Enhanced expression of the LDL receptor family member LR11 increases migration of smooth muscle cells in vitro.
LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima but not media. To further clarify the involvement of LR11 in the process of atherosclerosis, we have characterized the migration and invasion activities of LR11-overexpressing SMCs. LR11 cDNA was transfected into the rat SMC line A7r5. Compared with mock cells (C-1), in the presence of platelet-derived growth factor-BB, the transfected cells (R-1 and R-2) showed 3.5- to 4.0-fold higher expression of LR11 protein, 1.7- to 1.8-fold increased migration, and 2.0- to 2.2-fold elevated invasion activities, respectively. The increases were essentially abolished by the addition of receptor-associated protein, anti-LR11 antibodies, or apolipoprotein E. Immunological analyses showed that urokinase-type plasminogen activator receptor (uPAR) levels were increased in LR11-overexpressing cells. Anti-urokinase-type plasminogen activator (uPA) and anti-uPAR antibodies reduced the migration and invasion activities of R-1 and R-2 cells to baseline levels. Receptor-associated protein, anti-LR11 antibodies, and apolipoprotein E decreased uPAR expression in the LR11-overexpressing cells by approximately 50%. Cellular catabolism of uPAR was significantly decreased in R-1 and R-2 cells compared with control. Cultured SMCs isolated from intima of atherosclerotic rabbit aortas showed increased expression levels of LR11 and uPAR and enhanced migration and invasion compared with SMCs from medial layers. Overexpression of LR11 induces enhanced migration and invasion activities of intimal SMCs in vitro, probably through its regulation of the uPA/uPAR system.


Percutaneous lithotripsy in morbid obesity.
Percutaneous lithotripsy is an established, safe, effective method for the management of renal calculi. Obesity long has been associated with increased surgical morbidity and may eliminate a patient from shock wave treatment. We compared 44 obese patients to 226 nonobese patients undergoing percutaneous stone management. Stone number, location and total stone burden were comparable in the obese and nonobese groups. There was no significant difference between the groups in hospital time, operative time, fragment rate, access success rate or morbidity. Percutaneous procedures offer successful alternatives with low morbidity for patients with renal calculous disease.


Application of double ionization state-specific equation of motion coupled cluster method to organic diradicals.
The state-specific equation of motion coupled cluster method is applied to three systems of diradical character: automerization of cyclobutadiene, singlet-triplet gaps of trimethylmethylene, and Bergman reaction. The aim of the paper is to assess the performance of the method and test numerically the importance of orbital optimization, three-body terms in transformed Hamiltonian, and the choice of cluster equations.


Effects of different concentrations of metal ions on degradation of adenosine triphosphate in common carp (Cyprinus carpio) fillets stored at 4°C: An in vivo study.
The impact of different concentrations of Na(+), K(+), Ca(2+), Mg(2+), Fe(2+), and Zn(2+) on the degradation of adenosine triphosphate (ATP) and the influence of these ions on the activity of adenosine monophosphate deaminase (AMP-deaminase) and acid phosphatase (ACP) in common carp fillets (in vivo) during 4°C storage was examined. The content of ATP, inosine monophosphate (IMP), and hypoxanthine (Hx), and the activity of AMP-deaminase and ACP were determined. Results indicated that the effects of different concentrations of six kinds of metal ions on AMP-deaminase and ACP were not the same. Na(+), K(+), Fe(2+), and Zn(2+) enhanced AMP-deaminase activity, which led to the rapid degradation of ATP and to the generation of a large quantity of IMP within a short time. Ca(2+) and Mg(2+) delayed the change in AMP-deaminase and ACP activity in carp and caused a further delay in the degradation of ATP. Fe(2+) and Zn(2+) inhibited ACP activity, which reduced the decomposition of IMP and the formation of Hx.


Late bedtime reflects QTA30 anxiety symptoms in adolescents in a school checkup.
In adolescence, physical symptoms may develop due to psychosocial problems but such problems are not fully evaluated in school medical checkups. The aim of this study was to compare lifestyle factors with psychosomatic symptoms in adolescents using the subscales of the Questionnaire for Triage and Assessment with 30 items (QTA30) in school health checkups. The QTA30 was used in checkups for 3,414 students from the fifth grade of primary school to the third grade of junior high school in south Wakayama prefecture. The QTA is a self-completed questionnaire with five subscales of physical symptoms, depression symptoms, self-efficacy, anxiety symptoms, and family function. Each subscale is divided into three groups of clinical, borderline, and healthy, based on the subscale score. Subscale scores were compared with lifestyle items of gender, grade, habits, life events, and school attendance. The clinical rate for all subscales was significantly higher for a higher grade (P < 0.001). Anxiety symptoms were correlated with physical symptoms (r = 0.560). Anxiety and physical symptoms were significantly higher for students who went to bed at a later time with no absences in the last month and who had problems with friends and teachers (both P < 0.001). Family function correlated with self-efficacy (r = 0.418) but not with other subscales. Study time was most related to self-efficacy (P < 0.001). The QTA30 subscale scores facilitated detection of psychosomatic stress and latent risks of psychosomatic disease at an early stage. Thus, the use of the QTA30 in a school medical checkup may permit early intervention for psychosomatic stress in adolescents.


Compensatory lung growth in autologous lobar implant after pneumonectomy in dogs.
Evaluate compensatory lung growth (CLG) in lobar transplant and see if it is similar to CLG after lobectomy. We used 48 dogs in three groups (G1=control, G2=left cranial lobectomy, and G3=pneumonectomy with reimplantation of left caudal lobe). Five months after surgery animals underwent lung scintigraphy and were then sacrificed for lung morphometric study. There was no correlation between scintigraphy and lung mass or lung volume. There was both mass and residual volume CLG in the operated groups, both contralateral and epsilateral to surgery; there was no compensation for total lung capacity or compliance in the remaining caudal lobe (G2) or the reimplanted caudal lobe (G3) 5 months after surgery, there was more damage in the reimplanted lobe. As previous studies have show that CLG starts with increased mass and residual volume and that compliance is later compensated, this study seems to have documented the beginning of CLG, with lung compliance being the limiting factor of CLG after 5 months of study. There is CLG in both reimplanted lobe and contralateral lung but compliance is still reduced. CLG was similar in both groups but implanted lobe compliance was more prejudiced.


Pharmacokinetics of free platinum species following rapid, 3-hr and 24-hr infusions of cis-diamminedichloroplatinum (II) and its therapeutic implications.
The pharmacokinetics of free platinum species derived from cis-diamminedichloroplatinum (II) (cisplatin) was studied in three patients who received the drug as a single agent for the first time at equal doses (100 mg/m2) but with different infusion times. In rapid, 3-hr and 24-hr infusions, peak levels of free platinum were 8.62, 1.96 and 0.27 microgram Pt/ml respectively; half-lives of disposition calculated 0-30 min after the end of each infusion were 17.4, 22.7 and 26.2 min respectively. Free platinum availability, measured as the area under the curves of the free platinum concentration, was the same for the three modes of administration (290, 321 and 325 micrograms Pt/min/ml-1 respectively). This observation supports the clinical impression that antitumour activity of cisplatin is not dependent on the method of administration.


A case for the extreme antiquity of recombination.
Recombination is usually assumed to be a mode of reproduction that evolved long after asexual reproduction in response to specific genetic and environmental circumstances. Here the argument is made that recombination was an evolutionary development as ancient as the origins of life. To support this proposition four lines of evidence are given, in particular, the need for primordial genomes to acquire substantial length and to escape from Muller's Ratchet.


Clinical commissioning of Laitinen Stereoadapter for fractionated stereotactic radiotherapy.
The Laitinen Stereoadapter 5000 from Sandstroem Trade and Technology was acceptance tested and commissioned for clinical use in a Fractionated Stereotactic Radiotherapy Program at our facility. The frame was implemented to function as a localization device for target delineation rather than as an immobilization device. The frame is of non-invasive nature utilizing ear plugs and a nasion bridge adapter as the connecting points with the patient's head. The reproducibility of the head frame position with respect to external skull reference points was tested. CT and MRI imaging studies were performed on a patient phantom with the stereoadapter in place. The target was delineated and target coordinates were calculated for two implanted targets. The phantom was positioned according to the target coordinates on a Siemens MXE Linear Accelerator by aid of the target positioning lasers. Radiographic port film images were taken with the circular fields typically used in stereotactic radiosurgery. A complete treatment isodose plan was performed and dosimetric accuracy was tested by positioning a small volume ionization chamber at the center of the target volume in the head phantom. The results of these tests were found to be clinically acceptable.


Inhibition of matrix metalloproteinases ameliorates blood-brain barrier disruption and neuropathological lesions caused by avirulent Semliki Forest virus infection.
Semliki Forest virus (SFV) infection of mice is a useful model of viral neuropathogenesis in animals and avirulent strains such as SFV-A7 induce immune-mediated demyelination and death of neurones by necrosis and apoptosis. Matrix metalloproteinases (MMPs) have been implicated in various diseases including arthritis and cancer in many species. In this report, we show that MMP-2 and MMP-9 expression is induced in the brains of mice infected i.n. with SFV-A7. Treatment of mice with the pan MMP inhibitor GM6001 ameliorated the development of SFV-induced neuropathological lesions via an effect on the integrity of the blood-brain barrier. Low levels of neuronal necrosis and demyelination in GM6001-treated mice correlated with localisation of fibrinogen staining to thin-walled blood vessels and less intense staining of the perivascular neuropil.


Piroxicam and 5'-hydroxypiroxicam kinetics following multiple dose administration of piroxicam.
Piroxicam (20 mg once daily) was administered orally to six healthy young volunteers for 15 days. Trough steady-state levels of piroxicam and 5'-hydroxypiroxicam were 5.5 and 1.2 micrograms/ml, respectively. Piroxicam's plasma half-life (54.9 h) was significantly shorter than that of 5'-hydroxypiroxicam (70.5 h). Percent unbound piroxicam and 5'-hydroxypiroxicam in plasma at steady-state averaged 1.10 and 8.07 respectively. An average of 25.2% of the dose was recovered in urine as 5'-hydroxypiroxicam; approximately two-thirds (17.2%) in the form of the glucuronide conjugate. Average steady-state plasma levels (Css) of piroxicam (7.0 micrograms/ml) were significantly higher than predicted from a previously reported single dose study (5.3 micrograms/ml).


Risk of malignancy in Behcet disease: A meta-analysis with systematic review.
Several studies have reported the association of Behcet disease (BD) with the risk of diverse kinds of cancers. However, its association is controversial. Therefore, we conducted a bioinformatics-analysis to explore any possible association. We obtained relevant findings published before October 2018 through literature survey of the PubMed, EMBASE, and Web of Science databases. STATA 12.0 software was used for statistical analysis. After screening, the meta-analysis comprised 5 studies. We observed a significant positive association between BD and enhanced malignancy risk (pooled relative risk [RR], 1.19; 95% confidence interval [CI]: 1.09-1.30), especially for hematological cancer (pooled RR, 2.58; 95% CI: 1.61-3.55) and thyroid cancer (pooled RR, 1.25; 95% CI: 1.04-1.47). However, high heterogeneity was also observed in the results (I = 81.3%). Subgroup analysis indicated that female BD patients from Korean population are at highest predisposition to overall malignancy. Besides, publication bias was not observed with our choice of surveys. We conclude that patients suffering from BD have an overall increased risk for malignancy. Greater numbers of exhaustive temporal studies are essential for definitive inferences.


Reconstruction of Skull Base Defects.
"Endoscopic endonasal skull base surgery has dramatically changed and expanded over recent years due to significant advancements in instrumentation, techniques, and anatomic understanding. With these advances, the need for more robust skull base reconstructive techniques was vital. In this article, reconstructive options ranging from acellular grafts to vascular flaps are described, including the strengths, weaknesses, and common uses."


The immune system and the nervous system.
The immune system may interfere with brain function. The central nervous system may also influence the activity of the immune system. The central nervous system is functionally protected by the blood-brain barrier. The central nervous system is functionally protected by the blood-brain barrier. The endothelial cells of the brain capillaries are linked by tight junctions, resulting in an almost continuous interior wall which restricts the transfer of plasma proteins. The barrier function is modified by inflammatory meningeal lesions, stroke and epileptic seizures. Antigenic material may penetrate the barrier and enter the nerve tissue. The phagocytic cells in the central nervous system are mainly of haematogenous origin. The number of such cells in the brain is very low. There are also few lymphocytes under normal circumstances. These cells circulate from the blood, through the vessel walls and into the perivascular spaces, along the perivascular channels and to the CSF and back to the blood. This circulation may increase enormously during inflammatory conditions. In multiple sclerosis, the number of T-lymphocytes in the CSF is increased, corresponding to a preponderance of T-lymphocytes in the perivascular cell infiltrates in and around the lesions. Thus, the individual elements of the immune system are all present in the brain, which is only partially immunologically privileged. The mechanisms underlying the brain's immunological privilege may be of a non-immunological nature. As yet there are only few data which indicate that auto-immunity is a prominent feature in diseases of the human brain. The central nervous system also exerts a modulating influence upon the immune response. This may take place both by secretion of hormones and by a nervous/neurotransmitter influence upon the immune system.


Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development.
To review preclinical and clinical information on flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), tested as an antitumor agent. Primary and review articles were identified by MEDLINE search (1990-June 2001). Abstracts from recent meetings were also used as source materials. Flavopiridol was reviewed with regard to its mechanisms, preclinical and clinical results, pharmacokinetics, and metabolism. Flavopiridol is an inhibitor of several CDKs and displays unique anticancer properties. In addition to direct CDK inhibition, flavopiridol also exhibited other features such as inducing apoptosis in many cancer cell lines, decreasing cyclin D1 concentration, and inhibiting angiogenesis. Preclinical xenograft models showed significant antitumor activity for flavopiridol. The regimen using 72-hour continuous infusion every 2 weeks has been most extensively applied in clinical trials, with a 1-hour infusion currently being explored to achieve higher peak concentrations. Several Phase I and II trials have been reported, with some evidence of antitumor activity noted. Further Phase I and II trials using flavopiridol as a single agent and in combination with standard chemotherapeutic regimens and various tumor types are ongoing. Flavopiridol is the first CDK inhibitor to enter clinical trials. Several Phase I and Phase II clinical trials with different regimens (72-h or 1-h infusion) have been completed. Initial clinical trials have been intriguing, but many questions remain: What is the best regimen (< or =72-h infusion)? Does optimal future development of this drug depend on the combination with other chemotherapy? What is the best combination of flavopiridol with other chemotherapy?


Co-delivery of Cas9 mRNA and guide RNAs edits hepatitis B virus episomal and integration DNA in mouse and tree shrew models.
With 296 million chronically infected individuals worldwide, hepatitis B virus (HBV) causes a major health burden. The major challenge to cure HBV infection lies in the fact that the source of persistence infection, viral episomal covalently closed circular DNA (cccDNA), could not be targeted. In addition, HBV DNA integration, although normally results in replication-incompetent transcripts, considered as oncogenic. Though several studies evaluated the potential of gene-editing approaches to target HBV, previous in vivo studies have been of limited relevance to authentic HBV infection, as the models do not contain HBV cccDNA or feature a complete HBV replication cycle under competent host immune system. In this study, we evaluated the effect of in vivo codelivery of Cas9 mRNA and guide RNAs (gRNAs) by SM-102-based lipid nanoparticles (LNPs) on HBV cccDNA and integrated DNA in mouse and a higher species. CRISPR nanoparticle treatment decreased the levels of HBcAg, HBsAg and cccDNA in AAV-HBV1.04 transduced mouse liver by 53%, 73% and 64% respectively. In HBV infected tree shrews, the treatment achieved 70% reduction of viral RNA and 35% reduction of cccDNA. In HBV transgenic mouse, 90% inhibition of HBV RNA and 95% inhibition of DNA were observed. CRISPR nanoparticle treatment was well tolerated in both mouse and tree shrew, as no elevation of liver enzymes and minimal off-target was observed. Our study demonstrated that SM-102-based CRISPR is safe and effective in targeting HBV episomal and integration DNA in vivo. The system delivered by SM-102-based LNPs may be used as a potential therapeutic strategy against HBV infection.


Unusual pyramidal ice in the atmosphere as the origin of elliptical halos.
The formation mechanism of elliptical halos and Bottlinger's rings has long remained uncertain. The current model for elliptical halos requires multiple scattering from two different populations of ice crystals in a complex mode of motion. New evidence indicates that elliptical halos, and possibly Bottlinger's rings, are due to refraction through ice crystals shaped like obtuse pyramids. This unusual ice crystal may not have been documented previously.


The Impact of a Limb Preservation Service on the Incidence of Major Amputations for All Indications at a Level I Trauma Center.
Multidisciplinary limb preservation services (LPS) have improved the care of patients with limb-threatening vascular disease. However, the impact of an LPS on major amputations for nonvascular etiologies is unknown. We sought to characterize the trends in major amputations performed at a level I trauma center following the institution of an LPS. A retrospective review of all patients undergoing amputation at a level I trauma center from January 2009 to December 2018 was performed. Patients were divided into 2 cohorts: those undergoing amputation pre-LPS (2009-2013) and post-LPS (2014-2018). Major amputations were defined as any amputation at or proximal to the below-knee level. Indications for amputation included chronic limb-threatening ischemia (CLTI), acute limb ischemia (ALI), trauma, infection, and revision amputations. During the study period, 609 major amputations were performed, 490 pre-LPS and 119 post-LPS, representing a 76% reduction. Reductions were seen for every indication, including trauma (95%), ALI (90%), chronic infection (83%), revision (79%), CLTI (68%), and acute infection (62%). Although previous work has validated the role of an LPS in advanced vascular disease, its value extends beyond vascular disease alone. The drastic reductions seen in the number of amputations performed for a variety of indications, including trauma and diabetic foot infections, further validate the use of a multidisciplinary LPS.


Treatment of adverse digitalis effects by hemoperfusion through columns with antidigoxin antibodies bound to agarose polyacrolein microsphere beads.
Ten patients with an array of moderate to severe adverse effects resulting from digitalis were effectively treated by hemoperfusion through small columns which contained antidigoxin antibodies bound to polyacrolein microspheres in agarose macrospheres (APAMB). The procedure was well tolerated. There was no detectable damage to formed blood elements and no changes in electrolytes, liver enzymes, or other related biochemical parameters. Despite some theoretic considerations to the contrary, the removal of a relatively small load of digoxin resulted in amelioration of the clinical symptoms and ECG abnormalities associated with digitalis. No rebound phenomena of intoxication or posthemoperfusion increase in digoxin serum levels were noted over the subsequent 5 to 6 days. A further increase in the capacity of the columns may render this method a safe and convenient emergency procedure for patients with digitalis toxicity.


Elevated soil and blood lead levels with increasing residential proximity to a mine tailings facility in Soweto, South Africa.
Mining has long been associated with the release of a range of toxic metals including lead, elevated levels of which have been found in land surrounding mine dumps as far afield as Spain, India, Macedonia and Nigeria. Mining has been a key pillar of economic development in South Africa for around a century and a half, and has left a legacy of major environmental contamination, with the poorest experiencing the highest burden of exposure. The current study was undertaken to ascertain the concentrations of lead in soil and in the blood of adults and children residing at increasing distances from a cluster of large tailings facilities (MTFs) in greater Johannesburg, South Africa. Through a cross-sectional survey data on household characteristics were collected through a questionnaire survey, and supplemented with samples of soil from household gardens, together with blood samples from child-adult pairs from all households included in the study. Soil lead concentrations decreased significantly (median = 35.7 mg/kg closest to the mine tailings facility (MTF) and 8.6 mg/kg at the furthest point in the study site) with increasing distance from the MTF. Blood lead levels were highest in both adults (median = 3.0 μg/dL) and children (median = 4.0 μg/dL) who lived closest (≤500 m) to the MTF, and lowest (1.4 μg/dL in adults and 2.5 μg/dL in children) in those who lived furthest away (4-5 km). The study findings point to a need for greater emphasis on the precautionary principle in environmental health and for health impact assessments to inform decisions on planning, especially with regard to the location of human settlements relative to major, polluting development initiatives.


Characterizing lesion morphology of a novel diamond-tip temperature-controlled irrigated radiofrequency ablation catheter.
The DiamondTemp ablation (DTA) system is a novel temperature-controlled irrigated radiofrequency (RF) ablation system that accurately measures tip-tissue temperatures for real-time power modulation. Lesion morphologies from longer RF durations with the DTA system have not been previously described. We sought to evaluate lesion characteristics of the DTA system when varying the application durations. A bench model using porcine myocardium was used to deliver discrete lesions in a simulated clinical environment. The DTA system was power-limited at 50 W with temperature set-points of 50 °C and 60 °C (denoted Group_50 and Group_60). Application durations were randomized with a range of 5-120 s. In total, 280 applications were performed. Steam pops were observed in five applications: two applications at 90 s and three applications at 120 s. Lesion size (depth and maximum width) increased significantly with longer applications, until 60 s for both Group_50 and Group_60 (depth: 4.5 ± 1.2 mm and 5.6 ± 1.3 mm; maximum width: 9.3 ± 2.7mm and 11.2 ± 1.7mm, respectively). As lesions transition from resistive to conductive heating (longer than 10 s), the maximum width progressed in a sub-surface propagation. Using a "Time after Temperature 60 °C" (TaT60) analysis, depths of 2-3 mm occur in 0-5 s and depths plateau at 4.6 ± 0.8 mm between 20 and 30 s. The DTA system rapidly creates wide lesions with lesion depth increasing over time with application durations up to 60 s. Using a TaT60 approach is a promising ablation guidance that would benefit from further investigation.


Histone deacetylase inhibitors and transplantation.
Simply detecting the presence or absence of Foxp3, a transcription factor characteristic of naturally occurring CD4+ CD25+ regulatory T cells (Tregs), now appears of minimal value in predicting the outcome of immunologic responses, since dividing human CD4+ effector T cells can induce Foxp3 without attaining repressive functions, and additional molecular interactions, as well epigenetic events, affect Foxp3-dependent Treg functions in humans and mice. Experimentally, in vivo and in vitro studies show histone deacetylase inhibitors (HDACi) can enhance the numbers and suppressive function of regulatory T cells (Tregs) by promoting Foxp3+ cell production, enhancing chromatin remodeling within Tregs, and inducing acetylation of Foxp3 protein itself. Human studies consistent with a role for HDACi in controlling Fox3-dependent Treg functions are also available. We review these molecular interactions and how they may be exploited therapeutically to enhance Treg-dependent functions, including post-transplantation.


Progenitor cell (CFUc) reconstitution after autologous stem cell transfusion in lethally irradiated dogs: decreased CFUc populations in blood and bone marrow correlate with the fraction mobilizable by dextran sulphate.
The present study in dogs concerns the functional potentials of the myeloid progenitor cell system during hemopoietic recovery after lethal total-body irradiation and autotransfusion of cryopreserved stem cells derived from peripheral blood and bone marrow. CFUc were assayed in peripheral blood and bone marrow before and at various intervals after grafting. In addition, the net increase of CFUc mobilizable from extravascular sites into the blood was determined after i.v. injection of 15 mg/kg body weight of dextran sulphate (DS). The data indicate a sustained deficiency of CFUc in otherwise hematologically normal recipients. The DS-response was subnormal even 225 days after transplantation, suggesting residual damage of the hemopoietic system is present for a prolonged period of time. A significant correlation was found between the actual blood CFUc concentration and the numbers of CFUc mobilizable by DS. Insight into progenitor cell kinetics and corresponding changes in the size of a mobilizable pool in extravascular sites may be helpful in estimating the marrow reserve of transplanted individuals suffering myelosuppressive effects of chemotherapy.


[Effect of isobutylmethylxanthine on the adenylate cyclase system of the myocardium and skeletal muscles of the rat during the recovery period following physical loading].
The in vivo experiments established that isobutyl methyl xanthine inhibits phosphodiesterase activity and activates adenylate cyclase in the skeletal muscles and myocardium. The preparation prevents phosphodiesterase activity from increasing due to physical exercises. Against a background of the latter it activates adenylate cyclase and prevents the cAMP level from declining in skeletal muscles. In the myocardium this effect of isobutyl methyl xanthine is less pronounced.


Predominance of large VLDL particles in metabolic syndrome, detected by size exclusion liquid chromatography.
To study size heterogeneity of triglyceride rich lipoproteins (TRL) in metabolic syndrome (MS). Thirty MS patients and 14 healthy subjects were included. In fasting serum we measured: lipid profile, free fatty acids (FFA) and adiponectin; TRL were isolated (d<1.006 g/mL) and analysis by size exclusion HPLC followed by UV detection was performed; each subfraction was expressed as percentage of total TRL. MS patients, even those with normal triglycerides, presented higher proportion of very large VLDL (90 nm diameter) and large VLDL (60 nm) and slightly lower of typical VLDL (37 nm) (p<0.04); increased FFA (p=0.04) and lower adiponectin (p=0.001). FFA correlated with large VLDL% (r=0.58; p=0.003), independently of insulin-resistance and waist. Furthermore, the lower the adiponectin, the greater the predominance of large VLDL (r=-0.40; p=0.04). MS was associated with large VLDL, described as more atherogenic beyond triglyceride levels. Size exclusion HPLC would represent a useful tool for assessing subfractions' lipoprotein profile.


Effectiveness of Prophylactic Intraosseous Antibiotic versus Intravenous Antibiotic in Knee Surgeries in Pigs: Experimental Study.
Objective To demonstrate that the intraosseous (IO) access is more effective compared with the intravenous (IV) access for prophylactic antibiotic administration in knee joint surgeries, using 36 pigs as live models. Materials and Methods Skin, subcutaneous tissue, cartilage, and bone samples were collected, analyzed and compared after the administration of IV or IO antibiotic in different groups. Results When comparing the IO and IV groups, the IO group showed a higher concentration of prophylactic antibiotic in the skin ( p = 0.049), cartilage ( p = 0.018), and bone ( p = 0.002), in the analysis of the first 24 hours after 30 minutes of infusion. Conclusion Since complications regarding this practice are rare, the use of this pathway may be an alternative to reduce the risk of surgical site infection in orthopedic surgeries, leading to a decrease in morbidity and mortality and hospital expenses with readmission or prolonged hospitalization time. However, further research and further experimental studies in humans are required, as the effectiveness of the method in pigs has been proved.


The effect of intracoronary diltiazem on regional myocardial function and development of infarcts in porcine hearts.
The effect of intracoronary (i.c.) pretreatment with diltiazem on regional myocardial function and the development of infarcts was investigated in regionally ischemic, reperfused porcine hearts. The left anterior descending coronary artery (LAD) was distally ligated in 16 pigs for 20-90 min followed by 24 h of reperfusion. Eight pigs were treated with increasing doses of i.c. diltiazem (0.375 mg/min, 0.75 mg/min, 1 mg/min) prior to ischemia. Eight pigs served as controls. Regional myocardial function was assessed by implanted ultrasonic crystals. Infarct size was determined as ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). I.c. diltiazem mainly depressed early systolic shortening (isovolumetric contraction) and lengthening during the first half of diastole. Pretreatment with this calcium antagonist significantly delayed the development of infarcts. In control experiments, a mean infarct size of 74% was found after 45-min ischemia. At that time no infarction was observed in the treated group, where infarcts started to evolve after 60-min ischemia. It is concluded that the favorable action of i.c. diltiazem can mainly be ascribed to a reduced myocardial oxygen consumption at the onset of ischemia.


Genetic basis of STEM occupational choice and regional economic performance: a UK biobank genome-wide association study.
Science, technology, engineering, and mathematics (STEM) professionals are regarded as the highly skilled labor force that fosters economic productivity, enterprise innovation, and international competitiveness of a country. This study aims to understand the genetic predisposition to STEM occupations and investigate its associations with regional economic performance. We conducted a genome-wide association study on the occupational choice of STEM jobs based on a sample of 178,976 participants from the UK Biobank database. We identified two genetic loci significantly associated with participants' STEM job choices: rs10048736 on chromosome 2 and rs12903858 on chromosome 15. The SNP heritability of STEM occupations was estimated to be 4.2%. We also found phenotypic and genetic evidence of assortative mating in STEM occupations. At the local authority level, we found that the average polygenic score of STEM is significantly and robustly associated with several metrics of regional economic performance. The current study expands our knowledge of the genetic basis of occupational choice and potential regional disparities in socioeconomic developments.


S-Nitrosothiols as potential therapeutics to induce a mobilizable vascular store of nitric oxide to counteract endothelial dysfunction.
Endothelial dysfunction predisposing to cardiovascular diseases is defined as an imbalance in the production of vasodilating factors, such as nitric oxide (NO), and vasoconstrictive factors. To insure its physiological role, NO, a radical with very short half-life, requires to be stored and transported to its action site. S-nitrosothiols (RSNOs) like S-nitrosoglutathione (GSNO) represent the main form of NO storage within the vasculature. The NO store formed by RSNOs is still bioavailable to trigger vasorelaxation. In this way, RSNOs are an emerging class of NO donors with a potential to restore NO bioavailability within cardiovascular disorders. The aim of this study was to compare S-nitrosothiols ability, formed of peptide (glutathione) like the physiologic GSNO or derived from amino acids (cysteine, valine) like the synthetics S-nitroso-N-acetylcysteine (NACNO) and S-nitroso-N-acetylpenicillamine (SNAP), respectively, to produce a vascular store of NO either in endothelium-intact or endothelium-removed aortae in order to evaluate whether RSNOs can be used as therapeutics to compensate endothelial dysfunction. Sodium nitroprusside (SNP), a marketed drug already in clinics, was used as a non-RSNO NO-donor. Endothelium-intact or endothelium-removed aortae, isolated from normotensive Wistar rats, were exposed to RSNOs or SNP. Then, NO-derived (NOx) species, representing the NO store inside the vascular wall, were quantified using the diaminonaphthalene probe coupled to mercuric ions. The bioavailability of the NO store and its ability to induce vasodilation was tested using N-acetylcysteine, then its ability to counteract vasoconstriction was challenged using phenylephrine (PHE). All the studied RSNOs were able to generate a NO store materialized by a three to five times increase in NOx species inside aortae. NACNO was the most potent RSNO to produce a vascular NO store bioavailable for vasorelaxation and the most efficient to induce vascular hyporeactivity to PHE in endothelium-removed aortae. GSNO and SNAP were equivalent and more efficient than SNP. In endothelium-intact aortae, the NO store was also formed whereas it seemed less available for vasorelaxation and did not influence PHE-induced vasoconstriction. In conclusion, RSNOs - NACNO in a better extent - are able to restore NO bioavailability as a functional NO store within the vessel wall, especially when the endothelium is removed. This was associated with a hyporeactivity to the vasoconstrictive agent phenylephrine. Treatment with RSNOs could present a benefit to restore NO-dependent functions in pathological states associated with injured endothelium.


Long-Term Impact of Bariatric Surgery on Renal Outcomes at a Community-Based Publicly Funded Bariatric Program: The Regina Bariatric Study.
Obesity is recognized as an independent risk factor for chronic kidney disease through multiple direct and indirect biological pathways. Bariatric surgery is a proven, effective method for sustained weight loss. However, there is a relative paucity of data on the impact of bariatric surgery on renal outcomes. The primary objective was to evaluate the change in urine albumin/creatinine ratio (ACR) in patients undergoing bariatric surgery, at 12 months after the procedure. Secondary objectives were to determine the changes in ACR at (6 and 24 months), estimated glomerular filtration rate (eGFR; 6, 12, and 24 months), and hemoglobin A1c (HbA1c); 12 and 24 months) after the procedure. This observational retrospective cohort study included consecutive obese patients who underwent bariatric surgery. Provincial Bariatric Surgery Clinic at the Regina General Hospital, Saskatchewan. This study includes 471 consecutive obese adult patients who underwent bariatric surgery between 2008 and 2015. We studied the impact of bariatric surgery on body mass index (BMI), renal outcomes (urine ACR and eGFR) and metabolic outcomes (fasting glucose, total cholesterol, low-density lipoprotein, triglycerides, and HbA1c) in 471 patients. Patients were followed for 2 years postsurgery in the bariatric clinic. Mixed linear models that accounted for the repeated nature of the data were used to access changes in outcomes over time. Patients were predominantly female (81%) with a mean age (±SD) of 46 ± 10 years. Most patients (87%) had a BMI > 40 kg/m2 and 81% of the patients underwent Roux-en-Y gastric bypass. The mean BMI decreased from 47.7 ± 7.8 kg/m2 at baseline to 37.1 ± 7.9 kg/m2 at 6 months and 34.8 ± 8.8 kg/m2 at 12 months. In a subcohort of patients with microalbuminuria, ACR showed an improvement from a median [interquartile] value of 5.1 [3.7-7.5] mg/mmol at baseline to 2.3 [1.2-3.6] mg/mmol at 6 months (P = .007), to 1.4 [0.9-3.7] mg/mmol at 2-year follow-up (P < .001). Similarly, eGFR increased in patients with microalbuminuria from 109 ± 10 mL/min/1.73 m2 at baseline to 120 ± 36 mL/min/1.73 m2 at 2-year follow-up (P = .013). There were statistically significant reductions in triglycerides, fasting glucose, and HbA1c. This was a retrospective chart review, with the lack of a control group. Patients with eGFR less than 60 mL/min/1.73 m2 were not considered for surgery, and we had to measure renal outcomes predominantly on the presence of proteinuria. Our results suggest bariatric surgery significantly decreased weight and consequently improved renal and metabolic outcomes (eGFR, ACR, fasting glucose, cholesterol, and triglycerides) in patients with elevated BMI.


Plasma polymerized epoxide functional surfaces for DNA probe immobilization.
The development of functional surfaces for the immobilization of DNA probe is crucial for a successful design of a DNA sensor. In this report, epoxide functional thin films were achieved simply by pulsed plasma polymerization (PP) of glycidyl methacrylate (GMA) at low duty cycle. The presence of epoxide groups in the resulting ppGMA films was confirmed by Fourier transform infrared spectroscopy. The ppGMA coatings were found to be resistant to the non-specific adsorption of DNA strands, while the epoxide groups obtained could react with amine-modified DNA probes in a mild basic environment without any activation steps. A DNA sensor was made, and was successfully employed to distinguish different DNA sequences with one base pair mismatch as seen by surface plasmon enhanced fluorescence spectroscopy (SPFS). The regeneration of the present DNA sensor was also discussed. This result suggests that surface modification with ppGMA films is very promising for the fabrication of various DNA sensors.


The 180 KDa polypeptide contains the DNA-binding domain of RNA polymerase II.
Purification of RNA polymerase II from chicken myeloblastosis (leukemia) cells to homogeneity and subsequent structural analysis of the purified enzyme revealed that the enzyme contained seven polypeptides with molecular masses ranging from 27 KDa to 220 KDa. Inclusion of protease inhibitors in the buffer system during purification significantly increased the molar ratio of the largest (220 KDa) polypeptide to the second largest (180 KDa) polypeptide. However, proteolytic conversion of the 220 KDa to 180 KDa polypeptide did not inhibit the DNA binding activity of the enzyme. The enzyme, after dissociation into subunits in a SDS-polyacrylamide gel containing urea was blotted onto a nitrocellulose filter. The filter was incubated with 32P-labeled calf thymus DNA and both the 220 KDa and 180 KDa polypeptides of the enzyme bind DNA, suggesting that the DNA-binding site of the enzyme resides on the 180 KDa polypeptide of the largest subunit.


The future of contraception: innovations in contraceptive agents: tomorrow's hormonal contraceptive agents and their clinical implications.
Currently available contraceptive methods have not eliminated the burden of unintended pregnancy. Future progress will require technological advancements, leading to the development of novel and highly effective birth control strategies that will be acceptable to the general population. Included are highlights of some of the ongoing research, demonstrating the development of methods with the potential to be highly effective, widely accepted, easy to use, and more cost-effective, with fewer side effects, than currently available options.


Complications associated with preoperative radiation therapy and Iodine-125 brachytherapy for localized prostatic carcinoma.
Twenty-five consecutive patients with localized adenocarcinoma of the prostate treated with 1,050 rad preoperative radiation therapy and Iodine-125 seed brachytherapy arreviewed. Significant long-term postoperative complications included radiation cystitis (12%), radiation proctitis (4%), genital and leg edema (12%), stress incontinence (8%), total incontinence (4%), and impotence (26%). Complications occurred in 75 per cent of patients who received additional postoperative radiation. Improved staging with CT scan, lymphangiography, and Chiba needle biopsy of any possibly abnormal lymph nodes provided excellent preoperative staging with only 1 patient (6%) upstaged at surgery to Stage D1.


Factors affecting performance of usual activities during radiation therapy.
To examine factors that might affect patients' ability to perform their usual activities during radiation therapy. Prospective, longitudinal design. A community hospital radiation oncology department. 77 patients receiving radiation therapy for curative or adjuvant intent. The role function mode of the Roy Adaptation Model guided the study. Participants rated the extent to which they were performing their usual activities on a scale of 0 (not at all) to 10 (all the time). Data were collected at baseline prior to starting radiation, weekly during treatment, and one month post-treatment. Cross-sectional and longitudinal regression analyses were used to capture changes in performance of usual activities over time. Performance of usual activities, Karnofsky Performance Status (KPS), fatigue, and side effects. Participants maintained relatively high performance status throughout the course of treatment. The ability to perform usual activities decreased significantly from baseline to the end of treatment. Ability to perform usual activities was highly negatively correlated with fatigue and side effects. Work, sick-leave benefits, living situation, fatigue, KPS, and comorbidities were associated with ability to perform usual activities along the trajectory of radiation therapy. Fatigue and side effects of treatment negatively affected patients' ability to carry out their usual activities during radiation therapy. Management of side effects of treatment, including fatigue, and supporting patients' need to work or not work during treatment may help patients continue to perform activities that are important to them during radiation therapy.


Citrinal B, natural 11 beta-hydroxysteroid dehydrogennase type 1 inhibitor identified from structure-based virtual screening.
Citrinal B, a tricyclic compound from endophytic fungus Colletotrichum capsici in our previous studies, exhibited significant inhibitory activity against 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1) in vitro and showed strong binding affinity to 11β-HSD1. Moreover, citrinal B treatments decreased the lipid droplet accumulation associate with the inhibition of 11β-HSD1 expression in differentiate induced 3T3-L1 preadipocytes. Furthermore, the molecular docking demonstrated that citrinal B coordinated in the active site of 11β-HSD1 is essential for the ability of diminishing the enzyme activity.


Is the Gothic Arch a reliable radiographic landmark for migration percentage in children with cerebral palsy?
Reimers migration percentage (MP) is the gold standard for measuring hip displacement in children with cerebral palsy (CP). Hip surveillance registries proposed using the top of the Gothic arch (GA) as a modification in patients with acetabular dysplasia because the classical method (CM) described by Reimers may underestimate hip migration. The aim of this study is to assess the inter- and intra-observer reliability of the modified method (MM) versus the CM and identify their effect on the MP. We performed a retrospective review of 50 children with CP, who had a hip radiograph at our institution between 1st April 2014 and 28th February 2018. All hip radiographs were carefully selected to show the presence of a GA. Four observers measured the MP using the CM and MM for each patient. Interclass coefficient was used to estimate inter- and intra-observer reliability. Inter-observer reliability was excellent for the CM with ICC 0.96 (95% CI 0.94 to 0.97) and good for the MM, ICC 0.78 (95% CI 0.51 to 0.89) p < 0.001. Intra-observer reliability was excellent for both methods raging from ICC 0.94 to 0.99 for the CM and ICC 0.89 to 0.95 for the MM. The mean MP was 19% for the CM and 28% for the MM (p < 0.001). The CM is more reliable than the MM to measure hip migration in children with CP. If the CM is used and acetabular dysplasia with a GA are present on the hip radiograph, then a 9% hip migration underestimation should be considered on decisions for both referral and surgical management. II.


Chronic Pain Clinical and Prescriptive Practices in the Cannabis Era.
To explore how health care providers in the United States are adapting clinical recommendations and prescriptive practices in response to patient use of medical cannabis (MC) for chronic pain symptoms. Literature searches queried MeSH/Subject terms "chronic pain," "clinician," "cannabis," and Boolean text words "practice" and "analgesics" in EBSCOHost, EMBASE, PubMed, and Scopus, published 2010-2021 in the United States. Twenty-one primary, peer-reviewed studies met criteria. Studies are synthesized under major headings: recommending MC for chronic pain; MC and prescription opioids; and harm reduction of MC. MC is increasingly utilized by patients for chronic pain symptoms. Clinical recommendations for or against MC are influenced by scopes of practice, state or federal laws, institutional policies, education, potential patient harm (or indirect harm of others), and perceived confidence. Epidemiologic and cohort studies show downward trajectories of opioid prescribing and consumption in states with legal cannabis. However, clinicians' recommendations and prescription practices are nonuniform. Impacts of cannabis laws are clear between nongovernmental and governmental institutions. Strategies addressing MC and opioid use include frequent visits, and, to reduce harm, suggesting alternative therapies and treating substance use disorders. MC use for chronic pain is increasing with cannabis legalization. Provider practices are heterogenous, demonstrating a balance of treating chronic pain using available evidence, while being aware of potential harms associated with MC and opioids.


Hydrocarbon Oxidation by an Exposed, Multiply Bonded Iron(III) Oxo Complex.
The iron oxo unit, [Fe=O] n+ is a critical intermediate in biological oxidation reactions. While its higher oxidation states are well studied, relatively little is known about the least-oxidized form [FeIII=O]+. Here, the thermally stable complex PhB(AdIm)3Fe=O has been structurally, spectroscopically, and computationally characterized as a bona fide iron(III) oxo. An unusually short Fe-O bond length is consistent with iron-oxygen multiple bond character and is supported by electronic structure calculations. The complex is thermally stable yet is able to perform hydrocarbon oxidations, facilitating both C-O bond formation and dehydrogenation reactions.


Multi-walled carbon nanotube-impregnated agarose film microextraction of polycyclic aromatic hydrocarbons in green tea beverage.
A new microextraction procedure termed multi-walled carbon nanotube-impregnated agarose film microextraction (MWCNT-AFME) has been developed. The method utilized multi-walled carbon nanotubes (MWCNTs) immobilized in agarose film to serve as adsorbent in solid phase microextraction (SPME). The film was prepared by mixing the MWCNTs in agarose solution and drying the mixture in oven. Extraction of selected polycyclic aromatic hydrocarbons was performed by inserting a needle through circular MWCNT-impregnated agarose films (5 mm diameter) and the assembly was dipped into an agitated sample solution prior to micro high performance liquid chromatography-ultraviolet analysis. Back extraction was then performed using ultrasonication of the films in 100 μL of solvent. The film was discarded after single use, thus avoiding any analyte carry-over effect. Due to the mesoporous nature of the agarose film, the MWCNTs were immobilized easily within the film and thus allowing for close contact between adsorbent and analytes. Under the optimized extraction conditions, the technique achieved trace LODs in the range of 0.1 to 50 ng L(-1) for the targeted analytes, namely fluoranthene, phenanthrene and benzo[a]pyrene. The method was successfully applied to the analysis of spiked green tea beverage samples with good relative recoveries in the range of 91.1 to 107.2%. The results supported the feasibility of agarose to serve as adsorbent holder in SPME which then minimizes the consumption of chemicals and disposal cost of organic wastes.


Stem cell-derived hepatocytes: A novel model for hepatitis E virus replication.
Yearly, approximately 20million people become infected with the hepatitis E virus (HEV) resulting in over 3million cases of acute hepatitis. Although HEV-mediated hepatitis is usually self-limiting, severe cases of fulminant hepatitis as well as chronic infections have been reported, resulting annually in an estimated 60,000 deaths. We studied whether pluripotent stem cell (PSC)-derived hepatocytes, mesodermal and/or neuroprogenitor cells support HEV replication. Human PSC were differentiated towards hepatocyte-like cells, mesodermal cells and neuroprogenitors and subsequently infected with HEV. Infection and replication of HEV was analyzed by qRT-PCR, RNA in situ hybridization, negative strand RT-PCR, production of infectious virions and transfection with a transient HEV reporter replicon. PSC-derived hepatocytes supported the complete replication cycle of HEV, as demonstrated by the intracellular presence of positive and negative strand HEV RNA and the production of infectious virions. The replication of the virus in these cells was inhibited by the antiviral drugs ribavirin and interferon-α2b. In contrast to PSC-derived hepatocytes, PSC-derived mesodermal cells and neuroprogenitors only supported HEV replication upon transfection with a HEV subgenomic replicon. We demonstrate that PSC can be used to study the hepatotropism of HEV infection. The complete replication cycle of HEV can be recapitulated in infected PSC-derived hepatocytes. By contrast other germ layer cells support intracellular replication but are not infectable with HEV. Thus the early steps in the viral cycle are the main determinant governing HEV tissue tropism. PSC-hepatocytes offer a physiological relevant tool to study the biology of HEV infection and replication and may aid in the design of therapeutic strategies.


Virtual screening of anti-HIV1 compounds against SARS-CoV-2: machine learning modeling, chemoinformatics and molecular dynamics simulation based analysis.
COVID-19 caused by the SARS-CoV-2 is a current global challenge and urgent discovery of potential drugs to combat this pandemic is a need of the hour. 3-chymotrypsin-like cysteine protease (3CLpro) enzyme is the vital molecular target against the SARS-CoV-2. Therefore, in the present study, 1528 anti-HIV1compounds were screened by sequence alignment between 3CLpro of SARS-CoV-2 and avian infectious bronchitis virus (avian coronavirus) followed by machine learning predictive model, drug-likeness screening and molecular docking, which resulted in 41 screened compounds. These 41 compounds were re-screened by deep learning model constructed considering the IC50 values of known inhibitors which resulted in 22 hit compounds. Further, screening was done by structural activity relationship mapping which resulted in two structural clefts. Thereafter, functional group analysis was also done, where cluster 2 showed the presence of several essential functional groups having pharmacological importance. In the final stage, Cluster 2 compounds were re-docked with four different PDB structures of 3CLpro, and their depth interaction profile was analyzed followed by molecular dynamics simulation at 100 ns. Conclusively, 2 out of 1528 compounds were screened as potential hits against 3CLpro which could be further treated as an excellent drug against SARS-CoV-2.


Optimal Design of Clinical Trials Involving Persons with Disorders of Consciousness.
Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC. The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC. There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC. Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.


Sonographic diagnosis of perforation of the gastric antrum caused by a foreign body: A case report.
Ingestion of foreign bodies often occurs in clinical environments, especially in toddlers and aged patients. Although plain radiography and CT are widely used for the assessment of foreign bodies, sonography has an advantage in the diagnosis of some radiolucent foreign bodies, such as wood and bamboo materials. An 80-year-old woman presented with a 4-day history of right upper quadrant abdominal persistent distended pain without radiation. Radiographs, a preliminary abdominal ultrasound (US) and an abdominal computed tomography (CT) were unremarkable. A repeat abdominal US found a foreign body inserted in the gastric wall of antrum. But subsequent gastroscopy was negative. A laparotomy confirmed the diagnosis of bamboo stem penetration out of the gastric antrum. The patient was treated by laparotomy and the bamboo stem was removed successfully. Bamboo stem-caused digestive perforation was confirmed by laparotomy. The perforation site was at the gastric wall of antrum. Intravenous antibiotic therapy was administered for two weeks until her body temperature dropped to a normal level, and C-reactive protein (CRP) decreased to the normal limits. she was discharged from the hospital. Previous studies suggest that US can identify the location and shape of foreign bodies in the alimentary tract in toddlers. This case shows US is also effective in aged patients. The US can be utilized as a problem-solving tool when radiolucent foreign bodies are suspected, especially when the results of CT and gastroscopy are negative.


[Kidney function in test subjects: published results and clinical relevance].
Sevoflurane degrades in CO2 absorbents to produce compound A, which may have hepatotoxic potential in humans. Several recent studies in human volunteers have been performed to evaluate this potential. Three studies have evaluated sevoflurane administered to volunteers using a 3% concentration for 8 h duration at approximately 2 L/min flow rate. The initial investigation found high excretion of protein, glucose and renal tubular enzymes in the urine of the volunteers receiving sevoflurane. Subsequent investigations using identical protocols found more minor or absent changes in excretion of these markers. One additional investigation in volunteers studied 3% sevoflurane anesthesia for 4 h duration using a low-flow (1 L/min) technique. No significant excretion of protein, glucose or renal enzymes was observed. Application of these results to clinical practice must be interpreted in light of the experimental nature of the anesthetic administration. Although some controversy remains, these data, combined with results of recent studies in surgical patients, suggest that renal function following modest duration low-flow sevoflurane anesthesia is similar to that following isoflurane anesthesia.


Non-enolisable Knoevenagel condensate appended Schiff bases-metal (II) complexes: Spectral characteristics, DNA-binding and nuclease activities.
New Schiff base complexes [Cu(L1)Cl] (1), [Ni(L1)Cl] (2), [Zn(L1)Cl] (3), and [Fe(L2)H2OCl] (4) {L1=(4E)-3-(2-hydroxybenzylidene)-4-(2-hydroxyphenylimino)pentan-2-one, L2=2,2'-(1E,1'E)-(3-(2-hydroxybenzylidene)-pentane-2,4-diylidene)bis(azan-1-yl-1 idene)diphenol} have been synthesized and characterized by elemental analysis, UV-Vis, IR, FAB-mass, EPR, spectral studies and electrochemical studies, the ligands L1 &L2 were characterized by 1H and 13C NMR spectra. Complex 1 show a visible spectral d-d band near 600nm and display cyclic voltammetric quasireversible response for the Cu(II)/Cu(I) couple vs Ag/AgCl in DMSO. The EPR spectrum of 1 show g‖>g⊥ suggesting a square planar geometry around copper with dx2-y2 as the ground state. The mass spectral results have confirmed the proposed structure for complexes 1-4. DNA binding properties of these complexes 1-4 have been investigated by absorption titrations, cyclic voltammetric studies and circular dichroism studies. On titration with DNA, the complexes 1-4 show hypochromism at the MLCT band (13-31%) with a red shift of 1-8nm in the electronic spectrum and positive shift of voltammetric E1/2 in the CV studies are in favour of intercalative binding. CD spectra of 1 showed an increase in molar ellipticity (θ278) of the positive band with a minor red shift indicating the transition of B-form of DNA to A like form. DNA cleavage studies of complexes 1 and 4 with pUC18 DNA were studied by gel electrophoresis and complex 4 cleaves supercoiled pUC18 DNA in an oxidative manner in the presence of H2O2 and on photo irradiation at 312nm.


The "Hot Cross Bun Sign" in Spinocerebellar Ataxia Types 2 and 7-Case Reports and Review of Literature.
The "hot cross bun" sign is a cruciform hyperintensity is seen on T2 weighted imaging within the pons. The sign is considered to be pathognomic for Multiple system atrophy type C. The clinical and radiological features of Multiple system atrophy type C overlap with the autosomal dominant inherited ataxias. We present a case series of 3 African patients with genetically proven Spinocerebellar Ataxia presenting with the Hot cross bun sign and a scoping review of similar studies. We described the phenotypic and radiological presentation of genetically confirmed SCA-2 in two, and SCA-7 in one patient, with the "hot cross bun" sign. We performed a scoping review on the Hot Cross Bun Sign.A total of 66 articles were retrieved. We describe the diverse aetiologies of the sign and associated phenotypic and radiological features. We review the Spinocerebellar Ataxias described with a Hot cross bun sign and make comparisons to Multiple System Atrophy Type C [Ref. 1,2]. To our knowledge this is the first description of an African cohort presenting with the Hot Cross Bun Sign. We expand the differential diagnosis of the Hot Cross Bun Sign.


Assessment of landuse change impact on runoff and sediment yield of Patiala-Ki-Rao watershed in Shivalik foot-hills of northwest India.
Landuse change significantly alters the hydrologic characteristics of the land surface within a watershed. In the present study, the impact of landuse change (2006-2016) on runoff and sediment yield has been assessed in Patiala-Ki-Rao watershed (5140 ha) located in Shivalik foot-hills, using remote sensing, geographical information system (GIS), and Water Erosion Prediction Project (WEPP) watershed model. The watershed has seven major landuse classes, namely agriculture, built-up, fallow land, forest, grass land, streams, and water bodies. The landuse change analysis indicated that the area under all the landuses decreased except built-up that increased by 372.27 ha (112.04%). Forest is the most affected landuse among all watershed landuses that shrinked by 194.90 ha followed by agriculture (64.57 ha), grass land (50.81 ha), streams (30.42 ha), fallow land (21.86 ha), and water bodies (9.72 ha). Runoff and sediment yield for the landuse of the years 2006 and 2016 were simulated by the WEPP model using two climate scenarios (2006 and 2016). The simulated runoff, sediment yield, and sediment delivery ratio increased by 18.62%, 48.04%, and 32.23% under Climate-2006 and 26.78%, 30.23%, and 16.09% under Climate-2016 due to change in landuse during a period of 10 years. This clearly indicates that landuse change in 10 years has greatly influenced the hydrology of the watershed and requires urgent land allocation policy in place for sustainable development in the area.


A novel form of immunotherapy using antigen peptides conjugated on PD-L1 antibody.
Immune checkpoint inhibitors (ICIs), including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 have shown promising cancer clinical outcomes. However, IC therapy has low patient response rates (10%-15%). Thus, ICIs and sufficient antigen combinations into the tumor microenvironment (TME) is important to produce strong tumor-specific adaptive immune responses. Mice were treated with cisplatin, and human cancer cells were exposed to inflammatory cytokines, to confirm increased PD-L1 and major histocompatibility complex (MHC) I expression by tumor cells or dendritic cells. TC-1, CT26, B16-F1, or B16-F10 tumor cells, and bone marrow-derived dendritic cells, were treated with interferon (IFN)-β, IFN-γ, or tumor necrosis factor-α to identify the molecular mechanisms underlying tumor PD-L1 and MHC I upregulation, and to examine MHC I, CD40, CD80, CD86, or PD-L1 levels, respectively. For synergistic combination therapy, αPD-L1 monoclonal antibody (mAb) covalently linked to the long E7 peptide was generated. Chemotherapy shifted the TME to express high PD-L1 and MHC I, resulting in targeted ICI cargo delivery and enhanced generation and activation of tumor antigen-specific T cells. Synergistic effects of vaccination and IC blockade in the TME were demonstrated using an anti-PD-L1 mAb covalently conjugated to the E7 long peptide.


Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression. Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC-MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin. Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p<0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r=0.57, p<0.008) while Ruminococcaceae were positively correlated with DCA (r=0.4, p<0.05). A positive correlation between Ruminococcaceae and DCA/CA (r=0.82, p<0.012) and Blautia with LCA/CDCA (r=0.61, p<0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios. Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa.


Simultaneous pancreas-kidney transplantation in a large multicenter study: surgical complications.
Simultaneous pancreas-kidney (SPK) transplantation has evolved as an effective treatment modality for patients with end-stage nephropathy owing to type 1 diabetes mellitus. This kidney-pancreas transplant procedure includes a number of risks, one of them being surgical complications, which were analyzed in this large prospective multicenter study. The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporine ME (n = 102) in the Euro-SPK001 study. Surgical complications were defined as any intervention in the postoperative course related to the transplant procedure. The number of patients undergoing relaparotomy was significantly lower among the tacrolimus group (26.2%) as compared to the cyclosporine ME group (43.1%, P = .0109). Relaparotomy was performed earlier in the cyclosporine ME group (day 14 +/- 17) compared to patients in the tacrolimus group (day 26 +/- 26, P = .0506). Graft vessel thrombosis, intra-abdominal hemorrhage, and enteric or ureteral leakage within the first 3 months occurred significantly more frequently in cyclosporine ME-treated patients. Donor age above 45 years showed a negative impact on surgical complications. Relaparotomy had no impact on patient survival but significantly affected pancreas and kidney graft survival in both groups. This prospective, randomized, multicenter trial in patients undergoing primary SPK demonstrated a benefit of tacrolimus over cyclosporine ME with regard to the incidence of surgical complications and, consecutively, to kidney and pancreas graft survival.


Persistent rubella-specific IgM reactivity in the absence of recent primary rubella and rubella reinfection.
Between two and seven sera from cases of persistent detection of rubella-specific IgM for periods in excess of 2.5 months, but in the absence of recent primary rubella or rubella reinfection, were examined for rheumatoid factor, heterophile antibody, and IgM reactivity against toxoplasma and a number of viruses. The relative avidity of the rubella-specific IgG1 has been assessed in all the sera by two methods. None of the sera contained rheumatoid factor or heterophile antibody, nor did any contain detectable concentrations of IgM specific for any of the panel of antigens apart from five sera which contained low concentrations of IgM specific for some coxsackieviruses B. No sera were positive for low avidity specific IgG1 although three did give equivocal results with one avidity test and one gave equivocal results with the second avidity test.


Host cell properties and external pH affect proinsulin production by Saccharomyces yeast.
The expression of a hybrid gene encoding an alpha-factor prepro leader peptide-miniproinsulin (MPI) fusion [MPI is the same as the LysArg human insulin precursor described by Thim et al. (1986)] was tested in a series of isogenic yeast strains to investigate the influence of some genetic and physiological factors on heterologous production in yeast. We found that: (i) an MF alpha 1 gene disruption in haploid cells, as well as MF alpha 1 gene product expression in diploid cells, do not affect the MPI secretion level; (ii) under conditions of exogenous leucine availability, MPI production is hindered by leucine auxotrophy (a leu2 mutation); (iii) rho- mutations increase the per-cell MPI yield approximately three-fold; (iv) the MPI yield is apparently dependent on the pH of the culture medium: the higher the external pH, the larger the per-cell MPI yield.


Dynamic nature of nonculprit coronary artery lesion morphology in STEMI: a serial IVUS analysis from the HORIZONS-AMI trial.
The authors sought to report the temporal stability of an untreated, nonculprit lesion phenotype in patients presenting with ST-segment elevation myocardial infarction (STEMI). The temporal stability of the untreated, nonculprit lesion phenotype has been studied using intravascular ultrasound-virtual histology (IVUS) in patients with stable ischemic heart disease, but not in STEMI patients. As part of a formal substudy of the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, baseline and 13-month follow-up IVUS was performed in 99 untreated nonculprit lesions in 63 STEMI patients. Lesions were classified as pathological intimal thickening (PIT), IVUS-derived thin-cap fibroatheroma (TCFA), thick-cap fibroatheroma (ThCFA), fibrotic plaque, or fibrocalcific plaque. The frequency of TCFA increased from 41% at baseline to 54% at follow-up, whereas ThCFAs decreased from 41% to 34% and PIT decreased from 16% to 8%. Among the 41 lesions classified at baseline as TCFA, at follow-up, 32 (78%) were still classified as TCFA, whereas 9 (22%) were classified as ThCFAs or fibrotic plaques. An additional 21 lesions at follow-up were newly classified as TCFA, developing from either PIT or ThCFA. TCFA at baseline that evolved into non-TCFAs trended toward a more distal location than TCFA that did not change (p = 0.12). In lesions classified as TCFA, the minimum lumen area (MLA) decreased from 8.1 (interquartile range [IQR]: 7.4 to 8.8) mm(2) at baseline to 7.8 (IQR: 7.2 to 8.4) mm(2) at follow-up, p < 0.05; this was associated with an increase in percent necrotic core at the MLA site (14% [IQR: 12 to 16] to 19% [IQR: 17 to 22], p < 0.0001) and over the entire length of the lesion (14% [IQR: 12 to 16] to 18% [IQR: 17 to 20], p < 0.0001). Untreated nonculprit lesions in STEMI patients frequently have TCFA morphology that does not change during 13-month follow-up and is accompanied by a decrease in MLA and an increase in necrotic core. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).


Compatibility of state constraints and dynamics for multiagent control systems.
This study concerns the problem of compatibility of state constraints with a multiagent control system. Such a system deals with a number of agents so large that only a statistical description is available. For this reason, the state variable is described by a probability measure on R d representing the density of the agents and evolving according to the so-called continuity equation which is an equation stated in the Wasserstein space of probability measures. The aim of the paper is to provide a necessary and sufficient condition for a given constraint (a closed subset of the Wasserstein space) to be compatible with the controlled continuity equation. This new condition is characterized in a viscosity sense as follows: the distance function to the constraint set is a viscosity supersolution of a suitable Hamilton-Jacobi-Bellman equation stated on the Wasserstein space. As a byproduct and key ingredient of our approach, we obtain a new comparison theorem for evolutionary Hamilton-Jacobi equations in the Wasserstein space.


Dysautonomia in mitral valve prolapse.
Many of the clinical features of patients with mitral valve prolapse can logically be attributed to abnormal autonomic neural function. Accordingly, we have studied heart rate and blood pressure response to a standardized Valsalva maneuver and postural test in 44 untreated patients with demonstrated mitral valve prolapse. Fifteen healthy subjects of similar age served as controls. The directional changes of blood pressure and heart rate were similar in control subjects and patients in both tests, but patients differed from control subjects by their widely oscillating heart rate during the upright posture, and their exaggerated and prolonged bradycardia during the recovery phase of the Valsalva maneuver and following their return to recumbency in the postural test. This bradycardia persisted for 30 to 90 seconds after blood pressure returned to control values. Patients also showed a greater respiratory variation of R-R interval, which became especially marked during the adjustment to changes of posture. We postulate an abnormal central modulation of baroreflexes as the best explanation for the dysautonomic responses of symptomatic patients with prolapsed mitral valves.


Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders.
Patients with lymphoproliferative disorders such as chronic lymphocytic leukemia and mantle cell lymphoma (MCL) who are resistant to covalent Bruton tyrosine kinase inhibitors (cBTKis), especially if also venetoclax refractory, have an unmet therapeutic need. Pirtobrutinib, a noncovalent BTKi, achieves high response rates in patients who are refractory to cBTKi, regardless of mechanism of cBTKi resistance. This led to recent accelerated US Food and Drug Administration approval in MCL. The toxicity profile in early studies suggests suitability for use in combination approaches. We summarize existing preclinical and clinical data for pirtobrutinib.


Application of iron [Fe(0)]-rich substrate as a novel capping material for efficient simultaneous remediation of contaminated sediments and the overlying water body.
Release of contaminants from sediments has been one of the main pollution sources causing eutrophication and malodorous black of ponds. In this study, an iron-rich substrate (IRS) was developed based on iron‑carbon micro-electrolysis and applied for simultaneous sediments and overlying water remediation. IRS obtained high ammonia and phosphate adsorption capacities (Langmuir isotherm) of 13.02 and 18.12 mg·kg-1, respectively. In the 90-day long-term remediation, IRS reduced NH4+-N, PO43--P, organic-N, organic-P, TN and TP in overlying water by 48.6%, 97.9%, 34.2%, 67.1%, 53.2% and 90.4%, respectively. In sediments, IRS reduced NO3--N, NH4+-N and organic-N by 98.5%, 26.5% and 6.3%, respectively. The unstable P-compounds (i.e., organic-P, Ca-bounded-P and labile-P) were effectively transferred (20.1%, 54.3% and 98.2%, respectively) into inert P-compounds (i.e., Fe-bounded-P and residual-P). Meanwhile, flux rates of nitrogen and phosphorus from sediments to overlying water were reduced from 7.02 to 4.92 mg·m-2·d-1 (by 29.9%) and from 7.42 to 2.21 mg·m-2·d-1 (by 70.2%), respectively. Due to micro-electrolysis, Fe2+/Fe3+/[H] were in-situ generated from IRS and NO3--N was effectively reduced. Additionally, the generation of O2· was promoted by Fe2+/[H] and strengthened the NH4+-N, organic-N/P oxidation. Fe3+ enhanced the immobilization of PO43- (e.g., as FePO4·H2O and FenPO4(OH)3n-3). The released Fe2+/Fe3+ from IRS were finally stabilized as poorly reactive sheet silicate (PRS)-Fe and magnetite-Fe in the sediments and hardly showed side effect to sediments and water body. The developed IRS obtained advantages of high efficiency, ecologically safe and cost-effective in contaminated sediments and overlying water remediation.


Permanent left bundle branch area pacing utilizing intracardiac echocardiogram.
Recently, left bundle branch area pacing (LBBAP) has been shown to be feasible. However, the right ventricular (RV) implantation site for LBBAP remains elusive. We believe that the RV implantation site should be located at the posteromedial basal septum, and in this paper, we propose a new method to help guide lead implantation. The aim of this study is to demonstrate the feasibility of the proposed method. The RV implantation site was positioned by a combination of a nine-grid system on fluoroscopy and the use of intracardiac echocardiogram (ICE) and then verified by ICE. Fifteen patients were enrolled for LBBAP using our method. The acute success rate was 86.7% (13/15), which demonstrated that our method is useful for assisting with lead implantation. According to ICE, the distance between the implantation site and apex (the front) and the distance between the implantation site and tricuspid annulus (the back) were 44.9 ± 10.7 and 33.2 ± 10.4 mm, respectively, and the ratio of the front and the back was 1.57 ± 0.80. The distance between the implantation site and the front junction point of the left-right ventricle (the upper) and the distance between the implantation site and the back junction point (the lower) were 33.4 ± 10.6 and 24.5 ± 10.2 mm, respectively. The ratio of the upper to the lower was 1.76 ± 1.36. These results suggest that the implantation site was at the posteromedial basal septum. The width of the QRS duration increased from 110.4 ± 33.1 ms at baseline to 114.1 ± 16.1 ms post LBBAP (P > 0.05). The operation time was 133 ± 32.9 min. The time of X-ray fluoroscopy was 21.2 ± 5.9 min. The mean time for lead positioning during LBBAP was 33.8 ± 16.6 min. During a follow-up of 3 months, the LBB capture threshold remained stable in 12 patients, except for one patient who had an increase in the LBB capture threshold to 3.0 v/0.4 ms. Our preliminary results indicate that the posteromedial basal septum could be seen as the implantation site for LBBAP. As a technique for LBBAP, ICE is a useful method for assisting with lead implantation. It is feasible and safe to use a nine-grid system combined with ICE for LBBAP.


Risk factors for venous thromboembolism after acute trauma: A population-based case-cohort study.
Predictors of venous thromboembolism (VTE) after trauma are uncertain. To identify independent predictors of VTE after acute trauma. Using Rochester Epidemiology Project (REP) resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE within 92days after hospitalization for acute trauma over the 18-year period, 1988-2005. We also identified all Olmsted County residents hospitalized for acute trauma over this time period and chose one to two residents frequency-matched to VTE cases on sex, event year group and ICD-9-CM trauma code predictive of surgery. In a case-cohort study, demographic, baseline and time-dependent characteristics were tested as predictors of VTE after trauma using Cox proportional hazards modeling. Among 200 incident VTE cases, the median (interquartile range) time from trauma to VTE was 18 (6, 41) days. Of these, 62% cases developed VTE after hospital discharge. In a multiple variable model including 370 cohort members, patient age at injury, male sex, increasing injury severity as reflected by the Trauma Mortality Prediction Model (TMPM) Mortality Score, immobility prior to trauma, soft tissue leg injury, and prior superficial vein thrombosis were independent predictors of VTE (C-statistic=0.78). We have identified clinical characteristics which can identify patients at increased risk for VTE after acute trauma, independent of surgery. Almost two thirds of all incident VTE events occurred after initial hospital discharge (18day median time from trauma to VTE) which questions current practice of not extending VTE prophylaxis beyond hospital discharge.


Fluctuations in the detection of the HOM effect.
Hong-Ou-Mandel (HOM) effect is known to be one of the main phenomena in quantum optics. It is believed that the effect occurs when two identical single-photon waves enter a 1:1 beam splitter, one in each input port. When the photons are identical, they will extinguish each other. In this work, it is shown that these fundamental provisions of the HOM interference may not always be fulfilled. One of the main elements of the HOM interferometer is the beam splitter, which has its own coefficients of reflection [Formula: see text] and transmission [Formula: see text]. Here we consider the general mechanism of the interaction of two photons in a beam splitter, which shows that in the HOM theory of the effect it is necessary to know (including when planning the experiment) not only [Formula: see text] and [Formula: see text], but also their root-mean-square fluctuations [Formula: see text], which arise due to the dependence of [Formula: see text] and [Formula: see text] on the frequencies where [Formula: see text] are the frequencies of the first and second photons, respectively. Under certain conditions, specifically when the dependence of the fluctuations [Formula: see text] and [Formula: see text] can be neglected and [Formula: see text] is chosen, the developed theory coincides with previously known results.


Factors Associated With Suicidal Attempts in Iran: A Systematic Review.
Suicide prevention is a health service priority. Some surveys have assessed suicidal behaviors and potential risk factors. The current paper aimed to gather information about etiology of suicide attempts in Iran. Pubmed, ISI web of science, PsychInfo, IranPsych, IranMedex, IranDoc as well as gray literature were searched. By electronic and gray literature search, 128 articles were enrolled in this paper. Pubmed, ISI web of science, PsychInfo, IranPsych, IranMedex, IranDoc were searched for electronic search. After reading the abstracts, 84 studies were excluded and full texts of 44 articles were reviewed critically. Pubmed, ISI web of science, PsychInfo, IranPsych, IranMedex, IranDoc as well as gray literature were searched to find any study about etiologic factors of suicide attempt in Iran. Depressive disorder was the most common diagnosis in suicide attempters that is 45% of the evaluated cases had depression. One study that had used Minnesota multiphasic personality inventory (MMPI) found that Histrionics in females and Schizophrenia and Paranoia in males were significantly influential. Family conflicts with 50.7% and conflict with parents with 44% were two effective psychosocial factors in suicidal attempts. In around one fourth (28.7%) of the cases, conflict with spouse was the main etiologic factor. According to the methodological limitations, outcomes should be generalized cautiously. Further studies will help to plan preventive strategies for suicidal attempts; therefore, continued researches should be conducted to fill the data gaps.


Climate change impacts on respiratory health: exposure, vulnerability, and risk.
Anthropogenic climate change adversely impacts human health. In this perspective, we examine the impact of climate change on respiratory health risk. We describe five respiratory health threats-heat, wildfires, pollen, extreme weather events, and viruses-and discuss their impact on health outcomes in a warming climate. The risk of experiencing an adverse health outcome occurs at the intersection of exposure and vulnerability, consisting of sensitivity and adaptive capacity. Exposed individuals and communities most at risk are those with high sensitivity and low adaptive capacity, as influenced by the social determinants of health. We call for the implementation of a transdisciplinary strategy for accelerating respiratory health research, practice, and policy in the context of climate change.


[Selection of GC phases and optimization of separation of trichothecenes by means of computer simulation].
Gas chromatography combines high resolution with good sensitivity (ECD) for the simultaneous analysis of trichothecenes. With the aid of computer-supported GC simulation based on thermodynamic retention indices, optimized GC methods for 4 different phase polarities have been developed. The verification with polar and unpolar columns in 2 GCs under optimized separation conditions provides highly reliable results.


Obtundation in the elderly patient: presentation of a drug overdose.
The case of an obtunded elderly woman is presented. The patient initially was thought to have suffered a cardiovascular accident but was discovered to have taken an overdose of flurazepam hydrochloride. Depression is a common and under-recognized problem in the geriatric population. As a consequence, suicide rates are highest in the elderly. Over- and underdosing of both prescription and nonprescription drugs are common means available to the suicidal elderly patient. These overdoses are often attributed to unintentional patient errors and overlooked for what they are, attempted suicides, or they are missed entirely as a cause of the patient's presentation. This case illustrates the need to consider drug overdose in the obtunded elderly patient.


The depth of molecular recognition: voltage-sensitive blockage of synthetic multifunctional pores with refined architecture.
Voltage-sensitive blockage by ADP, ATP and phytate (IP6) demonstrates that active-site contraction toward the middle of newly synthesized rigid-rod beta-barrels provides a general strategy to rationally create and modulate the voltage sensitivity (and to increase the efficiency) of molecular recognition by synthetic multifunctional pores.


Thermoelastic analysis of laser iridectomies.
We have attempted to derive the stress-strain-temperature relationships of the iris stroma subject to a restrictive thermal burn from a laser. The corresponding displacement equation embodies the mechanical impulses due to this thermal insult. This thermoelastic analysis of laser iridectomy attempts to describe the mechanism involved in the surgical procedure. It is clear from this study that the flexural behaviour of the iris is principally due to thermal insult and not due to vapour bubbles or redistribution of the aqueous.


A promising approach to effectively reduce cramp susceptibility in human muscles: a randomized, controlled clinical trial.
To investigate if the cramp threshold frequency (CTF) can be altered by electrical muscle stimulation in a shortened position. A total of 15 healthy male sport students were randomly allocated to an intervention (IG, n = 10) and a non-treatment control group (CG, n = 5). Calf muscles of both legs in the IG were stimulated equally twice a week over 6 weeks. The protocol was 3×5 s on, 10 s off, 150 µs impulse width, 30 Hz above the individual CTF, and was at 85% of the maximal tolerated stimulation energy. One leg was stimulated in a shortened position, inducing muscle cramps (CT), while the opposite leg was fixated in a neutral position at the ankle, hindering muscle cramps (nCT). CTF tests were performed prior to the first and 96 h after the 6(th) (3 w) and 12(th) (6 w) training session. After 3 w, the CTF had significantly (p<0.001) increased in CT calves from 23.3±5.7 Hz to 33.3±6.9 Hz, while it remained unchanged in nCT (pre: 23.6±5.7 Hz, mid: 22.3±3.5 Hz) and in both legs of the CG (pre: 21.8±3.2 Hz, mid: 22.0±2.7 Hz). Only CT saw further insignificant increases in the CTF. The applied stimulation energy (mA² • µs) positively correlated with the effect on the CTF (r = 0.92; p<0.001). The present study may be useful for developing new non-pharmacological strategies to reduce cramp susceptibility. German Clinical Trials Register DRKS00005312.


Viral Infections of the Oral Cavity in Children.
Various viral infections can affect the oral cavities of pediatric patients [...].


Structure-activity relationship (SAR) studies on the mutagenic properties of 2,7-diaminofluorene and 2,7-diaminocarbazole derivatives.
We discovered that 2,7-diaminofluorene or 2,7-diaminocarbazole moiety can be employed as a core structure of highly effective NS5A inhibitors that are connected through amide bonds to proline-valine-carbamate motifs. Amide bonds can be easily cleaved via various metabolic pathways upon administration into the body, and metabolites containing 2,7-diaminofluorene and 2,7-diaminocarbazole core structures have been known to be strong mutagens. To avoid the mutagenesis issue of these core structures, we examined various functional groups at the C9 or N9 position of 2,7-diaminofluorene or 2,7-diaminocarbazole, respectively, through the Ames test in TA98 and TA100 mutants of Salmonella typhimurium LT-2. We discovered that, through proper alkyl substitution at the C9 or N9 position, 2,7-diaminofluorene and 2,7-diaminocarbazole moieties can be successfully employed in drug discovery without necessarily causing mutagenicity problems.


Effect of insulin on glycogen and protein synthesis in monolayer cultures of hepatocytes from normal and alloxan diabetic rats.
The effects of insulin on net glycogen synthesis and amino acid incorporation into protein were studied in cultured hepatocytes from adult normal and alloxan diabetic rats. Insulin stimulated glycogen synthesis in monolayer cells throughout a four day culture period and enhanced leucine incorporation into protein more effectively in normal cells with high glycogen levels than in cultured diabetic cells. These differences correlate well with the observed cellular ultrastructures which were maintained much better in the presence of insulin. Restoration of the morphological changes of alloxan diabetic hepatocytes to normal liver cell structures can be observed at any time during the culture period by giving insulin continuously.


Total creatine kinase and isoenzyme fractions in chronic dialysis patients.
We measured total serum creatine kinase (CK) and serum creatine kinase MB fraction (CK-MB) in 53 patients on continuous ambulatory peritoneal dialysis (CAPD) and 52 patients on maintenance hemodialysis (HD), using Scalva UV methodology for CK and electrophoresis for CK-MB. Seven of the 53 CAPD patients (13%) had an elevated total CK, and only one of these 7 patients had an elevated CK-MB greater than 5%. In contrast 22 HD patients (42%) had increased total CK values, and 6 of these 22 HD patients (27%) showed elevated CK-MB isoenzyme greater than 5%. For each sex, blacks had higher mean CK values than whites. Twenty-one out of the 43 HD patients who received intramuscular injections had elevated total CK values and 6 of these 21 patients had elevated CK-MB isoenzyme independent of the timing of injection. The increased frequency of higher total CK values in HD patients appears to be related to race and androgen administration. The modest elevations in CK-MB fraction (5 to 8%) in these patients require careful interpretation.


Comparative Effectiveness and Safety of Generic Versus Brand-Name Fluticasone-Salmeterol to Treat Chronic Obstructive Pulmonary Disease.
In 2019, the U.S. Food and Drug Administration (FDA) approved the first generic maintenance inhaler for asthma and chronic obstructive pulmonary disease (COPD). The inhaler, Wixela Inhub (fluticasone-salmeterol; Viatris), is a substitutable version of the dry powder inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline). When approving complex generic products like inhalers, the FDA applies a special "weight-of-evidence" approach. In this case, manufacturers were required to perform a randomized controlled trial in patients with asthma but not COPD, although the product received approval for both indications. To compare the effectiveness and safety of generic (Wixela Inhub) and brand-name (Advair Diskus) fluticasone-salmeterol among patients with COPD treated in routine care. A 1:1 propensity score-matched cohort study. A large, longitudinal health care database. Adults older than 40 years with a diagnosis of COPD. Incidence of first moderate or severe COPD exacerbation (effectiveness outcome) and incidence of first pneumonia hospitalization (safety outcome) in the 365 days after cohort entry. Among 45 369 patients (27 305 Advair Diskus users and 18 064 Wixela Inhub users), 10 012 matched pairs were identified for the primary analysis. Compared with Advair Diskus use, Wixela Inhub use was associated with a nearly identical incidence of first moderate or severe COPD exacerbation (hazard ratio [HR], 0.97 [95% CI, 0.90 to 1.04]) and first pneumonia hospitalization (HR, 0.99 [CI, 0.86 to 1.15]). Follow-up times were short, reflecting real-world clinical practice. The possibility of residual confounding cannot be completely excluded. Use of generic and brand-name fluticasone-salmeterol was associated with similar outcomes among patients with COPD treated in routine practice. National Heart, Lung, and Blood Institute.


Rapid detection of high-risk HPV16 and HPV18 based on microchip electrophoresis.
Researches on detection of human papillomavirus (HPV) high-risk samples were carried out by polymerase chain reaction (PCR) coupled with microchip electrophoresis (MCE). Herein, we introduced a simple, rapid, automated method for detecting high-risk samples HPV16 and HPV18. In this research, general primers were initially selected to obtain sufficient detectable yield by PCR to verify feasibility of MCM method for HPV detection, then type-specific primers were further used to evaluate the specificity of MCE method. The results indicated MCE method was capable of specifically detecting high-risk HPV16 and HPV18, and also enabled simultaneous detection of multiplex samples. This MCE method described here has been successfully applied to HPV detection and displayed excellent reliability demonstrating by sequencing results. The inherent capability of MCE facilitated HPV detection conducted in a small chip with automated, high throughput, massive parallelized analysis. We envision that MCE method will definitely pave a way for clinical diagnosis, and even on-site screening of cervical cancer.


Arthroscopic Iliac Crest Bone Allograft Combined With Subscapularis Upper-Third Tenodesis Shows a Low Recurrence Rate in the Treatment of Recurrent Anterior Shoulder Instability Associated With Critical Bone Loss.
To evaluate the clinical and radiologic outcomes of patients undergoing arthroscopic glenoid bone allograft combined with subscapularis upper-third tenodesis for anterior shoulder instability associated with clinically relevant bone loss and hyperlaxity. Between January 2016 and December 2017, patients with recurrent anterior shoulder instability associated with bone loss and hyperlaxity were selected and treated with arthroscopic iliac crest bone graft combined with subscapularis upper-third tenodesis. The selection criteria were as follows: more than 5 dislocations; positive apprehension, anterior drawer, and Coudane-Walch test results; glenoid bone defect between 15% and 30% and humeral bone defect with an engaging Hill-Sachs lesion; and no previous shoulder surgery. All patients were followed up with the Constant score, University of California-Los Angeles (UCLA) rating, Rowe score, and visual analog scale evaluation. Assessments were performed with plain radiographs and a PICO computed tomography scan before surgery and at 2 years of follow-up. Nineteen patients were included in the study, with a mean follow-up duration of 34.6 months (range, 24-48 months). In 17 patients (89%), excellent clinical results were recorded according to the Rowe score. The Constant score improved from 82.9 (standard deviation [SD], 5.2) to 88.9 (SD, 4.3) (P = .002); Rowe score, from 25.3 (SD, 5.3) to 89.1 (SD, 21.8) (P < .001); UCLA score, from 23.7 (SD, 3) to 31.5 (SD, 4.8) (P < .001); and visual analog scale score, from 3.2 to 1.3 (P < .001). Patients met the minimal clinically important difference 94.7%, 89.5%, and 47.3% of the time for the Rowe score, UCLA score, and Constant score, respectively. Bone graft resorption was observed in all patients: partial in 9 and complete in 10. We recorded 2 recurrent traumatic dislocations (11%), with no case of persistent anterior apprehension or other complication. An arthroscopic glenoid bone graft combined with subscapularis upper-third tenodesis may be a valid surgical option to treat recurrent anterior instability associated with both bone loss and hyperlaxity. Level IV, case series.