Alternating Therapy With Osimertinib and Afatinib Blockades EGFR Secondary Mutation in EGFR-Mutant Lung Cancer: A Single-Arm Phase II Trial.
Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial. Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment. Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected. The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment. jRCTs051180009.


Drinking on television; a preliminary study with emphasis on method.
A procedure designed to assess the frequency of alcohol-related events in television shows and commercials is described.


[Biological properties of sherry yeasts in the presence of antimicrobial preparations].
The wine yeasts Cheres were not sensitive to high concentration (500 gamma/ml) of benzylpenicillin, streptomycin, tetracycline, oxytetracycline, chlortetracycline, morphocycline, erythromycin, oleandomycin, monomycin, neomycin, kanamycin, polymyxin, ampicillin, oxacillin, methicillin, ceporin, ristomycin, levomycetin, furadonin and furazolidone. In concentrations of 50 to 500 gamma-ml oleadomycin, chlortetracycline, oxytetracycline, kanamycin and ristomycin inhibited synthesis of the Cheres yeast biomass. Benzylpenicillin, polymyxin, neomycin and ampicillin in concentrations of 50 to 100 gamma/ml had a stimulating effect on the yeast biomass synthesis.


Chemoprevention: from research to clinical oncology.
Chemoprevention is by now an emerging area of clinical oncology addressed to healthy individuals at higher risk for cancer, subjects with precancerous conditions, and patients who are at risk for a second primary cancer. The important results of large trials with various agents and the more accurate methods of risk assessment have already had implications in clinical practice. Recently, a number of compounds have shown to be clinically effective at various organ levels, often covering all the three settings of primary, secondary and tertiary prevention. There is proof today that at least 3 of the 4 'big killers' in oncology--breast, colon and prostate cancer--and oral cancer are to a certain extent preventable by chemopreventive drugs. The missing piece so far is lung cancer. The expanding molecular drug development is providing the tools for a more effective and safer molecular-targeted prevention. Combination chemoprevention and the use of agents with multiple effects are other particularly promising chemoprevention strategies.


Novel fractional-order decentralized control for nonlinear fractional-order composite systems with time delays.
A novel decentralized non-integer order controller applied on nonlinear fractional-order composite system(NFOCS) is proposed. In addition, some novel results for the asymptotic stabilization are shown with fractional parameter α∈0,1. First, we derive certain novel results useful for the Mittag-Leffler function. Then, we design a new decentralized fractional-order controller for the NFOCS according to the novel results applied to Mittag-Leffler function. Next, this novel asymptotic stabilization condition has been proposed. Compared with other controllers our controller has wider control gain range and weaker requirements. Moreover, we solve the asymptotic stabilization problem of the NFOCS with time delays via the novel controller. In the end, four general examples are performed to show the progressiveness of the new fractional-order decentralized controller.


Histologic and Immunohistochemical Findings of a Human Immature Permanent Tooth with Apical Periodontitis after Regenerative Endodontic Treatment.
Specimens of human immature permanent teeth after regenerative endodontic treatment (RET) are sparse. This case report describes the histologic and immunohistochemical findings of tissue formed in the canal space of a human immature permanent tooth with apical periodontitis after RET. A patient presenting with immature human permanent tooth #29 with apical periodontitis underwent RET. At the 10-month follow-up visit, radiographic examination revealed complete resolution of the periapical lesion, marked narrowing of the apical foramen, increased thickness of the canal walls, and minimal lengthening of the root. Notably, the tooth regained pulp sensibility. Tooth #29 was extracted for orthodontic reasons and processed for histologic and immunohistochemical examination. The canal space was filled with newly formed cementumlike tissue, bonelike tissue, and fibrous connective tissue. The apical closure, thickness, and length increment of the root were caused by the deposition of cementumlike tissue without dentin. Furthermore, neurons and nerve fibers were observed in the canal space; this observation was confirmed by immunohistochemistry. Based on the findings in the present case, after RET, the newly formed tissues in the canal space of the human immature permanent tooth with apical periodontitis were primarily fibrous connective tissue, cementumlike tissue, and bonelike tissue. Nerve regeneration was identified.


New Devices in Glaucoma.
Glaucoma remains a leading cause of blindness globally. Minimally invasive treatment techniques are rapidly expanding the availability of therapeutic options for glaucoma. These include devices aimed at enhancing outflow through the subconjunctival space, Schlemm's canal, and suprachoroidal space, sustained-release drug delivery devices, and extraocular devices aiming to reduce glaucomatous progression through other novel means. In this review, we provide an overview of several novel devices either newly available or in development for the medical and surgical management of glaucoma. Further studies are required to determine the long-term efficacy of these devices and how they will integrate into the current landscape of glaucoma management.


Accuracy of MELD scores in predicting mortality in decompensated cirrhosis from variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, or acute liver failure as well as mortality after non-transplant surgery or TIPS.
To systematically review literature on use of model for end-stage liver disease (MELD) score to determine severity and prognosis of liver disease in various clinical situations and to evaluate its use in decisions regarding therapeutic interventions. Computerized literature searches using key medical terms; review of authors' extensive files on this subject; and personal clinical experience. The MELD score, a prospectively developed and validated scale for severity of end-stage liver disease, utilizes serum bilirubin, serum creatinine, and international normalized ratio to predict mortality in cirrhotic patients. It has proven clinically useful in increasingly varied clinical situations. The United Network for Organ Sharing uses MELD scores, with bonus points assigned for hepatocellular cancer, to prioritize allocation of deceased donor livers for liver transplantation. This work reviews recent data demonstrating that MELD scores relatively accurately predict mortality in patients with variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, and acute liver failure, as well as assess risks of non-liver transplantation surgery or transjugular intrahepatic portosystemic shunts in cirrhotic patients. MELD scores fail to predict mortality in about 15% of patients with end-stage liver disease. Incorporation of additional parameters, including serum sodium level, serum albumin level, glucose intolerance, or APACHE II score, may potentially improve prognostic accuracy. MELD scores relatively accurately assess severity of liver disease and prognosis in patients with advanced liver disease in general, and in patients with individual complications of liver disease. It is useful in making decisions on potential therapies. Incorporating additional parameters may further improve its prognostic accuracy.


Selective isolation of genomic loci from complex genomes by transformation-associated recombination cloning in the yeast Saccharomyces cerevisiae.
Here, we describe a protocol for the selective isolation of any genomic fragment or gene of interest up to 250 kb in size from complex genomes as a circular yeast artificial chromosome (YAC). The method is based on transformation-associated recombination (TAR) in the yeast Saccharomyces cerevisiae between genomic DNA and a linearized TAR cloning vector containing targeting sequences homologous to a region of interest. Recombination between the vector and homologous sequences in the co-transformed mammalian DNA results in the establishment of a YAC that is able to propagate, segregate and be selected for in yeast. Yield of gene-positive clones varies from 1% to 5%. The entire procedure takes 2 weeks to complete once the TAR vector is constructed and genomic DNA is prepared. The TAR cloning method has a broad application in functional and comparative genomics, long-range haplotyping and characterization of chromosomal rearrangements, including copy number variations.


[Pneumoretroperitoneum due to pneumatosis cystoides intestinalis. An etiopathogenetic and clinico-diagnostic assessment. A clinical case report].
A case of pneumoretroperitoneum which came out to be caused by pneumatosis cystoides intestinalis, after careful and proper diagnostic evaluation, is described. Physiopathology, etiopathogenesis and clinical peculiarities of this infrequent pathology are examined; most useful tests to be performed in diagnostic differential evaluation, and clinical and surgical therapeutic approaches are also described, especially facing rare complications of PCI, such as pneumoperitoneum and pneumoretroperitoneum.


Cold plasma modification of food macromolecules and effects on related products.
The food industry is in search of innovative processing technologies that are capable of providing food safety and improving quality with low processing costs and fast operations. As a new technique, cold plasma (CP) fulfills these requirements and thus gained significant attraction from researchers. Apart from general microbial inactivation purposes, CP can effectively modify the food macromolecules through reactions with reactive plasma species. In this context, this review focuses on the interactions between reactive plasma species and proteins, lipids, and polysaccharides. It also covers the changes in interfacial and mechanical properties of proteins and polysaccharides, effects on oleogels and xerogels, modifications in the allergenicity of proteins, and trans-free hydrogenation of oils. On the other hand, the concepts underlying the interactions between reactive plasma species and these macromolecules and the effects of processing parameters should be better understood, thus further studies should focus on these aspects.


Total aortic occlusion caused by sustained balloon inflation: a previously unreported complication of intraaortic balloon counterpulsation.
A case of acute lower-body ischemia 2 days following intraaortic balloon pump insertion is reported. Fluoroscopy revealed persistent balloon inflation throughout the cardiac cycle with distal aortic occlusion. Attempts to manually deflate the balloon were unsuccessful until a guidewire was advanced through the gas-exchange lumen into the body of the balloon. The balloon catheter was removed without clinical sequelae other than transient oliguria and an asymptomatic increase in creatinine phosphokinase (CPK). This is a previously unreported complication of intraaortic balloon counterpulsation.


Optimization of supercritical carbon dioxide treatment for the inactivation of the natural microbial flora in cubed cooked ham.
This study aims to investigate the effects of supercritical carbon dioxide (SC-CO₂) treatment on the inactivation of the natural microbial flora in cubed cooked ham. Response surface methodology with a central composite design was applied to determine the optimal process conditions and investigate the effect of three independent variables (pressure, temperature and treatment time). Additionally, analyses of texture, pH and color together with a storage study of the product were performed to determine its microbial and qualitative stability. Response surface analysis revealed that 12 MPa, 50 °C, 5 min were the optimal conditions to obtain about 3.0, 1.6, and 2.5 Log(CFU/g) reductions of mesophilic aerobic bacteria, psychrophilic bacteria and lactic acid bacteria respectively. Inactivation to undetectable levels of yeasts and molds and coliforms was also obtained. A storage study of 30 days at 4 °C was carried out on the treated product (12 MPa, 50 °C, 5 min) monitoring microbial growth, pH, texture, and color parameters (L*, a*, b* and ΔE). Microbial loads slightly increased and after 30 days of storage reached the same levels detected in the fresh product. Color parameters (L*, a*, b*) showed slight variations while pH and texture did not change significantly. On the basis of the results obtained, SC-CO₂ can be considered a promising technique to microbiologically stabilize cubed cooked ham and, in general, cut/sliced meat products without affecting its quality attributes.


Acquired Stuttering in Parkinson's Disease.
Parkinson's disease frequently causes communication impairments, but knowledge about the occurrence of new-onset stuttering is limited. To determine the presence of acquired neurogenic stuttering and its relationship with cognitive and motor functioning in individuals with Parkinson's disease. Conversation, picture description, and reading samples were collected from 100 people with Parkinson's disease and 25 controls to identify the presence of stuttered disfluencies (SD) and their association with neuropsychological test performance and motor function. Participants with Parkinson's disease presented with twice as many stuttered disfluencies during conversation (2.2% ± 1.8%SD) compared to control participants (1.2% ± 1.2%SD; P < 0.01). 21% of people with Parkinson's disease (n = 20/94) met the diagnostic criterion for stuttering, compared with 1/25 controls. Stuttered disfluencies also differed significantly across speech tasks, with more disfluencies during conversation compared to reading (P < 0.01). Stuttered disfluencies in those with Parkinson's disease were associated with longer time since disease onset (P < 0.01), higher levodopa equivalent dosage (P < 0.01), and lower cognitive (P < 0.01) and motor scores (P < 0.01). One in five participants with Parkinson's disease presented with acquired neurogenic stuttering, suggesting that speech disfluency assessment, monitoring and intervention should be part of standard care. Conversation was the most informative task for identifying stuttered disfluencies. The frequency of stuttered disfluencies was higher in participants with worse motor functioning, and lower cognitive functioning. This challenges previous suggestions that the development of stuttered disfluencies in Parkinson's disease has purely a motoric basis.


Gene mapping in fishes: a means to an end.
Genetic research in fishes is poised to contribute a vast amount of information on the structural organization and function of vertebrate genomes. Recent advances in molecular biology have made possible the widescale characterization of genomes in all living organisms. This includes defining chromosomes at the cytological level down to their linear composition at individual nucleotide base pairs. Pioneering gene mapping studies into the genomes of fishes will only serve as the starting point for more detailed studies into the function of these genomes. Future research directed at understanding the mechanisms of gene actions and interactions will benefit all areas of biology, including ecology, ethology, evolution, and physiology. Gene mapping data from brown trout and rainbow trout are used to exemplify how basic information on gene transmission in a species may help to localize centromeres onto a genetic map and identify chromosomal regions possessing a high degree of segregation distortion. Genetic maps may also be used to identify differences in recombination levels among individuals and between the sexes when multiple mapping families are utilized in studies. Observations of this type are the antecedents to more complex biological investigations on the genetic architecture underlying these phenomena.


Ending surgical site infection by negative pressure wound therapy (NPWT): A case report.
Hundreds of millions of people may go through surgery every year worldwide. Surgical site infection (SSI) is one of the most common complications of the surgery. SSI increases the duration of treatment, delays wound healing, increases the use of antibiotics, and in severe cases, causes patient death and imposes high costs on the patient and the health care system. The present case report is a 45-year-old man with a history of 8-years type 2 diabetes who underwent surgery for a pilonidal cyst. Despite routine dressing changes (cleansing the wound with saline and applying sterile gauze) twice a day and intravenous (IV) antibiotic therapy, no improvement was observed and the wound became infected. The patient was referred to our wound care team. NPWT (applying a pressure of 125 mm Hg intermittently) was performed 4 times a day for one week. Also, after each session until the beginning of the next session, the patient's wound was bandaged. The patient's wound healed completely after about 2 months. Patients with diabetes mellitus will have difficulty in wound healing due to microvascular changes. Thus, efficient therapeutic methods such as surgical debridement, maggot therapy, and NPWT are necessary for management of surgical site infection. This case report was showed that NPWT is an affordable and highly efficacious treatment method for management of SSI in patients with diabetes mellitus. Therefore, it is suggested that wound care teams may use NPWT to treat SSIs.


Orthotopic liver transplantation for ornithine transcarbamylase deficiency with hyperammonemic encephalopathy.
Ornithine transcarbamylase (OTC) deficiency is an X chromosome-linked disorder causing hyperammonemic encephalopathy with a very poor prognosis. We describe here two patients with OTC deficiency, one a late on-set female patient (case 1) and the other a neonatal-onset male patient (case 2), who were successfully treated with orthotopic liver transplantation (OLTx). The OTC activity in the excised liver was 10% and 0% of control, respectively. Hyperammonemic encephalopathy was controlled with medical therapy in case 1 until the of 5 years, but the complicated course in case 2 in which hyperammonemia required peritoneal dialysis and hemodialysis in the neonatal period necessitated OLTx with a reduced-size liver at the age of 80 days. Both patients had restoration of serum ammonia level to normal in 2 and 3 days after liver replacement, and both patients have normal neurological and developmental status after 2 and 0.5 years of postoperative follow-up. These cases illustrate not only the metabolic cure of this disorder, but also the need to preserve neurological integrity by aggressive medical management of the hyperammonemia preoperatively and early surgical intervention when indicated, even if this is required very early in life.


A self-management plus mind body intervention for adolescents and young adults with type 2 diabetes: Trial design and methodological report.
The onset of type 2 diabetes (T2D) is increasingly common in adolescents and young adults (AYAs). Improving self-management skills and the mental health of this population is important, but understudied. The goal of this research was to develop a mind-body intervention which could serve as an adjunctive therapy to support AYAs with T2D (INTEND intervention). Toward that end, we used an iterative process, including use of focus groups, advisory board, and cognitive semi-structured interviews with patients, parents of patient and clinical providers, to understand the gaps in the current information provided to AYAs with T2D. Based on the data gathered from the focus groups and interviews, we enhanced an existing self-management intervention for adults with T2D to include an additional mind body intervention for AYAs with T2D. The INTEND intervention will be piloted in a group of AYAs with T2D. This report describes the methodology and design of the InterveNTion for Early oNset type 2 Diabetes (INTEND) study. The details of this single arm pre-post pilot feasibility trial are described. If successful, the INTEND approach has the potential to advance care for vulnerable youth with T2D.


Flow Cytometric Evaluation of Traditional and Novel Surface Markers for the Diagnosis of Plasma Cell Dyscrasias.
Increasing interest has been expressed for flow cytometric immunophenotyping for diagnosis and monitoring in plasma cell dyscrasias over the last decades. The aim of this investigation was to compare the expression strength of various cell surface markers used traditionally or currently under investigation on normal and abnormal PC populations. We enrolled 295 consecutive patients undergoing bone marrow aspiration in the workup of monoclonal gammopathies, selecting 54 normal and 241 abnormal PC populations via flow cytometry to characterize the expression of CD45, CD38, CD138, CD19, CD56, CD20, CD27, CD28, CD81, CD117 and CD200 on the cell surface of PCs. We observed significant differences in the expression strength of all assessed markers between normal and abnormal PC populations in all markers except for CD20. While none of them was conclusive on its own, the combination of CD81 positivity and CD117 negativity was present in 98.1% of normal PC populations tested. In contrast, particularly CD117 positivity, but also CD81 negativity was indicative of an abnormal PC phenotype. Our results highlight the descriptive value of CD81 and CD117 for the allocation of bone marrow PCs to a normal or abnormal phenotype.


Prevalence and antibiotic susceptibility patterns of enteric bacterial pathogens in human and non-human sources in an urban informal settlement in Cape Town, South Africa.
In light of rampant childhood diarrhoea, this study investigated bacterial pathogens from human and non-human sources in an urban informal settlement. Meat from informal abattoirs (n = 85), river water (n = 64), and diarrheic stool (n = 66) were collected between September 2015 and May 2016. A duplex real-time PCR, gel-based PCR, and CHROMagar™STEC were used to screen Tryptic Soy Broth (TSB) for diarrheic E. coli. Standard methods were used to screen for other selected food and waterborne bacterial pathogens. Pathogens isolated from stool, meat, and surface water included Salmonella enterica (6, 5, 0%), Plesiomonas shigelloides (9, 0, 17%), Aeromonas sobria (3, 3, 0%), Campylobacter jejuni (5, 5, 0%), Shigella flexneri (17, 5, 0%), Vibrio vulnificus (0, 0, 9%), and diarrheic E. coli (21, 3, 7%) respectively. All the isolates were resistant to trimethoprim-sulphamethoxazole. There was a high burden of drug resistant diarrheal pathogens in the stool, surface water and meat from informal slaughter. Integrated control measures are needed to ensure food safety and to prevent the spread of drug resistant pathogens in similar settings.


Employer perceptions of stress and resilience intervention.
To understand employers' perceived organizational strengths in addressing stress and resilience-building to help expand theoretical knowledge and guide interventions. Interviews and discussion groups with 46 employer representatives using grounded theory methodology for sampling and analysis of narrative data. Participants detailed three levels of approaches: (1) preventing stress/building resilience; (2) providing information, resources, and benefits to employees; and (3) intervening actively with troubled employees. Preventing stress through trusting work relationships and trust in stability of organizational structures emerged as a core concept explaining effectiveness of these approaches. Results are discussed using positive organizational scholarship, systems, and well-being frameworks. Psychosocial distress has unfavorable effects on human health and work performance. Greater attention to the systemic development and maintenance of trust in workplace relationships and systems is suggested.


Lipid accumulation in mouse hepatocytes after morphine exposure.
After morphine injection lipid accumulation in mouse hepatocytes begins within 2 h and continues for 24 h when most hepatocytes are filled with lipid droplets. In spite of morphine maintenance the liver recovers as the accumulated lipids are coupled with protein and subsequently transported and released into the perisinusoidal space of Disse.


Graphical displays for effective reporting of evidence quality tables in research syntheses.
When generating guidelines, quality of the evidence is tabulated to capture its several domains, often using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We developed a graphic display to capture deficiencies, outliers and similarities across comparisons contained in GRADE tables. Based on a systematic literature review capturing the effects of 32 different therapeutic comparisons on dysmenorrhoea, we synthesised evidence quality in tables and graphs. We evaluated time taken to accurately assess evident quality and preference for tables vs. graphs. The plots provided visually striking displays of strengths and weaknesses of the evidence across the spectrum of comparisons on a single page. Equivalent tabulated information spread over 4 pages. Participants preferred and interpreted graphs quicker and more accurately than tables. The graphic approach we developed makes interpreting evidence easier. Large tables are dry and cumbersome to read and assimilate. When guideline statements are accompanied by these plots, they have the scope for improving the credibility of the recommendations made, as the strength of the evidence used can be clearly seen. Further empirical research will establish the place for graphic displays.


Contextual fear conditioning differs for infant, adolescent, and adult rats.
Contextual fear conditioning was tested in infant, adolescent, and adult rats in terms of Pavlovian-conditioned suppression. When a discrete auditory-conditioned stimulus (CS) was paired with footshock (unconditioned stimulus, US) within the largely olfactory context, infants and adolescents conditioned to the context with substantial effectiveness, but adult rats did not. When unpaired presentations of the CS and US occurred within the context, contextual fear conditioning was strong for adults, weak for infants, but about as strong for adolescents as when pairings of CS and US occurred in the context. Nonreinforced presentations of either the CS or context markedly reduced contextual fear conditioning in infants, but, in adolescents, CS extinction had no effect on contextual fear conditioning, although context extinction significantly reduced it. Neither CS extinction nor context extinction affected responding to the CS-context compound in infants, suggesting striking discrimination between the compound and its components. Female adolescents showed the same lack of effect of component extinction on response to the compound as infants, but CS extinction reduced responding to the compound in adolescent males, a sex difference seen also in adults. Theoretical implications are discussed for the development of perceptual-cognitive processing and hippocampus role.


Renal accumulation and effects of intraperitoneal injection of extracted microcystins in omnivorous crucian carp (Carassius auratus).
An acute toxicological experiment was designed to characterize the sequence of renal ultrastructural changes with accumulated MCs in crucian carp injected intraperitoneally (i.p.) with extracted microcystins (mainly MC-RR and -LR) at two doses, 50 and 200 μg MC-LReq. kg⁻¹ body weight. Quantitative and qualitative determinations of MCs in the kidney were conducted by HPLC and LC-MS, respectively. MC-RR content in kidney of crucian carp showed a time dose-dependent increase within 48 h post-injection, followed by a sharp decline afterward, while no MC-LR in kidney was detectable throughout the experiment. Ultrastructural changes in the kidney of crucian carp progressed with increasing accumulated MCs and exposure times within 48 h post-injection, whereas renal ultrastructural recovery of crucian carp in the 50 μg MC-LReq. kg⁻¹ dose group was evident at 168 h post-injection. Our ultrastructural observation suggests that the membranous structure is the main action site of MCs in the kidney, among which mitochondria damage in the tubules is clearly an early, and presumably a critically important effect of MCs. The increases in blood urea nitrogen (BUN) and creatinine (CR) in both dose groups further revealed severe impairment occurred in the kidney of crucian carp.


An update on plant membrane rafts.
The dynamic segregation of membrane components within microdomains, such as the sterol-enriched and sphingolipid-enriched membrane rafts, emerges as a central regulatory mechanism governing physiological responses in various organisms. Over the past five years, plasma membrane located raft-like domains have been described in several plant species. The protein and lipid compositions of detergent-insoluble membranes, supposed to contain these domains, have been extensively characterised. Imaging methods have shown that lateral segregation of lipids and proteins exists at the nanoscale level at the plant plasma membrane, correlating detergent insolubility and membrane-domain localisation of presumptive raft proteins. Finally, the dynamic association of specific proteins with detergent-insoluble membranes upon environmental stress has been reported, confirming a possible role for plant rafts as signal transduction platforms, particularly during biotic interactions.


Complications and outcome of cats with congenital extrahepatic portosystemic shunts treated with thin film: Thirty-four cases (2008-2017).
Congenital extrahepatic portosystemic shunts (CEHPSS) are rare in cats. Outcome after attenuation of CEHPSS with thin film has been described in a small number of cases. To describe the clinical presentation, postoperative complications, and outcome of cats treated with thin film to attenuate CEHPSS. Thirty-four cats with CEHPSS were identified from the database of 3 institutions over 9 years. Retrospective study. Medical records were reviewed to identify cats with a diagnosis of a CEHPSS that underwent surgical attenuation. Congenital extrahepatic portosystemic shunts were suspected from clinical signs, clinicopathologic findings, and diagnostic imaging, and confirmed at exploratory laparotomy. Cats treated with thin film band attenuation were included. Postoperative complications and follow-up were recorded. Complications were recorded in 11 of 34 cats. Deaths related to CEHPSS occurred in 6 of 34; 4 cats did not survive to discharge. Persistent seizures were the cause of death in 4 cats. Seizures were recorded in 8 of 34 cats after surgery; all these cats received preoperative antiepileptic drugs. Serum bile acid concentrations normalized in 25 of 28 of the cats for which data was available. Three cats had persistently increased serum bile acid concentrations and underwent a second exploratory laparotomy. One had a patent shunt, the other 2 had multiple acquired portosystemic shunts. Median follow-up was 8 months (0.5-84 months). Congenital extrahepatic portosystemic shunts attenuation using thin film in cats carries a good short- and mid-term prognosis if they survive the postoperative period. Seizures were the most common cause of death.


Detection of human autoantibody against intercalated cells of kidney-collecting tubule.
Serum from a 24-year-old woman with a history of habitual abortions was examined for autoantibodies by indirect immunofluorescence microscopy. Fluorochrome-labelled antibodies to IgG revealed cytoplasmic staining of single cells in rat kidney collecting and connecting tubules. An identical staining pattern was reproducibly obtained in human and rabbit kidney, pointing to a cytoplasmic antigen concentrated in the apical pole of these cells. Lectin-binding histochemistry and immunohistochemical experiments using markers for different cell populations of the renal collecting tubule by double immunofluorescence technique, identified the cells recognized by the autoantibody as intercalated cells (ICC). Remarkably, this autoantibody reacted with a different antigen from those described to date in ICC, as evidenced by distribution and intracellular localization. The pattern of immunostaining suggests that all ICC are recognized in total rather than only one subpopulation. The connection between habitual abortions and this novel autoantibody are discussed.


Five new species in the idiocerine genus Busonia Distant (Hemiptera: Cicadellidae: Idiocerinae) from Thailand and Malaysia, with one new record from China.
Six species in the genus Busonia Distant are described and illustrated, including five new species from Thailand and Malaysia: Busonia curvata, B. fusca, B. lactata, B. micrata, B. serrata, spp. nov., and one newly recorded species from China: Busonia albilateralis Maldonado-Capriles. A redescription of this genus is provided together with a key to species for separation of males.


Age-dependent effects of parasites on anti-predator responses in two New Zealand freshwater fish.
Parasites of all kinds affect the behaviour of their hosts, often making them more susceptible to predators. The associated loss in expected future reproductive success of infected hosts will vary among individuals, with younger ones having more lose than older ones. For this reason, young hosts would benefit more by opposing the effects of parasites than old ones. In a laboratory study, the effects of the trematode Telogaster opisthorchis on the anti-predator responses of the upland bully (Gobiomorphus breviceps) and of the common river galaxias (Galaxias vulgaris) were examined in relation to fish age. In a bully population where parasites were very abundant, the magnitude of the fish's anti-predator responses decreased as the number of parasites per fish increased, and this effect was significantly more pronounced in age 2 + and, to a lesser extent, age 3 + fish than in age 1 + fish. In another bully population where parasites were 10 times less abundant, similar effects were noticeable but not significant, whereas no effects of parasites on the responses of galaxiids to predators were apparent. Differences in the abundance of parasites and in their sites of infection in fish may explain the variability among host populations or species. However, in the bully population with high parasite abundance, parasitism has age-dependent effects on responses to predators, providing some support for the prediction that young fish with high expected future reproductive success invest more energy into opposing the effects of parasites than do older fish.


R--pulse wave timing: a technique for continuous cardiovascular monitoring in obstetrics--preliminary report.
A simple, noninvasive technique for continuous cardiovascular monitoring in obstetrics using R--pulse wave timing is described. This preliminary study suggests that different maternal heart rate/R pulse patterns are found in different clinical circumstances. A significant decrease in the R pulse interval occurred in the third trimester in both normal and diabetic women in the left lateral position when compared to the supine position. The R pulse intervals were all prolonged in the standing position in both gravid and nongravid women. During labor R pulse interval usually shortened during uterine contraction. Prolongation of R pulse interval was observed during thiopental injection, hypotension, and excessive bleeding at cesarean section. Exercise testing in healthy male subjects suggested that the change in R pulse interval becomes constant when the oxygen consumption rate reaches a plateau at 100% maximal work load. Further extensive clinical study appears worthwhile since it may add another dimension to cardiovascular monitoring and give an early indication of cardiovascular reserve.


Beneficial effects of inhaled nitric oxide in hypoxaemic patients after coronary artery bypass surgery.
Arterial oxygenation may be impaired in the early period after open-heart surgery, with an associated increase in ventilation time, morbidity and hospital stay. We tested the hypothesis that inhaled nitric oxide could be a useful therapeutic adjunct in this setting. We sought to establish clinical benefits (if any), safety and the appropriate dose range of inhaled nitric oxide therapy in hypoxaemic patients after coronary artery bypass graft surgery. Forty patients who satisfied our definition of post-operative impaired oxygenation were prospectively randomised. The treatment group (n = 20) received nitric oxide in addition to ventilatory support. While the control group (n = 20) was managed only by conventional ventilatory support. Cardio-respiratory parameters and clinical outcome measures were compared. We determined the optimum concentration of inhaled nitric oxide as 20 ppm in the majority (60%) of patients. Treatment improved arterial oxygenation (8.4 +/- 1.4 kPa before, 11.8 +/- 1.5 kPa after 4 h, P < 0.001) and this benefit was sustained with lower oxygen fractions required at 24 h (P < 0.001). A significantly shorter period of mechanical ventilation was required in the treatment group (mean ventilation hours 67.0 +/- 5.9 vs. 85.0 +/- 6.5, P < 0.05), although the study did not have the power to distinguish differences in ITU or overall hospital stay. Nitrous oxide and met-haemoglobin levels did not rise appreciably. We have established the safety and efficacy of inhaled nitric oxide, at a dose of between 10 and 30 ppm, in this group of patients. We suggest that nitric oxide and a delivery system are useful adjuvants in a cardiac surgical intensive care unit.


Laparoscopic fenestration in combination with ethanol sclerotherapy prevents a recurrence of symptomatic giant liver cyst.
Laparoscopic fenestration in combination with ethanol sclerotherapy of the cyst wall was performed in four patients with symptomatic giant solitary liver cyst. Two of these patients had recurrent liver cysts, which were resistant to simple laparoscopic fenestration. After the combination therapy, none of the cysts recurred during follow-up periods ranging from 11 to 33 months.


The role of socioeconomic status and injury morbidity risk in adolescents.
To examine the patterns of socioeconomic status and injury morbidity in adolescents. Prospective cohort study. Metropolitan school district in Allegheny County, Pennsylvania. There were 1245 students (89%) recruited from 1400 aged 12 to 16 years. None. Baseline variables of socioeconomic status used for this analysis included township of residence (from the 1990 census data ranked by the percentage of households below the poverty level) and employment status of the parents (student self-report). Life-table analysis revealed no differential risk of injury by socioeconomic status. Similar results were found when stratified by gender, race, injury type (sport vs nonsport), and injury place (school vs home). The results indicate that in this cohort of adolescents, socioeconomic status does not seem to be a contributing risk factor for injury.


Serum leptin levels in patients with primary hyperaldosteronism before and after treatment: relationships to insulin sensitivity.
Leptin is a protein hormone produced predominantly by adipocytes that plays a role in food intake regulation and a series of other physiological processes including blood pressure regulation. The aim of our study was to compare serum leptin levels in patients with primary hyperaldosteronism (PA) with those of healthy subjects and to explore the relationship of serum leptin levels and the parameters of insulin action in these patients before and after surgical or pharmacological treatment. Serum potassium, leptin, aldosterone, insulin levels and plasma renin activity were measured and hyperinsulinaemic euglycaemic clamp was performed in 11 patients with PA and 11 healthy age-, gender- and body mass index (BMI)-matched subjects. In eight of 11 patients the same measurements were repeated at least 6 months after surgical or pharmacological treatment. The basal serum leptin levels in PA patients did not significantly differ from those of healthy subjects (mean+/-s.e.m. 8.4+/-1.9 vs 11.2+/-1.8 ng/ml, P=0.30), although their insulin sensitivity was significantly impaired (PA patients vs control subjects: glucose disposal rate in the last 20 min of clamp (M) 18.7+/-1.8 vs 30.6+/-3.3 micromol/kg/min, metabolic clearance rate of glucose (MCR(g)) 3.9+/-0.5 vs 7.2+/-1.1 ml/kg/min, P<0.05). The surgical or pharmacological treatment of PA patients increased significantly their serum leptin levels (10.9+/-3.7 vs 8.4+/-1.9 ng/ml, P<0.05) and simultaneously improved their insulin sensitivity. Basal serum leptin levels in both groups correlated positively with BMI and serum insulin levels. The inverse relationship between serum leptin levels and the insulin sensitivity parameters was found in both PA patients before treatment and healthy subjects. These relationships disappeared after treatment of PA patients except for those between serum leptin levels and MCR(g). Basal serum leptin levels in untreated patients with PA do not significantly differ from those of healthy subjects, but increase significantly after surgical or pharmacological treatment. The increase in serum leptin levels is paradoxically accompanied by the improvement of insulin sensitivity in these patients.


Ability of Bifidobacterium breve 702258 to transfer from mother to infant: the MicrobeMom randomized controlled trial.
The composition of the infant microbiome can have a variety of short- and long-term implications for health. It is unclear if maternal probiotic supplementation in pregnancy can affect the infant gut microbiome. This study aimed to investigate if maternal supplementation of a formulation of Bifidobacterium breve 702258 from early pregnancy until 3 months postpartum could transfer to the infant gut. This was a double-blinded, placebo-controlled, randomized controlled trial of B breve 702258 (minimum 1 × 109 colony-forming units) or placebo taken orally from 16 weeks' gestation until 3 months postpartum in healthy pregnant women. The primary outcome was presence of the supplemented strain in infant stool up to 3 months of life, detected by at least 2 of 3 methods: strain-specific polymerase chain reaction, shotgun metagenomic sequencing, or genome sequencing of cultured B breve. A total of 120 individual infants' stool samples were required for 80% power to detect a difference in strain transfer between groups. Rates of detection were compared using the Fisher exact test. A total of 160 pregnant women with average age of 33.6 (3.9) years and mean body mass index of 24.3 (22.5-26.5) kg/m2, of whom 43% were nulliparous (n=58), were recruited from September 2016 to July 2019. Neonatal stool samples were obtained from 135 infants (65 in intervention and 70 in control group). The presence of the supplemented strain was detected through at least 2 methods (polymerase chain reaction and culture) in 2 infants in the intervention group (n=2/65; 3.1%) and none in the control group (n=0; 0%; P=.230). Direct mother-to-infant strain transfer of B breve 702258 occurred, albeit infrequently. This study highlights the potential for maternal supplementation to introduce microbial strains into the infant microbiome.


Engineering E. coli-E. coli cocultures for production of muconic acid from glycerol.
cis, cis-Muconic acid is an important chemical that can be biosynthesized from simple substrates in engineered microorganisms. Recently, it has been shown that engineering microbial cocultures is an emerging and promising approach for biochemical production. In this study, we aim to explore the potential of the E. coli-E. coli coculture system to use a single renewable carbon source, glycerol, for the production of value-added product cis, cis-muconic acid. Two coculture engineering strategies were investigated. In the first strategy, an E. coli strain containing the complete biosynthesis pathway was co-cultivated with another E. coli strain containing only a heterologous intermediate-to-product biosynthetic pathway. In the second strategy, the upstream and downstream pathways were accommodated in two separate E. coli strains, each of which was dedicated to one portion of the biosynthesis process. Compared with the monoculture approach, both coculture engineering strategies improved the production significantly. Using a batch bioreactor, the engineered coculture achieved a 2 g/L muconic acid production with a yield of 0.1 g/g. Our results demonstrate that coculture engineering is a viable option for producing muconic acid from glycerol. Moreover, microbial coculture systems are shown to have the potential for converting single carbon source to value-added products.


Ratiometric electrochemical aptasensor for ultrasensitive detection of Ochratoxin A based on a dual signal amplification strategy: Engineering the binding of methylene blue to DNA.
A novel ratiometric electrochemical aptasensor was developed for Ochratoxin A (OTA) detection based on the binding of methylene blue (MB) to DNA with a dual signal amplification strategy. The formation of dsDNA structures between ferrocene-labeled complementary DNA (Fc-cDNA), the OTA aptamer, and complementary helper DNA (hDNA) caused Fc away from the electrode, and allowed dsDNA to bind with a certain amount of MB. Here, a small oxidation current of Fc (IFc) and a large oxidation current of MB (IMB) were obtained. In the presence of OTA, its specific recognition with the aptamer induced the release of aptamer and hDNA from the electrode and subsequently the formation of hairpin structure for cDNA, which caused Fc close to the electrode and a weaker binding ability with MB. Then, an increased IFc and a decreased IMB were obtained. Based on this principle, OTA could be accurately quantified by measuring the ratiometric signal of IFc/IMB. Herein, the dual signal amplification strategy of the introduction of hDNA and the binding with MB after the OTA recognition was exploited to amplify the response signal. The obtained aptasensor showed a linear detection range from 10 pg mL-1 to 10 ng mL-1 and a detection limit of 3.3 pg mL-1. The aptasensor was successfully applied to determine OTA in wheat, and the results were validated through HPLC-MS. Furthermore, by changing the target aptamers, this strategy could be universally used for the determination of various mycotoxins, showing promising potential applications for mycotoxins monitoring in agricultural products and foods.


[Decrease in the degree of lipoid infiltration of rabbit tissues during feeding with cholesterol freed from autoxidation products].
Lipid accumulation in the rabbit liver and myocardium has been investigated by histochemical and biochemical methods. The rabbits received cholesterol that contained 5% of autooxidation products or purified cholesterol. Lipid accumulation took place in the liver and intramural myocardial vessels during feeding of rabbits with autooxidated cholesterol. Feeding with pure cholesterol free from autooxidation products caused but slight changes or no changes at all.


Infantile bilateral striatal necrosis associated with human herpes virus-6 (HHV-6) infection.
A 1-year-old female with acute bilateral striatal necrosis secondary to exanthema subitum associated with human herpesvirus 6 (HHV-6) infection is reported. The patient was previously healthy. She presented with progressive neurologic signs of oral dyskinesia and involuntary movements, after suffering from exanthema subitum. Initial magnetic resonance imaging (MRI) demonstrated abnormal signals in the bilateral striatal regions. In addition, the serum HHV-6 IgM class antibody level was significantly increased. The patient is thought to be the first case of HHV-6 infection related infantile bilateral striatal necrosis (IBSN).


Collapse pressure measurement of single hollow glass microsphere using single-beam acoustic tweezer.
Microbubbles are widely used in medical ultrasound imaging and drug delivery. Many studies have attempted to quantify the collapse pressure of microbubbles using methods that vary depending on the type and population of bubbles and the frequency band of the ultrasound. However, accurate measurement of collapse pressure is difficult as a result of non-acoustic pressure factors generated by physical and chemical reactions such as dissolution, cavitation, and interaction between bubbles. In this study, we developed a method for accurately measuring collapse pressure using only ultrasound pulse acoustic pressure. Under the proposed method, the collapse pressure of a single hollow glass microsphere (HGM) is measured using a high-frequency (20-40 MHz) single-beam acoustic tweezer (SBAT), thereby eliminating the influence of additional factors. Based on these measurements, the collapse pressure is derived as a function of the HGM size using the microspheres' true density. We also developed a method for estimating high-frequency acoustic pressure, whose measurement using current hydrophone equipment is complicated by limitations in the size of the active aperture. By recording the transmit voltage at the moment of collapse and referencing it against the corresponding pressure, it is possible to estimate the acoustic pressure at the given transmit condition. These results of this study suggest a method for quantifying high-frequency acoustic pressure, provide a potential reference for the characterization of bubble collapse pressure, and demonstrate the potential use of acoustic tweezers as a tool for measuring the elastic properties of particles/cells.


Soluble fibrin causes an acquired platelet glycoprotein VI signaling defect: implications for coagulopathy.
Essentials Collagen and thrombin when used simultaneously generate highly activated platelets. The effect of thrombin stimulation on subsequent glycoprotein VI (GPVI) function was observed. Soluble fibrin, but not protease activated receptor (PAR) activation, prevented GPVI activation. Circulating soluble fibrin in coagulopathic blood may cause an acquired GPVI signaling defect. Background In coagulopathic blood, circulating thrombin may drive platelet dysfunction. Methods/Results Using calcium dye-loaded platelets, the effect of thrombin exposure and soluble fibrin generation on subsequent platelet GPVI function was investigated. Exposure of apixaban-treated platelet-rich plasma (12% PRP) to thrombin (1-10 nm), but not ADP or thromboxane mimetic U46619 exposure, dramatically blocked subsequent GPVI activation by convulxin, collagen-related peptide or fibrillar collagen. Consistent with soluble fibrin multimerizing and binding GPVI, the onset of convulxin insensitivity required 200-500 s of thrombin exposure, was not mimicked by exposure to PAR-1/4 activating peptides, was not observed with washed platelets, and was blocked by fibrin polymerization inhibitor (GPRP) or factor XIIIa inhibitor (T101). PAR-1 signaling through Gαq was not required because vorapaxar blocked thrombin-induced calcium mobilization but had no effect on the ability of thrombin to impair GPVI-signaling. Convulxin insensitivity was unaffected by the metalloprotease inhibitor GM6001 or the αIIb β3 antagonist GR144053, indicating negligible roles for GPVI shedding or αIIb β3 binding of fibrin. Thrombin treatment of washed platelets resuspended in purified fibrinogen also produced convulxin insensitivity that was prevented by GPRP. Exposure of apixaban/PPACK-treated whole blood to thrombin-treated fibrinogen resulted in > 50% decrease in platelet deposition in a collagen microfluidic assay that required soluble fibrin assembly. Conclusions Conversion of only 1% plasma fibrinogen in coagulopathic blood would generate 90 nm soluble fibrin, far exceeding ~1 nmGPVI in blood. Soluble fibrin, rather than thrombin-induced platelet activation throuh PAR-1 and PAR-4, downregulated GPVI-signaling in response to stimuli, and may lead to subsequent hypofunction of endogenous or transfused platelets.


MR for the evaluation of obstructive pulmonary disease.
Obstructive lung diseases include emphysema, chronic bronchitis, chronic obstructive pulmonary disease, asthma, and cystic fibrosis. These diseases are a heterogeneous group of pulmonary disorders that share in common obstruction of air flow and deranged gas exchange. Traditionally these diseases are evaluated with clinical testing, such as pulmonary function tests, but such tests provide only global measures of respiratory function. MR techniques designed for obstructive lung disease have the capability of directly imaging the anatomic and pathophysiologic derangements and may prove useful for monitoring response to therapy.


High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated with osteoblast differentiation.
The formation of bony spurs and ankylosis is a key pathognomic feature in ankylosing spondylitis (AS) and results in functional impairment. The aim of this study was to investigate the role of IL-32γ in osteoblast (OB) differentiation and its association with the pathogenesis of AS. The concentration and expression of IL-32γ were evaluated in synovial fluid and tissue from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA), using enzyme-linked immunosorbent assay and immunohistochemistry. To establish whether IL-32γ affects OB differentiation, we used calvarial cells of IL-32γ transgenic (TG) mice or wild-type (WT) mice. To elucidate the mechanism of osteoblastogenesis, levels of regulators were assayed in IL-32γ TG mice and in primary OBs after IL-32γ stimulation. The IL-32γ levels were higher in the synovial fluid of AS patients compared with RA or OA patients and the expression of IL-32 was higher in AS synovia than in RA or OA synovia. Additional IL-32γ stimulation in precursor cells enhanced OB differentiation potentially and IL-32γ TG mice showed higher rates of OB differentiation than WT mice. IL-32γ reduced the expression of DKK-1, a negative regulator, in both WT precursor cells and human OBs and the constitutive expression of DKK-1 was suppressed in calvarial cells from IL-32γ TG mice. The elevated level of IL-32γ in AS joint could enhance OB differentiation via DKK-1 suppression. Therefore, IL-32γ might be a putative molecular target to prevent the abnormal bone formation in AS.


Microvascular coronary flow comparison in acute myocardial infarction angioplasty treated with a mesh covered stent (MGUARD stent) versus bare metal stent: MICAMI-MGUARD.
Distal embolization of thrombus/platelet aggregates decreases myocardial reperfusion during primary percutaneous coronary intervention (PCI), and is associated with worse immediate and long-term prognosis of patients with ST-elevation myocardial infarction (STEMI). Assess the efficacy of a mesh covered stent (MGuard™ stent, MGS) in preventing distal embolization and microvascular reperfusion impairment during primary PCI, compared with a bare metal stent (BMS). Forty patients with STEMI referred for primary PCI were randomized for stenting the culprit lesion with the MGS (n = 20) or a BMS (n = 20). Blinded experts performed off-line measurements of angiographic epicardial and microvascular reperfusion criteria: TIMI flow grade, myocardial blush, corrected TIMI frame count (cTFC). At baseline clinical, angiographic and procedural variables were not different between groups. Post PCI TIMI flow grade was similar in both groups. We observed better myocardial Blush grade in group MGS compared to BMS (median value 3.0 vs 2.5, 2p = 0.006) and cTFC (mean cTFC: MGS 19.65 ± 4.07 vs BMS 27.35 ± 7.15, 2p < 0.001, cTFC mean difference MGS-BMS: 7.7, CI 95%: 3.94 to 11.46). MGS stent group had a higher percentage of successful angioplasty (cTFC ≤ 23: MGS 85% vs BMS 30%, 2p < 0.001). We had two cases of acute stent thrombosis (one for each group) at 30days follow up, but no clinical events at 6 months follow up. In this exploratory study, MGS significantly improved microvascular reperfusion criteria compared with a BMS in primary PCI. However its safety and impact on clinical outcomes should be verified in larger randomized clinical trials.


Circadian variation of cardiogenic pulmonary oedema.
Circadian variation of in-hospital acute cardiogenic pulmonary oedema (CPE) with the highest occurrence in the early morning has been reported repeatedly. However, no study evaluating circadian variation of CPE in the field has been published. Therefore, we decided to evaluate the circadian variation of CPE in the Central Bohemian Region of the Czech Republic in the patients treated by regional emergency medical service (EMS) and analyse its association with baseline blood pressure in the field. We extracted all dispatches to CPE cases from EMS database for the period from 1.11.2008 to 30.6.2014 and analysed for circadian variation. We identified the patients presenting with CPE coupled with arterial hypertension (systolic blood pressure >140mmHg) and hypotension (systolic blood pressure <90mmHg) and compared the subgroups (both subgroups include 2744 subjects). In 4747 episodes of CPE, maximal occurrence was detected in the ninth hour in the morning, representing 7.7% of all CPE episodes (p<0.05). While CPE with hypertension (2463 subjects) reached maximal occurrence also in the ninth hour (7.4% of all cases, p<0.05), CPE with hypotension (281 patients) was most frequent in the fourteenth hour (8.6% of all cases, p<0.05). The highest occurrence of CPE was observed in the ninth hour in the morning in our study. Moreover, differences in circadian variation between CPE with hypertension and hypotension were identified. Knowledge of these patterns may have an impact on the logistic of prehospital emergency care and on preventive measures in the patients who have previously undergone CPE.


Effect of ibopamine on peripheral haemodynamics.
Peripheral haemodynamics was studied in healthy volunteers by strain gauge plethysmography after administration of ibopamine (IB), diisobutyric ester of N-methyl-dopamine, an orally active dopaminergic agonist. Seven subjects received a single oral dose of ibopamine of 150 mg and 6 received a daily dose of 150 mg (50 mg t.i.d.) for 5 consecutive days. Arterial resting blood flow and venous capacity increased and peripheral resistance decreased significantly. Six further subjects were then studied; 3 h after an oral dose of ibopamine 150 mg, the parenteral administration of Sulpiride 50 mg, a specific vascular dopaminergic antagonist, was found significantly to counteract its peripheral activity. Heart rate and arterial blood pressure were never affected and tolerability was good.


What factors influence help-seeking for hearing impairment and hearing aid adoption in older adults?
The purpose of this review paper was to identify factors that influence older adults' decisions to seek help for hearing impairment and to adopt hearing aids. A literature search of abstracts within peer-reviewed journal articles published in English between 1990 and 2010 was conducted in online bibliographic databases using the keywords: hearing; impair* or loss; seek* or candidate* or applicant* or acquir*; and hearing aid* or help or advice. Twenty-two articles that were directly relevant to this topic were included in this review. The evidence suggests that individuals are more likely to seek help for hearing impairment and/or adopt hearing aids if they: (1) have a moderate to severe hearing impairment and self-reported hearing-related activity limitations or participation restrictions; (2) are older; (3) perceive their hearing as poor; (4) consider there to be more benefits than barriers to amplification; and (5) perceive their significant other/s as supportive of hearing rehabilitation. A barrier to help-seeking for hearing impairment and hearing aid adoption appears to be general practitioners' management of age-related hearing impairment.


The covalent structure of calf skin type III collagen. I. The amino acid sequence of the amino terminal region of the alpha 1(III) chain (position 1--222).
The amino terminal 227 amino acid residues of the alpha 1(III) chain contain four CNBr peptides: alpha 1(III)CB3A (79 residues), CB3B, CB3C (6 residues each), CB7 (37 residues) and CB6 (99 residues). Fragmentation of the CNBr peptides was carried out using trypsin, chymotrypsin and the protease from Staphylococcus aureus V8. The fragments obtained were isolated by a combination of molecular sieve and ion exchange chromatography. The sequence analysis was performed according to the automated Edman degradation procedure.


Timolol: a preliminary report of its pharmacological properties and therapeutic efficacy in angina and hypertension.
Timolol (MK 950) is a new beta-adrenergic receptor blocking drug. It has little or no membrane stabilising ('quinidine-like') or partial agonist (intrinsic sympathomimetic) activity and thus resembles sotalol. On a weight for.weight basis, timolol is more potent than sotalol or propranolol. A 2.5 mg dose of timolol causes about the same reduction in resting heart rate as 20mg of propranolol. Results of placebo-controlled and of comparative trials with other beta-adrenergic receptor blocking drugs, have shown that timolol effectively lowers blood pressure without producing orthostatic or exercise hypotension. Findings of an international multicentre trial in angina pectoris, indicate that timolol is effective in reducing the frequency of anginal attacks and the consumption of glyceryl trinitrate for their relief.


The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice.
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease caused by mutations in all of the major sarcomeric proteins, including the ventricular myosin regulatory light-chain (RLC). The E22K-RLC mutation has been associated with a rare variant of cardiac hypertrophy defined by mid-left ventricular obstruction due to papillary muscle hypertrophy. This mutation was later found to cause ventricular and septal hypertrophy. We have generated transgenic (Tg) mouse lines of myc-WT (wild type) and myc-E22K mutant of human ventricular RLC and have examined the functional consequences of this FHC mutation in skinned cardiac-muscle preparations. In longitudinal sections of whole mouse hearts stained with hematoxylin and eosin, the E22K-mutant hearts of 13-month-old animals showed signs of inter-ventricular septal hypertrophy and enlarged papillary muscles with no filament disarray. Echo examination did not reveal evidence of cardiac hypertrophy in Tg-E22K mice compared to Tg-WT or Non-Tg hearts. Physiological studies utilizing skinned cardiac-muscle preparations showed an increase by DeltapCa50>or=0.1 in Ca(2+) sensitivity of myofibrillar ATPase activity and force development in Tg-E22K mice compared with Tg-WT or Non-Tg littermates. Our results suggest that E22K-linked FHC is mediated through Ca(2+)-dependent events. The FHC-mediated structural perturbations in RLC that affect Ca(2+) binding properties of the mutated myocardium are responsible for triggering the abnormal function of the heart that in turn might initiate a hypertrophic process and lead to heart failure.


Gd(--) Abrami: a deficient G-6PD variant with hemizygous expression in blood cells of a woman with primary myelofibrosis.
A new deficient G-6PD variant, Gd(--) Abrami, was found in granulocytes, platelets and red blood cells of a 65-year-old woman with myelofibrosis. Enzyme and immunological titrations showed that only the deficient variant was present in blood cells whereas both the normal and abnormal enzymes were found in the fat cells of this patient. These results seem to indicate that the granulocytes, platelets and erythrocytes of this woman with myelofibrosis have arisen from a single abnormal precursor the functional X chromosome of which is the one carrying the abnormal G-6PD gene.


Incorporating patients' views and experiences of life with IBS in the development of an evidence based self-help guidebook.
To become active partners in chronic illness management, patients need relevant information which clearly explains treatment choices. This paper describes a method of producing information to feed into production of a guidebook for people with irritable bowel syndrome (IBS). Users were involved throughout the development process. Five focus groups were held involving 23 people with IBS out of 147 who responded to a newspaper article asking for help with a study of self-care in IBS. Qualitative analysis of transcripts from these meetings formed the basis of guidebook development. Patients described their experiences, coping strategies, experiences of the healthcare system, treatments and social consequences of the condition. Medical literature searches were made to find answers to identified areas of information need. The book includes direct quotes from patients describing their own experiences. Guided and practical ways of support are required for people with IBS who want to self-manage their condition.


Intensified removal of copper from waste water using activated watermelon based biosorbent in the presence of ultrasound.
Copper is one of the most toxic heavy metals having significant effects on the living organisms and hence effective removal of copper from waste water is crucial. The current work investigates the application of activated watermelon shell based biosorbent for the removal of copper from aqueous solution. The effect of activation using calcium hydroxide and citric acid as well as the effect of operating parameters like contact time, adsorbent dosage, temperature, pH, initial concentration and ultrasonic power on the extent of removal has been investigated. Experiments performed in the presence of ultrasound to investigate the degree of intensification as compared to the conventional agitation based treatment revealed that the adsorption rate significantly increases in the presence of ultrasound and also the time required for reaching the equilibrium reduces from 60 min in conventional approach to only 20 min in the presence of ultrasound. The extent of adsorption of Cu(II) on adsorbents was found to increase with an increase in the operating pH till an optimum value of 5. The extent of adsorption also increased with a decrease in the initial concentration and particle size as well as with an increase in ultrasonic power till an optimum. Kinetics and isotherm study revealed that all the experimental data was found to best fit the pseudo second order kinetics and Langmuir adsorption isotherm model respectively. Maximum adsorption capacity was found to be 31.25mg/g for watermelon treated with calcium hydroxide and 27.027 mg/g for watermelon treated with citric acid. Overall present study established that activated watermelon is an environmentally friendly, low cost and highly efficient biosorbent that can be successfully applied for the removal of copper from aqueous solution with intensification benefits based on the ultrasound assisted approach.


Avian feather development: relationships between morphogenesis and keratinization.
Morphogenesis and expression of the alpha and beta keratin polypeptides are controlled by epidermal-dermal interactions during development of avian skin derivatives. We have examined the relationship between morphogenesis of the embryonic feather and expression of the feather alpha and beta keratins by routine histology, indirect-immunofluorescence, and SDS-PAGE. Initially beta keratins are expressed only in the feather sheath. Following barb ridge morphogenesis beta keratins can be detected in the barb ridge, coincident with the differentiation of barb ridge cells into eight distinct morphological types. Beta keratinization occurs in gradients; from feather apex to base, and from periphery of the barb ridge to the interior. The onset of beta keratinization in the barb ridges is paralleled by an increase in the major feather beta keratin polypeptides, as detected by SDS-PAGE. The alpha keratins are present in both the periderm and feather sheath at early stages of feather development, but become greatly reduced after hatching, when the down feather emerges from the sheath.


Synergistic mechanisms for the superior sorptive removal of aquatic pollutants via functionalized biochar-clay composite.
This study investigated the successful synthesis of functionalized algal biochar-clay composite (FBKC). Subsequently, the sorption performance of FBKC towards norfloxacin (NFX) antibiotic and crystal violet dye (CVD) from water was extensively assessed in both batch and continuous flow systems. A series of characterization techniques were carried out for FBKC and the utilized precursors, indicating that the surface area of FBKC was increased thirty-fold with a well-developed pore structure compared to the original precursors. FBKC demonstrated a maximum sorption capacity of 192.80 and 281.24 mg/g for NFX and CVD, respectively. The suited fitting of the experimental data to Freundlich and Clark models suggested multi-layer sorption of NFX/CVD molecules. The mechanistic studies of NFX/CVD sorption onto FBKC unveiled multiple mechanisms, including π-π interaction, hydrogen bonding, electrostatic attraction, and surface/pore filling effect. The estimated cost of 5.72 €/kg and superior sorption capacity makes FBKC an efficient low-cost sorbent for emergent water pollutants.


Author Correction: Combining streptozotocin and unilateral nephrectomy is an effective method for inducing experimental diabetic nephropathy in the 'resistant' C57Bl/6J mouse strain.
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.


Structurally diverse biflavonoids from the fruits of Citrus medica L. var. sarcodactylis Swingle and their hypolipidemic and immunosuppressive activities.
The fruit of Citrus medica L. var. sarcodactylis Swingle is not only used as a traditional medicinal plant, but also served as a delicious food. Six new (3'→7″)-biflavonoids (1-6), and twelve known biflavonoid derivatives (7-18) were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. Their structures were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, and IR spectral data coupled with the data described in the literature. Compounds (1-18) were evaluated for their hypolipidemic activities with Orlistat as the positive control, and assayed for their immunosuppressive activities with Dexamethasone as the positive control, respectively. Among them, compounds (1-3) exhibited moderate inhibition of pancreatic lipase activity by inhibiting 68.56 ± 1.40%, 56.18 ± 1.57%, 53.51 ± 1.59% of pancreatic lipase activities at the concentration of 100 μM, respectively. Compounds (4-6) and 8 showed potent immunosuppressive activities with the IC50 values from 16.83 ± 1.32 to 50.90 ± 1.79 μM. The plausible biogenetic pathway and preliminary structure activity relationship of the selected compounds were scientifically summarized and discussed in this study.


Cell-type specific and multiscale dynamics of human focal seizures in limbic structures.
The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy.


Extinction, turnover and species diversity in an experimentally fragmented California annual grassland.
Many natural populations are subdivided among partially isolated habitat patches, but the influence of habitat patchiness per se on species immigration, extinction, and the resulting patterns of species diversity, has received virtually no experimental study. In an experiment designed to test the effects of habitat subdivision on local community structure, we compare the diversity and annual turnover of flowering plant species in 3 treatments of the same total area, but subdivided to different degrees. We experimentally fragmented a California winter annual grassland into isolated plots, two of 32 m2, eight of 8 m2, and 32 of 2 m2, each treatment representing a combined area of 64 m2. Insularization of the experimental habitat fragments is provided by grazing sheep. The effects of plot area on species diversity, extinction, and turnover are consistent with the MacArthur-Wilson model. Species richness increases with the degree of habitat subdivision. Extinction, immigration, and turnover, however, are relatively independent of the degree of subdivision. These experimental results contrast with predictions that habitat subdivision necessarily results in greater rates of extinction accompanied by reduced species diversity.


Bisphosphonate-associated osteonecrosis of the jaws. Report of a case and literature review.
This paper reviews the main aspects involved in the bisphosphonate-associated osteonecrosis of the jaws and report its occurrence in a 82-year-old man, who had received long-term treatment with zoledronate to manage bone metastases due to prostate cancer. The clinical aspects and the treatment are presented. Computerized tomography contributed to a more specific diagnosis, demonstrating the osteonecrosis in the maxilla, sinus involvement, and sclerotic areas in the entire body of the mandible and c-spine. Clinical trials and studies in animals are necessary to elucidate the pathogenesis of bisphosphonate-associated osteonecrosis of the jaws, and to determine whether the bisphosphonates produce sclerotic changes in the skeleton similar to those found in osteopetrosis. Nevertheless, patients taking bisphosphonates should receive prophylactic attention to maintain their oral health. Preventive measures must be taken before, during, and after treatment with bisphosphonates.


Aquaporin-4 expression in distal myopathy with rimmed vacuoles.
Distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy is clinically characterized by the early involvement of distal leg muscles. The striking pathological features of the myopathy are muscle fibers with rimmed vacuoles. To date, the role of aquaporin-4 water channel in distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy has not been studied. Here, we studied the expression of aquaporin-4 in muscle fibers of a patient with distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy. Immunohistochemical and immunofluorescence analyses showed that sarcolemmal aquaporin-4 immunoreactivity was reduced in many muscle fibers of the patient. However, the intensity of aquaporin-4 staining was markedly increased at rimmed vacuoles or its surrounding areas and in some muscle fibers. The fast-twitch type 2 fibers were predominantly involved with the strong aquaporin-4-positive rimmed vacuoles and TAR-DNA-binding protein-43 aggregations. Rimmed vacuoles with strong aquaporin-4 expression seen in the distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy patient were not found in control muscles without evidence of neuromuscular disorders and the other disease-controls. Aquaporin-4 might be crucial in determining the survival or degeneration of fast-twitch type 2 fibers in distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy.


Test of an anaerobic prototype reactor coupled with a filtration unit for production of VFAs.
The artificial ecosystem MELiSSA, supported by the European Space Agency is a closed loop system consisting of 5 compartments in which food, water and oxygen are produced out of organic waste. The first compartment is conceived as a thermophilic anaerobic membrane bioreactor liquefying organic waste into VFAs, ammonium and CO2 without methane. A 20 L reactor was assembled to demonstrate the selected design and process at prototype scale. We characterized system performance from start-up to steady state and evaluated process efficiencies with special attention drawn to the mass balances. An overall efficiency for organic matter biodegradation of 50% was achieved. The dry matter content was stabilized around 40-50 g L(-1) and VFA production around 5-6 g L(-1). The results were consistent for the considered substrate mixture and can also be considered relevant in a broader context, as a first processing step to produce building blocks for synthesis of primary energy vectors.


Evaluation of the Solutions for two Design Problems Presented at the 1998 Optical Interference Coatings Conference.
Two problems were proposed at the 1998 Conference on Optical Interference Coatings: dual-band antireflection coatings and bandpass filters. In excess of 40 solutions were submitted. An evaluation of those solutions is presented.


Mechanosensation of Tight Junctions Depends on ZO-1 Phase Separation and Flow.
Cell-cell junctions respond to mechanical forces by changing their organization and function. To gain insight into the mechanochemical basis underlying junction mechanosensitivity, we analyzed tight junction (TJ) formation between the enveloping cell layer (EVL) and the yolk syncytial layer (YSL) in the gastrulating zebrafish embryo. We found that the accumulation of Zonula Occludens-1 (ZO-1) at TJs closely scales with tension of the adjacent actomyosin network, revealing that these junctions are mechanosensitive. Actomyosin tension triggers ZO-1 junctional accumulation by driving retrograde actomyosin flow within the YSL, which transports non-junctional ZO-1 clusters toward the TJ. Non-junctional ZO-1 clusters form by phase separation, and direct actin binding of ZO-1 is required for stable incorporation of retrogradely flowing ZO-1 clusters into TJs. If the formation and/or junctional incorporation of ZO-1 clusters is impaired, then TJs lose their mechanosensitivity, and consequently, EVL-YSL movement is delayed. Thus, phase separation and flow of non-junctional ZO-1 confer mechanosensitivity to TJs.


Microtubule-targeted drugs inhibit VEGF receptor-2 expression by both transcriptional and post-transcriptional mechanisms.
Cytoskeletal polymers control a wide range of cellular functions, including proliferation, migration, and gene expression. As changes in endothelial cell shape and motility are required to form vascular networks, we hypothesized that disassembly of actin filaments or microtubules may impact endothelial vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) expression as a critical determinant of angiogenesis. We therefore investigated the effect of actin filament- and microtubule-disrupting agents on VEGFR1 and VEGFR2 expression by endothelial cells. Microtubule (MT) disassembly greatly inhibited endothelial VEGFR2 expression, whereas VEGFR1 expression levels remained largely unchanged. These suppressive effects were neither conveyed by increased VEGFR2 shedding nor by shortened protein half-life, suggesting that transcriptional mechanisms account for the observed effects. In line with this conclusion, MT disruption significantly suppressed endothelial VEGFR2 mRNA accumulation. The treatment considerably decreased transcriptional activity of 5'-deletional VEGFR2 promoter gene constructs. MT disruption-mediated repression was conveyed by a GC-rich region harboring two consensus Sp1-binding sites. Electrophoretic mobility-shift assay analysis demonstrated that constitutive Sp1-dependent DNA binding is decreased by MT disassembly. In addition, we provide evidence for additional post-transcriptional regulatory mechanisms, as the VEGFR2 mRNA half-life is significantly reduced by MT-disrupting agents. Hence, both inhibition of the rate of gene transcription and increased mRNA turnover represent critical molecular mechanisms by which MT disruption inhibits VEGFR2 expression.


Emergent coronary angiographic findings of patients with ST depression in the inferior or lateral leads, or both, during anterior wall acute myocardial infarction.
In conclusion, the present study indicates that there are several distinctive differences in emergent coronary angiographic findings according to the presence or absence of ST depression in the inferior or lateral leads, or both, and location of the leads showing ST depression on admission electrocardiograms in patients with anterior AMI. The coronary angiographic features of patients with this ECG finding greatly support a poor prognosis. In patients with anterior AMI, analysis of ST depression on an admission electrocardiogram should be routinely performed because it is useful in predicting coronary anatomy, the extent of infarction, and its prognosis.


The association between rs12885713 polymorphism in CALM1 and risk of osteoarthritis: A meta-analysis of case-control studies.
The single nucleotide polymorphism (SNP) rs12885713 of calmodulin 1 gene (CALM1) has been reported to involve in the etiology of osteoarthritis (OA) in several association studies with limited sample size and conflicting results. The purpose of the present systematic review and meta-analysis was to evaluate and synthesize the currently available data on the correlation between rs12885713 and OA susceptibility. Six electronic databases including PubMed, EMBASE, ISI Web of Science, CNETRAL, CNKI, and Wanfang were systematically retrieved to identify relevant observational articles published before October 2017. Summary odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated to indicate the association between CALM1 polymorphism and OA. Risk of bias was assessed through the Newcastle-Ottawa Scale. Predetermined subgroups and sensitivity analyses were performed using the RevMan 5.3 software. Publication bias was evaluated by Egger and Begg tests. Overall, 5 case-control studies involving 2183 OA patients 2654 healthy control subjects satisfied the meta-analysis. Recessive model was confirmed to be the best-matching genetic model (TT + TC versus CC). The pooled outcomes indicated that rs12885713 SNP was not significantly associated with OA vulnerability (OR 1.11, 95% CI 0.97, 1.27; P = .12). When stratified by different genders, OA sites, and population descents respectively, still non-significant associations were found. Based on the findings of our present study, the rs12885713 polymorphism of CALM1 did not appear to be associated with OA predisposition.


Characteristics of prostate cancer patients captured by facility-based versus geography-based cancer registries.
We determined differences in demographics, tumor factors, and treatment patterns of prostate cancer patients in a geographic-based cancer registry based on eligibility for a facility-based cancer registry system. We identified prostate cancer patients captured by the Surveillance, Epidemiology, and End Results (SEER) database from 2018 to 2019. Our exposure was receipt of cancer care at a facility accredited by the American College of Surgeons' Commission on Cancer (CoC) providing eligibility for inclusion in the National Cancer Database (NCDB). Outcomes included patient demographics, tumor factors (e.g., biopsy grade), and treatment with radical prostatectomy. We identified 113,733 prostate cancer patients of whom 65,708 (57%) were NCDB-eligible with an analytic abstract, and 11,010 (10%) were NCDB-eligible without an analytic abstract. NCDB-eligible men were younger (67.0 vs. 68.1 years, P < 0.001), less likely to be Hispanic/Latino (8.7% vs. 13.2%, P < 0.001), and more likely in a county with median income over $75,000 (40.9% vs. 30.0%, P < 0.001). NCDB eligibility varied widely by registry, from 95.9% in Connecticut to 42.6% in Utah. NCDB-ineligible patients were more likely to have unknown stage (17.2% vs. 2.9% NCDB-eligible) and missing PSA (22.9% vs 9.3% NCDB-eligible). NCDB-eligible men were less likely to have Grade Group 1 cancer on biopsy (28.2% vs. 39.2%, P < 0.001). Treatment with prostatectomy was more common among NCDB-eligible patients for low-risk (19.6% vs. 8.8%, adjusted OR 2.30, 95% CI 1.72-6.66) and high-risk tumors (43.5% vs. 26.0%, adjusted OR 1.95, 95% CI 1.33-2.86). Compared NCDB-ineligible patients, those eligible for inclusion in the NCDB have important differences in demographics, eligibility for active surveillance, and treatment patterns. Generalizations related to epidemiologic trends, practice patterns, and outcomes for this select population should be interpreted with caution.


The relationship between the pharmacokinetics, cholinesterase inhibition and facilitation of twitch tension of the quaternary ammonium anticholinesterase drugs, neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium.
1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethyl-ammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred. Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme.


Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature.
Information in the literature regarding causes of mortality in patients with hypereosinophilic syndrome (HES) is limited. This was a retrospective review of the morbidities and causes of death in HES patients at Mayo Clinic. Overall, out of the 247 diagnosed HES patients, 23 died during the 19 years that this review encompassed. The cause of death was identified in 15 patients (65%): cardiac dysfunction in 5 (33%), infection in 3 (20%), unrelated malignancy in 3 (20%), thromboembolic phenomena in 2 (13%), and vascular disease in 2 (13%). Targeted monitoring of the at-risk end organs, combined with early treatment, may have the ability to improve survival and reduce morbidity in HES patients.


Modeling monthly reference evapotranspiration process in Turkey: application of machine learning methods.
In this study, the predictive power of three different machine learning (ML)-based approaches, namely, multi-gene genetic programming (MGGP), M5 model trees (M5Tree), and K-nearest neighbor algorithm (KNN), for long-term monthly reference evapotranspiration (ET0) prediction were investigated. The input data consist of monthly solar radiation (Rs), maximum air temperature (Tmax), and wind speed (Ws) derived from 163 meteorological stations in Turkey. Different input combinations were created and analyzed. The model's performance was evaluated using criteria such as Nash-Sutcliffe efficiency, Kling-Gupta efficiency, relative root mean squared error, mean absolute percentage error, and determination coefficient. Moreover, Taylor, radar, and boxplot diagrams were created. It was determined that the MGGP model outperformed both the M5Tree and the KNN models. The equation obtained from the MGGP model, for the best-performed combination of Rs-Tmax-Ws, was presented. The best weather conditions were obtained as 0.029 to 31.814 MJ/m2, - 5.8 to 45.7 °C, and 0.140 to 5.086 m/s for Rs, Tmax, and Ws, respectively. It was also found that the Rs was the most potent input variable for ET0 estimation while Ws was the weakest.


Magnetique: an interactive web application to explore transcriptome signatures of heart failure.
Despite a recent increase in the number of RNA-seq datasets investigating heart failure (HF), accessibility and usability remain critical issues for medical researchers. We address the need for an intuitive and interactive web application to explore the transcriptional signatures of heart failure with this work. We reanalysed the Myocardial Applied Genomics Network RNA-seq dataset, one of the largest publicly available datasets of left ventricular RNA-seq samples from patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathy, as well as unmatched non-failing hearts (NFD) from organ donors and patient characteristics that allowed us to model confounding factors. We analyse differential gene expression, associated pathway signatures and reconstruct signaling networks based on inferred transcription factor activities through integer linear programming. We additionally focus, for the first time, on differential RNA transcript isoform usage (DTU) changes and predict RNA-binding protein (RBP) to target transcript interactions using a Global test approach. We report results for all pairwise comparisons (DCM, HCM, NFD). Focusing on the DCM versus HCM contrast (DCMvsHCM), we identified 201 differentially expressed genes, some of which can be clearly associated with changes in ERK1 and ERK2 signaling. Interestingly, the signs of the predicted activity for these two kinases have been inferred to be opposite to each other: In the DCMvsHCM contrast, we predict ERK1 to be consistently less activated in DCM while ERK2 was more activated in DCM. In the DCMvsHCM contrast, we identified 149 differently used transcripts. One of the top candidates is the O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), which catalyzes a common post-translational modification known for its role in heart arrhythmias and heart hypertrophy. Moreover, we reconstruct RBP - target interaction networks and showcase the examples of CPEB1, which is differentially expressed in the DCMvsHCM contrast. Magnetique ( https://shiny.dieterichlab.org/app/magnetique ) is the first online application to provide an interactive view of the HF transcriptome at the RNA isoform level and to include transcription factor signaling and RBP:RNA interaction networks. The source code for both the analyses ( https://github.com/dieterich-lab/magnetiqueCode2022 ) and the web application ( https://github.com/AnnekathrinSilvia/magnetique ) is available to the public. We hope that our application will help users to uncover the molecular basis of heart failure.


Efficacy of corrective exercise strategy in subjects with hyperkyphosis.
Age-related hyperkyphosis causes deleterious effects on health, physical function, and quality of life. Recently, health care providers recognized it as a major health concern. To identify the effect of corrective exercise strategy on hyperkyphosis and compare it with that of conventional exercise. Subjects were randomly categorized into two groups. Each group comprised 30 subjects. Group A received the corrective exercise strategy, and group B received conventional exercises for 8 weeks of the study duration (15 repetitions of each exercise for three sessions/day for a total duration of 45 min and 4 days/week. Pre- and post-interventional hyperkyphosis were analyzed according to posture number using the Posture Pro 8 postural analysis software. In addition, pectoralis minor flexibility was assessed using the ruler scale method in centimeters. Both groups showed highly significant postural alteration and changes in pectoralis minor muscle length (p< 0.001)CONCLUSIONS:The corrective exercise strategy seems to promote scapular stability and produce a more upright posture of the upper thoracic spine.


Regulation of telomere addition at DNA double-strand breaks.
Telomeres constitute the ends of linear eukaryotic chromosomes. Due to the conventional mode of DNA replication, telomeric DNA erodes at each cell division. To counteract this, a specialized reverse transcriptase, telomerase, can elongate chromosome ends to maintain them at a constant average length. Because of their similarity to DNA double-strand breaks (DSBs), telomeres might be expected to induce a DNA damage response, which would lead to repair reactions and the generation of translocations or fusions. Many proteins present at telomeres prevent this by protecting (capping) the chromosome termini. Conversely, a DSB occurring in other regions of the genome, due, for instance, to a stalled replication fork or genotoxic agents, must be repaired by homologous recombination or end-joining to ensure genome stability. Interestingly, telomerase is able to generate a telomere de novo at an accidental DSB, with potentially lethal consequences in haploid cells and, at a minimum, loss of heterozygosity (LOH) in diploid cells. Recent data suggest that telomerase is systematically recruited to DSBs but is prevented from acting in the absence of a minimal stretch of flanking telomere-repeat sequences. In this review, we will focus on the mechanisms that regulate telomere addition to DSBs.