Influence of methionine and vitamin E on fluoride concentration in bones and teeth of rats exposed to sodium fluoride in drinking water.
Increased exposure to fluorine-containing compounds leads to accumulation of fluorides in hard tissues of bones and teeth, which may result in numerous skeletal and dental disorders. This study evaluates the influence of methionine and vitamin E on fluoride concentration in bones and teeth of rats subjected to long-term exposure to sodium fluoride in drinking water. The study was conducted in 30 3-month-old female Wistar FL rats. The animals were divided into five groups, six rats per group. The control group consisted of rats receiving only distilled water as drinking water. All other groups received NaF in the amount of 10 mg/kg of body mass/day in their drinking water. In addition, respective animal groups received: NaF + Met group--10 mg of methionine/kg of body mass/day, NaF + Met + E group--10 mg of methionine/kg of body mass/day and 3 mg of vitamin E (tocopheroli acetas)/rat/day and NaF + E group--3 mg of vitamin E/rat/day. Femoral bones and incisor teeth were collected for the study, and the fluoride concentration was determined using a fluoride ion-selective electrode. Fluoride concentration in both bones and teeth was found to be higher in the NaF and NaF + Met groups compared to the control group. In groups NaF + Met + E and NaF + E, the study material contained much lower fluoride concentration compared to the NaF group, while the effect was more prominent in the NaF + E group. The results of the studies indicate that methionine and vitamin E have opposite effects on accumulation of fluorides in hard tissue in rats. By stimulating fluoride accumulation, methionine reduces the adverse effect of fluorides on soft tissue, while vitamin E, which prevents excessive accumulation of fluorides in bones and teeth, protects these tissues from fluorosis. Therefore, it seems that combined application of both compounds would be optimal for the prevention of the adverse effects of chronic fluoride intoxication.


Response strategies for COVID-19 epidemics in African settings: a mathematical modelling study.
The health impact of COVID-19 may differ in African settings as compared to countries in Europe or China due to demographic, epidemiological, environmental and socio-economic factors. We evaluated strategies to reduce SARS-CoV-2 burden in African countries, so as to support decisions that balance minimising mortality, protecting health services and safeguarding livelihoods. We used a Susceptible-Exposed-Infectious-Recovered mathematical model, stratified by age, to predict the evolution of COVID-19 epidemics in three countries representing a range of age distributions in Africa (from oldest to youngest average age: Mauritius, Nigeria and Niger), under various effectiveness assumptions for combinations of different non-pharmaceutical interventions: self-isolation of symptomatic people, physical distancing and 'shielding' (physical isolation) of the high-risk population. We adapted model parameters to better represent uncertainty about what might be expected in African populations, in particular by shifting the distribution of severity risk towards younger ages and increasing the case-fatality ratio. We also present sensitivity analyses for key model parameters subject to uncertainty. We predicted median symptomatic attack rates over the first 12 months of 23% (Niger) to 42% (Mauritius), peaking at 2-4 months, if epidemics were unmitigated. Self-isolation while symptomatic had a maximum impact of about 30% on reducing severe cases, while the impact of physical distancing varied widely depending on percent contact reduction and R0. The effect of shielding high-risk people, e.g. by rehousing them in physical isolation, was sensitive mainly to residual contact with low-risk people, and to a lesser extent to contact among shielded individuals. Mitigation strategies incorporating self-isolation of symptomatic individuals, moderate physical distancing and high uptake of shielding reduced predicted peak bed demand and mortality by around 50%. Lockdowns delayed epidemics by about 3 months. Estimates were sensitive to differences in age-specific social mixing patterns, as published in the literature, and assumptions on transmissibility, infectiousness of asymptomatic cases and risk of severe disease or death by age. In African settings, as elsewhere, current evidence suggests large COVID-19 epidemics are expected. However, African countries have fewer means to suppress transmission and manage cases. We found that self-isolation of symptomatic persons and general physical distancing are unlikely to avert very large epidemics, unless distancing takes the form of stringent lockdown measures. However, both interventions help to mitigate the epidemic. Shielding of high-risk individuals can reduce health service demand and, even more markedly, mortality if it features high uptake and low contact of shielded and unshielded people, with no increase in contact among shielded people. Strategies combining self-isolation, moderate physical distancing and shielding could achieve substantial reductions in mortality in African countries. Temporary lockdowns, where socioeconomically acceptable, can help gain crucial time for planning and expanding health service capacity.


Cystatins of parasitic organisms.
The cystatin superfamily comprises several groups of protease inhibitors. In this chapter we will focus on I25 family members, which consist predominantly of the type 2 cystatins. Recently, a wealth of information on these molecules and their activities has been described. Parasite cystatins are shown to have dual functions via interaction with both parasite and host proteases. Thereby, parasite cystatins are not only essentially involved in the regulation of physiological processes during parasite development, but also represent important pathogenicity factors. Interestingly, some studies indicate that parasite cystatins evolved exceptional immuno-modulatory properties. these capacities could be exploited to interfere with unwanted immune responses in unrelated human inflammatory diseases. We highlight the different biological roles of parasite cystatins and the anticipated future developments.


Efficient holmium-doped fluoride fiber laser emitting 2.1 µm and blue upconversion fluorescence upon excitation at 2 µm.
We demonstrate a highly efficient and high power Ho(3+)-doped fluoride glass fiber laser that is resonantly pumped with a Tm(3+)-doped silicate glass fiber laser operating at 2.051 µm. The laser operates at 2080 nm and generated 6.66 W at a slope efficiency of 72%. We observe strong visible upconversion fluorescence centered at a variety of wavelengths including 491 nm which results from three sequential energy transfer upconversion processes; the fluorescence to pump energy ratio for this emission is one the largest reported to date.


Human influence on California fire regimes.
Periodic wildfire maintains the integrity and species composition of many ecosystems, including the mediterranean-climate shrublands of California. However, human activities alter natural fire regimes, which can lead to cascading ecological effects. Increased human ignitions at the wildland-urban interface (WUI) have recently gained attention, but fire activity and risk are typically estimated using only biophysical variables. Our goal was to determine how humans influence fire in California and to examine whether this influence was linear, by relating contemporary (2000) and historic (1960-2000) fire data to both human and biophysical variables. Data for the human variables included fine-resolution maps of the WUI produced using housing density and land cover data. Interface WUI, where development abuts wildland vegetation, was differentiated from intermix WUI, where development intermingles with wildland vegetation. Additional explanatory variables included distance to WUI, population density, road density, vegetation type, and ecoregion. All data were summarized at the county level and analyzed using bivariate and multiple regression methods. We found highly significant relationships between humans and fire on the contemporary landscape, and our models explained fire frequency (R2 = 0.72) better than area burned (R2 = 0.50). Population density, intermix WUI, and distance to WUI explained the most variability in fire frequency, suggesting that the spatial pattern of development may be an important variable to consider when estimating fire risk. We found nonlinear effects such that fire frequency and area burned were highest at intermediate levels of human activity, but declined beyond certain thresholds. Human activities also explained change in fire frequency and area burned (1960-2000), but our models had greater explanatory power during the years 1960-1980, when there was more dramatic change in fire frequency. Understanding wildfire as a function of the spatial arrangement of ignitions and fuels on the landscape, in addition to nonlinear relationships, will be important to fire managers and conservation planners because fire risk may be related to specific levels of housing density that can be accounted for in land use planning. With more fires occurring in close proximity to human infrastructure, there may also be devastating ecological impacts if development continues to grow farther into wildland vegetation.


Health Action Zones and the problem of community.
Health Actions Zones (HAZs) have been identified as initiatives reflecting the 'third way' policies espoused by the UK New Labour Government. Like other area-based or zone initiatives, HAZ programmes are designed to tackle inequalities and exclusion in some of the most deprived areas of the UK. This is to be achieved through partnerships between the public, private and voluntary sectors, and most significantly, communities themselves. Health Action Zones embrace communities and attempt to foster involvement in health improvement, often using established community development models. The present paper uses the findings of an ongoing process study into the development of one zone in the north-east of England to consider community involvement in practice. The benefits and challenges of involving communities in the HAZ process are presented, and the relevance of this for future programmes and policy are discussed.


Insulin resistance and endothelial dysfunction: a mutual relationship in cardiometabolic risk.
Cardiometabolic risk comprises a cluster of traditional and emerging factors that are good indicators of a patient's overall risk for type 2 diabetes and cardiovascular disease. The insulin resistance, a key feature common to obesity and type 2 diabetes, is associated with impaired vascular response and contributes to increased cardiovascular risk. Abnormal vascular insulin signalling induces endothelial dysfunction, the initial step of atherosclerotic process, characterized by attenuated nitric oxide-mediated vasodilatation and atherogenic response. Insulin resistance and endothelial dysfunction are two pathological conditions that can co-exist, even if their cause-effect relationship is not yet clarified. Multiple signaling pathways shared by insulin resistance and endothelial dysfunction include hyperinsulinemia, glucotoxicity, lipotoxicity, and inflammation. These mechanisms selectively impair PI3K-dependent insulin in vascular endothelium harming endothelial balance and strengthening the evidence of the close association between metabolic and cardiovascular disease. The present review analyzes the close relationship between endothelial dysfunction and insulin resistance and explores the common mechanisms, with clinical considerations and pharmacological strategies.


Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo.
Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to fibrogenesis, our aim was to study the phagocytic NADPH oxidase NOX2. An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2(-/-) mice with lentiviral-green fluorescence protein (GFP) containing a hepatocyte-specific promoter, and adeno-tumor necrosis factor-related apoptosis-inducing ligand (ad-TRAIL). Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2(-/-) mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. In the phagocytosis model, engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-smooth muscle actin (α-SMA) and collagen I increased significantly in the wt but not in the NOX2(-/-) mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2(-/-) animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2(-/-) mice, suggesting that NOX2-expressing HSC are important in fibrogenesis. NOX2 was up-regulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, production of NOX2-mediated reactive oxygen species directly induced collagen promoter activity in HSC. Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase, plays a key role in this process and in liver fibrogenesis in vivo.


Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes.
The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).


Routines in facility-based maternity care: evidence from the Arab World.
To document facility-based practices for normal labour and delivery in Egypt, Lebanon, the West Bank (part of the Occupied Palestinian Territory) and Syria and to categorise common findings according to evidence-based obstetrics. Three studies (Lebanon, West Bank and Syria) interviewed a key informant (providers) in maternity facilities. The study in Egypt directly observed individual labouring women. Maternity wards. Nationally representative sample of hospitals drawn in Lebanon and Syria. In the West Bank, a convenience sample of hospitals was used. In Egypt, the largest teaching hospital's maternity ward was observed. Shared practices were categorised by adapting the World Health Organization's (WHO) 2004 classification of practices for normal birth into the following: practices known to be beneficial, practices likely to be beneficial, practices unlikely to be beneficial and practices likely to be ineffective or harmful. Routine hospital practices for normal labor and delivery. There was infrequent use of beneficial practices that should be encouraged and an unexpectedly high level of harmful practices that should be eliminated. Some beneficial practices were applied inappropriately and practices of unproven benefit were also documented. Some documented childbirth practices are potentially harmful to mothers and their babies. Facility practices for normal labour were largely not in accordance with the WHO evidence-based classification of practices for normal birth. The findings are worrying given the increasing proportion of facility-based births in the region and the improved but relatively high maternal and neonatal mortality ratios in these countries. Obstacles to following evidence-based protocols for normal labour require examination.


Enabling research in general practice--increasing functionality of electronic medical records.
With an estimated 80% of Australians visiting a general practitioner at least once a year, the data generated by GPs is a rich source of the overall health profile of patients. However, this data is rarely used to report on health outcomes. This article reports on the use of remote access of electronic medical records (EMRs) for the purpose of collecting data during a collaborative research project involving the staff of three general practices and an external research team. Throughout the project numerous benefits to remotely accessing general practice EMRs were identified. However, there remain some difficulties which need to be addressed. An increased functionality of the software programs used in general practice is required, along with improvements in the utilisation of the software capabilities. Collaboration between clinicians, researchers and clinical software developers will be vital to advance this process.


Extensor tendon gap reconstruction: a review.
The extensor tendons of the hand are located in a superficial position on the dorsal aspect of the hand and are highly susceptible to injury. Laceration, crush and avulsion injuries are common extensor tendon injuries presenting for acute care. Such injuries that involve tendon loss or gaps in the extensor tendons require specialised attention and can be some of the most challenging to repair, as extensor tendons have less excursion than flexor tendons. Reconstructive techniques for such defects may differ according to the location of the defect, especially in Verdan's extensor zones 1-5. Adequate repair of extensor tendon defects in zones 1-5 is especially important because (a) even a 1 mm tendon gap in those zones may cause 20° extension loss, and (b) shortening of the extensor tendon by as little as 1 mm may cause decreased finger flexion. This article reviews and discusses the literature on the various approaches and techniques for extensor tendon reconstruction, delineated by zone of injury (zones 1-8). CONCLSIONS: Awareness of the various techniques available to repair defects in each zone of injury is important so that surgeons can choose the technique most in alignment with the type of injury, the surgeon's skills, and patient characteristics, and optimise the repair of such injuries.


Sleep deprivation leads to a loss of functional connectivity in frontal brain regions.
The restorative effect of sleep on waking brain activity remains poorly understood. Previous studies have compared overall neural network characteristics after normal sleep and sleep deprivation. To study whether sleep and sleep deprivation might differentially affect subsequent connectivity characteristics in different brain regions, we performed a within-subject study of resting state brain activity using the graph theory framework adapted for the individual electrode level.In balanced order, we obtained high-density resting state electroencephalography (EEG) in 8 healthy participants, during a day following normal sleep and during a day following total sleep deprivation. We computed topographical maps of graph theoretical parameters describing local clustering and path length characteristics from functional connectivity matrices, based on synchronization likelihood, in five different frequency bands. A non-parametric permutation analysis with cluster correction for multiple comparisons was applied to assess significance of topographical changes in clustering coefficient and path length. Significant changes in graph theoretical parameters were only found on the scalp overlying the prefrontal cortex, where the clustering coefficient (local integration) decreased in the alpha frequency band and the path length (global integration) increased in the theta frequency band. These changes occurred regardless, and independent of, changes in power due to the sleep deprivation procedure. The findings indicate that sleep deprivation most strongly affects the functional connectivity of prefrontal cortical areas. The findings extend those of previous studies, which showed sleep deprivation to predominantly affect functions mediated by the prefrontal cortex, such as working memory. Together, these findings suggest that the restorative effect of sleep is especially relevant for the maintenance of functional connectivity of prefrontal brain regions.


Epibenthic assessment of a renewable tidal energy site.
Concern over global climate change as a result of fossil fuel use has resulted in energy production from renewable sources. Marine renewable energy devices provide clean electricity but can also cause physical disturbance to the local environment. There is a considerable paucity of ecological data at potential marine renewable energy sites that is needed to assess potential future impacts and allow optimal siting of devices. Here, we provide a baseline benthic survey for the Big Russel in Guernsey, UK, a potential site for tidal energy development. To assess the suitability of proposed sites for marine renewable energy in the Big Russel and to identify potential control sites, we compared species assemblages and habitat types. This baseline survey can be used to select control habitats to compare and monitor the benthic communities after installation of the device and contribute towards the optimal siting of any future installation.


YtrASa, a GntR-Family Transcription Factor, Represses Two Genetic Loci Encoding Membrane Proteins in Sulfolobus acidocaldarius.
In bacteria, the GntR family is a widespread family of transcription factors responsible for the regulation of a myriad of biological processes. In contrast, despite their occurrence in archaea only a little information is available on the function of GntR-like transcription factors in this domain of life. The thermoacidophilic crenarchaeon Sulfolobus acidocaldarius harbors a GntR-like regulator belonging to the YtrA subfamily, encoded as the first gene in an operon with a second gene encoding a putative membrane protein. Here, we present a detailed characterization of this regulator, named YtrASa, with a focus on regulon determination and mechanistic analysis with regards to DNA binding. Genome-wide chromatin immunoprecipitation and transcriptome experiments, the latter employing a ytrA Sa overexpression strain, demonstrate that the regulator acts as a repressor on a very restricted regulon, consisting of only two targets including the operon encoding its own gene and a distinct genetic locus encoding another putative membrane protein. For both targets, a conserved 14-bp semi-palindromic binding motif was delineated that covers the transcriptional start site and that is surrounded by additional half-site motifs. The crystallographic structure of YtrASa was determined, revealing a compact dimeric structure in which the DNA-binding motifs are oriented ideally to enable a specific high-affinity interaction with the core binding motif. This study provides new insights into the functioning of a YtrA-like regulator in the archaeal domain of life.


Evaluation of Preventive Fungicide Applications for Fairy Ring Control in Golf Putting Greens and In Vitro Sensitivity of Fairy Ring Species to Fungicides.
Fairy ring species induce symptoms on putting greens mostly indirectly, by modifying the soil physical or chemical properties. Therefore, preventive rather than curative fungicide applications may be more effective in managing fairy ring. Two field experiments were conducted on a creeping bentgrass research green to evaluate fairy ring control from preventive fungicide applications. A 3-year study investigated the optimal rate and soil temperature-based timing of a preventive application of triadimefon and tebuconazole. A 2-year study evaluated the impact of irrigation timing and fungicide + surfactant tank mixtures on the efficacy of preventive applications of triadimefon and triticonazole. Fungicide-treated plots in both studies exhibited less fairy ring severity than untreated plots. Data suggest that a 5-day average soil temperature range of 13 to 16°C may be suitable for initiating preventive applications. Symptoms occurred earlier in plots treated with a surfactant tank mix than in those treated with fungicide alone. Irrigation timing had no effect on fungicide performance. The sensitivity of 16 isolates representing major fairy ring species to flutolanil, propiconazole, tebuconazole, triadimefon, and triticonazole was determined with a mycelial growth assay. No significant differences in fungicide sensitivity were detected among species. Isolates had significantly higher 50% effective concentration values for triadimefon than for the other fungicides tested.


The clinical utility of Multiplate analyser measurement in platelet function testing following stroke and transient ischaemic attack.
Platelet responsiveness to aspirin in people with cerebrovascular disease is poorly understood. To determine: (i) normal reference range, imprecision and reproducibility of the Multiplate instrument in healthy volunteers naive to aspirin; (ii) imprecision and reproducibility of the Multiplate instrument in acute stroke and transient ischaemic attack (TIA); (iii) the relationship between aspirin responsiveness and clinical outcome. We evaluated platelet function response to three agonists [Adenosine Diphosphate (ADP), Arachidonic Acid (AA), Collagen (Col)] using the Mulitplate platelet function analyser in a two-phase pilot study. In phase 1, we recruited healthy volunteers to determine the normal reference range and imprecision of the Multiplate instrument. In phase 2, we assessed platelet function in acute stroke or TIA patients presenting to hospital. These patients were bled within 24 h of presentation and between 12 and 24 h after ≥75 mg dose of Aspirin. Patients were followed up to 1 yr to assess mortality and recurrent cardiovascular event. Overall, 29 healthy volunteers and 81 stroke/TIA patients were recruited. On assessing components of variance, Multiplate testing is reproducible and precise in volunteers and stroke/TIA patients. In stroke patients receiving aspirin, Bland-Altman plots show initial day 1 measurement provided a reliable measure of continuing response to aspirin at day 3. We defined one-third of patients as aspirin resistant [31.8% (95% CI: 22.1%-42.8%)] using cut off mean aggregation of ≥23.08% for AA and mean aggregation of ≥80.76% for ADP. The Multiplate device gives reproducible, precise results in volunteers and stroke/TIA patients.


Inward flux of lactate⁻ through monocarboxylate transporters contributes to regulatory volume increase in mouse muscle fibres.
Mouse and rat skeletal muscles are capable of a regulatory volume increase (RVI) after they shrink (volume loss resultant from exposure to solutions of increased osmolarity) and that this RVI occurs mainly by a Na-K-Cl-Cotransporter (NKCC)-dependent mechanism. With high-intensity exercise, increased extracellular osmolarity is accompanied by large increases in extracellular [lactate⁻]. We hypothesized that large increases in [lactate⁻] and osmolarity augment the NKCC-dependent RVI response observed with a NaCl (or sucrose)-induced increase in osmolarity alone; a response that is dependent on lactate⁻ influx through monocarboxylate transporters (MCTs). Single mouse muscle fibres were isolated and visualized under light microscopy under varying osmolar conditions. When solution osmolarity was increased by adding NaLac by 30 or 60 mM, fibres lost significantly less volume and regained volume sooner compared to when NaCl was used. Phloretin (MCT1 inhibitor) accentuated the volume loss compared to both NaLac controls, supporting a role for MCT1 in the RVI response in the presence of elevated [lactate⁻]. Inhibition of MCT4 (with pCMBS) resulted in a volume loss, intermediate to that seen with phloretin and NaLac controls. Bumetanide (NKCC inhibitor), in combination with pCMBS, reduced the magnitude of volume loss, but volume recovery was complete. While combined phloretin-bumetanide also reduced the magnitude of the volume loss, it also largely abolished the cell volume recovery. In conclusion, RVI in skeletal muscle exposed to raised tonicity and [lactate⁻] is facilitated by inward flux of solute by NKCC- and MCT1-dependent mechanisms. This work demonstrates evidence of a RVI response in skeletal muscle that is facilitated by inward flux of solute by MCT-dependent mechanisms. These findings further expand our understanding of the capacities for skeletal muscle to volume regulate, particularly in instances of raised tonicity and lactate⁻ concentrations, as occurs with high intensity exercise.


Contrast enhanced dynamic MRI of cervical carcinoma during radiotherapy: early prediction of tumour regression rate.
This prospective study investigated the relationship between changes in the MRI dynamic enhancement of cervical carcinoma early during radiotherapy, and tumour regression rate throughout radiotherapy. A total of 36 MRI examinations was performed in seven patients with cervical carcinoma, including a T2 weighted sequence weekly during radiotherapy and also a multislice dynamic Gd-DTPA enhanced sequence before and after the first 2 weeks of radiotherapy. Tumour enhancement was determined on dynamic images using a region of interest and signal-to-noise ratio method. Serial tumour volumes over time on T2 weighted images were estimated using the Cavalieri method of modern design-based stereology to obtain tumour regression rate. It was found that peak and mean enhancement prior to radiotherapy ranged from 3.0 to 13.3, and from 1.9 to 12.2, respectively. After 2 weeks of radiotherapy, peak and mean enhancement ranged from 7.5 to 13.0, and from 6.3 to 10.6, respectively. The change in peak and mean tumour enhancement between dynamic scans ranged, respectively, from -2.0 to 8.4 and from -4.5 to 8.5. Tumour volume decreased exponentially with time (p < 0.01). Tumour regression rates ranged from 2.0% to 15.2% per day, and correlated positively with changes of both peak and mean tumour enhancement (p < 0.01). It is concluded that MRI dynamic enhancement during the first 2 weeks of radiotherapy may provide early prediction of tumour regression rate, and therefore be of value in designing treatment schedules for cervical carcinoma.


Homology models guide discovery of diverse enzyme specificities among dipeptide epimerases in the enolase superfamily.
The rapid advance in genome sequencing presents substantial challenges for protein functional assignment, with half or more of new protein sequences inferred from these genomes having uncertain assignments. The assignment of enzyme function in functionally diverse superfamilies represents a particular challenge, which we address through a combination of computational predictions, enzymology, and structural biology. Here we describe the results of a focused investigation of a group of enzymes in the enolase superfamily that are involved in epimerizing dipeptides. The first members of this group to be functionally characterized were Ala-Glu epimerases in Eschericiha coli and Bacillus subtilis, based on the operon context and enzymological studies; these enzymes are presumed to be involved in peptidoglycan recycling. We have subsequently studied more than 65 related enzymes by computational methods, including homology modeling and metabolite docking, which suggested that many would have divergent specificities;, i.e., they are likely to have different (unknown) biological roles. In addition to the Ala-Phe epimerase specificity reported previously, we describe the prediction and experimental verification of: (i) a new group of presumed Ala-Glu epimerases; (ii) several enzymes with specificity for hydrophobic dipeptides, including one from Cytophaga hutchinsonii that epimerizes D-Ala-D-Ala; and (iii) a small group of enzymes that epimerize cationic dipeptides. Crystal structures for certain of these enzymes further elucidate the structural basis of the specificities. The results highlight the potential of computational methods to guide experimental characterization of enzymes in an automated, large-scale fashion.


Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: new data from the Patch in Practice trial and pooled analyses.
The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A45-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p=0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p=0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p=0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p=0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p=0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p=0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N=1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR)=1.25, 95% CI 0.89, 1.74, p=0.19; SS: OR=1.31, 95% CI 0.86, 1.98, p=0.21) or 26-week follow-up (Reference LL; SL: OR=0.93, 95% CI 0.64, 1.33, p=0.68; SS: OR=1.00, 95% CI 0.63, 1.58, p=1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.


Nocturnal Hemodialysis Leads to Improvement in Physical Performance in Comparison with Conventional Hemodialysis.
End-stage kidney disease patients treated with conventional hemodialysis (CHD) are known to have impaired physical performance and protein-energy wasting (PEW). Nocturnal hemodialysis (NHD) was shown to improve clinical outcomes, but the evidence is limited on physical performance and PEW. We investigate whether NHD improves physical performance and PEW. This prospective, multicenter, non-randomized cohort study compared patients who changed from CHD (2−4 times/week 3−5 h) to NHD (2−3 times/week 7−8 h), with patients who continued CHD. The primary outcome was physical performance at 3, 6 and 12 months, assessed with the short physical performance battery (SPPB). Secondary outcomes were a 6-minute walk test (6MWT), physical activity monitor, handgrip muscle strength, KDQOL-SF physical component score (PCS) and LAPAQ physical activity questionnaire. PEW was assessed with a dietary record, dual-energy X-ray absorptiometry, bioelectrical impedance spectroscopy and subjective global assessment (SGA). Linear mixed models were used to analyze the differences between groups. This study included 33 patients on CHD and 32 who converted to NHD (mean age 55 ± 15.3). No significant difference was found in the SPPB after 1-year of NHD compared to CHD (+0.24, [95% confidence interval −0.51 to 0.99], p = 0.53). Scores of 6MWT, PCS and SGA improved (+54.3 [95%CI 7.78 to 100.8], p = 0.02; +5.61 [−0.51 to 10.7], p = 0.03; +0.71 [0.36 to 1.05], p < 0.001; resp.) in NHD patients, no changes were found in other parameters. We conclude that NHD patients did not experience an improved SPPB score compared to CHD patients; they did obtain an improved walking distance and self-reported PCS as well as SGA after 1-year of NHD, which might be related to the younger age of these patients.


Potential for plant growth promotion of rhizobacteria associated with Salicornia growing in Tunisian hypersaline soils.
Soil salinity and drought are among the environmental stresses that most severely affect plant growth and production around the world. In this study the rhizospheres of Salicornia plants and bulk soils were collected from Sebkhet and Chott hypersaline ecosystems in Tunisia. Depiction of bacterial microbiome composition by Denaturing Gradient Gel Electrophoresis unveiled the occurrence of a high bacterial diversity associated with Salicornia root system. A large collection of 475 halophilic and halotolerant bacteria was established from Salicornia rhizosphere and the surrounding bulk soil, and the bacteria were characterized for the resistance to temperature, osmotic and saline stresses, and plant growth promotion (PGP) features. Twenty Halomonas strains showed resistance to a wide set of abiotic stresses and were able to perform different PGP activities in vitro at 5% NaCl, including ammonia and indole-3-acetic acid production, phosphate solubilisation, and potential nitrogen fixation. By using a gfp-labelled strain it was possible to demonstrate that Halomonas is capable of successfully colonising Salicornia roots in the laboratory conditions. Our results indicated that the culturable halophilic/halotolerant bacteria inhabiting salty and arid ecosystems have a potential to contribute to promoting plant growth under the harsh salinity and drought conditions. These halophilic/halotolerant strains could be exploited in biofertilizer formulates to sustain crop production in degraded and arid lands.


Social anxiety symptoms across diagnoses among outpatients attending a tertiary care mood and anxiety disorders service.
Social phobia is a common, persistent and disabling anxiety disorder in which co-existing depressive symptoms are common. However the prevalence of social anxiety symptoms in patients with other mood and anxiety disorders is uncertain. In consecutive patients attending a tertiary referral mood and anxiety disorders service, depressive symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) and social anxiety symptoms by the Liebowitz Social Anxiety Scale (LSAS). The Clinical Global Impression of Severity (CGI-S) was completed following the appointment. 75 patients (48 women, 27 men; mean age 45.9 years) completed the study. 38 had a single diagnosis and 37 co-morbid diagnoses: 15 patients had bipolar disorder, 35 unipolar depressive disorder, 19 an anxiety disorder, and 6 other disorders. Independent samples t-tests and one-way between-subjects ANOVA revealed that the severity of social anxiety symptoms but not depressive symptoms was significantly greater in patients with co-morbid diagnoses (LSAS 73.7 vs 54.2, t(72)=2.44, p<.05; MADRS 21.9 vs 18.0, t(73)=1.76, p=.08; CGI-S 3.7 vs 3.2, t(73)=2.64, p<.05); and in anxiety disorders than in unipolar depression or bipolar disorder (respectively; LSAS 78.8 vs 59.4 vs 50.0, F(2, 65)=3.13, p=.05; MADRS 22.2 vs 19.8 vs 17.5, F(2, 66)<1, ns; CGI-S 3.9 vs 3.3 vs 3.1, F(2, 66)=5.43, p<.01). In the overall sample, correlation coefficients were MADRS and LSAS, R(2)=0.2628, p<.001; MADRS and CGI-S, R(2)=0.5863, p<.001; and LSAS and CGI-S, R(2)=0.327, p<.001. Correlations between MADRS and LSAS scores were higher in bipolar disorder (R(2)=0.4900, p<.01) than in unipolar depression (R(2)=0.376, p<.01) or anxiety disorders (R(2)=0.0041, ns). Small size of convenience sample undergoing varying treatments within a single specialist tertiary referral centre. There was only a moderate correlation between depressive and social anxiety symptoms across a range of diagnoses. Depressive and social anxiety symptoms were most severe but least well correlated among tertiary care outpatients with anxiety disorders, emphasising the need for comprehensive evaluation and treatment.


"Is it just so my right?" Women repossessing breastfeeding.
Infant feeding occurs in the context of continued gender inequities and in the context of a feminist movement that left women vulnerable to a system that defined the male body and mind as the norm. This paper draws from a qualitative analysis of interviews conducted with women artists at the 2005 Mamapalooza music festival in New York City, and conference participants at the 2005 La Leche League International and International Lactation Consultant Association Conferences and at the 2007 Reproductive Freedom Conference to understand our collective alienation from breastfeeding and to outline a process for how we might repossess breastfeeding as a positive function in women's lives. These women find power in honoring and validating their own experiences, in claiming those experiences as legitimate feminist actions, and then drawing on these experiences to seek new meanings, customs and norms that similarly honor, value and support their rights to those experiences. They argue that we need a feminist movement that fully incorporates women's needs as biological and reproductive social beings, alongside their needs as productive beings, and a movement that defines the female body and mind as the norm.


IS1397 is active for transposition into the chromosome of Escherichia coli K-12 and inserts specifically into palindromic units of bacterial interspersed mosaic elements.
We demonstrate that IS1397, a putative mobile genetic element discovered in natural isolates of Escherichia coli, is active for transposition into the chromosome of E. coli K-12 and inserts specifically into palindromic units, also called repetitive extragenic palindromes, the basic element of bacterial interspersed mosaic elements (BIMEs), which are found in intergenic regions of enterobacteria closely related to E. coli and Salmonella. We could not detect transposition onto a plasmid carrying BIMEs. This unprecedented specificity of insertion into a well-characterized chromosomal intergenic repeated element and its evolutionary implications are discussed.


A Comparative Study of Totalitarian Style Partner Control in Seoul and Beijing: Confucian Sex Role Norms, Secrecy, and Missing Data.
Totalitarian style partner control is seldom studied apart from intimate partner violence (IPV) independently as an outcome. This article uses a comparative study of Beijing and Seoul to begin to address this gap in the research. We collected three-stage probability proportional to size cluster samples of married/partnered women from Beijing (n = 301) and Seoul (n = 459), using refusal conversion to keep response rates high. We hypothesized (1) totalitarian style partner control will be positively associated with Confucian sex role norms at the (a) individual and (b) neighborhood levels, (2) totalitarian style partner control will be positively associated with IPV secrecy at the (a) individual and (b) neighborhood levels, and (3) totalitarian style partner control will be positively associated with the need for refusal conversion. Mixed effects (multilevel) regression models supported all three hypotheses at the individual level. Surprisingly, neighborhood socioeconomic status was positively associated with totalitarian style partner control. The combined data conceal important differences between Beijing and Seoul. The rate of totalitarian style partner control is more than 5 times higher in Seoul, and Confucian sex role norms, at both the individual and neighborhood levels, predict totalitarian style control there. Based on our findings, we infer that cultural emphases on face may play very different roles in the etiology of totalitarian partner control in the two cities.


Distinct blood transcriptomic signature of treatment in latent tuberculosis infected individuals at risk of developing active disease.
Although only a small fraction will ever develop the active form of tuberculosis (ATB) disease, chemoprophylaxis treatment in latent TB infected (LTBI) individuals is an effective strategy to control pathogen transmission. Characterizing immune responses in LTBI upon chemoprophylactic treatment is important to facilitate treatment monitoring, and thus improve TB control strategies. Here, we studied changes in the blood transcriptome in a cohort of 42 LTBI and 8 ATB participants who received anti-TB therapy. Based on the expression of previously published gene signatures of progression to ATB, we stratified the LTBI cohort in two groups and examined if individuals deemed to be at elevated risk of developing ATB before treatment (LTBI-Risk) differed from others (LTBI-Other). We found that LTBI-Risk and LTBI-Other groups were associated with two distinct transcriptomic treatment signatures, with the LTBI-Risk signature resembling that of treated ATB patients. Notably, overlapping genes between LTBI-Risk and ATB treatment signatures were associated with risk of progression to ATB and interferon (IFN) signaling, and were selectively downregulated upon treatment in the LTBI-Risk but not the LTBI-Other group. Our results suggest that transcriptomic reprogramming following treatment of LTBI is heterogeneous and can be used to distinguish LTBI-Risk individuals from the LTBI cohort at large.


Determination of absolute configurations of 4-hydroxyequilenin-cytosine and -adenine adducts by optical rotatory dispersion, electronic circular dichroism, density functional theory calculations, and mass spectrometry.
Estrogen components of some hormone replacement formulations have been implicated in the initiation of breast cancer. Some of these formulations contain equine estrogens such as equilin and equilenin that are metabolized to the genotoxic catechol 4-hydroxyequilenin (4-OHEN). Auto-oxidation generates the o-quinone form that reacts with dC and dA in oligodeoxynucleotides to form unusual stable cyclic bulky adducts, with four different stereoisomers identified for each base adduct. The dC and dA adducts have the same unsaturated bicyclo[3.3.1]nonane type linkage site with identical stereochemical characteristics. Stereochemical effects may play an important part in the biological consequences of the formation of 4-OHEN-DNA adducts, and the assignment of the absolute configurations of the stereoisomeric 4-OHEN-dC and -dA adducts is therefore needed to understand structure-function relationships. We used density functional theory (DFT) to compute the specific optical rotations and electronic circular dichroism (ECD) spectra of the four 4-OHEN-C stereoisomers, and the results were compared with experimentally measured optical rotatory dispersion (ORD) and ECD spectra. The predicted ORD curves for the four stereoisomeric base adducts reproduced the shapes and signs of experimental spectra in the transparent spectral region. The stereochemistry of the C3' atom was determined by comparison of the calculated and experimental ORD and ECD spectra, and the stereochemistry of C2' was determined by mass spectrometric methods. Combining the ORD and mass spectrometry data, the absolute configurations of the four 4-OHEN-C and the stereochemically identical -dC adducts have been identified. The molecular architecture of the linkage site at the 4-OHEN-C/A and 4-OHEN-dC/dA is identical, and it is shown that the deoxyribose group does not substantially contribute to the optical activities. The absolute configurations of the 4-OHEN-dA adducts were thus deduced by comparing the experimental ORD with computed ORD values of 4-OHEN-A adducts.


Pseudo-trisomy 13 in a fetus: further support for autosomal recessive inheritance.
Pseudo-trisomy 13 is defined in chromosomally normal patients with holoprosencephaly and associating features suggestive of trisomy 13. An autosomal recessive pattern of inheritance for this situation is most likely, but a gene for this condition has not yet been mapped. A fetus is presented with phenotypic features reminiscent of trisomy 13 but a normal karyotype, 46, XY. The pregnancy was terminated due to severe fetal malformations. In autopsy, the fetus had semilobar holoprosencephaly, hydrocephaly and dysmorphic features such as hypotelorism, cleft lip, a flat nose with a single nostril, low-set ears, postaxial polydactyly in all extremities, left unilateral pes equinovarus and pulmonary segmentation defect on the right. The parents were 2nd cousins once removed. Holoprosencephaly and polydactyly with or without other findings in chromosomally normal patients should raise the suspicion of pseudo-trisomy 13 syndrome, particularly when parental consanguinity is present.


Identification and comparison of individual chromosomes of three accessions of Hordeum chilense, Hordeum vulgare, and Triticum aestivum by FISH.
Karyotypes of three accessions of Hordeum chilense (H1, H16, and H7), Hordeum vulgare, and Triticum aestivum were characterized by physical mapping of several repetitive sequences. A total of 14 repetitive sequences were used as probes for fluorescence in situ hybridization (FISH) with the aim of identifying inter- and intraspecies polymorphisms. The (AG)12 and 4P6 probes only produced hybridization signals in wheat, the BAC7 probe only hybridized to the centromeric region of H. vulgare, and the pSc119.2 probe hybridized to both wheat and H. chilense, but not to H. vulgare. The remaining repetitive sequences used in this study produced a hybridization signal in all the genotypes. Probes pAs1, pTa-535, pTa71, CCS1, and CRW were much conserved, showing no significant polymorphism among the genotypes studied. Probes GAA, (AAC)5, (CTA)5, HvT01, and pTa794 produced the most different hybridization pattern. We identified large polymorphisms in the three accessions of H. chilense studied, supporting the proposal of the existence of different groups inside species of H. chilense. The set of probes described in this work allowed the identification of every single chromosome in all three species, providing a complete cytogenetic karyotype of H. chilense, H. vulgare, and T. aestivum chromosomes, which could be useful in wheat and tritordeum breeding programs.


Risk of revision for fixed versus mobile-bearing primary total knee replacements.
Mobile-bearing total knee arthroplasty prostheses were developed to reduce wear and revision rates; however, these benefits remain unproven. The purposes of this study were to compare the short-term survivorship and to determine risk factors for revision of mobile-bearing and fixed-bearing total knee replacements. A prospective cohort study of primary total knee arthroplasties performed from 2001 to 2009 was conducted with use of a community total joint replacement registry. Patient characteristics and procedure details were identified. Cox regression models were used. Bearing type was investigated as a risk factor for revision while adjusted for other risk factors such as age, American Society of Anesthesiologists (ASA) score, body mass index, sex, race, diagnosis, bilateral procedures, cruciate-retaining versus posterior-stabilized components, surgical approach, fixation, patellar resurfacing, hospital and surgeon volumes, and fellowship training. The study cohort consisted of 47,339 total knee arthroplasties, with 62.6% of the procedures in women. Fixed bearings were used in 41,908 knees (88.5%) and mobile bearings in 4830 (10.2%). Rotating-platform designs were used in all mobile-bearing total knee arthroplasties (3112 had a Rotating-Platform Press-Fit Condylar posterior-stabilized design; 1053, a Low Contact Stress [LCS] design; and 665, a Rotating-Platform Press-Fit Condylar cruciate-retaining design). Patients who received fixed-bearing total knee arthroplasty systems were older (mean age, 68.1 years) than those who received mobile-bearing total knee arthroplasty systems (mean age, 62.2 years); the difference was significant (p < 0.001). Overall, 515 knees (1.1%) were revised for reasons other than infection. The survival rate was 97.8% (95% confidence interval [CI], 97.4% to 98.0%) at 6.7 years. The adjusted risk of aseptic revision for the LCS total knee replacements was 2.01 times (95% CI, 1.41 to 2.86) higher than that for fixed-bearing total knee replacements (p < 0.001).There was no significant revision risk for the other mobile-bearing total knee arthroplasty systems. There was no association with surgeon and hospital case volumes and the risk of revision total knee arthroplasty. Our study suggests the benefit of potential long-term wear reduction with the LCS implant may not be realized in a community-based setting, where a variety of surgical skills, surgical experience, and diverse patient demographic factors may affect early outcomes. Therapeutic Level II.


"Saturday night fever": ecstasy related problems in a London accident and emergency department.
To report on the extent and nature of acute MDMA (ecstasy) related problems presenting to a large London hospital's accident and emergency (A&E) department. The computerised attendance records for all patients attending the A&E department over a 15 month period were retrospectively screened. Potential cases thus identified had their case notes systematically reviewed to confirm the history of MDMA use and to extract other relevant data. Forty eight consecutive MDMA related cases were identified. All were in the 15-30 year age group with the majority presenting in the early hours at weekends and having consumed the drug at a night club. The mean number of tablets consumed was two and almost 40% had taken MDMA before. Polydrug use was common with half of the sample having concurrently taken another illicit substance--most commonly other stimulants (amphetamines and cocaine). A wide range of adverse clinical features was found. The most common symptoms were vague and non-specific such as feeling strange or unwell, however many patients had collapsed or lost consciousness. The most common signs elicited were related to sympathetic overactivity, agitation/disturbed behaviour, and increased temperature. The more serious complications of delirium, seizures, and profound unconsciousness (coma) were commoner when MDMA was used in combination with other substances. For young adults presenting late at night at weekends and exhibiting symptoms of sympathetic overactivity, disturbed behaviour, and increased temperature ("Saturday night fever") the use of stimulant dance drugs especially MDMA should be suspected. As MDMA use does not appear to occur in isolation, the clinical picture is likely to be complicated by multiple rather than single drug ingestion. This poses increased diagnostic and management challenges for A&E staff who typically represent the front line response to dance drug related problems.


Intralesional immunotherapy for difficult to treat warts with Mycobacterium w vaccine.
Immunotherapy is an evolving therapeutic modality for the treatment of warts. We conducted a study to assess the efficacy and safety of intralesional Mycobacterium w vaccine for the treatment of warts at sites that were difficult to treat. Thirty patients with at least one wart present on either the plantar surface of their feet, palms, volar aspect of their fingers, or periungual or subungual region, were treated with 0.1 ml of killed Mycobacterium w vaccine given intralesionally in a single wart, without any prior sensitisation dose. Thereafter, a single injection of 0.1 ml of vaccine was given at intervals of four weeks in a single wart till there was complete resolution of the warts or a maximum of 10 injections. Treatment was stopped if there was no response after three injections. The patients were followed up for at least six months. Out of the 30 patients, 28 (93.33%) patients had complete resolution of their warts, both at the injected and distant sites. The mean (SD) time for complete clearance of warts was 43.71(32.82) days and the mean (SD) dose of vaccine that was required for complete clearance of warts was 0.186 ml (0.101). Four patients (14.28%) had a recurrence of warts. The treatment was well-tolerated and the side effects were reversible in the majority of the patients. In comparison to the earlier studies using Mycobacterium w vaccine for the treatment of warts, our study was different in the following aspects: No sensitisation dose was given, only a single wart was injected at a time and the duration between the period of injections was increased to four weeks. With all these changes we eliminated the complications due to the sensitisation dose and achieved good results. This study provides new insight into the dose and schedule of treatment of this evolving therapeutic modality.


Blood pressure, heart rate and neuroendocrine responses to a high carbohydrate and a high fat meal in healthy young subjects.
1. The responses of blood pressure, heart rate, autonomic function and plasma insulin to a high carbohydrate and a high fat meal of equivalent energy value were studied in nine young volunteers. 2. Neither meal produced a significant change in supine or erect blood pressure. The high carbohydrate meal, however, resulted in an overall rise in both supine (6 beats/min) and erect (6 beats/min; P less than 0.05) heart rate, no such changes being seen after the high fat meal. 3. Plasma noradrenaline levels increased by a maximum of 126% at 90 min (0.98 to 2.22 nmol/l) after the high carbohydrate meal but were virtually unchanged after the high fat meal (P less than 0.01). Parasympathetic function showed no between-meal differences. Plasma insulin and glucose levels were significantly higher after the high carbohydrate meal than after the high fat meal. No postprandial difference in packed cell volume was found between meal types. 4. We conclude that, in young subjects, the postprandial blood pressure after a high carbohydrate meal is maintained by an increase in heart rate associated with increased sympathetic nervous system activity. These changes are at variance with the blood pressure and heart rate responses seen in the elderly after a high carbohydrate meal. A high fat meal has no significant cardiovascular or neuroendocrine effects in the young or old. The nutrient composition of meals has to be taken into account when studying the postprandial cardiovascular and neuroendocrine responses in the young.


Assessing risk to birds from industrial wind energy development via paired resource selection models.
When wildlife habitat overlaps with industrial development animals may be harmed. Because wildlife and people select resources to maximize biological fitness and economic return, respectively, we estimated risk, the probability of eagles encountering and being affected by turbines, by overlaying models of resource selection for each entity. This conceptual framework can be applied across multiple spatial scales to understand and mitigate impacts of industry on wildlife. We estimated risk to Golden Eagles (Aquila chrysaetos) from wind energy development in 3 topographically distinct regions of the central Appalachian Mountains of Pennsylvania (United States) based on models of resource selection of wind facilities (n = 43) and of northbound migrating eagles (n = 30). Risk to eagles from wind energy was greatest in the Ridge and Valley region; all 24 eagles that passed through that region used the highest risk landscapes at least once during low altitude flight. In contrast, only half of the birds that entered the Allegheny Plateau region used highest risk landscapes and none did in the Allegheny Mountains. Likewise, in the Allegheny Mountains, the majority of wind turbines (56%) were situated in poor eagle habitat; thus, risk to eagles is lower there than in the Ridge and Valley, where only 1% of turbines are in poor eagle habitat. Risk within individual facilities was extremely variable; on average, facilities had 11% (SD 23; range = 0-100%) of turbines in highest risk landscapes and 26% (SD 30; range = 0-85%) of turbines in the lowest risk landscapes. Our results provide a mechanism for relocating high-risk turbines, and they show the feasibility of this novel and highly adaptable framework for managing risk of harm to wildlife from industrial development.


Fatal canine distemper virus infection of giant pandas in China.
We report an outbreak of canine distemper virus (CDV) infection among endangered giant pandas (Ailuropoda melanoleuca). Five of six CDV infected giant pandas died. The surviving giant panda was previously vaccinated against CDV. Genomic sequencing of CDV isolated from one of the infected pandas (giant panda/SX/2014) suggests it belongs to the Asia-1 cluster. The hemagglutinin protein of the isolated virus and virus sequenced from lung samples originating from deceased giant pandas all possessed the substitutions V26M, T213A, K281R, S300N, P340Q, and Y549H. The presence of the Y549H substitution is notable as it is found at the signaling lymphocytic activation molecule (SLAM) receptor-binding site and has been implicated in the emergence of highly pathogenic CDV and host switching. These findings demonstrate that giant pandas are susceptible to CDV and suggest that surveillance and vaccination among all captive giant pandas are warranted to support conservation efforts for this endangered species.


FunctionAnnotator, a versatile and efficient web tool for non-model organism annotation.
Along with the constant improvement in high-throughput sequencing technology, an increasing number of transcriptome sequencing projects are carried out in organisms without decoded genome information and even on environmental biological samples. To study the biological functions of novel transcripts, the very first task is to identify their potential functions. We present a web-based annotation tool, FunctionAnnotator, which offers comprehensive annotations, including GO term assignment, enzyme annotation, domain/motif identification and predictions for subcellular localization. To accelerate the annotation process, we have optimized the computation processes and used parallel computing for all annotation steps. Moreover, FunctionAnnotator is designed to be versatile, and it generates a variety of useful outputs for facilitating other analyses. Here, we demonstrate how FunctionAnnotator can be helpful in annotating non-model organisms. We further illustrate that FunctionAnnotator can estimate the taxonomic composition of environmental samples and assist in the identification of novel proteins by combining RNA-Seq data with proteomics technology. In summary, FunctionAnnotator can efficiently annotate transcriptomes and greatly benefits studies focusing on non-model organisms or metatranscriptomes. FunctionAnnotator, a comprehensive annotation web-service tool, is freely available online at: http://fa.cgu.edu.tw/ . This new web-based annotator will shed light on field studies involving organisms without a reference genome.


A New Hydroxy Metabolite of 2-Oxoglutarate Regulates Metabolism in Hypoxia.
Two articles in this issue (Intlekofer et al., 2015; Oldham et al., 2015) show a new metabolic pathway regulated by hypoxia, but independently of HIF1 or HIF2. L-2-hydroxyglutarate, produced in hypoxia by malate dehydrogenases and LDHA, is a potent inhibitor of KDM4C, and through redox stress reduces glycolysis.


Making rats rise to erect bipedal stance for feeding partially prevented orchidectomy-induced bone loss and added bone to intact rats.
The objectives of this study were to investigate the different effects on muscle mass and cancellous (proximal tibial metaphysis [PTM]) and cortical (tibial shaft [TX]) bone mass of sham-operated and orchidectomized (ORX) male rats by making rats rise to erect bipedal stance for feeding. Specially designed raised cages (RC) were used so that the rats had to rise to erect bipedal stance to eat and drink for 12 weeks. Dual-energy X-ray absorptiometry (DEXA) and peripheral quantitative computerized tomography (pQCT) were used to estimate the lean leg mass and bone mineral. Static and dynamic histomorphometry were performed on the triple-labeled undecalcified sections. We found that making the intact rats rise to erect bipedal stance for feeding increased muscle mass, cortical bone volume, and periosteal bone formation. Orchidectomy increased net losses of bone next to the marrow by increasing bone turnover. Making the ORX rats rise to erect bipedal stance increased muscle mass, partially prevented cancellous bone loss in the PTM, and prevented net cortical bone loss in TX induced by ORX by depressing cancellous and endocortical high bone turnover and stimulating periosteal bone formation. The bone-anabolic effects were achieved mainly in the first 4 weeks in the PTM and by 8 weeks in the TX. These findings suggested that making the rats rise to erect bipedal stance for feeding helped to increase muscle mass and cortical bone mass in the tibias of intact rats, increase muscle mass, and partially prevented cancellous and net cortical bone loss in ORX rats.


Developmental Potential and Plasticity of Olfactory Epithelium Stem Cells Revealed by Heterotopic Grafting in the Adult Brain.
The neural stem cells (NSCs) residing in the olfactory epithelium (OE) regenerate damaged olfactory sensory neurons throughout adulthood. The accessibility and availability of these NSCs in living individuals, including humans, makes them a promising candidate for harvesting their potential for cell replacement therapies. However, this requires an in-depth understanding of their developmental potential after grafting. Here, we investigated the developmental potential and plasticity of mouse OE-derived NSCs after grafting into the adult subventricular zone (SVZ) neurogenic niche. Our results showed that OE-derived NSCs integrate and proliferate just like endogenous SVZ stem cells, migrate with similar dynamics as endogenous neuroblasts toward the olfactory bulb, and mature and acquire similar electrophysiological properties as endogenous adult-born bulbar interneurons. These results reveal the developmental potential and plasticity of OE-derived NSCs in vivo and show that they can respond to heterotopic neurogenic cues to adapt their phenotype and become functional neurons in ectopic brain regions.


Operative Exposure of a Surgical Trainee at a Tertiary Hospital in Kenya.
Background. Psychomotor domain training requires repetitive exposure in order to develop proficiency in skills. This depends on many training factors in any training institution. Objective. This study sought to look at the operative exposure of surgical trainees in a tertiary hospital in a developing country. Design and Setting. This was a six-month retrospective study performed in one surgical firm at Kenyatta National Hospital. Patients and Methods. The files of all patients admitted to the unit at that time were retrieved. The demographics, diagnosis at admission, need for surgery, and cadre of operating surgeon among others were recorded. Scientific Package for Social Sciences (SPSS) version 17.0 was used for data entry and analysis. Results. The study cohort was 402 patients of the 757 patients admitted in the study period. The average age was 36.7 years, a female to male ratio of 1 : 2.5. The majority (69.7%) of patients required surgery. Trauma was the most common reason for admission (44.5%). Year 2 residents received the most clinical exposure. Consultant was available in only 34.5% of the cases. Conclusion. The junior residents performed the vast majority of procedures with an unsatisfactory amount of supervision from the senior residents and faculty.


Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection.
Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs.


(Poly)cation-induced protection of conventional and wireframe DNA origami nanostructures.
DNA nanostructures hold immense potential to be used for biological and medical applications. However, they are extremely vulnerable towards salt depletion and nucleases, which are common under physiological conditions. In this contribution, we used chitosan and linear polyethyleneimine for coating and long-term stabilization of several three-dimensional DNA origami nanostructures. The impact of the degree of polymerization and the charge density of the polymer together with the N/P charge ratio (ratio of the amines in polycations to the phosphates in DNA) on the stability of encapsulated DNA origami nanostructures in the presence of nucleases and in low-salt media was examined. The polycation shells were compatible with enzyme- and aptamer-based functionalization of the DNA nanostructures. Additionally, we showed that despite being highly vulnerable to salt depletion and nucleolytic digestion, self-assembled DNA nanostructures are stable in cell culture media up to a week. This was contrary to unassembled DNA scaffolds that degraded in one hour, showing that placing DNA strands into a spatially designed configuration crucially affect the structural integrity. The stability of naked DNA nanostructures in cell culture was shown to be mediated by growth media. DNA origami nanostructures kept in growth media were significantly more resistant towards low-salt denaturation, DNase I and serum-mediated digestion than when in a conventional buffer. Moreover, we confirmed that DNA origami nanostructures remain not only structurally intact but also fully functional after exposure to cell media. Agarose gel electrophoresis and negative stain transmission electron microscopy analysis revealed the hybridization of DNA origami nanostructures to their targets in the presence of serum proteins and nucleases. The structural integrity and functionality of DNA nanostructures in physiological fluids validate their use particularly for short-time biological applications in which the shape and structural details of DNA nanodevices are functionally critical.


Solution conformation of the (-)-cis-anti-benzo[a]pyrenyl-dG adduct opposite dC in a DNA duplex: intercalation of the covalently attached BP ring into the helix with base displacement of the modified deoxyguanosine into the major groove.
This paper reports on the combined NMR-molecular mechanics computational studies of the solution structure of the (-)-cis-anti-[BP]dG adduct positioned opposite dC in the sequence context d(C1- C2-A3-T4-C5-[BP]G6-C7-T8-A9-C10-C11).d(G12-G13-T14- A15-G16-C17-G18-A19-T20- G21-G22) duplex [designated (-)-cis-anti-[BP]dG.dC 11-mer duplex]. This adduct is derived from cis addition at C10 of (-)-anti-7(S),8(R)-dihydroxy-9(R),10(S)-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene [(-)-anti-BPDE] to the N2 position of dG6 in this duplex sequence. The exchangeable and nonexchangeable protons of the benzo[a]pyrenyl moiety and nucleic acid of the major conformation were assigned following analysis of two-dimensional NMR data sets in H2O and D2O solution. There was a general broadening of proton resonances for a three-nucleotide segment centered about the lesion site which resulted in a tentative assignment for the sugar protons of the C7 residue in the spectrum of the adduct duplex. The solution conformation of the major conformation of the (-)-cis-anti-[BP]dG.dC 11-mer duplex has been determined by incorporating DNA-DNA and intermolecular BP-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results establish that the covalently attached benzo[a]pyrenyl ring intercalates between intact Watson-Crick dC5.dG18 and dC7.dG16 base pairs. The modified deoxyguanosine [BP]-dG6 and its partner cytosine dC17 are looped out of the helix into the major groove. The purine ring of the [BP]dG6 residue is directed toward the 5'-end of the modified strand and stacks over the major groove edge of its 5'-side neighbor dC5 residue. The solution structure of the (-)-cis-anti-[BP]dG.dC 11-mer duplex is compared with those of the stereoisomeric (+)-trans-anti-[BP]dG [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918], (-)-trans-anti-[BP]dG [de los Santos, C., et al. (1992) Biochemistry 31, 5245-5252], and (+)-cis-anti-[BP]dG [Cosman, M., et al. (1993a) Biochemistry 32, 4146-4155] adducts positioned opposite dC in the same duplex sequence context. A key finding is that the long axes of the intercalated benzo[a]pyrenyl rings in the solution structures of the (+)- and (-)- cis-anti-[BP]dG.dC 11-mer duplexes are oriented in opposite directions with the benzylic ring directed toward the minor groove in the (+)-cis isomer and toward the major groove in the (-)-cis isomer. In addition, a comparison is also made with the solution structure of the (+)-trans-anti-[BP]dG adduct opposite a deletion site [Cosman, M., et al. (1994a) Biochemistry 33, 11507-11517] since this adduct duplex displays several conformational features in common with the structure of the (-)-cis-anti-[BP]dG.dC 11-mer duplex. The structures of both duplex adducts exhibit intercalation of the covalently attached ligand into the helix and displacement of the modified deoxyguanosine into the major groove. Studies of the biological activities of stereochemically defined BP-DNA adducts and the comparison of the solution structure of the (-)-cis-anti-[BP]dG.dC 11-mer duplex with its stereoisomeric counterparts should lead to new insights into the relationships between defined helical distortions and mutagenic specificity and activity.


Fabrication of surface magnetic nanoclusters using low energy ion implantation and electron beam annealing.
Magnetic nanoclusters have novel applications as magnetic sensors, spintronic and biomedical devices, as well as applications in more traditional materials such as high-density magnetic storage media and high performance permanent magnets. We describe a new synthesis protocol which combines the advantages of ion implantation and electron beam annealing (EBA) to produce surface iron nanoclusters. We compare the structure, composition and magnetic properties of iron nanoclusters fabricated by low dose 15 keV Fe implantation into SiO(2) followed by 1000 °C EBA or furnace annealing. Atomic force microscopy (AFM) and high resolution transmission electron microscopy (HRTEM) images together with superconducting quantum interference device (SQUID) magnetometry measurements show that only EBA leads to the rapid formation of surface crystalline Fe spherical nanoclusters, showing magnetic moments per Fe atom comparable to that of bulk bcc Fe and superparamagnetic properties. We propose a fabrication mechanism which includes e-beam enhanced desorption of SiO(2). This method has potential for fabricating nanoscale magnetic sensors integrated in microelectronic devices.


Subacute Presentation of Central Cord Syndrome Resulting from Vertebral Osteomyelitis and Discitis: A Case Report.
Central cord syndrome (CCS) is a clinical syndrome of motor weakness and sensory changes. While CCS is most often associated with traumatic events. There have been few documented cases being caused by abscesses resulting from osteomyelitis. A 56-year-old male presented to a regional trauma center complaining of excruciating neck and bilateral upper extremity pain. Computed tomography of the cervical and thoracic regions revealed severe discitis and osteomyelitis of the fourth and fifth cervical (C4-C5) with near-complete destruction of the C4 vertebral body, as well as anterolisthesis of C4 on C5 causing compression of the central canal. Empiric intravenous (IV) antibiotic therapy with ampicillin/sulbactam and vancomycin was initiated, and drainage of the abscess was scheduled. After the patient refused surgery, he was planned to be transferred to a skilled nursing facility to receive a six-week course of IV vancomycin therapy. A month later, patient returned to emergency department with the same complaint due to non-compliance with antibiotic therapy. Delayed diagnosis and treatment of osteomyelitis can result in devastating neurological sequelae, and literature supports immediate surgical debridement. Although past evidence has suggested surgical intervention in similar patients with presence of abscesses, this case may suggest that antibiotic treatment may be an alternative approach to the management of CCS due to an infectious etiology. However, the patient had been non-compliant with medication, so it is unknown whether there was definite resolution of the condition. In patients presenting with non-traumatic central cord syndrome, it is vital to identify risk factors for infection in a thoroughly obtained patient history, as well as to maintain a low threshold for diagnostic imaging.


The Pittsburgh insulin-dependent diabetes mellitus (IDDM) registry. The incidence of insulin-dependent diabetes mellitus in Allegheny County, Pennsylvania (1965-1976).
An insulin-dependent Diabetes Mellitus Registry has been developed in Allegheny County, Pennsylvania, through hospital record review and surveillance of pediatric practices. The yearly incidence ranged from 10/100,000 for nonwhite males to 16/100,000 for white males. There were no temporal trends in incidence for 1965-1976 nor major sex differences. Nonwhites had a slightly lower incidence, primarily in the younger age groups.


Pixel-wise assessment of cardiovascular magnetic resonance first-pass perfusion using a cardiac phantom mimicking transmural myocardial perfusion gradients.
Cardiovascular magnetic resonance first-pass perfusion for the pixel-wise detection of coronary artery disease is rapidly becoming the clinical standard, yet no widely available method exists for its assessment and validation. This study introduces a novel phantom capable of generating spatially dependent flow values to enable assessment of new perfusion imaging methods at the pixel level. A synthetic multicapillary myocardial phantom mimicking transmural myocardial perfusion gradients was designed and manufactured with high-precision 3D printing. The phantom was used in a stationary flow setup providing reference myocardial perfusion rates and was scanned on a 3T system. Repeated first-pass perfusion MRI for physiological perfusion rates between 1 and 4 mL/g/min was performed using a clinical dual-sequence technique. Fermi function-constrained deconvolution was used to estimate pixel-wise perfusion rate maps. Phase contrast (PC)-MRI was used to obtain velocity measurements that were converted to perfusion rates for validation of reference values and cross-method comparison. The accuracy of pixel-wise maps was assessed against simulated reference maps. PC-MRI indicated excellent reproducibility in perfusion rate (coefficient of variation [CoV] 2.4-3.5%) and correlation with reference values (R2 = 0.985) across the full physiological range. Similar results were found for first-pass perfusion MRI (CoV 3.7-6.2%, R2 = 0.987). Pixel-wise maps indicated a transmural perfusion difference of 28.8-33.7% for PC-MRI and 23.8-37.7% for first-pass perfusion, matching the reference values (30.2-31.4%). The unique transmural perfusion pattern in the phantom allows effective pixel-wise assessment of first-pass perfusion acquisition protocols and quantification algorithms before their introduction into routine clinical use.


Interleaving bisection stimuli - randomly or in sequence - does not disrupt perceptual learning, it just makes it more difficult.
Presenting stimuli of two or more stimulus types randomly interleaved, so called roving, disrupts perceptual learning in many paradigms. Recently, it was shown that no disruption occurs when Gabor stimuli were presented interleaved in sequence, instead of randomly. Here, using bisection stimuli, we found the opposite pattern of results. Presenting bisection stimuli in a sequence disrupted perceptual learning, whereas we found improvement under roving conditions. A meta-analysis showed that parts of this deviation from previous studies is possibly caused by the initial performance level of participants. These results do not prove previous results wrong, they just show that multiple factors play a crucial role in perceptual learning which cannot always be easily controlled for.


The influence of temporary blockage of semicircular canals on the loss and recovery of vestibuloocular reflexes.
The efficacy of the technique of semicircular canal plugging in selectively blocking the function of individual semicircular canals was evaluated in rabbits. The horizontal and vertical vestibuloocular reflexes (HVOR, VVOR) and the horizontal optokinetic reflex (HOKR) were measured before the horizontal or anterior semicircular canals (HSCs, ASCs) were plugged bilaterally with small spindles of silver wire. These reflexes were also measured after the plugs were removed. The gain of the HVOR was reduced to less than 0.05 at all frequencies tested after plugs were inserted into the HSCs. The gain of the HOKR was not influenced by the plugging operation. These data were interpreted to mean that the plugs blocked the normal fluid dynamics of the HSCs, but did not alter the spontaneous activity of HSC afferents. The gain of the VVOR was not reduced by plugs of the HSCs. The gain of the VVOR was reduced by plugs of the ASCs. The residual VVOR was attributed to stimulation of the utricular otoliths at lower frequencies and stimulation of the posterior semicircular canals at higher frequencies. The gain of the HVOR was reduced 10-40% by plugs of the ASCs. These data, in conjunction with the presence of a small residual gain of the HVOR following bilateral plugs of the HSCs, suggest that the ASCs contribute to the HVOR. The gains of the HVOR and VVOR recovered to within 88% of the preplug values once the plugs of the HSCs or ASCs were removed. However, the protracted time course of this recovery, 10-15 d, indicated that the plugging operation, although reversible, does cause some temporary damage to the peripheral labyrinth.


Accelerated spike resampling for accurate multiple testing controls.
Controlling for multiple hypothesis tests using standard spike resampling techniques often requires prohibitive amounts of computation. Importance sampling techniques can be used to accelerate the computation. The general theory is presented, along with specific examples for testing differences across conditions using permutation tests and for testing pairwise synchrony and precise lagged-correlation between many simultaneously recorded spike trains using interval jitter.


Additional fossil evidence on the differentiation of the earliest euprimates.
Several well-preserved jaws of the rare North American omomyid primate Steinius vespertinus, including the first known antemolar dentitions, have been discovered in 1989 and 1990 in the early Eocene Willwood Formation of the Bighorn Basin, Wyoming. They indicate that its dental formula is as primitive as those in early Eocene Donrussellia (Adapidae) and Teilhardina (Omomyidae)--widely considered to be the most primitive known euprimates--and that in various dental characters Steinius is as primitive or more so than Teilhardina. Therefore, despite its occurrence at least 2 million years later than Teilhardina, S. vespertinus is the most primitive known omomyid and one of the most primitive known euprimates. Its primitive morphology further diminishes the dental distinctions between Omomyidae and Adapidae at the beginning of the euprimate radiation


Bacterial scaffolds assemble novel higher-order complexes to reengineer eukaryotic cell processes.
Many microbial pathogens use specialized secretion systems to inject proteins referred to as effectors directly into eukaryotic host cells. These effectors directly target various eukaryotic signaling pathways and cellular processes, often by mimicking the activity of host cell proteins. Effectors of pathogenic Escherichia coli and Salmonella typhimurium can also act as molecular scaffolds that not only recruit but also directly regulate the activity and localization of multiple eukaryotic proteins. By assembling and localizing disparate signaling pathways, the bacteria can reengineer host cell processes to generate novel processes not previously observed in eukaryotic cells.


Epigenetic biomarkers: a step forward for understanding periodontitis.
Periodontitis is a common oral disease that is characterized by infection and inflammation of the tooth supporting tissues. While its incidence is highly associated with outgrowth of the pathogenic microbiome, some patients show signs of predisposition and quickly fall into recurrence after treatment. Recent research using genetic associations of candidates as well as genome-wide analysis highlights that variations in genes related to the inflammatory response are associated with an increased risk of periodontitis. Intriguingly, some of the genes are regulated by epigenetic modifications, supposedly established and reprogrammed in response to environmental stimuli. In addition, the treatment with epigenetic drugs improves treatment of periodontitis in a mouse model. In this review, we highlight some of the recent progress identifying genetic factors associated with periodontitis and point to promising approaches in epigenetic research that may contribute to the understanding of molecular mechanisms involving different responses in individuals and the early detection of predispositions that may guide in future oral treatment and disease prevention.


Site of action of grayanotoxins in mad honey in rats.
Grayanotoxins are known to occur in honey produced from the nectar of Rhododendrons of the family Ericaceae. Grayanotoxins extracted from honey sample obtained from a patient who experienced severe bradycardia and hypotension after ingesting two tablespoonfuls corresponded to Rhododendron ponticum tetrades. Anaesthetized albino rats were injected with honey extract intracerebroventricularly or intraperitoneally. The intracerebroventricular dose was equivalent to 50 mg honey and i.p. doses were equivalent to 50 mg, 1 mg kg-1 and 5 g kg-1 honey. Marked bradycardia and respiratory rate depression were observed in rats injected with extract equivalent to 1 and 5 g kg-1 honey i.p. and in rats injected with 50 mg i.c.v., but not in rats given 50 mg i.p. In bilaterally vagotomized animals, grayanotoxin-contaminated honey extract was not bradycardic. These results suggest that the sites of cardiac and respiratory actions are within the central nervous system, and that the bradycardic effect of grayanotoxin is mediated by vagal stimulation at the periphery.


Inhibitory effects of calycosin isolated from the root of Astragalus membranaceus on melanin biosynthesis.
Tyrosinase is a key enzyme for melanin biosynthesis, and hyperpigmentation disorders are associated with abnormal accumulation of melanin pigments, which can be reduced by treatment with depigmenting agents. A methanol extract of Astragalus membranaceus showed inhibitory activity against mushroom tyrosinase. The active compound was purified from the methanol extract of A. membranaceus and, following several chromatographic methods, was identified as calycosin via spectroscopic analysis. The results showed that calycosin exhibited tyrosinase inhibitory activity with an IC(50) value of 38.4 microM. Moreover, calycosin showed a melanin biosynthesis inhibition zone in a culture plate of Streptomyces bikiniensis, which is commonly used as an indicator organism. Furthermore, calycosin dramatically reduced melanin synthesis of Melan-a cells without any apparent cytotoxicity and reduced expression of melanogenic enzyme, tyrosinase. These results suggest that calycosin may be an effective skin-lightening agent that regulates the expression of melanogenic enzymes.


Content Validity Index and Intra- and Inter-Rater Reliability of a New Muscle Strength/Endurance Test Battery for Swedish Soldiers.
The objective of this study was to examine the content validity of commonly used muscle performance tests in military personnel and to investigate the reliability of a proposed test battery. For the content validity investigation, thirty selected tests were those described in the literature and/or commonly used in the Nordic and North Atlantic Treaty Organization (NATO) countries. Nine selected experts rated, on a four-point Likert scale, the relevance of these tests in relation to five different work tasks: lifting, carrying equipment on the body or in the hands, climbing, and digging. Thereafter, a content validity index (CVI) was calculated for each work task. The result showed excellent CVI (≥0.78) for sixteen tests, which comprised of one or more of the military work tasks. Three of the tests; the functional lower-limb loading test (the Ranger test), dead-lift with kettlebells, and back extension, showed excellent content validity for four of the work tasks. For the development of a new muscle strength/endurance test battery, these three tests were further supplemented with two other tests, namely, the chins and side-bridge test. The inter-rater reliability was high (intraclass correlation coefficient, ICC2,1 0.99) for all five tests. The intra-rater reliability was good to high (ICC3,1 0.82-0.96) with an acceptable standard error of mean (SEM), except for the side-bridge test (SEM%>15). Thus, the final suggested test battery for a valid and reliable evaluation of soldiers' muscle performance comprised the following four tests; the Ranger test, dead-lift with kettlebells, chins, and back extension test. The criterion-related validity of the test battery should be further evaluated for soldiers exposed to varying physical workload.


In vitro characterization and in vivo behavior of human nucleus pulposus and annulus fibrosus cells in clinical-grade fibrin and collagen-enriched fibrin gels.
The intervertebral disc (IVD) presents a limited self-repair ability and cell-based therapies have been suggested to prevent or treat IVD lesions. Fibrin-based scaffolds as cell carriers are promising candidates in IVD tissue engineering, thanks to their ability to be easily delivered into the defect and to adapt to the lesion shape, to support/retain the injected cells into the implantation site and to favor the production of a suitable extracellular matrix (ECM). We evaluated the in vitro and in vivo behavior of human nucleus pulposus (NP) and annulus fibrosus (AF) cells in a clinical-grade collagen-enriched fibrin that has never been tested before for orthopedic applications, comparing it with clinical-grade fibrin. The survival of IVD cells seeded within fibrin or collagen-enriched fibrin and the ECM synthesis were evaluated by biochemical, immunohistochemical, and transcriptional analyses, prior and after subcutaneous implantation of the gels in nude mice. After 28 days of implantation, NP and AF cells were still detectable within explants, produced tissue-specific ECM, and showed a higher content of glycosaminoglycans (GAGs) and type I and II collagen compared to gels before implantation. Both the fibrin gels, enriched or not with collagen, seemed to be suitable for the culture of AF cells, being able to support the homogeneous synthesis of type I collagen, characteristic of the native fibrocartilaginous AF tissue. Differently, fibrin alone was a more suitable matrix for NP culture, supporting the homogeneous deposition of GAGs and type II collagen. In conclusion, our results suggest to combine AF cells with fibrin, enriched or not with collagen, and NP cells with fibrin alone to maintain the typical features of these cell populations, indicating these clinical-grade materials as viable options in cell-based treatments for IVD lesions.


Disability identity development model: Voices from the ADA-generation.
For persons with disabilities, 2015 was a historic year, marking the 25th anniversary of the Americans with Disability Act (ADA) and the 40th anniversary of the passing of the Individuals with Disabilities Education Act (IDEA). It is important to consider the effects of this fundamental shift towards equal opportunity and participation on persons with disabilities' identity development. In practice, however, there are few empirical studies that have looked at this phenomenon and even fewer models of disability identity development. We conducted a qualitative study to explore the disability identity development of college students with disabilities. At two research sites, we conducted individual interviews and observations with 17 college students with varying disabilities, and used in vivo and structural coding analysis to identify and develop themes. The results of this study led to establishing a model of psychosocial identity development for individuals with disabilities. The model highlights four developmental statuses: acceptance, relationship, adoption and engagement. Sharing voices from the participants themselves, we also provide commentary on the possible impacts of this work for healthcare professionals and areas for future research. Our findings suggest that this model of psychosocial disability identity development can help to provide an understanding of the psychological processes that individuals with disabilities go through. The model also has application as a framework for healthcare professionals and psychologists who are working with individuals with disabilities.


Laser treatment of solar lentigines on dorsum of hands: QS Ruby laser versus ablative CO2 fractional laser - a randomized controlled trial.
Lentigines solares (LS) on the dorsum of hands are often esthetically disturbing. Q-switched ruby laser treatment is highly effective in the treatment of these lesions. Ablative fractional photothermolysis may be a suitable alternative. We compared the Q-switched ruby laser with ablative CO2 fractional photothermolysis for the treatment of solar lentigines. To evaluate the efficacy and side-effects of 694nm Q-switched ruby laser (Sinon) with the ablative 10,600nm CO2 fractional laser (Quantel Excel O2) in an intra-individual side-to-side comparison in the treatment of LS on the dorsum of hands. Eleven patients were included in the study. The hands of each patient were randomized for treatment with the two laser systems. Three treatment sessions were scheduled at weeks 0, 4 and 8. Evaluations by patients, treating physician and blinded experts were scheduled at weeks 0, 4, 8, 16 and 24. The Q-switched ruby laser was significantly more efficacious than the ablative CO2 fractional laser for removing LS on the dorsum of hands (p = 0.01). In this first study on this topic, the Q-switched ruby laser was superior to the ablative CO2 fractional laser in the treatment of lentigines solares on the dorsum of hands.