Clinical factors associated with venous thromboembolism risk in patients undergoing craniotomy.
OBJECT Patients undergoing craniotomy are at risk for developing venous thromboembolism (VTE). The safety of anticoagulation in these patients is not clear. The authors sought to identify risk factors predictive of VTE in patients undergoing craniotomy. METHODS The authors reviewed a national surgical quality database, the American College of Surgeons National Surgical Quality Improvement Program. Craniotomy patients were identified by current procedural terminology code. Clinical factors were analyzed to identify associations with VTE. RESULTS Four thousand eight hundred forty-four adult patients who underwent craniotomy were identified. The rate of VTE in the cohort was 3.5%, including pulmonary embolism in 1.4% and deep venous thrombosis in 2.6%. A number of factors were found to be statistically significant in multivariate binary logistic regression analysis, including craniotomy for tumor, transfer from acute care hospital, age ≥ 60 years, dependent functional status, tumor involving the CNS, sepsis, emergency surgery, surgery time ≥ 4 hours, postoperative urinary tract infection, postoperative pneumonia, on ventilator ≥ 48 hours postoperatively, and return to the operating room. Patients were assigned a score based on how many of these factors they had (minimum score 0, maximum score 12). Increasing score was predictive of increased VTE incidence, as well as risk of mortality, and time from surgery to discharge. CONCLUSIONS Patients undergoing craniotomy are at low risk of developing VTE, but this risk is increased by preoperative medical comorbidities and postoperative complications. The presence of more of these clinical factors is associated with progressively increased VTE risk; patients possessing a VTE Risk Score of ≥ 5 had a greater than 20-fold increased risk of VTE compared with patients with a VTE score of 0.


Recollection and familiarity for words and faces: a study comparing Remember-Know judgements and the Process Dissociation Procedure.
Measures of recollection and familiarity often differ depending on the paradigm utilised. Remember-Know (R-K) and Process Dissociation Procedure (PDP) methods have been commonly used but rarely compared within a single study. In the current experiments, R-K and PDP were compared by examining the effect of attention at study and time to respond at test on recollection and familiarity using the same experimental procedures for each paradigm. We also included faces in addition to words to test the generality of the findings often obtained using words. The results from the R-K paradigm revealed that recollection and familiarity were similarly affected by attention at study and time to respond at test. However, in the case of PDP, the measures of recollection and familiarity showed a different pattern of results. The effects observed for recollection were similar to those obtained with the R-K method, whereas familiarity was affected by time to respond but not by attention at study. These results are discussed in relation to the controlled-automatic processing distinction and the contribution of each paradigm to research on recognition memory.


Biochemistry, proteomics, and phosphoproteomics of plant mitochondria from non-photosynthetic cells.
Mitochondria fulfill some basic roles in all plant cells. They supply the cell with energy in the form of ATP and reducing equivalents [NAD(P)H] and they provide the cell with intermediates for a range of biosynthetic pathways. In addition to this, mitochondria contribute to a number of specialized functions depending on the tissue and cell type, as well as environmental conditions. We will here review the biochemistry and proteomics of mitochondria from non-green cells and organs, which differ from those of photosynthetic organs in a number of respects. We will briefly cover purification of mitochondria and general biochemical properties such as oxidative phosphorylation. We will then mention a few adaptive properties in response to water stress, seed maturation and germination, and the ability to function under hypoxic conditions. The discussion will mainly focus on Arabidopsis cell cultures, etiolated germinating rice seedlings and potato tubers as model plants. It will cover the general proteome as well as the posttranslational modification protein phosphorylation. To date 64 phosphorylated mitochondrial proteins with a total of 103 phosphorylation sites have been identified.


Handheld echocardiographic screening for rheumatic heart disease by non-experts.
Handheld echocardiography (HAND) has good sensitivity and specificity for rheumatic heart disease (RHD) when performed by cardiologists. However, physician shortages in RHD-endemic areas demand less-skilled users to make RHD screening practical. We examine nurse performance and interpretation of HAND using a simplified approach for RHD screening. Two nurses received training on HAND and a simplified screening approach. Consented students at two schools in Uganda were eligible for participation. A simplified approach (HAND performed and interpreted by a non-expert) was compared with the reference standard (standard portable echocardiography, performed and interpreted by experts according to the 2012 World Heart Federation guidelines). Reasons for false-positive and false-negative HAND studies were identified. A total of 1002 children were consented, with 956 (11.1 years, 41.8% male) having complete data for review. Diagnoses included: 913 (95.5%) children were classified normal, 32 (3.3%) borderline RHD and 11 (1.2%) definite RHD. The simplified approach had a sensitivity of 74.4% (58.8% to 86.5%) and a specificity of 78.8% (76.0% to 81.4%) for any RHD (borderline and definite). Sensitivity improved to 90.9% (58.7% to 98.5%) for definite RHD. Identification and measurement of erroneous colour jets was the most common reason for false-positive studies (n=164/194), while missed mitral regurgitation and shorter regurgitant jet lengths with HAND were the most common reasons for false-negative studies (n=10/11). Non-expert-led HAND screening programmes offer a potential solution to financial and workforce barriers that limit widespread RHD screening. Nurses trained on HAND using a simplified approach had reasonable sensitivity and specificity for RHD screening. Information on reasons for false-negative and false-positive screening studies should be used to inform future training protocols, which could lead to improved screening performance.


[A prospective multicenter study on the prevalence and symptoms of erosive reflux esophagitis in secondary and tertiary hospitals in Korea].
Recent studies suggest that the prevalence of erosive esophagitis (EE) is increasing in Asia. The aims of this study were to determine the prevalence of EE among outpatients visiting gastroenterology clinics of secondary and tertiary hospitals in Korea, and to analyze their symptoms. From May to July 2003, outpatients undergoing their first upper gastrointestinal endoscopies after visiting gastroenterology clinics in secondary and tertiary hospitals in Korea were enrolled. Prevalence of EE was calculated from their endoscopic findings, and symptoms were analyzed from the validated symptom questionnaire. Among 4,275 cases from 24 hospitals, 506 (11.8%) had EE. Among 836 cases with predominantly typical GERD symptoms, EE was diagnosed in 140 (16.7%). Among 530 cases having predominantly typical GERD symptoms with a frequency of at least twice a week or with a significant impact on their daily lives, EE was found in 104 (19.6%). The prevalence of EE was positively associated with males irrespective of age, old aged (> or =65 years) females, predominantly typical GERD symptoms at least twice a week, and the numbers of typical GERD symptoms. The severity of GERD symptoms did not affect the prevalence of EE. The most common typical and atypical GERD symptoms in cases with EE were regurgitation and epigastric soreness, respectively. The prevalence of EE among outpatients visiting gastroenterology clinics in Korea was 11.8%. Independent factors associated with increased prevalence of EE were males irrespective of age, old aged (> or =65 years) females, number of typical GERD symptoms, and frequent typical GERD symptoms.


Metformin for overweight women at midlife: a double-blind, randomized, controlled trial.
This study was undertaken to determine whether metformin would ameliorate insulin resistance, reduce weight and waist circumference and improve lipids in obese, but not morbidly obese, euglycemic women. Obese women (body mass index (BMI) ≥ 30 and < 40 kg/m(2) and/or waist circumference > 88 cm), aged 35-65 were randomized (1:1) to metformin 850 mg or identical placebo, twice daily for 26 weeks. The primary outcome was the change in insulin resistance determined by the homeostasis model of assessment (HOMA-IR). Secondary outcomes included fasting insulin, glucose, weight, waist circumference and BMI. Of the 125 women screened, 117 enrolled and 100 women, mean age 53 years, were included in the primary intention-to-treat analysis. Metformin resulted in statistically significant between-group difference in the change in HOMA-IR (change in median - 0.04 vs. placebo + 0.1, p = 0.018) and BMI (mean change - 1.00 kg/m(2); 95% confidence interval (CI) 1.37 to - 0.62 vs. placebo mean change 0.00; 95% CI - 0.29 to 0.28, p < 0.001). Statistically significant reductions in HbA1c (p = 0.008) and fasting insulin (p = 0.03) and a borderline decrease in high density lipoprotein cholesterol (p = 0.07) were also observed for metformin, compared with placebo. No effects were seen for waist circumference, fasting glucose or other lipids. Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg per day reduced insulin resistance and weight compared with placebo. Further studies are needed to determine whether the use of metformin will prevent the progression of insulin resistance to type 2 diabetes mellitus in obese women.


A novel high-sensitivity, low-power, liquid crystal temperature sensor.
A novel temperature sensor based on nematic liquid crystal permittivity as a sensing magnitude, is presented. This sensor consists of a specific micrometric structure that gives considerable advantages from other previous related liquid crystal (LC) sensors. The analytical study reveals that permittivity change with temperature is introduced in a hyperbolic cosine function, increasing the sensitivity term considerably. The experimental data has been obtained for ranges from -6 °C to 100 °C. Despite this, following the LC datasheet, theoretical ranges from -40 °C to 109 °C could be achieved. These results have revealed maximum sensitivities of 33 mVrms/°C for certain temperature ranges; three times more than of most silicon temperature sensors. As it was predicted by the analytical study, the micrometric size of the proposed structure produces a high output voltage. Moreover the voltage's sensitivity to temperature response can be controlled by the applied voltage. This response allows temperature measurements to be carried out without any amplification or conditioning circuitry, with very low power consumption.


GroEL1, a heat shock protein 60 of Chlamydia pneumoniae, induces lectin-like oxidized low-density lipoprotein receptor 1 expression in endothelial cells and enhances atherogenesis in hypercholesterolemic rabbits.
Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) plays a major role in oxidized low-density lipoprotein-induced vascular inflammation. Chlamydia pneumoniae has been found in atherosclerotic lesions and is related to atherosclerotic pathogenesis, although its specific mechanism remains unknown. This study was conducted to investigate the mechanisms of LOX-1 expression in GroEL1 (a heat shock protein from C. pneumoniae)-administered human coronary artery endothelial cells (HCAECs) and atherogenesis in hypercholesterolemic rabbits. We demonstrated that in the hypercholesterolemic rabbit model, GroEL1 administration enhanced fatty streak and macrophage infiltration in atherosclerotic lesions, which may be mediated by elevated LOX-1 expression. In in vitro study using HCAECs, stimulation with GroEL1 increased TLR4 and LOX-1 expression. Increased LOX-1 expression was downregulated by Akt activation and PI3K-mediated endothelial NO synthase activation. PI3K inhibitor and NO synthase inhibitor induced LOX-1 mRNA production, whereas the NO donor ameliorated the increasing effect of LOX-1 mRNA in GroEL1-stimulated HCAECs. LOX-1 expression was regulated by NADPH oxidase, which mediates reactive oxygen species production and intracellular MAPK signaling pathway in GroEL1-stimulated HCAECs. Treatment with polyethylene-glycol-conjugated superoxide dismutase, apocynin, or diphenylene iodonium significantly decreased GroEL1-induced LOX-1 expression, as did the knockdown of Rac1 gene expression by RNA interference. In conclusion, the GroEL1 protein may induce LOX-1 expression in endothelial cells and atherogenesis in hypercholesterolemic rabbits. The elevated level of LOX-1 in vitro may be mediated by the PI3K-Akt signaling pathway, endothelial NO synthase activation, NADPH oxidase-mediated reactive oxygen species production, and MAPK activation in GroEL1-stimulated HCAECs. The GroEL1 protein of C. pneumoniae may contribute to vascular inflammation and cardiovascular disorders.


An Integrated Miniature Bioprocessing for Personalized Human Induced Pluripotent Stem Cell Expansion and Differentiation into Neural Stem Cells.
Human induced pluripotent stem cells (iPSCs) are ideal cell sources for personalized cell therapies since they can be expanded to generate large numbers of cells and differentiated into presumably all the cell types of the human body in vitro. In addition, patient specific iPSC-derived cells induce minimal or no immune response in vivo. However, with current cell culture technologies and bioprocessing, the cost for biomanufacturing clinical-grade patient specific iPSCs and their derivatives are very high and not affordable for majority of patients. In this paper, we explored the use of closed and miniature cell culture device for biomanufacturing patient specific neural stem cells (NSCs) from iPSCs. We demonstrated that, with the assist of a thermoreversible hydrogel scaffold, the bioprocessing including iPSC expansion, iPSC differentiation into NSCs, the subsequent depletion of undifferentiated iPSCs from the NSCs, and concentrating and transporting the purified NSCs to the surgery room, could be integrated and completed within two closed 15 ml conical tubes.


MODBASE, a database of annotated comparative protein structure models, and associated resources.
MODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb).


A meta-analysis comparing 48-week treatment outcomes of single and multi-tablet antiretroviral regimens for the treatment of people living with HIV.
To compare outcomes with single tablet regimens (STR) versus multi-tablet regimens (MTR) for human immunodeficiency virus (HIV) treatment using published data. Systematic review and random-effects meta-analysis of literature on approved and investigational HIV regimens. The research followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Single or un-blinded studies reporting a direct comparison between STR and MTR were eligible for the meta-analysis. Double-blinded studies were excluded due to lack of difference in pill burden between cohorts. The key outcomes of interest included: adherence rates/proportion meeting target, efficacy, safety/tolerability, non-clinical and economic outcomes. After screening 63 full-text articles and posters, 14 studies were eligible for the meta-analysis. The analysis showed that patients taking STR had improved outcomes over those taking MTR. Patients were significantly more adherent regardless of daily dosing frequency (odds ratio [OR]: 1.96, p < 0.001) and were more likely to achieve virological suppression (relative risk [RR]: 1.05, p = 0.002). There was a trend toward a lower discontinuation risk in the STR cohort, together with reported higher therapy satisfaction, better symptom control, improved health status, reduced healthcare resource utilization and demonstrated cost-effectiveness compared to MTR. There were no differences in CD4 cell count increase (at 48 weeks) or safety outcomes. The findings of this study confirm previously reported preliminary findings of the advantages of STR over MTR for HIV treatment in adherence, therapy continuation, viral suppression, tolerability, quality of life improvement, cost-effectiveness and healthcare resource utilization.


Clinical outcomes of totally implantable venous access port placement via the axillary vein in patients with head and neck malignancy.
To evaluate the clinical outcomes and complications of totally implantable venous access port implantation via the axillary vein in patients with head and neck malignancy. A total of 176 totally implantable venous access ports were placed via the axillary vein in 171 patients with head and neck malignancy between May 2012 and June 2015. The patients included 133 men and 38 women, and the mean age was 58.8 years (range: 19-84 years). Medical records were retrospectively reviewed. This study included a total of 93,237 totally implantable venous access port catheter-days (median 478 catheter-days, range: 13-1380 catheter-days). Of the 176 implanted totally implantable venous access port, complications developed in nine cases (5.1%), with the overall incidence of 0.097 events/1000 catheter-days. The complications were three central line-associated blood-stream infection cases, one case of keloid scar at the needling access site, and five cases of central vein stenosis or thrombosis on neck computed tomography images. The 133 cases for which neck computed tomography images were available had a total of 59,777 totally implantable venous access port catheter-days (median 399 catheter-days, range: 38-1207 catheter-days). On neck computed tomography evaluation, the incidence of central vein stenosis or thrombosis was 0.083 events/1000 catheter-days. Thrombosis developed in four cases, yielding an incidence of 0.067 events/1000 catheter-days. All four patients presented with thrombus in the axillary or subclavian vein. Stenosis occurred in one case yielding an incidence of 0.017 events/1000 catheter-days. One case was catheter-related brachiocephalic vein stenosis, and the other case was subclavian vein stenosis due to extrinsic compression by tumor progression. Of the nine complication cases, six underwent port removal. These data indicate that totally implantable venous access port implantation via the axillary vein in patients with head and neck malignancy is safe and feasible, with a low axillary vein access-related complication rate.


Using green fluorescent malaria parasites to screen for permissive vector mosquitoes.
The Plasmodium species that infect rodents, particularly Plasmodium berghei and Plasmodium yoelii, are useful to investigate host-parasite interactions. The mosquito species that act as vectors of human plasmodia in South East Asia, Africa and South America show different susceptibilities to infection by rodent Plasmodium species. P. berghei and P. yoelii infect both Anopheles gambiae and Anopheles stephensi, which are found mainly in Africa and Asia, respectively. However, it was reported that P. yoelii can infect the South American mosquito, Anopheles albimanus, while P. berghei cannot. P. berghei lines that express the green fluorescent protein were used to screen for mosquitoes that are susceptible to infection by P. berghei. Live mosquitoes were examined and screened for the presence of a fluorescent signal in the abdomen. Infected mosquitoes were then examined by time-lapse microscopy to reveal the dynamic behaviour of sporozoites in haemolymph and extracted salivary glands. A single fluorescent oocyst can be detected in live mosquitoes and P. berghei can infect A. albimanus. As in other mosquitoes, P. berghei sporozoites can float through the haemolymph and invade A. albimanus salivary glands and they are infectious in mice after subcutaneous injection. Fluorescent Plasmodium parasites can be used to rapidly screen susceptible mosquitoes. These results open the way to develop a laboratory model in countries where importation of A. gambiae and A. stephensi is not allowed.


MYH9 and APOL1 are both associated with sickle cell disease nephropathy.
Renal failure occurs in 5-18% of sickle cell disease (SCD) patients and is associated with early mortality. At-risk SCD patients cannot be identified prior to the appearance of proteinuria and the pathobiology is not well understood. The myosin, heavy chain 9, non-muscle (MYH9) and apolipoprotein L1 (APOL1) genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans. We genotyped 26 single nucleotide polymorphisms (SNPs) in MYH9 and 2 SNPs in APOL1 (representing the G1 and G2 tags) in 521 unrelated adult (18-83 years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria. Seven SNPs in MYH9 and one in APOL1 remained significantly associated with proteinuria after multiple testing correction (P < 0·0025). An MYH9 risk haplotype (P = 0·001) and the APOL1 G1/G2 recessive model (P < 0·0001) were strongly associated with proteinuria, even when accounting for the other. Glomerular filtration rate was negatively correlated with proteinuria (P < 0·0001), and was significantly predicted by an interaction between MYH9 and APOL1 in age-adjusted analyses. Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 and APOL1 are both associated with risk.


Unique Scattering Properties of Silicon Nanowires Embedded with Porous Segments.
The development of advanced imaging tools is important for the investigation of the fundamental properties of nanostructures composed of single or multiple nanomaterials. However, complicated preparation processes and irreversible alterations of the samples to be examined are inevitable in most current imaging techniques. In this work, we developed a simple method based on polarization-resolved light scattering measurements to characterize the structural and optical properties of complex nanomaterials. In particular, we examined a single Si nanowire embedded with porous Si segments, in which the porous Si could not be easily distinguished from solid Si by scanning electron microscopy. The dark-field optical images and polarization-resolved scattering spectra showed unique optical features of porous and solid Si. In particular, the porosity, diameter, and number of porous Si segments in the single Si nanowire were identified from the scattering measurements. In addition, we performed systematic optical simulations based on the effective medium model in individual porous and solid Si nanowires. A good agreement between the simulation and measurement results enabled the estimation of the structural parameters of the nanowires, such as diameter and porosity. We believe that our method will be useful for analyzing the structural and optical properties of nanomaterials prior to using complicated and uneconomical imaging tools.


Increased transfer of cholesteryl esters from high density lipoproteins to low density and very low density lipoproteins in patients with angiographic evidence of coronary artery disease.
Cholesterol esterification, transfer of cholesteryl esters from high density lipoproteins to very low density and low density lipoproteins (VLDL/LDL) and the composition of lipoproteins isolated by density gradient ultracentrifugation have been investigated in 18 men with angiographic evidence of severe coronary artery disease and in 27 healthy men without coronary artery disease. Patients had significantly higher serum cholesterol (P < 0.001), serum triglycerides (P < 0.02) and lower high density lipoprotein cholesterol (HDL) (P < 0.04) compared with healthy men. The transfer of cholesteryl ester from HDL to VLDL and LDL was 27.8 +/- 12.2 nmol/ml per h (mean +/- S.D.) in patients and was significantly higher than the value of 17.8 +/- 6.5 nmol/ml per h obtained in healthy men (P < 0.003) or 17.1 +/- 7.6 nmol/ml per h) in 16 controls (P < 0.03) with similar serum cholesterol and triglyceride concentrations. Lipoprotein protein concentrations were significantly higher in LDL (P < 0.05) and small VLDL (P < 0.01) in patients. In addition, patient LDL and large VLDL contained more free cholesterol than matched controls (P < 0.01, P < 0.05, respectively). This was reflected in the increased free cholesterol/phospholipid ratio (a measure of lipoprotein surface composition) in LDL (P < 0.002). These findings indicate that patients with established coronary artery disease have increased transfer of cholesteryl ester from HDL to VLDL and LDL, which is independent of serum triglyceride concentrations. This increased transfer of cholesteryl ester may be a result of the increased free cholesterol content of very low density lipoproteins.


Distance Traveled to Obtain Clinical Abortion Care in the United States and Reasons for Clinic Choice.
Introduction: Greater distance to abortion facilities is associated with greater out-of-pocket costs, emergency room follow-up care, negative mental health, and delayed care among U.S. abortion patients. However, the distance U.S. abortion patients travel has not been reported since 2008, and no study has examined reasons abortion patients choose the particular facility where they obtain their abortion. Materials and Methods: We analyzed data from the 2014 Abortion Patient Survey and Abortion Provider Census to report abortion patients' one-way travel from their resident zip code to their abortion clinic, whether they went to the closest clinic, and reasons for facility choice. We report unadjusted and adjusted associations of patients' characteristics with travel distance and differences in average travel distance by abortion patients' reported reasons for choosing their facility. Results: In 2014, 65% of abortion patients traveled less than 25 miles one-way, 17% traveled 25-49 miles, and 18% traveled more than 50 miles. Abortion patients who were white, college-educated, U.S.-born, ≥12 weeks pregnant, and lived outside metropolitan areas were more likely to travel farther. Nearly half of abortion patients went to their nearest provider and 32% chose their facility because it was the closest. Conclusion: These results indicate that travel distance is an important determinant of abortion care access in the United States. Nearly, one-fifth of U.S. abortion patients traveled more than 50 miles one-way and the most common reason reported for clinic choice was that it was the closest.


Combined effect of prophylactic lymphadenectomy and long term combination chemotherapy for curatively resected carcinoma of the stomach.
Effectiveness of prophylactic extensive lymph node dissection (PELD) plus postoperative long term combination chemotherapy (PLCC) for patients with curatively resected gastric carcinoma was assessed in terms of the degree of serosal invasion and lymph node metastasis. Either the Group 1 and Group 2 lymph nodes were eradicated by PELD. PLCC included intermittent intravenous administration of mitomycin C (0.4 mg/kg intraoperatively followed by 0.2 mg/kg every 3 months) and oral administration of Tegafur (600-800 mg/day) and PSK (3.0 g/day), an immunostimulator, for as long a period as possible. PELD alone resulted in a cure when the malignancy was confined to the mucosal and muscular layers of the stomach as well as to the Group 1 lymph nodes. In cases when the carcinoma involved the serosa and/or the Group 2 lymph nodes, the 5 year survival rate was about 55 per cent the PELD and PLCC groups, such being significantly higher than about 27 per cent in the PELD alone group. Therefore, PELD plus PLCC is highly effective for advanced gastric carcinoma, under a condition of curative resection.


Information Flow Between Resting-State Networks.
The resting brain dynamics self-organize into a finite number of correlated patterns known as resting-state networks (RSNs). It is well known that techniques such as independent component analysis can separate the brain activity at rest to provide such RSNs, but the specific pattern of interaction between RSNs is not yet fully understood. To this aim, we propose here a novel method to compute the information flow (IF) between different RSNs from resting-state magnetic resonance imaging. After hemodynamic response function blind deconvolution of all voxel signals, and under the hypothesis that RSNs define regions of interest, our method first uses principal component analysis to reduce dimensionality in each RSN to next compute IF (estimated here in terms of transfer entropy) between the different RSNs by systematically increasing k (the number of principal components used in the calculation). When k=1, this method is equivalent to computing IF using the average of all voxel activities in each RSN. For k≥1, our method calculates the k multivariate IF between the different RSNs. We find that the average IF among RSNs is dimension dependent, increasing from k=1 (i.e., the average voxel activity) up to a maximum occurring at k=5 and to finally decay to zero for k≥10. This suggests that a small number of components (close to five) is sufficient to describe the IF pattern between RSNs. Our method--addressing differences in IF between RSNs for any generic data--can be used for group comparison in health or disease. To illustrate this, we have calculated the inter-RSN IF in a data set of Alzheimer's disease (AD) to find that the most significant differences between AD and controls occurred for k=2, in addition to AD showing increased IF w.r.t. The spatial localization of the k=2 component, within RSNs, allows the characterization of IF differences between AD and controls.


Outcomes of Bilateral vs Unilateral Ankle Arthrodesis.
While ankle arthrodesis is a common treatment for severe ankle osteoarthritis, performing bilateral ankle arthrodesis is controversial because of associated problems, such as severe gait abnormality and bilateral loss of talocrural joint motion. Furthermore, few reports exist regarding the detailed outcomes of bilateral ankle arthrodesis. Therefore, we aimed to compare the outcomes of bilateral ankle arthrodesis with those of unilateral ankle arthrodesis, using both subjective and objective assessments. The data from 20 patients (10 each in the bilateral and unilateral groups), who underwent arthrodesis between 2005 and 2015, were retrospectively reviewed. The minimum follow-up duration was 2 years. Radiographic outcomes were assessed using radiographs and computed tomography. Clinical outcomes were assessed using the Japanese Society for Surgery of the Foot (JSSF) scale and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). With the numbers available, no significant group differences were observed for any of the patient characteristics or postoperative range of motion. Mean JSSF scale scores significantly improved in both groups ( P < .001); however, scores on the SAFE-Q subscale for "social functioning" were significantly lower in the bilateral group compared to the unilateral group ( P = .049). Within the limitations of the current study design, bilateral ankle arthrodesis did not appear to be inferior to unilateral ankle arthrodesis, with the possible exception of social functioning ability. Thus, bilateral ankle arthrodesis can be considered a viable treatment option. Level III, retrospective cohort study.


Immunolocalization of metabotropic glutamate receptor 1alpha (mGluR1alpha) in distinct classes of interneuron in the CA1 region of the rat hippocampus.
In the hippocampal CA1 region, metabotropic glutamate subtype 1 (mGluR1) receptors have been implicated in a variety of physiological responses to glutamate, which include modulation of synaptic transmission and plasticity, as well as neuronal excitability and synchronization. The mGluR1alpha isoform is characteristically expressed only by nonprincipal cells, and it is particularly enriched in somatostatin (SS)-containing interneurons in stratum oriensalveus. Anatomical and physiological data have indicated the presence of mGluR1alpha in several distinct classes of interneurons with their somata located also in strata pyramidale, radiatum, and lacunosum moleculare. Each different interneuron subtype, as defined by functionally relevant criteria, including input/ output characteristics and expression of selective molecular markers, subserves distinct functions in local hippocampal circuits. We have investigated which of the different CA1 interneuron classes express mGluR1alpha by immunofluorescent labeling, combining antibodies to mGluR1alpha, calcium-binding proteins, and neuropeptides, and by intracellular labeling in vitro. Several types of interneuron that are immunopositive for mGluR1alpha each targeted different domains of pyramidal cells and included (1) O-LM inter-neurons, found to coexpress both SS and parvalbumin (PV); (2) interneurons with target selectivity for other interneurons, expressing vasoactive intestinal polypeptide (VIP) and/or the calcium-binding protein calretinin; (3) procholecystokinin-immunopositive interneurons probably non-basket and dendrite-targeting; and (4) an as-yet unidentified SS-immunoreactive but PV-immunonegative interneuron class, possibly corresponding to oriens-bistratified cells. Estimation of the relative proportion of mGluR1alpha-positive interneurons showed 43%, 46%, and 30% co-labeling with SS, VIP, or PV, respectively. The identification of the specific subclasses of CA1 interneurons expressing mGluR1alpha provides the network basis for assessing the contribution of this receptor to the excitability of the hippocampus.


A mass-spectrometry-based framework to define the extent of disorder in proteins.
In the past decade, mass spectrometry (MS) coupled with electrospray ionization (ESI) has been extensively applied to the study of intact proteins and their complexes, often without the requirement of labels. Solvent conditions (for example, pH, ionic strength, and concentration) affect the observed desolvated species; the ease of altering such extrinsic factors renders ESI-MS an appropriate method by which to consider the range of conformational states that proteins may occupy, including natively folded, disordered and amyloid. Rotationally averaged collision cross sections of the ionized forms of proteins, provided by the combination of mass spectrometry and ion mobility (IM-MS), are also instructive in exploring conformational landscapes in the absence of solvent. Here, we ask the following question: "If the only technique you had was ESI-IM-MS, what information would it provide on the structural preferences of an unknown protein?" We have selected 20 different proteins, both monomeric and multimeric, ranging in mass from 2846 Da (melittin) to 150 kDa (Immunoglobulin G), and we consider how they are presented to a mass spectrometer under different solvent conditions. Mass spectrometery allows us to distinguish which of these proteins are structured (melittin, human beta defensin 1, truncated human lymphotactin, Cytochrome C, holo hemoglobin-α, ovalbumin, human transthyretin, avidin, bovine serum albumin, concanavalin, human serum amyloid protein, and Immunoglobulin G) from those that contain at least some regions of disorder (human lymphotactin, N-terminal p53, α-Synuclein, N-terminal MDM2, and p53 DNA binding domain) or denatured due to solvent conditions (ubiquitin, apo hemoglobin-α, apo hemoglobin-β) by considering two experimental parameters: the range of charge states occupied by the protein (Δz) and the range of collision cross sections in which the protein is observed (ΔCCS). We also provide a simple model to predict the difference between the collision cross sections of the most compact and the most extended form of a given protein, based on the volume of the amino acids it contains. We compare these calculated parameters with experimental values. In addition, we consider the occupancy of conformations based on the intensities of ions in the mass spectra. This allows us to qualitatively predict the potential energy landscape of each protein. Our empirical approach to assess order or disorder is shown to be more accurate than the use of charge hydropathy plots, which are frequently used to predict disorder, and could provide an initial route to characterization. Finally, we present an ESI-IM-MS methodology to determine if a given protein is structured or disordered.


Focal thinning of the cerebral cortex in multiple sclerosis.
Brain atrophy as determined by quantitative MRI can be used to characterize disease progression in multiple sclerosis. Many studies have addressed white matter (WM) alterations leading to atrophy, while changes of the cerebral cortex have been studied to a lesser extent. In vivo, the cerebral cortex has been difficult to study due to its complex structure and regional variability. Measurement of cerebral cortex thickness at different disease stages may provide new insights into grey matter (GM) pathology. In the present investigation, we evaluated in vivo cortical thickness and its relationship to disability, disease duration, WM T2 hyper-intense and T1 hypo-intense lesion volumes. High-resolution MRI brain scans were obtained in 20 patients with clinically definite multiple sclerosis and 15 age-matched normal subjects. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject's entire brain and computed cross-subject statistics based on the cortical anatomy. Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between cortical thickness and clinical variables. The mean overall thickness of the cortical ribbon was reduced in multiple sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients). In patients, we found significant main effects for disability, disease duration, T2 and T1 lesion volumes. The visualization of statistical difference maps of the cortical GM thickness on inflated brains across the cortical surface revealed a distinct distribution of significant focal thinning of the cerebral cortex in addition to the diffuse cortical atrophy. Focal cortical thinning in frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in temporal [2.65 mm (SD 0.15) versus 2.95 mm (SD 0.11)] brain regions was observed, even early in the course of the disease or in patients with mild disability. Patients with longstanding disease or severe disability, however, presented additionally with focal thinning of the motor cortex area [2.35 mm (SD 0.19) versus 2.74 mm (SD 0.15)]. We conclude that in vivo measurement of cortical thickness is feasible in patients suffering from multiple sclerosis. The data provide new insight into the cortical pathology in multiple sclerosis patients, revealing focal cortical thinning beside an overall reduction of the cortical thickness with disease progression.


The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients.
The killing of natural killer (NK) cells is regulated by activating and inhibitory NK receptors that recognize mainly class I major histocompatibility complex (MHC) proteins. In transporter associated with antigen processing (TAP2)-deficient patients, killing of autologous cells by NK cells is therefore expected. However, none of the TAP2-deficient patients studied so far have suffered from immediate NK-mediated autoimmune manifestations. We have previously demonstrated the existence of a novel class I MHC-independent inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) interactions. Here, we identified 3 new siblings suffering from TAP2 deficiency. NK cells derived from these patients express unusually high levels of the various killer cell inhibitory receptors (KIRs) and the CEACAM1 protein. Importantly, the patients' NK cells use the CEACAM1 protein to inhibit the killing of tumor and autologous cells. Finally, we show that the function of the main NK lysis receptor, NKp46, is impaired in these patients. These results indicate that NK cells in TAP2-deficient patients have developed unique mechanisms to reduce NK killing activity and to compensate for the lack of class I MHC-mediated inhibition. These mechanisms prevent the attack of self-cells by the autologous NK cells and explain why TAP2-deficient patients do not suffer from autoimmune manifestations in early stages of life.


A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis.
Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA. Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period. RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing. ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.


Origin and specification of type II sensory neurons in Drosophila.
The peripheral nervous system (PNS) of Drosophila is a preferred model for studying the genetic basis of neurogenesis because its simple and stereotyped pattern makes it ideal for mutant analysis. Type I sensory organs, the external (bristle-type) sensory organs (es) and the internal (stretch-receptive) chordotonal organs (ch), have been postulated to derive from individual ectodermal precursor cells that undergo a stereotyped pattern of cell division. Little is known about the origin and specification of type II sensory neurons, the multiple dendritic (md) neurons. Using the flp/FRT recombinase system from yeast, we have determined that a subset of md neurons derives from es organ lineages, another subset derives from ch organ lineages and a third subset is unrelated to sensory organs. We also provide evidence that the genes, numb and cut, are both required for the proper differentiation of md neurons.


Protected areas' role in climate-change mitigation.
Globally, 15.5 million km(2) of land are currently identified as protected areas, which provide society with many ecosystem services including climate-change mitigation. Combining a global database of protected areas, a reconstruction of global land-use history, and a global biogeochemistry model, we estimate that protected areas currently sequester 0.5 Pg C annually, which is about one fifth of the carbon sequestered by all land ecosystems annually. Using an integrated earth systems model to generate climate and land-use scenarios for the twenty-first century, we project that rapid climate change, similar to high-end projections in IPCC's Fifth Assessment Report, would cause the annual carbon sequestration rate in protected areas to drop to about 0.3 Pg C by 2100. For the scenario with both rapid climate change and extensive land-use change driven by population and economic pressures, 5.6 million km(2) of protected areas would be converted to other uses, and carbon sequestration in the remaining protected areas would drop to near zero by 2100.


Comment on "passively Q-switched fiber laser that uses saturable Raman gain".
Recently, an interesting pulsing behavior of a fiber laser with intracavity Raman conversion was reported [Y. Zhao and S. D. Jackson, Opt. Lett.31, 751 (2006)]. The pulsing has been interpreted as passive Q switching, but this interpretation needs to be revised. An alternative explanation predicts transient phenomena, which do not lead to a regular pulse train.


Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy.
Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.


Neuroprotective effects of the green tea components theanine and catechins.
The neuroprotective effects of theanine and catechins contained in green tea are discussed. Although the death of cultured rat cortical neurons was induced by the application of glutamic acid, this neuronal death was suppressed with exposure to theanine. The death of hippocampal CA1 pyramidal neurons caused by transient forebrain ischemia in the gerbil was inhibited with the ventricular preadministration of theanine. The neuronal death of the hippocampal CA3 region by kainate was also prevented by the administration of theanine. Theanine has a higher binding capacity for the AMPA/kainate receptors than for NMDA receptors, although the binding capacity in all cases is markedly less than that of glutamic acid. The results of the present study suggest that the mechanism of the neuroprotective effect of theanine is related not only to the glutamate receptor but also to other mechanisms such as the glutamate transporter, although further studies are needed. One of the onset mechanisms for arteriosclerosis, a major factor in ischemic cerebrovascular disease, is probably the oxidative alteration of low-density lipoprotein (LDL) by active oxygen species. The oxidative alterations of LDL were shown to be prevented by tea catechins. Scavenging of *O(2)(-) was also exhibited by tea catechins. The neuroprotective effects of theanine and catechins contained in green tea are a focus of considerable attention, and further studies are warranted.


The contribution of global aviation to anthropogenic climate forcing for 2000 to 2018.
Global aviation operations contribute to anthropogenic climate change via a complex set of processes that lead to a net surface warming. Of importance are aviation emissions of carbon dioxide (CO2), nitrogen oxides (NOx), water vapor, soot and sulfate aerosols, and increased cloudiness due to contrail formation. Aviation grew strongly over the past decades (1960-2018) in terms of activity, with revenue passenger kilometers increasing from 109 to 8269 billion km yr-1, and in terms of climate change impacts, with CO2 emissions increasing by a factor of 6.8 to 1034 Tg CO2 yr-1. Over the period 2013-2018, the growth rates in both terms show a marked increase. Here, we present a new comprehensive and quantitative approach for evaluating aviation climate forcing terms. Both radiative forcing (RF) and effective radiative forcing (ERF) terms and their sums are calculated for the years 2000-2018. Contrail cirrus, consisting of linear contrails and the cirrus cloudiness arising from them, yields the largest positive net (warming) ERF term followed by CO2 and NOx emissions. The formation and emission of sulfate aerosol yields a negative (cooling) term. The mean contrail cirrus ERF/RF ratio of 0.42 indicates that contrail cirrus is less effective in surface warming than other terms. For 2018 the net aviation ERF is +100.9 milliwatts (mW) m-2 (5-95% likelihood range of (55, 145)) with major contributions from contrail cirrus (57.4 mW m-2), CO2 (34.3 mW m-2), and NOx (17.5 mW m-2). Non-CO2 terms sum to yield a net positive (warming) ERF that accounts for more than half (66%) of the aviation net ERF in 2018. Using normalization to aviation fuel use, the contribution of global aviation in 2011 was calculated to be 3.5 (4.0, 3.4) % of the net anthropogenic ERF of 2290 (1130, 3330) mW m-2. Uncertainty distributions (5%, 95%) show that non-CO2 forcing terms contribute about 8 times more than CO2 to the uncertainty in the aviation net ERF in 2018. The best estimates of the ERFs from aviation aerosol-cloud interactions for soot and sulfate remain undetermined. CO2-warming-equivalent emissions based on global warming potentials (GWP* method) indicate that aviation emissions are currently warming the climate at approximately three times the rate of that associated with aviation CO2 emissions alone. CO2 and NOx aviation emissions and cloud effects remain a continued focus of anthropogenic climate change research and policy discussions.


Morphological and functional development of the spiral intestine in cloudy catshark (Scyliorhinus torazame).
Cartilaginous fish have a comparatively short intestine known as the spiral intestine that consists of a helical spiral of intestinal mucosa. However, morphological and functional development of the spiral intestine has not been fully described. Unlike teleosts, cartilaginous fish are characterized by an extremely long developmental period in ovo or in utero; for example, in the oviparous cloudy catshark (Scyliorhinus torazame), the developing fish remains inside the egg capsule for up to 6 months, suggesting that the embryonic intestine may become functional prior to hatching. In the present study, we describe the morphological and functional development of the spiral intestine in the developing catshark embryo. Spiral formation of embryonic intestine was completed at the middle of stage 31, prior to 'pre-hatching', which is a developmental event characterized by the opening of the egg case at the end of the first third of development. Within 48 h of the pre-hatching event, egg yolk began to flow from the external yolk sac into the embryonic intestine via the yolk stalk. At the same time, there was a rapid increase in mRNA expression of the peptide transporter pept1 and neutral amino acid transporter slc6a19 Secondary folds in the intestinal mucosa and microvilli on the apical membrane appeared after pre-hatching, further supporting the onset of nutrient absorption in the developing intestine at this time. We demonstrate the acquisition of intestinal nutrient absorption at the pre-hatching stage of an oviparous elasmobranch.


Biomimetic nanocomposites for bone graft applications.
Allograft bone, dematerialized bone matrix and calcium-based synthetic materials have long been used as bone graft substitutes. First-generation bone graft substitutes as stand-alone graft substitutes have not developed as hoped. It remains a great challenge to design an ideal bone graft that emulates nature's own structures or functions. To further improve the performance of such bone graft substitutes, scientists are investigating biomimetic processes to incorporate the desirable nano-features into the next generation of biomaterials. In this regard, nanostructured biomaterials less than 100 nm in at least one dimension, in particular nanocomposites, are perceived to be beneficial and potentially ideal for bone applications, owing to their nanoscale functional characteristics that facilitate bone cell growth and subsequent tissue formation. In fact, bone itself is a nanocomposite system with a complex hierarchical structure. This review reports the impact of biomimetically derived nanocomposite biomaterials for use in bone applications and provides possible suggestions for future research and development.


Short-term effects of hypoxia are more important than effects of ocean acidification on grazing interactions with juvenile giant kelp (Macrocystis pyrifera).
Species interactions are crucial for the persistence of ecosystems. Within vegetated habitats, early life stages of plants and algae must survive factors such as grazing to recover from disturbances. However, grazing impacts on early stages, especially under the context of a rapidly changing climate, are largely unknown. Here we examine interaction strengths between juvenile giant kelp (Macrocystis pyrifera) and four common grazers under hypoxia and ocean acidification using short-term laboratory experiments and field data of grazer abundances to estimate population-level grazing impacts. We found that grazing is a significant source of mortality for juvenile kelp and, using field abundances, estimate grazers can remove on average 15.4% and a maximum of 73.9% of juveniles per m2 per day. Short-term exposure to low oxygen, not acidification, weakened interaction strengths across the four species and decreased estimated population-level impacts of grazing threefold, from 15.4% to 4.0% of juvenile kelp removed, on average, per m2 per day. This study highlights potentially high juvenile kelp mortality from grazing. We also show that the effects of hypoxia are stronger than the effects of acidification in weakening these grazing interactions over short timescales, with possible future consequences for the persistence of giant kelp and energy flow through these highly productive food webs.


Correlation of Plasma Lipid Profile with Salivary Oxidative Stress Markers in Type II Diabetes Mellitus Patients.
Diabetes is known to be associated with greater production of reactive oxygen species (ROS) like malondialdehyde (MDA) and decreased antioxidants like total thiols and its estimation in plasma is used in monitoring the redox status. The aim of this study was to analyse the association between plasma lipid profile parameters like HDL and LDL with salivary MDA and thiols in diabetic patients. Sixty subjects between the age group 35- 70 years who were diagnosed with type II diabetes mellitus based on fasting blood glucose and glycated haemoglobin levels who attended the dental OPD at Kasturba Medical College and Hospital, Manipal consented to participate in this study. Plasma glucose, HDL and LDL were estimated in Cobas autoanalyser by hexokinase method, homogenous enzymatic colorimetric assay and Friedwald's formula respectively. Assessment of glycated hemoglobin was by ion exchange chromatography, MDA by thiobarbituric acid as a substrate and thiols by Ellmann's manual method in plasma and saliva. The association of plasma LDL with salivary MDA was found to be positive and significant and that with salivary thiols was negative and significant. Also, the association of plasma HDL with salivary MDA was found to be negative and significant and that with salivary thiols was positive and significant. RESULTS indicate the potential of saliva as a tool to monitor prognosis of diabetes.


Deciphering past human population movements in Oceania: provably optimal trees of 127 mtDNA genomes.
The settlement of the many island groups of Remote Oceania occurred relatively late in prehistory, beginning approximately 3,000 years ago when people sailed eastwards into the Pacific from Near Oceania, where evidence of human settlement dates from as early as 40,000 years ago. Archeological and linguistic analyses have suggested the settlers of Remote Oceania had ancestry in Taiwan, as descendants of a proposed Neolithic expansion that began approximately 5,500 years ago. Other researchers have suggested that the settlers were descendants of peoples from Island Southeast Asia or the existing inhabitants of Near Oceania alone. To explore patterns of maternal descent in Oceania, we have assembled and analyzed a data set of 137 mitochondrial DNA (mtDNA) genomes from Oceania, Australia, Island Southeast Asia, and Taiwan that includes 19 sequences generated for this project. Using the MinMax Squeeze Approach (MMS), we report the consensus network of 165 most parsimonious trees for the Oceanic data set, increasing by many orders of magnitude the numbers of trees for which a provable minimal solution has been found. The new mtDNA sequences highlight the limitations of partial sequencing for assigning sequences to haplogroups and dating recent divergence events. The provably optimal trees found for the entire mtDNA sequences using the MMS method provide a reliable and robust framework for the interpretation of evolutionary relationships and confirm that the female settlers of Remote Oceania descended from both the existing inhabitants of Near Oceania and more recent migrants into the region.


Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections.
Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1β and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. NCs had higher fatty acids, IL-8 and IL-1β versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. UFAs, IL-1β and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.


Evaluation protocol to assess maternal and child health outcomes using administrative data: a community health worker home visiting programme.
Emerging evidence suggests community health workers (CHWs) delivering preventive maternal and child health (MCH) interventions through home visiting improve several important health outcomes, including initiation of prenatal care, healthy birth weight and uptake of childhood immunisations. The Arizona Health Start Program is a behavioral-based home visiting intervention, which uses CHWs to improve MCH outcomes through health education, referral support, and advocacy services for at-risk pregnant and postpartum women with children up to 2 years of age. We aim to test our central hypothesis that mothers and children exposed to this intervention will experience positive health outcomes in the areas of (1) newborn health; (2) maternal health and healthcare utilisation; and (3) child health and development. This paper outlines our protocol to retrospectively evaluate Health Start Program administrative data from 2006 to 2015, equaling 15 576 enrollees. We will use propensity score matching to generate a statistically similar control group. Our analytic sample size is sufficient to detect meaningful programme effects from low-frequency events, including preterm births, low and very low birth weights, maternal morbidity, and differences in immunisation and hospitalisation rates. This work is supported through an inter-agency contract from the Arizona Department of Health Services and is approved by the University of Arizona Research Institutional Review Board (Protocol 1701128802, approved 25 January 2017). Evaluation of the three proposed outcome areas will be completed by June 2020.


The depiction of car light beams in a child born completely blind.
A 12-year-old child (DI) who was completely blind from birth, made a series of tactual (raised-lines) drawings of cars. Among them, there was the depiction of a 'fast car at night' in which DI drew beams of light projecting out of the car. We analyse this drawing, and the preceding ones. We argue that the way in which cars and light beams were depicted by DI cannot be fully and solely explained by graphic imprecision, executive or motor deficiencies, or by rote or verbal learning. Instead, we propose that the most plausible explanation is that DI's depiction of light in a fast car at night reflects the child's naïve knowledge of light propagation, and that this knowledge was gained through perceiving light as radiant heat.


Proteomic analysis of naturally-sourced biological scaffolds.
A key challenge to the clinical implementation of decellularized scaffold-based tissue engineering lies in understanding the process of removing cells and immunogenic material from a donor tissue/organ while maintaining the biochemical and biophysical properties of the scaffold that will promote growth of newly seeded cells. Current criteria for evaluating whole organ decellularization are primarily based on nucleic acids, as they are easy to quantify and have been directly correlated to adverse host responses. However, numerous proteins cause immunogenic responses and thus should be measured directly to further understand and quantify the efficacy of decellularization. In addition, there has been increasing appreciation for the role of the various protein components of the extracellular matrix (ECM) in directing cell growth and regulating organ function. We performed in-depth proteomic analysis on four types of biological scaffolds and identified a large number of both remnant cellular and ECM proteins. Measurements of individual protein abundances during the decellularization process revealed significant removal of numerous cellular proteins, but preservation of most structural matrix proteins. The observation that decellularized scaffolds still contain many cellular proteins, although at decreased abundance, indicates that elimination of DNA does not assure adequate removal of all cellular material. Thus, proteomic analysis provides crucial characterization of the decellularization process to create biological scaffolds for future tissue/organ replacement therapies.


Fluorescence detected linear dichroism of small molecules oriented on polyethylene film.
We have previously reported a novel method for measuring the spectral properties and orientation of fluorescent probes in solution, which we denoted fluorescence-detected linear dichroism (FDLD). In this work, we expand the scope of the technique by recording the FDLD spectra of the small organic fluorophores: anthracene, 4',6-diamidino-2-phenylindole (DAPI), 1,6-diphenylhexatriene (DPH), and 4-methylphenyl benzoate (MPB), oriented on stretched oxidised polyethylene film. Much like what was observed in solution, we found that the FDLD produced a large signal enhancement compared with absorbance LD, which lowers the sample requirement for measurement. We also found that FDLD has an increased sensitivity towards the immediate environment of the chromophore, revealing oligomeric structures on the film. We believe that FDLD has the potential to reveal important properties of molecules that are obscured or unattainable when using other methods.


Platelet-Rich Plasma Can Be Used to Successfully Treat Elbow Ulnar Collateral Ligament Insufficiency in High-Level Throwers.
We conducted a study to evaluate the effect of platelet-rich plasma (PRP) injections on partial ulnar collateral ligament (UCL) tears in high-level throwing athletes. We retrospectively reviewed the cases of 44 baseball players (6 professional, 14 college, 24 high school) treated with PRP injections for partial-thickness UCL tears. All tears were diagnosed by physical examination and confirmed by magnetic resonance imaging (MRI). Sixteen patients had 1 injection, 6 had 2, and 22 had 3. Once patients became asymptomatic after injection, they were started on an interval throwing program. Physical examination findings at final follow-up were classified according to a modified version of the Conway Scale. Mean age was 17.3 years (range, 16-28 years). All patients were available for follow-up after injection (mean, 11 months). Of the 44 patients, 15 (34%) had an excellent outcome, 17 had a good outcome, 2 had a fair outcome, and 10 had a poor outcome. After injection, 4 (67%) of the 6 professional players returned to professional play. Twenty-two patients had proximally based partial-thickness tears, 7 had distally based partial tears, and 15 had diffuse signal without partial tear on MRI. Mean time from injection to return to throwing was 5 weeks; mean time to return to competition was 12 weeks (range, 5-24 weeks). There were no injection-related complications. Our use of PRP in the treatment of UCL insufficiency produced outcomes much better than earlier reported outcomes of conservative treatment of these injuries. PRP injections may be particularly beneficial in young athletes who have sustained acute damage to an isolated part of the ligament and in athletes unwilling or unable to undergo the extended rehabilitation required after surgical reconstruction of the ligament.


Plasma cytokine levels in Tanzanian HIV-1-infected adults and the effect of antiretroviral treatment.
To evaluate the role immune activation leading to the production and circulation of cytokines has in the pathogenesis of HIV infection in sub-Saharan Africa and the effect of antiretroviral treatment (ART) on these parameters. Plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, IL-10, and IL-1 receptor antagonist; plasma HIV RNA; hemoglobin concentration; and white blood cells were measured in 229 HIV-infected, 54 HIV-uninfected, and after 2 and 4 months, respectively, of ART in 35 eligible individuals in northeastern Tanzania. Plasma levels of tumor necrosis factor-alpha, IL-6, IL-8, monocyte chemotactic protein-1, and IL-1 receptor antagonist were significantly higher in HIV-infected individuals compared with HIV-uninfected individuals and also significantly higher in HIV-infected individuals with CD4 cell counts below 200 cells per microliter than individuals with CD4 cell counts above 200 cells per microliter. HIV RNA was the strongest predictor of all cytokine expression in multivariate analysis. ART leads to a decrease in all cytokines to levels close to those of HIV-uninfected individuals. Our findings support the role of HIV viral replication as the most important promoter of immune activation and prove the importance of ART in reducing immune activation and viral replication even in sub-Saharan Africa where patients are exposed to an abundance of other infectious agents.


ortho-Fluoroazobenzenes: visible light switches with very long-Lived Z isomers.
Improving the photochemical properties of molecular photoswitches is crucial for the development of light-responsive systems in materials and life sciences. ortho-Fluoroazobenzenes are a new class of rationally designed photochromic azo compounds with optimized properties, such as the ability to isomerize with visible light only, high photoconversions, and unprecedented robust bistable character. Introducing σ-electron-withdrawing F atoms ortho to the NN unit leads to both an effective separation of the n→π* bands of the E and Z isomers, thus offering the possibility of using these two transitions for selectively inducing E/Z isomerizations, and greatly enhanced thermal stability of the Z isomers. Additional para-electron-withdrawing groups (EWGs) work in concert with ortho-F atoms, giving rise to enhanced separation of the n→π* transitions. A comprehensive study of the effect of substitution on the key photochemical properties of ortho-fluoroazobenzenes is reported herein. In particular, the position, number, and nature of the EWGs have been varied, and the visible light photoconversions, quantum yields of isomerization, and thermal stabilities have been measured and rationalized by DFT calculations.


An investigation of rainwater tanks quality and sediment dynamics.
Rainwater tanks are being introduced into urban areas in Australia to supplement centralised potable supply systems. A pilot scale tank study and a full-scale field tank study found that heavy metal concentrations in water samples taken from the tank's supply point can, in some cases, exceed levels recommended by guidelines. Both studies also found very high concentrations of heavy metals in the sediments accumulated at the base of rainwater tanks. Laboratory experiments are underway to investigate sediment transport processes within a full-scale tank. Preliminary results demonstrate the effect of sediment resuspension on the quality of water released from the tank outlet. Improved tank designs that reduce sediment resuspension and mitigate impacts on water quality are the focus of future work.


Can We Grow Valves Inside the Heart? Perspective on Material-based In Situ Heart Valve Tissue Engineering.
In situ heart valve tissue engineering using cell-free synthetic, biodegradable scaffolds is under development as a clinically attractive approach to create living valves right inside the heart of a patient. In this approach, a valve-shaped porous scaffold "implant" is rapidly populated by endogenous cells that initiate neo-tissue formation in pace with scaffold degradation. While this may constitute a cost-effective procedure, compatible with regulatory and clinical standards worldwide, the new technology heavily relies on the development of advanced biomaterials, the processing thereof into (minimally invasive deliverable) scaffolds, and the interaction of such materials with endogenous cells and neo-tissue under hemodynamic conditions. Despite the first positive preclinical results and the initiation of a small-scale clinical trial by commercial parties, in situ tissue formation is not well understood. In addition, it remains to be determined whether the resulting neo-tissue can grow with the body and preserves functional homeostasis throughout life. More important yet, it is still unknown if and how in situ tissue formation can be controlled under conditions of genetic or acquired disease. Here, we discuss the recent advances of material-based in situ heart valve tissue engineering and highlight the most critical issues that remain before clinical application can be expected. We argue that a combination of basic science - unveiling the mechanisms of the human body to respond to the implanted biomaterial under (patho)physiological conditions - and technological advancements - relating to the development of next generation materials and the prediction of in situ tissue growth and adaptation - is essential to take the next step towards a realistic and rewarding translation of in situ heart valve tissue engineering.


Risk factors for diabetic retinopathy among Saudi diabetics.
To describe the incidence of, and risk factors associated with, diabetic retinopathy in diabetic persons assessed at a Saudi diabetes centre. Five hundred and two patients with diabetes mellitus assessed by our service were studied. There were 174 patients (34.7%) with insulin-dependent diabetes mellitus (IDDM) and 328 patients (65.3%) with non-insulin-dependent diabetes mellitus (NIDDM). The incidence of retinopathy was 157/502 (31.3%). The incidence was 42.5% in patients with IDDM and 25.3% in those with NIDDM. By logistic regression analysis, it was shown that old age (>60 years), insulin use, long duration of diabetes (>10 years), poor diabetes control, and the presence of nephropathy were significantly associated with the incidence of retinopathy. On the basis of the magnitudes of the regression coefficients in the hazard function, long duration of diabetes was the most important independent risk factor for the development of retinopathy; the presence of nephropathy, age >60 years, poor diabetes control, and use of insulin were less important (regression coefficients: 1.9, 1.71, 1.331, 0.8508 and 0.6178, respectively). The incidence of macular oedema was significantly associated with the presence of hypertension and high cholesterol levels in patients with IDDM. Polycotomous regression analysis showed that the presence of nephropathy was the only factor significantly associated with the severity of retinopathy. The significant associations with poor control and duration of diabetes provide further strong evidence for the benefits of optimal glycaemic control. Other potentially modifiable risk factors for retinopathy may be important, including elevated blood pressure and serum cholesterol.


Modeling and simulation of a low-grade urinary bladder carcinoma.
In this work, we present a mathematical model of the initiation and progression of a low-grade urinary bladder carcinoma. We simulate the crucial processes affecting tumor growth, such as oxygen diffusion, carcinogen penetration, and angiogenesis, within the framework of the urothelial cell dynamics. The cell dynamics are modeled using the discrete technique of cellular automata, while the continuous processes of carcinogen penetration and oxygen diffusion are described by nonlinear diffusion-absorption equations. As the availability of oxygen is necessary for tumor progression, processes of oxygen transport to the tumor growth site seem most important. Our model yields a theoretical insight into the main stages of development and growth of urinary bladder carcinoma with emphasis on the two most common types: bladder polyps and carcinoma in situ. Analysis of histological structure of bladder tumor is important to avoid misdiagnosis and wrong treatment. We expect our model to be a valuable tool in the study of bladder cancer progression due to the exposure to carcinogens and the oxygen dependent expression of genes promoting tumor growth. Our numerical simulations have good qualitative agreement with in vivo results reported in the corresponding medical literature.


MRI of macrophages in infectious knee synovitis.
The objective of our study was to prospectively evaluate macrophage imaging using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI to depict bacterial knee infection in an experimental rabbit model. Unilateral knee infection was induced by intraarticular injection of Staphylococcus aureus in eight rabbits. The contralateral knees were used as internal controls. After a mean interval of 3 days, two MRI sessions (3-T MRI) were performed before and 24 hours after IV administration of USPIO. The protocol included T1-weighted spin-echo, T2-weighted spin-echo, and T2*-weighted gradient-echo images. A gadolinium-enhanced T1-weighted sequence was also performed in the first session to optimize detection of synovial hyperplasia. MR data were analyzed qualitatively and quantitatively and compared with histopathologic findings (H and E stain and Perls Prussian blue stain). Signal-to-noise ratio changes after USPIO administration were compared using Wilcoxon's signed rank test. All inoculated knees presented infectious synovitis with intense infiltration of iron-loaded macrophages. In these infected knees, signal loss was determined visually and quantitatively on T1-weighted (p < 0.01), T2-weighted (p < 0.01), and T2*-weighted images (p < 0.01) 24 hours after USPIO administration, reflecting the presence of USPIO-loaded macrophages in the synovium. In contrast, no significant MR signal changes were observed in the control knees (p = 0.07-0.48), which presented a normal synovium without infiltration of iron-loaded macrophages. Macrophage imaging using USPIO-enhanced MRI can depict infectious knee synovitis.


Alterations in transcription factor-binding activities to fibronectin promoter during aging of vascular endothelial cells.
Previously, we showed that the expression of the fibronectin (FN) gene is enhanced during aging of human endothelial cells and fibroblasts. To elucidate the mechanism, we explored binding proteins to the FN promoter. The promoter contains sites for the general transcription factors: CAAT-binding transcription factor (CTF), promoter-specific transcription factor-1 (Sp1), and transcription factor-IID (TFIID). The promoter also contains sites for inducible transcription factors, cAMP-responsive element (CRE)-binding protein (CREB), and Activator protein 2 (AP-2). We synthesized 10 different oligonucleotides for these and other potential transcription factor-binding sites. Using these oligonucleotides, we searched for binding proteins in young and old endothelial cells by electrophoretic mobility shift and supershift assays. Our results showed that AP-1 decreased with aging, but Sp1 and CREB1 were unaffected. However, decreased binding activities to CRE at positions -170 and -415 were shown in old cells. This could be explained by the decrease of AP-1 because these CREs bound not only CREB1 but also AP-1. Moreover, we observed that the binding activities of TFIID, CTF, and binding proteins to -40, -120 and -260 regions increased. These differential changes may cause the enhancement of FN expression in senescent cells.


Review of phase II trials of Taxol (paclitaxel) in patients with advanced ovarian cancer.
The efficacy and safety of paclitaxel in the treatment of advanced ovarian cancer has been assessed in several phase II trials. McGuire and associates at the Johns Hopkins Oncology Cancer reported results from a phase II trial in which paclitaxel-administered as a 24-hour intravenous (i.v.) infusion with premedication to avoid acute hypersensitivity reactions-yielded one complete response (CR) and 11 partial responses (PRs) (overall response rate, 30%) among 40 previously treated patients with ovarian cancer evaluable for response; 25 of the patients had been refractory to cisplatin therapy. Among 30 evaluable patients who took part in a study at the Albert Einstein Cancer Center, paclitaxel (180 to 250 mg/m2 as a 24-hour i.v. infusion every 21-28 days) produced an overall response rate of 20% (1 CR, 5 PRs). Four responding patients were resistant to previous cisplatin therapy. Median survival for responders was 27 months, and 6 months for nonresponders (P = 0.0001). The Gynecologic Oncology Group confirmed the activity of paclitaxel (175 mg/m2 as a continuous 24-hour i.v. infusion) in 41 evaluable cisplatin-resistant patients, among whom 15 (37%) responded (5 CR, 10 PR). A total of 8 of 27 (29%) patients with cisplatin-refractory disease responded (2/27 CR, 6/27 PR). Among 14 patients whose disease progressed more than 6 months following cisplatin therapy, 3 had CRs and 4 had PRs. Finally, the National Cancer Institute Treatment Referral Center protocol enrolled more than 2,000 patients; preliminary analysis of 1,000 patients included 663 evaluable for response with measurable disease. There are 27 CRs and 119 PRs; median time to progression for responding patients is 7 months.(ABSTRACT TRUNCATED AT 250 WORDS)


A study of dynamic nanoscale corrosion initiation events using HS-AFM.
Atomic force microscopes (AFMs) are capable of high-resolution mapping of structures and the measurement of mechanical properties on nanometre scales within gaseous, liquid and vacuum environments. The contact mode high-speed AFM (HS-AFM) developed at Bristol Nano Dynamics Ltd. operates at speeds that are orders of magnitude faster than conventional AFMs, and is capable of capturing multiple frames per second. This allows for direct observation of dynamic events in real-time, with nanometre lateral resolution and subatomic height resolution. HS-AFM is a valuable tool for the imaging of nanoscale corrosion initiation events, such as metastable pitting, grain boundary (GB) dissolution and short crack formation during stress corrosion cracking (SCC). Within this study HS-AFM was combined with SEM and FIB milling to produce a multifaceted picture of localised corrosion events occurring on thermally sensitised AISI 304 stainless steel in an aqueous solution of 1% sodium chloride (NaCl). HS-AFM measurements were performed in situ by imaging within a custom built liquid cell with parallel electrochemical control. The high resolution of the HS-AFM allowed for measurements to be performed at individual reaction sites, i.e. at specific GB carbide surfaces. Topographic maps of the sample surface allowed for accurate measurements of the dimensions of pits formed. Using these measurements it was possible to calculate, and subsequently model, the volumes of metal reacting with respect to time, and so the current densities and ionic fluxes at work. In this manner, the local electrochemistry at nanoscale reaction sites may be reconstructed.


Development of a new exposure monitoring system considering pulmonary ventilation (DEM 1).
Exposure evaluation is an essential facet in the assessment of the risks of exposure to toxic materials in the workplace. Presently, samples from the breathing atmosphere are measured in order to determine the level of individual exposure to toxic substances. This method, however, does not take into account the level of physical exertion during exposure. Physical activity is known to increase pulmonary ventilation by up to 10 times that of the level at rest. Thus, measurement of pulmonary ventilation, as well as the concentration of a toxic material in the air would provide valuable data in evaluating exposure. We have developed a device that measures and records the concentration of a toxic material in the air and pulmonary ventilation as predicted by heart rate both simultaneously and continuously. In this system, real time pulmonary ventilation is predicted from heart rate by using a regression equation that was obtained from the results of our study. The percentage error of predicted pulmonary ventilation at each heart rate is within 30%. The present study assessed the feasibility of the use of heart rate as the predictor of pulmonary ventilation. Our new exposure monitoring system is the first practical device that monitors the level of exposure dependent upon pulmonary ventilation and will be useful in the reevaluation of threshold limit values (TLV's) and in working management.


Nuclear import of cubitus interruptus is regulated by hedgehog via a mechanism distinct from Ci stabilization and Ci activation.
The Hedgehog (Hh) signal is transduced via Cubitus interruptus (Ci) to specify cell fates in the Drosophila wing. In the absence of Hh, the 155 kDa full-length form of Ci is cleaved into a 75 kDa repressor. Hh inhibits the proteolysis of full-length Ci and facilitates its conversion into an activator. Recently, it has been suggested that Hh promotes Ci nuclear import in tissue culture cells. We have studied the mechanism of Ci nuclear import in vivo and the relationship between nuclear import, stabilization and activation. We found that Ci rapidly translocates to the nucleus in cells close to the anteroposterior (AP) boundary and this rapid nuclear import requires Hh signaling. The nuclear import of Ci is regulated by Hh even under conditions in which Ci is fully stabilized. Furthermore, cells that exhibit Ci stabilization and rapid nuclear import do not necessarily exhibit maximal Ci activity. It has been previously shown that stabilization does not suffice for activation. Consistent with this finding, our results suggest that the mechanisms regulating nuclear import, stabilization and activation are distinct from each other. Finally, we show that cos2 and pka, two molecules that have been characterized primarily as negative regulators of Ci activity, also have positive roles in the activation of Ci in response to Hh.


Is there a role for benzodiazepines in the management of lumbar disc prolapse with acute sciatica?
Patients with acute lumbar disc prolapse with sciatica who are not considered candidates for surgery are usually treated with physiotherapy and non-steroidal anti-inflammatory agents. Moreover, the treatment with benzodiazepines is common practice in the absence of class I or II level of evidence. Here we assessed the role of benzodiazepines in the conservative management of acute lumbar disc prolapse. Using a placebo-controlled, double-blinded design, 60 patients were randomized to receive placebo or diazepam in addition to mechanical physiotherapy and analgesics for the first 7 days of conservative treatment of clinically and radiologically confirmed lumbar disc prolapse. The primary objective was to evaluate if physiotherapy plus analgesics, but without benzodiazepines, is equivalent to the same therapy plus benzodiazepines. The primary endpoint was centralization of referred pain at day 7. Twenty-six female and 34 male patients were enrolled. The median age was 42 years (range 22-68 years). Analysis of the primary endpoint demonstrated equivalence between placebo and diazepam (median 60% vs. 50% reduction of distance of referred pain at day 7) within the predefined equivalence tolerance of 20% at a significance level of p<0.05. Regarding the secondary endpoints, the median duration of the stay in hospital was shorter in the placebo arm (8 vs. 10 days, p=0.008), and the probability of pain reduction on a visual analog scale by more than 50% was twice as high in placebo patients (p<0.0015). Benzodiazepines should not be used routinely in patients treated with mechanical physiotherapy for lumbar disc prolapse.


Response of Pseudomonas aeruginosa PAO1 to low shear modelled microgravity involves AlgU regulation.
As a ubiquitous environmental organism that is occasionally part of the human flora, Pseudomonas aeruginosa could pose a health hazard for the immunocompromised astronauts during long-term missions. Therefore, insights into the behaviour of P. aeruginosa under spaceflight conditions were gained using two spaceflight-analogue culture systems: the rotating wall vessel (RWV) and the random position machine (RPM). Microarray analysis of P. aeruginosa PAO1 grown in the low shear modelled microgravity (LSMMG) environment of the RWV, compared with the normal gravity control (NG), revealed an apparent regulatory role for the alternative sigma factor AlgU (RpoE-like). Accordingly, P. aeruginosa cultured in LSMMG exhibited increased alginate production and upregulation of AlgU-controlled transcripts, including those encoding stress-related proteins. The LSMMG increased heat and oxidative stress resistance and caused a decrease in the oxygen transfer rate of the culture. This study also showed the involvement of the RNA-binding protein Hfq in the LSMMG response, consistent with its previously identified role in the Salmonella LSMMG and spaceflight response. The global transcriptional response of P. aeruginosa grown in the RPM was highly similar to that in NG. Fluid mixing was assessed in both systems and is believed to be a pivotal factor contributing to transcriptional differences between RWV- and RPM-grown P. aeruginosa. This study represents the first step towards the identification of virulence mechanisms of P. aeruginosa activated in response to spaceflight-analogue conditions, and could direct future research regarding the risk assessment and prevention of Pseudomonas infections during spaceflight and in immunocompromised patients.


Association of Attention deficit hyperactivity disorder and Kawasaki disease: a nationwide population-based cohort study.
The association between Kawasaki disease (KD) and Attention deficit hyperactivity disorder (ADHD) has rarely been studied. In this study, we investigated the hypothesis that KD may increase the risk of ADHD using a nationwide Taiwanese population-based claims database. Our study cohort consisted of patients who were diagnosed with KD between January 1997 and December 2005 (N = 651). For a comparison cohort, five age- and gender-matched control patients for every patient in the study cohort were selected using random sampling (N = 3255). The cumulative incidence of ADHD was 3.89/1000 (from 0.05 to 0.85) in this study. All subjects were tracked for 5 years from the date of cohort entry to identify whether or not they had developed ADHD. Cox proportional hazard regression analysis was performed to evaluate 5-year ADHD-free survival rates. Of all patients, 83 (2.1%) developed ADHD during the 5-year follow-up period, of whom 21 (3.2%) had KD and 62 (1.9%) were in the comparison cohort. The patients with KD seemed to be at an increased risk of developing ADHD (crude hazard ratio (HR): 1.71; 95% confidence interval (CI) = 1.04-2.80; p < 0.05). However, after adjusting for gender, age, asthma, allergic rhinitis, atopic dermatitis and meningitis, the adjusted hazard ratios (AHR) of the ADHD in patients with KD showed no association with the controls (AHR: 1.59; 95% CI = 0.96-2.62; p = 0.07). We also investigated whether or not KD was a gender-dependent risk factor for ADHD, and found that male patients with KD did not have an increased risk of ADHD (AHR: 1.62; 95% CI = 0.96-2.74; p = 0.07) compared with the female patients. The findings of this population-based study suggest that patients with KD may not have an increased risk of ADHD and whether or not there is an association between KD and ADHD remains uncertain.


Bottlenose dolphins (Tursiops truncatus) prefer to cooperate when petted: Integrating proximate and ultimate explanations II.
Cooperation poses theoretical problems because the behaviors of individuals can benefit others. Evolutionary and game-theory explanations that focus on maximizing one's own material outcomes are usually supported by experimental models with isolated and anonymous subjects. Cooperation in the natural world, however, is often a social act whereby familiar individuals coordinate behaviors for shared outcomes. Social cooperation is also associated with a cooperation bias expressed as a preference for cooperation even when noncooperation is immediately more beneficial. The authors report on evidence for such a bias in a captive group of bottlenose dolphins that voluntarily preferred to receive petting from human guides by using a pairwise coordinated approach, even though this was more difficult, and total petting amount was thereby reduced. To explain why this bias occurs, the authors propose an integrated behavioral-evolutionary approach whereby performance is determined by two kinds of immediate outcomes: material gains and intrinsic affective states associated with cooperating. The latter can provide reinforcement when immediate material gains are reduced, delayed, or absent. Over a lifetime, this proximate mechanism can lead to cooperative relationships whose long-term ultimate consequences can be adaptive.


Effects of movement protein mutations on the formation of tubules in plant protoplasts expressing a fusion between the green fluorescent protein and Cauliflower mosaic virus movement protein.
Fusions between the green fluorescent protein (GFP) and the Cauliflower mosaic virus (CaMV) movement protein (MP) induce the formation of fluorescent foci and surface tubules in Arabidopsis thaliana leaf mesophyll protoplasts. Tubules elongate coordinately and progressively in an assembly process approximately 6 to 12 h following transfection of protoplasts with GFP-MP constructs. Tubules are not formed in protoplasts transfected by GFP-MP(ER2A), a MP mutation that renders CaMV noninfectious. A small number of short tubules are formed on protoplasts transfected by GFP-MP(N6) and GFP-MP(N13), two second-site revertants of ER2A that partially restore infectivity. Protoplasts cotransfected with cyan fluorescent protein (CFP)-MP(WT) and GFP-MP(ER2A) form tubules containing both MP fusions, indicating that although the GFP-MP(ER2A) cannot induce tubule formation, GFP-MP(ER2A) can coassemble or colocalize with CFP-MP(WT) in tubules. Thus, CaMV MP-induced tubule formation in protoplasts correlates closely with the infectivity of mutation ER2A and its revertants, suggesting that tubule-forming capacity in plant protoplasts reflects a process required for virus infection or movement.


Self-mixing flow sensor using a monolithic VCSEL array with parallel readout.
The self-mixing sensing technique is a compact, interferometric sensing technique that can be used for measuring fluid flows. In this work, we demonstrate a parallel readout self-mixing flow velocity sensing system based on a monolithic Vertical-Cavity Surface-Emitting Laser (VCSEL) array. The parallel sensing scheme enables high-resolution full-field imaging systems employing electronic scanning with faster acquisition rates than mechanical scanning systems. The self-mixing signal is acquired from the variation in VCSEL junction voltage, thus markedly reducing the system complexity. The system was validated by measuring velocity distribution of fluid in a custom built diverging-converging planar flow channel. The results obtained agree well with simulation and demonstrate the feasibility of high frame-rate and resolution parallel self-mixing sensors.


The amygdala central nucleus and appetitive Pavlovian conditioning: lesions impair one class of conditioned behavior.
Rats with neurotoxic lesions of the amygdala central nucleus (CN) were trained using appetitive Pavlovian conditioning procedures. Conditioned responses (CRs) that are representative of 2 classes of behavior were monitored. One type of CR resembled the orienting responses that were elicited by the conditioned stimuli (CSs) prior to pairing with food reinforcement: the other type of CR resembled the behavior elicited by food reinforcement itself. Holland (1977, 1984) has referred to these as CS-generated and unconditioned stimulus (US)-generated CRs, respectively. During differential conditioning, some lesioned and unlesioned rats received reinforced presentations of a visual cue and nonreinforced presentations of an auditory cue, and the others in each lesion condition received reinforced auditory and nonreinforced visual cue presentations. Relative to the control group, the CN-lesioned rats were impaired in the acquisition of CS-generated CRs to both visual and auditory CSs. Orienting responses and habituation to the CSs were, however, comparable for the lesion and control groups. Moreover, rats with CN lesions readily acquired the US-generated CRs. Thus, a specific class of conditioned behavior was impaired by CN damage. Many studies using aversive Pavlovian procedures have suggested that CN lesions impair fear conditioning. The present results suggest another role for CN in the conditioning of orienting/attentional responses.