Carbon Nanotubes in Biology and Medicine: In vitro and in vivo Detection, Imaging and Drug Delivery.
Carbon nanotubes exhibit many unique intrinsic physical and chemical properties and have been intensively explored for biological and biomedical applications in the past few years. In this comprehensive review, we summarize the main results from our and other groups in this field and clarify that surface functionalization is critical to the behavior of carbon nanotubes in biological systems. Ultrasensitive detection of biological species with carbon nanotubes can be realized after surface passivation to inhibit the non-specific binding of biomolecules on the hydrophobic nanotube surface. Electrical nanosensors based on nanotubes provide a label-free approach to biological detection. Surface-enhanced Raman spectroscopy of carbon nanotubes opens up a method of protein microarray with detection sensitivity down to 1 fmol/L. In vitro and in vivo toxicity studies reveal that highly water soluble and serum stable nanotubes are biocompatible, nontoxic, and potentially useful for biomedical applications. In vivo biodistributions vary with the functionalization and possibly also size of nanotubes, with a tendency to accumulate in the reticuloendothelial system (RES), including the liver and spleen, after intravenous administration. If well functionalized, nanotubes may be excreted mainly through the biliary pathway in feces. Carbon nanotube-based drug delivery has shown promise in various In vitro and in vivo experiments including delivery of small interfering RNA (siRNA), paclitaxel and doxorubicin. Moreover, single-walled carbon nanotubes with various interesting intrinsic optical properties have been used as novel photoluminescence, Raman, and photoacoustic contrast agents for imaging of cells and animals. Further multidisciplinary explorations in this field may bring new opportunities in the realm of biomedicine.


β-Catenin activated hepatocellular adenoma: a report of three cases in Korea.
Hepatocellular adenoma (HCA) is an uncommon benign hepatic tumor, and the use of oral contraceptives is known to contribute to the development of HCA. Recently, a genotype and phenotype classification system for HCA was suggested, and malignant transformation to hepatocellular carcinoma (HCC) was shown to be strongly associated with activating mutations in β-catenin. Here, we report three cases of HCA in Korean patients: 7-cm, inflammatory and β-catenin-activated HCA with HCC transformation in a 46-year-old man; 13-cm, β-catenin-activated HCA with cytological atypia in a 23-year-old woman; and 10-cm, pigmented, inflammatory and β-catenin-activated HCA in a 36-year-old man. All cases exhibited the nuclear expression of β-catenin and diffuse cytoplasmic expression of glutamine synthetase upon immunohistochemical staining. All tumors were completely resected, and the patients were followed for 3 to 6 years with no evidence of local recurrence or metastasis.


Dissimilarity in Sulcal Width Patterns in the Cortex can be Used to Identify Patients With Schizophrenia With Extreme Deficits in Cognitive Performance.
Schizophrenia is a biologically complex disorder with multiple regional deficits in cortical brain morphology. In addition, interindividual heterogeneity of cortical morphological metrics is larger in patients with schizophrenia when compared to healthy controls. Exploiting interindividual differences in the severity of cortical morphological deficits in patients instead of focusing on group averages may aid in detecting biologically informed homogeneous subgroups. The person-based similarity index (PBSI) of brain morphology indexes an individual's morphometric similarity across numerous cortical regions amongst a sample of healthy subjects. We extended the PBSI such that it indexes the morphometric similarity of an independent individual (eg, a patient) with respect to healthy control subjects. By employing a normative modeling approach on longitudinal data, we determined an individual's degree of morphometric dissimilarity to the norm. We calculated the PBSI for sulcal width (PBSI-SW) in patients with schizophrenia and healthy control subjects (164 patients and 164 healthy controls; 656 magnetic resonance imaging scans) and associated it with cognitive performance and cortical sulcation index. A subgroup of patients with markedly deviant PBSI-SW showed extreme deficits in cognitive performance and cortical sulcation. Progressive reduction of PBSI-SW in the schizophrenia group relative to healthy controls was driven by these deviating individuals. By explicitly leveraging interindividual differences in the severity of PBSI-SW deficits, neuroimaging-driven subgrouping of patients is feasible. As such, our results pave the way for future applications of morphometric similarity indices for subtyping of clinical populations.


A Long-Lived Phosphorescence Amplification System Integrated with Graphene Oxide and a Stable Split G-Quadruplex Protector as an Isothermal "Off-On" Biosensor for the HBV Gene.
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). Chronic HBV infection is a major global health issue, causing an estimated 750,000 of deaths annually. Despite intense interest of biomedical and clinical researchers, the lack of an accurate, selective, and simple diagnostic approach for the early stage of the disease remains a major challenge. In this work, we developed a strand displacement amplification (SDA)-assisted G-quadruplex (GQ)-graphene oxide (GO) system for the accurate quantification of the HBV gene. Iridium (III) complex 2a, a red-emitting luminophore with a large Stokes shift and long-lived phosphorescence, was identified as the most effective probe for the split GQ-GO system among the eight selected complexes in the systematic optimization campaign. The length of nucleic acid bases in between the critical positions of the split GQ hybridization was also optimized using circular dichroism (CD) and phosphorescence experiments. Important rules on the proximity and flexibility of the stable split GQ-GO system were developed for the first time. This approach was selective for the wild HBV gene over the interfering anions, cations, proteins, and the mutated HBV genes differing by only one nucleotide base. Compared to the simple GQ-GO system, the SDA-assisted GQ-GO system produced a 211% higher phosphorescence restoration signal. The ability of the SDA-assisted GQ-GO system to detect the HBV gene in human serum and sheep red blood cells demonstrates the feasibility of using this system in practical applications.


KCOT Occurring in Bilateral Maxillary Sinus in Non-Syndromic Patient.
Odontogenic Keratocyst (OKC) also termed as Keratocystic Odontogenic Tumour (KCOT) (WHO 2005) is a pathology with unique behavior because of which it is under much scrutiny and continued study. The pathology usually presents itself commonly in mandible and less commonly in maxilla. The occurrence of KCOT in maxillary sinus is reported as rare and multiple occurrences are mostly associated along with the presence of Nevoid Basal Cell Carcinoma (NBCC) syndrome. Here, we present a rare case of bilateral Maxillary OKC involving maxillary sinuses, without the presence of NBCC syndrome. An interesting feature of this case is the presence of left upper third molar in ectopic position in maxillary sinus and a vertically impacted right third molar suggesting an origin from the dental lamina.


FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors.
The purpose of this work--the first of its kind--was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand (18)F-fluorodeoxyglucose and positron emission tomography ((18)FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1, 2 and 3, respectively. One day after the seventh treatment with Cpd-60 (22.5 mg/kg) or CI-994 (5 mg/kg), (18)FDG-PET experiments (n=11-12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2-17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that (18)FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response.


Spread tools: a systematic review of components, uptake, and effectiveness of quality improvement toolkits.
The objective was to conduct a systematic review of toolkit evaluations intended to spread interventions to improve healthcare quality. We aimed to determine the components, uptake, and effectiveness of publicly available toolkits. We searched PubMed, CINAHL, and the Web of Science from 2005 to May 2018 for evaluations of publicly available toolkits, used a forward search of known toolkits, screened references, and contacted topic experts. Two independent reviewers screened publications for inclusion. One reviewer abstracted data and appraised the studies, checked by a second reviewer; reviewers resolved disagreements through discussion. Findings, summarized in comprehensive evidence tables and narrative synthesis addressed the uptake and utility, procedural and organizational outcomes, provider outcomes, and patient outcomes. In total, 77 studies evaluating 72 toolkits met inclusion criteria. Toolkits addressed a variety of quality improvement approaches and focused on clinical topics such as weight management, fall prevention, vaccination, hospital-acquired infections, pain management, and patient safety. Most toolkits included introductory and implementation material (e.g., research summaries) and healthcare provider tools (e.g., care plans), and two-thirds included material for patients (e.g., information leaflets). Pre-post studies were most common (55%); 10% were single hospital evaluations and the number of participating staff ranged from 17 to 704. Uptake data were limited and toolkit uptake was highly variable. Studies generally indicated high satisfaction with toolkits, but the perceived usefulness of individual tools varied. Across studies, 57% reported on adherence to clinical procedures and toolkit effects were positive. Provider data were reported in 40% of studies but were primarily self-reported changes. Only 29% reported patient data and, overall, results from robust study designs are missing from the evidence base. The review documents publicly available toolkits and their components. Available uptake data are limited but indicate variability. High satisfaction with toolkits can be achieved but the usefulness of individual tools may vary. The existing evidence base on the effectiveness of toolkits remains limited. While emerging evidence indicates positive effects on clinical processes, more research on toolkit value and what affects it is needed, including linking toolkits to objective provider behavior measures and patient outcomes. PROSPERO registration number: PROSPERO 2014: CRD42014013930 .


Effect of wall stretch on coronary hemodynamics in isolated canine interventricular septum.
The effects of stretch on coronary pressure-flow relations are not well understood. To examine the role of wall stretch per se on coronary hemodynamics, we studied arterially perfused isolated canine interventricular septa in a noncontracting state with vasodilated vessels. We compared the hemodynamic parameters of zero-flow pressure and resistance during passive stretching in the circumferential and the base-to-apex directions alone as well as during simultaneous biaxial stretching in both directions. Even in the unloaded state the zero-flow pressure was positive. Any type of stretching significantly increased the zero-flow pressure and the resistance from their unloaded values. The pressure-flow responses also showed directional dependence. When stretches with matched strains or stresses in each direction were applied sequentially, the resistance increases corresponded to the direction of higher stress. Conversely, the zero-flow pressure response increase corresponded to the direction of greater strain. However, neither response correlated with a measure of global tissue stiffness. Thus there is a complex and tight mechanical interaction between the vessels and the surrounding tissue. These interactions, but not the tissue stiffness, are important determinants of coronary pressure-flow responses during stretch.


Interprofessional simulation training improves knowledge and teamwork in nursing and medical students during internal medicine clerkship.
Simulation is effective at improving healthcare students' knowledge and communication. Despite increasingly interprofessional approaches to medicine, most studies demonstrate these effects in isolation. We enhanced an existing internal medicine curriculum with immersive interprofessional simulations. For ten months, third-year medical students and senior nursing students were recruited for four, 1-hour simulations. Scenarios included myocardial infarction, pancreatitis/hyperkalemia, upper gastrointestinal bleed, and chronic obstructive pulmonary disease exacerbation. After each scenario, experts in medicine, nursing, simulation, and adult learning facilitated a debriefing. Study measures included pre- and post-tests assessing self-efficacy, communication skills, and understanding of each profession's role. Seventy-two medical students and 30 nursing students participated. Self-efficacy communication scores improved for both (medicine, 18.9 ± 3.3 pretest vs 23.7 ± 3.7 post-test; nursing, 19.6 ± 2.7 pretest vs 24.5 ± 2.5 post-test). Both groups showed improvement in "confidence to correct another healthcare provider in a collaborative manner" (Δ = .97 medicine, Δ = 1.2 nursing). Medical students showed the most improvement in "confidence to close the loop in patient care" (Δ = .93). Nursing students showed the most improvement in "confidence to figure out roles" (Δ = 1.1). This study supports the hypothesis that interdisciplinary simulation improves each discipline's self-efficacy communication skills and understanding of each profession's role. Despite many barriers to interprofessional simulation, this model is being sustained.


Single adjuster deformable mirror with four contact points for simultaneous correction of astigmatism and defocus.
We show that a deformable mirror with four point actuators is suitable for the simultaneous correction of astigmatism and defocus in a given optical system by adequately choosing the relative position of the actuators. An analytical model is developed that describes adequately the mirror deformation as a function of actuator position, showing that it is possible to continuously tune the weight of each aberration. Experimental measurements with a single adjuster deformable mirror assembly confirm the validity of the model.


Microglia Polarization and Antiglioma Effects Fostered by Dual Cell Membrane-Coated Doxorubicin-Loaded Hexagonal Boron Nitride Nanoflakes.
Microglial cells play a critical role in glioblastoma multiforme (GBM) progression, which is considered a highly malignant brain cancer. The activation of microglia can either promote or inhibit GBM growth depending on the stage of the tumor development and on the microenvironment conditions. The current treatments for GBM have limited efficacy; therefore, there is an urgent need to develop novel and efficient strategies for drug delivery and targeting: in this context, a promising strategy consists of using nanoplatforms. This study investigates the microglial response and the therapeutic efficacy of dual-cell membrane-coated and doxorubicin-loaded hexagonal boron nitride nanoflakes tested on human microglia and GBM cells. Obtained results show promising therapeutic effects on glioma cells and an M2 microglia polarization, which refers to a specific phenotype or activation state that is associated with anti-inflammatory and tissue repair functions, highlighted through proteomic analysis.


Effects of oral administration of acidogenic boluses at dry-off on performance and behavior of dairy cattle.
The aim of this study was to evaluate the potential of oral acidogenic mineral boluses (196 g) containing anionic salts to facilitate the transition from lactation to the dry stage by inducing a mild and temporary metabolic acidosis at dry-off. In experiment 1, 84 lactating cows were randomly allocated to 1 of 3 treatment groups consisting of an oral administration of 0, 1, or 2 boluses 5 d before dry-off to evaluate the effects on milk production. In experiment 2, 16 lactating cows were involved in a crossover study to evaluate the effects of the administration of 2 boluses on milk production, feed intake, and urine pH. In experiment 3, 152 lactating cows were allocated to 1 of 2 treatments (control: no treatment; bolus: 2 oral boluses the day before last milking) to evaluate udder pressure, incidence of milk leakage, and lying behavior during the first days following dry-off. Also, milk yield in the subsequent lactation for all enrolled cows was recorded during the first 60 DIM. In experiment 1, cows receiving 2 boluses had the greatest reduction in milk production (-2.56 kg/d of milk) compared with those receiving 1 bolus or no treatment (-1.15 and -0.23 kg/d, respectively) the second day after bolus application. In experiment 2, the application of oral boluses decreased feed intake of cows during the first 3 d following treatment, and milk production was reduced on d 2 and 3 after bolus application. Reduced urine pH at 8 and 24 h after treatment was observed in bolus cows compared with control cows. In experiment 3, bolus cows had lower udder pressure after drying off, but incidence of milk leakage did not differ between treatments. Bolus cows had an additional 85 min of lying time in the 24 h following dry-off. Serum P and β-OH-butyrate concentrations were lower in bolus cows than in control cows after dry-off, but no other differences in blood parameters between treatments were observed. Also, no differences in milk yield in the subsequent lactation were observed between treatments. It is concluded that oral bolus application diminishes feed intake and milk production, and, if applied at dry-off, it decreases udder pressure and increases lying time during the first 24 h after dry-off.


Predictors of Blood Transfusion for Endoscopic Assisted Craniosynostosis Surgery.
Blood loss is a main cause of morbidity after craniofacial procedures. The purpose of this study is to identify the incidence and predictors for transfusion of blood products in the endoscopic assisted strip craniectomy population. Data was prospectively collected from a single-center multi-surgeon cohort of 78 consecutive patients who underwent endoscopic assisted strip craniectomy for craniosynostosis between July 2013 and December 2020. The authors reviewed patient and treatment characteristics and outcomes. Of the 78 patients, 26 patients were transfused yielding an overall rate of transfusion of 33%. The most common fused suture was sagittal (n = 42, 54%) followed by metopic (n = 15, 19%), multiple (n = 10, 13%), coronal (n = 7, 9%) and finally lambdoid (n = 4, 5%). On univariate analysis, patients' weight in the transfusion cohort were significantly lower than those who did not receive a transfusion (5.6 ± 1.1 versus 6.5 ± 1.1 kg, P = 0.0008). The transfusion group also had significantly lower preoperative hemoglobin compared to the non-transfusion group (10.6 versus 11.1, P = .049). Eleven percent patients admitted to step-down received a transfusion, whereas 39% of patients admitted to the pediatric intensive care unit received a transfusion ( P = 0.042). On multivariate analysis, only higher patient weight (operating room [OR] 0.305 [0.134, 0.693], P = 0.005) was protective against a transfusion, whereas colloid volume (OR 1.018 [1.003, 1.033], P = 0.019) predicted the need for a transfusion.Our results demonstrate that endoscopic craniosynostosis cases carry a moderate risk of transfusion. individuals with lower weight and those that receive colloid volume are also at elevated risk.


Critical evaluation of different objective techniques of nasal airway assessment: a clinical review.
Objective tests for the nasal volume flow are needed for the assessment of nasal patency for diagnosis, documentation and medicolegal purposes. Three main techniques are nowadays established: active anterior rhinomanometry (AAR), 4-phase rhinomanometry (4PR) and acoustic rhinometry (AR). Several guidelines and consensus reports and the International Committee on Standardization have clarified the field of interest and the limitations of this technology. In the meantime, technical progress and the development of seemingly new methods have brought up many new facts which necessitate the re-evaluation of the test available. From our method of critical analysis we can conclude that AAR can be still considered as the standard technique for the objective assessment of the nasal airway. AR is a valid technique with limitations and cannot replace AAR because it measures different parameters thus forming a complementary technique. 4PR might provide supplementary information although not yet all open technical and mathematical inconsistencies conjoint with this technique have been clarified. Still the individual subjective sensations of the patient do not always match the objective measurements. In conclusion, a combination of information given by the patient, the rhinoscopic findings and the carefully interpreted results of AAR and AR will increase considerably the success of surgical interventions and the feeling of satisfaction by the patient after surgery, when matched thoughtfully.


Decoding pathogenesis factors involved in the progression of ATLL or HAM/TSP after infection by HTLV-1 through a systems virology study.
Human T-cell Leukemia Virus type-1 (HTLV-1) is a retrovirus that causes two diseases including Adult T-cell Leukemia/Lymphoma (ATLL cancer) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP, a neurodegenerative disease) after a long latency period as an asymptomatic carrier (AC). There are no obvious explanations about how each of the mentioned diseases develops in the AC carriers. Finding the discriminative molecular factors and pathways may clarify the destiny of the infection. To shed light on the involved molecular players and activated pathways in each state, differentially co-expressed modules (DiffCoEx) algorithm was employed to identify the highly correlated genes which were co-expressed differently between normal and ACs, ACs and ATLL, as well as ACs and HAM/TSP samples. Through differential pathway analysis, the dysregulated pathways and the specific disease-genes-pathways were figured out. Moreover, the common genes between the member of DiffCoEx and differentially expressed genes were found and the specific genes in ATLL and HAM/TSP were introduced as possible biomarkers. The dysregulated genes in the ATLL were mostly enriched in immune and cancer-related pathways while the ones in the HAM/TSP were enriched in immune, inflammation, and neurological pathways. The differential pathway analysis clarified the differences between the gene players in the common activated pathways. Eventually, the final analysis revealed the involvement of specific dysregulated genes including KIRREL2, RAB36, and KANK1 in HAM/TSP as well as LTB4R2, HCN4, FZD9, GRIK5, CREB3L4, TACR2, FRMD1, LHB, FGF3, TEAD3, GRIN2D, GNRH2, PRLH, GPR156, and CRHR2 in ATLL. The identified potential prognostic biomarkers and therapeutic targets are proposed as the most important platers in developing ATLL or HAM/TSP. Moreover, the proposed signaling network clarifies the differences between the functional players in the activated pathways in ACs, ATLL, and HAM/TSP.


Hypopituitarism with arachnoid cyst.
Arachnoid cysts, most characteristically situated in the middle cranial fossa, have been described at other situations, in the posterior fossa and in the interpeduncular region. A case of primary amenorrhoea, obesity, with short stature, proved to be associated with a huge arachnoid cyst involving the L. middle and anterior cranial fossae; and pituitary fossa, producing panhypopituitarism with right faciobrachial paresis, normal visual fields and visual acuity. No evidence of progress of the lesion has been found after 3 years of observation, and further conservative management with regular CT scanning and oestrogen replacements is proposed.


Community Power Structure Analysis and the Ethical Considerations of "Studying Up".
This narrative outlines our challenges in studying power and power structures within an individual-level ethical framework. Taking a social ethics perspective, we share the story of our "sticky situation" (Campbell, ) that transpired during a multi-year community partnership. We were asked, by our community partners, to help collect interview data without informed consent. As a team of community-engaged university researchers, we were faced with a seemingly easy ethical situation (no consent, no research) that had unexpectedly complicated and long-lasting consequences. This experience revealed to us how community-engaged research and action, under a traditional ethics framework, can often work to protect those in positions of power and offer little to disrupt the status quo. Reflecting on the tension between individual and social ethics, we discuss the limitations of an individual-level framework, including the definitions for respect for persons, justice, and beneficence, on our ability as a field to understand, critique, and contribute to the dismantling of oppressive power structures.


[Hepatic abscess and bacteremia due to Lactobacillus rhamnosus].
The incidence of severe infections caused by Lactobacillus spp. is very low. This paper reports a case of a liver abscess and bacteremia due to Lactobacillus rhamnosus. The patient is a 73 year-old woman with antecedent of diabetes mellitus. She has undergone surgery and received antimicrobial therapy (ampicillin plus gentamicin). The clinical outcome was favorable.


Left ventricular non-compaction (LVNC) is characterized by hypertrabecularity (thickened non-compact layer) with deep intertrabecular recesses that are continuous with the ventricle cavity, and a thin compact layer. The phenotypes of LVNС are extremely variable: the left or right ventricular variant, biventricular form, LVNC with symptoms of heart failure or arrhythmia, asymptomatic forms or variants with thromboembolic events. In 30-50 % of patients with LVNC genetic mutations of genes encoding sarcomeric or cytoskeletal proteins are revealed by a genetic study. The article presents a literature review on the problems of diagnosis, visualization, pathogenesis, variability of clinical manifestations of LVNC and its genetic heterogeneity. Clinical cases demonstrating LVNC as a concomitant anatomical syndrome due to monogenic Danone disease, as well as the family cardiomyopathy with the digenic inheritance of two phenotypes (LVNC with DCM) and the unique case of peripartum evolution of the acquired LVNC syndrome, all these cases are reflect the current uncertainty regarding to the pathogenesis and significance of LVNC. The main question is whether LVNC is a distinct cardiomyopathy or a morphologic trait and a composite anatomical syndrome of congenital heart disease or other cardiomyopathies (DCM, HCM, ARVC) remains controversial. Achievement of professional consensus guidelines about unification of diagnostic criteria and risk-stratification of LVNC, improvement of visualization tools and expansion of genetic testing will help to significantly expand our knowledge and understanding of the pathogenesis, clinical significance and prognosis of LVNC for optimization of the treatment strategy.


Dehydration kinetics of salmon and trout fillets using ultrasonic vacuum drying as a novel technique.
In this study, a novel ultrasonic vacuum (USV) drying technique was used to shorten the drying time of fish fillets. For this purpose, ultrasonic treatment and vacuum-drying were simultaneously performed to dehydrate salmon and trout fillets at 55°C, 65°C, and 75°C. In addition, the USV technique was compared with vacuum-drying and oven-drying techniques. The dehydration kinetics of the fillets was successfully described by seven thin-layer drying models with R(2) range between 0.944 and 1.000. Depending on drying temperatures and fish species, the drying times could be shortened using the USV technique between 7.4% and 27.4% compared with vacuum-drying. The highest effective moisture diffusivity was determined in the fillets dried with the USV technique and they increased with increasing drying temperatures. Ultrasonic treatment accelerated the vacuum drying process for the fillets; therefore, this technique could be used to improve the efficiency of vacuum-drying for the fillets.


Liquid Biopsy for Colorectal Adenoma: Is the Exosomal miRNA Derived From Organoid a Potential Diagnostic Biomarker?
MicroRNAs (miRNAs) can serve as tumor biomarkers; however, their role in evaluating colorectal adenoma (CRA) is unclear. Recently, the organoid culture system enabled long-term expansion of human colon epithelium. This study aimed to examine the potential of exosomal miRNAs extracted from CRA organoids as biomarkers in the clinical liquid biopsy CRA test. We established organoid cultures from normal colon and CRA using resected specimens. Exosomes were isolated from the conditioned medium organoids. MiRNAs were isolated from the exosomes, and their expression profiles were compared using microarray analysis. To identify miRNA candidates for liquid biopsy, we prospectively compared changes in their expression in serum and exosomes before and after endoscopic resection in 26 patients with CRA. Seven exosomal miRNAs were overexpressed in CRA organoids: miR-4323, miR-4284, miR-1268a, miR-1290, miR-6766-3p, miR-21-5p, and miR-1246. The expression levels of 4 exosomal miRNAs (miR-4323, miR-4284, miR-1290, and miR-1246) and 2 serum miRNAs (miR-1290 and miR-1246) were significantly lower in posttreatment sera. The combined expression of 4 exosomal miRNAs could identify both CRA and large-size (>12.6 cm2) CRA with respective areas under the curve of 0.698 (95% confidence interval [CI] = 0.536-0.823) and 0.834 (95% CI = 0.660-0.929). Combinations of 2-serum miRNA expression values could identify both CRA and large-size CRA with respective area under the curves of 0.691 (95% CI = 0.528-0.817) and 0.834 (95% CI = 0.628-0.938). We found that exosomal miRNAs derived from the CRA organoid culture could be potential diagnostic biomarkers for CRA.


1/f alpha fluctuations in a ricepile model
The temporal fluctuation of the average slope of a ricepile model is investigated. It is found that the power spectrum S(f) scales as 1/f alpha with alpha approximately 1.3 when grains of rice are added only to one end of the pile. If grains are randomly added to the pile, the power spectrum exhibits 1/f2 behavior. The profile fluctuations of the pile under different driving mechanisms are also discussed.


The DNA damage checkpoint pathways exert multiple controls on the efficiency and outcome of the repair of a double-stranded DNA gap.
A DNA gap repair assay was used to determine the effect of mutations in the DNA damage checkpoint system on the efficiency and outcome (crossover/non-crossover) of recombinational DNA repair. In Saccharomyces cerevisiae gap repair is largely achieved by homologous recombination. As a result the plasmid either integrates into the chromosome (indicative of a crossover outcome) or remains extrachromosomal (indicative of a non-crossover outcome). Deletion mutants of the MEC1 and RAD53 checkpoint kinase genes exhibited a 5-fold decrease in gap repair efficiency, showing that 80% of the gap repair events depended on functional DNA damage checkpoints. Epistasis analysis suggests that the DNA damage checkpoints affect gap repair by modulating Rad51 protein-mediated homologous recombination. While in wild-type cells only approximately 25% of the gap repair events were associated with a crossover outcome, Mec1-deficient cells exhibited a >80% crossover association. Also mutations in the effector kinases Rad53, Chk1 and Dun1 were found to affect crossover association of DNA gap repair to various degrees. The data suggest that the DNA damage checkpoints are important for the optimal functioning of recombinational DNA repair with multiple terminal targets to modulate the efficiency and outcome of homologous recombination.


miR-365a-3p regulates ADAM10-JAK-STAT signaling to suppress the growth and metastasis of colorectal cancer cells.
Purpose: MicroRNAs (miRNAs) are key regulators of the growth and development of a wide range of cancer types such as colorectal cancer (CRC). A number of previously studies have observed that the levels of miR-365a-3p expression are dysregulated in many cancers, but the specific role of this miRNA in CRC and its association with patient prognosis remains unclear. Methods: The expression of miR-365a-3p in CRC tissues and cell lines was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between miR-365a-3p expression and clinicopathological characteristics was further analyzed. After increasing the expression of miR-365a-3p by plasmid transfection in CRC cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among miR-365a-3p, ADAM10 and JAK in CRC, was explored by luciferase reporter assay. Results: In the present study, we determined that CRC cells and clinical samples exhibited decreased miR-365a-3p expression, and this was associated with larger tumor size, lymph node metastasis, and local invasion. Patients with lower expression of miR-365a-3p had significantly decreased recurrence-free survival (RFS) and overall survival (OS) relative to those with higher levels of this miRNA. In a multivariate analysis, we confirmed that reduced miR-365a-3p levels were independently predictive of poorer CRC patient outcomes. In a functional study, we determined that elevated miR-365a-3p expression inhibited the ability of CRC cells to proliferate and metastasize in vitro and in vivo. We further identified ADAM10 as a direct miR-365a-3p target, resulting in the suppression of ADAM10 expression in cells expressing this miRNA and ADAM10 levels were in turn closely linked to JAK/STAT signaling. Conclusion: Our study suggested the ability of miR-365a-3p to inhibit the progression of CRC at least in part via suppressing ADAM10 expression and associated JAK/STAT signaling, thus identifying this signaling axis as a possible prognostic and therapeutic target in CRC.


Prolonged Drainage and Intrapericardial Bleomycin Administration for Cardiac Tamponade Secondary to Cancer-Related Pericardial Effusion.
Malignant pericardial effusion (MPE) is a serious complication of several cancers. The most commonly involved solid tumors are lung and breast cancer. MPE can give rise to the clinical picture of cardiac tamponade, a life threatening condition that needs immediate drainage. While simple pericardiocentesis allows resolution of the symptoms, MPE frequently relapses unless further procedures are performed. Prolonged drainage, talcage with antineoplastic agents, or surgical creation of a pleuro-pericardial window are the most commonly suggested ones. They all result in MPE resolution and high rates of long-term control. Patients suitable for further systemic treatments can have a good prognosis irrespective of the pericardial site of disease. We prospectively enrolled patients with cardiac tamponade treated with prolonged drainage associated with Bleomycin administration. Twenty-two consecutive patients with MPE and associated signs of hemodynamical compromise underwent prolonged drainage and subsequent Bleomycin administration. After injection of 100 mg lidocaine hydrochloride, 10 mg Bleomycin was injected into the pericardial space. The catheter was clumped for 48 h and then reopened. Removal was performed when the drainage volume was <25 mL daily. Twelve patients (54%) achieved complete response and 9 (41%) a partial response. Only 1 (5%) had a treatment failure and underwent a successful surgical procedure. Acute toxicity was of a low degree and occurred in 7 patients (32%). It consisted mainly in thoracic pain and supraventricular arrhythmia. The 1-year pericardial effusion progression-free survival rate was 74.0% (95% confidence interval [CI]: 51.0-97.3). At a median follow-up of 75 months, a pericardial progression was detected in 4 patients (18%). One- and two-year overall survival rates were 33.9% (95% CI: 13.6-54.2) and 14.5% (95% CI: 0.0-29.5), respectively, with lung cancer patients having a shorter survival than breast cancer patients. The worst prognosis, however, was shown in patients not suitable for systemic treatments, irrespective of the site of the primary tumor.Prolonged drainage and intrapericardial Bleomycin is a safe and effective treatment, which should be considered as first choice at least in patients suitable for active systemic treatment.


Exemplar longest common subsequence.
In this paper, we investigate the computational and approximation complexity of the Exemplar Longest Common Subsequence of a set of sequences (ELCS problem), a generalization of the Longest Common Subsequence problem, where the input sequences are over the union of two disjoint sets of symbols, a set of mandatory symbols and a set of optional symbols. We show that different versions of the problem are APX-hard even for instances with two sequences. Moreover, we show that the related problem of determining the existence of a feasible solution of the Exemplar Longest Common Subsequence of two sequences is NP-hard. On the positive side, we first present an efficient algorithm for the ELCS problem over instances of two sequences where each mandatory symbol can appear in total at most three times in the sequences. Furthermore, we present two fixed-parameter algorithms for the ELCS problem over instances of two sequences where the parameter is the number of mandatory symbols.


Capecitabine cardiotoxicity--case reports and literature review.
This study presents 3 case reports of patients who experienced anginous pain during treatment with capecitabine. The interruption of capecitabine and sublingual or intravenous nitroglycerine treatment lead to recovery. Rechallenge of capecitabine with dose reduction of 30% lead to repeated anginous pain in 2 patients. Treatment with capecitabine had been replaced with weekly bolus 5FU-LV, without further cardiotoxicity. The literature contains data from about 50 patients who experienced cardiotoxicity during capecitabine treatment. The most frequent manifestations of capecitabine cardiotoxicity included: anginous pain in 38/53 (71.7%), arrhythmia in 6/53 (11.3%), myocardial infarction in 6/53 (11.3%). Cardiotoxicity of capecitabine lead to death in 6/53 (11.3%) patients. Risk factors for cardiotoxicity are associated with the grade 4 and the fatal outcome of cardiotoxicity (p = 0.035, p = 0.015), but not with the symptom recurrence upon capecitabine rechallenge (p = 0.18). The combination chemotherapy regimens are associated with the grade 4 of cardiotoxicity (p = 0.048), but not with the fatal outcome (p = 0.3). Rechallenge of capecitabine lead to symptoms recurrence in 10/16 patients. Neither the dose reduction of capecitabine (p = 0.18) nor the additional medical prophylaxis (p = 0.37) were important for the outcome of capecitabine rechallenge.


Diving behavior of Cuvier's beaked whales inferred from three-dimensional acoustic localization and tracking using a nested array of drifting hydrophone recorders.
Echolocation pulses from Cuvier's beaked whales are used to track the whales' three-dimensional diving behavior in the Catalina Basin, California. In 2016, five 2-element vertical hydrophone arrays were suspended from the surface and drifted at ∼100-m depth. Cuvier's beaked whale pulses were identified, and vertical detection angles were estimated from time-differences-of-arrival of either direct-path signals received on two hydrophones or direct-path and surface-reflected signals received on the same hydrophone. A Bayesian state-space model is developed to track the diving behavior. The model is fit to these detection angle estimates from at least four of the drifting vertical arrays. Results show that the beaked whales were producing echolocation pulses and are presumed to be foraging at a mean depth of 967 m (standard deviation = 112 m), approximately 300 m above the bottom in this basin. Some whales spent at least some time at or near the bottom. Average swim speed was 1.2 m s-1, but swim direction varied during a dive. The average net horizontal speed was 0.6 m s-1. Results are similar to those obtained from previous tagging studies of this species. These methods may allow expansion of dive studies to other whale species that are difficult to tag.


Primary stiffness of a modified transforaminal lumbar interbody fusion cage with integrated screw fixation: cadaveric biomechanical study.
In vitro biomechanical study using human fresh-frozen vertebrae. To investigate the influence of the additional screw fixation on the stability of a noncommercially available prototype transforaminal lumbar interbody fusion (TLIF) cage, when used as a stand-alone fusion device and in combination with pedicle screws (PSs). Generally interbody fusion cages are supplemented by additional fixation devices such as PS. However, such posterior instrumented techniques are associated with additional soft-tissue trauma and potentially increased complication rate. To limit such drawbacks, a conventional posterior TLIF cage was modified to allow supplemental screw fixation to the adjacent vertebral bodies, to increase initial stiffness and possibly allow as a stand-alone posterior interbody cage. Six monosegmental lumbar spine segments were loaded in a spine simulator with pure bending moments of 7.5 Nm in lateral bending, flexion/extension, and axial rotation. The following paradigms were tested: intact spines; a destabilized spine (i.e., after discectomy and unilateral facetectomy); and the modified TLIF cage with (i.e., fixed TLIF cage) and without (i.e., TLIF cage) integrated screw fixation as a stand-alone model and with and without additional posterior fixation with bilateral PS. The range of motion (RoM) was recorded by a 3-dimensional motion analysis system. The TLIF cage with integrated screw fixation had minimal additional stabilizing effect in all motion planes with or without supplemental PS fixation. Moreover, compared with the intact spines, the stand-alone TLIF cage with and without integrated screw fixation did not reduce the RoM in any of the 3 motion planes. Comparison of the TLIF cage with integrated screw fixation to the TLIF cage supplemented with PS showed a significantly greater RoM in all testing conditions (P < 0.05). In several testing paradigms, the prototype TLIF cage with the integrated screw fixation had limited effect in reducing RoM and providing stability. The PS was the main contributor in reducing RoM in the destabilized spine and remains the current "gold standard" in posterolateral spinal fixation. N/A.


Temperature and density evolution during decay in a 2.45 GHz hydrogen electron cyclotron resonance plasma: off-resonant and resonant cases.
Time resolved electron temperature and density measurements during the decay stage in a hydrogen electron cyclotron resonance (ECR) plasma are presented for a resonance and off-resonance magnetic field configurations. The measurements are conducted on a ECR plasma generator excited at 2.45 GHz denominated test-bench for ion-sources plasma studies at ESS Bilbao. The plasma parameters evolution is studied by Langmuir probe diagnostic with synchronized sample technique developed for repetitive pulsed plasmas with a temporal resolution of 200 ns in typical decay processes of about 40 μs. An afterglow transient is clearly observed in the reflected microwave power signal from the plasma. Simultaneously, the electron temperature evolution shows rebounding peaks that may be related to the interplay between density drop and microwave coupling with deep impact on the Electron Energy Distribution Function. The correlation of such structures with the plasma absorbed power and the coupling quality is also reported.


Bidirectional erosion of cartilage in the rheumatoid knee joint.
Specimens of cartilage with contiguous bone and overlying synovial pannus were obtained from 22 rheumatoid knee joints and examined histologically using specific histochemical staining techniques. All showed significant erosions of cartilage by synovial cells, but seven specimens also showed substantial cartilage erosion by cells from the subchondral bone region. This bidirectional attack on rheumatoid knee cartilage did not represent an 'underpinning' of cartilage by synovial pannus, as judged by serial sectioning and the identification of specific cells. Whereas cartilage-pannus junctions had mainly macrophagic or fibroblastic cells, cartilage-bone lesions were usually characterised by chondroclasts and blood vessels. Lymphocytes were generally absent from all sites of cartilage erosion. The bidirectional attack on articular knee cartilage suggests that changes have occurred within the cartilage that make it vulnerable to cellular invasion and erosion. Such changes might reflect a deficiency in 'anti-invasion factors', or the exposure of hidden epitopes and subsequent immunogenicity, or a combination of both.


Effect of age on vascularization during fracture repair.
Age affects fracture repair; however, the underlying mechanisms are not well understood. The goal of this study was to assess the effects that age has on vascularization during fracture healing. Tibial fractures were created in juvenile (4-week-old), middle-aged (6-month-old), and elderly (18-month-old) mice. The length density and surface density of blood vessels within fracture calluses were analyzed using stereology at 7 days after fracture. The expression of molecules that regulate vascular invasion of the fracture callus was also compared among the three age groups by immunohistochemistry and in situ hybridization. At 7 days after fracture, juvenile mice had a higher surface density of blood vessels compared to the middle-aged and elderly. Hypoxia-inducible factor-1 alpha protein and transcripts of vascular endothelial growth factor were detected at 3 days postinjury in juvenile but not middle-aged and elderly mice. Stronger Mmp-9 and -13 expression was detected in fracture calluses at day 7 in the juvenile compared to the middle-aged and elderly mice. At 21 days postfracture, expression of both Mmps was more robust in the elderly than juvenile and middle-aged animals. These data indicate that age affects vascularization during fracture repair, and the changes we observed are directly correlated with altered expression of biochemical factors that regulate the process of angiogenesis. However, whether the increased vascularization is the cause or result of accelerated bone repair in juvenile animals remains unknown. Nonetheless, our results indicate that enhancing vascularization during fracture repair in the elderly may provide unique therapeutic opportunities.


Image Quality and Clinical Usefulness of Ray-summation Image Reconstructed from CT Data, Compared with Digital Radiography.
Ray-summation (raysum) images reconstructed from computed tomography (CT) volume data resemble digital radiography (DR) images. Therefore, they have a potential to be used instead of DR images.The aim of this study was to compare the physical image quality evaluated by signal-difference-to-noise ratio (SDNR) and clinical usefulness between raysum and DR images. We employed an oval water phantom simulating adult abdomen for image quality measurement. Raysum images were reconstructed from CT volume data using an assumed x-ray quality of 70 keV. DR images were obtained using an indirect-type flat panel detector system. The normalized noise-power spectrum (NNPS) for various same dose indices (DR: entrance surface dose, CT: CT dose index volume) were measured from raysum and DR images. SDNRs were calculated from the results of NNPSs, modulation transfer function (MTF), and cartilage material contrast. Five experienced observers visually compared each pair of a clinical raysum image and a DR image for nine clinical cases (head, finger, pelvis, and foot). MTF of raysum was significantly lower than that of DR. SDNRs of DR were superior to those of raysum for each dose index, by an average factor of 1.24. For head and pelvis images, raysum images were comparable or a little superior compared with the DR images, because the radiation doses of raysum was much higher than those of DR. For finger and foot cases, the raysum images were inferior to DR images due to its lower resolution. Our results indicated a limited clinical usefulness of raysum compared with DR.


Dynamic article: combined endoscopic-laparoscopic surgery for complex colonic polyps: postoperative outcomes and video demonstration of 3 key operative techniques.
Combined endoscopic-laparoscopic surgery is a novel technique that can be used to avoid bowel resection for complex colon polyps that are not amenable to colonoscopic resection. The aim of this study was to evaluate the safety and outcomes of combined endoscopic-laparoscopic surgery for complex colonic polyps. This study is a retrospective review of consecutive combined endoscopic-laparoscopic surgeries. This study was conducted at a single institution. All patients that underwent combined endoscopic-laparoscopic surgery for a complex colonic polyp at our center from October 2009 to October 2013 were followed. Each patient's lesion was assessed by a therapeutic endoscopist before referral for combined endoscopic-laparoscopic surgery, and was deemed unresectable based on size, broad base, or location of the polyp. Intraoperative and postoperative complications, length of hospital stay, and recurrence were the primary outcomes measured. Thirty consecutive patients underwent combined endoscopic-laparoscopic surgery. Twenty (66.7%) patients underwent laparoscopic-assisted colonoscopic polyp excision (10 of these excisions were facilitated by Endoloop placement at the polyp base), 9 (30%) patients underwent colonoscopic-assisted laparoscopic cecectomy, and 1 (3.3%) patient was converted from a colonoscopic-assisted laparoscopic cecectomy to a laparoscopic ileocolic resection. The median length of hospital stay was 2 days (range, 1-16). Twenty-nine (96.7%) of the final pathology results were benign, with 10 (33.3%) showing high-grade dysplasia. One (3.3%) final pathology result was positive for a well-differentiated adenocarcinoma. This patient subsequently underwent a laparoscopic right hemicolectomy and chemotherapy for node-positive disease. One (3.3%) patient experienced a recurrent benign polyp at the previous excision site, which was removed by colonoscopy. The time to detection of recurrence was 274 days. This study looked at a small group of patients, over a short follow-up period. However, all consecutive patients were captured, and there were no losses to follow-up. Combined endoscopic-laparoscopic surgery for complex benign colonic polyps is a safe procedure, with good clinical outcomes and low recurrence rates.


Recent advances and prognosis in idiopathic membranous nephropathy.
Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome. Recently, progress has been made in understanding the pathogenesis of idiopathic MN with the finding of M-type phospholipase A2 receptor (PLA2R) antibodies in the serum and immune complexes of glomeruli in the majority of adult idiopathic MN patients. In the future, the detection of M-type PLA2R antibodies may help distinguish patients with primary MN who require aggressive immunosuppressive therapy from those with secondary disease. Levels of circulating antibody to this receptor may help in monitoring disease activity and in gauging response to therapy, as changes in antibody levels may precede changes in proteinuria. The degree of renal dysfunction or change in renal function over time and the level of persistent proteinuria are key prognostic factors in the decision to initiate therapy in idiopathic MN patients. Although spontaneous remissions occur in ~30% of patients, partial and complete remissions help to define the clinical course of an individual patient.


NSAID-induced cyclooxygenase inhibition differentially depresses long-lasting versus brief synaptically-elicited responses of rat spinal dorsal horn neurons in vivo.
This electrophysiological study examined the effects of NSAID administration on synaptically-elicited responses of rat single spinal dorsal horn neurons to natural stimulation of peripheral receptive fields. Nociceptive responses consisted of a fast initial discharge during the stimulus followed by a slowly-decaying afterdischarge. The cyclooxygenase inhibitor, indomethacin (2.0-8.0 mg/kg, i.v.), was without effect on the on-going rate of discharge but dose-dependently inhibited synaptically-elicited responses to noxious cutaneous mechanical stimulation (fast initial discharge: n = 3/3 with 2 mg/kg, 5/8 with 4 mg/kg, 5/6 with 8 mg/kg; slowly-decaying afterdischarge: n = 3/3 with 2 mg/kg, 6/8 with 4 mg/kg, 6/6 with 8 mg/kg) and thermal (fast initial discharge: n = 7/9 with 8 mg/kg; slowly-decaying afterdischarge: n = 3/4 with 4 mg/kg, n = 7/9 with 8 mg/kg). The inhibitory effect of indomethacin started within 2-4 min and lasted up to 120 min. To eliminate any effect of indomethacin via cutaneous sensory receptors it was tested on the responses of some neurons to high intensity electrical stimulation of the sciatic nerve; indomethacin depressed these evoked responses (fast initial discharge: n = 5/6 with 2 mg/kg, n = 7/7 with 4 mg/kg; slowly-decaying afterdischarge: n = 6/6 with 2 mg/kg, n = 7/7 with 4 mg/kg). The brief excitatory responses to innocuous pressure (fast initial discharge: n = 2/3 with 2 mg/kg, n = 6/8 with 4 mg/kg, n = 4/6 with 8 mg/kg) and hair (n = 2/7 with 2 and 4 mg/kg, respectively) stimulation in both non-nociceptive and wide dynamic range neurons were also depressed but to a lesser extent. However, the prolonged excitation of three wide dynamic range neurons to continuous hair stimulation was almost entirely inhibited by indomethacin. Overall, inhibition of the afterdischarge and the excitatory effect of long-lasting synaptic input were greater than inhibition of the fast synaptic input-evoked initial discharge. The evidence supports the suggestion that systemically-administered indomethacin has an effect in the spinal cord and demonstrates an action specifically in the dorsal horn. The data are interpreted to suggest that sensory inputs are more involved than input-independent excitation of dorsal horn neurons in leading to de novo synthesis of eicosanoids and that the time course of this synthesis brings the levels to a point where COX inhibition can have an observable effect during prolonged excitation. Although the data suggest that COX inhibition differentially inhibits nociceptive versus non-nociceptive mechanisms at the cellular level, irrespective of the modality of the stimulus, this is the first direct demonstration that prolonged activation of synaptic mechanisms are preferentially inhibited. According to this it would be predictable that NSAIDs would be more effective on nociceptive types of pain characterized by time or prolonged inputs of primary afferents.


Study of arteriovenous fistula function by the temperature gradient method using the Twister™ device.
Periodic blood flow (QA) measurement is the preferred way for arteriovenous fistula (AVF) surveillance in chronic hemodialysis (HD) patients. Objectives. 1) Assess the efficacy of the temperature gradient method (TGM) on the QA determinations using the Twister™ device and to compare the functional results with the Delta-H method. 2) Evaluate the effect of blood pressure on the AVF function. Patients and method. We measured the QA non invasively in 30 AVF (24 radial and 6 brachial; mean duration 53.4 +/- 78.5 months) during HD in 30 stable patients (mean age 59.9 +/- 14.1 years, males 60 %, females 40 %; mean time on HD 37.4 +/- 40.6 months, diabetic nephropathy 20 %) by the TGM, described and validated by Wijnen et al (Kidney Int 2007;72:736). The QA was calculated from the temperature values obtained by means of the blood temperature monitor (BTM), integrated into the Fresenius Medical Care 4008-S machine, at normal and reverse configurations of the HD blood lines, with no need for a thermal bolus. The Twister™ device was used for reversing the blood lines without the need to disconnect them from the AVF lines nor to stop the blood pump. The QA was measured within the first hour of two consecutive HD sessions (the values were averaged). The mean arterial pressure MAP (diastolic pressure + 1/3 pulse pressure) was calculated simultaneous with the QA. In addition, the AVF blood flow was also determined during the same week in all patients by the Delta-H method using the Crit-Line III Monitor (ABF-mode, HemaMetrics, USA) during HD (manually switching lines). The mean QA was 1132.5 +/- 515.4 ml/min (range, 446-2233 ml/min). The mean coefficient of variation for duplicate QA measurements was 6.8 +/- 4.7 %; the MAP was not different when the reproducibility tests were performed (96.1 +/- 13.7 versus 96.6 +/- 12.8 mmHg, p = .72). No significant difference was found when comparing the mean QA between diabetic (n = 6, 966.4 +/- 340.7 ml/min) and nondiabetic (n = 24, 1174.4 +/- 548.3 ml/min) patients (p = .39). The mean QA was similar for patients with mean MAP < 100 mmHg (n = 18, 1101.0 +/- 552.7 ml/min) and for patients with mean MAP >_ 100 mmHg (n = 12, 1180.4 +/- 473.3 ml/min) (p = .69). No correlation was found between the mean QA and: age (r = 0.09, p = .62), time on HD (r = 0.06, p = .76), MAP (r = -0.21, p = .27), Kt/V index (r = 0.12, p = .51), distance between needles (r = - 0.17, p = .37) and AVF duration (r = -0.01, p = .96). The mean time required to measure QA with the TGM using the Twister™ device (5.9+/- 1.9 min) was significantly shorter compared with the Delta-H technique (26.8 +/- 1.9 min) or with the TGM (n = 35, 8.9 +/- 3.5 min, manually reversing lines) reported by Wijnen et al (Kidney Int 2007;72:736).) (for both comparisons, p < .001). The mean QA obtained by the TGM was not different when compared to mean ABF determined by the Delta-H method (1138.4 +/- 502.3 ml/min) (p=.83).The calculated values of AVF blood flow obtained by TGM were highly correlated with those determined by the Delta-H technique (r = 0.963, p < .001). 1) The TGM is a valuable and reproducible indicator of QA during HD. 2) The Twister™ device is useful to reduce the time for QA measurement by the TGM. 3) The AVF blood flow values obtained by the TGM and the Delta-H technique correlated highly with each other. 4) It has been shown the lack of relationship between the AVF function and the patient's blood pressure.


CHI3L1 polymorphisms associate with asthma in a Taiwanese population.
A genome-wide association study uncovered Chitinase 3 like 1 (CHI3L1) as a candidate gene for asthma susceptibility. CHI3L1, which encodes the YKL-40 protein, is associated with asthma in Western European and American populations and with atopy in a Korean population. However, asthma-associated polymorphisms remain unknown for a Taiwanese population. We enrolled 628 adult asthmatic patients and 1:1 age-sex matched community-based controls in southern Taiwan and performed a combined effect sizes analysis to test if CHI3L1 polymorphisms were related to genetic risks for asthma in the Asian population. Ten tagSNP polymorphisms for the CHI3L1 gene were selected from the HapMap database and genotyped using a TaqMan allelic discrimination assay. Adjusted odds ratios of the CHI3L1 rs1538372 CC genotype (aOR = 1.97, 95% CI: 1.23-3.14) and the rs10399931 GG genotype (aOR = 1.77, 95% CI: 1.13-2.77) were significantly associated with asthma in the Taiwanese populations. Predictive values of forced expiratory volume in the first second of the forced vital capacity (12.37%, P = 0.03) and of forced vital capacity (12.10%, P = 0.036) decreased in conjunction with an increase in YKL-40 levels among CHI3L1 rs1538372 CC carriers; these values were 16.1% (P = 0.004) and 14.5% (P = 0.011), respectively, among CHI3L1 rs10399931 GG carriers. Furthermore, steroid use by asthma patients did not affect serum YKL-40 levels, but both polymorphisms had significant effects on YKL-40 levels in asthma patients who used steroids. Our findings suggest that the CHI3L1 polymorphisms rs1538372 and rs10399931 can be used as genetic markers for predicting asthma risk in the Taiwanese population.


Decreased liver activity of porphyrin-metal chelatase in hepatic porphyria caused by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Studies in rats and mice.
1. A difference has been found between rats and mice in their sensitivity to the porphyrogenic effect of drugs. Mice are more sensitive than rats to 3,5-diethoxycarbonyl-1,4-dihydrocollidine, but less sensitive than rats to 2-allyl-2-isopropylacetamide. 2. Use has been made of this difference in sensitivity to ascertain the importance of the decrease of liver porphyrin-metal chelatase activity in porphyria caused by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Mice, which are more sensitive than rats to the stimulation of 5-aminolaevulinate caused by this drug, are also more sensitive with respect to the decrease of chelatase activity. 3. In both species, after treatment with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, the ratio between chelatase activity and 5-aminolaevulinate activity is linear with respect to the reciprocal of the liver porphyrin concentration. This suggests that under these conditions the degree of porphyrin accumulation depends on the balance between rate of porphyrin formation and rate of porphyrin utilization. 4. Compound SKF 525-A (2-diethylaminoethyl 3,3-diphenylpropylacetate) when given before 3,5-diethoxycarbonyl-1,4-dihydrocollidine prevents the appearance of porphyria in the rat and also largely prevents the decrease of chelatase activity. In the mouse it is much less effective in preventing porphyria and it is almost completely inactive in protecting the chelatase from a decrease in activity. 5. Cycloheximide, when given before 3,5-diethoxycarbonyl-1,4-dihydrocollidine also inhibits the induction of 5-aminolaevulinate synthetase and the appearance of porphyria in the rat, but does not prevent the decrease of chelatase activity. These results suggest that two successive stages can be distinguished in the induction process: a first stage leading to inhibition of haem synthesis and a second stage requiring synthesis of protein in the liver and leading to stimulation of 5-aminolaevulinate synthetase.


The inhibition by diphenyleneiodonium and its analogues of superoxide generation by macrophages.
Peritoneal macrophages were elicited in rats by using casein as a stimulus; when stimulated with phorbol 12-myristate 13-acetate (PMA) they produced O2.-. Nearly 60% of the total cytochrome b had a low Em,7.0 of -247 mV, typical of the cytochrome b component found in the NADPH-dependent O2(.-)-generating oxidase of neutrophils. The rate of O2.- generation by macrophages was 1.23 mol of O2.-/s per mol of cytochrome b. Treatment of intact macrophages with diphenyleniodonium (DPI) at 0.9 microM caused 50% inhibition of PMA-induced O2.- generation, with little effect on mitochondrial respiratory activity; KCN inhibited respiratory activity without affecting PMA-induced O2.- generation. A similar specificity of inhibition was found for di-2-thienyliodonium (50% inhibition of O2.- generation at 0.5 microM) and, at higher concentrations, for diphenyl iodonium. When macrophage suspensions were incubated with [125I]DPI followed by autoradiography of SDS/polyacrylamide-gel-electrophoresis-separated polypeptides, radioactivity was most strongly associated with a band of Mr 45,000, similar to that found in neutrophils [Cross & Jones (1986) Biochem. J. 237, 111-116]. The O2(.-)-generating oxidase of macrophages appears to have components in common with the NADPH oxidase of neutrophils, despite differences in activity. Its sensitivity to DPI suggests that selective prevention of radical generation by macrophages in vivo is possible.


Beyond low-pass filtering on large-scale graphs via Adaptive Filtering Graph Neural Networks.
Graph Neural Networks (GNNs) have emerged as a crucial deep learning framework for graph-structured data. However, existing GNNs suffer from the scalability limitation, which hinders their practical implementation in industrial settings. Many scalable GNNs have been proposed to address this limitation. However, they have been proven to act as low-pass graph filters, which discard the valuable middle- and high-frequency information. This paper proposes a novel graph neural network named Adaptive Filtering Graph Neural Networks (AFGNN), which can capture all frequency information on large-scale graphs. AFGNN consists of two stages. The first stage utilizes low-, middle-, and high-pass graph filters to extract comprehensive frequency information without introducing additional parameters. This computation is a one-time task and is pre-computed before training, ensuring its scalability. The second stage incorporates a node-level attention-based feature combination, enabling the generation of customized graph filters for each node, contrary to existing spectral GNNs that employ uniform graph filters for the entire graph. AFGNN is suitable for mini-batch training, and can enhance scalability and efficiently capture all frequency information from large-scale graphs. We evaluate AFGNN by comparing its ability to capture all frequency information with spectral GNNs, and its scalability with scalable GNNs. Experimental results illustrate that AFGNN surpasses both scalable GNNs and spectral GNNs, highlighting its superiority.


Finite element analysis of a three-dimensional open-celled model for trabecular bone.
Based on a regular array of cubic unit cells, each containing a body-centered spherical void, we created an idealized three-dimensional model for both subchondral trabecular bone and a class of porous foams. By considering only face-to-face stacking of unit cells, the inherent symmetry was such that, except at the surface, the displacements and stresses within any one unit cell were representative of the entire porous structure. Using prescribed displacements the model was loaded in both uniaxial compressive strain and uniaxial shear strain. Based on the response to these loads, we found the tensor of elastic constants for an equivalent homogeneous elastic solid with cubic symmetry. We then compared the predicted modulus with our experimental values for bovine trabecular bone and literature values for an open-celled latex rubber foam.


Clinical burden of asynchrony in patients with asthma when using metered-dose inhalers for control.
Background: Asynchrony, or lack of coordination between inhalation and actuation when using a pressurized metered-dose inhaler (MDI), could theoretically impact the delivery of inhaled medications and treatment efficacy. Objective: To assess the real-world association between asynchrony and clinical outcomes among patients with asthma who receive controller therapy delivered by MDIs. Methods: A cohort of patients was assembled via electronic health records. The patients were aged ≥12 years, with one or more documentations of an asthma diagnosis, no diagnosis of chronic obstructive pulmonary disease, and two or more prescriptions for an inhalation aerosol corticosteroid alone or with long-acting beta-2-agonist delivered via MDI. Their inhaler technique, demonstrated by using a placebo MDI, was evaluated at a clinic visit by study nurses who used a standardized 10-step checklist. Asynchrony was defined as any gap in timing between inhalation and actuation. Clinical outcomes were assessed via electronic health records during the 6 months before the clinic visit and were compared between patients with and patients without asynchrony by using multivariable regression analyses adjusted for age, gender, asthma severity proxy, and baseline comorbidities. Results: Of the total 254 eligible patients, mean age of 49.3 years, 90 males (35.4%), 32 (12.6%) had asynchrony. Patients with asynchrony had higher odds of an asthma exacerbation (adjusted odds ratio, 2.99; p = 0.009), and lower odds of risk domain asthma control (adjusted odds ratio, 0.41; p = 0.04) compared with patients without asynchrony. Conclusion: This study provided real-world evidence that asynchrony in MDI use among patients with asthma who were treated with controller MDIs was associated with clinical burden in terms of asthma exacerbations and control.


The impact of hearing loss on quality of life in older adults.
The authors investigate the impact of hearing loss on quality of life in a large population of older adults. Data are from the 5-year follow-up Epidemiology of Hearing Loss Study, a population-based longitudinal study of age-related hearing impairment conducted in Beaver Dam, WI. Participants (N = 2,688) were 53-97 years old (mean = 69 years) and 42% were male. Difficulties with communication were assessed by using the Hearing Handicap for the Elderly-Screening version (HHIE-S), with additional questions regarding communication difficulties in specific situations. Health-related quality of life was assessed by using measures of activities of daily living (ADLs), instrumental ADLs (IADLs) and the Short Form 36 Health Survey (SF-36). Hearing loss measured by audiometry was categorized on the basis of the pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz. Of participants, 28% had a mild hearing loss and 24% had a moderate to severe hearing loss. Severity of hearing loss was significantly associated with having a hearing handicap and with self-reported communication difficulties. Individuals with moderate to severe hearing loss were more likely than individuals without hearing loss to have impaired ADLs and IADLs. Severity of hearing loss was significantly associated with decreased function in both the Mental Component Summary score and the Physical Component Summary score of the SF-36 as well as with six of the eight individual domain scores. Severity of hearing loss is associated with reduced quality of life in older adults.


The Extensor Mechanism: Imaging and Intervention.
We present an overview of imaging and intervention of the extensor mechanism of the knee. Particular focus is placed on the evaluation of patellofemoral tracking disorders, patellar and quadriceps tendinosis and tears, patellar fracture, lateral patellar condyle patellar friction syndrome, and prepatellar bursitis. Anatomical and biomechanical factors contributing to these disorders are considered. Imaging evaluation is presented in a clinical context, and therapeutic options for these disorders are discussed. Image-guided therapy options for symptomatic patellar tendinosis are also described and illustrated.


Laparoscopic management in stone disease.
While most renal and ureteral stones can be efficiently managed using endourologic techniques, the use of laparoscopy for the management of urolithiasis is increasing. The application of laparoscopy for stone removal will further reduce the need for open stone surgery. Laparoscopic ureterolithotomy, pyelolithotomy, and anatrophic nephrolithotomy are highly successful techniques with regard to their one-session, high stone-free rates. These procedures could be considered as the preferred approaches when endourologic procedures are not available or have failed. Laparoscopic stone surgery (LSS) in patients with urinary tract anomalies offers a reliable minimally invasive procedure as an alternative to a complex endourologic technique. Although laparoscopy still has a limited role in the urologist's armamentarium for the surgical management of urolithiasis, it can further reduce the need for open stone surgery in complex circumstances. LSS duplicates its open counterpart and offers a high one-session, stone-free rate in most patients with a lower morbidity and quicker convalescence. More comparative studies are needed to define the role and indications of LSS in relation to endourologic and open techniques, especially in complex circumstances.


New 434 MHz interstitial hyperthermia system monitored by microwave radiometry: theoretical and experimental results.
A new complete microwave interstitial hyperthermia system monitored automatically by microwave radiometry and working at 434 MHz is described in this paper. This system, which includes a new radiometer with two internal temperature references, is detailed. All its characteristics for microwave heating and radiometry are presented. The new possibilities are shown through numerous experiments on acrylamide phantom and excised tissues, which have been carried out for different antennae implantation corresponding to the clinical situation. The clinic protocol, associate to the brachytherapy, imposes the use of semi-loop catheters. Coaxial antennae, inserted in these catheters, are not, therefore, positioned in a rectilinear manner but undergo a curve. So, models based on the FDTD formalism are developed to determine the theoretical power deposition. Owing to these models, the effects of this physical motive on radiation diagrams can be taken into account. The results of the power deposition are presented for two antennae. Thermal patterns can then be determined by the solution of the bioheat-transfer equation in the steady state. Also, the comparison of the results given by the new interstitial hyperthermia system with those obtained with the previous 915 MHz one shows an improvement of the thermal performances.


Complete switchgrass genetic maps reveal subgenome collinearity, preferential pairing and multilocus interactions.
Polyploidy is an important aspect of the evolution of flowering plants. The potential of gene copies to diverge and evolve new functions is influenced by meiotic behavior of chromosomes leading to segregation as a single locus or duplicated loci. Switchgrass (Panicum virgatum) linkage maps were constructed using a full-sib population of 238 plants and SSR and STS markers to access the degree of preferential pairing and the structure of the tetraploid genome and as a step toward identification of loci underlying biomass feedstock quality and yield. The male and female framework map lengths were 1645 and 1376 cM with 97% of the genome estimated to be within 10 cM of a mapped marker in both maps. Each map coalesced into 18 linkage groups arranged into nine homeologous pairs. Comparative analysis of each homology group to the diploid sorghum genome identified clear syntenic relationships and collinear tracts. The number of markers with PCR amplicons that mapped across subgenomes was significantly fewer than expected, suggesting substantial subgenome divergence, while both the ratio of coupling to repulsion phase linkages and pattern of marker segregation indicated complete or near complete disomic inheritance. The proportion of transmission ratio distorted markers was relatively low, but the male map was more extensively affected by distorted transmission ratios and multilocus interactions, associated with spurious linkages.


Registration methods for surgical navigation of the mandible: a systematic review.
Image-to-patient registration in navigated mandibular surgery is complex due to the mobile nature of the mandible compared with other craniofacial bones. As a result, surgical navigation is rarely employed in the mandibular region. This systematic review provides an overview of the different registration methods that are used for surgical navigation of the mandible. A systematic search was performed in the MEDLINE Ovid, Scopus, and Embase databases on March 25, 2021. Search terms included synonyms for mandibular surgery, surgical navigation, and registration methods. Articles about navigated mandibular surgery, where the registration method was explicitly mentioned, were included. The database search yielded a total of 2952 articles, from which 81 articles remained for analysis. Four main registration methods were identified: point registration, surface registration, hybrid registration, and computer vision-based registration. The mobility of the mandible is accounted for by either keeping the mandible in a fixed position during preoperative imaging and surgery, or by tracking the mandibular movements. Although different registration methods are available for navigated mandibular surgery, there is always a trade-off between accuracy, registration time, usability, and invasiveness. Future studies should focus on testing the different methods in larger patient studies and should report the registration accuracy.


Expression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependency.
Children present a higher susceptibility to developing thyroid cancer after radioiodine exposure and also a higher frequency of functional metastases than adults. To assess the mRNA expression of the sodium/iodide (Na(+)/I(-)) symporter (NIS), the Pendred syndrome gene (PDS), thyroperoxidase (TPO), thyroglobulin (Tg) and TSH receptor (TSH-R) in normal thyroid tissues (NTTs) and papillary thyroid carcinomas (PTCs) among different age groups. Analysis included 59 samples: 21 NTTs and 38 PTCs, of which 21 were the classic type (CPTC) and 17 the follicular variant (FVPTC). Patients were divided into three age groups: I (n = 16) 5-21 years, II (n = 13) 22-59 years, and III (n = 10) 60-91 years. The relative mRNA expression of the five target genes was determinate by quantitative reverse transcription polymerase chain reaction (QRT-PCR). Expression of all genes was significantly higher in NTTs than in PTCs, and it was not age dependent in the NTT group. Among PTCs, the mean expression of PDS, TPO and TSH-R was significantly lower in group II than in group I. PDS, TPO and Tg expression was significantly lower in classic PTCs than in FVPTCs. The difference was related to a higher frequency of the BRAF(V600E) mutation in the former group. The finding of higher PDS, TPO and TSH-R mRNA expression in paediatric vs. adult primary tumour tissues supports the hypothesis that this might contribute to the increased functional activity of metastases in the paediatric group. The finding that mRNA expression of the target genes in NTT was not age dependent does not provide an explanation for the higher susceptibility in the paediatric group.


Attitudes and health beliefs associated with breast cancer screening behaviors among Turkish women.
This research was undertaken to determine the attitudes and health beliefs of a sample of Turkish women about breast self-examination (BSE), clinical breast examination, and mammography. Data were collected by means of a researcher-designed questionnaire and the Champion Health Belief Model Scale. A total of 1,342 women participated in this study. It was found that 10.1% of the women practiced BSE once a month, 19.8% of the women had had a clinical breast examination, and 15.0% had had a mammogram. Age and marital status were significant variables that influenced whether the women used only one or multiple methods for early detection of breast cancer. Participants who had higher levels of confidence for BSE and lower perceptions of barriers to BSE were more likely to perform BSE. Participants who perceived higher levels of confidence to perform BSE were more likely to be using all three early detection methods. Interventions and strategies that help women develop confidence in their abilities to perform early breast cancer detection methods are likely to encourage them to engage in regular screening for breast cancer.


Did high sugar-sweetened beverage purchasers respond differently to the excise tax on sugar-sweetened beverages in Mexico?
To estimate changes in taxed and untaxed beverages by volume of beverage purchased after a sugar-sweetened beverage (SSB) tax was introduced in 2014 in Mexico. We used household purchase data from January 2012 to December 2015. We first classified the sample into four groups based on pre-tax purchases of beverages: (i) higher purchases of taxed beverages and lower purchases of untaxed beverages (HTLU-unhealthier); (ii) higher purchases of both types of beverages (HTHU); (iii) lower purchases of taxed and untaxed beverages (LTLU); and (iv) lower purchases of taxed beverages and higher purchases of untaxed beverages (LTHU-healthier). Next, we estimated differences in purchases after the tax was implemented for each group compared with a counterfactual based on pre-tax trends using a fixed-effects model. Areas with more than 50 000 residents in Mexico. Households (n 6089). The HTLU-unhealthier and HTHU groups had the largest absolute and relative reductions in taxed beverages and increased their purchases of untaxed beverages. Households with lower purchases of untaxed beverages (HTLU-unhealthier and LTLU) had the largest absolute and relative increases in untaxed beverages. We also found that among households with higher purchases of taxed beverages, the group with lowest socio-economic status had the greatest reduction in purchases of taxed beverages. Evidence associating the SSB tax with larger reductions among high purchasers of taxed beverages prior to the tax is relevant, as higher SSB purchasers have a greater risk of obesity, diabetes and other cardiometabolic outcomes.


Impact of the industrial freezing process on selected vegetables - Part I. Structure, texture and antioxidant capacity.
In this work, the impact of the industrial freezing process on structure, texture and total antioxidant capacity was studied using green asparagus stems, zucchini and green beans. Samples were analysed as raw/uncooked, blanched, raw/boiled and industrially frozen/boiled. A consistent damage of the vegetable tissue was revealed by the histological analysis on vegetables boiled after freezing. The cells appeared to be dehydrated, contracted and separated at different levels depending on the anatomical structure of each vegetable. The initial textural quality was partially retained in all blanched vegetables, and enhanced in cut tested asparagus stems, in relation to the action of phenolic acids at cell wall level. Raw/boiled and industrially frozen/boiled asparagus stems exhibited comparable forces of penetration and cut tests. On the other hand, zucchini, both raw and frozen, completely softened after boiling making the texture measurement impossible. Industrially frozen/boiled green beans showed higher values of cut and penetration forces, probably due to a higher presence of swollen cell walls, in comparison to those raw/boiled. Blanching and boiling significantly increased the ferric reducing antioxidant power values of asparagus stems and green beans compared to uncooked/raw samples, while boiling after the freezing process significantly deprived both vegetables of the initial antioxidant capacity. On the other hand, boiling the frozen zucchini proved to be detrimental to the antioxidant capacity. In conclusion, manufacturers and researchers should join together to develop specific industrial freezing process conditions according to the matrix of each vegetable.


Self-assembled ordered polymer nanocomposites directed by attractive particles.
We theoretically investigate general conditions under which an inorganic phase can direct the self-assembly of an ordered polymer nanocomposite. For this purpose, we consider a solution of triblock copolymers forming a hexagonal phase of micelles and investigate the effect of adding attractive particles. We show that if the triblock is functionalized at its ends by attaching groups with specific affinity for the particles, thus effectively becoming a pentablock, the particles direct the self-assembly of the system into phases where both the polymers and the particles exhibit mesoscopic order. Different lamellar and gyroid phases (both with Ia3d and I4(1)32 space symmetries) are presented in detail. Our results show that functionalization is a very powerful route for directing self-assembly of polymer nanocomposites. We briefly discuss the connections with recent theoretical and experimental results in diblock melts with nanoparticles as well as for problems where polymers are used to template the growth of an inorganic phase in solution.


Thermal stability and inactivation of hepatitis C virus grown in cell culture.
Hepatitis C virus (HCV) is a blood-borne flavivirus that infects many millions of people worldwide. Relatively little is known, however, concerning the stability of HCV and reliable procedures for inactivating this virus. In the current study, the thermostability of cell culture-derived HCV (HCVcc, JFH-1 strain) under different environmental temperatures (37 degrees C, room temperature, and 4 degrees C) and the ability of heat, UVC light irradiation, and aldehyde and detergent treatments to inactivate HCVcc were evaluated. The infectious titers of treated viral samples were determined by focus-forming unit (FFU) assay using an indirect immunofluorescence assay for HCV NS3 in hepatoma Huh7-25-CD81 cells highly permissive for HCVcc infection. MTT cytotoxicity assay was performed to determine the concentrations of aldehydes or detergents at which they were no longer cytotoxic. HCVcc in culture medium was found to survive 37 degrees C and room temperature (RT, 25 +/- 2 degrees C) for 2 and 16 days, respectively, while the virus was relatively stable at 4 degrees C without drastic loss of infectivity for at least 6 weeks. HCVcc in culture medium was sensitive to heat and could be inactivated in 8 and 4 min when incubated at 60 degrees C and 65 degrees C, respectively. However, at 56 degrees C, 40 min were required to eliminate HCVcc infectivity. Addition of normal human serum to HCVcc did not significantly alter viral stability at RT or its susceptibility to heat. UVC light irradiation (wavelength = 253.7 nm) with an intensity of 450 microW/cm2 efficiently inactivated HCVcc within 2 min. Exposures to formaldehyde, glutaraldehyde, ionic or nonionic detergents all destroyed HCVcc infectivity effectively, regardless of whether the treatments were conducted in the presence of cell culture medium or human serum. The results provide quantitative evidence for the potential use of a variety of approaches for inactivating HCV. The ability of HCVcc to survive ambient temperatures warrants precautions in handling and disposing of objects and materials that may have been contaminated with HCV.


Increased heart rate and atherosclerosis: potential implications of ivabradine therapy.
Despite all the therapeutic advances in the field of cardiology, cardiovascular diseases, and in particular coronary artery disease, remain the leading cause of death and disability worldwide, thereby underlining the importance of acquiring new therapeutic options in this field. A reduction in elevated resting heart rate (HR) has long been postulated as a therapeutic approach in the management of cardiovascular disease. An increased HR has been shown to be associated with increased progression of coronary atherosclerosis in animal models and patients. A high HR has also been associated with a greatly increased risk of plaque rupture in patients with coronary atherosclerosis. Endothelial function may be an important link between HR and atherosclerosis. An increased HR has been shown experimentally to cause endothelial dysfunction. Inflammation plays a significant role in the pathogenesis and progression of atherosclerosis. In the literature, there is data that shows an association between HR and circulating markers of vascular inflammation. In addition, HR reduction by pharmacological intervention with ivabradine (a selective HR-lowering agent that acts by inhibiting the pacemaker ionic current I(f) in sinoatrial node cells) reduces the formation of atherosclerotic plaques in animal models of lipid-induced atherosclerosis. The aim of this editorial is to review the possible role of ivabradine on atherosclerosis.


Management of refractory esophageal stenosis in the pediatric age.
Refractory esophageal stenosis (RES) is a major health problem in the pediatric population. Several techniques such as stent placement or C-mitomycin (CM) have been described as alternative treatments. We present our experience with both techniques, in our case with biodegradable stents (BS) and sometimes the association with stents and CM. Six patients have been included: 2 post-operative fistulas in patients with type I esophageal atresia; 1 operated atresia without fistula; and 3 caustic strictures. 5 BS were placed in 4 children: 3 of them in cases of atresia (2 prosthesis in one case) and the other one in a case of stricture. CM was used in 5 cases: in 2 of them from the beginning, and in the other 3 cases after failure of the stent. When placed in fistulas, BS were fully covered. One of them successfully treated the fistula, but the other one was not effective. One stenosis was successfully treated with SB (in the case of persistent fistula), but recurrence was observed in the other 2 cases. One of these was solved with CM, and the other one needed a second stent. In the remaining 2 cases (one atresia and one caustic stricture) CM was effective after 1 and 2 sessions respectively. Overall, 5 out of 6 stenosis have been successfully treated (83.3%), and 1 out of 2 fistulas (50%). Association of BS and CM has been effective in the management of RES in children.


Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid.
Lactic acid or lactate, a key byproduct of anaerobic glycolysis, plays pivotal roles in routine metabolism. An increase in lactic acid is observed in various pathological conditions such as cancer, diabetes, genetic mitochondrial disease, and aging. While several groups have proposed small molecule inhibitors to reduce circulating lactic acid, there are few clinically relevant ways to manage acute or chronic elevations in lactic acid in patients. In addition, recent evidence suggests that lactic acid exchanges between the gut, blood, and peripheral tissues, and professional marathon runners harbor specific gut microbial species that more efficiently metabolize lactic acid. Inspired by these findings, this work sought to engineer probiotic B. subtilis strains to express lactate oxidase that could increase circulating lactic acid catabolism after delivery to the gut. After optimization, oral administration of engineered B. subtilis to the gut of mice reduced the elevation in blood lactic acid levels after exogenous lactic acid challenge without affecting normal gut microbiota composition, inflammation or liver enzymes. Taken together, through the oral delivery of engineered probiotics to the gastrointestinal tract, our proof-of-concept study offers a new opportunity to therapeutically target diseases where blood lactic acid is elevated, and provides a new approach to "knocking down" metabolites to help understand the roles of metabolites in host physiological and pathological processes.


Neurophysiological indices of perceptual object priming in the absence of explicit recognition memory.
The aim of this study was to identify ERP correlates of perceptual object priming that are insensitive to factors affecting explicit, episodic memory. EEG was recorded from 21 participants while they performed a visual object recognition test on a combination of unstudied items and old items that were previously encountered during either a 'deep' or 'shallow' levels-of-processing (LOP) study task. The results demonstrated a midline P150 old/new effect which was sensitive only to objects' old/new status and not to the accuracy of recognition responses to old items, or to the LOP manipulation. Similar outcomes were observed for the subsequent P200 and N400 effects, the former of which had a parietal scalp maximum and the latter, a broadly distributed topography. In addition an LPC old/new effect typical of those reported in past ERP recognition studies was observed. These outcomes support the proposal that the P150 effect is reflective of perceptual object priming and moreover, provide novel evidence that this and the P200 effect are independent of explicit recognition memory process(es).


Gridded meteorological data as a resource for mechanistic macroecology in coastal environments.
Gridded weather data were evaluated as sources of forcing variables for biophysical models of intertidal animal body temperature with model results obtained using local weather station data serving as the baseline of comparison. The objective of the study was to determine which gridded data are sufficient to capture observed patterns of thermal stress. Three coastal sites in western North America were included in this analysis: Boiler Bay, Oregon; Bodega Bay, California; and Pacific Grove, California. The gridded data with the highest spatial resolution, the 32-km North American Regional Reanalysis (NARR) and the 38-km Climate Forecasting System Reanalysis (CFSR), predicted daily maximum intertidal animal temperature most similarly to the local weather Station data. Time step size was important for variables that change rapidly throughout the day, such as solar radiation. There were site-based differences in the ability of the model to predict daily maximum intertidal animal temperature, with the gridded data predictions being the closest to local weather station predictions in Boiler Bay, Oregon. In a review of gridded data used as part of ecological studies, there was broad use of the data across subject areas and ecosystems so the recent improvements in the spatial (from 2 degrees to 32 km) and temporal scales (from 6 hours to 1 hour) of gridded data will further add to the applicability within the ecological community particularly for mechanistic studies.


Cancer in Angola, resources and strategy for its control.
Cancer is an increasingly important health problem in Africa. The number of cancer cases in this region could double, ranging between 700 000 and 1 600 000 new cases in 2030. The mortality rate is higher than 80% and is explained, mainly, by a lack of early detection, diagnostics and treatment resources. In Angola, about 7,000 patients die of cancer every year. Data were derived from open-ended interviews conducted in 2010-11 with health authorities, clinicians, nurses and Administration of Hospitals. According Angola epidemiological data, results of interviews and international published advocacy for cancer control we develop a potential strategy for its control. The objectives are to identify existing resources for cancer control and describe the needs thereto, in order to establish an oncological program to guide the development of Angola cancer control strategies. Malaria remains the leading cause of illness and death in Angola, and other communicable diseases remain a public health problem. However, 9 000 new cases of cancer are diagnosed each year.The most common types of cancer are: cancer of the cervix, breast, prostate, esophagus, stomach and head and neck, as well as cancers with infectious origin, such as Kaposi's sarcoma and liver and bladder cancer. The foundation for developing national cancer control strategies includes: oncological data; investment and training; identifying and removing barriers; guidance and protection of the patient. Angolan National Cancer Centre, Sagrada Esperança Clinic and Girassol Clinic are now developing a cancer program. Improving the economic situation of Angola creates conditions for an increase in life expectancy which in itself is associated with an increased risk of oncological diseases. On the other hand, infectious diseases, associated with the risk of malignant tumors, are endemic. Thus, an increase in patients with malignant disease is expected. A plan is therefore necessary to organize the response to this old but less visible nosologic situation.


Patients with bone marrow failure demonstrate decreased cutaneous reactivity to human C5a.
In vivo studies have shown that human C5a, a potent complement-derived anaphylatoxin and chemoattractant, produces immediate inflammatory reactions following intradermal injection in human skin. At concentrations within its potential physiologic range, intradermal injection of C5a elicits immediate wheal and flare reactions, increased vascular permeability, mast cell degranulation, and neutrophil-rich infiltrates. To assess the relative contribution of interacting cellular elements to C5a-induced inflammation in normal human skin, purified human C5a was tested intradermally in 8 patients with bone marrow failure (BMF). Reactions to C5a in patients with BMF were compared with responses at identical test sites in healthy volunteers and other patients with cutaneous disorders. Patients with BMF demonstrated significantly less wheal and flare reactivity following intradermal injection of C5a than controls (p less than 0.05 and less than 0.02, respectively). In these studies, patients with the greatest cytopenia generally showed the least cutaneous reactivity to human C5a. Biopsies of C5a test sites in patients with BMF revealed an absence of leukocytes in marked contrast to neutrophil-rich infiltrates observed at test sites in healthy volunteers. Avidin-fluorescent and/or Giemsa staining of skin biopsies revealed no difference between the number of dermal mast cells in patients with BMF and samples of normal human skin. In addition, skin test studies with histamine (2 micrograms) and morphine (5 micrograms) performed to assess cutaneous vascular and mast cell responsiveness in patients with BMF, normal volunteers and controls with rhinitis revealed no significant differences in cutaneous reactivity to these pharmacologic agents. These in vivo studies demonstrate that patients with BMF specifically exhibit decreased cutaneous reactivity to human C5a and suggest that neutrophils make an important and an immediate contribution to inflammatory responses elicited by this anaphylatoxin.