Retinal changes and cardiac biomarker assessment in relation to chronic kidney disease: a single centre study.
The prevalence of chronic kidney disease (CKD) is rising in Malaysia. Early detection is necessary to prevent disease progression, especially in terms of cardiovascular (CV) risk, the main cause of death in end-stage renal disease (ESRD). Retinal changes have proven to be a good predictor of CKD whereas cardiac biomarkers are useful in cardiovascular risk stratification. We aimed to demonstrate the correlation between retinal changes and cardiac biomarkers with CKD. This single-centre cross-sectional study was conducted among patients with CKD stages 3, 4, and 5 (not on dialysis) from the Nephrology Clinic, Universiti Kebangsaan Malaysia Medical Centre. A total of 84 patients were recruited with an even distribution across all three stages. They underwent fundus photography where images were analysed for vessel calibre (central retinal venular equivalent (CRVE), central retinal arterial equivalent (CRAE), and tortuosity indices. Optical coherence tomography was used to measure macular volume. Blood samples were sent for laboratory measurement of high-sensitivity C-reactive protein (hs-CRP) and asymmetric dimethylarginine (ADMA). These parameters were analysed in relation to CKD. The mean age was 58.8 ± 11.7 years, with 52.4% male and 47.6% female patients. Among them, 64.3% were diabetics. Retinal vessel tortuosity (r = -0.220, p-value = 0.044) had a negative correlation with the estimated glomerular filtration rate (eGFR). CRVE showed a positive correlation with proteinuria (r = 0.342, p = 0.001) but negative correlation with eGFR (r = -0.236, p = 0.031). Hs-CRP positively correlated with proteinuria (r = 0.313, p = 0.04) and negatively correlated with eGFR (r = -0.370, p = 0.001). Diabetic patients had a higher CRVE compared to non-diabetic patients (p = 0.02). History of ischaemic heart disease was associated with a smaller macula volume (p = 0.038). Male gender (r2 = 0.066, p = 0.031) and HbA1c had a positive influence (r2 = 0.066, p = 0.047) on retinal vessel tortuosity. There was a positive influence of age (r2 = 0.183, p = 0.012) and hs-CRP (r2 = 0.183, p = 0.045) on CRVE. As for macula volume, it negatively correlated with diabetes (r2 = 0.015, p = 0.040) and positively correlated with smoking (r2 = 0.015, p = 0.012). Our study showed that eGFR value affects retinal vessel tortuosity, CRVE and hs-CRP. These parameters bear potential to be used as non-invasive tools in assessing CKD. However, only macula volume may be associated with CVD risk among the CKD population.


A new stochastic diffusion model for influence maximization in social networks.
Most current studies on information diffusion in online social networks focus on the deterministic aspects of social networks. However, the behavioral parameters of online social networks are uncertain, unpredictable, and time-varying. Thus, deterministic graphs for modeling information diffusion in online social networks are too restrictive to solve most real network problems, such as influence maximization. Recently, stochastic graphs have been proposed as a graph model for social network applications where the weights associated with links in the stochastic graph are random variables. In this paper, we first propose a diffusion model based on a stochastic graph, in which influence probabilities associated with its links are unknown random variables. Then we develop an approach using the set of learning automata residing in the proposed diffusion model to estimate the influence probabilities by sampling from the links of the stochastic graph. Numerical simulations conducted on real and artificial stochastic networks demonstrate the effectiveness of the proposed stochastic diffusion model for influence maximization.


Flow-cytometric analysis of peripheral blood lymphocytes in patients with chronic idiopathic neutropenia of adults.
Flow-cytometric analysis of peripheral blood lymphocytes was performed in 96 patients with chronic idiopathic neutropenia of adults (CINA) and in 36 age- and sex-matched healthy volunteers (controls) using a panel of monoclonal antibodies. Patients were classified arbitrarily into group A (68 patients with 2500-1500 neutrophils/microliter) and group B (28 patients with neutrophil counts below 1500/microliter). We found that CINA patients displayed low numbers of peripheral blood lymphocytes compared with the controls, which correlated with the numbers of circulating neutrophils. This decrease was due mainly to the reduction of T lymphocytes and, to lesser degree, to the decline of NK cells. Both CD4+ and CD8+ T cells decreased, so that the CD4+/CD8+ cell ratio remained within normal range. Moreover, decrease of T lymphocytes was due essentially to the diminution of CD45RO+ T-cell subsets (CD4+/CD45RO+ and CD8+/CD45RO+), while CD45RA+ T cells did not change. A highly significant positive correlation was found between the numbers of CD45RO+ T cells and the numbers of circulating neutrophils. All these alterations were more pronounced in the patients of group B than in those of group A. NK cells were found to be significantly reduced in the patients of group B, but not in those of group A. The numbers of both CD16+ and CD56+ cells correlated with the numbers of circulating neutrophils. Patients of group B had also low numbers of CD57+ cells, probably due to the reduction of T cells and NK cells. B cells did not change significantly. No significant changes were found also in the numbers of lymphocytes carrying activation-related cell surface markers. We concluded that lymphocyte reduction in CINA patients is due mainly to the diminution of CD45RO+ cells, and we postulated that the most probable explanation for this abnormality is an increased extravasation of these cells, which pass into the tissues following an accelerated adhesion to endothelial cells. This hypothesis and its relationship with the underlying neutropenia in CINA patients remain to be clarified.


Cyclic AMP, the hyperresponsiveness factor from hog kidney.
The isolation and identification of a material present in the plasma of hypertensive dogs and hypertensive human patients has been under study since 1972. The earliest experiments in relation to this work, noted that plasma from hypertensive dogs cause a hyperresponse to norepinephrine when both were administered by way of the vein. Employing a rat assay system that consisted of an anesthetized rat with polyethylene catheters in the vein for giving norepinephrine and the test fractions and a catheter in the artery for blood pressure monitoring, fractions from hog kidney were tested for hyperresponsiveness activity. The active material is very comparable to cyclic AMP in molecular weight, ultraviolet spectrum, paper chromatography, Enzyme hydrolysis and activity in the anesthetized rat system. This evidence indicates that the hyperresponsiveness factor of renal origin is cyclic AMP.


Inhibition of acid sialidase by inorganic sulfate.
Sulfated glycosaminoglycans are known to inhibit mammalian acid-active sialidase. Although the inhibition depends clearly on the presence of sulfate groups on these macromolecules, there was no information on the intrinsic inhibitory potency of inorganic sulfate. In this study, we demonstrate that inorganic sulfates inhibit acid-active Mu-Neu5Ac sialidase of U937 cells. This inhibition was found to be reversible and it appeared to be of the mixed competitive type. Sulfate-induced inhibition was also observed in other cells as well as with other substrates such as sialyl lactose and bovine mixed brain gangliosides. We conclude that the intrinsic inhibitory potency of sulfate groups may be significantly involved in the inhibition of acid-active sialidase by sulfated glycosaminoglycans. In addition, inorganic sulfate by its apparent potency to selectively inhibit acid sialidases might constitute an interesting tool for the characterisation of the minor forms of sialidases occurring in mammalian cells.


Survival after adjuvant radiation therapy in localized small cell lung cancer treated with complete resection.
To determine whether there is an overall survival (OS) benefit to the addition of thoracic radiation therapy (RT) following R0 resection of pathologic (p) T1 or pT2 N0 M0 small cell lung cancer. Using the National Cancer Database, we performed a retrospective cohort analysis. Patients who underwent R0 resection for pT1 or p2 N0 M0 small cell lung cancer, stratified by receipt of adjuvant thoracic RT, were compared on the basis of OS using hierarchical Cox Proportional hazards models. Of 4969 patients diagnosed with pT1or pT2 N0 M0 SCLC from 2004 to 2014, 1617 (33%) underwent R0 resection of their primary tumor; of these resected patients, 146 (9.0%) had adjuvant thoracic RT. In unadjusted analysis, there was no significant difference in OS between groups (median survival: surgery alone, 62.2 months vs surgery+RT, 43.8 months; P = .1436). In multivariable analysis, RT was not associated with improved survival (P = .099). There was no significant difference in unadjusted or adjusted survival associated with receipt of RT in both a young and healthy cohort (P = .647 for unadjusted and P = .858 for adjusted) and a matched cohort (P = .867 and P = .954). In the matched cohort, improved OS was associated with younger patient age (adjusted hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .001), female sex (adjusted hazard ratio, 0.68, 95% confidence interval, 0.47-0.97; P = .035), and smaller tumors (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .005). Having 2 or more comorbidities was associated with worse OS (adjusted hazard ratio, 2.16; 95% confidence interval, 1.21-3.86; P = .009). Although complete resection was accomplished in a minority of patients, for these patients, survival was good. The addition of thoracic RT to complete resection does not appear to confer additional survival benefit.


In vivo fluoride uptake in enamel and dentin from fluoride-containing materials.
The ability of fluoride-containing materials to deposit fluoride into the cavity walls could be a measure of their anticariogenic properties. Great penetration depths of fluoride were found in all groups in this study, with deeper penetration in dentin compared to enamel.


Penetration of topically applied levofloxacin 0.5% and ofloxacin 0.3% into the vitreous of the non-inflamed human eye.
The aim of the study was to evaluate the vitreous penetration of two commercially available ophthalmic fluoroquinolones: ofloxacin and levofloxacin. This prospective, double-blind, randomized clinical trial comprised 16 patients scheduled for vitrectomy surgery of one eye for macular hole or macular pucker. The patients were randomly assigned to receive topical ofloxacin 0.3% (n=9) or levofloxacin 0.5% (n=7) the day before, one drop at noon, 4 p.m., 8 p.m. and midnight. The next morning, patients were given their assigned masked antibiotic every 5 min for four doses starting 1 h before surgery. The vitreous humour samples, at least 0.3 ml each, were collected 1 h after the administration of the last dose, at the beginning of the pars plana vitrectomy with infusion disconnected. Samples were assayed for ofloxacin and levofloxacin concentrations by a method using high-performance liquid chromatography (HPLC) coupled with single mass spectrometry with electrospray ionization Equal topical administration of levofloxacin yielded 2.5 times higher vitreal concentration than ofloxacin. The mean vitreous concentrations of ofloxacin and levofloxacin were 5.30+/-3.04 (SD) ng/ml and 13.09+/-5.24 ng/ml, respectively (P=0.002). Equal dosing with topical administration of levofloxacin 0.5% and ofloxacin 0.3% allows better penetration into the vitreous for levofloxacin, but the levels of mean concentrations of each drug did not exceed the MIC(90) or MIC(50) for most ocular pathogenic bacteria in terms of conventional endophthalmitis therapy.


C/EBPbeta suppression by interruption of CUGBP1 resulting from a complex rearrangement of MLL.
Translocations involving the mixed-lineage leukemia gene (MLL) confer a poor prognosis in acute leukemias. In t(1;11)(q21;q23), MLL is fused reciprocally with AF1q. Here we describe a t(1;11)(q21;q23) with a secondary event involving insertion of the telomeric portion of MLL into the p arm of chromosome 11 (11p11). We show that this latter event interrupts the CUG triplet repeat binding protein-1 (CUGBP1) gene, a translational enhancer of C/EBPbeta. We then showed that these cells have reduced expression of CUGBP1 and C/EBPbeta when compared to other AML blasts. This is the first report to describe insertional disruption of the CUGBP1 gene and to suggest a role for the CUGBP1-C/EBPbeta pathway in leukemogenesis.


Electrosurgical Injuries in Gynecologic Laparoscopy
We reviewed the 396 operative laparoscopies performed from March 1994 to March 1996 to determine the numbers and causes of electrical injuries. Electrical injuries were reported in four (1.01%) patients. Capacitive coupling induced by a laparoscope inserted through a conductive cannula sleeve with a nonconductive collar caused two bowel injuries that required laparotomy. Insulation failure of an electric cable resulted in a skin burn. A small surface contact area of a cannula sleeve being pulled out of the abdominal wall led to a surface burn in the abdominal wall. Lack of knowledge and insufficient attention on the part of laparoscopic surgeons and operating room personnel may result in electrosurgical accidents.


Definitive and sustained increase in prostate cancer metastases in the United States.
We examined the most recent Surveillance, Epidemiology, and End Results release to corroborate temporal trends in nonmetastatic and distant prostate cancer metastases in the United States. Surveillance, Epidemiology, and End Results was analyzed for the incidence of nonmetastatic and distant metastasis for men with prostate cancer aged 50-74 and ≥75 years during 2004-2015. Incidence ratios (IR) were calculated relative to the year prior. The incidence of distant metastasis significantly increased from 451.0 to 504.0 per million (IR:1.12, 95% CI:1.01-1.24) from 2011 to 2012 and 532.3 to 586.1 per million (IR:1.10, 95% CI:1.00-1.21) from 2014 to 2015 in men aged ≥75 years. The incidence of distant metastasis did not significantly increase in men aged 55-74 over the study period. We demonstrate a sustained and definitive increase in prostate cancer distant metastases in men aged ≥75 years. Although our observational study design cannot pinpoint the exact cause of this increase, which is likely multifactorial, this shift reverses declines in metastases at diagnoses that followed the advent of prostate-specific antigen screening.


CENP-A regulates chromosome segregation during the first meiosis of mouse oocytes.
Proper chromosome separation in both mitosis and meiosis depends on the correct connection between kinetochores of chromosomes and spindle microtubules. Kinetochore dysfunction can lead to unequal distribution of chromosomes during cell division and result in aneuploidy, thus kinetochores are critical for faithful segregation of chromosomes. Centromere protein A (CENP-A) is an important component of the inner kinetochore plate. Multiple studies in mitosis have found that deficiencies in CENP-A could result in structural and functional changes of kinetochores, leading to abnormal chromosome segregation, aneuploidy and apoptosis in cells. Here we report the expression and function of CENP-A during mouse oocyte meiosis. Our study found that microinjection of CENP-A blocking antibody resulted in errors of homologous chromosome segregation and caused aneuploidy in eggs. Thus, our findings provide evidence that CENP-A is critical for the faithful chromosome segregation during mammalian oocyte meiosis.


Prevalence of hearing loss among 18-year-old Swedish men during the period 1971-1995.
To study the hearing of 18-year-old men by using screening audiograms obtained at military conscription. The study group comprised 301,873 Swedish men belonging to six age cohorts born from 1953 to 1977 who had been screened at age 18 years from 1971 to 1995. The prevalence of mild to moderate hearing loss was investigated. Of the entire study group, 13.1% had elevation of one or more pure tone thresholds. In most cases, 11.9%, the elevation was situated in the high-frequency region. High-frequency hearing loss was more common in the left ear (7.5%) than in the right ear (6.2%). The prevalence of hearing loss decreased during the period 1971 to 1981 from 15.7% to 8.3%. During the last part of the study period, 1986 to 1995, the prevalence increased from 9.8% to 16.3%. The increase included mild to moderate degrees of hearing loss with thresholds below 35 dB HL. The prevalence of threshold elevations was highest in sparsely populated areas of Sweden and lowest in large, metropolitan areas of Sweden from 1971 to 1986. During the last part of the study period the geographical differences decreased or disappeared. The total prevalence of hearing loss was in accordance with other reports. The frequency 6 kHz was most affected by threshold elevations. The prevalence of hearing loss decreased in the first part of the study period, and increased at the end of the study period. Hearing loss was most commonly seen in rural areas.


Clinical presentation, genetic etiology and outcome associated with fetal cardiomyopathy: comparison of two eras.
To assess the rate and type of genetic diagnosis and clinical outcome of cases of fetal cardiomyopathy (CM) during two eras, in order to examine the impact of advanced genetic testing and improved perinatal management strategies. All diagnoses of fetal CM in Alberta, Canada, encountered between 2003 and 2019, were reviewed retrospectively. Genetic, cardiac and non-cardiac diagnoses and clinical outcome were documented. Cases with CM secondary to extracardiac pathology and maternal conditions were excluded. Cases diagnosed in the earlier era of the study period (2003-2012) were compared with those diagnosed in the later era (2013-2019). Thirty-eight cases of fetal CM met the inclusion criteria. Median gestational age (GA) at diagnosis was 22.8 (range, 13.4-37.4) weeks. Associated structural heart disease was present in 39% (15/38) of cases and 24% (9/38) had arrhythmia. Hydrops was identified in 29% (11/38) of cases at presentation, and a further 18% (7/38) developed hydrops later in gestation. Twenty-six percent (10/38) of cases underwent termination of pregnancy and 24% (9/38) had intrauterine death. Of liveborn cases, neonatal death occurred in 16% (3/19), late death occurred in 21% (4/19) and 63% (12/19) were alive at the last follow-up. Excluding cases that had termination of pregnancy and those with a liveborn infant who received planned palliative care, the rate of neonatal survival was higher in the later compared with the earlier era (69% (11/16) vs 45% (5/11)), although the difference was not statistically significant (P = 0.26). A genetic etiology was confirmed in 39% (15/38) of cases and strongly suspected in 24% (9/38). A significantly higher proportion of cases had a confirmed or strongly suspected genetic etiology in the later era compared with in the earlier era (76% (19/25) vs 38% (5/13); P = 0.04). In the recent era, a higher proportion of fetal CM cases had a confirmed or strongly suspected genetic etiology than reported previously. Based on comparison with older series, modern perinatal management strategies may not have a significant impact on neonatal survival in cases of fetal CM; however, a larger study would be better powered to detect more subtle differences. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.


Effect of daily fraction size on laryngoesophageal dysfunction after chemoradiation for squamous cell carcinomas of the larynx and hypopharynx.
The purpose of this study was to determine the effect of fraction size on laryngoesophageal dysfunction among patients treated by chemoradiotherapy for laryngeal and hypopharyngeal cancer. Forty patients underwent chemoradiotherapy for stage III/IV squamous cell carcinomas of the larynx and hypopharynx. Median radiation dose was 70 Gy (range, 69.3-70.4 Gy) with daily fractionation ranging from 2 Gy to 2.2 Gy. When comparing 2 Gy versus >2 Gy daily fractionation, there was no difference in 2-year overall survival (71% vs 72%; p = .68), locoregional control (79% vs 77%; p = .43), or laryngectomy-free survival (60% vs 61%; p = .72). Use of 2 Gy versus >2 Gy fractionation improved laryngoesophageal dysfunction-free survival (2-year estimates, 49% vs 27%; p = .07). Patient-reported voice and swallowing were improved with the former. As the importance of a functional larynx becomes recognized as an endpoint for patients treated by voice preservation, the results of our study help refine treatment guidelines. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1322-1326, 2017.


Further notes on the behavior of induced asymmetric dyads in the male of Drosophila melanogaster.
The present study confirms the findings of Zimmering and Bendbow [28], that there is preferential recovery of the shorter elements of asymmetric dyads following induced exchanges in irradiated T(2;-3)bwv4 males. Deletion studies giving rough estimates of contaminations of phenotypic crossovers by deletions (or point mutations) have now provided more accurate estimates of the degrees of non-randomness (c) in the regions studied. The significance of the V4 studies and their implications on the mechanisms of meiotic drive are discussed.


The threat of hepatitis B from dental school patients. A one-year study.
A study was conducted at the Louisiana State University School of Dentistry using the radioimmunoassay technique of serum analysis for presence of hepatitis B surface antigen (HBsAg) in all new patients accepted for treatment over a period of one year. The prevalence was 0.61 percent (22 seropositive patients from a total of 3,626 patients screened). Chronic HBsAg carriers, presence of e antigen, and high titers of antibody to hepatitis B core antigen (anti-HBc) were documented. Eighteen of the 22 seropositive patients had no past history of hepatitis, indicating the inadequacy of a history for revealing carriers of HBsAg.


Streptococcus pyogenes pbp2x Mutation Confers Reduced Susceptibility to β-Lactam Antibiotics.
Two near-identical clinical Streptococcus pyogenes isolates of emm subtype emm43.4 with a pbp2x missense mutation (T553K) were detected. Minimum inhibitory concentrations (MICs) for ampicillin and amoxicillin were 8-fold higher, and the MIC for cefotaxime was 3-fold higher than for near-isogenic control isolates, consistent with a first step in developing β-lactam resistance.


Sperm concentration and semen volume increase after smoking cessation in infertile men.
Smoking has negative reproductive consequences. This study investigated the effect of smoking cessation on the main semen parameters. We included 90 participants who applied to our infertility clinic and smoked at least 20 cigarettes a day for at least 1 year. Of the 90 participants, 48 were in the study group and 42 were in the control group. Semen analysis was performed before and at least 3 months after quitting smoking in the study group. Semen analysis was repeated at baseline and at least 3 months later in the control group. Semen parameters such as volume, sperm concentration, total sperm count, morphology, and motility were evaluated according to the World Health Organization criteria. Patient characteristics as well as the duration of the smoking period, the number of cigarettes smoked per day and the time elapsed since smoking cessation were recorded. The mean age of the participants was 34.69 ± 5.3 years, and the duration of infertility was 34.12 ± 12.1 months (n = 90). The number of cigarettes smoked per day was 30.14 ± 6.69, and the smoking time was 8.31 ± 3.53 years. The average time to quit smoking was 104.2 ± 11.51 days (n = 48). A significant increase in semen volume, sperm concentration and total sperm count was observed 3 months after smoking cessation (2.48 ± 0.79 ml vs. 2.90 ± 0.77 ml, p = 0.002; 18.45 × 106/ml ± 8.56 vs. 22.64 × 106/ml ± 11.69, p = 0.001; 45.04 ± 24.38 × 106 vs. 65.1 ± 34.9 × 106, p < 0.001, respectively). This study showed that smoking cessation had a positive effect on sperm concentration, semen volume, and total sperm count. Although smoking cessation contributed positively to sperm motility and morphology, the difference was not statistically significant.


Establishment and assessment of a simple and easily reproducible incision model of spinal cord neuron cells in vitro.
A growing number of in vitro models have been introduced to study the mechanisms of spinal cord injury. A potential drawback of these models is that they are difficult to reproduce. In this study, an in vitro incision model was established using primary cultured neuronal cells from fetal rat spinal cords. The neurons were subjected to incision in a simple and reproducible way. To assess whether this model could simulate the responses of spinal cord neuron cells in vivo after a spinal cord transection, apoptosis, and the expression of immediate early genes were detected in the neurons at various time points after injury. The results indicated that: (1) significantly more terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were observed at 1, 3, and 7 d following injury and (2) the expression of both c-Jun and c-Fos was induced 10 min after incision and had markedly higher levels 2 h post-injury. These results suggested that our model can partially imitate the responses of in vivo neuronal cells after a spinal cord transection and such models may facilitate further understanding of biochemical and cellular events associated with spinal cord injury.


Silicon dermabrasion tools for skin resurfacing applications.
Miniature abrasion tools for potential skin resurfacing applications are created using microelectromechanical systems (MEMS) fabrication technology. The abrading microstructures are formed on silicon wafers by a bulk micromachining process based on isotropic xenon difluoride etching. The micromachined abraders (microdermabraders) are packaged and applied to human cadaveric skin to assess abrasion quality. Plastic (acrylic) microreplicated structures, non-coated and aluminum-coated versions, are also used in a similar fashion. Non-textured silicon and plastic samples are used as study controls. Dermabraded and intact skin regions are analyzed qualitatively and quantitatively by light microscopy, image processing techniques, and histology. The microdermabraders exhibit a cleaner, more uniform abrading pattern on the cadaveric skin compared to the plastic microreplicated structures. Furthermore, the microdermabraders provide a consistently uniform cut through the epidermal layer, leaving little debris and minimal pitting. In contrast, the plastic microreplicated structures exhibit non-uniform abrading patterns and leave behind more debris and eccentric pits. The results suggest micromachined dermabraders can successfully abrade fine dermatological flaws in human skin.


Review of the temporal and geographical distribution of measles virus genotypes in the prevaccine and postvaccine eras.
Molecular epidemiological investigation of measles outbreaks can document the interruption of endemic measles transmission and is useful for establishing and clarifying epidemiological links between cases in geographically distinct clusters. To determine the distribution of measles virus genotypes in the prevaccine and postvaccine eras, a literature search of biomedical databases, measles surveillance websites and other electronic sources was conducted for English language reports of measles outbreaks or genetic characterization of measles virus isolates. Genotype assignments based on classification systems other than the currently accepted WHO nomenclature were reassigned using the current criteria. This review gives a comprehensive overview of the distribution of MV genotypes in the prevaccine and postvaccine eras and describes the geographically diverse distribution of some measles virus genotypes and the localized distributions of other genotypes.


Confined Spaces in [n]Cyclo-2,7-pyrenylenes.
A set of strained aromatic macrocycles based on [n]cyclo-2,7-(4,5,9,10-tetrahydro)pyrenylenes is presented with size-dependent photophysical properties. The K-region of pyrene was functionalized with ethylene glycol groups to decorate the outer rim and thereby confine the space inside the macrocycle. This confined space is especially pronounced for n=5, which leads to an internal binding of up to 8.0×104 m-1 between the ether-decorated [5]cyclo-2,7-pyrenylene and shape-complementary crown ether-cation complexes. Both the ether-decorated [n]cyclo-pyrenylenes as well as one of their host-guest complexes have been structurally characterized by single-crystal X-ray analysis. In combination with computational methods the structural and thermodynamic reasons for the exceptionally strong binding have been elucidated. The presented rim confinement strategy makes cycloparaphenylenes an attractive supramolecular host family with a favorable, size-independent read-out signature and binding capabilities extending beyond fullerene guests.


Clinical Evaluation of Exercise-Induced Physiological Changes in Military Working Dogs (MWDs) Resulting from the Use or Non-Use of Cooling Vests during Training in Moderately Hot Environments.
Nose work with military working dogs (MWDs) in warmer-than-usual areas has led us to look for new tools to reduce both heat stress and the risk of heat stroke. One of the different strategies to manage heat stress is the use of cooling vests, such as those used in humans. The aim was to assess three cooling conditions (using two different cooling vests during exercise and the non-use of such garments) by measuring core body temperature, systemic blood pressure and pulse rate before and after the exercise (moment: four measurement times) in military dogs of the I Military Police Battalion (in Valencia, Spain). All dogs were evaluated under all three conditions during the three days of the study. Significant differences were observed between condition, moment, and the interaction of these two factors, in relation to core body temperature and pulse rate. Therefore, the use of an evaporative cooling vest may further be useful as a routine thermal control and conditioning measure in MWDs.


Efficient Nitrogen Fixation to Ammonia through Integration of Plasma Oxidation with Electrocatalytic Reduction.
Present one-step N2 fixation is impeded by tough activation of the N≡N bond and low selectivity to NH3 . Here we report fixation of N2 -to-NH3 can be decoupled to a two-step process with one problem effectively solved in each step, including: 1) facile activation of N2 to NOx - by a non-thermal plasma technique, and 2) highly selective conversion of NOx - to NH3 by electrocatalytic reduction. Importantly, this process uses air and water as low-cost raw materials for scalable ammonia production under ambient conditions. For NOx - reduction to NH3 , we present a surface boron-rich core-shell nickel boride electrocatalyst. The surface boron-rich feature is the key to boosting activity, selectivity, and stability via enhanced NOx - adsorption, and suppression of hydrogen evolution and surface Ni oxidation. A significant ammonia production of 198.3 μmol cm-2 h-1 was achieved, together with nearly 100 % Faradaic efficiency.


Autoimmune autonomic ganglionopathy: a possible postganglionic neuropathy.
To evaluate postganglionic autonomic and somatic nerve fiber involvement in a patient with chronic autoimmune autonomic ganglionopathy. Case report. Department of Neurological Sciences, University Federico II of Naples. A patient with a 16-year history of severe autonomic failure and a high nicotinic acetylcholine receptor antibody titer underwent an extensive laboratory evaluation. Evaluation of sympathetic and parasympathetic functions and sural nerve and skin biopsies. Clinical and laboratory evaluations showed the involvement of cardiovascular, pupillary, sudomotor, gastrointestinal, and bladder functions. Sudomotor function study and skin biopsy findings revealed postganglionic autonomic damage. Moreover, sural nerve and skin biopsy specimens provided clear evidence of somatic nerve fiber involvement. We demonstrated postganglionic autonomic damage that could be related to a prolonged and severe impaired synaptic transmission and we report, for the first time to our knowledge, a somatic nerve fiber involvement in autoimmune autonomic ganglionopathy.


Treatment of hepatocellular carcinoma with radiofrequency ablation: radiologic-histologic correlation during follow-up periods.
To determine whether radiographic images after radiofrequency (RF)-induced coagulation necrosis are correlated with the pathologic effects, we evaluated the morphology and histologic characteristics of RF ablation lesions over a 6-month follow-up period and compared the results with those of radiologic studies. Thirty-three hepatocellular carcinoma (HCC) tumors with a maximum diameter of 3 cm or less were treated percutaneously by using RF ablation in 26 patients. Six treated tumors were resected 4 weeks after ablation; the remaining 27 treated tumors underwent a biopsy procedure by using an 18-gauge fine needle 3 days, 4 weeks, and 24 weeks after ablation. The excised or biopsied lesions were examined by using histologic methods; the findings were then compared with those of contrast-enhanced computed tomography (CT). Three days after ablation, a core of hypoattenuation surrounded by an enhanced/hemorrhagic rim was observed on the contrast-enhanced CT images. Hematoxylin-eosin-stained specimens were inconclusive as to whether or not cellular viability remained; however, cell viability as determined by the presence of histochemical (lactate-dehydrogenase, maleate-dehydrogenase, and the reduced form of nicotinamide-adenine dinucleotide phosphate [NADPH]-diaphorase) stains was absent, suggesting 100% cellular destruction in the ablated lesion. Four and 24 weeks after ablation, the sizes of the ablated lesions were progressively smaller on the CT images; the histochemical stains remained superior to the hematoxylin-eosin stains for obtaining a definite diagnosis of cell death. We conclude that irreversible cellular destruction, as determined by the absence of positive histochemical staining patterns, was useful for evaluating the pathologic thermal effect of RF ablation. These pathologic findings can be correlated with those of contrast-enhanced CT.


Association of genetic variants of mannan-binding (MBL) lectin-2 gene, MBL levels and function in ulcerative colitis and Crohn's disease.
Ulcerative colitis and Crohn's disease are the two major forms of inflammatory bowel disease (IBD). A series of reports have hypothesized interplay of genetic and environmental factors in the pathogenesis of IBD. Polymorphism in the mannan-binding lectin-2 (MBL-2) gene is known to affect the structural assembly and function thereby predisposing subjects to various diseases. The present study was designed to evaluate effect of MBL-2 gene polymorphism on MBL levels and function in IBD patients. Genomic DNA was isolated from blood samples collected from 157 ulcerative colitis, 42 Crohn's disease and 204 control subjects. Genotyping for different polymorphic sites at exon1 of MBL-2 gene was performed by refractory mutation system-PCR and amplification followed by restriction digestion (PCR-RFLP). Serum MBL concentration and C4 deposition levels were estimated using ELISA. Mannan-binding lectin-2 genotypic variants were calculated in IBD and healthy controls. The frequency of single nucleotide polymorphisms at codon 54 was significantly higher in ulcerative colitis patients than controls (P < 0.0001). Ulcerative colitis patients with 'codon 54'-variation showed low serum MBL concentrations coupled with altered MBL function compared to controls. In conclusion, single nucleotide polymorphism in the MBL-2 gene is an important risk factor significantly affecting MBL levels and function in the development of ulcerative colitis among Indians.


What Factors Increase Odds of Long-Stay Delayed Discharge in Alternate Level of Care Patients?
The objective of this study was to determine the factors that increase the odds of long-stay delayed discharge in alternate level of care (ALC) patients using data collected from the Ontario Wait Time Information System (WTIS) database. Retrospective cohort study utilizing data from Niagara Health's WTIS database. WTIS includes individuals admitted to any of the Niagara Health sites that have been designated as ALC. Sample consisted of 16,429 ALC patients who received care in Niagara Health hospitals from September 2014 to September 2019 and were recorded in the WTIS database. ALC designation of 30 or more days was used as the threshold for a long-stay delayed discharge. This study used binary logistic regression modeling to analyze sex, age, admission source, and discharge destination as well needs/barriers requirements to assess the likelihood of a long-stay delayed discharge among acute care (AC) and post-acute care (PAC) patients given the presence of each variable. Sample sizes calculations and receiver operating characteristic curves were used to verify the validity of the regression model. Overall, 10.2% of the sample were considered long-stay ALC patients. Both AC and PAC long-stay ALC patients were more likely to be male [OR = 1.23, (1.06-1.43); OR = 1.28, (1.03-1.60)] and have a discharge destination of a long-term care bed [OR = 28.68, (22.83-36.04); OR = 6.22, (4.75-8.15)]. AC patients had bariatric [OR = 7.16, (3.45-14.83)], behavioral [OR = 1.89, (1.22-2.91)], infection (isolation) [OR = 2.31, (1.63-3.28)], and feeding [OR = 6.38, (1.82-22.30)] barriers hindering discharge. PAC patients had no significant barriers hindering patient discharge. Shifting the focus from ALC patient designation to short- vs long-stay ALC patients allowed this study to focus on the subset of patients that are disproportionately affecting delayed discharges. Understanding the importance of specialized patient requirements in addition to clinical factors can help hospitals become more prepared in preventing delayed discharges.


Prevalence and Associated Factors of SARS by Covid-19 in Adults and Aged People with Chronic Cardiovascular Disease.
The presence of Cardiovascular Disease (CVD) in individuals infected with COVID-19 may imply a worse prognosis. To describe the prevalence of Severe Acute Respiratory Syndrome (SARS) by COVID-19 and to analyze the factors associated with this condition in adults and the elderly with cardiovascular disease in Brazil until the 30th Epidemiological Week of 2020. Cross-sectional study conducted with data from the Influenza Epidemiological Surveillance Information System (Sistema de Informação de Vigilância Epidemiológica da Gripe - SIVEP-Gripe), referring to the SARS notification forms of hospitalized individuals in Brazil, between the 1st and 30th Epidemiological Week of 2020. Adults and the aged (≥ 18 years old) with CVD. The dependent variable was SRAG confirmation by COVID-19 and factors related to sociodemographic characteristics, signs and symptoms, and clinical factors were analyzed. Poisson regression with robust variance was applied. The level of significance adopted was 5%. Notifications from 116,343 individuals were analyzed. Of these, 61.9% were diagnosed with SARS by COVID-19. The prevalence of the outcome was 4% lower in women (95%CI: 0.94-0.99) and 18% lower in rural areas (95%CI: 0.77-0.87). There was a higher prevalence in the 50 to 59 age group (95%CI: 1.09-1.48) and in the northeast region (95%CI: 1.72-1.91). Fever, cough, admission to the ICU, use of ventilatory support, and nosocomial cases were also significantly associated with a higher probability of SRAS by COVID-19 in these individuals. There is a high prevalence of SARS by COVID-19 in adults and aged people with CVD in Brazil. Factors associated with sociodemographic and clinical characteristics, signs, and symptoms were associated.


Emergency research without consent under Polish law.
Although Directive 2001/20/EC of the European Parliament and of Council of 4 April 2001 on the approximation of the laws regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use does not contain an exception for emergency situations, and requires the informed consent of a legal representative in all cases where research is conducted on legally competent individuals who are unable to give informed consent, in Poland, emergency research can be conducted without consent. Polish regulations on emergency research can hardly be treated as a result of intentional legislative policy. Our provisions arise from multiple and sophisticated interpretations of different regulations that govern medical experiments on human subjects and clinical trials. These interpretations can be summarized as follows: (1) There are two categories of medical experiments: therapeutic and non-therapeutic experiments. Emergency research without consent may be conducted in the category of therapeutic experiment only (therapeutic experiment consists of the introduction by the physician of new or only partially proven diagnostic, therapeutic or preventive methods in order to achieve direct benefit to the health of the patients, and it can be carried out when hitherto applied methods were ineffective or their effectiveness was insufficient). (2). Emergency research may be conducted without consent if there is a situation of great urgency in which the research subject's life is in danger and there is no possibility of obtaining immediate consent from the research subject him or herself, or from his or her legal representative or guardianship court, and the research subject has not refused to give consent for the participation in an emergency therapeutic experiment. The legal representative or guardianship court shall be provided with all the relevant information concerning subject's participation in an experiment as soon as possible. All projects of emergency research with intent to be done without the research subject's consent must be approved by an independent bioethics committee. Because these five requirements seem to provide insufficient protection for a subject's autonomy and rights it is necessary to add to them two other conditions: (1) the emergency research could not be conducted using other research participants capable of giving informed consent; and (2) informed consent for continued participation in the emergency research shall be obtained from either the participant him or herself or the legally authorized representative as soon as possible (requirement of obtaining deferred consent). A consolidated single Act that will govern all aspects of medical experiments on human subjects, including emergency research, should be prepared and enacted as soon as possible.


Improved Fecundity and Fertility Assay for Aedes aegypti using 24 Well Tissue Culture Plates (EAgaL Plates).
Mosquitoes represent a significant public health problem as vectors of various pathogens. For those studies that require an assessment of mosquito fitness parameters, in particular egg production and hatch rates at the individual level, conventional methods have put a substantial burden on investigators due to high labor intensity and laboratory space requirements. Described is a simple method using 24 well tissue culture plate with agarose in each well and digital imaging of each well to determine egg numbers and hatch rates at an individual level with substantially reduced time and space requirements.


Identification, characterization, and lipid profiling of microalgae Scenedesmus sp. NC1, isolated from coal mine effluent with potential for biofuel production.
An autoflocculating microalgal strain was isolated from coal mine effluent wastewater which was named as Scenedesmus sp. NC1 after morphological and molecularly characterization. Further analysis of internal transcribed spacer 2 (ITS2) and compensatory base changes (CBCs) showed it does not belong to the clade comprising Scenedesmus sensu stricto. In stationary phase of growth, Scenedesmus sp. NC1 exhibited excellent autoflocculation efficiency (> 88 %) within 150 min of setting. Temperature, pH, and inorganic metals exhibited minor influence on the autoflocculation activity of Scenedesmus sp. NC1. The fatty acid profiling of Scenedesmus sp.NC1 showed that palmitic acid (C16:0), oleic acid (C18:1), and stearic acid (18:0) accounted for more than 68 % of total fatty acids. Moreover, Scenedesmus sp. NC1 demonstrated significant bioflocculation potential over non-flocculating freshwater microalgae, Chlorella sp. NCQ and Micractinium sp. NCS2. Hence, Scenedesmus sp. NC1 could be effective for economical harvesting of other non-flocculating microalgae for productions of biodiesel and other metabolites.


Nerolidol: a potential approach in rheumatoid arthritis through reduction of TNF-α, IL-1β, IL-6, NF-kB, COX-2 and antioxidant effect in CFA-induced arthritic model.
Rheumatoid arthritis is primarily associated with inflammation and increased level of proinflammatory cytokines which are released by immune cells, macrophages or activation of arachidonic acid metabolism. The expression of these cytokines, oxidative free radicals and the activation of COX-2 enzymes are crucial targets for chronic inflammation. On the basis of established anti-inflammatory efficacy of nerolidol, the primary study was further appraised to determine its approach against Freund's complete adjuvant (CFA) rheumatoid model. Arthritis was induced by inoculation of 0.1 mL CFA injection into the left hind footpad of rats. Anti-arthritic potential of nerolidol (at 200, 400 and 800 mg/kg doses) was assessed by measuring the paw volume, body weight, serum analysis, histopathological and radiographs of ankle joints. Expressions of cytokine's panels such as IL-10, IL-4, COX-2, NF-kB, TNF-α, IL-6, PGE-2 and IL-1β were determined by real-time qPCR. Antioxidant enzyme analyses were conducted by measuring the SOD, POD and catalase activity from serum and equated with arthritic control group. Nerolidol prevented body weight loss, stabilized biochemical and haematological homeostasis and significantly reduced the paw volume. Furthermore, X-ray and histopathological assessment of ankle joints showed an improvement in the joint structure of rats treated with nerolidol. Besides that, overexpression of gene pointers like TNF-α, IL-1β, IL-6, NF-kB, PGE-2 and COX-2 in CFA-treated control rats were also reversed with nerolidol. This anti-arthritic mechanism was further supported by the increased level of IL-10, IL-4 and serum antioxidant activity. The present findings demonstrate that nerolidol reduced adjuvant arthritis by downregulating the proinflammatory cytokines and upregulating the aforementioned anti-inflammatory cytokines and may be used as a therapeutic substance for the management of human rheumatoid arthritis.


In vivo immunostimulatory effect of the amoebocyte lysate and plasma of Asian horseshoe crab, Tachypleus gigas in a piscine model.
Antimicrobial proteins/peptides are becoming a new generation of immunostimulants for prevention and disease control in human and animals, including aquatic animals. As the haemolymph of horseshoe crabs (Tachypleus) contains broad ranges of bioactive compounds, we have explored the in vivo immunostimulating potential of amoebocyte lysate and plasma using a fish model. Indian major carp, Labeo rohita, yearlings were injected intraperitoneally with two doses of lysate and plasma at 50 and 100 µg protein per fish. No abnormalities and/or mortalities were recorded in any group. L. rohita injected with 50 µg lysate and 100 µg plasma protein showed significant enhancement (P < 0.01) of various haematological and immunological parameters. There was a significant rise in the total protein and globulin content, myeloperoxidase and respiratory burst activity following injection with 50 µg lysate and 100 µg plasma protein. The agglutinating and haemagglutinating activities were increased albeit not significantly (P > 0.01) in any groups. On the contrary, a significantly high hemolysin titre was recorded in fish that received 100 µg plasma protein. Following challenge with Aeromonas hydrophila, both lysate and plasma protein(s) cross protected the fish after 30 days. The highest survival (50%) was recorded in group injected with 50 µg lysate protein, followed by 45% in both 100 µg lysate and plasma protein injected groups.


Impact of epinephrine volume on further bleeding due to high-risk peptic ulcer disease in the combination therapy era.
In monotherapy studies for bleeding peptic ulcers, large volumes of epinephrine were associated with a reduction in rebleeding. However, the impact of epinephrine volume in patients treated with combination endoscopic therapy remains unclear. To assess whether epinephrine volume was associated with bleeding outcomes in individuals who also received endoscopic thermal therapy and/or clipping. Data from 132 patients with Forrest class Ia, Ib, and IIa peptic ulcers were reviewed. The primary outcome was further bleeding at 7 d; secondary outcomes included further bleeding at 30 d, need for additional therapeutic interventions, post-endoscopy blood transfusions, and 30-day mortality. Logistic and linear regression and Cox proportional hazards analyses were performed. There was no association between epinephrine volume and all primary and secondary outcomes in multivariable analyses. Increased odds for further bleeding at 7 d occurred in patients with elevated creatinine values (aOR 1.96, 95%CI 1.30-3.20; P < 0.01) or hypotension requiring vasopressors (aOR 6.34, 95%CI 1.87-25.52; P < 0.01). Both factors were also associated with all secondary outcomes. Epinephrine maintains an important role in the management of bleeding ulcers, but large volumes up to a range of 10-20 mL are not associated with improved bleeding outcomes among individuals receiving combination endoscopic therapy. Further bleeding is primarily associated with patient factors that likely cannot be overcome by increased volumes of epinephrine. However, in carefully-selected cases where ulcer location or size pose therapeutic challenges or when additional modalities are unavailable, it is conceivable that increased volumes of epinephrine may still be beneficial.


Structural genes for alpha-amylases are located on barley chromosomes 1 and 6.
Genomic DNA from six euplasmic wheat-barley addition lines and from the wheat and barley parents were analyzed for the presence of alpha-amylase gene sequences, using plasmid DNAs from two different alpha-amylase cDNA clones as hybridization probes. Barley-specific alpha-amylase gene sequences were detected only in addition lines 1 and 6 carrying barley chromosomes 1 and 6, respectively. One cDNA clone probe hybridized strongly to sequences on chromosome 6 but not to those on chromosome 1. The other cDNA clone probe preferentially hybridized to sequences on chromosome 1. It is concluded that structural genes for alpha-amylases are located on barley chromosomes 1 and 6. alpha-Amylase genes on the same chromosome appear to be closely related to one another but substantially different from those on the other chromosome.


Cervical vascular malformation as a cause of antepartum and intrapartum bleeding in three diethylstilbestrol-exposed progeny.
Adverse pregnancy outcome in diethylstilbestrol-exposed progeny has been described by many authors. These three cases demonstrate many of the features discussed in the literature as well as a previously unreported cause of antepartum and intrapartum bleeding: a cervical vascular malformation.


Physiological variation in amethyst sunbirds (Chalcomitra amethystina) over an altitudinal gradient: a seasonal comparison.
Southern Africa is characterised by an unpredictable environment with daily and seasonal temperature fluctuations, thus posing challenging thermal conditions and increased energetic stress for endothermic vertebrates. Amethyst Sunbirds (Chalcomitra amethystina) are relatively large African sunbirds (15 g). They are considered non-migratory and thus have to cope with the temperature changes and physiological stresses a new season brings. This study compared altitudinal subpopulations and the seasonal shifts in metabolic parameters between and within the subpopulations in metabolic parameters. Amethyst Sunbirds were caught in summer and winter at three different altitudinal subpopulations; Underberg (1555 m asl), Howick (1075 m asl) and Oribi Gorge (541 m asl). Upon capture, metabolic rates of the sunbirds were measured indirectly by quantifying oxygen consumption ((.)VO2) using flow through respirometry, at 5 and 25 degrees C. Birds then underwent a 6-week acclimation period at 25 degrees C on a 12 L: 12D cycle. (.)VO2 was measured post-acclimation at 8 different temperatures (15, 5, 10, 20, 30, 28, 25 and 33 degrees C), which were ordered randomly in the experimental protocol to avoid acclimation bias. Experiments were repeated for a winter and summer season. In general, Amethyst Sunbird subpopulations from Underberg and Howick showed higher post-acclimation resting metabolic rates per temperature in winter than in summer trials. Underberg and Howick subpopulations respectively showed a significant difference between summer and winter (.)VO2 at 5 and 10 degrees C. Thermal neutral zones of all of the subpopulations of sunbirds shifted between winter and summer. Post-acclimation basal metabolic rate of sunbirds decreased significantly by 38.8% from winter to summer for the Underberg subpopulation, increased by 44.8% for the Howick subpopulation and did not change significantly for the Oribi Gorge subpopulation (5.8% decrease).


Frontiers in biological psychiatry: new drug development.
This past decade has been a fertile time for new drug developments for the central nervous system. This article discusses cutting edge treatments for depression, anxiety, and psychosis. Some of these medications now are approved; many still are being researched.


Iliac branch graft in the treatment of complex aortoiliac aneurysms: early results from a North American institution.
To describe early experience with the use of iliac branch grafts (IBGs) in aortoiliac aneurysm repair. From July 2007 to August 2009 (25 months), 14 patients (13 men, one woman) with a mean age of 70.1 years (range, 59.3-80.0 y) were treated with IBGs. Indications were abdominal aneurysm with common iliac artery (CIA) involvement (n = 11), juxtarenal aortic aneurysm with CIA involvement (n = 1), and bilateral CIA and internal iliac artery (IIA) aneurysms (n = 1). Postoperative endoleaks and patency rate were determined with computed tomography within 1 month of implantation and 1 year thereafter, with concurrent clinical evaluation for pelvic ischemia. Mean follow-up period was 18.7 months (range, 6-35 mo). Technical success rate, as defined by successful implantation of IBG with no intraprocedural type I or type III endoleak, was 86% (12 of 14). A total of 14 IBGs were successfully deployed in 12 patients. Two cases of technical failure were related to excessive iliac tortuosity. The mean hospitalization duration was 6.5 days (range, 3-14 d), with zero mortality at 30 days. There were two cases of type II endoleak treated conservatively and a single case of IBG-related type III endoleak that required repeat intervention. The rest of the stent-implanted aortic and iliac aneurysms remained stable in size, with no aneurysm rupture or death recorded. All stent-implanted iliac branches remained patent on follow-up. None of the patients who received IBGs had new symptoms of pelvic ischemia. Iliac branch graft placement is a feasible technique with excellent short-term results in the treatment of aortoiliac aneurysms.


Diagnosis of hepatitis E.
Hepatitis E, caused by infection with hepatitis E virus (HEV), is a common cause of enterically-transmitted acute hepatitis in developing countries. Occasional cases of sporadic hepatitis E have been increasingly recognized in developed countries over the past decade. These cases differ from those in developing countries in being possibly caused by zoonotic transmission, often affecting people with a suppressed immune system and occasionally leading to persistent HEV infection. The commonly used tests for HEV infection include detection of IgM and IgG anti-HEV antibodies and detection of HEV RNA. IgM anti-HEV antibodies can be detected during the first few months after HEV infection, whereas IgG anti-HEV antibodies represent either recent or remote exposure. The presence of HEV RNA indicates current infection, whether acute or chronic. Although several diagnostic assays for anti-HEV antibodies are available, they have undergone fairly limited testing and often provide discordant results, particularly for IgG antibodies. Thus, although the available antibody assays might be useful for case diagnosis in areas with high disease endemicity, their use for case diagnosis in areas with low endemicity and for seroprevalence studies remains problematic. Improved validation of existing anti-HEV antibody assays or development of new assays with superior performance characteristics is urgently needed.


Resolution of Behçet's syndrome associated pulmonary arterial aneurysms with infliximab.
We describe the successful treatment of pulmonary arterial aneurysms in Behçet's syndrome using a tumor necrosis factor (TNF) inhibitor. A case is reported of Behçet's syndrome complicated by pulmonary arterial aneurysms that responded to anti-TNF therapy. This is accompanied by a literature review of previously published cases. We searched the English language medical literature using the PubMed and Medline search terms: "Behçet's," "Pulmonary aneurysms," and "infliximab," "etanercept," or "adalimumab." A 43-year-old man with a 6-month history of oral and genital ulcers, weight loss, and fatigue developed arterial aneurysms in the common carotid and common iliac arteries and thromboses in a femoral vein and pulmonary arteries. Treatment with high-dose oral corticosteroids and pulsed intravenous cyclophosphamide was initiated but while on treatment he developed pulmonary arterial aneurysms with hemoptysis. His treatment was changed to intravenous infliximab with methotrexate to which he showed a good response with marked clinical improvement, reduction in his inflammatory markers, and regression of the pulmonary arterial aneurysms. The review of the literature identified 3 reported cases of treatment of pulmonary arterial aneurysms in Behçet's syndrome with anti-TNF therapy, with good outcomes in each case. Pulmonary artery aneurysms are important complications of Behçet's syndrome. Anti-TNF inhibitors should be considered in patients who do not respond to treatment with corticosteroids and cyclophosphamide.


Assays for mechanistic investigations of protein/histone acetyltransferases.
Protein/histone acetyltransferases (PATs/HATs) have been implicated in a number of cellular functions including gene regulation, DNA synthesis, and repair. This paper reviews methods that can be used to quantitatively determine the activity and ultimately the catalytic/kinetic mechanism of PAT/HATs in vitro. Two methods will be described in detail. The first method is a filter-binding assay that measures the transfer of radiolabeled acetate from acetyl-CoA to protein. The second method is a continuous, spectroscopic, enzyme-coupled assay that links the PAT/HAT reaction to the reduction of NAD+ by pyruvate or alpha-ketoglutarate dehydrogenase. Both methods are highly applicable in determining steady-state reaction rates, and obtaining the kinetic constants Vmax, Km, and V/K from substrate saturation curves. We describe a new application of the filter-binding assay to determine the kinetic parameters for HATs using low concentrations of nucleosomal substrates.


Lyn and Fgr are activated in distinct membrane fractions of human granulocytic cells.
We have previously shown that the src-family protein-tyrosine kinase Hck is localized on the azurophil granules of human granulocytes, translocates towards the phagosomes during phagocytosis of opsonized zymosan and is activated during this process. Hck is also activated upon cell stimulation with the calcium ionophore A23187, but not with PMA or the chemotactic peptide fMLP. Here, we investigated whether the src-family kinases Lyn and Fgr are activated under the same conditions. Upon stimulation of human neutrophils or retinoic acid-differentiated NB4 cells with fMLP, only Lyn is activated. Cell stimulation with opsonized zymosan or A23187 leads to simultaneous activation of Lyn and Fgr. In cell fractionation experiments with differentiated NB4 cells, the kinases show a similar subcellular localization: Both co-fractionate quantitatively with plasma-membrane marker in two fractions that sediment at 11000 g and 200000 g. Lyn is selectively activated in the 200000 g fraction, whereas Fgr is activated in the 11000 g fraction and distinct sets of tyrosine phosphorylated proteins are found in these fractions. The results suggest that these kinases exert their functional roles in distinct cellular compartments in human granulocytic cells.


Genotoxic properties of Betonica officinalis, Gratiola officinalis, Vincetoxicum luteum and Vincetoxicum hirundinaria extracts.
Genotoxicity of B. officinalis, G. officinalis, V. luteum and V. hirundinaria extracts, which demonstrated strong antioxidant capacity, was tested using chromosome aberration, sister chromatid exchange (SCE), cytokinesis-block micronucleus and alkaline single-cell gel electrophoresis (comet) assays in human lymphocytes in vitro and Ames Salmonella/microsome test. All tested extracts were not mutagenic in S. typhimurium strains TA98 and TA100 with and without metabolic activation and did not induce chromosome aberrations in human lymphocytes in vitro. Extract from G. officinalis was the only one, which induced significant increase in micronuclei, indicating possible aneugenic effect. All investigated plant extracts induced DNA damage evaluated by the comet assay, while B. officinalis and V. luteum extracts induced slight increase in SCE values. The determined variation in response might be due to the plant extract tested and donor susceptibility.


Regulation of Bcl-2 and Bcl-xL anti-apoptotic protein expression by nuclear receptor PXR in primary cultures of human and rat hepatocytes.
The pregnane X receptor (PXR) plays a major role in the protection of the body by regulating the genes involved in the metabolism and elimination of potentially toxic xeno- and endobiotics. We previously described that PXR activator dexamethasone protects hepatocytes from spontaneous apoptosis. We hypothesise a PXR-dependent co-regulation process between detoxication and programmed cell death. Using primary cultured human and rat hepatocytes, we investigated to determine if PXR is implicated in the regulation of Bcl-2 and Bcl-xL, two crucial apoptosis inhibitors. In the present study we demonstrated that the treatment of primary cultured hepatocytes with PXR agonists increased hepatocyte viability and protects them from staurosporine-induced apoptosis. The anti-apoptotic capacity of PXR activation was correlated with Bcl-2 and Bcl-xL induction at both the transcriptional and protein levels in man and rats, respectively. The inhibition of PXR expression by antisense oligonucleotide abolished PXR activators Bcl-xL induction. Accordingly, PXR overexpression in HepG2 cells led to bcl-2 induction upon clotrimazole treatment and protects cells against Fas-induced apoptosis. Our results demonstrate that PXR expression is required for Bcl-2 and Bcl-xL up-regulation upon PXR activators treatment in human and rat hepatocytes. They also suggest that PXR may protect the liver against chemicals by simultaneously regulating detoxication and the apoptotic pathway.


Understanding systemic disruption from the Covid-19-induced semiconductor shortage for the auto industry.
Covid-19 has allowed us to study systemic disruptions that impact entire industries. This paper explores how disruptions start, propagate, and continue over time by examining the semiconductor chip shortage faced by the auto industry during the years following Covid-19 in 2020. First, we carried out a thematic analysis of 209 pertinent newspaper articles. The analysis resulted in a thematic model of such disruptions with the interplay of various factors leading to the prolonged disruption to the auto sector. Second, we present the results from a stylized supply chain planning model run at different times to show how disruptions propagate to the auto and other sectors, causing systemic shortages. Overall, we contribute to the supply chain risk literature by focusing on system disruptions impacting entire industries versus normal disruptions affecting a particular company's supply chain.


Web-based video and feedback in the teaching of cardiopulmonary resuscitation.
Knowledge and skills relating to cardiopulmonary resuscitation tend to be lost over time. The combination of simulation sessions with online video records and online feedback allows for an enduring record of skills sessions to assist students in retaining and revising their learning. This paper reports a qualitative evaluation of such a combination used in inter-disciplinary sessions for volunteer nursing and medical students. Methods included focus groups and free text questionnaires; data were gathered from fourteen students and three teachers. Students had used the online material in a variety of personal ways, and found that the addition to their learning was significant. Their memories of the simulation sessions and of the feedback received immediately afterwards were incomplete, and repeated viewing enabled them to identify good and poor practice with more confidence, and to reflect more carefully on their own and others' practice. Teachers found it easier to give more detailed feedback when given the chance to watch the video than immediately after the session. All felt that the sessions would ideally be embedded in the curriculum.


Laparoscopic management of complicated urachal remnants.
To report our experience with a laparoscopic approach to managing symptomatic urachal anomalies. Five patients (median age 19 years, range 2-43) had a laparoscopic excision of a complicated urachal remnant between 2001 and 2004. Three ports were routinely used, although their positioning varied as our technique developed with experience. The urachal remnant was dissected from the umbilicus to the bladder dome and then removed intact. All five operations had no serious immediate complications and minimal blood loss. One patient developed a small peri-umbilical haematoma after surgery and another had a persistent umbilical discharge at follow-up, and required open excision of residual remnant tissue. The laparoscopic approach appears to be a safe and effective alternative to open surgery for this condition. Despite the slight risk of incomplete excision, the reduced morbidity of this procedure and better cosmetic result would appear advantageous.


Secretory production of spider silk proteins in metabolically engineered Corynebacterium glutamicum for spinning into tough fibers.
Spider dragline silk is a remarkable fiber made of unique proteins-spidroins-secreted and stored as a concentrated aqueous dope in the major ampullate gland of spiders. This feat has inspired engineering of microbes to secrete spidroins for spinning into tough synthetic fibers, which remains a challenge due to the aggregation-prone feature of the spidroins and low secretory capacity of the expression hosts. Here we report metabolic engineering of Corynebacterium glutamicum to efficiently secrete recombinant spidroins. Using a model spidroin MaSpI16 composed of 16 consensus repeats of the major ampullate spidroin 1 of spider Trichonephila clavipes, we first identified the general Sec protein export pathway for its secretion via N-terminal fusion of a translocation signal peptide. Next we improved the spidroin secretion levels by selection of more suitable signal peptides, multiplexed engineering of the bacterial host, and by high cell density cultivation of the resultant recombinant strains. The high abundance (>65.8%) and titer (554.7 mg L-1) of MaSpI16 in the culture medium facilitated facile, chromatography-free recovery of the spidroin with a purity of 93.0%. The high solubility of the purified spidroin enabled preparation of highly concentrated aqueous dope (up to 66%) amenable for spinning into synthetic fibers with an appreciable toughness of 70.0 MJ m-3. The above metabolic and processing strategies were also found applicable for secretory production of the higher molecular weight spidroin MaSpI64 (64 consensus repeats) to yield similarly tough fibers. These results suggest the good potential of secretory production of protein polymers for sustainable supply of fibrous materials.


The effects of controlled release urea on maize productivity and reactive nitrogen losses: A meta-analysis.
Application of controlled release urea (CRU) is recommended to reduce the undesirable environmental effects resulting from urea application. However, the overall effects of CRU on maize productivity and reactive nitrogen (N) losses remain unclear. Our global meta-analysis based on 866 observations of 120 studies indicated that application of CRU instead of urea (same N rate) increased maize yield by 5.3% and nitrogen use efficiency (NUE) by 24.1%, and significantly decreased nitrous oxide (N2O) emission, N leaching and ammonia (NH3) volatilization by 23.8%, 27.1% and 39.4%, respectively. The increase of NUE and reduction of N2O emission by CRU application were greater with medium and high N rates (150 ≤ N < 200 and N ≥ 200 kg N ha-1) than with low N rates. The reduction in N2O emission and N leaching with CRU application were enhanced when soil organic carbon (SOC) content was <15.0 g kg-1, and soil texture was medium or coarse. The reduction in N2O emission and NH3 volatilization with CRU were greater in soils with pH ≥ 6.0. We concluded that use of CRU should be encouraged for maize production, especially on light-textured soils with low organic matter content.


Implications for Systemic Approaches to COVID-19: Effect Sizes of Remdesivir, Tocilizumab, Melatonin, Vitamin D3, and Meditation.
COVID-19 poses a chronic threat to inflammatory systems, reinforcing the need for efficient anti-inflammatory strategies. The purpose of this review and analysis was to determine the efficacy of various interventions upon the inflammatory markers most affected by COVID-19. The focus was on the markers associated with COVID-19, not the etiology of the virus itself. Based on 27 reviewed papers, information was extracted on the effects of COVID-19 upon inflammatory markers, then the effects of standard treatments (Remdesivir, Tocilizumab) and adjunctive interventions (vitamin D3, melatonin, and meditation) were extracted for those markers. These data were used to approximate effect sizes for the disease or interventions via standardized mean differences (SMD). The data that were available indicated that adjunctive interventions affected 68.4% of the inflammatory markers impacted by COVID-19, while standard pharmaceutical medication affected 26.3%. Nonstandard adjunctive care appeared to have comparable or superior effects in comparison to Remdesivir and Tocilizumab on the inflammatory markers most impacted by COVID-19. Alongside standards of care, melatonin, vitamin D3, and meditation should be considered for treatment of SARS-COV-2 infection and COVID-19 disease.


MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells.
Chemotherapy with anti PD-1/PD-L1 antibodies has become the standard of care for patients with metastatic non-small cell lung cancer (mNSCLC). Using lung tumor models, where pemetrexed and cisplatin (PEM/CDDP) chemotherapy remains unable to synergize with immune checkpoint inhibitors (ICIs), we linked the failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, sensitizing it to ICIs. PEM/CDDP plus a MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA- and TLR9-dependent manner. TLR9 or autophagy/mitophagy inhibition abolishes the anti-tumor efficacy of PEM/CDDP plus MEKi/anti-PD-L1 therapy. In human NSCLCs, high OPTN, TLR9, and CXCL10 expression is associated with a better response to ICIs. Our results underline the role of TLR9- and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.


Visualisation of Range Shortening in Carbon Ion Beams and Washout of Positron Emitter: First-in-Human Report.
Auto-activation positron emission tomography (AAPET) is one of the most promising methods to verify beam range in carbon ion radiotherapy (C-ion RT). We aimed to confirm this for the first time in a clinical setting by performing AAPET in a patient with pancreatic cancer previously receiving coil embolisation of hepatic artery pseudoaneurysm. A 70-year-old pancreatic head cancer patient was treated with C-ion RT on a clinical dose of 4.6 Gy (RBE), followed by AAPET, to verify beam ranges in C-ion RT. Positron emission tomography (PET) revealed low positron emitter concentrations at the distal side of the internal metals and in the aorta compared to the dose distribution of the treatment plan, indicating range shortening by internal metals in C-ion beams and positron emitter transportation by biofluids. AAPET may detect range shortening by internal metals in the trajectory and washout of intravascular positron emitter compared to plan dose distribution.


The word frequency effect in first- and second-language word recognition: a lexical entrenchment account.
We investigate the origin of differences in the word frequency effect between native speakers and second-language speakers. In a large-scale analysis of English word identification times we find that group-level differences are fully accounted for by the individual language proficiency scores. Furthermore, exactly the same quantitative relation between word frequency and proficiency is found for monolinguals and three different bilingual populations (Dutch-English, French-English, and German-English). We conclude that the larger frequency effects for second-language processing than for native-language processing can be explained by within-language characteristics and thus need not be the consequence of "being bilingual" (i.e., a qualitative difference). More specifically, we argue that language proficiency increases lexical entrenchment, which leads to a reduced frequency effect, irrespective of bilingualism, language dominance, and language similarity.


Pretreatment of extruded Napier grass byhydrothermal process with dilute sulfuric acid and fermentation using a cellulose-hydrolyzing and xylose-assimilating yeast for ethanol production.
One of the potential bioresources for bioethanol production is Napier grass, considering its high cellulose and hemicellulose content. However, the cost of pretreatment hinders the bioethanol produced from being economical. This study examines the effect of hydrothermal process with dilute acid on extruded Napier grass, followed by enzymatic saccharification prior to simultaneous saccharification and co-fermentation (SScF). Extrusion facilitated lignin removal by 30.2 % prior to dilute acid steam explosion. Optimum pretreatment condition was obtained by using 3% sulfuric acid, and 30-min retention time of steam explosion at 190 °C. Ethanol yield of 0.26 g ethanol/g biomass (60.5% fermentation efficiency) was attained by short-term liquefaction and fermentation using a cellulose-hydrolyzing and xylose-assimilating Saccharomyces cerevisiae NBRC1440/B-EC3-X ΔPHO13, despite the presence of inhibitors. This proposed method not only reduced over-degradation of cellulose and hemicellulose, but also eliminated detoxification process and reduced cellulase loading.


Insulin-like growth factors in patients with liver cysts.
Insulin-like growth factors (IGFs) play an important role in cell growth and differentiation, and the liver is the main source of IGFs and IGF-binding proteins (IGFBPs) that appear in the circulation. The effect of liver cysts on the circulating IGF system was studied in this work. Serum concentrations of IGF-I and -II were measured by radioimmunoassay, IGFBP patterns were characterised by ligand-affinity and immunoblotting, and a lectin-binding assay was used to investigate the glyco component of IGFBP-3 complexes. IGF-I and -II concentrations in patients with cysts were significantly lower compared to those in healthy individuals (P<0.0001 and P<0.01, respectively), and the decrease was related to age but not sex. The overall mean concentrations of IGF-I and -II were not significantly different whether the cysts were caused by Echinococcus granulosus, cross-reactive pathologies, or some other factor. IGFBP profiles correlated with the amount of IGF present: patients with lower IGF-I concentrations expressed decreased IGFBP-3 and elevated IGFBP-2 levels. Increased IGFBP-3 proteolytic activity in the patients' blood was not detected by immunoblotting. In the lectin-binding assay, IGFBP-3 complexes in the circulation of patients demonstrated reactivity similar to that in healthy persons, suggesting that the overall structure of the saccharide moieties of the IGFBP-3 complexes was not significantly altered due to liver cyst formation.


Cosecretion of peptide histidine methionine (PHM) and vasoactive intestinal peptide (VIP) in patients with VIP-producing tumors.
Regional specific antibodies and chromatography were used to analyze the concentration and molecular forms of vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in plasma from 39 patients with VIP-producing tumors. Plasma VIP concentrations ranged from 29 to 2550 pmol/l and the corresponding PHM immunoreactive values measured with C-terminally directed antibody were 42 to 2100 pmol/l which correlated closely with the VIP concentrations. N-terminal PHM concentrations were significantly higher than the C-terminal values ranging from 92 to 5850 pmol/l and correlated poorly with the corresponding VIP concentrations. Infusion experiments with PHM disclosed that the higher levels of N-terminal immunoreactivity could not be explained by slower metabolic clearance or by degradation to smaller N-terminal immunoreactive forms. N-terminally directed PHM antibody revealed, in addition to intact PHM, a larger immunoreactive form in patient plasma which constituted the major proportion of the total immunoreactivity. In conclusion, VIP and PHM are cosecreted from VIPomas and measurement of PHM, especially N-terminal immunoreactivity, may be useful in this condition.


Performance characteristics of the Duopath® cereus enterotoxins assay for rapid detection of enterotoxinogenic Bacillus cereus strains.
The Duopath® Cereus Enterotoxins test (Merck KGaA) is a newly developed gold-labeled lateral flow immunoassay for the detection of Bacillus cereus enterotoxins. The test uses monoclonal antibodies (MAbs) against the L(2) component of hemolysin BL (Hbl) and NheB of the non-hemolytic enterotoxin (Nhe), respectively. The inclusivity and exclusivity of the assay was tested using 44 B. cereus, B. cereus group and Bacillus spp. strains. Apart from the B. mycoides type strain the results were in full agreement with those obtained by other immunological and molecular biological methods. The detection limit of the assay was 6ng/ml for NheB and 20ng/ml for the Hbl-L(2)-component, respectively. Using artificially and naturally contaminated food samples (n=76) the assay was positive after 18-24h enrichment if at least 10(2) enterotoxin producing B. cereus/g were present. After 30h enrichment samples contaminated with as low as 1 enterotoxin producing B. cereus/g gave positive results. In addition, testing of suspected colonies for enterotoxin production is possible. The assay is easy to perform and results can be clearly read without instrumentation.


[Maxillary tumor revealing primary hyperparathyroidism].
Primary hyperparathyroidism can infrequently present as a giant cell tumor of the jaw. We report the case of a patient presenting with a giant cell tumor leading to the discovery of a parathyroid adenoma. A 70-year-old male patient consulted for a stiffly swollen right jaw. The radiological assessment revealed osteolytic lesions of the right maxilla. The calcium and phosphate levels were disrupted and the parathyroid hormone level was high. A neck ultrasonography revealed a parathyroid adenoma. The patient underwent excision of the maxillary mass and of the parathyroid adenoma; the outcome was marked by normalization of calcium and phosphate levels. Giant cell tumors unusually reveal primary hyperparathyroidism and their maxillary location is exceptionally rare. The diagnosis is made on parathyroid hormone level and imaging. The treatment is surgical.


Lymph node dissections in cutaneous malignancy: Where are we now? A review of 10 years' experience at a tertiary centre.
The surgical management of cutaneous malignancies has evolved over recent years with the introduction of novel medical therapies and an increasing emphasis upon early adjuvant systemic therapy. As such, completion lymph node dissection (cLND) is now no longer recommended following a positive sentinel lymph node biopsy (SLNB) in melanoma. We evaluated our ten-year practice at a regional tertiary centre, assessing the change in lymph node dissection (LND) caseload volume, anatomical distribution, and indication for the procedure. A retrospective search was carried out of all LNDs performed by the Plastic Surgery department at Cambridge University Hospitals NHS Trust, UK from 1 January 2010 to 31 December 2019. Case notes were retrospectively analysed for each procedure, with the site and pathology recorded. A total of 491 LNDs were performed over the 10-year period. Surgical volume peaked in 2015 with 67 cases, followed by a decline to 41 cases in 2019. The number of neck dissections increased over the decade, as well as the proportion of cases due to macroscopic nodal disease. We sub-analysed the number of LNDs in three contiguous 18-month intervals, corresponding to changes in practice due to evidence from the DeCOG and MSLT-II Trials. We found a 41.67% reduction in LNDs caseload between July 2018-Dec 2019, compared to a similar period prior to trial evidence (July 2015-Dec 2016) (p=0.0.14). In summary, the surgical volume of LNDs has decreased significantly since 2018, reflecting emerging evidence and changes to national guidelines. This will require ongoing monitoring for workforce planning and surgical training.


A DNA damage-induced phosphorylation circuit enhances Mec1ATR Ddc2ATRIP recruitment to Replication Protein A.
The cell cycle checkpoint kinase Mec1ATR and its integral partner Ddc2ATRIP are vital for the DNA damage and replication stress response. Mec1-Ddc2 "senses" single-stranded DNA (ssDNA) by being recruited to the ssDNA binding Replication Protein A (RPA) via Ddc2. In this study, we show that a DNA damage-induced phosphorylation circuit modulates checkpoint recruitment and function. We demonstrate that Ddc2-RPA interactions modulate the association between RPA and ssDNA and that Rfa1-phosphorylation aids in the further recruitment of Mec1-Ddc2. We also uncover an underappreciated role for Ddc2 phosphorylation that enhances its recruitment to RPA-ssDNA that is important for the DNA damage checkpoint in yeast. The crystal structure of a phosphorylated Ddc2 peptide in complex with its RPA interaction domain provides molecular details of how checkpoint recruitment is enhanced, which involves Zn2+. Using electron microscopy and structural modeling approaches, we propose that Mec1-Ddc2 complexes can form higher order assemblies with RPA when Ddc2 is phosphorylated. Together, our results provide insight into Mec1 recruitment and suggest that formation of supramolecular complexes of RPA and Mec1-Ddc2, modulated by phosphorylation, would allow for rapid clustering of damage foci to promote checkpoint signaling.


Fetal and uteroplacental blood flow in prolonged pregnancies. A clinical study.
In a prospective study during 1 year, 102 women with prolonged pregnancies (more than 294 completed gestational days) were followed with serial pulsed Doppler blood flow examinations every 2nd day, either to spontaneous onset of labor (n = 82) or to induction of labor due to subsequently occurring complications (n = 20). Mean aortic blood velocity did not change significantly with gestational age beyond 294 days either in fetuses with normal outcome or in fetuses that developed asphyxia at birth. The flow velocity waveforms in the descending aorta, the umbilical artery, the common carotid artery and the uterine artery did not change significantly compared to the values at term. Abnormal flow velocity waveforms in the fetal descending aorta, umbilical artery or uterine artery had no significant relationship to fetal asphyxia. Absence of diastolic flow velocities was not found in any of the vessels examined, indicating that the fetuses did not suffer from chronic hypoxia in utero and that aging of the placenta did not alter fetal and uteroplacental blood flow. Notching of the aortic flow velocity waveform was a common finding among prolonged pregnancies. The hemodynamic implications and consequences of this phenomenon are discussed.


Rainfall and temperature change drive Arnica montana population dynamics at the Northern distribution edge.
Plant species of semi-natural grasslands are threatened by several simultaneous global change drivers, most notably land-use and climate change. In this study, we explore spatiotemporal variation and changes in deterministic (λ) and stochastic population growth rates (λs), and the underlying vital rates of eight populations of Arnica montana at the species' north-western range margin in Norway. We assess to what extent variation in the demographic rates could be attributed to environmental correlates of the key global change drivers likely to operate at the range edge, including population size, surrogates of habitat quality, temperature and precipitation. We found no relationship between λ and population size or habitat quality, but λ declined in response to both increasing precipitation and increasing temperature. Life-table response experiments revealed that the temporal variability was driven by survival and clonality, whereas the spatial variation was driven by clonality. Our results suggest that A. montana has a threshold response to increasing precipitation, likely due to adaptations to local climatic conditions. Growth and flowering were both negatively affected by increasing temperature, but these effects had a low influence on the spatiotemporal variability in λ. In contrast, the stochastic growth rate was negatively influenced by climate change, indicating an increased extinction risk for marginal populations, possibly leading to range contraction of A. montana as climate change proceeds. Altogether, our study illustrates how the fates of peripheral populations, which are critically important in species range dynamics, may be affected by both deterministic and stochastic effects of multiple coinciding global change drivers.


Magnetic Anomalies over a Young Oceanic Ridge off Vancouver Island.
The recent speculation that the magnetic anomalies observed over oceanic ridges might be explained in terms of ocean-floor spreading and periodic reversals of the earth's magnetic field may now be reexamined in the light of suggested reversals during the past 4 million years and the newly described Juan de Fuca Ridge.


Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes.
Ischemic post-conditioning (iPoCo) by coronary re-occlusion/reperfusion during immediate reperfusion after prolonged myocardial ischemia reduces infarct size. Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo's cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3's impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200-380 g), buffer-perfused and subjected to 30 min/120 min global zero-flow ischemia/reperfusion (I/R). In additional hearts, either iPoCo (2 × 30 s/30 s I/R) was performed or T3 (100-500 µg/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16 ± 7% vs. 36 ± 4% with I/R only. The maximum infarct size reduction was observed with 300 µg/L T3 (14 ± 2%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3's cardioprotection (35 ± 10%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30 min/5 min hypoxia/reoxygenation (H/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500 µg/L T3 after H/R (27 ± 4% of all cells vs. 5 ± 3% in time-matched controls). Again, RISK-BL abrogated protection (11 ± 3%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300 µg/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3's protection is a cardiomyocyte phenomenon and targets mitochondria.


Mechanisms of lead biosorption on cellulose/chitin beads.
Environment-friendly cellulose/chitin beads being prepared by coagulating a blend of cellulose and chitin in 6 wt% NaOH/5 wt% thiourea aqueous solution with 5% H2SO4 possessed higher heavy metals uptake capacity than pure chitin flakes. The mechanisms of Pb2+ adsorption on cellulose/chitin beads at pH0=5 were investigated at the molecular levels by scanning electron micrographs (SEM), transmission electron micrographs (TEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction (XRD). The result revealed that mechanisms for the adsorption of Pb2+ on the cellulose/chitin beads could be described as complexation between Pb2+ and N atom in the chitin, and further adsorption of Pb2+ nearby the complexed Pb2+ and precipitation of the hydrolysis product of the Pb2+ complex on the beads as the crystalline state. Furthermore, structural factors such as larger surface area of the beads resulted from microporous-network structure, low crystallinity of cellulose/chitin beads and high hydrophilicity induced by hydrophilic skeleton of cellulose played an important role in increasing adsorption ability.


Colorectal cancer in familial polyposis coli and ulcerative colitis.
The records of all patients with familial polyposis coli and ulcerative colitis operated at The Mount Sinai Hospital were reviewed to determine the proportion of patients with cancer at the time of colon resection. Sixty-nine patients with familial polyposis coli undergoing operation between 1947 and 1983 were identified and 25 (36 percent) were found to have cancer. In the group with ulcerative colitis, 548 patients had surgical treatment between 1957 and 1983 and 65 (12 percent) had colonic cancer. There was a significant decrease in the proportion of patients with familial polyposis coli having cancer at the time of colon resection from 50 percent before 1968 to 20 percent since 1978. This change in cancer incidence was found to correlate with a decrease in the mean age at operation from 40 to 25 years. In the group with ulcerative colitis, the mean age at operation has remained essentially unchanged at 36 years. The proportion of patients with ulcerative colitis having cancer at the time of colon resection has remained constant throughout this study. Progression to carcinoma is still a significant concern in both familial polyposis coli and ulcerative colitis. Although removal of the colon and rectum prevents cancer development, patient selection and timing of the operation remain a difficult problem.


Modified enhanced recovery after surgery protocol in patients with acute cholecystitis: efficacy, safety and feasibility. Multicenter randomized control study.
Laparoscopic cholecystectomy (LC) is a common surgical procedure in acute cholecystitis (AC). Patients often suffer from considerable postoperative pain and indigestion, which prolongs in-hospital stay. The enhanced recovery after surgery (ERAS) program has proven its efficacy in elective surgery and could hypothetically improve outcomes of emergency LC. Currently, there is no ERAS program for LC in patients with AC. A modified ERAS (mERAS) protocol was studied in a prospective, randomized non-blinded clinical trial (NCT03754751). The mERAS group consisted of 88 patients the control group of 101 patients. The modified protocol included a patient information brochure; minimizing drain use; local anesthesia; low-pressure pneumoperitoneum; PONV prophylaxis, early mobilization and oral diet. The primary outcome was postoperative length of stay (pLOS). The postoperative length of stay in the mERAS group was shorter (24 (21-45.5) h) than in the control (45 (41-68) h) (p < 0.0001). One re-admission in the mERAS group was reported (p = 0.466). There difference in complications was insignificant (mERAS 6.8% vs 5% p = 0.757). Post-operative pain intensity was significantly lower in the mERAS group immediately after awaking (3.7 ± 1.8 vs 5.4 ± 1.3 p < 0.0001), 2 h (3.3 ± 1.7 vs 4.9 ± 1.6 p = 0.0006), 6 h (2.9 ± 1.5 vs 4.2 ± 1.2 p < 0.0001), 12 h (2.7 ± 0.9 vs 4.1 ± 1.2 p = 0.0001) and 24 h after surgery (2.1 ± 1.2 vs 3 ± 1.2 p < 0.0001). The incidence of shoulder and neck pain was lower in mERAS group (13.6% vs 34.7% p = 0.0009). Peristalsis recovery was similar in both groups. The proposed protocol improved postoperative recovery and reduced hospital stay in patients with AC without increasing the rate of complications or re-admissions.


Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly.
Cytochrome c oxidase (COX) assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia, and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here, we show that loss of COA7 blocks complex IV assembly after the initial step where the COX1 module is built, progression from which requires the incorporation of copper and addition of the COX2 and COX3 modules. The crystal structure of COA7, determined to 2.4 Å resolution, reveals a banana-shaped molecule composed of five helix-turn-helix (α/α) repeats, tethered by disulfide bonds. COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and catalyzes the reduction of disulfide bonds within these proteins, which are crucial for copper relay to COX2. COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. We therefore propose that COA7 is a heme-binding disulfide reductase for regenerating the copper relay system that underpins complex IV assembly.


The yield of tuberculosis contact investigation in low- and middle-income settings: a systematic review and meta-analysis.
Contact investigation, the systematic evaluation of individuals in close contact with an infectious tuberculosis (TB) patient, is a key active case-finding strategy for global TB control. Better estimates of the yield of contact investigation can guide strategies to reduce the number of underreported and underdiagnosed TB cases, approximately three million cases per year globally. A systematic review (Prospero ID # CRD42019133380) and meta-analysis was conducted to update and enhance the estimates of the yield of TB contact investigation in low- and middle-income countries (LMIC). Pubmed, Web of Science, Embase and the WHO Global Index Medicus were searched for peer-reviewed studies (published between January 2006-April 2019); studies reporting the number of active TB or latent tuberculosis infection (LTBI) found through contact investigation were included. Pooled data were meta-analyzed using a random effects model and risk of bias was assessed. Of 1,644 unique citations obtained from database searches, 110 studies met eligibility criteria for descriptive data synthesis and 95 for meta-analysis. The pooled yields of contact investigation activities for different outcomes were: secondary cases of all active TB (defined as those bacteriologically confirmed or clinically diagnosed) 2.87% (2.61-3.14, I2 97.79%), bacteriologically confirmed active TB 2.04% (1.77-2.31, I2 98.06%), and LTBI 43.83% (38.11-49.55, I2 99.36%). Yields are interpreted as the percent of contacts screened who are diagnosed with active TB as a result of TB contact investigation activities. Pooled estimates were substantially heterogenous (I2 ≥ 75%). This study provides methodologically rigorous and up-to-date estimates for the yield of TB contact investigation activities in low- and middle-income countries (LMIC). While the data are heterogenous, these findings can inform strategic and programmatic planning for scale up of TB contact investigation activities.