CDKN2A/p16 Loss Implicates CDK4 as a Therapeutic Target in Imatinib-Resistant Dermatofibrosarcoma Protuberans.
Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in approximately 50% of patients with unresectable or metastatic DFSP. However, efficacious medical therapies have not been developed for imatinib-resistant DFSP. We established a model of imatinib-resistant DFSP and evaluated CDK4/6 inhibition as a genomically credentialed targeted therapy. DFSP105, an imatinib-resistant human cell line, was established from a fibrosarcomatous DFSP (FS-DFSP), and was studied by SNP arrays and sequencing to identify targetable genomic alterations. Findings were validated in vitro and in vivo, and confirmed in a series including 12 DFSP and 6 FS-DFSP. SNP analysis of DFSP105 revealed a homozygous deletion encompassing CDKN2A and CDKN2B. The resultant p16 loss implicated CDK4/6 as a potential therapeutic target in DFSP. We further demonstrated CDKN2A homozygous deletion in 1 of 12 conventional DFSP and 2 of 6 FS-DFSP, whereas p16 expression was lost in 4 of 18 DFSP. In vitro treatment of DFSP105 with two structurally distinct selective CDK4/6 inhibitors, PD-0332991 and LEE011, led to inhibition of RB1 phosphorylation and inhibition of proliferation (GI50 160 nmol/L and 276 nmol/L, respectively). In vivo treatment of DFSP105 with PD-0332991 (150 mg/kg) inhibited xenograft growth in mice, in comparison with imatinib-treated or -untreated tumors. In conclusion, CDKN2A deletion can contribute to DFSP progression. CDK4/6 inhibition is a preclinically effective treatment against p16-negative, imatinib-resistant FS-DFSP, and should be evaluated as a therapeutic strategy in patients with unresectable or metastatic imatinib-resistant DFSP.


Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide.
We report detailed peptide-binding affinities between 438 HLA Class I and Class II proteins and complete proteomes of seven pandemic human viruses, including coronaviruses, influenza viruses and HIV-1. We contrast these affinities with HLA allele frequencies across hundreds of human populations worldwide. Statistical modelling shows that peptide-binding affinities classified into four distinct categories depend on the HLA locus but that the type of virus is only a weak predictor, except in the case of HIV-1. Among the strong HLA binders (IC50 ≤ 50), we uncovered 16 alleles (the top ones being A*02:02, B*15:03 and DRB1*01:02) binding more than 1% of peptides derived from all viruses, 9 (top ones including HLA-A*68:01, B*15:25, C*03:02 and DRB1*07:01) binding all viruses except HIV-1, and 15 (top ones A*02:01 and C*14:02) only binding coronaviruses. The frequencies of strongest and weakest HLA peptide binders differ significantly among populations from different geographic regions. In particular, Indigenous peoples of America show both higher frequencies of strongest and lower frequencies of weakest HLA binders. As many HLA proteins are found to be strong binders of peptides derived from distinct viral families, and are hence promiscuous (or generalist), we discuss this result in relation to possible signatures of natural selection on HLA promiscuous alleles due to past pathogenic infections. Our findings are highly relevant for both evolutionary genetics and the development of vaccine therapies. However they should not lead to forget that individual resistance and vulnerability to diseases go beyond the sole HLA allelic affinity and depend on multiple, complex and often unknown biological, environmental and other variables.


Effect of dietary supplementation with selenium-enriched yeast or sodium selenite on selenium tissue distribution and meat quality in beef cattle.
The objective was to determine the concentration of total Se and the proportion of total Se comprised as selenomethionine (SeMet) and selenocysteine (SeCys) in postmortem tissues of beef cattle offered diets containing graded additions of selenized enriched yeast (SY; Saccharomyces cerevisiae CNCM I-3060) or sodium selenite (SS). Oxidative stability and tissue glutathione peroxidase (GSH-Px) activity of edible muscle tissue were assessed 10 d postmortem. Thirty-two beef cattle were offered, for a period of 112 d, a total mixed ration that had been supplemented with SY (0, 0.15, or 0.35 mg of Se/kg of DM) or SS (0.15 mg of Se/kg of DM). At enrollment (0 d) and at 28, 56, 84, and 112 d following enrollment, blood samples were taken for Se and Se species determination, as well as whole blood GSH-Px activity. At the end of the study beef cattle were killed and samples of heart, liver, kidney, and skeletal muscle (LM and psoas major) were retained for Se and Se species determination. Tissue GSH-Px activity and thiobarbituric acid reactive substances were determined in skeletal muscle tissue (LM only). The incorporation into the diet of ascending concentrations of Se as SY increased whole blood total Se and the proportion of total Se comprised as SeMet, as well as GSH-Px activity. There was also a dose-dependent response to the graded addition of SY on total Se and proportion of total Se as SeMet in all tissues and GSH-Px activity in skeletal muscle tissue. Furthermore, total Se concentration of whole blood and tissues was greater in those animals offered SY when compared with those receiving a comparable dose of SS, indicating an improvement in Se availability and tissue Se retention. Likewise, GSH-Px activity in whole blood and LM was greater in those animals offered SY when compared with those receiving a comparable dose of SS. However, these increases in tissue total Se and GSH-Px activity appeared to have little or no effect in meat oxidative stability.


A clinical evaluation of a screening (Microstix) for urinary tract infections.
The effectiveness of a screening device for urinary tract infection (Microstix**) was compared to routine laboratory cultures, sensitivities, and colony counts. The Microstix were highly effective in determining the presence or absence of urinary tract infections. In addition, they could be subcultured to provide meaningful bacterial sensitivities. Microstix are economical, easy to use, and accurate. Their use in the diagnosis and follow-up of urinary tract infections is therefore recommended.


Cancer epidemiology in South-West Asia - past, present and future.
South-West Asia, stretching from Lebanon and Syria in the north, through to Yemen in the south and Iraq in the east, is the home of more than 250 million people. Cancer is already a major problem and the markedly increasing rates for diabetes suggest that the burden of adenocarcinomas will only become heavier over time, especially with increasing obesity and aging of what are now still youthful populations. The age-distributions of the affected patients in fact might also indicate cohort effects in many cases. There are a number of active registries in the region and population-based data are now available for a considerable number of countries. Scientists from the region are also contributing to epidemiological research into the causes of cancer and how to develop effective control programs. The present review covers the relevant PubMed literature and cancer incidence data from various sources, highlighting similarities and variation in the different cancer types, with attempts to explain disparities with reference to environmental factors. In males, the most prevalent cancers vary, with lung urinary bladder or liver in first place, while for females throughout the region breast cancer is the major problem. In both sexes, non-Hodgkins lymphomas and leukemias are relatively prevalent, along with lung in males and thyroid in certain female populations. Coordination of activities within the Arab world, as well as Israel, could bring major benefits to cancer control in the eastern Mediterranean region.


Site of origin of deep vein thrombus in the calf.
A phlebographic technique is described for demonstrating as fully as possible the stem and muscle veins of the calf. The findings in 103 examinations containing calf thrombus demonstrated by this method are presented. It is concluded that calf vein thrombosis is as likely to originate in stem veins as from the soleal muscle veins.


Respiratory muscle strength in children and adolescents with asthma: similar to that of healthy subjects?
To compare children/adolescents with mild or moderate asthma and healthy subjects in terms of respiratory muscle strength, correlating it with spirometric variables in the former group. This was a cross-sectional study involving individuals 6-16 years of age and clinically diagnosed with mild/moderate asthma, together with a group of healthy, age- and gender-matched subjects. We determined spirometric values, as well as MIP and MEP, and we selected three reproducible measurements (variation < 10%). We evaluated 75 patients with asthma and 90 controls. The mean age was 10.0 ± 2.6 years. There were no statistically significant differences between the controls and the asthma group regarding MIP (-89.7 ± 26.7 cmH2O vs. -92.2 ± 26.3 cmH2O; p = 0.541) or MEP (79.2 ± 22.9 cmH2O vs. 86.4 ± 24.0 cmH2O; p = 0.256). The groups were subdivided by age (children and adolescents: 6-12 and 13-16 years of age, respectively). Within the asthma group, there was a significant difference between the child and adolescent subgroups in terms of MEP (74.1 ± 24.1 cmH2O vs. 92.1 ± 21.9 cmH2O; p < 0.001) but not MIP (p = 0.285). Within the control group, there were significant differences between the child and adolescent subgroups in terms of MIP (-79.1 ± 17.7 cmH2O vs. -100.9 ± 28.1 cmH2O; p < 0.001) and MEP (73.9 ± 18.7 cmH2O vs. 90.9 ± 28.1cmH2O; p < 0.001). In the asthma group, spirometric variables did not correlate with MIP or MEP. In our sample, asthma was found to have no significant effect on respiratory muscle strength.


Research advances of antimicrobial peptides and applications in food industry and agriculture.
Antimicrobial peptides (AMPs) are produced by a wide range of organisms and serve as their natural defenses against infection caused by bacteria, viruses and fungi. Because of the positively charge and amphipathic structure, AMPs kill target cells through diverse and complex mechanisms once in a target membrane and these special mechanisms are considered to be the critical factors for the less tendency of drug resistance development. Thus AMPs may become a new generation of promising antimicrobial agents in future anti-infection application. Additionally, AMPs can also be used in food industry and agriculture. On the basis of discussing the structural features, action mechanisms and sources, the applications of AMPs were reviewed in this paper, including in food industry, feedstuff, cultivation of disease-resistant transgenic plant, cultivation of transgenic animal, and aquaculture, especially the patented applications.


The metabolism in vitro of human low-density lipoprotein by the human hepatoma cell line Hep G2.
The human hepatoma cell line Hep G2 was studied with respect to metabolism of human low-density lipoprotein (LDL). The Hep G2 cells bind, take up and degrade human LDL with a high-affinity saturable and with a low-affinity non-saturable component. The high-affinity binding possesses a KD of 25 nM-LDL and a maximal amount of binding of about 70 ng of LDL-apoprotein/mg of cell protein. The high-affinity binding, uptake and degradation of LDL by Hep G2 cells is dependent on the extracellular Ca2+ concentration and is down-regulated by the presence of fairly high concentrations of extracellular LDL. Incubation of the Hep G2 cells with LDL results in suppression of the intracellular cholesterol synthesis. It is concluded that the human hepatoma cell line Hep G2 possesses specific LDL receptors similar to the LDL receptors demonstrated on extrahepatic tissue cells.


Identification of RAPD markers linked to digestive amylase genes using near isogenic lines of the silkworm, Bombyx mori.
Digestive amylase has been identified as a useful marker for breeding in the silkwrom, Bombyx mori L (Lepidoptera: Bombycidae), due to its wide genetic divergence, its role in better digestibility and robustness. The low yielding indigenous B. mori breeds of tropics like India are characterized by high activity amylase genes controlled by Amy d(iv) or d(v) alleles, while the high yielding breeds of temperate origin are endowed with 'null' type (Amy d(n)) with low activity. For improving the digestibility and survival of temperate breeds of Japanese origin, Near Isogenic Lines (NILs) were developed introgressing the Amy d(iv) and d(v) alleles from the Donor Parents (DPs) into the genetic background of the Recurrent Parents (RPs) with 'null' type of amylase, which showed significant improvement in viability of the NILs. With the objective to know whether the amylase gene itself may confer higher survival by improving digestibility or some other closely linked genes flanking the amylase locus is responsible for better viability of the NILs, RAPD profiles among six B. mori breeds comprising of the DPs, RPs, and NILs developed through introgression of Amy d(iv) or d(v) alleles were analysed using 27 sets of RAPD primers. Out of the 27 primers, six (OPA01, OPA06, OPA09, OPA15, OPAH03, and OPAH05) showed RAPD products linked to the amylase genes of the DPs introgressed in the NILs, which were absent in their respective RPs. Three amplicons of 1584 bp, 1904 bp, and 1232 bp were specific to Amy d(iv) allele and one amplified product of 1776 bp was found to be linked with the Amy d(v) allele. Interestingly, two PCR products of 2628 and 1375 bp were associated with both Amy d(iv) and d(v) alleles. The results are discussed in light of further characterization of these amplified products leading to identification of DNA sequences that may be responsible for better digestibility and higher survival in B. mori.


[Electroanatomical mapping systems in catheter ablation of cardiac arrhythmias].
Due to the recent technical development of the past years, most cardiac electrophysiological laboratories are equipped with computer-based electroanatomical mapping systems that precisely describe both the temporal and spatial characteristics of cardiac activation. This development has also been driven by the need for increased accuracy in arrhythmia localization as required for catheter ablation. Computer-based electroanatomical mapping systems are able to reconstruct cardiac anatomy and provide a straightforward representation of chamber activation. These systems capture and display details of intracardiac physiology and mark the site of interventions. Nowadays, several mapping technologies are available in the electrophysiological labs: CARTO XP, EnSite NavX and Array, Real-time Position Management. In this paper we aim to briefly present the principal technological and practical characteristics of these mapping systems regarding eligibility, ability and limitations. The development of computer-based mapping technologies is also discussed in detail, since future systems will be able to display any parametric process including vectors, strains, contraction patterns etc., a wide variety of physiologic parameters beyond activation times and voltage. Using electroanatomical mapping systems, the specific recording of both anatomy and physiology has contributed substantially to the expansion of ablation to atypical atrial flutters, ventricular tachycardia, congenital heart-disease-related arrhythmias and atrial fibrillation. While the technology is already facilitating, the obvious down-side to this technological explosion is cost. Subsequent studies will be needed, however, to show that this translates into improved outcomes and cost savings.


The diagnostic value of automated flicker threshold perimetry.
Automated perimetry techniques have advanced from the standard white-on-white threshold perimetry to a myriad of perimetric models. These models include motion detection, frequency-doubling contrast sensitivity, and spatial contrast sensitivity perimetry. The research findings for the more popular of the automated perimetry models, in particular those of blue-on-yellow and critical fusion frequency perimetry, are discussed and compared with findings for flicker threshold perimetry. Flicker threshold perimetry demonstrates resistance to such factors as test variability and retinal image blur and has great promise in its ability to detect early visual field loss in the presence of primary open-angle glaucoma.


[Cognitive profile of elderly residents in Long-stay Institutions of Brasilia-DF].
Aging exposes the individuals to a number of limitations, such as the physical, nutritional and cognitive, which can cause them to hospitalization in long-stay institutions. In this study, it was aimed to evaluate to evaluate the cognitive profile of elderly institutionalized through three instruments. Sixty institutionalized elderly people in long-stay institutions underwent assessment through the Mini Mental State Examination (MMSE), the Trail Making Test and the Clinical Dementia Rating. It was found that the percentage of seniors with cognitive impairment by the MMSE was 30% of the sample, being more prevalent in women (36.2% of cognitive loss) compared to men (7.7% of cognitive loss). There was no consistency between the results obtained by the MMSE with the other instruments tested.


Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma.
Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence. Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed. Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2 x 10(6) CD34(+) cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%. A tandem HDT/SCR regimen for high-risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival.


Hybrid palliation of interrupted aortic arch in a high-risk neonate.
We report a case of a high-risk neonate with interrupted aortic arch (IAA) and ventricular septal defect who underwent a successful hybrid palliative procedure using a ductal stent and bilateral branch pulmonary artery banding. This case represents not only a successful use of hybrid approach in high-risk neonates with IAA, but also introduces an alternative and safe access for ductal stent insertion through the right ventricular infundibulum.


Efficient Everolimus Treatment for Metastatic Castration Resistant Prostate Cancer with AKT1 Mutation: A Case Report.
Metastatic castration resistant prostate cancer (mCRPC), the advanced stage of prostate cancer (PCa), develops resistance to first line androgen deprivation therapy (ADT). Aberrant androgen receptor (AR) and PI3K-Akt-mTOR signaling pathway are responsible for the development and progression of mCRPC. We herein describe a case of a 64-year-old male mCRPC patient with somatic AKT1 and AR mutations. The patient, who had been heavily pretreated by ADT and AR inhibitors, showed stable disease progression when he received everolimus, an mTOR inhibitor. The PSA level dropped drastically from 1493.0 ng/mL to 237.6 ng/mL, after 3 months of treatment. The overall survival (OS) was 43 months, of which the progression-free survival (PFS) with everolimus treatment was 7 months. The administration of mTOR inhibitor, everolimus, could achieve good clinical responses along with prolonging PFS for mCRPC patients harboring AKT1 mutations. Technology in precision medicine, such as targeted next-generation sequencing (NGS) of cancer-relevant genes, has promising function in personalized therapy.


Relationships between language structure and language learning: the suffixing preference and grammatical categorization.
It is a reasonable assumption that universal properties of natural languages are not accidental. They occur either because they are underwritten by genetic code, because they assist in language processing or language learning, or due to some combination of the two. In this paper we investigate one such language universal: the suffixing preference across the world's languages, whereby inflections tend to be added to the end of words. A corpus analysis of child-directed speech in English found that suffixes were more accurate at cuing the grammatical category of the root word than were prefixes. An artificial language experiment found that there was a learning advantage for suffixes over prefixes in terms of grammatical categorization within an artificial language. The results are consistent with an account of language universals that originate in general purpose learning mechanisms.


Art-delivered episodic future thinking reduces delay discounting: A phase IIa proof-of-concept trial.
High rates of delay discounting (DD), or the preference for immediate rewards over delayed rewards, is associated with substance use disorder (SUD). Lower rates of DD predict better treatment outcomes, thus strategies that reduce DD may support SUD recovery. The process of vividly imagining a future event, known as episodic future thinking (EFT), may be a particularly viable approach to reduce DD. Some limited research has examined delivery of EFT in treatment settings, using verbal prompts that are typical of studies in non-treatment settings. We propose that the creation of visual art represents a unique alignment of the purpose of EFT with an innovative delivery modality in treatment settings. The present single arm, proof-of-concept trial evaluated art-delivered EFT (ArtEFT) to reduce DD in a sample of women (N = 39) in a residential SUD treatment center. Participants engaged in a single, 1-h ArtEFT session during which they engaged in EFT and created a visual representation using art materials. The study collected DD measures for hypothetical money ($50 and $1000 magnitude conditions) before and after ArtEFT. Using area-under-the-curve (AUCord) as the index of DD, the study observed predicted changes following the ArtEFT session. The ANOVA revealed statistically significant main effects of both magnitude [F(1,38) = 11.184, p = .002] and time [F(1. 38) = 4.731, p = .036], with a non-significant interaction [F(1,38) = 3.821, p = .058]. This study reveals positive preliminary indicators that art may be an effective modality to deliver EFT, with particular advantages for implementation given the popularity of art programming in SUD treatment programs.


5'-tRF-19-Q1Q89PJZ Suppresses the Proliferation and Metastasis of Pancreatic Cancer Cells via Regulating Hexokinase 1-Mediated Glycolysis.
tRNA-derived small RNAs (tDRs) are dysregulated in several diseases, including pancreatic cancer (PC). However, only a limited number of tDRs involved in PC progression are known. Herein, a novel tDR, 5'-tRF-19-Q1Q89PJZ (tRF-19-Q1Q89PJZ), was verified in PC plasma using RNA and Sanger sequencing. tRF-19-Q1Q89PJZ was downregulated in PC tissues and plasma, which was related to advanced clinical characteristics and poor prognosis. tRF-19-Q1Q89PJZ overexpression inhibited the malignant activity of PC cells in vitro, while tRF-19-Q1Q89PJZ inhibition produced an opposite effect. The differentially expressed genes induced by tRF-19-Q1Q89PJZ overexpression were enriched in "pathways in cancer" and "glycolysis". Mechanistically, tRF-19-Q1Q89PJZ directly sponged hexokinase 1 (HK1) mRNA and inhibited its expression, thereby suppressing glycolysis in PC cells. HK1 restoration relieved the inhibitory effect of tRF-19-Q1Q89PJZ on glycolysis in PC cells and on their proliferation and mobility in vitro. tRF-19-Q1Q89PJZ upregulation inhibited PC cell proliferation and metastasis in vivo and suppressed HK1 expression in tumor tissues. Furthermore, tRF-19-Q1Q89PJZ expression was attenuated under hypoxia. Collectively, these findings indicate that tRF-19-Q1Q89PJZ suppresses the malignant activity of PC cells by regulating HK1-mediated glycolysis. Thus, tRF-19-Q1Q89PJZ may serve as a key target for PC therapy.


Mapping QTL for vernalization requirement identified adaptive divergence of the candidate gene Flowering Locus C in polyploid Camelina sativa.
Vernalization requirement is an integral component of flowering in winter-type plants. The availability of winter ecotypes among Camelina species facilitated the mapping of quantitative trait loci (QTL) for vernalization requirement in Camelina sativa. An inter and intraspecific crossing scheme between related Camelina species, where one spring and two different sources of winter-type habit were used, resulted in the development of two segregating populations. Linkage maps generated with sequence-based markers identified three QTLs associated with vernalization requirement in C. sativa; two from the interspecific (chromosomes 13 and 20) and one from the intraspecific cross (chromosome 8). Notably, the three loci were mapped to different homologous regions of the hexaploid C. sativa genome. All three QTLs were found in proximity to Flowering Locus C (FLC), variants of which have been reported to affect the vernalization requirement in plants. Temporal transcriptome analysis for winter-type Camelina alyssum demonstrated reduction in expression of FLC on chromosomes 13 and 20 during cold treatment, which would trigger flowering, since FLC would be expected to suppress floral initiation. FLC on chromosome 8 also showed reduced expression in the C. sativa ssp. pilosa winter parent upon cold treatment, but was expressed at very high levels across all time points in the spring-type C. sativa. The chromosome 8 copy carried a deletion in the spring-type line, which could impact its functionality. Contrary to previous reports, all three FLC loci can contribute to controlling the vernalization response in C. sativa and provide opportunities for manipulating this requirement in the crop.


[Cardiac risk patients in anesthesia].
Cardiac complications are the major cause of morbidity and mortality in patients undergoing noncardiac operations. The perioperative risk of adverse cardiac events is particularly high in patients with significant coronary artery disease, heart failure or critical aortic stenosis. Prolonged intraperitoneal and intrathoracic operations, major vascular surgery, emergency procedures, and intraoperative hypotension and tachycardia promote and increase incidence and severity of cardiac complications. Recent experience has shown, however, that elective noncardiac operations can be performed with justifiable risk even in patients with endstage cardiac disease awaiting heart transplantation. Surgery, if indicated, can thus nowadays hardly be denied even in the presence of high cardiac risk. Successful anesthetic management requires detailed information about the cause and severity of the underlying disease, thorough understanding of its specific hemodynamic particularities, indepth knowledge about hemodynamic effects and interactions of anesthetic drugs, and experience with extended hemodynamic monitoring. Anesthetic choice by itself appears to be of minor significance. Cardiac surgery prior to major elective noncardiac procedures is advocated in patients with significant coronary artery disease or severe valve lesions. The incidence of life-threatening cardiac complications is particularly high in the postoperative period; prolonged hemodynamic monitoring in an intensive care unit is therefore mandatory.


Factors Associated With Hospital Decisions to Purchase Robotic Surgical Systems.
Background. Robotic surgical systems are expensive to own and operate, and the purchase of such technology is an important decision for hospital administrators. Most prior literature focuses on the comparison of clinical outcomes between robotic surgery and other laparoscopic or open surgery. There is a knowledge gap about what drives hospitals' decisions to purchase robotic systems. Objective. To identify factors associated with a hospital's acquisition of advanced surgical systems. Method. We used 2002 to 2011 data from the State of California Office of Statewide Health Planning and Development to examine robotic surgical system purchase decisions of 476 hospitals. We used a probit estimation allowing heteroscedasticity in the error term including a set of two equations: one binary response equation and one heteroscedasticity equation. Results. During the study timeframe, there were 78 robotic surgical systems purchased by hospitals in the sample. Controlling for hospital characteristics such as number of available beds, teaching status, nonprofit status, and patient mix, the probit estimation showed that market-level directly relevant surgery volume in the previous year (excluding the hospital's own volume) had the largest impact. More specifically, hospitals in high volume (>50,000 surgeries v. 0) markets were 12 percentage points more likely to purchase robotic systems. We also found that hospitals in less competitive markets (i.e., Herfindahl index above 2500) were 2 percentage points more likely to purchase robotic systems. Limitations. This study has limitations common to observational database studies. Certain characteristics such as cultural factors cannot be accurately quantified. Conclusions. Our findings imply that potential market demand is a strong driver for hospital purchase of robotic surgical systems. Market competition does not significantly increase the adoption of new expensive surgical technologies.


Should the Selective Arterial Secretagogue Injection Test for Insulinoma Localization Be Evaluated at 60 or 120 Seconds?
Objective The selective arterial secretagogue injection (SASI) test is considered indispensable for the accurate localization of insulinoma. However, the optimum timing of the post-injection evaluation is controversial, as some studies recommend 60 seconds [SASI (60 seconds)] while others support 120 seconds [SASI (120 seconds)]. The aim of this study was to determine the optimum timing for the SASI test evaluation for insulinoma localization. Methods Thirteen patients with surgically proven insulinoma were studied retrospectively. For the SASI test, immunoreactive insulin (IRI) was determined at baseline and at 30, 60, 90, and 120 seconds after calcium gluconate injection. A two-fold or greater increase in IRI over the baseline value was considered positive. The localization abilities of SASI (60 seconds) and SASI (120 seconds) were then compared. Results In 13 patients, a secretagogue was injected into 40 arteries supplying the pancreas. In the SASI (60 seconds) and SASI (120 seconds), the respective findings were as follows: positive predictive value, 72.2% and 68.2%; false positive rate, 25.0% and 35.0%; and rate of positivity in the head and body/tail, 38.5% and 46.2%. When the artery with the largest change was taken as the dominant artery, the localization detection sensitivity was 76.9% for SASI (60 seconds) and 92.3% for SASI (120 seconds). The sensitivity of morphological imaging techniques for localization ranged from 61.5-91.7%. Conclusion Compared with SASI (60 seconds) or morphological imaging, the insulinoma localization ability of SASI (120 seconds) was superior. Given these findings, we believe that the IRI level should be measured at 120 seconds in the SASI test.


Veterinary medical student perceptions of companion animal primary care as a career choice over an academic year.
Despite companion animal primary care being the most common career choice for veterinarians, relatively little is known about students' perception of this career choice. In this study, the authors examined students' (233 at Time 1 and 119 at Time 2) perceptions of careers in companion animal primary care and whether perceptions changed over the course of an academic year or differed by year in veterinary school. The study was conducted by an online questionnaire sent to the student email listserv and the results analyzed by Mixed ANOVAs for each perception outcome. The study concluded that a majority of veterinary students have companion animal primary care as their preferred career choice and have a positive perception of it as a career choice. This positive perception increased over the course of an academic year, but did not differ significantly by year in school. First year students had a decrease in perception of level of training over time. This study sets a baseline for students' perceptions of companion animal primary care as a career choice at one college of veterinary medicine.


Immediate natural tooth pontic: a viable yet temporary prosthetic solution: a patient reported outcome.
In patients with hopeless prognosis of the anterior teeth there is still a strong desire to save them for the sake of esthetics. If not grossly carious, broken down or discolored the extracted tooth after suitable modifications can be placed back in its original site by splinting it to the adjacent stable teeth. Fifteen patients (10 males, 5 females) in the age range of 40-65 years with pathologically migrated, unsalvageable teeth were treated by splinting the extracted teeth immediately with the stable adjacent teeth. After 12 weeks, all the patients were explained various treatment options available for replacement of the lost teeth. The patients were asked to fill out a simple closed ended questionnaire citing the various difficulties encountered during this transitional period, selection of further treatment modalities and the reasons for their choice. The feedback obtained was then analyzed statistically. Hundred percent of patients were happy with the esthetics; however, 60% of them were dissatisfied with the function that it provided. The primary problem being apprehension of splint fracture and difficulty while incising and the data was found to be statistically significant (P=0.01**). All patients demanded a permanent treatment option following this with a fixed prosthesis. None of the patients were interested in the implant supported prosthesis due to cost, treatment time involved, and need for surgery. The concept of immediate pontic placement is surely a viable treatment option and promises an excellent transient esthetic solution for a lost tooth as well as enables good preparation of the extraction site for future prosthetic replacement.


Abscisic acid-mediated cytosolic Ca2+ modulates triterpenoid accumulation of Ganoderma lucidum.
Ganoderma lucidum is a mushroom widely used for its edible and medicinal properties. Primary bioactive constituents of G. lucidum are ganoderic triterpenoids (GTs), which exhibit important pharmacological activity. Abscisic acid (ABA), a plant hormone, is associated with plant growth, development, and stress responses. ABA can also affect the growth, metabolism, and physiological activities of different fungi and participates in the regulation of the tetracyclic triterpenes of some plants. Our findings indicated that ABA treatment promoted GT accumulation by regulating the gene expression levels (squalene synthase (sqs), 3-hydroxy-3-methylglutaryl-CoA reductase (hmgr), and lanosterol synthase (ls)), and also activated cytosolic Ca2+ channels. Furthermore, under ABA mediation, exogenous Ca2+ donors and inhibitors directly affected the cytosolic Ca2+ concentration and related gene expression in Ca2+ signaling. Our study also revealed that ABA-mediated cytosolic Ca2+ played a crucial regulatory role in GT biosynthesis, accompanied by antioxidant defense modulation with increasing superoxide dismutase (SOD) activity and ascorbate peroxidase (APX) activity, and the resistance ability of O2•- and glutathione (GSH) contents.


Temperature control in Lowicryl K4M and glycol methacrylate during polymerization: is there a low-temperature embedding method?
An apparatus for embedding tissues at resin temperatures down to 228 K is described. By placing thermocouples in the resin the temperature has been monitored during embedding at low temperature with glycol methacrylate (GMA) and Lowicryl K4M. Even in this apparatus with a liquid cooling bath the heat of polymerization is not dissipated and the resin temperature rises. This rise is directly proportional to the resin temperature at the onset of polymerization and is higher in Lowicryl K4M than GMA. The initial resin temperature also affects the time taken for polymerization. The time to the onset of the peak and its duration are both increased as the temperature is lowered. This effect is more pronounced with GMA than Lowicryl K4M and polymerization of GMA is inhibited at the lowest temperature used. When Lowicryl K4M, polymerized at low temperature, is warmed up to ambient a further exothermic reaction occurs, which causes the resin temperature to rise well above ambient. Both this temperature peak and that during polymerization are reduced, but not totally eliminated, by reducing the resin volume. Air-cooled systems are inefficient compared with the low-temperature apparatus used here and the resin temperature rise is consequently greater and, even with small resin volumes, it can be very high. It is therefore unlikely for published methods that the temperature specified has been maintained in the resin during polymerization. The implications of these findings are discussed in relation to enzyme and antigen survival. Recommendations include use of very small volumes of resin, refrigerated liquid-bath rather than air-cooled systems and contact with a heat sink when specimens are warmed up to ambient temperature. Examples of enzyme reaction, antigen survival and structural preservation obtained with the method are presented.


In situ polymerized superhydrophobic and superoleophilic nanofibrous membranes for gravity driven oil-water separation.
Creating an efficient, cost-effective method that can provide simple, practical and high-throughput separation of oil-water mixtures has proved extremely challenging. This work responds to these challenges by designing, fabricating and evaluating a novel fluorinated polybenzoxazine (F-PBZ) modified nanofibrous membrane optimized to achieve gravity driven oil-water separation. The membrane design is then realized by a facile combination of electrospun poly(m-phenylene isophthalamide) (PMIA) nanofibers and an in situ polymerized F-PBZ functional layer incorporating SiO2 nanoparticles (SiO2 NPs). By employing the F-PBZ/SiO2 NP modification, the pristine hydrophilic PMIA nanofibrous membranes are endowed with promising superhydrophobicity with a water contact angle of 161° and superoleophilicity with an oil contact angle of 0°. This new membrane shows high thermal stability (350 °C) and good repellency to hot water (80 °C), and achieves an excellent mechanical strength of 40.8 MPa. Furthermore, the as-prepared membranes exhibited fast and efficient separation of oil-water mixtures by a solely gravity driven process, which makes them good candidates for industrial oil-polluted water treatments and oil spill cleanup, and also provided new insights into the design and development of functional nanofibrous membranes through F-PBZ modification.


Inefficient muscular stabilization of the lumbar spine associated with low back pain. A motor control evaluation of transversus abdominis.
The contribution of transversus abdominis to spinal stabilization was evaluated indirectly in people with and without low back pain using an experimental model identifying the coordination of trunk muscles in response to a disturbances to the spine produced by arm movement. To evaluate the temporal sequence of trunk muscle activity associated with arm movement, and to determine if dysfunction of this parameter was present in patients with low back pain. Few studies have evaluated the motor control of trunk muscles or the potential for dysfunction of this system in patients with low back pain. Evaluation of the response of trunk muscles to limb movement provides a suitable model to evaluate this system. Recent evidence indicates that this evaluation should include transversus abdominis. While standing, 15 patients with low back pain and 15 matched control subjects performed rapid shoulder flexion, abduction, and extension in response to a visual stimulus. Electromyographic activity of the abdominal muscles, lumbar multifidus, and the surface electrodes. Movement in each direction resulted in contraction of trunk muscles before or shortly after the deltoid in control subjects. The transversus abdominis was invariably the first muscle active and was not influenced by movement direction, supporting the hypothesized role of this muscle in spinal stiffness generation. Contraction of transversus abdominis was significantly delayed in patients with low back pain with all movements. Isolated differences were noted in the other muscles. The delayed onset of contraction of transversus abdominis indicates a deficit of motor control and is hypothesized to result in inefficient muscular stabilization of the spine.


The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet.
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in the Western population. By mechanisms that are not completely understood, this disease may progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). db/db mice spontaneously develop hepatic steatosis, which progresses to NASH when these mice are fed a methionine choline-deficient (MCD) diet. The goal of our studies was to identify lipid and methionine metabolism pathways affected by MCD feeding to determine potential causal events leading to the development of NASH from benign steatosis. db/db mice fed the MCD diet for 2 weeks exhibited signs of incipient NASH development such as upregulated cytokines and chemokines. At this time point, MCD diet feeding caused S-adenosylmethionine (SAMe) depletion in db/db mice, while wild-type mice on the same diet retained hepatic SAMe levels. SAMe depletion exerts pleiotropic effects upon liver homeostasis and is commonly associated with a variety of liver insults such as thioacetamide, CCL4, and alcohol treatment; thus, SAMe depletion may serve as the second hit in NASH development. It is possible that differences in hepatic lipid and/or methionine metabolism between wild-type and db/db mice underlay the differential maintenance of SAMe levels during methionine and choline restriction. Indeed, db/db mice exhibited inhibited lipid oxidation pathways, which may be a priming factor for NASH development, and db/db mice fed the MCD diet had differential methionine adenosyltransferase (MAT) expression. The occurrence of SAMe depletion at this early, benign stage of NASH development in db/db mice with fatty liver suggests that SAMe supplementation may be (A) targeted to individuals susceptible to NASH (i.e., NAFLD patients) and (B) preventative of NASH before substantial liver injury has occurred.


An exploration of the midwifery continuity of care program at one Australian University as a symbiotic clinical education model.
This discussion paper analyses a midwifery Continuity of Care program at an Australian University with the symbiotic clinical education model, to identify strengths and weakness, and identify ways in which this new pedagogical approach can be improved. In 2002 a major change in Australian midwifery curricula was the introduction of a pedagogical innovation known as the Continuity of Care experience. This innovation contributes a significant portion of clinical experience for midwifery students. It is intended as a way to give midwifery students the opportunity to provide continuity of care in partnership with women, through their pregnancy and childbirth, thus imitating a model of continuity of care and continuity of carer. A qualitative study was conducted in 2008/9 as part of an Australian Learning and Teaching Council Associate Fellowship. Evidence and findings from this project (reported elsewhere) are used in this paper to illustrate the evaluation of midwifery Continuity of Care experience program at an Australian university with the symbiotic clinical education model. Strengths of the current Continuity of Care experience are the strong focus on relationships between midwifery students and women, and early clinical exposure to professional practice. Improved facilitation through the development of stronger relationships with clinicians will improve learning, and result in improved access to authentic supported learning and increased provision of formative feedback. This paper presents a timely review of the Continuity of Care experience for midwifery student learning and highlights the potential of applying the symbiotic clinical education model to enhance learning. Applying the symbiotic clinical education framework to evidence gathered about the Continuity of Care experience in Australian midwifery education highlights strengths and weaknesses which may be used to guide curricula and pedagogical improvements.


Decomposing complex links between the childhood environment and brain structure in school-aged youth.
Childhood experiences play a profound role in conferring risk and resilience for brain and behavioral development. However, how different facets of the environment shape neurodevelopment remains largely unknown. Here we sought to decompose heterogeneous relationships between environmental factors and brain structure in 989 school-aged children from the Adolescent Brain Cognitive Development Study. We applied a cross-modal integration and clustering approach called 'Similarity Network Fusion', which combined two brain morphometrics (i.e., cortical thickness and myelin-surrogate markers), and key environmental factors (i.e., trauma exposure, neighborhood safety, school environment, and family environment) to identify homogeneous subtypes. Depending on the subtyping resolution, results identified two or five subgroups, each characterized by distinct brain structure-environment profiles. Notably, more supportive caregiving and school environments were associated with greater myelination, whereas less supportive caregiving, higher family conflict and psychopathology, and higher perceived neighborhood safety were observed with greater cortical thickness. These subtypes were highly reproducible and predicted externalizing symptoms and overall mental health problems. Our findings support the theory that distinct environmental exposures are differentially associated with alterations in structural neurodevelopment. Delineating more precise associations between risk factors, protective factors, and brain development may inform approaches to enhance risk identification and optimize interventions targeting specific experiences.


A new method for fabrication of latex cuffs.
A new and simple method is presented that is suitable for the fabrication of inflatable cuffs for any gross vascular size. The method lends itself to mass production which is particularly useful for the fabrication of small cuffs. The procedure generally consists of spraying latex on a rotating cylinder in two separable layers. An activating tube is inserted between the layers and the edges sealed. Outward expansion is prevented by means of a suitable backing material.


Hypoxia upregulates neutrophil degranulation and potential for tissue injury.
The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.


A novel normalization and differential abundance test framework for microbiome data.
Microbial communities have been proved to have close relationship with many diseases. The identification of differentially abundant microbial species is clinically meaningful for finding disease-related pathogenic or probiotic bacteria. However, certain characteristics of microbiome data have hurdled the accuracy and effectiveness of differential abundance analysis. The abundances or counts of microbiome species are usually on different scales and exhibit zero-inflation and over-dispersion. Normalization is a crucial step before the differential abundance test. However, existing normalization methods typically try to adjust counts on different scales to a common scale by constructing size factors with the assumption that count distributions across samples are equivalent up to a certain percentile. These methods often yield undesirable results when differentially abundant species are of low to medium abundance level. For differential abundance analysis, existing methods often use a single distribution to model the dispersion of species which lacks flexibility to catch a single species' distinctiveness. These methods tend to detect a lot of false positives and often lack of power when the effect size is small. We develop a novel framework for differential abundance analysis on sparse high-dimensional marker gene microbiome data. Our methodology relies on a novel network-based normalization technique and a two-stage zero-inflated mixture count regression model (RioNorm2). Our normalization method aims to find a group of relatively invariant microbiome species across samples and conditions in order to construct the size factor. Another contribution of the paper is that our testing approach can take under-sampling and over-dispersion into consideration by separating microbiome species into two groups and model them separately. Through comprehensive simulation studies, the performance of our method is consistently powerful and robust across different settings with different sample size, library size and effect size. We also demonstrate the effectiveness of our novel framework using a published dataset of metastatic melanoma and find biological insights from the results. The R package 'RioNorm2' can be installed from Github athttps://github.com/yuanjing-ma/RioNorm2. Supplementary data are available at Bioinformatics online.


SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression.
Prostate Cancer (PCa)-related deaths are mostly due to metastasization of poorly differentiated adenocarcinomas often endowed with neuroendocrine differentiation (NED) areas.The SNAI2/Slug gene is a major regulator of cell migration and tumor metastasization. We here assessed its biological significance in NED, and metastatic potential of PCa.SNAI2 expression was down-regulated in most PCa epithelia, in association with gene promoter methylation, except for cell clusters forming: a. the expansion/invasion front of high-grade PCa, b. NED areas, or c. lymph node metastasis.Knockdown of SNAI2 in PC3 cells down-regulated the expression of neural-tissue-associated adhesion molecules, Neural-Cadherin, Neural-Cadherin-2, Neuronal-Cell-Adhesion-Molecule, and of the NED marker Neuron-Specific Enolase, whereas it abolished Chromogranin-A expression. The metastasis-suppressor genes, Nm23-H1 and KISS1, were up-regulated, while the pluripotency genes SOX2, NOTCH1, CD44v6, WWTR1/TAZ and YAP1 were dramatically down-regulated. Over-expression of SNAI2 in DU145 cells substantiated its ability to regulate metastasis-suppressor, NED and pluripotency genes. In PCa and lymph node metastasis, expression of SOX2 and NOTCH1 was highly related to that of SNAI2.In conclusion, I. SNAI2 silencing in PCa may turn-off the expression of NED markers and pluripotency genes, while turning-on that of specific metastasis-suppressors, II. SNAI2 expression in selected PCa cells, by regulating their self-renewal, NED and metastatic potential, endows them with highly malignant properties. SNAI2 may thus constitute a key target for modern approaches to PCa progression.


Factors that predict thrombosis in relatives of patients with venous thromboembolism.
When counseling first-degree relatives of patients with venous thromboembolism (VTE), it is important to know whether factors other than thrombophilia influence their risk for thrombosis. We assessed the risk for VTE in 915 first-degree relatives of patients with provoked VTE, compared this with the risk in 1752 first-degree relatives of patients with unprovoked VTE, and then combined data from the 2 groups of relatives to identify predictors of thrombosis. There had been 123 VTEs in 2617 first-degree relatives (0.12 per 100 person-years). The risk for VTE in first-degree relatives was higher if the index cases had an unprovoked compared with a provoked VTE (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.43-3.85), if the index case was younger (OR, 0.97 per year older; 95% CI, 0.96-0.99), and if an additional family member had VTE (OR, 2.71; 95% CI, 2.22-3.31). Among first-degree relatives of an index case with factor V Leiden or the prothrombin 20210A gene variant, the presence of these abnormalities also predicted thrombosis (OR, 4.42; 95% CI, 1.35-14.38). We conclude that thrombosis at a young age and unprovoked VTE predict VTE in first-degree relatives, and that the influence of these 2 factors is additive.


Ethanol disrupts fear conditioning in C57BL/6 mice.
Ethanol has been demonstrated to disrupt numerous forms of learning. For example, ethanol disrupts fear conditioning in rats. Surprisingly, the opposite result was reported for mice. Because of the importance of mouse models in ethanol research and the predominance of transgenic mice generated on a C57BL/6 background, the present study examined the effects of acute ethanol administration on fear conditioning in C57BL/6 mice. Fear conditioning was chosen because of the apparent contradiction in results between mice and rats, because of its popularity in assessing forebrain-dependent learning and because the task examines two types of learning: (i) the hippocampus-dependent contextual learning and (ii) the hippocampus-independent conditioned stimulus-unconditioned stimulus learning. Dose-response curves were generated for ethanol (0.5, 1.0 and 1.5 g/kg) given on either training day, testing day, or both days. Ethanol, in a dose-dependent manner, disrupted fear conditioning when given on training day or given on both training and testing days. Ethanol given on testing day only did not disrupt fear conditioning. The present results demonstrate that ethanol disrupts fear conditioning in C57BL/6 mice.


Antibacterial activity and in vitro cytotoxicity of extracts and fractions of Parkia biglobosa (Jacq.) Benth. stem bark and Ageratum conyzoides Linn. leaves.
Many species of plants in African countries are widely used in the rural communities where there is little or no access to modern medicine. However, the safety and effectiveness of these medicinal plants are poorly evaluated. The stem bark of Parkia biglobosa Jacq. and leaves of Ageratum conyzoides Linn. were investigated for their antibacterial and cytotoxic activities. The plant materials were extracted with 95% ethanol, and fractionated with petroleum ether, chloroform and ethyl acetate. The antibacterial effects of the extracts and fractions of the plant materials were assayed on the bacterial cultures of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin Resistant Staphylococcus aureus (MRSA) and Clostridium perfringes. Ethanol extracts of P. biglobosa and A. conyzoides were screened for cytotoxicity using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. Two cancer cell lines (SK-MES 1 and SK-LU 1) and one normal cell line (human skin fibroblast cell line, FS5) were used for the screening of the extracts and the fractions obtained. The ethanolic extracts and fractions of P. biglobosa and A. conyzoides showed the best activity against E. coli, S. aureus and MRSA. All fractions of A. conyzoides leaves have no activity against P. aeruginosa. Human lung cancer cell lines (SK-LU 1 and SK-MES 1) and human skin fibroblast cell line (FS5 cells) were treated with various concentrations (3.9μg/ml-2mg/ml) of the extracts and fractions for 24h. SK-MES 1 cells are more susceptible to treatment with the plant fractions. All the fractions of A. conyzoides leaves and the petroleum ether fraction of P. biglobosa were cytotoxic to SK-MES 1 cells, which to some extent may support their traditional inclusion in herbal preparations for treatment of cancer. The overall results provided evidence that the studied plant extracts might be potential sources of new antibacterial and anticancer drug.


Solo extracorporeal shock wave lithotripsy for management of upper ureteral calculi with hydronephrosis.
The aim of this study was to evaluate extracorporeal shock wave lithotripsy (SWL) outcomes as a solo therapy in patients with upper ureteral calculi and varying degrees of hydronephrosis. Eighty patients with upper ureteral calculi and a body mass index between 19.5 kg/m2 and 22.5 kg/m2 were included. They were categorized into 4 groups according to the severity of hydronephrosis as seen on ultrasonography and intravenous urography: group 1, no dilatation; group 2, mild dilatation; group 3, moderate dilatation; and group 4, severe dilatation of the pyelocaliceal system. The size of calculi, time to calculus clearance, success rate of solo SWL, and the need for additional therapeutic methods were recorded and compared between the four groups of patients. The median size of the calculi was 13.5 mm, and the mean time to calculus clearance was 56.0 +/- 24.2 days. In 71.3% of the patients, solo SWL was successful in the treatment of the calculi. Twenty-three patients required other therapies including double-J stenting, ureteroscopy, and nephrolithotomy. The patients without hydronephrosis and those with severe hydronephrosis (groups 1 and 4) showed a significant difference in the days to clearance of the calculus (mean, 31.7 days versus 85.6 days; P < .001). Patients with upper ureteral calculi and mild hydronephrosis can be effectively treated with solo SWL therapy. In those with moderate hydronephrosis, clearance takes longer or requires secondary interventions. In patients with severe hydronephrosis, we recommend alternative/adjunctive procedures.


An investigation into the relation between step height and ground reaction forces in step exercise: a pilot study.
The aim of this study was to investigate the effect that changing step height had on ground reaction force. Using a randomised crossover design, 12 volunteers with no previous experience of step aerobics were recruited to perform at three different step heights: 6, 8 and 10 inches. Subjects performed a basic step at a cadence of 120 beats/min and performed three one minute trials during which ground reaction force was measured. Measurement of peak impact force, time to achieve peak impact, and total time of foot contact was made, and impulse of the force was calculated. Statistically significant differences were found to exist for peak impact force between the 6 and 8 inch and 6 and 10 inch, but not between the 8 and 10 inch conditions. No significant differences were found in any other parameters. The study supports the present advice that participants should use low step heights, and possible mechanisms of injury are discussed.


Role of Slit and Robo proteins in the development of dopaminergic neurons.
Dopamine plays a number of important roles in the nervous system and the dopaminergic system is affected in several brain disorders. It is therefore of great interest to study the axonal guidance systems that specifically participate in the correct establishment of dopaminergic projections during development and possibly during regenerative processes. In recent years, several reports have shown that Slits and their Robo receptors control the growth of longitudinal (both ascending and descending) mesodiencephalic dopaminergic axons to their appropriate target areas. In vitro studies have shown that Slit1, 2 and 3 are potent repellents of dopamine neurite extension. In vivo studies using both mice and zebrafish mutants for Slits and Robos have shown that Slits and Robos control the lateral and dorsoventral positioning of dopaminergic longitudinal projections during early development. In the present review, we aimed to compile the existing knowledge from both in vitro and in vivo studies on the role of Slit and Robo proteins in the development of dopaminergic neurons as a basis for future studies.


The effects of mesh bioprosthesis on the spermatic cord structures: a preliminary report in a canine model.
The use of mesh bioprosthesis during inguinal herniorrhaphy is now considered routine. To our knowledge, no studies have examined the effects of mesh induced fibrosis on the structure and function of the adjacent spermatic cord. We present our experience in a canine model. Unilateral inguinal hernia defects were created in 12 male beagle dogs. Half were repaired using Marlex mesh and half using a classic Shouldice technique. The inguinal anatomy was then re-examined at 6 and 12 months. Testicular temperature and volume, peripheral and testicular vein testosterone levels, testicular blood flow, vasography, testicular and cord histology, and sperm motility/morphology were recorded. Groups were compared with each other as well as to the non-operated (control) side. Although post-operative testicular volumes from both the mesh and Shouldice groups were similar to controls (p >0.05), there was a downward trend after mesh repair (17.8 cc pre versus 12.6 cc post) but this did not reach statistical significance (p = 0.17). Testicular temperatures and blood flow did not differ between experimental groups and controls. While testicular vein testosterone levels were significantly higher than peripheral venous levels after Shouldice repair, this difference was lost after mesh repair. Contralateral (control) testicular vein testosterone levels were higher in animals repaired with mesh than by an anatomic Shouldice repair (p <0.05). There was a significant decrease in cross sectional vasal luminal diameter in both the anatomic and mesh repair groups versus their respective contralateral controls (p <0.05). This was correlated with a marked foreign body reaction to the mesh in the soft tissues surrounding the vas in spermatic cords exposed to Marlex. All vasograms demonstrated patency. Gross pathology was abnormal in 3/6 dogs with mesh repair (2 hydroceles and 1 ischemic testis) and 0/6 animals after Shouldice repair. A traumatic neuroma was identified in the mesh group. Sperm morphology and motility did not differ between the two groups. Half of the testicles had gross abnormalities after mesh repair versus none in the control and Shouldice dogs. Although all vasograms were patent, vasal luminal size was significantly decreased with a marked soft tissue foreign body reaction identified after mesh repair. A traumatic neuroma was identified suggesting nerve entrapment in the fibrotic mesh reaction, which may account for post-operative pain seen in some patients. Marlex mesh may adversely affect spermatic cord structure and function and further work is required to fully elucidate its effects.


Oxidoreductase regulation of Kv currents in rat ventricle.
Oxidative stress contributes to the arrhythmogenic substrate created by myocardial ischemia-reperfusion partly through a shift in cell redox state, a key modulator of protein function. The activity of many oxidation-sensitive proteins is controlled by oxidoreductase systems that regulate the redox state of cysteine thiol groups, but the impact of these systems on ion channel function is not well defined. Thus, we examined the roles of the thioredoxin and glutaredoxin systems in controlling K(+) channels in the ventricle. An oxidative shift in redox state was elicited in isolated rat ventricular myocytes by brief exposure to diamide, a thiol-specific, membrane-permeable oxidant. Voltage-clamp studies showed that diamide decreased peak outward K(+) current (I(peak)) evoked by depolarizing test pulses by 41% (+60 mV; p<0.05) while steady-state outward current (I(ss)) measured at the end of the test pulse was decreased by 45% (p<0.05). These electrophysiological effects were not prevented by protein kinase C blockers, but the tyrosine kinase inhibitors genistein or lavendustin A blocked the suppression of both K(+) currents by diamide. Moreover, inhibition of I(peak) and I(ss) by diamide was reversed by dichloroacetate and an insulin-mimetic. The effect of dichloroacetate to normalize I(peak) after diamide was blocked by the thioredoxin system inhibitors auranofin or 13-cis-retinoic acid, but I(ss) was not affected by either compound. A pan-specific inhibitor of glutaredoxin and thioredoxin systems, 1,3-bis-(2-chloroethyl)-1-nitrosourea, also blocked the dichloroacetate effect on I(peak) but only partially inhibited the recovery of I(ss). These data suggest that acute regulation of cardiac K(+) channels by oxidoreductase systems is mediated by redox-sensitive tyrosine kinase/phosphatase pathways. The pathways controlling I(peak) channels are targets of the thioredoxin system whereas those regulating I(ss) channels are likely controlled by the glutaredoxin system. Thus, cardiac oxidoreductase systems may be important regulators of ion channels affected by pathogenic oxidative stress.


A review of surrogate safety measures on road safety at unsignalized intersections in developing countries.
In recent times, the assessment of unsignalized intersection safety has received significant research attention because of the complex and diverse traffic movements and driving behaviour at such locations. However, priority traffic regulations are not well followed in comparison to the unsignalized junctions, which leads to more conflicts. Additionally, the severity of conflicts increases with continuous traffic manoeuvres, including right-turns and through traffic, combined with different driving behaviours. Several studies have compared crash-based analysis to proactive traffic safety measures. Current research outcomes imply that surrogate safety measures (SSMs) have the potential to elucidate the sequence of events that result in collisions, their underlying causes, and their outcomes. Therefore, to further understand the appropriateness of SSMs, further study is required based on heterogeneity in traffic along with driver behaviour that incorporates turning vehicle factors. This study presents an all-inclusive evaluation of the recent advancements in SSMs and their practical implementation, with a particular emphasis on unsignalized intersections in developing nations. The findings of this investigation would be helpful in identifying the appropriate safety indicators for evaluating traffic safety at unsignalized intersections.


Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease.
As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P < 0.005; 10 months: 53% vs. 80%) and significantly (P < 0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 +/- 3 vs. 127 +/- 42; 10 months, 53 +/-5 vs. 140 +/- 37 mg/dl). Appearance of anti-DNA antibodies was retarded and survival significantly (P < 0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7 - 12-fold in 8- 10-month-old mice vs. 2-month-old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies proteinuria and survival of lupus mice, in an additional group of animals (N = 16). Thus, at 14.5 months when all mice given bindarit alone died, 50% of mice on combined therapy were still alive (P < 0.023). Studies are needed to establish whether bindarit may function as a steroid sparing drug in human lupus.


Semi-Automated Identification of Motor Units Concurrently Recorded in High-Density Surface and Intramuscular Electromyography.
An increasing focus on extending automated surface electromyography (EMG) decomposition algorithms to operate under non-stationary conditions requires rigorous and robust validation. However, relevant benchmarks derived manually from iEMG are laborsome to obtain and this is further exacerbated by the need to consider multiple contraction conditions. This work demonstrates a semi-automatic technique for extracting motor units (MUs) whose activities are present in concurrently recorded high-density surface EMG (HD-sEMG) and intramuscular EMG (iEMG) during isometric contractions. We leverage existing automatic surface decomposition algorithms for initial identification of active MUs. Resulting spike times are then used to identify (trigger) the sources that are concurrently detectable in iEMG. We demonstrate this technique on recordings targeting the extensor carpi radialis brevis in five human subjects. This dataset consists of 117 trials across different force levels and wrist angles, from which the presented method yielded a set of 367 high-confidence decompositions. Thus, our approach effectively alleviates the overhead of manual decomposition as it efficiently produces reliable benchmarks under different conditions.Clinical Relevance- We present an efficient method for obtaining high-quality in-vivo decomposition particularly useful in the verification of new surface decomposition approaches.


Ginsenoside 25-OCH3-PPD Promotes Activity of LXRs To Ameliorate P2X7R-Mediated NLRP3 Inflammasome in the Development of Hepatic Fibrosis.
Ginseng is widely used in energy drinks, dietary supplements, and herbal medicines, and its pharmacological actions are related with energy metabolism. As an important modulating energy metabolism pathway, liver X receptors (LXRs) can promote the resolving of hepatic fibrosis and inflammation. The present study aims to evaluate the regulation of 25-OCH3-PPD, a ginsenoside isolated from Panax ginseng, against hepatic fibrosis and inflammation in thioacetamide (TAA)-stimulated mice by activating the LXRs pathway. 25-OCH3-PPD decreases serum ALT/AST levels and improves the histological pathology of liver in TAA-induced mice; attenuates transcripts of pro-fibrogenic markers associated with hepatic stellate cell activation; attenuates the levels of pro-Inflammatory cytokines and blocks apoptosis happened in liver; inhibits NLRP3 inflammasome by affecting P2X7R activation; and regulates PI3K/Akt and LKB1/AMPK-SIRT1. 25-OCH3-PPD also facilitates LX25Rs and FXR activities decreased by TAA stimulation. 25-OCH3-PPD also decreases α-SMA via regulation of LXRs and P2X7R-NLRP3 in vitro. Our data suggest the possibility that 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.


Particle-associated denitrification is the primary source of N2O in oxic coastal waters.
The heavily human-perturbed coastal oceans are hotspots of nitrous oxide (N2O) emission to the atmosphere. The processes underpinning the N2O flux, however, remain poorly understood, leading to large uncertainties in assessing global N2O budgets. Using a suite of nitrogen isotope labeling experiments, we show that multiple processes contribute to N2O production throughout the estuarine-coastal gradient, sustaining intensive N2O flux to the atmosphere. Unexpectedly, denitrification, rather than ammonia oxidation as previously assumed, constitutes the major source of N2O in well-oxygenated coastal waters. Size-fractionated manipulation experiments with gene analysis further reveal niche partitioning of ammonia oxidizers and denitrifiers across the particle size spectrum; denitrification dominated on large particles and ammonia oxidizers on small particles. Total N2O production rate increases with substrate and particle concentrations, suggesting a crucial interplay between nutrients and particles in controlling N2O production. The controlling factors identified here may help understand climate feedback mechanisms between human activity and coastal oceans.


The effects of reversible inactivations of the hippocampus on exploratory activity and spatial memory.
This study was aimed at testing the effects of a reversible inactivation of the ventral hippocampus on behavior in response to a change, following a period of habituation with a hippocampus that functions normally. A new dishabituation paradigm was used, which allowed the testing of visuospatial memory. A salient stimulus was placed under the glass floor of the apparatus during initial exploration and was removed during the test session. The time spent above the zone where the stimulus was initially located indicated the rats' reaction to the change. Unlike the control rats who reacted to the removal of the salient stimulus by reexploring its previous location, lidocaine-injected subjects did not display any similar searching behavior. Experiment 2 examined the hypothesis that landmarks located under the floor could help hippocampus-inactivated animals to accurately react to the change. Two objects were located either close to the stimulus or some distance away from it. Even when the objects were closely associated to the stimulus, the same failure to react to the removal of the stimulus was found in lidocaine-injected rats. However, these animals displayed a higher activity level measured by the time spent on a "neutral" zone. This behavioral pattern suggests a specific localization deficit. The method of reversible inactivation appears to be a promising approach to the study of the time course of memory process with short-term experimental paradigms such as those used in the present study.


The evolution, development and skeletal identity of the crocodylian pelvis: revisiting a forgotten scientific debate.
Unlike most tetrapods, in extant crocodylians the acetabulum is formed by only two of the three skeletal elements that constitute the pelvis, the ilium, and ischium. This peculiar arrangement is further confused by various observations that suggest the crocodylian pelvis initially develops from four skeletal elements: the ilium, ischium, pubis, and a novel element, the prepubis. According to one popular historical hypothesis, in crocodylians (and many extinct archosaurs), the pubis fuses with the ischium during skeletogenesis, leaving the prepubis as a distinct element, albeit one which is excluded from the acetabulum. Whereas the notion of a distinct prepubic element was once a topic of considerable interest, it has never been properly resolved. Here, we combine data gleaned from a developmental series of Alligator mississippiensis embryos, with a revised interpretation of fossil evidence from numerous outgroups to Crocodylia. We demonstrate that the modern crocodylian pelvis is composed of only three elements: the ilium, ischium, and pubis. The reported fourth pelvic element is an unossified portion of the ischium. Interpretations of pelvic skeletal homology have featured prominently in sauropsid systematics, and the unambiguous identification of the crocodylian pubis provides an important contribution to address larger scale evolutionary questions associated with locomotion and respiration.


Pulmonary function recovery demonstrated by ventilation-perfusion scan after posterior vertebral column resection for severe adolescent idiopathic scoliosis: a case report.
Case report. To describe a case in which a patient regained pulmonary function, assessed by ventilation-perfusion scans, after undergoing posterior vertebral column resection (VCR) to correct severe adolescent idiopathic scoliosis (AIS) with associated pulmonary dysfunction. Pulmonary improvement after corrective surgery for AIS has been reported. Ventilation-perfusion scans are useful for assessing pulmonary function. However, these scans have not been used to examine the recovery of pulmonary function after VCR for severe AIS with pulmonary dysfunction. A patient was described in whom ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery for severe AIS. The relevant literature was reviewed. An 18-year-old male came to Keio University Hospital with exertional dyspnea associated with severe AIS. Radiographs showed severe scoliosis of 91° at T6-T12, and hypokyphosis of 6° at T5-T12. Computed tomographic scans showed narrowing of the thoracic cage on the convex side of the main thoracic curve, with the vertebral bodies at the apex of the curve obstructing the right main bronchus. Pulmonary function tests revealed a percent vital capacity of 44% and percent forced expiratory volume in 1 second of 76%. A ventilation-perfusion scan showed decreased air ventilation and blood perfusion in the right lung. The patient underwent posterior correction surgery, which used segmental pedicle screws with a VCR at T9. The scoliosis was corrected to 28°, and the kyphosis to 14°. Postoperative computed tomographic scans showed expansion of the right main bronchus. A ventilation-perfusion scan conducted 1 year after surgery showed clear improvement in both ventilation and blood perfusion in the right lung. The patient's forced expiratory volume in 1 second had increased to 91%. This is the first report in which ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery in a patient with severe AIS. N/A.


Extrafoveal preview benefit during free-viewing visual search in the monkey.
Previous studies have shown that subjects require less time to process a stimulus at the fovea after a saccade if they have viewed the same stimulus in the periphery immediately prior to the saccade. This extrafoveal preview benefit indicates that information about the visual form of an extrafoveally viewed stimulus can be transferred across a saccade. Here, we extend these findings by demonstrating and characterizing a similar extrafoveal preview benefit in monkeys during a free-viewing visual search task. We trained two monkeys to report the orientation of a target among distractors by releasing one of two bars with their hand; monkeys were free to move their eyes during the task. Both monkeys took less time to indicate the orientation of the target after foveating it, when the target lay closer to the fovea during the previous fixation. An extrafoveal preview benefit emerged even if there was more than one intervening saccade between the preview and the target fixation, indicating that information about target identity could be transferred across more than one saccade and could be obtained even if the search target was not the goal of the next saccade. An extrafoveal preview benefit was also found for distractor stimuli. These results aid future physiological investigations of the extrafoveal preview benefit.


The complete mitochondrial genome of Cobitis lutheri (Cypriniformes: Cobitidae: Cobitis).
The traditional polymerase chain reaction method was employed to obtain the complete mitochondrial genome of Cobitis lutheri from Fuyuan country, Heilongjiang province, China. The mitogenome was determined to be 16,639 bp in length. It contains 13 protein-coding genes, 2 rRNAs and 22 tRNAs. This is the first report on the complete mitogenome sequence of C. lutheri.


Coping with social stress: implications for psychopathology in young adolescent girls.
This study investigated the impact of social stress on symptoms of psychopathology at the entry into adolescence (111 girls, Mage = 11.84, SD = 0.77). We examined whether peer stress and pubertal timing were associated with internalizing distress and aggression, and whether responses to stress and cortisol reactivity mediated or moderated these associations. Cortisol samples were collected from saliva samples during in-home visits, and the YSR was used to assess psychopathology. Interestingly, pubertal timing demonstrated a trend association with cortisol. Responses to stress mediated the association between social stress and symptoms of internalizing distress and aggression. Specifically, early maturers and girls with higher levels of peer stress exhibited more problematic responses to stress, in turn demonstrating higher levels of internalizing distress and aggression. Significant moderation effects also emerged. For example, early maturers who experienced higher levels of emotional/cognitive numbing in response to peer stress were at greater risk for aggression. Findings identify coping strategies that may be used in evidence-based programming to help girls transition more successfully into adolescence will be discussed.


Human acute myeloblastic leukemia cells differentiate in vitro into mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias.
An immune response is involved in the control of leukemias as demonstrated by allogeneic bone marrow transplantation, by the eradication of residual leukemic cells by cytotoxic T cells and finally by the identification of tumor antigens which are recognized by effector T cells. Dendritic cells (DC) are professional antigen-presenting cells (APC) able to present antigens in the context of co-stimulatory signals necessary for T cell activation. Although tumor cells may express tumor antigens, they are usually unable to elicit an immune response since they are devoid of co-stimulatory capacities. To overcome this problem, engineering tumors to provide APC function could potentially result in polyvalent immunization to multiple tumor antigens. We have tested the differentiation of AML-5 (monoblastic, promonocytic and monocytic) leukemia cells and demonstrated that eight out of the ten fresh human acute myeloid leukemia populations tested can differentiate in vitro into bona fide APC. Leukemic cells acquire in vitro DC morphology, mature DC markers such as CD83, the up-regulation of MHC and co-stimulatory molecules and the ability to produce IL-12 upon maturation, while retaining their characteristic caryotypic abnormalities. However, we could not obtain an immature DC phenotype. They also acquire the ability to induce the differentiation of allogeneic naive cord blood CD4 and CD8 T cells as well as resting autologous cytotoxic T cells. These results demonstrate that some tumor cells acquire APC phenotype and functions and can thereby induce a potent autologous immune response that will be a valuable tool for detection of new tumor antigens and for in vivo immunization.


Peroxidasin-like protein: a novel peroxidase homologue in the human heart.
Peroxidases serve diverse biological functions including well-characterized activities in host defence and hormone biosynthesis. More recently, peroxidasin (PXDN) was found to be involved in collagen IV cross-linking in the extracellular matrix (ECM). The aim of this study was to characterize the expression and function of peroxidasin-like protein (PXDNL), a previously unknown peroxidase homologue. We cloned the PXDNL cDNA from the human heart and identified its expression pattern by northern blot, in situ hybridization, and immunohistochemistry. PXDNL is expressed exclusively in the heart and it has evolved to lose its peroxidase activity. The protein is produced by cardiomyocytes and localizes to cell-cell junctions. We also demonstrate that PXDNL can form a complex with PXDN and antagonizes its peroxidase activity. Furthermore, we show an increased expression of PXDNL in the failing myocardium. PXDNL is a unique component of the heart with a recently evolved inactivation of peroxidase function. The elevation of PXDNL levels in the failing heart may contribute to ECM dysregulation due to its antagonism of PXDN function.


Evaluating physiological signal salience for estimating metabolic energy cost from wearable sensors.
Body-in-the-loop optimization algorithms have the capability to automatically tune the parameters of robotic prostheses and exoskeletons to minimize the metabolic energy expenditure of the user. However, current body-in-the-loop algorithms rely on indirect calorimetry to obtain measurements of energy cost, which are noisy, sparsely sampled, time-delayed, and require wearing a respiratory mask. To improve these algorithms, the goal of this work is to predict a user's steady-state energy cost quickly and accurately using physiological signals obtained from portable, wearable sensors. In this paper, we quantified physiological signal salience to discover which signals, or groups of signals, have the best predictive capability when estimating metabolic energy cost. We collected data from 10 healthy individuals performing 6 activities (walking, incline walking, backward walking, running, cycling, and stair climbing) at various speeds or intensities. Subjects wore a suite of physiological sensors that measured breath frequency and volume, limb accelerations, lower limb EMG, heart rate, electrodermal activity, skin temperature, and oxygen saturation; indirect calorimetry was used to establish the 'ground truth' energy cost for each activity. Evaluating Pearson's correlation coefficients and single and multiple linear regression models with cross validation (leave-one- subject-out and leave-one- task-out), we found that 1) filtering the accelerations and EMG signals improved their predictive power, 2) global signals (e.g., heart rate, electrodermal activity) were more sensitive to unknown subjects than tasks, while local signals (e.g., accelerations) were more sensitive to unknown tasks than subjects, and 3) good predictive performance was obtained combining a small number of signals (4-5) from multiple sensor modalities. NEW & NOTEWORTHY In this paper, we systematically compare a large set of physiological signals collected from portable sensors and determine which sensor signals contain the most salient information for predicting steady-state metabolic energy cost, robust to unknown subjects or tasks. This information, together with the comprehensive data set that is published in conjunction with this paper, will enable researchers and clinicians across many fields to develop novel algorithms to predict energy cost from wearable sensors.


Pulse wave transmission times in central aorta and peripheral arteries in normal children.
Pulse wave transmission times and pulse wave velocities in central aorta and peripheral arteries were measured in a group of 85 healthy children and adolescents between the ages of 1 and 21 years. A new external plethysmograph is described which gives reliable tracings of external pulsations. A method is given to calculate real pulse wave transmission time from the aortic valves to the groin.


The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity.
The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dynein-dependent FAT rates were evaluated by video microscopy. Although perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino-acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.


Physicochemical properties of bread dough and finished bread with added pectin fiber and phenolic antioxidants.
Comparative studies were conducted in this paper to investigate the effects of added dietary fiber (DF) and/or phenolic antioxidants on the properties of bread dough and finished bread. Breads were developed in the absence (control bread), or presence of apple pectin and/or fruit phenolic extracts (treated breads), and subjected to quality evaluation (attributes including color, weight, and volume) and characterization of chemical and rheological properties. Chemical analyses revealed that breads with added phenolic extracts had greater antioxidant activity and higher extractable phenolic content, than control bread and the treated breads with added apple pectin(s). The measured antioxidant activity was mainly derived from the phenolics present in bread. Storage modulus G' (elasticity) and loss modulus G″ (viscocity) of the treated bread dough with added pectin(s) only were higher than those of control dough. The G' or G″ of the treated breads incorporated with a combination of a pectin and fruit phenolic extract depended on the type of phenolic extract (that is, apple and blackcurrant extracts behaved differently from kiwifruit extract). The G' and G″ at the final baking step were higher than those of other stages, indicating an increase in cross-linking among polymeric molecules and bread particles of high molecular weight. We conclude that the added pectin and/or phenolic extract had influenced bread dough cross-linking microstructure and bread properties through being involved in the interactions with bread components such as wheat proteins during dough development and bread baking. Dietary fibers and phytochemicals (including phenolic antioxidants) have long been recognized as the active nutrients responsible for the health benefits of fruit and vegetables to humans. Interest in incorporating bioactive ingredients such as dietary fiber and phenolic antioxidants into popular foods like bread has grown rapidly, due to the increased consumer health awareness. The added bioactive ingredients may or may not promote the development of bread dough. This paper reports the findings associated with the properties of the functional breads enhanced with apple pectin and apple, blackcurrant, and kiwifruit phenolic extracts. Results of this paper indicate that the success of the development of such functional breads is ultimately determined by the interactions among added bioactive ingredients and other bread components.


Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats.
The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.


Au(III) complexes with tetradentate-cyclam-based ligands.
Chiral cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives were synthesized stepwise from chiral mono-Boc-1,2-diamines and (dialkyl)malonyl dichloride via open diamide-bis(N-Boc-amino) intermediates (65-91%). Deprotection and ring closure with a second malonyl unit afforded the cyclam tetraamide precursors (80-95%). The new protocol allowed the preparation of the target cyclam derivatives (53-59%) by a final optimized hydride reduction. Both the open tetraamine intermediates and the cyclam derivatives successfully coordinated with AuCl3 to give moderate to excellent yields (50-96%) of the corresponding novel tetra-coordinated N,N,N,N-Au(III) complexes with alternating five- and six-membered chelate rings. The testing of the catalytic ability of the cyclam-based N,N,N,N-Au(III) complexes demonstrated high catalytic activity of some complexes in selected test reactions (full conversion in 1-24 h, 62-97% product yields).


Culture characterization of the skin microbiome in Type 2 diabetes mellitus: A focus on the role of innate immunity.
The current study aimed at determining the differences between the cutaneous microbial flora of patients with Type 2 diabetes mellitus (T2DM) and those without, and thus evaluate for cutaneous microbiome dysbiosis in diabetes. We employed a case-control study design with 41 participants in each group. The skin over the toe-web space was swabbed and cultured aerobically. Data was analyzed for differences in microbial prevalences and growths between the two groups. Predictors for heavy colonization by microbes were analysed using logistic regression. We found significantly higher prevalences of Staphylococcus epidermidis among patients with T2DM (77.5% vs. 53.7%, p=0.02). Further, when prevalent, these bacteria showed a significantly greater degree of skin colonization i.e. CFUs/cm2 among these patients, p=0.03. Highly pathogenic bacteria such as S. aureus were more prevalent among patients with T2DM. The regression model determined a significant association between T2DM status and heavy colonization by S. epidermidis (OR - 5.40, p=0.02). Also, agricultural workers were significantly more likely to have heavy colonization by S. epidermidis (OR - 3.75, p=0.02). Other predictor variables did not show significant association with heavy colonization by any of the isolated microbes. Our findings support the existence of cutaneous microbiome dysbiosis among patients with T2DM. Literature suggests that microbiome dybiosis in T2DM could stem from the same activated innate immune response that is thought to be central to the development of T2DM. This dysbiosis could increase the risk of developing skin infections.