Does race influence the provision of care to persons with sickle cell disease? Perceptions of multidisciplinary providers.
This study examined whether multidisciplinary health care providers (HCPs) perceived race of persons with sickle cell disease (SCD) as an influence in the delivery of health care. A total of 227 multidisciplinary HCPs completed the three-item Influence of Patient Race on Provision of Health Care Services Index (Cronbach's alpha = 0.77). Results suggest that African American HCPs were more likely to perceive race as an influence along all scale items, whereas Caucasian and other race HCPs did not. Female HCPs and those who serve adults were more likely than male HCPs and those who serve children to perceive race as having an influence on the quality of health care. Findings suggest a need for the examination of the health care delivery systems in which persons with SCD receive care to determine if race does, in fact, affect the delivery of health care and to explain the discrepancies in the perceptions of the HCPs.


Lipolysis and lactate production in human skeletal muscle and adipose tissue following glucose ingestion.
1. Using microdialysis, we compared lipolysis, as well as the production of lactate, in human adipose tissue and muscle after the ingestion of carbohydrate. 2. The absolute concentrations of glycerol and lactate were measured in subcutaneous adipose tissue, skeletal muscle and arterialized venous blood in eight normal subjects during basal conditions and 4 h after a 75 g oral glucose load. Nutritive blood flow in muscle and adipose tissue was monitored simultaneously with the microdialysis ethanol clearance technique. 3. At baseline, the concentrations of glycerol in adipose tissue and in muscle were about 7 times and about 2.5 times higher respectively than those in plasma. After glucose ingestion, the changes in glycerol concentrations differed significantly between the three compartments (P < 0.0001). In plasma and adipose tissue, the concentrations decreased rapidly and markedly, but returned to baseline levels after 4 h. In muscle, the decrease in glycerol was less pronounced and more protracted. 4. At baseline, the concentrations of lactate in muscle and in adipose tissue were about 3 times and about 1.5 times higher respectively than those in plasma. After the ingestion of glucose, the levels increased transiently in similar ways in muscle, adipose tissue and plasma. The differences in absolute lactate concentrations between the three compartments were maintained after the glucose load (P < 0.001). 5. Adipose tissue blood flow increased transiently after glucose ingestion, whereas muscle blood flow remained unchanged. 6. Both muscle and adipose tissue are a source of glycerol and lactate release during basal conditions and after glucose ingestion. The regulation of lactate production, but not of lipolysis, after carbohydrate ingestion is similar in the two tissues.


Assessment of population genetic structure in the arbovirus vector midge, Culicoides brevitarsis (Diptera: Ceratopogonidae), using multi-locus DNA microsatellites.
Bluetongue virus (BTV) is a major pathogen of ruminants that is transmitted by biting midges (Culicoides spp.). Australian BTV serotypes have origins in Asia and are distributed across the continent into two distinct episystems, one in the north and another in the east. Culicoides brevitarsis is the major vector of BTV in Australia and is distributed across the entire geographic range of the virus. Here, we describe the isolation and use of DNA microsatellites and gauge their ability to determine population genetic connectivity of C. brevitarsis within Australia and with countries to the north. Eleven DNA microsatellite markers were isolated using a novel genomic enrichment method and identified as useful for genetic analyses of sampled populations in Australia, northern Papua New Guinea (PNG) and Timor-Leste. Significant (P < 0.05) population genetic subdivision was observed between all paired regions, though the highest levels of genetic sub-division involved pair-wise tests with PNG (PNG vs. Australia (FST = 0.120) and PNG vs. Timor-Leste (FST = 0.095)). Analysis of multi-locus allelic distributions using STRUCTURE identified a most probable two-cluster population model, which separated PNG specimens from a cluster containing specimens from Timor-Leste and Australia. The source of incursions of this species in Australia is more likely to be Timor-Leste than PNG. Future incursions of BTV positive C. brevitarsis into Australia may be genetically identified to their source populations using these microsatellite loci. The vector's panmictic genetic structure within Australia cannot explain the differential geographic distribution of BTV serotypes.


Expanding Alternative Splicing Identification by Integrating Multiple Sources of Transcription Data in Tomato.
Tomato (Solanum lycopersicum) is an important vegetable and fruit crop. Its genome was completely sequenced and there are also a large amount of available expressed sequence tags (ESTs) and short reads generated by RNA sequencing (RNA-seq) technologies. Mapping transcripts including mRNA sequences, ESTs, and RNA-seq reads to the genome allows identifying pre-mRNA alternative splicing (AS), a post-transcriptional process generating two or more RNA isoforms from one pre-mRNA transcript. We comprehensively analyzed the AS landscape in tomato by integrating genome mapping information of all available mRNA and ESTs with mapping information of RNA-seq reads which were collected from 27 published projects. A total of 369,911 AS events were identified from 34,419 genomic loci involving 161,913 transcripts. Within the basic AS events, intron retention is the prevalent type (18.9%), followed by alternative acceptor site (12.9%) and alternative donor site (7.3%), with exon skipping as the least type (6.0%). Complex AS types having two or more basic event accounted for 54.9% of total AS events. Within 35,768 annotated protein-coding gene models, 23,233 gene models were found having pre-mRNAs generating AS isoform transcripts. Thus the estimated AS rate was 65.0% in tomato. The list of identified AS genes with their corresponding transcript isoforms serves as a catalog for further detailed examination of gene functions in tomato biology. The post-transcriptional information is also expected to be useful in improving the predicted gene models in tomato. The sequence and annotation information can be accessed at plant alternative splicing database (http://proteomics.ysu.edu/altsplice).


Potentiated antitumor effects of butyrate and actinomycin D in melanoma model in mice.
Butyrate and butyric acid derivatives are well known to induce differentiation and apoptosis of tumor cells and have also recently gained acceptance as potential anticancer agents. In this study we observed an increased expression of mTNFalpha in tumor tissues in mice treated with butyrate prodrug tributyrin. Since in in vitro experiments we observed a potentiating effects of TNFalpha and actinomycin D on B16F10 cells and also a synergistic interaction was previously claimed between those agents, we investigated the anti-tumor activity of the combination therapy with butyrate and actinomycin D in the B16F10 melanoma model in mice. The combination of the drugs resulted in a strongly potentiated tumor growth retardation in melanoma bearing mice. However the B16F10 cells in vitro did not produce any detectable amounts of TNFalpha. The presented data strongly suggest that one of the mechanism of this successful drug combination could depend on the interaction of the actinomycin D with butyrate-induced TNFalpha produced by stromal or tumor infiltrating immune cells. The results illustrate also the possible application of this combination in cancer therapy.


Elastosonographic evaluation after extracorporeal shockwave treatment in plantar fasciopathy.
To assess the ultrasound features in patients with plantar fasciopathy before and after extracorporeal shock waves therapy (ESWT), using conventional grey-scale imaging and both strain (SE) and shear wave (SWE) elastosonographic evaluation. Consecutive patients of both sexes attending our outpatient's clinic, with diagnosis of unilateral plantar fasciopathy, were enrolled. Patients were treated with 3 sessions of ESWT once a week, and underwent clinical and ultrasound evaluation at baseline and at one and three months after treatment. Roles and Maudsley score (RM), visual analog scale (VAS) and 17-Italian Foot Function Index (FFI), were used to assess pain and functional improvement. Twenty patients (11 female and 9 male) were enrolled in the study. Contralateral asymptomatic healthy plantar fascia was used as a control. At baseline, SWE velocity (SWEv) showed statistically significant difference between affected 3.8 (1.5; 5.1) m/s and healthy side 4.7 (4.07; 7.04) m/s, (p=0.006); no significant difference was found for strain ratio values (p=0.656). SWEv post hoc test results showed a significant difference from baseline 3.8 (1.5-5.1) m/s and three month 5.23 (4.55-6.74) m/s follow up visit (p=0.003). Significant statistical negative correlation was found between the SWEv and VAS (p=0.001) and positive correlation between the SWEv and FFI (p=0.012). SWE was effective in assessing plantar fascia elasticity and its alteration in fasciopathy. Furthermore, on the basis of the correlation with pain and functional scales, this technique appears to be a useful additional technique to conventional ultrasound for monitoring the efficacy of treatment.


Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.
Periodic endoscopic screening for oesophageal varices is recommended in patients with cirrhosis, but might be limited to a subgroup of patients if a simple non-invasive test was available to select those at risk of bleeding. We studied in 165 patients with cirrhosis the relation between the presence of oesophageal varices assessed by endoscopy, and liver stiffness measurement by Fibroscan, a non-invasive parameter related to liver fibrosis. The results were compared to those of other parameters reflecting portal hypertension, splenic size, platelet count, and platelet count/spleen size ratio. Liver stiffness measurement was correlated to the grade of oesophageal varices (r = 0.6, p < 0.0001). AUROC values of liver stiffness measurement were 0.84 (95% CI: 0.78-0.90) for the presence of oesophageal varices and 0.83 (0.76-0.89) for varices grade > or = II. Liver stiffness measurement value < 19 kPa was highly predictive of the absence of oesophageal varices grade > or = II (Se: 84%, PPV: 47%, NPV: 93%). Liver stiffness measurement allows to predict the presence of large oesophageal varices in patients with cirrhosis, and may help to select patients for endoscopic screening.


Adenovirus-vector-mediated cytokine gene transfer to lung tissue.
In summary, we have been able to demonstrate that adenovirus vectors are valuable tools in examining the roles played by individual cytokines in lung responses and inflammation. These viral vectors have marked trophism for the epithelial cells of the lung and are highly efficient in transferring the genes into these lining cells. This results in significant expression of cytokines both within the lumen and the parenchyma of the lung. As a result of an individual cytokine being overexpressed, there are cytokine-specific changes seen-IL-6 resulting in lymphocytosis, MIP2 resulting in neutrophil accumulation, RANTES resulting in monocyte accumulation, TGF beta resulting in monocytosis but no fibrosis, and GM-CSF most surprisingly resulting in tissue eosinophilia, granuloma formation, and subsequently the onset of fibrosis. These vectors have helped pinpoint the role of a number of the cytokines in inducing chronic inflammatory changes to the lung and imply that a single cytokine may not be the only trigger resulting in chronic changes within the lung parenchyma.


Physicians' personal values in determining medical decision-making capacity: a survey study.
Decision-making capacity (DMC) evaluations are complex clinical judgements with important ethical implications for patients' self-determination. They are achieved not only on descriptive grounds but are inherently normative and, therefore, dependent on the values held by those involved in the DMC evaluation. To date, the issue of whether and how physicians' personal values relate to DMC evaluation has never been empirically investigated. The present survey study aimed to investigate this question by exploring the relationship between physicians' value profiles and the use of risk-relative standards in capacity evaluations. The findings indicate that physicians' personal values are of some significance in this regard. Those physicians with relatively high scores on the value types of achievement, power-resource, face and conformity to interpersonal standards were more likely to apply risk-relative criteria in a range of situations, using more stringent assessment standards when interventions were riskier. By contrast, those physicians who strongly emphasise hedonism, conformity to rules and universalism concern were more likely to apply equal standards regardless of the consequences of a decision. Furthermore, it has been shown that around a quarter of all respondents do not appreciate that their values impact on their DMC evaluations, highlighting a need to better sensitise physicians in this regard. The implications of these findings are discussed, especially in terms of the moral status of the potential and almost unavoidable influence of physicians' values.


The upregulated expression of vascular endothelial growth factor in surgically treated patients with recurrent/radioresistant cervical cancer of the uterus.
Vascular endothelial growth factor (VEGF) inhibitors have been utilized for the treatment against advanced or recurrent cervical carcinoma as a novel therapeutic modality. However, the expression level of VEGF in post-radiotherapy relapsed/persistent cervical cancer remains to be elucidated. The aim of the present study was to investigate the expression of VEGF and associated molecules using tumor samples from patients with post-radiotherapy relapsed/persistent cervical cancer. From a database of 826 patients who were treated at our institution between 2003 and 2015, eight patients with post-radiotherapy relapsed/persistent cervical cancer were identified, and 20 patients who underwent initial surgery alone were used as a control. Using samples from these patients, the expression levels of VEGF-A, VEGF receptor-1 (VEGFR-1) and hypoxia inducible factor-1α (HIF-1α) were immunohistochemically categorized as negative or weakly, moderately, or strongly positive according to the size of the staining area, and intensity. In carcinoma cells, the expression levels of VEGF-A, VEGFR-1 and HIF-1α were significantly higher in post-radiotherapy relapsed/persistent cervical cancer compared with control patients (P=0.0003, 0.0003, and 0.0001, respectively). In stroma cells, similar tendencies with statistical significance were observed (P=0.0014 and P<0.0001, respectively). In addition, the expression levels of VEGF-A and VEGFR-1 in carcinoma cells were significantly correlated with each other (P<0.0001). A significantly higher expression of VEGF was identified in post-radiotherapy relapsed/persistent cervical cancer compared with typical specimens from cervical cancer. The findings provide a novel insight into the clinical treatment for recurrent/persistent cervical cancer using a VEGF antagonist.


Potential underestimation of the internal target volume (ITV) from free-breathing CBCT.
Localization prior to delivery of SBRT to free-breathing patients is performed by aligning the planning internal target volume (ITV) from 4DCT with an on-board free-breathing cone-beam CT (FB-CBCT) image. The FB-CBCT image is assumed to also generate an ITV that captures the full range of motion, due to the acquisition spanning multiple respiratory cycles. However, the ITV could potentially be underestimated when the ratio of time spent in inspiration versus time spent in expiration (I/E ratio) deviates from unity. Therefore, the aim of this study was to investigate the effect of variable I/E ratios on the FB ITV generated from a FB-CBCT scan. This study employed both phantom and patient imaging data. For the phantom study, five periodic respiratory cycles were simulated with different I/E ratios. Six patient respiratory cycles with variable I/E ratios were also selected. All profiles were then programmed into a motion phantom for imaging and modified to exhibit three peak-to-peak motion amplitudes (0.5, 1.0, and 2.0 cm). Each profile was imaged using two spherical targets with 1.0 and 3.0 cm diameters. 2D projections were acquired with full gantry rotation of a kiloVoltage (kV) imager mounted onto the gantry of a modem linear accelerator. CBCT images were reconstructed from 2D projections using a standard filtered back-projection reconstruction algorithm. Quantitative analyses for the phantom study included computing the change in contrast along the direction of target motion as well as determining the area (which is proportional to the target volume) inside of the contour extracted using a Canny edge detector. For the patient study, projection data that were previously acquired under an investigational 4D CBCT slow-gantry imaging protocol were used to generate both FB-CBCT and 4D CBCT images. Volumes were then manually contoured from both datasets (using the same window and level) for quantitative comparison. The phantom study indicated a reduction in contrast at the inferior edge of the ITV (corresponding to inspiration) as the ratio decreased, for both simulated and patient respiratory cycles. For the simulated phantom respiratory cycles, the contrast reduction of the smallest I/E ratio was 27.6% for the largest target with the smallest amplitude and 89.7% for the smallest target with the largest amplitude. For patient respiratory cycles, these numbers were 22.3% and 94.0%, respectively. The extracted area from inside of the target contours showed a decreasing trend as the I/E ratio decreased. In the patient study, the FB-CBCT ITVs of both lung tumors studied were underestimated when compared with their corresponding 4D CBCT ITV. The underestimations found were 40.1% for the smaller tumor and 24.2% for the larger tumor. The ITV may be underestimated in a FB-CBCT image when a patient's respiratory pattern is characterized by a disparate length of time spent in inspiration versus expiration. Missing the full target motion information during on-board verification imaging may result in localization errors.


Clinical characteristics of peanut allergy.
Current clinical advice regarding peanut allergy is based on small series of patients. To determine, in a large group of peanut allergic subjects, the patterns of clinical severity, symptom progression and availability and use of rescue medications. Questionnaire study of 622 self-reported allergic subjects. A total of 406 patients (66%) reported symptoms on contact with peanut. Only 121 (19%) had been knowingly exposed to peanut before the first documented reaction, implying a high frequency of occult sensitization. Severe symptoms were more common in adults. Abdominal symptoms were significantly associated with collapse. Fifty per cent reported reactions in the previous year. Only 82 (13%) had been admitted to hospital because of a reaction. Adrenaline was carried in some form by 65% though only 78 subjects (12.5%) had ever received injected adrenaline. Only 18/43 subjects (41%) who collapsed were given adrenaline. Skin-prick test weal size correlated weakly with severity but there were large overlaps between the groups. Peanut-specific IgE peaked in the teenage group, but did not correlate with severity. Peanut allergy is characterized by more severe symptoms than other food allergies and by high rates of symptoms on minimal contact. Skin-prick testing and peanut-specific IgE levels do not predict clinical severity. Avoidance of peanut is difficult. Many people suffering severe relations are inadequately treated. Sufferers need education and training in the use of rescue medication.


Electrophysiological Evidence for a Sensory Recruitment Model of Somatosensory Working Memory.
Sensory recruitment models of working memory assume that information storage is mediated by the same cortical areas that are responsible for the perceptual processing of sensory signals. To test this assumption, we measured somatosensory event-related brain potentials (ERPs) during a tactile delayed match-to-sample task. Participants memorized a tactile sample set at one task-relevant hand to compare it with a subsequent test set on the same hand. During the retention period, a sustained negativity (tactile contralateral delay activity, tCDA) was elicited over primary somatosensory cortex contralateral to the relevant hand. The amplitude of this component increased with memory load and was sensitive to individual limitations in memory capacity, suggesting that the tCDA reflects the maintenance of tactile information in somatosensory working memory. The tCDA was preceded by a transient negativity (N2cc component) with a similar contralateral scalp distribution, which is likely to reflect selection of task-relevant tactile stimuli at the encoding stage. The temporal sequence of N2cc and tCDA components mirrors previous observations from ERP studies of working memory in vision. The finding that the sustained somatosensory delay period activity varies as a function of memory load supports a sensory recruitment model for spatial working memory in touch.


Computer image analysis of comparative genomic hybridization.
We describe and evaluate the image-processing and analysis techniques we have developed for the quantitative analysis of comparative genomic hybridization (CGH; Science 258:818, 1992). In a typical CGH application, two genomic DNA samples are simultaneously hybridized to metaphase chromosomes and detected with different fluorochromes. The primary data in CGH are contained in the intensity ratios of the fluorochromes as a function of position on the chromosomes, which reflect variation in DNA copy number ratio between the two DNA samples. Analysis involves chromosome segmentation, intensity normalization, background corrections, and calculation of the fluorescence intensity profiles and the ratio profile along the chromosome's length. Profiles from several copies of the same chromosome in different metaphases are averaged to reduce the noise. Confidence intervals are calculated and displayed for the mean profiles. The techniques were evaluated by examining the variability found in comparisons of two normal genomic DNAs, where the ratio was expected to be constant, and by measuring the ratios obtained for cell lines with cytogenetically documented copy number changes involving several chromosomal segments. The limits of sensitivity of CGH analysis were investigated by simulation. Guidelines for the interpretation of CGH data and indications of areas for future development of the analytical techniques are also presented.


Fast voluntary trunk flexion movements in standing: primary movements and associated postural adjustments.
Movement patterns were studied during fast voluntary forward flexions of the trunk from an erect standing position. Three healthy subjects performed three series of six consecutive trunk flexions at maximum velocity and with successively increasing amplitude, covering a major part of the range of motion (range for all subjects: 13-97 degrees). Angular displacements of the trunk, hip, knee and ankle were measured together with the tilt of the pelvis and the flexion of the spine using a Selspot optoelectronic system. Trunk flexion was the result of a simultaneous forward pelvic tilt and flexion of the spine. For trunk movements up to 55 degrees, spine flexion dominated the movement, whereas for larger movements a major part of the amplitude was caused by pelvic tilt. During flexion of the trunk a simultaneous hip flexion and ankle extension was seen. At the knee there was an initial flexion and a subsequent extension. The net amplitude of the knee flexion showed a negative correlation with net trunk flexion amplitude for movements up to 50 degrees, whereas for larger amplitudes the correlation was positive. Time from onset of the trunk movement to peak knee flexion showed a weak correlation to net trunk flexion amplitude (r = 0.34) whereas the corresponding correlation was higher for pelvic tilt, spine flexion, hip flexion, ankle extension, and knee extension (r = 0.60-0.91). Each successive trial during a series of trunk movements was started from an increasing degree of knee flexion. This gradual adaptation was also present when successive trunk flexions were performed with constant movement amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)


Chromatin dynamics during interphase and cell division: similarities and differences between model and crop plants.
Genetic information in the cell nucleus controls organismal development and responses to the environment, and finally ensures its own transmission to the next generations. To achieve so many different tasks, the genetic information is associated with structural and regulatory proteins, which orchestrate nuclear functions in time and space. Furthermore, plant life strategies require chromatin plasticity to allow a rapid adaptation to abiotic and biotic stresses. Here, we summarize current knowledge on the organization of plant chromatin and dynamics of chromosomes during interphase and mitotic and meiotic cell divisions for model and crop plants differing as to genome size, ploidy, and amount of genomic resources available. The existing data indicate that chromatin changes accompany most (if not all) cellular processes and that there are both shared and unique themes in the chromatin structure and global chromosome dynamics among species. Ongoing efforts to understand the molecular mechanisms involved in chromatin organization and remodeling have, together with the latest genome editing tools, potential to unlock crop genomes for innovative breeding strategies and improvements of various traits.


Tangeretin protects human brain microvascular endothelial cells against oxygen-glucose deprivation-induced injury.
Tangeretin, a citrus flavonoid extracted from the peel of citrus fruits, was reported to possess antiasthmatic, antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of tangeretin on human brain microvascular endothelial cells (HBMECs) has not been examined. This study was designed to investigate the protective effects of tangeretin on oxygen-glucose deprivation (OGD)-induced injury of HBMECs, and explore the underlying mechanisms. Our results showed that tangeretin improved HBMECs viability in response to OGD. In addition, tangeretin was able to increase the activity of superoxide dismutase and decrease the levels of reactive oxygen species and malondialdehyde (MDA), as well as ameliorate cell apoptosis in OGD-stimulated HBMECs. Mechanistic studies showed that tangeretin prevented the activation of JNK signaling pathway in OGD-stimulated HBMECs. Taken together, our current study demonstrated that tangeretin could ameliorate OGD-induced HBMECs injury through the JNK signaling pathway. Thus, tangeretin might be used as a therapeutic strategy for ischemia-reperfusion brain injury and related diseases.


A new family of optical systems employing φ-polynomial surfaces.
Unobscured optical systems have been in production since the 1960s. In each case, the unobscured system is an intrinsically rotationally symmetric optical system with an offset aperture stop, a biased input field, or both. This paper presents a new family of truly nonsymmetric optical systems that exploit a new fabrication degree of freedom enabled by the introduction of slow-servos to diamond machining; surfaces whose departure from a sphere varies both radially and azimuthally in the aperture. The benefit of this surface representation is demonstrated by designing a compact, long wave infrared (LWIR) reflective imager using nodal aberration theory. The resulting optical system operates at F/1.9 with a thirty millimeter pupil and a ten degree diagonal full field of view representing an order of magnitude increase in both speed and field area coverage when compared to the same design form with only conic mirror surfaces.


Chronic Achilles tendon pain treated with eccentric calf-muscle training.
Injuries involving the Achilles tendon and manifested as chronic tendon pain are common, especially among recreational athletes. In a pilot study on a small group of patients with chronic painful mid-portion Achilles tendinosis, eccentric calf-muscle training was shown to give good clinical results. The aim of this prospective study was to investigate if the previously achieved good clinical results could be reproduced in a larger group of patients, and also to investigate the effects of eccentric calf-muscle training in patients with chronic insertional Achilles tendon pain. Seventy-eight consecutive patients, having chronic painful Achilles tendinosis at the mid-portion (2-6 cm level) in a total of 101 tendons (55 unilateral and 23 bilateral), and thirty consecutive patients with chronic insertional Achilles tendon pain in 31 tendons (29 unilateral and one bilateral) were treated with eccentric calf-muscle training for 12 weeks. Most patients were recreational athletes. Evaluation of the amount of tendon pain during activity was recorded on a visual analogue scale (VAS), before and after treatment. In 90 of the 101 Achilles tendons (89%) with chronic painful mid-portion Achilles tendinosis, treatment was satisfactory and the patients were back on their pre-injury activity level after the 12-week training regimen. In these patients, the amount of pain during activity, registered on the VAS-scale (mean+/-SD), decreased significantly from 66.8+/-19.4 to 10.2+/-13.7. On the contrary, in only ten of the tendons (32%) with chronic insertional Achilles tendon pain was treatment satisfactory, with a significant decrease on the VAS-scale (mean+/-SD), from 68.3+/-7.0 to 13.3+/-13.2. Our conclusion is that treatment with eccentric calf-muscle training produced good clinical results in patients with chronic painful mid-portion Achilles tendinosis, but not in patients with chronic insertional Achilles tendon pain.


Measurement of the forward-backward asymmetry in the production of B(±) mesons in pp̄ collisions at √s=1.96 TeV.
We present a measurement of the forward-backward asymmetry in the production of B(±) mesons, A(FB)(B(±)), using B(±)→J/ψK(±) decays in 10.4 fb(-1) of pp̄ collisions at sqrt[s]=1.96 TeV collected by the D0 experiment during Run II of the Tevatron collider. A nonzero asymmetry would indicate a preference for a particular flavor, i.e., b quark or ̄b antiquark, to be produced in the direction of the proton beam. We extract A(FB)(B(±)) from a maximum likelihood fit to the difference between the numbers of forward- and backward-produced B(±) mesons. We measure an asymmetry consistent with zero: A(FB)(B(±))=[-0.24±0.41 (stat)±0.19 (syst)]%.


Full-cost determination of different levels of care in the intensive care unit. An activity-based costing approach.
We applied an activity-based costing methodology to determine the full cost of intensive care service at a community hospital, a university hospital and a health maintenance organisation (HMO)-affiliated hospital. A total of 5 patient care units were analysed: the intensive care unit (ICU) and surgical ICU (SICU) at the university setting, the ICU at the community setting, and the SICU and cardiac care unit at the HMO setting. The selection of the different ICU types was based on the types of critical care units that were found in each setting (e.g. the HMO did not have an ICU). Institution-specific cost data and clinical management parameters were collected through surveys and site visits from the 3 respective organisation types. The analysis revealed a marked increase in patient-minute cost associated with mechanical ventilation. Higher costs associated with prolonged neuromuscular blockade have important economic implications with respect to selection of an appropriate neuromuscular blocking agent.


The acute effects of exercise and glucose ingestion on circulating angiotensin-converting enzyme in humans.
Angiotensin-converting enzyme (ACE) activity has been suggested as a determinant of some exercise phenotypes via some studies that have associated the ACE gene with exercise performance, although several studies provide conflicting evidence regarding the influence of the ACE gene. The relationships between ACE phenotype (ACE activity) and various exercise parameters should also be examined. An early step in this process is to determine whether common environmental stimuli such as exercise and diet have acute effects on ACE activity. In this study, the acute effects of aerobic exercise, resistance exercise and glucose ingestion on circulating ACE activity were examined. On three separate occasions, 20 healthy adult volunteers (9 female and 11 male) performed 20 min of submaximal cycle exercise at 70-80% of maximal heart rate, four sets of ten repetitions of unilateral leg extension resistance exercise at ten-repetition maximum load, or ingested 1 g kg(-1) glucose. Circulating ACE activity was assessed for 1 h after each intervention using a modified fluorometric method. Pre-intervention ACE activity remained remarkably stable across test days (difference < or =1.8%). Furthermore, there was no significant change in circulating ACE activity following any of the interventions (difference from pre-intervention values < or =6.8% when unadjusted for plasma volume changes, < or =4.5% when adjusted for plasma volume changes). These results suggest that acute exercise and glucose ingestion interventions as used here do not affect circulating ACE activity. These findings are an early step in illuminating the relationships between ACE activity and various exercise parameters.


[Trichinellosis serology in blood-donors from a non-endemic area of Argentina].
The aim of the present study was to determine the presence of human trichinellosis in an area of Argentina historically regarded as free of this parasitic disease. This parasitosis was assessed on 150 blood donors by means of immunoserological tests, and their relation with risk alimentary habits by a questionnaire. The questionnaires showed that 98.0% (n=147) of the individuals consumed pork and pork products at a high frequency. The main pork products incorporated to the habitual diet were the stuffed ones. A 80.3% (n=118) of the individuals had acquired such products at butchers, a 38.1% (n=56) at home slaughters and a 34.0% (n=50) at supermarkets. The immunoserological techniques employed were: enzyme immunoanalysis, indirect immunofluorescence and/or immunoelectrotransfer blot assay. Anti-Trichinella antibodies were detected in 8.0% (n=12) of the serum samples by more than one of the methodologies employed, considering these results as confirmatory of trichinellosis. The studies carried out herein demonstrate the existence of human trichinellosis in an area historically regarded as free of this parasitic disease and suggest its relationship with the ingestion of pork or pork products as a risk factor. These results indicate that the lack of reports should not be the only criterion for an area to be considered as Trichinella-free. The awareness of the existence of the parasite in a region will favor the establishment of control and prevention strategies which is of fundamental importance to avoid the spread of the disease.


Crystallographic structure of the octameric histone core of the nucleosome at a resolution of 3.3 A.
The structure of the (H2A-H2B-H3-H4)2 histone octamer has been determined by means of x-ray crystallographic techniques at a resolution of 3.3 angstroms. The octamer is a prolate ellipsoid 110 angstroms long and 65 to 70 angstroms in diameter, and its general shape is that of a rugby ball. The size and shape are radically different from those determined in earlier studies. The most striking feature of the histone octamer is its tripartite organization, that is, a central (H3-H4)2 tetramer flanked by two H2A-H2B dimers. The DNA helix, placed around the octamer in a path suggested by the features on the surface of the protein, appears like a spring holding the H2A-H2B dimers at either end of the (H3-H4)2 tetramer.


Dietary change among hominins and cercopithecids in Ethiopia during the early Pliocene.
The incorporation of C4 resources into hominin diet signifies increased dietary breadth within hominins and divergence from the dietary patterns of other great apes. Morphological evidence indicates that hominin diet became increasingly diverse by 4.2 million years ago but may not have included large proportions of C4 foods until 800 thousand years later, given the available isotopic evidence. Here we use carbon isotope data from early to mid Pliocene hominin and cercopithecid fossils from Woranso-Mille (central Afar, Ethiopia) to constrain the timing of this dietary change and its ecological context. We show that both hominins and some papionins expanded their diets to include C4 resources as early as 3.76 Ma. Among hominins, this dietary expansion postdates the major dentognathic morphological changes that distinguish Australopithecus from Ardipithecus, but it occurs amid a continuum of adaptations to diets of tougher, harder foods and to committed terrestrial bipedality. In contrast, carbon isotope data from cercopithecids indicate that C4-dominated diets of the earliest members of the Theropithecus oswaldi lineage preceded the dental specialization for grazing but occurred after they were fully terrestrial. The combined data indicate that the inclusion of C4 foods in hominin diet occurred as part of broader ecological changes in African primate communities.


A novel regulatory role of HrpD6 in regulating hrp-hrc-hpa genes in Xanthomonas oryzae pv. oryzicola.
Xanthomonas oryzae pv. oryzicola, the causal agent of bacterial leaf streak in the model plant rice, possesses a hypersensitive response and pathogenicity (hrp), hrp-conserved (hrc), hrp-associated (hpa) cluster (hrp-hrc-hpa) that encodes a type III secretion system (T3SS) through which T3SS effectors are injected into host cells to cause disease or trigger plant defenses. Mutations in this cluster usually abolish the bacterial ability to cause hypersensitive response in nonhost tobacco and pathogenicity in host rice. In Xanthomonas spp., these genes are generally assumed to be regulated by the key master regulators HrpG and HrpX. However, we present evidence that, apart from HrpG and HrpX, HrpD6 is also involved in regulating the expression of hrp genes. Interestingly, the expression of hpa2, hpa1, hpaB, hrcC, and hrcT is positively controlled by HrpD6. Transcriptional expression assays demonstrated that the expression of the hrcC, hrpD5, hrpE, and hpa3 genes was not completely abolished by hrpG and hrpX mutations. As observed in analysis of their corresponding mutants, HrpG and HrpX exhibit contrasting gene regulation, particularly for hpa2 and hrcT. Other two-component system regulators (Zur, LrpX, ColR/S, and Trh) did not completely inhibit the expression of hrcC, hrpD5, hrpE, and hpa3. Immunoblotting assays showed that the secretion of HrpF, which is an HpaB-independent translocator, is not affected by the mutation in hrpD6. However, the mutation in hrpD6 affects the secretion of an HpaB-dependent TAL effector, AvrXa27. These novel findings suggest that, apart from HrpG and HrpX, HrpD6 plays important roles not only in the regulation of hrp genes but also in the secretion of TAL effectors.


Veterans Affairs Providers' Beliefs About the Contributors to and Responsibility for Reducing Racial and Ethnic Health Care Disparities.
Purpose: Providers' beliefs about the causes of disparities and the entities responsible for addressing these disparities are important in designing disparity-reduction interventions aimed at providers. This secondary analysis of a larger study is aimed at evaluating perceptions of providers regarding the underlying causes of racial health care disparities and their views of who is responsible for reducing them. Methods: We surveyed 232 providers at 3 Veterans Affairs (VA) Medical Centers. Results: Sixty-nine percent of participants believed that minority patients in the United States receive lower quality health care. Most participants (64%) attributed differences in quality of care for minority patients in the VA health care system primarily to patients' socioeconomic status, followed by patient behavior (43%) and provider behaviors (33%). In contrast, most participants believed that the VA and other health care organizations (75%) and providers (70%) bear the responsibility for reducing disparities, while less than half (45%) believed that patients were responsible. Among provider-level contributors to disparities, providers' poor communication was the most widely endorsed (48%), while differences in prescribing of medications (13%) and in provision of specialty referrals (12%) were the least endorsed. Conclusions: Although most providers in the study did not believe that providers contribute to disparities, they do believe that they, along with health care organizations, have the responsibility to help reduce them. Interventions might focus on directly offering providers concrete ways that they can help reduce disparities, rather than focusing on simply raising awareness about disparities and their contributions to them.


Galectin-3-binding protein is a novel predictor of venous thromboembolism in systemic lupus erythematosus.
Venous (VTE) and arterial (AT) thrombosis in systemic lupus erythematosus (SLE) are poorly explained and difficult to predict. Leptin and tumour necrosis factor-like weak inducer of apoptosis (TWEAK) have been linked to subclinical atherosclerosis and galectin-3-binding protein (G3BP) to type I interferon activation and a pro-thrombotic environment. Thus, we explore serum G3BP, interferon gamma-induced protein 10 (IP-10), soluble CD163 (sCD163), TWEAK and leptin as predictors of VTE and AT, damage accrual, and all-cause mortality during follow-up in a Swedish SLE cohort. Baseline data were available from 162 SLE patients. VTE (deep vein thrombosis and/or pulmonary embolism), AT (myocardial infarction and/or stroke), damage accrual, and survival data were the main study outcomes and available at follow-up (median of five years). Baseline serum G3BP, IP-10, sCD163, TWEAK and leptin were measured and analysed by univariable and multivariable methods for association to the study outcomes. During the follow-up, 10 (6%) VTE and 13 (8%) AT events occurred. The SLICC/ACR Damage Index increased in 78 (48%) patients, and 19 (12%) patients died. In the univariable regression analysis G3BP levels were significantly associated with an increased risk of VTE (hazard ratio (HR) 1.11, 95% confidence interval (CI): 1.01-1.22, p=0.03). This persisted in the adjusted multivariable analyses (HR 1.18, 95% CI: 1.05-1.33, p=0.007). The other biomarkers were not associated with AT/VTE, damage accrual, or all-cause mortality. Our study identifies serum G3BP as a novel predictor of VTE in SLE. Further studies are needed to understand the role of G3BP in VTE and translate this into clinical practice.


Effect of cholinergic agonists and antagonists on rat hypothalamic corticotropin-releasing hormone secretion in vitro.
Several lines of experimental evidence suggest that acetylcholine (ACh) is excitatory to the hypothalamic-pituitary-adrenal (HPA) axis. Since previous experiments have shown that ACh does not affect pituitary adrenocorticotropin secretion in vitro, we hypothesized that ACh stimulates the HPA axis by causing hypothalamic corticotropin-releasing hormone (CRH) secretion. We examined this hypothesis using an organ culture system that measures the ability of single rat hypothalami to secrete immunoreactive CRH (IR-rCRH) in vitro. ACh stimulated hypothalamic IR-rCRH secretion in a dose-dependent fashion, at concentrations ranging from 3.3 x 10(-10) to 10(-5) M. This effect was antagonized by the simultaneous presence of atropine and hexamethonium, a muscarinic and a nicotinic receptor antagonist, respectively (p less than 0.05). Further evidence for the cholinergic regulation of the CRH neuron was provided by the findings that both carbachol, a muscarinic receptor agonist, and nicotine, a nicotinic receptor agonist, stimulated IR-rCRH secretion in a dose-dependent fashion. These effects were antagonized by atropine and hexamethonium, respectively, suggesting that both muscarinic and nicotinic receptors are involved in the process. ACh stimulated hypothalamic IR-rCRH secretion in the presence of phentolamine, an alpha-adrenergic antagonist, and ritanserin, a serotonin2 receptor antagonist, suggesting that the cholinergic stimulation of CRH secretion is not mediated by alpha-adrenergic or serotonergic interneurons. We conclude that ACh stimulates hypothalamic CRH secretion via both muscarinic and nicotinic receptor mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)


Origin of the High-Frequency Doublet in the Vibrational Spectrum of Vitreous SiO2
The vibrational properties of amorphous SiO2 were studied within first-principles density functional theory. The calculated spectrum is in good agreement with neutron data, showing, in particular, a double peak in the high-frequency region. This doublet results from different local modes of the tetrahedral subunits and cannot be ascribed to a longitudinal-optic-transverse-optic (LO-TO) effect. This solves a long-standing controversy about the origin of the doublet in neutron spectra. A LO-TO splitting is recovered only when the long-wavelength limit is probed, as in optical experiments. These findings should be a general feature of tetrahedral AX2 amorphous networks.


Observation of Berry's phase in a solid-state qubit.
In quantum information science, the phase of a wave function plays an important role in encoding information. Although most experiments in this field rely on dynamic effects to manipulate this information, an alternative approach is to use geometric phase, which has been argued to have potential fault tolerance. We demonstrated the controlled accumulation of a geometric phase, Berry's phase, in a superconducting qubit; we manipulated the qubit geometrically by means of microwave radiation and observed the accumulated phase in an interference experiment. We found excellent agreement with Berry's predictions and also observed a geometry-dependent contribution to dephasing.


Mechanisms of vitamin D action in skeletal muscle.
Vitamin D receptor expression and associated function have been reported in various muscle models, including C2C12, L6 cell lines and primary human skeletal muscle cells. It is believed that 1,25-hydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has a direct regulatory role in skeletal muscle function, where it participates in myogenesis, cell proliferation, differentiation, regulation of protein synthesis and mitochondrial metabolism through activation of various cellular signalling cascades, including the mitogen-activated protein kinase pathway(s). It has also been suggested that 1,25(OH)2D3 and its associated receptor have genomic targets, resulting in regulation of gene expression, as well as non-genomic functions that can alter cellular behaviour through binding and modification of targets not directly associated with transcriptional regulation. The molecular mechanisms of vitamin D signalling, however, have not been fully clarified. Vitamin D inadequacy or deficiency is associated with muscle fibre atrophy, increased risk of chronic musculoskeletal pain, sarcopenia and associated falls, and may also decrease RMR. The main purpose of the present review is to describe the molecular role of vitamin D in skeletal muscle tissue function and metabolism, specifically in relation to proliferation, differentiation and protein synthesis processes. In addition, the present review also includes discussion of possible genomic and non-genomic pathways of vitamin D action.


Differential iridoid production as revealed by a diversity panel of 84 cultivated and wild blueberry species.
Cultivated blueberry (Vaccinium corymbosum, Vaccinium angustifolium, Vaccinium darrowii, and Vaccinium virgatum) is an economically important fruit crop native to North America and a member of the Ericaceae family. Several species in the Ericaceae family including cranberry, lignonberry, bilberry, and neotropical blueberry species have been shown to produce iridoids, a class of pharmacologically important compounds present in over 15 plant families demonstrated to have a wide range of biological activities in humans including anti-cancer, anti-bacterial, and anti-inflammatory. While the antioxidant capacity of cultivated blueberry has been well studied, surveys of iridoid production in blueberry have been restricted to fruit of a very limited number of accessions of V. corymbosum, V. angustifolium and V. virgatum; none of these analyses have detected iridoids. To provide a broader survey of iridoid biosynthesis in cultivated blueberry, we constructed a panel of 84 accessions representing a wide range of cultivated market classes, as well as wild blueberry species, and surveyed these for the presence of iridoids. We identified the iridoid glycoside monotropein in fruits and leaves of all 13 wild Vaccinium species, yet only five of the 71 cultivars. Monotropein positive cultivars all had recent introgressions from wild species, suggesting that iridoid production can be targeted through breeding efforts that incorporate wild germplasm. A series of diverse developmental tissues was also surveyed in the diversity panel, demonstrating a wide range in iridoid content across tissues. Taken together, this data provides the foundation to dissect the molecular and genetic basis of iridoid production in blueberry.


Study of the effective point of measurement for ion chambers in electron beams by Monte Carlo simulation.
In current dosimetry protocols for electron beams, for plane-parallel chambers, the effective point of measurement is at the front face of the cavity, and, for cylindrical chambers, it is at a point shifted 0.5r upstream from the cavity center. In this study, Monte Carlo simulations are employed to study the issue of effective point of measurement for both plane-parallel chambers and cylindrical thimble chambers in electron beams. It is found that there are two ways of determining the position of the effective point of measurement: One is to match the calculated depth-ionization curve obtained from a modeled chamber to a calculated depth-dose curve; the other is to match the electron fluence spectrum in the chamber cavity to that in the phantom. For plane-parallel chambers, the effective point of measurement determined by the first method is generally not at the front face of the chamber cavity, which is obtained by the second method, but shifted downstream toward the cavity center by an amount that could be larger than one-half a millimeter. This should not be ignored when measuring depth-dose curves in electron beams. For cylindrical chambers, these two methods also give different positions of the effective point of measurement: The first gives a shift of 0.5r, which is in agreement with measurements for high-energy beams and is the same as the value currently used in major dosimetry protocols; the latter gives a shift of 0.8r, which is closer to the value predicted by a theoretical calculation assuming no-scatter conditions. The results also show that the shift of 0.8r is more appropriate if the cylindrical chamber is to be considered as a Spencer-Attix cavity. In electron beams, since the water/air stopping-power ratio changes with depth in a water phantom, the difference of the two shifts (0.3r) will lead to an incorrect evaluation of the water/air stopping-power ratio at the point of measurement, thus resulting in a systematic error in determining the absorbed dose by cylindrical chambers. It is suggested that a shift of 0.8r be used for electron beam calibrations with cylindrical chambers and a shift of 0.4r-0.5r be used for depth-dose measurements.


Desiccation Tolerance Evolved through Gene Duplication and Network Rewiring in Lindernia.
Although several resurrection plant genomes have been sequenced, the lack of suitable dehydration-sensitive outgroups has limited genomic insights into the origin of desiccation tolerance. Here, we utilized a comparative system of closely related desiccation-tolerant (Lindernia brevidens) and -sensitive (Lindernia subracemosa) species to identify gene- and pathway-level changes associated with the evolution of desiccation tolerance. The two high-quality Lindernia genomes we assembled are largely collinear, and over 90% of genes are conserved. L. brevidens and L. subracemosa have evidence of an ancient, shared whole-genome duplication event, and retained genes have neofunctionalized, with desiccation-specific expression in L. brevidens Tandem gene duplicates also are enriched in desiccation-associated functions, including a dramatic expansion of early light-induced proteins from 4 to 26 copies in L. brevidens A comparative differential gene coexpression analysis between L. brevidens and L. subracemosa supports extensive network rewiring across early dehydration, desiccation, and rehydration time courses. Many LATE EMBRYOGENESIS ABUNDANT genes show significantly higher expression in L. brevidens compared with their orthologs in L. subracemosa Coexpression modules uniquely upregulated during desiccation in L. brevidens are enriched with seed-specific and abscisic acid-associated cis-regulatory elements. These modules contain a wide array of seed-associated genes that have no expression in the desiccation-sensitive L. subracemosa Together, these findings suggest that desiccation tolerance evolved through a combination of gene duplications and network-level rewiring of existing seed desiccation pathways.


Elevated Expression of miR302-367 in Endothelial Cells Inhibits Developmental Angiogenesis via CDC42/CCND1 Mediated Signaling Pathways.
Rationale: Angiogenesis is critical for embryonic development and microRNAs fine-tune this process, but the underlying mechanisms remain incompletely understood. Methods: Endothelial cell (EC) specific miR302-367 line was used as gain-of-function and anti-miRs as loss-of-function models to investigate the effects of miR302-367 on developmental angiogenesis with embryonic hindbrain vasculature as an in vivo model and fibrin gel beads and tube formation assay as in vitro models. Cell migration was evaluated by Boyden chamber and scratch wound healing assay and cell proliferation by cell count, MTT assay, Ki67 immunostaining and PI cell cycle analysis. RNA high-throughput sequencing identified miR-target genes confirmed by chromatin immunoprecipitation and 3'-UTR luciferase reporter assay, and finally target site blocker determined the pathway contributing significantly to the phenotype observed upon microRNA expression. Results: Elevated EC miR302-367 expression reduced developmental angiogenesis, whereas it was enhanced by inhibition of miR302-367, possibly due to the intrinsic inhibitory effects on EC migration and proliferation. We identified Cdc42 as a direct target gene and elevated EC miR302-367 decreased total and active Cdc42, and further inhibited F-actin formation via the WASP and Klf2/Grb2/Pak1/LIM-kinase/Cofilin pathways. MiR302-367-mediated-Klf2 regulation of Grb2 for fine-tuning Pak1 activation contributing to the inhibited F-actin formation, and then the attenuation of EC migration. Moreover, miR302-367 directly down-regulated EC Ccnd1 and impaired cell proliferation via the Rb/E2F pathway. Conclusion: miR302-367 regulation of endothelial Cdc42 and Ccnd1 signal pathways for EC migration and proliferation advances our understanding of developmental angiogenesis, and meanwhile provides a rationale for future interventions of pathological angiogenesis that shares many common features of physiological angiogenesis.


A double-masked placebo-controlled trial assessing effects of various doses of BTS 67,582, a novel insulinotropic agent, on fasting hyperglycemia in NIDDM patients.
To determine the effect over a 4-week period of varying doses of BTS 67,582, a novel nonsulfonylurea insulinotropic agent, on fasting plasma glucose (FPG) levels in sulfonylurea-responsive NIDDM patients. This was a 12-week multicenter, double-masked, placebo-controlled trial. Patients entered a 4-week stabilization period during which they received their previously prescribed sulfonylurea. Qualified patients (FPG < or = 10 mmol/l) then entered a 4-week sulfonylurea withdrawal single-masked placebo run-in period. Qualified patients (FPG 8.9-16.7 mmol/l) were randomized to either placebo (n = 14), 50 mg b.i.d. BTS 67,582 (n = 18), 250 mg b.i.d. BTS 67,582 (n = 18), 500 mg b.i.d. BTS 67,582 (n = 15), 100 mg q.d. BTS 67,582 (n = 17), or 500 mg q.d. BTS 67,582 (n = 16). The primary efficacy variables were mean changes from baseline in FPG and fructosamine (FRUC). Additional variables included mean changes from baseline in HbA1c, fasting serum insulin (FSI), and fasting serum C-peptide. After 4 weeks of treatment, all BTS 67,582 dose groups showed a decrease from baseline in FPG and FRUC compared with the placebo group. The treatment groups of 250 mg b.i.d. (-3.1 +/- 0.7 mmol/l), 500 mg b.i.d. (-2.3 +/- 0.6 mmol/l), and 500 mg q.d. (-1.2 +/- 0.7 mmol/l) had statistically significant (P < 0.05) decreases in FPG compared with placebo (0.7 +/- 0.6 mmol/l). Similarly, there were statistically significant (P < 0.05) decreases from baseline in FRUC for the 250 mg b.i.d (-55 +/- 10 mumol/l), 500 mg b.i.d. (-40 +/- 12 mumol/l), and 500 mg q.d. (-13 +/- 9 mumol/l) treatment groups compared with placebo (15 +/- 11 mumol/l). Although the treatment period was only 4 weeks in duration, there were also significant differences (P < 0.05) in the HbA1c changes from baseline for the 250 mg b.i.d. (0.0 +/- 0.1%) and 500 mg b.i.d. (-0.2 +/- 0.1%) treatment groups compared with placebo (0.6 +/- 0.2%). There were no significant differences among the treatment groups in the changes from baseline for FSI or C-peptide levels. The most frequently reported side effects were headache, asthenia, infection, and thirst, and the incidence of these events as well as the incidence of study drug discontinuation was comparable in all treatment groups including placebo. Four weeks of treatment with BTS 67,582 at doses of 250 mg b.i.d. and 500 mg b.i.d. in NIDDM patients was effective in reducing FPG and FRUC, with significant results also seen for HbA1c. The drug was well tolerated with an incidence of discontinuations and laboratory side-effect safety profiles comparable to placebo. BTS 67,582 is a safe and effective oral treatment for NIDDM patients.


Recognition and management of iatrogenically induced opioid dependence and withdrawal in children.
Opioids are often prescribed to children for pain relief related to procedures, acute injuries, and chronic conditions. Round-the-clock dosing of opioids can produce opioid dependence within 5 days. According to a 2001 Consensus Paper from the American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine, dependence is defined as "a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist." Although the experience of many children undergoing iatrogenically induced withdrawal may be mild or goes unreported, there is currently no guidance for recognition or management of withdrawal for this population. Guidance on this subject is available only for adults and primarily for adults with substance use disorders. The guideline will summarize existing literature and provide readers with information currently not available in any single source specific for this vulnerable pediatric population.


Association between anthropometry and lifestyle factors and risk of B-cell lymphoma: An exposome-wide analysis.
To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single-study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL.


An incredible decade for the primary cilium: a look at a once-forgotten organelle.
Since the discovery that numerous proteins involved in mammalian disease localize to the basal bodies and cilia, these organelles have emerged from relative obscurity to the center of intense research efforts in an expanding number of disease- and developmental-related fields. Our understanding of the association between cilia and human disease has benefited substantially from the use of lower organisms such as Chlamydomonas and Caenorhabditis elegans and the availability of murine models and cell culture. These research endeavors led to the discovery that loss of normal ciliary function in mammals is responsible for cystic and noncystic pathology in the kidney, liver, brain, and pancreas, as well as severe developmental patterning abnormalities. In addition, the localization of proteins involved in rare human disorders such as Bardet-Biedl syndrome has suggested that cilia-related dysfunction may play a role in modern human epidemics such as hypertension, obesity, and diabetes. Although we have made great advances in demonstrating the importance of cilia over the past decade, the physiological role that this organelle plays in most tissues remains elusive. Research focused on addressing this issue will be of critical importance for a further understanding of how ciliary dysfunction can lead to such severe disease and developmental pathologies.


Endoscopic hemostasis using endoclip in early gastrointestinal hemorrhage after gastric bypass surgery.
Roux-en-Y gastric bypass (RYGBP) is the most commonly performed bariatric operation in the USA. In the early postoperative stage, gastrointestinal (GI) bleeding is an infrequent but potentially serious complication that usually results from bleeding at the gastrojejunostomy staple-line. Observant management with transfusion for stable patients and surgical exploration for unstable patients is typically recommended for early GI bleeding. We hypothesized that use of endoclips, which do not cause thermal injury to the surrounding tissues (or anastomosis), may be preferable to thermal approaches which could cause tissue injury. We report 2 cases of early GI bleeding after RYGBP that were successfully managed with endoclip application to bleeding lesions. Emergent endoscopy was performed, and major stigmata such as active spurting vessel and adherent clot were noted at the gastrojejunostomy staple-lines. Endoscopic hemostasis using endoclips was readily applied to bleeding lesions at staple-lines. Primary hemostasis was achieved, and there was no recurrent bleeding or complication. We conclude that therapeutic endoscopy can be performed safely for early bleeding after RYGBP. In patients with early bleeding after RYGBP, use of endoclips is mechanistically preferable to other options.


Interleukin-22: biomarker of maternal and fetal inflammation?
Histologic chorioamnionitis (HCA) is an intrauterine status of inflammation which may lead to the fetal inflammatory response syndrome. Inflammation is a pathogenetic mechanism also of preeclampsia, although not of microbial origin. The aim of the present pilot study was to evaluate the pattern of inflammatory cytokines in mothers and high-risk preterm infants during the perinatal period. Concentrations of proinflammatory and anti-inflammatory cytokines and C-reactive protein were evaluated in maternal, cord, and neonatal blood of very preterm infants <1,500 g birth weight. Histologic examinations of placentae and umbilical cords were performed. The 65 mother-neonate pairs enrolled were subdivided into three groups: (1) HCA group (n = 15), (2) preeclampsia group (n = 17), and (3) control group, in the absence of HCA/preeclampsia (n = 33). Maternal Interleukin (IL)-6 levels were significantly higher in women of the HCA group compared with the preeclampsia and control groups (p < 0.05). IL-22 was detected in nearly all maternal samples [median value 693.115 pg/ml (599.91-809.91 pg/ml)], with no statistical difference between the groups, but with a tendency to increased levels among preeclamptic women. Increased concentrations of IL-22 were detected in cord blood of neonates exposed to preeclampsia, compared with controls and infants exposed to HCA (p < 0.05). We speculate that the tendentially higher concentrations of IL-22 in preeclamptic mothers and the significantly higher concentrations in cord blood may reflect placental dysfunction and the underlying reparative processes at the maternal-fetal interface. Therefore, IL-22 could be an important biomarker of inflammation in preeclampsia.


Smart-phone obesity prevention trial for adolescent boys in low-income communities: the ATLAS RCT.
The goal of this study was to evaluate the impact of the Active Teen Leaders Avoiding Screen-time (ATLAS) intervention for adolescent boys, an obesity prevention intervention using smartphone technology. ATLAS was a cluster randomized controlled trial conducted in 14 secondary schools in low-income communities in New South Wales, Australia. Participants were 361 adolescent boys (aged 12-14 years) considered at risk of obesity. The 20-week intervention was guided by self-determination theory and social cognitive theory and involved: teacher professional development, provision of fitness equipment to schools, face-to-face physical activity sessions, lunchtime student mentoring sessions, researcher-led seminars, a smartphone application and Web site, and parental strategies for reducing screen-time. Outcome measures included BMI and waist circumference, percent body fat, physical activity (accelerometers), screen-time, sugar-sweetened beverage intake, muscular fitness, and resistance training skill competency. Overall, there were no significant intervention effects for BMI, waist circumference, percent body fat, or physical activity. Significant intervention effects were found for screen-time (mean ± SE: -30 ± 10.08 min/d; P = .03), sugar-sweetened beverage consumption (mean: -0.6 ± 0.26 glass/d; P = .01), muscular fitness (mean: 0.9 ± 0.49 repetition; P = .04), and resistance training skills (mean: 5.7 ± 0.67 units; P < .001). This school-based intervention targeting low-income adolescent boys did not result in significant effects on body composition, perhaps due to an insufficient activity dose. However, the intervention was successful in improving muscular fitness, movement skills, and key weight-related behaviors.


How Much Does WAIS-IV Perceptual Reasoning Decline Across the 20 to 90-Year Lifespan When Processing Speed is Controlled?
The most prominent pattern of cognitive change over the lifespan centers on the difference between patterns of maintained abilities on tests of crystallized knowledge and patterns of steady decline on tests of problem solving and processing speed. Whereas the maintained-vulnerable dichotomy is well established in the literature, questions remain about cognitive decline in problem solving when processing speed is controlled. This relationship has been examined in cross-sectional studies that typically used non-clinical tests with non-representative samples of adults. This study extended these findings to the most popular clinical test, the Wechsler Adult Intelligence Scale -4th ed. (WAIS-IV), using its carefully stratified sample as the source of data (ages 20-90 for Indexes, ages 16-90 for Perceptual Reasoning subtests). Multivariate Analysis of Covariance (MANCOVA) revealed that 70-80% of the variance in declining reasoning ability was shared with the speed factor. This was true (a) on the index and subtest level and (b) regardless of the type of problem-solving task employed. Such robust findings have important clinical and research implications for neuropsychologists, who most frequently use the Wechsler scales as part of their assessment battery.


Warming and fertilization alter the dilution effect of host diversity on disease severity.
An essential ecosystem service is the dilution effect of biodiversity on disease severity, yet we do not fully understand how this relationship might change with continued climate warming and ecosystem degradation. We designed removal experiments in natural assemblages of Tibetan alpine meadow vegetation by manipulating plot-level plant diversity to investigate the relationship between different plant biodiversity indices and foliar fungal pathogen infection, and how artificial fertilization and warming affect this relationship. Although pathogen group diversity increased with host species richness, disease severity decreased as host diversity rose (dilution effect). The dilution effect of phylogenetic diversity on disease held across different levels of host species richness (and equal abundances), meaning that the effect arises mainly in association with enhanced diversity itself rather than from shifting abundances. However, the dilution effect was weakened by fertilization. Among indices, phylogenetic diversity was the most parsimonious predictor of infection severity. Experimental warming and fertilization shifted species richness to the most supported predictor. Compared to planting experiments where artificial communities are constructed from scratch, our removal experiment in natural communities more realistically demonstrate that increasing perturbation adjusts natural community resistance to disease severity.


Global gray-level thresholding based on object size.
In this article, we propose a fast and robust global gray-level thresholding method based on object size, where the selection of threshold level is based on recall and maximum precision with regard to objects within a given size interval. The method relies on the component tree representation, which can be computed in quasi-linear time. Feature-based segmentation is especially suitable for biomedical microscopy applications where objects often vary in number, but have limited variation in size. We show that for real images of cell nuclei and synthetic data sets mimicking fluorescent spots the proposed method is more robust than all standard global thresholding methods available for microscopy applications in ImageJ and CellProfiler. The proposed method, provided as ImageJ and CellProfiler plugins, is simple to use and the only required input is an interval of the expected object sizes. © 2016 International Society for Advancement of Cytometry.


Plant diversity patterns in neotropical dry forests and their conservation implications.
Seasonally dry tropical forests are distributed across Latin America and the Caribbean and are highly threatened, with less than 10% of their original extent remaining in many countries. Using 835 inventories covering 4660 species of woody plants, we show marked floristic turnover among inventories and regions, which may be higher than in other neotropical biomes, such as savanna. Such high floristic turnover indicates that numerous conservation areas across many countries will be needed to protect the full diversity of tropical dry forests. Our results provide a scientific framework within which national decision-makers can contextualize the floristic significance of their dry forest at a regional and continental scale.


The ecology of Colorado tick fever in Rocky Mountain National Park in 1974. II. Infection in small mammals.
Field studies of Colorado tick fever (CTF) in small mammals in Rocky Mountain National Park (RMNP) in 1974 established that Eutamias minimus and Spermophilus lateralis were the most important hosts for CTF virus and were the source of virus for immature stages of the tick vector, Dermacentor andersoni. Other species (Peromyscus maniculatus, Spermophilus richardsonii, Eutamias umbrinus) are secondary hosts. The intensity of viral activity in rodents varied greatly from locality to locality. Highest rodent infection rates were found to occur in the Moraine Park area of RMNP. Lowest infection rates occurred above 3,290 meters in altitude at Rainbow Curve and on the tundra. The prevalence of infection in rodents was constant from April--July (5--6% of animals captured were viremic) and then declined to 1.7--2.5% in August and September coincident with a decline in nymphal tick ectoparasitism. Many animals were captured which were simultaneously viremic and antibody-positive. Under field conditions, neutralizing antibody seroconversion does not always occur.


A Polysaccharide-Based Antibacterial Coating with Improved Durability for Clear Overlay Appliances.
Clear overlay appliances (COAs) are widely used in orthodontic fields because they offer many advantages, such as cost-effectiveness, good formability, and good optical characteristics. However, it is necessary to frequently replace COAs because the thermoplastic polymers that are used to fabricate COAs have poor abrasion resistance and have a tendency to induce bacterial accumulation. Here, we have developed polysaccharide-based antibacterial multilayer films with enhanced durability, intended for COA applications. First, multilayer films composed of carboxymethylcellulose (CMC) and chitosan (CHI) were fabricated on polyethylene terephthalate glycol-modified (PETG), which was preferred material for COA fabrication, via a layer-by-layer (LbL) technique. Next, chemical cross-linking was introduced within the LbL-assembled multilayer films. The LbL-assembled CMC/CHI film, which was made porous and rough by the cross-linking, formed a superhydrophilic surface to prevent the adhesion of bacteria and exhibited a bacterial reduction ratio of ∼75%. Furthermore, the cross-linking of the multilayer film coated on the PETG also improved the chemical resistance and mechanical stability of the PETG under simulated intraoral conditions with artificial saliva, by increasing the bond strength between the polysaccharide chains. We attempted to accumulate datasets using our experimental design and to develop sophisticated methods to assess nanoscale changes through large-scale measurements.


The Scope of Planning Serial Actions during Typing.
Human activities consisting of multiple component actions require the generation of ordered sequences. This study investigated the scope of response planning in highly serial task, typing, by means of ERPs indexing motor response preparation. Specifically, we compared motor-related ERPs yielded by words typed using a single hand against words that had all keystrokes typed with a single hand, except for a deviant one, typed with the opposite hand. The deviant keystroke occurred either early in the typed sequence, corresponding to the second or third letters, or late, corresponding to the penultimate or last letter. Motor-related ERPs detected before response onset were affected only by deviant keystrokes located at the beginning of the sequence, whereas deviant keystrokes located at the end yielded ERPs that were undistinguishable from unimanual responses. These results impose some constraints on the notion of parallel processing of component actions.


Drugs used to alleviate symptoms with life shortening as a possible side effect: end-of-life care in six European countries.
We investigated the drugs used in the alleviation of pain and symptoms (APS) with a possible life-shortening side effect in six European countries' end-of-life care. We sent mail questionnaires to physicians who signed a representative sample of death certificates in each country. APS with a possible life-shortening effect occurred from 19% of all deaths in Italy to 26% in Denmark. Physicians usually administered opioids (from 76% of APS cases in Italy to 96% in The Netherlands), but the type of opioids and administration practice differed markedly between countries. The doses of opioids given in the last 24 hours also varied significantly and were usually lower than 300 mg oral morphine equivalent (from 83% of cases in Belgium to 93% in Sweden). The highly variable results bring into question whether existing guidelines for pain relief were applied appropriately and to what extent unfounded concerns about the possible life-shortening effect of opioids resulted in less than optimal symptom management in end-of-life care.


Enhancement of potassium-sensitive current in heart cells by pinacidil. Evidence for modulation of the ATP-sensitive potassium channel.
Pinacidil belongs to a novel group of compounds that enhance the potassium permeability of vascular smooth muscle. Evidence also exists that this drug enhances the potassium permeability of cardiac tissue. The purpose of the present investigation was to determine if pinacidil alters potassium-channel activity in heart and, if so, which potassium channel is the target. We used the whole-cell arrangement of the patch voltage clamp to record membrane currents from isolated guinea pig ventricular cells. In solutions designed to isolate potassium currents, pinacidil enhances a time-independent current positive to the potassium equilibrium potential. Current measured at voltages negative to the potassium equilibrium potential are essentially unaltered by the drug. The potassium sensitivity of outward current indicates that the target for the drug is a potassium channel. Experiments designed to test for voltage-dependent channel gating strongly suggest that the pinacidil-sensitive current is not voltage gated. Pinacidil-sensitive current is blocked by externally applied Ba2+, Cs+, and tetraethylammonium ion. In addition, it is potently blocked after external application of 100 nM glibenclamide. Taken along with the time- and voltage-independent properties of pinacidil-sensitive current, this pharmacology strongly suggests that the target for pinacidil in heart is the ATP-sensitive potassium channel.


BRENDA in 2015: exciting developments in its 25th year of existence.
The BRENDA enzyme information system (http://www.brenda-enzymes.org/) has developed into an elaborate system of enzyme and enzyme-ligand information obtained from different sources, combined with flexible query systems and evaluation tools. The information is obtained by manual extraction from primary literature, text and data mining, data integration, and prediction algorithms. Approximately 300 million data include enzyme function and molecular data from more than 30,000 organisms. The manually derived core contains 3 million data from 77,000 enzymes annotated from 135,000 literature references. Each entry is connected to the literature reference and the source organism. They are complemented by information on occurrence, enzyme/disease relationships from text mining, sequences and 3D structures from other databases, and predicted enzyme location and genome annotation. Functional and structural data of more than 190,000 enzyme ligands are stored in BRENDA. New features improving the functionality and analysis tools were implemented. The human anatomy atlas CAVEman is linked to the BRENDA Tissue Ontology terms providing a connection between anatomical and functional enzyme data. Word Maps for enzymes obtained from PubMed abstracts highlight application and scientific relevance of enzymes. The EnzymeDetector genome annotation tool and the reaction database BKM-react including reactions from BRENDA, KEGG and MetaCyc were improved. The website was redesigned providing new query options.


Identification of the WNK-SPAK/OSR1 signaling pathway in rodent and human lenses.
To identify whether the kinases that regulate the activity of cation chloride cotransporters (CCC) in other tissues are also expressed in rat and human lenses. The expression of with-no-lysine kinase (WNK 1, 3, 4), oxidative stress response kinase 1 (OSR1), and Ste20-like proline alanine rich kinase (SPAK) were determined at either the transcript or protein levels in the rat and human lenses by reverse-transcriptase PCR and/or Western blotting, respectively. Selected kinases were regionally and subcellularly characterized in rat and human lenses. The transparency, wet weight, and tissue morphology of lenses extracted from SPAK knock-out animals was compared with wild-type lenses. WNK 1, 3, 4, SPAK, and OSR1 were identified at the transcript level in rat lenses and WNK1, 4, SPAK, and OSR1 expression confirmed at the protein level in both rat and human lenses. SPAK and OSR1 were found to associate with membranes as peripheral proteins and exhibited distinct subcellular and region-specific expression profiles throughout the lens. No significant difference in the wet weight of SPAK knock-out lenses was detected relative to wild-type lenses. However, SPAK knock-out lenses showed an increased susceptibility to opacification. Our results show that the WNK 1, 3, 4, OSR1, and SPAK signaling system known to play a role in regulating the phosphorylation status, and hence activity of the CCCs in other tissues, is also present in the rat and human lenses. The increased susceptibility of SPAK lenses to opacification suggests that disruption of this signaling pathway may compromise the ability of the lens to control its volume, and its ability to maintain its transparency.


The best of both worlds-bringing together cell biology and infection at the Institut Pasteur.
Only a profound understanding of the structure and function of cells-either as single units or in the context of tissues and whole organisms-will allow a comprehension of what happens in pathological conditions and provides the means to fight disease. The Cell Biology and Infection (BCI for Biologie Cellulaire et Infection) department was created in 2002 at the Institut Pasteur in Paris to develop a research program under the umbrella of cell biology, infection biology, and microbiology. Its visionary ambition was to shape a common framework for cellular microbiology, and to interface the latter with hard sciences like physics and mathematics and cutting-edge technology. This concept, ahead of time, has given high visibility to the field of cellular microbiology and quantitative cell biology, and it has allowed the successful execution of highly interdisciplinary research programs linking a molecular understanding of cellular events with disease. Now, the BCI department embraces additional pathologies, namely cancer and neurodegenerative diseases. Here, we will portray how the integrative research approach of BCI has led to major scientific breakthroughs during the last 10 years, and where we see scientific opportunities for the near future.


Introduction: philosophy in and philosophy of cognitive science.
Despite being there from the beginning, philosophical approaches have never had a settled place in cognitive research and few cognitive researchers not trained in philosophy have a clear sense of what its role has been or should be. We distinguish philosophy in cognitive research and philosophy of cognitive research. Concerning philosophy in cognitive research, after exploring some standard reactions to this work by nonphilosophers, we will pay particular attention to the methods that philosophers use. Being neither experimental nor computational, they can leave others bewildered. Thought experiments are the most striking example but not the only one. Concerning philosophy of cognitive research, we will pay particular attention to its power to generate and test normative claims, claims about what should and should not be done.


sfDM: Open-Source Software for Temporal Analysis and Visualization of Brain Tumor Diffusion MR Using Serial Functional Diffusion Mapping.
A major challenge in the diagnosis and treatment of brain tumors is tissue heterogeneity leading to mixed treatment response. Additionally, they are often difficult or at very high risk for biopsy, further hindering the clinical management process. To overcome this, novel advanced imaging methods are increasingly being adapted clinically to identify useful noninvasive biomarkers capable of disease stage characterization and treatment response prediction. One promising technique is called functional diffusion mapping (fDM), which uses diffusion-weighted imaging (DWI) to generate parametric maps between two imaging time points in order to identify significant voxel-wise changes in water diffusion within the tumor tissue. Here we introduce serial functional diffusion mapping (sfDM), an extension of existing fDM methods, to analyze the entire tumor diffusion profile along the temporal course of the disease. sfDM provides the tools necessary to analyze a tumor data set in the context of spatiotemporal parametric mapping: the image registration pipeline, biomarker extraction, and visualization tools. We present the general workflow of the pipeline, along with a typical use case for the software. sfDM is written in Python and is freely available as an open-source package under the Berkley Software Distribution (BSD) license to promote transparency and reproducibility.


A somitic Wnt16/Notch pathway specifies haematopoietic stem cells.
Haematopoietic stem cells (HSCs) are a self-renewing population of cells that continuously replenish all blood and immune cells during the lifetime of an individual. HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune-compatible donors remain serious problems. These difficulties have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in the specification of HSCs during embryonic development. Here we demonstrate in zebrafish that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signalling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are, in turn, required for the establishment of definitive haematopoiesis. Notch signalling downstream of Dlc and Dld is earlier than, and distinct from, known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite-specific gene expression is required for the production of haemogenic endothelium.


Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch.
alpha(2)-adrenergic receptors (alpha(2)AR) couple to multiple effectors including adenylyl cyclase and phospholipase C. We hypothesized that signaling selectivity to these effectors is dynamically directed by kinase-sensitive domains within the third intracellular loop of the receptor. Substitution of Ala for Ser232, which is in the N-terminal region of this loop in the alpha(2A)AR, resulted in a receptor that was markedly uncoupled ( approximately 82% impairment) from stimulation of inositol phosphate accumulation while the capacity to inhibit adenylyl cyclase remained relatively intact. In S232A alpha(2A)AR transfected cell membranes, agonist-promoted [(35)S]GTPgammaS binding was reduced by approximately 50%. Coexpression of modified G proteins rendered insensitive to pertussis toxin revealed that the S232A receptor was uncoupled from both G(i) and G(o). S232 is a potential PKC phosphorylation site, and whole cell phosphorylation studies showed that the mutant had depressed phosphorylation compared to wild type (1.3- vs 2.1-fold/basal). Consistent with S232 directing coupling to phospholipase C, PMA exposure resulted in approximately 67% desensitization of agonist-promoted inositol phosphate accumulation without significantly affecting inhibition of adenylyl cyclase. The dominant effect of mutation or phosphorylation at this site on inositol phosphate as compared to cAMP signaling was found to most likely be due to the low efficiency of signal transduction via phospholipase C vs adenylyl cyclase. Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.


Intraluminal suture occlusion of the middle cerebral artery in Spontaneously Hypertensive rats.
In models of middle cerebral artery occlusion using intraluminal suture, the size and the distribution of ischemic injury vary considerably among laboratories. In transcranial models of cerebral ischemia, a more consistent cerebral ischemic lesion is seen in Spontaneously Hypertensive rats (SHR). In the present study, we performed intraluminal suture occlusion of the MCA in SHR and compared its reproducibility with those in Sprague-Dawley (SD) rats. Male SHR and SD rats were anesthetized with halothane and subjected to 2 h of temporary middle cerebral artery occlusion by an intraluminal suture. Comparisons of regional cerebral blood flow figures taken throughout the experiment and lesion volume figures taken at 24 h after occlusion were made between the two groups. Total lesion volume in the SHR group was 263.6+/-30.5 mm3 (mean +/- SD), significantly larger and less variable than that in the SD group (145.4+/-123.7 mm3, p < 0.02). Throughout the ischemic period there was a tendency for rCBF to be lower in the SHR group than in the SD group. In some animals of both groups, recirculation could not be produced by withdrawal of the suture from the ICA. The mortality rate was 9% in the SD group and 17% in the SHR group. Intraluminal MCA occlusion in SHRs is associated with a more consistent, reliable and reproducible volume of ischemic injury. In the studies of temporary focal cerebral ischemia, this model must be accompanied by the monitoring of regional cerebral blood flow so as to obtain more reliable results.


Chemical speciation of nanoparticles surrounding metal-on-metal hips.
Spectromicroscopy of tissue surrounding failed CoCr metal-on-metal hip replacements detected corroded nanoscale debris in periprosthetic tissue in two chemical states, with concomitant mitochondrial damage. The majority of debris contained Cr(3+), with trace amounts of oxidised cobalt. A minority phase containing a core of metallic chromium and cobalt was also observed.


Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation.
Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL, P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP) responses were not (P=0.3). The response to ACh improved with infliximab treatment (P=0.004) in particular, with infliximab alone (P=0.03). AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.


Autoregulatory and paracrine control of synaptic and behavioral plasticity by octopaminergic signaling.
Adrenergic signaling has important roles in synaptic plasticity and metaplasticity. However, the underlying mechanisms of these functions remain poorly understood. We investigated the role of octopamine, the invertebrate counterpart of adrenaline and noradrenaline, in synaptic and behavioral plasticity in Drosophila. We found that an increase in locomotor speed induced by food deprivation was accompanied by an activity- and octopamine-dependent extension of octopaminergic arbors and that the formation and maintenance of these arbors required electrical activity. Growth of octopaminergic arbors was controlled by a cAMP- and CREB-dependent positive-feedback mechanism that required Octβ2R octopamine autoreceptors. Notably, this autoregulation was necessary for the locomotor response. In addition, octopamine neurons regulated the expansion of excitatory glutamatergic neuromuscular arbors through Octβ2Rs on glutamatergic motor neurons. Our results provide a mechanism for global regulation of excitatory synapses, presumably to maintain synaptic and behavioral plasticity in a dynamic range.


Watermelon extract supplementation reduces ankle blood pressure and carotid augmentation index in obese adults with prehypertension or hypertension.
Ankle-brachial index (ABI) and ankle blood pressure (BP) are associated with increased carotid wave reflection (augmentation index, AIx). Oral L-citrulline and L-arginine from synthetic or watermelon sources have reduced brachial BP, aortic BP, and aortic AIx. A directly measured carotid AIx (cAIx) rather than aortic AIx has been proposed as a better measurement of central AIx. We evaluated the effects of watermelon extract on ankle BP and cAIx in individuals with normal ABI and prehypertension or stage 1 hypertension. Ankle and brachial systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), cAIx, ABI, and heart rate (HR) were evaluated in the supine position in 14 adults (11 women/3 men, age 58 ± 1 years) with prehypertension or stage 1 hypertension (153 ± 4 mm Hg). Subjects were randomly assigned to 6 weeks of watermelon extract supplementation (L-citrulline/L-arginine, 6 g daily) or placebo followed by a 2-week washout period and then crossover. Ankle and brachial SBP (-11.5 ± 3.8 and -15.1 ± 2.8 mm Hg), DBP (-7.8 ± 2.3 and -7.6 ± 1.8 mm Hg), and MAP (-9.8 ± 2.6 and -7.3 ± 1.8 mm Hg), and cAIx (-8.8 ± 2.6 %) decreased significantly (P < 0.05) after watermelon supplementation compared to placebo. Watermelon supplementation had no significant effect (P > 0.05) on ABI and HR. This study shows that watermelon extract supplementation reduces ankle BP, brachial BP, and carotid wave reflection in obese middle-aged adults with prehypertension or stage 1 hypertension and normal ABI, which may reflect improved arterial function.


CPAP and measures of cardiovascular risk in males with OSAS.
Obstructive sleep apnoea syndrome (OSAS) has been associated with hypertension, stroke and myocardial ischaemia in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on established risk factors for cardiovascular disease remains incompletely understood. A total of 102 males with moderate-to-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 51) CPAP treatment for 4 weeks to investigate the effects of active treatment on 24-h urinary catecholamine excretion, baroreflex sensitivity (BRS), arterial stiffness (augmentation index) and 24-h ambulatory blood pressure (ABP). After 4 weeks of therapeutic CPAP, significant reductions were seen in urine normetanephrine excretion (from mean+/-sd 179.7+/-80.1 to 132.7+/-46.5 micromol x mol(-1) creatinine) and augmentation index (from 14.5+/-11.3 to 9.1+/-13.8%) compared with the subtherapeutic control group. Furthermore, therapeutic CPAP significantly improved BRS (from 7.1+/-3.3 to 8.8+/-4.2 ms x mmHg(-1)) and reduced mean arterial ABP by 2.6+/-5.4 mmHg. In conclusion, treatment of obstructive sleep apnoea with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness and by increasing sensitivity of the arterial baroreflex.