Calorie restriction, stress and the ubiquitin-dependent pathway in mouse livers.
Calorie restriction (R) is the only known method to delay the aging process and extend mean and maximal lifespan in rodents. R has been shown to delay the age-related accumulation of damaged proteins and to protect organisms from various stresses which can produce damaged proteins. Such stresses include irradiation, heat shock, and oxidative stress. The ubiquitin- and ATP-dependent proteolytic pathway (UPP) has been associated with the degradation of abnormal and/or damaged proteins. We examined the effect of diet and oxidative stress on activities of the UPP in supernatants from livers taken from 23-month-old Emory mice which had been exposed to an in-vivo injection of paraquat. Paraquat induces oxidative stress by generating superoxide radicals. In livers from non-stressed animals, steady-state levels of endogenous ubiquitin conjugates, de novo conjugate formation, and E1 and E2 activities were significantly lower in R animals than in control (C) animals. However, after exposure to paraquat, levels of endogenous ubiquitin conjugates were significantly higher in R versus C animals, and de novo conjugate formation and E1 and E2 activities in R animals rose to levels which were indistinguishable from levels of these activities noted in C animals. R was associated with an increased ability to degrade beta-lactoglobulin by the UPP after an oxidative stress was imposed. Ability to degrade beta-lactoglobulin by the C or R livers in non-stressed animals was not significantly different. Taken together, these data indicate that oxidative stress in R animals is associated with enhanced levels of ubiquitin conjugates and that this enhancement may be due to an increase in UPP activity. These data also indicate that the ability to form ubiquitin conjugates and the UPP system does not change with oxidative stress in C animals. The latter is consistent with prior reports that suggests that older C animals may already be in a state of enhanced oxidative stress and that activities of the UPP provide a sensitive indicator of levels of cellular redox status.


Association of physical activity with psychological distress and happiness in mothers of children with autism spectrum disorders during the COVID-19 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic may have severely impacted the psychological status of mothers of children with autism spectrum disorder (ASD). Although a previous study reported that physical activity (PA) moderated psychological distress in parents of children with ASD during the COVID-19 pandemic, the effect of PA on the happiness levels of such parents during the pandemic remains unclear. This study investigated the associations among PA, psychological distress, and happiness in mothers of children with ASD during the COVID-19 pandemic. This cross-sectional study was designed to evaluate mothers of children with disabilities. Questionnaires were collected from mothers living in Yamaguchi and Okayama Prefectures, Japan, between February and December 2022. During this period, three large waves of the COVID-19 pandemic occurred in Japan. Of the 601 respondents, 334 mothers had children with ASD and offered valid data. PA was assessed using the short form of the International Physical Activity Questionnaire. Psychological distress and happiness were assessed using the six-item Kessler Psychological Distress Scale (K6) and the Subjective Happiness Scale (SHS). The mothers had markedly higher K6 scores (6.49) and more than half of them had moderate-to-severe psychological distress, whereas the SHS scores (4.46) were similar to that of the general Japanese population. In a multivariable-adjusted model based on the analysis of covariance, the K6 score was not associated with any PA items. In contrast, SHS scores were positively associated with moderate-intensity PA (MPA) and total moderate- to vigorous-intensity PA (MVPA), independent of K6. In the post-hoc test, mothers who did some (4.52) or enough (≥ 150 min/week) MPA (4.56) had a higher SHS score than those who did not (4.09). Similarly, mothers who engaged in sufficient (≥ 600 MET-min/week) total MVPA had higher SHS scores (4.57) than those who did not engage in MVPA (4.12). The mothers of children with ASD during the COVID-19 pandemic had markedly higher psychological distress, though none of the PA items were associated with stress levels. However, PA was positively associated with happiness in mothers of children with ASD independent of their stress levels.


Effects of orally administered tetracycline on the intestinal community structure of chickens and on tet determinant carriage by commensal bacteria and Campylobacter jejuni.
There is a growing concern that antibiotic usage in animal production has selected for resistant food-borne bacteria. Since tetracyclines are common therapeutic antibiotics used in poultry production, we sought to evaluate the effects of oral administration on the resistance of poultry commensal bacteria and the intestinal bacterial community structure. The diversity indices calculated from terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA amplicons did not indicate significant changes in the cecal bacterial community in response to oxytetracycline. To evaluate its effects on cultivable commensals, Enterococcus spp., Escherichia coli, and Campylobacter spp. were isolated from the cecal droppings of broiler chickens. Enterococcus spp. and E. coli expressed tetracycline MICs of >8 microg/ml and harbored a variety of tet resistance determinants regardless of the tetracycline exposure history of the birds. The enterococcal isolates possessed tetM (61%), tetL (25.4%), and tetK (1.3%), as well as tetO (52.5%), the determinant known to confer a tetracycline resistance phenotype in Campylobacter jejuni. E. coli isolates harbored tetA (32.2%) or tetB (30.5%). Tetracycline MICs remained at <2 microg/ml for Campylobacter isolates before and after tetracycline treatment of the chickens, even though isolates expressing MICs of >16 mug/ml were commonly cultured from flocks that did not receive oxytetracycline. The results imply that complex ecological and genetic factors contribute to the prevalence of antibiotic resistance arising from resistance gene transfer in the production environment.


Halloysite nanotubes modified poly(vinylidenefluoride-co-hexafluoropropylene)-based polymer-in-salt electrolyte to achieve high-performance Li metal batteries.
Solid-state Li metal batteries (SSLMBs) are one of the most promising energy storage devices, as they offer high energy density and improved safety compared to conventional Li-ion batteries. However, the large-scale application of SSLMBs at room temperature is restricted by the main challenges such as low ionic conductivity and poor cyclic performance. Herein, a composed polymer-in-salt electrolyte (CPISE) is fabricated, which is composed of polyvinylidene vinylidene hexafluoropropene (PVDF-HFP) and high-concentration Li bis(trifluoromethanesulphonyl)imide (LiTFSI), reinforced with natural halloysite nanotubes (HNTs). The High concentration of LiTFSI and introduced HNTs synergized with PVDF-HFP to provide more various Li+ transport pathways. Additionally, the backbones of the uniform dispersion of HNTs in the CPISE effectively boosts the physicochemical nature of the CPISE. As a result, the prepared CPISE achieves excellent mechanical strength, high ionic conductivity (1.23*10-3 S cm-1) and high Li+ transference number (0.57) at room temperature. Consequently, in existence of the CPISE, the Li symmetric cell cycles stably beyond 800 h at 0.15 mA cm-2 and the LiFePO4/Li cell displays impressive cyclic performance with capacity retention of 79% after 1000 cycles at 30 °C. Furthermore, the superiority and the functional mechanism of the CPISE are discovered in detail. This work provides a promising strategy for the development of high-performance SSMLBs at room temperature.


Developmental gene regulation during tomato fruit ripening and in-vitro sepal morphogenesis.
Red ripe tomatoes are the result of numerous physiological changes controlled by hormonal and developmental signals, causing maturation or differentiation of various fruit tissues simultaneously. These physiological changes affect visual, textural, flavor, and aroma characteristics, making the fruit more appealing to potential consumers for seed dispersal. Developmental regulation of tomato fruit ripening has, until recently, been lacking in rigorous investigation. We previously indicated the presence of up-regulated transcription factors in ripening tomato fruit by data mining in TIGR Tomato Gene Index. In our in-vitro system, green tomato sepals cultured at 16 to 22 degrees C turn red and swell like ripening tomato fruit while those at 28 degrees C remain green. Here, we have further examined regulation of putative developmental genes possibly involved in tomato fruit ripening and development. Using molecular biological methods, we have determined the relative abundance of various transcripts of genes during in vitro sepal ripening and in tomato fruit pericarp at three stages of development. A number of transcripts show similar expression in fruits to RIN and PSY1, ripening-associated genes, and others show quite different expression. Our investigation has resulted in confirmation of some of our previous database mining results and has revealed differences in gene expression that may be important for tomato cultivar variation. We present new and intriguing information on genes that should now be studied in a more focused fashion.


Resolving the DDT target protein in insects as a subunit of the ATP synthase.
1,1-bis-(p-Chlorophenyl)-2,2,2-trichloroethane (DDT) inhibited the ATP hydrolytic activity of the ATP synthase from a DDT-susceptible insect (Apis mellifera) as well as a DDT-tolerant insect (Spodoptera littoralis), and from rat liver and bovine heart in a parallel way to its insecticidal properties and selectivity of action. Inhibition of the ATPase activity of these preparations by DDT was parallel to the poisoning of the source organism with DDT. Furthermore, both the inhibition and poisoning of insects were affected similarly by temperature. Inhibition of the insect enzyme activity by DDT was specific and differed from that by oligomycin or N,N-dicyclohexylcarbodi-imide (DCCD). PAGE analysis of the various preparations of the enzyme showed that the inhibition of the enzyme activity by DDT was associated with the presence of a selective protein band with an apparent molecular mass of 23 kDa. This protein band exists in the preparations from the DDT-susceptible insects but was absent from the preparations of the enzyme from the DDT-insensitive sources. Removal of this protein band from the enzyme rendered its activity insensitive to inhibition by DDT. The protein was purified directly from mitochondria and the DDT sensitivity was reconstituted upon its addition to the DDT-insensitive F1-ATPase. We conclude that this identified protein of the ATP synthase is the DDT target protein in insects.


Coronary Sparing Aneurysmectomy.
Repairing left ventricular aneurysms that form after myocardial infarction may be challenging, especially if located close to the important native coronary arteries. Here, we describe a rare case of anterolateral aneurysm of the basal LV wall and a safe, efficient approach for a patch plasty sparing the native left anterior descending.


Physiological and pathophysiological regulation of regional adipose tissue in the development of insulin resistance and type 2 diabetes.
To survey the latest state of knowledge concerning the regulation of regional adipocytes and their role in the development of insulin resistance and type 2 diabetes. Data from the English-language literature on regional adipocytes, including abdominal, intramyocellular, intrahepatic and intra-islet fat as well as the adipokines and their relations to insulin resistance and type 2 diabetes, were reviewed. It is not the total amount of fat but the fat that resides within skeletal muscle cell (intramyocellular fat), hepatocytes and intra-abdominally (visceral fat), via systemic and local secretion of several adipokines, that influences insulin resistance. Among the adipokines that relate to insulin resistance, adiponectin and leptin appear to have clinical relevance to human insulin resistance and others may also contribute, but their role is still inconclusive. The intra-islet fat also adversely affects beta-cell function and number (beta-cell apoptosis), eventually leading to deterioration of glucose tolerance. The abnormal location of fat observed in patients with type 2 diabetes and their relatives is conceivably partly the results of the genetically determined, impaired mitochondrial fatty acid oxidative capacity. Restriction or elimination of the fat load by weight control, regular exercise and thiazolidinediones has been shown to improve insulin resistance and beta-cell function and to delay the development of type 2 diabetes. These data support the plausibility of an essential role of regional adipose tissue in the development of insulin resistance and type 2 diabetes.


Study protocol for pragmatic trials of Internet-delivered guided and unguided cognitive behavior therapy for treating depression and anxiety in university students of two Latin American countries: the Yo Puedo Sentirme Bien study.
Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent among university students and predict impaired college performance and later life role functioning. Yet most students do not receive treatment, especially in low-middle-income countries (LMICs). We aim to evaluate the effects of expanding treatment using scalable and inexpensive Internet-delivered transdiagnostic cognitive behavioral therapy (iCBT) among college students with symptoms of MDD and/or GAD in two LMICs in Latin America (Colombia and Mexico) and to investigate the feasibility of creating a precision treatment rule (PTR) to predict for whom iCBT is most effective. We will first carry out a multi-site randomized pragmatic clinical trial (N = 1500) of students seeking treatment at student mental health clinics in participating universities or responding to an email offering services. Students on wait lists for clinic services will be randomized to unguided iCBT (33%), guided iCBT (33%), and treatment as usual (TAU) (33%). iCBT will be provided immediately whereas TAU will be whenever a clinic appointment is available. Short-term aggregate effects will be assessed at 90 days and longer-term effects 12 months after randomization. We will use ensemble machine learning to predict heterogeneity of treatment effects of unguided versus guided iCBT versus TAU and develop a precision treatment rule (PTR) to optimize individual student outcome. We will then conduct a second and third trial with separate samples (n = 500 per arm), but with unequal allocation across two arms: 25% will be assigned to the treatment determined to yield optimal outcomes based on the PTR developed in the first trial (PTR for optimal short-term outcomes for Trial 2 and 12-month outcomes for Trial 3), whereas the remaining 75% will be assigned with equal allocation across all three treatment arms. By collecting comprehensive baseline characteristics to evaluate heterogeneity of treatment effects, we will provide valuable and innovative information to optimize treatment effects and guide university mental health treatment planning. Such an effort could have enormous public-health implications for the region by increasing the reach of treatment, decreasing unmet need and clinic wait times, and serving as a model of evidence-based intervention planning and implementation. IRB Approval of Protocol Version 1.0; June 3, 2020. Recruitment began on March 1, 2021. Recruitment is tentatively scheduled to be completed on May 30, 2024. ClinicalTrials.gov NCT04780542 . First submission date: February 28, 2021.


Hormonal regulation of uterine chemokines and immune cells.
The ultimate function of the endometrium is to allow the implantation of a blastocyst and to support pregnancy. Cycles of tissue remodeling ensure that the endometrium is in a receptive state during the putative 'implantation window', the few days of each menstrual cycle when an appropriately developed blastocyst may be available to implant in the uterus. A successful pregnancy requires strict temporal regulation of maternal immune function to accommodate a semi-allogeneic embryo. To preparing immunological tolerance at the onset of implantation, tight temporal regulations are required between the immune and endocrine networks. This review will discuss about the action of steroid hormones on the human endometrium and particularly their role in regulating the inflammatory processes associated with endometrial receptivity.


Case report: A balance of survival and quality of life in long-term survival case of lung adenocarcinoma with synchronous bone metastasis.
Bone metastasis is one of the comorbidities of advanced lung cancer, eventually leading to an impaired quality of life. We present a case of a lung adenocarcinoma patient with synchronous bone metastasis. The patient possessed a superior survival time of more than five years under multidisciplinary treatment. Considering the balance of life expectancy and limb function, the metastatic site on the right humerus was successively surgically managed. Based on the present case, we emphasized the importance of treatment choice between anti-tumor and bone management in the long-term survival of cancer patients with synchronous bone metastasis.


Fabrication of microscalpels by electrolysis of tungsten wire in a meniscus.
A simple technique has been devised for generating consistent microscalpel blades from tungsten wire for use in microdissections. Electrolysis of the tungsten wire held horizontally in contact with the extended, up-lifted meniscus of an aqueous solution of 1.0 N NaOH sculps the metal into a blade configuration with a very sharp cutting edge. These microscalpels are suitable for dissection of embryonic neural tissues.


Performance on the CERAD Word List Memory task: a comparison of university-based and community-based groups.
Evaluation of patients for Alzheimer's disease often compares an individual's performance on cognitive tests to established norms. The purpose of this study was to compare performance on the CERAD Word List Memory tasks in normal controls from an Alzheimer's disease registry and in community volunteers. Scores on Word List Memory tasks were evaluated in cognitively intact participants enrolled in a university-based Alzheimer's disease registry (n=103) and in a sample of community volunteers (n=51). Scores for the two samples were also compared with previously published data from registry-based normal controls and from a representative community-based sample. University-based participants outperformed community volunteers, with most marked differences on Delayed Recall and on a Savings score that contrasted immediate to delayed recall. University-based participants performed similarly to previously published scores for normal controls from another university-based Alzheimer's disease registry, while community volunteers were consistent with published scores available from a representative community sample. Accurate neuropsychological assessment of Alzheimer's disease may require consideration of potentially subtle differences between older adults tested at university centers and those tested in the community.


Mechanisms influencing the BFR distribution patterns in office dust and implications for estimating human exposure.
The availability of indoor dust for human exposure by hand adhesion depends on size of dust particle. This paper investigates the distribution patterns of brominated flame retardants (BFRs) with particle size in indoor dust. A mixed sample of office dust was obtained from twenty eight high-level offices at Haidian District, Beijing, China. The composite dust (<2mm) was classified into thirteen size fractions (F1-F13: 2000-900-500-400-300-200-100-75-50 μm, 39.58 ± 33.56 μm, 27.93 ± 23.79 μm, 20.15 ± 17.92 μm, 11.38 ± 15.01 μm and 5.64 ± 6.78 μm), by which 18BFRs contents were analyzed. Dust adhered to floc (FD) was also sampled for a separate analysis and was found to contain extremely high level of BFR concentration. The BFR level determined from all fractions of the sampled office dust ranged from ND (not detected) (F1, BDE28, 66) to 5455.4 (FD, BDE209) ng g(-1), in which BDE 209 and BTBPE (1,2-bis (2,4,6-tribromphenoxy) ethane) were found to be the most abundant BFR residue. The influencing factors of BFR distribution patterns in office dust were deduced to be specific surface area, organic content of particles, and origin process (fragmentation and absorption) of BFRs. Selection of dust fraction was demonstrated to be influential on both BFR analytical results and human exposure estimation.


Toll-like receptor expression and function in the COV434 granulosa cell line.
Bacterial infections perturb ovarian follicle function, despite the lack of immune cells such as macrophages within healthy ovarian follicles. This study examined whether the granulosa cells that line ovarian follicles could, like macrophages, use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns (PAMPs) and initiate inflammation. The COV434 human granulosa and THP-1 macrophage cell lines were used to determine the expression of TLRs and measure the production of cytokines, chemokines and estradiol in response to the PAMPs lipopolysaccharide, peptidoglycan, lipoteichoic acid and flagellin from bacteria. The THP-1 and granulosa cells expressed mRNA for TLR1-10 and TLR4-10, respectively. The supernatants of THP-1 cells accumulated IL-1β, IL-6, IL-8 and CCL5 in response to PAMPs. Treatment of granulosa cells with PAMPs increased expression of IL1B mRNA after 3 hr, but did not change the accumulation of IL-1β, IL-6, IL-8, CCL5 or estradiol. Granulosa cells produced IL-8 constitutively, and this was reduced using chemical inhibitors for p38 and JNK mitogen-activated protein kinases. The COV434 human granulosa cell line expresses TLRs and constitutively secretes IL-8 but only mounts an inflammatory response to PAMPs at the transcriptional level.


Education and Training to Address Specific Needs During the Career Progression of Surgeons.
Surgeons have specific education and training needs as they enter practice, progress through the core period of active practice, and then as they wind down their clinical work before retirement. These transitions and the career progression process, combined with the dynamic health care environment, present specific opportunities for innovative education and training based on practice-based learning and improvement, and continuous professional development methods. Cutting-edge technologies, blended models, simulation, mentoring, preceptoring, and integrated approaches can play critical roles in supporting surgeons as they provide the best surgical care throughout various phases of their careers.


MANAGEMENT OF HYPERPARATHYROIDISM IN KIDNEY TRANSPLANTATION CANDIDATES: A NEED FOR CONSENSUS.
Objective: To assess the evolving standards of care for hyperparathyroidism in kidney transplant candidates. Methods: An 11-question, Institutional Review Board-approved survey was designed and reviewed by multiple institutions. The questionnaire was made available to the American Society of Transplantation's Kidney Pancreas Community of Practice membership via their online hub from April through July 2019. Results: Twenty percent (n = 41) of kidney transplant centers responded out of 202 programs in the United States. Forty-one percent (n = 17) of respondents believed medical literature supports the concept that a serum parathyroid hormone level greater than 800 pg/mL could endanger the survival of a transplanted kidney and therefore makes transplantation in an affected patient relatively or absolutely contraindicated. Sixty-six percent (n = 27) said they occasionally recommend parathyroidectomy for secondary hyperparathyroidism prior to transplantation, and 66% (n = 27) recommend parathyroidectomy after transplantation based on persistent, unsatisfactory posttransplantation parathyroid hormone levels. Forty-six percent (n = 19) prefer subtotal parathyroidectomy as their choice; 44% (n = 18) had no standard preference. Endocrine surgery and otolaryngology were the most common surgical specialties consulted to perform parathyroidectomy in kidney transplant candidates. The majority of respondents (71%, n = 29) do not involve endocrinologists in the management of kidney transplantation candidates. Conclusion: Our survey shows wide divergence of clinical practice in the area of surgical management of kidney transplantation candidates with hyperparathyroidism. We suggest that medical/surgical societies involved in the transplantation care spectrum convene a multidisciplinary group of experts to create a new section in the kidney transplantation guidelines addressing the collaborative management of parathyroid disease in transplantation candidates. Abbreviations: AACE = American Association of Clinical Endocrinologists; AAES = American Association of Endocrine Surgeons; AHNS = American Head and Neck Society; CKD = chronic kidney disease; CKD-MBD = chronic kidney disease-mineral and bone disorder; ESRD = end-stage renal disease; HPT = hyperparathyroidism; KDIGO = Kidney Disease Improving Global Outcomes; KT = kidney transplantation; KTC = kidney transplant candidate; PTH = parathyroid hormone; PTX = parathyroidectomy; US = ultrasonography.


SOD mineralized zeolitic imidazole framework-8 for the treatment of chemotherapy-related acute kidney injury.
Acute kidney injury (AKI), a prevalent and fatal adverse event, seriously affects cancer patients undergoing chemotherapy. The most important pathological mechanism of AKI is oxidative stress from reactive oxygen species (ROS). Currently, ROS scavenging is a promising strategy to manage the risk of chemotherapy-induced AKI. Herein, we successfully synthesized SOD@ZIF-8 nanoparticles by biomimetic mineralization, which were taken up by cells and could improve cell viability by limiting oxidative stress damage, as found in in vitro studies. Moreover, SOD@ZIF-8 nanoparticles exhibit broad-spectrum antioxidant properties in addition to significant renal accumulation in AKI mice, preventing clinically related cisplatin-induced AKI in murine models. AKI alleviation in the model was validated by measuring blood serum, staining kidney tissue, and related biomarkers. SOD@ZIF-8 nanoparticle therapeutic efficiency exceeds NAC, a small molecular antioxidant functioning through free radical scavenging. The results suggest SOD@ZIF-8 nanoparticles as a potential therapeutic option for AKI and other ROS-related disorders.


Associations between supernormality ('faking good'), narcissism and depression: An exploratory study in a clinical sample.
We explored underreporting of mental health symptoms and its correlates in adults receiving psychological treatment. We administered the Supernormality Scale (SS), the Minnesota Multiple Personality Inventory-2 (Restructured Form, MMPI-2-RF), the Narcissistic Personality Inventory (NPI) and the Beck Depression Inventory-II (BDI-2) to 147 patients at the start of their treatment. Supernormality (i.e., denial of common symptoms) was positively associated with MMPI-2(-RF) faking good parameters supporting the construct validity of the SS. Narcissism was negatively related to self-reported depression symptoms, but this association failed to reach significance (r = -.15, p = .07). This suggests that patients high on grandiose/overt narcissism might tend to deny common symptoms. The link between supernormality and depression symptoms as measured by the BDI-2 was substantial and negative (r = -.72). Our data suggest that supernormality is associated with constricted self-reports of depression. Given the clinical relevance of symptom underreporting, our preliminary findings require a large-scale replication.


Population-based organized screening by faecal immunochemical testing and colorectal cancer mortality: a natural experiment.
Population-based organized screening programmes for colorectal cancer (CRC) are underway worldwide, with many based on the faecal immunochemical test (FIT). No clinical trials assessing FIT compared with no screening are planned, and few studies have assessed the population impact of such programmes. Before 2010, 11 out of 50 Spanish provinces initiated population-based organized screening programmes with FIT for an average-risk population aged 50-69 years. We used a quasi-experimental design across Spanish provinces between 1999 and 2016 to evaluate their impact on population age-standardized mortality and incidence rates due to CRC. Difference-in-differences and synthetic control analyses were performed to test for validation of statistical assumptions and to assess the dynamics of screening-associated changes in outcomes over time. No differences in outcome trends between exposed (n = 11) and control (n = 36) provinces were observed for up to 7 years preceding the implementation of screening. Relative to controls, exposed provinces experienced a mean increase in age-standardized incidence of 10.08% [95% confidence interval (CI) (5.09, 15.07)] 2 years after implementation, followed by a reduction in age-standardized mortality rates due to CRC of 8.82% [95% CI (3.77, 13.86)] after 7 years. Results were similar for both women and men. No associated changes were observed in adjacent age bands not targeted by screening, nor for 10 other major causes of death in the exposed provinces. FIT-based organized screening in Spain was associated with reductions in population colorectal cancer mortality. Further research is warranted in order to assess the replicability and external validity of our findings, and on gender-specific use of FIT in organized screening.


Terbutaline-induced desensitization of human cardiac beta 2-adrenoceptor-mediated positive inotropic effects: attenuation by ketotifen.
In patients with chronic heart failure cardiac beta 1-adrenoceptors are desensitized whereas beta 2-adrenoceptors are only marginally affected. The mechanism underlying this differential regulation is not known. To find out whether or not human cardiac beta 2-adrenoceptors might be 'resistant' to agonist-induced desensitization and whether or not the antiallergic drug ketotifen might attenuate possible desensitization. We investigated, in a single blinded, randomised, placebo-controlled, cross-over study of ten healthy male volunteers (mean age, 25.3 +/- 0.7 years), the effects of two weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3x5 mg/day p.o.) with and without simultaneous treatment with ketotifen (2x1 mg/day p.o. for three weeks) or placebo on beta-adrenoceptor-mediated cardiovascular effects. Cardiovascular effects were assessed as isoprenaline (3.5-35 ng/kg/min)- and terbutaline (25-150 ng/kg/min)-infusion-induced increases in heart rate and systolic blood pressure, decreases in diastolic blood pressure and shortening of the systolic time intervals (STIs), heart rate corrected duration of electromechanical systole (QS2c) and pre-ejection period (PEP; as a measure of inotropism). Ketotifen did not significantly affect basal haemodynamics in the volunteers. Isoprenaline- and terbutaline-infusion caused dose-dependent increases in systolic blood pressure and heart rate, decreases in diastolic blood pressure and shortening of QS2c and PEP, whereby isoprenaline effects were more pronounced. After two weeks of treatment with terbutaline p.o., isoprenaline- and terbutaline-infusion-induced increases in heart rate, shortening of QS2c and PEP were significantly reduced whereby terbutaline-infusion effects were markedly more attenuated than isoprenaline-infusion effects. Ketotifen significantly reduced terbutaline p.o. treatment-induced attenuation of all terbutaline-infusion effects (largely beta 2-adrenoceptor-mediated) and the isoprenaline-infusion-induced increase in heart rate (beta 1- and beta 2-adrenoceptor-mediated), but did not (or only marginally) affect reduction in isoprenaline-induced shortening of QS2c and PEP (largely beta 1-adrenoceptor-mediated). Human cardiac beta 2-adrenoceptors are not 'resistant' to agonist-induced desensitization: Ketotifen might prevent such beta 2-adrenoceptor-agonist-evoked desensitization.


Vitamin B12 Status before and after Outpatient Treatment of Severe Acute Malnutrition in Children Aged 6-59 Months: A Sub-Study of a Randomized Controlled Trial in Burkina Faso.
Severe acute malnutrition (SAM) is treated with ready-to-use therapeutic foods (RUTF) containing a vitamin-mineral premix. Yet little is known about micronutrient status in children with SAM before and after treatment. We aimed to investigate vitamin B12 status in children with uncomplicated SAM, aged 6-59 months in Burkina Faso, before and after treatment with a standard or a reduced dose of RUTF. Blood samples were collected at admission and discharge. Serum B12 was determined with microbiological assay and serum methylmalonic acid (MMA) and total homocysteine (tHcy) were analyzed with gas chromatography-tandem mass spectrometry. B12 status was classified using the combined indicator (3cB12). Among 374 children, the median [interquartile range] age was 11.0 [7.7-16.9] months, and 85.8% were breastfed. Marked or severe B12 deficiency, as judged by 3cB12, decreased from 32% to 9% between admission and discharge (p < 0.05). No differences in B12 status following treatment with either standard (n = 194) or reduced (n = 180) doses of RUTF were observed. Breastfed children showed a lower B12 status (3cB12) than non-breastfed ones (-1.10 vs -0.18, p < 0.001 at admission; -0.44 vs 0.19; p < 0.001 at discharge). In conclusion, treatment of SAM with RUTF improved children's B12 status but did not fully correct B12 deficiency.


Prevention of N-methylnitrosourea-induced colon tumorigenesis by ursodeoxycholic acid in F344 rats.
Bile acids are known to promote colon carcinogenesis. However, there is one study showing that ursodeoxycholic acid (UDCA) supplemented in the diet at the concentration of 0.4% prevented azoxymethane-induced rat colon tumorigenesis. The aim of our study was to explore the inhibitory effect of a much smaller dose of UDCA on colon carcinogenesis in rats. One hundred 7-week-old F344 rats were given 2 mg of N-methylnitrosourea 3 times a week for 3 weeks by intrarectal instillation, and were fed a 0% (control), 0.4% or 0.08% UDCA-supplemented diet for the next 27 weeks. All the rats were killed and examined for tumor development at week 30. The tumor incidence and number were significantly lower and smaller, respectively, in the UDCA-fed rats than in the control rats: 40% and 36% vs. 68%; 0.5 +/- 0.1 (mean +/- SEM) and 0.4 +/- 0.1 vs. 1.0 +/- 0.2. All the tumors were located in the distal half of the colon and were plaque-shaped or polypoid, being well-differentiated adenocarcinomas restricted to the mucosa or submucosa. Bile acids in the feces and the blood obtained at weeks 20 and 30, respectively, were analyzed by HPLC. A significant increase of UDCA was confirmed in both the feces and the blood of the UDCA-fed rats compared with the control rats. The results suggest that the continuous feeding of a small dose of UDCA may prevent colon carcinogenesis.


Similar hematologic changes in children receiving trimethoprim-sulfamethoxazole or amoxicillin for otitis media.
We report the hematologic changes in 90 black children who were randomized to receive a 10-day course of either trimethoprim-sulfamethoxazole (TMP-SMZ) or amoxicillin as therapy for acute otitis media. Absolute neutrophil counts less than 1500/mm3 developed at least once during the 23-day evaluation in 28 (57%) of the 49 children given TMP-SMZ and in 22 (54%) of the 41 who received amoxicillin. Incidence of leukopenia, thrombocytopenia, and anemia was negligible in both groups. Pancytopenia did not occur in any child. Absolute neutrophil counts had increased to greater than 1500/mm3 by the end of the study period in all of the patients but six, whose recovery required an additional 1 to 63 days. Decreased neutrophil counts in antibiotic-treated subjects remained within the range of findings for healthy black children, suggesting that a count less than 1500/mm3 may be an inappropriate criterion for an adverse drug effect. Neither TMP-SMZ nor amoxicillin produced hematologic effects that would detract from their continued use in children with infections caused by antibiotic-susceptible organisms.


Association between decreased ipsilateral renal function and aggressive behavior in renal cell carcinoma.
To assess prognostic value of pre-operative ipsilateral split renal function (SRF) on disease-free survival (DFS) and its association with aggressive pathological features in renal cell carcinoma (RCC) patients. METHODS: We examined patients registered in SNUG-RCC-Nx who underwent partial or radical nephrectomy at Seoul National University Hospital between January 1, 2010 and December 31, 2020. Patients with the following criteria were excluded from the study. 1) non-kidney origin cancer or benign renal tumor, 2) no pre-operative Tc 99 m-DTPA renal scan, 3) single kidney status or previous partial or radical nephrectomy, and 4) bilateral renal mass. Finally, 1,078 patients were included. Among 1,078 patients, 899 (83.4%) showed maintained ipsilateral SRF on DTPA renal scan; 179 patients (16.6%) showed decreased SRF. The decreased SRF group showed significantly large tumor size (maintained vs. decreased SRF; 3.31 ± 2.15 vs. 6.85 ± 3.25, p < 0.001), high Fuhrman grade (grade 3-4) (41.7% vs. 55.6%, p < 0.001), and high T stage (T stage 3-4) (9.0% vs. 20.1%, p < 0.001). Pathological invasive features, including invasion of the renal capsule, perirenal fat, renal sinus fat, vein, and collecting duct system, were associated with low SRF of the ipsilateral kidney. Univariate Cox regression analysis identified higher SSIGN (The stage, size, grade, and necrosis) score and decreased ipsilateral SRF as significant risk factors, while multivariate analysis showed SSIGN (5-7) (hazard ratio [HR] 11.9, p < 0.001) and SSIGN (8-10) (HR 69.2, p < 0.001) were significantly associated with shortened DFS, while decreased ipsilateral SRF (HR 1.75, p = 0.065) showed borderline significance. Kaplan-Meier analysis showed that decreased ipsilateral SRF (< 45%) group had shorter DFS than the other group (median DFS: 90.3 months vs. not reached, p < 0.001). Among unilateral RCC patients, those with low ipsilateral SRF showed poor prognosis with pathologically invasive features. Our novel approach may facilitate risk stratification in RCC patients, helping formulate a treatment strategy.


US state policies for Medicaid coverage of donor human milk.
Donor human milk is recommended by the American Academy of Pediatrics for high-risk infants when mother's own milk is absent or insufficient in quantity. Several factors may contribute to the inequitable use of or access to donor human milk, including a limited knowledge of its effects, cost, reimbursement, and regulatory barriers. The American Academy of Pediatrics and the United States Surgeon General have called for investigating barriers that prevent use of donor human milk for high-risk infants and for changes to public policy known to improve availability and affordability. We review the current legislative, regulatory, and economic landscape surrounding donor human milk use in the United States, as well as suggest state- and federal-level solutions to increase access to donor human milk.


WITHDRAWN: Implementation Science for nursing: Evidence needed! Call for papers for a Special Issue.
The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:<10.1016/j.ijnurstu.2011.09.001>. The duplicate article has therefore been withdrawn.


Ornithine decarboxylase attenuates leukemic chemotherapy drugs-induced cell apoptosis and arrest in human promyelocytic HL-60 cells.
Ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway, plays an important role in cell cycle, tumor promotion and anti-apoptosis. In our previous studies, overexpression of ODC prevented apoptosis induced by tumor necrosis factor-alpha and methotrexate. We further investigated the apoptotic mechanisms of the cancer chemotherapeutic drugs, including etoposide (VP-16), paclitaxel (TAX) and cisplatin (CDDP), and the influences of ODC on apoptosis and cell cycle. Our results showed that the investigated drugs induced caspase-dependent apoptosis, the generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (Deltapsi m) in HL-60 cells, all of which were reversed by putrescine, glutathione or N-acetyl-l-cysteine. Overexpression of ODC prevented the cancer chemotherapeutic drugs-induced apoptosis, ROS generation and the disruption of Deltapsi m. After drug administrations, the decline of Bcl-2, cytochrome c release and caspases' activation were inhibited by ODC overexpression. In cell cycle, ODC overexpressed cells seemed to overcome the G1 arrest and G2/M arrest, caused by VP-16 and TAX, respectively, and kept on the cell cycle rolling. Overexpression of ODC increased the expression of Cyclin A, D, E and Cdk4 and the enzyme activity of Cdk1 and Cdk2 after the treatment of VP-16 and TAX, respectively. In conclusions, the cancer chemotherapeutic drugs-induced apoptosis is through ROS-related, mitochondria-mediated and caspase-dependent pathways. With higher ODC activity, cells are resistant to the cancer chemotherapeutic drugs-induced apoptosis and keep on the cell cycle rolling with the significant interference in G1/S arrest caused by VP-16 and G2/M arrest by TAX.


Study on the temperature-dependent coupling among viscosity, conductivity and structural relaxation of ionic liquids.
The frequency-dependent viscosity and conductivity of three imidazolium-based ionic liquids were measured at several temperatures in the MHz region, and the results are compared with the intermediate scattering functions determined by neutron spin echo spectroscopy. The relaxations of both the conductivity and the viscosity agree with that of the intermediate scattering function at the ionic correlation when the relaxation time is short. As the relaxation time increases, the relaxations of the two transport properties deviate to lower frequencies than that of the ionic structure. The deviation begins at a shorter relaxation time for viscosity than for conductivity, which explains the fractional Walden rule between the zero-frequency values of the shear viscosity and the molar conductivity.


The impact of major depressive disorder and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes: A nationwide population-based study.
To investigate the impact of major depressive disorder (MDD) and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes. A national register-based cohort study of pregnant women born in Sweden, and their first child born in 2012-2015 (n = 262 329). Women diagnosed with MDD and who had redeemed an antidepressant one year before becoming pregnant ("before pregnancy") and women who were diagnosed with MDD and who had redeemed an antidepressant both before and during pregnancy ("before and during pregnancy") were compared with each other and with women who had neither been diagnosed with MDD nor been prescribed antidepressants (population controls). In comparison to population controls, the "before pregnancy" and the "before and during pregnancy" groups had increased likelihoods of operative childbirth (aOR = 1.19, 95 % CI 1.12-1.27, aOR = 1.38, 95 % CI 1.28-1.48 respectively), and with an increased likelihood for the child being admitted to a neonatal intensive care unit (NICU) (aOR = 1.51, 95 % CI 1.17-1.95, aOR = 1.55, 95 % CI 1.14-2.11). Children born to mothers in the "before and during pregnancy" group had an increased likelihood of preterm birth (aOR = 1.72, 95 % CI 1.52-1.95,), while children to mothers in the "before pregnancy" group had an increased likelihood of low birthweight (aOR = 1.15, 95 % CI 1.00-1.33) compared to population controls. Women in the "before and during pregnancy" group had an increased likelihood for hyperemesis during pregnancy (aOR = 1.93, 95 % CI = 1.60-2.32), having an operative childbirth (aOR = 1.17, 95 % CI = 1.06-1.29) or a preterm birth (aOR = 1.53, 95 % CI = 1.28-1.81) compared to the "before pregnancy" group. Women with MDD and antidepressant medication prior to becoming pregnant are at increased risk for adverse obstetric and neonatal outcomes compared to women without an MDD. Continuation of antidepressant medication during pregnancy somewhat increased the risk for adverse obstetric and neonatal outcomes.


Evaluation of the Green Cross Method Regarding Patient Safety Culture and Incidence Reporting.
The Green Cross (GC) method is a visual method for health service staff to recognize risks and preventable adverse events (PAEs) on a daily basis. The aim was to compare patient safety culture and the number of reported PAEs in units using the GC method with units that do not. This study has a retrospective cross-sectional design in the setting of psychiatric and somatic care departments in a Swedish hospital. In total, 1476 staff members from 62 different units participate in the study. Units who had implemented the GC method scored higher than non-GC units in overall quality. The dimensions Feedback and communication about error, Nonpunitive response to errors, Organizational learning-continuous improvement, Handoffs and transitions between units and shifts, and Teamwork within units scored significantly higher in GC units. More risks were reported in the incident reporting system in GC units than in non-GC units, but the number of PAEs was similar. Units with nursing staff who used the GC method scored higher on patient safety culture than those who did not use the method. This difference was not seen in physician units. The implementation of the GC method has a positive impact on patient safety culture and PAE reporting. However, the method does not seem to have the same impact in physician units as in units with nursing staff, which calls for further investigation.


Genetic Counselors' Perspectives and Practices Regarding Expanded Carrier Screening after Initial Clinical Availability.
Expanded carrier screening (ECS), introduced in 2009, identifies carriers for dozens or hundreds of recessive diseases. At the time of its introduction into clinical use, perspectives of the genetic counseling community regarding ECS were unknown. We conducted a survey in early 2012 of GCs and report the results here. They represent a snapshot of opinions and usage at that time, providing a baseline for comparison as the technology continues to evolve and as usage increases. The survey assessed personal perspectives, opinions on clinical implementation and clinical utilization of ECS. The sample included 337 GCs of varying clinical fields, of whom 150 reported practicing in reproductive settings. Our findings demonstrate that, at the time, GCs indicated general agreement with ECS as a concept - for example, most GCs agreed that carrier screening should address diseases outside of current guidelines and also indicated personal interest in electing ECS. There were also disagreements or concerns expressed regarding appropriate pre- and post-test counseling (e.g., the content and delivery mode of adequate informed consent) and practical implementation (e.g., the amount of time available for follow-up care). This was the first quantitative study of a large number of GCs and it revealed initial overall support for ECS among the GC profession. The authors plan to re-administer a similar survey, which may reveal changes in opinions and/or utilization over time. A follow up survey would also allow further exploration of questions uncovered by these data.


Integrated bioinformatics analysis elucidates granulosa cell whole-transcriptome landscape of PCOS in China.
Polycystic ovary syndrome (PCOS) is a common reproductive, neuroendocrine, and metabolic disorder in women of reproductive age that affects up to 5-10% of women of reproductive age. The aetiology of follicle development arrest and critical issues regarding the abnormal follicular development in PCOS remain unclear. The present study aims to systematically evaluate granulosa cell whole-transcriptome sequencing data to gain more insights into the transcriptomic landscape and molecular mechanism of PCOS in China. In the present study, the microarray datasets GSE138518, GSE168404, GSE193123, GSE138572, GSE95728, and GSE145296 were downloaded from the Gene Expression Omnibus (GEO) database. Subsequently, differential expression analysis was performed on the PCOS and control groups, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in PCOS. Finally, hub genes and their associated ncRNAs were validated by qPCR in human-luteinized granulosa (hGL) cells and were correlated with the clinical characteristics of the patients. A total of 200 differentially expressed mRNAs, 3 differentially expressed miRNAs, 52 differentially expressed lncRNAs, and 66 differentially expressed circRNAs were found in PCOS samples compared with controls. GO and KEGG enrichment analyses indicated that the DEGs were mostly enriched in phospholipid metabolic processes, steroid biosynthesis and inflammation related pathways. In addition, the upregulated miRNA hsa-miR-205-5p was significantly enriched in the ceRNA network, and two hub genes, MVD and PNPLA3, were regulated by hsa-miR-205-5p, which means that hsa-miR-205-5p may play a fundamental role in the pathogenesis of PCOS. We also found that MVD and PNPLA3 were related to metabolic processes and ovarian steroidogenesis, which may be the cause of the follicle development arrest in PCOS patients. In summary, we systematically constructed a ceRNA network depicting the interactions between the ncRNAs and the hub genes in PCOS and control subjects and correlated the hub genes with the clinical characteristics of the patients, which provides valuable insights into the granulosa cell whole-transcriptome landscape of PCOS in China.


Labelled acetone and levulinic acid are formed when [14C]acetate is being converted to mycophenolic acid in Penicillium brevicompactum.
Evidence is presented that is compatible with the hypothesis that the farnesyl unit involved in the biosynthesis of mycophenolic acid in Penicillium brevicompactum is degraded by two successive oxidative cleavages at the double bonds distal from the phthalide nucleus. Acetone and levulinic acid are two non-aromatic degradation products.


Phenotypic frailty in people living with HIV is not correlated with age or immunosenescence.
It has been hypothesized that HIV-1 infection prematurely "ages" individuals phenotypically and immunologically. We measured phenotypic frailty and immune "aging" markers on T-cells of people living with HIV on long term, suppressive anti-retroviral therapy (ART) to determine if there is an association between frailty and immunosenescence. Thirty-seven (37) community-dwelling people living with HIV were measured for frailty using a sensor-based frailty meter that quantifies weakness, slowness, rigidity, and exhaustion. An immunological profile of the patients' CD4+ and CD8+ T-cell expression of cell surface proteins and cytokines was performed (n = 20). Phenotypic frailty prevalence was 19% (7/37) and correlated weakly with the number of past medical events accrued by the patient (r = 0.34, p = .04). There was no correlation of frailty with age, sex, prior AIDS diagnosis or HIV-1 viral load, or IFN-γ expression by CD4+ or CD8+ T-cells. There were more immune competent (CD28+ CD57-) cells than exhausted/senescent (CD28- CD57+) T cells. Frailty in people living with HIV on long term, suppressive ART did not correlate with aging or T cell markers of exhaustion or immunosenescence.


[Surgical treatment of carcinomas of the oesophagogastric junction - results achieved in multicentre studies].
Adenocarcinomas of the oesophagogastric junction are increasingly being considered as a separated tumour entity. The prognosis is rather poorer compared with that for distal gastric cancer. Data from a multicentre study as part of research on clinical care aim to reflect the current situation in surgical treatment after inauguration of neoadjuvant modalities. As part of the ongoing prospective multicentre observational study QCGC 2 (German Gastric Cancer Study 2), 544 adenocarcinomas of the oesophagogastric junction (AEG 1-3) were registered from 01/01/2007 to 12/31/2009. Patients underwent surgical intervention in 108 (76.6 %) of the 141 surgical departments which provided data to the study. In 391 patients (82.5 %), R0 resection was achieved. Almost 60 % of the carcinomas of the oesophagogastric junction were approached in departments with no more than 10 of these tumour lesions through the whole study period (3 years). Endoscopic ultrasonography was performed in 283 cases (53 %); the rate of neoadjuvant treatment was 34.4 % (n = 187). Intraoperative fresh frozen section was only included in intraoperative decision-making in 242 patients (60.8 %). In the revealed heterogeneous spectrum of surgical interventions, a limited number of transthoracic approaches (20 %) and a mediastinal lymphadenectomy rate of only 47 % were found. Hospital lethality was 6.6 %. In the adenocarcinomas of the oesophagogastric junction, a significantly lower median survival (25 months) compared with distal gastric cancer (38 months) was observed depending on the tumour stage. In addition, 5-year survival rate of AEG patients (33.1 %) was distinctly lower than for patients with distal gastric cancer (41.4 %). There was no significantly better survival by neoadjuvant treatment in the group of investigated patients. The results in the treatment of carcinomas of the oesophagogastric junction in the multicentre setting including surgical departments of each profile and region even after introduction of multimodal therapeutic concepts are not satisfying. In particular, modern diagnostic and surgical strategies need to be widely used or their percentage has to be increased. In this context, centralisation of the surgical care of this specific tumour entity appears reasonable.


Encapsulation of menthol into cyclodextrin metal-organic frameworks: Preparation, structure characterization and evaluation of complexing capacity.
Cyclodextrin (CD)-metal-organic frameworks (MOFs) are developed as a new type of food-acceptable multi-porous material, which shows a great potential for controlled volatile compound release. This study aimed to synthesize CD-MOFs from potassium nitrate, crystallized with α-cyclodextrin (α-CD), β-CD or γ-CD, and their complex capacities were further evaluated using menthol encapsulation. Compared with CD, all the CD-MOFs had highly ordered crystal structures and more regular shapes. β-CD-MOF showed better thermal stability, with an initial thermal degradation temperature of 253 °C, higher than the other two CD-MOFs. The CD-MOFs were used for menthol encapsulation and the resulting menthol concentration within the inclusion complexes (ICs) was determined. The menthol concentration in ICs followed the order: β-CD-MOF > β-CD > γ-CD-MOF > γ-CD > α-CD ≥ α-CD-MOF. The menthol content and encapsulation efficiency of β-CD-MOF were 21.76% (w/w) and 22.54% (w/w) respectively, significantly higher than those of other reported solid materials, such as amylose, CD and V-type starch.


The dynamics of serum antibodies and metaplasia of the lung respiratory epithelium in influenza-virus-preimmunized mice subjected to immunosuppression.
Mice preimmunized with influenza virus A Scotland 840/74 H3N2 were given cyclophosphamide or hydrocortisone, then challenged with the same active virus. Serum antibody levels and metaplasia of the respiratory epithelium were followed for the next two weeks. Administration of the immunosuppressors was found to decrease antibody levels, and to delay the appearance of metaplasia by 7 days as compared with controls.


Sequential Sedimentation-Biofiltration System for the purification of a small urban river (the Sokolowka, Lodz) supplied by stormwater.
The study analyses the efficiency of a Sequentional Sedimentation-Biofiltration System (SSBS) built on the Sokolowka river in Lodz (Poland). It was constructed to purify a small urban river whose hydrological regime is dominated by stormwater and meltwater. The SSBS was constructed on a limited area as multi-zone constructed wetlands. The SSBS consists of three zones: sedimentation zone with structures added to improve sedimentation, a geochemical barrier made of limestone deposit and biofiltration zone. The purification processes of total suspended solids (TSS), total phosphorus (TP), total nitrogen (TP) and other nutrients: phosphates (PO43-), ammonium (NH4+) and nitrates (NO3-) of the SSBS were analyzed. Chloride (Cl-) reduction was investigated. Monitoring conducted in the first two hydrological years after construction indicated that the SSBS removed 61.4% of TSS, 37.3% of TP, 30.4% of PO43-, 46.1% of TN, 2.8% of NH4+, 44.8% of NO3- and 64.0% of Cl-. The sedimentation zone played a key role in removing TSS and nutrients. The geochemical barrier and biofiltration zone each significantly improved overall efficiency by 4-10% for TSS, PO43-, TN, NO3- and Cl-. Although the system reduced the concentration of chloride, further studies are needed to determine the circulation of Cl- in constructed wetlands (CWs), and to assess its impact on purification processes.


Redox-responsive carrier based on fluorinated gemini amphiphilic polymer for combinational cancer therapy.
Polymeric micelle has emerged as an efficient implement to overcome the shortcomings of conventional cancer chemotherapy due to its superior solubility of hydrophobic drugs and less side effects of drugs. However, insufficient dilution resistance and ordinary therapeutic effect severely restrict the further translation of current drug-loaded polymeric micelles. Here, we showed that well-defined G-Fn (n = 5, 9, 13) polymeric micelles possessed excellent capabilities as a drug carrier in light of high drug loading content, high stability and precise drug release combined with wonderful endocytosis efficiency to tumors. The representative G-F13 exhibited an excellent dilution resistance, outstanding high drug loading content (22 wt%) and drug loading efficiency (82%), which might be attributed to the extremely low critical micelle concentration conferred by its special Gemini structure and the superhydrophobicity of the fluorocarbon chain. Furthermore, the "cross-linked" internal fluoride membrane consisted of the two chains of the Gemini structure made G-F13 stable even after 24 h of incubation in 10% fetal bovine serum (FBS). The camptothecin (CPT) release was selectively triggered by glutathione (GSH) and H2O2, reaching 75% and 85% after 24 h respectively, in which only 15% of drugs leak under physiological conditions. The CCK-8 assays of Hela cells showed that CPT-loaded G-F13 micelles had high cell compatibility (200 μg/mL, 93% cell viability, 48 h) and high cancer cytotoxicity (IC50 0.1 μg/mL). Notably, a tenfold lower dosage of loaded CPT had an higher tumor growth inhibition than the free CPT. This result was attributed to the combined treatment of fluorinated drug carriers were more likely to penetrate the cell membrane to enter tumor cells, the cytotoxicity of selenic acid generated after the oxidation of G-F13 and the large amounts of CPT after redox release. Excellent physical and chemical properties as well as good therapeutic effects reveal that G-F13 can act as a promising drug carrier to widely use in cancer chemotherapy.


Insulin-Like Growth Factor-1 Contributes to Mucosal Repair by β-Arrestin2-Mediated Extracellular Signal-Related Kinase Signaling in Experimental Colitis.
Insulin-like growth factor-1 (IGF-1) possesses the ability to attenuate intestinal damage and promote mucosal repair of colitis. β-Arrestins, as the scaffolding proteins of G protein-coupled receptors or non-G protein-coupled receptors signaling, can be involved in IGF-1-mediated signaling pathways. However, the interaction of IGF-1 and β-arrestin2 in the mucosal repair of experimental colitis remains unexplored. Ulcerative colitis was induced in β-arrestin2 wild-type mice and β-arrestin2 knockout littermates by using 3% dextran sulfate sodium for 5 days, followed by regular water consumption for 1, 2, 3, and 4 weeks to analyze the mucosal repair from experimental colitis. Disease activity index and histologic score analyses were performed. Apoptosis and proliferation were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Ki-67 staining, respectively. The expressions of β-arrestin2, phospho (p)-IGF-1R, and p-extracellular signal-regulated kinase (ERK)1/2 were examined. Furthermore, β-arrestin2 was overexpressed or altered in HCT116 cells by transfection before IGF-1 treatment in vitro. IGF-1 and β-arrestin2 expression was up-regulated in the repairing phase of experimental colitis. Targeted deletion of β-arrestin2 delayed the repair of colitis by inhibiting cell proliferation without affecting the levels of IGF-1 and p-IGF-1R. The β-arrestin2/ERK signaling pathway was involved in IGF-1-mediated mucosal repair through promoting epithelial cell and goblet cell regeneration from experimental colitis. These results indicate that IGF-1 contributes to the mucosal repair by β-arrestin2-mediated ERK signaling in experimental colitis.


Design of novel porphyrin-binding peptides based on antibody CDR.
Novel porphyrin-binding peptides were designed on the basis of an antigen binding site of an antiheme monoclonal antibody. Synthetic peptides were modified with a pyrene moiety. The spectroscopic measurements revealed that the synthetic peptides bound a porphyrin effectively.


Glycogen in retinal horizontal cells of the African mud catfish Clarias gariepinus (Burchell, 1822) and its physiological significance.
This paper reports on glycogen store in the retinal horizontal cells (HC) of the African mud catfish Clarias gariepinus, as seen by histochemical reaction with periodic acid Schiff (PAS) and transmission electron microscopy in light- as well as dark-adapted state. Glycogen is abundant in the large somata and less in their axons, characterised ultrastructurally by many microtubules and extensive gap junctions interconnecting them. There was no apparent difference in glycogen content in HC somata between light- and dark adaptation, but the axons clearly showed absence of glycogen in dark condition. The HC somata (presynaptic) make synapses with dendrites in the outer plexiform layer. Müller cell inner processes, which contain more densely packed glycogen, invest the HC. Other cells of the inner nuclear layer do not show any appreciable content of glycogen. Rods, but not cones, contain abundant glycogen in their inner segments and synaptic terminals. It is likely that glycogen is used as energy substrate in hypoxia for this species that dwell muddy aquatic environment with low oxygen content. They appear to have high energy demand, and a high glycogen content in HC could act as a ready source to fulfil physiological processes, like microtubule-based transport of cargo from the large somata to axons and the maintenance of electrical activities across the gap junctions between the axonal processes. It is also likely that they can supplement glucose to the neighbouring inner nuclear layer neurons, which are clearly devoid of glycogen.


Convergence of cerebral inputs onto dentate neurons in monkey.
The patterns of convergence of inputs from different areas of the cerebral cortex and the peripheral nerves onto single dentate neurons was studied in cebus monkeys. Dentate neurons receive their strongest and most numerous inputs from the premotor and supplementary motor regions of area 6. The sensorimotor and frontal cortices have weaker projections to the dentate nucleus, while peripheral nerves and many other association cortical areas were found to be effective in influencing cells of the lateral cerebellum. Dentate cells that respond to stimulation of hindlimb regions of the sensorimotor cortex tend to receive their principal input from the supplementary motor area and medial premotor regions, while neurons responding to forelimb sensorimotor cortex tend to receive lateral premotor inputs. In addition there is a topographical organization within the ventral pole of dentate with the hindlimb represented in the anterior regions and the forelimb in the posterior regions. These results are compared with those of similar studies of interpositus and dentate neurons in cat and monkey. The differences between the afferent inputs to dentate and interpositus are consistent with the suggestion that the lateral cerebellum is involved in programming movement parameters before movement initiation while the intermediate zone is involved in up-dating the evolving movement.


Patient-Friendly, Olfactory-Targeted, Stimuli-Responsive Hydrogels for Cerebral Degenerative Disorders Ensured > 400% Brain Targeting Efficiency in Rats.
Non-invasive brain therapy for chronic neurological disorders is in high demand. Vinpocetine (VIN) tablets for cerebrovascular degenerative disorders ensued < 7% oral bioavailability. The olfactory pathway (providing direct brain access) can improve VIN pharmacokinetic/pharmacodynamic profile. In this context, VIN hydrogels based on temperature-, pH-, and ion-triggered gelation in physiological milieu were formulated. Poloxamer-chitosan (PLX-CS) and carbopol-HPMC-alginate (CP-HPMC-SA) systems were optimized for appropriate gelation time, temperature, and pH. PLX-CS-hydrogels exhibited strong mucoadhesion for > 8 h, while CP-HPMC-SA hydrogels were mucoadhesive in simulated nasal fluid, owing to pH and ion-activated gelation. Along with prolonged mucosal residence, hydrogels confirmed sustained VIN release (> 24 h), especially from CP-HPMC-SA hydrogels. As proof of concept, brain exposure of intranasal VIN hydrogels was investigated in rats versus VIN-IV bolus. PLX-CS provided 146% increase in AUC0-30 and 3-fold maximum brain concentration (BCmax) relative to IV bolus. BCmax was reached after 4 h versus 1 h (IV bolus). CP-HPMC-SA hydrogel showed superior brain targeting efficiency (460%) and brain direct transport percentage (78.23%). VIN plasma pharmacokinetics confirmed 45-60% reduction in AUCplasma versus IV bolus, while PCmax of CP-HPMC-SA and PLX-CS represented 17 and 28% that of IV bolus, respectively. Olfactory-targeted hydrogels grant effective, sustainable VIN brain level with minimal systemic exposure, thus, assuring lower dose, dose frequency, side effects, and per se better patient compliance.


Does a combination of two radiographs increase accuracy in detecting acid-induced periapical lesions and does it approach the accuracy of cone-beam computed tomography scanning?
The purpose of this study was to determine whether the use of a combination of 2 images (storage phosphor plates [SPPs] and F-speed films [Eastman Kodak, Rochester, NY]) with a 10° difference in horizontal beam angulation resulted in better detectability of chemically created periapical defects than when only 1 image was used and whether a detectability as good as that achieved by limited cone-beam computed tomography (LCBCT) scanning could be achieved. Lesions were created by 1, 1.5, and 2 hours of acid application apical to extracted teeth in jaw specimens. After repositioning, teeth were radiographed with Accu-I-Tomo LCBCT, Digora Optime SPP system, and F-speed films. The SPPs and films were exposed at 0° and 10° horizontal angulations. The diagnostic accuracy (Az) was compared using 2-way analysis of variance; pair-wise comparisons were performed using the post hoc t test. Kappa was used to measure interobserver agreement. A combination of 2 exposures with a 10° difference in horizontal angulation caused an increase, although not statistically significant, in the accuracy of both films and SPPs for all acid durations (P > .05) compared with when only 1 exposure was used. The accuracy did not approach that of LCBCT. Using a combination of 2 exposures instead of 1 did not significantly increase the accuracy in detecting acid-induced lesions at the apices of single-rooted premolars. The accuracy of LCBCT was superior.


B-mode ultrasound-detected carotid artery lesions with and without acoustic shadowing and their association with markers of inflammation and endothelial activation: the atherosclerosis risk in communities study.
In a cross-sectional study of 8695 men and women free of clinical CVD, aged 45-64 years at the 1987-1989 baseline Atherosclerosis Risk in Communities (ARIC) study exam, we examined the relationship between carotid artery lesions (CALs), with and without acoustic shadowing (AS) as an index of plaque mineralization, to systemic markers of inflammation and markers of endothelial function, including endothelial adhesion molecules. A three-level variable, based on the presence of extracranial CALs and AS, identified by B-mode ultrasound of six 1 cm arterial segments, defined the outcome. Among subjects without evidence of AS, after controlling for age, gender, ethnicity, study site, body mass index, hypertension, diabetes, and smoking status, CALs were associated with systemic markers of inflammation, including higher levels of fibrinogen [OR=1.24 (95% CI: 1.09, 1.40)] and white blood cell count [OR=1.37 (95% CI: 1.21, 1.56)]. Among subjects with a CAL, after controlling for the above risk factors as well as mean far wall intima-media thickness, AS was associated with higher levels of von Willebrand factor [OR=1.38 (95% CI: 1.10, 1.74)], a marker of endothelial activation. Associations with endothelial adhesion molecules were inconsistent. Further studies aimed at elucidating the mechanisms of arterial mineralization are warranted.


Controlling polymersome size through microfluidic-assisted self-assembly: Enabling 'ready to use' formulations for biological applications.
The self-assembly of poly(ethylene glycol)-block-poly(trimethylene carbonate) PEG-b-PTMC copolymers into vesicles, also referred as polymersomes, was evaluated by solvent displacement using microfluidic systems. Two microfluidic chips with different flow regimes (micromixer and Herringbone) were used and the impact of process conditions on vesicle formation was evaluated. As polymersomes are sensitive to osmotic variations, their preparation under conditions allowing their direct use in biological medium is of major importance. We therefore developed a solvent exchange approach from DMSO (Dimethylsulfoxide) to aqueous media with an osmolarity of 300 mOsm L-1, allowing their direct use for biological evaluation. We evidenced that the organic/aqueous solvent ratio does not impact vesicle size, but the total flow rate and copolymer concentration have been observed to influence the size of polymersomes. Finally, nanoparticles with diameters ranging from 76 nm to 224 nm were confirmed to be vesicles through the use of multi-angle light scattering in combination with cryo-TEM (Cryo-Transmission Electron Microscopy) characterization.


Centelloside accumulation in leaves of Centella asiatica is determined by resource partitioning between primary and secondary metabolism while influenced by supply levels of either nitrogen, phosphorus or potassium.
In the present study we aimed to investigate the relevance of either N, P or K supply for herb and leaf yield and for centelloside concentrations in Centella asiatica L. Urban leaves. In this regard, we elucidated the causal relationship between assimilation rate, leaf N, P and K concentrations, herb and leaf production, and centelloside accumulation. The experiments were conducted consecutively in a greenhouse where C. asiatica was grown in hydroponic culture and fertigated with nutrient solutions at either 0, 30, 60, 100 or 150% of the N, P or K amount in a standard Hoagland solution. In general, the increase in N, P or K supply enhanced assimilation rate and herb and leaf yield. However, exceeding specific thresholds, the high availability of one single nutrient caused lower leaf N concentrations and a decline in assimilation rate and plant growth. Irrespective of N, P and K supply, the leaf centelloside concentrations were negatively associated with herb and leaf yield, which is in accordance with the assumptions of the carbon/nutrient balance and the growth differentiation balance hypotheses. Moreover, we found strong negative correlations between saponins and leaf N concentrations, while the respective sapogenins were negatively correlated with K concentrations. Using C. asiatica as model system, our experiments reveal for the first time that the accumulation of saponins and sapogenins is affected by resource allocation between primary and secondary metabolism and that besides carbon, also nutrient availability is relevant for the regulation of the centelloside synthesis. Finally, our results highlight the huge potential of optimized and carefully controlled mineral nutrition of medicinal plants for steering the bio-production of high-quality natural products.


Fluram-Kemptide-Lys8 Non-radioactive Assay for Protein Kinase A.
The cAMP-dependent protein kinase (PKA) is the best understood member of the superfamily of serine-threonine protein kinases and is involved in controlling a variety of cellular processes. Measurements of PKA activity traditionally relied on the use of [(32)P]-labeled ATP as the phosphate donor and a protein or peptide substrate as the phosphoaceptor. Recently non-isotopic assays for the PKA have been developed and this paper presents an improvement of a fluorometric assay for measuring the activity of PKA. Three peptides were synthesized with the following sequences: LRRASLG (Kemptide), LRRASLGK (Kemptide-Lys8) and LRRASLGGGLRRASLG (Bis-Kemptide), these have in common the substrate sequence recognized by the PKA (RRXS/TΨ), where X is any amino acid and Ψ is a hydrophobic amino acid. Optimal conditions were established for the non-radioactive assay to detect the PKA activity by phosphorylation of these three peptides that are covalently linked to fluorescamine at their N-terminus. The phosphorylated and non-phosphorylated peptides were easily separated by electrophoresis, identified and quantified with optical densitometry and ultraviolet light. The fluorescamine-labeled Kemptide-Lys8 substrate (Fluram-Kemptide-Lys8) was used to calculate the Km and Vmax of the catalytic subunit of PKA from pig heart and showed a detection limit of 260 pmol, a linear range between 700 and 1150 pmol with a linear regression R (2) = 0.956.


Single- and Multifraction Stereotactic Radiosurgery Dose/Volume Tolerances of the Brain.
As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy investigating normal tissue complication probability (NTCP) after hypofractionated radiation therapy, data from published reports (PubMed indexed 1995-2018) were pooled to identify dosimetric and clinical predictors of radiation-induced brain toxicity after single-fraction stereotactic radiosurgery (SRS) or fractionated stereotactic radiosurgery (fSRS). Eligible studies provided NTCPs for the endpoints of radionecrosis, edema, or symptoms after cranial SRS/fSRS and quantitative dose-volume metrics. Studies of patients with only glioma, meningioma, vestibular schwannoma, or brainstem targets were excluded. The data summary and analyses focused on arteriovenous malformations (AVM) and brain metastases. Data from 51 reports are summarized. There was wide variability in reported rates of radionecrosis. Available data for SRS/fSRS for brain metastases were more amenable to NTCP modeling than AVM data. In the setting of brain metastases, SRS/fSRS-associated radionecrosis can be difficult to differentiate from tumor progression. For single-fraction SRS to brain metastases, tissue volumes (including target volumes) receiving 12 Gy (V12) of 5 cm3, 10 cm3, or >15 cm3 were associated with risks of symptomatic radionecrosis of approximately 10%, 15%, and 20%, respectively. SRS for AVM was associated with modestly lower rates of symptomatic radionecrosis for equivalent V12. For brain metastases, brain plus target volume V20 (3-fractions) or V24 (5-fractions) <20 cm3 was associated with <10% risk of any necrosis or edema, and <4% risk of radionecrosis requiring resection. The risk of radionecrosis after SRS and fSRS can be modeled as a function of dose and volume treated. The use of fSRS appears to reduce risks of radionecrosis for larger treatment volumes relative to SRS. More standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses that can refine predictive models of brain toxicity risks.


Deyeuxia angustifolia Kom. encroachment changes soil physicochemical properties and microbial community in the alpine tundra under climate change.
Plant encroachment in alpine regions, caused by global changes and human activities, has been well documented. However, our knowledge of the effects of plant encroachment on belowground microbial communities is limited. Here, we investigated soil physicochemical properties and microbial community structures under the impact of plant encroachment along an elevation gradient in the alpine tundra of the Changbai Mountain, China. We found that plant encroachment had insignificant (P > 0.05) and inconsistent effects on the α-diversity (number of observed OTUs, Shannon, Chao1, Faith's PD) of soil microbial communities. Plant encroachment indirectly influenced soil microbial community structures by altering soil physicochemical properties, which differed between elevations and plant types (P < 0.05). In all, 40 bacterial indicator taxa and 57 fungal indicator taxa significantly shifted in response to plant encroachment, some of which were involved in soil biogeochemical cycle. Overall, our results documented the impacts of plant encroachment on soil microbial diversity and community composition, and provided a scientific basis for predicting future changes in alpine ecosystem structure and function and its subsequent feedbacks to global change.


Cycloartane and friedelane triterpenoids from the leaves of Caloncoba glauca and their evaluation for inhibition of 11β-hydroxysteroid dehydrogenases.
Five new triterpenoids, caloncobic acids A and B (1 and 2), caloncobalactones A and B (3 and 4), and glaucalactone (5), along with the known compounds 3β,21β-dihydroxy-30-nor-(D:A)-friedo-olean-20(29)-en-27-oic acid (6) and acetyltrichadenic acid B (7), were isolated from the leaves of Caloncoba glauca. The structures of 1-5 were elucidated using spectroscopic methods. Compounds 1-7 were evaluated for their inhibitory activities against two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2). Compounds 1 and 2 exhibited strong inhibitory activities against mouse (EC(50) 132 and 13 nM) and human (EC(50) 105 and 72 nM) 11β-HSD1.


Automatic diagnosis of COVID-19 from CT images using CycleGAN and transfer learning.
The outbreak of the corona virus disease (COVID-19) has changed the lives of most people on Earth. Given the high prevalence of this disease, its correct diagnosis in order to quarantine patients is of the utmost importance in the steps of fighting this pandemic. Among the various modalities used for diagnosis, medical imaging, especially computed tomography (CT) imaging, has been the focus of many previous studies due to its accuracy and availability. In addition, automation of diagnostic methods can be of great help to physicians. In this paper, a method based on pre-trained deep neural networks is presented, which, by taking advantage of a cyclic generative adversarial net (CycleGAN) model for data augmentation, has reached state-of-the-art performance for the task at hand, i.e., 99.60% accuracy. Also, in order to evaluate the method, a dataset containing 3163 images from 189 patients has been collected and labeled by physicians. Unlike prior datasets, normal data have been collected from people suspected of having COVID-19 disease and not from data from other diseases, and this database is made available publicly. Moreover, the method's reliability is further evaluated by calibration metrics, and its decision is interpreted by Grad-CAM also to find suspicious regions as another output of the method and make its decisions trustworthy and explainable.


Cross cultural verbal cues to deception: truth and lies in first and second language forensic interview contexts.
The verbal deception literature is largely based upon North American and Western European monolingual English speaker interactions. This paper extends this literature by comparing the verbal behaviors of 88 south Asian bilinguals, conversing in either first (Hindi) or second (English) languages, and 48 British monolinguals conversing in English. All participated in a live event following which they were interviewed having been incentivized to be either deceptive or truthful. Event details, complications, verifiable sources, and plausibility ratings were analyzed as a function of veracity, language and culture. Main effects revealed cross cultural similarities in both first and second language interviews whereby all liar's verbal responses were impoverished and rated as less plausible than truthtellers. However, a series of cross-cultural interactions emerged whereby bi-lingual South Asian truthtellers and liars interviewed in first and second languages exhibited varying patterns of verbal behaviors, differences that have the potential to trigger erroneous assessments in practice. Despite limitations, including concerns centered on the reductionary nature of deception research, our results highlight that while cultural context is important, impoverished, simple verbal accounts should trigger a 'red flag' for further attention irrespective of culture or interview language, since the cognitive load typically associated with formulating a deceptive account apparently emerges in a broadly similar manner.


Micromolded PDMS planar electrode allows patch clamp electrical recordings from cells.
The patch clamp method measures membrane currents at very high resolution when a high-resistance 'gigaseal' is established between the glass microelectrode and the cell membrane (Pflugers Arch. 391 (1981) 85; Neuron 8 (1992) 605). Here we describe the first use of the silicone elastomer, poly(dimethylsiloxane) (PDMS), for patch clamp electrodes. PDMS is an attractive material for patch clamp recordings. It has low dielectric loss and can be micromolded (Annu. Rev. Mat. Sci. 28 (1998) 153) into a shape that mimics the tip of the glass micropipette. Also, the surface chemistry of PDMS may be altered to mimic the hydrophilic nature of glass (J. Appl. Polym. Sci. 14 (1970) 2499; Annu. Rev. Mat. Sci. 28 (1998) 153), thereby allowing a high-resistance seal to a cell membrane. We present a planar electrode geometry consisting of a PDMS partition with a small aperture sealed between electrode and bath chambers. We demonstrate that a planar PDMS patch electrode, after oxidation of the elastomeric surface, permits patch clamp recording on Xenopus oocytes. Our results indicate the potential for high-throughput patch clamp recording with a planar array of PDMS electrodes.


A pilot study on the feasibility, acceptability, and preliminary efficacy of a brief text message intervention for co-occurring alcohol misuse and PTSD symptoms in a community sample.
Accessible, brief, and self-directed intervention are needed to improve treatment access for individuals with co-occuring PTSD and alcohol misuse. This pilot study tests the feasibility, acceptability, and preliminary efficacy of a brief text message intervention based on cognitive behavioral therapy plus message framing (CBT + Framing) compared to active control providing kind support and attention (KAM), to reduce PTSD symptoms and alcohol use. Two waves of community-based data collection (Wave 1 n = 50; Wave 2 n = 59) were completed. Participants self-reported symptoms at baseline, post-intervention, and 8-week follow-up. Engagement and retention were high, suggesting messages were feasible and acceptable. Across waves and conditions, from baseline to follow-up primary outcomes of PTSD symptoms (medium to large effects), weekly drinks (medium effects), and heavy episodic drinking (small to medium effects) decreased. Consistent with hypotheses, CBT + Framing outperformed KAM for PTSD at post in Wave 2 and for number of heavy drinking episodes at both post and follow-up in Wave 1. Contrary to hypotheses, KAM outperformed CBT + Framing for PTSD at post in Wave 1, and minimal differences were observed between conditions for weekly drinks in both waves. Future studies should continue to develop and test brief, accessible interventions.


Optimization of Serum Immunoglobulin Free Light Chain Analysis for Subclassification of Cardiac Amyloidosis.
Accurate and rapid classification of cardiac amyloidosis is important for patient management. We have optimized the use of serum free light chain kappa and lambda values to differentiate immunoglobulin light chain amyloid (AL) amyloidosis from transthyretin amyloid and amyloid A using 85 cases of tissue-proven cardiac amyloidosis, in which there was direct classification of amyloidosis by mass spectrometry or immunofluorescence. The serum free light chain kappa/lambda ratios were non-overlapping for the three major groups: AL-lambda (0.01-0.41, n = 30), non-AL (0.52-2.7, n = 43), and AL-kappa (6.7-967, n = 12). A kappa/lambda ratio value between 0.5 and 5.0 had 100 % sensitivity and 100 % specificity for distinguishing AL amyloidosis from non-AL amyloidosis. This optimized range for serum light chain kappa/lambda ratio provides extremely robust classification of cardiac amyloidosis. Cases of cardiac amyloidosis in which the serum kappa/lambda free light chain ratio falls close to these new cutoff values may benefit most from direct amyloid subtyping.


Hypertrophic cardiomyopathy--pathology and pathogenesis.
Genes on five loci on separate chromosomes are responsible for a familial disease in which all or part of the ventricular muscle undergoes thickening with a histological picture of irregular hypertrophy and disorganized arrangement of myocytes (disarray). The three genes identified so far encode for beta heavy chain myosin (chromosome 14), troponin T (chromosome 1) and alpha tropomyosin (chromosome 15). It is postulated that the phenotype within the heart is produced by abnormal myofibril formation and alignment leading to an abnormal cell shape and, thus, disarray. While all the myocytes carry the gene, the regional selectivity of the hypertrophy is unexplained. The phenotypic expression of the disease within affected members of one family, all of whom are heterozygous for the same gene abnormality, is very varied. Asymptomatic carriers are common, and new mutations do not account for most apparently isolated cases. The phenotypic expression of the disease was studied in 75 hearts. The increase in total heart weight ranged from near normal to over 800 g. Ventricular involvement was diffuse and symmetric in 42%. The commonest asymmetric form involved the anteroseptal region (31%) but sporadic cases involved only the posterior or lateral wall. A minority of cases (9.5%) did not show macroscopic wall thickening. Fibrosis is often associated with dysplastic changes in the media of small intramyocardial arteries and may lead to the ventricular wall simulating a dilated cardiomyopathy. A subaortic patch of endocardial thickening on the ventricular septum due to contact with the anterior cusp of the mitral valve was found in a third of cases.(ABSTRACT TRUNCATED AT 250 WORDS)


A Polysomnographic Study of Effects of Sleep Deprivation on Novice and Senior Surgeons during Simulated Vitreoretinal Surgery.
To assess the impact of a 3-hour polysomnography (PSG)-recorded night of sleep deprivation on next-morning simulated microsurgical skills among vitreoretinal (VR) surgeons with different levels of surgical experience and associate the sleep parameters obtained by PSG with Eyesi-generated performance. Self-controlled cohort study. Eleven junior VR surgery fellows with < 2 years of surgical experience and 11 senior surgeons with > 10 years of surgical practice. Surgical performance was assessed at 7am after a 3-hour sleep-deprived night using the Eyesi simulator and compared with each subject's baseline performance. Changes in Eyesi-generated score (0-700, worst to best), time for task completion (minutes), tremor-specific score (0-100, worst to best), and out-of-tolerance tremor percentage. Polysomnography was recorded during sleep deprivation. Novice surgeons had worse simulated surgical performance after sleep deprivation compared with self-controlled baseline dexterity in the total score (559.1 ± 39.3 vs. 593.8 ± 31.7; P = 0.041), time for task completion (13.59 ± 3.87 minutes vs. 10.96 ± 1.95 minutes; P = 0.027), tremor-specific score (53.8 ± 19.7 vs. 70.0 ± 15.3; P = 0.031), and out-of-tolerance tremor (37.7% ± 11.9% vs. 28.0% ± 9.2%; P = 0.031), whereas no performance differences were detected in those parameters among the senior surgeons before and after sleep deprivation (P ≥ 0.05). Time for task completion increased by 26% (P = 0.048) in the post-sleep deprivation simulation sessions for all participants with a high apnea-hypopnea index (AHI) and by 37% (P = 0.008) among surgeons with fragmented sleep compared with those with normal AHI and < 10 arousals per hour, respectively. Fragmented sleep was the only polysomnographic parameter associated with a worse Eyesi-generated score, with a 10% (P = 0.005) decrease the following morning. This study detected impaired simulated surgical dexterity among novice surgeons after acute sleep deprivation, whereas senior surgeons maintained their surgical performance, suggesting that the impact of poor sleep quality on surgical skills is offset by increased experience. When considering the 2 study groups together, sleep fragmentation and AHI were associated with jeopardized surgical performance after sleep deprivation. The authors have no proprietary or commercial interest in any materials discussed in this article.


Measuring eye position with the double magnetic induction method.
The double magnetic induction method of monitoring eye movements eliminates problems associated with the external wire leads of the standard magnetic search-coil technique by substituting a closed metal ring for the eye coil. However, external coils used in the double-induction method must be adjusted at the beginning of each session, and the system is very sensitive to mechanical disturbances. An apparatus is described whose ease of adjustment and good mechanical stability make the double-induction method as convenient and reliable as the standard method. The performance of the system is evaluated for different physical arrangements of critical components, and some practical advice on various aspects of the double-induction method is offered.


[Vitiligo revealing Vogt -Koyanagi-Harada disease].
Vitiligo is a chronic auto-immune skin disease, often associated or discovers other autoimmune pathologies. His association with Ophthalmological type pan uveitis and/or neurological type of meningitis and/or inner ear type of hearing loss determines the disease or Vogt -Koyanagi-Harada syndrome (VKH). We related the case of a young woman who consulted for recurrent uveitis for a year, and it was only with the onset of vitiligo lesions that VKH disease diagnosis was discussed and confirmed.


Development of a novel scintillation proximity radioimmunoassay for platelet-activating factor measurement: comparison with bioassay and GC/MS techniques.
A novel, facile and sensitive scintillation proximity radioimmunoassay (SPRIA) for quantitation of PAF has been developed. No separation of antibody bound [3H]PAF from free [3H]PAF is required as the assay employs protein A - coated fluomicrospheres (beads containing scintillant). The assay system was suitable for the quantitation of 0.03 to 2 pmol of 1-hexadecyl-2-acetyl-sn-glycero-3- phosphocholine. The cross-reactivity was high with 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine but was very low with PAF analogs such as 1-alkyl- and 1-acyl-2-lyso-sn-glycero-3-phosphocholine, 1-acyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine. The specificity of SPRIA was higher than that of bioassay (platelet degranulation assay). PAF receptor antagonists (L-652,731, WEB2086, and FR900452) at up to 10 nmol per tube had no affect on the SPRIA. These observations indicate that the specificity of the PAF antibody is quite different from that of the platelet receptor. The values obtained using SPRIA for the measurement of PAF produced in polymorphonuclear leukocytes with stimuli are comparable to those obtained by SIM/GC/MS analysis.


'You learn better under the gun': intimidation and harassment in surgical education.
Medical literature has documented a high prevalence of intimidation and harassment in the educational context. However, the research has failed to adequately delineate the nature of these phenomena as well as the different ways in which diverse actors perceive the behaviours in question. Based on qualitative methodology anchored in a social constructionism framework, how teachers (staff surgeons) and learners (surgical residents) define intimidation and harassment were documented and compared. In addition, teachers' and learners' perceptions of the impact of these behaviours on the learning environment, including their effects on the socialisation of surgeons in training, were examined. Five group interviews and 22 individual interviews were conducted across 2 university departments of surgery with a total of 22 faculty and 14 resident participants. Interviewees acknowledged the existence of intimidation and harassment, while at the same time rationalising its occurrence. This paradox was encapsulated in participant descriptions using terms such as 'good intimidation'. Our examination of the data helped us to understand that participants sustained the paradox of beneficial intimidation and harassment by rationalising questionable behaviours on 3 specific dimensions, namely: whether an acceptable purpose could be attributed to the perpetrator; whether positive effects of the behaviour existed, and whether there was a perceived necessity for the behaviour. Even while their dysfunctional characteristics are recognised, intimidation and harassment are often seen as functional educational tools. The cultural value currently accorded these behaviours needs to be taken into account in educational interventions designed to shift attitudes and actions in this domain.


Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.
Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.


Habitat selection by two streamside plethodontid salamanders.
A series of experiments was conducted to test the hypothesis that habitat selection by the salamanders Desmognathus monticola and Desmognathus quadramaculatus is influenced differently by interspecific interference than by intraspecific interference. Individuals of neither species were influenced differently by the presence of heterospecifics than by the presence of conspecifics in their activity away from cover sites, in selection of different substrate moisture levels, in selection of different substrate textures, nor in selection of microhabitats relative to the streambed. Both species generally selected substrates with the highest moisture and the coarsest texture. Selection of different cover sizes by D. monticola depended on microhabitat, with larger rocks being selected most frequently when salamanders were farther from the streambed. D. quadramaculatus was seldom found away from the streambed and did not discriminate among the cover sizes available. The strong affinity of D. quadramaculatus for streambed microhabitat, compared with the much more variable microhabitat selection of D. monticola, resulted in spatial separation of individuals of the two species most of the time. Results of this study do not support the hypothesis that interspecific inference is more important than intraspecific interference in the microhabitat distributions of D. monticola and D. quadramaculatus.


Bovine serum hemopexin: properties of the protein from a single animal.
1. Hemopexin was isolated from bovine serum of a single animal in a yield of 0.5 mg/ml. 2. Bovine hemopexin was found to exist in two isoforms of mol. wt 68,000 and 65,000. 3. Treatment of hemopexin with glycopeptidase F yields a single band corresponding to a mol. wt of 51,000. 4. The protein binds heme on an equimolar ratio and shows a single component in reverse-phase high performance liquid chromatography. 5. The amino acid composition of bovine hemopexin compares with that of hemopexin isolated form other animals.


Draft Genome Sequences of Mycobacterium bovis BZ 31150 and Mycobacterium bovis B2 7505, Pathogenic Bacteria Isolated from Archived Captive Animal Bronchial Washes and Human Sputum Samples in Uganda.
Bovine tuberculosis (BTB), a zoonotic infection of cattle caused by Mycobacterium bovis, results in losses of $3 billion to the global agricultural industry and represents the fourth most important livestock disease worldwide. M. bovis as a source of human infection is likely underreported due to the culture medium conditions used to isolate the organism from sputum or other sample sources. We report here the draft genome sequences of M. bovis BZ 31150, isolated from a bronchial washing from a captive chimpanzee, and M. bovis B2 7505, isolated from a human sputum sample in Uganda.