Endoscopic treatment of urinary tract calculi.
Removal of urinary tract calculi by endourological techniques is now widely practised and has reduced the indications for open surgical removal to a minority of cases. A review of 270 consecutive patients who presented to the Meath Hospital Urology department with urinary tract calculi and were treated by percutaneous or transurethral endoscopy is herein reported. The rates of successful clearance of renal (95%) and ureteric (78%) calculi compare well with previous reports. The majority of complications were minor and a low overall complication rate was experienced at ureterorenoscopy. In our experience, endourological treatment of urinary tract calculi is successful, efficient and safe and is the recommended approach to urinary tract calculi that require surgical intervention.


Brief report: The impact of the broad autism phenotype on parent perception of autism symptoms in their children with and without autism spectrum disorder compared to teachers.
Evaluation of children with autism spectrum disorder (ASD) includes caregiver-reported rating scales of symptom presentation. The extent to which a broad autism phenotype (BAP) in parents of children with ASD might impact their endorsement of autism symptoms in their children with and without ASD has not been well evaluated. This study analyzed whether varying degrees of parental BAP were associated with reported autism symptoms in offspring with and without ASD. We used the Broad Autism Phenotype Questionnaire as a measure of BAP in parents and parent- and teacher-report on the Social Responsiveness Scale (SRS) to assess autism symptoms in children with ASD and their typically developing (TD) siblings (N = 5714). We assessed the relationship between parental BAP and parent-teacher discordance. We compared teacher reports of autism symptoms in children with varying degrees of BAP exposure. Mothers with higher levels of BAP over-reported autism symptoms in their children (compared to teachers) than mothers with lower BAP. TD children from parents with greater BAP displayed more autism symptoms than children from households with less BAP. BAP is associated with parent report of autism symptoms when compared to teacher report. For children with ASD, it is possible that differences in ratings reflect parent perception and not autism symptomatology; whereas, TD children from households with higher levels of BAP exposure showed more phenotypic autism symptom presentation on teacher-completed measures. Researchers and clinicians should consider BAP when interpreting caregiver and teacher reports.


A rational approach to the assessment of aluminium solubility controls in freshwaters.
The problem of assessing aluminium equilibrium solubility controls in freshwaters using thermodynamic techniques is placed in a statistical hypothesis testing framework. As an aid in interpreting field information, artificial data are generated which correspond to ideal equilibrium conditions, but which incorporate realistic analytical and temperature related uncertainties. These artificial data are then subjected to thermodynamic interpretations. The technique is useful in answering "what if" questions by showing the scatter to be expected in real data under true equilibrium conditions. Aluminium hydroxide is used as the example in this report. Reasons for discarding the conventional dependent axis plot (pAl3+ vs pH) in favour of a plot with independent or nearly independent axes are emphasized. An improved method is suggested allowing for temperature variations in the equilibrium constants when constructing stability diagrams. Also, the need for caution when regressing variables which both contain errors is noted.


Dusty Deep Convection in the Mars Year 34 Planet-Encircling Dust Event.
Dusty convection, convective activity powered by radiative heating of dust, is a ubiquitous phenomenon in Mars's atmosphere but is especially deep (that is, impactful on the middle atmosphere) and widespread during planet-encircling dust events (PEDE) that occur every few Mars Years (MY). Yet the relative roles of dusty deep convection and global dynamics, such as the principal meridional overturning cell (PMOC) and the radiative tides, in dust storm development and the vertical transport of dust and water are still unclear. Here, observations from the Mars Climate Sounder on board Mars Reconnaissance Orbiter (MRO-MCS) are used to study dusty deep convection and its impact on middle atmospheric water content during the MY 34 PEDE (commenced June 2018). Additional context is provided by MRO-MCS observations of the MY 28 PEDE (commenced June 2007). This investigation establishes that a few, localized centers of dusty deep convection in the tropics formed in the initial phases of both PEDE simultaneously with a substantial increase in middle atmospheric water content. The growth phase of the MY 34 PEDE was defined by episodic outbreaks of deep convection along the Acidalia and Utopia storm tracks as opposed to less episodic, more longitudinally distributed convective activity during the MY 28 PEDE. The most intense convection during both PEDE was observed in southern/eastern Tharsis, where MRO-MCS observed multiple instances of deep convective clouds transporting dust to altitudes of 70-90 km. These results suggest that Martian PEDE typically contain multiple convectively active mesoscale weather systems.


Negative workplace behavior and coping strategies among nurses: A cross-sectional study.
Negative workplace behavior affecting nurses is an internationally recognized problem. This study examines the types and extent of negative workplace behavior experienced by nurses in non-metropolitan, regional acute care settings and their ways of coping when subject to that behavior. A cross-sectional study was conducted involving 74 nurse participants in four regional hospitals in Australia. The structured questionnaire consisted of four parts: demographic questions, the Negative Acts Questionnaire - Revised, questions on exposure to bullying and/or incivility and policy awareness and use of pathways, and the Ways of Coping Questionnaire. Overall, 34% of participants were exposed to bullying and 49% to incivility over the previous month. The most common type of negative workplace behavior reported was "work-related bullying," which included exposure to excessive workloads, unrealistic deadlines, and information being withheld. Nurses reported the use of a variety of coping mechanisms, including problem-focused coping strategies and seeking social support. The findings imply that negative workplace behaviors occur not only at individual nurses' level but also derive from the broader contexts of organizational management and systemic factors.


Bioactivity Potential of Aesculus hippocastanum L. Flower: Phytochemical Profile, Antiradical Capacity and Protective Effects on Human Plasma Components under Oxidative/Nitrative Stress In Vitro.
Horse chestnut (Aesculus hippocastanum) flower is a traditional medicine applied to alleviate symptoms of chronic venous insufficiency (CVI). However, its flavonoid-based composition has not been sufficiently recognized, and the data supporting its traditional application are lacking. In the work, 43 constituents were detected by UHPLC-PDA-ESI-TQ-MS/MS (flavonoids, phenolic acids, flavanols, and coumarins), including 31 reported in the flower for the first time. The quantitative HPLC-PDA study (developed and validated for quality control purposes) indicated the fractionated extraction as an efficient method for enhancing the total polyphenol content (TPHC) in the extracts (up to 414.06 mg/g) and kaempferol glycosides as their dominant constituents (75.05-82.14% TPHC). The activity studies showed significant scavenging properties of the extracts and their constituents towards reactive oxygen species (especially against highly reactive hydroxyl radical, with capacities up to 7.85 mmol ascorbic acid equivalents/g). Moreover, the analytes relevantly protected human plasma biomolecules from peroxynitrite-induced oxidative/nitrative damage; at 1-50 µg/mL, they hindered the protein nitration and lipid peroxidation, decreasing the levels of 3-nitrotyrosine (by up to 50%) and thiobarbituric acid reactive substances (by up to 70%), respectively. The extracts also averted the depletion of plasma thiols (by up to 67%) and improved the non-enzymatic antioxidant capacity of plasma. The demonstrated mechanisms might be partly responsible for the efficacy of the flower in CVI. Additionally, the anti-aggregatory and anticoagulant properties of the extracts were found only mild or negligible, which suggests that they may be safely applied with drugs impacting the coagulation process.


[Therapy of portal hypertension in childhood].
From 1980 to 1984 fortyeight children with portal hypertension were treated, 37 out of these had a prehepatic bloc. In 19 children a sclerotherapy was performed. Seven times a bleeding recurrency occurred and an esophageal stenosis was seen in 2 cases. The distal splenorenal shunt (Warren) was performed 16 times. All children survived, one pneumonia and one slight pancreatitis were observed post-operatively. Four times a shunt obstruction was found at follow-up examinations. Bleeding recurrencies did not appear.


Integrated age-related immunohistological changes occur in human olfactory epithelium and olfactory bulb.
Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity. However, this capability diminishes with advancing age and a decrease in odor perception in older individuals is well established. To characterize changes associated with age in the peripheral olfactory system, an in-depth analysis of the OE and its neuronal projections onto the olfactory bulb (OB) as a function of age was performed. Human olfactory tissue autopsy samples from 36 subjects with an average age of 74.1 years were analyzed. Established cell type-specific antibodies were used to identify OE component cells in whole mucosal sheets and epithelial sections as well as glomeruli and periglomerular structures in OB sections. With age, a reduction in OE area occurs across the mucosa progressing in a posterior-dorsal direction. Deterioration of the olfactory system is accompanied with diminution of neuron-containing OE, mature olfactory sensory neurons (OSNs) and OB innervation. On an individual level, the neuronal density within the epithelium appears to predict synapse density within the OB. The innervation of the OB is uneven with higher density at the ventral half that decreases with age as opposed to stable innervation at the dorsal half. Respiratory metaplasia, submucosal cysts, and neuromata, were commonly identified in aged OE. The finding of respiratory metaplasia and aneuronal epithelium with reduction in global basal cells suggests a progression of stem cell quiescence as an underlying pathophysiology of age-related smell loss in humans. KEY POINTS: A gradual loss of olfactory sensory neurons with age in human olfactory epithelium is also reflected in a reduction in glomeruli within the olfactory bulb. This gradual loss of neurons and synaptic connections with age occurs in a specific, spatially inhomogeneous manner. Decreasing mitotically active olfactory epithelium basal cells may contribute to age-related neuronal decline and smell loss in humans.


Chemical cross-linking and mass spectrometry for protein structural modeling.
The growth of gene and protein sequence information is currently so rapid that three-dimensional structural information is lacking for the overwhelming majority of known proteins. In this review, efforts towards rapid and sensitive methods for protein structural characterization are described, complementing existing technologies. Based on chemical cross-linking and offering the analytical speed and sensitivity of mass spectrometry these methodologies are thought to contribute valuable tools towards future high throughput protein structure elucidation.


Exploring Barriers and Facilitators to Reducing the Environmental Impact of the Operating Room.
The operating room (OR) is a major contributor to greenhouse gas emissions both nationally and globally. Successful implementation of quality improvement initiatives requires understanding of key stakeholders' perspectives of the issues at hand. Our aim was to explore surgical, anesthesia, and OR staff member perspectives on barriers and facilitators to reducing OR waste. Identified stakeholders from a single academic medical center were interviewed to identify important barriers and facilitators to reducing surgical waste. Two team members with qualitative research experience used deductive logic guided by the Theoretical Domains Framework of behavior change to identify themes within transcripts. Nineteen participants including surgeons (n = 3, 15.8%), surgical residents (n = 5, 26.3%), an anesthesiologist (n = 1, 5.3%), anesthesia residents (n = 2, 10.5%), nurse anesthetists (n = 2, 10.5%), nurses (n = 5, 26.3%), and a surgical technologist (n = 1, 5.3%) were interviewed. Twelve of the 14 themes within the Theoretical Domains Framework were discovered in transcripts. Barriers within these themes included lack of resources to pursue environmental sustainability in the OR and the necessity of maintaining sterility for patient safety. Facilitators included emphasizing surgeon leadership within the OR to reduce unused supplies and spreading awareness of the environmental and economic impact of surgical waste. Interviewed stakeholders were able to identify areas where improvements around surgical waste reduction and management could be made at the institution by describing barriers and facilitators to sustainability-driven interventions. Future surgical waste reduction initiatives at this institution will be guided by these important perspectives.


The interaction between Helicobacter pylori culture filtrate and indomethacin: effects on the integrity of human gastric antral mucosa and its prostaglandin E2 production in vitro.
Histopathological methods and radioimmunoassay were used to assess the microstructure and prostaglandin E2 production by paired specimens of human gastric antral mucosa; the specimens were studied after 48 h of incubation in base-line tissue culture medium, Helicobacter pylori culture filtrate, H. pylori culture control fluid, indomethacin, and H. pylori culture filtrate plus indomethacin. When applied alone, the filtrate did not affect the structure of the mucosal tissue or its prostaglandin E2 synthesis. In the overall group (n = 21), specimens incubated with the mixture of H. pylori filtrate and indomethacin had a median histological grade of 1 and prostaglandin E2 of 29 pg/mg tissue, compared to 2 pg/mg (P = 0.04) and 60 pg/mg (P = 0.0007) respectively, in specimens incubated with indomethacin alone. These results indicate that an interaction may exist between indomethacin and a factor contained in H. pylori culture filtrate. Such interaction is damaging to the human gastric antral mucosa, and its understanding might have therapeutic implications.


Ferric-ellagate complex: A promising multifunctional photocatalyst.
The semiconductors have exhibited great potential in the field of photocatalytic energy production, environmental remediation and bactericidal. Nevertheless, those inorganic semiconductors are still restricted in commercial application due to the drawbacks of easy agglomeration and low solar energy conversion efficiency. Herein, ellagic acid (EA) based metal-organic complexes (MOCs) were synthesized through a facile stirring process at room temperature with Fe3+, Bi3+ and Ce3+ as the metal center. The EA-Fe photocatalyst exhibited superior photocatalytic activity toward Cr(VI) reduction, where Cr(VI) were completely removed within 20 min. Meanwhile, EA-Fe also displayed good photocatalytic degradation of organic contaminants and photocatalytic bactericidal performance. The photodegradation rates of TC and RhB by EA-Fe were 15 and 5 times that by bare EA, respectively. Moreover, EA-Fe was capable of effectively eliminating both E. coli and S. aureus bacteria. It was found that EA-Fe was capable of generating superoxide radicals, which could participate in the reduction of heavy metals, degradation of organic contaminants and inactivation of bacteria. A photocatalysis-self-Fenton system could be established by EA-Fe solely. This work would provide a new insight for designing multifunctional MOCs with high photocatalytic efficiency.


Comparative study of translation termination sites and release factors (RF1 and RF2) in procaryotes.
Translation termination is catalyzed by release factors that recognize stop codons. However, previous works have shown that in some bacteria, the termination process also involves bases around stop codons. Recently, Ito et al. analyzed release factors and identified the amino acids therein that recognize stop codons. However, the amino acids that recognize bases around stop codons remain unclear. To identify the candidate amino acids that recognize the bases around stop codons, we aligned the protein sequences of the release factors of various bacteria and searched for amino acids that were conserved specifically in the sequence of bacteria that seemed to regulate translation termination by bases around stop codons. As a result, species having several highly conserved residues in RF1 and RF2 showed positive correlations between their codon usage bias and conservation of the bases around the stop codons. In addition, some of the residues were located very close to the SPF motif, which deciphers stop codons. These results suggest that these conserved amino acids enable the release factors to recognize the bases around the stop codons.


The prognostic significance of nodal ratio on breast cancer recurrence and its potential for incorporation in a new prognostic index.
Axillary nodal status is an inherent part of prognostic tools such as the Nottingham Prognostic Index (NPI). Literature suggests that nodal ratio is a stronger predictive parameter than the total number of positive nodes sampled. Studies also note improved survival in node-negative patients with a larger proportion of nodes excised. The aim of this study was to assess disease-free survival (DFS) comparing the number of negative and positive nodes excised and nodal ratio as the predictive parameters. Consecutive axillary lymph node dissections (ALND) were analyzed over a 25-year period. Data were analyzed using Cox Regression and Kaplan-Meier survival curves. Eight hundred and forty-nine ALNDs were identified, with 327 positive ALNDs and 268 node negative ALNDs incorporated in the study following exclusions. A prognostic index based on nodal ratio was devised and applied retrospectively to 327 positive ALNDs prior to 2002. This index was then prospectively validated in 116 consecutive positive ALNDs from 2002 to 2005. In node negative ALNDs, no significant difference in DFS was noted in patients having </≥ 10 nodes, or having </≥ 14 nodes removed. In node-positive patients, nodal ratio was a stronger predictor of DFS than total positive nodes excised. A prognostic index incorporating nodal ratio more accurately predicts survival than the NPI in node-positive patients as assessed in both a retrospective and a prospective patient cohort. Prognostic indices incorporating nodal ratio may prove more accurate than the current NPI. The extent of ALND did not impact survival in node-negative patients.


Relationship of insulin dynamics to body composition and resting energy expenditure following weight loss.
To examine associations of baseline insulin dynamics with changes in body composition and resting energy expenditure (REE) following weight loss. Twenty-one participants with overweight or obesity achieved 10-15% weight loss and then received 3 weight loss maintenance diets (high-carbohydrate, moderate-carbohydrate, and low-carbohydrate) in random order, each for 4 weeks. Body composition was measured at baseline and after weight loss. Insulin 30 min after glucose consumption (insulin-30; insulin response), C-peptide deconvolution analysis, HOMA, hepatic insulin sensitivity (IS), and REE were assessed at baseline and after each maintenance diet. Insulin-30, but not maximal insulin secretion, hepatic IS, or HOMA, predicted changes in fat mass (standardized β = 0.385, 1.7 kg difference between 10th and 90th centile of insulin-30, P = 0.04) after weight loss. Insulin-30 (β = -0.341, -312 kcal day(-1) , P = 0.008), maximal insulin secretion (β = -0.216, -95 kcal day(-1) , P = 0.0002), HOMA (β = -0.394, -350 kcal day(-1) , P = 0.002), and hepatic IS (β = 0.217, 225 kcal day(-1) , P = 0.0003) predicted change in REE during weight loss maintenance, independent of changes in body composition. The inverse relationship between insulin-30 and REE was substantially attenuated when the low-carbohydrate diet was consumed first. These findings distinguish a novel phenotype, characterized by high insulin response, at risk for weight regain, and identify a dietary approach to ameliorate this risk.


NetCapDB: measuring bioinformatics capacity development in Africa.
The National Institutes of Health (USA) has committed 5 years of funding to the Bioinformatics Network of the Human Heredity and Health in Africa initiative. This pan-African network aims to develop capacity for bioinformatics research, in order to provide support to human health genomics research programs ongoing on the continent. Over the 5 years of funding, it is imperative to track changes in bioinformatics capacity at the funded centres and to document how the funding has translated into capacity development during this time frame. The Network capacity database, NetCapDB, is a relational database that captures quantitative metrics for bioinformatics capacity, and tracks the changes in these metrics over time. A graphical user interface allows for straight-forward, browser-based data entry by users across Africa; and for visual and graph-based exploration of captured data. A reporting interface allows for semi-automated generation of standardized reports for monitoring and evaluation purposes.


Purification of acidic Z protein from human liver.
Preparation of Z protein from human liver is described. Z protein consists of 2 forms which have different isoelectric points, pI 5.8 and pI 8.7 respectively. The acidic Z protein has a molecular weight of about 11,000 and has binding affinity for BSP using gel filtration.


Single-shot diffusion-weighted RARE sequence: application for temperature monitoring during hyperthermia session.
A diffusion-sensitive single-shot RARE (rapid acquisition with relaxation enhancement) sequence was implemented on a 2T whole-body MRI system. The sequence was optimized for diffusion-based MR thermometry, both on a conventional whole-body gradient system and on a high-performance gradient insert. The use of spin-echo versus stimulated-echo diffusion weighting is discussed as a function of gradient performance. Diffusion-based temperature mapping was used to observe the effect of the geometry of the antenna used for radiofrequency (RF) hyperthermia on the temperature distribution. Temperature changes of +/-.5 degrees C in gel and +/-2 degrees C in a muscle sample in vitro could be detected within 16 seconds (gel) or 1 minute (muscle) at a spatial resolution of 2 x 2 x 8 mm. Temperature changes in vivo were also observed on human muscle cooled with ice with comparable sensitivity for the measured apparent diffusion coefficient (ADC) values.


Stream drift, size-specific predation, and the evolution of ovum size in an amphibian.
A stream-breeding race of small-mouthed salamanders (Ambystoma texanum) in central Kentucky produces ova that are twice as large as those of a pond-breeding race found nearby. Embryos of stream-breeders also hatch at a more advanced developmental stage than those of pond-breeders. Morphological evidence indicates that stream-breeders were derived from pond-breeding stock. Assuming that differences between stream and pond-breeders reflect evolutionary change, and that the ancestral pond stock that invaded streams was similar to extant pond-breeders, we examined three hypotheses that might explain changes in ovum size and stage at hatching following the invasion of streams. (1) Larger ovum size evolved indirectly as a consequence of selection for rapid development which minimizes mortality risk from stream drying. (2) Increased ovum (hatchling) size and stage at hatching of stream-breeders are adaptations to resist stream current. (3) Increased ovum (hatchling) size and stage at hatching are adaptations to reduce predation on hatchlings from stream invertebrates. The results of field and laboratory studies only support hypotheses (2) and (3). Hatchlings that were relatively large or at a more advanced developmental stage had slower drift rates and were less vulnerable to predation by Phagocata gracilis, a flatworm abundant in streams in central Kentucky. Developmental and growth parameters were not correlated significantly with ovum size in populations of either geographic race. Differences in degree of parental care among races also cannot explain variation in ovum size since both races abandon their eggs immediately after oviposition.


The identification and oxidative stress response of a zeta class glutathione S-transferase (GSTZ1) gene from Apis cerana cerana.
Glutathione-S-transferases (GSTs) play an important role in protecting organisms against the toxicity of reactive oxygen species (ROS). However, no information is available for GSTs in the Chinese honey bee (Apis cerana cerana). In this study, we isolated and characterized a zeta class GST gene (AccGSTZ1) from the Chinese honey bee. This gene is present in a single copy and harbors five exons. The deduced amino acid sequence of AccGSTZ1 shared high sequence identity with homologous proteins and contained the highly conserved features of this gene family. The temporal and spatial expression profiles of AccGSTZ1 showed that AccGSTZ1 was highly expressed in fourth instar larvae during development, and the mRNA level of AccGSTZ1 was higher in the epidermis than that in other tissues. The expression pattern under oxidative stress revealed that AccGSTZ1 transcription was significantly upregulated by external factors, such as temperature challenges and H(2)O(2) treatment. The characterization of the purified protein revealed that AccGSTZ1 had low glutathione-conjugating activity, but the recombinant AccGSTZ1 protein displayed high antioxidant activity under oxidative stress. These data suggest that AccGSTZ1 is an oxidative stress-inducible antioxidant enzyme that plays an important role in the protection against oxidative stress and may be of critical importance for the survival of the honey bees.


Trajectories of neighborhood environmental factors and their associations with asthma symptom trajectories among children in Australia: evidence from a national birth cohort study.
This study aims to investigate the prospective associations of neighborhood environmental exposure trajectories with asthma symptom trajectories during childhood developmental stages. We considered asthma symptom, neighborhood environmental factors, and socio-demographic data from the "Longitudinal Study of Australian Children (LSAC)". Group-based trajectory modeling was applied to identify the trajectories of asthma symptom, neighborhood traffic conditions, and neighborhood livability scales (considered for safety and facilities). We used multivariable logistic regression models to assess associations between various neighborhood environmental factors and asthma symptom trajectories. We included 4,174 children from the LSAC cohort in our study. Three distinct trajectories for asthma symptom were the outcome variables of this study. Among the neighborhood environmental factors, we identified two distinct trajectories for the prevalence of heavy traffic on street, and two trajectories of neighborhood liveability scale. Compared to the 'Low/no' asthma symptoms trajectory group, children exposed to a 'persistently high' prevalence of heavy traffic on street was also significantly associated with both 'transient high' [relative risk ratio (RRR):1.40, 95% CI:1.25,1.58) and 'persistent high' (RRR: 1.33, 95% CI:1.17,1.50)] asthma symptom trajectory groups. Trajectory of moderate and static neighborhood liveability score was at increased risk of being classified as 'transient high' (RRR:1.16, 95% CI:1.07,1.25) and 'persistent high' (RRR:1.38, 95% CI:1.27,1.50) trajectories of asthma symptom. Exposure to heavy traffic and poor neighborhood liveability increased the risk of having an unfavourable asthma symptom trajectory in childhood. Reducing neighborhood traffic load and improving neighborhood safety and amenities may facilitate a favorable asthma symptom trajectory among these children. The online version contains supplementary material available at 10.1007/s40201-022-00824-z.


Development and analysis of observational data bases.
Medical data bases have become an increasingly popular tool in clinical research. The observational data can be used to generate hypotheses for the development of clinical prediction rules and confirmation or extension of findings from other studies. When the analyses are carefully performed, the results from observational data bases generally have confirmed and complemented the findings of major randomized trials. In recent years, important clinical insights have been derived from analyses of data bases of large scale epidemiologic investigations; such insights may provide significant information on the impact of health policy decisions on patient care. To maximally and carefully use observational data, certain principles in both study design and the data collection and analysis phases should be applied.


Longitudinal trajectory of frailty in blood or marrow transplant survivors: Report from the Blood or Marrow Transplant Survivor Study.
Blood or bone marrow transplantation (BMT) survivors with frailty are at a higher risk of subsequent mortality. Longitudinal trends in the frailty state are not known and could help identify vulnerable subpopulations at risk of subsequent adverse events. This study included a cohort of 470 autologous and allogeneic BMT recipients who had survived ≥2 years after BMT and completed a baseline questionnaire (t1) at a median of 7.3 years after BMT and a follow-up questionnaire (t2) 13.2 years after t1. The main outcome was change in frailty state between t1 and t2. Frailty phenotype was defined as exhibiting ≥3 of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The following categories of change in frailty state were evaluated: worsened, improved, and stable. Of the 470 participants, 36.4% were aged ≥60 years at t1, and 50.6% were men. The prevalence of frailty increased from 4.8% at t1 to 9.6% at t2. Worsening was observed in 18.8% of patients, and improvement was reported in 9.7%. Pre-BMT exposure to vincristine (odds ratio [OR], 2.1; 95% CI, 1.3-3.39) was associated with worsening. Female sex (OR, 1.5; 95% CI, 0.93-2.4) was associated with a trend toward worsening. Pre-BMT exposure to vincristine (OR, 2.79; 95% CI, 1.44-5.43), a history of chronic graft-versus-host disease (OR, 2.58; 95% CI, 1.2-5.5), and grade 3 and 4 chronic health conditions at t1 (OR, 2.1; 95% CI, 1.08-4.33) were associated with frailty at t2. In a cohort of BMT survivors who were followed longitudinally for a median of 20.6 years from BMT, the frailty status worsened for approximately20% over a 13-year timespan. BMT survivors who are at risk for worsening frailty could benefit from targeted interventions.


Self-rated health and depressive symptoms in older adults: A growth mixture modeling approach.
Self-Rated Health (SRH) and depressive symptoms are important indicators of global quality of life in older adults. Prior research suggests associations between SRH and depressive symptoms. The current study assessed latent groups in levels and trajectories of these two subjective health indicators and how the latent groups relate to each other. Participants from the Australian Longitudinal Study of Aging (N = 2,087, ages 65+) were assessed over six waves of data collection, spanning eight years. Growth Mixture Models were run for SRH and depressive symptoms, each yielded three latent groups with similar patterns: for both SRH and depressive symptoms two groups differing in their level with worsening status over time, and a third stable, but poorer functioning group. Analysis of the assignment of the latent groups revealed a consistent pattern for the majority, but some people were high in depression and high in SRH and some were low in depression and low in SRH. SRH and depressive symptoms yielded both three latent groups whose combination supported the expected assignment for the majority and an unexpected assignment for some people. This may be a result of a protective factor existing for one variable but not the other.


Use of CO-oximetry to confirm carboxyhemoglobinemia in cats involved in secondary arson homicide.
The body of a deceased human and 4 deceased cats were found in a house while a fire was being extinguished. As a result of these findings, arson, homicide, and animal death investigations were opened. As part of the animal death investigation, all of the cats were submitted for veterinary forensic autopsies. All cats had soot on the fur and had soot deposits within the oral cavity, esophagus, and respiratory tract. Two cats had soot within the stomach. Cardiac blood was analyzed for carboxyhemoglobin using a CO-oximeter, and all cats had levels >65%. The cause of death was determined to be due to toxic smoke inhalation from the structure fire. Case findings support the potential use of CO-oximeter for determination of carboxyhemoglobin levels in cats and continued research in this area of forensic practice.


[Aspects worth knowing about intensive care medicine in the United States].
There exist profound differences in the training and professional duties of intensive care physicians and the way intensive care units are managed between the United States and Europe and particularly Spain. Some of the remarkable characteristics of intensive care medicine in the united states include the application process for residency, continuing evaluation during training, phased training with employability at every level, competency based training, scientific research as a core value during training and medical practice, and clinical activity reaching beyond the intensive care unit to include regular hospital wards and ambulatory clinics. The characteristics of intensive care units and the role of intensive care physicians are flexible and change according to the needs of the hospitals where they are located.


Age-Dependent Utilization of Shelters and Habitat in Two Reptile Species with Contrasting Intraspecific Interactions.
Reptiles undergo worldwide decline driven mostly by habitat change. Detailed recognition of factors underlying spatial structure and habitat utilization is therefore a prerequisite of effective conservation of this group. While the body of data on spatial ecology of reptiles is rapidly growing, studies on social factors remain still underrepresented. We studied age-specific patterns of shelter use, range size, and habitat preferences in the context of intraspecific interactions in the smooth snake Coronella austriaca-known to exhibit intraspecific predation-and the limbless lizard slow worm Anguis fragilis-with no such behavior observed. Despite smaller availability of preferred microhabitats, juveniles of smooth snakes occupied habitat and shelters located at the edge of the population range that did not overlap with adults. No such pattern was observed in the slow worm. Our study indicates that intraspecific interactions affect the spatial ecology of squamates. Passive and active protection of habitat must include wide buffers to preserve the poorly detectable young fraction of the population.


The effect of cyclic AMP on the growth and morphology of a normal human fibroblast parent strain and its transformed progeny line.
A normal human diploid fibroblast cell strain, Lederle 130 (Led 130), and its virus-transformed progeny line, transformed Led 130, were subjected to 0.75 and 1.5 mM concentrations of adenosine-5'-monophosphate (AMP), cyclic AMP (cAMP) and dibutyryl cyclic AMP (Bt2cAMP). While cAMP was markedly inhibitory to neoplastic cells at 1.5 mM, Bt2-cAMP was even more effective at this concentration, producing 85% inhibition by 4 days and 91% inhibition by 6 days. Bt2-cAMP was the only nucleotide to reverse morphological transformation effects in the neoplastic fibroblasts. Normal fibroblasts were inhibited in growth rate to a comparable extent by all nucleotides, and were not altered morphologically.


Recovery of renal lactate dehydrogenase (LDH) isoenzyme pattern after obstruction relief in experimental hydronephrosis.
The release of ureteral occlusion leads to a progressive recovery in LDH isoenzyme pattern with gradual increase of anodic fractions and decrease of middle and cathodic ones. Our findings demonstrate that the recovery is accomplished on the 10-14th day, in agreement with morphological and metabolic observation.


Muscle activation and coactivation during five-time-sit-to-stand movement in patients undergoing total knee arthroplasty.
Quadriceps weakness is prevalent with knee osteoarthritis (OA) and after total knee arthroplasty (TKA). To compensate for quadriceps dysfunction, patients often alter movement strategies. Little is known about muscle coordination during sit-to-stand (concentric) and stand-to-sit (eccentric) movements in the acute postoperative period. This investigation characterized the distribution of muscle activation between the concentric and eccentric phases during a five-time-sit-to-stand (FTSTS) movement in late stage OA and one month after TKA. Patients and healthy participants performed a FTSTS while recording bilateral ground reaction forces (GRFs) and electromyography (EMG). Concentric and eccentric ensemble averages of the GRF and EMG were calculated for the concentric and eccentric phases. Coactivation indices, integrated EMG, and GRF were calculated for each limb and phase. Patients demonstrated higher eccentric coactivation than the healthy group. Postoperative loading was higher in the nonsurgical limb. Postoperative quadriceps activity was lower in the concentric phase and higher in the eccentric phase than the healthy group. Higher coactivation in the patients resulted from sustained distribution of quadriceps activity throughout the eccentric phase. This indicated an inability to coordinate muscle firing when rapidly lowering to a chair and occurred despite unloading of the surgical limb. Although these patterns may serve as a protective strategy, they may also impede recovery of muscle function after TKA.


Bone matrix and marrow versus cancellous bone in rabbit radial defects.
Implants of demineralized bone matrix induce new bone formation. In order to estimate the possible clinical usefulness of this phenomenon, autologous cancellous bone grafts were compared with composite grafts of bone matrix and marrow. Cancellous bone from the tuber ischii of the rabbit was transplanted to a preformed radial defect in the same animal. On the opposite side, a similar defect was filled with a mixture of either allogenous or autogenous bone-matrix particles and autogenous bone marrow. After 25 days, calcium 45 was injected intravenously. Three days later the animals were killed. Standardized segments of the rabbit's forearms, containing the middle of the defect, were cut out, ashed, and analyzed for 45Ca activity. No side difference in 45Ca deposition was found. The callus ash weight of the allogenous matrix-transplanted side was approximately 60% of that of the cancellous bone side. This side difference of ash weights corresponds to the estimated initial mineral content of the cancellous graft. Nontransplanted defects had very low ash weight and 45Ca activity. Thus, in the rabbit, composite grafts of bone matrix and marrow produce a bone yield comparable to that of cancellous bone.


Diastolic dysfunction in asymptomatic hemodialysis patients in the light of the current echocardiographic guidelines.
The prevalence of the left ventricular hypertrophy (LVH) is very high in end-stage renal disease treated by hemodialysis. Diastolic dysfunction is a frequent consequence and leads to the development of heart failure with preserved ejection fraction. New American/European echocardiographic guidelines for the assessment of diastolic function simplified the evaluation and were published recently. The aim of this study was to reveal if the new guidelines stratify asymptomatic hemodialysis patients by the levels of brain-natriuretic peptide (BNP). A cohort of 46 patients hemodialyzed in one center with the lack of overt heart failure, systolic dysfunction, arrhythmia or significant valvular disease were examined by echocardiography before and after a single hemodialysis and blood samples for BNP analysis were drawn at both occasions. The LVH was present in 53% of patients, concentric remodeling in another 17%. Higher indexed left ventricular mass was related to higher BNP levels (r = 0.58, p = 0.0001). Before hemodialysis, diastolic dysfunction was present in 61%: grade 1 in 25%, grade 2 in 21% and grade 3 in 8%. The higher grade of diastolic dysfunction was associated with the incremental increase of BNP. The post-dialysis echocardiography did not allow the assessment of diastolic function in as many as 37% of patients. Our study has shown that the application of the current guidelines for the assessment of diastolic function based on simple four criteria differentiate hemodialysis symptomless patients with preserved systolic function according to BNP levels. BNP levels also rose together with the left ventricular mass. The ratio E/e' medial seemed to be a better predictor of increased BNP than E/e' lateral or E/e' averaged.


Genetics-based risk scores for prediction of premature coronary artery disease.
Premature coronary artery disease (CAD) is endemic in India. Global Burden of Diseases study has reported that it led to 286,000 deaths in 2019 in India. Many of these patients have standard risk factors but a third have none. Clinical risk algorithms and imaging provide limited risk information in premature CAD. CAD is multifactorial and studies have now focused on the predictive capability of clusters of genes and single nucleotide polymorphisms (SNPs) using gene risk score (GRS). Older studies combined data from 10 to 12 genes and 100-500 SNPs to calculate GRS, however, following the advent of genome-wide association studies (GWAS), millions of SNPs have been incorporated. Studies have reported that GWAS-based GRS may be more discriminative than conventional tools. Recent studies, especially among South Asians, have reported that GRS improves net reclassification by 15% (12-19%) for younger individuals. Aggressive lifestyle interventions and lipid-lowering therapies can ameliorate risk in high-GRS individuals and potentially prevent premature CAD.


Mucosal immunization with purified ClpP could elicit protective efficacy against pneumococcal pneumonia and sepsis in mice.
Caseinolytic protease (ClpP) has been found to be highly conserved among different strains of Streptococcus pneumoniae and intraperitoneal immunization with ClpP could elicit protection against invasive pneumococcal infections. In this study, mucosal immunization with ClpP antigen induced both systemic and mucosal antibodies, and in this way reduced lung colonization in an invasive pneumococcal pneumonia model and also protected mice against death in an intraperitoneal-sepsis model. Surface localization of ClpP was confirmed using flow cytometry analysis. Furthermore, characterization of human sera for anti-ClpP IgG antibody levels demonstrated that ClpP protein was immunogenic in healthy children and was expressed during disease based on the elevated antibody levels in infected individuals. Finally, we describe that in vitro functional anti-ClpP antibody could kill streptococcus pneumoniae by polymorphonuclear leukocytes in a complement-dependent assay. To our knowledge, this is the first study about the protective efficacy of mucosal immunization with ClpP as a promising pneumococcal protein antigen.


Sustained efficacy of mepolizumab in patients with severe chronic rhinosinusitis with nasal polyps: SYNAPSE 24-week treatment-free follow-up.
In the 52-week Phase III SYNAPSE study, mepolizumab given every 4 weeks (100 mg subcutaneously) reduced nasal polyp (NP) size, improved symptoms and quality of life (QoL), and reduced corticosteroid use and number of sinus surgeries in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP), versus placebo. Because the durability of mepolizumab's efficacy after discontinuation is poorly understood in CRSwNP, the efficacy of mepolizumab after discontinuation was analyzed in severe CRSwNP, over a 24-week follow-up. Changes from SYNAPSE baseline to end of treatment (week 52) and end of follow-up (week 76) were assessed for total endoscopic NP score, nasal obstruction and overall symptoms visual analog scale scores, and 22-item Sino-Nasal Outcome Test score. Time to first sinus surgery, time to first corticosteroid use, and geometric mean blood eosinophil counts (BECs) were also assessed. Among 134 follow-up patients, clinical improvements observed with mepolizumab versus placebo were partially evident 24 weeks after discontinuation despite BEC returning to baseline. The mean (95% confidence interval [CI]) change from baseline in NP score (week 52: -1.3 [1.8 to -0.9] vs. -0.3 [-0.6 to 0.1]; week 76: -1.2 [-1.6 to -0.7] vs. -0.1 [-0.5 to 0.3]) and the proportion of patients having sinus surgery (week 52: 4% vs. 25%; week 76: 9% vs. 31%) remained substantially improved with mepolizumab versus placebo. Mepolizumab-associated improvements in overall symptoms, quality of life, and corticosteroid use versus placebo were partially sustained at week 76. Fifty-two weeks of mepolizumab treatment is associated with sustained clinical benefits up to 24 weeks after discontinuation in patients with severe CRSwNP, which should be considered by physicians when making treatment decisions.


A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy.
Calstabins 1 and 2 bind to Ryanodine receptors regulating muscle excitation-contraction coupling. Mutations in Ryanodine receptors affecting their interaction with calstabins lead to different cardiac pathologies. Animal studies suggest the involvement of calstabins with dilated cardiomyopathy. We tested the hypothesis that calstabins mutations may cause dilated cardiomyopathy in humans screening 186 patients with idiopathic dilated cardiomyopathy for genetic alterations in calstabins 1 and 2 genes (FKBP12 and FKBP12.6). No missense variant was found. Five no-coding variations were found but not related to the disease. These data corroborate other studies suggesting that mutations in FKBP12 and FKBP12.6 genes are not commonly related to cardiac diseases.


A concerted DNA methylation/histone methylation switch regulates rRNA gene dosage control and nucleolar dominance.
Eukaryotes regulate the effective dosage of their ribosomal RNA (rRNA) genes, expressing fewer than half of the genes at any one time. Likewise, genetic hybrids displaying nucleolar dominance transcribe rRNA genes inherited from one parent but silence the other parental set. We show that rRNA gene dosage control and nucleolar dominance utilize a common mechanism. Central to the mechanism is an epigenetic switch in which concerted changes in promoter cytosine methylation density and specific histone modifications dictate the on and off states of the rRNA genes. A key component of the off switch is HDT1, a plant-specific histone deacetylase that localizes to the nucleolus and is required for H3 lysine 9 deacetylation and subsequent H3 lysine 9 methylation. Collectively, the data support a model in which cytosine methylation and histone deacetylation are each upstream of one another in a self-reinforcing repression cycle.


Pain and analgesia: the value of salience circuits.
Evaluating external and internal stimuli is critical to survival. Potentially tissue-damaging conditions generate sensory experiences that the organism must respond to in an appropriate, adaptive manner (e.g., withdrawal from the noxious stimulus, if possible, or seeking relief from pain and discomfort). The importance we assign to a signal generated by a noxious state, its salience, reflects our belief as to how likely the underlying situation is to impact our chance of survival. Importantly, it has been hypothesized that aberrant functioning of the brain circuits which assign salience values to stimuli may contribute to chronic pain. We describe examples of this phenomenon, including 'feeling pain' in the absence of a painful stimulus, reporting minimal pain in the setting of major trauma, having an 'analgesic' response in the absence of an active treatment, or reporting no pain relief after administration of a potent analgesic medication, which may provide critical insights into the role that salience circuits play in contributing to numerous conditions characterized by persistent pain. Collectively, a refined understanding of abnormal activity or connectivity of elements within the salience network may allow us to more effectively target interventions to relevant components of this network in patients with chronic pain.


Relation between plasma prolactin and plasma homovanillic acid in normal subjects.
The relation between fasting, a.m. plasma prolactin and plasma/homovanillic acid (HVA) was studied in 9 healthy males on one occasion and in 9 healthy females on two occasions (in the follicular and luteal phase of the menstrual cycle). There was a significant inverse correlation between plasma HVA and plasma prolactin in females in the follicular phase only. The correlation between these two measures, although also in the same direction, was not significant in females in the luteal phase or in males. The theoretical implications of these findings are discussed.


Contribution of allelic imbalance to colorectal cancer.
Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.


The effect of initial cell concentration on xylose fermentation by Pichia stipitis.
Xylose was fermented using Pichia stipitis CBS 6054 at different initial cell concentrations. A high initial cell concentration increased the rate of xylose utilization, ethanol formation, and the ethanol yield. The highest ethanol concentration of 41.0 g/L and a yield of 0.38 g/g was obtained using an initial cell concentration of 6.5 g/L. Even though more xylitol was produced when the initial cell concentrations were high, cell density had no effect on the final ethanol yield. A two-parameter mathematical model was used to predict the cell population dynamics at the different initial cell concentrations. The model parameters, a and b correlate with the initial cell concentrations used with an R(2) of 0.99.


Isoproterenol Triggers ROS/P53/S100-A9 Positive Feedback to Aggravate Myocardial Damage Associated with Complement Activation.
Negative feelings caused by external stress can continually agonize adrenergic receptors via promoting catecholamine secretion, causing cardiovascular disease. This study examines the mechanism by which persistent β-adrenergic receptor agonism induces myocardial injury. A rat model of cardiac injury was herein established using isoproterenol (5 mg/kg, continuous intraperitoneal injection for 3 days), and multiomics technology combined with metabolomics and proteomics was used to explore the mechanism by which persistent β-adrenergic receptor agonism induces myocardial injury. The mechanism underlying this phenomenon was further verified at the cellular level. Isoproterenol-induced persistent β-adrenergic receptor agonism promoted the release of reactive oxygen species, and P53, S100-A9, and complement 3 were shown to be involved in complement system activation pathways. Our data have demonstrated that isoproterenol could trigger ROS/P53/S100-A9 positive feedback to aggravate myocardial damage associated with complement activation.


Baseline serum 25-hydroxyvitamin D concentrations in the Tromsø Study 1994-95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up.
We wanted to test the hypothesis that low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with increased risk of developing Type 2 diabetes mellitus (DM) in a population-based cohort during 11 years of follow-up. The analyses included 4157 non-smokers and 1962 smokers from the Tromsø Study 1994-95 without diabetes at baseline. Subsequent Type 2 DM was defined using a hospital journal-based end-point registry, completed through the year 2005. Participants were allocated into quartiles of serum 25(OH)D within each month to account for seasonal variation, and serum 25(OH)D values both as a continuous variable and in quartiles were used in Cox regression models. The analyses were stratified by smoking. Adjustments were made for age, sex, body mass index (BMI), physical activity and, in non-smokers, former smoking. Type 2 DM was registered in 183 non-smoking and 64 smoking participants. Using the fourth (highest) quartile of serum 25(OH)D as the reference, non-smoking participants in the third, second and first quartiles had age- and sex-adjusted hazard ratios (95% confidence intervals) of incident Type 2 DM of 1.00 (0.62-1.61), 1.50 (0.97-2.31) and 1.89 (1.25-2.88), respectively, whereas the corresponding values for smokers were 1.79 (0.77-4.19), 2.33 (1.02-5.35) and 2.68 (1.18-6.08). Adjustment for BMI attenuated the hazard ratios, and they were no longer significant. Baseline serum 25(OH)D was inversely associated with subsequent Type 2 DM in a population-based 11 year follow-up study, but not after adjustment for BMI. Randomized trials are needed to define the possible role of serum 25(OH)D status, and thereby the role of supplementation, in the prevention of Type 2 DM.


Functional characteristics of veiled cells from canine prenodal lymph.
The surgical interruption of afferent lymphatics in the hind limb of dog leads to peripheral lymph stasis. The stagnated lymph contains large numbers of immunocompetent cells originating solely from the skin. This experimental model allows a study of the functions of the afferent skin-draining lymph cell population, the recovery and assessment of the lymphokines and other mediators liberated by these cells during the culture, and the production of anti-sera against different types of lymph cells. In the present study, we focused on the functional, morphological and cytochemical evaluation of the non-lymphoid cells, isolated from the whole lymph cell population by means of the gradient centrifugation technique. The non-lymphoid cells were large, with an irregularly-shaped nucleus and numerous cytoplasmic projections, giving them a "veiled" cell (VC) appearance. All VC were strongly positive for DLA-class II antigens and membrane-associated ATP-ase, and 60% of them exhibited the activity of non-specific esterase. In the functional assays, VC displayed the potent accessory-cell activity in the mitogen-induced response of autologous blood- and lymph-derived lymphocytes. In the mixed leukocyte cultures, VC acted as stimulators of the allogeneic and autologous lymphocyte proliferation. The high spontaneous and mitogen-induced responsiveness of the whole lymph cell population was found to be dependent on the presence of VC. The small number of VC (5% of cultured cells) was sufficient to produce the above-mentioned effects. These results indicate that VC is a cell responsible for the antigen presentation in the skin-associated immune reactions in dog, which is relevant to the observations on similar cells from the other species.


Does hemofiltration protect the brain after head trauma? An experimental study in rabbits.
Traumatic brain injury (TBI) is one of the most frequent and severe neurological diseases. In the last few decades, significant advances have been made in TBI pathophysiology and monitoring, however new treatments have not emerged. Although the central nervous system (CNS) has been historically defined as an immunologically privileged organ, recent studies show the increasingly predominant role of inflammatory and apoptotic phenomena in the pathogenesis of TBI. Inflammatory response mediators can be eliminated with continuous renal replacement therapies (CRRT). Our aim was to investigate whether hemofiltration protects the brain after head trauma in an experimental study in animals. A model of TBI and CVVH was performed in anesthetized New Zealand white rabbits without acute renal failure. The experimental group TBI ( +)-CVVH ( +) was compared with a TBI ( +)-CVVH (-) and a TBI (-)-CVVH ( +) control groups. Rabbits were assessed immediately (NES1) and 24 h hours after (NES2) TBI and/or CVVH using a functional Neurological Evaluation Score (NES) and histology of the brains after sacrifice. There was evidence to support a difference of NES1 comparing with the TBI (-)-CVVH ( +), but not with TBI ( +)-CVVH (-) with only 15% of the rabbits treated with CVVH and TBI showing a favorable neurological course. The final neurological outcome (mortality at 24 h) was 0%, 22% and 53% in the TBI(-) + CVVH( +), TBI( +)-CVVH(-) and TBI( +)-CVVH( +) groups respectively. The use of hemofiltration before or after TBI did not make a difference in regards the outcome of the rabbits. There was evidence in the histology to support an increase of mild ischemia, hemorrhage and edema in the experimental group compared with the other two groups. CVVH in rabbits without renal failure used with the intention to protect the brain may worsen the prognosis in TBI.


New classes of potent heparanase inhibitors from ligand-based virtual screening.
Heparanase is a validated target in cancer therapy and a potential target for several inflammatory pathologies. A ligand-based virtual screening of commercial libraries was performed to expand the chemical space of small-molecule inhibitors. The screening was based on similarity with known inhibitors and was performed in several runs, starting from literature compounds and progressing through newly discovered inhibitors. Among the fifty-five tested compounds, nineteen had IC50 values lower than 5 µM and some showed remarkable potencies. Importantly, tere- and isophthalamides derivatives belong to new structural classes of heparanase inhibitors and some of them showed enzyme affinities (61 and 63, IC50 = 0.32 and 0.12 µM, respectively) similar to those of the most potent small-molecule inhibitors reported so far. Docking studies provided a comprehensive binding hypothesis shared by compounds with significant structural diversity. The most potent inhibitors reduced cell invasiveness and inhibited the expression of proangiogenic factors in tumour cell lines.


Deferoxamine-activated hypoxia-inducible factor-1 restores cardioprotective effects of sevoflurane postconditioning in diabetic rats.
The cardioprotective effects of sevoflurane postconditioning (SpostC) are eliminated under diabetic conditions, and the underlying mechanism for this phenomenon remains unclear. Many studies have demonstrated that the hypoxia-inducible factor-1 (HIF-1) signalling pathway in the myocardium is impaired under diabetic conditions. This study was to investigate whether deferoxamine (DFO)-induced activation of HIF-1 signalling pathway can restore the cardioprotective effects of SpostC in diabetic rats. A model of myocardial ischaemia/reperfusion (I/R) injury was induced via ligation of the left anterior descending artery. SpostC was conducted by administering 1.0 MAC sevoflurane. After inducing the I/R injury, the following parameters were measured: myocardial infarct size, cardiac function, myocardial ultrastructure, mitochondrial respiratory function, respiratory chain enzyme activity, rate of reactive oxygen species (ROS) generation, and protein expression of HIF-1α, vascular endothelial growth factor (VEGF), cleaved caspase-3, Bcl-2 and Bax. After DFO activated HIF-1 in the impaired myocardium of diabetic rats, SpostC significantly upregulated the protein expression of HIF-1α and its downstream mediator VEGF. This improved myocardial mitochondrial respiratory function and respiratory chain enzyme activity and reduced ROS generation as well as the protein expression of cleaved caspase-3 and Bax. As a result, myocardial infarct size decreased, and cardiac function and mitochondrial ultrastructure improved. This study demonstrates for the first time that abolishment of the cardioprotective effects of SpostC in diabetic rats is associated with impairment of the HIF-1 signalling pathway and that DFO can activate HIF-1 to restore these cardioprotective effects of SpostC in diabetic rats.


Primary large cell neuroendocrine carcinoma of the skin: An under-recognized entity and a mimic of metastatic disease.
Primary large cell neuroendocrine carcinomas of the skin are exceptionally rare and can be diagnosed only when a metastasis from another organ has been excluded. We report the case of a 62-year-old woman with a cutaneous papule on the mid-chest which generated a differential diagnosis of vascular lesion and basal cell carcinoma. Following excision, microscopic evaluation revealed a dermal large cell undifferentiated carcinoma, with a brisk mitotic rate and focal geographic necrosis. Mucin production was absent. On immunohistochemistry, the lesion expressed CK7, AE1AE3, CK8/18, chromogranin, synaptophysin, CD56, calcitonin (patchy) and TTF-1 (minimal focal). Stains for neurofilament, CK20, CK5/6, p40, p63, SOX10, MART-1, EMA, CEA, ER/PR, GATA3, GCDFP, mammoglobin, PAX-8, CDX2, napsin, ERG and MCPyV proved negative. The histopathological diagnosis was of a large cell neuroendocrine carcinoma, probably metastatic. The patient underwent comprehensive clinical, laboratory and radiographic investigations and no underlying primary carcinoma was detected. During a 20-month follow-up period with an oncologist, the patient remains well and free of any apparent carcinoma. This suggests a primary large cell neuroendocrine carcinoma of skin. To date, 3 such cases have been reported in Japanese patients. This is the first in a Caucasian resident of North America.


Temporal bone showing otosclerosis, paget's disease and adenocarcinoma.
In a pair of temporal bones serial sectioning revealed widespread Paget's disease with otosclerosis on both sides and, at the right side, adenocarcinoma added. Stapedial fixation was produced on the right by otosclerosis, and on the left by Paget's disease. In the contest to reach the inner cochlear space, Paget was the winner on the left, where, at the tympanic scala, otosclerosis and Paget's disease almost met, while the immediately adjacent organ o Corti was uninvolved.


Enhancing the Stability of Nicotine via Crystallization Using Enantiopure Tartaric Acid Salt Formers.
Crystallization of nicotine, an oil prone to degradation at room temperature, has been demonstrated to be an effective means of creating nicotine-based materials with tunable thermal properties and improved resistance to photo-induced degradation. Herein, we show that both isomers of enantiomerically pure tartaric acid are highly effective salt formers when combined with nicotine. Both salts exhibit enhanced photostability, and with a melting point of 143.1 °C, the salt prepared using d-(-)-tartaric acid possesses one of the highest melting points for a crystalline nicotine solid reported to date.


N-Terminal Pro B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin T Levels Are Related to the Extent of Hibernating Myocardium in Patients With Ischemic Heart Failure.
Increased N-terminal pro b-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) can identify patients with heart failure (HF) who are at increased risk of cardiac events. The relationship of these biomarkers to the extent of hibernating myocardium and scar has not been previously characterized in patients with ischemic left ventricular dysfunction and HF. Patients with ischemic HF meeting recruitment criteria and undergoing perfusion and fluorodeoxyglucose-positron emission tomography to define myocardial hibernation and scar were included in the study. A total of 39 patients (mean age 67 ± 8 years) with New York Heart Association class II-IV HF and ischemic cardiomyopathy (ejection fraction [EF], 27.9% ± 8.5%) were enrolled in the study. Serum NT-proBNP and hs-cTnT levels were elevated in patients with ≥ 10% hibernating myocardium compared with those with < 10% (NT-pro-BNP, 7419.10 ± 7169.5 pg/mL vs 2894.6 ± 2967.4 pg/mL; hs-cTnT, 789.3 ± 1835.3 pg/mL vs 44.8 ± 78.9 pg/mL; P < 0.05). The overall receiver operating characteristic under the curve value for NT-proBNP and hs-cTnT to predict hibernating myocardium was 0.76 and 0.78, respectively (P < 0.05). The NT-proBNP (P = 0.02) and hs-cTnT (P < 0.0001) levels also correlated with hibernation, particularly in patients with ≥ 10% scar, independent of EF, age, and estimated glomerular filtration rate. No differences were noted in biomarker levels for patients with vs those without ≥ 10% scar. NT-proBNP and hs-cTnT levels are elevated in patients with ischemic HF hibernation and are correlated with the degree of hibernation but not with the presence or extent of scar. Taken together, these data support the novel concept that NT-proBNP and hs-cTnT release in patients with ischemic HF reflects the presence and extent of hibernating myocardium.


Subcellular localization of bioactive cholecystokinin-like peptides in the rat cerebral cortex.
The subcellular distribution of cholecystokinin (CCK), especially its exact localization within the synaptosome, was studied in the rat cerebral cortex. Highest CCK-like bioactivity was measured in the synaptic membrane fractions, paralleling the distribution of (Na+ + K+)-dependent ATPase. In the synaptic vesicles, which were characterized by high acetylcholine content and by the absence of (Na+ + K+)-ATPase, only minimal quantities of CCK were detected.


[Epidemiologic studies on multiple cancers in Japan].
During a 21-year period, 3040 patients with malignant tumors were treated at the Division of Surgery, Fukuyama National Hospital. Of these 86 (2.8%) were diagnosed as having double cancers. The simultaneous double cancer rate was 27.3%. Statistical study showed that the etiology had a relation to family history and previous therapy, but not to immunology. The prognosis was good and diagnosis by RI was non-specific.


Giant juvenile fibroadenomas with and without prominent pseudoangiomatous stromal hyperplasia (PASH)-like change: clinicopathological and molecular characteristics.
Juvenile fibroadenomas (JFA) are biphasic fibroepithelial lesions (FEL) usually occurring in adolescent female patients. Giant (G) JFA, like other FEL, may exhibit prominent pseudoangiomatous stromal hyperplasia (PASH)-like change. We sought to determine clinicopathological and molecular characteristics of GJFA with and without PASH. Archives were searched for cases of GJFA (1985-2020). All were stained for androgen receptor (AR), beta-catenin, CD34 and progesterone receptor (PR). Cases were sequenced using a custom 16-gene panel - MED12 (exons 1 and 2), TERT promoter (-124C>T and -146Ctable>T), SETD2, KMT2D, RARA (exons 5-9), FLNA, NF1, PIK3CA (exons 10, 11 and 21), EGFR, RB1, BCOR, TP53, PTEN, ERBB4, IGF1R and MAP3K1. Twenty-seven GJFA from 21 female patients aged 10.1-25.2 years were identified. Size ranged from 5.2 to 21 cm. Two patients had multiple, bilateral and later recurrent GJFA. Thirteen (48%) cases showed prominent PASH-like stroma. All were positive for stromal CD34, negative for AR and beta-catenin and one case showed focal PR expression. Sequencing showed MAP3K1 and SETD2 mutations in 17 samples, with KMT2D, TP53 and BCOR aberrations in 10 (45%), 10 (45%) and seven (32%) cases, respectively. Tumours with a PASH-like pattern had higher prevalence of SETD2 (P = 0.004) and TP53 (P = 0.029) mutations, while those without PASH had more RB1 mutations (P = 0.043). MED12 mutation was identified in one case. TERT promoter mutation was observed in four (18%), including two recurrences. Gene mutations along more advanced phases of the proposed FEL pathogenetic pathway in GJFA are unusual, and suggest a mechanism for more aggressive growth in these tumours.


Human Epicardial Adipose Tissue Activin A Expression Predicts Occurrence of Postoperative Atrial Fibrillation in Patients Receiving Cardiac Surgery.
Activin A secreted by epicardial adipose tissue (EAT) plays a major role in the progress of atrial fibrosis. However, the potential of Activin A in predicting the occurrence of postoperative atrial fibrillation (POAF) has yet to be elucidated. We aimed to investigate the predicable value of Activin A expression in EAT on POAF. A total of 89 patients receiving cardiac surgery without atrial fibrillation (AF) history were enrolled in this study, including 49 patients with valvular heart disease (VHD) and 40 patients with non-valvular heart disease (NVHD). Activin A expression in EAT was determined by quantitative polymerase chain reaction (qPCR), while the thickness of EAT (EATT) was estimated by echocardiography. New onset POAF before discharge was documented. Eventually 32 patients (36.0%) developed POAF, including 20 patients with VHD (40.8%) and 12 patients with NVHD (30.0%). Activin A expression was higher in POAF than sinus rhythm (SR) patients, whether for VHD or NVHD group (All p<0.001). In general, Activin A expression predicted the occurrence of POAF with a sensitivity of 65.6% and specificity of 91.2% (AUC: 0.795; 95%CI: 0.693-0.897, p<0.001). Subgroup analysis showed that EATT was not significant for the VHD group in predicting POAF (p=0.07), while Activin A expression demonstrated a sensitivity of 60.0% and specificity of 89.7% (AUC: 0.745; 95%CI: 0.601-0.889, p<0.001). Multivariate regression analysis showed that Activin A expression in EAT was an independent risk factor for POAF (OR: OR=1.067, 95%CI:1.002-1.136, p=0.042). Activin A expression in EAT is an independent risk factor for POAF, which can be used for prediction of POAF, especially for patients with VHD.


Effect of seizure on hippocampus in mesial temporal lobe epilepsy and neocortical epilepsy: an MRS study.
This study was performed to evaluate the effect of seizures on the bilateral hippocampus in mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy by single voxel proton magnetic resonance spectroscopy (MRS). Forty-one patients with mTLE having unilateral hippocampal sclerosis and 43 patients with a neocortical epilepsy who underwent subsequent epilepsy surgery were recruited. Ninety-five percent confidence intervals of N-acetyl aspartate/choline (NAA/Cho) and NAA/creatine (NAA/Cr) ratios in 20 healthy control subjects were used as threshold values to determine abnormal NAA/Cho and NAA/Cr. NAA/Cho and NAA/Cr were significantly lower in the ipsilateral hippocampus of mTLE and neocortical epilepsy. Using asymmetry indices for patients with bilaterally abnormal ratios of NAA/Cho and NAA/Cr in addition to using unilateral abnormal ratio, the seizure focus was correctly lateralized in 65.9% of patients with mTLE and 48.8% of neocortical epilepsy patients. Bilateral NAA/Cho abnormality was significantly related to a poor surgical outcome in mTLE. No significant relationship was found between the results of NAA/Cho or NAA/Cr and surgical outcome in neocortical epilepsy. The mean contralateral NAA/Cr ratio of the hippocampus in mTLE was significantly lower in patients with a history of secondary generalized tonic-clonic seizure (SGTCS) than in those without. Our results demonstrate effects of seizures on the hippocampi in neocortical epilepsy and the relation between SGTCS and NAA/Cr of the contralateral hippocampus in mTLE. This proves the presence of a seizure effect on the hippocampus in neocortical epilepsy as well as in mTLE.


Social control of drinking among the Aztec Indians of Mesoamerica.
In the Aztec culture of pre-Columbian Mexico the rules for the use of alcoholic beverages were clearly defined and strictly enforced. Drinking was permitted only on religious occasions and the amount drunk was restricted.


Effects and outcomes of septostomy in twin-to-twin transfusion syndrome after fetoscopic laser therapy.
To evaluate the incidence and outcomes of septostomy in twin-to-twin transfusion syndrome (TTTS) after fetoscopic laser therapy. A retrospective analysis of TTTS postlaser septostomy between 2005 and 2018 was performed. Postlaser septostomy was diagnosed using both (1) a free-floating intertwin membrane flap visible on ultrasound examination and (2) the rapid equalization of amniotic fluid maximum vertical pocket in the donor and recipient amniotic sacs observed after laser therapy. Perinatal survival, neonatal brain image anomaly, gestational age at operation and birth, incidence of premature rupture of membranes (PROM) within 3 weeks after operation, pseudoamniotic band syndrome, and cord entanglement were evaluated. In the 159 TTTS cases included, 12 had postlaser septostomy. Relative to the group without septostomy, the septostomy group had a lower total fetal survival rate (54.2% vs 73.6%, p = 0.041), an earlier mean gestational age at delivery (27.8 vs 34.4 weeks, p = 0.009), a higher risk of PROMs within 3 weeks after operation (33.3% vs 5.4%, p = 0.004), a higher cord entanglement rate (16.7% vs 0%, p = 0.005), and a higher brain image anomaly rate (23.0% [3/13] vs 5.0% [11/218], p = 0.035). After considering the severe Quintero stages (stage III and IV), postlaser septostomy was the only variable [p = 0.003, odds ratio = 5.1] to predict neonatal brain image anomaly. Postlaser septostomy combined with severe Quintero stages could predict PROMs within 3 weeks after laser therapy [p = 0.001, odds ratio = 14.1 and p = 0.03, odds ratio = 5.4, respectively] and delivery before the gestational age of 28 weeks [p = 0.017, odds ratio = 4.5 and p = 0.034, odds ratio = 2.3, respectively]. The risk of pseudoamniotic band syndrome was not increased by postlaser septostomy in this case series. Postlaser septostomy in TTTS was associated with poorer fetal survival and more adverse perinatal outcomes even after considering severe Quintero stages before laser therapy. Efforts should be made to prevent septostomy during laser therapy, and septostomy as the primary method to treat TTTS is not advisable.


Comparison of the ventricular response during atrial fibrillation in patients with enhanced atrioventricular node conduction and Wolff-Parkinson-White syndrome.
Although ventricular fibrillation is a well known sequel to atrial fibrillation in the Wolff-Parkinson-White syndrome, ventricular fibrillation is not generally associated with supraventricular tachycardia in the presence of enhanced atrioventricular (AV) node conduction without pre-excitation. It was hypothesized that the ventricular response during atrial fibrillation may be less in patients with enhanced AV node conduction than in their counterparts with Wolff-Parkinson-White syndrome matched for anterograde effective refractory period. Slower ventricular rates during atrial fibrillation would suggest an increased propensity for concealed conduction in the enhanced AV node conduction group than in the group with an accessory pathway. Three groups of patients aged 16 to 65 years underwent electrophysiologic testing for supraventricular tachycardia or after surgical correction of Wolff-Parkinson-White syndrome. Sixteen patients had enhanced AV node conduction, 16 had Wolff-Parkinson-White syndrome and 16 had normal AV node conduction. Patients with enhanced AV node conduction and Wolff-Parkinson-White syndrome were well matched for anterograde effective refractory period (245 +/- 22 versus 258 +/- 25 ms) and minimal cycle length, maintaining 1:1 anterograde conduction (261 +/- 21 versus 260 +/- 40). There was no difference in intervals during atrial fibrillation (average RR interval = 372 +/- 37 versus 346 +/- 66) or shortest RR interval (266 +/- 27 versus 243 +/- 51). Thus, patients with Wolff-Parkinson-White syndrome and those with enhanced AV node conduction matched for anterograde refractory period exhibit similar ventricular rates during atrial fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)


Dioxin-like effects observed in male rats following exposure to octachlorodibenzo-p-dioxin (OCDD) during a 13-week study.
Octachlorodibenzo-p-dioxin (OCDD) is a ubiquitous environmental pollutant which has been reported to be nontoxic following acute exposure but has recently been shown to accumulate upon repeated exposure. To determine if this accumulation results in toxic effects, male Fischer 344 rats were treated with 50 micrograms/kg [14C]OCDD by gavage for 10, 20, 40, or 65 times (once a day, 5 days/week) and terminated 3 days postexposure. OCDD accumulated linearly with increasing number of doses and the liver was the major depot, while the adipose served as a secondary sink. Hepatic accumulation resulted in alteration of several biochemical parameters. In animals given 65 doses of OCDD, 7-ethoxyresorufin-O-deethylase activity was elevated 40-fold over controls. Total cytochrome P-450 content doubled and exhibited a 2-nm blue-shift in the Soret maximum for the CO-reduced complex. Treatment-related cytoplasmic fatty vacuolization in the liver was observed concomitant with the biochemical alterations. Thus, subchronic exposure to OCDD appears to cause effects similar to those observed following exposure to low levels of TCDD, but is only 1/100-1/1000 as potent. Such a potency, given the persistent environmental levels to which man may be exposed during a lifetime, suggests that OCDD may pose a potential risk to human health.


Visual acuity deficits in the fellow eyes of children with unilateral amblyopia.
To study the visual acuity deficits and maturation in the fellow eyes of children with unilateral amblyopia who were treated with patching. Medical records of patients aged 4-13 years visiting a tertiary eye care center between January 2003 and December 2007 who were diagnosed for the first time with unilateral amblyopia were reviewed. Subjects included in the study were followed through April 2009. The baseline visual acuity in the fellow eye of amblyopic subjects was compared with that of age-matched healthy subjects. Changes in visual acuity in the amblyopic and fellow eyes during subsequent visits were analyzed. A total of 112 children with amblyopia were included (strabismic, 14; anisometropic, 51; combined mechanism, 47). Baseline visual acuity in the fellow eye of these children differed significantly from that of age-matched controls up to 8 years of age. Average logMAR acuity reached 0.0 at age 5 years in controls versus age 9 years in patients. Although the mean visual acuity of the fellow eyes improved during treatment, 21% developed temporary occlusion amblyopia. Full-time patching had no additional benefit when compared with part-time patching. Visual acuity in the fellow eye of children with unilateral amblyopia is reduced at baseline and matures more slowly than in healthy control patients. The risk for temporary occlusion amblyopia in the fellow eye is similar what has been previously reported.


Sphingomyelin: What is it good for?
Sphingomyelin has been considered as a merely structural lipid for many years. However, this organelle-specific lipid has many other roles, including increasing membrane molecular order, acting as a source of ceramide in cell signaling and apoptosis, and forming clusters/nanodomains with cholesterol and ceramide. This contribution is dedicated to Professor E. Carafoli, on occasion of his 90th anniversary.


[Rare malpositions of the colon (author's transl)].
3 unusual cases of colon malposition are presented which were detected primarily radiologically. The clinical and diagnostic significance in adults is discussed. These rare anomalies can be explaned by embryology. Previous results presented in the same issue are discussed also.


Intake of Mediterranean foods associated with positive affect and low negative affect.
To examine associations between consumption of foods typical of Mediterranean versus Western diets with positive and negative affect. Nutrients influence mental states yet few studies have examined whether foods protective or deleterious for cardiovascular disease affect mood. Participants were 9255 Adventist church attendees in North America who completed a validated food frequency questionnaire in 2002-6. Scores for affect were obtained from the positive and negative affect schedule questionnaire in 2006-7. Multiple linear regression models controlled for age, gender, ethnicity, BMI, education, sleep, sleep squared (to account for high or low amounts), exercise, total caloric intake, alcohol and time between the questionnaires. Intake of vegetables (β=0.124 [95% CI 0.101, 0.147]), fruit (β=0.066 [95% CI 0.046, 0.085]), olive oil (β=0.070 [95% CI 0.029, 0.111]), nuts (β=0.054 [95% CI 0.026, 0.082]), and legumes (β=0.055 [95% CI 0.032, 0.077]) were associated with positive affect while sweets/desserts (β=-0.066 [95% CI -0.086, -0.046]), soda (β=-0.025 [95% CI -0.037, -0.013]) and fast food frequency (β=-0.046 [95% CI -0.062, -0.030]) were inversely associated with positive affect. Intake of sweets/desserts (β=0.058 [95% CI 0.037, 0.078]) and fast food frequency (β=0.052 [95% CI 0.036, 0.068]) were associated with negative affect while intake of vegetables (β=-0.076 [95% CI -0.099, -0.052]), fruit (β=-0.033 [95% CI -0.053, -0.014]) and nuts (β=-0.088 [95% CI -0.116, -0.060]) were inversely associated with negative affect. Gender interacted with red meat intake (P<.001) and fast food frequency (P<.001) such that these foods were associated with negative affect in females only. Foods typical of Mediterranean diets were associated with positive affect as well as lower negative affect while Western foods were associated with low positive affect in general and negative affect in women.


A novel nuclear export inhibitor JBIR-02, a new piericidin discovered from Streptomyces sp. ML55.
A new member of the piericidin family, JBIR-02, was isolated from mycelium of Streptomyces sp. ML55 together with two known piericidin derivatives, piericidin A(1) and IT-143-B. The structure was determined on the basis of spectroscopic data. JBIR-02 inhibited nuclear export of beta-arrestin in HeLa cells at the concentration of 20 microM.


Application of adaptive filtering to steady-state evoked response.
A new method to detect steady-state evoked potentials (EPs) is presented. The technique is based on a two-weight recursive least squares (RLS) adaptive filter and the Tcirc2 statistic. Simulations with known sinusoids buried in Gaussian noise and in EEG noise indicate that the adaptive filter can detect signals at 3 or 4 times lower signal-to-noise ratios that the discrete Fourier transform (DFT). Qualitatively similar results were obtained with human visual evoked potential recordings.


Cost-effectiveness analysis (CEA) of IMRT plus C12 boost vs IMRT only in adenoid cystic carcinoma (ACC) of the head and neck.
Particle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost vs IMRT alone was performed in order to objectivise and substantiate more widespread use of this technology in ACC. Patients with pathologically confirmed ACC received a combination regimen of IMRT plus C12 boost. Patients presenting outside C12 treatment slots received IMRT only. Clinical results were published; economic analysis on patient-level data was carried out from a healthcare purchaser's perspective based on costs of healthcare utilization. Cost histories were generated from resource use recorded in individual patient charts and adjusted for censoring using the Lin I method. Cost-effectiveness was measured as incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed regarding potentially differing management of recurrent disease. The experimental treatment increased overall costs by € 18,076 (€13,416 - €22,922) at a mean survival benefit of 0.86 years. Despite improved local control, following costs were also increased in the experimental treatment. The ICER was estimated to 26,863 €/LY. After accounting for different management of recurrent disease in the two cohorts, the ICER was calculated to 20,638 €/LY. The combined treatment (IMRT+C12 boost) substantially increased initial and overall treatment cost. In view of limited treatment options in ACC, costs may be acceptable though. Investigations into quality of life measures may support further decisions in the future.


Temporary epicardial wire electrodes in the diagnosis and treatment of arrhythmias after open heart surgery.
The demonstrated safety, efficacy, and ease of utilization of the temporarily placed epicardial wire electrodes strongly support their routine use. By having temporary stainless steel wire electrodes available in the postoperative period, the diagnosis of arrhythmias after open heart surgery is greatly facilitated. Furthermore, because of the clinical advantages of cardiac pacing, it has become the treatment of choice for many, if not most, arrhythmias in the postoperative period.


LINC00675 Suppresses Cell Proliferation and Migration via Downregulating the H3K4me2 Level at the SPRY4 Promoter in Gastric Cancer.
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are dysregulated in diverse tumors and take a pivotal role in modulating biological processes. In our study, a decreased expression level of LINC00675 in gastric cancer (GC) was first determined by data from The Cancer Genome Atlas (TCGA) and was identified using specimens from GC patients. Then, in vitro and in vivo functional experiments elaborated that LINC00675 could suppress cell proliferation and migration in GC. Multiple differentially expressed genes (DEGs) in LINC00675-overexpressing cells were identified through RNA sequencing analysis. An RNA-binding protein immunoprecipitation (RIP) assay was conducted to reveal that LINC00675 competitively bound with lysine-specific demethylase 1 (LSD1). A coimmunoprecipitation (coIP) assay indicated that LINC00675 overexpression may strengthen the binding of LSD1 and H3K4me2, whereas the chromatin immunoprecipitation (ChIP) assay results verified lower expression of H3K4me2 at the sprouty homolog 4 (SPRY4) promoter region. Together, our research identified that LINC00675 was remarkably downregulated in GC tissues and cells relative to nontumor tissues and cells. LINC00675 could repress GC tumorigenesis and metastasis via competitively binding with LSD1 and intensifying the binding of LSD1 and its target H3K4me2. Importantly, this contributed to attenuated binding of H3K4me2 at the promoter region of oncogene SPRY4 and suppressed SPRY4 transcription, thus suppressing GC cell proliferation and migration.


Neutrophil-to-lymphocyte ratio an inflammatory biomarker, and prognostic marker in heart failure, cardiovascular disease and chronic inflammatory diseases: New insights for a potential predictor of anti-cytokine therapy responsiveness.
In the 20th century, research focused on cholesterol and lipoproteins as the key mechanism in establishing atherosclerotic cardiovascular disease (ASCVD). Given that some studies demonstrated subclinical atherosclerosis in subjects without conventional cardiovascular risk factors, the elevated low-density lipoprotein (LDL) levels alone cannot account for the entire burden of atherosclerosis. Hence, large-scale clinical trials demonstrated the operation of immune and inflammatory pathways in ASCVD. In this regard, the evidence establishes that cells of the immune system, both the innate (neutrophils, macrophages) and adaptive (T cell and other lymphocytes) limbs, contribute to atherosclerosis and atherothrombosis. Besides, basic science studies have identified proatherogenic cytokines such as interleukin (IL)-1, IL-12, and IL-18. In this regard, some studies showed that antiinflammatory therapy targeting the immune system by modulating or blocking interleukins, also known as anti-cytokine therapy, can reduce the risk of major cardiovascular adverse events. The neutrophils play a key role in the innate immune system, representing the acute phase of an inflammatory response. In contrast, lymphocytes represent the adaptive immune system and promote the induction of autoimmune inflammation, especially in the chronic inflammatory response. Through the literature review, we will highlight the inflammatory pathway for the physiopathology of ASCVD, HF, and COVID-19. In this regard, the neutrophil-to-lymphocyte ratio (NLR) integrates the innate immune and adaptive immune systems, making the NLR a biomarker of inflammation. In addition, we provided an update on the evidence showing that high NLR is associated with worse prognosis in heart failure (HF), ASCVD, and COVID-19, as well as their clinical applications showing that the normalization of NLR after anti-cytokine therapy is a potential predictor of therapy responsiveness and is associated with reduction of major adverse cardiovascular events.


Evidence for more than two central benzodiazepine receptors in rat spinal cord.
Competitive binding assays were performed in rat spinal cord membranes at 0 degrees C against [3H]Ro15-1788. The displacement curves of Ro15-1788 and alpidem produced pseudo-Hill slopes of 1.0 and 0.5, respectively. In addition, 5-10% of the specifically bound [3H]Ro15-1788 could not be displaced by greater than 100 microM of alpidem. These two pieces of evidence strongly suggest the presence of at least three central benzodiazepine binding sites in the spinal cord.


Previous encapsulation response enhances within individual protection against fungal parasite in the mealworm beetle Tenebrio molitor.
Immune defenses of insects show either broad reactions or specificity and durability of induced protection against attacking parasites and pathogens. In this study, we tested whether encapsulation response against nylon monofilament increases between two attempts of activation of immune system in mealworm beetles Tenebrio molitor, and whether previous exposure to nylon monofilament may also increase protection against an entomopathogenic fungus. We found that survival of beetles subjected to immune activation by nylon implant and subsequent fungal exposure a week later was significantly higher than survival of beetles which had been subjected to fungal infection only. This result suggests that previous immune activation by the nylon implant may be considered as broad spectrum "immune priming" which helps to fight not only the same intruder but also other parasites.


Type locality and species identity of Pareuchiloglanis sinensis (Hora & Silas) with a description of a new species of the genus from the upper Yangtze River basin in southern China.
The genus Pareuchiloglanis, distributed in the Salween, Mekong, Red, Pearl and Yangtze River basins in China, Laos, Myanmar and Vietnam, consists of 20 valid species and 5 uncertain species. This study provided a taxonomic revision to Pareuchiloglanis occurring in the Yangtze River. According to the results of a morphological comparison, the type locality of Pareuchiloglanis sinensis was updated to the Nanpan-jiang (the upper Pearl River) basin; five species were identified in Pareuchiloglanis from the Yangtze River basin. Specimens formerly identified as Pareuchiloglanis sinensis from this basin were described as a new species, Pareuchiloglanis chui sp. nov. Moreover, Pareuchiloglanis tianquanensis was synonymized with Pareuchiloglanis sichuanensis. This study provided a key to these two species and three others (Pareuchiloglanis anteanalis, Pareuchiloglanis hupingshanensis and Pareuchiloglanis robusta) from the Yangtze River basin, including information about their geographical distribution. These findings provide an insight into the evolution, distribution and taxonomy of this genus for future studies.


Effect of polymeric stabilizers on the size and stability of PLGA paclitaxel nanoparticles.
The aim of this study is to formulate polymeric paclitaxel nanoparticles with various stabilizers to improve solubility, enhance stability, maximize therapeutic efficacy and minimize detrimental toxicities of paclitaxel. In this study, trastuzumab-guided poly lactic-co-glycolic acid (PLGA)-loaded paclitaxel nanoparticles were formulated with pluronic F-127, polyvinyl alcohol (PVA), poloxamer 407, Tween-80, span 20, sodium dodecyl sulfate (SDS), and sodium lauryl sulfate (SLS) at different concentrations (0.5, 1, 1.5 and 2%) using the solvent evaporation method. The nanoparticles were evaluated for physicochemical characteristics and short and long-term stability. The optimum particle size (190 nm ± 12.42 to 350 nm ± 11.1), PDI (0.13 ± 0.02 to 0.2 ± 0.01), surface charge (-19.1mv ± 1.5 to -40.4mv ± 1.6), drug loading (2.43 to 9.5 %) and encapsulation efficiency (greater than 80 %) were obtained with these stabilizers while keeping the polymer concentration, temperature, probe size, amplitude and sonication time constant. The nanoformulations were stably stored at 4 °C. The nanoformulations of paclitaxel with pluronic F-127, polyvinyl alcohol (PVA), and poloxamer 407 were found to be more soluble, stable, uniform in physicochemical properties, and efficient in drug loading and encapsulation for improved therapeutic effects.


Multi-channeled single chain variable fragment (scFv) based microfluidic device for explosives detection.
The development of explosives detection technologies has increased significantly over the years as environmental and national security agencies implement tighter pollution control measures and methods for improving homeland security. 2, 4, 6-Trinitrotoluene (TNT), known primarily as a component in munitions, has been targeted for both its toxicity and carcinogenic properties that if present at high concentrations can be a detriment to both humans, marine and plant ecosystems. Enabling end users with environmental detection and monitoring systems capable of providing real-time, qualitative and quantitative chemical analysis of these toxic compounds would be extremely beneficial. Reported herein is the development of a multi-channeled microfluidic device immobilized with single chain fragment variable (scFv) recombinant proteins specific for the explosive, TNT. Fluorescence displacement immunoassays performed under constant flow demonstrated trace level sensitivity and specificity for TNT. The utility of three multi-channeled devices immobilized with either (1) scFv recombinant protein, (2) biotinylated-scFv (bt-scFv) and (3) monoclonal anti-TNT (whole IgG molecule) were investigated and compared. Fluorescence dose response curves, crossreactivity measurements and limits of detection (LOD) for TNT were determined. Fluorescence displacement immunoassays for TNT in natural seawater demonstrated detection limits at sub-parts-per-billion levels (0.5 ppb) utilizing the microfluidic device with immobilized bt-scFv.


Morning sickness drug is not linked to increased risk of birth defects.
A new study has found no evidence of a link between anti-nausea drug Zofran, also known as ondansetron, to an increased risk of having a child with birth defects.


Spontaneous formation of an anti-S alloantibody in association with mixed connective tissue disease.
A spontaneous anti-S alloantibody developed without prior transfusion in a 33-year-old male with mixed connective tissue disease. It was detectable by indirect antiglobulin testing using anti-IgG specific, as well as polyspecific anti-human globulin. All previously reported naturally occurring anti-S antibodies had been cold reactive agglutinins, presumably IgMs.


Agreement of clinical tests for the diagnosis of peripheral arterial disease.
The aim of this study was to compare different screening modalities in the detection of PAD in a primary care setting. Fifty participants living with Type 2 diabetes were recruited. Pulse palpation, waveform analysis, ankle brachial pressure index, absolute toe pressure, toe brachial pressure index and transcutaneous oxygen pressure were compared in the detection of peripheral arterial disease. One hundred limbs were included for analysis. This study showed different results in peripheral arterial disease screening tests in the same group of participants. The highest percentage of participants who had PAD was for the Doppler Waveform (93.0%). This was followed by TBPI (72.0%), ABPI (57.0%), ATP (35.0%), TCPO (30.0%) and pulse palpation (23.0%). The difference between these percentages is significant (p<0.0005). The magnitude of the effect size is medium/moderate (Cramer's V=0.498). This study demonstrates that inconsistencies exist between the agreement of the 6 different modalities used to detect PAD. These findings should create an awareness amongst clinicians when interpreting results of these tests. The authors advocate for urgent, more robust studies utilizing a gold standard modality for the diagnosis of PAD in order to provide evidence regarding which screening modalities would yield the most valid results.