A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate.
Creatine monohydrate (CrM) has been consistently reported to increase muscle creatine content and improve high-intensity exercise capacity. However, a number of different forms of creatine have been purported to be more efficacious than CrM. The purpose of this study was to determine if a buffered creatine monohydrate (KA) that has been purported to promote greater creatine retention and training adaptations with fewer side effects at lower doses is more efficacious than CrM supplementation in resistance-trained individuals. In a double-blind manner, 36 resistance-trained participants (20.2 ± 2 years, 181 ± 7 cm, 82.1 ± 12 kg, and 14.7 ± 5% body fat) were randomly assigned to supplement their diet with CrM (Creapure® AlzChem AG, Trostberg, Germany) at normal loading (4 x 5 g/d for 7-days) and maintenance (5 g/d for 21-days) doses; KA (Kre-Alkalyn®, All American Pharmaceutical, Billings, MT, USA) at manufacturer's recommended doses (KA-L, 1.5 g/d for 28-days); or, KA with equivalent loading (4 x 5 g/d for 7-days) and maintenance (5 g/d) doses of CrM (KA-H). Participants were asked to maintain their current training programs and record all workouts. Muscle biopsies from the vastus lateralis, fasting blood samples, body weight, DEXA determined body composition, and Wingate Anaerobic Capacity (WAC) tests were performed at 0, 7, and 28-days while 1RM strength tests were performed at 0 and 28-days. Data were analyzed by a repeated measures multivariate analysis of variance (MANOVA) and are presented as mean ± SD changes from baseline after 7 and 28-days, respectively. Muscle free creatine content obtained in a subgroup of 25 participants increased in all groups over time (1.4 ± 20.7 and 11.9 ± 24.0 mmol/kg DW, p = 0.03) after 7 and 28-days, respectively, with no significant differences among groups (KA-L -7.9 ± 22.3, 4.7 ± 27.0; KA-H 1.0 ± 12.8, 9.1 ± 23.2; CrM 11.3 ± 23.9, 22.3 ± 21.0 mmol/kg DW, p = 0.46). However, while no overall group differences were observed (p = 0.14), pairwise comparison between the KA-L and CrM groups revealed that changes in muscle creatine content tended to be greater in the CrM group (KA-L -1.1 ± 4.3, CrM 11.2 ± 4.3 mmol/kg DW, p = 0.053 [mean ± SEM]). Although some significant time effects were observed, no significant group x time interactions (p > 0.05) were observed in changes in body mass, fat free mass, fat mass, percent body fat, or total body water; bench press and leg press 1RM strength; WAC mean power, peak power, or total work; serum blood lipids, markers of catabolism and bone status, and serum electrolyte status; or, whole blood makers of lymphocytes and red cells. Serum creatinine levels increased in all groups (p < 0.001) with higher doses of creatine promoting greater increases in serum creatinine (p = 0.03) but the increases observed (0.1 - 0.2 mg/dl) were well within normal values for active individuals (i.e., <1.28 ± 0.2 mg/dl). Serum LDL was decreased to a greater degree following ingesting loading doses in the CrM group but returned to baseline during the maintenance phase. No side effects were reported. Neither manufacturers recommended doses of KA (1.5 g/d) or KA with equivalent loading (20 g/d for 7-days) and maintenance doses (5 g/d for 21-days) of CrM promoted greater changes in muscle creatine content, body composition, strength, or anaerobic capacity than CrM (20 g/d for 7-days, 5 g/d for 21-days). There was no evidence that supplementing the diet with a buffered form of creatine resulted in fewer side effects than CrM. These findings do not support claims that consuming a buffered form of creatine is a more efficacious and/or safer form of creatine to consume than creatine monohydrate.


Virulence gene pool detected in bovine group C Streptococcus dysgalactiae subsp. dysgalactiae isolates by use of a group A S. pyogenes virulence microarray.
A custom-designed microarray containing 220 virulence genes of Streptococcus pyogenes (group A Streptococcus [GAS]) was used to test group C Streptococcus dysgalactiae subsp. dysgalactiae (GCS) field strains causing bovine mastitis and group C or group G Streptococcus dysgalactiae subsp. equisimilis (GCS/GGS) isolates from human infections, with the latter being used for comparative purposes, for the presence of virulence genes. All bovine and all human isolates carried a fraction of the 220 genes (23% and 39%, respectively). The virulence genes encoding streptolysin S, glyceraldehyde-3-phosphate dehydrogenase, the plasminogen-binding M-like protein PAM, and the collagen-like protein SclB were detected in the majority of both bovine and human isolates (94 to 100%). Virulence factors, usually carried by human beta-hemolytic streptococcal pathogens, such as streptokinase, laminin-binding protein, and the C5a peptidase precursor, were detected in all human isolates but not in bovine isolates. Additionally, GAS bacteriophage-associated virulence genes encoding superantigens, DNase, and/or streptodornase were detected in bovine isolates (72%) but not in the human isolates. Determinants located in non-bacteriophage-related mobile elements, such as the gene encoding R28, were detected in all bovine and human isolates. Several virulence genes, including genes of bacteriophage origin, were shown to be expressed by reverse transcriptase PCR (RT-PCR). Phylogenetic analysis of superantigen gene sequences revealed a high level (>98%) of identity among genes of bovine GCS, of the horse pathogen Streptococcus equi subsp. equi, and of the human pathogen GAS. Our findings indicate that alpha-hemolytic bovine GCS, an important mastitis pathogen and considered to be a nonhuman pathogen, carries important virulence factors responsible for virulence and pathogenesis in humans.


Treatment of advanced or recurrent squamous cell carcinoma of the uterine cervix with mitomycin-C, bleomycin, and cisplatin chemotherapy.
Fifty-nine patients with recurrent/persistent, or advanced local/metastatic squamous cell cancer of the cervix were treated with combination chemotherapy consisting of mitomycin-C, bleomycin, and cisplatin. Response to therapy and survival analysis was determined for 44 of 49 patients who had previously been treated with radiation therapy and/or surgery and for 10 patients with advanced, previously untreated disease. Seven (16%) of the 44 previously treated patients experienced either complete response (CR) or partial response (PR). The median progression-free interval for responders (CR + PR) was 14.5 months, compared with 2.6 months for the nonresponders (significant, P < 0.001). The median survival time for responders (CR + PR) was 15.9 months, compared with 5.9 months for nonresponders (significant, P < 0.01). The 10 previously untreated patients were separately evaluated for response to chemotherapy. Of these, there was 1 CR, 2 PR, 1 < PR, and 6 SD. The 3 responders (CR + PR), who subsequently underwent radiation therapy, were alive and without evidence of disease 7.9, 13.7, and 27.6 months after treatment. Toxicities were mild to moderate, with no treatment-related deaths. In this study, this combination of mitomycin-C, bleomycin, and cisplatin chemotherapy was found to have activity in local, previously untreated disease and in patients with disease recurrence outside pelvic radiation fields.


Speed of presentation influences story recall in college students and persons with multiple sclerosis.
Story memory tests are commonly used in clinical neuropsychology. Surprisingly, no guidelines are provided for speed of presentation for two of the most commonly used story memory tests in clinical neuropsychology. The current investigation was designed to explore whether speed of presentation influences recall on the Story subtest from the Rivermead Behavioural Memory Test. Consistent with predictions, college students in Study 1 and multiple sclerosis participants in Study 2 recalled significantly more story elements at immediate recall when the story was presented slow versus fast. This effect, however, was limited to the conditions where the fast story was presented before the slow story. At delayed recall, participants in both studies recalled more story elements in the slow versus fast story independent of presentation conditions. Both studies also revealed that significantly more participants fell in the "impaired" range on immediate recall for the fast story in the condition where it was presented first. Data from these studies show that speed of presentation can substantially alter story recall in a wide range of individuals. It will be important to develop story tests for which speed of presentation is standardized to ensure that erroneous conclusions regarding memory are not drawn about individuals seen in clinical neuropsychological practice.


Predictors of Medical Serious Adverse Events in Hip Fracture Patients Treated With Arthroplasty.
Patients with hip fractures are often frail with multiple comorbidities and at risk of medical serious adverse events (SAEs). We investigated the HEALTH trial patient population to ascertain predictors of SAEs. We performed a multivariable Cox regression analysis. Occurrence of SAEs was included as the dependent variable with 31 potential prognostic factors being included as independent variables. One thousand four hundred forty-one patients were included in this analysis. Three hundred seventy (25.6%) patients suffered from an SAE. The most common events were cardiac (38.4%, n = 105), respiratory (20.8%, n = 77), and neurological (14.1%, n = 77). The majority of SAEs (50.8%, n = 188) occurred in the first 90 days after hip fracture with 35.4% occurring in the first 30 days (n = 131). Body mass index (BMI) between 18.5 and 24.9 compared with BMI between 25 and 29.9 [hazard ratio (HR) 1.32, P = 0.03] and receiving a total hip arthroplasty compared with a bipolar hemiarthroplasty (HR 1.36, P = 0.03) were associated with a higher risk of a medical SAE within 24 months of femoral neck fracture. Age (P = 0.09), use of femoral cement (P = 0.59), and use of canal pressurization (P = 0.37) were not associated with a medical SAE. Total hip arthroplasty is associated with more SAEs in the immediate postoperative period, and care should be taken in selecting patients for this treatment compared with a hemiarthroplasty. A higher BMI may be protective in hip fracture patients while age alone does not predict SAEs and neither does the use of femoral cement and/or pressurization. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Gain in quality-adjusted life-years in patients with rheumatoid arthritis during 1 year of biological therapy: a prospective study in clinical practice.
The quality-adjusted life-year (QALY) is used to measure outcome in rheumatoid arthritis (RA) studies; identification of drivers of a gain in QALY might help predict a treatment response. We investigated how changes in components of the Disease Activity Score-28 joints (DAS28) were associated with the European League Against Rheumatism (EULAR) and European Quality of Life 5 Dimensions (EQ-5D) responses; and what baseline variables predicted the change in QALY following 1 year of biological therapy. Data were collected at baseline and after 3, 6, and 12 months of biological therapy in Danish patients with RA and included bDAS28, sociodemographic data, comorbidity, Health Assessment Questionnaire (HAQ), and EQ-5D scored using the Danish algorithm. A cross-tabulation based on EULAR versus EQ-5D responses was performed, and the association of each DAS28 component across the EULAR/EQ-5D response groups was tested. Predictors of a change in QALY were assessed in a multiple regression model including baseline clinical and patient-reported data as explanatory variables. In total, 315 patients entered the study; 77% were women, 78% IgM rheumatoid factor-positive, with mean age 55 (SD 13) years, disease duration 10 (SD 8) years, mean DAS28 4.9 (SD 1.2), HAQ score 1.22 (SD 0.70), and EQ-5D score 0.60 (SD 0.19). Sixty-eight percent of patients gained QALY; the mean gain was 0.14 (SD 0.13). The patient global score was strongly correlated with both EULAR and EQ-5D responses. The gain in QALY increased with increasing patient global score and number of swollen joints, but not with C-reactive protein (CRP). The subjective patient global score was the best baseline predictor of gain in QALY following biological therapy, while the objective CRP measure had no predictive value. It seems that no sharp demarcation between objective and subjective measures could be determined.


Investigation of correlates of protection against pharyngeal carriage of Neisseria meningitidis genogroups W and Y in the African meningitis belt.
Serum bactericidal antibody titres that correlate with protection against invasive meningococcal disease have been characterised. However, titres that are associated with protection against acquisition of pharyngeal carriage of Neisseria meningitidis are not known. Sera were obtained from the members of a household in seven countries of the African meningitis belt in which a pharyngeal carrier of N. meningitidis had been identified during a cross-sectional survey. Serum bactericidal antibody titres at baseline were compared between individuals in the household of the carrier who became a carrier of a meningococcus of the same genogroup during six months of subsequent follow-up and household members who did not become a carrier of a meningococcus of this genogroup during this period. Serum bacterial antibody titres were significantly higher in carriers of a serogroup W or Y meningococcus at the time of recruitment than in those who were not a carrier of N. meningitidis of the same genogroup. Serum bactericidal antibody titres to a strain of N. meningitis of the same genogroup as the index cases were no different in individuals who acquired carriage with a meningococcus of the same genogroup as the index case than in those who did not become a carrier during six months of follow-up. Serum bacterial antibody titres to N. meningitidis of genogroup W or Y in the range of those acquired by natural exposure to meningococci of these genogroups, or with cross-reactive bacteria, are not associated with protection against acquisition of carriage with meningococci of either of these genogroups.


Lattice deformation and thermal stability of crystals in spider silk.
The X-ray diffraction of dragline silks, produced by Nephila and Cyrtophora spiders, were measured by synchrotron radiation in their original states or in situ during stretching and heating. Nephila pilipes spiders construct a two-dimensional orb web that must be rebuilt in one or 2 days, but Cyrtophora spiders form a three-dimensional tent web that can exist for several weeks in a tropical forest. Diffraction patterns of N. pilipes and Cyrtophora draglines resemble each other. Crystals of two kinds are identified in these draglines; one is aligned parallel to the silk direction and another is less oriented. The less oriented crystal in Cyrtophora dragline is aligned better than that in N. pilipes dragline, which generates about three times stronger diffract intensity. Crystals in N. pilipes and C. moluccensis dragline silks have remarkable thermal stability. Equatorial reflections remain undiminished until 350 and 450 degrees C for N. pilipes and C. moluccensis, respectively. In contrast, the meridional reflections S and (002), which are parallel to the silk thread, disappear at a temperature less than 100 degrees C for C. moluccensis but remain for Nephila up to 100 degrees C. Meridional reflections S and (002) shift to a smaller angle during stretching, whereas equatorial reflections remain constant in a range 1.0-1.3 times the original length. The position of the S reflection shifts rapidly in the first 10% of elongation from the original length but remains constant during subsequent stretching, whereas the (002) reflection shifts rapidly during the first 5% elongation from the original length and continues to shift subsequently. In contrast, the features of N. pilipes dragline alter insignificantly during stretching. Examination of the composition of amino acids of the draglines of N. pilipes and C. moluccensis indicates that a dragline of N. pilipes contains more glycine, but much less alanine, than that of C. moluccensis.


Interpretation of the photoelectron, ultraviolet, and vacuum ultraviolet photoabsorption spectra of bromobenzene by ab initio configuration interaction and DFT computations.
New photoelectron, ultraviolet (UV), and vacuum UV (VUV) spectra have been obtained for bromobenzene by synchrotron study with higher sensitivity and resolution than previous work. This, together with use of ab initio calculations with both configuration interaction and time dependent density functional theoretical methods, has led to major advances in interpretation. The VUV spectrum has led to identification of a considerable number of Rydberg states for the first time. The Franck-Condon (FC) analyses including both hot and cold bands lead to identification of the vibrational structure of both ionic and electronically excited states including two Rydberg states. The UV onset has been interpreted in some detail, and an interpretation based on the superposition of FC and Herzberg-Teller contributions has been performed. In a similar way, the 6 eV absorption band which is poorly resolved is analysed in terms of the presence of two ππ* states of (1)A1 (higher oscillator strength) and (1)B2 (lower oscillator strength) symmetries, respectively. The detailed analysis of the vibrational structure of the 2(2)B1 ionic state is particularly challenging, and the best interpretation is based on equation-of-motion-coupled cluster with singles and doubles computations. A number of equilibrium structures of the ionic and singlet excited states show that the molecular structure is less subject to variation than corresponding studies for iodobenzene. The equilibrium structures of the 3b13s and 6b23s (valence shell numbering) Rydberg states have been obtained and compared with the corresponding ionic limit structures.


Population-based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence.
The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5-year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5-year relative survival was close to normal for 40-year-old, but considerably lower for 80-year-old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.


LRRK2 regulates synaptic vesicle endocytosis.
The leucine-rich repeat kinase 2 (LRRK2) has been identified as the defective gene at the PARK8 locus causing the autosomal dominant form of Parkinson's disease (PD). Although several LRRK2 mutations were found in familial as well as sporadic PD patients, its physiological functions are not clearly defined. In this study, using yeast two-hybrid screening, we report the identification of Rab5b as an LRRK2-interacting protein. Indeed, our GST pull down and co-immunoprecipitation assays showed that it specifically interacts with LRRK2. In addition, subcellular fractionation and immunocytochemical analyses confirmed that a fraction of both proteins co-localize in synaptic vesicles. Interestingly, we found that alteration of LRRK2 expression by either overexpression or knockdown of endogenous LRRK2 in primary neuronal cells significantly impairs synaptic vesicle endocytosis. Furthermore, this endocytosis defect was rescued by co-expression of functional Rab5b protein, but not by its inactive form. Taken together, we propose that LRRK2, in conjunction with its interaction with Rab5b, plays an important role in synaptic function by modulating the endocytosis of synaptic vesicles.


Early motor abilities in infants at heightened versus low risk for ASD: A Baby Siblings Research Consortium (BSRC) study.
Research has identified early appearing differences in gross and fine motor abilities in infants at heightened risk (HR) for autism spectrum disorder (ASD) because they are the younger siblings of children with ASD, and it suggests that such differences may be especially apparent among those HR infants themselves eventually diagnosed with ASD. The present study examined overall and item-level performance on the gross (GM) and fine motor (FM) subscales of the Mullen Scales of Early Learning (MSEL) administered at 6 months to a large, geographically diverse sample of HR infants with varying developmental outcomes (ASD, elevated ADOS without ASD, low ADOS without ASD) and to infants with low ASD risk (low risk [LR]). We also explored whether motor abilities assessed at 6 months predicted ASD symptom severity at 36 months. FM (but not GM) performance distinguished all 3 HR groups from LR infants with the weakest performance observed in the HR-Elevated ADOS children, who exhibited multiple differences from both LR and other HR infants in both gross and fine motor skills. Finally, 6-month FM (but not GM) scores significant predicted 36-month ADOS severity scores in the HR group; but no evidence was found of specific early appearing motor signs associated with a later ASD diagnosis. Vulnerabilities in infants' fine and gross motor skills may have significant consequences for later development not only in the motor domain but in other domains. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Genetic import and phenotype specific alleles associated with hyper-invasion in Campylobacter jejuni.
Campylobacter jejuni is a major zoonotic pathogen, causing gastroenteritis in humans. Invasion is an important pathogenesis trait by which C. jejuni causes disease. Here we report the genomic analysis of 134 strains to identify traits unique to hyperinvasive isolates. A total of 134 C. jejuni genomes were used to create a phylogenetic tree to position the hyperinvasive strains. Comparative genomics lead to the identification of mosaic capsule regions. A pan genome approach led to the discovery of unique loci, or loci with unique alleles, to the hyperinvasive strains. Phylogenetic analysis showed that the hyper-invasive phenotype is a generalist trait. Despite the fact that hyperinvasive strains are only distantly related based on the whole genome phylogeny, they all possess genes within the capsule region with high identity to capsule genes from C. jejuni subsp. doylei and C. lari. In addition there were genes unique to the hyper-invasive strains with identity to non-C. jejuni genes, as well as allelic variants of mainly pathogenesis related genes already known in the other C. jejuni. In particular, the sequence of flagella genes, flgD-E and flgL were highly conserved amongst the hyper-invasive strains and divergent from sequences in other C. jejuni. A novel cytolethal distending toxin (cdt) operon was also identified as present in all hyper-invasive strains in addition to the classic cdt operon present in other C. jejuni. Overall, the hyper-invasive phenotype is strongly linked to the presence of orthologous genes from other Campylobacter species in their genomes, notably within the capsule region, in addition to the observed association with unique allelic variants in flagellar genes and the secondary cdt operon which is unlikely under random sharing of accessory alleles in separate lineages.


FertiPROTEKT, Oncofertility Consortium and the Danish Fertility-Preservation Networks - What Can We Learn From Their Experiences?
Fertility preservation is an increasingly important discipline. It requires close coordination between reproductive medicine specialists, reproductive biologists, and oncologists in various disciplines. In addition, it represents a particular health policy challenge, since fertility-protection measures are to be understood as a treatment for side effects of gonadotoxic treatments and would therefore normally have to be reimbursed by health insurance companies. Therefore, it is inevitable that fertility-preservation activities should organise themselves into a network structure both as a medical-logistic network and as a professional medical society. The necessary network structures can differ significantly at regional, national, and international level, as the size of the regions to be integrated and the local cultural and geographical conditions, as well as the political conditions are very different. To address these issues, the current review aims to point out the basic importance and the chances but also the difficulties of fertility-protection networks and give practical guidance for the development of such network structures. We will not only discuss network structures theoretically but also present them based on three established, different sized networks, such as the Danish Network (www.rigshospitalet.dk), representing a centralised network in a small country; the German-Austrian-Swiss network FertiPROTEKT® (www.fertiprotekt.com), representing a centralised as well as decentralised network in a large country; and the Oncofertility® Consortium (www.oncofertility.northwestern.edu), representing a decentralised, internationally oriented network, primarily serving the transfer of knowledge among its members.


Ion-specific interactions at calcite-brine interfaces: a nano-scale study of the surface charge development and preferential binding of polar hydrocarbons.
This research provides an atomic-level insight into the synergic contribution of mono- and divalent ions to interfacial characteristics of calcite surfaces exposed to electrolyte solution containing organic compounds. The emphasis was placed on the ionic interactions responsible for charge developing mechanisms of calcite surfaces and also the capacity for adsorption of polar hydrocarbons, represented by benzoic acid (BA), at different brine compositions. For this purpose, molecular dynamics (MD) simulations were employed to explore the interplay of the main constituent ions of natural brines (Na+, Cl-, Mg2+, and SO42-) and BA at the interface of CaCO3. It was observed that surface accumulation of Na+ cations produces a positively charged layer immediate to the basal plane of calcite, validating the typical positive surface charge of carbonates reported by laboratory experiences. Meanwhile, a negatively charged layer appears beyond the sodium layer as a result of direct and solvent-mediated pairing of anions with Na+ cations lodged on the calcite substrate. In this process, sulfate adsorption severely diminishes surface charge to even a negative value in the case of a SO42--rich solution, providing an interpretation for the measurements reported in the literature. Our results revealed the inhibition of direct binding of BA molecules onto the calcite surface through complexation with protruding oxygen atoms of basal carbonates by the residing Na+ cations. Further, we noticed the sulfate-mediated pairing of BA molecules to the Na+ layer, which in effect intensifies surface adsorption of BA. However, BA-SO42- interaction is considerably reduced by magnesium cations shielding sulfate sites in the Mg2+-augmented brine. The findings presented in this study are of fundamental importance to advance our microscopic understanding of interfacial interactions in brine/oil/carbonate systems; with broad scientific and applied implications in the context of mobilizing organic contaminants trapped in aquifer sediments and enhancement of hydrophilicity of subsurface oil-bearing carbonate reservoirs by injecting ion-modified brine solutions.


ASYMMETRIC LEAVES1 and auxin activities converge to repress BREVIPEDICELLUS expression and promote leaf development in Arabidopsis.
Leaf development in higher plants requires the specification of leaf initials at the flanks of a pluripotent structure termed the shoot apical meristem. In Arabidopsis, this process is facilitated by negative interactions between class I KNOTTED1-like homeobox (KNOX) and ASYMMETRIC LEAVES1 (AS1) transcription factors, such that KNOX proteins are confined to the meristem and AS1 to leaf initials. Sites of leaf inception are also defined by local accumulation of the hormone auxin; however, it is unknown how auxin and AS1 activities are integrated to control leaf development. Here, we show that auxin and AS1 pathways converge to repress expression of the KNOX gene BREVIPEDICELLUS (BP) and thus promote leaf fate. We also demonstrate that regulated auxin gradients control leaf shape in a KNOX-independent fashion and that inappropriate KNOX activity in leaves perturbs these gradients, hence altering leaf shape. We propose that regulatory interactions between auxin, AS1 and KNOX activities may both direct leaf initiation and sculpt leaf form.


Local spatial and temporal processes of influenza in Pennsylvania, USA: 2003-2009.
Influenza is a contagious respiratory disease responsible for annual seasonal epidemics in temperate climates. An understanding of how influenza spreads geographically and temporally within regions could result in improved public health prevention programs. The purpose of this study was to summarize the spatial and temporal spread of influenza using data obtained from the Pennsylvania Department of Health's influenza surveillance system. We evaluated the spatial and temporal patterns of laboratory-confirmed influenza cases in Pennsylvania, United States from six influenza seasons (2003-2009). Using a test of spatial autocorrelation, local clusters of elevated risk were identified in the South Central region of the state. Multivariable logistic regression indicated that lower monthly precipitation levels during the influenza season (OR = 0.52, 95% CI: 0.28, 0.94), fewer residents over age 64 (OR = 0.27, 95% CI: 0.10, 0.73) and fewer residents with more than a high school education (OR = 0.76, 95% CI: 0.61, 0.95) were significantly associated with membership in this cluster. In addition, time series analysis revealed a temporal lag in the peak timing of the influenza B epidemic compared to the influenza A epidemic. These findings illustrate a distinct spatial cluster of cases in the South Central region of Pennsylvania. Further examination of the regional transmission dynamics within these clusters may be useful in planning public health influenza prevention programs.


Functional and anatomical reorganization of the sensory-motor cortex after incomplete spinal cord injury in adult rats.
A lateral hemisection injury of the cervical spinal cord results in Brown-Séquard syndrome in humans and rats. The hands/forelimbs on the injured side are rendered permanently impaired, but the legs/hindlimbs recover locomotor functions. This is accompanied by increased use of the forelimb on the uninjured side. Nothing is known about the cortical circuits that correspond to these behavioral adaptations. In this study, on adult rats with cervical spinal cord lateral hemisection lesions (at segment C3/4), we explored the sensory representation and corticospinal projection of the intact (ipsilesional) cortex. Using blood oxygenation level-dependent functional magnetic resonance imaging and voltage-sensitive dye (VSD) imaging, we found that the cortex develops an enhanced representation of the unimpaired forepaw by 12 weeks after injury. VSD imaging also revealed the cortical spatio-temporal dynamics in response to electrical stimulation of the ipsilateral forepaw or hindpaw. Interestingly, stimulation of the ipsilesional hindpaw at 12 weeks showed a distinct activation of the hindlimb area in the intact, ipsilateral cortex, probably via the injury-spared spinothalamic pathway. Anterograde tracing of corticospinal axons from the intact cortex showed sprouting to recross the midline, innervating the spinal segments below the injury in both cervical and lumbar segments. Retrograde tracing of these midline-crossing axons from the cervical spinal cord (at segment C6/7) revealed the formation of a new ipsilateral forelimb representation in the cortex. Our results demonstrate profound reorganizations of the intact sensory-motor cortex after unilateral spinal cord injury. These changes may contribute to the behavioral adaptations, notably for the recovery of the ipsilesional hindlimb.


Effect of valine 106 on structure-function relation of cytosolic human thymidine kinase. Kinetic properties and oligomerization pattern of nine substitution mutants of V106.
Information on the regulation and structure-function relation of enzymes involved in DNA precursor synthesis is pivotal, as defects in several of these enzymes have been found to cause depletion or deletion of mitochondrial DNA resulting in severe diseases. Here, the effect of amino acid 106 on the enzymatic properties of the cell-cycle-regulated human cytosolic thymidine kinase 1 (TK1) is investigated. On the basis of the previously observed profound differences between recombinant TK1 with Val106 (V106WT) and Met106 (V106M) in catalytic activity and oligomerization pattern, we designed and characterized nine mutants of amino acid 106 differing in size, conformation and polarity. According to their oligomerization pattern and thymidine kinetics, the TK1 mutants can be divided into two groups. Group I (V106A, V106I and V106T) behaves like V106WT, in that pre-assay exposure to ATP induces reversible transition from a dimer with low catalytic activity to a tetramer with high catalytic activity. Group II (V106G, V106H, V106K, V106L and V106Q) behaves like V106M in that they are permanently high activity tetramers, irrespective of ATP exposure. We conclude that size and conformation of amino acid 106 are more important than polarity for the catalytic activity and oligomerization of TK1. The role of amino acid 106 and the sequence surrounding it for dimer-tetramer transition was confirmed by cloning the putative interface fragment of human TK1 and investigating its oligomerization pattern.


Transgenic and knockout mice in the study of neurodegenerative diseases.
Accurate animal models are essential for detailed analysis of the mechanisms underlying human neurodegenerative diseases. In addition, they can offer useful paradigms for the development and evaluation of new therapeutic strategies. We review the most popular techniques for modification of the mammalian genome in vivo, and provide a critical evaluation of the available transgenic mouse models for several neurological conditions of humans, including prion diseases, human retroviral diseases, Alzheimer's disease, and motor neuron diseases.


EnvRtype: a software to interplay enviromics and quantitative genomics in agriculture.
Envirotyping is an essential technique used to unfold the nongenetic drivers associated with the phenotypic adaptation of living organisms. Here, we introduce the EnvRtype R package, a novel toolkit developed to interplay large-scale envirotyping data (enviromics) into quantitative genomics. To start a user-friendly envirotyping pipeline, this package offers: (1) remote sensing tools for collecting (get_weather and extract_GIS functions) and processing ecophysiological variables (processWTH function) from raw environmental data at single locations or worldwide; (2) environmental characterization by typing environments and profiling descriptors of environmental quality (env_typing function), in addition to gathering environmental covariables as quantitative descriptors for predictive purposes (W_matrix function); and (3) identification of environmental similarity that can be used as an enviromic-based kernel (env_typing function) in whole-genome prediction (GP), aimed at increasing ecophysiological knowledge in genomic best-unbiased predictions (GBLUP) and emulating reaction norm effects (get_kernel and kernel_model functions). We highlight literature mining concepts in fine-tuning envirotyping parameters for each plant species and target growing environments. We show that envirotyping for predictive breeding collects raw data and processes it in an eco-physiologically smart way. Examples of its use for creating global-scale envirotyping networks and integrating reaction-norm modeling in GP are also outlined. We conclude that EnvRtype provides a cost-effective envirotyping pipeline capable of providing high quality enviromic data for a diverse set of genomic-based studies, especially for increasing accuracy in GP across untested growing environments.


Windbeutel is required for function and correct subcellular localization of the Drosophila patterning protein Pipe.
Drosophila embryonic dorsal-ventral polarity originates in the ovarian follicle through the restriction of pipe gene expression to a ventral subpopulation of follicle cells. Pipe, a homolog of vertebrate glycosaminoglycan-modifying enzymes, directs the ventral activation of an extracellular serine proteolytic cascade which defines the ventral side of the embryo. When pipe is expressed uniformly in the follicle cell layer, a strong ventralization of the resulting embryos is observed. Here, we show that this ventralization is dependent on the other members of the dorsal group of genes controlling dorsal-ventral polarity, but not on the state of the Epidermal Growth Factor Receptor signal transduction pathway which defines egg chamber polarity. Pipe protein expressed in vertebrate tissue culture cells localizes to the endoplasmic reticulum. Strikingly, coexpression of the dorsal group gene windbeutel in those cells directs Pipe to the Golgi. Similarly, Pipe protein exhibits an altered subcellular localization in the follicle cells of females mutant for windbeutel. Thus, Windbeutel protein enables the correct subcellular distribution of Pipe to facilitate its pattern-forming activity.


Development of the Drosophila tracheal system occurs by a series of morphologically distinct but genetically coupled branching events.
The tracheal (respiratory) system of Drosophila melanogaster is a branched network of epithelial tubes that ramifies throughout the body and transports oxygen to the tissues. It forms by a series of sequential branching events in each hemisegment from T2 to A8. Here we present a cellular and initial genetic analysis of the branching process. We show that although branching is sequential it is not iterative. The three levels of branching that we distinguish involve different cellular mechanisms of tube formation. Primary branches are multicellular tubes that arise by cell migration and intercalation; secondary branches are unicellular tubes formed by individual tracheal cells; terminal branches are subcellular tubes formed within long cytoplasmic extensions. Each level of branching is accompanied by expression of a different set of enhancer trap markers. These sets of markers are sequentially activated in progressively restricted domains and ultimately individual tracheal cells that are actively forming new branches. A clonal analysis demonstrates that branching fates are not assigned to tracheal cells until after cell division ceases and branching begins. We further show that the breathless FGF receptor, a tracheal gene required for primary branching, is also required to activate expression of markers involved in secondary branching and that the pointed ETS-domain transcription factor is required for secondary branching and also to activate expression of terminal branch markers. The combined morphological, marker expression and genetic data support a model in which successive branching events are mechanistically and genetically distinct but coupled through the action of a tracheal gene regulatory hierarchy.


gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.
InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimulating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidyl- inositol (PI) 3-kinase. Using affinity chromatography and enzyme-linked immunosorbent assay, we demonstrate a direct interaction between InlB and the mammalian protein gC1q-R, the receptor of the globular part of the complement component C1q. Soluble C1q or anti-gC1q-R antibodies impair InlB-mediated entry. Transient transfection of GPC16 cells, which are non-permissive to InlB-mediated entry, with a plasmid-expressing human gC1q-R promotes entry of InlB-coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB-gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q-R constitutes a cellular receptor involved in InlB-mediated activation of PI 3-kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E-cadherin, the receptor for internalin, gC1q-R is the second identified mammalian receptor promoting entry of L. monocytogenes into mammalian cells.


[A retrospective study of intoxications admitted to the university hospital/UFJF from 2000 to 2004].
Poisonings may have their consequences minimized by the acquisition of knowledge concerning its etiologies, evolutions and means of prevention. In Brazil, the progressive increase of toxic emergencies justifies the acquisition and analysis of regional and decentralized data concerning toxic emergencies. The aim of this retrospective and descriptive study was to evaluate data on the toxicology occurrence registered at the University Hospital/UFJF from 2000 to 2004. Data were collected using a structured instrument which comprised: age range, gender, profession, average hospitalization time, etiology and possible reasons for the intoxication, drug categories, where the patients live and the most important exposure route to the poisonous agent. The possible relationship among the data was also examined. The profile found for poisoning in the 50 cases analyzed, was that accidents are more common from 0 to 5 years old (24%) and male gender (68%), the majority of the cases happened in the city of Juiz de Fora (78%) and oral exposure. The most important poisonous agents were found to be the psychotropics (60%). Definition of a profile helps promoting educative activities and expands poisoning prevention campaigns by public health agencies. Therefore, these facts strengthen the importance of an Information Service net to prevent and reduce intoxications and the irrational use of drugs.


Timing of fluoride intake and dental fluorosis on late-erupting permanent teeth.
Very few studies have examined the relationship between timing of fluoride intake and development of dental fluorosis on late-erupting permanent teeth using period-specific fluoride intake information. This study examined this relationship using longitudinal fluoride intake information from the Iowa Fluoride Study. Participants' fluoride exposure and intake (birth to 10 years of age) from water, beverages, selected food products, dietary fluoride supplements, and fluoride toothpaste was collected using questionnaires sent to parents at 3- and 4- month intervals from birth to 48 months of age and every 6 months thereafter. Three trained and calibrated examiners used the Fluorosis Risk Index (FRI) categories to assess 16 late-erupting teeth among 465 study participants. A tooth was defined as having definitive fluorosis if any of the zones on that tooth had an FRI score of 2 or 3. Participants with questionable fluorosis were excluded from analyses. Descriptive and logistic regression analyses were performed to assess the importance of fluoride intake during different time periods. Most dental fluorosis in the study population was mild, with only four subjects (1%) having severe fluorosis (FRI Score 3). The overall prevalence of dental fluorosis was 27.8%. Logistic regression analyses showed that fluoride intake from each of the individual years from age 2 to 8 plays an important role in determining the risk of dental fluorosis for most late-erupting permanent teeth. The strongest association for fluorosis on the late-erupting permanent teeth was with fluoride intake during the sixth year of life. Late-erupting teeth may be susceptible to fluorosis for an extended period from about age 2 to 8. Although not as visually prominent as the maxillary central incisors, some of the late-erupting teeth are esthetically important and this should be taken into consideration when making recommendations about dosing of fluoride intake.


Schools for health, education and development: a call for action.
In 2007, the World Health Organization, together with United Nations and international organization as well as experts, met to draw upon existing evidence and practical experience from regions, countries and individual schools in promoting health through schools. The goal of the meeting was to identify current and emerging global factors affecting schools, and to help them respond more effectively to health, education and development opportunities. At the meeting, a Statement was developed describing effective approaches and strategies that can be adopted by schools to promote health, education and development. Five key challenges were identified. These described the need to continue building evidence and capturing practical experience in school health; the importance of improving implementation processes to ensure optimal transfer of evidence into practice; the need to alleviating social and economic disadvantage in access to and successful completion of school education; the opportunity to harness media influences for positive benefit, and the continuing challenge to improve partnerships among different sectors and organizations. The participants also identified a range of actions needed to respond to these challenges, highlighting the need for action by local school communities, governments and international organizations to invest in quality education, and to increase participation of children and young people in school education. This paper describes the rationale for and process of the meeting and the development of the Statement and outlines some of the most immediate efforts made to implement the actions identified in the Statement. It also suggests further joint actions required for the implementation of the Statement.


Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status.
Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was analyzed. In addition, immunohistochemistry was performed for programmed cell death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8), and forkhead box protein P3 (Foxp3). Seventy-four patients with ICC were classified into normal weight (BMI < 25.0 kg/m2, n = 48) and obesity groups (BMI ≥ 25.0 kg/m2, n = 26), respectively. Serum carbohydrate antigen 19-9 levels were higher in the obesity group than in the normal weight group. Tumor size and the intrahepatic metastasis rate were significantly larger in the obesity group. Patients in the obesity group had significantly worse prognoses than those in the normal weight group. Moreover, BMI displayed a positive correlation with SUVmax on 18F-FDG PET/CT (n = 46, r = 0.5152). Patients with high 18F-FDG uptake had a significantly higher rate of PD-L1 expression, lower CD8 + tumor-infiltrating lymphocyte (TIL) counts, and higher Foxp3 + TIL counts. The elevated BMI might predict the outcomes of patients with ICC. Obesity might be associated with ICC progression, possibly through alterations in metabolic activity and the immune status.


Aspirin: 120 years of innovation. A report from the 2017 Scientific Conference of the International Aspirin Foundation, 14 September 2017, Charité, Berlin.
Acetylsalicylic acid was first synthesised by Dr FeIix Hoffman on 10th August 1897 and Aspirin was born. It quickly became the best-known pain killer in the world and in the 120 years since this event, aspirin has continued to attract interest, innovation and excitement. Set within the walls of the preserved ruins of Rudolf Virchow's lecture hall at Charité, within Berlin's Museum of Medical History, the International Aspirin Foundation's 28th Scientific Conference served to facilitate international, multi-disease, multidisciplinary discussion about the current understanding of aspirin's mechanisms of action and its utility in modern medicine as well as ideas for future research into its multifaceted applications to enhance global health. In addition to the delegates in Berlin, 300 medical doctors at the 19th Annual Scientific Congress of the Chinese Society of Cardiology were able to join the cardiology sessions from Taiyuan, Shangxi province via a live streaming link to and from China. This led to useful discussion and allowed a truly international perspective to the meeting.


Laser in situ keratomileusis disrupts the aberration compensation mechanism of the human eye.
To study how changes induced on corneal optics by myopic and hyperopic laser in situ keratomileusis (LASIK) refractive surgery affect the aberration compensation mechanism. Interventional case series and modeling theory. We measured ocular, corneal, and internal aberrations for a 6-mm pupil in 15 myopic and 6 hyperopic eyes with similar age range before and 6 months after standard LASIK. Ocular aberrations were measured using our own developed Hartmann-Shack wavefront sensor, whereas corneal aberrations were calculated by using the elevation data obtained by corneal topography. Ocular, corneal, and internal root mean square (RMS), spherical aberration (SA), coma, and compensation factor were compared for each patient. After myopic LASIK, we obtained an average 1.6-fold increase in ocular RMS, mainly positive SA, and coma, associated with a similar increase in corneal aberrations. In the hyperopes, we found a higher (2.3-fold) induction of ocular aberrations after surgery, mainly negative SA and coma, but without net increases of corneal aberrations. Aberration compensation clearly decreased or even inverted after hyperopic LASIK, decreasing the ocular optical quality in a higher level than myopic LASIK. Although ocular aberrations after myopic LASIK usually were smaller than corneal aberrations because of partial compensation of SA, after hyperopic LASIK, because of induction of negative SA and change in coma, disruption of the compensation mechanism lead to a larger increase of ocular aberrations. Customized procedures should maintain the natural compensation to achieve improved visual outcomes.


Sedation and analgesia in adult patients: evaluation of a staged-dose system based on body weight for use in abdominal interventional radiology.
To evaluate the safety and effectiveness of a systematic protocol for sedation and analgesia in interventional radiology. Ninety-one adult patients underwent 113 abdominal interventional procedures. Fentanyl citrate and midazolam hydrochloride were administered in one to five steps (A, B, C, D, E) until the patient was drowsy and tranquil at the effective loading dose (ELD). Doses per step were as follows: A, fentanyl 1 microg per kilogram of body weight; B, midazolam 0.010-0.035 mg/kg; C, repeat dose in A; D, repeat half the dose in B; and E, midazolam 1-2-mg boluses (maximum, 0.15 mg/kg). The ELD was reached in no procedure after step A, in 70 after B, in 23 after C, and in 18 after D. Step E was needed in two procedures. The mean maximum pain score (scale of 0 to 10) was 3.4; pain scores in 85 (75%) procedures were 4 or less (discomforting). Severe pain occurred in seven (6%) procedures. Hypoxia (oxygen saturation < 90%) occurred in 11 (22%) procedures performed in patients breathing room air and four (6%) performed in those breathing supplemental oxygen (P: =.04). All patients responded to supplemental oxygen. This stepwise "ABCDE protocol" allows safe and effective sedation of patients. It is easy to use and may be useful in training radiology residents, staff, and nurses in the techniques of sedation and analgesia. Supplemental oxygen should be used routinely.


Cross-modal plasticity in the human thalamus: evidence from intraoperative macrostimulations.
During stereotactic functional neurosurgery, stimulation procedure to control for proper target localization provides a unique opportunity to investigate pathophysiological phenomena that cannot be addressed in experimental setups. Here we report on the distribution of response modalities to 487 intraoperative thalamic stimulations performed in 24 neurogenic pain (NP), 17 parkinsonian (PD) and 10 neuropsychiatric (Npsy) patients. Threshold responses were subdivided into somatosensory, motor and affective, and compared between medial (central lateral nucleus) and lateral (ventral anterior, ventral lateral and ventral medial) thalamic nuclei and between patients groups. Major findings were as follows: in the medial thalamus, evoked responses were for a large majority (95%) somatosensory in NP patients, 47% were motor in PD patients, and 54% affective in Npsy patients. In the lateral thalamus, a much higher proportion of somatosensory (83%) than motor responses (5%) was evoked in NP patients, while the proportion was reversed in PD patients (69% motor vs. 21% somatosensory). These results provide the first evidence for functional cross-modal changes in lateral and medial thalamic nuclei in response to intraoperative stimulations in different functional disorders. This extensive functional reorganization sheds new light on wide-range plasticity in the adult human thalamocortical system.


Strategic management of the health workforce in developing countries: what have we learned?
The study of the health workforce has gained in prominence in recent years, as the dynamic interconnections between human resource issues and health system effectiveness have come into sharper focus. This paper reviews lessons relating to strategic management challenges emerging from the growing literature in this area. Workforce issues are strategic: they affect overall system performance as well as the feasibility and sustainability of health reforms. Viewing workforce issues strategically forces health authorities to confront the yawning gaps between policy and implementation in many developing countries. Lessons emerge in four areas. One concerns imbalances in workforce structure, whether from a functional specialization, geographical or facility lens. These imbalances pose a strategic challenge in that authorities must attempt to steer workforce distribution over time using a limited range of policy tools. A second group of lessons concerns the difficulties of central-level steering of the health workforce, often critically weak due to the lack of proper information systems and the complexities of public sector decentralization and service commercialization trends affecting the grassroots.A third cluster examines worker capacity and motivation, often shaped in developing countries as much by the informal norms and incentives as by formal attempts to support workers or to hold them accountable. Finally, a range of reforms centering on service contracting and improvements to human resource management are emerging. Since these have as a necessary (but not sufficient) condition some flexibility in personnel practices, recent trends towards the sharing of such functions with local authorities are promising. The paper identifies a number of current lines of productive research, focusing on the relationship between health policy reforms and the local institutional environments in which the workforce, both public and private, is deployed.


Psychosocial work exposures and health outcomes: a meta-review of 72 literature reviews with meta-analysis.
This meta-review aimed to present all available quantitative pooled estimates for the associations between psychosocial work exposures and health outcomes using a systematic literature review of literature reviews with meta-analysis. A systematic review of the literature from 2000 to 2020 was conducted using PubMed, Web of Science, Scopus, and PsycINFO databases following the PRISMA guidelines. All literature reviews and Individual-Participant Data (IPD)-Work consortium studies exploring an association between psychosocial work exposures and health outcomes and providing pooled estimates using meta-analysis were included. All types of psychosocial work exposures and health outcomes were studied. The quality of each included review was assessed. A total of 72 reviews and IPD-Work consortium studies were included. These mainly focused on job strain as exposure and cardiovascular diseases and mental disorders as outcomes. The associations between psychosocial work factors and cardiovascular diseases and mental disorders were in general significant, and the magnitude of these associations was stronger for mental disorders than for cardiovascular diseases. Based on high-quality reviews, significant associations were found between job/high strain and long working hours as exposures and coronary heart diseases, (ischemic) stroke, and depression as outcomes. A few additional significant associations involved other exposures and health outcomes. The included reviews brought convincing findings on the associations of some psychosocial work factors with mental disorders and cardiovascular diseases. More research may be needed to explain these associations, explore other exposures and outcomes, and make progress towards determining the causality of the associations.


Sumatran megathrust earthquakes: from science to saving lives.
Most of the loss of life, property and well-being stemming from the great Sumatran earthquake and tsunami of 2004 could have been avoided and losses from similar future events can be largely prevented. However, achieving this goal requires forging a chain linking basic science-the study of why, when and where these events occur-to people's everyday lives. The intermediate links in this chain are emergency response preparedness, warning capability, education and infrastructural changes. In this article, I first describe our research on the Sumatran subduction zone. This research has allowed us to understand the basis of the earthquake cycle on the Sumatran megathrust and to reconstruct the sequence of great earthquakes that have occurred there in historic and prehistoric times. On the basis of our findings, we expect that one or two more great earthquakes and tsunamis, nearly as devastating as the 2004 event, are to be expected within the next few decades in a region of coastal Sumatra to the south of the zone affected in 2004. I go on to argue that preventing future tragedies does not necessarily involve hugely expensive or high-tech solutions such as the construction of coastal defences or sensor-based tsunami warning systems. More valuable and practical steps include extending the scientific research, educating the at-risk populations as to what to do in the event of a long-lasting earthquake (i.e. one that might be followed by a tsunami), taking simple measures to strengthen buildings against shaking, providing adequate escape routes and helping the residents of the vulnerable low-lying coastal strips to relocate their homes and businesses to land that is higher or farther from the coast. Such steps could save hundreds and thousands of lives in the coastal cities and offshore islands of western Sumatra, and have general applicability to strategies for helping the developing nations to deal with natural hazards.


An oxygen conserving nasal cannula.
Oxygen administration via a nasal cannula incorporating a small collapsible reservoir (Oxymizer, Chad Therapeutics Inc, California) was compared with delivery via a standard nasal cannula. Twelve patients with chronic, stable hypoxaemia (arterial oxygen tension less than 60 mm Hg (8.0 kPa)) were studied. Transcutaneous oxygen and carbon dioxide tensions were recorded by skin electrodes and oxygen saturation by ear oximetry. Baseline measurements during the breathing of air were compared with those made during the breathing of oxygen at flow rates of 0.5, 1.0, and 2.0 l/min via each device. Increases in saturation and transcutaneous oxygen tension were significantly greater at each flow rate with the reservoir device than with the conventional cannula. To produce similar improvements in oxygenation the reservoir device required an oxygen flow rate about half that of the conventional cannula. Use of the reservoir device may reduce the inconvenience and perhaps the cost of supplying domiciliary oxygen, and prolong the time during which patients may rely on a portable cylinder.


Use of a monoclonal antibody for comparative studies of monoamine oxidase B in mitochondrial extracts of human brain and peripheral tissues.
Monoamine oxidase B (MAO B; EC 126.96.36.199) activity in detergent extracts of mitochondria from autopsy brain (gray matter and medulla), liver, lung, and kidney from a single individual and from pooled, human platelets could be immunoprecipitated by a monoclonal anti-human platelet MAO B antibody (MAO-1C2) in combination with appropriate secondary reagents. MAO A activity, which was detected in brain, liver, lung, and kidney, was not immunoprecipitated under the same conditions. All MAO B-containing extracts, regardless of tissue source, inhibited immunoprecipitation of [3H]pargyline-labeled human platelet MAO, and the shapes of the inhibition curves were identical. The concentration of immunologically detectable MAO B protein in the extracts was estimated from immunoprecipitation competition data by reference to a standard curve relating observed inhibition of immunoprecipitation to the concentration of catalytically active platelet MAO added (estimated from [3H]pargyline binding data). MAO B protein concentrations measured by this radioimmunoassay were similar to concentrations of active MAO B as measured by pargyline binding. These results demonstrate that in the brain and peripheral tissues studied, molecules with MAO B activity share a unique antigenic determinant and similar catalytic efficiency. They also extend previous observations that MAO B molecules extracted from mitochondria bear an antigenic determinant which is not present on MAO A molecules. These results demonstrate the validity of a new competitive radioimmunoassay for active plus inactive MAO B concentration in human platelet extracts and extracts of mitochondria from human tissues. This radioimmunoassay should complement [3H]pargyline binding assays and enzyme activity assays in studies designed to clarify the mechanisms of genetic, disease, and treatment factors which lead to differences in MAO B function among individuals.


Long-range comparison between genes and languages based on syntactic distances.
To propose a new approach for comparing genetic and linguistic diversity in populations belonging to distantly related groups. Comparisons of linguistic and genetic differences have proved powerful tools to reconstruct human demographic history. Current models assume on both sides that similarities reflect either descent from common ancestry or the balance between isolation and contact. Most linguistic phylogenies are ultimately based on lexical evidence (roughly, words and morphemes with their sounds and meanings). However, measures of lexical divergence are reliable only for closely related languages, thus large-scale comparisons of genetic and linguistic diversity have appeared problematic so far. Syntax (abstract rules to combine words into sentences) appears more measurable, universally comparable, and stable than the lexicon, and hence certain syntactic similarities might reflect deeper linguistic relationships, such as those between distant language families. In this study, we for the first time compared genetic data to a matrix of syntactic differences among selected populations of three continents. Comparing two databases of microsatellite (Short Tandem Repeat) markers and Single Nucleotides Polymorphisms (SNPs), with a linguistic matrix based on the values of 62 grammatical parameters, we show that there is indeed a correlation of syntactic and genetic distances. We also identified a few outliers and suggest a possible interpretation of the overall pattern. These results strongly support the possibility of better investigating population history by combining genetic data with linguistic information of a new type, provided by a theoretically more sophisticated method to assess the relationships between distantly related languages and language families.


Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer's disease.
Quercetin has been identified as a promising compound with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clinical application of quercetin is hampered by its low oral bioavailability. The aim of this work was to evaluate the capability of nanoencapsulated quercetin in zein nanoparticles (NPQ), that significantly improves the oral absorption and bioavailability of the flavonoid, as potential oral treatment for AD. For this purpose, SAMP8 mice were orally treated for two months with either NPQ (25mg/kg every 48h) or a solution of quercetin (Q; 25mg/kg daily). NPQ displayed a size of 260nm and a payload of about 70μg/mg. For Q, no significant effects were observed in animals. On the contrary, the oral administration of NPQ improved the cognition and memory impairments characteristics of SAMP8 mice. These observations appeared to be related with a decreased expression of the hippocampal astrocyte marker GFAP. Furthermore, significant levels of quercetin were quantified in the brain of mice treated with nanoparticles. These findings highlight the potential of zein nanoparticles to promote the oral absorption of quercetin as well as the therapeutic potential of this flavonoid in AD pathogenesis.


Head Movements Allow Listeners Bilaterally Implanted With Cochlear Implants to Resolve Front-Back Confusions.
We report on the ability of patients fit with bilateral cochlear implants (CIs) to distinguish the front-back location of sound sources both with and without head movements. At issue was (i) whether CI patients are more prone to front-back confusions than normal hearing listeners for wideband, high-frequency stimuli; and (ii) if CI patients can utilize dynamic binaural difference cues, in tandem with their own head rotation, to resolve these front-back confusions. Front-back confusions offer a binary metric to gain insight into CI patients' ability to localize sound sources under dynamic conditions not generally measured in laboratory settings where both the sound source and patient are static. Three-second duration Gaussian noise samples were bandpass filtered to 2 to 8 kHz and presented from one of six loudspeaker locations located 60° apart, surrounding the listener. Perceived sound source localization for seven listeners bilaterally implanted with CIs, was tested under conditions where the patient faced forward and did not move their head and under conditions where they were encouraged to moderately rotate their head. The same conditions were repeated for 5 of the patients with one implant turned off (the implant at the better ear remained on). A control group of normal hearing listeners was also tested for a baseline of comparison. All seven CI patients demonstrated a high rate of front-back confusions when their head was stationary (41.9%). The proportion of front-back confusions was reduced to 6.7% when these patients were allowed to rotate their head within a range of approximately ± 30°. When only one implant was turned on, listeners' localization acuity suffered greatly. In these conditions, head movement or the lack thereof made little difference to listeners' performance. Bilateral implantation can offer CI listeners the ability to track dynamic auditory spatial difference cues and compare these changes to changes in their own head position, resulting in a reduced rate of front-back confusions. This suggests that, for these patients, estimates of auditory acuity based solely on static laboratory settings may underestimate their real-world localization abilities.


Quality in upper gastrointestinal endoscopic submucosal dissection.
Progress in the endoscopy technology field led to an increase in the diagnosis of early gastrointestinal (GI) superficial lesions and to an improvement of their treatment. Endoscopic submucosal dissection (ESD) has been developed in Japan with the aim of removing such lesions in one piece, in order to obtain a curative resection and to minimize the risk of local recurrence, and to preserve the native organ. ESD is widely used in Asia for the treatment of early upper and lower GI lesions and is currently gaining attention in Western countries too. However, ESD can be safely performed only by expert endoscopists and in specific clinical settings. Therefore, prior to decide whether ESD is feasible or not, the target lesion must be carefully assessed, in order to understand whether or not it is eligible for submucosal dissection. The aim of this paper is to review indications, limitations and technical aspects of upper GI ESD.


Ascorbic acid lowers central blood pressure and asymmetric dimethylarginine in chronic kidney disease.
Premature cardiovascular disease in patients with chronic kidney disease (CKD) is not explained by traditional risk factors and oxidative stress may contribute via endothelial and vascular dysfunction. We investigated the effect of ascorbic acid on oxidative stress and vascular function in CKD patients compared with controls with hypertension (HTN). A crossover study of intravenous saline and ascorbic acid was conducted. Biomarkers of oxidative stress were measured, while pulse wave analysis and brachial flow-mediated dilatation were performed to assess large artery and endothelial function. Twenty HTN and 30 CKD patients Stages 3-5 were recruited. Serum ascorbic acid was significantly lower in patients with CKD. In both groups, ascorbic acid significantly increased total antioxidant potential and superoxide. Asymmetric dimethylarginine (ADMA) was reduced significantly by ascorbic acid in the CKD group and on multivariate regression analysis, age and the presence of CKD were predictors of ADMA response to ascorbic acid. Although no effect on FMD was observed, central blood pressure and augmentation index were reduced significantly in both groups. Ascorbic acid has pro- and antioxidant effects, reducing central blood pressure and augmentation index in HTN and CKD. Ascorbic acid reduces serum ADMA in CKD, which may have longer-term benefits.


Socioeconomically Disadvantaged Adolescents with Elevated Externalizing Symptoms Show Heightened Emotion Reactivity to Daily Stress: An Experience Sampling Study.
Numerous theories assert that youth with externalizing symptomatology experience intensified emotion reactivity to stressful events; yet scant empirical research has assessed this notion. Using in-vivo data collected via experience sampling methodology, we assessed whether externalizing symptoms conditioned adolescents' emotion reactivity to daily stressors (i.e. change in emotion pre-post stressor) among 206 socioeconomically disadvantaged adolescents. We also assessed whether higher externalizing symptomology was associated with experiencing more stressors overall, and whether adolescents' emotional upheavals resulted in experiencing a subsequent stressor. Hierarchical linear models showed that adolescents higher in externalizing symptoms experienced stronger emotion reactivity in sadness, anger, jealously, loneliness, and (dips in) excitement. Externalizing symptomatology was not associated with more stressful events, but a stress-preventative effect was found for recent upheavals in jealousy among youth low in externalizing. Findings pinpoint intense emotion reactivity to daily stress as a risk factor for youth with externalizing symptoms living in socioeconomic disadvantage.


A prospective population study of resting heart rate and peak oxygen uptake (the HUNT Study, Norway).
We assessed the prospective association of resting heart rate (RHR) at baseline with peak oxygen uptake (VO(2peak)) 23 years later, and evaluated whether physical activity (PA) could modify this association. Both RHR and VO(2peak) are strong and independent predictors of cardiovascular morbidity and mortality. However, the association of RHR with VO(2peak) and modifying effect of PA have not been prospectively assessed in population studies. In 807 men and 810 women free from cardiovascular disease both at baseline (1984-86) and follow-up 23 years later, RHR was recorded at both occasions, and VO(2peak) was measured by ergospirometry at follow-up. We used Generalized Linear Models to assess the association of baseline RHR with VO(2peak), and to study combined effects of RHR and self-reported PA on later VO(2peak). There was an inverse association of RHR at baseline with VO(2peak) (p<0.01). Men and women with baseline RHR greater than 80 bpm had 4.6 mL.kg(-1).min(-1) (95% confidence interval [CI], 2.8 to 6.3) and 1.4 mL.kg(-1).min(-1) (95% CI, -0.4 to 3.1) lower VO(2peak) at follow-up compared with men and women with RHR below 60 bpm at baseline. We found a linear association of change in RHR with VO(2peak) (p=0.03), suggesting that a decrease in RHR over time is likely to be beneficial for cardiovascular fitness. Participants with low RHR and high PA at baseline had higher VO(2peak) than inactive people with relatively high RHR. However, among participants with relatively high RHR and high PA at baseline, VO(2peak) was similar to inactive people with relatively low RHR. RHR is an important predictor of VO(2peak), and serial assessments of RHR may provide useful and inexpensive information on cardiovascular fitness. The results suggest that high levels of PA may compensate for the lower VO(2peak) associated with a high RHR.


The RNA polymerase II kinase Ctk1 regulates positioning of a 5' histone methylation boundary along genes.
In yeast and other eukaryotes, the histone methyltransferase Set1 mediates methylation of lysine 4 on histone H3 (H3K4me). This modification marks the 5' end of transcribed genes in a 5'-to-3' tri- to di- to monomethyl gradient and promotes association of chromatin-remodeling and histone-modifying enzymes. Here we show that Ctk1, the serine 2 C-terminal domain (CTD) kinase for RNA polymerase II (RNAP II), regulates H3K4 methylation. We found that CTK1 deletion nearly abolished H3K4 monomethylation yet caused a significant increase in H3K4 di- and trimethylation. Both in individual genes and genome-wide, loss of CTK1 disrupted the H3K4 methylation patterns normally observed. H3K4me2 and H3K4me3 spread 3' into the bodies of genes, while H3K4 monomethylation was diminished. These effects were dependent on the catalytic activity of Ctk1 but are independent of Set2-mediated H3K36 methylation. Furthermore, these effects are not due to spurious transcription initiation in the bodies of genes, to changes in RNAP II occupancy, to changes in serine 5 CTD phosphorylation patterns, or to "transcriptional stress." These data show that Ctk1 acts to restrict the spread of H3K4 methylation through a mechanism that is independent of a general transcription defect. The evidence presented suggests that Ctk1 controls the maintenance of suppressive chromatin in the coding regions of genes by both promoting H3K36 methylation, which leads to histone deacetylation, and preventing the 3' spread of H3K4 trimethylation, a mark associated with transcriptional initiation.


Buffer capacity of the coelomic fluid in echinoderms.
The increase in atmospheric CO2 due to anthropogenic activity results in an acidification of the surface waters of the oceans. The impact of these chemical changes depends on the considered organisms. In particular, it depends on the ability of the organism to control the pH of its inner fluids. Among echinoderms, this ability seems to differ significantly according to species or taxa. In the present paper, we investigated the buffer capacity of the coelomic fluid in different echinoderm taxa as well as factors modifying this capacity. Euechinoidea (sea urchins except Cidaroidea) present a very high buffer capacity of the coelomic fluid (from 0.8 to 1.8mmolkg(-1) SW above that of seawater), while Cidaroidea (other sea urchins), starfish and holothurians have a significantly lower one (from -0.1 to 0.4mmolkg(-1) SW compared to seawater). We hypothesize that this is linked to the more efficient gas exchange structures present in the three last taxa, whereas Euechinoidea evolved specific buffer systems to compensate lower gas exchange abilities. The constituents of the buffer capacity and the factors influencing it were investigated in the sea urchin Paracentrotus lividus and the starfish Asterias rubens. Buffer capacity is primarily due to the bicarbonate buffer system of seawater (representing about 63% for sea urchins and 92% for starfish). It is also partly due to coelomocytes present in the coelomic fluid (around 8% for both) and, in P. lividus only, a compound of an apparent size larger than 3kDa is involved (about 15%). Feeding increased the buffer capacity in P. lividus (to a difference with seawater of about 2.3mmolkg(-1) SW compared to unfed ones who showed a difference of about 0.5mmolkg(-1) SW) but not in A. rubens (difference with seawater of about 0.2 for both conditions). In P. lividus, decreased seawater pH induced an increase of the buffer capacity of individuals maintained at pH7.7 to about twice that of the control individuals and, for those at pH7.4, about three times. This allowed a partial compensation of the coelomic fluid pH for individuals maintained at pH7.7 but not for those at pH7.4.


Twelve tips for making the best use of feedback.
Feedback is generally regarded as crucial for learning. We focus on feedback provided through instruments developed to inform self-assessment and support learners to improve performance. These instruments are being used commonly in medical education, but they are ineffective if the feedback is not well received and put into practice. The authors formulated twelve tips to make the best use of feedback based on widely cited publications on feedback. To include recent developments and hands-on experiences in the field of medical education, the authors discussed the tips with their research team consisting of experts in the field of medical education and professional performance, to reach agreement on the most practical strategies. When utilizing feedback for performance improvement, medical students, interns, residents, clinical teachers and practicing physicians could make use of the twelve tips to put feedback into practice. The twelve tips provide strategies to reflect, interact and respond to feedback one receives through (validated) feedback instruments. Since the goal of those involved in medical education and patient care is to perform at the highest possible level, we offer twelve practical tips for making the best use of feedback in order to support learners of all levels.


Clients' perceptions of the quality of care in Mexico city's public-sector legal abortion program.
In 2007, first-trimester abortion was legalized in Mexico City. Limited research has been conducted to understand clients' perceptions of the abortion services available in public-sector facilities. Perceptions of quality of care were measured among 402 women aged 18 or older who had obtained abortions at any of three public-sector sites in Mexico City in 2009. Six domains of quality of care (client-staff interaction, information provision, technical competence, postabortion contraceptive services, accessibility and the facility environment) were assessed, and ordinal logistic regression analysis was conducted to identify the domains that were important in women's overall evaluation of care. Clients gave overall services a high rating, with a mean of 8.8 out of 10. In multivariate analysis, overall ratings were higher among women who said the doctor made them feel comfortable (odds ratio, 3.3), the receptionist was respectful (1.7), the staff was very careful to protect their privacy (2.5), they had received sufficient information on self-care at home following the abortion and on postabortion emotions (1.9 and 2.0, respectively) and they felt confident in the doctor's technical skill (2.5). Rating site hours as very convenient (2.4), waiting time as acceptable (2.8) and the facility as very clean (1.9) were all associated with higher overall scores. Compared with women who had given birth, those who had not rated the services lower overall (0.6). Efforts to improve patient experiences with abortion services should focus on client-staff interaction, information provision, service accessibility, technical competence and the facility environment. The most highly significant factor appears to be whether a doctor makes a woman feel comfortable during her visit.


Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention.
Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.


Analysis of competitive binding of several metal cations by graphene oxide reveals the quantity and spatial distribution of carboxyl groups on its surface.
The sorption capacity of graphene oxide (GO) toward different metal cations has been the subject of several recent studies. However, the reported quantitative data are controversial, and the mechanism of chemical bonding between GO and metal cations is poorly understood. Clarifying these questions can eventually help to reveal the fine chemical structure of GO that remains ambiguous. In this work, we study the binding of Gd3+ and Mn2+ by GO in the presence of several competing metal cations by the 1H NMR relaxation method. As a general trend, the efficiency of the metal cations to bind to GO increases with ionic charge, and depends on their ability to form coordinate-covalent bonds with GO oxygen groups. The efficiency of the competing metal cations to "replace" Gd3+ and Mn2+ increases in the order Na+ < Cs+ < Ca2+ < Sr2+ < Ga3+ < Lu3+. GO contains two different types of binding sites, bonding to which results in either high or low NMR relaxivity of the resulting Gd3+-GO and Mn2+-GO solutions. Gd3+ and Mn2+, being replaced from the high-relaxivity sites by the large excess of competing cations, are not released into the bulk solution, but only migrate to the low-relaxivity sites, remaining covalently bonded to GO. The absolute majority of the existing carboxyl groups in GO are located at tiny few-carbon-atom-vacancy defects on the major planes. The density of these vacancy defects is estimated as one per every 200 carbon atoms.


Embedment in the environment: a new paradigm for well-being?
Dominant models of health view people as essentially separable from their environment, affected directly by specific physical events or indirectly through idiosyncratic perceptions. Health is therefore a function of the individual, whether they are treated alone or in a group of similar individuals. A different (ecopsychological) view is that we are embedded within the environment; that notions of self, illness and well-being relate to where we are. Health practitioners and policy makers have realized that mind and body cannot be seen as being separate when promoting well-being, but 'self' and 'environment' is an equally false dichotomy. Although rarely acknowledged, we are continually interconnected via two-way physical interactions (electromagnetic, chemical and mechanical), and all we can know of the world comes via such interactions. Our concepts of self and other, health and disease, and all the relationships between them, are based on such interactions. If our environment changes, then these interactions change, yet our concepts often remain rigidly fixed. By introducing research into restorative, natural environments, the notion of adaptive mental states and the practices of ecotherapy, this paper offers an alternative view of well-being, shifting the emphasis away from the individual and his/her illness and instead inviting consideration of the more dynamic relationships between people and place.


Using opioids in general practice for chronic non-cancer pain: an overview of current evidence.
Chronic non-cancer pain (lasting more than 3 months) is highly prevalent in Australia (17% of males and 20% of females) and its optimal management is crucial to the health and wellbeing of the community. For 5% of the population, such pain interferes markedly with daily function. Part of the treatment for acute non-cancer pain for many people will include opioid analgesics at least for days to weeks. However, as pain becomes chronic, evidence to support ongoing prescription of opioids is lacking. There is increasing pressure to ensure that prescribing opioid analgesics is minimised to reduce not only the risk of dependence and illicit diversion but also the potential harms associated with tolerance, side effects and complications. Frameworks for considering opioid prescribing include assessing suitability of the patient for opioids; initiating a trial of therapy; and monitoring long term use. There is limited evidence of the long term efficacy of opioids for chronic non-cancer pain, and documented clinical consequences beyond addiction include acceleration of loss of bone mineral density, hypogonadism and an association with increased risk of acute myocardial infarction. Careful clinical selection of patients can help optimise the evidence-based use of opioids for chronic non-cancer pain: only treat pain that has been as well defined as possible when non-opioid therapies have not been effective; consider referral to specialist services for assessment if doses are above 100 mg oral morphine equivalent per 24 hours or the duration of therapy is longer than 4 weeks; limit prescribing to only one practitioner; seek an agreement with the patient for the initiation and potential withdrawal of opioids if the therapeutic trial is not effective.


Hispidulin-7-O-Neohesperidoside from Cirsium japonicum var. ussuriense Attenuates the Production of Inflammatory Mediators in LPS-Induced Raw 264.7 Cells and HT-29 Cells.
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and involves secretion of inflammatory mediators. The flavone diglycoside hispidulin-7-O-neohesperidoside (HN) isolated from the methanolic extract of aerial parts of Cirsium japonicum var. ussuriense, but its pharmacologic activities, with the exception of alleviation of alcohol toxicity, have not been investigated to date. The aim of the present study was to investigate the anti-inflammatory activities of HN for the treatment of chronic inflammatory illnesses, including IBD. In lipopolysaccharide (LPS)-induced RAW264.7 cells and HT-29 cells, the effects of HN on cell viability and nitric oxide (NO) production were examined via MTT assay and the Griess reaction, respectively. The expression levels of interleukin (IL)-1α, IL-8, and tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) protein levels were measured by enzyme-linked immunosorbent assay and Western blotting, respectively. HN concentration-dependently inhibited NO production in LPS-induced RAW 264.7 cells. Treatment with HN considerably downregulated the levels of the pro-inflammatory cytokines, IL-1β and TNF-α and the iNOS protein level in LPS-induced RAW 264.7 cells. Furthermore, HN inhibited the production of the chemotactic cytokine, IL-8, in LPS-induced HT-29 cells. HN has potential as an anti-inflammatory agent to prevent and/or treat IBD. Hispidulin-7-O-neohesperidoside (HN) is flavone diglycoside isolated from the methanolic extract of aerial parts of Cirsium japonicum var. ussuriense.HN concentration-dependently inhibited NO production and considerably downregulated the levels of the proinflammatory cytokines, IL-1β and TNF-α, and the iNOS protein level in LPS-induced RAW 264.7 cells.HN inhibited the production of the chemotactic cytokine, IL-8, in LPS-induced HT-29 cells.HN has potential as an anti-inflammatory agent to prevent and/or treat IBD. Abbreviations used: IBD: Inflammatory bowel disease, HN: hispidulin-7-O-neohesperidoside, LPS: lipopolysaccharide, NO: nitric oxide, IL: interleukin, TNF: tumor necrosis factor, iNOS: inducible nitric oxide synthase, CD: Crohn's disease, UC: ulcerative colitis, RT: room temperature, DMEM: Dulbecco's modified Eagle's medium, FBS: fetal bovine serum, PBS: phosphate buffered saline, SDS: sodium dodecyl sulfate, PVDF: polyvinylidene difluoride, SD: standard deviation.


Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis.
Atherogenesis involves inflammatory processes in which infections are incriminated as possible contributors. We evaluated cardiovascular risk factors as well as seropositivity to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus in a population-based study. A significant association between prevalence and severity of atherosclerosis in carotid and femoral arteries and IgA antibodies to C pneumoniae was demonstrated that was not substantially altered after adjustment for established risk factors. For anti-H pylori IgG antibodies, significant correlations to vascular disease were restricted to low social status and lesions in carotid arteries. In addition, the study design allowed us to monitor lesion progression over time. In this prospective analysis, C pneumoniae seropositivity emerged as a significant risk predictor. Antibody titers against cytomegalovirus were not a marker for prevalence or incidence of atherosclerosis in this population. Further infection parameters added to the predictive value of chlamydial serology in risk assessment: Mean odds ratios for the prevalence of carotid atherosclerosis were 4.2 and 6.3 for seropositive subjects with elevated C-reactive protein levels and clinical evidence for chronic respiratory infection, respectively. For subjects with all 3 infection parameters, the odds ratio of carotid atherosclerosis reached 10.3 (P<0.0001). Concomitantly, serum antibodies to mycobacterial heat-shock protein 65 (mHSP65) correlated with seropositivity to C pneumoniae and H pylori but not to cytomegalovirus. This prospective population-based study provides strong evidence for a potential atherogenic role of persistent bacterial infection, especially C pneumoniae, as indicated by serological and clinical data and demonstrates a correlation between immune reactions to mHSP65 and bacterial infections in atherogenesis.


Baseline strength can influence the ability of salivary free testosterone to predict squat and sprinting performance.
The objective of this study was to determine if salivary free testosterone can predict an athlete's performance during back squats and sprints over time and the influence baseline strength on this relationship. Ten weight-trained male athletes were divided into 2 groups based on their 1 repetition maximum (1RM) squats, good squatters (1RM > 2.0 × body weight, n = 5) and average squatters (1RM < 1.9 × body weight, n = 5). The good squatters were stronger than the average squatters (p < 0.05). Each subject was assessed for squat 1RM and 10-m sprint times on 10 separate occasions over a 40-day period. A saliva sample was collected before testing and assayed for free testosterone and cortisol. The pooled testosterone correlations were strong and significant in the good squatters (r = 0.92 for squats, r = -0.87 for sprints, p < 0.01), but not significant for the average squatters (r = 0.35 for squats, r = -0.18 for sprints). Cortisol showed no significant correlations with 1RM squat and 10-m sprint performance, and no differences were identified between the 2 squatting groups. In summary, these results suggest that free testosterone is a strong individual predictor of squat and sprinting performance in individuals with relatively high strength levels but a poor predictor in less strong individuals. This information can assist coaches, trainers, and performance scientists working with stronger weight-trained athletes, for example, the preworkout measurement of free testosterone could indicate likely training outcomes or a readiness to train at a certain intensity level, especially if real-time measurements are made. Our results also highlight the need to separate group and individual hormonal data during the repeated testing of athletes with variable strength levels.


A clinically validated prediction method for facial soft-tissue changes following double-jaw surgery.
It is clinically important to accurately predict facial soft-tissue changes prior to orthognathic surgery. However, the current simulation methods are problematic, especially in anatomic regions of clinical significance, e.g., the nose, lips, and chin. We developed a new 3-stage finite element method (FEM) approach that incorporates realistic tissue sliding to improve such prediction. In Stage One, soft-tissue change was simulated, using FEM with patient-specific mesh models generated from our previously developed eFace template. Postoperative bone movement was applied on the patient mesh model with standard FEM boundary conditions. In Stage Two, the simulation was improved by implementing sliding effects between gum tissue and teeth using a nodal force constraint scheme. In Stage Three, the result of the tissue sliding effect was further enhanced by reassigning the soft-tissue-bone mapping and boundary conditions using nodal spatial constraint. Finally, our methods have been quantitatively and qualitatively validated using 40 retrospectively evaluated patient cases by comparing it to the traditional FEM method and the FEM with sliding effect, using a nodal force constraint method. The results showed that our method was better than the other two methods. Using our method, the quantitative distance errors between predicted and actual patient surfaces for the entire face and any subregions thereof were below 1.5 mm. The overall soft-tissue change prediction was accurate to within 1.1 ± 0.3 mm, with the accuracy around the upper and lower lip regions of 1.2 ± 0.7 mm and 1.5 ± 0.7 mm, respectively. The results of qualitative evaluation completed by clinical experts showed an improvement of 46% in acceptance rate compared to the traditional FEM simulation. More than 80% of the result of our approach was considered acceptable in comparison with 55% and 50% following the other two methods. The FEM simulation method with improved sliding effect showed significant accuracy improvement in the whole face and the clinically significant regions (i.e., nose and lips) in comparison with the other published FEM methods, with or without sliding effect using a nodal force constraint. The qualitative validation also proved the clinical feasibility of the developed approach.