE in women was approximately six times higher than in men (odds ratio = 6.16). The highest and lowest incidence was recorded in 2001 and 2015, respectively. Despite the stable incidence of SLE, the findings of the study confirms that the prevalence of SLE has increased over the 16-year period. The increase in prevalence of SLE in Alberta will have an impact on health service utilizations. This finding can be used for planning and evaluating health services for this group of patients. Further studies are required to determine the economic burden of the condition.


Characterization of repetitive sequences controlling phase variation of Haemophilus influenzae lipopolysaccharide.
Phase variation of lipopolysaccharide epitopes of an Haemophilus influenzae serotype b strain (strain RM.7004) occurs through a mechanism which depends on multiple tandem repeats of the DNA sequence 5'-CAAT-3' situated within the chromosomal locus lic1. We report here that the same tetranucleotide repeats are also found in two other genomic loci (lic2 and lic3) of RM.7004. Similar to lic1, there are multiple tandem repeats of 5'-CAAT-3' present at the 5' ends of long open reading frames in lic2 and lic3. Variation in the number of repeats of CAAT, by shifting the upstream initiation codons in or out of phase with the remainder of the open reading frame, could switch on or off the translation of downstream genes. Similar to previously reported findings for lic1, site-directed mutations in the open reading frame downstream (3') from the repeats of CAAT in lic2 abolished phase variation and identified DNA sequences required for the expression of additional oligosaccharide epitopes. When we used an oligonucleotide comprising five repeats of CAAT or DNA sequences specific for lic1, lic2, and lic3 as probes, a survey of other encapsulated H. influenzae strains (serotypes a through f) and nontypable H. influenzae strains (including biotype aegyptius) showed that the chromosome of H. influenzae can have from two to five regions which contain multiple tandem repeats of CAAT in addition to other sequences which hybridize to lic1 and lic2.


Relationship of semicircular canal size to vestibular-nerve afferent sensitivity in mammals.
The relationship between semicircular canal radius of curvature and afferent sensitivity has not been experimentally determined. We characterized mouse semicircular canal afferent responses to sinusoidal head rotations to facilitate interspecies and intraspecies comparisons of canal size to sensitivity. The interspecies experiment compared the horizontal canal afferent responses among animals ranging in size from mouse to rhesus monkey. The intraspecies experiment compared afferent responses from the larger anterior canal to those from the smaller horizontal canal of mice. The responses of mouse vestibular-nerve afferents showed a low- and high-frequency phase lead and high-frequency gain enhancement. Regular horizontal-canal afferents showed a sensitivity to 0.5-Hz sinusoidal rotations of 0.10 +/- 0.03 (SD) spike . s(-1)/deg . s(-1) and high-gain irregular afferents showed a sensitivity of 0.25 +/- 0.11 spike . s(-1)/deg . s(-1). The interspecies comparison showed that the sensitivity of regular afferents was related to the radius of curvature R according to the formula G(r) = 0.23R - 0.09 (r(2) = 0.86) and the sensitivity of irregular afferents was related to radius according to the formula G(i) = 0.32R + 0.01 (r(2) = 0.67). The intraspecies comparison showed that regularly firing anterior canal afferents were significantly more sensitive than those from the relatively smaller horizontal canal, with G(r) = 0.25R. This suggests that canal radius of curvature is closely related to afferent sensitivity both among and within species. If the relationship in humans is similar to that demonstrated here, the sensitivity of their regular vestibular-nerve afferents to 0.5-Hz rotations is likely to be about 0.67 spike . s(-1)/deg . s(-1) and of their high-gain irregular afferents about 1.06 spikes . s(-1)/deg . s(-1).


Racialized genetics and the study of complex diseases: the thrifty genotype revisited.
Current debate on the use of population genetic data for complex disease research is driven by the laudable goals of disease prevention and harm reduction for all, especially dispossessed, formerly enslaved, or colonized populations. This article examines one of the oldest gene-based theories of complex disease causation: the thrifty genotype hypothesis (THG). This hypothesis is emblematic of the way in which genetic research into complex disease attracts a high investment of scientific resources while contributing little to our capacity to understand these diseases and perpetuating problematic conceptions of human variation. Although there are compelling reasons to regard the high prevalence of type 2 diabetes mellitus as a by-product of our biological incapacity to cope with modern affluent and sedentary lifestyles, there is at present no consistent evidence to suggest that minority populations are especially genetically susceptible. Nor is it clear why such genetic differences would be expected, given the original pan-species orientation of the TGH. The limitations inherent in current applications of the TGH demonstrate that genetic research into complex disease demands careful attention to key environmental, social, and genetic risk factors operating within and between groups, not the simplistic attribution of between-group differences to racialized genetics. A robust interdisciplinary approach to genetic epidemiological research is proposed.


Maternal reasons for requesting planned cesarean section in Norway: a qualitative study.
Pregnant women who request a cesarean section in the absence of obstetric indication have become a highly debated issue in academic as well as popular literature. In order to find adequate, targeted treatment and preventive strategies, we need a better understanding of this phenomenon. The aim of this study is to provide a qualitative exploration of maternal requests for a planned cesarean section in Norway, in the absence of obstetric indications. A descriptive qualitative study was conducted consisting of 17 semi-structured, in-depth interviews with women requesting cesarean section and six focus group discussions with 20 caregivers (nine midwives, 11 obstetricians) working at a university hospital in Norway. Data were analyzed with Systematic Text Condensation, a method for thematic cross-case analysis. Fear of birth emerged most commonly as a result of a previous traumatic birth experience that prompted a preference for a planned cesarean to avoid a repetition of the trauma. For some women in our study, postnatal care and the puerperal period were their crucial past experiences, and giving birth by planned cesarean was seen as a way to ensure mental rather than physical capability to care for the expected child after birth. Others were under the impression of being at high risk for an emergency C-section, and requesting a planned one was based on their perceived risk. Such perceptions included having a narrow pelvis, hereditary factors or previous birth outcomes. Some primiparas requested a planned cesarean based on a deep-seated fear since their early teens, accompanied by alienation towards the idea of giving birth. Some obstetricians participating in our study also experienced requests that lacked what they regarded as any well-grounded reason or significant fear. Behind a maternal request for a planned cesarean section are various rationales and life experiences needing carefully targeted attention and health care. Previous births are an important driver; thus, maternally requested cesareans should be regarded partly as an iatrogenic problem.


Why Is Eradicating Typhoid Fever So Challenging: Implications for Vaccine and Therapeutic Design.
Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi, namely typhoidal Salmonellae, are the cause of (para) typhoid fever, which is a devastating systemic infectious disease in humans. In addition, the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. Typhi in many low and middle-income countries poses a significant risk to human health. While currently available typhoid vaccines and therapeutics are efficacious, they have some limitations. One important limitation is the lack of controlling individuals who chronically carry S. Typhi. However, due to the strict host specificity of S. Typhi to humans, S. Typhi research is hampered. As a result, our understanding of S. Typhi pathogenesis is incomplete, thereby delaying the development and improvement of prevention and treatment strategies. Nonetheless, to better combat and contain S. Typhi, it is vital to develop a vaccine and therapy for controlling both acutely and chronically infected individuals. This review discusses how scientists are trying to combat typhoid fever, why it is so challenging to do so, which approaches show promise, and what we know about the pathogenesis of S. Typhi chronic infection.


Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites.
Cyclic ADP-ribose is an important calcium mobilizing metabolite produced by the ADP-ribosyl cyclase (cyclases) family of enzymes. Three evolutionarily conserved ADP-ribosyl cyclase superfamily members have been identified, one from the invertebrate Aplysia californica and two from mammalian tissues, CD38 and CD157. CD38 regulates calcium signaling in a number of cell types, and it was recently shown that cyclic ADP-ribose produced by CD38 modulates calcium mobilization induced upon chemokine receptor engagement. Excitingly, because immunocytes deficient in CD38 are unable to migrate to inflammatory sites in vivo, this enzyme has now become an attractive target for drug development. To rationally design inhibitors it is critical to understand the mechanism(s) by which CD38 catalyzes the transformation of its substrate NAD+ into cyclic ADP-ribose. Likewise, it is necessary to identify the CD38 substrate-binding site. Importantly, significant progress has been made in these two areas and much is now known about the structure and enzymology of CD38 and the other ADP-ribosyl cyclase superfamily members. In this review, we will outline the critical data demonstrating a role for CD38 in regulating calcium mobilization in mammalian cells. We will also describe the crystallographic data and site-directed mutagenesis studies that have helped to elucidate the CD38 structure and the identification of its active site and key catalytic residues. Finally, we will address the important advances in our understanding of the kinetic and molecular mechanisms that control cyclic ADP-ribose production by CD38.


Perinodal slow potential as a local guide for transcatheter radiofrequency ablation of atrioventricular nodal reentrant tachycardia: therapeutic efficacy and electrophysiological mechanisms of success.
A specific local indicator in the Koch's triangle could be critical to the complication-free treatment of atrioventricular nodal reentrant tachycardia by transcatheter radiofrequency ablation. Recording of perinodal slow potential reflects a slow conduction area, and probably indicates the location of the slow pathway component of the circuit. Specific ablation of the slow pathway would carry the least risk of atrioventricular block. Guided by the mapped perinodal slow potential, atrioventricular nodal reentrant tachycardia was successfully eliminated in all of 55 consecutive patients in one session. Fifty two patients (94.5%) had confirmed slow potential at the final success sites. Despite the good result, the underlying electrophysiological mechanisms of early success from slow-potential-guiding catheter ablation were heterogeneous: selective slow pathway eradication in 31 patients (56.4%, group A), selective slow pathway modification in 18 patients (32.7%, group B), inadvertent fast pathway damage in six patients (10.9%, group C). Group B patients had the preservation of dual atrioventricular nodal pathways, adequate atrio-Hisian delay, fast pathway facilitation, and a higher frequency of inducible, single non-conducted nodal echo (15/18, 83.3% v 6/31, 19.4% in group A, P << 0.001). The upper communicating path of the circuit was implicated as another site of radiofrequency destruction. Three recurrences were documented in follow up study. However, reablation by the same approach caused complete atrioventricular block in one patient (1.7%, 1/58 procedures). None of the local characteristics of ablation sites was an independent predictor of procedure outcome. Perinodal slow potential is not a specific slow pathway indicator in transcatheter radiofrequency ablation of atrioventricular nodal reentrant tachycardia. Multiple strategic sites of the reentry circuit may be damaged through similar local signals.


Translocation of heparanase into nucleus results in cell differentiation.
We recently reported that heparanase, one of the extracellular matrix-degrading enzymes, which plays a critical role in cancer progression, is located not only in the cytoplasm but also in the nucleus. Here we identified nuclear translocation of heparanase as a key step in cell differentiation. We applied an in vitro differentiation model of HL-60 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA), in which nuclear translocation of heparanase was observed using immunohistochemical analysis. In this system, nuclear translocation of heparanase was abolished by inhibitors of heat shock protein 90 (HSP90), suggesting the involvement of HSP90 in translocation of heparanase. We further confirmed that overexpression of active form of heparanase induced differentiation of HL-60 cells, although the catalytic negative form of heparanase did not. Therefore we speculate that nuclear translocation of enzymatically active heparanase may be involved in cellular differentiation. Our results suggest that a novel function of heparanase upon cell differentiation would raise a potential new strategy for cancer therapy of promyeloid leukemia and other types of cancer.


Activating without inhibiting: left-edge boundary tones and syntactic processing.
Right-edge boundary tones have earlier been found to restrict syntactic processing by closing a clause for further integration of incoming words. The role of left-edge intonation, however, has received little attention to date. We show that Swedish left-edge boundary tones selectively facilitate the on-line processing of main clauses, the syntactic structure they are associated with. In spoken Swedish, main clauses are produced with a left-edge boundary tone, which is absent in subordinate clauses. Main and subordinate clauses are further distinguished syntactically by word order when containing sentence adverbs. The effects of tone and word order on the processing of embedded main, subordinate, and neutral clauses (lacking sentence adverbs) were measured using ERPs. A posterior P600 in embedded main clauses and a smaller P600 in subordinate clauses indicated that embedded clauses with sentence adverbs were structurally less expected than neutral clauses and thus were reanalyzed. The tone functioned as a cue for main clause word order, selectively reducing the P600 in embedded main clauses, without affecting the processing of subordinate or neutral clauses. Its perception was reflected in a right frontal P200 effect. The left-edge boundary tone thus seems to activate a main clause structure, albeit without suppressing alternative structures. The P600 was also preceded by a short positive effect in cases where a left-edge boundary tone was absent.


D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways.
Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of G GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D2-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D2-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D2DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D2DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D2DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D2DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.


Linkage analysis and exclusion of regions of chromosomes 3 and 8 in Gilles de la Tourette syndrome following the identification of a balanced reciprocal translocation 46 XY, t(3:8)(p21.3 q24.1) in a case of Tourette syndrome.
Gilles de la Tourette syndrome (GTS) and related disorders such as chronic multiple tics and obsessive compulsive behaviour are likely to be genetically transmitted with a Mendelian autosomal dominant mode of transmission. Following our discovery of a patient with GTS who also carried a balanced translocation 46 XY, t(3:8) (p21.3 q24.1), a linkage study of several families was performed covering the areas on chromosomes 3 and 8 implicated by the cytogenetic abnormality in this unique GTS patient. A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB and D3S11. Subsequently, the genetic map of this region was improved and new polymorphic markers close to our original three markers were identified. With the new map the maximum two-point lod with any marker was reduced to 1.77 at RAF1, and the FASTMAP approximate multipoint lod excluded the likely region of the breakpoint. After constructing a somatic cell hybrid, the original three markers were mapped relative to the break point of the translocation and to other new markers. It was confirmed that the original markers were at least 20 cM away from the position of the break point. In addition, we traced further family members of our translocation GTS proband, and identified affected individuals who did not possess the translocation. We concluded that the translocation was not responsible for the GTS symptoms in our affected proband.


An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2.
Thyroid transcription factor-1 (TTF1) immunohistochemistry (IHC) is used clinically to differentiate primary lung adenocarcinomas (LUAD) from squamous lung cancers and metastatic adenocarcinomas from other primary sites. However, a subset of LUAD (15%-20%) does not express TTF1, and TTF1-negative patients have worse clinical outcomes. As there are no established targeted agents with activity in TTF1-negative LUAD, we performed an integrated molecular analysis to identify potential therapeutic targets. Using two clinical LUAD cohorts (274 tumors), one from our institution (PROSPECT) and The Cancer Genome Atlas, we interrogated proteomic profiles (by reverse phase protein array, RPPA), gene expression, and mutational data. Drug response data from 74 cell lines were used to validate potential therapeutic agents. Strong correlations were observed between TTF1 IHC and TTF1 measurements by RPPA (Rho = 0.57, P < 0.001) and gene expression (NKX2-1, Rho = 0.61, P < 0.001). Established driver mutations (e.g., BRAF and EGFR) were associated with high TTF1 expression. In contrast, TTF1-negative LUAD had a higher frequency of inactivating KEAP1 mutations (P = 0.001). Proteomic profiling identified increased expression of DNA repair proteins (e.g., Chk1 and the DNA repair score) and suppressed PI3k/mTOR signaling among TTF1-negative tumors, with differences in total proteins confirmed at the mRNA level. Cell line analysis showed drugs targeting DNA repair to be more active in TTF1-low cell lines. Combined genomic and proteomic analyses demonstrated infrequent alteration of validated lung cancer targets (including the absence of BRAF mutations in TTF1-negative LUAD), but identified novel potential targets for TTF1-negative LUAD, including KEAP1/Nrf2 and DNA repair pathways.


Slice-to-volume registration and its potential application to interventional MRI-guided radio-frequency thermal ablation of prostate cancer.
In this study, we registered live-time interventional magnetic resonance imaging (iMRI) slices with a previously obtained high-resolution MRI volume that in turn can be registered with a variety of functional images, e.g., PET, SPECT, for tumor targeting. We created and evaluated a slice-to-volume (SV) registration algorithm with special features for its potential use in iMRI-guided radio-frequency (RF) thermal ablation of prostate cancer. The algorithm features included a multiresolution approach, two similarity measures, and automatic restarting to avoid local minima. Imaging experiments were performed on volunteers using a conventional 1.5-T MR scanner and a clinical 0.2-T C-arm iMRI system under realistic conditions. Both high-resolution MR volumes and actual iMRI image slices were acquired from the same volunteers. Actual and simulated iMRI images were used to test the dependence of SV registration on image noise, receive coil inhomogeneity, and RF needle artifacts. To quantitatively assess registration, we calculated the mean voxel displacement over a volume of interest between SV registration and volume-to-volume registration, which was previously shown to be quite accurate. More than 800 registration experiments were performed. For transverse image slices covering the prostate, the SV registration algorithm was 100% successful with an error of <2 mm, and the average and standard deviation was only 0.4 mm +/- 0.2 mm. Visualizations such as combined sector display and contour overlay showed excellent registration of the prostate and other organs throughout the pelvis. Error was greater when an image slice was obtained at other orientations and positions, mostly because of inconsistent image content such as that from variable rectal and bladder filling. These preliminary experiments indicate that MR SV registration is sufficiently accurate to aid image-guided therapy.


Disseminated form of Langerhans cell histiocytosis discovered in stomatological examination--a case report.
Langerhans cell histiocytosis (LCH) is a disease involving formation of granulomatous infiltrations consisting of Langerhans cells, histiocytes, lymphocytes and eosinophilic granulocytes. Etiopathogenesis of this disease has not been fully clarified yet. It can present as a focal and disseminated form (acute and chronic). Rare incidence of this disease in the population causes progress in research and new therapeutic methods to be slow. Basing upon a case of a patient treated for gingivo-osseous lesions in the course of LCH, we tried to prove that a dental or maxillofacial surgeon may be the first contact medical professional who contributes to the diagnosis of LCH as a systemic disease.


Identification and characterization of osteoclast-like cells and their progenitors in cultures of feline marrow mononuclear cells.
The predominant cell responsible for bone resorption, the multinucleated osteoclast, has been difficult to study because of inaccessibility. When feline marrow-derived mononuclear cells are established in long-term culture, multinucleated cells form within 48 h, reaching maximum numbers at 16 d. We have observed that these cultured cells have many of the features of osteoclasts. Morphologically, they are multinucleated, contain large numbers of branched mitochondria, have a peripheral cytoplasm lacking organelles (a clear zone), and have extensive cell-surface processes. In addition to these ultrastructural features, the cells contain a tartrate-resistant acid phosphatase, the activity of which is increased by parathyroid hormone (PTH) and inhibited by calcitonin. PTH, prostaglandin E2, and 1,25(OH)2 vitamin D3 increased multinucleated cell formation, while calcitonin inhibited the stimulatory effects of PTH. Time-lapse cinemicrographic and autoradiographic studies indicated that the multinucleated cells formed by fusion of the mononuclear progenitors. The multinucleated cells were phagocytic and stained with nonspecific esterase, consistent with their being derived from immature monocytes. Further, cell populations enriched for multinucleated cells release 45Ca from devitalized bone. Density-gradient centrifugation on Percoll was used to enrich and characterize the mononuclear progenitors of these multinucleated cells. The progenitor cells were found predominantly in Percoll density layers of 1.065 to 1.08 g/ml and were enriched up to 30-fold as compared to unfractionated cells. The bone marrow mononuclear cells that formed the multinucleated cells were initially nonadherent to plastic, stained heavily with nonspecific esterase, and appeared to be immature monocytes histologically. These data indicate that the multinucleated osteoclast-like cells in our cultures are derived from nonadherent monocytic progenitor cells that are responsive to osteotropic hormones. The ability to grow and characterize these cells in vitro should facilitate studies to elucidate the role these cells play in normal and pathologic states of bone resorption.


The clinical management of abdominal ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: a review of current guidelines and recommendations.
Several pathogenic processes have been implicated in the development of abdominal ascites. Portal hypertension, most usually in the context of liver cirrhosis, can explain about 75% of the cases, whereas infective, inflammatory and infiltrative aetiologies can account for the rest. In this article, we discuss the consensus best practice as published by three professional bodies for the management of ascites, spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS). The aim of this study was to compare available clinical guidelines and identify areas of agreement and conflict. We carried out a review of the guidance documentation published by three expert bodies including the British Society of Gastroenterology, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), as well as a wider literature search for ascites, SBP and HRS. Abdominal ultrasonography, diagnostic paracentesis and ascitic fluid cultures are recommended by all three guidelines, especially when there is strong clinical suspicion for infection. EASL and AASLD advocate the use of ascitic amylase and mycobacterial cultures/PCR when there is strong suspicion for tuberculosis and pancreatitis, respectively. Ascitic cytology can be useful when cancer is suspected and has a good diagnostic yield if performed correctly. EASL supports the use of urinary electrolytes for all patients; however, the British Society of Gastroenterology and AASLD only recommend their use for therapy monitoring. All three societies recommend cefotaxime as the antibiotic of choice for SBP and large-volume paracentesis for the management of ascites greater than 5 l in volume. For HRS, cautious diuresis, volume expansion with albumin and the use of vasoactive drugs are recommended. There appears to be good concordance between recommendations by the European, American and British guidelines for the management of ascites and the possible complications arising from it.


The herpes simplex virus gE-gI complex facilitates cell-to-cell spread and binds to components of cell junctions.
The herpes simplex virus (HSV) glycoprotein complex gE-gI mediates the spread of viruses between adjacent cells, and this property is especially evident for cells that form extensive cell junctions, e.g., epithelial cells, fibroblasts, and neurons. Mutants lacking gE or gI are not compromised in their ability to enter cells as extracellular viruses. Therefore, gE-gI functions specifically in the movement of virus across cell-cell contacts and, as such, provides a molecular handle on this poorly understood process. We expressed gE-gI in human epithelial cells by using replication-defective adenovirus (Ad) vectors. gE-gI accumulated at lateral surfaces of the epithelial cells, colocalizing with the adherens junction protein beta-catenin but was not found on either the apical or basal plasma membranes and did not colocalize with ZO-1, a component of tight junctions. In subconfluent monolayers, gE-gI was found at cell junctions but was absent from those lateral surfaces not in contact with another cell, as was the case for beta-catenin. Similar localization of gE-gI to cell junctions was observed in HSV-infected epithelial cells. By contrast, HSV glycoprotein gD, expressed using a recombinant Ad vectors, was found primarily along the apical surfaces of cells, with little or no protein found on the basal or lateral surfaces. Expression of gE-gI without other HSV polypeptides did not cause redistribution of either ZO-1 or beta-catenin or alter tight-junction functions. Together these results support a model in which gE-gI accumulates at sites of cell-cell contact by interacting with junctional components. We hypothesize that gE-gI mediates transfer of HSV across cell junctions by virtue of these interactions with cell junction components.


Why do patients with schizophrenia who have poor insight still take antipsychotics? Memory deficits as moderators between adherence belief and behavior.
While lack of insight is often predictive of antipsychotic nonadherence, some inconsistency in the literature remains unexplained. Verbal memory deficits may moderate the association between insight and adherence. Based on cross-sectional data, outpatients treated with antipsychotics for a psychotic disorder were divided into those with good (n=53) and poor (n=59) memory. Poor insight predicted nonadherence only among the subgroup with relatively good memory (r=0.43; P<0.01), but had no effect in the subgroup with worse memory (r=0.08; ns). Structural equation modelling revealed significant moderation (χ=4.72; df=1; P<0.05), which means that a significantly better model fit was found by allowing the analysis to differentiate between the two memory groups. Thus, poor insight was only associated with poor medication adherence among patients with relatively good memory. We speculate that memory deficits commonly associated with schizophrenia may partly explain why poor insight does not always lead to poor medication adherence.


Prognostic factors associated with hepatitis C disease: a case-control study utilizing U.S. multiple-cause-of-death data.
Hepatitis C, an important cause of premature mortality, is the most common chronic bloodborne infection in the United States. The severity of disease is strongly affected by a number of other medical conditions and health behaviors. We sought to estimate the association of several exposures with hepatitis C on death certificates. We enrolled 63,189 hepatitis C deaths as cases in a case-control study using multiple-cause-of-death data for the U.S. from 1999 to 2004. Three control groups were assembled from all remaining deaths with no mention of hepatitis C, including a random sample of all deaths, digestive disease deaths, and circulatory disease deaths. Hepatitis B, human immunodeficiency virus (HIV), hemochromatosis, and alcohol use were all strongly associated with hepatitis C, even after controlling for confounding variables. The simultaneous presence of many of these exposures had a synergistic association with hepatitis C being listed as a cause of death. Hepatitis B, HIV, and alcohol use were recorded among 6.4%, 10.5%, and 18.2% of case deaths, respectively. The strong association of alcohol use, HIV, and hepatitis B with hepatitis C, as well as the frequent occurrence of these conditions, indicates that targeted interventions for mitigating the potential effect of these exposures may present an efficient means of limiting progression of hepatitis C-related liver disease and reducing the population burden of hepatitis C mortality.


Benzodiazepine Use During Pregnancy Alone or in Combination With an Antidepressant and Congenital Malformations: Systematic Review and Meta-Analysis.
To summarize the effects of antenatal benzodiazepine exposure as monotherapy and in combination with antidepressants on the risk of congenital malformations. MEDLINE, PsycINFO, CINAHL, Embase, and the Cochrane Library were searched from inception to June 30, 2018, using controlled vocabulary and keywords (eg, prenatal, benzodiazepines, malformation). English-language cohort studies with prospectively collected data on the risk of malformations in benzodiazepine-exposed and -unexposed offspring were evaluated. 23,909 records were screened, 56 studies were assessed for eligibility, and 8 studies were included. Quality was assessed by 2 independent reviewers and data extracted. Random-effects models were used for outcomes (≥ 3 studies). Subanalyses examined effect of potential moderators including study quality and timing of exposure, among others. Prenatal benzodiazepine use was not associated with an increased risk of congenital malformations (odds ratio [OR] = 1.13; 95% CI, 0.99 to 1.30, 8 studies, n = 222/5,195 exposed and 64,335/2,082,467 unexposed), including with first trimester exposure specifically (OR = 1.08; 95% CI, 0.93 to 1.25, P = .33; 5 studies, n = 181/4,331 exposed and 64,308/2,081,463 unexposed). There was no significant association with cardiac malformation following exposure (OR = 1.27; 95% CI, 0.98 to 1.65, P = .07; 4 studies, n = 61/4,414 exposed and 19,260/2,033,402 unexposed). However, concurrent use of benzodiazepine and antidepressants during pregnancy was associated with a significantly increased risk of congenital malformations (OR = 1.40; 95% CI, 1.09 to 1.80, P = .008; 3 studies). Benzodiazepine exposure during pregnancy does not appear to be associated with congenital malformations or with cardiac malformations specifically. There may be an increased risk of congenital malformations when benzodiazepines are used in conjunction with antidepressants, suggesting that caution with this combination is warranted.


Human intracranial recordings link suppressed transients rather than 'filling-in' to perceptual continuity across blinks.
We hardly notice our eye blinks, yet an externally generated retinal interruption of a similar duration is perceptually salient. We examined the neural correlates of this perceptual distinction using intracranially measured ECoG signals from the human visual cortex in 14 patients. In early visual areas (V1 and V2), the disappearance of the stimulus due to either invisible blinks or salient blank video frames ('gaps') led to a similar drop in activity level, followed by a positive overshoot beyond baseline, triggered by stimulus reappearance. Ascending the visual hierarchy, the reappearance-related overshoot gradually subsided for blinks but not for gaps. By contrast, the disappearance-related drop did not follow the perceptual distinction - it was actually slightly more pronounced for blinks than for gaps. These findings suggest that blinks' limited visibility compared with gaps is correlated with suppression of blink-related visual activity transients, rather than with "filling-in" of the occluded content during blinks.


The effect of high versus low intensity heat acclimation on performance and neuromuscular responses.
This study examined the effect of exercise intensity and duration during 5-day heat acclimation (HA) on cycling performance and neuromuscular responses. 20 recreationally trained males completed a 'baseline' trial followed by 5 consecutive days HA, and a 'post-acclimation' trial. Baseline and post-acclimation trials consisted of maximal voluntary contractions (MVC), a single and repeated countermovement jump protocol, 20km cycling time trial (TT) and 5×6s maximal sprints (SPR). Cycling trials were undertaken in 33.0 ± 0.8°C and 60 ± 3% relative humidity. Core (Tcore), and skin temperatures (Tskin), heart rate (HR), rating of perceived exertion (RPE) and thermal sensation were recorded throughout cycling trials. Participants were assigned to either 30min high-intensity (30HI) or 90min low-intensity (90LI) cohorts for HA, conducted in environmental conditions of 32.0 ± 1.6°C. Percentage change time to complete the 20km TT for the 90LI cohort was significantly improved post-acclimation (-5.9 ± 7.0%; P=0.04) compared to the 30HI cohort (-0.18 ± 3.9%; P<0.05). The 30HI cohort showed greatest improvements in power output (PO) during post-acclimation SPR 1 and 2 compared to 90LI (546 ± 128W and 517 ± 87W, respectively; P<0.02). No differences were evident for MVC within 30HI cohort, however, a reduced performance indicated by % change within the 90LI (P=0.04). Compared to baseline, mean Tcore was reduced post-acclimation within the 30HI cohort (P=0.05) while mean Tcore and HR were significantly reduced within the 90LI cohort (P=0.01 and 0.04, respectively). Greater physiological adaptations and performance improvements were noted within the 90LI cohort compared to the 30HI. However, 30HI did provide some benefit to anaerobic performance including sprint PO and MVC. These findings suggest specifying training duration and intensity during heat acclimation may be useful for specific post-acclimation performance.


Microbial Contamination Level Profiles Attributed to Contamination of Beef Carcasses, Personnel, and Equipment: Case of Small and Medium Enterprise Slaughterhouses.
The microbial contamination level profiles (MCLPs) attributed to contamination of beef carcasses, personnel, and equipment in five Kenyan small and medium enterprise slaughterhouses were determined. Aerobic plate counts, Enterobacteriaceae, Staphylococcus, and Salmonella were used to determine contamination at four different slaughter stages, namely, dehiding, evisceration, splitting, and dispatch. Microbiological criteria of the four microorganisms were used to score contamination levels (CLs) as poor (0), poor to average (1), average (2), or good (3). MCLPs were further assigned to carcasses, personnel, and equipment at each stage by summing up the CL scores. The CL score attributed to aerobic plate count contamination was 2 or 3 for carcasses but 0 for personnel and equipment in almost all slaughterhouses. A score of 0 on carcasses was mostly attributed to Enterobacteriaceae at evisceration and to Salmonella at dehiding and evisceration. In addition, a score of 0 was mostly attributed to Staphylococcus contamination of personnel at dehiding. A score of 3 was attributed mostly to Enterobacteriaceae on hands at splitting, whereas a score of 2 was mostly attributed to the clothes at dehiding and evisceration. A CL score of 3 was mostly attributed to Enterobacteriaceae and Salmonella contamination of equipment at dehiding and splitting, respectively. Although CLs attributed to contamination of carcasses, personnel, and equipment ranged from 0 to 3, the maximum MCLP score of 9 was only attained in carcasses from two slaughterhouses at dehiding and from one slaughterhouse at dispatch. There is, therefore, a lot of room for small and medium enterprise slaughterhouses to improve their food safety objectives by improving food safety management systems at the points characterized by low CL scores.


Anterior sphincteroplasty for fecal incontinence: predicting incontinence relapse.
This study was designed to evaluate the efficiency of anterior sphincteroplasty in preventing fecal incontinence relapsing in 85 female patients. This observational study followed individuals for up to 10 years after intervention. Fecal incontinence relapse was analyzed using Generalized Linear Models and Kaplan-Meier tables. Bias due to informative censoring and missing data were assessed. Two postoperative cutoff Wexner scores (4 and 8) were used to classify individuals into continent or incontinent, and their model implications were examined. The hazard of relapsing appeared constant over time. This led to exponential time-to-relapse functions, and a linear increase of cumulative hazard over time. Predicted median relapsing time was 33 years, and overall risk 0.09 ± 0.03, when using a cutoff Wexner score of 8 (moderate), and 5 years, overall risk 0.45 ± 0.05, when using a cutoff of 4 (mild). There was a potential underestimation in parameters (bias) due to informative censoring, i.e., individual with better prognoses were more likely to drop out before relapsing compared to those with worse prognoses. Thus, true relapsing times may be longer than our current estimates. The predictive model can be used in practice for individual prognosis after intervention, based on preoperative Wexner scores. The effect of anterior sphincteroplasty on fecal incontinence does not seem to deteriorate over time. A consensus Wexner cutoff is necessary to compare data and interventions.


Planning Marine Reserve Networks for Both Feature Representation and Demographic Persistence Using Connectivity Patterns.
Marine reserve networks must ensure the representation of important conservation features, and also guarantee the persistence of key populations. For many species, designing reserve networks is complicated by the absence or limited availability of spatial and life-history data. This is particularly true for data on larval dispersal, which has only recently become available. However, systematic conservation planning methods currently incorporate demographic processes through unsatisfactory surrogates. There are therefore two key challenges to designing marine reserve networks that achieve feature representation and demographic persistence constraints. First, constructing a method that efficiently incorporates persistence as well as complementary feature representation. Second, incorporating persistence using a mechanistic description of population viability, rather than a proxy such as size or distance. Here we construct a novel systematic conservation planning method that addresses both challenges, and parameterise it to design a hypothetical marine reserve network for fringing coral reefs in the Keppel Islands, Great Barrier Reef, Australia. For this application, we describe how demographic persistence goals can be constructed for an important reef fish species in the region, the bar-cheeked trout (Plectropomus maculatus). We compare reserve networks that are optimally designed for either feature representation or demographic persistence, with a reserve network that achieves both goals simultaneously. As well as being practically applicable, our analyses also provide general insights into marine reserve planning for both representation and demographic persistence. First, persistence constraints for dispersive organisms are likely to be much harder to achieve than representation targets, due to their greater complexity. Second, persistence and representation constraints pull the reserve network design process in divergent directions, making it difficult to efficiently achieve both constraints. Although our method can be readily applied to the data-rich Keppel Islands case study, we finally consider the factors that limit the method's utility in information-poor contexts common in marine conservation.


Different haemodynamic patterns in head-up tilt test on 400 paediatric cases with unexplained syncope.
To assess haemodynamic patterns in head-up tilt testing on 400 paediatric cases with unexplained syncope. Medical records of 520 children who underwent head-up tilt testing in the preceding year were retrospectively evaluated, and 400 children, 264 (66%) girls and 136 (34%) boys, aged 12.6±2.6 years (median 13; range 5-18), with unexplained syncope were enrolled in the study. Age, sex, baseline heart rate, baseline blood pressure, frequency of symptoms, and/or fainting attacks were recorded. The test protocol consisted of 25 minutes of supine resting followed by 20 minutes of 70° upright positioning. Subjects were divided into nine groups according to their differing haemodynamic patterns. There were no statistically significant differences between the groups with regard to age, gender, baseline blood pressure, and frequency of syncope (p>0.05). The response was compatible with orthostatic intolerance in 28 cases (7.0%), postural orthostatic tachycardia syndrome in 24 cases (6.0%), asymptomatic postural orthostatic tachycardia syndrome in 26 cases (6.5%), orthostatic hypotension in seven cases (1.7%), vasovagal syncope in 38 cases (9.5%), and negative in 274 cases (69.2%). Vasovagal syncope response patterns were of type 3 in nine cases (2.2%), type 2A in 10 cases (2.5%), type 2B in two cases (0.5%), and type 1 (mixed) in 17 cases (4.25%). In the 400 paediatric cases with unexplained syncope, nine different haemodynamic response patterns to head-up tilt testing were discerned. Children with orthostatic intolerance syndromes are increasingly referred to hospitals because of difficulty in daily activities. Therefore, there is need for further clinical trials in these patient groups.


Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature.
Based on the hypothesis that cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary or alternative therapy for treatment of malignant gliomas. We report here our experience in treating two glioma patients with an IRB-approved energy-restricted ketogenic diet (ERKD) protocol as monotherapy and review the literature on KD therapy for human glioma patients. An ERKD protocol was used in this pilot clinical study. In addition to the two patients who enrolled in this study, we also reviewed findings from 30 other patients, including 5 patients from case reports, 19 patients from a clinical trial reported by Rieger and 6 patients described by Champ. A total of 32 glioma patients have been treated using several different KD protocols as adjunctive/complementary therapy. The two patients who enrolled in our ERKD pilot study were monitored with twice daily measurements of blood glucose and ketones and daily weights. However, both patients showed tumor progression while on the ERKD therapy. Immunohistochemistry reactions showed that their tumors had tissue expression of at least one of the two critical mitochondrial ketolytic enzymes (succinyl CoA: 3-oxoacid CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1). The other 30 glioma patients in the literature were treated with several different KD protocols with varying responses. Prolonged remissions ranging from more than 5 years to 4 months were reported in the case reports. Only one of these patients was treated using KD as monotherapy. The best responses reported in the more recent patient series were stable disease for approximately 6 weeks. No major side effects due to KD have been reported in any of these patients. We conclude that 1. KD is safe and without major side effects; 2. ketosis can be induced using customary foods; 3. treatment with KD may be effective in controlling the progression of some gliomas; and 4. further studies are needed to determine factors that influence the effectiveness of KD, whether as a monotherapy, or as adjunctive or supplemental therapy in treating glioma patients. ClinicalTrials.gov# NCT01535911.


Efficacy of vitamin D supplementation in depression in adults: a systematic review.
Randomized controlled trials (RCTs) investigating the efficacy of vitamin D (Vit D) in depression provided inconsistent results. We aim to summarize the evidence of RCTs to assess the efficacy of oral Vit D supplementation in depression compared to placebo. We searched electronic databases, two conference proceedings, and gray literature by contacting authors of included studies. We selected parallel RCTs investigating the effect of oral Vit D supplementation compared with placebo on depression in adults at risk of depression, with depression symptoms or a primary diagnosis of depression. Two reviewers independently extracted data from relevant literature. Classical and Bayesian random-effects meta-analyses were used to pool relative risk, odds ratio, and standardized mean difference. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Six RCTs were identified with 1203 participants (72% females) including 71 depressed patients; five of the studies involved adults at risk of depression, and one trial used depressed patients. Results of the classical meta-analysis showed no significant effect of Vit D supplementation on postintervention depression scores (standardized mean difference = -0.14, 95% confidence interval = -0.41 to 0.13, P = .32; odds ratio = 0.93, 95% confidence interval = 0.54 to 1.59, P = .79). The quality of evidence was low. No significant differences were demonstrated in subgroup or sensitivity analyses. Similar results were found when Bayesian meta-analyses were applied. There is insufficient evidence to support the efficacy of Vit D supplementation in depression symptoms, and more RCTs using depressed patients are warranted.


Associations between the five-factor model of personality and leukocyte telomere length in elderly men and women: The Helsinki Birth Cohort Study (HBCS).
Personality traits have been associated with cardiometabolic diseases and mental disorders as well as with longevity. However, the underlying mechanisms are not fully understood. Accelerated cellular aging may play a role in this process. We studied whether personality traits in late adulthood, as defined in the five-factor model (FFM), were associated with a biomarker of cellular vitality, leukocyte telomere length (LTL). At a mean age of 63.4 (SD=2.8) years, 1671 (742 men, 929 women) participants from the Helsinki Birth Cohort Study filled in the Neuroticism, Extraversion and Openness Personality Inventory (NEO-PI). LTL was measured at a mean age of 61.5 (SD=2.9) years by using a real-time quantitative PCR method. None of the FFM personality dimensions were significantly associated with the LTL in the analyses of both sexes combined. We however found interaction between sex and agreeableness (B=0.020, 95% CI=.008, 0.032, p=.001) and in the sex-specific analyses, men who scored higher on agreeableness (B=-0.086, 95% CI=-0.155, -0.016, p=.016) and women who scored lower on agreeableness (B=0.074, 95% CI=0.014, 0.134, p=.016) had shorter LTL. FFM dimensions of personality were not associated with LTL in a sample of elderly individuals. The counterintuitive and sporadic sex specific finding on agreeableness requires replication. Overall our findings suggest that LTL, a biomarker of cellular aging, may not offer insight into the associations between personality, longevity and health.


Shoulder muscle activity during the modified dynamic relocation test and side-lying shoulder external rotation: a cross-sectional study on asymptomatic individuals.
(1) to compare activity levels between monitored muscles during the dynamic relocation test (DRT); (2) to assess changes in muscle activation variability over 10 trials; (3) to assess within-muscle difference activity levels between the DRT and the unloaded side-lying shoulder external rotation exercise. This is a cross-sectional, laboratory-based, repeated measures study. Thirty asymptomatic individuals performed the DRT and unloaded side-lying external rotation. The order of exercises was randomized. Superficial electromyography was used for recording the supraspinatus, infraspinatus, middle deltoid, posterior deltoid, pectoralis major, and latissimus dorsi muscles. The main outcome measures were mean muscle activity, expressed as % of maximal isometric voluntary contraction. We found significant between-muscles differences in activity (Ft = 14.11, p < 0.001) during the DRT. Post hoc analysis suggested between-trial variability did not change over the 10 trials, (F = 18.2, p < 0.001). Within-muscle comparisons between the DRT and side-lying shoulder external rotation suggested significant differences between these exercises (F = 32.37, p < 0.001). considering the monitored muscles, supraspinatus, infraspinatus, pectoralis major, and latissimus dorsi are the main muscles contracting during the DRT. Of all monitored muscles, supraspinatus muscle was the only one presenting higher activity levels during the DRT when compared to the unloaded side-lying shoulder external rotation.


Automated segmentation of endometrial cancer on MR images using deep learning.
Preoperative MR imaging in endometrial cancer patients provides valuable information on local tumor extent, which routinely guides choice of surgical procedure and adjuvant therapy. Furthermore, whole-volume tumor analyses of MR images may provide radiomic tumor signatures potentially relevant for better individualization and optimization of treatment. We apply a convolutional neural network for automatic tumor segmentation in endometrial cancer patients, enabling automated extraction of tumor texture parameters and tumor volume. The network was trained, validated and tested on a cohort of 139 endometrial cancer patients based on preoperative pelvic imaging. The algorithm was able to retrieve tumor volumes comparable to human expert level (likelihood-ratio test, [Formula: see text]). The network was also able to provide a set of segmentation masks with human agreement not different from inter-rater agreement of human experts (Wilcoxon signed rank test, [Formula: see text], [Formula: see text], and [Formula: see text]). An automatic tool for tumor segmentation in endometrial cancer patients enables automated extraction of tumor volume and whole-volume tumor texture features. This approach represents a promising method for automatic radiomic tumor profiling with potential relevance for better prognostication and individualization of therapeutic strategy in endometrial cancer.


Heavy-atom-free BODIPY photosensitizers with intersystem crossing mediated by intramolecular photoinduced electron transfer.
Organic photosensitizers possessing efficient intersystem crossing (ISC) and forming long-living triplet excited states, play a crucial role in a number of applications. A common approach in the design of such dyes relies on the introduction of heavy atoms (e.g. transition metals or halogens) into the structure, which promote ISC via spin-orbit coupling interaction. In recent years, alternative methods to enhance ISC have been actively studied. Among those, the generation of triplet excited states through photoinduced electron transfer (PET) in heavy-atom-free molecules has attracted particular attention because it allows for the development of photosensitizers with programmed triplet state and fluorescence quantum yields. Due to their synthetic accessibility and tunability of optical properties, boron dipyrromethenes (BODIPYs) are so far the most perspective class of photosensitizers operating via this mechanism. This article reviews recently reported heavy-atom-free BODIPY donor-acceptor dyads and dimers which produce long-living triplet excited states and generate singlet oxygen. Structural factors which affect PET and concomitant triplet state formation in these molecules are discussed and the reported data on triplet state yields and singlet oxygen generation quantum yields in various solvents are summarized. Finally, examples of recent applications of these systems are highlighted.


The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.
Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.


Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens.
The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.


FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells.
FBXL5 is the substrate recognition subunit of an SCF-type ubiquitin ligase that serves as a master regulator of iron metabolism in mammalian cells. We previously showed that mice with systemic deficiency of FBXL5 fail to sense intracellular iron levels and die in utero at embryonic day 8.5 (E8.5) as a result of iron overload and subsequent oxidative stress. This early embryonic mortality has thus impeded study of the role of FBXL5 in brain development. We have now generated mice lacking FBXL5 specifically in nestin-expressing neural stem progenitor cells (NSPCs) in the brain. Unexpectedly, the mutant embryos manifested a progressive increase in the number of NSPCs and astroglia in the cerebral cortex. Stabilization of iron regulatory protein 2 (IRP2) as a result of FBXL5 deficiency led to accumulation of ferrous and ferric iron as well as to generation of reactive oxygen species. Pharmacological manipulation suggested that the phenotypes of FBXL5 deficiency are attributable to aberrant activation of mammalian target of rapamycin (mTOR) signaling. Our results thus show that FBXL5 contributes to regulation of NSPC proliferation during mammalian brain development.