The Intercostal NMJ Assay: a new alternative to the conventional LD50 assay for the determination of the therapeutic potency of botulinum toxin preparations.
Therapeutic botulinum neurotoxin type A preparations have found an increasing number of clinical uses for a large variety of neuromuscular disorders and dermatological conditions. The accurate determination of potency in the clinical application of botulinum toxins is critical to ensuring clinical efficacy and safety, and is currently achieved by using a lethal dose (LD50) assay in mice. Ethical concerns and operational constraints associated with this assay have prompted the development of alternative assay systems that could potentially lead to its replacement. As one such alternative, we describe the development and evaluation of a novel ex vivo assay (the Intercostal Neuromuscular Junction [NMJ] Assay), which uses substantially fewer animals and addresses ethical concerns associated with the LD50 assay. The assay records the decay of force from electrically-stimulated muscle tissue sections in response to the toxin, and thus combines the important mechanisms of receptor binding, translocation, and the enzymatic action of the toxin molecule. Toxin application leads to a time-related and dose-related reduction in contractile force. A regression model describing the relationship between the applied dose and force decay was determined statistically, and was successfully tested as able to correctly predict the potency of an unknown sample. The tissue sections used were found to be highly reproducible, as determined through the innervation pattern and the localisation of NMJs in situ. Furthermore, the efficacy of the assay protocol to successfully deliver the test sample to the cellular target sites, was critically assessed by using molecular tracer molecules.


Running-Intensity Fluctuations in Elite Rugby Sevens Performance.
To investigate temporal variation in running intensity across and within halves and evaluate the agreement between match-analysis indices used to identify fluctuations in running intensity in rugby sevens. Data from a 15-Hz global positioning system (GPS) were collected from 12 elite rugby sevens players during the IRB World Sevens Series (N = 21 full games). Kinematic (eg, relative distance [RD]) and energetic (eg, metabolic power [MP]) match-analysis indices were determined from velocity-time curves and used to investigate between-halves variations. Mean MP and RD were used to identify peak 2-minute periods of play. Adjacent 2-minute periods (prepeak and postpeak) were compared with peak periods to identify changes in intensity. MP and RD were expressed relative to maximal oxygen uptake (VO2max) and speed at VO2max, respectively, and compared in their ability to describe the intensity of peak periods and their temporal occurrence. Small to moderate reductions were present for kinematic (RD; 8.9%) and energetic (MP; 6%) indices between halves. Peak periods (RD = 130 m/min, MP =13 W/kg) were higher (P < .001) than the match average (RD = 94 m/min, MP = 9.5 W/kg) and the prepeak and postpeak periods (P < .001). RD underestimated the intensity of peak periods compared with MP (bias 16%, limits of agreement [LoA] ± 6%). Peak periods identified by RD and MP were temporally dissociated (bias 21 s, LoA ± 212 s). The findings suggest that running intensity varies between and within halves; however, the index used will influence both the magnitude and the temporal identification of peak periods.


Modulatory effects of Mentha piperita on lung tumor incidence, genotoxicity, and oxidative stress in benzo[a]pyrene-treated Swiss albino mice.
Mentha piperita or peppermint is currently used for alleviating nausea, flatulence, and vomiting. In the present investigation, we evaluated the chemopreventive, antigenotoxic, and antioxidative effects of an aqueous extract of Mentha piperita leaves. One-day-old Swiss albino mice were treated with a single subcutaneous injection of 0.5 mg benzo[a]pyrene (BP) and then given either water or a Mentha extract (ME; 1 g/kg body weight) by gavage starting at 3 weeks of age (weaning). The mice were killed at 9 weeks of age and tested for lung tumor incidence (chemoprevention); bone marrow micronucleus and chromosome aberration frequency (antigenotoxicity); and levels of liver and lung sulfhydral groups, superoxide dismutase (SOD) and catalase (CAT) activity, and lipid peroxidation (LPO) (antioxidative properties). The ME treatment resulted in a significant reduction in the number of lung adenomas from an incidence of 67.92% in animals given only BP to 26.31%, an inhibition of 61.26%. Tumor multiplicity was 1.22 in the BP-alone group and 1.15 in the BP + ME group. In addition, compared with the animals in the BP-alone group, ME reduced the frequency of chromosomal aberrations and micronuclei in bone marrow cells and decreased the levels of LPO and increased reduced glutathione content, and SOD and CAT activities in liver as well as lung. The results of this study indicate that ME is chemopreventive and antigenotoxic when given subsequent to an initiating dose of BP in newborn Swiss albino mice. The chemopreventive action and antigenotoxic effects observed in the present study may be due to the antioxidative properties of ME.


The impact of an educational DVD on cancer patients considering participation in a phase I clinical trial.
The quality of informed consent in phase I trials is controversial, partially due to gaps in patient understanding. We assessed an educational DVD's impact on knowledge and satisfaction in cancer patients newly referred to a phase I clinic. Forty-nine patients were randomly assigned to view an educational DVD (n = 22) which explained phase I trials or a placebo DVD (n = 27). Patients completed a questionnaire assessing knowledge of phase I studies and satisfaction with the DVD. The blinded interviewing physician (n = 8) rated the patient's understanding of phase I trials. The mean patient age was 56; 61% were male. Patients who viewed the educational DVD were less likely to believe that phase I trials determine drug efficacy (p = 0.019), more likely to know that phase I drugs have not been thoroughly studied in humans (p = 0.003), and less likely to believe that these agents have proven activity against human cancers (p = 0.008). More patients who viewed the educational DVD agreed/strongly agreed that the DVD provided useful information (p < 0.001), were confident in their knowledge of phase I trials (p = 0.031), felt aided in their decision to enter a phase I study (p = 0.011), and would have more questions for their physicians because of the DVD (p = 0.017). No statistically significant difference in physician perception of patient understanding or phase I trial accrual was observed between the educational and placebo DVD groups. An educational DVD increased patient knowledge and satisfaction regarding participation in phase I clinical trials.


Contribution of branched-chain amino acids to purine nucleotide cycle: a pilot study.
Branched-chain amino acids (BCAAs) and purine nucleotide cycle (PNC) are both associated with energy metabolism. The purpose of this study was to explore the influences of BCAA supplementation on the PNC activity of male athletes in response to a bout of endurance running exercise. Twelve male athletes (20.3±1.4 years) participated in the study. Each of the athletes received 12 g of a BCAA supplement (leucine 54%, isoleucine 19% and valine 27%) per day during the study. They performed two identical 60-min running exercises (65-70% maximum heart rate reserved) before and after receiving the BCAA supplements for 15 days. In addition to body composition measurement, plasma and urinary samples were also collected. Plasma samples were examined for the concentrations of glucose, lactate, BCAAs, alanine, glutamine, aspartate, hypoxanthine and uric acid. Urinary samples were examined for the concentrations of urea nitrogen, hydroxyproline, 3-methylhistidine and creatinine. Body composition and the concentrations of urinary metabolites were not affected by BCAA supplementation, whereas clearance of plasma lactate after recovery from exercise was enhanced by BCAA supplementation (P<0.05). Plasma aspartate concentration was increased (P<0.05), whereas plasma glutamine, hypoxanthine and uric acid concentrations were decreased (P<0.05) by BCAA supplementation. The findings suggest that BCAA supplements not only provided additional substrate to meet the energy demands of the athletes during endurance exercise but also reduced their PNC activity, and subsequently decreased uric acid production and reduced the incidence of gout in a person engaging in endurance exercise.


A review of exosome separation techniques and characterization of B16-F10 mouse melanoma exosomes with AF4-UV-MALS-DLS-TEM.
Exosomes participate in cancer metastasis, but studying them presents unique challenges as a result of their small size and purification difficulties. Asymmetrical field flow fractionation with in-line ultraviolet absorbance, dynamic light scattering, and multi-angle light scattering was applied to the size separation and characterization of non-labeled B16-F10 exosomes from an aggressive mouse melanoma cell culture line. Fractions were collected and further analyzed using batch mode dynamic light scattering, transmission electron microscopy and compared with known size standards. Fractogram peak positions and computed radii show good agreement between samples and across fractions. Ultraviolet absorbance fractograms in combination with transmission electron micrographs were able to resolve subtle heterogeneity of vesicle retention times between separate batches of B16-F10 exosomes collected several weeks apart. Further, asymmetrical field flow fractionation also effectively separated B16-F10 exosomes into vesicle subpopulations by size. Overall, the flow field flow fractionation instrument combined with multiple detectors was able to rapidly characterize and separate exosomes to a degree not previously demonstrated. These approaches have the potential to facilitate a greater understanding of exosome function by subtype, as well as ultimately allow for "label-free" isolation of large scale clinical exosomes for the purpose of developing future exosome-based diagnostics and therapeutics.


Constructional morphology within the head of hammerhead sharks (sphyrnidae).
The study of functional trade-offs is important if a structure, such as the cranium, serves multiple biological roles, and is, therefore, shaped by multiple selective pressures. The sphyrnid cephalofoil presents an excellent model for investigating potential trade-offs among sensory, neural, and feeding structures. In this study, hammerhead shark species were chosen to represent differences in head form through phylogeny. A combination of surface-based geometric morphometrics, computed tomography (CT) volumetric analysis, and phylogenetic analyses were utilized to investigate potential trade-offs within the head. Hammerhead sharks display a diversity of cranial morphologies where the position of the eyes and nares vary among species, with only minor changes in shape, position, and volume of the feeding apparatus through phylogeny. The basal winghead shark, Eusphyra blochii, has small anteriorly positioned eyes. Through phylogeny, the relative size and position of the eyes change, such that derived species have larger, more medially positioned eyes. The lateral position of the external nares is highly variable, showing no phylogenetic trend. Mouth size and position are conserved, remaining relatively unchanged. Volumetric CT analyses reveal no trade-offs between the feeding apparatus and the remaining cranial structures. The few trade-offs were isolated to the nasal capsule volume's inverse correlation with braincase, chondrocranial, and total cephalofoil volume. Eye volume also decreased as cephalofoil width increased. These data indicate that despite considerable changes in head shape, much of the head is morphologically conserved through sphyrnid phylogeny, particularly the jaw cartilages and their associated feeding muscles, with shape change and morphological trade-offs being primarily confined to the lateral wings of the cephalofoil and their associated sensory structures.


Effect of Urate Lowering Therapy on Renal Disease Progression in Hyperuricemic Patients with Chronic Kidney Disease.
To determine whether urate lowering therapy (ULT) could delay renal disease progression in hyperuricemic patients with chronic kidney disease (CKD). We performed a retrospective review of hyperuricemic patients with stage 3 CKD followed from September 2005 to July 2014 in Dongguk University Ilsan Hospital, Goyang, Korea. A total of 158 eligible patients were identified and 65 of them were treated with ULT in addition to the usual CKD management. We divided the patients according to the use of ULT and compared the estimated glomerular filtration rate (eGFR) change from baseline value and the proportion of renal disease progression (decline of eGFR > 30% of the baseline value, initiation of dialysis or eGFR < 15 ml/min/1.73m(2)) at the time of last followup. Risk factors for renal disease progression were identified by logistic regression analysis. After a median followup of 118.5 weeks (minimum 25, maximum 465), the ULT group showed better outcomes compared to the non-ULT group in terms of eGFR change from baseline (-1.19 ± 12.07 vs -7.37 ± 11.17 ml/min/1.73 m(2), p = 0.001) and the proportion of renal disease progression (12.3% vs 27.9%, p = 0.01). Goal-directed ULT showed better clinical outcomes compared to maintaining the initial ULT dose. Actual (area under the SUA-time curve adjusted by total observation time period) serum uric acid was significantly associated with the risk of renal disease progression (p for trend = 0.04) and actual serum uric acid level < 7 mg/dl reduced the risk of renal disease progression by 69.4%. ULT significantly delayed renal disease progression in hyperuricemic patients with CKD. Goal-directed ULT seems to be better than continuing the initial ULT prescription.


Genome-wide characterization, molecular evolution and expression profiling of the metacaspases in potato (Solanum tuberosum L.).
Metacaspases are distant relatives of animal caspases found in plants, protozoa and fungi. Some recent studies have demonstrated that metacaspases are involved in regulating the developmental and environmentally induced programmed cell death in plants. In this study, we identified metacaspase gene family in potato (Solanum tuberosum L.) and analyzed their expression pattern in various developmental tissues and stress responses of plants. There were eight metacaspase genes identified in the Peptidase (Cysteine protease) C14 family and based upon sequence alignment and phylogenetic analysis, a systematic nomenclature of potato metacaspases (SotubMCs) has been proposed. Three of the eight candidate genes showing homology with Arabidopsis thaliana type I metacaspase, AtMC1 were given name SotubMC1, SotubMC2 and SotubMC3 as per the degree of relatedness. Similarly, the next three being homologous to A. thaliana type I metacaspase, AtMC3 were named SotubMC4, SotubMC5, and SotubMC6. The remaining two were named SotubMC7 and SotubMC8, showing significant similarity with type II metacaspases of A. thaliana, AtMC4 and AtMC9, respectively. Evolutionary divergence analysis of SotubMCs from its orthologs in seven other members of Solanaceae family as well as with A. thaliana, Vitis vinifera and Oryza sativa was also carried out. The dN/dS ratios of the orthologous pairs suggested the SotubMCs were under purifying (negative) selection in course of plant evolution. Splicing patterns of potato metacaspases were also analyzed. Amongst all SotubMCs, SotubMC2, SotubMC4, SotubMC6 and SotubMC7 genes appeared to produce multiple alternative spliced variants of different lengths. Furthermore using protein modeling tools, we have predicted the protein structure of identified metacaspases. The cis-regulatory elements analysis was also performed exhibiting the presence of development, stress and hormones related cis-elements in the promoter regions of the SotubMCs. This indicates that potato metacaspases might be playing important roles in the development, stress and hormone responsive pathways. Moreover, relative expression analysis of identified genes was carried out using qRT-PCR in various developmental tissues that also include stolons and tubers. The eight metacaspases showed differential expression in different tissues. Some of the tissues such as leaf undergoing senescence among different leaf developmental stages (immature, mature and senescent) displayed higher relative expression of some of the metacaspases, implying their involvement in leaf senescence. The expression pattern of SotubMCs under various abiotic, biotic and hormonal stresses was also analysed. The results showed that many members of the potato metacaspase gene family displayed differential expression patterns under various stress conditions. Taken together, the study could provide crucial resources for further investigations to understand the functional roles of the identified metacaspases in potato.


Continuous-wave tri-wavelength operation at 1064, 1319 and 1338 nm of LD end-pumped Nd:YAG ceramic laser.
We demonstrated a laser-diode (LD) end-pumped continuous-wave (CW) tri-wavelength Nd:YAG ceramic laser operating at 1064, 1319 and 1338 nm. For the 1064 nm laser, one of the Nd:YAG polished end faces was used as the output coupler. As references, Nd:YVO(4) and Nd:YAG crystal lasers were also investigated under the same structure. We found that the maximum output power came from Nd:YAG ceramic which was 1.74 W, corresponding an optical conversion efficiency of 16.3%. Using a three mirror cavity, we realized efficient multi-wavelength operation at (4)F(3/2)-(4)F(11/2) and (4)F(3/2)-(4)F(13/2) transitions for Nd:YAG ceramic, simultaneously. The maximum output power was 3.2 W, which included 1064, 1319, and 1338 nm three wavelength, and the optical conversion efficiency was 30%.


Feasibility of outpatient management of fever in cancer patients with low-risk neutropenia: results of a prospective randomized trial.
We recently demonstrated the efficacy of single-agent oral ofloxacin in the management of hospitalized neutropenic febrile patients. Ofloxacin was particularly effective in patients with short duration of neutropenia and fever of undetermined origin. These results prompted us to study the feasibility of outpatient management of neutropenic febrile patients who are otherwise at low risk of morbidity and mortality. This multi-institutional, prospective, randomized trial included 182 low-risk neutropenic febrile episodes. After an initial work-up for fever, patients were randomized to receive oral ofloxacin 400 mg immediately and twice daily thereafter in the hospital or as outpatients. Close monitoring and follow-up were carried out in all patients. Those who failed to respond and remained febrile were given parenteral antibiotics. Nonresponding outpatients were admitted to the hospital for parenteral therapy. One hundred sixty-nine episodes were evaluable. The hospital and outpatient treatment groups had comparable clinical characteristics. Pyrexias of undetermined origin (PUO) comprised 69% of episodes managed in hospital and 73% of episodes treated outside. The success rate with PUO was similar with inpatient and outpatient management. Patients with clinical and microbiologic infections fared less well than those with PUO. Overall, 78% of inpatient and 77% of outpatient fevers resolved with no modification of the initial treatment. Twenty-one percent of patients originally assigned to outside management required hospitalization. Mortality was 2% among inpatients and 4% among outpatients. One early death in a nonhospitalized patient underscores the need for close monitoring and surveillance in these cases. Outpatient management of low-risk neutropenic febrile patients with ofloxacin is as effective as inpatient management with the same agent. This approach should be limited to the subset of patients with low-risk factors who are not otherwise on quinolone prophylaxis.


Restriction of AID activity and somatic hypermutation by PARP-1.
Affinity maturation of the humoral immune response depends on somatic hypermutation (SHM) of immunoglobulin (Ig) genes, which is initiated by targeted lesion introduction by activation-induced deaminase (AID), followed by error-prone DNA repair. Stringent regulation of this process is essential to prevent genetic instability, but no negative feedback control has been identified to date. Here we show that poly(ADP-ribose) polymerase-1 (PARP-1) is a key factor restricting AID activity during somatic hypermutation. Poly(ADP-ribose) (PAR) chains formed at DNA breaks trigger AID-PAR association, thus preventing excessive DNA damage induction at sites of AID action. Accordingly, AID activity and somatic hypermutation at the Ig variable region is decreased by PARP-1 activity. In addition, PARP-1 regulates DNA lesion processing by affecting strand biased A:T mutagenesis. Our study establishes a novel function of the ancestral genome maintenance factor PARP-1 as a critical local feedback regulator of both AID activity and DNA repair during Ig gene diversification.


The naloxone test in Klinefelter syndrome.
AIM TO THE STUDY: The investigation of the influence of anti-opioid drug on hypophyseal and gonadal hormones secretion in case of Klinefelter syndrome. The naloxone test (0,4 mg iv) was performed in 14 patients with Klinefelter syndrome aged from 19 to 32 and in 12 age matched control subjects with azoospermia and normal spermatogenesis in testicular histology. The plasma levels of FSH, LH, prolactin, testosterone and estradiol were established before and after 30, 60, 60 and 120 minutes respectively, following the drug administration. Basal FSH, prolactin and estradiol levels were significantly higher whereas basal testosterone was significantly lower in patients with Klinefelter syndrome than in the control group. After the naloxone administration the mean plasma prolactin level decreased significantly (p=0.01) in Klinefelter subjects. The respective diminution in control group was not significant. The levels of FSH and LH as well as testosterone and estradiol did not change during the naloxone test in both Klinefelter and control subjects. The naloxone administration in Klinefelter syndrome caused the decrease in plasma prolactin levels but did not affect the plasma level of another hypophyseal and gonadal hormones. The opioid controlled gonadotropin secretion is altered in case of Klinefelter syndrome.


Chemically characterised Pimenta dioica (L.) Merr. essential oil as a novel plant based antimicrobial against fungal and aflatoxin B1 contamination of stored maize and its possible mode of action.
The chemical characterisation of Pimenta dioica essential oil (PDEO) revealed the presence of 50 components, amongst which α-Terpineol (30.31%) was the major component followed by β-Linalool (6.75%) and γ-Terpinene (4.64%). The oil completely inhibited the growth of aflatoxin B1 secreting strain Aspergillus flavus LHP-VS-8 and aflatoxin B1 production at 2.5 µL/mL and 1.5 µL/mL, respectively. The oil caused dose dependent reduction of methylglyoxal (an AFB1 inducer), enhanced leakage of Ca2+, Mg2+ and K+ ions and significantly reduced ergosterol content of fungal plasma membrane. During in situ experiments, PDEO exhibited complete protection of fumigated maize cob slices from fungal infestation without affecting seed germination. The chemically characterised PDEO is recommended as a plant based preservative and shelf life enhancer of food commodities by preventing fungal growth, AFB1 production and lipid peroxidation. This is the first report on PDEO as inhibitor of AFB1 secretion and methylglyoxal biosynthesis.


Serum vitamin D and risk of bladder cancer.
Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH)D; i.e., <25, 25 to <37.5, 37.5 to <50, ≥50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (versus ≥50 nmol/L; <25 nmol/L: OR, 1.73; 95% CI, 1.03-2.91; 25 to <37.5 nmol/L: OR, 1.81; 95% CI, 1.05-3.14; 37.5 to <50 nmol/L: OR, 1.76; 95% CI, 1.02-3.02; P trend=0.04). Similarly, increased risks for the lowest vitamin D category were observed when season-specific quartiles were used (Q1 versus Q4: OR, 1.63; 95% CI, 0.96-2.75; P trend=0.03). In this prospective study of male smokers, lower serum 25(OH)D was associated with an increased risk of bladder cancer. Future studies should examine the association in other populations, especially nonsmokers and women.


Revisiting the enniatins: a review of their isolation, biosynthesis, structure determination and biological activities.
Enniatins are cyclohexadepsipeptides isolated largely from Fusarium species of fungi, although they have been isolated from other genera, such as Verticillium and Halosarpheia. They were first described over 60 years ago, and their range of biological activities, including antiinsectan, antifungal, antibiotic and cytotoxic, drives contemporary interest. To date, 29 enniatins have been isolated and characterized, either as a single compound or mixtures of inseparable homologs. Structurally, these depsipeptides are biosynthesized by a multifunctional enzyme, termed enniatin synthetase, and are composed of six residues that alternate between N-methyl amino acids and hydroxy acids. Their structure elucidation can be challenging, particularly for enniatins isolated as inseparable homologs; however, several strategies and tools have been utilized to solve these problems. Currently, there is one drug that has been developed from a mixture of enniatins, fusafungine, which is used as a topical treatment of upper respiratory tract infections by oral and/or nasal inhalation. Given the range of biological activities observed for this class of compounds, research on enniatins will likely continue. This review strives to digest the past studies, as well as, describe tools and techniques that can be utilized to overcome the challenges associated with the structure elucidation of mixtures of enniatin homologs.


The flaws in the detail of an observational study on transcatheter aortic valve implantation versus surgical aortic valve replacement in intermediate-risks patients.
The PARTNER group recently published a comparison between the latest generation SAPIEN 3 transcatheter aortic valve implantation (TAVI) system (Edwards Lifesciences, Irvine, CA, USA) and surgical aortic valve replacement (SAVR) in intermediate-risk patients, apparently demonstrating superiority of the TAVI and suggesting that TAVI might be the preferred treatment method in this risk class of patients. Nonetheless, assessment of the non-randomized methodology used in this comparison reveals challenges that should be addressed in order to elucidate the validity of the results. The study by Thourani and colleagues showed several major methodological concerns: suboptimal methods in propensity score analysis with evident misspecification of the propensity scores (PS; no adjustment for the most significantly different covariates: left ventricular ejection fraction, moderate-severe mitral regurgitation and associated procedures); use of PS quintiles rather than matching; inference on not-adjusted Kaplan-Meier curves, although the authors correctly claimed for the need of balancing score adjusting for confounding factors in order to have unbiased estimates of the treatment effect; evidence of poor fit; lack of data on valve-related death.These methodological flaws invalidate direct comparison between treatments and cannot support authors' conclusions that TAVI with SAPIEN 3 in intermediate-risk patients is superior to surgery and might be the preferred treatment alternative to surgery.


ACO-Affiliated Hospitals Reduced Rehospitalizations From Skilled Nursing Facilities Faster Than Other Hospitals.
Medicare's more than 420 accountable care organizations (ACOs) provide care for a considerable percentage of the elderly in the United States. One goal of ACOs is to improve care coordination and thereby decrease rates of rehospitalization. We examined whether ACO-affiliated hospitals were more effective than other hospitals in reducing rehospitalizations from skilled nursing facilities. We found a general reduction in rehospitalizations from 2007 to 2013, which suggests that all hospitals made efforts to reduce rehospitalizations. The ACO-affiliated hospitals, however, were able to reduce rehospitalizations more quickly than other hospitals. The reductions suggest that ACO-affiliated hospitals are either discharging to the nursing facilities more effectively compared to other hospitals or targeting at-risk patients better, or enhancing information sharing and communication between hospitals and skilled nursing facilities. Policy makers expect that reducing readmissions to hospitals will generate major savings and improve the quality of life for the frail elderly. However, further work is needed to investigate the precise mechanisms that underlie the reduction of readmissions among ACO-affiliated hospitals.


Occupational advice to help people return to work following lower limb arthroplasty: the OPAL intervention mapping study.
Hip and knee replacements are regularly carried out for patients who work. There is little evidence about these patients' needs and the factors influencing their return to work. There is a paucity of guidance to help patients return to work after surgery and a need for structured occupational advice to enable them to return to work safely and effectively. To develop an occupational advice intervention to support early recovery to usual activities including work that is tailored to the requirements of patients undergoing hip or knee replacements. To test the acceptability, practicality and feasibility of this intervention within current care frameworks. An intervention mapping approach was used to develop the intervention. The research methods employed were rapid evidence synthesis, qualitative interviews with patients and stakeholders, a prospective cohort study, a survey of clinical practice and a modified Delphi consensus process. The developed intervention was implemented and assessed during the final feasibility stage of the intervention mapping process. Orthopaedic departments in NHS secondary care. Patients who were in work and intending to return to work following primary elective hip or knee replacement surgery, health-care professionals and employers. Occupational advice intervention. Development of an occupational advice intervention, fidelity of the developed intervention when delivered in a clinical setting, patient and clinician perspectives of the intervention and preliminary assessments of intervention effectiveness and cost. A cohort study (154 patients), 110 stakeholder interviews, a survey of practice (152 respondents) and evidence synthesis provided the necessary information to develop the intervention. The intervention included information resources, a personalised return-to-work plan and co-ordination from the health-care team to support the delivery of 13 patient and 20 staff performance objectives. To support delivery, a range of tools (e.g. occupational checklists, patient workbooks and employer information), roles (e.g. return-to-work co-ordinator) and training resources were created. Feasibility was assessed for 21 of the 26 patients recruited from three NHS trusts. Adherence to the defined performance objectives was 75% for patient performance objectives and 74% for staff performance objectives. The intervention was generally well received, although the short time frame available for implementation and concurrent research evaluation led to some confusion among patients and those delivering the intervention regarding its purpose and the roles and responsibilities of key staff. Implementation and uptake of the intervention was not standardised and was limited by the study time frame. Evaluation of the intervention involved a small number of patients, which limited the ability to assess it. The developed occupational advice intervention supports best practice. Evaluation demonstrated good rates of adherence against defined performance objectives. However, a number of operational and implementation issues require further attention. The intervention warrants a randomised controlled trial to assess its clinical effectiveness and cost-effectiveness to improve rates and timing of sustained return to work after surgery. This research should include the development of a robust implementation strategy to ensure that adoption is sustained. Current Controlled Trials ISRCTN27426982 and PROSPERO CRD42016045235. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 45. See the NIHR Journals Library website for further project information.


Plasma and cellular fibronectin: distinct and independent functions during tissue repair.
Fibronectin (FN) is a ubiquitous extracellular matrix (ECM) glycoprotein that plays vital roles during tissue repair. The plasma form of FN circulates in the blood, and upon tissue injury, is incorporated into fibrin clots to exert effects on platelet function and to mediate hemostasis. Cellular FN is then synthesized and assembled by cells as they migrate into the clot to reconstitute damaged tissue. The assembly of FN into a complex three-dimensional matrix during physiological repair plays a key role not only as a structural scaffold, but also as a regulator of cell function during this stage of tissue repair. FN fibrillogenesis is a complex, stepwise process that is strictly regulated by a multitude of factors. During fibrosis, there is excessive deposition of ECM, of which FN is one of the major components. Aberrant FN-matrix assembly is a major contributing factor to the switch from normal tissue repair to misregulated fibrosis. Understanding the mechanisms involved in FN assembly and how these interplay with cellular, fibrotic and immune responses may reveal targets for the future development of therapies to regulate aberrant tissue-repair processes.


Surface-induced photorefractivity in twistable nematics: toward the all-optical control of gain.
We report the first two-beam coupling investigation of the surface-induced photorefractive effect (SIPRE) in optically twistable nematic liquid crystal cell. The unique space-charge field of SIPRE is exploited to achieve optical tuning of the photorefractive gain. A reconfigurable photoaligning substrate is used to adjust the twist angle, which is proved to be a control parameter for the photorefractive gain. The amplitude of the optical modulation increases gradually with the twist. Its phase shift changes from 0 degrees to 90 degrees with the polarization state of the two interfering beams. These results pave the way to the all-optical control of the photorefractive gain.


Identification of FABP7 in fibroblastic reticular cells of mouse lymph nodes.
Fatty acids and their metabolites regulate immune cell function. The present study was undertaken to examine the detailed distribution of fatty acid binding proteins (FABPs), the cytosolic chaperones of fatty acids, in mouse peripheral immune organs. Using immunohistochemistry, FABP7 was localized to the alpha-smooth muscle actin (SMA)(+) fibroblastic reticular cells, which construct the stromal reticula in the T cell areas of the peripheral lymph nodes and spleen. Immunoelectron microscopy showed that FABP7(+) cells enclosed the collagen fibers, forming a conduit system, which transport lymph and associated low-molecular-mass proteins. In contrast, FABP5(+) cells were distributed throughout the lymph node and contained well-developed lysosome and phagocytic materials within the cytoplasm. The mesenteric lymph nodes of FABP7 knockout mice showed normal histological features, but the percentage of CD4(+) cells was significantly increased compared with that in wild-type mice. These data indicate that FABP7 may be involved in T cell homeostasis, possibly by modulating lipid metabolism in fibroblastic reticular cells within the peripheral lymph nodes.


Physical function and health-related quality-of-life in a population-based sample.
BACKGROUND. It is of interest to understand whether impaired physical function is associated with health-related quality-of-life (HRQOL). We examined upper and lower body physical function and its relationship with two domains of HRQOL among men. METHODS. We conducted a population-based observational study of musculoskeletal health among Boston, MA residents, the Boston Area Community Health/Bone Survey. Participants were 1219 randomly-selected Black, Hispanic, and White males (30-79 years). Upper body function was measured using hand grip strength, while lower body function was measured by combining a timed walk and a chair stand test. HRQOL was measured using the physical (PCS-12) and mental health (MCS-12) component scores of the SF-12. Multivariate linear regression models were used to estimate the association between poor function and HRQOL. RESULTS. There was a significant association of poor upper body physical function with the MCS-12 (β coefficient: -4.12, p = 0.003) but not the PCS-12 (β coefficient: 0.79, p = 0.30) compared to those without poor function. Those with poor lower body physical function had significantly lower PCS-12 scores (β: -2.95, p = 0.007), compared to those without poor function, but an association was not observed for MCS-12 scores. CONCLUSIONS. Domains of physical function were not consistently related to domains of HRQOL.


Downstream vascular changes after flow-diverting device deployment in a rabbit model.
Flow diverters (FDs) are increasingly used in the treatment of intracranial aneurysms, and carry the risk of thromboembolic complications, even in patients treated with dual antiplatelet therapy. The effect of FDs on the downstream vascular is unknown. The aim of the study was to investigate vascular wall pulse wave velocity (PWV) and contractility changes following FD treatment in a rabbit model. FDs (Pipeline Embolic Device, Medtronic Inc., Irvine, California, USA) were implanted in the aorta of normal rabbits and sham-operated aorta were used as controls (n=6 per group). Pulse wave imaging with ultra-fast ultrasound at 1600 frames per second (Vantage, Verasonics, Inc., Kirkland, WA) was performed in the vessel wall distal to FD prior to device implantation and at 8- week follow-up to measure the PWV. Force contraction vascular reactivity studies were conducted in the aortic rings using an organ bath. The difference in mean PWV in the follow-up compared with pre-implantation was significantly higher in the distal vessels compared with sham controls (1.18 m/s [SD=0.54] vs. 0.37 m/s [SD=1.09], P=0.03). Conversely, the aortic segments distal to the FD exhibited a 55% increase in vascular contractility compared with proximal segments (P=0.002). We observed a significant positive correlation between mean PWV and mean vascular contractility. Implantation of FD was associated with increased PWV and vascular contractility, suggesting that FD implantation causes changes to the vascular wall. Further studies are needed to understand the clinical implication of changes in vascular PWV and contractility.


IsdA protects Staphylococcus aureus against the bactericidal protease activity of apolactoferrin.
An important facet of the Staphylococcus aureus host-pathogen interaction is the ability of the invading bacterium to evade host innate defenses, particularly the cocktail of host antimicrobial peptides. In this work, we showed that IsdA, a surface protein of S. aureus which is required for nasal colonization, binds to lactoferrin, the most abundant antistaphylococcal polypeptide in human nasal secretions. The presence of IsdA on the surface of S. aureus confers resistance to killing by lactoferrin. In addition, the bactericidal activity of lactoferrin was inhibited by addition of phenylmethylsulfonyl fluoride, implicating the serine protease activity of lactoferrin in the killing of S. aureus. Recombinant IsdA was a competitive inhibitor of lactoferrin protease activity. Reciprocally, antibody reactive to IsdA enhanced killing of S. aureus. Thus, IsdA can protect S. aureus against lactoferrin and acts as a protease inhibitor.


Electrocoagulation of synthetic dairy wastewater.
This study compares the effectiveness of pollutant removal from synthetic dairy wastewater electrocoagulated by means of aluminum and iron anodic dissolution. A method based on the cubic function (third degree polynomial) was proposed for electrocoagulant dosing. Mathematical methods for calculating the optimal electrocoagulant doses proved to be quite precise and useful for practical applications. The results of gravimetric measurements of electrocoagulant (electrode) consumption demonstrated that theoretical doses of Al determined based on Faraday's law were substantially lower than those produced by electrode weighing. The above phenomenon was also discussed in the light of the results of polarization resistance measurements for Al and Fe electrodes used in the study.


Preclinical Applications of Multi-Platform Imaging in Animal Models of Cancer.
In animal models of cancer, oncologic imaging has evolved from a simple assessment of tumor location and size to sophisticated multimodality exploration of molecular, physiologic, genetic, immunologic, and biochemical events at microscopic to macroscopic levels, performed noninvasively and sometimes in real time. Here, we briefly review animal imaging technology and molecular imaging probes together with selected applications from recent literature. Fast and sensitive optical imaging is primarily used to track luciferase-expressing tumor cells, image molecular targets with fluorescence probes, and to report on metabolic and physiologic phenotypes using smart switchable luminescent probes. MicroPET/single-photon emission CT have proven to be two of the most translational modalities for molecular and metabolic imaging of cancers: immuno-PET is a promising and rapidly evolving area of imaging research. Sophisticated MRI techniques provide high-resolution images of small metastases, tumor inflammation, perfusion, oxygenation, and acidity. Disseminated tumors to the bone and lung are easily detected by microCT, while ultrasound provides real-time visualization of tumor vasculature and perfusion. Recently available photoacoustic imaging provides real-time evaluation of vascular patency, oxygenation, and nanoparticle distributions. New hybrid instruments, such as PET-MRI, promise more convenient combination of the capabilities of each modality, enabling enhanced research efficacy and throughput.


The influence of lifestyle on the incidence of dental caries among 3-year-old Japanese children.
The present cohort study examined how lifestyle, household environment, and caries activity test score of Japanese children at age 1.5 years affected their dental caries incidence at age 3. Inclusion criteria were 1.5-year-old children with no dental caries. Dental examinations were performed for 33,655 children who participated in routine dental examinations at 1.5 years of age, and the exam was repeated approximately 21 months later (at age 3) at the Kobe City Public Health Center in Japan. After excluding 622 children who had caries at age 1.5 and 1831 children with missing lifestyle and household environment data in the questionnaires, the final data analysis was performed on a total of 31,202 children (16,052 boys, 15,150 girls).The multivariate logistic regression analysis indicated a strong association of the consumption of sugar-sweetened beverages/snacks, less frequent tooth brushing by the parents, lack of fluoride varnish, family history of smoking, with the risk of developing dental caries. A child's late bedtime is also one of the major risk factors for dental caries development. Further investigation is needed to examine whether the short duration or the irregularity of the sleep-wake cycle would affect early childhood oral health and whether there is a relationship between late bedtime and late night snack intake.


Early events responsible for aluminum toxicity symptoms in suspension-cultured tobacco cells.
We investigated the aluminum (Al)-induced alterations in zeta potential, plasma membrane (PM) potential and intracellular calcium levels to elucidate their interaction with callose production induced by Al toxicity. A noninvasive confocal laser microscopy has been used to analyse the live tobacco (Nicotiana tabacum) cell events by means of fluorescent probes Fluo-3 acetoxymethyl ester (intracellular calcium) and DiBAC4 (PM potential) as well as to monitor callose accumulation. Log-phase cells showed no detectable changes in the PM potential during the first 30 min of Al treatment, but sustained large depolarization from 60 min onwards. Measurement of zeta potential confirmed the depolarization effect of Al, but the kinetics were different. The Al-treated cells showed a moderate increase in intracellular Ca2+ levels and callose production in 1 h, which coincided with the time course of PM depolarization. Compared with the Al treatment, cyclopiazonic acid, an inhibitor of endoplasmic reticulum Ca(2+)-ATPase, facilitated a higher increase in intracellular Ca2+ levels, but resulted in accumulation of only moderate levels of callose. Calcium channel modulators and Al induced similar levels of callose in the initial 1 h of treatment. Callose production induced by Al toxicity is dependent on both depolarization of the PM and an increase in intracellular Ca2+ levels.


Implementing practice-linked pre-visit electronic journals in primary care: patient and physician use and satisfaction.
Electronic health records (EHRs) and EHR-connected patient portals offer patient-provider collaboration tools for visit-based care. During a randomized controlled trial, primary care patients completed pre-visit electronic journals (eJournals) containing EHR-based medication, allergies, and diabetes (study arm 1) or health maintenance, personal history, and family history (study arm 2) topics to share with their provider. Assessment with surveys and usage data showed that among 2027 patients invited to complete an eJournal, 70.3% submitted one and 71.1% of submitters had one opened by their provider. Surveyed patients reported they felt more prepared for the visit (55.9%) and their provider had more accurate information about them (58.0%). More arm 1 versus arm 2 providers reported that eJournals were visit-time neutral (100% vs 53%; p<0.013), helpful to patients in visit preparation (66% vs 20%; p=0.082), and would recommend them to colleagues (78% vs 22%; p=0.0143). eJournal integration into practice warrants further study.


Syndecans and Enzymes Involved in Heparan Sulfate Biosynthesis and Degradation Are Differentially Expressed During Human Odontogenesis.
Syndecans belong to a four-member family of cell surface heparan sulfate proteoglycans (HSPGs) abundantly present in various tissues. They are primarily recognized as extracellular matrix (ECM) receptors able to bind various ECM components and form gradients of morphogens and growth factors. Syndecans are composed of core protein with distinctive cytoplasmic, transmembrane, and extracellular domains to which several HS glycosaminoglycan (GAG) chains are covalently attached. In development of composite organs, such as teeth, expression patterns of syndecans display temporo-spatial shifts between epithelial and mesenchymal tissue compartments. Along with diverse functional properties of syndecans and generally large number of their interactors due to HS GAG chain content, this suggests possible involvement of syndecans in modulation of epithelial-to-mesenchymal crosstalk. Functional versatility of syndecans greatly depends upon the biochemical properties of attached HS GAG chains. These are specifically determined during the HS biosynthesis by the combinatorial action of glycosyl-transferases (Exts/EXTs) and bi-functional sulfotransferases (Ndsts/NDSTs), as well as by post-biosynthetic enzymatic cleavage of HS by the only active endoglucuronidase in mammals, heparanase 1 (Hpse1/HPSE1). Matching the essential requirement for HS during organogenesis, null-mutant animals for genes encoding these enzymes display severe developmental anomalies of mineralized tissues (including teeth) with embryonic or perinatal lethality. In this study, we analyzed expression of syndecan HSPGs (syndecans 1, 2, and 4), enzymes involved in HS biosynthesis (EXT1, NDST1, NDST2) and HS cleavage (HPSE1) in human tooth germs during the early stages of odontogenesis. All of the investigated factors displayed temporo-spatial differences in expression patterns, and some of them showed distinctive asymmetries of expression domains. Our findings suggest that these factors might be differentially involved in cellular processes which take place during the early odontogenic sequence in humans.


NCCN Oncology Research Program's Investigator Steering Committee and NCCN Best Practices Committee Molecular Profiling Surveys.
With advances such as next-generation sequencing (NGS) increasing understanding of the basis of cancer and its response to treatment, NCCN believes it is important to understand how molecular profiling/diagnostic testing is being performed and used at NCCN Member Institutions and their community affiliates. The NCCN Oncology Research Program's Investigator Steering Committee and the NCCN Best Practices Committee gathered baseline information on the use of cancer-related molecular testing at NCCN Member Institutions and community members of the NCCN Affiliate Research Consortium through 2 separate surveys distributed in December 2013 and September 2014, respectively. A total of 24 NCCN Member Institutions and 8 affiliate sites provided quantitative and qualitative data. In the context of these surveys, "molecular profiling/diagnostics" was defined as a panel of at least 10 genes examined as a diagnostic DNA test in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Results indicated that molecular profiling/diagnostics are used at 100% of survey respondents' institutions to make patient care decisions. However, challenges relating to reimbursement, lack of data regarding actionable targets and targeted therapies, and access to drugs on or off clinical trials were cited as barriers to integration of molecular profiling into patient care. Frameworks for using molecular diagnostic results based on levels of evidence, alongside continued research into the predictive value of biomarkers and targeted therapies, are recommended to advance understanding of the role of genomic biomarkers. Greater evidence and consensus regarding the clinical and cost-effectiveness of molecular profiling may lead to broader insurance coverage and increased integration into patient care.


Bards, poets, and cliques: frequency-dependent selection and the evolution of language genes.
The ability of humans to communicate via language is a complex, adapted phenotype, which undoubtedly has a recently evolved genetic component. However, the evolutionary dynamics of language-associated alleles are poorly understood. To improve our knowledge of such systems, a population-genetics model for language-associated genes is developed. (The model is general and applicable to social interactions other than communication.) When an allele arises that potentially improves the ability of individuals to communicate, it will experience positive frequency-dependent selection because its fitness will depend on how many other individuals communicate the same way. Consequently, new and rare alleles are selected against, posing a problem for the evolutionary origin of language. However, the model shows that if individuals form language-based cliques, then novel language-associated alleles can sweep through a population. Thus, the origin of language ability can be sufficiently explained by Darwinian processes operating on genetic diversity in a finite population of human ancestors.


Crude Turmeric Extract Improves the Suppressive Effects of Lactobacillus rhamnosus GG on Allergic Inflammation in a Murine Model of House Dust Mite-Induced Asthma.
There is a strong correlation between dysregulation of the gastrointestinal microbiota and development of allergic diseases. The most prevalent therapies for relieving asthma symptoms are associated with serious side effects, and therefore novel approaches are needed. Our objective was to elucidate whether oral administration of Lactobacillus rhamnosus GG (LGG) as a probiotic or turmeric powder (TP) as a prebiotic or both as a synbiotic mitigate allergic inflammation including lung function, airway inflammatory cell infiltration, Th2 cytokines/chemokine in a murine model of house dust mite (HDM)-induced asthma. BALB/c mice were intranasally sensitized and challenged with HDM received TP (20 mg/Kg mouse), or/and LGG (105 or 107 cfu/ml), or both orally. Interestingly, the synbiotic intervention (HDM-TP-LGG E7) specifically suppress the developement of airway hyperresponsiveness in response to methacholine. Besides, our synbiotic, TP, and LGG strongly down-regulated eosinophilia, IL-5, CCL17, IL-13. In terms of T cell response, CD4+ Th2 cells and CD4+ Th17 population were reduced in the splenocytes of the treatment groups compared to control. The synbiotic group not only elevated CD25+Foxp3+Treg frequency compared to asthmatic group, but also increased T reg cells compared to the probiotic group. The synbiotic also indicated the superior effect in suppressing Th2 cells compared to probiotic. Although, TP and LGG alone displayed suppressive effects, this study showed that the combination therapy consisting of TP and LGG (synbiotic) is more effective in some of the parameters than either of the treatments alone. This novel synbiotic, might be considered as a potential food-based drug for translational medicine and can possibly be used along with corticosteroid treatment.


A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-alpha down-regulation in breast cancer cells: the role of nuclear factor-kappaB.
Estrogen receptor alpha (ERalpha) negative breast tumors often present with enhanced expression and/or activation of growth factor receptors, resulting in increased growth factor signaling and hyperactivation of MAPK (ERK1 and ERK2). We have pre-viously shown that ERalpha(+) MCF-7 cells with elevated growth factor signaling lose expression of ERalpha without any ligand-independent transcriptional activation, and this is a reversible effect attributable to ERK1/2 hyperactivation. Here, we show that down-regulation of ERalpha is not mediated by a specific ERK-1 vs. ERK-2 substrate. Despite up-regulated activator protein-1 activity in response to ERK1/2 activation, and in ERalpha(-) and hormone-independent breast cancers, we find that increased activator protein-1 activity is not responsible for ERalpha down-regulation. Interestingly, our findings implicate a cytoplasmic substrate of ERK1/2. However, RSK1, the best-characterized cytoplasmic ERK1/2 substrate, does not down-regulate ERalpha in our models. On the other hand, inhibition of nuclear factor-kappaB (which is linked to chemoresistance in cancer in general and has elevated activity in hormone-independent and ERalpha- breast cancer) significantly enhances ERalpha activity, suggesting that indirect elevation in nuclear factor-kappaB activity (due to hyperactive ERK1/2) is at least partially responsible for ERalpha down-regulation in these cell line models.


Autocrine actions of endothelin-1 as a growth factor in human ovarian carcinoma cells.
The production of endothelin 1 (ET-1) and its receptor-mediated actions on calcium signaling and growth responses were analyzed in human ovarian carcinoma cells. Immuno-reactive ET-1 was released from three of four ovarian tumor cell lines as a function of time in amounts ranging from 56 to 74 fmol/10(6) cells. Reverse-phase HPLC and radioimmuno-assay of conditioned media from tumor cells revealed a single peak coeluting with authentic ET-1. Radioligand binding studies showed that the ET-1-producing cell lines also expressed high-affinity ETA receptors (Kd < 0.1 nM) that ranged in abundance from 2,600 to 43,600 sites/cell. In fura-2-loaded ovarian carcinoma cells, ET-1 induced dose-dependent increases in cytoplasmic Ca2+ concentration. ET-1 also stimulated thymidine incorporation in the three cell lines that expressed ET receptors. In OVCA 433 cells, BQ 123 inhibited the stimulatory actions of ET-1 on thymidine incorporation and cell proliferation, and substantially reduced the basal growth rate of unstimulated ovarian tumor cells. These results demonstrate that ET-1 is produced in ovarian cancer cells and acts as an autocrine growth factor on ETA receptors to stimulate calcium signaling and proliferative responses. Such findings suggest that ET-1 participates in the progression of neoplastic growth in certain ovarian tumors.


Evaluation of a closed-system cytotoxic transfer device in a pharmaceutical isolator.
The occupational risk associated with handling of cytotoxic anticancer drugs is well documented and, in many countries, pharmaceutical isolators are used to contain cytotoxic residues during preparation of cytotoxic infusions. Isolators are difficult to clean leading to concerns that cytotoxic contamination from the work area could be transferred to surfaces of products leaving the isolator. This study investigated the surface contamination arising from the preparation of five anticancer drug infusions (Epirubicin, Fluorouracil, Cisplatin, Oxaliplatin and Carboplatin) in a pharmaceutical isolator and compared use of a conventional syringe and needle technique with a closed-system drug transfer device (CSDTD). Wipe samples were taken over 1 week from pre-defined areas in the isolator, gloves, preparation mats, and also from the surfaces of prepared cytotoxic infusion bags and pre-filled syringes to obtain baseline surface contamination data. Following operator familiarisation, the CSDTD was then introduced and sampling repeated for a further week (intervention period). The samples obtained were analysed using validated HPLC-UV, HPLC-FL and ICP-MS techniques, as appropriate. All surfaces sampled during baseline, including external surfaces of infusions and syringes, were contaminated with each marker drug. During the intervention phase, isolator surfaces were free from detectable contamination and the contamination measured on gloves, preparation mats and surface of infusions was markedly reduced. The frequency of contamination on syringe and infusion surfaces was also lower. Surface contamination from cytotoxic infusion preparation in a pharmaceutical isolator was significant and could transmit cytotoxic residues to patient and public areas via infusion surfaces. The frequency and amount of contamination were reduced by the CSDTD.


Paradoxical effects of tumour necrosis factor-alpha in adjuvant-induced arthritis.
Anti-tumour necrosis factor (TNF)alpha therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFalpha reduced the severity of adjuvant-induced arthritis and decreased IFNgamma expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFalpha expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFalpha in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFalpha may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses.


Interventions to prevent weight gain: a systematic review of psychological models and behaviour change methods.
To identify and review published interventions aimed at the prevention of weight gain. A systematic review of published interventions aimed at the prevention of weight gain. Search strategies-we searched eight databases, manually checked reference lists and contacted authors. Inclusion and exclusion criteria-studies of any design, in which participants were selected regardless of weight or age, were included. Interventions targeting a specific subgroup, multifactorial interventions, interventions aimed at weight loss, and those with an ambiguous aim were excluded. Data extraction-data were extracted on behaviours targeted for change, psychological model, behaviour change methods and modes of delivery, methodological quality, characteristics of participants, and outcomes related to body weight and self-reported diet and physical activity. Classification and validation-a taxonomy of behaviour change programmes was developed and used for classification of underlying model, behaviour change methods, and modes of delivery. The data extraction and subsequent classification were independently validated. Eleven publications were included, describing five distinct interventions in schools and four in the wider community. Where diet and physical activity were described, positive effects were usually obtained, but all were measured by self-report. Effects on weight were mixed but follow-up was generally short. Smaller effects on weight gain were found among low-income participants, students and smokers. Many participants in the community-based studies were overweight or obese. Study dropout was higher among thinner and lower-income subjects. Interventions to prevent weight gain exhibited various degrees of effectiveness. Definite statements about the elements of the interventions that were associated with increased effect size cannot be made as only one of the five studies that involved an RCT design reported a significant effect on weight. This intervention involved a correspondence programme and a mix of behaviour change methods including goal setting, self-monitoring and contingencies. Future interventions might be more effective if they were explicitly based on methods of behaviour change that have been shown to work in other contexts. Effective interventions would be more easily replicated if they were explicitly described. Effectiveness might be more precisely demonstrated if more objective measures of physical activity and diet were used, and if the follow-up was over a longer period. International Journal of Obesity (2000) 24, 131-143


The role of inputs of marine wrack and carrion in sandy-beach ecosystems: a global review.
Sandy beaches are iconic interfaces that functionally link the ocean with the land via the flow of organic matter from the sea. These cross-ecosystem fluxes often comprise uprooted seagrass and dislodged macroalgae that can form substantial accumulations of detritus, termed 'wrack', on sandy beaches. In addition, the tissue of the carcasses of marine animals that regularly wash up on beaches form a rich food source ('carrion') for a diversity of scavenging animals. Here, we provide a global review of how wrack and carrion provide spatial subsidies that shape the structure and functioning of sandy-beach ecosystems (sandy beaches and adjacent surf zones), which typically have little in situ primary production. We also examine the spatial scaling of the influence of these processes across the broader land- and seascape, and identify key gaps in our knowledge to guide future research directions and priorities. Large quantities of detrital kelp and seagrass can flow into sandy-beach ecosystems, where microbial decomposers and animals process it. The rates of wrack supply and its retention are influenced by the oceanographic processes that transport it, the geomorphology and landscape context of the recipient beaches, and the condition, life history and morphological characteristics of the macrophyte taxa that are the ultimate source of wrack. When retained in beach ecosystems, wrack often creates hotspots of microbial metabolism, secondary productivity, biodiversity, and nutrient remineralization. Nutrients are produced during wrack breakdown, and these can return to coastal waters in surface flows (swash) and aquifers discharging into the subtidal surf. Beach-cast kelp often plays a key trophic role, being an abundant and preferred food source for mobile, semi-aquatic invertebrates that channel imported algal matter to predatory invertebrates, fish, and birds. The role of beach-cast marine carrion is likely to be underestimated, as it can be consumed rapidly by highly mobile scavengers (e.g. foxes, coyotes, raptors, vultures). These consumers become important vectors in transferring marine productivity inland, thereby linking marine and terrestrial ecosystems. Whilst deposits of organic matter on sandy-beach ecosystems underpin a range of ecosystem functions and services, they can be at variance with aesthetic perceptions resulting in widespread activities, such as 'beach cleaning and grooming'. This practice diminishes the energetic base of food webs, intertidal fauna, and biodiversity. Global declines in seagrass beds and kelp forests (linked to global warming) are predicted to cause substantial reductions in the amounts of marine organic matter reaching many beach ecosystems, likely causing flow-on effects for food webs and biodiversity. Similarly, future sea-level rise and increased storm frequency are likely to alter profoundly the physical attributes of beaches, which in turn can change the rates at which beaches retain and process the influxes of wrack and animal carcasses. Conservation of the multi-faceted ecosystem services that sandy beaches provide will increasingly need to encompass a greater societal appreciation and the safeguarding of ecological functions reliant on beach-cast organic matter on innumerable ocean shores worldwide.


Effect of surfactant on lycopene-loaded nanostructured lipid carriers.
Nanostructured lipid carriers (NLC) have gained high interest as enhancing drug delivery systems via topical application during the last few years. NLC can enhance stability of many active substances against environmental stress. The extremely small size of NLC plays an important role in skin penetration. The unchanged size of NLC upon storage indicates its physical stability. The aim of this work was to investigate the effect of surfactant type on physical properties and stability of lycopene-loaded NLC. The preparation of the NLC was achieved by means of high pressure homogenization. The results indicate that different types of surfactant yield NLC with different properties. We also explored the effect of contact angle on the size of the NLC. It was found that the small contact angle gave NLC with small size. Among two small contact angle surfactants, Plantacare 1200 gave lycopene-loaded NLC with smaller size, higher zeta potential and narrower size distribution. The particle size, size distribution, and zeta potential of lycopene-loaded NLC prepared with Plantacare 1200 was unchanged during 30 days of storage. It was concluded that Plantacare 1200 is the most suitable surfactant for lycopene-loaded NLC. The chemical stability of lycopene entrapped in the NLC was significantly enhanced.


Selenium-fertilized forage as a way to supplement lactating dairy cows.
Fertilization with Se improves forage organic Se concentration, but comparisons with other forms of Se supplementation in feeding lactating dairy cows are scarce. Our objective was to compare the effect of Se-enriched forages to dietary sources of inorganic and organic Se. Digestibility, retention, and balance were assessed by measuring Se concentrations in feces, urine, milk, and blood. The resulting effect on antioxidant status and lactation performance of dairy cows was also determined. High-Se silages [1.72 mg of Se/kg of dry matter (DM)] were produced following a spring application of 2.5 kg/ha of Selcote Ultra, whereas low-Se silages (0.05 mg of Se/kg of DM) were produced in the Se-unfertilized portion of the same fields. After a 77±17 d period of Se depletion, 33 late-lactation primiparous Holstein cows were blocked and randomly assigned for 43 d to 1 of 4 experimental total mixed rations fed for ad libitum intake in an unbalanced randomized block design. Treatments consisted of 4 diets: control with low-Se silages, without Se supplement (0.12±0.04 mg of Se/kg of DM); ISe with low-Se silages and inorganic Se (0.80±0.14 mg of Se/kg of DM); YSe with low-Se silages and organic Se from yeast (0.70±0.11 mg of Se/kg of DM); and FSe with high-Se silages, without Se supplement (0.79±0.14 mg of Se/kg of DM). Organic Se, either as YSe or FSe, was more available and more effective to increase blood and milk Se concentrations than ISe. Moreover, FSe was more available than YSe, as cows fed FSe excreted 16 and 22% less Se (as percentage of intake) in feces and urine, respectively, had higher Se apparent absorption (17%), retention (37%), and balance (45%), and had greater concentration of Se in serum (16%) and milk (11%) than cows fed YSe. Antioxidant status (whole blood and plasma glutathione peroxidase, and milk thioredoxin reductase and malondialdehyde) was not affected by treatments. Dry matter intake, yield of actual, energy-corrected, and fat-corrected milk, as well as milk fat and lactose concentrations, were not affected by the dietary treatments. Cows fed ISe had lower milk protein concentration (3.44%) than cows fed YSe (3.58%) or FSe (3.51%). Cows fed Se-supplemented diets had a lower milk somatic cell count than cows fed the control diet. Results from the current study showed that the production of Se-enriched forages is an effective method to supplement dairy cows in Se as it was more available than YSe, and did not alter antioxidant status and performances of lactating dairy cows.


The role of hereditary spastic paraplegia related genes in multiple sclerosis. A study of disease susceptibility and clinical outcome.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.


Crosstalk of two-component signal transduction systems in regulating central carbohydrate and energy metabolism during autotrophic and photomixotrophic growth of Synechocystis sp. PCC 6803.
Unicellular model cyanobacterium Synechocystis sp. PCC 6803 has received considerable attention as a sustainable energy resource because of its photosynthetic machinery. However, two-component signal transduction systems (TCSTSs) in regulating central carbohydrate and energy metabolism of cyanobacteria are still poorly understood due to their diversity and functional complication. In this study, by comparing the growth of knockout mutants of 44 response regulators (RRs) of TCSTSs in Synechocystis, several RR mutants demonstrating differential growth patterns were identified under auto- or photomixotrophic conditions. However, in spite of no growth difference observed for the remaining RR mutants, liquid chromatography-mass spectrometry based metabolomic profile analysis showed that a widespread crosstalk of TCSTSs in regulating central carbohydrate and energy metabolism of Synechocystis was identified, while most of them showed diverse patterns during different trophic types or growth stages. Furthermore, an integrative analysis between evolutionary relationships and metabolomic profiles revealed some pairs of paralogous RRs with highly functional convergence, suggesting the possible conserved functions of Synechocystis TCSTSs during evolution. This study laid an important basis for understanding the function of TCSTSs in photosynthetic cyanobacteria.


Implementing a Systematic Approach to Reduce Cesarean Birth Rates in Nulliparous Women.
To implement a systematic approach to safely reduce nulliparous cesarean birth rates. This is a quality improvement project at two rural community hospitals and one urban community hospital in North Carolina. These facilities implemented a systematic approach to reduce nulliparous cesarean birth rates, aligning with recommendations developed by the Council on Patient Safety in Women's Health Care: Patient Safety Bundle on the Safe Reduction of Primary Cesarean Births. Health care providers and nurses received education on contemporary labor management guidelines developed by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine Obstetric Care Consensus regarding safe prevention of primary cesarean deliveries and nurses were instructed on labor support techniques. The preguideline implementation period was January 1, 2015, to June 30, 2015. The postguideline implementation period was July 1, 2016, to December 31, 2016. The primary outcome measured was the nulliparous, term, singleton, vertex cesarean birth rate. Secondary outcomes included maternal and neonatal outcomes. Standard statistical analysis was used and a P value of <.05 was considered significant. There were 434 women identified in the preguideline period and 401 women in the postguideline period. The nulliparous, term, singleton, vertex cesarean birth rate decreased from 27.9% to 19.7% [odds ratio (OR) 0.63, CI 0.46-0.88]. There were improvements in health care provider compliance with following the labor management guidelines from 86.2% to 91.5% (OR 1.73, 95% CI 1.11-2.70), the use of maternal position changes from 78.7% to 87.5% (OR 1.86, 95% CI 1.29-2.68), and use of the peanut birthing ball from 16.8% to 45.2% (OR 3.83, 95% CI 2.84-5.16) as provisions for labor support. Implementing a systematic approach for care of nulliparous women is associated with a decrease in term, singleton, vertex cesarean birth rates.


Long-term follow-up on the use of vascularized fibular graft for the treatment of congenital pseudarthrosis of the tibia.
Congenital pseudoarthrosis of the tibia (CPT) is one of the most difficult conditions to treat. Five girls and 3 boys with CPT were treated by vascularized fibular grafting (VFG). The average age at VFG was 7.0 years (range: 1.9-11.5 years) with an average follow-up term of 11.7 years (range: 4.9-19.6 years). Five of the children had undergone multiple operations before VFG, while the other 3 had no such history. Bone consolidation was obtained in all cases after an average term of 6.6 months (range: 4-10 months); this was with the first VFG in 7 cases but with the second VFG in 1 case. Complication of stress fracture and ankle pain occurred in 1 and 3 cases, respectively, only in cases undergoing multiple operations. Leg-length discrepancy was more prominent in the patients with multiple previous operations (mean: 7.5 cm), than in the cases with no prior surgery (mean: 0.7 cm). The long-term results of VFG for CPT were excellent, especially in the cases, with no prior surgery. VFG should be considered as a primary treatment option for CPT.


Do Children with Autism Spectrum Disorder Benefit from Structural Alignment When Constructing Categories?
Individuals with ASD seem to construct categories via processes different to typically developing individuals. We examined whether individuals with ASD engage in structural alignment of exemplars when constructing categories. We taught children with ASD and typically developing children novel nouns for either single or multiple exemplars, and then examined their extensions of the learned nouns to objects that were either a perceptual or conceptual match to the original exemplar(s). Results indicated that, unlike typically developing participants, those with ASD gained no benefit from seeing multiple exemplars of the category and, thus, did not appear to engage in structural alignment in their formation of categories. However, they demonstrated superior performance compared to typically developing children when presented with a single exemplar.


Genome sequence of the brown rot fungal pathogen Monilinia fructigena.
Monilinia fructigena (phylum Ascomycota, family Sclerotiniaceae) is a plant pathogen that causes brown rot and blossom blight in pome fruit and stone fruit of the Rosaceae family, which can cause significant losses in the field and mainly postharvest. The aim of this study was to create a high-quality draft of the M. fructigena genome assembly and annotation that provides better understanding of the epidemiology of the pathogen and its interactions with the host(s) and will thus improve brown rot management. We report here on the genome sequence of M. fructigena strain Mfrg269 that was collected from plum in southern Italy. This is assembled into 131 scaffolds, with a total size of 43.125 Mb, with 9960 unique protein-coding genes. The novel genomic resources allow improved genomic comparisons among the most important pathogens belonging to the Monilinia genus, with the aim being to improve the knowledge of their plant-pathogen interactions, population biology, and control.


Non-invasive Neurite Mechanics in Differentiated PC12 Cells.
Thermal Fluctuations Spectroscopy (TFS) in combination with novel optical-based instrumentation was used to study mechanical properties of cell-cultured neurites with a spatial resolution limited only by the light diffraction. The analysis of thermal fluctuations together with a physical model of cellular elasticity allow us to determine relevant mechanical properties of neurite as axial tension σ, flexural rigidity B , plasma membrane tension γ, membrane bending rigidity K , and cytoskeleton to membrane-coupling ρ bk, whose values are consistent with previously reported values measured using invasive approaches. The value obtained for the membrane-coupling parameter was used to estimate the average number of coupling elements between the plasma membrane and the cytoskeleton that fell in the range of 30 elements per area of the laser spot used to record the fluctuations. Furthermore, to expand the TFS analysis, we investigate the correlation between F-actin linear density and the mechanical features of PC12 neurites. Using a hybrid instrument that combines TFS and a simple fluorescent technique, our results show that the fluctuations are related with the F-actin concentration. These measurements have an advantage of not requiring the application of an external force, allowing as to directly establish a correlation between changes in the mechanical parameters and cytoskeleton-protein concentrations. The sensibility of our method was also tested by the application of TFS technique to PC12 neurite under Paraformaldehyde and Latrunculin-A effect. These results show a dramatic modification in the fluctuations that are consistent with the reported effect of these drugs, confirming the high sensitivity of this technique. Finally, the thermal fluctuation approach was applied to DRG axons to show that its utility is not limited to studies of PC12 neurites, but it is suitable to measure the general characteristic of various neuron-like cells.


Late cretaceous polar wander of the pacific plate: evidence of a rapid true polar wander event
We reexamined the Late Cretaceous-early Tertiary apparent polar wander path for the Pacific plate using 27 paleomagnetic poles from seamounts dated by (40)Ar/(39)Ar geochronology. The path shows little motion from 120 to 90 million years ago (Ma), northward motion from 79 to 39 Ma, and two groups of poles separated by 16 to 21 degrees with indistinguishable mean ages of 84 +/- 2 Ma. The latter phenomenon may represent a rapid polar wander episode (3 to 10 degrees per million years) whose timing is not adequately resolved with existing data. Similar features in other polar wander paths imply that the event was a rapid shift of the spin axis relative to the mantle (true polar wander), which may have been related to global changes in plate motion, large igneous province eruptions, and a shift in magnetic field polarity state.


Analysis of Eustachian Tube Dysfunction by Dynamic Slow Motion Video Endoscopy and Eustachian Tube Dysfunction Questionnaire in Chronic Otitis Media.
Eustachian tube dysfunction has been associated with most cases of middle-ear disease. We aimed to assess the effectiveness of dynamic slow motion video endoscopy (DSVE) as a test of eustachian tube dysfunction. Furthermore, we assessed the correlation of the test with the Valsalva maneuver, the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7), and intraoperative findings of the eustachian tube. We retrospectively reviewed medical records from April to September 2014 to identify patients who were diagnosed with chronic otitis media (COM) at Korea University Ansan Hospital. They all underwent surgery because of COM without cholesteatoma and were assessed via the DSVE and ETDQ-7 to determine eustachian tube function. We reviewed 46 COM patients and examined 46 ears with COM and 46 ears on the contralateral side to COM that were thought to be normal. The mean DSVE grade in COM ears was 1.57±0.96, while the mean DSVE grade in contralateral ears was 1.15±0.94. The difference in DSVE between COM ears and normal ears was statistically significant (P=0.006). In the ETDQ-7, a higher score was related to intraoperative obstruction of the eustachian tube (P=0.012). DSVE and ETDQ-7 can provide information regarding preoperative status of eustachian tube dysfunction by measuring dynamic structural changes of the eustachian tube in combination with other diagnostic tests.


A PCR-RFLP test for simultaneous detection of two single-nucleotide insertions in the Connexin-26 gene promoter.
Comparisons of Connexin-26 (GJB2) gene sequences available in the GenBank data base indicate the presence of a polymorphism in the promoter, but no easy method is available for the detection of this polymorphism. We have developed a PCR-RFLP test for simultaneous detection of two single nucleotide insertions (G and A) in the GJB2 promoter. The test is based on amplification of a 146-bp DNA fragment, which was digested with Mae I to detect the G insertion in the promoter. A similar digestion with Hinf I detects the A insertion. The test was validated using direct DNA sequencing of amplified DNA from 33 samples. After validation, we have used it to investigate DNA samples from 160 control subjects and 51 unrelated patients with nonsyndromic autosomal recessive deafness. All of the samples analyzed using the PCR test and DNA sequencing were found to contain both the G and A insertions in the GJB2 gene promoter. This PCR test will be useful in studying the prevalence of these two insertions in other populations.


Membrane restructuring by phospholipase A2 is regulated by the presence of lipid domains.
Secretory phospholipase A(2) (sPLA(2)) catalyzes the hydrolysis of glycerophospholipids. This enzyme is sensitive to membrane structure, and its activity has been shown to increase in the presence of liquid-crystalline/gel (L(α)/L(β)) lipid domains. In this work, we explore whether lipid domains can also direct the activity of the enzyme by inducing hydrolysis of certain lipid components due to preferential activity of the enzyme toward lipid domains susceptible to sPLA(2). Specifically, we show that the presence of L(α)/L(β) and L(α)/P(β') phase coexistence in a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/1,2 distearoyl-sn-glycero-3-phosphocholine (DSPC) system results in the preferential hydrolysis of the shorter-chained lipid component in the mixture, leading to an enrichment in the longer-chained component. The restructuring process is monitored by atomic force microscopy on supported single and double bilayers formed by vesicle fusion. We observe that during preferential hydrolysis of the DMPC-rich L(α) regions, the L(β) and P(β') regions grow and reseal, maintaining membrane integrity. This result indicates that a sharp reorganization of the membrane structure can occur during sPLA(2) hydrolysis without necessarily destroying the membrane. We confirm by high-performance liquid chromatography the preferential hydrolysis of DMPC within the phase coexistence region of the DMPC/DSPC phase diagram, showing that this preferential hydrolysis is accentuated close to the solidus phase boundary. Differential scanning calorimetry results show that this preferential hydrolysis in the presence of lipid domains leads to a membrane system with a higher-temperature melting profile due to enrichment in DSPC. Together, these results show that the presence of lipid domains can induce specificity in the hydrolytic activity of the enzyme, resulting in marked differences in the physical properties of the membrane end-product.


Ultrastructural study of GERL in beige mouse alveolar macrophages.
Alveolar macrophages of the beige mouse mutant have a system of smooth-surfaced elements with the hallmarks of GERL. GERL also appears to produce residual bodies, and both organelles show cytochemically demonstrable acid phosphatase activity. When cells are exposed to colloidal silver, the tracer is endocytosed via pinocytic vacuoles to GERL.


The effects of increased dose of exercise-based therapies to enhance motor recovery after stroke: a systematic review and meta-analysis.
Exercise-based therapy is known to enhance motor recovery after stroke but the most appropriate amount, i.e. the dose, of therapy is unknown. To determine the strength of current evidence for provision of a higher dose of the same types of exercise-based therapy to enhance motor recovery after stroke. An electronic search of: MEDLINE, EMBASE, CINHAL, AMED, and CENTRAL was undertaken. Two independent reviewers selected studies using predetermined inclusion criteria: randomised or quasi randomised controlled trials with or without blinding of assessors; adults, 18+ years, with a clinical diagnosis of stroke; experimental and control group interventions identical except for dose; exercise-based interventions investigated; and outcome measures of motor impairment, movement control or functional activity. Two reviewers independently extracted outcome and follow-up data. Effect sizes and 95% confidence intervals were interpreted with reference to risk of bias in included studies. 9 papers reporting 7 studies were included. Only 3 of the 7 included studies had all design elements assessed as low risk of bias. Intensity of the control intervention ranged from a mean of 9 to 28 hours over a maximum of 20 weeks. Experimental groups received between 14 and 92 hours of therapy over a maximum of 20 weeks. The included studies were heterogeneous with respect to types of therapy, outcome measures and time-points for outcome and follow-up. Consequently, most effect sizes relate to one study only. Single study effect sizes suggest a trend for better recovery with increased dose at the end of therapy but this trend was less evident at follow-up Meta-analysis was possible at outcome for: hand-grip strength, -10.1 [-19.1,-1.2] (2 studies, 97 participants); Action Research Arm Test (ARAT), 0.1 [-5.7,6.0] (3 studies, 126 participants); and comfortable walking speed, 0.3 [0.1,0.5] (2 studies, 58 participants). At follow-up, between 12 and 26 weeks after start of therapy, meta-analysis findings were: Motricity Arm, 10.7 [1.7,19.8] (2 studies, 83 participants); ARAT, 2.2 [-6.0,10.4] (2 studies, 83 participants); Rivermead Mobility, 1.0 [-0.6, 2.5] (2 studies, 83 participants); and comfortable walking speed, 0.2 [0.0,0.4] (2 studies, 60 participants). Current evidence provides some, but limited, support for the hypothesis that a higher dose of the same type of exercised-based therapy enhances motor recovery after stroke. Prospective dose-finding studies are required.


A simple model of circadian rhythms based on dimerization and proteolysis of PER and TIM.
Many organisms display rhythms of physiology and behavior that are entrained to the 24-h cycle of light and darkness prevailing on Earth. Under constant conditions of illumination and temperature, these internal biological rhythms persist with a period close to 1 day ("circadian"), but it is usually not exactly 24h. Recent discoveries have uncovered stunning similarities among the molecular circuitries of circadian clocks in mice, fruit flies, and bread molds. A consensus picture is coming into focus around two proteins (called PER and TIM in fruit flies), which dimerize and then inhibit transcription of their own genes. Although this picture seems to confirm a venerable model of circadian rhythms based on time-delayed negative feedback, we suggest that just as crucial to the circadian oscillator is a positive feedback loop based on stabilization of PER upon dimerization. These ideas can be expressed in simple mathematical form (phase plane portraits), and the model accounts naturally for several hallmarks of circadian rhythms, including temperature compensation and the per(L) mutant phenotype. In addition, the model suggests how an endogenous circadian oscillator could have evolved from a more primitive, light-activated switch.


The prognosis of ankle sprains.
We developed a new diagnostic tool for predicting the severity of ankle sprains just after injury. Since hard data obtained by diagnostic imaging techniques are still imperfect, we decided to use data from individual medical history and signs and symptoms that are part of the admission routine. During a three month-period data were collected on thirty-five patients with lateral ankle sprains who visited the first aid department of the University Hospital of Maastricht. Assessments took place at admission and at two and four weeks after injury. Assessors were the first-aid physician, a physiotherapist and the patient. Dependent variables were healed ankle in two and four weeks. Predicting variables were the data obtained at admission by the physician, the physiotherapist and the patient. The ability to predict outcome after two and four weeks was determined in a bivariate analysis, followed by logistic modelling. Accurate prediction of recovery time at admission appeared to be possible. Best two weeks predictor was the modified function score, an accuracy of 97% was achieved. Four weeks prediction was most accurate when function score was used together with the report mark from the doctor and the palpation score (accuracy of 81%).


Priority actions for the non-communicable disease crisis.
The UN High-Level Meeting on Non-Communicable Diseases (NCDs) in September, 2011, is an unprecedented opportunity to create a sustained global movement against premature death and preventable morbidity and disability from NCDs, mainly heart disease, stroke, cancer, diabetes, and chronic respiratory disease. The increasing global crisis in NCDs is a barrier to development goals including poverty reduction, health equity, economic stability, and human security. The Lancet NCD Action Group and the NCD Alliance propose five overarching priority actions for the response to the crisis--leadership, prevention, treatment, international cooperation, and monitoring and accountability--and the delivery of five priority interventions--tobacco control, salt reduction, improved diets and physical activity, reduction in hazardous alcohol intake, and essential drugs and technologies. The priority interventions were chosen for their health effects, cost-effectiveness, low costs of implementation, and political and financial feasibility. The most urgent and immediate priority is tobacco control. We propose as a goal for 2040, a world essentially free from tobacco where less than 5% of people use tobacco. Implementation of the priority interventions, at an estimated global commitment of about US$9 billion per year, will bring enormous benefits to social and economic development and to the health sector. If widely adopted, these interventions will achieve the global goal of reducing NCD death rates by 2% per year, averting tens of millions of premature deaths in this decade.


Advances in aluminum hydroxide-based adjuvant research and its mechanism.
In the past few decades, hundreds of materials have been tried as adjuvant; however, only aluminum-based adjuvants continue to be used widely in the world. Aluminum hydroxide, aluminum phosphate and alum constitute the main forms of aluminum used as adjuvants. Among these, aluminum hydroxide is the most commonly used chemical as adjuvant. In spite of its wide spread use, surprisingly, the mechanism of how aluminum hydroxide-based adjuvants exert their beneficial effects is still not fully understood. Current explanations for the mode of action of aluminum hydroxide-based adjuvants include, among others, the repository effect, pro-phagocytic effect, and activation of the pro-inflammatory NLRP3 pathway. These collectively galvanize innate as well as acquired immune responses and activate the complement system. Factors that have a profound influence on responses evoked by aluminum hydroxide-based adjuvant applications include adsorption rate, strength of the adsorption, size and uniformity of aluminum hydroxide particles, dosage of adjuvant, and the nature of antigens. Although vaccines containing aluminum hydroxide-based adjuvants are beneficial, sometimes they cause adverse reactions. Further, these vaccines cannot be stored frozen. Until recently, aluminum hydroxide-based adjuvants were known to preferentially prime Th2-type immune responses. However, results of more recent studies show that depending on the vaccination route, aluminum hydroxide-based adjuvants can enhance both Th1 as well as Th2 cellular responses. Advances in systems biology have opened up new avenues for studying mechanisms of aluminum hydroxide-based adjuvants. These will assist in scaling new frontiers in aluminum hydroxide-based adjuvant research that include improvement of formulations, use of nanoparticles of aluminum hydroxide and development of composite adjuvants.


A descriptive analysis of oral health systematic reviews published 1991-2012: cross sectional study.
To identify all systematic reviews (SRs) published in the domain of oral health research and describe them in terms of their epidemiological and descriptive characteristics. Cross sectional, descriptive study. An electronic search of seven databases was performed from inception through May 2012; bibliographies of relevant publications were also reviewed. Studies were considered for inclusion if they were oral health SRs defined as therapeutic or non-therapeutic investigations that studied a topic or an intervention related to dental, oral or craniofacial diseases/disorders. Data were extracted from all the SRs based on a number of epidemiological and descriptive characteristics. Data were analysed descriptively for all the SRs, within each of the nine dental specialities, and for Cochrane and non-Cochrane SRs separately. 1,188 oral health (126 Cochrane and 1062 non-Cochrane) SRs published from 1991 through May 2012 were identified, encompassing the nine dental specialties. Over half (n = 676; 56.9%) of the SRs were published in specialty oral health journals, with almost all (n = 1,178; 99.2%) of the SRs published in English and almost none of the non-Cochrane SRs (n = 11; 0.9%) consisting of updates of previously published SRs. 75.3% of the SRs were categorized as therapeutic, with 64.5% examining non-drug interventions, while approximately half (n = 150/294; 51%) of the non-therapeutic SRs were classified as epidemiological SRs. The SRs included a median of 15 studies, with a meta-analysis conducted in 43.6%, in which a median of 9 studies/1 randomized trial were included in the largest meta-analysis conducted. Funding was received for 25.1% of the SRs, including nearly three-quarters (n = 96; 76.2%) of the Cochrane SRs. Epidemiological and descriptive characteristics of the 1,188 oral health SRs varied across the nine dental specialties and by SR category (Cochrane vs. non-Cochrane). There is a clear need for more updates of SRs in all the dental specialties.


Multiplicative noise can induce a velocity change of propagating dissipative solitons.
We investigate the influence of spatially homogeneous multiplicative noise on propagating dissipative solitons (DSs) of the cubic complex Ginzburg-Landau equation stabilized by nonlinear gradient terms. Here we focus on the nonlinear gradient terms, in particular on the influence of the Raman term and the delayed nonlinear gain. We show that a fairly small amount of multiplicative noise can lead to a change in the mean velocity for such systems. This effect is exclusively due to the presence of the stabilizing nonlinear gradient terms. For a range of parameters we find a velocity change proportional to the noise intensity for the Raman term and for delayed nonlinear gain. We note that the dissipative soliton decreases the modulus of its velocity when only one type of nonlinear gradient is present. We present a straightforward mean field analysis to capture this simple scaling law. At sufficiently high noise strength the nonlinear gradient stabilized DSs collapse.