Purification and characterization of pre-S-containing hepatitis B surface antigens produced in recombinant mammalian cell culture.
Heterogeneous, pre-S-rich HBsAg particles were expressed in recombinant mammalian cell culture and purified to near homogeneity. The purification process comprises: concentration of cell culture medium, protein precipitation by poly(ethylene glycol), gel filtration column chromatography, isopycnic ultracentrifugation by KBr and sucrose density gradient ultracentrifugation. The resulting HBsAg product was greater than 98% pure, and contained much of pre-S1 and pre-S2 components. Scanning densitometry analysis of the silver-stained HBsAg product showed approximately 70-80% S protein, approximately 10-20% pre-S2 protein, and approximately 5-15% pre-S1 protein. It was estimated that the amount of HBV-specific DNA present the final product was less than 7 pg mg-1 HBsAg. Further biochemical analysis has demonstrated that the HBsAg particles are very heterogeneous in charge and density. Charge heterogeneity was quite random among the particles, but density heterogeneity could be related to the different amounts of pre-S2 component in the particles.


Modeling nicotine addiction in rats.
Among the human population, 15% of drug users develop a pathological drug addiction. This figure increases substantially with nicotine, whereby more than 30% of those who try smoking develop a nicotine addiction. Drug addiction is characterized by compulsive drug-seeking and drug-taking behaviors (craving), and loss of control over intake despite impairment in health, social, and occupational functions. This behavior can be accurately modeled in the rat using an intravenous self-administration (IVSA) paradigm. Initial attempts at establishing nicotine self-administration had been problematic, yet in recent times increasingly reliable models of nicotine self-administration have been developed. The present article reviews different characteristics of the nicotine IVSA model that has been developed to examine nicotine reinforcing and motivational properties in rats.


Loss of E-cadherin and cytoplasmic-nuclear expression of beta-catenin are the most useful immunoprofiles in the diagnosis of solid-pseudopapillary neoplasm of the pancreas.
Solid-pseudopapillary neoplasm of the pancreas occurs preferentially in young women and has a favorable prognosis. Differentiation of solid-pseudopapillary neoplasm from pancreatic endocrine neoplasm or adenocarcinoma can be difficult in the small biopsy specimen because they share common morphological features and immunoprofiles. Alterations of adenomatous polyposis coli (APC)/beta-catenin pathway have been identified as a genetic event contributing to the development of solid-pseudopapillary neoplasm. In the present study, to establish the diagnostic utility of beta-catenin and E-cadherin as markers for solid-pseudopapillary neoplasm, we performed immunohistochemical staining in 4 core biopsy specimens diagnosed as solid-pseudopapillary neoplasm and in tissue microarray blocks that contained histologically confirmed samples of 302 cases of adenocarcinoma, 56 cases of pancreatic endocrine neoplasm, and 50 cases of solid-pseudopapillary neoplasm. We compared the immunohistochemical results for beta-catenin and E-cadherin with those for known markers. Of the solid-pseudopapillary neoplasm cases, 51 (94.4%) were positive for nuclear beta-catenin, 45 (83.3%) were positive for CD10, 30 (55.5%) were positive for CD56, 15 (27.8%) were positive for synaptophysin, 3 (5.6%) were positive for cytokeratin (CK), and none was positive for E-cadherin and chromogranin. Of the adenocarcinoma cases, all were positive for CK, 300 (99.3%) were positive for E-cadherin, 30 (9.9%) were positive for CD10, 2 (0.7%) were positive for synaptophysin, 1 (0.3%) was positive for CD56, and none was positive for chromogranin and nuclear expression of beta-catenin. Of the pancreatic endocrine neoplasm cases, 54 (96.4%) were positive for synaptophysin and E-cadherin, 50 (89.3%) were positive for chromogranin, 26 (46.4%) were positive for CK, 15 (26.8%) were positive for CD56, 6 (10.7%) were positive for CD10, and none was positive for nuclear expression of beta-catenin. In conclusion, nuclear expression of beta-catenin and loss of E-cadherin can be used in the definite diagnosis of solid-pseudopapillary neoplasm on small biopsy specimens. CD10 immunopositivity should be carefully interpreted in the diagnosis of solid-pseudopapillary neoplasm because pancreatic adenocarcinoma or pancreatic endocrine neoplasm can also stain for CD10.


The utility of technetium-99m pertechnetate thyroid scintigraphy assessing thyroid/salivary ratio as an alternative to thyroid uptake percentage in evaluation of thyroid function, with establishing normal reference values of both parameters: single Egyptian center study.
Management of thyroid disorders depends on accurate clinical assessment, appropriate investigations and radionuclide imaging, which plays an established important role either qualitatively or quantitatively. The aim of this study was to assess the utility of the thyroid/salivary ratio (TSR) as an alternative to technetium-99m (Tc99m) pertechnetate thyroid uptake (TcU) percentage in the evaluation of thyroid function and in the same time to establish reference range for the thyroid uptake of Tc99m-pertechnetate and TSR among Egyptian populations. This retrospective study enrolled 270 patients, out of which 250 with different thyroid disorders and 20 without thyroid diseases, as a control group who all underwent full clinical examination, thyroid function tests and Tc99m pertechnetate thyroid scintigraphy. The TcU percentage and TSR were calculated and then correlated to the thyroid hormonal profile. The normal reference ranges of TcU and TSR were 0.75-3.5% and 1.25-4.8%, respectively. The sensitivity and specificity of TSR to diagnose hyperthyroidism were slightly lower compared with TcU (84.5 and 92.3% vs. 86.2 and 98.3%, respectively) at TSR cutoff value of more than 4.8 and TcU cutoff value of more than 3.5. Meanwhile, they had comparable sensitivity and specificity to diagnose hypothyroidism (86.0 and 93.3% vs. 86.5 and 94.5%) at cutoff values <0.75 and <1.25, respectively. The current study established a reference range for TcU and TSR in our institution. TSR is comparable to TcU in the evaluation of thyroid function among hyper-and hypothyroid patients and TSR can be used in doubtful cases of mal-thyroid function for confirmation of the diagnosis.


Coronin 1A depletion protects endothelial cells from TNFα-induced apoptosis by modulating p38β expression and activation.
Coronins are conserved actin-binding proteins that regulate various cellular processes such as migration and endocytosis. Among coronin family members, coronin 1A is highly expressed in hematopoietic lineage cells where it regulates cell homeostasis. However, the expression and function of coronin 1A in endothelial cells have not yet been elucidated. We found that coronin 1A is expressed in the human umbilical vein endothelial cell (HUVEC) and human brain microvascular endothelial cell (HBMVEC). In HUVEC depleted of coronin 1A by siRNA transfection, tumor necrosis factor α (TNFα)+cyclohexamide (CHX) treatment resulted in a decrease in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive apoptotic cells. Coronin 1A depletion also resulted in the suppression of caspase 3 and poly(ADP-ribose) polymerase cleavage and a reduction in caspase 3 activity. Next, we examined TNFα-induced activation of several pro- and anti-apoptotic signaling molecules to find the target molecule of coronin 1A and found that p38 phosphorylation was enhanced by TNFα stimulation in coronin 1A-depleted HUVEC. Among the p38 isoforms, the expression of p38β was significantly upregulated after coronin 1A depletion, suggesting that the expression and phosphorylation of anti-apoptotic p38β were significantly induced in coronin 1A-depleted HUVEC. Inhibition of p38β upregulation in coronin 1A-depleted HUVEC restored the cleavage of caspase 8 and caspase 3 and induced more apoptosis than in coronin 1A-depleted HUVEC in response to TNFα+CHX. These findings suggest that coronin 1A modulates endothelial cell apoptosis by regulating p38β expression and activation.


Lifetime risk of diabetes in metropolitan cities in India.
We aimed to estimate the lifetime risk of diabetes and diabetes-free life expectancy in metropolitan cities in India among the population aged 20 years or more, and their variation by sex, age and BMI. A Markov simulation model was adopted to estimate age-, sex- and BMI-specific lifetime risk of developing diabetes and diabetes-free life expectancy. The main data inputs used were as follows: age-, sex- and BMI-specific incidence rates of diabetes in urban India taken from the Centre for Cardiometabolic Risk Reduction in South Asia (2010-2018); age-, sex- and urban-specific rates of mortality from period lifetables reported by the Government of India (2014); and prevalence of diabetes from the Indian Council for Medical Research INdia DIABetes study (2008-2015). Lifetime risk (95% CI) of diabetes in 20-year-old men and women was 55.5 (51.6, 59.7)% and 64.6 (60.0, 69.5)%, respectively. Women generally had a higher lifetime risk across the lifespan. Remaining lifetime risk (95% CI) declined with age to 37.7 (30.1, 46.7)% at age 60 years among women and 27.5 (23.1, 32.4)% in men. Lifetime risk (95% CI) was highest among obese Indians: 86.0 (76.6, 91.5)% among 20-year-old women and 86.9 (75.4, 93.8)% among men. We identified considerably higher diabetes-free life expectancy at lower levels of BMI. Lifetime risk of diabetes in metropolitan cities in India is alarming across the spectrum of weight and rises dramatically with higher BMI. Prevention of diabetes among metropolitan Indians of all ages is an urgent national priority, particularly given the rapid increase in urban obesogenic environments across the country. Graphical abstract.


Calcium transport by pigeon erythrocyte membrane vesicles.
Membrane vesicles from pigeon erythrocytes show a rapid, ATP-dependent accumulation of 45Ca2+.Ca2+ accumulation ratios greater than or approximately equal to 10(4) are readily attained. For ATP-dependent Ca2+ uptake, V is 1.5 mmol.1(-1).min(-1) at 27 degrees C (approx. 0.9 nmol.mg-1 protein.min-1), [Ca2+]1/2 is 0.18 microM, [ATP]1/2 is 30--60 microM, the Ca2+ uptake rate depends on [Ca2+]2 and the dependence of uptake rate on ATP concentration implies strong ATP-ATP cooperativity. The Arrhenius activation energy is 19.1 +/- 1.4 kcal/mol and the pH optimum is approx. 6.9.


Should Buprenorphine Be Considered a First-Line Opioid for the Treatment of Moderate to Severe Cancer Pain?
Cancer pain remains a significant problem worldwide, affecting more than half of patients receiving anti-cancer treatment and most patients with advanced disease. Opioids remain the cornerstone of therapy, and morphine, given its availability, multiple formulations, price, and evidence base, is typically considered the first-line treatment for moderate to severe cancer pain. Buprenorphine has emerged in recent decades as an alternative opioid for treating chronic pain and substance use disorder (SUD). However, it remains controversial whether buprenorphine should be considered a first-line opioid for moderate to severe cancer pain. In this "Controversies in Palliative Care" article, three expert clinicians independently answer this question. Specifically, each group provides a synopsis of the key studies that inform their thought process, share practical advice on their clinical approach, and highlight the opportunities for future research. All three groups agree that there is a place for the use of buprenorphine as a first-line opioid in cancer pain. Specifically, they mention populations of elderly patients, patients with renal failure, and those with (SUD). They also underscore many unique and favorable characteristics of buprenorphine, such as the low risk for respiratory depression, lack of adverse effects on testosterone levels in men, no risk of serotonin syndrome when combined with antidepressants, and ease of use given its transdermal, transmucosal, and sublingual formulations. However, further studies are needed to guide the use of buprenorphine for cancer pain-primarily randomized clinical trials (RCTs) comparing buprenorphine with other opioids in various pain syndromes.


Design of online formative assessment of nursing humanities curriculum during the COVID-19 pandemic: A teaching practice research.
Under the digital transformation trend nursing education, online formative assessment (OFA) provides a new opportunity. However, the OFA of nursing humanities course lacks design and practice, and faces the challenge of enhancing effective communication between teachers and students, student participation and autonomous learning. To enhance the reliability of OFA in nursing humanities courses and provide practical experience for online teaching in the nursing profession. A quantitative research approach was used. This study was conducted in a comprehensive university in China. We conducted teaching practice on 185 nursing undergraduates, with 89 students in the experimental group, and 96 students in the control group. In the 2020-2021 multicultural nursing course, student learning outcomes and questionnaires were analyzed through the online learning tool Superstar Learning, student feedback and satisfaction questionnaires, and descriptive analysis and independent sample t-tests were conducted using SPSS 25.0 software. The OFA of students using Superstar Learning differed in learning performance and time to receive feedback from teachers between the experimental and control groups, and both groups had higher satisfaction levels. The experimental group's instructional design contained a synchronous classroom discussion module with better participation. During the COVID-19 pandemic, the use of online learning tools can support the implementation of OFA, build an environment where teachers and students participate together, have a positive impact on the continuous updating of teachers' teaching programs and students' learning outcomes. Simultaneous classroom discussions are expected to be an effective way to improve the reliability of OFA. Our instructional design, provides best practice suggestions for future online teaching and learning.


The Norwegian preeclampsia family cohort study: a new resource for investigating genetic aspects and heritability of preeclampsia and related phenotypes.
Preeclampsia is a major pregnancy complication without curative treatment available. A Norwegian Preeclampsia Family Cohort was established to provide a new resource for genetic and molecular studies aiming to improve the understanding of the complex pathophysiology of preeclampsia. Participants were recruited from five Norwegian hospitals after diagnoses of preeclampsia registered in the Medical birth registry of Norway were verified according to the study's inclusion criteria. Detailed obstetric information and information on personal and family disease history focusing on cardiovascular health was collected. At attendance anthropometric measurements were registered and blood samples were drawn. The software package SPSS 19.0 for Windows was used to compute descriptive statistics such as mean and SD. P-values were computed based on t-test statistics for normally distributed variables. Nonparametrical methods (chi square) were used for categorical variables. A cohort consisting of 496 participants (355 females and 141 males) representing 137 families with increased occurrence of preeclampsia has been established, and blood samples are available for 477 participants. Descriptive analyses showed that about 60% of the index women's pregnancies with birth data registered were preeclamptic according to modern diagnosis criteria. We also found that about 41% of the index women experienced more than one preeclamptic pregnancy. In addition, the descriptive analyses confirmed that preeclamptic pregnancies are more often accompanied with delivery complications. The data and biological samples collected in this Norwegian Preeclampsia Family Cohort will provide an important basis for future research. Identification of preeclampsia susceptibility genes and new biomarkers may contribute to more efficient strategies to identify mothers "at risk" and contribute to development of novel preventative therapies.


Urgent Start Peritoneal Dialysis: A Population-Based Cohort Study.
It is a common practice to start patients in urgent need of dialysis on hemodialysis via a central venous catheter. Because central venous catheter use is associated with increased risk of infections, hospitalizations, and mortality, urgent start peritoneal dialysis (PD) increasingly represents a viable alternative. This study aimed to examine clinical outcomes, complications, mortality, and modality retention in patients who initiated urgent start PD. Retrospective cohort study. Eighty-four adult members of a large integrated health care system who initiated urgent start PD between January 1, 2011, and December 31, 2014. Urgent start PD. Retention rates at 30, 90, and 365 days; time to the development of noninfectious and infectious complications, modality failure, and all-cause mortality. Cumulative incidence of all-cause mortality was estimated using the Kaplan-Meier method. Retention rates for PD were computed using binomial proportions. Occurrence of major complications was less than 5%. Catheter malfunction occurred in 6% of cases; of those, catheter patency could be established in 80%. Infectious complications occurred in 20% of patients who initiated PD and included peritonitis and exit site infections. At 365 days after initiation, the cumulative incidence of all-cause mortality was 9.7% (95% CI, 4.7%-19.4%). PD retention rates were 98.8%, 91.3%, and 80.0% at 30 days, 90 days, and 1 year, respectively. Retrospective cohort design, a well-matched comparable group of urgent start hemodialysis patients could not be identified, small number of patients in a single integrated health care system, uncertain or limited generalizability of findings to other health care systems. At 1 year after initiation, patients who initiated urgent start PD had high survival and modality retention rates. In unplanned initiation of dialysis, urgent start PD is a viable and sustainable option and should be considered in selected patients to optimize care.


Impacts of intervals between sequential development of depression and dementia in older adults: A nationwide population-based study.
Depression has been reported as a risk factor for dementia, as well as the continuation of dementia development. This study aimed to stratify older people with dementia (PwD) into three groups (no depression, early depression and recent depression) to compare their inpatient health care utilization and to explore related clinical impacts. Overall, 11,612 PwD were identified from Taiwan's National Health Insurance Research Database and were further divided into 9,257 PwD without depression, 1,179 PwD with recent depression (< 2 years from dementia diagnosis), and 1,176 PwD with early depression (> 2 years from dementia diagnosis). Three matched cohort pairs (Cohort 1: no depression versus recent depression, Cohort 2: no depression versus early depression, and Cohort 3: recent depression versus early depression) were constructed to compare inpatient health care utilization three years after dementia onset. The incidence of hospitalization related to mental illness among PwD with a recent or early depression onset were significantly higher than their matched cohort without depression. The recent depression group had a greater rate ratio (RR) with a longer length of stay due to depression (RR: 8.29, 95% CI: 2.74-25.12) compared to the no depression group, and the early depression group had 4.24 times (95% CI: 1.56-11.59) and 6.40 times (95% CI: 2.18-18.82) longer length of stay than the no depression group due to depression, and mood disorders. Depression significantly increased inpatient health care utilization of depression and mood disorder among older PwD with early depression.


Biochemical and population genetics of the rabbit, Oryctolagus cuniculus, carbonic anhydrases I and II, from the Iberian Peninsula and France.
Available studies on the biochemical and electrophoretic characterization of European rabbit (Oryctolagus cuniculus) carbonic anhydrases I and II (CAI, CAII) show contradictory results about their relative electrophoretic mobility and substrate specificity. After positive identification of carbonic anhydrase activity by CO2 hydration, the differential esterase activity of CAI and CAII toward beta-napththyl acetate and flourescein diacetate,respectively, were used to identify the banding patterns corresponding to each locus. Electrophoretic and hybrid isoelectric focusing analyses of the CAI and CAII loci in 1 domestic and 19 wild rabbit populations led to the recognition of genetic polymorphism at the CAI locus and of extensive variability at the CAII locus. Four and nine alleles at the CAI and CAII loci, respectively, are described. The geographic distribution of genetic variability is consistent with the existence of two evolutionary groups within O. cuniculus.


The era of low-permeability sites remediation and corresponding technologies: A review.
Rational utilization of soil resources and remediation of contaminated soils are imperative due to the rapidly growing demand for clean soils. Currently, many in-situ remediation technologies are less suitable at low-permeability sites due to the limitations of soil permeability. This work defines a low-permeability site as a site with hydraulic conductivity less than 10-4 cm/s, and summarizes the migration characteristics of representative contaminants at low-permeability sites, and discusses the principles and practical applications of different technologies suitable for the remediation of low-permeability sites, including electrokinetic remediation technology, polymer flushing technology, fracturing technology, and in-situ thermal remediation technology. Enhanced and combined remediation technologies are further described because one remediation technology cannot remediate all contaminants. The prospects for the application of remediation technologies to low-permeability sites are also proposed. This work highlights the necessity of low-permeability sites remediation and the urgent need for new remediation technologies, with the hope to inspire future research on low-permeability sites.


Microwave-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann coupling.
Microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling is described. Using the optimized conditions, a panel of macrocycles, with different substitution patterns, ring sizes, and linkers, has been successfully synthesized using microwave irradiation. To the best of our knowledge, this work represents the first examples of the microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling.


Endocardial irregularities of the left atrial roof as seen on coronary CT angiography.
To describe and characterize morphological characteristics of endocardial irregularities in the roof of the left atrium as seen on coronary CT angiography. We retrospectively evaluated the left atrium in 50 consecutive coronary CT patients with multiplanar reformatting, volume rendering, and virtual endoscopy. Twenty-one of the 50 patients had an endocardial irregularity at the roof of the left atrium. The most common finding (n = 14) was a smooth diverticulum, arising near the venoatrial junction of the right superior pulmonary vein. Endocardial irregularities of the left atrium can be identified on coronary CT and may be more common than previously considered. The findings probably represent remnants of the cardinal venous system during embryological development. Further work should focus on the true prevalence and potential clinical significance.


Dynamics of calcium fluxes in human platelets assessed in calcium-free medium.
Dynamics of changes in cytosolic calcium concentration resulting from facilitation of calcium leakage from the stores and (or) blocking the pathways of its reuptake back into the stores or extrusion out of the cell (or both) have been investigated experimentally. It has been found that: (a) no mechanisms other than the membrane leakage, PMCA or SERCA, are involved in the discharge of calcium stores and calcium extrusion or reuptake; (b) the discharge of calcium stores in the absence of both its extrusion and reuptake back into the stores depends only on membrane leakage, the asymptotic calcium concentration in cytosol depending only on the initial content of the stores and being independent of the leakage; (c) the dynamics of the activity of both PMCA and SERCA depend on the initial rate of calcium influx, the dynamics differing from each other at high initial rates of calcium influx; (d) whereas there is no observable background activity of PMCA, background activity of SERCA is observed.


Adenoid cystic carcinoma in a bronchial washing. A case report.
A case of adenoid cystic carcinoma of the trachea and bronchi diagnosed on a bronchial washing is reported. This tumor has characteristic cytomorphology best elucidated by May-Grünwald-Giemsa stain.


Theoretical Benefits of Dynamic Collimation in Pencil Beam Scanning Proton Therapy for Brain Tumors: Dosimetric and Radiobiological Metrics.
To quantify the dosimetric benefit of using a dynamic collimation system (DCS) for penumbra reduction during the treatment of brain tumors by pencil beam scanning proton therapy (PBS PT). Collimated and uncollimated brain treatment plans were created for 5 patients previously treated with PBS PT and retrospectively enrolled in an institutional review board-approved study. The in-house treatment planning system, RDX, was used to generate the plans because it is capable of modeling both collimated and uncollimated beamlets. The clinically delivered plans were reproduced with uncollimated plans in terms of target coverage and organ at risk (OAR) sparing to ensure a clinically relevant starting point, and collimated plans were generated to improve the OAR sparing while maintaining target coverage. Physical and biological comparison metrics, such as dose distribution conformity, mean and maximum doses, normal tissue complication probability, and risk of secondary brain cancer, were used to evaluate the plans. The DCS systematically improved the dose distribution conformity while preserving the target coverage. The average reduction of the mean dose to the 10-mm ring surrounding the target and the healthy brain were 13.7% (95% confidence interval [CI] 11.6%-15.7%; P<.0001) and 25.1% (95% CI 16.8%-33.4%; P<.001), respectively. This yielded an average reduction of 24.8% (95% CI 0.8%-48.8%; P<.05) for the brain necrosis normal tissue complication probability using the Flickinger model, and 25.1% (95% CI 16.8%-33.4%; P<.001) for the risk of secondary brain cancer. A general improvement of the OAR sparing was also observed. The lateral penumbra reduction afforded by the DCS increases the normal tissue sparing capabilities of PBS PT for brain cancer treatment while preserving target coverage.


Light-induced water oxidation catalyzed by an oxido-bridged triruthenium complex with a Ru-O-Ru-O-Ru motif.
A μ-oxido-bridged triruthenium complex (RuT(2+)), formed by air-oxidation of a previously reported monoruthenium water oxidation catalyst (WOC), serves as an efficient photochemical WOC with the turnover frequency (TOF) and turnover number (TON) 0.90 s(-1) and 610, respectively. The crystal structures of RuT(2+) and its one-electron oxidized RuT(3+) are also reported.


μ-PIV measurements of the ensemble flow fields surrounding a migrating semi-infinite bubble.
Microscale particle image velocimetry (μ-PIV) measurements of ensemble flow fields surrounding a steadily-migrating semi-infinite bubble through the novel adaptation of a computer controlled linear motor flow control system. The system was programmed to generate a square wave velocity input in order to produce accurate constant bubble propagation repeatedly and effectively through a fused glass capillary tube. We present a novel technique for re-positioning of the coordinate axis to the bubble tip frame of reference in each instantaneous field through the analysis of the sudden change of standard deviation of centerline velocity profiles across the bubble interface. Ensemble averages were then computed in this bubble tip frame of reference. Combined fluid systems of water/air, glycerol/air, and glycerol/Si-oil were used to investigate flows comparable to computational simulations described in Smith and Gaver (2008) and to past experimental observations of interfacial shape. Fluorescent particle images were also analyzed to measure the residual film thickness trailing behind the bubble. The flow fields and film thickness agree very well with the computational simulations as well as existing experimental and analytical results. Particle accumulation and migration associated with the flow patterns near the bubble tip after long experimental durations are discussed as potential sources of error in the experimental method.


Involvement of granzyme B and perforin gene expression in the lytic potential of human natural killer cells.
Natural killer (NK) cells (CD3- LGL) spontaneously kill K562 targets but are unable to kill Daudi cells in the absence of IL-2 stimulation. IL-4 is reported to prevent or inhibit the IL-2 driven lymphokine activated killer (LAK) generation in NK cells. Therefore, we asked whether the antagonistic effect of IL-4 on the IL-2 induced LAK activity might regulate the expression of genes encoding proteins involved in lysis, like perforin the pore-forming protein or associated to lysis like granzymes A and B. By using in situ hybridization we show that, besides inducing LAK activity, IL-2 stimulation increases the amount of perforin and granzyme B mRNA at the single cell level in 40 to 100% of the total CD3- LGL population, which suggests the preferential implication of a cell subset within the LGL population. In addition, our results indicate that the stimulatory effect of IL-2 can be down-regulated by IL-4 with respect to both LAK activity and granzyme B and perforin gene expression. Here again one can notice a decrease in the amount of specific mRNA per cell. These findings suggest that the modulation of the lytic machinery via lymphokines might be associated to the regulation of the lytic potentiality of NK/LAK cells.


The association of dietary patterns and adherence to WHO healthy diet with metabolic syndrome in children and adolescents: Tehran lipid and glucose study.
The optimal dietary pattern for reducing the extent of metabolic syndrome (MetS) has not been well established yet. The aim of this study was to evaluate dietary patterns and adherence to WHO healthy diet in children and adolescents and their associations with MetS. Subjects of this cohort study were selected from among children and adolescents of the Tehran Lipid and Glucose Study participants, aged 6-18 years (n = 424). Dietary measurements were collected using a valid and reliable food frequency questionnaire. MetS was defined as the existence of at least 3 risk factors according to the Cook criteria. Diet was assessed based on dietary components of the WHO healthy diet. Dietary patterns were defined by principal component analysis. The mean ± SD age of participants (42% boys and 57% girls) was 13.5 ± 3.7 years. The most consistency with the WHO healthy diet was observed for cholesterol, free sugar and protein consumption in both genders, and the least was for n-3 poly-unsaturated fatty acid, trans-fatty acid and salt. Intake of SFA up to 12% of energy intake (third quartile) reduced the risk of MetS, compared to the first quartile. Subjects in the third quartile of n-6 poly-unsaturated fatty acid intake (6.2% of energy) showed the lowest odds ratio of MetS compared to the first quartile (OR: 0.18, CI: 0.04-0.66). In the adjusted model, the risk of MetS reduced across quartiles of MUFA intake by 60% (OR: 1, 0.40, 0.40, 0.42; P trend = 0.05). No significant trends were observed in the risk of MetS components across quartiles of the WHO healthy diet components. Three major dietary patterns were identified, the healthy, unhealthy and cereal/meat. An increased risk of MetS was observed in the highest quartile of unhealthy dietary pattern score compared to the lowest quartile (OR: 1, 0.81, 0.93, 2.49; P trend = 0.03). Our results demonstrated that the majority of our population did not meet some components of WHO healthy diet recommendations. The quality and quantity of fatty acid intakes were associated with risk of MetS. Adherence to unhealthy dietary pattern was associated with two-fold increase in MetS risk.


The influence of carbon source on the level and composition of ceramides of the Candida lipolytica yeast.
Candida lipolytica yeast was grown batchwise on two different carbon sources, glucose and n-hexadecane. Free ceramides were quantitatively isolated from sphingolipid fractions of total lipids by a combination of column chromatography and preparative thin-layer chromatography. Their composition, after acid methanolysis, was analysed by gas-liquid chromatography. The ceramide content accounted for 2.6% of the total cell lipids in hexadecane-grown cells, which was 1.5 times higher than in glucose-grown cells. The fatty acid composition of ceramides was characterized by the predominance of fatty acids shorter than 20 carbon atoms and by high concentrations of fatty acids with 16 carbon atoms after growth on both carbon sources. The dominant fatty acid was hydroxylated 16:0 in the glucose-grown cells and 16:0 in the hexadecane-grown cells. The striking finding was the low degree of fatty acid hydroxylation and relatively high proportion of odd-numbered fatty acids in ceramide of the n-hexadecane-grown cells. The ceramides contained an unusual long-chain base composition. In hexadecane-grown cells more than 60% of the long-chain bases were C19 phytosphingosine. In glucose-grown cells more than one-half of the total long-chain bases were tetrahydroxy bases, 4,5-dihydroxysphinganine and 4,5-dihydroxyeicosasphinganine.


ROLLER COASTER RETINOPATHY: CASE REPORT OF SYMPTOMATIC BILATERAL INTRARETINAL HEMORRHAGES AFTER SHAKING INJURY IN AN OTHERWISE HEALTHY ADULT.
Traumatic head injuries not involving the eye have been known to cause retinal injury through multiple mechanisms. Abusive head trauma remains the prototypical example. We propose to demonstrate the first case of bilateral multiple retinal hemorrhages in a young healthy adult related to riding multiple theme park roller coasters. The patient was evaluated with a complete ophthalmic examination including dilated extended ophthalmoscopy, fluorescein angiography, optical coherence tomography, and fundus photography. The patient was found to have a bilateral symptomatic macular retinopathy characterized by multiple intraretinal hemorrhages. Given the lack of other systemic findings and negative medical workup, her signs and symptoms were thought to be attributed to the same day attendance of a theme park and riding of multiple roller coasters. Theme park roller coasters, as well as other attractions, may affect the eye at the vitreoretinal interface. This type of acceleration-deceleration injury should be considered in the differential of an adolescent or adult patient with retinal hemorrhage in the absence of other pathologic processes to explain clinical findings.


Patient safety and nursing: interface with stress and Burnout Syndrome.
To analyze studies on stress, Burnout Syndrome, and patient safety in the scope of nursing care in the hospital environment. This was an integrative literature review. Data collection was performed in February 2016 in the following databases: Medical Literature Analysis and Retrieval System Online - PubMed/MEDLINE, Latin American and Caribbean Literature in Health Sciences - LILACS. Ten scientific productions were selected, which listed that factors contributing to stress and Burnout Syndrome of nursing professionals are the work environment as a source of stress, and excessive workload as a source of failures. The analysis found that the stress and Burnout Syndrome experienced by these professionals lead to greater vulnerability and development of unsafe care, and factors such as lack of organizational support can contribute to prevent these failures. Analisar estudos que versam sobre o estresse e Síndrome de Burnout, bem como a segurança do paciente no âmbito da assistência de enfermagem no ambiente hospitalar. Tratou-se de uma revisão integrativa de literatura. O levantamento dos dados foi efetuado nas bases de dados Medical Literature Analysis and Retrieval System Online - PubMed / MEDLINE, Literatura Latino-Americana e do Caribe em Ciências da Saúde -LILACS em fevereiro de 2016. Foram selecionadas10 produções científicas que apontaram que os fatores que contribuem para o estresse e a Síndrome de Burnout dos profissionais de enfermagem são o ambiente de trabalho como fonte de estresse e a carga de trabalho excessiva como geradora de falhas. A análise apontou que o estresse e a Síndrome de Burnout vivenciada por esses profissionais acarretam maior vulnerabilidade ao desenvolvimento de uma assistência insegura e que fatores como a falta de apoio organizacional podem contribuir para dirimir essas falhas.


Evaluation of tracheal stenosis: comparison between computed tomography virtual tracheobronchoscopy with multiplanar reformatting, flexible tracheofiberoscopy and intra-operative findings.
The aim of the study was to evaluate and compare various helical CT display modes [virtual endoscopy (VE)] and multiplanar reformations (MPR), conventional flexible tracheobronchoscopy (FT) and intra-operative (IO) findings in patients with tracheal stenosis and to analyze the advantage of MPR and VE in diagnosis and treatment planning and in postoperative follow-up. Thirty-seven patients with tracheal stenosis underwent standard neck and chest CT followed by MPR and VE. Results were correlated with the results of FT and IO findings. Thirty-three of the 37 stenoses were correctly graded and measured adequately using VE. Complete correlation among CT, fiberoptic tracheoscopy, and surgery of stenosis grading, stenosis length and length of planned resection segment of the trachea was noted between 33 of 37 patients with tracheal stenosis. Correlation between VE and IO was noted in 35 of 37 patients and between FT and VE was noted in 33 of 37 patients with tracheal stenosis. The sensitivity of VE was 94-97%, specificity was 100% with comparison to IO findings. The sensitivity and accuracy of MPR was 86-89% and specificity was 100% with comparison to FT findings. The results of the study indicate that VE is an excellent, consistent, and objective technique. VE with MPR is very useful in diagnostic evaluation and treatment planning in patients with tracheal stenosis.


[Rare cause of death in pulmonary recurrence of uterine cancer].
A brief report on endometrium carcinoma with lung metastases is given. The obturation of the main bronchus and trachea by lymphonodular metastases is a rare cause of death.


Muscle performance in octogenarians: Factors affecting dynapenia.
The muscle performance is associated with several health outcomes in adults, however modifiable and non-modifiable risk factors in octogenarians have not yet been fully investigated. The aim of this study was to analyze the potential risk factors that negatively affect muscle strength in octogenarians. This observational, descriptive, cross-sectional study included 87 older adult participants (56 women and 31 men) attending a geriatric clinic. General anthropometrics, health history, and body composition data were collected. Muscle strength was assessed by handgrip strength (HGS), appendicular skeletal muscle mass (ASMM) and the percentage of body fat were identified by Dual Energy X-ray Absorptiometry, and muscle quality index (MQI) was defined as the ratio of HGS by upper limbs ASMM. Multiple linear regression was conducted to determine predictive factors of the muscle strength. Females had lower HGS (1.39 kg) than male participants (p = 0.034). An increase of one unit MQI was associated with an increase of 3.38 kg in the HGS (p = 0.001). Each additional year of age was associated with a decrease of 0.12 kg in the HGS (p = 0.047). Regarding ASMM, an increase of one unit was associated with an increase of 0.98 kg in the HGS (p = 0.001). There was no association between dynapenia, body fat percentage, diseases and polypharmacy (p > 0.05). The gender, age, MQI, and ASMM influenced muscle strength of octogenarians. These intrinsic and extrinsic factors are relevant to improve our understanding of age-related complications and outline treatment guidance by healthcare professionals.


Retracted: Operating Room Planning for Emergency Surgery: Optimization in Multiobjective Modeling and Management from the Latest Developments in Computational Intelligence Techniques.
[This retracts the article DOI: 10.1155/2022/2290644.].


Suppressing Aneuploidy-Associated Phenotypes Improves the Fitness of Trisomy 21 Cells.
An abnormal number of chromosomes, or aneuploidy, accounts for most spontaneous abortions, causes developmental defects, and is associated with aging and cancer. The molecular mechanisms by which aneuploidy disrupts cellular function remain largely unknown. Here, we show that aneuploidy disrupts the morphology of the nucleus. Mutations that increase the levels of long-chain bases suppress nuclear abnormalities of aneuploid yeast independent of karyotype identity. Quantitative lipidomics indicates that long-chain bases are integral components of the nuclear membrane in yeast. Cells isolated from patients with Down syndrome also show that abnormal nuclear morphologies and increases in long-chain bases not only suppress these abnormalities but also improve their fitness. We obtained similar results with cells isolated from patients with Patau or Edward syndrome, indicating that increases in long-chain bases improve the fitness of aneuploid cells in yeast and humans. Targeting lipid biosynthesis pathways represents an important strategy to suppress nuclear abnormalities in aneuploidy-associated diseases.


Erratum: Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome.
[This corrects the article DOI: 10.1016/j.isci.2021.102741.].


Hypotensive effect of intravenous injection of tachykinins in conscious, freely moving spontaneously hypertensive and Wistar Kyoto rats.
The present study evaluated the sensitivity of spontaneously hypertensive (SHR) and of Wistar Kyoto (WKY) rats to the hypotensive effect of tachykinins (TKs). Eledoisin, substance P, and the NK-1-selective agonist [Sar9,Met(O2)11]substance P evoked a smaller hypotensive response in SHR than in WKY rats. The hypotensive effect of NKA was slightly smaller in SHR, but no significant strain difference was observed. The NK-2-selective agonist [beta Ala8]NKA(4-10) was a very weak hypotensive agent in WKY rats, while being completely inactive in SHR. The NK-3-selective agonists [Asp5,6,MePhe8]substance P(5-11) and [MePhe7]NKB did not modify blood pressure in both strains. Heart rate was essentially unmodified following the NK-3 agonists, while it was increased after injection of substance P, [Sar9,Met(O2)11]substance P, and neurokinin A, the increase being greater in WKY than in SHR. Surprisingly, eledoisin increased heart rate in SHR, but not in WKY rats, despite the greater hypotensive effect elicited in the latter strain. The present results confirm that the hypotensive effect of peripheral TKs is mediated by NK-1 receptors and show that SHR are less sensitive than WKY rats to this effect.


Isotope effects accompanying evaporation of water from leaky containers.
Laboratory experiments aimed at quantifying isotope effects associated with partial evaporation of water from leaky containers have been performed under three different settings: (i) evaporation into dry atmosphere, performed in a dynamic mode, (ii) evaporation into dry atmosphere, performed in a static mode, and (iii) evaporation into free laboratory atmosphere. The results demonstrate that evaporative enrichment of water stored in leaky containers can be properly described in the framework of the Craig-Gordon evaporation model. The key parameter controlling the degree of isotope enrichment is the remaining fraction of water in the leaking containers. Other factors such as temperature, relative humidity, or extent of kinetic fractionation play only minor roles. Satisfactory agreement between observed and predicted isotope enrichments for both (18)O and (2)H in experiments for the case of evaporation into dry atmosphere could be obtained only when molecular diffusivity ratios of isotope water molecules as suggested recently by Cappa et al. [J. Geophys. Res., 108, 4525-4535, (2003).] were adopted. However, the observed and modelled isotope enrichments for (2)H and (18)O could be reconciled also for the ratios of molecular diffusivities obtained by Merlivat [J. Chem. Phys., 69, 2864-2871 (1978).], if non-negligible transport resistance in the viscous liquid sub-layer adjacent to the evaporating surface is considered. The evaporation experiments revealed that the loss of mass of water stored in leaky containers in the order of 1%, will lead to an increase of the heavy isotope content in this water by ca. 0.35 and 1.1 per thousand, for delta (18)O and delta (2)H, respectively.


Stilbenes with potent cytotoxicity from the seedcases of Paeonia suffruticosa Andrews.
Stilbenes (based on the 1,2-diphenylethylene skeleton) are a class of plant polyphenols with rich structural and bioactive diversity. Twenty-six stilbenes, including five undescribed compounds (7,8-dioxy-4,3',5'-trihydroxystilbene, trans-13'-methoxygnetin H, suffruticosol E, paestibenetrimerols A and B), were isolated from the seedcases of Paeonia suffruticosa Andrews. Their structures were elucidated by spectroscopic analyses and comparison with previously reported data. The absolute configurations of trans-13'-methoxygnetin H, suffruticosol E, paestibenetrimerols A and B were assigned from their respective electronic circular dichroism (ECD) spectra. Additionally, the structures of known compounds suffruticosols A, B and rockiol B were revised and the absolute configurations of them, and along with (+)-davidiol A, were also further determined by ECD. The isolated compounds, trans-gnetin H, cis-gnetin H and suffruticosol E, were found to have potent cytotoxicity against the DU-145 and MDA-MB-231 cell lines with IC50 values of 4.89-8.61 μM. The preliminary antitumor structure-activity relationship of these stilbenes is discussed as well.


Left ventricular epicardial pacing achieved hyper-responsiveness in young children with dilated cardiomyopathy with left bundle branch block.
The management of heart failure (HF) in young children is challenging. The present study aimed to clarify the effect of left univentricular epicardial pacing on dilated cardiomyopathy with left bundle branch block (LBBB) in children. A total of five cases (30.86 ± 16.39 months, three female) of children weighing 5.8-15 kg with dilated cardiomyopathy and LBBB were included in this study. LBBB in one child occurred after device closure of peri-membranous ventricular septal defects, and the remaining four were idiopathically discovered early after birth. Before implantation, all children suffered from refractory HF and cardiac dilatation; the left ventricular ejection fraction was 33.48 ± 5.84% with Ross Heart Failure Classification III-IV. Electrical and mechanical dyssynchrony were observed in all children with QRS duration >140 ms and prolonged septal-to-left posterior wall motion delay. Left univentricular epicardial pacing was successfully implanted via left axillary minithoracotomy in the five children. Sensed atrioventricular delays (83 ± 15 ms) were optimized by velocity time integral of aortic blood flow before discharge. During the follow-up period (10.8 ± 2.68 months), the dilated failing heart was reversed significantly in terms of decreased left ventricular dimension (55.62 ± 3.46 vs. 38.94 ± 3.69 mm, P = 0.005), while the left ventricular ejection fraction improved to 60.18 ± 8.78% (P = 0.006). In young children with low body weight, if HF is caused by or related to LBBB, left ventricular epicardial pacing still has an excellent effect.


A chemiluminescent assay for hydroperoxide level of phosphatidylcholine hydroperoxide fraction purified by two Sep-Pak cartridges in biological samples.
A chemiluminescent assay for hydroperoxide level of phosphatidylcholine hydroperoxide (PCOOH) fraction purified from biological samples was presented. This method utilized of two Sep-Pak cartridges. A lipid soluble fraction was isolated from each homogenized tissue or blood by Folch's method. The mixture of phosphatidylcholine (PC) and PCOOH was separated from the lipid soluble fraction by a Sep-Pak silica cartridge. A Sep-Pak tC18 cartridge made complete separation of both PCOOH and PC possible. The hydroperoxide level of PCOOH fraction was quantified by the reaction with ferrous ion using 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-a]pyrazin++ +-3-one as a chemiluminescent dye. The mixture of positional isomers, 1-hexadecanoyl-2-[9, or 10-hydroperoxyl octadecanoyl]-sn-glycero-3-phosphocholine was used as an authentic standard. The good recovery rate for authentic PCOOH of 87.1 +/- 11.6% (mean +/- S.E., n = 4) was obtained by using two Sep-Pak cartridges. Linear calibration curve was obtained in the range from 2.5 to 20 nmol, and the detection limit of the standard was 10 pmol (signal-to-noise ratio > 3). This method was applied to the investigation of the lipid peroxidation induced by reperfusion of the liver with cold preservation, mimicking liver transplantation in rats. The effect of liposome-encapsulated dichloromethylene diphosphonate (LEDD), which eliminate of Kupffer cells to prevent the generation of oxygen radicals on the lipid peroxidation, was compared with the untreated group as a control. After 1 h reperfusion at 37 degrees C the hydroperoxide level obtained the liver without preservation in the untreated group was 12.4 +/- 2.4 nmol/100 mg lipid (n = 4) and levels increased significantly by prolongation of the preservation time. On the other hand, the hydroperoxide level in the LEDD treated group did not change up to 24 h preservation. These results suggest that this improved assay for hydroperoxide level of PCOOH fraction in biological samples can be applied to investigations involving lipid peroxidation because of its simplicity and accuracy.


Emphysematous cystitis presenting as painless gross hematuria.
A case of emphysematous cystitis in an immunocompetent male is described. The diagnosis is generally rare, but may be made in the Emergency Department. A history of pneumaturia is highly suggestive of the entity, but is rarely offered by the patient. The evaluation and management of emphysematous cystitis are discussed.


Crossed renal ectopia and asymmetric fused kidney, with special reference to associated vertebral anomalies.
Crossed renal ectopia and/or asymmetric fused kidney are unusual congenital anomalies. The deformity itself usually produces no symptoms and the clinical presentation generally suggests obstruction and infection. In our series, 10 of 11 patients presented with various vertebral anomalies. A theory of embryogenesis was reviewed to explain asymmetric patterns of renal fusion with special reference to vertebral anomalies.


Smart sustainable biorefineries for lignocellulosic biomass.
Lignocellulosic biomass (LCB) is considered as a sustainable feedstock for a biorefinery to generate biofuels and other bio-chemicals. However, commercialization is one of the challenges that limits cost-effective operation of conventional LCB biorefinery. This article highlights some studies on the sustainability of LCB in terms of cost-competitiveness and environmental impact reduction. In addition, the development of computational intelligence methods such as Artificial Intelligence (AI) as a tool to aid the improvement of LCB biorefinery in terms of optimization, prediction, classification, and decision support systems. Lastly, this review examines the possible research gaps on the production and valorization in a smart sustainable biorefinery towards circular economy.


Fibrous histiocytoma: an analysis of the storiform pattern.
A storiform pattern is an important structural feature of fibrous histiocytoma (FH). In this analysis reconstructions of histological patterns were carried out from drawings. Highly FH with only a suggestion of storiform pattern and small star-formations were seen, there were other lesions with more pronounced fiber formation which showed more distinct and larger storiform stars. These structures can frequently be followed for only 3 sections of 5 micron thickness. In contrast to leiomyomas or meningioma, no regular or consistent orientation of these structures with respect to vessels is evident. Storiform structures apparently develop at the periphery of adjacent proliferating cells groups. They show a typical and diagnostically significant histological pattern, which was found to some degree in all FH examined.


Predictors of noncompliance to pulmonary tuberculosis treatment: An insight from South America.
To investigate the factors associated with a higher risk of noncompliance to tuberculosis (TB) treatment in Porto Alegre, Brazil. We identified 478 adult patients for this case-control study undergoing treatment for confirmed pulmonary TB. Cases (noncompliance) were defined as patients who stopped treatment for more than 30 consecutive days (n = 118). Controls were defined as all patients who completed treatment and were cured (n = 360). Factors associated with noncompliance were calculated with unadjusted and adjusted odds ratio (OR). The rate of noncompliance in our study was 25%. The factors of noncompliance after adjustments in the overall population were, in order of magnitude, living in an area of lower income (OR = 4.35, 95%CI: 2.50-7.58), abuse of drugs (OR = 2.73, 95%CI: 1.47-5.09), nonadherence to a previous treatment regimen (OR = 2.1, 95%CI: 1.28-3.45), and history of smoking (OR = 1.72, 95%CI: 1.00-3.00). Age, race, gender, level of education, HIV infection or diabetes status were not associated with a higher risk of noncompliance. In the subgroup of re-treatment cases, poverty (OR = 2.65; 95%CI = 1.06-6.66), smoking history (OR = 2.94; 95%CI = 1.09-7.92), male gender (OR = 3.25; 95%CI = 1.32-8.0), and younger age (OR = 4.3; 95%CI = 1.15-16.07) were also associated with a higher risk of dropout. Predictors of poor compliance to TB treatment were low income, abuse of drugs, re-treatment cases and history of smoking.


Shedding Light on the Hidden Curriculum: A Systematic Review of Ethics Education during General Surgery and Subspecialty Training.
Ethics education in surgical residencies is often delivered in an informal and nonstructured manner as part of a "hidden curriculum", leading to few residencies routinely including it in their core curriculum. This systematic review aimed to summarize the delivery modes, curriculum, structure, and effectiveness of ethics educational interventions for surgical trainees. We performed a comprehensive database search including MEDLINE, Embase, Scopus and CENTRAL to search for articles describing the implementation of ethics educational interventions for general surgery or subspecialty trainees. A total of 14 studies were included. Only 2 centers performed targeted needs assessment. Curricula covered included informed consent, the doctor-patient relationship, breaking bad news, decision-making, end-of-life care, conflicts of interest, considering patients' personal contexts, and surgical research ethics. Modes of delivery varied across studies, including case-based learning, group discussions, didactic lectures, reading material, role-playing, simulated patients, and ethics morbidity and mortality (M&M) meetings. Evaluations were most commonly via surveys exploring knowledge and self-reported confidence, with only 3 studies measuring actual trainee performance using objective structured clinical examinations. In general, the educational interventions increased trainees' confidence/preparedness in handling ethical dilemmas. We recommend comprehensive local needs assessment to guide curricular development and designing specific learning objectives and measurable milestones to ensure evaluation. Educational interventions are best delivered in a graduated manner with the complexity of the topic mirroring residents' real-life clinical responsibilities and experiences. Teaching modalities should be tailored according to the nature of the curricular content being taught to make the learning experience more interactive and effective.


Twins and their mildly affected mother with Weaver syndrome.
A pair of twins, a brother and sister, with the complete form of Weaver syndrome (overgrowth, macrocephaly, facial, skeletal, nail and feet anomalies) and their mildly affected mother are reported, suggesting autosomal dominant inheritance. They all have plantar and palmar hyperhydrosis and twins also have nail dysplasia, symptoms which have not yet been described in this syndrome.


Acute and chronic heroin dependence in mice: contribution of opioid and excitatory amino acid receptors.
Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7-benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; delta1, delta2, and kappa opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas delta1, delta2, NMDA, and AMPA receptors enable acute and chronic heroin dependence, kappa receptor activity limits the dependence liability of chronic heroin. With the exception of delta1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of kappa receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute and chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.


Effects of monosodium glutamate on eating and drinking behavior in rats.
The effect of monosodium glutamate (MSG) on eating and drinking behavior of rats was studied by means of preference tests in free choice situations. Low or high protein casein diets containing up to 3% MSG were selected indifferently compared to plain casein diet in 7 day trials. The acceptability of diets containing 7% MSG, particularly those of low protein level, was significantly reduced. Except for Day 1, the proportional intake (MSG flavored diet intake/total diet intake) of 9% protein--7% MSG diet was consistently lower than 18% protein--7% MSG diet. In brief exposure tests (10 min) solutions of MSG (0.02-8%) were preferred over deionized water. The acceptance of solutions containing higher concentrations of MSG was significantly reduced. The total volume intake of both choices (MSG flavored water and water) was significantly increased in tests using solutions containing 3-8% MSG. In long-term tests (1-14 days), solutions containing 0.05-1% MSG were preferred over water. The acceptance of a solution containing 5% MSG was significantly reduced. For maximum intake of moles of MSG, rats selected solutions which offered 3-5 x 10(-1) M MSG whether the experimental period was 10 min or up to 2 weeks. In a series of two choice preference tests using solutions where Na+ content and pH were kept equal, MSG was preferred over sodium acetate and over sodium glutamate but was less preferred than monosodium aspartate. The results of this study can be explained in terms of sensory quality.


Genome-wide identification and expression analysis of the JAZ gene family in turnip.
JAZ is a plant-specific protein family involved in the regulation of plant development, abiotic stresses, and responses to phytohormone treatments. In this study, we carried out a bioinformatics analysis of JAZ genes in turnip by determining the phylogenetic relationship, chromosomal location, gene structure and expression profiles analysis under stresses. The 36 JAZ genes were identified and classified into four subfamilies (ZML, JAZ, PPD and TIFY). The JAZ genes were located on 10 chromosomes. Two gene pairs were involved in tandem duplication events. We identified 44 collinear JAZ gene pairs in the turnip genome. Analysis of the Ka/Ks ratios indicated that the paralogs of the BrrJAZ family principally underwent purifying selection. Expression analysis suggested JAZ genes may be involved in the formation of turnip tuberous root, and they also participated in the response to ABA, SA, MeJA, salt stress and low-temperature stress. The results of this study provided valuable information for further exploration of the JAZ gene family in turnip.


T cell fate and clonality inference from single-cell transcriptomes.
We developed TraCeR, a computational method to reconstruct full-length, paired T cell receptor (TCR) sequences from T lymphocyte single-cell RNA sequence data. TraCeR links T cell specificity with functional response by revealing clonal relationships between cells alongside their transcriptional profiles. We found that T cell clonotypes in a mouse Salmonella infection model span early activated CD4(+) T cells as well as mature effector and memory cells.


The hUC-MSCs cell line CCRC-1 represents a novel, safe and high-yielding HDCs for the production of human viral vaccines.
MRC-5 represents the most frequent human diploid cells (HDCs)-type cell substrate in the production of human viral vaccines. However, early-passage MRC-5 is diminishing and, due to both technical and ethical issues, it is extremely difficult to derive novel HDCs from fetal lung tissues, which are the common sources of HDCs. Our previous studies suggested that human umbilical cord may represent an alternative but convenient source of new HDCs. Here, we established a three-tiered cell banking system of a hUC-MSC line, designated previously as Cell Collection and Research Center-1 (CCRC-1). The full characterization indicated that the banked CCRC-1 cells were free from adventitious agents and remained non-tumorigenic. The CCRC-1 cells sustained its rapid proliferation even at passage 30 and were susceptible to the infection of a wide spectrum of viruses. Interestingly, the CCRC-1 cells showed much higher production of EV71 or Rubella viruses than MRC-5 and Vero cells when growing in serum-free medium. More importantly, the EV71 vaccine produced from CCRC-1 cells induced immunogenicity while eliciting no detectable toxicities in the tested mice. Collectively, these studies further supported that CCRC-1, and likely other hUC-MSCs as well, may serve as novel, safe and high-yielding HDCs for the production of human viral vaccines.


Aging of human muscle: understanding sarcopenia at the single muscle cell level.
The loss of muscle mass with age, also known as sarcopenia, is a major scientific and public health problem. Muscle atrophy is associated with the loss of functional capacity and poor health outcomes in elderly men and women. A detailed understanding of this problem in humans can be enhanced by the use of experiments with single muscle fibers. It is likely that both muscle atrophy and a decrease in muscle-fiber quality contribute to muscle dysfunction among the elderly. A better understanding of sarcopenia at the single-fiber level may lead to the design of more effective rehabilitative interventions.


Mini-sphenoidal electrodes in the investigation of seizures.
A technique to record from the mesiobasal temporal region is described which can be performed as part of the routine EEG recording. The mini-sphenoidal electrodes were tolerated by all of the patients and were found to be fast, reliable and applicable to outpatient recordings. A small population of patients was studied which demonstrated that the electrodes added useful information not supplied by traditional scalp electrodes in the evaluation of patients with seizure disorders. The electrodes provided information comparable to traditional sphenoidal electrodes, although decreased in amplitude.


Quantal Ca2+ release mediated by very few IP3 receptors that rapidly inactivate allows graded responses to IP3.
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that link extracellular stimuli to Ca2+ signals. Ca2+ release from intracellular stores is "quantal": low IP3 concentrations rapidly release a fraction of the stores. Ca2+ release then slows or terminates without compromising responses to further IP3 additions. The mechanisms are unresolved. Here, we synthesize a high-affinity partial agonist of IP3Rs and use it to demonstrate that quantal responses do not require heterogenous Ca2+ stores. IP3Rs respond incrementally to IP3 and close after the initial response to low IP3 concentrations. Comparing functional responses with IP3 binding shows that only a tiny fraction of a cell's IP3Rs mediate incremental Ca2+ release; inactivation does not therefore affect most IP3Rs. We conclude, and test by simulations, that Ca2+ signals evoked by IP3 pulses arise from rapid activation and then inactivation of very few IP3Rs. This allows IP3Rs to behave as increment detectors mediating graded Ca2+ release.


Attachment, emotion regulation, and well-being in couples: Intrapersonal and interpersonal associations.
There is a well-established link in the literature between secure romantic attachment orientation and psychological well-being. The underlying processes of this link and the couple interplay between attachment and well-being are notably less explored. Using a dyadic framework, this study examines both couple members' emotion regulation strategies as potential mediators of this link. One hundred and nineteen heterosexual couples completed self-report measures on attachment style, psychological well-being, tendency to suppress emotions, and emotion expression. Analyses were performed using the actor-partner interdependence mediation model that distinguishes between intrapersonal and interpersonal influences. Results showed that controlling for relationship length, there was an intrapersonal indirect effect of attachment avoidance on psychological well-being through emotion suppression. Moreover, interpersonal indirect effects were found (a) with individual attachment avoidance being associated with partner's psychological well-being through own emotion expression and (b) individual's attachment anxiety being associated with partner's psychological well-being through both own's emotion expression and partner's emotion suppression. These findings highlight the complex associations among attachment, emotion regulation, and well-being and point out the role of emotion regulation as a potential underlying pathway explaining these associations. The results suggest the importance of considering the relational nature of emotional and attachment dynamics in couples.


Integrated Chinese herbal medicine and Western medicine successfully resolves spontaneous subcutaneous emphysema and pneumomediastinum in a patient with severe COVID-19 in Taiwan: A case report.
Serious complications of severe coronavirus disease 2019 (COVID-19) include subcutaneous emphysema (SE) and pneumomediastinum, which are complicated to treat with conventional Western medicine. We report how combining Chinese herbal medicine (CHM) with Western medicine quickly resolved a patient's COVID-19-associated pulmonary complications, shortened hospital stay and improved quality of life. A 59-year-old male with a history of smoking and tumors was diagnosed with COVID-19 in May 2021. At hospitalization, his oxygen saturation (SpO2) was 80%, he had a continuous severe cough, rapid shallow breathing, spontaneous SE and pneumomediastinum. By Day 4 of hospitalization, his condition was worsening despite standard care, so CHM was added. After 3-5 days, his coughing had lessened and supplementary oxygen therapy was de-escalated. Nine days after starting CHM, the SE had completely resolved and the patient avoided intubation. His WHO OS 10-point Scale score had fallen from 6 to 3 points and the modified Medical Research Council Dyspnea Scale score from 4 to 2 points. He was hospitalized for 19 days. At 1 week post-discharge, the patient could handle most of his daily activities and experienced minor shortness of breath only when performing labor-intensive tasks. At 1 month, his work output was restored to pre-COVID-19 levels. CHM combined with standard Western medicine improved pulmonary function, respiratory rate, blood oxygen saturation and shortened the hospital stay of a patient with severe COVID-19 complicated by SE and pneumomediastinum.


Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae.
Collagen characteristics contribute to bone biomechanical properties. Yet, few studies have analyzed the independent contributions of bone mineral density (BMD) and post-translational modifications of type I collagen to whole bone strength. Thus, the aim of this study was to determine the relative contributions of BMD and both enzymatic and non-enzymatic collagen crosslink concentration to the biomechanical properties of human vertebrae. Nineteen L3 vertebrae were collected after necropsy (age 26-93; 10 males, 9 females). BMD of the vertebral body was measured by DXA, and the vertebrae were compressed to failure to assess the stiffness, failure load and work to fracture. After mechanical testing, the concentration of both enzymatic crosslinks pyridinoline (PYD), and deoxypyridinoline (DPD) as well as, and the non-enzymatic crosslinks pentosidine (PEN) were analyzed in trabecular and cortical bone by reversed-phase HPLC. The extent of aspartic acid isomerization of type I collagen C telopeptide (CTX) was evaluated by ELISA of native (alpha CTX) and isomerized (beta CTX) forms. BMD was significantly positively related with stiffness (R(2) = 0.74; P < 0.0001), failure load (R(2) = 0.69; P < 0.0001) and work to fracture (R(2) = 0.44; P = 0.002). Bivariate regression analysis showed no association between collagen traits and biomechanical properties. However, in a multiple regression model, BMD and trabecular PEN were both significantly associated with failure load and work to fracture (multiple R(2) = 0.83, P = 0.001 and R(2) = 0.67, P = 0.001, respectively). Similarly, BMD and trabecular alpha/beta CTX ratio were both associated with stiffness (multiple R(2) = 0.83, P = 0.015). These findings indicate that post-translational modifications of type I collagen have an impact on skeletal fragility.


Diagnosis and treatment of cardiac arrhythmias.
Cardiac arrhythmias are probably more common in horses than in any other domestic animal species. The most frequent clinical complaint associated with cardiac arrhythmias is exercise intolerance. Physical examination is characterized by auscultation abnormalities such as fast or slow heart rate, irregular rhythm, extra sounds, long pauses, or abnormal heart sounds. The electrocardiogram is used to make a definitive diagnosis of the dysrhythmia. Other laboratory and cardiac function tests are employed to determine the etiology and to assess the significance of the arrhythmia. Antiarrhythmic therapy is given when clinical signs specifically related to the arrhythmia are present, when hemodynamic parameters are compromised by the arrhythmia, or when the ECG reveals abnormalities that put the patient at risk for development of more severe arrhythmias. The cardiovascular drugs most frequently used are digoxin and quinidine. Digoxin is most commonly used for supraventricular arrhythmias, especially arrhythmias characterized by fast heart rates. Quinidine is very effective for short-term treatment of ventricular and supraventricular arrhythmias but must be used with caution because of the potential for toxic side effects. The cardiac arrhythmias due to vagal tone (sinus arrhythmia, sinus block, sinus arrest, sinus bradycardia, wandering pacemaker, first-degree AV block, and second-degree AV block) that are found in resting horses are generally considered to be normal and generally do not require therapy.


Editorial for the Beyond Moore's Law: Hardware Specialization and Advanced System on Chip.
In the absence of a new transistor technology to replace CMOS, design specialization has emerged as one of the most immediate options for achieving high-performance computing [...].


Fluoride varnish reduces white spot lesions during orthodontic treatment.
This was a randomised controlled trial (RCT) set in a community dental practice. The test varnish was a commercially available product, Fluor Protector (Ivoclar Vivadent, Schaan, Liechtenstein), containing 0.1% fluoride as difluorosilane in a polyurethane varnish base. The placebo varnish applied had an identical composition but without fluoride. The incidence and prevalence of white spot lesions (WSL) on the upper incisors, cuspids and premolars were recorded, as scored from digital photographs by two independent examiners. In the case of disagreement, cases were re-examined until a consensus was achieved. The incidence of WSL during the treatment period was 7.4% in the fluoride varnish group compared with 25.3% placebo group (P <0.001). The mean progression score was significantly lower in the fluoride varnish group than in the placebo group, (0.8 +/- 2.0 vs 2.6 +/- 2.8; P <0.001). The absolute risk reduction was 18% and the number-needed-to-treat was calculated to be 5.5 (95% confidence interval, 3.7-10.9). The results strongly suggest that regular topical fluoride varnish applications may reduce the development of WSL adjacent to the bracket base during treatment with fixed appliances.


Rational engineering of semiconductor QDs enabling remarkable 1O2 production for tumor-targeted photodynamic therapy.
Semiconductor quantum dots (QDs) have served as superior optically active nanomaterials for molecular imaging and photodynamic therapy (PDT), but the low singlet oxygen (1O2) quantum yield and lack of tumor selectivity have limited their applications for tumor PDT in vivo. Here, we report the rational engineering of QDs into tumor-targeting hybrid nanoparticles through micelle-encapsulating a pre-assembled unique QD-Zn-porphyrin complex, a highly fluorescent organic photosensitizer rhodamine 6G (R6G), and a near-infrared fluorophore NIR775 with folic acid labeled phospholipid polymers. These nanoparticles have large porphyrin payloads and strong light absorption capability, thus contributing to an extremely high 1O2 quantum yield (∼0.91) via an efficient dual energy transfer process. In vivo studies show that they can preferably accumulate in tumors through folate receptor-mediated active delivery, permitting non-invasive fluorescence imaging and effective PDT of tumors in living mice. This study highlights the utility of hybrid semiconductor QDs for both tumor imaging and PDT in vivo.


Role of ambulatory blood pressure monitoring in hypertension and diabetes.
The prevalence of hypertension and diabetes are both rising in the USA and around the globe. The treatment of hypertension in the ambulatory setting begins with proper blood pressure measurement, and often the involvement of home blood pressure monitoring. If the diagnosis of hypertension is confirmed, then education on lifestyle modifications is the foundation to reaching blood pressure goals. If it is unclear, then ambulatory blood pressure monitoring should be performed to properly evaluate daily trends in blood pressure. The National Institute for Health and Clinical excellence (NICE) recommends 24-hour ambulatory blood pressure evaluation in all newly diagnosed patients with hypertension. The much-anticipated JNC 2013, while not likely to endorse this approach, will likely recommend an office goal systolic blood pressure of less than 140 mmHg in patients with diabetes as do the most recent American Diabetes Association clinical practice guidelines. All new guidelines are derived from a critical evidence based evaluation of the available data.


Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice.
Normal aging is characterized with a decline in hippocampal memory functions that is associated with changes in long-term potentiation (LTP) of the CA3-to-CA1 synapse. Age-related deficit of the dopaminergic system may contribute to impairment of CA1 LTP. Here we assessed how the modulation of CA1 LTP by dopamine is affected by aging and how it is dependent on the Ca2+ source. In slices from adult mice, the initial slope of the field potential showed strong LTP, but in slices from aged mice LTP was impaired. Dopamine did not affect LTP in adult slices, but enhanced LTP in aged slices. The dopamine D1/D5 receptor (D1R/D5R) agonist SKF-81297 did not affect LTP in adult but caused a relative small increase in LTP in aged slices; however, although there was no difference in dopamine D4 receptor (D4R) expression, the D4R agonist PD168077 increased LTP in aged slices to a magnitude similar to that in adult slices. The N-Methyl-D-aspartate receptor antagonist D-AP5 reduced LTP in adult slices, but not in aged slices. However, in the presence of D-AP5, PD168077 completely blocked LTP in aged slices. The voltage-dependent calcium channel (VDCC) blocker nifedipine reduced LTP in adult slices, but surprisingly enhanced LTP in aged slices. Furthermore, in the presence of nifedipine, PD168077 caused a strong enhancement of LTP in aged slices to a magnitude exceeding LTP in adult slices. Our results indicate that the full rescue of impaired LTP in aging by the selective D4R activation and that a large potentiation role on LTP by co-application of D4R agonist and VDCC blocker may provide novel strategies for the intervention of cognitive decline of aging and age-related diseases.


Total parenteral nutrition during acute pancreatitis: clinical experience with 156 patients.
Over a 3-year period, 156 of 815 patients admitted to a single institution with acute pancreatitis received total parenteral nutrition (TPN) for 2,572 patient days. Seventy had "simple" acute pancreatitis (group I) and 86 (group II) developed local complex disease (pseudocyst, abscess, or necrotic gland). In groups I and II, respectively, days without oral intake (NPO) were 13.6 +/- 1.5 (SEM) and 24.0 +/- 2.1 (p less than 0.005), hospital days were 19.8 +/- 1.7 and 35.8 +/- 3.2 (p less than 0.005), and duration of TPN was 10.9 +/- 1.0 and 21.0 +/- 2.3 days (p less than 0.005). Thirty-three patients in group I and 53 in group II required exogenous insulin. Alteration of standard formulas was necessary in 87 patients, but cessation of therapy was necessary in only one instance. Twenty catheters were removed for suspected sepsis with only 3 confirmed cases. Fat-based formulas were well tolerated in 15% of patients. During TPN, body weight rose from 95.0 +/- 2.4% to 97.4 +/- 4.3% of ideal in group I and remained at 90.5 +/- 1.8% in group II. Albumin rose from 3.36 +/- 0.10 to 3.50 +/- 0.08 g/dl in group I and from 3.01 +/- 0.07 to 3.35 +/- 0.07 g/dl in group II. The entire cohort differed from 10 randomly chosen patients who did not receive TPN in terms of days NPO (2.8 +/- 0.3) and hospital days (5.5 +/- 0.6). Variables associated with prolongation of hospital stay and time NPO were number of prognostic criteria, local complex disease, and underlying chronic pancreatitis only in select groups. We conclude that during acute pancreatitis, TPN can be administered safely but with careful monitoring and we recommend early aggressive therapy in the subgroups noted above and when underlying malnutrition exists. In the borderline patient, TPN may be administered by peripheral vein until the severity of disease is manifest.


Nephrogenic diabetes insipidus induced by ureter obstruction due to benign prostatic hyperplasia: A case report.
Diabetes insipidus can be a common cause of polyuria and hydronephrosis in the kidneys. However, there is few reported case of urinary obstruction induced nephrogenic diabetes insipidus. A 60-year-old Chinese man came to our hospital with the complaints of polydipsia and polyuria for 1 month. His examination showed chronic kidney disease stage III with eGFR of 48.274 ml/min, and the plasma osmolality was 338.00 mOsm/(kg·H2O) with a urinary osmolality of 163.00 mOsm/(kg·H2O). Moreover, imagological examination of the urinary system showed benign prostatic hyperplasia and hydronephrosis. He was considered with benign prostatic hyperplasia induced ureter hydronephrosis and nephrogenic diabetes insipidus. He got the transurethral resection of the prostate to alleviate urinary retention. After that, the urine output gradually decreased, and the administered hydrochlorothiazide was stopped due to the improved renal function. Our study presents a case of nephrogenic diabetes insipidus caused by urinary obstruction. Differential diagnoses for diabetes insipidus as well as the relationship between nephrogenic diabetes insipidus and urinary obstruction are also considered in this study.


Effectiveness of Rose Bengal test and fluorescence polarization assay in the diagnosis of Brucella spp. infections in free range cattle reared in endemic areas in Zambia.
The effectiveness of Rose Bengal test (RBT) and fluorescence polarization assay (FPA) in diagnosing cattle brucellosis in endemic areas was assessed and RBT and FPA test agreement was compared (n = 319). The sensitivity of RBT and FPA in detecting low Brucella titres were evaluated in paired sera (n = 34). A logistic regression model was constructed to predict cattle test result in FPA using RBT as the main predictor and incorporating bio-data and animal history. There was 79.3% agreement between the RBT and FPA (Kappa = 0.59; Std error = 0.05; p = 0.000) and a high correspondence between high RBT scores and positive FPA results suggesting that sera with high RBT score may not require confirmation with tests such as competitive-ELISA or CFT. High FPA cut-off points were more likely to miss animals with low antibody titres. The RBT had a reduced ability in detecting low antibody titres compared to the FPA. FPA test interpretation was improved if a priori information, such as sex and age was used. Under the challenging disease surveillance conditions prevailing in rural Africa, field-testing methods that are sensitive and specific; allow single animal contact, low technical skills in data interpretation are suitable.


Sperm morphology: classification drift over time and clinical implications.
To assess sperm morphology with Tygerberg (strict) and World Health Organization (WHO) 3rd criteria for intrauterine inseminations (IUI) between two eras to determine if there was a difference in pregnancy rates. Retrospective study. Academic institution. 127 couples with 290 IUI treatments during 1996-97 (era 1) and 133 couples with 317 IUI treatments during 2005-06 (era 2). None. Pregnancy rates per cycle and couple. Average sperm morphology was higher in era 1 than era 2 for both WHO 3rd (37 ± 13% vs. 23 ± 10%) and strict criteria (8.0 ± 5.0% vs. 4.0 ± 3.0%). Pregnancy rates per cycle were 5.9% versus 19.8% in era 1 and 16.7% versus 19.3% in era 2 for couples with WHO 3rd morphology <30% or ≥30%, respectively. Pregnancy rates per cycle were 2.7% versus 15.0% in era 1 and 13.3% versus 14.7% in era 2 for couples with strict morphology ≤4% or >4%, respectively. There was a strong relationship between morphology and IUI outcome in era 1 that was not present in era 2. These results suggest that classification drift increased the percentage of men diagnosed with teratozoospermia and resulted in a loss of predictive value.


A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma.
The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70-2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.


Rating scales in old age psychiatry.
There is a vast array of scales available to assess all aspects of mental and physical health in older people which may be of relevance to the work of old age psychiatrists. To summarise some of the scales that may be commonly used in clinical and research practice and to give the reader guidelines as to where further information can be obtained. The scales were selected on the basis of the authors' own clinical and research knowledge and information was gathered from a comprehensive text on assessment scales in old age psychiatry. Results The selected scales are described in brief and a table outlines the purposes for which they are most suitable. Although many scales are available, the choice of the individual scale relies specifically on the question that is to be asked. The ideal scale does not exist.


Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization.
Nectins are a family of Ca(2+)-independent immunoglobulin-like cell-cell adhesion molecules consisting of four members, which homophilically and heterophilically trans-interact and cause cell-cell adhesion. Nectin-based cell-cell adhesion is involved in the formation of cadherin-based adherens junctions in epithelial cells and fibroblasts. The nectin-based cell-cell adhesion induces activation of Cdc42 and Rac small G proteins, which eventually regulate the formation of adherens junctions through reorganization of the actin cytoskeleton, gene expression through activation of a mitogen-activated protein kinase cascade, and cell polarization through cell polarity proteins. Five nectin-like molecules (necls), which have domain structures similar to those of nectins, have recently been identified and appear to play different roles from those of nectins. One of them, named necl-5, which does not homophilically trans-interact, but heterophilically trans-interacts with nectin-3, regulates cell migration and adhesion. In this article, the roles and modes of action of nectins and necls in cell adhesion, migration, and polarization are reviewed.


pH-responsive aggregates consisted of oligodeoxynucleotides bearing nitrophenol group that deliver drugs into acidic cells.
A decrease in pH is observed in most solid tumors, thus, the development of drug delivery systems that respond to slightly acidic extracellular pH environment is important in providing tumor-targeted therapies. DNA aggregates can act as useful drug delivery agents, and therefore, we designed an artificial oligodeoxynucleotides (ODNs) that formed an aggregate only under acidic conditions in this study. In other words, we expected that if we could make DNA aggregates that form only in an acidic environment and that encapsulate drugs, it would be possible to transport drugs to tumor tissues selectively. Nitrophenol derivatives, which underwent protonation and deprotonation in response to pH changes, was introduced into ODNs. The ODNs formed aggregates under weakly acidic conditions because of expression of amphiphilicity, which was induced by protonation of nitrophenol unit, and were smoothly taken up into cells. We also found that the aggregates transported anticancer drug, 5FU, into acidified cells to show cytotoxic effects.


Investigation of Fusobacterium Nucleatum in saliva and colorectal mucosa: a pilot study.
As evidence has been linking the oral bacterium Fusobacterium nucleatum (F. nucleatum) to colorectal tumorigenesis, we aimed to produce preliminary data on the expression of F. nucleatum in both oral and colorectal body sites in cases diagnosed with colorectal neoplasms (CRN) and CRN-free controls. We conducted a pilot hospital-based case-control study among patients who underwent colonoscopy examination. Saliva samples and biopsies from healthy colon mucosa from CRN cases and CRN-free controls, and from tumors in cases, were collected, as well as data on periodontal condition and potential CRN risk factors. A total of 22 CRN cases and 21 CRN-free controls participated in this study, with a total of 135 biospecimens collected and analyzed by qPCR for detection and quantification of F. nucleatum. The detection rate of F. nucleatum was 95% in saliva samples and 18% in colorectal mucosa specimens. The median (95% CI) salivary F. nucleatum level was 0.35 (0.15-0.82) and 0.12 (0.05-0.65) in case and control groups, respectively, with a Spearman correlation of 0.64 (95% CI 0.2-0.94) between F. nucleatum level in saliva and healthy colorectal mucosa in controls. Our study results support the need for and the feasibility of further studies that aim to investigate the association between oral and colorectal levels of F. nucleatum in CRN cases and controls.Clinical Relevance: Considering the current evidence linking F. nucleatum to colorectal carcinogenesis, investigating the role of oral F. nucleatum expression in its colorectal enrichment is crucial for colorectal cancer screening and prevention avenues.


Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin.
The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level. Studies of BCL11A exemplify how contextual gene regulation may often be the substrate for trait-associated common genetic variation. These discoveries have suggested novel rational approaches for the β-hemoglobin disorders including therapeutic genome editing.


Three new species of Rhabdias Stiles et Hassall, 1905 (Nematoda: Rhabdiasidae) parasitic in Ptychadena spp. (Amphibia: Anura: Ptychadenidae) and an identification key to Rhabdias spp. from Afrotropical anurans.
Three new species of lung-dwelling nematodes are described from the frogs Ptychadena anchietae (Bocage), P. oxyrhynchus (Smith), and P. uzungwensis (Loveridge) in southern Africa. All three species are medium-sized species of Rhabdias Stiles et Hassall, 1905, with the thick-walled buccal capsules measuring 11-13 μm × 6-11 μm, consisting of longer anterior and shorter posterior parts. Rhabdias athos n. sp. and R. porthos n. sp. are characterised by the rounded anterior end of the body and the presence of short dilatation of the oesophagus at its mid-length. Rhabdias porthos n. sp. has distinct excretory glands which are absent in two other species. Rhabdias aramis n. sp. is characterised by the truncated anterior end and the slight constriction of the oesophagus at the level of its mid-length. Phylogenetic analysis based on ITS-28S rDNA sequences placed R. aramis n. sp. in the clade consisting of R. engelbrechti Kuzmin et al., 2017 from South Africa and Eurasian Rhabdias spp., while R. athos n. sp. and R. porthos n. sp. formed a sister group to that clade. Identification key to 14 Rhabdias spp. parasitic in anuran amphibians from the Afrotropical Realm is provided.


G-protein-coupled receptors as fat sensors.
It has been demonstrated that fatty acids (FAs) are physiological ligands of G-protein-coupled receptors (GPRs). Activation of the GPRs (40, 41, 43, 84, 119 and 120) by FAs or synthetic agonists modulates several responses. In this review, we discuss the current knowledge on the actions of FA-activated GPRs and their relevance in normal and pathological conditions. Studies have shown that FA-activated GPRs modulate hormone secretion (incretin, insulin and glucagon), activation of leukocytes and several aspects of metabolism. Understanding GPR actions and their involvement in the development of insulin-resistance, β-cell failure, dyslipidemia and inflammation associated with obesity, type 2 diabetes, metabolic syndrome and cardiovascular diseases is important for the comprehension of the mechanisms underlying these pathological conditions and for the establishment of new and effective interventions.


Idiopathic pulmonary fibrosis in the United States: time to diagnosis and treatment.
Create a timeline of diagnosis and treatment for IPF in the US. A retrospective analysis was performed in collaboration with the OptumLabs Data Warehouse using an administrative claims database of Medicare Fee for Service beneficiaries. Adults 50 and over with IPF were included (2014 to 2019). To focus on IPF, the following diagnoses were excluded: post-inflammatory fibrosis, hypersensitivity pneumonitis, rheumatoid arthritis, sarcoidosis, scleroderma, and connective tissue disease. Data were collected from periods prior, during, and following initial clinical diagnosis of IPF. This included prior respiratory diagnoses, number of respiratory-related hospitalizations, anti-fibrotic and oxygen use, and survival. A total of 44,891 with IPF were identified. The most common diagnoses prior to diagnosis of IPF were upper respiratory infections (47%), acute bronchitis (13%), other respiratory disease (10%), chronic obstructive pulmonary disease and bronchiectasis (7%), and pneumonia (6%). The average time to a diagnosis of IPF was 2.7 years after initial respiratory diagnosis. Half of patients had two or more respiratory-related hospitalizations prior to IPF diagnosis. Also, 37% of patients were prescribed oxygen prior to diagnosis of IPF. These observations suggest delayed diagnosis. We also observed only 10.4% were treated with anti-fibrotics. Overall survival declined each year after diagnosis with median survival of 2.80 years. Our retrospective cohort demonstrates that IPF is often diagnosed late, usually preceded by other respiratory diagnoses and hospitalizations. Use of available therapies is low and outcomes remain poor.