Detection of Fungi and Oomycetes by Volatiles Using E-Nose and SPME-GC/MS Platforms.
Fungi and oomycetes release volatiles into their environment which could be used for olfactory detection and identification of these organisms by electronic-nose (e-nose). The aim of this study was to survey volatile compound emission using an e-nose device and to identify released molecules through solid phase microextraction-gas chromatography/mass spectrometry (SPME-GC/MS) analysis to ultimately develop a detection system for fungi and fungi-like organisms. To this end, cultures of eight fungi (Armillaria gallica, Armillaria ostoyae, Fusarium avenaceum, Fusarium culmorum, Fusarium oxysporum, Fusarium poae, Rhizoctonia solani, Trichoderma asperellum) and four oomycetes (Phytophthora cactorum, P. cinnamomi, P. plurivora, P. ramorum) were tested with the e-nose system and investigated by means of SPME-GC/MS. Strains of F. poae, R. solani and T. asperellum appeared to be the most odoriferous. All investigated fungal species (except R. solani) produced sesquiterpenes in variable amounts, in contrast to the tested oomycetes strains. Other molecules such as aliphatic hydrocarbons, alcohols, aldehydes, esters and benzene derivatives were found in all samples. The results suggested that the major differences between respective VOC emission ranges of the tested species lie in sesquiterpene production, with fungi emitting some while oomycetes released none or smaller amounts of such molecules. Our e-nose system could discriminate between the odors emitted by P. ramorum, F. poae, T. asperellum and R. solani, which accounted for over 88% of the PCA variance. These preliminary results of fungal and oomycete detection make the e-nose device suitable for further sensor design as a potential tool for forest managers, other plant managers, as well as regulatory agencies such as quarantine services.


Overcoming psychological barriers to good discovery decisions.
Better individual and team decision-making should enhance R&D performance. Reproducible biases affecting human decision-making, known as cognitive biases, are well understood by psychologists. These threaten objectivity and balance and so are credible causes for continuing unpleasant surprises in Development and high operating costs. For four of the most common and insidious cognitive biases, we consider the risks to R&D decision-making and contrast current practice with use of evidence-based medicine by healthcare practitioners. Feedback on problem-solving performance in simulated environments could be one of the simplest ways to help teams improve their selection of compounds and effective screening sequences. Computational tools that encourage objective consideration of all of the available information might also contribute.


Radiation-induced cell death mechanisms.
The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. One approach to achieve this is by inducing tumor cell apoptosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. It has become obvious in the last few years that inhibition of the proliferative capacity of malignant cells following irradiation, especially with solid tumors, can occur via alternative cell death modalities or permanent cell cycle arrests, i.e., senescence. In this review, apoptosis and mitotic catastrophe, the two major cell deaths induced by radiation, are described and dissected in terms of activating mechanisms. Furthermore, treatment-induced senescence and its relevance for the outcome of radiotherapy of cancer will be discussed. The importance of p53 for the induction and execution of these different types of cell deaths is highlighted. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation. Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.


Incorporating a right to health perspective into the resolution of patent law disputes.
This article adopts the view that the courts in developing countries can play an important role in improving access to medicines in their countries if they incorporate a right to health perspective when adjudicating patent cases involving pharmaceutical products. The article argues that, since patent rights are not human rights, they should not be allowed to trump the right to health. The paper examines two notable cases decided by the courts in Kenya that illustrate the crucial role that incorporating a right to health perspective can play in improving access to medicines. Finally, the paper provides five reasons why courts in developing countries cannot afford to ignore the right to health when adjudicating cases involving patent rights on pharmaceutical products.


Survival of HIV-infected children: a cohort study from the Asia-Pacific region.
Combination antiretroviral therapy (ART) has been used for HIV-infected children in many Asian countries since 2002. This study describes survival outcomes among HIV-infected children in a multicenter regional cohort in Asia. Retrospective and prospective data collected through March 2009 from children in 5 countries enrolled in TREAT Asia's Pediatric HIV Observational Database were analysed. Multivariate Cox proportional hazard models were used to assess factors associated with mortality in children who received ART. Among 2280 children, 1752 (77%) had received ART. During a median follow-up of 3.1 years after ART, 115 (6.6%) deaths occurred, giving a crude mortality rate of 1.9 per 100 child-years [95% confidence interval (CI): 1.6 to 2.4]. The mortality rate was highest in the first 3 months of ART (10.2 per 100 child-years; 95% CI: 7.5 to 13.7) and declined after 12 months (0.9 per 100 child-years; 95% CI: 0.7 to 1.3). Those with a low recent CD4 percentage, who started ART with lower baseline weight-for-age Z score, or with WHO clinical stage 4 had an increased risk of death. Of 528 (23%) children who never received ART, 36 (6.8%) died after presenting to care, giving a crude mortality rate of 4.1 per 100 child-years (95% CI: 3.0 to 5.7), with a lost-to-program rate of 31.5 per 100 child-years (95% CI: 28.0 to 35.5). The high mortality during the first 3 months of ART and in those with low CD4 percentage support the implementation of early diagnosis and ART initiation.


Radioimmunoassay for hepatitis B core antigen.
Serum hepatitis B core antigen (HBcAg) is an important marker of hepatitis B virus replication. We describe an easy, sensitive radioimmunoassay for determination of HBcAg in detergent-treated serum pellets containing Dane particles. Components of a commercial kits for anti-core determination are used, and HBcAG is measured by competitive inhibition of binding of 125I-labeled antibodies to HBcAg with HBcAg-coated beads. We assayed of HBcAG in the sera of 49 patients with hepatitis B surface antigen (HBsAg)-positive chronic hepatitis, 50 patients with HBsAg-negative chronic hepatitis, and 30 healthy volunteers. HBcAg was detected in 41% of patients with HBsAg-positive chronic hepatitis but not in patients with HBsAg-negative chronic hepatitis. Hepatitis Be antigen (an antigen closely associated with the core of Dane particles) determined in the same sera by radioimmunoassay, was not detected in 50% of HBcAg-positive sera.


Cardiac metastasis of squamous cell carcinoma of the thyroid gland with severe disseminated intravascular coagulation: A case report.
Distant metastasis of primary squamous cell carcinoma (SCC) of the thyroid gland is rare and, to the best of our knowledge, cardiac metastasis has not been reported to date. A 57-year-old man underwent surgery and adjuvant chemoradiotherapy for stage IVA SCC of the thyroid gland. After 3 months, the patient was admitted to the Kyushu University Hospital (Fukuoka, Japan) with subcutaneous hematomas of the left thigh and lower leg, and he was diagnosed with cardiac and mediastinal lymph node metastases of SCC of the thyroid gland with severe disseminated intravascular coagulation (DIC). Echocardiography revealed a mass, 52 mm in greatest diameter, protruding from the interventricular septum towards the right ventricle. Weekly administration of paclitaxel and concurrent irradiation of the cardiac and lymph node metastases were performed. Eighteen days after the initiation of chemoradiotherapy, the DIC and hematomas had significantly improved, and the cardiac metastasis was stable. However, 2 months after admission, the patient developed dyspnea and multiple nodular shadows appeared to be spreading in the subpleura of the lungs bilaterally, which were initially suspected to be pulmonary tumor embolisms. Prednisolone and subsequent administration of lenvatinib were not effective and the patient succumbed to respiratory failure. Severe DIC caused by extremely rare cardiac metastasis of SCC of the thyroid gland was effectively controlled by chemoradiotherapy. However, intensive local control appears to be required for this condition.


Controlled Hopf bifurcation of a storage-ring free-electron laser.
Local bifurcation control is a topic of fundamental importance in the field of nonlinear dynamical systems. We discuss an original example within the context of storage-ring free-electron laser physics by presenting a new model that enables analytical insight into the system dynamics. The transition between the stable and the unstable regimes, depending on the temporal overlapping between the light stored in the optical cavity and the electrons circulating into the ring, is found to be a Hopf bifurcation. A feedback procedure is implemented and shown to provide an effective stabilization of the unstable steady state.


Signs and Symptoms of Acute Bowel Inflammation and the Risk of Progression to Inflammatory Bowel Disease: A Retrospective Analysis.
Episodes of acute ileitis or colitis have been associated with future development of inflammatory bowel diseases (IBD). Nevertheless, the rate of future IBD among patients diagnosed with signs or symptoms of acute bowel inflammation is unknown. We aimed to assess the risk of IBD development among patients presenting with signs or symptoms of ileitis or colitis. We searched for all patients that visited the emergency department (ED) and underwent abdominal computed tomography (CT) who were eventually diagnosed with IBD during gastroenterology follow-ups within 9 years from the index admission. Multivariable models identified possible predictors of patients to develop IBD. Overall, 488 patients visited the ED and underwent abdominal imaging with abnormal findings, and 23 patients (4.7%) were eventually diagnosed with IBD (19 Crohn's, 4 ulcerative colitis). Patients with a future IBD diagnosis were significantly younger (28 vs. 56 years, p < 0.001) with higher rates of diarrhea as a presenting symptom (17.4% vs. 4.1%, p = 0.015) compared to non-IBD patients. On multivariable analysis, age (p < 0.001), colitis (p = 0.004) or enteritis (p < 0.001) on imaging and a diagnosis of diarrhea in the ED (p = 0.02) were associated with development of IBD. Although alarming to patients and families, ED admission with intestinal inflammatory symptoms leads to eventual diagnosis of IBD in <5% of patients during long-term follow-up.


Seed rain and seed bank reveal that seed limitation strongly influences plant community assembly in grasslands.
Dispersal is an important factor in plant community assembly, but assembly studies seldom include information on actual dispersal into communities, i.e. the local propagule pool. The aim of this study was to determine which factors influence plant community assembly by focusing on two phases of the assembly process: the dispersal phase and the establishment phase. At 12 study sites in grazed ex-arable fields in Sweden the local plant community was determined and in a 100-m radius around the centre of each site, the regional species pool was measured. The local seed bank and the seed rain was explored to estimate the local propagule pool. Trait-based models were then applied to investigate if species traits (height, seed mass, clonal abilities, specific leaf area and dispersal method) and regional abundance influenced which species from the regional species pool, dispersed to the local community (dispersal phase) and which established (establishment phase). Filtering of species during the dispersal phase indicates the effect of seed limitation while filtering during the establishment phase indicates microsite limitation. On average 36% of the regional species pool dispersed to the local sites and of those 78% did establish. Species with enhanced dispersal abilities, e.g. higher regional abundance, smaller seeds and dispersed by cattle, were more likely to disperse to the sites than other species. At half the sites, dispersal was influenced by species height. Species establishment was however mainly unlinked to the traits included in this study. This study underlines the importance of seed limitation in local plant community assembly. It also suggests that without information on species dispersal into a site, it is difficult to distinguish between the influence of dispersal and establishment abilities, and thus seed and microsite limitation, as both can be linked to the same trait.


HIV risk reduction for substance using seriously mentally ill adults: test of the information-motivation-behavior skills (IMB) model.
The information-motivation-behavioral skills (IMB) model (Fisher & Fisher, 1992) was used as the theoretical framework for predicting unprotected sexual behavior among substance abusing men and women diagnosed with serious mental illnesses (n = 320; 150 men and 170 women, primarily of minority ethnicity). In a structural equation model, gender, HIV transmission knowledge, and motivational variables of pro-condom norms and attitudes, and perceived susceptibility predicted behavioral skills markers: condom use skills and condom use self-efficacy. Along with the other variables in the model, condom skills and condom self-efficacy were hypothesized to predict condom use over a six-month period. Results showed that greater condom skills were predicted by female gender, positive condom attitudes, and transmission knowledge. Engaging in lower rates of unprotected sex was predicted by pro-condom norms, less perceived susceptibility, and greater condom self-efficacy. Positive attitudes toward condoms had a significant indirect effect on rates of unprotected sex, exerting its influence through condom use self-efficacy. Results suggest that changing personal attitudes about condoms and reinforcing pro-condom attitudes among significant others will encourage condom use among seriously mentally ill (SMI) adults who are at high risk for HIV and other sexually transmitted diseases (STDs).


Chiropractic care and the risk of vertebrobasilar stroke: results of a case-control study in U.S. commercial and Medicare Advantage populations.
There is controversy surrounding the risk of manipulation, which is often used by chiropractors, with respect to its association with vertebrobasilar artery system (VBA) stroke. The objective of this study was to compare the associations between chiropractic care and VBA stroke with recent primary care physician (PCP) care and VBA stroke. The study design was a case-control study of commercially insured and Medicare Advantage (MA) health plan members in the U.S. population between January 1, 2011 and December 31, 2013. Administrative data were used to identify exposures to chiropractic and PCP care. Separate analyses using conditional logistic regression were conducted for the commercially insured and the MA populations. The analysis of the commercial population was further stratified by age (<45 years; ≥45 years). Odds ratios were calculated to measure associations for different hazard periods. A secondary descriptive analysis was conducted to determine the relevance of using chiropractic visits as a proxy for exposure to manipulative treatment. There were a total of 1,829 VBA stroke cases (1,159 - commercial; 670 - MA). The findings showed no significant association between chiropractic visits and VBA stroke for either population or for samples stratified by age. In both commercial and MA populations, there was a significant association between PCP visits and VBA stroke incidence regardless of length of hazard period. The results were similar for age-stratified samples. The findings of the secondary analysis showed that chiropractic visits did not report the inclusion of manipulation in almost one third of stroke cases in the commercial population and in only 1 of 2 cases of the MA cohort. We found no significant association between exposure to chiropractic care and the risk of VBA stroke. We conclude that manipulation is an unlikely cause of VBA stroke. The positive association between PCP visits and VBA stroke is most likely due to patient decisions to seek care for the symptoms (headache and neck pain) of arterial dissection. We further conclude that using chiropractic visits as a measure of exposure to manipulation may result in unreliable estimates of the strength of association with the occurrence of VBA stroke.


HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression.
Production of renin is critically dependent on modulation of REN mRNA stability. Here we sought to elucidate the molecular mechanisms involved. Transfections of renin-expressing Calu-6 cells with reporter constructs showed that a cis-acting 34-nucleotide AU-rich "renin stability regulatory element" in the REN 3'-untranslated region (3'-UTR) contributes to basal REN mRNA instability. Yeast three-hybrid screening with the REN 3'-UTR as bait isolated HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein) beta-subunit) as a novel REN mRNA-binding protein. Recombinant HADHB bound specifically to the 3'-UTR of REN mRNA, as did the known mRNA stabilizers HuR and CP1 (poly(C)-binding protein-1). This required the renin stability regulatory element. Forskolin, which augments REN mRNA stability in Calu-6 cells, increased binding of several proteins, including HuR and CP1, to the REN 3'-UTR, whereas 4-bromocrotonic acid, a specific thiolase inhibitor, decreased binding and elevated renin protein levels. Upon decreasing HADHB mRNA with RNA interference, renin protein and mRNA stability increased, whereas RNA interference against HuR caused these to decrease. Immunoprecipitation and reverse transcription-PCR of Calu-6 extracts confirmed that HADHB, HuR, and CP1 each associate with REN mRNA in vivo. Intracellular imaging revealed distinct localization of HADHB to mitochondria, HuR to nuclei, and CP1 throughout the cell. Immunohistochemistry demonstrated enrichment of HADHB in renin-producing renal juxtaglomerular cells. In conclusion, HADHB, HuR, and CP1 are novel REN mRNA-binding proteins that target a cis-element in the 3'-UTR of REN mRNA and regulate renin production. cAMP-mediated increased REN mRNA stability may involve stimulation of HuR and CP1, whereas REN mRNA decay may involve thiolase-dependent pathways.


Ghana's neglected chronic disease epidemic: a developmental challenge.
This paper charts a brief history of Ghana's chronic disease burden over the last fifty years, focusing on prevalence, risk and illness experiences. Two arguments are made. First, chronic diseases in Ghana constitute public health and developmental challenges, requiring the same intellectual and financial commitments afforded to communicable and infectious diseases such as malaria and HIV/AIDS. Second, to understand and respond to the multifaceted roots and consequences of chronic diseases, research, interventions and policies have to be informed by multidisciplinary - biomedical and social science - collaborations.


Bone morphogenetic protein (RhBMP-2) as a substitute for iliac crest bone graft in multilevel adult spinal deformity surgery: minimum two-year evaluation of fusion.
Prospective, single center, nonblinded radiographic analysis of anterior and posterior adult spinal deformity fusions performed with bone morphogenetic protein (rhBMP-2). To determine the ability of rhBMP-2 to achieve multilevel spinal fusion in the deformity patient. No previous study has evaluated rhBMP-2 for multilevel adult spinal deformity fusion with 2-year results. We postulated fusion could be achieved without distant autogenous graft harvest. Prospective analysis was performed for 98 patients (308 levels; mean age, 51.4 years) who underwent multilevel anterior or posterior spinal fusion (PSF) with minimum 2-year follow-up (average, 2.6 years). Group 1 (10 mg/level) contained 47 patients (109 levels; 2.33 levels/patient) who underwent anterior spinal fusion (ASF): BMP on an absorbable collagen sponge (ACS) with a titanium mesh cage. Group 2 (20 mg/level) included 43 patients (156 levels; 3.63 levels/patient) with PSF: BMP on an ACS with local bone graft (LBG) and bulking agent [tricalcium phosphate/hydroxyapatite (TCP-HA)]. Group 3 (40 mg/level) contained 8 patients (43 levels; 5.38 levels/patient) with PSF: rhBMP-2 and TCP-HA with no autologous bone. Confounding negative factors were present in the study population: medical comorbidities (26%), tobacco use (17%), revision surgery (34%), previous laminectomy (51%), and preoperative pseudarthrosis (27%). Postoperative films (AP, lateral, oblique) were evaluated by independent observers. Average fusion grade was based on a published scale. Overall fusion rate was 95%. (group 1 91%, group 2 97%, group 3 100%). No confounding factor demonstrated a detrimental statistical significance to fusion. In multilevel ASF, BMP (10 mg/level) generates fusion without autogenous bone. In multilevel PSF, BMP (20 mg/level) with LBG and TCP-HA produced fusion. BMP (40 mg/level) and TCP-HA without LBG achieved fusion. In multilevel spinal fusion, rhBMP-2 eliminated the necessity for iliac crest bone graft and yielded an excellent fusion rate.


Laser-Capture Microdissection RNA-Sequencing for Spatial and Temporal Tissue-Specific Gene Expression Analysis in Plants.
The development of a complex multicellular organism is governed by distinct cell types that have different transcriptional profiles. To identify transcriptional regulatory networks that govern developmental processes it is necessary to measure the spatial and temporal gene expression profiles of these individual cell types. Therefore, insight into the spatio-temporal control of gene expression is essential to gain understanding of how biological and developmental processes are regulated. Here, we describe a laser-capture microdissection (LCM) method to isolate small number of cells from three barley embryo organs over a time-course during germination followed by transcript profiling. The method consists of tissue fixation, tissue processing, paraffin embedding, sectioning, LCM and RNA extraction followed by real-time PCR or RNA-seq. This method has enabled us to obtain spatial and temporal profiles of seed organ transcriptomes from varying numbers of cells (tens to hundreds), providing much greater tissue-specificity than typical bulk-tissue analyses. From these data we were able to define and compare transcriptional regulatory networks as well as predict candidate regulatory transcription factors for individual tissues. The method should be applicable to other plant tissues with minimal optimization.


Photo-annealing of Microtissues Creates High-Density Capillary Network Containing Living Matter in A Volumetric-Independent Manner.
The vascular tree is crucial for the survival and function of large living tissues. Despite breakthroughs in 3D bioprinting to endow engineered tissues with large blood vessels, there is currently no approach to engineer high-density capillary networks into living tissues in a scalable manner. We here present photo-annealing of living microtissues (PALM) as a scalable strategy to engineer capillary-rich tissues. Specifically, in-air microfluidics was used to produce living microtissues composed of cell-laden microgels in ultra-high throughput, which could be photo-annealed into a monolithic living matter. Annealed microtissues inherently give rise to an open and interconnected pore network within the resulting living matter. Interestingly, utilizing soft microgels enables microgel deformation, which leads to the uniform formation of capillary-sized pores. Importantly, the ultra-high throughput nature underlying the microtissue formation uniquely facilitates scalable production of living tissues of clinically relevant sizes (>1 cm3 ) with an integrated high-density capillary network. In short, PALM generates monolithic, microporous, modular tissues that meet the previously unsolved need for large engineered tissues containing high-density vascular networks, which is anticipated to advance the fields of engineered organs, regenerative medicine, and drug screening. This article is protected by copyright. All rights reserved.


Novel isobavachalcone derivatives induce apoptosis and necroptosis in human non-small cell lung cancer H1975 cells.
In this study, seventeen isobavachalcone (IBC) derivatives (1-17) were synthesised, and evaluated for their cytotoxic activity against three human lung cancer cell lines. Among these derivatives, compound 16 displayed the most potent cytotoxic activity against H1975 and A549 cells, with IC50 values of 4.35 and 14.21 μM, respectively. Compared with IBC, compound 16 exhibited up to 4.11-fold enhancement of cytotoxic activity on human non-small cell lung cancer H1975 cells. In addition, we found that compound 16 suppressed H1975 cells via inducing apoptosis and necroptosis. The initial mechanism of compound 16 induced cell death in H1975 cells involves the increasing of Bax/Bcl-2 ratio and Cyt C protein level, down-regulating of Akt protein level, and cleaving caspase-9 and -3 induced apoptosis; the up-regulation of RIP3, p-RIP3, MLKL, and p-MLKL levels induced necroptosis. Moreover, compound 16 also caused mitochondrial dysfunction, thereby decreasing cellular ATP levels, and resulting in excessive reactive oxygen species (ROS) accumulation.


First clinical results with the new sinus prosthesis used for valve-sparing aortic root replacement.
Sinuses of Valsalva are important in assuring the physiological function of the aortic valve. This study evaluates short-term clinical results of the reimplantation technique for aortic valve-sparing root replacement using a new prosthesis with three separate sinuses of Valsalva (sinus prosthesis). Between February 2009 and February 2011, a total of 23 patients (20 m/3 f; mean age 52 ± 14.8 years; range 24-70 years) with aortic root aneurysm underwent aortic valve-sparing procedures according to the David reimplantation technique using the new sinus prosthesis. Eighteen patients had tricuspid and five patients bicuspid aortic valves. All patients received clinical as well as echocardiographic examinations postoperatively (mean 13 ± 9.3 months; 0.3-28 months). There was no death and no reoperation of the aortic valve. At latest follow-up, most patients were in New York Heart Association class I (n = 22; 95.7%). In 95.7% aortic valve regurgitation (AR) was 0 or 1+; one patient had AR 2+. Pressure gradients were between the normal range (mean pressure gradient 4.7 ± 1.9 mmHg). Echocardiographic images demonstrate physiological aortic root dimensions and configuration with three separate sinuses of Valsalva without systolic contact of leaflets to the wall. The new sinus prosthesis provides near normal root geometry and hemodynamics in valve-sparing aortic root replacement using the reimplantation technique, applicable for tricuspid and also bicuspid aortic valves.


Effect of seasonal host reproduction on host-macroparasite dynamics.
The impact of seasonal host reproduction on the population dynamics of host-macroparasite interactions is considered. We modify the classic Anderson and May model so that parameters associated with host reproduction are periodic functions of time with a period corresponding to a year. This allows us to compare our findings with those already well documented. If, in the absence of any seasonality, a stable steady-state solution exists annual reproduction gives rise to stable annual population cycles. Moreover, the parameter domain for which there is stability is increased by the seasonality. However, if the life span of the free-living stages is reasonably long, and the continuous model has limit cycle solutions, complex behavior can be observed in the seasonally forced case. Results also indicate that if seasonal effects are ignored, regulation of the hosts by the parasite population is overestimated.


Diffusion-weighted imaging with apparent diffusion coefficient mapping and spectroscopy in prostate cancer.
Prostate cancer is a major health problem, and the exploration of noninvasive imaging methods that have the potential to improve specificity while maintaining high sensitivity is still critically needed. Tissue changes induced by tumor growth can be visualized by magnetic resonance imaging (MRI) methods. Current MRI methods include conventional T2-weighted imaging, diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping and magnetic resonance spectroscopy (MRS). Techniques such as DWI/ADC provide functional information about the behavior of water molecules in tissue; MRS can provide biochemical information about the presence or absence of certain metabolites, such as choline, creatine, and citrate. Finally, vascular parameters can be investigated using dynamic contrast-enhanced MRI. Moreover, with whole-body MRI and DWI, metastatic disease can be evaluated in 1 session and may provide a way to monitor treatment. Therefore, when combining these various methods, a multiparametric data set can be built to assist in the detection, localization, assessment of prostate cancer aggressiveness, and tumor staging. Such a comprehensive approach offers more power to evaluate prostate disease than any single measure alone. In this article, we focus on the role of DWI/ADC and MRS in the detection and characterization using both in vivo and ex vivo imaging of prostate pathology.


Functional outcome of arthroscopic assisted fixation of distal radius fractures.
Many studies in literature have supported the role of wrist arthroscopy as an adjunct to the stable fixation of unstable intraarticular distal radial fractures. This article focuses on the surgical technique, indications, advantages, and results using wrist arthroscopy to assess articular reduction and evaluates the treatment of carpal ligament injuries and triangular fibrocartilage complex (TFCC) injuries in conjunction with the stable fixation of distal radial fractures. We retrospectively evaluated 27 patients (16 males and 11 females), who underwent stable fixation of intraarticular distal radial fractures with arthroscopic evaluation of the articular reduction and repair of associated carpal injuries. As per the AO classification, they were 9 C 1, 12 C2, 2 C3, 3 B 1, and 1 B2 fractures. The final results were evaluated by modified Mayo wrist scoring system. The average age was 41 years (range: 18-68 years). The average followup was of 26 months (range 24-52 months). Five patients needed modification of the reduction and fixation after arthroscopic joint evaluation. Associated ligament lesions found during the wrist arthroscopy were TFCC tears (n=17), scapholunate ligament injury (n=8), and luno-triquetral ligament injury (n=1). Five patients had combined injuries i.e. included TFCC tear, scapholunate and/or lunotriquetral ligament tear. There were 20 excellent, 3 good, and 4 fair results using this score. The radiocarpal and mid carpal arthroscopy is a useful adjunct to stable fixation of distal radial fractures.


Contamination of synthetic HuD protein spanning peptide pools with a CMV-encoded peptide.
To detect HuD-specific T cells in patients with Hu-antibody associated paraneoplastic neurological syndromes (Hu-PNS), we used short-term stimulation assays with HuD protein spanning peptide pools (PSPP) with purities of at least 70% and found reproducible false-positive CD8+ T-cell responses in three of 127 individuals (two healthy controls and one Hu-PNS patient), which all shared HLA-A*2402 and HLA-B*1801. After testing the 15-mer peptides of the HuD antigen separately, we discovered that the same three 15-mers yielded the CD8+ T cell response in those three individuals. This highly unusual result could not be reproduced when using new batches of peptides with a higher level of purity (>82% and >95%). Therefore, we assumed this response was not directed against the HuD peptides and analyzed the HuD 15-mers by Fourier transform ion cyclotron resonance (FT-ICR) tandem mass spectrometry (MS/MS), which showed the presence of a cytomegalovirus (CMV)-encoded peptide (AIAEESDEEEAIVAY) as a contaminant. The three responding individuals all were CMV-seropositive and the contaminating peptide appeared to fit in the binding groove of HLA-B*18. Our data reveal that synthetic PSPP may contain immunogenic contaminations which may cause false positive results in T-cell stimulation assays.


Prevalence of addictive behaviours among adolescents from 73 low-and middle-income countries.
Adolescence is a critical developmental stage for the initiation of substance use worldwide. However, the prevalence of various types of substances consumed by adolescents living in low- and middle- income countries (LMICs) across different continents is not fully understood.The aims of the present study were to estimate the prevalence of regular and problematic substance use among adolescents in 73 LMICs across different continents and to explore the role of country-specific factors on this prevalence. Data of 314,187 adolescents (52.79% girls; median age = 15 years old) who participated in the Global School-based Student Health Survey (GSHS) were analysed. After estimating the weighted prevalence for each country, multilevel models were used to examine the influence of country-specific factors on the prevalence of substance use across 73 LMICs. The results indicated that problematic alcohol use was more prevalent in LMICs with higher income levels. The prevalence of regular alcohol use was the highest in Zambia. Regular and problematic alcohol use was the least prevalent in Senegal and Myanmar. The findings also revealed that smoking and the consumption of marijuana and amphetamine were the most common among adolescents in Samoa, whereas the prevalences for these substances were the lowest in Laos. Economic wealth, religion and geographical factors seem to have a role in determining the prevalence of substance use among adolescents in LMICs.


Genome-wide analysis of DNA turnover and gene expression in stationary-phase Saccharomyces cerevisiae.
Exponential-phase yeast cells readily enter stationary phase when transferred to fresh, carbon-deficient medium, and can remain fully viable for up to several months. It is known that stationary-phase prokaryotic cells may still synthesize substantial amounts of DNA. Although the basis of this phenomenon remains unclear, this DNA synthesis may be the result of DNA maintenance and repair, recombination, and stress-induced transposition of mobile elements, which may occur in the absence of DNA replication. To the best of our knowledge, the existence of DNA turnover in stationary-phase unicellular eukaryotes remains largely unstudied. By performing cDNA-spotted (i.e. ORF) microarray analysis of stationary cultures of a haploid Saccharomyces cerevisiae strain, we demonstrated on a genomic scale the localization of a DNA-turnover marker [5-bromo-2'-deoxyuridine (BrdU); an analogue of thymidine], indicative of DNA synthesis in discrete, multiple sites across the genome. Exponential-phase cells on the other hand, exhibited a uniform, total genomic DNA synthesis pattern, possibly the result of DNA replication. Interestingly, BrdU-labelled sites exhibited a significant overlap with highly expressed features. We also found that the distribution among chromosomes of BrdU-labelled and expressed features deviates from random distribution; this was also observed for the overlapping set. Ty1 retrotransposon genes were also found to be labelled with BrdU, evidence for transposition during stationary phase; however, they were not significantly expressed. We discuss the relevance and possible connection of these results to DNA repair, mutation and related phenomena in higher eukaryotes.


Dynamic changes in DNA methylation during embryonic and postnatal development of an altricial wild bird.
DNA methylation could shape phenotypic responses to environmental cues and underlie developmental plasticity. Environmentally induced changes in DNA methylation during development can give rise to stable phenotypic traits and thus affect fitness. In the laboratory, it has been shown that the vertebrate methylome undergoes dynamic reprogramming during development, creating a critical window for environmentally induced epigenetic modifications. Studies of DNA methylation in the wild are lacking, yet are essential for understanding how genes and the environment interact to affect phenotypic development and ultimately fitness. Furthermore, our knowledge of the establishment of methylation patterns during development in birds is limited. We quantified genome-wide DNA methylation at various stages of embryonic and postnatal development in an altricial passerine bird, the great tit Parus major. While, there was no change in global DNA methylation in embryonic tissue during the second half of embryonic development, a twofold increase in DNA methylation in blood occurred between 6 and 15 days posthatch. Though not directly comparable, DNA methylation levels were higher in the blood of nestlings compared with embryonic tissue at any stage of prenatal development. This provides the first evidence that DNA methylation undergoes global change during development in a wild bird, supporting the hypothesis that methylation mediates phenotypic development. Furthermore, the plasticity of DNA methylation demonstrated during late postnatal development, in the present study, suggests a wide window during which DNA methylation could be sensitive to environmental influences. This is particularly important for our understanding of the mechanisms by which early-life conditions influence later-life performance. While, we found no evidence for differences in genome-wide methylation in relation to habitat of origin, environmental variation is likely to be an important driver of variation in methylation at specific loci.


Precise temperature mapping of GaN-based LEDs by quantitative infrared micro-thermography.
A method of measuring the precise temperature distribution of GaN-based light-emitting diodes (LEDs) by quantitative infrared micro-thermography is reported. To reduce the calibration error, the same measuring conditions were used for both calibration and thermal imaging; calibration was conducted on a highly emissive black-painted area on a dummy sapphire wafer loaded near the LED wafer on a thermoelectric cooler mount. We used infrared thermal radiation images of the black-painted area on the dummy wafer and an unbiased LED wafer at two different temperatures to determine the factors that degrade the accuracy of temperature measurement, i.e., the non-uniform response of the instrument, superimposed offset radiation, reflected radiation, and emissivity map of the LED surface. By correcting these factors from the measured infrared thermal radiation images of biased LEDs, we determined a precise absolute temperature image. Consequently, we could observe from where the local self-heat emerges and how it distributes on the emitting area of the LEDs. The experimental results demonstrated that highly localized self-heating and a remarkable temperature gradient, which are detrimental to LED performance and reliability, arise near the p-contact edge of the LED surface at high injection levels owing to the current crowding effect.


Microinjection of substance P and ACh into rat intermediolateral nucleus elicits cardiovascular responses.
The effects of substance P (SP) or acetylcholine (ACh) microinjected into the intermediolateral nucleus of the spinal cord (IMLn) on arterial pressure (AP) and heart rate (HR) were investigated in 22 male Wistar rats under urethan and artificial ventilation. L-Glutamate (Glu) was microinjected into the IMLn between C7 and T4 to locate cardiovascular sites. Micropipettes containing Glu were stereotaxically positioned in 82 histologically verified sites in the IMLn between C7 and T4 on both the right and left sides. Microinjection of 4-10 nl of 0.18 M Glu in 30 of 39 explored sites at the T2 level elicited significant increases in HR (+24.2 +/- 3.1 beats/min). These changes were accompanied by significant increases in mean AP (+11.4 +/- 1.2 mmHg) at the T2 level (32/47 sites). Microinjection of 4-10 nl of SP (3 X 10(-7) to 3 X 10(-4) M) or ACh (0.005-0.5 M) in the right IMLn at the T2 level elicited increases in HR but did not affect AP. The duration of the responses to SP or ACh was significantly longer than the duration of the responses to Glu. The responses to ACh could be blocked by prior microinjection of 5 X 10(-2) M atropine. No responses were ever obtained in the left IMLn by microinjection of Glu, SP, or ACh. These results support the hypothesis that Glu, ACh, and SP mediate sympathoexcitation in the IMLn of the rat and that these excitatory responses have different temporal patterns.


A clinician's perspective on yellow fever vaccine-associated neurotropic disease.
Yellow fever (YF) causes high fever, liver dysfunction, renal failure, hypercoagulopathy and platelet dysfunction and can lead to shock and death with a case-fatality ratio of 20-50%. YF vaccination results in long-lasting protective immunity. Serious adverse events (SAEs), such as YF vaccine-associated neurotropic disease (YEL-AND) are rare. We present a case of a 56-year-old Caucasian man with fever, headache, cognitive problems at the emergency department. He received a primary YF vaccination 4 weeks prior to symptom onset. Cerebrospinal fluid tested positive (POS) for YF virus by reverse transcriptase polymerase chain reaction and confirmed diagnosis of YEL-AND. The patient recovered with symptomatic treatment. We reviewed published clinical reports on YEL-AND indexed for MEDLINE. We identified and analyzed 53 case reports. Forty-five patients were male and eight were female. Twenty-nine cases met criteria for definite YEL-AND and twenty-four for suspected YEL-AND according to YF Vaccine Safety Working Group. We applied the Brighton Collaboration diagnostic criteria to assess the diagnostic accuracy of the clinical diagnoses and found meningoencephalitis in 38 reported YEL-AND cases, Guillain Barré Syndrome (GBS) in seven, Acute Disseminated Encephalomyelitis (ADEM) in six and myelitis in five. Thirty-five patients recovered or improved; however, not all cases had a complete follow-up. The prognosis of YEL-AND presenting with GBS, ADEM or myelitis was poor. Fourteen patients received therapy (corticosteroids, intravenous immunoglobulins and/or plasmapheresis). In conclusion, YF vaccine-associated neurotropic disease is a very rare but SAE after YF vaccination. We described a case of YEL-AND and propose a standardized clinical workup of this condition based on a review of the literature. Centralized registration of complications of YF vaccination is encouraged.


Exposure to authoritarian values leads to lower positive affect, higher negative affect, and higher meaning in life.
Five studies tested the effect of exposure to authoritarian values on positive affect (PA), negative affect (NA), and meaning in life (MIL). Study 1 (N = 1,053) showed that simply completing a measure of right-wing authoritarianism (vs. not) prior to rating MIL led to higher MIL. Preregistered Study 2 (N = 1,904) showed that reading speeches by real-world authoritarians (e.g., Adolf Hitler) led to lower PA, higher NA, and higher MIL than a control passage. In preregistered Studies 3 (N = 1,573) and 4 (N = 1,512), Americans read authoritarian, egalitarian, or control messages and rated mood, MIL, and evaluated the passages. Both studies showed that egalitarian messages led to better mood and authoritarian messages led to higher MIL. Study 5 (N = 148) directly replicated these results with Canadians. Aggregating across studies (N = 3,401), moderational analyses showed that meaning in life, post manipulation, was associated with more favorable evaluations of the authoritarian passage. In addition, PA was a stronger predictor of MIL in the egalitarian and control conditions than in the authoritarian condition. Further results showed no evidence that negative mood (or disagreement) spurred the boost in MIL. Implications and future directions are discussed.


An antigenic analysis of the adenovirus type 2 fibre polypeptide.
Twenty-seven monoclonal antisera were generated against the SDS-denatured fibre of adenovirus type 2. The antisera were characterized using radioimmune assay, fluorescent antibody tests, immune precipitation, Western blotting, haemagglutination and neutralization, and formed six groups as follows: A, type-specific neutralizing antisera which exhibited haemagglutination inhibition (Hi+); B, type-specific non-neutralizing antisera which did not exhibit haemagglutination inhibition (Hi-); C, subgroup-specific neutralizing antisera Hi+; D, a subgroup-specific neutralizing antiserum Hi-; E, subgroup-specific non-neutralizing antisera Hi-; F, a subgroup-specific neutralizing antiserum Hi- which did not react in Western blotting tests. The C-terminal 201 amino acids of the fibre were expressed in Escherichia coli and a total of six antisera from groups A, B and C recognized five epitopes carried on this region which in several models is thought to form the knob of the fibre. At least eight epitopes were expressed by the entire native fibre. The five epitopes of the C-terminal end of the fibre formed three antigenic sites. Two sites each consisted of a neutralizing type-specific and a neutralizing group-specific epitope which overlapped in position. The remaining site consisted of a type-specific, non-neutralizing epitope.


Lifelong learning along the education and career continuum: meta-analysis of studies in health professions.
Lifelong learning is an integral part of health professionals' maintenance of competence. Several studies have examined the orientation toward lifelong learning at various stages of the education and career continuum; however, none has looked at changes throughout training and practice. The objective of the present study was to determine if there are differences between groups defined by their places on the education and career continuum. The authors performed a group-level meta-analysis on studies that used the 14-item Jefferson Scale of Physician Lifelong Learning or its variants. Eleven published articles, which reported on studies with post-secondary health professions students, residents, and practicing health professionals met the inclusion criteria. In total, there were 12 independent data sets, with four data sets per group. In total, over seven thousand students, residents, and practicing health professionals responded to the Jefferson Scale (N=7.269). Individual study means tendency to be high, suggesting a high orientation toward lifelong learning among the trainees (students and residents) and practicing health professionals. Meta-analysis results indicated that the orientation toward lifelong learning tended to increase gradually along the education and career continuum. Significant differences in the group means were found between the trainees and practicing health professionals. In the reviewed studies, the orientation toward lifelong learning among students, residents, and practicing professionals was high. Nonetheless, although based on separate cohorts, it appears that the orientation toward lifelong learning continues to develop even after the completion of formal training.


Observation of the Fluctuation Spin Hall Effect in a Low-Resistivity Antiferromagnet.
The spin Hall effect (SHE) can generate a pure spin current by an electric current, which is promisingly used to electrically control magnetization. To reduce the power consumption of this control, a giant spin Hall angle (SHA) in the SHE is desired in low-resistivity systems for practical applications. Here, critical spin fluctuation near the antiferromagnetic (AFM) phase transition in chromium (Cr) is proven to be an effective mechanism for creating an additional part of the SHE, named the fluctuation spin Hall effect. The SHA is significantly enhanced when the temperature approaches the Néel temperature (TN) of Cr and has a peak value of -0.36 near TN. This value is higher than the room-temperature value by 153% and leads to a low normalized power consumption among known spin-orbit torque materials. This study demonstrates the critical spin fluctuation as a prospective way to increase the SHA and enriches the AFM material candidates for spin-orbitronic devices.


Advancements in 2D and 3D In Vitro Models for Studying Neuromuscular Diseases.
Neuromuscular diseases (NMDs) are a genetically or clinically heterogeneous group of diseases that involve injury or dysfunction of neuromuscular tissue components, including peripheral motor neurons, skeletal muscles, and neuromuscular junctions. To study NMDs and develop potential therapies, remarkable progress has been made in generating in vitro neuromuscular models using engineering approaches to recapitulate the complex physical and biochemical microenvironments of 3D human neuromuscular tissues. In this review, we discuss recent studies focusing on the development of in vitro co-culture models of human motor neurons and skeletal muscles, with the pros and cons of each approach. Furthermore, we explain how neuromuscular in vitro models recapitulate certain aspects of specific NMDs, including amyotrophic lateral sclerosis and muscular dystrophy. Research on neuromuscular organoids (NMO) will continue to co-develop to better mimic tissues in vivo and will provide a better understanding of the development of the neuromuscular tissue, mechanisms of NMD action, and tools applicable to preclinical studies, including drug screening and toxicity tests.


Metabolic profiles from two different breakfast meals characterized by 1H NMR-based metabolomics.
It is challenging to measure dietary exposure with techniques that are both accurate and applicable to free-living individuals. We performed a cross-over intervention, with 24 healthy individuals, to capture the acute metabolic response of a cereal breakfast (CB) and an egg and ham breakfast (EHB). Fasting and postprandial urine samples were analyzed using 1H nuclear magnetic resonance (NMR) spectroscopy and multivariate data analysis. Metabolic profiles were distinguished in relation to ingestion of either CB or EHB. Phosphocreatine/creatine and citrate were identified at higher concentrations after consumption of EHB. Beverage consumption (i.e., tea or coffee) could clearly be seen in the data. 2-furoylglycine and 5-hydroxymethyl-2-furoic acid - potential biomarkers for coffee consumption were identified at higher concentrations in coffee drinkers. Thus 1H NMR urine metabolomics is applicable in the characterization of acute metabolic fingerprints from meal consumption and in the identification of metabolites that may serve as potential biomarkers.


Syntheses, crystal structures and magnetic properties of two mixed-valence Co(iii)Co(ii) compounds derived from Schiff base ligands: field-supported single-ion-magnet behavior with easy-plane anisotropy.
Two μ-phenoxo-μ1,1-azide dinuclear CoIIICoII complexes [CoIII(N3)2L1(μ1,1-N3)CoII(N3)]·MeOH (1) and [CoIII(N3)2L2(μ1,1-N3)CoII(N3)]·MeOH (2) (HL1 and HL2 are two Schiff base ligands having N2O-N2O compartments) both possess one hexacoordinate Co(iii) and one pentacoordinate Co(ii) center. DC magnetic susceptibility and magnetization measurements show an appreciable amount of positive magnetic anisotropy (D/hc∼ 40 cm-1) that is also confirmed by ab initio CASSCF calculations. AC susceptibility measurements of 1 reveal that it exhibits a slow magnetic relaxation with two relaxation channels. The external magnetic field supports the low-frequency (LF) channel that escapes on heating more progressively than the high-frequency (HF) branch. The relaxation time is as slow as τ = 255 ms at T = 1.9 K and BDC = 0.6 T, where the LF mole fraction is 69%. The complex 2 also displays similar field-supported slow magnetic relaxation with two relaxation channels.


Epidemiology of major respiratory pathogens.
A vast literature attests to the fact that Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis represent the prevailing bacterial pathogens of community-acquired lower respiratory tract infections. Their specific incidence as causative agents of the more common syndromes is known to vary even profoundly, depending on geographic area, and the same holds true for their rates of resistance to antimicrobial drugs. Europe does not escape the threat posed by the present pandemic spread of penicillin resistance in S. pneumoniae although, as expected, some countries like Spain and France are highly affected and others including Germany, Italy, The Netherlands and the Scandinavian region, are relatively spared. In several sites multiple resistance has been described in S. pneumoniae with the most affected drugs being penicillin, the macrolides, co-trimoxazole and tetracycline. In H. influenzae synthesis of beta-lactamases is the main resistance trait expressed. Lack of susceptibility to beta-lactams dictated by a different mechanism remains extremely rare. Large variations in the incidence of this character are apparent when considering European countries. France and Spain are again widely affected while Germany, The Netherlands and Italy display rates of beta-lactamase-positive H. influenzae of about 16%. M. catarrhalis must be considered generally resistant to non-protected aminopenicillins since over 90% of these organisms produce beta-lactamases.


Characterization of a mcr-1 and CRISPR-Cas System Co-harboring Plasmid in a Carbapenemase-Producing High-Risk ST11 Klebsiella pneumoniae Strain.
We set out to study the prevalence of the mcr-1 gene in carbapenemase-producing Klebsiella pneumoniae (CPKP) strains, and to determine whether its presence is associated with a fitness cost. A total of 234 clinical CPKP isolates were collected from a tertiary medical center in Taiwan from January 2018 to January 2019. The mcr-1 and carbapenemase genes were detected by polymerase chain reaction (PCR) followed by Sanger sequencing. The mcr-1-positive carbapenemase-producing strain was characterized by whole genome sequencing, a plasmid stability test and a conjugation assay. In vitro growth rate and an in vivo virulence test were compared between the parental mcr-1-positive strain and its mcr-1 plasmid-cured strain. We identified only one mcr-1 positive strain (KP2509), co-harboring bla KPC- 2 and bla OXA- 48, among 234 (1/234, 0.43%) CPKP strains. KP2509 and its Escherichia coli mcr-1 transconjugant showed moderate colistin resistance (MIC = 8 mg/L). The mcr-1 is located on a large conjugative plasmid (317 kb), pKP2509-MCR, with three replicons, IncHI, IncFIB, and IncN. Interestingly, a complete Type IV-A3 CRISPR-Cas system was identified in pKP2509-MCR. Plasmid pKP2509-MCR was highly stable in KP2509 after 270 generation of passage, and the pKP2509-MCR cured strain PC-KP2509 showed similar growth rate and in vivo virulence in comparison to KP2509. The prevalence of mcr-1 in CPKP strains remains low in our center. Notably, we identified a large plasmid with multiple replicons containing both the mcr-1 and the Type IV-3A CRISPR-Cas genes. The further spread of this highly stable plasmid raises concern that it may promote the increase of mcr-1 prevalence in CPKP.


Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice.
Intra-uterine growth restriction is an independent risk factor for adult psychiatric and cardiovascular diseases. In humans, intra-uterine growth restriction is associated with increased placental and fetal oxidative stress, as well as down-regulation of placental 11β-HSD (11β-hydroxysteroid dehydrogenase). Decreased placental 11β-HSD activity increases fetal exposure to maternal glucocorticoids, further increasing fetal oxidative stress. To explore the developmental origins of co-morbid hypertension and anxiety disorders, we increased fetal glucocorticoid exposure by administering the 11β-HSD inhibitor CBX (carbenoxolone; 12 mg·kg-1 of body weight·day-1) during the final week of murine gestation. We hypothesized that maternal antioxidant (tempol throughout pregnancy) would block glucocorticoid-programmed anxiety, vascular dysfunction and hypertension. Anxiety-related behaviour (conditioned fear) and the haemodynamic response to stress were measured in adult mice. Maternal CBX administration significantly increased conditioned fear responses of adult females. Among the offspring of CBX-injected dams, maternal tempol markedly attenuated the behavioural and cardiovascular responses to psychological stress. Compared with offspring of undisturbed dams, male offspring of dams that received daily third trimester saline injections had increased stress-evoked pressure responses that were blocked by maternal tempol. In contrast, tempol did not block CBX-induced aortic dysfunction in female mice (measured by myography and lucigenin-enhanced chemiluminescence). We conclude that maternal stress and exaggerated fetal glucocorticoid exposure enhance sex-specific stress responses, as well as alterations in aortic reactivity. Because concurrent tempol attenuated conditioned fear and stress reactivity even among the offspring of saline-injected dams, we speculate that antenatal stressors programme offspring stress reactivity in a cycle that may be broken by antenatal antioxidant therapy.


Species differences in the metabolism of 2-acetylaminofluorene by hepatocytes in primary monolayer culture.
Monolayers of hepatocytes from mouse, hamster, rat, and guinea pig metabolized 2-acetylaminofluorene (AAF) to ether-extractable, water-soluble as well as covalently macromolecular bound products. Hamster hepatocytes showed the highest rate of formation of ether-extractable metabolites, rat and guinea pig the lowest. These species differences reflected mainly differences in the formation of 2-aminofluorene, the dominating ether-extractable metabolite formed. Detectable levels of N-hydroxy-AAF (greater than 1 nmol/10(6) cells) were only obtained with hamster hepatocytes. The major C-hydroxylated metabolites in the species tested were 7- and 9-hydroxy-AAF. Hepatocytes from guinea pig and hamster showed the highest rate of formation of C-hydroxylated and water-soluble metabolites, rat hepatocytes the lowest. The highest rate of covalent macromolecular binding by AAF metabolites was found with hamster hepatocytes, followed by hepatocytes from rat, guinea pig, and mouse. The balance between activation and detoxification reactions of AAF in hepatocytes may be expressed as the ratio between covalently bound metabolites and the sum of C-hydroxylated and stable water-soluble metabolites. This ratio was far greater in rat hepatocytes followed by hamster, guinea pig, and mouse, and it correlated better with the species susceptibility to liver cancer than covalent binding as such. Thus, AAF-induced liver cancer may depend more on the relative degree of activation versus detoxification of the administered dose than on the absolute capacity of the liver to activate the carcinogen.


Low-Frequency Cortical Oscillations Entrain to Subthreshold Rhythmic Auditory Stimuli.
Many environmental stimuli contain temporal regularities, a feature that can help predict forthcoming input. Phase locking (entrainment) of ongoing low-frequency neuronal oscillations to rhythmic stimuli is proposed as a potential mechanism for enhancing neuronal responses and perceptual sensitivity, by aligning high-excitability phases to events within a stimulus stream. Previous experiments show that rhythmic structure has a behavioral benefit even when the rhythm itself is below perceptual detection thresholds (ten Oever et al., 2014). It is not known whether this "inaudible" rhythmic sound stream also induces entrainment. Here we tested this hypothesis using magnetoencephalography and electrocorticography in humans to record changes in neuronal activity as subthreshold rhythmic stimuli gradually became audible. We found that significant phase locking to the rhythmic sounds preceded participants' detection of them. Moreover, no significant auditory-evoked responses accompanied this prethreshold entrainment. These auditory-evoked responses, distinguished by robust, broad-band increases in intertrial coherence, only appeared after sounds were reported as audible. Taken together with the reduced perceptual thresholds observed for rhythmic sequences, these findings support the proposition that entrainment of low-frequency oscillations serves a mechanistic role in enhancing perceptual sensitivity for temporally predictive sounds. This framework has broad implications for understanding the neural mechanisms involved in generating temporal predictions and their relevance for perception, attention, and awareness.SIGNIFICANCE STATEMENT The environment is full of rhythmically structured signals that the nervous system can exploit for information processing. Thus, it is important to understand how the brain processes such temporally structured, regular features of external stimuli. Here we report the alignment of slowly fluctuating oscillatory brain activity to external rhythmic structure before its behavioral detection. These results indicate that phase alignment is a general mechanism of the brain to process rhythmic structure and can occur without the perceptual detection of this temporal structure.


Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS.
Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2', 3'-didehydro-2', 3'-deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3' azido-3'-deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs.


Phosphatidylcholine metabolism in rat liver after partial hepatectomy. Evidence for increased activity and amount of CTP:phosphocholine cytidylyltransferase.
The effect of partial (70%) hepatectomy on phosphatidylcholine (PC) synthesis in rat liver was investigated during the first 4 post-operative days. Between 4 and 96 h after partial hepatectomy, the mass of PC increased from 30% to 80% of sham-operation values, being comparable with the restoration of total liver mass after partial hepatectomy. Relative to control (sham-operation), the incorporation in vivo of [3H]choline into PC was stimulated 2.6-fold at 22 h after partial hepatectomy. Moreover, CTP:phosphocholine cytidylyltransferase (EC 22.214.171.124) activity was significantly enhanced, and the pool size of phosphocholine decreased at 22 and 48 h after partial hepatectomy, whereas the activity of choline kinase (EC 22.214.171.124) was augmented at a later stage of liver regeneration (48 and 96 h). Stimulation of CTP:phosphocholine cytidylyltransferase activity by partial hepatectomy occurred in both the microsomal and cytosolic fractions. The stimulatory effect in the cytosolic fraction was mainly due to an increase in the number of enzyme molecules, as demonstrated by immunotitration of the amount of cytosolic cytidylyltransferase protein.


Does workplace health promotion contribute to job stress reduction? Three-year findings from Partnering Healthy@Work.
Workplace health promotion (WHP) has been proposed as a preventive intervention for job stress, possibly operating by promoting positive organizational culture or via programs promoting healthy lifestyles. The aim of this study was to investigate whether job stress changed over time in association with the availability of, and/or participation in a comprehensive WHP program (Healthy@Work). This observational study was conducted in a diverse public sector organization (~28,000 employees). Using a repeated cross-sectional design with models corroborated using a cohort of repeat responders, self-report survey data were collected via a 40 % employee population random sample in 2010 (N = 3406) and 2013 (N = 3228). Outcomes assessed were effort and reward (self-esteem) components of the effort-reward imbalance (ERI) measure of job stress. Exposures were availability of, and participation in, comprehensive WHP. Linear mixed models and Poisson regression were used, with analyses stratified by sex and weighted for non-response. Higher WHP availability was positively associated with higher perceived self-esteem among women. Women's mean reward scores increased over time but were not statistically different (p > 0.05) after 3 years. For men, higher WHP participation was associated with lower perceived effort. Men's mean ERI increased over time. Results were supported in the cohort group. For women, comprehensive WHP availability contributed to a sense of organizational support, potentially impacting the esteem component of reward. Men with higher WHP participation also benefitted but gains were modest over time and may have been hindered by other work environment factors.


Fluorescence spectroscopy application in the express-evaluation of the gastrointestinal microflora.
Possible application is studied for fluorescence spectroscopy in the express-evaluation of the gastrointestinal microflora. This diagnostic approach is feasible because of the difference in fluorescent spectra from different microorganisms, with anaerobic microorganisms exhibiting the most pronounced fluorescence. It was found that fluorescence strength raised with an increase in the bacteria Bacteroides and bifid bacteria, whereas it decreased with an increase in Escherichia coli. The bacteria Bacteroides and bifid bacteria are the most typical representatives of anaerobic bacteria, whereas the bacteria Escherichia coli are the typical representatives of aerobic bacteria. According to the literature, Bacteroides and bifid bacteria reveal an intense fluorescence. Bearing in mind that these genera of bacteria play an important role in the gastrointestinal microbiocenosis, fluorescence spectroscopy can be used as a diagnostic means for gastrointestinal dysbacteriosis.


Planar cell polarity-dependent asymmetric organization of microtubules for polarized positioning of the basal body in node cells.
For left-right symmetry breaking in the mouse embryo, the basal body must become positioned at the posterior side of node cells, but the precise mechanism for this has remained unknown. Here, we examined the role of microtubules (MTs) and actomyosin in this basal body positioning. Exposure of mouse embryos to agents that stabilize or destabilize MTs or F-actin impaired such positioning. Active myosin II was detected at the anterior side of node cells before the posterior shift of the basal body, and this asymmetric activation was lost in Prickle and dachsous mutant embryos. The organization of basal-body associated MTs (baMTs) was asymmetric between the anterior and posterior sides of node cells, with anterior baMTs extending horizontally and posterior baMTs extending vertically. This asymmetry became evident after polarization of the PCP core protein Vangl1 and before the posterior positioning of the basal body, and it also required the PCP core proteins Prickle and dachsous. Our results suggest that the asymmetry in baMT organization may play a role in correct positioning of the basal body for left-right symmetry breaking.


Primary Cutaneous Acral CD8+ T-Cell Lymphoma-A Single Center Review of 3 Cases and Recent Literature Review.
The recently published 2016 revision of the WHO classification of lymphoid neoplasms includes primary cutaneous acral CD8-positive T-cell lymphoma (PCATCL) as a provisional entity. This is a rare indolent lymphoma characterized by papules or nodules on the ear and a dermal infiltrate of CD8-positive T-lymphocytes with cytotoxic marker expression. A retrospective review of a single institutional experience with PCATCL identified 3 patients (mean age 54; range 49-62) with papules or nodules on the ear. Lesional biopsies demonstrated a dense diffuse dermal infiltrate of atypical lymphocytes with a Grenz zone in 2 cases and focal epidermotropism in 1 case. The atypical lymphocytes were predominantly CD3 and CD8 positive with expression of cytotoxic marker TIA1. Staging evaluation failed to reveal systemic disease. Two patients underwent local excision, and the third received local radiation therapy all with complete response and no disease recurrence at last follow-up 3 months (range 2-5 months). Our cases add to the existing limited literature on the clinical and histopathological features of PCATCL. We also performed an updated systematic literature view of the entity.


Meso- and microplastics monitoring in harbour environments: A case study for the Port of Durban, South Africa.
An investigation into the abundance and distribution of meso- and microplastics within the Port of Durban was conducted using a static immersible water pump and particle filtration system to collect meso- and microplastics from the water column, microplastics from sediment samples and corresponding CTD. Microplastics were detected in all samples under investigation. Results suggest that sewage overflow, stormwater drains, port operations, followed by rivers are input areas for mitigation to focus on. Identifying meso- and microplastics inputs, baselines and distribution allow for long term monitoring and management in a harbour environment. This can potentially contribute to the control and regulation of small plastics particles in harbours, and the subsequent transport of these pollutants via dredged material into other ecosystems.


Influence of biologic factors and anatomic site in completely resected liposarcoma.
Soft tissue sarcoma (STS) encompasses a group of neoplasms that are anatomically and biologically diverse. Retroperitoneal/visceral (RP/V) tumors have a poorer prognosis than extremity/trunk (E/T) lesions, and this has been attributed to frequent presentation with tumors of large size and multiorgan involvement that precludes complete resection. The worse prognosis that is associated with RP/V tumors has also been thought to be histopathologically dependent and not necessarily related to anatomic site. The aim of this study was to determine the role of anatomic site and biologic features in prognosis and outcome in patients after complete resection by examining a large cohort of STS patients with a single histopathology, ie, liposarcoma. All patients who were treated for liposarcoma from July 1, 1982, through July 1, 1998, were included. Univariate analyses were performed using log-rank test and Kaplan-Meier estimates, and multivariate analyses were performed using Cox regression. The three end points examined were local recurrence (LR), distant recurrence, and disease-specific survival (DSS). Seven hundred twenty patients with liposarcoma were evaluated, and of these, 460 had completely resected primary or completely resected locally recurrent disease. Breakdown of anatomic site was 65% E/T (n = 301) and 35% RP/V (n = 159). The median follow-up period for patients who underwent complete resection was 42 months (range, 1 to 194 months). We found that RP/V site is a poor prognosticator that is independent of patient sex and age; tumor size, grade, and margin; and recurrent presentation. Sixty-nine percent of patients with RP/V tumors who died had local disease only and no distant metastasis at the time of death. In liposarcoma, tumor location exerts as strong an influence on prognosis as biology. In contrast to extremity liposarcoma, LR without distant metastasis often results in death for patients with RP/V tumors. For these patients, local control accomplished by complete surgical resection +/- adjuvant radiation therapy should impact strongly on DSS.


Calpain inhibitor I reduces colon injury caused by dinitrobenzene sulphonic acid in the rat.
Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leucocyte infiltration, upregulation of expression of intercellular adhesion molecule 1 (ICAM-1), and upregulation of P-selectin in the colon. The aim of the present study was to examine the effects of calpain inhibitor I in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulphonic acid (DNBS). Rats experienced haemorrhagic diarrhoea and weight loss. Four days after administration of DNAB, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as by an increase in myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1 and P-selectin as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) showed intense staining in the inflamed colon. Staining of sections of colon obtained from DNBS treated rats with an anti-cyclooxygenase 2 antibody showed diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase was found mainly in macrophages located within the inflamed colon of DNBS treated rats. Calpain inhibitor I (5 mg/kg daily intraperitoneally) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. Calpain inhibitor I also caused a substantial reduction in (i) degree of colon injury, (ii) rise in myeloperoxidase activity (mucosa), (iii) increase in tissue levels of malondialdehyde, (iv) increase in staining (immunohistochemistry) for nitrotyrosine and PARP, as well as (v) upregulation of ICAM-1 and P-selectin caused by DNBS in the colon. Calpain inhibitor I reduces the degree of colitis caused by DNBS. We propose that calpain inhibitor I may be useful in the treatment of inflammatory bowel disease.


Close correlation between the ankle-brachial index and symptoms of depression in hemodialysis patients.
As both of peripheral arterial disease (PAD) and depression carried a poor prognosis in patients on maintenance hemodialysis (MHD), we investigated the correlation between the ankle-brachial index (ABI), an indicator of subclinical PAD, and symptoms of depression in patients on MHD. One hundred and twenty-nine patients on MHD (75 males and 54 females, mean age 64.8 ± 12 years) were enrolled in this cross-sectional study, which aimed at evaluating the relationship between symptoms of depression and ABI. Demographic as well as clinical and laboratory variables including status of diabetes, chronic hepatitis C infection, dialysis duration, Charlson comorbidity index (CCI), plasma levels of albumin, C-peptide, insulin, high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), adiponectin, and lipid profile were obtained. The self-administered beck depression inventory (BDI) was used to determine the presence or absence of symptoms of depression, and depression was defined as a BDI score ≧14. Multivariable-adjusted linear regression models were constructed to confirm the independent association of biologic parameters of symptoms of depression. Significance was defined as P < 0.05. Statistical analyses were performed using SPSS/Windows software (SPSS Science, v. 15.0, Chicago, IL). The mode of multivariate analysis showed that diabetes (β = 3.594; P = 0.040), hepatitis C infection (β = 4.057; P = 0.008), levels of serum albumin (β = -5.656; P = 0.024), C-peptide (β = -0.292; P = 0.002), ABI (β = -9.041; P = 0.031), and Ln-transformed hsCRP were significantly associated with BDI. Hepatitis C infection, serum levels of albumin, C-peptide, and ABI levels were found to be correlated with BDI (P < 0.05).


Association between body composition and the risk of mortality in the obese population in the United States.
Recent studies have presented the concept of the obesity paradox, suggesting that individuals with obesity have a lower risk of death than those without obesity. This paradox may arise because body mass index (BMI) alone is insufficient to understand body composition accurately. This study investigated the relationship between fat and muscle mass and the risk of mortality in individuals with overweight/obesity. We used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2006 and 2011 to 2018, which were linked to mortality information obtained from the National Death Index. Multiple Cox regression analyses were performed to estimate mortality risk. Subgroup analysis was conducted using propensity score-matched (PSM) data for age, sex, and race/ethnicity. This study included 16,555 participants who were overweight/obese (BMI≥25 kg/m2). An increase in appendicular skeletal muscle mass index was associated with a lower mortality risk (hazard ratio [HR]: 0.856; 95% confidence interval [CI]: 0.802-0.915). This finding was consistent with the subgroup analysis of the PSM data. Contrastingly, a high fat mass index was associated with an increased risk of mortality. Sarcopenic overweight/obesity was significantly associated with high mortality compared to obesity without sarcopenia (HR: 1.612, 95%CI: 1.328-1.957). This elevated risk was significant in both age- and sex-based subgroups. This finding was consistent with the subgroup analysis using PSM data. In contrast to the obesity paradox, a simple increase in BMI does not protect against mortality. Instead, low body fat and high muscle mass reduce mortality risk.


Liver metastases from breast cancer: long-term survival after curative resection.
Liver metastases from breast cancer are associated with a poor prognosis (median survival < 6 months). A subgroup of these patients with no dissemination in other organs may benefit from surgery. Available data in the literature suggest that only in exceptional cases do these patients survive more than 2 years when given chemohormonal therapy or supportive care alone. We report the results of liver resection in patients with isolated hepatic metastases from breast cancer and evaluate the rate of long-term survival, prognostic factors, and the role of neoadjuvant high-dose chemotherapy. Over the past decade, 17 women underwent hepatic metastectomy with curative intent for metastatic breast cancer. The follow-up was complete in each patient. The median age at the time breast cancer was diagnosed was 48 years. Neoadjuvant high-dose chemotherapy (HDC) with hematopoietic progenitor support was used in 10 patients before liver resection. Perioperative complications, long-term outcome, and prognostic factors were evaluated. Seven of the 17 patients are currently alive, with follow-up of up to 12 years. Four of these patients are free of tumors after 6 and 17 months and 6 and 12 years. The actuarial 5-year survival rate is 22%. One patient died postoperatively (mortality rate, 6%) of carmustine-induced fibrosing pneumonitis. There was no further major morbidity in the other patients. The liver was the primary site of recurrent disease after liver resection in 67% of the patients. Patients in whom liver metastases were found more than 1 year after resection of the primary breast cancer had a significantly better outcome than those with early (< 1 year) metastatic disease (P = .04). The type of liver resection, the lymph node status at the time of the primary breast cancer resection, and HDC had no significant impact on patient survival in this series. Favorable 22% long-term survival can be achieved with metastasectomy in this selected group of patients. Careful evaluation of pulmonary toxicity from carmustine and exclusion of patients with extrahepatic disease are critical. Improved survival might be achieved with better selection of patients and the use of liver-directed adjuvant therapy.


Identification of tyrosine 189 and asparagine 358 of the cholecystokinin 2 receptor in direct interaction with the crucial C-terminal amide of cholecystokinin by molecular modeling, site-directed mutagenesis, and structure/affinity studies.
The cholecystokinin (CCK) receptors CCK1R and CCK2R exert important central and peripheral functions by binding the neuropeptide cholecystokinin. Because these receptors are potential therapeutic targets, great interest has been devoted to the identification of efficient ligands that selectively activate or inhibit these receptors. A complete mapping of the CCK binding site in these receptors would help to design new CCK ligands and to optimize their properties. In this view, a molecular model of the CCK2R occupied by CCK was built to identify CCK2R residues that interact with CCK functional groups. No such study has yet been reported for the CCK2R. Docking of CCK in the receptor was performed by taking into account our previous mutagenesis data and by using, as constraint, the direct interaction that we demonstrated between His207 in the CCK2R and Asp8 of CCK (Mol Pharmacol 54:364-371, 1998; J Biol Chem 274:23191-23197, 1999). Two residues that had not been revealed in our previous mutagenesis studies, Tyr189 (Y4.60) and Asn358 (N6.55), were identified in interaction via hydrogen bonds with the C-terminal amide of CCK, a crucial functional group of the peptide. Mutagenesis of Tyr189 (Y4.60) and Asn358 (N6.55) as well as structure-affinity studies with modified CCK analogs validated these interactions and the involvement of both residues in the CCK binding site. These results indicate that the present molecular model is an important tool to identify direct contact points between CCK and the CCK2R and to rapidly progress in mapping of the CCK2R binding site. Moreover, comparison of the present CCK2R.CCK molecular model with that of CCK1R.CCK, which we have previously published and validated, clearly argues that the positioning of CCK in these receptors is different.


Synthesis of nanoparticles, their biocompatibility, and toxicity behavior for biomedical applications.
Nanomaterials research has in part been focused on their use in biomedical applications for more than several decades. However, in recent years this field has been developing to a much more advanced stage by carefully controlling the size, shape, and surface-modification of nanoparticles. This review provides an overview of two classes of nanoparticles, namely iron oxide and NaLnF4, and synthesis methods, characterization techniques, study of biocompatibility, toxicity behavior, and applications of iron oxide nanoparticles and NaLnF4 nanoparticles as contrast agents in magnetic resonance imaging. Their optical properties will only briefly be mentioned. Iron oxide nanoparticles show a saturation of magnetization at low field, therefore, the focus will be MLnF4 (Ln = Dy3+, Ho3+, and Gd3+) paramagnetic nanoparticles as alternative contrast agents which can sustain their magnetization at high field. The reason is that more potent contrast agents are needed at magnetic fields higher than 7 T, where most animal MRI is being done these days. Furthermore we observe that the extent of cytotoxicity is not fully understood at present, in part because it is dependent on the size, capping materials, dose of nanoparticles, and surface chemistry, and thus needs optimization of the multidimensional phenomenon. Therefore, it needs further careful investigation before being used in clinical applications.


Paediatric traumatic brain injury: prognostic insights and outlooks.
Traumatic brain injury (TBI) is a leading cause of death and disability in children. Prognostication of outcome following TBI is challenging in this population and likely requires complex, multimodal models to achieve clinically relevant accuracy. This review highlights injury characteristics, physiological indicators, biomarkers and neuromonitoring modalities predictive of outcome that may be integrated for future development of sensitive and specific prognostic models. Paediatric TBI is responsible for physical, psychosocial and neurocognitive deficits that may significantly impact quality of life. Outcome prognostication can be difficult in the immature brain, but is aided by the identification of novel biomarkers (neuronal, astroglial, myelin, inflammatory, apoptotic and autophagic) and neuromonitoring techniques (electroencephalogram and MRI). Investigation in the future may focus on assessing the prognostic ability of combinations of biochemical, protein, neuroimaging and functional biomarkers and the use of mathematical models to develop multivariable predication tools to improve the prognostic ability following childhood TBI. Prognostication of outcome following paediatric TBI is multidimensional, influenced by injury severity, age, physiological factors, biomarkers, electroencephalogram and neuroimaging. Further development, integration and validation of combinatorial prognostic algorithms are necessary to improve the accuracy and timeliness of prognosis in a meaningful fashion.


Neurons in the vagal complex of the rat respond to mechanical and chemical stimulation of the GI tract.
Perfusing the duodenum with acid solutions dramatically reduces gastric motility and acid secretion. We propose that the presence of acid in the proximal small intestine initiates a vagovagal reflex that excites inhibitory neurons in the nucleus of the solitary tract (NST) and reduces the activity of the neurons in the dorsal motor nucleus of the vagus nerve (DMNV). However, results from several investigations suggest that the relevant circuit may not be as simple as we had believed. The present study was designed to address this dilemma by employing intracellular and extracellular recording and intracellular labeling techniques to provide direct information on the activity of neurons in the NST and DMNV during and after intestinal exposure to acid solutions. The results obtained prove that NST and DMNV neurons respond to HCl in the duodenum. In some instances, these neurons were very stimulus specific, although the majority of the cells in our sample (47% of NST neurons and 86% of DMNV neurons) also responded to distension of the stomach and/or duodenum. It is important to note, however, that many of the more broadly responsive neurons in the dorsal vagal complex were able to distinguish between mechanical and chemical stimulation of the gastrointestinal (GI) tract. Most of the NST neurons that responded to duodenal perfusion with HCl were excited by this stimulus. Conversely, activity of most of the DMNV neurons decreased after the onset of the HCl stimulus. These findings verify the existence of a vagovagal reflex pathway initiated by duodenal perfusion with acid. Presumably, this reflex would decrease gastric motility and acid secretion, reducing the amount of acid that enters the duodenum and ultimately protecting the intestinal mucosa.


Low-order non-spatial effects dominate second-order spatial effects in the texture quantifier analysis of 18F-FDG-PET images.
There is increasing interest in applying image texture quantifiers to assess the intra-tumor heterogeneity observed in FDG-PET images of various cancers. Use of these quantifiers as prognostic indicators of disease outcome and/or treatment response has yielded inconsistent results. We study the general applicability of some well-established texture quantifiers to the image data unique to FDG-PET. We first created computer-simulated test images with statistical properties consistent with clinical image data for cancers of the uterine cervix. We specifically isolated second-order statistical effects from low-order effects and analyzed the resulting variation in common texture quantifiers in response to contrived image variations. We then analyzed the quantifiers computed for FIGOIIb cervical cancers via receiver operating characteristic (ROC) curves and via contingency table analysis of detrended quantifier values. We found that image texture quantifiers depend strongly on low-effects such as tumor volume and SUV distribution. When low-order effects are controlled, the image texture quantifiers tested were not able to discern only the second-order effects. Furthermore, the results of clinical tumor heterogeneity studies might be tunable via choice of patient population analyzed. Some image texture quantifiers are strongly affected by factors distinct from the second-order effects researchers ostensibly seek to assess via those quantifiers.


Interrogating biomineralization one amino acid at a time: amplification of mutational effects in protein-aided titania morphogenesis through reaction-diffusion control.
To emulate the control that biomineralizing organisms exert over reactant transport, we construct a countercurrent reaction-diffusion chamber in which an agarose hydrogel regulates the fluxes of inorganic precursor and precipitating solid-binding protein. We show that the morphology of the bioprecipitated titania can be changed from monolithic to interconnected particle networks and dispersed nanoparticles either by decreasing reaction time or by increasing agarose weight percentage at constant precursor and protein concentrations. More strikingly, protein variants with one or two substitutions in their metal oxide-binding domain yield unique peripheral morphologies (needles, threads, plates, and peapods) with distinct crystallography and photocatalytic activity. Our results suggest that diffusional control can magnify otherwise subtle mutational effects in biomineralizing proteins and provide a path for the green synthesis of morphologically and functionally diverse inorganic materials.


Identification of Seizure Onset Zone from Intracranial EEG Using Source Selection-Based Domain Adaptation.
For focal epilepsy patients, correctly identifying the seizure onset zone (SOZ) is essential for surgical treatment. In automated realistic SOZ identification, it is necessary to identify the SOZ of an unknown patient using another patient's electroencephalogram (EEG). However, in such cases, the influence of individual differences in EEG becomes a bottleneck. In this paper, we propose the method with domain adaptation and source patient selection to address the issue of individual differences in EEG and improve performance. The proposed method was evaluated on intracranial EEG data from 11 patients with epilepsy caused by focal cortical dysplasia. The results showed that the proposed method significantly improved SOZ identification performance compared to existing methods without domain adaptation and source patient selection. In addition, it was suggested that data from residual-seizure patients may have adversely affected estimation performance. Visualization of the prediction on MRI images showed that the proposed method might detect SOZs missed by epileptologists.


Loss of normal G1 checkpoint control is an early step in carcinogenesis, independent of p53 status.
Recent studies have described a diminished radiation-induced G1 arrest in some wild-type (wt) p53 human tumor cell lines compared to normal human fibroblasts. However, the significance of this finding was unclear, particularly because tumor cell lines may have accumulated additional genetic changes after long periods in culture. Because malignant transformation of individual cells is thought to be an early step in carcinogenesis, we have used a model system of normal and transformed mouse fibroblast 10T1/2 cell clones to examine whether loss of G1 checkpoint control may be an early event in tumor development and to study the relationships between G1 arrest, radiosensitivity, and genetic alterations. Twelve transformed clones were established from type III foci induced by irradiation of normal 10T1/2 cells and were compared with six clones derived from wt 10T1/2 cells. Three of the transformed clones expressed mutant p53; two of these had the same point mutation at codon 132 (exon 5), and one had a point mutation at codon 135. The remaining transformed and normal clones had wt p53 status. The radiosensitivity of transformed clones, as measured by a clonogenic assay, was similar to that of normal clones; the three clones with mutant p53 did not differ from the others. There was no relationship between G1 arrest and radiosensitivity. Normal 10T1/2 cell clones showed a transient G1 arrest lasting approximately 9 h after 6 Gy of irradiation. This G1 arrest was either absent or markedly reduced in all of the transformed clones, regardless of p53 status. These results suggest that diminished G1 checkpoint control is an early event in the process of carcinogenesis that is associated with the malignant transformation of individual cells and is independent of p53 status.


Bioorthogonal chemical imaging of metabolic changes during epithelial-mesenchymal transition of cancer cells by stimulated Raman scattering microscopy.
Study of metabolic changes during epithelial-mesenchymal transition (EMT) of cancer cells is important for basic understanding and therapeutic management of cancer progression. We here used metabolic labeling and stimulated Raman scattering (SRS) microscopy, a strategy of bioorthogonal chemical imaging, to directly visualize changes in anabolic metabolism during cancer EMT at a single-cell level. MCF-7 breast cancer cell is employed as a model system. Four types of metabolites (amino acids, glucose, fatty acids, and choline) are labeled with either deuterium or alkyne (C≡C) tag. Their intracellular incorporations into MCF-7 cells before or after EMT are visualized by SRS imaging targeted at the signature vibration frequency of C-D or C≡C bonds. Overall, after EMT, anabolism of amino acids, glucose, and choline is less active, reflecting slower protein and membrane synthesis in mesenchymal cells. Interestingly, we also observed less incorporation of glucose and palmitate acids into membrane lipids, but more of them into lipid droplets in mesenchymal cells. This result indicates that, although mesenchymal cells synthesize fewer membrane lipids, they are actively storing energy into lipid droplets, either through de novo lipogenesis from glucose or direct scavenging of exogenous free fatty acids. Hence, metabolic labeling coupled with SRS can be a straightforward method in imaging cancer metabolism.


Sitagliptin therapy improves myocardial perfusion and arteriolar collateralization in chronically ischemic myocardium: A pilot study.
Dipeptidyl peptidase 4 inhibitors (DPP4i) may be cardioprotective based on several small animal and clinical studies, though randomized control trials have demonstrated limited benefit. Given these discrepant findings, the role of these agents in chronic myocardial disease, particularly in the absence of diabetes, is still poorly understood. The purpose of this study was to determine the effects of sitagliptin, a DPP4i, on myocardial perfusion and microvessel density in a clinically relevant large animal model of chronic myocardial ischemia. Normoglycemic Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (CON, n = 8) or 100 mg oral sitagliptin (SIT) daily (n = 5). Treatment continued for 5 weeks, followed by hemodynamic measurements, euthanasia, and tissue harvest of ischemic myocardium. There were no significant differences in myocardial function between CON and SIT as measured by stroke work (p > 0.5), cardiac output (p = 0.22), and end-systolic elastance (p = 0.17). SIT was associated with increased absolute blood flow at rest (17% increase, IQR 12-62, p = 0.045) and during pacing (89% increase, IQR 83-105, p = 0.002). SIT was also associated with improved arteriolar density (p = 0.045) compared with CON, without changes in capillary density (p = 0.72). SIT was associated with increased expression of pro-arteriogenic markers MCP-1 (p = 0.003), TGFß (p = 0.03), FGFR1 (p = 0.002), and ICAM-1 (p = 0.03), with a trend toward an increase in the ratio of phosphorylated/active PLCγ1 to total PLCγ1 (p = 0.11) compared with CON. In conclusion, in chronically ischemic myocardium, sitagliptin improves myocardial perfusion and arteriolar collateralization via the activation of pro-arteriogenic signaling pathways.