Characterization of the Obese Phenotype of Heart Failure With Preserved Ejection Fraction: A RELAX Trial Ancillary Study.
To characterize the obese heart failure with preserved ejection fraction (HFpEF) phenotype in a multicenter cohort. This was a secondary analysis of the randomized clinical trial RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) performed between October 1, 2008, and February 1, 2012. Patients with HFpEF were classified by body mass index (BMI) as obese (BMI≥35 kg/m2) and nonobese (BMI<30 kg/m2) for comparison. Obese patients with HFpEF (n=81) were younger (median age, 64 [interquartile range (IQR), 67-79] years vs 73 [IQR, 56-70] years; P<.001) but had greater peripheral edema (31% [25] vs 9% [6]; P<.001), more orthopnea (76% [56] vs 53% [35]; P=.005), worse New York Heart Association class (P=.006), and more impaired quality of life (P<.001) as compared with nonobese patients with HFpEF (n=70). Despite more severe signs and symptoms, obese patients with HFpEF had lower N-terminal pro B-type natriuretic peptide level (median, 481 [IQR, 176-1183] pg/mL vs 825 [IQR, 380-1679] pg/mL [to convert to pmol/L, multiply by 0.118]; P=.007) and lower left atrial volume index (median, 38 [IQR, 31-47] mL/m2 vs 54 [IQR, 41-63] mL/m2; P<.001). Serum C-reactive protein (median, 5.0 [IQR, 2.4-9.9] mg/dL vs 2.7 [IQR, 1.6-5.4] mg/dL [to convert to mg/L, multiply by 10-3]; P<.001) and uric acid (median, 7.8 [IQR, 6.1-8.7] mg/dL vs 6.8 [IQR, 5.5-8.3] mg/dL; P=.03) levels were higher in obese HFpEF, indicating greater systemic inflammation, than in nonobese HFpEF. Peak oxygen consumption was impaired in obese HFpEF (median, 11.1 [IQR, 9.6-14.4] mL/kg per minute vs 13.1 [IQR, 11.3-14.7] mL/kg per minute; P=.008), as was submaximal exercise capacity (6-minute walk distance, 272 [IQR, 200-332] m vs 355 [IQR, 290-415] m; P<.0001). Obese HFpEF is associated with decreased quality of life, worse symptoms of heart failure, greater systemic inflammation, worse exercise capacity, and higher metabolic cost of exertion as compared with nonobese HFpEF. Further study is required to understand the pathophysiology and potential distinct treatments for patients with the obese phenotype of HFpEF. clinicaltrials.gov Identifier: NCT00763867.


The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes.
The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.


Analysis of the 1998 outbreak of leptospirosis in Missouri in humans exposed to infected swine.
To determine the extent of leptospirosis in persons exposed to infected swine, confirm the source of disease, define risk factors for infection, and identify means for preventing additional infections during an outbreak in Missouri in 1998. Cross-sectional study. 240 people and 1,700 pigs. An epidemiologic investigation was conducted of people exposed to infected pigs from the University of Missouri-Columbia swine herd. The investigation included review of health of the pigs, a cross-sectional study of the people handling the pigs, serologic testing of human and porcine sera, and risk-factor analysis for leptospirosis within the human population. Serologic testing of samples collected at the time of the investigation indicated that 59% of the pigs had titers to leptospires, denoting exposure. Of the 240 people in the exposed study population, 163 (68%) were interviewed, and of these, 110 (67%) submitted a blood sample. Nine (8%) cases of leptospirosis were confirmed by serologic testing. Risk factors associated with leptospirosis included smoking (odds ratio [OR], 14.4; 95% confidence interval [CI], 1.39 to 137.74) and drinking beverages (OR, 5.1; 95% CI, 1.04 to 24.30) while working with infected pigs. Washing hands after work was protective (OR, 0.2; 95% CI, 0.03 to 0.81). Leptospirosis is a risk for swine producers and slaughterhouse workers, and may be prevented through appropriate hygiene, sanitation, and animal husbandry. It is essential to educate people working with animals or animal tissues about measures for reducing the risk of exposure to zoonotic pathogens.


Does pterygopalatine canal injection with local anaesthetic and adrenaline decrease bleeding during functional endoscopic sinus surgery?
To determine the effect of pterygopalatine fossa injection with xylocaine and adrenaline on: surgical field bleeding and blood loss during functional endoscopic sinus surgery for chronic rhinosinusitis, and the duration of the procedure. A prospective, single-blinded, controlled trial was performed in a tertiary care academic centre. A total of 45 patients undergoing functional endoscopic sinus surgery for chronic rhinosinusitis, whose disease was symmetrical based on computed tomography grading, were included. A unilateral pterygopalatine fossa injection with 1 per cent xylocaine and 1:100 000 adrenaline was performed after the induction of anaesthesia. The contralateral side served as the control. The operating surgeon, who was blinded to the injected side, assessed the surgical field using a validated six-item grading system. Blood loss, blood pressure, heart rate and end-tidal carbon dioxide were recorded every 15 minutes for each side separately, and duration of surgery was noted. There was no statistically significant difference in the surgical field grade between the injected and non-injected sides (p = 0.161). There were no differences in blood loss or duration of surgery. Pterygopalatine fossa injection prior to functional endoscopic sinus surgery did not decrease intra-operative surgical field bleeding, blood loss or duration of surgery.


Natural zinc ribbon HNH endonucleases and engineered zinc finger nicking endonuclease.
Many bacteriophage and prophage genomes encode an HNH endonuclease (HNHE) next to their cohesive end site and terminase genes. The HNH catalytic domain contains the conserved catalytic residues His-Asn-His and a zinc-binding site [CxxC](2). An additional zinc ribbon (ZR) domain with one to two zinc-binding sites ([CxxxxC], [CxxxxH], [CxxxC], [HxxxH], [CxxC] or [CxxH]) is frequently found at the N-terminus or C-terminus of the HNHE or a ZR domain protein (ZRP) located adjacent to the HNHE. We expressed and purified 10 such HNHEs and characterized their cleavage sites. These HNHEs are site-specific and strand-specific nicking endonucleases (NEase or nickase) with 3- to 7-bp specificities. A minimal HNH nicking domain of 76 amino acid residues was identified from Bacillus phage γ HNHE and subsequently fused to a zinc finger protein to generate a chimeric NEase with a new specificity (12-13 bp). The identification of a large pool of previously unknown natural NEases and engineered NEases provides more 'tools' for DNA manipulation and molecular diagnostics. The small modular HNH nicking domain can be used to generate rare NEases applicable to targeted genome editing. In addition, the engineered ZF nickase is useful for evaluation of off-target sites in vitro before performing cell-based gene modification.


A nurse-led structured education program improves self-management skills and reduces hospital readmissions in patients with chronic heart failure: a randomized and controlled trial in China.
Patient self-management skills are an important part of heart failure (HF) management. However, there is a lack of knowledge about the effectiveness of nurse-led education on patient self-management and the associated clinical outcomes of rural Chinese patients with chronic heart failure (CHF). As such, this study was designed to evaluate the impact of a nurse-led education program on patient self-management and hospital readmissions in rural Chinese patients with CHF. Ninety-six patients in the eastern Chinese province of Shandong with CHF were randomly divided into intervention and control groups. A structured education program was delivered to the intervention group during hospitalization and after discharge. Control group patients were managed as per clinical guidelines without structured education. Medication adherence, dietary modifications, social support, and symptom control were assessed 12 months after the educational intervention. The mean score of medication adherence, dietary modifications, social support and symptom control in the intervention group was higher than in the control group at the end of the study (p<0.01). The readmission rates for HF in the intervention and control group were 10.4% and 27.1%, respectively (p=0.036). This study has demonstrated that a structured education program was associated with a significant improvement in medication adherence, dietary modifications, social support, and symptom control in rural CHF patients. Furthermore, this program was associated with a significant reduction in hospital readmission. This study indicates that implementation of a nurse-led education program improves self-management and clinical outcomes of rural CHF patients, who may not have regular access to cardiac management services as per metropolitan populations.


Behavioral responses to mammalian blood odor and a blood odor component in four species of large carnivores.
Only little is known about whether single volatile compounds are as efficient in eliciting behavioral responses in animals as the whole complex mixture of a behaviorally relevant odor. Recent studies analysing the composition of volatiles in mammalian blood, an important prey-associated odor stimulus for predators, found the odorant trans-4,5-epoxy-(E)-2-decenal to evoke a typical "metallic, blood-like" odor quality in humans. We therefore assessed the behavior of captive Asian wild dogs (Cuon alpinus), African wild dogs (Lycaon pictus), South American bush dogs (Speothos venaticus), and Siberian tigers (Panthera tigris altaica) when presented with wooden logs that were impregnated either with mammalian blood or with the blood odor component trans-4,5-epoxy-(E)-2-decenal, and compared it to their behavior towards a fruity odor (iso-pentyl acetate) and a near-odorless solvent (diethyl phthalate) as control. We found that all four species displayed significantly more interactions with the odorized wooden logs such as sniffing, licking, biting, pawing, and toying, when they were impregnated with the two prey-associated odors compared to the two non-prey-associated odors. Most importantly, no significant differences were found in the number of interactions with the wooden logs impregnated with mammalian blood and the blood odor component in any of the four species. Only one of the four species, the South American bush dogs, displayed a significant decrease in the number of interactions with the odorized logs across the five sessions performed per odor stimulus. Taken together, the results demonstrate that a single blood odor component can be as efficient in eliciting behavioral responses in large carnivores as the odor of real blood, suggesting that trans-4,5-epoxy-(E)-2-decenal may be perceived by predators as a "character impact compound" of mammalian blood odor. Further, the results suggest that odorized wooden logs are a suitable manner of environmental enrichment for captive carnivores.


Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology.
The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma. Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm(2)). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen. Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma. This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.


Mathematical modelling of anisotropy in fibrous connective tissue.
We present two modelling frameworks for studying dynamic anistropy in connective tissue, motivated by the problem of fibre alignment in wound healing. The first model is a system of partial differential equations operating on a macroscopic scale. We show that a model consisting of a single extracellular matrix material aligned by fibroblasts via flux and stress exhibits behaviour that is incompatible with experimental observations. We extend the model to two matrix types and show that the results of this extended model are robust and consistent with experiment. The second model represents cells as discrete objects in a continuum of ECM. We show that this model predicts patterns of alignment on macroscopic length scales that are lost in a continuum model of the cell population.


Enzymatic degradation of urinary indoxyl sulfate by Providencia stuartii and Klebsiella pneumoniae causes the purple urine bag syndrome.
The etiology of the purple urine bag syndrome (PUBS), in which the urinary catheter bag of some elderly patients develops intense purple coloration, was studied. The purple was found to be a mixture of indirubin dissolved in the plastic and indigo on its surface. Six patients with PUBS were studied, and Providencia stuartii was isolated from the urine of five and Klebsiella pneumoniae was isolated from the urine of one. These strains produced indigo in 7.9 mM indoxyl sulfate-containing agar. One hundred and fifty isolates of 41 species of bacteria were tested for their ability to produce indigo on agar containing indoxyl sulfate, but only 17 of 27 strains of P. stuartii, a single strain of Klebsiella pneumoniae, and Enterobacter agglomerans were positive. All of the indigo-producing bacteria had an indoxyl phosphatase with a pI of 6.4. This enzyme also possessed indoxyl sulfatase activity and was not present in strains that were unable to produce indigo from indoxyl sulfate. We conclude that PUBS results from the decomposition of urinary indoxyl sulfate to indigo and indirubin by bacteria (notably P. stuartii). As elderly catheterized patients often have high urinary indoxyl sulfate levels and colonization of their urinary tract with P. stuartii, the condition is most commonly seen in them.


Culture- and metagenomics-enabled analyses of the Methanosphaera genus reveals their monophyletic origin and differentiation according to genome size.
The genus Methanosphaera is a well-recognized but poorly characterized member of the mammalian gut microbiome, and distinctive from Methanobrevibacter smithii for its ability to induce a pro-inflammatory response in humans. Here we have used a combination of culture- and metagenomics-based approaches to expand the representation and information for the genus, which has supported the examination of their phylogeny and physiological capacity. Novel isolates of the genus Methanosphaera were recovered from bovine rumen digesta and human stool, with the bovine isolate remarkable for its large genome size relative to other Methanosphaera isolates from monogastric hosts. To substantiate this observation, we then recovered seven high-quality Methanosphaera-affiliated population genomes from ruminant and human gut metagenomic datasets. Our analyses confirm a monophyletic origin of Methanosphaera spp. and that the colonization of monogastric and ruminant hosts favors representatives of the genus with different genome sizes, reflecting differences in the genome content needed to persist in these different habitats.


Differential activity for animals and manipulable objects in the anterior temporal lobes.
Neuropsychological evidence has highlighted the role of the anterior temporal lobes in the processing of conceptual knowledge. That putative role is only beginning to be investigated with fMRI as methodological advances are able to compensate for well-known susceptibility artifacts that affect the quality of the BOLD signal. In this article, we described differential BOLD activation for pictures of animals and manipulable objects in the anterior temporal lobes, consistent with previous neuropsychological findings. Furthermore, we found that the pattern of BOLD signal in the anterior temporal lobes is qualitatively different from that in the fusiform gyri. The latter regions are activated to different extents but always above baseline by images of the preferred and of the nonpreferred categories, whereas the anterior temporal lobes tend to be activated by images of the preferred category and deactivated (BOLD below baseline) by images of the nonpreferred category. In our experimental design, we also manipulated the decision that participants made over stimuli from the different semantic categories. We found that in the right temporal pole, the BOLD signal shows some evidence of being modulated by the task that participants were asked to perform, whereas BOLD activity in more posterior regions (e.g., the fusiform gyri) is not modulated by the task. These results reconcile the fMRI literature with the neuropsychological findings of deficits for animals after damage to the right temporal pole and suggest that anterior and posterior regions within the temporal lobes involved in object processing perform qualitatively different computations.


A potential case of remission of Parkinson's disease.
We present the case of a 78-year-old male who, 16 years ago, was diagnosed with Parkinson's disease (PD) by a neurologist. He initially presented with left-hand tremor, stooped posture, shuffling gait, and frequent falls, which eventually progressed to bilateral motor symptoms after 3 years. Since 2012, his symptoms and signs have almost completely remitted, and he has been off all pharmacotherapy for that time. The accuracy of the initial PD diagnosis is supported by an appropriate clinical presentation, history of positive response to Sinemet, and an abnormal SPECT DaT scan; thus this case suggests the possibility of remission of symptoms in some patients. We propose that the patient's long history of meditation practice may have been one contributing factor of this improvement as meditation has been shown to release dopamine in the striatum.


Perspectives on next steps in classification of oro-facial pain - part 1: role of ontology.
The purpose of this study was to review existing principles of oro-facial pain classifications and to specify design recommendations for a new system that would reflect recent insights in biomedical classification systems, terminologies and ontologies. The study was initiated by a symposium organised by the International RDC/TMD Consortium Network in March 2013, to which the present authors contributed. The following areas are addressed: problems with current classification approaches, status of the ontological basis of pain disorders, insufficient diagnostic aids and biomarkers for pain disorders, exploratory nature of current pain terminology and classification systems, and problems with prevailing classification methods from an ontological perspective. Four recommendations for addressing these problems are as follows: (i) develop a hypothesis-driven classification structure built on principles that ensure to our best understanding an accurate description of the relations among all entities involved in oro-facial pain disorders; (ii) take into account the physiology and phenomenology of oro-facial pain disorders to adequately represent both domains including psychosocial entities in a classification system; (iii) plan at the beginning for field-testing at strategic development stages; and (iv) consider how the classification system will be implemented. Implications in relation to the specific domains of psychosocial factors and biomarkers for inclusion into an oro-facial pain classification system are described in two separate papers.


Nicotinamide riboside regulates inflammation and mitochondrial markers in AML12 hepatocytes.
The NAD+ precursor nicotinamide riboside (NR) is a type of vitamin B3 found in cow's milk and yeast-containing food products such as beer. Recent studies suggested that NR prevents hearing loss, high-fat diet-induced obesity, Alzheimer's disease, and mitochondrial myopathy. The objective of this study was to investigate the effects of NR on inflammation and mitochondrial biogenesis in AML12 mouse hepatocytes. A subset of hepatocytes was treated with palmitic acid (PA; 250 µM) for 48 h to induce hepatocyte steatosis. The hepatocytes were treated with NR (10 µM and 10 mM) for 24 h with and without PA. The cell viability and the levels of sirtuins, inflammatory markers, and mitochondrial markers were analyzed. Cytotoxicity of NR was examined by PrestoBlue assay. Exposure to NR had no effect on cell viability or morphology. Gene expression of sirtuin 1 (Sirt1) and Sirt3 was significantly upregulated by NR in PA-treated hepatocytes. However, Sirt1 activities were increased in hepatocytes treated with low-dose NR. Hepatic pro-inflammatory markers including tumor necrosis factor-alpha and interleukin-6 were decreased in NR-treated cells. NR upregulated anti-inflammatory molecule adiponectin, and, tended to down-regulate hepatokine fetuin-A in PA-treated hepatocytes, suggesting its inverse regulation on these cytokines. NR increased levels of mitochondrial markers including peroxisome proliferator-activated receptor γ coactivator-1α, carnitine palmitoyltransferase 1, uncoupling protein 2, transcription factor A, mitochondrial and mitochondrial DNA in PA-treated hepatocytes. These data demonstrated that NR attenuated hepatic inflammation and increased levels of mitochondrial markers in hepatocytes.


Standardizing the evaluation criteria on treatment outcomes of mandibular implant overdentures: a systematic review.
The aim of this review was to analyze the evaluation criteria on mandibular implant overdentures through a systematic review and suggest standardized evaluation criteria. A systematic literature search was conducted by PubMed search strategy and hand-searching of relevant journals from included studies considering inclusion and exclusion criteria. Randomized clinical trials (RCT) and clinical trial studies comparing attachment systems on mandibular implant overdentures until December, 2011 were selected. Twenty nine studies were finally selected and the data about evaluation methods were collected. Evaluation criteria could be classified into 4 groups (implant survival, peri-implant tissue evaluation, prosthetic evaluation, and patient satisfaction). Among 29 studies, 21 studies presented implant survival rate, while any studies reporting implant failure did not present cumulative implant survival rate. Seventeen studies evaluating peri-implant tissue status presented following items as evaluation criteria; marginal bone level (14), plaque Index (13), probing depth (8), bleeding index (8), attachment gingiva level (8), gingival index (6), amount of keratinized gingiva (1). Eighteen studies evaluating prosthetic maintenance and complication also presented following items as evaluation criteria; loose matrix (17), female detachment (15), denture fracture (15), denture relining (14), abutment fracture (14), abutment screw loosening (11), and occlusal adjustment (9). Atypical questionnaire (9), Visual analog scales (VAS) (4), and Oral Health Impact Profile (OHIP) (1) were used as the format of criteria to evaluate patients satisfaction in 14 studies. For evaluation of implant overdenture, it is necessary to include cumulative survival rate for implant evaluation. It is suggested that peri-implant tissue evaluation criteria include marginal bone level, plaque index, bleeding index, probing depth, and attached gingiva level. It is also suggested that prosthetic evaluation criteria include loose matrix, female detachment, denture fracture, denture relining, abutment fracture, abutment screw loosening, and occlusal adjustment. Finally standardized criteria like OHIP-EDENT or VAS are required for patient satisfaction.


How good is cola for dissolution of gastric phytobezoars?
To evaluate the efficacy of cola treatment for gastric phytobezoars, including diospyrobezoars. A total of 17 patients (range: 48 to 78 years) with symptomatic gastric phytobezoars treated with cola and adjuvant endoscopic therapy were reviewed. Three liters of cola lavage (10 cases) or drink (7 cases) were initially used, and then endoscopic fragmentation was done for the remnant bezoars by using a lithotripsy basket or a polypectomy snare. The overall success of dissolving a gastric phytobezoars with using three liters of cola and the clinical and endoscopic findings were compared retrospectively between four cases of complete dissolution by using only cola and 13 cases of partial dissolution with cola. After 3 L of cola lavage or drinking, a complete dissolution of bezoars was achieved in four patients (23.5%), while 13 cases (76.5%) were only partially dissolved. Phytobezoars (4 of 6 cases) were observed more frequently than diospyrobezoars (0 of 11) in the group that underwent complete dissolution (P = 0.006). Gender, symptom duration, size of bezoar and method of cola administration were not significantly different between the two groups. Twelve of 13 patients with residual bezoars were completely treated with a combination of cola and endoscopic fragmentation. The rate of complete dissolution with three liters of cola was 23.5%, but no case of diospyrobezoar was completely dissolved using this method. However, pretreatment with cola may be helpful and facilitate endoscopic fragmentation of gastric phytobezoars.


Effects of time delay in cardiac blood flow measurements by bolus H2(15)O.
Myocardial blood flow (rMBF) can be measured using dynamic positron emission tomography (PET) and bolus injection of H2(15)O. Recent studies indicate that large errors in the estimates of flow (f) can be produced by time shifts between the true arterial input function and the measured input function [A(t)]. We have investigated this phenomenon further using A(t) derived from patient data, and using simulated myocardial time activity curves [M(t)]. We found that with judicious choice of scan parameters and region of interest (ROI) placement, these errors can be greatly reduced. In particular, when A(t) is measured from the left ventricular (LV) cavity, the bias in f is negligible over a wide range of circumstances. However, when A(t) is not measured from the LV cavity, the bias in flow can be large for short scans (< 2 min) or low flow values (f < 0.4 ml/g/min). We show that the bias is primarily due to the spill-over term in the model that is most commonly used to compute rMBF and suggest some correction methods. We conclude that it is possible to avoid errors in estimates of flow due to time delay.


Evaluation of publicly available documents to trace chiropractic technique systems that advocate radiography for subluxation analysis: a proposed genealogy.
The purpose of this study was to evaluate publicly available information of chiropractic technique systems that advocate radiography for subluxation detection to identify links between chiropractic technique systems and to describe claims made of the health effects of the osseous misalignment component of the chiropractic subluxation and radiographic paradigms. The Internet and publicly available documents were searched for information representing chiropractic technique systems that advocate radiography for subluxation detection. Key phrases including chiropractic, x-ray, radiography, and technique were identified from a Google search between April 2013 and March 2014. Phrases in Web sites and public documents were examined for any information about origins and potential links between these techniques, including the type of connection to BJ Palmer, who was the first chiropractor to advocate radiography for subluxation detection. Quotes were gathered to identify claims of health effects from osseous misalignment (subluxation) and paradigms of radiography. Techniques were grouped by region of the spine and how they could be traced back to B.J Palmer. A genealogy model and summary table of information on each technique were created. Patterns in year of origination and radiographic paradigms were noted, and percentages were calculated on elements of the techniques' characteristics in comparison to the entire group. Twenty-three techniques were identified on the Internet: 6 full spine, 17 upper cervical, and 2 techniques generating other lineage. Most of the upper cervical techniques (14/16) traced their origins to a time when the Palmer School was teaching upper cervical technique, and all the full spine techniques (6/6) originated before or after this phase. All the technique systems' documents attributed broad health effects to their methods. Many (21/23) of the techniques used spinal realignment on radiographs as one of their outcome measures. Chiropractic technique systems in this study (ie, those that advocate for radiography for subluxation misalignment detection) seem to be closely related by descent, their claims of a variety of health effects associated with chiropractic subluxation, and their radiographic paradigms.


A candidate for the attentional bottleneck: set-size specific modulation of the right TPJ during attentive enumeration.
Several recent behavioral studies have shown that the enumeration of a small number of items (a process termed subitizing) depends on the availability of attentional resources and is not a preattentive process as previously thought. Here we studied the neural correlates of visual enumeration under different attentional loads in a dual-task paradigm using fMRI. Relatively intact subitizing under low attentional load compared to impaired subitizing under high attentional load was associated with an increase in BOLD signal in the right temporo-parietal junction (rTPJ). Crucially, attentionally modulated response in the rTPJ was specific to small set sizes (up to 3 items) and did not occur at larger set sizes (5-7 items). This result has two implications: (1) Subitizing involves part of the fronto-parietal network for stimulus-driven attention providing neural evidence against preattentive subitizing. (2) Activity in rTPJ is set-size modulated. Together with similar evidence from studies probing visual short-term memory, this result suggests that rTPJ modulation might reflect the brain's ability to attentively handle small set sizes. Thus, the rTPJ may play an important role for the emergence of a capacity limit in both enumeration and visual short-term memory.


Revisiting blood pressure and body fluid status.
Homeostasis of body fluid is a key component for maintaining health. An imbalance of body sodium and water causes various pathological states, such as dehydration, volume overload, hypertension, cardiovascular and renal diseases, and metabolic disorders. Conventional concepts regarding physiology and pathophysiology of body sodium and water balance have been established by several assumptions. These assumptions are that the kidneys are the master regulator of body sodium and water content, and that sodium moves inside the body in parallel with water. However, recent clinical and basic studies have proposed alternative concepts. These concepts are that body sodium and water balance are regulated by various organs and multiple factors, such as physical activity and the environment, and that sodium accumulates locally in tissues independently of the blood status and/or water. Various concerns remain unclear, and the regulatory mechanism of body sodium, fluid, and blood pressure needs to be readdressed. In the present review article, we discuss novel concepts regarding the regulation of body sodium, water, and blood pressure with a particular focus on the systemic water conservation system and fluid loss-triggered elevation in blood pressure.


Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex.
We imaged axons in layer (L) 1 of the mouse barrel cortex in vivo. Axons from thalamus and L2/3/5, or L6 pyramidal cells were identified based on their distinct morphologies. Their branching patterns and sizes were stable over times of months. However, axonal branches and boutons displayed cell type-specific rearrangements. Structural plasticity in thalamocortical afferents was mostly due to elongation and retraction of branches (range, 1-150 microm over 4 days; approximately 5% of total axonal length), while the majority of boutons persisted for up to 9 months (persistence over 1 month approximately 85%). In contrast, L6 axon terminaux boutons were highly plastic (persistence over 1 month approximately 40 %), and other intracortical axon boutons showed intermediate levels of plasticity. Retrospective electron microscopy revealed that new boutons make synapses. Our data suggest that structural plasticity of axonal branches and boutons contributes to the remodeling of specific functional circuits.


Mycobacterium abscessus phospholipase C expression is induced during coculture within amoebae and enhances M. abscessus virulence in mice.
Mycobacterium abscessus is a pathogenic, rapidly growing mycobacterium involved in pulmonary and cutaneo-mucous infections worldwide, to which cystic fibrosis patients are exquisitely susceptible. The analysis of the genome sequence of M. abscessus showed that this bacterium is endowed with the metabolic pathways typically found in environmental microorganisms that come into contact with soil, plants, and aquatic environments, where free-living amoebae are frequently present. M. abscessus also contains several genes that are characteristically found only in pathogenic bacteria. One of them is MAB_0555, encoding a putative phospholipase C (PLC) that is absent from most other rapidly growing mycobacteria, including Mycobacterium chelonae and Mycobacterium smegmatis. Here, we report that purified recombinant M. abscessus PLC is highly cytotoxic to mouse macrophages, presumably due to hydrolysis of membrane phospholipids. We further showed by constructing and using an M. abscessus PLC knockout mutant that loss of PLC activity is deleterious to M. abscessus intracellular survival in amoebae. The importance of PLC is further supported by the fact that M. abscessus PLC was found to be expressed only in amoebae. Aerosol challenge of mice with M. abscessus strains that were precultured in amoebae enhanced M. abscessus lung infectivity relative to M. abscessus grown in broth culture. Our study underlines the importance of PLC for the virulence of M. abscessus. Despite the difficulties of isolating M. abscessus from environmental sources, our findings suggest that M. abscessus has evolved in close contact with environmental protozoa, which supports the argument that amoebae may contribute to the virulence of opportunistic mycobacteria.


Chromatin immunoprecipitation (ChIP) for analysis of histone modifications and chromatin-associated proteins.
Disruption of epigenetic regulators of transcription is a central mechanism of oncogenesis. Many of the advances in the understanding of these mechanisms are attributable to the successful development of chromatin immunoprecipitation (ChIP) for in vivo detection of histone modifications as well as chromatin binding regulatory proteins. This is a powerful technique for analyzing histone modifications as well as binding sites for proteins that bind either directly or indirectly to DNA. Here we present two ChIP protocols. The first is particularly useful for identifying histone modifications or binding at specific, known genomic sites. The second, employing serial analysis of gene expression, is particularly powerful for the discovery of previously unidentified sites of modification or binding.


[Measurement of methylmalonic acid, homocysteine and methionine in cobalamin and folate deficiencies and homocysteinuria].
Deficiencies of cobalamin (vitamin B12) or folate are common conditions that predispose for anemia and chronic diseases. An elevated concentration of methylmalonic acid in plasma/serum is an indicator of cobalamin deficiency, whereas an increased concentration of total homocysteine in plasma occurs with deficiency of both cobalamin and folate. The biomarkers methylmalonic acid and homocysteine are therefore complementary, and the combination is often requested when conventional tests fail to provide an unambiguous diagnosis. This article summarizes publications, retrieved through Medline, describing novel strategies for laboratory diagnostics of cobalamin and folate deficiencies. Adverse health effects of food fortification and uncritical supplementation with folic acid are explanations for a renewed interest in individual diagnosis of B-vitamin deficiency. Interpretation of methylmalonic acid and homocysteine test results requires knowledge of kidney function, as renal failure causes an increase in the concentrations of both metabolites. Homocystinuria is a condition that also causes increased levels of plasma homocysteine. This condition is an inborn error with a higher prevalence (1 : 6400) than previously recognized; which usually responds favourably to homocysteine-lowering therapy. Patients with homocysteinuria have high levels of methionine in plasma and knowledge of plasma methionine concentration may therefore distinguish these patients from those with conditions like B-vitamin deficiencies or renal failure, which are accompanied by normal or low to normal methionine concentrations. Complementarity, logistics, small sample volumes and costs therefore favour a combined analysis of methylmalonic acid, homocysteine and methionine in a single sample. Such an approach also allows assessment of cobalamin status in small volume capillary blood samples drawn from newborns and infants.


AKT pathway genes define 5 prognostic subgroups in glioblastoma.
Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.


Disparities in Breastfeeding Among Military Veterans.
Although breastfeeding is a major public health priority and provides numerous benefits, women veterans encounter many barriers to initiating and sustaining breastfeeding. Women veterans are a growing population with unique health care needs related to exposures and injuries experienced during military service. These military experiences are linked to health diagnoses known to impact postpartum health behaviors, such as breastfeeding. The aim of this study was to identify factors associated with breastfeeding at 4 weeks postpartum among women veterans. We used 2016-to-2018 survey data from women veterans (N = 420), interviewed before and after delivery, who were enrolled in maternity care coordination at a national sample of Veterans Health Administration facilities. Using the social ecological model, logistic regression was employed to explore the relationship between breastfeeding at least 4 weeks and postpartum and maternal/infant characteristics, interpersonal dynamics, community influences, and system factors. The rate of breastfeeding at 4 weeks postpartum was 78.6% among this sample of veterans. Self-employed participants were 2.8 times more likely to breastfeed than those who were employed outside the home. Participants who had been deployed at any point in their military career were twice as likely to breastfeed compared with those who never deployed. In this study sample, race independently predicted lower rates of breastfeeding, with African American participants being 48% less likely to breastfeed as compared with white participants. Our analysis suggests significant racial disparities in breastfeeding within veteran populations utilizing Veterans Health Administration, despite access to multiple sources of support from both the Veterans Health Administration and the community.


The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells.
The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 mumol/l ATP (with 2 mM Mg2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 mumol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.


Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia.
The purpose of this randomized, double-blind, placebo-controlled, parallel comparison study was to evaluate the lipid-lowering effect of orally administrated nattokinase and nattokinase combined with red yeast rice (RYR) extract on blood lipids in patients with hyperlipidemia. A total of 47 patients with hyperlipidemia were assigned to one of three groups: 1. nattokinase-mono formula (50 mg/capsule), 2. combined formula of nattokinase with RYR (300 mg of extract/capsule) and 3. placebo. Subjects received a twice daily dose of two capsules for six months. The mono formula showed no effects on blood lipids until month six, while the combined formula ameliorated all of measured lipids starting from month one. In the combined group significant decreases were found with regard to: triglycerides (TG) by 15%, total cholesterol (TC) by 25%, low-density lipoprotein cholesterol (LDL-C) by 41%, TC/high-density lipoprotein cholesterol (HDL-C) ratio by 29.5%, and increases in HDL-C by 7.5%. These changes were sustained until the end of study. After controlling for baseline levels, only the combined group, but not mono group, showed a significant difference (p<0.0001) in TC, LDL-C and TC/HDL-C ratio when compared with the placebo group. In summary, this study provides long-term efficacy of nattokinase supplementation and shows that the combined formula has relatively more potent effects than the mono formula on lowering of blood lipids, suggesting that combined nattokinase with RYR will be a better neutraceutical for patients with hyperlipidemia than nattokinase alone.


[Acute effects of adaptive servo-ventilation therapy on neurohormones and Cheyne-Stokes respiration in the patients with heart failure].
Cheyne Stokes respiration (CSR) is frequently seen in the patients with heart failure (HF) and it increases mortality. In the present study, we aimed to evaluate acute effects of adaptive servo ventilation (ASV) on CSR and neurohormones in the patients with HF. Nineteen males and 1 female patients with HF in the functional capacity of NYHA II-III were included into the study prospectively. One night polysomnography (PSG) was performed to all patients. In addition to medical treatment, 10 patients having CSR were applied ASV in another night together with PSG.. Arterial blood gases, plasma epinephrine and norepinephrine, serum N-terminal -pro-B type brain natriuretic peptide (NT-pro-BNP) were studied in the first night and after ASV treatment. A Wilcoxon test was used for comparison of parameters before and after treatment;and Mann-Whitney-U test was used for comparison of parameters between the patients with CSR and without CSR. Mean age of 10 patients with CSR was 62.2+/-11.1 years. Their etiologies were ischemic in 9 patients and idiopathic dilated cardiomyopathy in 1 patient. While there were no significant differences in the levels of PaCO2, HCO3, PH, before and after treatment; PaO2 (75.3 mmHg) and SatO2 (94.7%) significantly increased after the therapy (84.7 mmHg, 96.5% and p=0.007 and p=0.008 respectively). While NT-proBNP (3029.6+/-1450.5 pg/ml), norepinephrine (625.4+/-304.7 pg/ml) and epinephrine (65.4+/-24.1 pg/ml) were higher than normal before ASV treatment, all of them showed significant reductions after treatment (1694.0+/-925.9 pg/ml, 333.9+/-165.4 pg/ml and 45.0+/-20.5 pg/ml; p=0.005, p=0.005 and p=0.02, respectively). One night ASV treatment improves CSR, partial pressure of oxygen in arterial blood, and oxygen saturation and provides significant reductions in plasma catecholamines and NT-proBNP levels in the patients with HF and CSR. Prospective studies are needed to evaluate long-term effects of ASV treatment on morbidity and mortality in the patients with HF.


Nitrous oxide from moving bed based integrated fixed film activated sludge membrane bioreactors.
The present paper reports the results of a nitrous oxide (N2O) production investigation in a moving bed based integrated fixed film activated sludge (IFAS) membrane bioreactor (MBR) pilot plant designed in accordance with the University of Cape Town layout for biological phosphorous removal. Gaseous and liquid samples were collected in order to measure the gaseous as well as the dissolved concentration of N2O. Furthermore, the gas flow rate from each reactor was measured and the gas flux was estimated. The results confirmed that the anoxic reactor represents the main source of nitrous oxide production. A significant production of N2O was, however, also found in the anaerobic reactor, thus indicating a probable occurrence of the denitrifying phosphate accumulating organism activity. The highest N2O fluxes were emitted from the aerated reactors (3.09 g N2ON m-2 h-1 and 9.87 g N2ON m-2 h-1, aerobic and MBR tank, respectively). The emission factor highlighted that only 1% of the total treated nitrogen was emitted from the pilot plant. Furthermore, the measured N2O concentrations in the permeate flow were comparable with other reactors. Nitrous oxide mass balances outlined a moderate production also in the MBR reactor despite the low hydraulic retention time. On the other hand, the mass balance showed that in the aerobic reactor a constant consumption of nitrous oxide (up to almost 15 mg N2O h-1) took place, due to the high amount of stripped gas.


Structural Brain MRI Trait Polygenic Score Prediction of Cognitive Abilities.
Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygenic scores for these traits in three Scottish samples: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115-8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction samples that closely match the demographics of the GWA samples from which prediction is based. Ideally, these analyses should be repeated in larger samples with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.


Task-invariant brain responses to the social value of faces.
In two fMRI experiments (n = 44) using tasks with different demands-approach-avoidance versus one-back recognition decisions-we measured the responses to the social value of faces. The face stimuli were produced by a parametric model of face evaluation that reduces multiple social evaluations to two orthogonal dimensions of valence and power [Oosterhof, N. N., & Todorov, A. The functional basis of face evaluation. Proceedings of the National Academy of Sciences, U.S.A., 105, 11087-11092, 2008]. Independent of the task, the response within regions of the occipital, fusiform, and lateral prefrontal cortices was sensitive to the valence dimension, with larger responses to low-valence faces. Additionally, there were extensive quadratic responses in the fusiform gyri and dorsal amygdala, with larger responses to faces at the extremes of the face valence continuum than faces in the middle. In all these regions, participants' avoidance decisions correlated with brain responses, with faces more likely to be avoided evoking stronger responses. The findings suggest that both explicit and implicit face evaluation engage multiple brain regions involved in attention, affect, and decision making.


Shiitake Culinary-Medicinal Mushroom, Lentinus edodes (Agaricomycetes): A Species with Antioxidant, Immunomodulatory, and Hepatoprotective Activities in Hypercholesterolemic Rats.
Lentinus edodes is a culinary-medicinal mushroom that has an established history of use in Asian therapies. The mushroom offers well-documented beneficial health effects such as antihypercholesterolemic, antitumor, and antibacterial activities. In this study, dried powder of L. edodes fruiting bodies was used to evaluate immunomodulatory, hepatoprotective, and antioxidant effects in hypercholesterolemic rats. Albino rats (n = 24) were divided into 3 groups: the control (CON) group, the hypercholesterolemia-only group (HCG), and the L. edodes group (LEG). Hypercholesterolemia was induced in rats in the HCG and LEG by feeding cholesterol and cholic acid in a chow maintenance diet (CMD) for 24 days. The CON group was fed the CMD throughout the experiment. The HCG continued on the high-cholesterol diet without any L. edodes supplement. The LEG was fed the high-cholesterol diet supplemented with L. edodes for an additional 42 days. Various biological health biomarkers, such as total antioxidant capacity, total oxidant status, arylesterase, paraoxonase activity, and liver enzymes in serum were studied to evaluate antioxidant and hepatoprotective responses. Cell-mediated immunity was evaluated in each group through a delayed type of hypersensitivity reaction. The total oxidant status decreased significantly (P ≤ 0.05) after administration of L. edodes in the diet. The cell-mediated immune response significantly increased (P ≤ 0.05) in the LEG. The significant decrease in liver enzymes supports the hepatoprotective effect of L. edodes. In conclusion, the results show the immunomodulatory, hepatoprotective, and antioxidant activities of L. edodes supplementation in hypercholesterolemic rats.


A regional health care system partnership with local communities to impact chronic disease.
Regional health care systems have significant opportunities to adopt community-oriented approaches that impact the incidence and burden of chronic disease. In 1998, a vertically integrated, regional health care system established a community health institute to identify, understand, and respond to health needs from a community perspective. The project was implemented in four communities (two rural counties, a rural/urban transitional county, and an inner-city community) using five steps: 1) support or form a local community coalition; 2) hire and support a local coordinator; 3) prepare a formal community assessment; 4) fund locally designed interventions; and 5) evaluate each project. In four narrative case studies, we present the steps, challenges, and common principles faced at the local level by Carolinas Community Health Institute. The case studies were prepared using three data sources: reviews of written documents, interviews with the seven-member steering committee, and interviews with six key informants from each county. Data were coded and analyzed using standard qualitative software to identify common themes and sources of variance between cases. The project model was generally well accepted. Local autonomy and domain disputes were challenges in all four sites. Funding for local projects was the most frequently cited benefit. The project was successful in increasing local capacity and supporting well-designed interventions to prevent chronic disease. This approach can be used by large health care systems and by other organizations to better support local health initiatives.


Effects of novel tubing gait on neuromuscular imbalance in cerebral palsy.
Gait impairments from a neuromuscular imbalance are crucial issues in cerebral palsy. The purpose of our study was to compare the effects of the assistive tubing gait (ATG) and assistive-resistive tubing gait (ARTG) on improving the vasti and hamstring muscle imbalance during the initial contact to mid-stance phases in individuals with spastic diplegic cerebral palsy (CP). Fourteen age-matched individuals including seven normal individuals (11.7 years) and seven individuals with CP (12.9 years) were recruited. All participants underwent electromyography (EMG) measurement of the unilateral vasti and hamstring muscle activity during the three gait training conditions of no-tubing gait (NTG), ATG, and ARTG. A statistical one-way repeated-measure analysis of variance (ANOVA) was used to determine differences in the vasti and hamstring activity, the vasti/hamstring ratio, and the knee joint angle across the three gait training conditions for each group. The initial vasti and hamstring muscle imbalance in CP was significantly improved by applying the ARTG compared with the ATG. The vasti/hamstring ratio during the ARTG was compatible with the ratio value obtained from the NTG of normal individuals. The knee joint angle in CP was not improved in this short-term intervention. The ARTG proportionately increased the vasti activation and reciprocally inhibited the hamstring activity, subsequently improving the neuromuscular imbalance associated with the flexed-knee gait in individuals with spastic diplegic CP.


Kickboxing power hour: case report of fifth metatarsal apophysitis (Iselin disease) and its magnetic resonance imaging features.
Youth now-a-days are getting more involved in mixed martial arts, with increasing number of cases of lateral foot pain due to various causes. The differential diagnoses of lateral foot pain in the pediatric population include avulsion fracture of the fifth metatarsal base, Jones fracture, diaphyseal stress fracture as well as os vesalianum pedis. We present a case of a 15-year-old athletic boy who presented with left lateral foot pain for a few weeks. The patient was actively involved in Kickboxing as well as active running. Left foot radiographs were normal, including normal radiographic appearance of the fifth metatarsal apophysis. Due to ongoing pain, magnetic resonance imaging of the left foot was performed, which revealed apophysitis of the fifth metatarsal, known as Iselin disease. Iselin disease has been postulated to be caused by traction on the fifth metatarsal apophysis by performing sidekicks or round kicks during the kickboxing practice. Iselin disease should be suspected in young children of 10-15 years age involved in physical activity presenting with lateral foot pain. Magnetic resonance imaging is extremely useful to correctly diagnose this condition and avoid misdiagnosis of a fracture.


The interaction between self-bias and reward: Evidence for common and distinct processes.
The perceptual matching of shapes and labels can be affected by both self- and reward-biases when shapes are linked either to labels referring to particular individuals (you, friend, stranger) or to different reward values (£8, £2, £0). We investigated the relations between these biases by varying the reward value associated with particular shape-label pairs (circle-you, square-friend, triangle-stranger). Self shape-label pairs (circle-you) always received no reward, while friend shape-label pairs (square-friend) received high reward and stranger shape-label pairs low reward (triangle-stranger), or the reverse (friend-low reward; stranger-high reward). Despite receiving no reward, responses to self-related pairs were advantaged relative to those to low-reward stimuli and did not differ from those to high-reward items. There was also an advantage for responses to high-reward friend pairs relative to low-reward stranger stimuli, and for high-reward stranger stimuli compared to low-reward friends. Correlations across individuals were found across trial blocks for both the self-advantage and the high-reward advantage, but the self- and reward-advantages were uncorrelated. This suggests that the self- and reward-advantage effects have different origins. In addition, the magnitude of the self-advantage varied according to the rated personal distance between a participant and a stranger. For individuals manifesting a close personal distance to strangers, the self-advantage was smaller, and sensitivity to reward influenced the difference between the self- and high-reward conditions. For individuals manifesting a large personal distance to strangers, sensitivity to reward did not affect self-matching. We suggest that self-advantages on perceptual matching arise independent of reward for individuals with a large personal distance to strangers. On the other hand, in individuals with a weak self-bias, high reward and the self modulate a common subjective value system.


Quantification and statistical modeling--part I: breathing-zone concentrations of monomeric and polymeric 1,6-hexamethylene diisocyanate.
We conducted a repeated exposure-assessment survey for task-based breathing-zone concentrations (BZCs) of monomeric and polymeric 1,6-hexamethylene diisocyanate (HDI) during spray painting on 47 automotive spray painters from North Carolina and Washington State. We report here the use of linear mixed modeling to identify the primary determinants of the measured BZCs. Both one-stage (N = 98 paint tasks) and two-stage (N = 198 paint tasks) filter sampling was used to measure concentrations of HDI, uretidone, biuret, and isocyanurate. The geometric mean (GM) level of isocyanurate (1410 microg m(-3)) was higher than all other analytes (i.e. GM < 7.85 microg m(-3)). The mixed models were unique to each analyte and included factors such as analyte-specific paint concentration, airflow in the paint booth, and sampler type. The effect of sampler type was corroborated by side-by-side one- and two-stage personal air sampling (N = 16 paint tasks). According to paired t-tests, significantly higher concentrations of HDI (P = 0.0363) and isocyanurate (P = 0.0035) were measured using one-stage samplers. Marginal R(2) statistics were calculated for each model; significant fixed effects were able to describe 25, 52, 54, and 20% of the variability in BZCs of HDI, uretidone, biuret, and isocyanurate, respectively. Mixed models developed in this study characterize the processes governing individual polyisocyanate BZCs. In addition, the mixed models identify ways to reduce polyisocyanate BZCs and, hence, protect painters from potential adverse health effects.


Single-walled carbon nanotube incorporated novel three phase carbon/epoxy composite with enhanced properties.
In the present work, single-walled carbon nanotubes were dispersed within the matrix of carbon fabric reinforced epoxy composites in order to develop novel three phase carbon/epoxy/single-walled carbon nanotube composites. A combination of ultrasonication and high speed mechanical stirring at 2000 rpm was used to uniformly disperse carbon nanotubes in the epoxy resin. The state of carbon nanotube dispersion in the epoxy resin and within the nanocomposites was characterized with the help of optical microscopy and atomic force microscopy. Pure carbon/epoxy and three phase composites were characterized for mechanical properties (tensile and compressive) as well as for thermal and electrical conductivity. Fracture surfaces of composites after tensile test were also studied in order to investigate the effect of dispersed carbon nanotubes on the failure behavior of composites. Dispersion of only 0.1 wt% nanotubes in the matrix led to improvements of 95% in Young's modulus, 31% in tensile strength, 76% in compressive modulus and 41% in compressive strength of carbon/epoxy composites. In addition to that, electrical and thermal conductivity also improved significantly with addition of carbon nanotubes.


Eye-hand coordination in object manipulation.
We analyzed the coordination between gaze behavior, fingertip movements, and movements of the manipulated object when subjects reached for and grasped a bar and moved it to press a target-switch. Subjects almost exclusively fixated certain landmarks critical for the control of the task. Landmarks at which contact events took place were obligatory gaze targets. These included the grasp site on the bar, the target, and the support surface where the bar was returned after target contact. Any obstacle in the direct movement path and the tip of the bar were optional landmarks. Subjects never fixated the hand or the moving bar. Gaze and hand/bar movements were linked concerning landmarks, with gaze leading. The instant that gaze exited a given landmark coincided with a kinematic event at that landmark in a manner suggesting that subjects monitored critical kinematic events for phasic verification of task progress and subgoal completion. For both the obstacle and target, subjects directed saccades and fixations to sites that were offset from the physical extension of the objects. Fixations related to an obstacle appeared to specify a location around which the extending tip of the bar should travel. We conclude that gaze supports hand movement planning by marking key positions to which the fingertips or grasped object are subsequently directed. The salience of gaze targets arises from the functional sensorimotor requirements of the task. We further suggest that gaze control contributes to the development and maintenance of sensorimotor correlation matrices that support predictive motor control in manipulation.


Iron Chelation with Transdermal Deferoxamine Accelerates Healing of Murine Sickle Cell Ulcers.
Objective: Sickle cell ulcers (SCUs) are a devastating comorbidity affecting patients with sickle cell disease (SCD). SCUs form over the medial or lateral malleoli of the lower extremity, are slow to heal, and prone to recidivism. Some SCUs may never heal, leading to chronic pain and foot deformities. There is no specific and effective therapy for SCUs. Systemic deferoxamine (DFO) has been demonstrated to prevent some of the sequelae of SCD by chelating iron. In this study, we tested the ability of DFO delivered via a transdermal delivery system (DFO-TDDS) to accelerate healing in a murine model of SCU. Approach: Excisional wounds were created in a transgenic murine model of SCD expressing >99% human sickle hemoglobin, and healing rates were compared with wounds in wild-type mice. Next, excisional wounds in SCD mice were treated with DFO-TDDS, DFO injection, or left untreated. Wound closure rates, histology, and iron in the healed wounds were analyzed. Results: Wounds in SCD mice healed significantly slower than wild-type mice (***p < 0.001). DFO-TDDS-treated wounds demonstrated significantly accelerated time to closure, reduced size, and improved wound remodeling compared with untreated wounds (***p < 0.001) and DFO injection treatment (*p < 0.05). DFO released from the TDDS into wounds resulted in chelation of excessive dermal-free iron. Innovation: DFO-TDDS is a novel therapeutic that is effective in healing wounds in sickle cell mice. Conclusion: DFO-TDDS significantly accelerates healing of murine SCUs by chelation of excessive free iron and is currently manufactured in an FDA-compliant facility to be translated for treating human SCUs.


CozE is a member of the MreCD complex that directs cell elongation in Streptococcus pneumoniae.
Most bacterial cells are surrounded by a peptidoglycan cell wall that is essential for their integrity. The major synthases of this exoskeleton are called penicillin-binding proteins (PBPs)1,2. Surprisingly little is known about how cells control these enzymes, given their importance as drug targets. In the model Gram-negative bacterium Escherichia coli, outer membrane lipoproteins are critical activators of the class A PBPs (aPBPs)3,4, bifunctional synthases capable of polymerizing and crosslinking peptidoglycan to build the exoskeletal matrix1. Regulators of PBP activity in Gram-positive bacteria have yet to be discovered but are likely to be distinct due to the absence of an outer membrane. To uncover Gram-positive PBP regulatory factors, we used transposon-sequencing (Tn-Seq)5 to screen for mutations affecting the growth of Streptococcus pneumoniae cells when the aPBP synthase PBP1a was inactivated. Our analysis revealed a set of genes that were essential for growth in wild-type cells yet dispensable when pbp1a was deleted. The proteins encoded by these genes include the conserved cell wall elongation factors MreC and MreD2,6,7, as well as a membrane protein of unknown function (SPD_0768) that we have named CozE (coordinator of zonal elongation). Our results indicate that CozE is a member of the MreCD complex of S. pneumoniae that directs the activity of PBP1a to the midcell plane where it promotes zonal cell elongation and normal morphology. CozE homologues are broadly distributed among bacteria, suggesting that they represent a widespread family of morphogenic proteins controlling cell wall biogenesis by the PBPs.


Novel anti-CD4 monoclonal antibodies separate human immunodeficiency virus infection and fusion of CD4+ cells from virus binding.
Human immunodeficiency virus (HIV) binds to cells via an interaction between CD4 and the virus envelope glycoprotein, gp120. Previous studies have localized the high affinity binding site for gp120 to the first domain of CD4, and monoclonal antibodies (mAbs) reactive with this region compete with gp120 binding and thereby block virus infectivity and syncytium formation. Despite a detailed understanding of the binding of gp120 to CD4, little is known of subsequent events leading to membrane fusion and virus entry. We describe two new mAbs reactive with the third domain of CD4 that inhibit steps subsequent to virus binding critical for HIV infectivity and cell fusion. Binding of recombinant gp120 or virus to CD4 is not inhibited by these antibodies, whereas infection and syncytium formation by a number of HIV isolates are blocked. These findings demonstrate that in addition to virus binding, CD4 may have an active role in membrane fusion.


Medical school attrition-beyond the statistics a ten year retrospective study.
Medical school attrition is important--securing a place in medical school is difficult and a high attrition rate can affect the academic reputation of a medical school and staff morale. More important, however, are the personal consequences of dropout for the student. The aims of our study were to examine factors associated with attrition over a ten-year period (2001-2011) and to study the personal effects of dropout on individual students. The study included quantitative analysis of completed cohorts and qualitative analysis of ten-year data. Data were collected from individual student files, examination and admission records, exit interviews and staff interviews. Statistical analysis was carried out on five successive completed cohorts. Qualitative data from student files was transcribed and independently analysed by three authors. Data was coded and categorized and key themes were identified. Overall attrition rate was 5.7% (45/779) in 6 completed cohorts when students who transferred to other medical courses were excluded. Students from Kuwait and United Arab Emirates had the highest dropout rate (RR = 5.70, 95% Confidence Intervals 2.65 to 12.27;p < 0.0001) compared to Irish and EU students combined. North American students had a higher dropout rate than Irish and EU students; RR = 2.68 (1.09 to 6.58;p = 0.027) but this was not significant when transfers were excluded (RR = 1.32(0.38, 4.62);p = 0.75). Male students were more likely to dropout than females (RR 1.70, .93 to 3.11) but this was not significant (p = 0.079).Absenteeism was documented in 30% of students, academic difficulty in 55.7%, social isolation in 20%, and psychological morbidity in 40% (higher than other studies). Qualitative analysis revealed recurrent themes of isolation, failure, and despair. Student Welfare services were only accessed by one-third of dropout students. While dropout is often multifactorial, certain red flag signals may alert us to risk of dropout including non-EU origin, academic struggling, absenteeism, social isolation, depression and leave of absence. Psychological morbidity amongst dropout students is high and Student Welfare services should be actively promoted. Absenteeism should prompt early intervention. Behind every dropout statistic lies a personal story. All medical schools have a duty of care to support students who leave the medical programme.


Tetrahydrobiopterin-deficient nitric oxide synthase has a modified heme environment and forms a cytochrome P-420 analogue.
Optical absorption and resonance Raman spectra of neuronal nitric oxide synthase (b-NOS) isolated in the absence of tetrahydrobiopterin demonstrate that the enzyme preparation is very unstable. This unstable form of the enzyme has properties analogous to those of cytochrome P-420cam, an inactive form of cytochrome P-450cam. Although cysteine is preserved as the proximal ligand in both the ferric and ferrous forms of unstable b-NOS, the lack of tetrahydrobiopterin significantly increases the hexacoordinate low-spin fraction of the heme content, resulting in a loss of the enzymatic activity. Upon the addition of CO, the unstable b-NOS converts from a species exhibiting a Soret absorption maximum at 443 nm, as reported for the CO adducts of stable b-NOS and cytochrome P-450cam, to a species with a Soret maximum at 421 nm. The resonance Raman spectrum of the 421-nm form is the same as those of CO-bound myoglobin at low pH and CO-bound cytochrome P-420cam. The heme in this form of the enzyme is coordinated by a weaker ligand than thiolate; histidine coordination in the CO-bound form of the P-420-like species of NOS is consistent with all of the available data. A similar unstable form of the macrophage (i-NOS) enzyme was also detected. Not only does the heme pocket of NOS have the same coordination as cytochrome P-450 in its stable form, but the partially denatured form has the same properties as cytochrome P-420, the inactive form of cytochrome P-450. Among other possible roles, tetrahydrobiopterin may play a significant role in the stabilization of the active enzyme.


Cultural constructions of the concept of household in sample surveys.
We analyse the use of the concept of household in sample surveys, with evidence drawn from a review of survey definitions, a series of in-depth interviews with data producers and users, and a systematic study of recent literature. We consider the place of the concept within the discipline of demography, and demonstrate how its definition and use interact with cultural values and core concepts integral to the discipline. Focusing on Tanzania as a case study, we examine the diversity of factors that influence the construction of household-level data from cross-sectional household surveys. Throughout the survey process, contrasting interpretations of the meaning of household and different motivations for using specific definitions of the term interact. This generates data and outputs with potential for undercounting, bias, and misrepresentations, with adverse effects on the quality of data used for monitoring development indicators. Some ways of improving data collection on households are proposed.


Trehalose glass-facilitated thermal reduction of metmyoglobin and methemoglobin.
The reduction of ferric derivatives of hemeproteins in solution typically requires moderate to strong reducing agents. Reducing sugars are not adequate to reduce ferric myoglobins or hemoglobins under solution conditions favorable to protein stability. We find that embedding aquo-met derivatives of horse myoglobin and human adult hemoglobin in a glucose-doped glassy matrix derived from trehalose facilitates an efficient thermally initiated reduction that yields a five-coordinate high-spin ferrous heme. The trehalose glass plays a central role by stabilizing the reduction-prone bis-histidine heme (hemichrome) intermediate under the high-temperature conditions that favor the open reducing form of glucose. Due to glass-imposed limitations on conformational reorganization, this process has clear applications in biophysics where it can be used to generate nonequilibrium ferrous derivatives having the initial conformation of the aquo-met derivative. Since the glassy matrix can be redissolved to release the embedded protein, this technique is not only a basis for a relatively benign method of reducing hemoglobin-based blood substitutes that have undergone autoxidation during storage but may also be a way to reactivate stored proteins that have undergone oxidation.


An activated sulfonylating agent that undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis.
Activated sulfonyl derivatives, similar to acyl ones, usually undergo aminolysis with amines in water as nucleophilic attack by the amine is preferred to hydrolysis. However, despite being active sulfonyl derivatives, four-membered heterocyclic sulfonamides, beta-sultams, do not undergo aminolysis in aqueous solution but preferentially react to give hydrolysis products only. The rate of the reaction of beta-sultams in buffered solutions of simple primary amines shows a first-order dependence on amine concentrations attributed to general base-catalyzed hydrolysis by the amine. Even N-benzyl-4,4-dimethyl-3-oxo-beta-sultam, which is both a beta-sultam and a beta-lactam, undergoes hydrolysis at the sulfonyl center rather than aminolysis at either the sulfonyl or acyl center. The solvent kinetic isotope effects (SKIE, k(H(2)O)/k(D(2)O)) for the amine-catalyzed hydrolyses are 1.4 and 1.9 for the hydrolysis of N-benzoyl-beta-sultam and N-benzyl-4,4-dimethyl-3-oxo-beta-sultam, respectively, compatible with a general base-catalyzed mechanism. The amine-catalyzed hydrolysis gives a Bronsted beta value of +0.9 for both N-benzoyl beta-sultam and N-benzyl-4,4-dimethyl-3-oxo-beta-sultam, indicating that the general base amine is almost fully protonated in the transition state. A general base-catalyzed mechanism for hydrolysis rather than nucleophilic attack was also deduced for the reaction of N-benzyl-4,4-dimethyl-3-oxo-beta-sultam with carboxylate anions based on a SKIE of 1.7-1.9 and rate constants which fit the Bronsted plot for amines. In contrast to acyl transfer reactions, those for sulfonyl transfer appear to show an inverse reactivity-selectivity relationshipthe most active compounds being the most selective. The lack of reactivity of beta-sultams toward amine nucleophiles appears to be related to the mechanism of ring opening of beta-sultams with a decreased reactivity toward amines relative to hydroxide ion, probably related to the expulsion of the relatively poor leaving group amide anion.


Upper limb disability in Norwegian workers with hand-arm vibration syndrome.
Hand-arm vibration syndrome (HAVS) is a well-known disease among workers using hand-held vibrating tools. These patients experience major symptoms from their upper limbs. However, there are few studies on disability in this patient group. In this study we wanted to describe the disability of HAVS patients. All HAVS patients diagnosed at Haukeland University Hospital in Bergen, Norway in a five-year period were invited. The disabilities of the arm, shoulder and hand (DASH) questionnaire was sent by mail. Clinical data were extracted from their hospital journals. Descriptive statistics and regression analyses were performed. Thirty-eight patients were recruited. Mean DASH score was 41.2, while the mean of a normal population is 10. Ability to perform tasks related to work and everyday life was affected in these patients. We found a significant association between the DASH score, hand grip strength and tendinitis, also after adjustment for age and smoking in pack-years. HAVS patients demonstrate a high level of upper limb disability as assessed by the DASH score. Ability to perform tasks related to work and everyday life was affected. We found a significant association between the DASH score, hand grip strength and tendinitis. This should be focused upon in future research.


Solidification of a supercooled liquid in a narrow channel.
We simulate solidification in a narrow channel through the use of a phase-field model with an adaptive grid. In different regimes, we find that the solid can grow in fingerlike steady-state shapes, or become unstable, exhibiting unsteady growth. At low melt undercoolings, we find good agreement between our results, theoretical predictions, and experiment. For high undercoolings, we report evidence for a new stable steady-state finger shape which exists in experimentally accessible ranges for typical materials.


Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway.
In a previous study we demonstrated the ability of dopamine (DA) to stimulate phospholipid methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.


Daily positive spillover and crossover from mothers' work to youth health.
Prior research shows that employees' work experiences can "spill over" into their family lives and "cross over" to affect family members. Expanding on studies that emphasize negative implications of work for family life, this study examined positive work-to-family spillover and positive and negative crossover between mothers and their children. Participants were 174 mothers in the extended care (nursing home) industry and their children (ages 9-17), both of whom completed daily diaries on the same 8 consecutive evenings. On each workday, mothers reported whether they had a positive experience at work, youth reported on their mothers' positive and negative mood after work, and youth rated their own mental (positive and negative affect) and physical health (physical health symptoms, sleep quality, sleep duration). Results of 2-level models showed that mothers' positive mood after work, on average, was directly related to youth reports of more positive affect, better sleep quality, and longer sleep duration. In addition, mothers with more positive work experiences, on average, displayed less negative mood after work, and in turn, adolescents reported less negative affect and fewer physical health symptoms. Results are discussed in terms of daily family system dynamics.


Patient-centered outcome criteria for successful treatment of facial pain and fibromyalgia.
To define treatment success from the facial pain and fibromyalgia pain patient perspective across four domains (pain, fatigue, emotional distress, interference with daily activities) through the use of the Patient-Centered Outcomes (PCO) Questionnaire. Participants included 53 facial pain (46 women, seven men) and 52 fibromyalgia (49 women, three men) patients who completed the PCO Questionnaire. The PCO assesses four relevant domains of chronic pain: pain, fatigue, distress, and interference in daily activities. Participants rated their usual levels, expected levels, levels they considered successful improvements, and how important improvements were in each of the four domains following treatment. Repeated-measures analyses of variance were performed to determine whether differences existed across domains and across pain groups. Both groups of participants defined treatment success as a substantial decrease in their pain, fatigue, distress, and interference ratings (all approximately 60%). Fibromyalgia participants reported high levels of pain (mean = 7.08, SD = 2.04), fatigue (mean = 7.82, SD = 1.71), distress (mean = 6.35, SD = 2.46), and interference (mean = 7.35, SD = 2.21). Facial pain participants' ratings of these domains were significantly lower for pain (mean = 5.62, SD = 2.38), fatigue (mean = 5.28, SD = 2.64), distress (mean = 4.34, SD = 2.78), and interference (mean = 4.10, SD = 3.06). These results demonstrate the high expectations of individuals with facial pain and fibromyalgia regarding treatment of their symptoms. Health care providers should incorporate these expectations into their treatment plans and discuss realistic treatment goals with their pain patients.


Spatially complex distribution of dissolved manganese in a fjord as revealed by high-resolution in situ sensing using the autonomous underwater vehicle Autosub.
Loch Etive is a fjordic system on the west coast of Scotland. The deep waters of the upper basin are periodically isolated, and during these periods oxygen is lost through benthic respiration and concentrations of dissolved manganese increase. In April 2000 the autonomous underwater vehicle (AUV) Autosub was fitted with an in situ dissolved manganese analyzer and was used to study the spatial variability of this element together with oxygen, salinity, and temperature throughout the basin. Six along-loch transects were completed at either constant height above the seafloor or at constant depth below the surface. The ca. 4000 in situ 10-s-average dissolved Mn (Mnd) data points obtained provide a new quasi-synoptic and highly detailed view of the distribution of manganese in this fjordic environment not possible using conventional (water bottle) sampling. There is substantial variability in concentrations (<25 to >600 nM) and distributions of Mnd. Surface waters are characteristically low in Mnd reflecting mixing of riverine and marine end-member waters, both of which are low in Mnd. The deeper waters are enriched in Mnd, and as the water column always contains some oxygen, this must reflect primarily benthic inputs of reduced dissolved Mn. However, this enrichment of Mnd is spatially very variable, presumably as a result of variability in release of Mn coupled with mixing of water in the loch and removal processes. This work demonstrates how AUVs coupled with chemical sensors can reveal substantial small-scale variability of distributions of chemical species in coastal environments that would not be resolved by conventional sampling approaches. Such information is essential if we are to improve our understanding of the nature and significance of the underlying processes leading to this variability.


Association of Traumatic Brain Injury With Vestibular Dysfunction and Dizziness in Post-9/11 Veterans.
To describe the prevalence and impact of vestibular dysfunction and nonspecific dizziness diagnoses and explore their associations with traumatic brain injury (TBI) severity, mechanism, and postconcussive comorbidities among post-9/11 veterans. Administrative medical record data from the US Departments of Defense and Veterans Affairs (VA). Post-9/11 veterans with at least 3 years of VA care. Cross-sectional, retrospective, observational study. International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for TBI, vestibular dysfunction, dizziness, and other commonly associated postconcussive conditions; Neurobehavioral Symptom Inventory. Of the 570 248 post-9/11 veterans in this sample, 0.45% had a diagnosis of vestibular dysfunction and 2.57% had nonspecific dizziness. Those with either condition were more likely to have evidence of TBI (57.11% vs 28.51%) and reported more disruption from neurobehavioral symptoms. Blast and nonblast injuries were associated with greater symptom disruption, particularly in combination. There was a consistent, significant association between TBI and vestibular dysfunction or nonspecific dizziness, after controlling for sociodemographic factors, injury mechanism, and comorbid conditions. Given that most deployed post-9/11 veterans report blast and/or nonblast injuries, the need for prompt identification and management of these conditions and symptoms is clear.


Dielectric Mirror Damage by Laser Radiation over a Range of Pulse Durations and Beam Radii.
Laser induced damage characteristics have been studied for twelve, multiple-layer dielectric, 95% reflecting mirrors irradiated with single ruby laser pulses of 20 nsec and 20-psec duration and Gaussian beam radii ranging from 0.06 mm to 0.24 mm. During measurements to determine damage threshold the pulse energy, an oscilloscope trace of the pulse, and the beam's transverse energy density profile at the surface being damaged are recorded for each shot. In a separate set of experiments, the temporal development of coating breakup and plasma formation is investigated. The experimental results are discussed in the context of possible damage mechanisms.


The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.
Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis. Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults. A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients.


Sensitivity analysis of pharmacokinetic and pharmacodynamic systems: I. A structural approach to sensitivity analysis of physiologically based pharmacokinetic models.
Based on a frequency response approach to the sensitivity analysis of pharmacokinetic models, the concept of structural sensitivity is introduced. The core of this concept is the factorization of the system sensitivity into two multipliers. The first one, called structural sensitivity index, has an analytical form, which depends solely on the structure and connectivity of the system and does not depend on the drug administered or the factor perturbed. The second multiplier, the parameter sensitivity index, depends on the drug properties, the tissue of interest and the parameter perturbed, but is largely independent of the structure of the system. The structural and parametric sensitivity indices can be evaluated and analyzed separately. The most important feature of the proposed approach is that the conclusions drawn from the analysis of the structural sensitivity index are valid across all mammalian species, as the latter share a common anatomical and physiological structure. The concept of structural sensitivity is illustrated on the commonly used structure of the whole body physiologically based pharmacokinetic models by showing that the factorization of the sensitivity carried out arises naturally from the mechanism of the distribution of perturbations throughout the organism. The concept of structural sensitivity has interesting practical implications. It enables the formal proof of relationships and facts that have been observed previously. Moreover, the conclusions drawn introduce in fact a ranking of the tissues or subsystems with respect to their impact on the model outputs. From this ranking, direct recommendations regarding the design of experiments for whole-body physiologically based pharmacokinetic models are derived.


Influence of bilateral vestibular loss on spinal stabilization in humans.
The control of upper body (UB) orientation relative to the pelvis in the frontal plane was characterized in bilateral vestibular loss subjects (BVLs) and compared with healthy control subjects (Cs). UB responses to external perturbations were evoked using continuous pelvis tilts (eyes open and eyes closed) at various amplitudes. Lateral sway of the lower body was prevented on all tests. UB sway was summarized using root-mean-square measures and dynamic behavior was characterized using frequency response functions (FRFs) from 0.023 to 10.3 Hz. Both subject groups had similar FRF variations as a function of stimulus frequency and were relatively unaffected by visual availability, indicating that visual orientation cues contributed very little to UB control. BVLs had larger UB sway at frequencies below ∼1 Hz compared with Cs. A feedback model of UB orientation control was used to identify sensory contributions to spinal stability and differences between subject groups. The model-based interpretation of experimental results indicated that a phasic proprioceptive signal encoding the angular velocity of UB relative to lower body motion was a major contributor to overall system damping. Parametric system identification showed that BVLs used proprioceptive information that oriented the UB toward the pelvis to a greater extent compared with Cs. Both subject groups used sensory information that oriented the UB vertical in space to a greater extent as pelvis tilt amplitudes increased. In BVLs, proprioceptive information signaling the UB orientation relative to the fixed lower body provided the vertical reference, whereas in Cs, vestibular information also contributed to the vertical reference.


Improving Assessment of Lifetime Solar Ultraviolet Radiation Exposure in Epidemiologic Studies: Comparison of Ultraviolet Exposure Assessment Methods in a Nationwide U.S. Occupational Cohort.
Solar ultraviolet radiation is the primary risk factor for skin cancers and sun-related eye disorders. Estimates of individual ambient ultraviolet irradiance derived from ground-based solar measurements and from satellite measurements have rarely been compared. Using self-reported residential history from 67 189 persons in a nationwide occupational US radiologic technologists' cohort, we estimated ambient solar irradiance using data from ground-based meters and noontime satellite measurements. The mean distance moved from city of longest residence in childhood increased from 137.6 km at ages 13-19 to 870.3 km at ages ≥65, with corresponding increases in absolute latitude difference moved. At ages 20/40/60/80, the Pearson/Spearman correlation coefficients of ground-based and satellite-derived potential solar ultraviolet exposure, using irradiance and cumulative radiant exposure metrics, were high (=0.87-0.92). There was also moderate correlation (Pearson/Spearman correlation coefficients = 0.51-0.60) between irradiance at birth and at last-known address, for ground-based and satellite data. Satellite-based lifetime estimates of ultraviolet radiation were generally 14-15% lower than ground-based estimates, albeit with substantial uncertainties, possibly because ground-based estimates incorporate fluctuations in cloud and ozone, which are incompletely incorporated in the single noontime satellite-overpass ultraviolet value. If confirmed elsewhere, the findings suggest that ground-based estimates may improve exposure assessment accuracy and potentially provide new insights into ultraviolet radiation-disease relationships in epidemiologic studies.