Selective hypertrophy of the quadriceps musculature after 14 weeks of isokinetic and conventional resistance training.
One of the fundamental adaptations observed with resistance training (RT) is muscle hypertrophy. Conventional and isokinetic machines provide different forms of mechanical stress, and it is possible that these two training modes could promote differing degrees of hypertrophic adaptations. There is a lack of data comparing the selective hypertrophy of the quadriceps musculature after training with a conventional knee extension machine versus an isokinetic machine. The purpose of this study was to evaluate the selective hypertrophy of the quadriceps musculature and knee extension maximal isometric torque after 14 weeks of conventional versus isokinetic RT. Thirty-five men were assigned to three groups: control group and training groups (conventional and isokinetic) performed three sets of unilateral knee extensions per session with a progressive loading scheme twice a week. Prior to and following the intervention, maximal isometric knee extensor torque was measured using an isokinetic dynamometer, and muscle thickness (MT) of quadriceps femoris muscles was assessed via ultrasound. The results indicated non-uniform changes in MT between the muscles that comprise the quadriceps femoris group. For the conventional group, significantly greater increases in rectus femoris thickness were evident versus all other quadriceps muscles (14%). For the isokinetic group, increases in RF thickness (11%) were significantly greater in comparison with the vastus intermedius only. Although the muscle thickness did not increase for all the quadriceps femoris muscles, the relative rectus femoris adaptation suggested a selective hypertrophy favouring this portion.


Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer's disease.
There is an urgent need for peripheral surrogates of Alzheimer's disease (AD) that accurately reflect disease state and severity as well as correlate with key features of its neuropathology. The aim of this study was to identify plasma proteins associated with known in vivo markers of disease activity. In an earlier proteomic study of plasma, we discovered a panel of 15 proteins that were differentially expressed in AD and further validated complement factor-H (CFH) and alpha-2-macroglobulin (A2M) as AD-specific plasma biomarkers. In the present study, we extended these findings by testing the associations of these plasma proteins with neuro-imaging measures of disease progression in AD. We combined (1)H-magnetic resonance spectroscopy of the hippocampus and MRI-based hippocampal volumetry with proteomic analysis of plasma in early AD and mild cognitive impairment (MCI) to achieve this goal. Using (1)H-magnetic resonance spectroscopy, we derived estimates of the hippocampal metabolite ratio N-acetylaspartate/myo-inositol (NAA/mI), a biochemical measure that is associated with cognitive decline in early AD. We also undertook a proteomic analysis of plasma in these individuals using two-dimensional gel electrophoresis (2DGE). We observed that two plasma proteins previously shown to be differentially expressed in AD, complement factor-H (CFH) and alpha-2-macroglobulin (A2M) showed significant positive correlations with hippocampal NAA/mI ratio in AD. The association of plasma CFH and A2M with hippocampal NAA/mI in this cohort of AD subjects suggests that these proteins may reflect disease progression in early AD. These findings warrant validation in large population-based datasets.


Imaging fatigue of interference control reveals the neural basis of executive resource depletion.
Executive control coordinates, prioritizes, and selects task-relevant representations under conditions of conflict. Behavioral evidence has documented that executive resources are separable, finite, and can be temporarily depleted; however, the neural basis for such resource limits are largely unknown. Here, we investigate the neural correlates underlying the fatigue or depletion of interference control, an executive process hypothesized to mediate competition among candidate memory representations. Using a pre/post continuous acquisition fMRI design, we demonstrate that, compared with a nondepletion control group, the depletion group showed a fatigue-induced performance deficit that was specific to interference control and accompanied by a left-to-right shift in the network of active regions. Specifically, we observed decreased BOLD signal in the left inferior frontal gyrus (IFG), striatum, and the cerebellum, along with a corresponding increase in right hemisphere regions including the IFG, insular, and temporal cortex. Depletion-related changes in activation magnitude correlated with behavioral changes, suggesting that decreased recruitment of task-relevant regions, including left IFG, contributes to impaired interference control. These results provide new evidence about the brain dynamics of "process-specific" fatigue and suggest that depletion may pose a significant limitation on the cognitive and neural resources available for executive control.


Treatment of diffuse large B-cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS-penetrating R-IDARAM chemotherapy.
Diffuse large B-cell lymphoma with secondary involvement of the central nervous system (SCNS-DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS-DLBCL treated with R-IDARAM (rituximab 375 mg/m(2) IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m(2) /day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1-3; cytosine arabinoside 1000 mg/m(2) /day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m(2) IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation ('new disease'), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded - 6 (26%) complete response, 8 (35%) partial response. Grade 3-4 haematological toxicity was seen in all cycles, with no grade 3-4 or long-term neurological toxicity. Median follow-up for surviving patients was 49 months. At 2 years, estimated progression-free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5-year estimated PFS of 50% and OS 75%. R-IDARAM is a well-tolerated regimen with encouraging efficacy in patients with SCNS-DLBCL, although patients with relapsed or refractory disease continue to fare poorly.


Hydroxyapatite and Other Calcium Phosphates for the Conservation of Cultural Heritage: A Review.
The present paper reviews the methods and the performance of in situ formation of calcium phosphates (CaP) for the conservation of materials belonging to cultural heritage. The core idea is to form CaP (ideally hydroxyapatite, HAP, the most stable CaP at pH > 4) by reaction between the substrate and an aqueous solution of a phosphate salt. Initially proposed for the conservation of marble and limestone, the treatment has been explored for a variety of different substrates, including sandstones, sulphated stones, gypsum stuccoes, concrete, wall paintings, archaeological bones and paper. First, the studies aimed at identifying the best treatment conditions (e.g., nature and concentration of the phosphate precursor, solution pH, treatment duration, ionic and organic additions to the phosphate solution, mineralogical composition of the new CaP phases) are summarized. Then, the treatment performance on marble and limestone is reviewed, in terms of protective and consolidating effectiveness, compatibility (aesthetic, microstructural and physical) and durability. Some pilot applications in real case studies are also reported. Recent research aimed at extending the phosphate treatment to other substrates is then illustrated. Finally, the strengths of the phosphate treatment are summarized, in comparison with alternative products, and some aspects needing future research are outlined.


[Primary cutaneous histoplasmosis: case report on an immunocompetent patient and review of the literature].
This report describes a case of primary cutaneous histoplasmosis in a 45-year-old male. The presentation consisted of an erythematous nodule on the back of the right hand, accompanied by nontender regional lymphadenomegaly that developed following local trauma that occurred during military training in a tunnel inhabited by bats. Histological examination of a biopsy specimen from the skin lesion showed granulomatous infiltrate, but did not show fungal elements. Culturing of this material, incubated in Sabouraud agar, showed growth of Histoplasma capsulatum. No evidence of systemic involvement or immunosuppression was found. Treatment with 400 mg/day of itraconazole orally for six months resulted in complete remission of the lesion, which was maintained one year after the end of the treatment.


Derivation and Validation of a Nomogram for Predicting 90-Day Survival in Patients With HBV-Related Acute-on-Chronic Liver Failure.
Background: Conventional prognostic models do not fully reflect the severity of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to establish an effective and convenient nomogram for patients with HBV-related ACLF. Methods: A nomogram was developed based on a retrospective cohort of 1,353 patients treated at the Third Affiliated Hospital of Sun Yat-sen University from January 2010 to June 2016. The predictive accuracy and discriminatory ability of the nomogram were determined by a concordance index (C-index) and calibration curve, and were compared with current scoring systems. The results were validated using an independent retrospective cohort of 669 patients consecutively treated at the same institution from July 2016 to March 2018. This study is registered at ClinicalTrials.gov (NCT03992898). Results: Multivariable analysis of the derivation cohort found that independent predictors of 90-day survival were age, white blood cell (WBC) count, hemoglobin (Hb), aspartate aminotransferase (AST), total bilirubin (TBil), international normalized ratio, serum creatinine (Cr), alpha fetoprotein (AFP), serum sodium (Na), hepatic encephalopathy (HE), pre-existing chronic liver disease(PreLD), and HBV DNA load. All factors were included in the nomogram. The nomogram calibration curve for the probability of 90-day survival indicated that nomogram-based predictions were in good agreement with actual observations. The C-index of the nomogram was 0.790, which was statistically significantly greater than those for the current scoring systems in the derivation cohort (P < 0.001). The results were confirmed in the validation cohort. Conclusions: The proposed nomogram is more accurate in predicting the 90-day survival of patients with HBV-related ACLF than current commonly used methods.


VeriStrat® has a prognostic value for patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab in the first line: pooled analysis of SAKK19/05 and NTR528.
VeriStrat(®) is a serum proteomic test used to determine whether patients with advanced non-small cell lung cancer (NSCLC) who have already received chemotherapy are likely to have good or poor outcomes from treatment with gefitinib or erlotinib. The main objective of our retrospective study was to evaluate the role of VS as a marker of overall survival (OS) in patients treated with erlotinib and bevacizumab in the first line. Patients were pooled from two phase II trials (SAKK19/05 and NTR528). For survival analyses, a log-rank test was used to determine if there was a statistically significant difference between groups. The hazard ratio (HR) of any separation was assessed using Cox proportional hazards models. 117 patients were analyzed. VeriStrat classified patients into two groups which had a statistically significant difference in duration of OS (p = 0.0027, HR = 0.480, 95% confidence interval: 0.294-0.784). VeriStrat has a prognostic role in patients with advanced, nonsquamous NSCLC treated with erlotinib and bevacizumab in the first line. Further work is needed to study the predictive role of VeriStrat for erlotinib and bevacizumab in chemotherapy-untreated patients.


Characterization of specific growth hormone binding sites in mouse fibroblasts.
The demonstration that mouse embryo mesenchymal cells produce somatomedin-like immunoreactivity suggests that fibroblasts may be a target tissue for GH action. The aim of this study was to investigate the interaction of GH with mouse fibroblasts. Specific binding sites for GH in mouse fibroblasts (BALB/c and Swiss 3T3) have been characterized. Binding of [125I]iodo-human GH (hGH) was rapid, reversible, and time and temperature dependent. Maximal binding was achieved within 2 h at 30 C and was rapidly dissociable at this temperature with or without excess unlabeled hormone. Specific binding of [125I]iodo-hGH was similar over the pH range 6.6-8.2. Half-maximal inhibition of specific binding was obtained with 10 ng/ml hGH. A linear relationship between specific binding and cell number was found and negligible degradation of [125I]iodo-hGH occurred during the binding studies. Somatogenic hormones from various species, including mouse GH, rat GH, porcine GH, and bovine GH competed for binding with [125I]iodo-hGH. Lactogenic hormones did not displace [125I]iodo-hGH at low concentrations. Scatchard analysis revealed curvilinear plots suggesting that [125I]iodo-hGH was binding to two sites. The affinity constants and capacities of these binding sites on BALB/c 3T3 cells were 7.46 X 10(9) M-1 and 4,000 sites per cell and 0.26 X 10(9) M-1 and 67,000 sites per cell. Using [125I]iodo-bovine GH and [125I]iodo-human placental lactogen as labeled ligands two distinct binding sites were found with affinity constants of 6.1 X 10(9) M-1 and 1.1 X 10(9) M-1, respectively. These data are consistent with the presence of cell surface somatogenic and lactogenic receptors in mouse fibroblasts and suggest GH receptors may be present on many cell types not previously considered to be target tissues for GH action. The mouse fibroblast GH receptor may provide a useful model for somatogenic receptors, particularly if it is coupled to somatomedin production as appears to be the case with human fibroblasts.


Foam dressings for treating pressure injuries in patients of any age in any care setting: An abridged Cochrane systematic review.
Pressure injuries are localised areas of injury to the skin and/or underlying tissues. To assess foam dressings compared to other dressings in healing pressure injuries. Systematic review and meta-analysis DATA SOURCES: The review team searched: the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; EBSCO CINAHL Plus and the NHS Economic Evaluation Database. Authors also searched clinical trials registries and scanned reference lists for reviews, meta-analyses and health technology reports. No restrictions were applied to language, publication date or study setting. Published or unpublished randomised controlled trials and cluster- randomised controlled trials that examined the clinical or cost effectiveness of foam dressings for healing pressure injuries. Patients of any age with a pressure injury of Stage II or above in any care setting. Use of any foam wound dressing for treating Stage II pressure injuries or above. Full-text were assessed for eligibility using a priori criteria by two authors. Risk of bias was assessed using the Grading of Recommendations, Assessment, Development and Evaluation criteria, and Consolidated Health Economic Evaluation Reporting Standards. Risk ratio and mean difference with 95% confidence intervals were used to measure the effect. The review team used Review Manager 5 to enter narrative and qualitative data of included studies. Authors found nine studies published between 1994 and 2016 involving 483 participants with pressure injuries at Stage II or above. Included studies compared foam dressings with other types of dressings. However, it was unclear if the foam dressing affected healing (RR 1.00, 95% CI 0.78-1.28), time to complete healing (MD 5.67 days 95% CI-4.03-15.37), adverse events (RR 0.33, 95% CI 0.01-7.65), or reduction in pressure injury size (MD 0.30 cm2 per day, 95% CI -0.15 to 0.75), as the certainty of the evidence was very low. Using the Grading of Recommendations, Assessment, Development and Evaluation criteria, the certainty and completeness of evidence was low to very low, making it difficult to draw comparisons between foam and other dressings. It is uncertain whether foam dressings are more clinically effective, more acceptable to users, or more cost effective compared to alternative dressings in treating pressure injuries.


Anti-infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: 12-month outcomes of a randomized controlled clinical trial.
The objective of the study is to compare the clinical, microbiological and host-derived effects in the non-surgical treatment of initial peri-implantitis with either adjunctive local drug delivery (LDD) or adjunctive photodynamic therapy (PDT) after 12 months. Forty subjects with initial peri-implantitis, that is, pocket probing depths (PPD) 4-6 mm with bleeding on probing (BoP) and radiographic bone loss ≤2 mm, were randomly assigned to two treatment groups. All implants were mechanically debrided with titanium curettes and with a glycine-based powder airpolishing system. Implants in the test group (N = 20) received adjunctive PDT, whereas minocycline microspheres were locally delivered into the peri-implant pockets of control implants (N = 20). At sites with residual BoP, treatment was repeated after 3, 6, 9 and 12 months. The primary outcome variable was the change in the number of peri-implant sites with BoP. Secondary outcome variables included changes in PPD, clinical attachment level (CAL), mucosal recession (REC) and in bacterial counts and crevicular fluid (CF) levels of host-derived biomarkers. After 12 months, the number of BoP-positive sites decreased statistically significantly (P < 0.05) from baseline in both groups (PDT: 4.03 ± 1.66-1.74 ± 1.37, LDD: 4.41 ± 1.47-1.55 ± 1.26). A statistically significant (P < 0.05) decrease in PPD from baseline was observed at PDT-treated sites up to 9 months (4.19 ± 0.55 mm to 3.89 ± 0.68 mm) and up to 12 months at LDD-treated sites (4.39 ± 0.77 mm to 3.83 ± 0.85 mm). Counts of Porphyromonas gingivalis and Tannerella forsythia decreased statistically significantly (P < 0.05) from baseline to 6 months in the PDT and to 12 months in the LDD group, respectively. CF levels of IL-1β decreased statistically significantly (P < 0.05) from baseline to 12 months in both groups. No statistically significant differences (P > 0.05) were observed between groups after 12 months with respect to clinical, microbiological and host-derived parameters. Non-surgical mechanical debridement with adjunctive PDT was equally effective in the reduction of mucosal inflammation as with adjunctive delivery of minocycline microspheres up to 12 months. Adjunctive PDT may represent an alternative approach to LDD in the non-surgical treatment of initial peri-implantitis.


Genetic divergence in the common bean (Phaseolus vulgaris L.) in the Cerrado-Pantanal ecotone.
Evaluating genetic diversity among genotypes is important for providing parameters for the identification of superior genotypes, because the choice of parents that form segregating populations is crucial. Our objectives were to i) evaluate agronomic performance; ii) compare clustering methods; iii) ascertain the relative contributions of the variables evaluated; and iv) identify the most promising hybrids to produce superior segregating populations. The trial was conducted in 2015 at the State University of Mato Grosso do Sul, Brazil. We used a randomized block design with three replications, and recorded the days to emergence, days to flowering, days to maturity, plant height, number of branches, number of pods, number of seeds per pod, weight of 100 grains, and productivity. The genetic diversity of the genotypes was determined by cluster analysis using two dissimilarity measures: the Euclidean distance and the standardized mean Mahalanobis distance using the Ward hierarchical method. The genotypes 'CNFC 10762', 'IAC Dawn', and 'BRS Style' had the highest grain yields, and clusters that were based on the Euclidean distance differed from those based on the Mahalanobis distance, the second being more precise. The yield grain character has greater relevance to the dispute. Hybrids with a high heterotic effect can be obtained by crossing 'IAC Alvorada' with 'CNFC 10762', 'IAC Alvorada' with 'CNFC 10764', and 'BRS Style' with 'IAC Alvorada'.


Incidence and prevalence of psoriatic arthritis in Denmark: a nationwide register linkage study.
To examine the incidence and temporal trends of psoriatic arthritis (PsA) in the general population in Denmark. Using nationwide registry data, we estimated the number of patients with incident PsA within each 1-year period between 1997 and 2011 and calculated the rate of PsA cases within gender and age subgroups. Incidence rates were presented per 100 000 person-years. There was a female predominance ranging from 50.3% (1998) to 59.2% (2010), and the mean age at time of diagnosis was 47-50 years. We identified a total of 12 719 patients with PsA (prevalence=0.22%), including 9034 patients where the PsA diagnosis was made by a rheumatologist (prevalence=0.16%). Incidence rates of PsA (per 100 000 person-years) increased from 7.3 in 1997 to a peak incidence of 27.3 in 2010. Incidence rates were highest for women and patients aged 50-59 years, respectively. The use of systemic non-biologic agents, that is, methotrexate, leflunomide, ciclosporin or sulfasalazine increased over the 15-year study course and were used in 66.3% of all patients. Biologic agents (etanercept, infliximab, adalimumab, certolizumab pegol, golimumab or ustekinumab) were used in 17.7% of patients with PsA. We found a clear trend of rising PsA incidence on a national level. While the cause remains unclear, our findings might be explained by increased attention by patients and physicians.


Effect of intravenous tiludronate disodium administration on the radiographic progression of osteoarthritis of the fetlock joint in Standardbred racehorses.
To compare the effects of tiludronate disodium and 3 other medical treatments on clinical and radiographic findings and biomarkers of disease progression in horses with osteoarthritis of the fetlock joint. 100 Standardbred racehorses with spontaneous traumatic injury of the fetlock joint. Horses were retrospectively grouped by whether they received tiludronate IV or triamcinolone acetonide and hyaluronan, polysulfated glycosaminoglycan, or interleukin-1 receptor antagonist protein intra-articularly. Data were collected on clinical, radiographic, and ultrasonographic findings and results for serum and synovial samples obtained before and 6 months after treatment. Lameness score, joint flexion test response, radiographic score, serum concentrations of tumor necrosis factor-α and carboxy-terminal telopeptides of collagen types I and II (CTX-I and II, respectively), and synovial fluid concentrations of interleukin-1β, prostaglandin E2, and CTX-II were compared among treatments. All treatments resulted in a significant improvement in lameness score and joint flexion test response at 6 months. In horses that received triamcinolone acetonide and hyaluronan, synovial fluid interleukin-1β, prostaglandin E2, and CTX-II concentrations decreased after treatment, suggesting this treatment inhibited progression of hyaline cartilage degeneration and inflammatory processes. Horses that received tiludronate were the only group that had a decrease in radiographic score and serum CTX-I concentration after treatment, supporting the effect of tiludronate on bone metabolism. Tiludronate treatment was also followed by increases in serum and synovial fluid concentrations of CTX-II, a marker of cartilage damage. Tiludronate appeared to inhibit the radiographic progression of osteoarthritis in high-motion joints of racehorses at 6 months after treatment by inhibiting subchondral bone remodeling. Whether this effect was associated with a worsening of progressive cartilage damage remains to be ascertained.


Effect of changes in arterial oxygen content on circulation and physical performance.
To evaluate the effect of different levels of arterial oxygen content on hemodynamic parameters during exercise nine subjects performed submaximal bicycle or treadmill exercise and maximal treadmill exercise under three different experimental conditions: 1) breathing room air (control); 2) breathing 50% oxygen (hyperoxia); 3) after rebreathing a carbon monoxide gas mixture (hypoxia). Maximal oxygen consumption (Vo2 max) was significantly higher in hyperoxia (4.99 1/min) and significantly lower in hypoxia (3.80 1/min) than in the control experiment (4.43 1/min). Physical performance changes in parallel with Vo2 max. Maximal cardiac output (Qmax) was similar in hyperoxia as in control but was significantly lower in hypoxia mainly due to a decreased stroke volume. A correlation was found between Vo2 max and transported oxygen, i.e., Cao2 times Amax, thus suggesting that central circulation is an important limiting factor for human maximal aerobic power. During submaximal work HR was decreased in hyperoxia and increased in hypoxia. Corresponding Q values were unchanged except for a reduction during high submaximal exercise in hyperoxia.


A proteomic approach to the identification of lung cancer markers.
We have developed a comprehensive approach to the identification of protein markers in lung cancer that includes profiling of tumor tissue and cell lines as well as the analysis of serum for autoantibodies to lung tumor antigens. A large number of proteins that are differentially expressed in the major subtypes of lung cancer have been identified by mass spectrometry. A database of protein expression in lung cancer and other types of cancer has been constructed that integrates two-dimensional gel profiles, mass spectrometry data, quantitative protein data and gene expression data at the RNA level, that serves as a resource for biomarker identification. Analysis of the serological response in lung cancer has led to the identification of novel markers detectable in serum of lung cancer patients at the time of diagnosis. The proteomic approach is likely to yield novel classification schemes and novel markers for early diagnosis of lung cancer.


GANN: genetic algorithm neural networks for the detection of conserved combinations of features in DNA.
The multitude of motif detection algorithms developed to date have largely focused on the detection of patterns in primary sequence. Since sequence-dependent DNA structure and flexibility may also play a role in protein-DNA interactions, the simultaneous exploration of sequence- and structure-based hypotheses about the composition of binding sites and the ordering of features in a regulatory region should be considered as well. The consideration of structural features requires the development of new detection tools that can deal with data types other than primary sequence. GANN (available at http://bioinformatics.org.au/gann) is a machine learning tool for the detection of conserved features in DNA. The software suite contains programs to extract different regions of genomic DNA from flat files and convert these sequences to indices that reflect sequence and structural composition or the presence of specific protein binding sites. The machine learning component allows the classification of different types of sequences based on subsamples of these indices, and can identify the best combinations of indices and machine learning architecture for sequence discrimination. Another key feature of GANN is the replicated splitting of data into training and test sets, and the implementation of negative controls. In validation experiments, GANN successfully merged important sequence and structural features to yield good predictive models for synthetic and real regulatory regions. GANN is a flexible tool that can search through large sets of sequence and structural feature combinations to identify those that best characterize a set of sequences.


PFG-NMR investigations of the binding of cationic neuropeptides to anionic and zwitterionic micelles.
The mechanism by which peptides bind to micelles is believed to be a two-phase process, involving (i). initial electrostatic interactions between the peptide and micelle surface, followed by (ii). hydrophobic interactions between peptide side chains and the micelle core. To better characterize the electrostatic portion of this process, a series of pulse field gradient nuclear magnetic resonance (PFG-NMR) spectroscopic experiments were conducted on a group of neuropeptides with varying net cationic charges (+1 to +3) and charge location to determine both their diffusion coefficients and partition coefficients when in the presence of detergent micelles. Two types of micelles were chosen for the study, namely anionic sodium dodecylsulfate (SDS) and zwitterionic dodecylphosphocholine (DPC) micelles. Results obtained from this investigation indicate that in the case of the anionic SDS micelles, peptides with a larger net positive charge bind to a greater extent than those with a lesser net positive charge (bradykinin > substance P > neurokinin A > Met-enkephalin). In contrast, when in the presence of zwitterionic DPC micelles, the degree of mixed-charge nature of the peptide affects binding (neurokinin A > substance P > Met-enkephalin > bradykinin). Partition coefficients between the peptides and the micelles follow similar trends for both micelle types. Diffusion coefficients for the peptides in SDS micelles, when ranked from largest to smallest, follow a trend where increasing net positive charge results in the smallest diffusion coefficient: Met-enkephalin > neurokinin A > bradykinin > substance P. Diffusion coefficients when in the presence of DPC micelles, when ranked from largest to smallest, follow a trend where the presence of negatively-charged side chains results in the smallest diffusion coefficient: bradykinin > Met-enkephalin > substance P > neurokinin A.


Very-high-energy gamma rays from a distant quasar: how transparent is the universe?
The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts. Because high-energy gamma rays may be stopped by interacting with the diffuse background light in the universe, the observations by MAGIC imply a low amount for such light, consistent with that known from galaxy counts.


Omega-3 nutraceuticals, climate change and threats to the environment: The cases of Antarctic krill and Calanus finmarchicus.
The nutraceutical market for EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) is promoting fishing for Euphasia superba (Antarctic krill) in the Southern Ocean and Calanus finmarchicus in Norwegian waters. This industry argues that these species are underexploited, but they are essential in their ecosystems, and climate change is altering their geographical distribution. In this perspective, we advocate the cessation of fishing for these species to produce nutraceuticals with EPA and DHA. We argue that this is possible because, contrary to what this industry promotes, the benefits of these fatty acids only seem significant to specific population groups, and not for the general population. Next, we explain that this is desirable because there is evidence that these fisheries may interact with the impact of climate change. Greener sources of EPA and DHA are already available on the market, and their reasonable use would ease pressure on the Arctic and Antarctic ecosystems.


Liposomal formulations of amphotericin B: differences according to the scientific evidence.
This article presents an overview of the characteristics of liposomes as drug carriers, particularly in relation to liposomal formulations of amphotericin B. General features regarding structure, liposome-cell interactions, stability, encapsulation of active substances and elimination of liposomes are described. Up to the present time extensive efforts to produce similar or bioequivalent products of amphotericin B formulations, in particular in the case of liposomal amphotericin B, have been unsuccessful in spite of having a very similar composition and even an apparently identical manufacturing process. Guidelines for the development of generic liposomal formulations developed by the FDA and EMA are also summarized. Based on the available evidence of the composition of liposomes, any differences in the manufacturing process even if the same lipid composition is used may result in different final products. Therefore, it seems unreasonable to infer that all amphotericin B liposomal formulations are equal in efficacy and safety.


Gingival bleeding on probing: relationship to change in periodontal pocket depth and effect of sodium hypochlorite oral rinse.
This study evaluated the potential of gingival bleeding on probing to serve as a predictor of future periodontal breakdown. It also assessed the ability of 0.25% sodium hypochlorite twice-a-week oral rinse to convert periodontal pockets showing bleeding on probing to nonbleeding sites. The study was performed as a randomized, single-blinded, clinical trial in parallel groups. Seven periodontitis patients rinsed twice-weekly for 3 mo with 15 mL of a fresh solution of 0.25% sodium hypochlorite, and five periodontitis patients rinsed with water. The 12 study patients received no subgingival or supragingival scaling. Clorox(®) Regular-Bleach was the source of sodium hypochlorite. At baseline and 3-mo visits, gingival bleeding was assessed within 30 s after probing to full pocket depth using an approximate force of 0.75 N. A total of 470 (38%) of 1230 periodontal pockets in the bleach-rinse group revealed bleeding on probing at the initial visit but not at the 3-mo visit; only 71 (9%) of 828 pockets in the control group became bleeding-negative during the study (p < 0.001). Bleeding on probing in 4- to 7-mm-deep pockets decreased by 53% in the bleach-rinse group but increased by 6% in the water-rinse group (p < 0.001). Ninety-seven pockets showed depth increases of ≥ 2 mm after 3 mo: 60 (62%) of those pockets exhibited bleeding on probing at both the initial and the 3-mo visits; 24 (25%) bled at only one of the two visits; and 13 (13%) never demonstrated gingival bleeding (p < 0.001). Persistent gingival bleeding on probing was associated with an increased risk for periodontal breakdown, and the absence of gingival bleeding seemed to be a useful, although not perfect, indicator of disease stability. Twice-weekly oral rinsing with dilute bleach (0.25% sodium hypochlorite) produced a significant reduction in bleeding on probing, even in deep unscaled pockets. Sodium hypochlorite constitutes a valuable antiseptic in periodontal self-care.


The evolution of female ornaments and weaponry: social selection, sexual selection and ecological competition.
Ornaments, weapons and aggressive behaviours may evolve in female animals by mate choice and intrasexual competition for mating opportunities-the standard forms of sexual selection in males. However, a growing body of evidence suggests that selection tends to operate in different ways in males and females, with female traits more often mediating competition for ecological resources, rather than mate acquisition. Two main solutions have been proposed to accommodate this disparity. One is to expand the concept of sexual selection to include all mechanisms related to fecundity; another is to adopt an alternative conceptual framework-the theory of social selection-in which sexual selection is one component of a more general form of selection resulting from all social interactions. In this study, we summarize the history of the debate about female ornaments and weapons, and discuss potential resolutions. We review the components of fitness driving ornamentation in a wide range of systems, and show that selection often falls outside the limits of traditional sexual selection theory, particularly in females. We conclude that the evolution of these traits in both sexes is best understood within the unifying framework of social selection.


The nematode story: Hox gene loss and rapid evolution.
The loss in some taxa of conserved developmental control genes that are present in the vast majority of animal lineages is an understudied phenomenon. It is likely that in those lineages in which loss has occurred it may be a strong signal of the mode, tempo and direction of developmental evolution and thus identify ways of generating morphological novelties. Intuitively we might expect these novelties to be particularly those associated with morphological simplifications. One striking example of this has occurred within the nematodes. It appears that over half the ancestral bilaterian Hox cluster has been lost from the model organism Caenorhabditis elegans and its closest related species. Studying the Hox gene complement of nematodes across the phylum has shown that many, if not all these losses occurred within the phylum. Other nematode clades only distantly related to C. elegans have additional Hox genes orthologous to those present in the ancestral bilaterian but absent from the model nematode. In some of these cases rapid sequence evolution of the homeodomain itself obscures orthology assignment until comparison is made with sequences from multiple nematode clades with slower evolving Hox genes. Across the phylum the homeodomains of the Hox genes that are present are evolving very rapidly. In one particular case the genomic arrangement of two homeodomains suggests a mechanism for gene loss. Studying the function in nematodes of the Hox genes absent from C. elegans awaits further research and the establishment of new nematode models. However, what we do know about Hox gene functions suggests that the genetic circuits within which Hox genes act have changed significantly within C. elegans and its close relatives.


HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo.
Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation. To address this we assessed the ability of Ganetespib, a non-geldanamycin HSP90 blocker, to suppress lipopolysaccharide (LPS)-induced cellular infiltrates, proteases and inflammatory mediator and transcriptional profiles. Ganetespib (10-100 mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dose-dependently suppressed LPS-induced neutrophil mobilization into blood and neutrophil- and mononuclear cell-rich steroid-refractory lung inflammation. Ganetespib also suppressed B cell and NK cell accumulation, inflammatory cytokine and chemokine induction and MMP9 levels. These data identify non-myelosuppresssive HSP90 inhibitors as potential therapies for inflammatory diseases refractory to conventional therapy, in particular those of the lung.


Application of capacitively coupled electric field enhances periimplant osteogenesis in the dog mandible.
Expeditious postoperative ingrowth of bone into dental implants is desired for clinically successful fixation of oral implants. The present study was performed to evaluate the effect of applying a capacitively coupled electric field (CCEF) on periimplant osteogenesis in the dog mandible. Twelve adult male beagles were used in this study. All of the premolars on both sides of the mandible were removed from each dog. A POI (Ti-6Al-4V) 3-piece implant (3.7 mm in diameter and 8.0 mm in length) whose surface had been treated with anodic oxidation was placed into each test site by self-tapping. Daily application of CCEF (8 h/day) was initiated on the day following the surgery and was continued through the day of sacrifice. A CCEF was induced by an external source delivering 10-Vp-p, 60-kHz sine-wave signals through an oral electrode plate. One side of the mandible of each dog was treated with CCEF, while the other side was not. On the control side, an oral electrode plate was attached for 8 hours per day, but CCEF was not applied. The effect of daily application of CCEF on the ingrowth of bone into the implant was examined at 14, 21, or 30 days after implant placement. A fourth control group was not treated with CCEF and was maintained for 90 days to confirm that CCEF treatment enhances bone ingrowth in dental implants. Daily application of CCEF significantly increased the bone-contact ratio at days 14, 21, and 30 after implant placement in comparison with the respective controls. The bone-area ratios of the 14- and 21-day CCEF-treated groups were significantly larger than those of the respective controls and were similar to those of the 90-day control group. CCEF treatment increases periimplant osteogenesis in the dog mandible, confirming its usefulness in oral implantology.


Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study.
Heart failure (HF) pathophysiology is believed to be mediated by autonomic dysfunction, including chronic sympathoexcitation and diminished baroreflex sensitivity, which correlate with mortality risk. Baroreflex activation therapy (BAT) is a device-based treatment providing chronic baroreflex activation through electrical stimulation of the carotid sinus. BAT chronically reduces sympathetic activity in resistant hypertension. The purpose of this investigation is to determine BAT effects in clinical HF. In a single-centre, open-label evaluation, patients with NYHA class III HF, EF <40%, optimized medical therapy, and ineligible for cardiac resynchronization received BAT for 6 months. Efficacy was assessed with serial measurement of muscle sympathetic nerve activity (MSNA) and clinical measures of quality of life and functional capacity. Eleven patients participated in the trial. MSNA was reduced over 6 months from 45.1 ± 7.7 to 31.3 ± 8.3 bursts/min and from 67.6 ± 12.7 to 45.1 ± 11.6 bursts/100 heartbeats, decreases of 31% and 33%, respectively (P < 0.01). Concomitant improvements occurred in baroreflex sensitivity, EF, NYHA class, quality of life and 6 min hall walk (6 MHW) distance (P ≤ 0.05 each). On an observational basis, hospitalization and emergency department visits for worsening HF were markedly reduced. One complication, perioperative anaemia requiring transfusion, occurred during the study. BAT was safe and provided chronic improvement in MSNA and clinical variables. Based on present understanding of HF pathophysiology, these results suggest that BAT may improve outcome in HF by modulating autonomic balance. Prospective, randomized trials to test the hypothesis are warranted.


Characterisation and Antioxidant Activity of Crude Extract and Polyphenolic Rich Fractions from C. incanus Leaves.
Cistus incanus (Cistaceae) is a Mediterranean evergreen shrub. Cistus incanus herbal teas have been used as a general remedy in traditional medicine since ancient times. Recent studies on the antioxidant properties of its aqueous extracts have indicated polyphenols to be the most active compounds. However, a whole chemical characterisation of polyphenolic compounds in leaves of Cistus incanus (C. incanus) is still lacking. Moreover, limited data is available on the contribution of different polyphenolic compounds towards the total antioxidant capacity of its extracts. The purpose of this study was to characterise the major polyphenolic compounds present in a crude ethanolic leaf extract (CEE) of C. incanus and develop a method for their fractionation. Superoxide anion, hydroxyl and DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging assays were also performed to evaluate the antioxidant properties of the obtained fractions. Three different polyphenolic enriched extracts, namely EAC (Ethyl Acetate Fraction), AF1 and AF2 (Aqueos Fractions), were obtained from CEE. Our results indicated that the EAC, enriched in flavonols, exhibited a higher antiradical activity compared to the tannin enriched fractions (AF1 and AF2). These findings provide new perspectives for the use of the EAC as a source of antioxidant compounds with potential uses in pharmaceutical preparations.


The role of Arg445 and Asp498 in the human thyroid hormone transporter MCT8.
Monocarboxylate transporter 8 (MCT8) facilitates cellular influx and efflux of the thyroid hormones (THs) T(4) and T(3). Mutations in MCT8 lead to severe psychomotor retardation. Here, we studied the importance of 2 highly conserved residues (Arg445 in transmembrane domain 8 and Asp498 in transmembrane domain 10) for substrate recognition and helix interactions. We introduced single and double mutations (R445A, R445C, R445D, R445K, D498A, D498E, D498N, D498R, R445A+D498A, R445D+D498R, and R445K+D498E) in human MCT8 cDNA and studied the effects on MCT8-mediated TH uptake and metabolism in transfected cells. The impact of these mutations on MCT8 protein expression, dimerization capacity, and subcellular localization was studied by Western blotting and confocal microscopy. We found that mutations in Arg445 or Asp498 that alter the local charge resulted in a near-complete loss of TH uptake capacity, whereas the expression, stability, and subcellular localization of these mutant proteins was similar to those for wild-type MCT8. Given the impaired TH uptake, TH efflux could not be adequately studied. The importance of opposite charges at Arg445 and Asp498 was studied by exchanging these residues (R445D+D498R). In particular, T(4) uptake was less severely reduced by the exchange mutation than by the single mutations. Mutations of Arg445 and Asp498 to equally charged residues (R445K and/or D498E) resulted in TH uptake levels similar to wild-type MCT8. The presence of 2 oppositely charged residues at positions Arg445 and Asp498 that are predicted in close structural proximity is crucial for efficient TH uptake, which may indicate the presence of an, at least transient, charge pair between these residues.


Idiopathic short stature in children.
Idiopathic short stature represents a group of conditions that are not definable by current biochemical criteria but usually respond to GH therapy. Natural-history studies confirm adult height will be short in untreated ISS individuals. Children and adults with short stature have disadvantages compared with their peers. The evidence for benefit from treatment of children with idiopathic short stature is strong. Numerous studies, now including a placebo-controlled study, have demonstrated the positive effect of GH treatment on final height. The effect of GH treatment is quantitatively similar to results seen in other non-GH-deficient conditions. Although currently very expensive, rhGH treatment is relatively safe. GH treatment of children with idiopathic short stature should not be withheld because of our inability to explain the etiology or because of the inadequacy of our current diagnostic tests. Continued efforts to delineate specific causes of poor growth in ISS individuals may result in our being able to predict subsets of individuals who will respond well to GH and subgroups who may be considered for other treatments, such as IGF-1 or a combination of IGF-1 and IGFBP-3.


Barriers and Facilitators of PrEP Adherence for Young Men and Transgender Women of Color.
We aimed to discover barriers and facilitators of HIV pre-exposure prophylaxis (PrEP) adherence in young men and transgender women of color who have sex with men (YMSM/TW). Short-term and sustained adherence were measured by urine tenofovir concentration and pharmacy refills, respectively. Optimal adherence was defined as having both urine tenofovir concentration consistent with dose ingestion within 48 h and pharmacy refills consistent with ≥ 4 doses per week use. Participants completed semi-structured interviews exploring adherence barriers and facilitators. Participants (n = 31) were primarily African-American (68%), mean age 22 years (SD: 1.8), and 48% had optimal adherence. Adherence barriers included stigma, health systems inaccessibility, side effects, competing stressors, and low HIV risk perception. Facilitators included social support, health system accessibility, reminders/routines, high HIV risk perception, and personal agency. Our findings identify targets for intervention to improve PrEP adherence in these populations, including augmenting health activation and improving accuracy of HIV risk perception.


No detectable carotenoid concentrations in serum of llamas and alpacas.
Carotenoids are lipid-soluble pigments and important for a variety of physiological functions. They are major dietary vitamin A precursors and act as lipophilic antioxidants in a variety of tissues and are associated with important health benefits in humans and animals. All animals must acquire carotenoids from their diet, but to our knowledge, there are no studies investigating the intestinal carotenoid absorption and their blood concentrations in New World camelids. The present study aimed to assess the serum concentrations of selected carotenoids in llamas (n = 13) and alpacas (n = 27). Serum carotenoids as well as retinol (vitamin A) and α-tocopherol (vitamin E) were determined by high-performance liquid chromatography coupled with mass spectrometry and these were unable to detect any carotenoids (α- and β-carotene, α- and β-cryptoxanthin, lutein, zeaxanthin, lycopene) in the samples. The concentrations of retinol in alpacas (2.89 ± 1.13 μmol/l; mean ± SD) were higher (p = 0.024) than those found in llamas (2.05 ± 0.87 μmol/l); however, the concentrations of α-tocopherol were not significantly (p = 0.166) different (llamas: 3.98 ± 1.83 μmol/l; alpacas: 4.95 ± 2.14 μmol/l). The results show that both llamas and alpacas are not able to absorb intact carotenoids, but efficiently convert provitamin A carotenoids to retinol.


Psychological pain treatment in fibromyalgia syndrome: efficacy of operant behavioural and cognitive behavioural treatments.
The present study focused on the evaluation of the effects of operant behavioural (OBT) and cognitive behavioural (CBT) treatments for fibromyalgia syndrome (FMS). One hundred and twenty-five patients who fulfilled the American College of Rheumatology criteria for FMS were randomly assigned to OBT (n = 43), CBT (n = 42), or an attention-placebo (AP) treatment (n = 40) that consisted of discussions of FMS-related problems. Assessments of physical functioning, pain, affective distress, and cognitive and behavioural variables were performed pre-treatment and post-treatment as well as 6 and 12 months post-treatment. Patients receiving the OBT or CBT reported a significant reduction in pain intensity post-treatment (all Fs > 3.89, all Ps < 0.01). In addition, the CBT group reported statistically significant improvements in cognitive (all Fs > 7.95, all P < 0.01) and affective variables (all Fs > 2.99, all Ps < 0.02), and the OBT group demonstrated statistically significant improvements in physical functioning and behavioural variables (all Fs > 5.99, all Ps < 0.001) compared with AP. The AP group reported no significant improvement but actually deterioration in the outcome variables. The post-treatment effects for the OBT and CBT groups were maintained at both the 6- and 12-month follow-ups. These results suggest that both OBT and CBT are effective in treating patients with FMS with some differences in the outcome measures specifically targeted by the individual treatments compared with an unstructured discussion group. The AP group showed that unstructured discussion of FMS-related problems may be detrimental.


The rise of oxygen over the past 205 million years and the evolution of large placental mammals.
On the basis of a carbon isotopic record of both marine carbonates and organic matter from the Triassic-Jurassic boundary to the present, we modeled oxygen concentrations over the past 205 million years. Our analysis indicates that atmospheric oxygen approximately doubled over this period, with relatively rapid increases in the early Jurassic and the Eocene. We suggest that the overall increase in oxygen, mediated by the formation of passive continental margins along the Atlantic Ocean during the opening phase of the current Wilson cycle, was a critical factor in the evolution, radiation, and subsequent increase in average size of placental mammals.


Loss of suppressor T cells in adult NZB/NZW mice.
We have investigated suppressor T-cell activity in female NZB/NZW F1 mice using PWM-driven IgM biosynthesis in vitro as an indicator system. In initial we studied we observed that spleen cells from normal mice (BALB/c, C57BL/6), as well as from young (4 wk) and adult (18 wk) NZB/NZW mice, cultured in the presence of PWM synthesize 860 +/- 120 ng IgM/10(6) cells/7 days. However, when Con A (at 2 mug/ml) was added directly to the cultures (along with PWM), cells obtained from adult normal mice and young NZB/NZW mice showed a 94% suppression of IgM synthesis, whereas cells obtained from adult NZB/NZW mice were suppressed significantly less. To analyze these findings we studied the effect of Con A-induced suppressor cells (cells cultured with Con A for 24 h and washed free of Con A) on PWM-driven IgM biosynthesis. Spleen cells obtained from normal mice cultured in the presence of Con A-pulsed cells obtained from normal mice and young NZB/NZW mice showed an 83-88% suppression of PWM-driven IgM synthesis. Similarly, supernates obtained from Con A-pulsed cells of normal mice or of young NZB/NZW mice suppressed PWM-driven IgM synthesis. This suppression by Con A-pulsed cells and their supernates required T cells since T-cell fractions but not B-cell fractions eluted from anti-Fab Sephadex columns mediated suppression of co-cultured normal cells; in addition, Con A-pulsed cells treated with anti-theta and complement do not mediate suppression. These studies of Con A-induced suppressor cell activity in normal mice and young NZB/NZW mice contrast with studies of Con A-induced suppressor cell activity in adult NZB/NZW mice. We found that adult NZB/NZW Con A-pulsed cells and supernates obtained from the Con A-pulse cells had vastly decreased suppressor potential; in this case the Con A-pulse cells and supernatant fluids derived from such cells did not suppress PWM-driven IgM synthesis by normal cells. Finally, whereas spleen cells from young and adult NZB/NZW mice differ in their suppressor cell potential, cells from both sources could respond equally to suppressor signals in that Con A-pulsed normal cells or supernates derived from such cells caused equivalent suppression of PWM-driven IgM synthesis by young and adult NZB/NZW cells. These observations allow us to conclude that NZB/NZW mice lose suppressor T-cell activity as they age.


Long-term lemonade based dietary manipulation in patients with hypocitraturic nephrolithiasis.
Citrus fruits and juices are a known natural source of dietary citrate. Of all the citrus juices, lemon juice appears to have the highest concentration of citrate. Therefore, lemonade therapy has been proposed as a potential treatment for patients with hypocitraturia. We retrospectively evaluated the impact of long-term lemonade therapy on urinary metabolic parameters and stone formation in patients with hypocitraturic nephrolithiasis. A total of 32 patients were identified as being on long-term lemonade therapy for hypocitraturic nephrolithiasis. The 11 patients on lemonade therapy who met the entrance criteria for evaluation were compared to an age and sex matched control group of patients treated with oral slow release potassium citrate. Pre-therapy and post-therapy urinary parameters were recorded for both groups. The effect of lemonade therapy on stone burden and stone formation rate was calculated. New stone formation was defined as passage, surgical removal or appearance of new stones, or an increase in the size of existing stones on radiographic imaging. Four males and 7 females (mean age 52.7 years) were treated with lemonade therapy for a mean of 44.4 months. The control group consisted of 4 males and 7 females (mean age 54.5 years) treated with potassium citrate for a mean of 42.5 months. Of the 11 patients on lemonade 10 demonstrated increased urinary citrate levels (mean increase +383 mg per day, p <0.05). All potassium citrate therapy subjects demonstrated an increase in urinary citrate (mean increase +482 mg per day, p <0.0001). Mean pretreatment and posttreatment stone burden in the lemonade group was 37.2 and 30.4 mm(2), respectively (p >0.05). During lemonade therapy the stone formation rate decreased from 1.00 to 0.13 stones per patient per year (p >0.05). Due to its significant citraturic effect, lemonade therapy appears to be a reasonable alternative for patients with hypocitraturia who cannot tolerate first line therapy. Future study in the form of a prospective, randomized trial is needed to validate these findings.


The CCAAT-binding complex (CBC) in Aspergillus species.
The CCAAT binding complex (CBC), consisting of a heterotrimeric core structure, is highly conserved in eukaryotes and constitutes an important general transcriptional regulator. Scope of the review. In this review we discuss the scientific history and the current state of knowledge of the multiple gene regulatory functions, protein motifs and structure of the CBC in fungi with a special focus on Aspergillus species. Major conclusions and general significance. Initially identified as a transcriptional activator of respiration in Saccharomyces cerevisiae, in other fungal species the CBC was found to be involved in highly diverse pathways, but a general rationale for its involvement was missing. Subsequently, the CBC was found to sense reactive oxygen species through oxidative modifications of cysteine residues in order to mediate redox regulation. Moreover, via interaction with the iron-sensing bZIP transcription factor HapX, the CBC was shown to mediate adaptation to both iron starvation and iron excess. Due to the control of various pathways in primary and secondary metabolism the CBC is of crucial importance for fungal virulence in both animal and plant hosts as well as antifungal resistance. Consequently, CBC-mediated control affects biological processes that are of high interest in biotechnology, agriculture and infection medicine. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.


SU-E-I-56: Threshold Effect of ASIR Before Which Image Improve and After Which Image Degrades.
This study showed to what extent ASIR improves CT-image and to what extent it degrades it. In our study we used GE HD750 CT-scanner, Siemens Sensation CT-scanner, Catphan, PTW-pin-ion- chamber, CTDI-phantom. We measured the CT-dose using the PTW-pinion-chamber and CTDI-phantom. Image-quality and noise were evaluated using catphan and GE water phantom. Image noise reduce as higher levels of ASIR are applied. A phantom scan showed that 50%ASIR with 50% lower-dose (10.8mGy) achieved the same image noise of standard FBP image with full dose 21.7mGy (noise∼5). To confirm that the two same-noise images retain same image-quality, two scans were compared; one with full dose 260mAs(21.7mGy) and the other one with 50% lower dose 130mAs(10.8mGy). The results showed that ASIR failed to retain the same quality. For high contrast resolution, 50%ASIR reduced the resolution of patterns = 71p/cm, however it improved the detectability of patterns = 61p/cm. ASIR has degraded the CNR of the low-contrast-objects of = 5HU (CNR of 1.4 at 260mAs STND to CNR of 1.08 at 130mAs ASIR), however it improved the CNR of the low-contrast-objects of = 10HU (CNR of 2.35 at 260mAs STND to CNR of 2.63 at 130mAs ASIR). ASIR degraded the edges and killed some of the small objects. This shows that ASIR has a critical point of improve/degrade. Also, ASIR can improve images for the same dose, but with high levels of ASIR (e.g. 100%ASIR), cause disapear of small low contrast objects (e.g. 2mm). People think that ASIR only improves image and reduces patient dose. Our study showed that ASIR has some drawbacks. There is a threshold before wich ASIR is positive and after which ASIR is negative. Recently only GE provide ASIR in the market but our study showed that other CTs such as Siemens can do similar performance like ASIR.


In vitro evaluation of a multifunctional nano drug delivery system based on tigecycline-loaded calcium-phosphate/ poly-DL-lactide-co-glycolide.
Most drug delivery systems as treatment modalities for osteomyelitis have not been evaluated for resistant infections. Tigecycline (TG) is an antimicrobial agent that could be used in the treatment of multi-drug-resistant orthopedic infections. The objective of this in vitro study has been to determine what dosage of TG causes changes in the morphology and number of osteoblasts. We have also investigated whether nanoparticulate tigecycline-loaded calcium-phosphate/poly-DL-lactide-co-glycolide is biocompatible and whether it could release bioactive TG in a controlled manner during the observation time. The cytotoxicity was tested by analyzing the release of lactate dehydrogenase from dead osteoblasts to the medium. Staphylococcus aureus was used to verify the antibacterial effect of the multifunctional drug delivery system. At concentrations as achieved by local application, TG caused high toxic effect and impaired the normal osteoblastic morphology. The nanoparticulate multifunctional drug delivery system showed good compatibility and antibacterial effect during the observation time and thus appears to be suitable for the treatment of osteomyelitis caused by multi-drug-resistant microbes.


[Markers and regulatory mechanisms in ovarian carcinoma].
Ovarian carcinoma is one of widely spread malignant diseases of female reproductive system. Mortality rate from it is much higher than from other female malignant diseases. During last 20 years the level of ovarian carcinoma in Ukraine and vast majority of other countries remains high manifesting no signs of decrease. This arouses interest of researchers to development of new methods of early diagnosis, therapeutic approach, prognostic criteria, especially biochemical ones, and means of prophylaxis of this pathology in medical scientific society. At present there are no specific diagnostic tests which would allow revealing the tumor on the initial stages of its development. In spite of vide arsenal of tumor markers, the only reliable test for ovarian carcinoma is determination of antigen CA-125. The results of basic modern research are discussed in this survey. They are aimed at finding out regulatory mechanisms connected with metabolism of L-arginine, activities of ATP-hydrolase systems and searching new markers of ovarian carcinoma. The main possible candidates for this role are determined.


A survey of health problems of Nepalese female migrants workers in the Middle-East and Malaysia.
Nepal is a key supplier of labour for countries in the Middle East, India and Malaysia. As many more men than women leave Nepal to work abroad, female migrant workers are a minority and very much under-researched. The aim of the study was to explore the health problems of female Nepalese migrants working in the Middle-East and Malaysia. The study was conducted among 1010 women who were registered as migrant returnees at an organisation called Pourakhi Nepal. Secondary data were extracted from the records of the organisation covering the five-year period of July 2009 to July 2014. The 1010 participants were aged 14 to 51 with a median age of 31 (IQR: 38-25) years. A quarter of respondents (24%) reported having experienced health problems while in the country of employment. Fever, severe illness and accidents were the most common health problems reported. Working for unlimited periods of time and not being able to change one's place of work were independently associated with a greater likelihood of health problems. Logistic regression shows that migrant women who are illiterate [OR = 1.56, 95% CI: 1.02 to 2.38, p = 0.042], who had changed their workplace [OR = 1.63, 95% CI: 1.14 to 2.32, p = 0.007], who worked unlimited periods of time [OR = 1.64, 95% CI: 1.44 to 1.93, p = 0.020], had been severely maltreated or tortured in the workplace [OR = 1.84, 95% CI: 1.15 to 2.92, p = 0.010], were not being paid on time [OR = 2.38, 95% CI: 1.60 to 3.55, p = 0.038] and migrant women who had family problems at home [OR = 3.48, CI 95%: 1.22 to 9.98, p = 0.020] were significantly associated with health problems in their host country in the Middle East. Female migrant workers face various work-related health risks, which are often related to exploitation. The Government of Nepal should initiate awareness campaigns about health risks and rights in relation to health care services in the host countries. Recruiting agencies/employers should provide information on health risks and training for preventive measures. Raising awareness among female migrant workers can make a change in their working lives.


Preoperative high-intensity strength training improves postural control after TKA: randomized-controlled trial.
This study investigates the effectiveness of preoperative high-intensity strength training (with a special emphasis on lower limb muscle strength and secondarily on balance training) on postural control after TKA. Forty-four subjects (7 men, 37 women, and mean age 66.7 ± 3.9 years) scheduled for unilateral TKA for osteoarthritis (OA) participated in this randomized-controlled trial. Each patient performed two postural control tests: Romberg test with eyes open and closed. These tests were assessed at 8 weeks before surgery (T1), after 8 weeks of training (T2), 1 month after TKA (T3), and finally 3 months after TKA (T4). The intervention group completed an 8-week training program 3 days per week prior to surgery, while the control group received no intervention. The Center of Pressure area (COP) was lower (i.e., better score) for the intervention group at T2, T3, and T4. The anteroposterior range of COP with eyes open was lower in the intervention group at T2, T3, and T4 and with eyes closed at T2. The medial-lateral standard deviation of COP with eyes open was lower in the intervention group at T2 and T4 and with eyes closed at T2 and T3. The anteroposterior standard deviation of COP with eyes open did not change, while that with eyes closed the intervention group showed lower score at T2. Preoperative high-intensity strength training is effective for improving postural control before and early after TKA. Recommendations should include preoperative strength training, and not only balance training, to speed-up recovery of postural control after TKA. 1.


Delocalization transition of a rough adsorption-reaction interface
We introduce a kinetic interface model suitable for simulating adsorption-reaction processes which take place preferentially at surface defects such as steps and vacancies. As the average interface velocity is taken to zero, the self-affine interface with Kardar-Parisi-Zhang-like scaling behavior undergoes a delocalization transition with critical exponents that fall into a different universality class. As the critical point is approached, the interface becomes a multivalued, multiply connected self-similar fractal set. The scaling behavior and critical exponents of the relevant correlation functions are determined from Monte Carlo simulations and scaling arguments.


Invariable biomass-specific primary production of taxonomically discrete picoeukaryote groups across the Atlantic Ocean.
Oceanic photosynthetic picoeukaryotes (< 3 µm) are responsible for > 40% of total primary production at low latitudes such as the North-Eastern tropical Atlantic. In the world ocean, warmed by climate changes, the expected gradual shift towards smaller primary producers could render the role of photosynthetic picoeukaryotes even more important than they are today. Little is still known, however, about how the taxonomic composition of this highly diverse group affects primary production at the basin scale. Here, we combined flow cytometric cell sorting, NaH¹⁴CO₃ radiotracer incubations and class-specific fluorescence in situ hybridization (FISH) probes to determine cell- and biomass-specific inorganic carbon fixation rates and taxonomic composition of two major photosynthetic picoeukaryote groups on a ∼7500-km-long latitudinal transect across the Atlantic Ocean (Atlantic Meridional Transect, AMT19). We show that even though larger cells have, on average, cell-specific CO₂ uptake rates ∼5 times higher than the smaller ones, the average biomass-specific uptake is statistically similar for both groups. On the other hand, even at a high taxonomic level, i.e. class, the contributions to both groups by Prymnesiophyceae, Chrysophyceae and Pelagophyceae are significantly different (P < 0.001 in all cases). We therefore conclude that these group's carbon fixation rates are independent of the taxonomic composition of photosynthetic picoeukaryotes across the Atlantic Ocean. Because the above applies across different oceanic regions the diversity changes seem to be a secondary factor determining primary production.


The nphp-2 and arl-13 genetic modules interact to regulate ciliogenesis and ciliary microtubule patterning in C. elegans.
Cilia are microtubule-based cellular organelles that mediate signal transduction. Cilia are organized into several structurally and functionally distinct compartments: the basal body, the transition zone (TZ), and the cilia shaft. In vertebrates, the cystoprotein Inversin localizes to a portion of the cilia shaft adjacent to the TZ, a region termed the "Inversin compartment" (InvC). The mechanisms that establish and maintain the InvC are unknown. In the roundworm C. elegans, the cilia shafts of amphid channel and phasmid sensory cilia are subdivided into two regions defined by different microtubule ultrastructure: a proximal doublet-based region adjacent to the TZ, and a distal singlet-based region. It has been suggested that C. elegans cilia also possess an InvC, similarly to mammalian primary cilia. Here we explored the biogenesis, structure, and composition of the C. elegans ciliary doublet region and InvC. We show that the InvC is conserved and distinct from the doublet region. nphp-2 (the C. elegans Inversin homolog) and the doublet region genes arl-13, klp-11, and unc-119 are redundantly required for ciliogenesis. InvC and doublet region genes can be sorted into two modules-nphp-2+klp-11 and arl-13+unc-119-which are both antagonized by the hdac-6 deacetylase. The genes of this network modulate the sizes of the NPHP-2 InvC and ARL-13 doublet region. Glutamylation, a tubulin post-translational modification, is not required for ciliary targeting of InvC and doublet region components; rather, glutamylation is modulated by nphp-2, arl-13, and unc-119. The ciliary targeting and restricted localization of NPHP-2, ARL-13, and UNC-119 does not require TZ-, doublet region, and InvC-associated genes. NPHP-2 does require its calcium binding EF hand domain for targeting to the InvC. We conclude that the C. elegans InvC is distinct from the doublet region, and that components in these two regions interact to regulate ciliogenesis via cilia placement, ciliary microtubule ultrastructure, and protein localization.


Ex situ diet influences the bacterial community associated with the skin of red-eyed tree frogs (Agalychnis callidryas).
Amphibians support symbiotic bacterial communities on their skin that protect against a range of infectious pathogens, including the amphibian chytrid fungus. The conditions under which amphibians are maintained in captivity (e.g. diet, substrate, enrichment) in ex situ conservation programmes may affect the composition of the bacterial community. In addition, ex situ amphibian populations may support different bacterial communities in comparison to in situ populations of the same species. This could have implications for the suitability of populations intended for reintroduction, as well as the success of probiotic bacterial inoculations intended to provide amphibians with a bacterial community that resists invasion by the chytrid fungus. We aimed to investigate the effect of a carotenoid-enriched diet on the culturable bacterial community associated with captive red-eyed tree frogs (Agalychnis callidryas) and make comparisons to bacteria isolated from a wild population from the Chiquibul Rainforest in Belize. We successfully showed carotenoid availability influences the overall community composition, species richness and abundance of the bacterial community associated with the skin of captive frogs, with A. callidryas fed a carotenoid-enriched diet supporting a greater species richness and abundance of bacteria than those fed a carotenoid-free diet. Our results suggest that availability of carotenoids in the diet of captive frogs is likely to be beneficial for the bacterial community associated with the skin. We also found wild A. callidryas hosted more than double the number of different bacterial species than captive frogs with very little commonality between species. This suggests frogs in captivity may support a reduced and diverged bacterial community in comparison to wild populations of the same species, which could have particular relevance for ex situ conservation projects.


Increasing crop heterogeneity enhances multitrophic diversity across agricultural regions.
Agricultural landscape homogenization has detrimental effects on biodiversity and key ecosystem services. Increasing agricultural landscape heterogeneity by increasing seminatural cover can help to mitigate biodiversity loss. However, the amount of seminatural cover is generally low and difficult to increase in many intensively managed agricultural landscapes. We hypothesized that increasing the heterogeneity of the crop mosaic itself (hereafter "crop heterogeneity") can also have positive effects on biodiversity. In 8 contrasting regions of Europe and North America, we selected 435 landscapes along independent gradients of crop diversity and mean field size. Within each landscape, we selected 3 sampling sites in 1, 2, or 3 crop types. We sampled 7 taxa (plants, bees, butterflies, hoverflies, carabids, spiders, and birds) and calculated a synthetic index of multitrophic diversity at the landscape level. Increasing crop heterogeneity was more beneficial for multitrophic diversity than increasing seminatural cover. For instance, the effect of decreasing mean field size from 5 to 2.8 ha was as strong as the effect of increasing seminatural cover from 0.5 to 11%. Decreasing mean field size benefited multitrophic diversity even in the absence of seminatural vegetation between fields. Increasing the number of crop types sampled had a positive effect on landscape-level multitrophic diversity. However, the effect of increasing crop diversity in the landscape surrounding fields sampled depended on the amount of seminatural cover. Our study provides large-scale, multitrophic, cross-regional evidence that increasing crop heterogeneity can be an effective way to increase biodiversity in agricultural landscapes without taking land out of agricultural production.


Dispatcher Identification of Out-of-Hospital Cardiac Arrest and Neurologically Intact Survival: A Retrospective Cohort Study.
To date, there are no published data on the association of patient-centered outcomes and accurate public-safety answering point (PSAP) dispatch in an American population. The goal of this study is to determine if PSAP dispatcher recognition of out-of-hospital cardiac arrest (OHCA) is associated with neurologically intact survival to hospital discharge. This retrospective cohort study is an analysis of prospectively collected Quality Assurance/Quality Improvement (QA/QI) data from the San Antonio Fire Department (SAFD; San Antonio, Texas USA) OHCA registry from January 2013 through December 2015. Exclusion criteria were: Emergency Medical Services (EMS)-witnessed arrest, traumatic arrest, age <18 years old, no dispatch type recorded, and missing outcome data. The primary exposure was dispatcher recognition of cardiac arrest. The primary outcome was neurologically intact survival (defined as Cerebral Performance Category [CPC] 1 or 2) to hospital discharge. The secondary outcomes were: bystander cardiopulmonary resuscitation (CPR), automated external defibrillator (AED) use, and prehospital return of spontaneous return of circulation (ROSC). Of 3,469 consecutive OHCA cases, 2,569 cases were included in this analysis. The PSAP dispatched 1,964/2,569 (76.4%) of confirmed OHCA cases correctly. The PSAP dispatched 605/2,569 (23.6%) of confirmed OHCA cases as another chief complaint. Neurologically intact survival to hospital discharge occurred in 99/1,964 (5.0%) of the recognized cardiac arrest group and 28/605 (4.6%) of the unrecognized cardiac arrest group (OR = 1.09; 95% CI, 0.71-1.70). Bystander CPR occurred in 975/1,964 (49.6%) of the recognized cardiac arrest group versus 138/605 (22.8%) of the unrecognized cardiac arrest group (OR = 3.34; 95% CI, 2.70-4.11). This study found no association between PSAP dispatcher identification of OHCA and neurologically intact survival to hospital discharge. Dispatcher identification of OHCA remains an important, but not singularly decisive link in the OHCA chain of survival.


Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching.
Angiogenesis, an essential component of a variety of physiological and pathological processes, offers attractive opportunities for therapeutic regulation. We hypothesized that matrix metalloproteinase-9 genetic deficiency (MMP-9-/-) will impair angiogenesis triggered by tissue ischemia, induced experimentally by femoral artery ligation in mice. To investigate the role of MMP-9, we performed a series of biochemical and histological analyses, including zymography, simultaneous detection of perfused capillaries, MMP-9 promoter activity, MMP-9 protein, and macrophages in MMP-9-/- and wild-type (WT) mice. We found that ischemia resulted in doubling of capillary density in WT and no change in the MMP-9-/- ischemic tissues, which translated into increased (39%) perfusion capacity only in the WT at 14 days after ligation. We also confirmed that capillaries in the MMP-9-/- presented significantly (P<0.05) less points of capillary intersections, interpreted by us as decreased branching. The combined conclusions from simultaneous localizations of MMP-9 expression, capillaries, and macrophages suggested that macrophage MMP-9 participates in capillary branching. Transplantation of WT bone marrow into the MMP-9-/-, restored capillary branching, further supporting the contribution of bone marrow-derived macrophages in supplying the necessary MMP-9. Our study indicates that angiogenesis triggered by tissue ischemia requires MMP-9, which may be involved in capillary branching, a potential novel role for this MMP that could be exploited to control angiogenesis.


Physical and social environmental characteristics of physical activity for Mexican-origin children: examining differences between school year and summer perceptions.
Colonias are substandard residential areas along the U.S.-Mexico border. Families of Mexican-origin living in colonias face health burdens characterized by environmental and socioeconomic hardships. Mexican Americans and low-income families, including colonias children, do not frequently participate in physical activity despite the known link to disease risk reduction. For colonias children, schools are the most commonly reported location for physical activity. School closures and extreme temperatures during summer months create a need to explore seasonal differences in environmental supports and barriers in this population. The purpose of this study was to examine the effect of seasonality on perceived environmental barriers, opportunities, and social support for physical activity among colonias children. As a secondary aim, mother-child discordance for each factor was analyzed. Promotora-researchers recruited mother-child dyads (n=101 dyads, n=202 participants) from colonias in Hidalgo County, Texas. Mothers and children were separately administered surveys at two time points to capture perceived barriers, opportunities, and social support for physical activity (school-year: February-May; summertime: July-August). Summative scores for each outcome were calculated and three multilevel longitudinal models for continuous outcomes were examined; children were nested within households. Mother-child discordance was measured using Cohen's Kappa statistic. Physical activity barriers and environmental opportunities (household and neighborhood) increased from school-year to summer by 1.16 and 2.83 points respectively (p≤0.01), after adjusting for covariates. Significant predictors of increased barriers included household income of >$900/month and having more household members. Children of mothers with significant others who were employed part-time or full-time saw significant decreases in barriers. Mother-child agreement of barriers, environmental opportunities, and social support across seasons was slight to fair (range: median κ=0.047 to κ=0.262). These results suggest a complex relationship between dimensions of economic hardship (employment status, household income, etc…) and perceived opportunities and barriers of children's physical activity engagement during the school-year and summer. In this study, both barriers and opportunities increased from school-year to summer, further demonstrating that interactions among these characteristics need to be better understood and addressed when considering physical activity initiatives for colonias and other Mexican-American children, specifically during summer when school-based physical activity resources are unavailable.


Prophylactic antibiotic treatment following laparoscopic robot-assisted radical prostatectomy for the prevention of catheter-associated urinary tract infections: did the AUA guidelines make a difference?
We sought to evaluate the effectiveness of the American Urological Association (AUA) antibiotic prophylaxis guidelines in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP). Our prospective registry database was reviewed for all RALP cases. The following variables were evaluated: age, associated comorbidities, body mass index (BMI), total operative time, length of stay (LOS), prostate weight, pathological grade and stage. Until 11/2011, RALP patients were treated with antibiotics administered in the operating room and continued until urethral catheter removal. Since 11/2011, all patients were treated with a single intravenous dose of Cephalosporin and Aminoglycoside given within 30 min of surgical incision. The rate of catheter-associated urinary tract infection (CAUTI) was evaluated in both groups. 229 RALP patients were identified. The first 60 patients (26.2%) were treated according to the old protocol (Group 1) while the remaining 169 (73.8%) were treated according to the new protocol (Group 2). Group match was identified in all categories but LOS. Moreover, LOS was found to be longer in Group 1 compared with Group 2 (5.8 vs. 4.5 days, p < 0.001). CAUTI rate was similar in both groups (8.3 vs. 8.9%, respectively, p = 0.89). Logistic regression analysis did not demonstrate any association between treatment protocol and potential risk for CAUTI. Therefore, a single preoperative dose of antibiotics does not increase the rate of CAUTI following RALP compared with prolonged antibiotic treatment. Moreover, it was found to be associated with shorter LOS. Complying with the AUA guidelines may reduce morbidity and medical costs.


[Self medication among patients with musculoskeletal symptoms in Araucanía region].
Self-medication is a common behavior in the general population, specially among those suffering from chronic pain. To study the prevalence and characteristics of self medication. Aiming to know the prevalence and features of self medication, a structured interview was applied to 272 out of 419 individuals from the general population, that reported musculoskeletal symptoms. Sixty five percent of those interviewed recognised self medication. No gender differences were observed and there was a trend towards a higher frequency of self medication among older individuals. The frequency of self-medication was higher in low socioeconomic groups, subjects with long lasting pain, those with more severe pain and among subjects with a previous prescription. The drugs more frequently used were dipyrone, piroxicam and aspirin. The average daily piroxicam dose reported was 27 mg. Self medication was not associated with the labor condition of the subjects or the time of occurrence of symptoms. Self medication is a frequent behavior, particularly among low socio-economic groups and those with long lasting and more severe pain.


Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.
Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.


Yeast-Expressed SARS-CoV Recombinant Receptor-Binding Domain (RBD219-N1) Formulated with Aluminum Hydroxide Induces Protective Immunity and Reduces Immune Enhancement.
We developed a severe acute respiratory syndrome (SARS) subunit recombinant protein vaccine candidate based on a high-yielding, yeast- engineered, receptor-binding domain (RBD219-N1) of the SARS beta-coronavirus (SARS-CoV) spike (S) protein. When formulated with Alhydrogel®, RBD219-N1 induced high-level neutralizing antibodies against both pseudotyped virus and a clinical (mouse-adapted) isolate of SARS-CoV. Here, we report that mice immunized with RBD219-N1/Alhydrogel® were fully protected from lethal SARS-CoV challenge (0% mortality), compared to ~ 30% mortality in mice when immunized with the SARS S protein formulated with Alhydrogel®, and 100% mortality in negative controls. An RBD219-N1 formulation Alhydrogel® was also superior to the S protein, unadjuvanted RBD, and AddaVax (MF59-like adjuvant)-formulated RBD in inducing specific antibodies and preventing cellular infiltrates in the lungs upon SARS-CoV challenge. Specifically, a formulation with a 1:25 ratio of RBD219-N1 to Alhydrogel® provided high neutralizing antibody titers, 100% protection with non-detectable viral loads with minimal or no eosinophilic pulmonary infiltrates. As a result, this vaccine formulation is under consideration for further development against SARS-CoV and potentially other emerging and re-emerging beta-CoVs such as SARS-CoV-2.


A combined analysis of 48 type 2 diabetes genetic risk variants shows no discriminative value to predict time to first prescription of a glucose lowering drug in Danish patients with screen detected type 2 diabetes.
To investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes. We studied type 2 diabetes progression in 1,480 patients with screen-detected type 2 diabetes from the ADDITION-Denmark study using information of redeemed prescriptions from the Register of Medicinal Products Statistics from 2001-2009 in Denmark. Patients were cluster randomized by general practitioners, who were randomized to treat type 2 diabetes according to either a conventional or a multifactorial intensive treatment algorithm. We investigated the genetic influence on diabetes progression by constructing a genetic risk score (GRS) of all 48 validated type 2 diabetes susceptibility variants, a GRS of 11 variants linked to β-cell function and a GRS of 3 variants linked to insulin sensitivity and assessed the association between number of risk alleles and time from diagnosis until first redeemed prescription of either any glucose lowering drug or an insulin drug. The GRS linked to insulin sensitivity only nominally increased the risk of an early prescription redemption with an insulin drug by 39% (HR [95% C.I.] = 1.39 [1.09-1.77], p = 0.009] in patients randomized to the intensive treatment group. Furthermore, the strongest univariate predictors of diabetes progression for the intensive treatment group (measured as time to first insulin) were younger age (HR [95% C.I.] = 0.96 [0.93-0.99]), increased BMI (1.05 [1.01-1.09]), increased HbA1c (1.50 [1.36-.66]), increased TG (1.24 [1.11-1.39]) and reduced fasting serum HDL (0.37 [0.17-0.80]) at baseline. Similar results were obtained for the conventional treatment group. Higher levels of HbA1c, fasting circulating levels of triglyceride, lower HDL, larger BMI and younger age are significant determinants of early pharmacological intervention in type 2 diabetes. However, known common type 2 diabetes-associated gene variants do not appear to significantly affect disease progression.


Phototoxic evaluation of marine sediments collected from a PAH-contaminated site.
The phototoxicity potential of PAH-contaminated field sediment was evaluated and compared to standard sediment toxicity test results. Marine sediments were collected from 30 sites along a presumed PAH sediment pollution gradient in Elliot Bay, WA. Standard 10-day acute and 28-day chronic sediment toxicity tests were conducted with the infaunal amphipods Rhepoxynius abronius and Leptocheirus plumulosus using mortality and the ability to rebury as endpoints. The survivors of these tests were then subjected to 1-h exposures to UV radiation with mortality and reburial again determined. The most highly toxic sediments identified in these experiments were evaluated further for toxicity and phototoxicity by serially diluting them with uncontaminated sediment and repeating the toxicity tests. Standard 10-day toxicity test results indicated that over 70% of the sites sampled in Elliot Bay exhibited measurable toxicity with nine sites being highly toxic to both species of amphipods. Results of standard 28-day chronic sediment toxicity tests were similar. In contrast, almost all of the sites were found to be highly phototoxic. Results indicated that exposure to UV increased toxicity five- to eightfold. This suggests that standard toxicity tests underestimate the potential ecological risk of PAH-contaminated sediments in animals exposed to sunlight. However, only when PAH contamination was between 0.05 and 1.0 toxic units would conducting a phototoxicity evaluation add information to that gained from conducting a standard sediment toxicity test alone.


Surface modification and its effect on attachment, spreading, and proliferation of human gingival fibroblasts.
The purpose of this study was to exploit potential methods of surface modification for improving the seal between the neck portion of a dental implant and the surrounding soft tissue. Titanium surfaces were modified by machining (SM-Ti group); machining and acid etching (AE-Ti group); or machining, acid etching, and depositing 4.5 collagen/hyaluronic acid (col/HA) polyelectrolyte bilayers (CHC-Ti group). These were analyzed using scanning electron microscopy, scanning force microscopy, x-ray photoelectron spectroscopy, contact angle measurement, and quartz crystal microbalance measurement. The degradation behavior of the col/HA multilayer coating was measured. Next, human gingival fibroblasts (HGFs) were cultured on the different surfaces, and cell morphology and spreading were observed using fluorescence microscopy and a shape factor measurement. Cell proliferation was examined by fluorometric quantification of the amount of cellular DNA. Matrix formation of HGFs was determined via enzyme-linked immunosorbent assay. Gene expression was analyzed via reverse transcriptase polymerase chain reaction. Similar surface topology for these three groups was observable on a microscopic scale, and morphologic differences were apparent on the nanoscale. Both acid etching and col/HA deposition improved the hydrophilicity of the titanium surface, in contrast to machining alone. Each col/HA bilayer was about 5 nm thick. The col/HA coating degraded in about a week. Attachment and spreading of HGFs was better on the CHC-Ti surface than on the SM-Ti or AE-Ti surfaces. Moreover, the proliferation and differentiation of HGFs were greatly stimulated when cultured on CHC-Ti. In contrast to two control surfaces (one machined, one machined and acid-etched), col/HA treatment of Ti improved the attachment, spreading, proliferation, and differentiation of HGFs.


Sexual selection and mating systems.
Sexual selection is among the most powerful of all evolutionary forces. It occurs when individuals within one sex secure mates and produce offspring at the expense of other individuals within the same sex. Darwin was first to recognize the power of sexual selection to change male and female phenotypes, and, in noting that sexual selection is nonubiquitous, Darwin was also first to recognize the importance of mating system--the "special circumstances" in which reproduction occurs within species. Analyses of mating systems since Darwin have emphasized either the genetic relationships between male and female mating elements, usually among plants, or the numbers of mates males and females may obtain, usually among animals. Combining these schemes yields a quantitative methodology that emphasizes measurement of the sex difference in the variance in relative fitness, as well as phenotypic and genetic correlations underlying reproductive traits that may arise among breeding pairs. Such information predicts the degree and direction of sexual dimorphism within species, it allows the classification of mating systems using existing genetic and life history data, and with information on the spatial and temporal distributions of fertilizations, it may also predict floral morphology in plants. Because this empirical framework identifies selective forces and genetic architectures responsible for observed male-female differences, it compliments discoveries of nucleotide sequence variation and the expression of quantitative traits. Moreover, because this methodology emphasizes the process of evolutionary change, it is easier to test and interpret than frameworks emphasizing parental investment in offspring and its presumed evolutionary outcomes.


Test Accuracy of the Montreal Cognitive Assessment in Screening for Early Poststroke Neurocognitive Disorder: The Nor-COAST Study.
We determined the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) for poststroke neurocognitive disorder defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria in a prospective observational study. Consecutive participants able to complete a cognitive test battery and MoCA 3 months poststroke were included. The reference standard of neurocognitive disorder was defined as a score of ≥1.5 SD below the normative mean in ≥1 cognitive domain on the cognitive test battery. Among 521 participants (43.6% women; mean age/SD, 71.5/12.0 years; mean education/SD, 12.4/3.8 years), the area under the receiver operating characteristic curve of MoCA for neurocognitive disorder was 0.80 (95% CI, 0.76-0.84). Using the standard MoCA cutoff <26, sensitivity was 0.71 (0.69-0.79) with specificity of 0.73 (0.66-0.76). MoCA cutoff of <27 gave higher sensitivity (0.82 [0.77-0.85]) at the expense of specificity (0.60 [0.53-0.66]). MoCA has reasonable accuracy for poststroke neurocognitive disorder diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02650531.