Determining the isotopic compositions of uranium and fission products in radioactive environmental microsamples using laser ablation ICP-MS with multiple ion counters.
This paper presents the application of a multicollector inductively coupled plasma mass spectrometer (MC-ICP-MS)--a Nu Plasma HR--equipped with three ion-counting multipliers and coupled to a laser ablation system (LA) for the rapid and sensitive determination of the 235U/238U, 236U/238U, 145Nd/143Nd, 146Nd/143Nd, 101Ru/(99Ru+99Tc) and 102Ru/(99Ru+99Tc) isotope ratios in microsamples collected in the vicinity of Chernobyl. Microsamples with dimensions ranging from a hundred mum to about 1 mm and with surface alpha activities of 3-38 mBq were first identified using nuclear track radiography. U, Nd and Ru isotope systems were then measured sequentially for the same microsample by LA-MC-ICP-MS. The application of a zoom ion optic for aligning the ion beams into the ion counters allows fast switching between different isotope systems, which enables all of the abovementioned isotope ratios to be measured for the same microsample within a total analysis time of 15-20 min (excluding MC-ICP-MS optimization and calibration). The 101Ru/(99Ru+99Tc) and 102Ru/(99Ru+99Tc) isotope ratios were measured for four microsamples and were found to be significantly lower than the natural ratios, indicating that the microsamples were contaminated with the corresponding fission products (Ru and Tc). A slight depletion in 146Nd of about 3-5% was observed in the contaminated samples, but the Nd isotopic ratios measured in the contaminated samples coincided with natural isotopic composition within the measurement uncertainty, as most of the Nd in the analyzed samples originates from the natural soil load of this element. The 235U/238U and 236U/238U isotope ratios were the most sensitive indicators of irradiated uranium. The present work yielded a significant variation in uranium isotope ratios in microsamples, in contrast with previously published results from the bulk analysis of contaminated samples originating from the vicinity of Chernobyl. Thus, the 235U/238U ratios measured in ten microsamples varied in the range from 0.0073 (corresponding to the natural uranium isotopic composition) to 0.023 (corresponding to initial 235U enrichment in reactor fuel). An inverse correlation was observed between the 236U/238U and 235U/238U isotope ratios, except in the case of one sample with natural uranium. The heterogeneity of the uranium isotope composition is attributed to the different burn-up grades of uranium in the fuel rods from which the microsamples originated.


Colored motifs reveal computational building blocks in the C. elegans brain.
Complex networks can often be decomposed into less complex sub-networks whose structures can give hints about the functional organization of the network as a whole. However, these structural motifs can only tell one part of the functional story because in this analysis each node and edge is treated on an equal footing. In real networks, two motifs that are topologically identical but whose nodes perform very different functions will play very different roles in the network. Here, we combine structural information derived from the topology of the neuronal network of the nematode C. elegans with information about the biological function of these nodes, thus coloring nodes by function. We discover that particular colorations of motifs are significantly more abundant in the worm brain than expected by chance, and have particular computational functions that emphasize the feed-forward structure of information processing in the network, while evading feedback loops. Interneurons are strongly over-represented among the common motifs, supporting the notion that these motifs process and transduce the information from the sensor neurons towards the muscles. Some of the most common motifs identified in the search for significant colored motifs play a crucial role in the system of neurons controlling the worm's locomotion. The analysis of complex networks in terms of colored motifs combines two independent data sets to generate insight about these networks that cannot be obtained with either data set alone. The method is general and should allow a decomposition of any complex networks into its functional (rather than topological) motifs as long as both wiring and functional information is available.


Safety and Efficacy of Vitamin K Antagonists versus Rivaroxaban in Hemodialysis Patients with Atrial Fibrillation: A Multicenter Randomized Controlled Trial.
In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown. In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding. Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups. In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA. Oral Anticoagulation in Hemodialysis, NCT03799822.


Day-to-Day Contact and Help Among Neighbors Measured in the Natural Environment.
Empirical evidence suggests that the concept of "neighboring" (i.e., social contact and social support within a neighborhood) is related to between-person differences in well-being among older adults. However, little is known about the within-person differences in older adults' everyday lives, which limits the ecological validity of prior findings. This study examined within-person associations between neighboring and the existence of positive valence, loneliness, and attachment to one's neighborhood. The sample consisted of 4,620 observations of 20 days, drawn from 77 adults aged between 61 and 90 years. A mobile application on a smartphone was used for data collection. The results of the multilevel analysis suggest that daily contact with one's neighbors was not significantly associated with daily positive valence, but it was positively related to daily feelings of not being alone and daily attachment to one's neighborhood. The study makes noteworthy contributions to the field of gerontology by applying a micro-longitudinal research design to assess real-life within-person information.


Biosorption of copper(II) and cobalt(II) from aqueous solutions by crab shell particles.
Biosorption of each of the heavy metals, copper(II) and cobalt(II) by crab shell was investigated in this study. The biosorption capacities of crab shell for copper and cobalt were studied at different particle sizes (0.456-1.117 mm), biosorbent dosages (1-10 g/l), initial metal concentrations (500-2000 mg/l) and solution pH values (3.5-6) in batch mode. At optimum particle size (0.767 mm), biosorbent dosage (5 g/l) and initial solution pH (pH 6); crab shell recorded maximum copper and cobalt uptakes of 243.9 and 322.6 mg/g, respectively, according to Langmuir model. The kinetic data obtained at different initial metal concentrations indicated that biosorption rate was fast and most of the process was completed within 2h, followed by slow attainment of equilibrium. Pseudo-second order model fitted the data well with very high correlation coefficients (>0.998). The presence of light and heavy metal ions influenced the copper and cobalt uptake potential of crab shell. Among several eluting agents, EDTA (pH 3.5, in HCl) performed well and also caused low biosorbent damage. The biosorbent was successfully regenerated and reused for five cycles.


Incidental findings in maxillary sinus area on cone-beam-computed-tomographic-scans: A retrospective study with emphasis on gender and ethnicity.
The aim was to assess the presence of incidental-findings (IFs) on cone-beam computed tomography (CBCT) scans of faciomaxillary region with emphasis on gender and ethnicity. A retrospective analysis of incidental findings (IFs) in the maxillary sinus was performed. All CBCT-scans were performed using a Cone Beam 3D imaging system and examined using a software program. These images were taken for treatment planning for dental implant therapy of partially edentulous individuals. Four-hundred CBCT scans were retrospectively evaluated. Data regarding age, gender and ethnicity (Saudi Arabian, Egyptian, Filipino and Pakistani) of the patients was recorded. When P-value were lesser than 0.05, the difference was deemed significant. Four hundred CBCT-based scans were investigated. The IFs were seen in 30.2%, 32.1%, 35.1% and 34.4% individuals belonging to the Egyptian, Saudi Arabian, Pakistani and Filipino ethnicities, respectively. Mucosal-thickening was more often identified in Saudi-Arabian (P < 0.05), Pakistani (P < 0.05) and Filipino males (P < 0.05) than females in the respective ethnic group. There was no difference in the identification of IFs (mucous retention cysts, opacifications, sinus septa and sinus floor discontinuation) related to the maxillary sinus region among males belonging to the Egyptian, Saudi-Arabian, Filipino and Pakistani ethnic groups. The CBCT-based technology is valuable resource for the identification of IFs.


Correlation between adenosine triphosphate levels, dopamine release and electrical activity in the carotid body: support for the metabolic hypothesis of chemoreception.
An unsolved issue for the arterial chemoreceptors is the mechanism by which hypoxia and other natural stimuli lead to an increase of activity in the carotid sinus nerve. According to the 'metabolic hypothesis', the hypoxic activation of the carotid body (CB) is mediated by a decrease of the ATP levels in the type I cells, which then release a neurotransmitter capable of exciting the sensory nerve endings. Using an in vitro preparation of cat CB, we report that ATP levels in the CB do in fact decrease when the organs are exposed to moderate, short lasting hypoxia (5 min 20% O2). Additionally, we found that decreases in ATP levels induced by 2-deoxyglucose (2 mM) or sodium cyanide (0.1 mM) are closely correlated with dopamine release from type I cells and electrical activity in the carotid sinus nerve elicited by these agents. The possible cause-effect relationship of these events is discussed.


The issues and complexities of establishing methodologies to differentiate between vertical and horizontal impact mechanisms in the analysis of skeletal trauma: An introductory femoral test.
Understanding skeletal trauma characteristics is fundamental for the examination and interpretation of blunt force trauma (BFT). BFT is the most complex type of trauma to interpret based on the analysis of skeletal fractures alone, with comminuted fractures presenting additional complications to assess and interpret. Considerable variation exists within each type of BFT injury dependent on direction, magnitude of force, plus a myriad of biological/environmental factors. Given the complex processes governing the nature of BFT skeletal injuries determining whether differences between impact mechanisms and skeletal trauma can be quantified requires investigation. this study aims to determine the feasibility of quantifying outcomes between two separate loading conditions by using a formula created from transformed variables recorded from specific trauma cases involving BFT to the femur. Displacement, comminution, and femoral midshaft area data were recorded from full body postmortem computed tomography scans of 103 individuals (males, mean age 42.5, and females, mean age 48.9) where cause of death was the result of rapid horizontal deceleration impact events (pedestrian motor vehicular accidents, n = 59) and vertical (>3-metre falls, n = 44). These measurements were standardised and transformed into a continuous variable. Independent t-tests, binary logistic regression and K Nearest- Neighbours (KNN) were used to analyse the data. The standardised values showed mean group differences between falls (9.62) and pedestrian motor vehicular impacts (pedestrian MVAs) (9.53), however, these results were not statistically significant. The results indicate that similarities in variance between types of trauma outcomes and impact mechanisms demonstrate low equivalency (samples have limited differences), and the overall limitations in relying on using single elements to explain complex skeletal trauma outcomes.


Considerations for the safe prescribing and use of COX-2-specific inhibitors.
The majority of the "Australian COX-2-Specific Inhibitor (CSI) Prescribing Group" endorse the following points: CSIs are equivalent to non-steroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory agents. CSIs and NSAIDs modify symptoms but do not alter the course of musculoskeletal disease. CSIs do not eliminate the occurrence of ulcers or their serious complications, but are associated with considerably fewer peptic ulcers, slightly fewer upper GI symptoms and, according to published reports, fewer serious upper GI complications, notably bleeding, than CSIs and NSAIDs have similar effects on renal function and blood pressure. Whether any CSI poses a risk to cardiovascular safety remains subject to debate. Comorbidities and coprescribed drugs must be considered before initiating CSI (or NSAID) therapy. Patients prescribed CSIs (or NSAIDs) should be reviewed within the first few weeks of therapy to assess effectiveness, identify adverse effects and determine the need for ongoing therapy.


Preferential regulation of protein synthesis initiation complex formation by purine nucleotides.
A comparison of the affinities of eukaryotic initiation factor 2 and eukaryotic elongation factor 1 for GTP and GDP, and of the responses of initiation and elongation complex formation to various GTP mol fractions indicated that the initiation reaction was more sensitive to changes in the GTP: GDP ratio. In vitro regulation of the GTP: GDP ratio by the adenylate energy charge, a sensitive control parameter, also demonstrated a preference for regulation of formation of initiation complexes when compared to elongation complexes. These studies suggest that, based on the availability of energy, initiation is the rate-limiting step in the overall protein synthetic process.


In-situ synchrotron imaging, experimental, and computational investigations on the efficiency of Trametes versicolor laccase on detoxification of P-Cresyl Sulfate (PCS) Protein Bound Uremic Toxin (PBUT).
Protein bound uremic toxins (PBUTs) are small substances binding to larger proteins, mostly human serum albumin (HSA), and are challenging to remove by hemodialysis (HD). Among different classes of PBUTs, p-cresyl sulfate (PCS) is the most widely used marker molecule and major toxin, as 95 % is bound to HSA. PCS has a pro-inflammatory effect and increases both the uremia symptom score and multiple pathophysiological activities. High-flux HD to clear PCS leads to serious loss of HSA, which results in a high mortality rate. The goal of the present study is to investigate the efficacy of PCS detoxification in serum of HD patients using a biocompatible laccase enzyme from Trametes versicolor. Molecular docking was used to gain an in-depth understanding of the interactions between PCS and the laccase to identify the functional group(s) responsible for ligand-protein receptor interactions. UV-Vis spectroscopy and gas chromatography-mass spectrometry (GC-MS) were used to assess the detoxification of PCS. GC-MS was used to identify the detoxification byproducts and their toxicity was assessed using docking commutations. In situ synchrotron radiation micro-computed tomography (SR-µCT) imaging available at the Canadian Light Source (CLS) was conducted to assess HSA binding with PCS before and after detoxification with laccase and undertake the corresponding quantitative analysis. GC-MS analyses confirmed the detoxification of PCS with laccase at a concentration of 500 mg/L. The potential pathway of PCS detoxification in the presence of the laccase was identified. Increasing laccase concentration led to the formation of m-cresol, as indicated by the corresponding absorption in the UV-Vis spectra and a sharp peak on the GC-MS spectra. Our analysis provides insight into the general features of PCS binding on Sudlow site II, as well as insights into PCS detoxification product interactions. The average affinity energy for detoxification products was lower than that of PCS. Even though some byproducts showed potential toxicity, the level was lower than for PCS based on toxicity indexes (e.g., LD50/LC50, carcinogenicity, neurotoxicity, mutagenicity). In addition, these small compounds can also be more easily removed by HD compared to PCS. SR-µCT quantitative analysis showed adhesion of the HSA to a significant reduced extent in the presence of the laccase enzyme in bottom sections of the polyarylethersulfone (PAES) clinical HD membrane tested. Overall, this study opens new frontiers for PCS detoxification.


KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy.
Cardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy. Human and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR. The mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy. Our findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.


Utility of cyclic variation of heart rate score as a screening tool for sleep-disordered breathing in patients with heart failure.
Patients with sleep-disordered breathing have cyclic variation of heart rate (CVHR) in response to respiratory events. However, limited data are available regarding the utility of CVHR as a screening tool for sleep-disordered breathing in patients with mixed heart failure (HF) and those without HF. We enrolled consecutive patients with and without HF who underwent full polysomnographies with simultaneous Holter electrocardiogram monitoring. We determined the temporal position of the individual dips comprising the CVHR score using time-domain methods. The data of 101 patients, including 70 with and 31 without HF, were analyzed. The CVHR score was significantly correlated with the apnea-hypopnea index (r = .667, P < .001) and limits of agreement between the apnea-hypopnea index and CVHR score were -21.8 to 35.2. The receiver operating characteristic analysis demonstrated that the CVHR score (best cut-off of 23.5 events/h) identified severe sleep-disordered breathing with a sensitivity of 83.3%, specificity of 79.5%, and the area under the curve of 0.856. In addition, there was no interaction between the presence or absence of HF and the apnea-hypopnea index-CVHR score relationship (P = .323). The CVHR score, determined by Holter electrocardiogram monitoring, is a useful tool for evaluating sleep-disordered breathing even in patients with mixed HF and patients without HF. Yatsu S, Kasai T, Naito R, et al. Utility of cyclic variation of heart rate score as a screening tool for sleep-disordered breathing in patients with heart failure. J Clin Sleep Med. 2021;17(11):2187-2196.


Dynamics of protoporphyrin IX in the heme pocket of horseradish peroxidase.
The local motion of protoporphyrin IX in the heme pocket of horseradish peroxidase has been studied using fluorescence methods. The temperature dependence of the anisotropy and lifetime of a protoporphyrin IX-apo-horseradish peroxidase complex, dissolved in a solution of 80% glycerol and 20% buffer (0.1 M phosphate, pH 7.4), was determined. Anisotropy data were analyzed in terms of the thermal coefficient of the frictional resistance to fluorophore movement. The resultant 'Y' plot was characterized by three distinct slopes. The slope corresponding to the lowest temperature regime agreed with the value obtained for fluorophores not complexed with protein. The slope corresponding to an intermediate temperature was lower indicating a larger resistance to porphyrin rotation. At higher temperatures this resistance to rotation diminished as evidenced by the increased slope. These results are contrasted with those obtained with the protoporphyrin IX-apomyoglobin complex.


Reactive oxygen species mediated placental oxidative stress, mitochondrial content, and cell cycle progression through mitogen-activated protein kinases in intrauterine growth restricted pigs.
Intrauterine growth restriction (IUGR) remains a significant obstacle in pig production; however, information regarding the relationship between reactive oxygen species (ROS)-induced placental dysfunction and IUGR is still unknown. This study aimed to explore the placental redox status, mitochondrial content, cellular progression, and mitogen-activated protein kinase (MAPK) pathways in IUGR. Placental tissues were collected from normal intrauterine gestation (NIUG) and IUGR fetuses at delivery. Compared with the NIUG, placental ROS production, lipid peroxidation, and DNA damage were increased in IUGR. Placental mitochondrial DNA (mtDNA) content and mtDNA-encoded gene expression decreased in IUGR. Moreover, p21 phosphorylation increased, cyclin E expression decreased in IUGR cases, which showed senescence characteristics. Analysis of signaling pathways showed that the ERK1/2 phosphorylation increased whereas the p38 and JNK phosphorylation decreased in IUGR. In cultured porcine trophectoderm (pTr) cells, exogenous H2O2 increased intracellular ROS production, decreased cell viability in a dose-dependent manner. Cell cycle distribution was found to arrest in S and G2/M phases. Our findings suggested that IUGR was associated with greater placental ROS and oxidative injury, which might be a factor that resulted in lower mitochondrial content, microvilli loss and senescence, and activation of MAPK pathways.


Applications of Frameless Image-Guided Robotic Stereotactic Radiotherapy and Radiosurgery in Pediatric Neuro-Oncology: A Systematic Review.
CyberKnife-based robotic radiosurgery (RRS) is a widely used treatment modality for various benign and malignant tumors of the central nervous system (CNS) in adults due to its high precision, favorable safety profile, and efficacy. Although RRS is emerging in pediatric neuro-oncology, scientific evidence for treatment indications, treatment parameters, and patient outcomes is scarce. This systematic review summarizes the current experience and evidence for RRS and robotic stereotactic radiotherapy (RSRT) in pediatric neuro-oncology. We performed a systematic review based on the databases Ovid Medline, Embase, Cochrane Library, and PubMed to identify studies and published articles reporting on RRS and RSRT treatments in pediatric neuro-oncology. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied herein. Articles were included if they described the application of RRS and RSRT in pediatric neuro-oncological patients. The quality of the articles was assessed based on their evidence level and their risk for bias using the original as well as an adapted version of the Newcastle Ottawa Quality Assessment Scale (NOS). Only articles published until 1 August 2021, were included. A total of 23 articles were included after final review and removal of duplicates. Articles reported on a broad variety of CNS entities with various treatment indications. A majority of publications lacked substantial sample sizes and a prospective study design. Several reports included adult patients, thereby limiting the possibility of data extraction and analysis of pediatric patients. RRS and RSRT were mostly used in the setting of adjuvant, palliative, and salvage treatments with decent local control rates and acceptable short-to-intermediate-term toxicity. However, follow-up durations were limited. The evidence level was IV for all studies; the NOS score ranged between four and six, while the overall risk of bias was moderate to low. Publications on RRS and RSRT and their application in pediatric neuro-oncology are rare and lack high-quality evidence with respect to entity-related treatment standards and long-term outcomes. The limited data suggest that RRS and RSRT could be efficient treatment modalities, especially for children who are unsuitable for surgical interventions, suffer from tumor recurrences, or require palliative treatments. Nevertheless, the potential short-term and long-term adverse events must be kept in mind when choosing such a treatment. Prospective studies are necessary to determine the actual utility of RRS and RSRT in pediatric neuro-oncology.


LDL-cholesterol reduction in patients with hypercholesterolemia by modulation of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase.
To review the profile of ETC-1002, as shown in preclinical and clinical studies, including LDL-cholesterol (LDL-C)-lowering activity and beneficial effects on other cardiometabolic risk markers as they relate to the inhibition of adenosine triphosphate-citrate lyase and the activation of adenosine monophosphate-activated protein kinase. ETC-1002 is an adenosine triphosphate-citrate lyase inhibitor/adenosine monophosphate-activated protein kinase activator currently in Phase 2b clinical development. In seven Phase 1 and Phase 2a clinical studies, ETC-1002 dosed once daily for 2-12 weeks has lowered LDL-C and reduced high-sensitivity C-reactive protein by up to 40%, with neutral to positive effects on glucose levels, blood pressure, and body weight. Importantly, use of ETC-1002 in statin-intolerant patients has shown statin-like lowering of LDL-C without the muscle pain and weakness responsible for discontinuation of statin use by many patients. ETC-1002 has also been shown to produce an incremental benefit, lowering LDL-C as an add-on therapy to a low-dose statin. In over 300 individuals in studies of up to 12 weeks, ETC-1002 has been well tolerated with no serious adverse effects. Because adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase play central roles in regulating lipid and glucose metabolism, pharmacological modulation of these two enzymes could provide an important therapeutic alternative for statin-intolerant patients with hypercholesterolemia.


Catheter ablation of tachycardia arising from the pulmonary venous atrium after surgical repair of congenital heart disease.
Tachycardia arising from the pulmonary venous atrium (PVA) has not been adequately characterized in the setting of surgically repaired congenital heart disease (CHD). The purpose of this study was to determine the mechanisms, approach, and outcomes of catheter ablation of PVA tachycardia after CHD repair. The adult CHD procedural database was searched for consecutive ablation procedures over a 4-year period. Procedural characteristics of the population with tachycardia arising from the PVA were compared to those without PVA tachycardia. Groups were classified as (1) biventricular CHD, (2) single ventricle, or (3) d-transposition of the great arteries (DTGA)-baffle. Complete 3-dimensional mapping was possible for 113 of 124 sustained tachycardias during 81 procedures. Of these, 31 (19%) arose from the PVA, including 11 (15%) tachycardias in biventricular CHD, 8 (31%) in single ventricle, and 12 (80%) in DTGA-baffle procedures. Intra-atrial reentrant tachycardia was less frequently observed in the PVA vs the systemic venous atrium (SVA) (P = .012). Independent predictors of PVA tachycardia were absence of biventricular CHD (odds ratio 0.19, confidence interval 0.05-0.64, P = .010) and ipsilateral atrial surgery (odds ratio 15.7, confidence interval 4.8-59.9, P <.001). PVA procedure duration was greater than SVA-only procedures (median 5.3 hours vs 4.0 hours, P = .012), but acute success was similar (87% vs 82%, respectively, P = NS). PVA tachycardia is not unusual after surgical repair of CHD. Predictors include ipsilateral atrial surgery and absence of biventricular CHD. Such procedures involve increased complexity and unique tachycardia substrates but appear equally amenable to catheter ablation.


On selection dynamics for competitive interactions.
In this paper, we are interested in an integro-differential model that describe the evolution of a population structured with respect to a continuous trait. Under some assumption, we are able to find an entropy for the system, and show that some steady solutions are globally stable. The stability conditions we find are coherent with those of Adaptive Dynamics.


Meta-Analysis on the Impact of Ventricular Arrhythmias on Mortality in Patients With Continuous Flow Left Ventricular Assist Devices.
Patients with continuous flow left ventricular assist devices (CFLVADs) have an increased risk of ventricular arrhythmias (VA), but the impact of VA on survival is unclear. A systematic search of electronic databases was conducted to identify studies that reported the impact of VA on all-cause mortality and right ventricular failure (RVF) in patients with CFLVAD. The Mantel-Haenszel method was used to calculate the 95% confidence interval (CI) and pooled risk ratio (RR) with a random-effects model. A total of 19 observational studies with 4,544 patients and a median follow-up of 18.5 months (interquartile range 11.5 to 26.4) were included. There was statistically significantly higher mortality in patients with any VA than in those with no VA after CFLVAD implantation (RR 1.33, 95% CI 1.01 to 1.75, p = 0.04, I2 = 78%). On sensitivity analysis, after removing the largest study by Rehorn et al,10 the association between overall mortality and VA was lost, suggesting that these results should be interpreted with caution. Early VA developing within 30 days after implantation was associated with a higher risk of mortality (RR 1.37, 95% CI 1.15 to 1.63, p <0.01, I2 = 52%), whereas late VA developing after 30 days after CFLVAD implantation was not associated with any significant difference in mortality (RR: 1.00; 95% CI: 0.80 to 1.24; p = 0.98, I2 = 35%). In addition, there was a statistically significant higher risk of RVF in patients with VA than in those with no VA (RR 1.58, 95% CI 1.20 to 2.08, p <0.01, I2 = 0%). In conclusion, in patients with CFLVAD, the development of any VA was associated with a 33% higher risk of all-cause mortality. Early VA developing within 30 days after implantation was significantly associated with a higher risk of mortality, whereas late VA was not associated with mortality. VA after left ventricular assist device was significantly associated with a higher risk of developing RVF.


Protective role of ginseng in endometriosis during covid-19.
The coronavirus disease 2019 (COVID) pandemic began in December 2019. Many countries have implemented restrictions such as mandatory mask wearing and social distancing. These measures have caused diverse and complex health problems, particularly in women's health, anxiety, and depression. This review examines an alternative approach to the treatment of endometriosis during the COVID pandemic. The efficacy of ginseng with anti-inflammatory activity and ability to relieve or prevent symptoms of endometriosis is discussed and reviewed.


Prognostic value of induction of atrial fibrillation before and after pulmonary vein isolation.
Apart from pulmonary vein isolation, catheter ablation of atrial fibrillation (AF) lacks reliable electrophysiological endpoints. The present study investigated the prognostic value of changes in AF inducibility due to ablation. Between 10/2006 and 10/2009 121 patients referred for catheter ablation of symptomatic, drug refractory paroxysmal AF were included. Sinus rhythm immediately before ablation was a prerequisite for study entry. Two respective attempts to induce AF (>1min) by decremental coronary sinus stimulation before and after ablation were performed. A total of 121 patients aged 59.5±10.4years undergoing pulmonary vein isolation due to paroxysmal AF were included. The median follow-up duration was 12.1months [quartiles: 6.5-20.3months]. In 36 (30%) patients AF was inducible before, but not after ablation. Forty-nine (41%) patients were neither inducible before nor after the procedure, whereas 25 patients (21%) displayed unchanged inducibility. In 11 patients (9%) AF was inducible only after ablation. Patients with inducibility solely after the ablation had the highest risk of AF recurrence (HR 6.71 [95%-CI 2.76-16.30], p=0.0005) compared to patients without inducibility before and after the procedure. The results of attempted AF induction before and after ablation have significance with respect to ablation outcome. Both patient groups with either unchanged inducibility or facilitated induction after ablation had the highest recurrence rates of AF.


Formation pathways and precursors of furfural during Zhenjiang aromatic vinegar production.
As a flavor and quality parameter, furfural has potential undesirable effects. This study aimed to elucidate furfural formation, including generation, pathways, and possible precursors during the production of Zhenjiang aromatic vinegar. A cereal vinegar model, rich in saccharides, amino acids, and organic acids, was used to explore the potential precursors. Furfural and 5-hydroxymethylfurfural (HMF) mainly generated during the decoction process, but the HMF also increased during the aging process. Three pathways were found to coexist for the formation of furfural: (i) the Maillard reaction induced by saccharides and nitrogenous compounds, (ii) the direct cleavage of pentose, and (iii) indirect conversion from pentosan, which only made a minor contribution. Furfural was not formed from HMF or l-ascorbic acid in vinegar. Instead, ribose, xylose, arabinose, galacturonic acid, glucuronic acid, and pentosan were the main precursors. These insights may be useful for the risk/benefit balance and improve the flavor quality and safety.


A mitochondria-targeted thiazoleorange-based photothermal agent for enhanced photothermal therapy for tumors.
Organic small molecules with near-infrared (NIR) absorption hold great promise as the phototheranostic agents for clinical translation by virtue of their inherent merits such as well-defined chemical structure, high purity and good reproducibility. Probes that happen to be based on cyanine dyes exhibit strong NIR-absorbing and efficient photothermal conversion, representing a new class of photothermal agents (PAs) for photothermal therapy (PTT), and taking into account the heat susceptibility of Mitochondria (Mito), we designed and prepared a mitochondria-targeted organic small molecule (Mito-BWQ) based on thiazole orange maternal unit that can effectively kill tumor cells through the hyperpyrexia generated in the lesions under exogenous laser irradiation. The Confocal laser scanning microscope was employed to determine the preferential targeting of Mito-BWQ to the mitochondria of MCF-7 cells and U87 cells. When subjected to 600 nm laser radiation, Mito-BWQ produced an increase in temperature in test systems and this increase was dependent on both the laser power and probe concentration. In vitro tests, cytotoxicity was observed when cells were incubated with Mito-BWQ and exposed to laser irradiation. The PTT in vivo also showed that Mito-BWQ performed remarkably in tumor inhibition. This study thus provides a vital starting point for the creation of thiazole orange-based PTT formulations and promotes further advances in the field of PAs-based anticancer research and therapy.


A simplified scoring model for predicting bacteremia in the unscheduled emergency department revisits: The SADFUL score.
Bacteremia is a severe complication of infectious disease. Patients with a high bacteremia risk in the emergency department (ED) but misidentified would lead to the unscheduled revisits. This study aimed to develop a simplified scoring model to predict bacteremia in patients with unscheduled ED revisits. Adult patients with unscheduled ED revisits within 72 h with a final diagnosis of infectious disease were retrospectively included. The development cohort included patients visiting the ED from January 1, 2019 to December 31, 2021. Internal validation was performed in patients visiting the ED from January 1, 2022 to March 31, 2022. Variables including demographics, pre-comorbidities, triage levels, vital signs, chief complaints, and laboratory data in the index visit were analyzed. Bacteremia was the primary outcome determined by blood culture in either index visits or revisits. The SADFUL score for predicting bacteremia comprised the following predictors: "S"egmented neutrophil percentage (+3 points), "A"ge > 55 years (+1 point), "D"iabetes mellitus (+1 point), "F"ever (+2 points), "U"pper respiratory tract symptoms (-2 points), and "L"eukopenia (2 points). The area under receiver operating characteristic curve with 95% confidence interval in the development (1802 patients, 190 [11%] with bacteremia) and the validation cohort (134 patients, 17 [13%] with bacteremia) were 0.78 (0.74-0.81) and 0.79 (0.71-0.88), respectively. The SADFUL score is a simplified useful tool for predicting bacteremia in patients with unscheduled ED revisits. The scoring model could help ED physicians decrease misidentification of patients at a high risk for bacteremia and potential complications.


BRCA2 mutation in Icelandic prostate cancer patients.
Molecular genetic analysis of prostate cancer has gained considerable attention in recent years. The hope is to find genetic markers that can help to determine which patients are likely to develop a progressive or lethal disease and would therefore benefit from early treatment. The BRCA2 gene on chromosome 13 has been associated with familial male and female breast cancer. A founder mutation in this gene has been detected in the Icelandic population. This is a 5-bp deletion that leads to an early termination and truncated protein. Clustering of prostate cancers in some of the Icelandic BRCA2 families implies that mutation carriers are at increased risk of developing cancer of the prostate. The aim of the study was to investigate this mutation in Icelandic prostate cancer patients related to BRCA2 positive breast cancer probands and to estimate the prevalence of this mutation in unselected prostate cancer patients. To examine the potential role of this mutation in prostate cancer we analyzed prostate cancer cases from 16 BRCA2 families and all available samples from individuals diagnosed with prostate cancer in Iceland over a period of 1 year. The risk ratio of prostate cancer was 4.6 (1.9-8.8) in first-degree relatives and 2.5 (1.2-4.6) in second-degree relatives of the 16 BRCA2 positive breast cancer probands. Of 26 prostate cancer cases found in these families 12 were analyzed, and 8 of these (66.7%) had the BRCA2 mutation. All of these patients developed an advanced disease, and all have died of prostate cancer (median survival 22.5 months). Among unselected cases 3.1% (2/65) had the mutation and developed an advanced disease as well. This specific mutation in the BRCA2 gene is found in a subset of Icelandic prostate cancer cases and appears to be a marker for poor prognosis.


Prognostic significance of oxidative DNA damage evaluated by 8-hydroxy-2'-deoxyguanosine in patients undergoing radical nephrectomy for renal cell carcinoma.
To determine whether the degree of oxidative DNA damage in renal cell carcinoma (RCC) can be used as a useful prognostic predictor for patients who undergo radical nephrectomy. We measured 8-hydroxy-2'-deoxyguanosine (8-OHdG), one of the most commonly used markers for evaluating oxidative stress, in DNA isolated from 72 RCC specimens, as well as adjacent normal kidney tissue using a quantitative sandwich enzyme-linked immunosorbent assay. The mean value of 8-OHdG in RCC was significantly greater than that in the adjacent normal tissue. The level of 8-OHdG in RCC compared with that in normal tissue (8-OHdG ratio) was significantly associated with other prognostic parameters, including mode of detection, maximal tumor size, distant metastasis, pathologic stage, tumor grade, and microscopic venous invasion. Furthermore, cancer-specific survival in patients with an elevated 8-OHdG ratio was significantly lower than that in patients with a normal 8-OHdG ratio; however, multivariate analysis using a Cox proportional hazards model showed that maximal tumor size and distant metastasis could be used as independent predictors of cancer-related death. These findings suggest that despite the lack of independent significance, the 8-OHdG ratio could be a useful prognostic indicator for patients with RCC; therefore, careful follow-up should be considered in those with an elevated 8-OHdG ratio.


Publisher Correction: Shape and fluctuations of frustrated self-assembled nano ribbons.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Urban greenery cushions the decrease in leisure-time physical activity during the COVID-19 pandemic: A natural experimental study.
The coronavirus disease 2019 (COVID-19) pandemic and related social distancing measures have altered the daily lifestyles of people worldwide. Although studies on this disease are emerging rapidly, less is known about the impacts of COVID-19 and urban greenery on leisure-time physical activity, which is critical to maintain health for urban residents during the pandemic. In this study, we used a natural experimental research design to identify whether urban greenery cushions the decrease in leisure-time physical activity caused by the pandemic and related social distancing measures in a high-density city. The two-wave physical activity data (before and during the pandemic) were collected for urban residents in neighborhoods with high or low levels of greenery. The results of difference-in-differences model suggest that urban greenery mitigated the decrease in physical activity during the pandemic. People who lived in greener neighborhoods experienced a lesser decrease in the leisure-time physical activity level than those who lived in less green neighborhoods. Additionally, people who lived in greener neighborhoods experienced increased levels of physical activity related to visits to country parks during the pandemic. These findings suggest that urban green spaces play a significant role in shaping physical activity and providing a refuge for the public during crises. Our study is among the first to investigate the impact of urban greenery on pandemic-induced changes in leisure-time physical activity in densely populated Asian cities, and our findings shed light on the potential protective role of urban greenery on public health during the COVID-19 pandemic and beyond.


A public health approach to the prevention of inhibitors in hemophilia.
The development of an antibody in people with hemophilia to products used in the treatment and prevention of bleeding, also referred to as an inhibitor, is the most serious complication of hemophilia care today. CDC, together with healthcare providers, consumer organizations, hemophilia organizations, and federal partners, has developed a public health agenda to prevent the development of inhibitors. This paper describes a public health approach that combines a national surveillance program with epidemiologic, laboratory, and prevention research to address knowledge gaps in rates and risk factors for inhibitor development, and in knowledge and behaviors of patients and providers, in addition to screening and treatment practices.


Genetic control of soluble NAD-dependent sorbitol dehydrogenase in Drosophila melanogaster.
Experiments utilizing standard techniques of cell fractionation and disc electrophoresis have revealed the presence of three distinctly different enzymes which catalyze the oxidation of D-sorbitol in crude extracts of Drosophila melanogaster adults. These include (1) a soluble NAD-dependent sorbitol dehydrogenase (NAD-SoDHS), (2) a mitochondrial NAD-dependent sorbitol dehydrogenase (NAD-SoDHm), and (3) a soluble NADP-dependent sorbitol dehydrogenase (NADP-SoDH). The structural gene for NAD-SoDHS has been mapped to a locus between 65.3 and 65.6 on the third chromosome by means of an electrophoretic variant and a low-activity allele. Through the use of segmental aneuploidy, this gene has been localized to the region limited by salivary bands 91B-93F. Because mutants which alter either the activity or electrophoretic effect on the mitochondrial or NADP-dependent forms, it is suggested that the enzymes in this system are coded for autonomously by different genes.


Evidence for the importance of land use, site characteristics and vegetation composition for rooting in European Alps.
Plant rooting strongly affects most hydrological, biogeochemical and ecological processes in terrestrial ecosystems, as it presents the main pathway for carbon, water and nutrient transfer from soil to the atmosphere and is a key factor in stabilizing the soil layer. Few studies have actually investigated the link between phytosociological and structural vegetation composition and diversity in soil rooting parameters. Our study provides a comprehensive evaluation of plant cover and diversity effects on rooting parameters dependent on different land-use types along a north-south transect in the Eastern Alps. We conducted field studies of root biomass, rooting density and rooting depth for the six main land-use types: intensively and lightly used hay meadows, pastures, arable land, agriculturally unused grasslands and forests. The variation in rooting parameters was explained by different aspects of species and functional richness, species and functional composition, functional traits, abundance of key species and site variables depending on the land-use types. Our results showed that different characteristics of biodiversity explained the variance in root parameters (mass, density and depth) to a high degree (determination coefficient R2 values varied between 0.621 and 0.891). All rooting parameters increased with increasing plant species richness, as well as with a higher diversity of plant functional traits. The inclusion of site parameters significantly increased the explained variance, while we could not find evidence for key species and their abundance to provide additional explanatory power. Allowing the effects to vary depending on land-use types turned out to be a necessity supporting the importance of considering land-use types for rooting. The findings indicate that vegetation composition has a clear relationship with rooting parameters across different habitats in the European Alps. As the effect of plant composition differs with respect to the land-use type, rooting can be monitored by land management to achieve the desired benefits. For example, intensified rooting through extensive management decreases erosion risk and increases carbon uptake.


Mineralization regulation and biological influence of bioactive glass-collagen-phosphatidylserine composite scaffolds.
Biomimetic scaffolds are appealing products for the repair of bone defects using tissue engineering strategies. In the present study, novel biomimetic composite scaffolds, with similar properties to natural bone, were prepared, blended and cross-linked with bioactive glass, type I collagen and phosphatidylserine. When exposed to cell culture solution in the absence of a cellular source, the composite scaffolds form crystals with octahedral structure. These crystals are similar to the products derived from MC3T3-E1 cell mineralization within the composite scaffolds, with respect to both composition and morphology. Furthermore, crystals with octahedral structure were observed to develop into plate-like hydroxyapatite. The bio-mineralization behavior of the composite scaffolds is likely influenced by inorganic components. Finally, a rabbit tibia defect model shows that the highly bioactive properties of the investigated composites result in excellent bone repair.


Venous thromboembolism is rare after total hip and knee joint arthroplasty with long thromboprophylaxis in Finnish fast-track hospitals.
Pharmacological thromboprophylaxis effectively prevents venous thromboembolism (VTE) after total knee (TKA) and total hip arthroplasty (THA). Less is known about the influence of fast-track arthroplasty on VTE risk. We conducted a register-based study to determine the incidence of VTE after fast-track TKA and THA in Finland using long thromboprophylaxis. All primary TKAs and THAs operated during 2015-2016 in 3 fast-track hospitals were identified from the Finnish Arthroplasty Register. Pulmonary embolism (PE) and deep vein thrombosis (DVT) diagnosed in this patient cohort within 90 days of surgery were identified from the Finnish Hospital Discharge Register. The recommended length of thromboprophylaxis was 10 to 14 days for TKA and 28 days for THA during study period. During the study period, 3 831 THAs, 4 394 TKAs and 286 bilateral TKAs (BTKAs) were performed. Of all these patients, 60% were females. Venous thromboembolism (VTE) incidence within 90 days of surgery was 0.3% (95% CI 0.2-0.4). These VTEs comprised 10 PEs and 15 DVTs. None of the VTE patients´ died within the 90-day period. VTE incidence is low in Finnish fast-track TKA and THA patients with long thromboprophylaxis.


Electrocardiogram-based algorithm to predict the left ventricular lead position in recipients of cardiac resynchronization systems.
Biventricular pacing is associated with various electrocardiographic patterns depending on the position of the left ventricular (LV) lead. We aimed to develop an electrocardiogram-based algorithm to predict the position of the LV lead. The algorithm was developed in 100 consecutive recipients of cardiac resynchronization therapy (CRT) systems. QRS axis, morphology, and polarity were analyzed with a view to define the specific electrocardiographic characteristics associated with the various LV lead positions. The algorithm was prospectively validated in 50 consecutive CRT device recipients. The first analysis of the algorithm was the QRS morphology in V(1). A positive R wave in V(1) suggested LV lateral or posterior wall stimulation. A QS pattern was specific of anterior LV leads. In the presence of an R wave in V(1), V(6) was analyzed to distinguish between an inferior and anterior LV lead. Inferior leads were never associated with a positive V(6). To differentiate between lateral and posterior positions, we analyzed the pattern in V(2). Lateral leads were associated with an R morphology in V(1) and a negative V(2). Posterior leads were associated with an R morphology in V(1) and V(2). The algorithm allowed a reliable distinction between an inferior or anterior and a lateral or posterior lead position in 90% of patients. Inferior, anterior, lateral, and posterior positions were reliably distinguished in 80% of patients. This algorithm predicted the position of the LV lead with a high sensitivity and predictive value.


Synthesis, antimicrobial evaluation and QSAR analysis of novel nalidixic acid based 1,2,4-triazole derivatives.
Novel nalidixic acid based 1,2,4-triazole derivatives were synthesized and characterized using spectral techniques like (1)H NMR, (13)C NMR, IR and mass spectrometry. All these compounds were screened for antimicrobial activity against five bacteria and two pathogenic fungi. Most of these compounds showed better antimicrobial activity than the parent compound, 4-amino-5-mercapto-1,2,4-triazole. Among all the screened compounds, 3-{6-(2-chlorophenyl)-1,2,4-triazolo [3,4-b] [1,3,4]thiadiazol-3-yl}-1-ethyl-7-methyl-1,8-naphthyridin-4(1H)-one (23) was emerged as promising antimicrobial agent (MIC = 16 μg/mL). Quantitative structure activity relationship (QSAR) analysis was carried out using various distance-based topological indices, steric and hydrophobic parameters. Based on the QSAR analysis it is indicative that lipophilic and steric parameters are the pre-requisites for these molecules to act as potent antimicrobial agents.


Characterization of pain-related behaviors, changes in bone microarchitecture and sensory innervation induced by chronic cadmium exposure in adult mice.
Because of the relative lack of understanding of the neurobiological mechanisms that drive toxic effects of cadmium in bone, the purpose of this study was to characterize a preclinical model of chronic cadmium exposure. Adult male C57BL/6 J mice were exposed to cadmium 25 mg/L (as CdCl2) in drinking water for 16 weeks. During this time, pain-related behaviors including hindpaw mechanical sensitivity and vertical rears were evaluated every four weeks. We assessed changes in bone microarchitecture at the femoral neck and L5 vertebra by microcomputed tomography and quantified the density of nerve fibers expressing PGP 9.5 (a pan-neuronal marker) and CGRP (a marker of sensory nerve fibers subfamily) at the femoral neck and glabrous skin of the hindpaw using immunohistochemistry. Cadmium exposure produced mechanical hypersensitivity in both hindpaws along with decreased rearing activity (surrogate for musculoskeletal-related pain) without affecting the horizontal activity (a measure of locomotor behavior) in comparison to the control group. Intraperitoneal acute treatment with morphine and gabapentin reversed pain-related behaviors in cadmium-exposed mice. Furthermore, exposure to cadmium resulted in significant trabecular bone deterioration at the femoral neck and L5 vertebra. We also observed a significant reduction in the density of both CGRP+ and PGP 9.5+ nerve fibers in the femoral neck, but not in the hindpaw glabrous skin, suggesting tissue-dependent neurotoxicity. This model may help in developing a mechanism-based understanding of the factors that generate and maintain musculoskeletal pain and bone loss caused by chronic cadmium exposure and in translating these findings into new therapies for treating cadmium-induced bone toxicity.


Mechanism of induction of heme oxygenase by metalloporphyrins in primary chick embryo liver cells: evidence against a stress-mediated response.
Heme oxygenase catalyzes the first and rate-controlling step in heme catabolism. One of the two forms of heme oxygenase (heme oxygenase-1) has been shown to be increased by heme, metals, and in some systems, by certain environmental stresses. However, it remains uncertain whether heme induces hepatic heme oxygenase-1 by a general stress response, or a specific heme-dependent cellular response. The work communicated here explores this issue by examining possible mechanisms whereby heme and other metalloporphyrins induce heme oxygenase-1 in normal liver cells. Primary cultures of chick embryo liver cells were tested for their ability to increase heme oxygenase mRNA after exposure to selected metalloporphyrins (heme, chromium mesoporphyrin, cobalt protoporphyrin and manganese protoporphyrin). The ability of antioxidants to decrease metalloporphyrin-mediated induction of heme oxygenase-1 mRNA was also tested. Our results indicate that: 1) the increase in heme oxygenase-1 mRNA mediated by heme or other metalloporphyrins may involve a short-lived protein(s) since the increase was prevented by several inhibitors of protein synthesis; and 2) in normal liver cells, heme-dependent oxidative stress does not play a key role in the heme-mediated induction of heme oxygenase-1. We conclude that heme and other non-heme metalloporphyrins induce heme oxygenase-1 through a mechanism requiring protein synthesis, not because metalloporphyrins increase cellular oxidative or other stress.


The pediatrician's concept of the normal adolescent.
Complete medical assessment of an adolescent requires understanding of the normal psychological state, including self-image. To determine the pediatrician's knowledge about the self-image of normal adolescents, 33 house staff and 36 attending pediatricians in a major teaching center completed the Offer Physician-Adolescent Questionnaire (OPAQ), a scale that measures adult perceptions of adolescent self-image. Forty-one male and 28 female pediatricians completed the 50-item questionnaire as they believed a "mentally healthy, well-adjusted adolescent" would. Pediatricians' responses did not differ by sex, age, or status as resident or attending. Percentage endorsements for each item were converted to standard scores for 11 scales. The scale scores were then compared with previously established norms for healthy adolescents and adolescents with cystic fibrosis. Pediatricians accurately predicted the normal adolescent responses for only two scales: vocational and educational goals and superior adjustment. Pediatricians responded more positively than the adolescents to items on the idealism scale. For the remaining eight scales, the pediatricians responded more negatively than did normal adolescents and teens with cystic fibrosis. The pediatricians' view of normal adolescent self-image seems to be more pessimistic than what adolescents report.


Molecular mechanism and energetics of coupling between substrate binding and product release in the F1-ATPase catalytic cycle.
F1-ATPase is a motor protein that couples the rotation of its rotary [Formula: see text] subunit with ATP synthesis or hydrolysis. Single-molecule experiments indicate that nucleotide binding and release events occur almost simultaneously during the synthesis cycle, allowing the energy gain due to spontaneous binding of ADP to one catalytic [Formula: see text] subunit to be directly harnessed for driving the release of ATP from another rather than being dissipated as heat. Here, we examine the unknown mechanism of this coupling that is critical for an exceptionally high mechanochemical efficiency of F1-ATPase by means of all-atom free-energy simulations. We find that nondissipative and kinetically fast progression of the motor in the synthesis direction requires a concerted conformational change involving the closure of the ADP-binding [Formula: see text] subunit followed by the gradual opening of the ATP-releasing [Formula: see text] subunit over the course of the 30 to 40° rotary substep of the [Formula: see text] subunit. This rotary substep, preceding the ATP-dependent metastable state, allows for the recovery of a large portion of the ADP binding energy in the conformation of ATP-bound [Formula: see text] that gradually adopts the low-affinity conformation, captured also by the recent cryo-EM structure of this elusive state. The release of ATP from this nearly open conformation leads to its further opening, which enables the progression of the motor to the next catalytic metastable state. Our simulations explain this energy conversion mechanism in terms of intersubunit and ligand-protein interactions.


delta-9-tetrahydrocannabinol (THC) increases brain prostaglandins in the rat.
Intraperitoneal administration of 9-trans-delta-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, in doses of 0.5, 1.0 and 2.0 mg/kg, produced a dose-related increase in the brain concentrations of prostaglandin (PG) E2 and PGF2 alpha in male rats 4 h after THC administration, as assessed by radioimmunoassay. A time-course investigation indicated that THC (2 mg/kg, IP) induced maximal increases in rat brain concentration of both PGs 2 and 4 h after administration; PG levels declined appreciably by 8 h and were normal by 24 h. A time-course study on the hexobarbitone (100 mg/kg, IP)-induced hypnosis potentiating effect of THC (2.0 mg/kg, IP) in male rats revealed that this pharmacological action of the cannabinoid correlated well with the time-course of the THC-induced increase in rat brain PG concentrations. The present study lends support to earlier reports contending that PGs may mediate some of the central actions of THC.


Perioperative adverse events attributed to α2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis.
Several systematic reviews have reported the benefits of perioperative α2-adrenoceptor agonist use for various conditions, but safety evidence is poorly documented. We performed a systematic review focusing on adverse events. We searched the MEDLINE, Embase, LILACS, Cochrane, and Clinical Trials Register databases for RCTs comparing the effects of α2-adrenoceptor agonists and placebo during non-cardiovascular surgery under general anaesthesia, for any indication, in patients not at risk of cardiovascular events. The primary outcome was the incidence of severe adverse events during or after α2-adrenoceptor agonist administration. The secondary endpoints were other adverse events. A meta-analysis was carried out on the combined data. Evidence quality was rated by the Grading of Recommendations Assessment, Development and Evaluation method. We included 56 studies (4868 patients). Our review, based on moderate-quality evidence, revealed that hypotension occurred frequently during the preoperative and postoperative periods, for both clonidine and dexmedetomidine. Bradycardia was reported only with dexmedetomidine. In contrast, dexmedetomidine seemed to protect against intraoperative hypertension and tachycardia. Subgroup analysis suggested that the risk of hypotension and bradycardia persisted after cessation of treatment. Interestingly, intraoperative hypotension and postoperative bradycardia were not observed with a bolus dosage of dexmedetomidine less than 0.5 μg kg-1 or with continuous administration alone. Pooled data for the incidence of adverse events associated with use of α2-adrenoceptor agonists in various perioperative contexts provide high-confidence evidence for a risk of hypotension and bradycardia, and protective effects against hypertension and tachycardia. CRD42017071583.


[Quality assurance using routine data. Is outcome quality now measurable?].
Health service quality in Germany can be shown by the data from the external quality assurance program (BQS) but as these records are limited to the period of in-hospital stay no information about outcome after discharge from hospital can be obtained. Secondary routine administrative data contain information about long-term outcome, such as mortality, subsequent revision and the need for care following surgical treatment due to a hip fracture.Experiences in the use of secondary data dealing with treatment of hip fractures from the BQS are available in our department. In addition we analyzed routine administrative data from the health insurance companies Knappschaft Bahn-See and AOK in a cooperative study with the WidO (scientific institute of the AOK). These routine data clearly show a bias because of poor quality in coding as well as broad interpretation possibilities of some of the ICD-10 codes used.Consequently quality assurance using routine data is less valid than register-based conclusions. Nevertheless medical expertise is necessary to avoid misinterpretation of routine administrative data.


Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.
Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.


Physicians as mothers: breastfeeding practices of physician-mothers in Newfoundland and Labrador.
To determine the initiation rate and duration of breastfeeding among female physicians in Newfoundland and Labrador, and to identify demographic factors that might influence duration of breastfeeding in this population. Mailed survey. Newfoundland and Labrador. One hundred eighty licensed female physicians. Self-reported initiation of breastfeeding for each baby born, duration of breastfeeding in number of months, and reasons for ending breastfeeding. The response rate was 68%. The breastfeeding initiation rate among respondents was 96.6%. More physicians who graduated in 1980 or later breastfed for longer periods (63.9% vs 33.3%, P = .008). More family doctors than specialists breastfed their babies for longer periods (65.5% vs 33.3%, P = .004). More physicians whose partners were working part-time breastfed for longer periods than physicians whose partners were working full-time (83.3% vs 50.8%, P = .037). Other factors, such as age, income, maternity leave and benefits, part-time or full-time work, and urban or rural practice, did not affect duration of breastfeeding. Personal issues accounted for 51% of respondents' ending breastfeeding; baby issues accounted for 38%, practice issues for 33%, medical school issues for 4%, and societal issues for 1%. The breastfeeding initiation rate among female physician respondents in Newfoundland and Labrador was 96.6%; more than 50% of these physicians breastfed for longer than 7 months. Physicians graduating in 1980 or later breastfed their babies for longer.


Cardiovascular Magnetic Resonance Imaging-Incremental Value in a Series of 361 Patients Demonstrating Cost Savings and Clinical Benefits: An Outcome-Based Study.
This study was designed to assess the clinical impact and cost-benefit of cardiovascular magnetic resonance imaging (CMR). In the face of current health care cost concerns, cardiac imaging modalities have come under focused review. Data related to CMR clinical impact and cost-benefit are lacking. Retrospective review of 361 consecutive patients (pts) who underwent CMR exams was conducted. Indications for CMR were tabulated for appropriateness criteria. Components of the CMR exam were identified along with evidence of clinical impact. The cost of each CMR exam was ascertained along with cost savings attributable to the CMR exam for calculation of an incremental cost-effectiveness ratio. A total of 354 of 361 pts (98%) had diagnostic quality studies. Of the 361 pts, 350 (97%) had at least 1 published Appropriateness Criterion for CMR. A significant clinical impact attributable to CMR exam results was observed in 256 of 361 pts (71%). The CMR exam resulted in a new diagnosis in 69 of 361 (27%) pts. Cardiovascular magnetic resonance imaging results avoided invasive procedures in 38 (11%) pts and prevented additional diagnostic testing in 26 (7%) pts. Comparison of health care savings using CMR as opposed to current standards of care showed a net cost savings of $833 037, ie, per patient cost savings of $2308. Cardiovascular magnetic resonance imaging provides diagnostic image quality in >98% of cases. Cardiovascular magnetic resonance imaging findings have documentable clinical impact on patient management in 71% of pts undergoing the exam, in a cost beneficial manner.


Exercise capacity in people with Parkinson's disease: which clinical characteristics are important?
People with Parkinson's (PwP) are suffering from reduced exercise capacity. However, little information is known about clinical correlates of exercise capacity in this population. This study aimed to evaluate correlations between motor and non-motor symptoms with exercise capacity in PwP. A total of 50 individuals with Parkinson's disease participated in the study. Exercise capacity was measured by 6 minutes' walk test (6MWT). Besides, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III used to evaluate disease motor severity, Berg Balance Scale to assess balance, Montréal Cognitive Assessment to evaluate cognitive status, hospital anxiety and depression scale to assess depression and anxiety, Modified Fatigue Impact scale to evaluate fatigue, and the Pittsburgh Sleep Quality Index to evaluate sleep quality. The results showed that exercise capacity, when measured by the 6MWT, can be significantly predicted by balance, disease motor severity, anxiety, and age (R2 = 0.61 P < .0001). These results suggest that exercise capacity in PwP is multifactorial and can potentially be predicted by balance, motor severity, anxiety, and age.


The Radon transform as a tool for 3D reciprocal-space mapping of epitaxial microcrystals.
This work presents a new approach suitable for mapping reciprocal space in three dimensions with standard laboratory equipment and a typical X-ray diffraction setup. The method is based on symmetric and coplanar high-resolution X-ray diffraction, ideally realized using 2D X-ray pixel detectors. The processing of experimental data exploits the Radon transform commonly used in medical and materials science. It is shown that this technique can also be used for diffraction mapping in reciprocal space even if a highly collimated beam is not available. The application of the method is demonstrated for various types of epitaxial microcrystals on Si substrates. These comprise partially fused SiGe microcrystals that are tens of micrometres high, multiple-quantum-well structures grown on SiGe microcrystals and pyramid-shaped GaAs/Ge microcrystals on top of Si micropillars.


Percutaneous Mitral Balloon Valvuloplasty for Patients with Rheumatic Mitral Stenosis.
Percutaneous balloon dilatation of stenotic cardiac valves is used for the treatment of pulmonic, mitral, aortic, and tricuspid stenosis. Percutaneous mitral balloon valvuloplasty (PMV) has been used successfully as an alternative to open or closed surgical mitral commissurotomy in the treatment of symptomatic rheumatic mitral stenosis. PMV produces good immediate hemodynamic outcome, low complication rates, and clinical improvement in the majority of patients. PMV is safe and effective and provides clinical and hemodynamic improvement in rheumatic mitral stenosis. PMV is the preferred form of therapy for relief of mitral stenosis for a selected group of patients with symptomatic mitral stenosis.


Cerebellum: history.
This paper will outline the history of study of the cerebellum from its beginnings to relatively recent times. Although there is no unanimous agreement about what the cerebellum does or how it does it, some principles of its structure and function are well understood. The historical approach can help to identify remaining questions and point the way to future progress. We make no effort to separate anatomical, physiological and clinical studies; rather, we hope to emphasize their interrelation. The cerebellum has always been seen as a distinct subdivision of the brain. Over the years there was an increasingly accurate description of its gross appearance and major subdivisions. By the beginning of the 19th century, the classical descriptive anatomical work was completed, and experimental study of the functions of the cerebellum began. Lesions were made in the cerebellum of experimental animals, and the behavioral deficits that were caused by the lesion were studied and described. These early animal studies powerfully influenced clinical interpretation of the symptoms seen in patients with cerebellar disease. Several questions are implicit in the anatomical and clinical studies of the nineteenth and early twentieth centuries, some of which remain incompletely answered. Many of these are addressed in other chapters in this volume. 1. Do different parts of the cerebellum do different things? The uniformity of the neuronal architecture of the cerebellar cortex suggests that each small region must operate in a similar way, but it is also clear that different regions control different functions. Is there a systematic sensory and/or body representation? 2. What are the functions of the cerebellar hemispheres? Massive in humans and very large in primates, their functions remain in dispute. Because the size of the cerebellar hemispheres parallels the development of the cerebral cortex, some have suggested that the hemispheres in humans and the higher primates may play a role in cognitive functions. 3. If one part of the cerebellum is damaged, can another part take over? A related question is whether normal motor function is possible in cases of complete or near-complete agenesis of the cerebellum. 4. What are the functions of the two distinctly different afferent systems to the cerebellum; the climbing and mossy fibers?


Innate immune response to peritoneal bacterial infection.
Spontaneous and secondary peritoneal infections, mostly of bacterial origin, easily spread to cause severe sepsis. Cellular and humoral elements of the innate immune system are constitutively present in peritoneal cavity and omentum, and play an important role in peritonitis progression and resolution. This review will focus on the description of the anatomic characteristics of the peritoneal cavity and the composition and function of such innate immune elements under both steady-state and bacterial infection conditions. Potential innate immune-based therapeutic interventions in bacterial peritonitis alternative or adjunctive to classical antibiotic therapy will be briefly discussed.


Stable improvement in classical B-cell chronic lymphocytic leukemia with dietary interventions: A personal experience.
If the lymphocyte count is still low enough, the first part of the wait-and-see approach for asymptomatic Rai stage 0 classical B-CLL can be used to find out if the lymphocyte counts follow an exponential growth curve. If they do, the whole food, plant-based (WFPB) diet intervention can be started.


Cross-sex hormone treatment does not change sex-sensitive cognitive performance in gender identity disorder patients.
Cognitive performance in untreated early onset gender identity disorder (GID) patients might correspond to their born sex and not to their perceived gender. As a current mode of intervention, cross-sex hormone treatment causes considerable physical changes in GID patients. We asked, as has been suggested, whether this treatment skews cognitive performance towards that of the acquired sex. Somatically healthy male and female early onset GID patients were neuropsychologically tested before, 3 and 12 months after initiating cross-sex hormone treatment, whereas untreated healthy subjects without GID served as controls (C). Performance was assessed by testing six cognitive abilities (perception, arithmetic, rotation, visualization, logic, and verbalization), and controlled for age, education, born sex, endocrine differences and treatment by means of repeated measures analysis of variance. GID patients and controls showed an identical time-dependent improvement in cognitive performance. The slopes were essentially parallel for males and females. There was no significant three-way interaction of born sex by group by time for the six investigated cognitive abilities. Only education and age significantly influenced this improvement. Despite the substantial somatic cross-sex changes in GID patients, no differential effect on cognition over time was found between C and GID participants. The cognitive performance of cross-sex hormone-treated GID patients was virtually identical to that of the control group. The documented test-retest effect should be taken into consideration when evaluating treatment effects generally in psychiatry.


PVDF Membrane-Based Dual-Channel Acoustic Sensor Integrating the Fabry-Pérot and Piezoelectric Effects.
A resonant acoustic wave detector combined with Fabry-Pérot interference (FPI) and piezoelectric (PE) effects based on a polyvinylidene fluoride (PVDF) piezoelectric film was proposed to enhance the ability of the sensor to detect acoustic signals in a specific frequency band. The deformation of circular thin films was indicated by the interference and piezoelectric effects simultaneously, and the noise level was decreased by the real-time convolution of the two-way parallel signal. This study reveals that, at the film's resonance frequency, the minimum detection limits for the FPI and piezoelectric impacts on acoustic waves are 3.39 μPa/Hz1/2 and 20.8 μPa/Hz1/2, respectively. The convolution result shows that the background noise was reduced by 98.81% concerning the piezoelectric signal, and by 85.21% concerning the FPI signal. The convolution's signal-to-noise ratio (SNR) was several times greater than the other two signals at 10 mPa. Therefore, this resonance sensor, which the FPI and the piezoelectric effect synergistically enhance, can be applied to scenarios of acoustic wave detection in a specific frequency band and with ultrahigh sensitivity requirements.


The effectiveness of preliminary traction in the treatment of congenital dislocation of the hip.
Historical papers on the treatment of congenital dislocation of the hip suggest the use of preliminary traction to facilitate closed reduction or to decrease the risk of avascular necrosis (AVN) of the femoral head. In the 1980s, some authors questioned the role of preliminary traction and suspended its use, yielding satisfactory results. Since then, several studies called into question this method, and some authors have continued to recommend preliminary traction while other authors have discouraged its use. We reanalysed the full set of radiographs of 71 hips (52 patients) surgically treated by a medial approach after 4 weeks of preoperative longitudinal traction. The mean age at operation was 16 months. Before and after traction, the height of the dislocation was graded according to the Gage and Winter method. The hips were divided into two groups: group 1, in which the traction was effective, and group 2, in which the traction was not effective. These two groups were statistically analysed regarding the severity of the dislocation, the age of the patient at surgery and the incidence of AVN. Preliminary traction was effective in 48 hips (68%, group 1), while it was not effective in the remaining 23 (32%, group 2). The effectiveness of preliminary traction was statistically related to the height of the dislocation and to the age of the patient at surgery, with traction being less effective in more severe dislocations and in older children. The incidence of AVN was statistically lower in group 1 than in group 2. In our study population, despite not having a control group, preliminary traction-when effective-seemed to reduce the incidence of AVN in patients surgically treated for congenital dislocation of the hip. The effectiveness of the traction was influenced by the severity of the dislocation and the age of the patient; it worked better for less severe dislocations and in younger children. To reduce hospital costs, traction should be applied at home. 3.


Combination of Neutrophil-to-Lymphocyte Ratio and Admission Glasgow Coma Scale Score Is Independent Predictor of Clinical Outcome in Diffuse Axonal Injury.
The neutrophil-to-lymphocyte ratio (NLR) is an independent predictor of clinical outcome of different diseases, such as acute ischemic stroke, intracerebral hemorrhage, malignant tumor, and traumatic brain injury. However, the prognostic value of NLR plus admission Glasgow Coma Scale score (NLR-GCS) is still unclear in patients with diffuse axonal injury (DAI). Therefore this study assessed the relationship between the NLR-GCS and 6-month outcome of DAI patients. The clinical characteristics of DAI patients admitted to our department between January 2014 and January 2020 were retrospectively analyzed. The candidate risk factors were screened by using univariate analysis, and the independence of resultant risk factors was evaluated by the binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis. The predictive value of NLR-GCS in an unfavorable outcome was assessed by the receiver operating characteristics curve analysis. A total of 93 DAI patients were included. Binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis showed the level of NLR on admission was an independent risk factor of unfavorable outcomes in DAI patients. The ROC curve analysis showed that the predictive capacity of the combination of NLR and admission GCS score and combination of NLR and coma duration outperformed NLR, admission GCS score, and coma duration alone. The higher NLR level on admission is independently associated with unfavorable outcomes of DAI patients at 6 months. Furthermore, the combination of NLR and admission GCS score provides the superior predictive capacity to either NLR or GCS alone.


Carbon Nanotube Exposure Triggers a Cerebral Peptidomic Response: Barrier Compromise, Neuroinflammation, and a Hyperexcited State.
The unique physicochemical properties of carbon nanomaterials and their ever-growing utilization generate a serious concern for occupational risk. Pulmonary exposure to these nanoparticles induces local and systemic inflammation, cardiovascular dysfunction, and even cognitive deficits. Although multiple routes of extrapulmonary toxicity have been proposed, the mechanism for and manner of neurologic effects remain minimally understood. Here, we examine the cerebral spinal fluid (CSF)-derived peptidomic fraction as a reflection of neuropathological alterations induced by pulmonary carbon nanomaterial exposure. Male C57BL/6 mice were exposed to 10 or 40 µg of multiwalled carbon nanotubes (MWCNT) by oropharyngeal aspiration. Serum and CSFs were collected 4 h post exposure. An enriched peptide fraction of both biofluids was analyzed using ion mobility-enabled data-independent mass spectrometry for label-free quantification. MWCNT exposure induced a prominent peptidomic response in the blood and CSF; however, correlation between fluids was limited. Instead, we determined that a MWCNT-induced peptidomic shift occurred specific to the CSF with 292 significant responses found that were not in serum. Identified MWCNT-responsive peptides depicted a mechanism involving aberrant fibrinolysis (fibrinopeptide A), blood-brain barrier permeation (homeobox protein A4), neuroinflammation (transmembrane protein 131L) with reactivity by astrocytes and microglia, and a pro-degradative (signal transducing adapter molecule, phosphoglycerate kinase), antiplastic (AF4/FMR2 family member 1, vacuolar protein sorting-associated protein 18) state with the excitation-inhibition balance shifted to a hyperexcited (microtubule-associated protein 1B) phenotype. Overall, the significant pathologic changes observed were consistent with early neurodegenerative disease and were diagnostically reflected in the CSF peptidome.


Fructose-1,6-diphosphatase deficiency: diagnosis using leukocytes and detection of heterozygotes with radiochemical and spectrophotometric methods.
The first two cases of fructose-1,6-diphosphatase (FDPase) deficiency from the Middle East have been diagnosed on leukocytes using a spectrophotometric assay and a new radiochemical technique. The control mean for FDPase measured by the spectrophotometric assay was 178.2 nm mg-1 h-1 (n = 12), 66.8 nm mg-1 h-1 for obligate heterozygotes (n = 4) and non-detectable in the two patients. By the radiochemical assay the values were controls, 103.3; heterozygotes, 20.6; patients, 0.46 and 3.5 nm mg-1 h-1. Using both methods it was possible to identify two certain FDPase heterozygotes and three non-carriers in the family of one of the probands. The radiochemical method was found to be more effective in differentiating heterozygotes from controls than the spectrophotometric method. However, either technique may be conveniently used for the diagnosis of FDPase deficiency in leukocytes.


The influence of cone-beam computed tomography and periapical radiographic evaluation on the assessment of periapical bone destruction in dog's teeth.
The aim of this study was to determine the influence of periapical radiographs, cone beam computed tomography (CBCT) sections, and cone beam volumetric data on the determination of periapical bone destruction in endodontically treated distal root canals of premolar canine teeth. Nontreated mesial roots were used as controls. Enterococcus faecalis strain (ATCC 29212) was inoculated into 30 root canals of 2 mongrel dogs to induce apical periodontitis. After 60 days, the root canals of the distal roots of the 11 mandibular and 4 maxillary premolars were endodontically treated (n = 15). The mesial root canals were used as controls (no treatment). The bone destruction was evaluated after 6 months by 5 evaluators using periapical radiographs and by CBCT (coronal and sagittal sections). After the experimental period, the area of the lesions in periapical radiographs and CBCT sections were measured in mm(2) using the ImageTool software. A single evaluator measured the volumetric data using the OsiriX software. The comparison between the diagnosis methods in treated root canals and controls was performed using parametric and nonparametric criteria. The Pearson correlation coefficient was computed between radiographic values and CBCT volumetric data in treated root canals and controls. The results showed the presence of chronic apical periodontitis in every inoculated tooth. After 6 months, periapical radiographs, coronal CBCT sections, and volumetric data showed lower bone destruction in endodontically treated teeth in comparison with the control group (P < .05). The 5 evaluators found no differences between the apical periodontitis area of treated teeth and controls when CBCT sagittal sections were used (P > .05). No correlation was found between x-ray and CBCT volumetric values in treated root canals. Although selected CBCT sagittal sections showed similar values of bone destruction in endodontically and nontreated root canals, volumetric CBCT data showed that periapical lesions of endodontically treated root canals had half of the volume of periapical lesions in nontreated root canals. No relationship could be found between the periapical values of bone destruction and volumetric data found in CBCT of treated rood canals.


Association of muscular strength with pulsatile and steady hemodynamics in patients with acute myocardial infarction.
Grip strength and blood pressure are strongly interrelated. Blood pressure is an essential component of arterial load, which modulates cardiac output. We aimed to asses the correlation between grip strength and both steady and pulsatile components of arterial load in patients with acute myocardial infarction. We included 295 participants (mean age, 63 years) with acute myocardial infarction. The following data were assessed: grip strength, echocardiography, local arterial stiffness, arterial tonometry, continuous arterial pulse, and beat‑to‑beat wave. In univariable analyses, grip strength correlated with arterial stiffness (pulse wave velocity), ventricular-arterial coupling, and measures of pulsatile arterial load: aortic characteristic impedance (Zao), total arterial compliance (TAC), and central fractional arterial pulse pressure (cFPP). In a multivariable model including age, grip strength, body mass index, systolic blood pressure, sex, and descriptors of pulsatile load, the following remained associated with grip strength: Zao (R2 for the model = 0.58; P <0.001), TAC (R2 = 0.23 for the model; P <0.001), and cFPP (R2 for the model = 0.2; P <0.001). In the second model that included sex, only Zao remained associated with grip strength (R2 for the model = 0.67). Comparisons between men and women of the adjusted mean value demonstrated that Zao and cFPP were considerably higher (P <0.001 and P = 0.02, respectively) and TAC was lower in women (P <0.001). In a cohort of patients with acute myocardial infarction, grip strength correlated independently and significantly with descriptors of the pulsatile arterial load. The role of sex in these interrelations needs further study.


Body Condition Score in Danish Horses Related to Type, Use, and Training Level: Patterns, Risk, and Protective Factors.
Body condition in horses is a growing concern that has different patterns of development in horses that are above and below the ideal range. This study used professional and para-professional evaluators (veterinarians, farriers, trainers, Danish Equestrian Federation (DEF) officials) who were trained and certified in the use of a modified Henneke scoring system to assign a body condition score (BCS) on a scale of 1-9. Scores of 5-6 are regarded as ideal, and 78.6% of the evaluated horses were in these groups. Only 4.8% of horses were below ideal BCS but 16.5% were above ideal BCS, and this was influenced by type, age, and training. A significant protective effect towards above ideal BCS was shown for horses trained at higher intensities. Cold-blooded horses and traditional ponies had increased risk for being above ideal BCS. Although BCS increased with age, a large proportion of geriatric horses were both above and below ideal BCS. Discipline was not related to BCS. Patterns of BCS distribution for horses attended by different professionals were investigated. Veterinarians attended more horses with BCS above and below ideal values, farriers mostly saw horses that were above ideal BCS, and officials at competitions mainly saw horses with ideal BCS.


In vivo optical imaging of revascularization after brain trauma in mice.
Revascularization following brain trauma is crucial to the repair process. We used optical micro-angiography (OMAG) to study endogenous revascularization in living mice following brain injury. OMAG is a volumetric optical imaging method capable of in vivo mapping of localized blood perfusion within the scanned tissue beds down to capillary level imaging resolution. We demonstrated that OMAG can differentiate revascularization progression between traumatized mice with and without soluble epoxide hydrolase (sEH) gene deletion. The time course of revascularization was determined from serial imaging of the traumatic region in the same mice over a one-month period of rehabilitation. Restoration of blood volume at the lesion site was more pronounced in sEH knockout mice than in wild-type mice as determined by OMAG. These OMAG measurements were confirmed by histology and showed that the sEH knockout effect may be involved in enhancing revascularization. The correlation of OMAG with histology also suggests that OMAG is a useful imaging tool for real-time in vivo monitoring of post-traumatic revascularization and for evaluating agents that inhibit or promote endogenous revascularization during the recovery process in small rodents.


Navigated direct photocoagulation with a 30-ms short-pulse laser for treating microaneurysms in diabetic macular edema exhibits a high closure rate.
This study carried out direct photocoagulation for treating microaneurysms (MAs) in diabetic macular edema (DME) using a navigation laser system with a 30-ms pulse duration. The MA closure rate after 3 months was investigated using pre and postoperative fluorescein angiography images. MAs primarily inside the edematous area based on optical coherence tomography (OCT) maps were selected for treatment, and leaking MAs (n = 1151) were analyzed in 11 eyes (eight patients). The total MA closure rate was 90.1% (1034/1151), and the mean MA closure rate in each eye was 86.5 ± 8.4%. Mean central retinal thickness (CRT) decreased from 471.9 ± 73.0 μm to 420.0 ± 87.5 μm (P = 0.049), and there was a correlation between the MA closure rate and the CRT reduction rate (r = 0.63, P = 0.037). There was no difference in the MA closure rate depending on the degree of edema thickness based on a false-color topographic OCT map image. Direct photocoagulation for DME with a short pulse using the navigated photocoagulator resulted in a high MA closure rate in just 3 months and a corresponding improvement in retinal thickness. These findings encourage the use of a new therapeutic approach for DME.


Diversity and guaiacol production of Alicyclobacillus spp. from fruit juice and fruit-based beverages.
Alicyclobacillus acidoterrestris is an acido-thermophilic, spore-forming bacterial species that can spoil acidic fruit juice and fruit-based beverages. The metabolism of taint compounds by this bacterial species has led to its status as a targeted microorganism in the fruit juice industry. This study aims to assess the genetic diversity of Alicyclobacillus spp. including A. acidoterrestris and its correlation to spoilage taint metabolism. Alicyclobacillus cultures, which were previously isolated from a wide range of domestic and international products including fruit juice, fruit drinks and fruit juice concentrates, were subjected to DNA fingerprint analysis by using randomly amplified polymorphic DNA (RAPD) - polymerase chain reaction. Isolates were classified on the basis of their RAPD profile and the results were used to select representative strains to undergo taint production assessment. The taint guaiacol produced by Alicyclobacillus spp. was measured by headspace gas chromatography and mass spectrometry. From produced RAPD profiles, two genotypic groups and two sub-groups were identified. The groups were independent of product types and geographical origins. A significant number of isolates were clustered in genotypic group I, including A. acidoterrestris ATCC 49025. These isolates produced significant levels of guaiacol, 8.7 mg/L on average. A smaller number of isolates was found in genotypic group II including A. acidocaldarius and they produced no guaiacol. Primer F-64 was useful to identify Alicyclobacillus at the species level, and permitted rapid identification of strains producing fruit juice taint compounds such as guaiacol.


Use of a subpalpebral lavage system as salvage therapy for Pseudomonas aeruginosa panophthalmitis due to an infected scleral buckle.
To present a case and surgical technique for management of Pseudomonas aeruginosa panophthalmitis secondary to an infected scleral buckle. Surgical technique video for management of an infected scleral buckle resulting in panophthalmitis with scleral buckle and suture explant and insertion of a subpalpebral lavage system. After two months, the visual acuity was restored to hand motion, likely secondary to a fibrotic secondary membrane, and the retina remain attached. This reports the first description of globe salvage for panophthalmitis from a P. aeruginosa-infected scleral buckle. This case encourages surgeons to remove all aspects of an exposed scleral buckle, including sutures, and emphasizes the importance of routine culture of all explanted material, even in the absence of clinical infection. In addition, this case encourages the use of a subpalpebral lavage in cases of severe P. aeruginosa ocular infections.