Evidence of birth seasonality and clustering of Mycobacterium avium subspecies paratuberculosis infection in US dairy herds.
Paratuberculosis (Johne's disease) is a contagious intestinal infection of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). In cattle, young calves are at the highest risk for acquiring the infection which occurs mainly through ingestion of MAP from contaminated milk, colostrum and feces or environmental contacts. Data consisted of birth dates and ELISA results of 8000 mature cows from 24 Jersey herds from throughout the US and 4 Wisconsin Holstein herds. Some herds also had complete fecal culture (FC) results. The first infection (case) definition (CD1) relied on only ELISA results. A second case definition (CD2) was used in which results of both ELISA and FC tests were considered: animals testing positive to either test were considered "test-positives" and cows testing negative to ELISA or to both ELISA and FC were regarded as "test-negatives". Objective one was to assess seasonality in birth of MAP-infected animals. The effects of age, breed, herd and season of birth (expressed as the sine and cosine functions of birth days within year) were examined using logistic regression. Age was significantly associated with the MAP infection status of dairy cows for both CDs (OR=1.11; 95% CI 1.09, 1.14; P<0.0001 for CD1; OR=1.16; 95% CI 1.08, 1.24; P<0.0001 for CD2). Season of birth had a significant effect on the risk of MAP infection based on CD1 (OR=0.79; 95% CI 0.71, 0.89; P<0.001 for cosine of birth days) with a peak in summer and a trough in winter based on the fitted model. Objective two was to assess whether test-positive animals were randomly distributed or were clustered by date of birth within herds. A temporal cluster analysis approach (scan statistic) implemented in SaTScan software was used for each case definition to detect clusters of birth cohorts using birthdates. Results identified significant clustering of MAP infection cases for CD1 in multiple herds (P<0.05). These results necessitate matching cases and controls of MAP infection on their birth dates to control for non-uniform exposure to MAP in paratuberculosis case-control genome wide association studies, candidate gene studies or in on-farm disease intervention trials.


Endoplasmic reticulum stress induces degradation of glucose transporter proteins during hyperglycemic hepatotoxicity: Role of PERK-eIF2α-ATF4 axis.
Hyperglycemia induced reactive oxygen species oxidize macromolecules including cellular proteins leading to their accumulation in Endoplasmic Reticulum (ER) lumen which in turn activates unfolded protein response (UPR) sensors including, PERK (Protein Kinase RNA-Like ER Kinase). Activated PERK induces ER associated degradation of misfolded proteins to lower the ER stress. In the present study, we hypothesized that ER stress leads to the degradation of glucose transporter proteins resulting in complex glucose metabolism. In vivo studies were carried out in the experimental model of hyperglycemia using streptozotocin/nicotinamide induced diabetic male Wistar rats. High glucose (30 mM) treated HepG2 cells were used to perform the mechanistic study at different time points. PERK gene knockdown (siRNA transfection) and inhibition by ISRIB (Integrated Stress Response Inhibitor, a potent inhibitor of PERK signaling) confirmed the involvement of PERK axis in regulating the expression and translocation of hepatic glucose transporters. Co-immunoprecipitation and dual immunostaining studies further demonstrated increased degradation of GLUT proteins under high glucose conditions. Moreover, Morin (3,5,7,2',4' pentahydroxyflavone) treatment prevented PERK-eIF2α-ATF4 mediated degradation of glucose transporters and enhanced glucose uptake in both, HepG2 cells and diabetic rats. Targeting aberrant regulation of the expression and translocation of facilitative glucose transporter proteins (GLUT proteins) may provide novel therapeutic strategies for the better management of diabetes.


In vitro analysis of Nd:YAG laser damage to hydrophilic intraocular lenses.
Damaged optics of an intraocular lens (IOL) can impair visual functioning. Damage can occur during the manufacturing process, during implantation, or during post-implantation Nd:YAG laser posterior capsulotomy. An in vitro experiment was performed to identify the potential IOL damage patterns associated with the use of the Nd:YAG laser for posterior capsulotomy. A review of the literature regarding Nd:YAG laser damage to IOLs was performed. The objectives were to describe the damage patterns to a sample IOL by performing virtual posterior capsulotomies. Patterns of damage were demonstrated and described. Although optic damage can occur with use of the Nd:YAG laser, it is infrequent and usually the result of improper depth of focus.


White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy.
Neurocognitive impairment (NCI) remains a significant cause of morbidity in human immunodeficiency virus (HIV)-positive individuals despite highly active antiretroviral therapy (HAART). White matter abnormalities have emerged as a key component of age-related neurodegeneration, and accumulating evidence suggests they play a role in HIV-associated neurocognitive disorders. Viral persistence in the brain induces chronic inflammation associated with lymphocytic infiltration, microglial proliferation, myelin loss, and cerebrovascular lesions. In this study, gene expression profiling was performed on frontal white matter from 34 older HIV+ individuals on HAART (18 with NCI) and 24 HIV-negative controls. We used the NanoString nCounter platform to evaluate 933 probes targeting inflammation, interferon and stress responses, energy metabolism, and central nervous system-related genes. Viral loads were measured using single-copy assays. Compared to HIV- controls, HIV+ individuals exhibited increased expression of genes related to interferon, MHC-1, and stress responses, myeloid cells, and T cells and decreased expression of genes associated with oligodendrocytes and energy metabolism in white matter. These findings correlated with increased white matter inflammation and myelin pallor, suggesting interferon (IRFs, IFITM1, ISG15, MX1, OAS3) and stress response (ATF4, XBP1, CHOP, CASP1, WARS) gene expression changes are associated with decreased energy metabolism (SREBF1, SREBF2, PARK2, TXNIP) and oligodendrocyte myelin production (MAG, MOG), leading to white matter dysfunction. Machine learning identified a 15-gene signature predictive of HIV status that was validated in an independent cohort. No specific gene expression patterns were associated with NCI. These findings suggest therapies that decrease chronic inflammation while protecting mitochondrial function may help to preserve white matter integrity in older HIV+ individuals.


A comparison of three fatigue measures in veterans with cancer.
Fatigue is a highly prevalent and distressing symptom in cancer patients. The purpose of this study was to assess the validity of three fatigue measures [the Brief Fatigue Inventory (BFI), the Functional Assessment of Cancer Therapy Fatigue Subscale (FACT-F), and the lack of energy item from the Memorial Symptom Assessment Scale Short Form (MSAS-SF)] and compare these measures in relation to broader quality-of-life (QOL) constructs and clinical factors in veteran cancer patients. One-hundred-eighty cancer patients completed the BFI, FACT-F, FACT-G, MSAS-SF, and the Zung depression scale with concurrent Karnofsky performance status (KPS), laboratory tests, and demographic data. The Cronbach alpha coefficient was from 0.93 to 0.94 for BFI fatigue scales and 0.94 for FACT-F. There were significant correlations between BFI subscales, FACT-F, and lack of energy from MSAS-SF (p < 0.0001). All three fatigue measures showed significant correlation with MSAS-SF symptom subscales (p < 0.0001), FACT-G subscales (p < 0.0001), depression (p < 0.0001), KPS (p < 0.0001), inpatient status (P < 0.0001), insomnia (p < 0.05), hemoglobin (p < 0.05), and albumin levels (p < 0.01). Distress from lack of energy discriminated among levels from the BFI, FACT-F, and FACT-G subscales and MSAS-SF subsclea by one-way of variance analysis. Patient responses to BFI, FACT-F, and the lack of energy item yielded similar information about broader QOL constructs and clinical factors. Single questions about lack of energy, or fatigue severity, may provide a simple and acceptable way to assess fatigue.


Preemptive living donor liver transplantation in glycogen storage disease Ia: case report.
Even with substantial progress in the management of patients with glycogen storage disease type Ia (GSD-Ia), hepatic and renal complications may still develop during long-term follow-up. Herein, we report a case of preemptive living donor liver transplantation in a patient with GSD-Ia. The patient was a 5-year-old boy in whom GSD-Ia was diagnosed at age 10 months. Clinical symptoms included frequent hypoglycemic episodes, hyperlipidemia, hyperuricemia, and growth retardation, which were poorly controlled using conventional treatments. At age 5 years, frequent massive nasal bleeds developed, which led to severe anemia. The patient was brought to our institute for living donor liver transplantation (LDLT). Because GSD-Ia usually responds to dietary and medical treatments, we had a long discussion to determine whether preemptive LDLT was indicated. Transplantation was performed using the left lateral liver segment from the patients mother. The weight of his native liver was almost 2 kg. After reperfusion of the graft, the blood glucose concentration rapidly increased, and regular glucose was administered throughout the operation. The posttransplantation course was uneventful. The patient had no episodes of hypoglycemia with a regular diet. Total cholesterol, triglyceride, and uric acid concentrations also reverted to normal without medication. The patient had a few episodes of nasal bleeding after transplantation, which stopped spontaneously. He was discharged from our hospital with normal liver function. Patients with GSD-Ia should be considered for preemptive LDLT to improve their quality of life when clinical symptoms do not respond to appropriate treatment.


Membrane fluidity of trophoblast cells and susceptibility to natural cytotoxicity.
This study examines the relationship between membrane lipid microviscosity and susceptibility of villous trophoblast to lysis by natural cytotoxic cells. Trophoblast-enriched cell suspensions prepared from term human placentae were treated with cholesteryl hemisuccinate (CHS)--a modulator of membrane lipid microviscosity. CHS-treated cells were more susceptible targets for natural lymphocyte cytotoxicity than were untreated controls. In binding experiments, increased binding of lymphocytes to CHS-treated target cells was found. Preincubation with progesterone prevented membrane rigidification by CHS. Progesterone, cortisol, and estriol restored the impaired resistance of CHS-treated trophoblast cells to lysis. We determined microviscosity and progesterone concentration in villous surface membranes, prepared from placentae from idiopathic spontaneous abortions and normal first-trimester pregnancies. An inverse relationship was found between progesterone content and microviscosity of the membranes. Microviscosity of the membranes from abortion placentae was significantly higher (P less than .01) and progesterone concentration was significantly lower (P less than .001) than those in the membranes of normal first trimester placentae.


Diagnostic value of nasopharyngeal endoscopy for the early recognition of tumours.
It is reported on own experiences gathered with the endoscopy of the nasopharyngeal space by means of an angular optic according to Hopkins (70 degrees). The nasopharyngeal endoscopy is indicated for an early diagnosis of malignant tumour growth and clears up a clinically uncertain nasopharyngeal picture. In addition to the generally known examination methods, the endoscopy of the nasopharynx enables a direct local finding.


Seminal vesicle inter- and intra-fraction motion during radiotherapy for prostate cancer: A review.
A review of studies on seminal vesicle motion was performed to improve the understanding of these treatment uncertainties. This will aid planning target volume margin reduction, which is necessary for hypofractionation of high-risk prostate cancer. Embase, Medline, Web of science Core collection, Cochrane CENTRAL register of trials and Google scholar were searched for publications including 3D information on seminal vesicle motion. In total 646 publications were found of which 22 publications were eligible for inclusion. The mean, systematic and random error of inter- and intra-fraction translations are reported, as well as rotations. The translations of the seminal vesicles is smallest in the left-right direction, whereas the rotation was largest around this axis. Although rectal and bladder filling status were the main cause for seminal vesicle motion, no apparent effect on magnitude of motion was seen when different bladder and rectal preparation protocols were used. Inter- and intra-fraction motion of the seminal vesicles is significant. In the studies, systematic and random errors range between 1-7 mm and 1-5 mm respectively, and are largely uncorrelated to prostate motion. The maximum correlation between seminal vesicle and prostate motion was reported with an R2 of 0.7, while 3 other studies report lower and/or non-significant correlations. Five studies report a planning target volume margin of approximately 8 mm. This margin is in line with the results of four relevant dosimetric studies. Mitigating the inter- and intra-fraction motion of the seminal vesicles, including prostate tracking, has the potential to reduce planning target volume margins.


Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study.
Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer. Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment. To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.


Mechanism of glycine protection in hypoxic injury: analogies with glycine receptor.
Addition of glycine to the recirculating perfusate of isolated perfused rat kidneys protects against hypoxic injury to the medullary thick ascending limb and slows functional deterioration in the course of perfusion. This effect is dependent on dose; the earliest significant protection is seen at 0.25 mM, and the protective effects increase as glycine concentration is increased to 2 mM, the highest level tested. Two specific agonists of the strychnine-insensitive (NMDA) glycine receptor in neural membranes, 1-aminocyclopropane carboxylic acid (ACC) and d-serine, also exerted a cytoprotective effect at a concentration of 2 mM. On the other hand, 1-serine and taurine, ineffective agonists of the NMDA-glycine receptor but effective agonists of the strychnine-sensitive glycine receptor, had no protective effect in this system. Two antagonists to glycine at its binding site on the N-methyl-D-Aspartate (NMDA) receptor, 7-chlorokynurenic acid (2 mM) and indole-2-carboxylic acid (12.5 mM), did not reverse the cytoprotective action of 0.25 mM glycine. The data are consistent with a ligand-acceptor type of interaction to account for cytoprotection. The configuration of the glycine acceptor may resemble, but is not identical with, that of certain glycine receptors in the nervous system.


Bilayer lead oxide X-ray photoconductor for lag-free operation.
Polycrystalline Lead Oxide (poly-PbO) was considered one of the most promising photoconductors for the direct conversion X-ray medical imaging detectors due to its previous success in optical imaging, i.e., as an optical target in so-called Plumbicon video pick-up tubes. However, a signal lag which accompanies X-ray excitation, makes poly-PbO inapplicable as an X-ray-to-charge transducer in real-time X-ray imaging. In contrast, the recently synthesized Amorphous Lead Oxide (a-PbO) photoconductor is essentially lag-free. Here, we report on our approach to a PbO detector where a thin layer of a-PbO is combined with a thick layer of poly-PbO for lag-free operation. In the presented a-PbO/poly-PbO bilayer structure, the poly-PbO layer serves as an X-ray-to-charge transducer while the a-PbO acts as a lag prevention layer. The hole mobility in the a-PbO/poly-PbO bilayer structure was measured by photo-Charge Extraction by Linearly Increasing Voltage technique at different temperatures and electric fields to investigate charge transport properties. It was found that the hole mobility is similar to that in a-Se-currently the only commercially viable photoconductor for the direct conversion X-ray detectors. Evaluation of the X-ray temporal performance demonstrated complete suppression of signal lag, allowing operation of the a-PbO/poly-PbO detector in real-time imaging.


Principles of scarce medical resource allocation in natural disaster relief: a simulation approach.
A variety of triage principles have been proposed. The authors sought to evaluate their effects on how many lives can be saved in a hypothetical disaster. To determine an optimal scarce resource-rationing principle in the emergency response domain, considering the trade-off between lifesaving efficiency and ethical issues. A discrete event simulation model is developed to examine the efficiency of four resource-rationing principles: first come-first served, random, most serious first, and least serious first. Seven combinations of available resources are examined in the simulations to evaluate the performance of the principles under different levels of resource scarcity. The simulation results indicate that the performance of the medical resource allocation principles is related to the level of the resource scarcity. When the level of the scarcity is high, the performances of the four principles differ significantly. The least serious first principle performs best, followed by the random principle; the most serious first principle acts worst. However, when the scarcity is relieved, there are no significant differences among the random, first come-first served, and least serious first principles, yet the most serious first principle still performs worst. Although the least serious first principle exhibits the highest efficiency, it is not ethically flawless. Considering the trade off between the lifesaving efficiency and the ethical issues, random selection is a relatively fair and efficient principle for allocating scarce medical resources in natural disaster responses.


Using Imaging Flow Cytometry to Quantify Neutrophil Phagocytosis.
Neutrophils are professional phagocytes that are important for innate host defenses against pathogens and resolution of inflammation. Traditionally, the phagocytic capacity of neutrophils was quantified by enumeration of cells containing either internalized or bound bacteria or other cargo from a series of microscopic images. Here we describe an imaging flow cytometry-based protocol and analysis method for quantifying the binding and uptake of Neisseria gonorrhoeae by primary adherent human neutrophils. Imaging flow cytometry combines the capacity for quantitative, high-throughput analysis of tens of thousands of cells per condition, with the imaging power of fluorescence microscopy. Here, all bacteria are labeled with Tag-it Violet™ and bound bacteria are differentially stained with a DyLight™ 650-conjugated antibody. Images are analyzed using spot count and other algorithms. Outputs include the percent of neutrophils associated with bacteria, the percent of neutrophils with internalized bacteria, and the percent of internalized bacteria. This basic protocol can be adapted to a variety of particle types and can be used for multiplex analysis in combination with staining for different neutrophil surface and intracellular markers.


A radiation badge survey for family members living with patients treated with a (103)Pd permanent breast seed implant.
Sixty-seven patients with early-stage breast cancer were treated in a Phase I/II clinical trial using a (103)Pd permanent breast seed implant as adjuvant radiotherapy after breast-conserving surgery. We report the dose received by family members living with these patients and compare measured doses with theoretical worst-case scenario estimates. Exposure-rate measurements were taken at 1 m from the patient by using a calibrated low-energy survey meter. Landauer (Landauer Inc., Glenwood, IL) Luxel badges, with sensitivity of 0.01 mSv, were given to family members to wear after the implantation. Badge readings for 33 spouses and 28 other family members were used to estimate effective doses, and these were compared with theory. Average preimplantation planning target volume from computed tomography was 50.3 ml (range, 18.0-96.7 ml), and average preimplantation distance between the skin and the most anterior planning target volume margin was 0.57 cm. The average maximum exposure rate was measured to be 2.4 +/- 1.1 mR/h, and average measured dose to a spouse was 0.99 +/- 1.0 mSv. The calculated exposure rates and spousal doses using preimplantation computed tomography scan data overestimated those measured. Average measured family member dose (excluding spouses) was 0.20 +/- 0.58 mSv. Based on measured and calculated spousal doses, a permanent breast seed implant using (103)Pd is safe for the public. However, it is recommended that extra precautions in the way of a breast patch be used when patients with an implant will be in the vicinity of toddlers or pregnant women.


Biomonitoring of per- and polyfluoroalkyl substances (PFAS) exposure in firefighters: Study design and lessons learned from stakeholder and participant engagement.
Firefighters may be occupationally exposed to per- and polyfluoroalkyl substances (PFASs) through Aqueous Film-Forming Foam (AFFF), smoke, dust and turnout gear, in addition to other background exposure sources. Epidemiological assessment of PFAS exposure in an occupational cohort of firefighting staff commenced in 2013-2014, following cessation of PFAS-based AFFF in Australian aviation. Here we present the study design and methodology of a follow-up study conducted in 2018-2019. We focus on our experiences engaging with stakeholders and participants with the establishment of an inclusive study group and highlight the key lessons learned from implementing a co-design process in the study. The study included a cross-sectional assessment of blood serum concentrations of 40 PFASs, including perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS), and 14 health-related biomarkers in 799 current and former Aviation Rescue Firefighting Services employees. A large proportion (87%) of the participants from the preliminary exposure study in 2013-2014 were re-recruited in the follow-up study. This enabled further longitudinal analyses in this subset of 130 participants. Participants included employees from different work roles and timeframes, reflecting the periods when three different firefighting foams were utilised in Australia. Establishment of a collaborative and inclusive study group (including stakeholders and participants) contributed to several components of the study design, including the expansion of robust analytical quality assurance and control measurements, and tailoring of communication and dissemination strategies. These outcomes were key factors that improved transparency of the research design, methods and results. Additionally, implementing elements of co-design helped build trust between researchers and participants, which is an important consideration for studies funded by stakeholders related to the exposure source.


Cytostatic therapy, its value and indications in the management of prostatic carcinoma.
Observations with cytostatic therapy of generalized prostatic carcinoma (PC) over 5 years are reported, cyclophosphamide (cpa) having been administered to hormone-resistant patients. A standard therapeutic and follow-up scheme, enabling the results to be assessed objectively, had been elaborated. Objective remission or stagnation, confirmed on this basis, was attained in 50%, relief of pain in 60% of the cases. Side effects were negligible. Withdrawal of cytostatics was required in 2 cases. The results indicate that secondary cytostatic therapy significantly potentiated the effect of hormone therapy in generalized PC, and in case of hormone resistance it offers the only chance of therapeutic benefit.


In vitro bioactivity and degradation behaviour of β-wollastonite derived from natural waste.
Calcium silicate ceramics, in particular wollastonite (CaSiO3), is the most commonly used bioactive material for bone regeneration and repairing applications. The present study aims to synthesize cost effective wollastonite using natural waste materials such as rice husk ash (RHA) and eggshells, sources of silica and calcium oxide respectively. Wollastonite was prepared by sol-gel method and based on thermogravimetric and differential thermal analysis (TG/DTA) results the samples were sintered at 850 °C. X-ray diffractometer (XRD) revealed that the sintered samples possess single phasic β-wollastonite. The assessment of bioactivity was examined using in vitro studies by immersing the pellets in simulated body fluid (SBF) for different time periods (3, 7, 14, 21 days). The growth of hydroxyapatite layer on the surface of the sample was analysed using XRD, Fourier transform infrared (FTIR) spectroscopy and Scanning electron microscopy-energy dispersive spectrometer (SEM-EDS). The significant change in pH of the SBF solution was observed during the first 11 days of immersion, after which the pH was saturated. Biodegradation test was performed in SBF and Tris buffer solutions according to ISO 10993-14 standard, and the test revealed that the ceramic pellets showed lower degradation rates with slow dissolution of ionic species. MTT assay demonstrated that the prepared wollastonite exhibits cytocompatibility with MG-63 cells at different dosage (1000-50 μg/mL) for 48 h. The results suggested that β-wollastonite can be a low cost bioactive material, which can be useful in biomedical applications.


Chemiluminometric evaluation of melatonin and selected melatonin precursors' interaction with reactive oxygen and nitrogen species.
Melatonin is a hormone, a derivative of tryptophan, that possesses a potent scavenging capacity for the most reactive and dangerous free radicals, being an important protection against oxidative stress. In this work, an automated flow-based procedure for assessment of melatonin, tryptophan, and 5-hydroxytryptophan scavenging capacity was developed. The presented methodology involved a multi-pumping flow system and exploited the ability of selected compounds to inhibit the chemiluminescence reaction of luminol with hydrogen peroxide, hydroxyl radical, and peroxynitrite anion. The system was based on the use of several solenoid actuated micro-pumps as the only active components of the flow manifold. This enabled the reproducible insertion and efficient mixing of very low volumes of sample and reagents as well as the transportation of the sample zone toward detection for monitoring the chemiluminometric response. Furthermore, the high versatility of the proposed multi-pumping flow system allowed the implementation of distinct reactions for the in-line generation of the different reactive species assayed without requiring physical reconfiguration. The results obtained demonstrated that 5-hydroxytryptophan is the most potent scavenger, followed by melatonin and tryptophan. The developed multi-pumping flow system exhibited good measurement precision (relative standard deviations typically <2%, n=10), low operational costs, and low reagent consumption.


Prevalence of isomeric plastomes and effectiveness of plastome super-barcodes in yews (Taxus) worldwide.
Taxus (yew) is both the most species-rich and taxonomically difficult genus in Taxaceae. To date, no study has elucidated the complexities of the plastid genome (plastome) or examined the possibility of whole plastomes as super-barcodes across yew species worldwide. In this study, we sequenced plastomes from two to three individuals for each of the 16 recognized yew species (including three potential cryptics) and Pseudotaxus chienii. Our comparative analyses uncovered several gene loss events that independently occurred in yews, resulting in a lower plastid gene number than other Taxaceous genera. In Pseudotaxus and Taxus, we found two isomeric arrangements that differ by the orientation of a 35 kb fragment flanked by "trnQ-IRs". These two arrangements exist in different ratios within each sampled individual, and intraspecific shifts in major isomeric arrangements are first reported here in Taxus. Moreover, we demonstrate that entire plastomes can be used to successfully discriminate all Taxus species with 100% support, suggesting that they are useful as super-barcodes for species identification. We also propose that accD and rrn16-rrn23 are promising special barcodes to discriminate yew species. Our newly developed Taxus plastomic sequences provide a resource for super-barcodes and conservation genetics of several endangered yews and serve as comprehensive data to improve models of plastome complexity in Taxaceae as a whole and authenticate Taxus species.


A probe into the possible mechanism underlying the interceptive action of aristolic acid.
Oral administration of aristolic acid (90 mg/kg body weight) on day 6 pregnant and pseudopregnant mice resulted in the termination of pregnancy with in utero fetal death but the length of pseudopregnancy remained unaffected. Peripheral level of progesterone remained statistically uninfluenced in both conditions and exogenous progesterone failed to prevent aristolic acid-induced pregnancy loss, both of which rule out the involvement of luteolysis as the causal factor for the termination of pregnancy. In another experiment, aristolic acid was found to have no inhibitory effect over the maintenance of decidual cell reaction which indicates no inhibitory influence of the compound on uterine utilization of progesterone but points to the fact that presence of concepts is an essential component in the array of mechanism(s) leading to the termination of pregnancy. Probable toxic effect of aristolic acid on the concepts is discussed.


National Trends in the Use of Cardiac Resynchronization Therapy With or Without Implantable Cardioverter-Defibrillator.
Candidates for cardiac resynchronization therapy (CRT) receive either a biventricular pacemaker or a biventricular pacemaker with an implantable cardioverter-defibrillator (CRT-D). Optimal device selection remains challenging because the benefit of implantable cardioverter-defibrillator therapy may not be uniform, particularly in patients at competing risk of nonsudden death. In this serial cross-sectional study using the National Inpatient Sample database, we identified 311,086 admissions associated with CRT implant between 2006 to 2012. CRT-D was the most common device type (86.1%), including in patients ≥ 75 years of age with ≥ 5 Elixhauser comorbidities (75.5%). Multivariate predictors of CRT-D implant included demographic, clinical, and geographic factors: prior ventricular arrhythmia (rate ratio [RR], 1.14; 95% CI, 1.13-1.14), ischemic heart disease (RR, 1.11; 95% CI, 1.10-1.11), male sex (RR, 1.10; 95% CI, 1.09-1.10), black race (RR, 1.06; 95% CI: 1.04-1.07), and Northeast geographic region (RR, 1.06; 95% CI, 1.04-1.09). There was significant interhospital variation in the use of CRT-D (10-90 percentile range, 72.9%-98.0% CRT-D). The majority of patients in this contemporary US cohort underwent implantation of CRT-D. Predictors of CRT-D implant included demographic, clinical, and geographic factors. In patient subgroups predicted to have an attenuated benefit from implantable cardioverter-defibrillator therapy (older adults with multiple comorbidities), CRT-D remained the dominant device type. An improved understanding of the determinants of device selection may aid in decision making and ultimately better align patient risk with device benefit at the time of CRT implantation.


Cell-cycle-regulated translation of histone mRNA in Physarum plasmodia.
In Physarum polycephalum, histone mRNA begins to accumulate 3 h before the S phase. We show that histone synthesis was limited to the S phase and that the mRNA that accumulated in the G2-phase cytoplasm could be translated in vitro. Thus, recruitment of stored mature histone mRNA did not occur until the S phase began.


2-Fluoro-N'-[(2-hydroxynaphthalen-1-yl)methylidene]benzohydrazide.
In the title mol-ecule, C(18)H(13)FN(2)O(2), the hy-droxy group is involved in an intra-molecular O-H⋯N hydrogen bond. The naphthyl ring system and the benzene ring form a dihedral angle of 31.0 (2)°. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into chains propagating in [101].


Gaps in facilities available at Community Health Centers/Rural Hospitals as per Indian public health standards - Study from Western Maharashtra.
The launch of the National Rural Health Mission (NRHM) gives us the opportunity to review the functioning and bring up the Community Health Centers (CHC) services to the level of Indian Public Health Standards and thus improve the lives of citizens. Assessment of the gaps in the facilities available at Community health centers/Rural hospitals as per Indian Public health standards. Facility based cross-sectional study was conducted in the Satara district of Maharashtra. This study in the majority showed that the gap in the delivery of healthcare according to IPHS. It was observed that the Funded CHCs had a better quality of services than the non-funded CHCs. The non-funded CHCs lacked essential emergency services. Along with ANC care, newborn care in the first few minutes of life is very crucial, but very little priority was given to the newborn care as those services were not as per norms. Specialists as well as paramedical and other support staff are deficient in both funded and non funded CHCs/rural hospitals (RHs). Standards were greatly influenced by funds delivered by IPHS itself. A staffing pattern is one of the important pillars in delivering various health services. A better salary, working place with continuous water supply, electricity, and cleanliness will improve the staffing pattern. Therefore, competent manpower and well-built infrastructure will help in the standard delivery of healthcare at CHC/RH and will thus serve the purpose of dispensing basic health services to every individual in the remotest areas.


Evaluation of renal function in rats with moderate and mild brain trauma.
We aimed to diagnose possible acute kidney injury (AKI) with new early biochemical markers in patients who were admitted to the emergency department frequently with mild and moderate brain trauma, and to prevent possible complications, shorten the duration of treatment and hospital stay. With this purpose, we decided to reach our scientific target using the experimental rat model. Wistar albino rats were included our experiment. Fifteen rats were randomly separated into three groups: Sham control (n=1: Underwent craniotomy alone), control (n=7: Without craniotomy), and trauma group (n=7: Underwent craniotomy followed by brain injury). There were no significant differences groups creatinine levels within 0 and 24 h (0.35±0.02 and 0.33±0.03, respectively, p>0.05). Plasma NGAL and KIM1 concentrations were statistically significant different in both control and trauma groups (Friedman p<0.05) and significant differences at both NGAL and KIM-1 concentrations at dual comparisons by means of all sampling time (0-2 h, 0-24 h, and 2-24 h) (Wilcoxon p<0.001, after Bonferroni correction). The presence of AKI in patients with mild-to-moderate brain trauma increases the risk of mortality. Early diagnosis of AKI reduces the hospitalization period and requiring of dialysis. Diagnosis of AKI within 24 h with early biomarkers and starting therapy is crucial issues.


Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.
High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival.


Co-morbid anxiety and depression in childhood asthma and its effect on symptom control: A cross sectional study.
Anxiety and depression are co-morbidities that affect symptom control in children with asthma and are often overlooked in busy practice. To find out the proportion of children with asthma who have co-morbid anxiety and depression, to study the association of co-morbid anxiety and depression on symptom control and to study the clinic-sociodemographic factors associated with anxiety and depression in children with asthma. Assuming 13% prevalence of anxiety and depression, with 95% confidence level and 5% absolute precision, a total of 176 children with asthma aged 6 years and above were enrolled from the asthma clinic. Clinical and sociodemographic details were collected for all. Symptom control was assessed using asthma control test questionnaire. Center for epidemiological studies-depression scale for children and screen for child anxiety related emotional disorders was used to assess depression and anxiety, respectively. Association of independent variables with outcome variables was assessed using χ2 . Statistical tests were done using SPSS version 26. Out of the 176 children enrolled, 13.1%, 8%, and 16.5% had anxiety, depression, and combined anxiety and depression, respectively. A higher proportion of children with uncontrolled asthma had depression and combined anxiety and depression than children with controlled asthma. Combined anxiety and depression was more common than either anxiety or depression alone and along with depression, was significantly associated with uncontrolled symptoms.


Anti-PD-1 therapy using cemiplimab for advanced cutaneous squamous cell carcinoma in HIV patient: A case report.
This is a case of a 60-year-old man living with HIV who presented with advanced cutaneous squamous cell carcinoma. After workup, medical and surgical treatment, and disease recurrence, he achieved a complete response with no unexpected toxicities after immunotherapy with cemiplimab.


Full-length transcriptome sequencing from multiple immune-related tissues of Paralichthys olivaceus.
Olive flounder (Paralichthys olivaceus) is an important economical flatfish in Japan, Korea and China, but its production has been greatly threatened by various of diseases. Although RNA-seq has provided valuable insights into the host-pathogen interaction, there are still some disadvantages, such as a short sequencing length, the incomplete or inaccurate splicing. Therefore, we generated a full-length transcriptome using mixed immune-related tissues of P. olivaceus with PacBio Sequel platform. In this study, 379,671 full-length non-chimeric (flnc) reads were generated with average length of 2482 bp, which is longer than any previously reported in P. olivaceus. A total of 66,420 isoforms of transcript were identified, 46,850 of which were novel isoforms of known genes accounting for 70.54%. In addition, 7720 novel genes, 12,540 alternative splicing (AS) events, 9296 alternative polyadenylation (APA) events, 2298 transcription factors (TFs), 10,270 lncRNAs and 5400 fusion transcripts were identified. Furthermore, functional annotation showed that most of the full-length transcripts were enriched in immune-related signaling pathways. Otherwise, the mRNA-miRNA interacting networks confirmed that 28.5% of mRNAs were predicted to be targeted by more than one miRNA. These results facilitate the understanding of gene structure, post-transcriptional regulatory networks, and subsequently proteomic diversity. In conclusion, our study provides the full-length transcriptome from multiple immune-related tissues of P. olivaceus, which is valuable for exploring its immune responses.


No synergistic effect of carbon monoxide and oxygen during static gaseous persufflation preservation of DCD livers.
The benefit of carbon monoxide and/or oxygen as applied by controlled, continuous gaseous persufflation during liver preservation on postischemic graft recovery was investigated in an isolated rat liver model. Livers from male Wistar rats were retrieved 30 min after cardiac arrest of the donor and subjected to 18 h of cold storage. Some grafts were subjected to gaseous persufflation during static cold storage either with pure oxygen or with CO dissolved in oxygen. Graft integrity was assessed thereafter upon warm reperfusion in vitro. Oxygen persufflation significantly reduced cellular enzyme loss and metabolic recovery (bile production and ATP recovery) upon reperfusion by about 50%. The effect was associated with a reduction of vascular perfusion resistance, mitigated gene up-regulation of the mitochondrial stress protein GRP 75, and improved mitochondrial ultra-structure. Similar results were obtained by persufflation with CO in oxygen, while no additive benefit of CO and oxygen could be seen in our model. Hepatocellular injury of cold stored liver grafts can be notably reduced by gaseous ex vivo application of oxygen with or without additional admixture of CO to the isolated organ but no superiority or additive effect is seen with respect to persufflation with oxygen.


Definitive management of rectal cancer by contact (endocavitary) irradiation.
In a retrospective review, 62 patients treated for rectal cancer by contact (endocavitary) irradiation at The Cleveland Clinic Foundation were analyzed. This treatment modality delivers high dose, low penetration irradiation to a rectal cancer by direct contact of a 50 KV x-ray source through a special proctoscope. Cancers selected for this treatment include small (3 cm or less), mobile tumors without presacral lymphadenopathy that are within reach of digital examination and are well- or moderately well-differentiated adenocarcinomas. Between 1973 and 1984, 62 patients (37 males, 25 females) were treated--46 by contact irradiation alone and 16 by contact irradiation after excisional biopsy. The median tumor dose was 12,000 rads administered in four fractions at monthly intervals. Mean follow-up was 31 months. Fifty-six patients (90 percent) were disease-free at the time of review or death (ten died from unrelated causes). Eleven patients (18 percent) developed local recurrence but eight of these without distant metastases were rendered disease-free by other treatment--six by surgical resection and two by further radiotherapy. Mean time since secondary treatment is 20 months. Three patients are alive with incurable disease and three have died from cancer--in three of these six patients there was no evidence of local disease. Ulcerated tumors developed local recurrence in five of 17 cases (29 percent) while polypoid tumors recurred locally in six cases (14 percent). Morbidity from the treatment was minor in nature. It is suggested that contact (endocavitary) irradiation is effective treatment for carefully selected cases of rectal cancer.


Disordered eating symptoms in Austrian men of different ages in the context of fitness centers.
To assess eating behavior and associated factors in male fitness-center attendees. An anonymous questionnaire was administered to male fitness center members of Innsbruck (Austria), aged 18-80 years to assess socio-demographic features, weight history, sports activity, eating behavior including disordered eating based on the Eating Disorder Examination Questionnaire (EDE-Q) and DSM-5 key symptoms for eating disorders (anorexia nervosa, binge eating, bulimia nervosa, purging disorder) and body image. Three age groups (younger-middle-aged-older men) were compared regarding the variables described above. A total of 307 men included displayed high rates of disordered eating as described by EDE-Q cutoff scores (5-11%) as well as by DSM-5 eating disorder symptoms (10%). While EDE-Q cutoff scores did not differentiate between the groups, the prevalences of DSM-5 eating disorder symptoms yielded significant differences indicating a clear decrease with increasing age. Binge eating and bulimic symptoms with excessive exercising as the purging method were the most often reported symptoms. Although described as typically female, disordered eating does occur in male fitness-gym attendees across all ages. The older the men, the less prevalent are the symptoms. Awareness of disordered eating and possible negative effects need to be addressed for attendees and trainers of the gym. V-descriptive survey study.


Problems in the case for psychotherapeutic integration.
The arguments in favor of therapeutic integration are summarized and evaluated. Weaknesses of the position are: (1) the false claim that all therapies are equally effective; (2) the lack of a clear and accurate specification of what makes a school of therapy "legitimate"; (3) the lack of a clear case for an accurate and comprehensive list of common elements across therapies; (4) a lack of clarity concerning "clinical strategy"; (5) the incorrect claim that cognitive therapy provides a useful and neutral meta-language; (6) inadequate evidence of trends toward integration; (7) fallacious reasoning based on these alleged trends; and (8) a misunderstanding of the history and philosophy of science.


Increased c-fos gene expression in alpha motoneurons in rat loaded hindlimb muscles with inclined locomotion.
The potential usefulness of c-fos gene expression as an indicator of the activity level of spinal alpha motoneurons was examined in loaded locomotive rats. The motor pools of the plantaris (PL) and soleus muscles (SOL), mainly composed respectively of fast- and slow-twitch muscle fibers, were investigated in rats under locomotion at 25 m/min on a 20% incline. We first labeled motoneurons with a retrograde tracer, Nuclear Yellow (NY), and then quantified the c-fos mRNA expression level in the NY-labeled alpha motoneurons by means of in situ hybridization. Electromyographic (EMG) activities were also recorded. The c-fos expression level per alpha motoneuron showed a greater increase in the PL (75%) than in the SOL motor pool (38%). EMG activities also showed a greater increase in the PL (159%) than in the SOL (43%). Taken together, these results suggest that c-fos expression levels in alpha motoneurons are associated with the activity levels of their corresponding muscle. This cytochemical method for identifying the c-fos expression level has potential for use as a tool for estimating the activity level of large populations of alpha motoneurons in unrestricted animals.


N-terminal amino acid sequence of intact human fibrinogen.
N-Terminal amino acid sequence analysis by Edman's phenylisothiocyanate method on intact human fibrinogen revealed the first seven amino acids of the gamma-chain: H-Tyr-Val-Ala-Thr-Arg-Asp-Asn-.


Respiratory viral coinfection in a birth cohort of infants in rural Nepal.
Acute respiratory illnesses are a leading cause of global morbidity and mortality in children. Coinfection with multiple respiratory viruses is common. Although the effects of each virus have been studied individually, the impacts of coinfection on disease severity are less understood. A secondary analysis was performed of a maternal influenza vaccine trial conducted between 2011 and 2014 in Nepal. Prospective weekly household-based active surveillance of infants was conducted from birth to 180 days of age. Mid-nasal swabs were collected and tested for respiratory syncytial virus (RSV), rhinovirus, influenza, human metapneumovirus (HMPV), coronavirus, parainfluenza (HPIV), and bocavirus by RT-PCR. Coinfection was defined as the presence of two or more respiratory viruses detected as part of the same illness episode. Of 1730 infants with a respiratory illness, 327 (19%) had at least two respiratory viruses detected in their primary illness episode. Of 113 infants with influenza, 23 (20%) had coinfection. Of 214 infants with RSV, 87 (41%) had coinfection. The cohort of infants with coinfection had increased occurrence of fever lasting ≥ 4 days (OR 1.4, 95% CI: 1.1, 2.0), and so did the subset of coinfected infants with influenza (OR 5.8, 95% CI: 1.8, 18.7). Coinfection was not associated with seeking further care (OR 1.1, 95% CI: 0.8, 1.5) or pneumonia (OR 1.2, 95% CI: 0.96, 1.6). A high proportion of infants had multiple viruses detected. Coinfection was associated with greater odds of fever lasting for four or more days, but not with increased illness severity by other measures.


Chorda tympani nerve modulates the rat's avoidance of calcium chloride.
Calcium intake depends on orosensory factors, implying the presence of a mechanism for calcium detection in the mouth. To better understand how information about oral calcium is conveyed to the brain, we examined the effects of chorda tympani nerve transection on calcium chloride (CaCl(2)) taste preferences and thresholds in male Wistar rats. The rats were given bilateral transections of the chorda tympani nerve (CTX) or control surgery. After recovery, they received 48-h two-bottle tests with an ascending concentration series of CaCl(2). Whereas control rats avoided CaCl(2) at concentrations of 0.1mM and higher, rats with CTX were indifferent to CaCl(2) concentrations up to 10mM. Rats with CTX had significantly higher preference scores for 0.316 and 3.16 mM CaCl(2) than did control rats. The results imply that the chorda tympani nerve is required for the normal avoidance of CaCl(2) solution.


An autoradiographic study of binding of iodinated spider toxin to lobster muscle.
Distribution of the binding sites of Joro spider toxin (JSTX), a specific inhibitor of the glutamate receptors in the crustacean neuromuscular synapse, was studied by using autoradiography. JSTX was synthesized and made radioactive by conjugation with iodine-125. 125I-JSTX irreversibly blocked the excitatory postsynaptic potentials of the lobster neuromuscular synapse in a similar manner as the natural spider toxin. Light microscopic autoradiography of 125I-JSTX treated muscle showed sporadic aggregates of reduced silver grains on the surface of muscles. Electron microscopy of adjoining ultrathin sections revealed that these spots corresponded to the fraction of sarcolemma apposed to axonal terminals with or without synaptic junctional profiles. This finding gives morphological support to the formulation that JSTX binds to the glutamate receptor-ion channel molecules.


Geotoxicology of multiple sclerosis: the Henribourg, Saskatchewan, Cluster Focus. I. The water.
Some childhood-related, geographically-linked factor predisposes towards (or protects against) multiple sclerosis (MS). It is quite plausible that this factor could be one or more chemicals in the environment, and that chemical study of the environment or "focus" of an MS cluster might maximize the chances of detecting such an etiological link. The water chemistry of such a focus (Henribourg, Saskatchewan) was compared with North American norms, and with the chemistry of water from a nearby control area with a near-zero incidence of MS and of childhood homes of MS cases. Overall, the results suggest that an environment predisposing to MS may have a number of water chemistry characteristics such as: relative deficiency of selenium and sulfate, but relative abundance of barium, calcium, chloride, chromium, magnesium, manganese, molybdenum, nitrate plus nitrite, strontium and zinc. Possible explanations for the apparent link between the excess rate of MS and the water geochemistry findings at Henribourg are discussed.


Endogenous prostaglandins in peptic ulcer disease.
Plasma concentrations of prostaglandins E and F have been measured by radioimmunoassay in patients undergoing diagnostic upper intestinal endoscopy. The results fail to support a previously reported deficiency of plasma PGE in duodenal ulcer patients. Plasma prostaglandin concentrations failed to correlate with the parameters of gastric secretion studied; and were unaffected by histamine H2-receptor blockade or the activity of duodenal ulceration. During combined pentagastrin and insulin secretory studies there was a significant correlation between the outputs of PGE and acid into gastric juice.


Bladder filling in mice: an experimental in vivo model to evaluate the reservoir function of the urinary bladder in a long term study.
We report a simple, reproducible, and low-invasive in vivo method for repeated examination of bladder well properties in mice. Over a period of 21 days transurethral bladder fillings were performed every second day on the same animal. Analysis of the bladder volume at an intravesical pressure of 10 and 20 mm. Hg and at the leakage point showed no trend during the 21 day study period with regard to changes in bladder volume. The model has been applied to a group of mice treated with a single fraction bladder irradiation dose of 20 Gy. These mice were investigated repeatedly during the following year. The end point selected for data evaluation in the irradiated group of mice was a 50% decrease in bladder volume at an intravesical pressure of 20 mm. Hg relative to the control value (bladder volume before irradiation). The results clearly demonstrate a biphasic change in the bladder reservoir function, in the form of an acute, reversible change, a period of normalization and then a late irreversible damage. The latter stage is consistent with the clinically found contracted bladder. In a control group there was no significant change in bladder volume during the study period of more than 200 days. The model thus appears feasible for future studies of bladder irradiation damage.


The younger siblings of childbearing adolescents: parenting influences on their academic and social-emotional adjustment.
The younger siblings of childbearing adolescents have poorer school outcomes and exhibit more internalizing and externalizing problems compared to their peers without a childbearing sister. We test a model where living with an adolescent childbearing sister constitutes a major family stressor that disrupts mothers' parenting and well-being, and through which, adversely affect youths' adjustment. Data came from 243 Latino younger siblings (62% female, M age 13.7 years) and their mothers, 121 of whom lived with a childbearing adolescent sister and 122 of whom did not. Individual fixed-effects models controlled for earlier measures of each respective model construct, thereby reducing omitted variable bias from pre-existing group differences. Results show that, for boys, the relationship between living with a childbearing adolescent sister and youth outcomes was sequentially mediated through mothers' stress and parenting (i.e., monitoring and nurturance). For girls, however, the relationship was mediated through mothers' monitoring only. Findings elucidate the within-family processes that contribute to the problematic outcomes of youth living with childbearing adolescent older sisters.


Permanent effector phenotype of neuroantigen-specific T cells acquired in the central nervous system during experimental allergic encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is regarded as an animal model of the human autoimmune disease multiple sclerosis (MS). Autoreactive T cells are present in the peripheral T cell repertoire of healthy mice and mediate clinical autoimmune disease only after activation by immunization or pathogens and migrate into the central nervous system (CNS). Because it is not known whether autoreactive T cells are regulated differentially once entering the CNS we investigated cytokine regulation in T cells from peripheral lymphatic organs and from the inflamed CNS ex vivo obtained from SJL mice after inducing relapsing-remitting EAE with PLP peptide 139-151. We show here that during acute EAE, an interleukin-2 (IL-2) biased T cell response exists in the spleen, while an interferon-gamma (IFN-gamma) biased T cell response prevails in the CNS of mice with acute EAE. The IFN-gamma biased phenotype was stable with optimized costimulation and even after in vitro stimulation with IL-2. After adoptive transfer into naïve syngeneic mice these T cells were only partially reversed to an IL-2 biased phenotype. These findings of our work suggest that a permanent effector phenotype of neuroantigen-specific T cells is finally acquired in the CNS in EAE.


Adherence, control of cardiometabolic factors and therapeutic inertia in patients with type 2 diabetes in the primary care setting.
Studies on treatment adherence to glucose-lowering drugs among patients with type 2 diabetes (T2D) including concomitant treatment for other cardiovascular risk factors are scarce. We aimed to estimate the prevalence of good adherence to all medications used to control diabetes, hypertension and dyslipidemia and to analyse cardiometabolic control and its associated factors in T2D patients in the primary care (PC) setting. Observational, retrospective study conducted in adult patients with T2D who were followed in the PC setting in Spain. Patients were classified as adherent in a particular category if the summary of the proportion of days covered (PDC) for a particular medication category was ≥80% and were considered globally adherent if the PDC was ≥80% for each of the 3 medication categories. A total of 457 evaluable patients were recruited, among which 321 patients (70.3%, 95% CI 65.8 to 74.4) were adherent to the three drug categories. The proportion of patients controlled for the 3 cardiometabolic risk factors was 31% according to the contemporary clinical practice guideline criteria, 58% according to investigator judgment and 36% when the objective for HbA1c was individualized. In a multivariate analysis, presenting comorbidities was associated with a lower likelihood of showing adequate control of dyslipidemia (odds ratio [OR] 0.25, 95% CI, 0.16-0.40) and the three cardiometabolic factors as a whole (OR 0.43, 95% CI 0.26-0.70). In a post hoc analysis, therapeutic inertia was found to be greater for dyslipidemia and hypertension than for T2D. Despite a relatively high adherence to all medications for treating diabetes, hypertension and dyslipidemia in patients with T2D in the PC setting in Spain, the control of cardiometabolic risk factors as a whole is far from optimal. This could be related, at least in part, to the high frequency of comorbidity of these patients.


Signaling pathways of magnolol-induced adrenal steroidogensis.
This study focused on identifying the signalling mediating the effect of magnolol on corticosterone production. Magnolol-induced corticosterone production was completely inhibited by mitogen-activated protein kinase kinase (MEK)-inhibitor PD98059, tyrosine kinase (TK)-inhibitor genistein or Janus tyrosine kinase 2 (JAK2)-inhibitor AG490, suggesting that extracellular signal-regulated kinase (ERK) and JAK2 are both involved in this signaling cascade. Further, magnolol induced the transient phosphorylation of MEK, ERK, cAMP response-element binding protein (CREB) and the expression of 32 and 30 kDa steroidogenic acute regulatory protein (StAR) in a time-dependent manner. Inhibition of TK or JAK2 activities blocked magnolol-induced phosphorylation of MEK and ERK, again supporting the upstream role of JAK2. The activation of JAK2 or MEK apparently mediated the magnolol-induced phosphorylation of CREB and the upregulation of StAR. These findings demonstrate a novel pathway for magnolol to induce the expression of StAR, which regulates the rate-limiting step in sterodiogenesis.


Hypermethylated ZNF582 and PAX1 genes in mouth rinse samples as biomarkers for oral dysplasia and oral cancer detection.
Effective biomarkers for oral cancer screening are important for early diagnosis and treatment of oral cancer. Oral epithelial cell samples collected by mouth rinse were obtained from 65 normal control subjects, 108 patients with oral potentially malignant disorders, and 94 patients with oral squamous cell carcinoma (OSCC). Methylation levels of zinc-finger protein 582 (ZNF582) and paired-box 1 (PAX1) genes were quantified by real-time methylation-specific polymerase chain reaction after bisulfite conversion. An abrupt increase in methylated ZNF582 (ZNF582m ) and PAX1 (PAX1m ) levels and positive rates from mild dysplasia to moderate/severe dysplasia, indicating that both ZNF582m and PAX1m are effective biomarkers for differentiating moderate dysplasia or worse (MODY+) oral lesions. When ZNF582m /PAX1m tests were used for identifying MODY+ oral lesions, the sensitivity, specificity, and odds ratio (OR) were 0.65/0.64, 0.75/0.82, and 5.6/8.0, respectively. Hypermethylated ZNF582 and PAX1 genes in oral epithelial cells collected by mouth rinse are effective biomarkers for the detection of oral dysplasia and oral cancer.


[Influence of daily set-up errors on dose distribution during pelvis radiotherapy].
An external beam radiotherapy (EBRT) using megavoltage beam of linear accelerator is usually the treatment of choice in cancer patients. The goal of EBRT is to deliver the prescribed dose to the target volume, with as low as possible dose to the surrounding healthy tissue. A large number of procedures and different professions involved in radiotherapy, uncertainty of equipment and daily patient set-up errors can cause a difference between the planned and delivered dose.We investigated a part of this difference caused by measuring daily patient set-up errors for 35 patients. These set-up errors were simulated on five patients, using 3D treatment planning software XiO. The simulation investigated differences in dose distributions between the planned and shifted geometry. Additionally, we investigated the influence of the error on treatment plan selection by analysing changes in dose volume histograms, planning target volume conformity index (CIPTV), and homogeneity index (HI).Simulations showed that patient daily set-up errors can cause significant differences between the planned and actual dose distributions. Moreover, for some patients, those errors could affect the choice of treatment plan since CIPTV fell under 97%. Surprisingly, HI was not as sensitive to set-up errors as CIPTV. Our results have confirmed the need to minimise daily set-up errors through quality assurance programmes.


Quantitative RNA imaging in single live cells reveals age-dependent asymmetric inheritance.
Asymmetric inheritance of cellular content through cell division plays an important role in cell viability and fitness. The dynamics of RNA segregation are so far largely unaddressed. This is partly due to a lack of approaches to follow RNAs over multiple cellular divisions. Here, we establish an approach to quantify RNA dynamics in single cells across several generations in a microfluidics device by tagging RNAs with the diSpinach aptamer. Using S. cerevisiae as a model, we quantitatively characterize intracellular RNA transport from mothers into their buds. Our results suggest that, at cytokinesis, ENO2 diSpinach RNA is preferentially distributed to daughters. This asymmetric RNA segregation depends on the lifespan regulator Sir2 and decreases with increasing replicative age of mothers but does not result from increasing cell size during aging. Overall, our approach opens more opportunities to study RNA dynamics and inheritance in live budding yeast at the single-cell level.


The Sandwich Generation Diner: Development of a Web-Based Health Intervention for Intergenerational Caregivers.
Women are disproportionately likely to assist aging family members; approximately 53 million in the United States are involved with the health care of aging parents, in-laws, or other relatives. The busy schedules of "sandwich generation" women who care for older relatives require accessible and flexible health education, including Web-based approaches. This paper describes the development and implementation of a Web-based health education intervention, The Sandwich Generation Diner, as a tool for intergenerational caregivers of older adults with physical and cognitive impairments. We used Bartholomew's Intervention Mapping (IM) process to develop our theory-based health education program. Bandura's (1997) self-efficacy theory provided the overarching theoretical model. The Sandwich Generation Diner website features four modules that address specific health care concerns. Our research involves randomly assigning caregiver participants to one of two experimental conditions that are identical in the type of information provided, but vary significantly in the presentation. In addition to structured Web-based assessments, specific website usage data are recorded. The Sandwich Generation Diner was developed to address some of the informational and self-efficacy needs of intergenerational female caregivers. The next step is to demonstrate that this intervention is: (1) attractive and effective with families assisting older adults, and (2) feasible to embed within routine home health services for older adults.


Engineering the yeast Yarrowia lipolytica for the production of therapeutic proteins homogeneously glycosylated with Man₈GlcNAc₂ and Man₅GlcNAc₂.
Protein-based therapeutics represent the fastest growing class of compounds in the pharmaceutical industry. This has created an increasing demand for powerful expression systems. Yeast systems are widely used, convenient and cost-effective. Yarrowia lipolytica is a suitable host that is generally regarded as safe (GRAS). Yeasts, however, modify their glycoproteins with heterogeneous glycans containing mainly mannoses, which complicates downstream processing and often interferes with protein function in man. Our aim was to glyco-engineer Y. lipolytica to abolish the heterogeneous, yeast-specific glycosylation and to obtain homogeneous human high-mannose type glycosylation. We engineered Y. lipolytica to produce homogeneous human-type terminal-mannose glycosylated proteins, i.e. glycosylated with Man₈GlcNAc₂ or Man₅GlcNAc₂. First, we inactivated the yeast-specific Golgi α-1,6-mannosyltransferases YlOch1p and YlMnn9p; the former inactivation yielded a strain producing homogeneous Man₈GlcNAc₂ glycoproteins. We tested this strain by expressing glucocerebrosidase and found that the hypermannosylation-related heterogeneity was eliminated. Furthermore, detailed analysis of N-glycans showed that YlOch1p and YlMnn9p, despite some initial uncertainty about their function, are most likely the α-1,6-mannosyltransferases responsible for the addition of the first and second mannose residue, respectively, to the glycan backbone. Second, introduction of an ER-retained α-1,2-mannosidase yielded a strain producing proteins homogeneously glycosylated with Man₅GlcNAc₂. The use of the endogenous LIP2pre signal sequence and codon optimization greatly improved the efficiency of this enzyme. We generated a Y. lipolytica expression platform for the production of heterologous glycoproteins that are homogenously glycosylated with either Man₈GlcNAc₂ or Man₅GlcNAc₂ N-glycans. This platform expands the utility of Y. lipolytica as a heterologous expression host and makes it possible to produce glycoproteins with homogeneously glycosylated N-glycans of the human high-mannose-type, which greatly broadens the application scope of these glycoproteins.


An estimate of the number of white sharks Carcharodon carcharias interacting with ecotourism in Guadalupe Island.
The aim of the present study is to provide an estimate of the number of white sharks Carcharodon carcharias that seasonally interact with ecotourism boats in Guadalupe Island using Schnabel's mark-recapture method and 6316 records of white sharks during 2012-2014. The results of the estimation highlight an abundance of 78 white sharks 95% C.I. (62.1, 105.6) interacting with ecotourism. The regulations regarding the number of tourists, boats and the monitoring of white sharks should be assessed to improve management decisions regarding the conservation and sustainable use of this threatened species.


Blood and urine histamine levels in normal and pathological states as measured by a radiochemical assay.
The utility of the enzymatic radiochemical assay of histamine in diagnosing diseases with known abnormalities in histamine production was investigated. Whole blood histamine levels were abnormal only in patients with basophilia, i.e. chronic myelocytic leukemia or polycythemia vera. Histamine was not detectable (less than 1 ng/ml) in normal plasma but was detected in plasma of some patients witheither mastocytosis or chronic myelocytic leukemia. These patients also had symptoms which could be attributed to histamine release as, for example, hyperchlorhydria and hypotension. Urinary histamine excretion was also abnormally high in these diseases compared to normal subjects (range less than 5-42 microgram/24 h, n = 31). Patients with systemic mastocytosis had higher urine values (greater than 150 microgram/24 h) than those with cutaneous mastocytosis (39-88 microgram/24 h), and the urinary histamine excretion appeared to be an index of the severity of the diseases. Studies with L-histidine loading suggest that the kidney is one possible source of urinary histamine.


Construction of a diverse set of terpenoid decalin subunits from a common enantiomerically pure scaffold obtained by a biomimetic cationic cyclization.
An unprecedented biomimetic cationic cyclization reaction of an alkyne-containing geraniol-derived epoxide is used for the stereoselective synthesis of a novel enantiomerically pure scaffold that is easily transformed into a set of structurally diverse decalin derivatives with potential application in the synthesis of targeted natural products and/or natural-product-inspired new molecules.


[Total asthenospermia with an ultrastructural anomaly of the flagellum in two sterile brothers (author's transl)].
The two sterile brothers were found to have the same sperm abnormalities. The flagella were short or absent. The constituent elements of the flagellum were disorganized, and the axone structure was disturbed. These abnormalities give rise to a problem of explaining the genetic origin of certain sperm defects similar to those found particularly in mice.


Effects of psychological, sensory, and metabolic energy prime manipulation on the acute endocrine stress response in fasted women.
The stress response supports survival through energy mobilization. Paradoxically, a low blood glucose level dampens the endocrine stress response, and sugar consumption prior to stress restores it. Thus, energy availability may play a causal role in the endocrine stress response. Yet, it has never been tested whether sweet taste or expectations towards a drink content modulate the stress response. We investigated the potential role of sweetness, energy load and expectations towards energy load of a drink consumed prior to stress in restoring stress reactivity after fasting. N = 152 women (meanage=21.53, sdage=2.61) participated in the Trier Social Stress Test for groups in the morning after an overnight fast. Prior to stress induction, participants consumed a drink containing saccharose (sugar, n = 51), an equally sweet drink containing non-caloric sweetener (sweetener, n = 46), or water (n = 56). Additionally, participants in the sugar and sweetener group (n = 97) were informed whether or not their drink contained any calories (energy prime), which was deceptive in 50% of the cases. Eight salivary cortisol (-30, -20, -10, 0, +12, +25, +35, +45 min) and three blood glucose samples (-30, 0, +25 min) were assessed throughout the experiment. The effects of the experimental manipulations on cortisol trajectories were tested using multilevel mixed models. We found that compared with water, sugar and sweetener both significantly increased cortisol stress reactivity and with comparable intensity. However, our sensitivity analysis revealed a significant effect of sugar on cortisol trajectories compared to water and to sweetener. Drink-induced changes in blood glucose concentration were not associated with increases in cortisol. The energy prime did not affect the stress response. Overall, we could replicate the boosting effect of sugar consumption in a female sample after 8 h of fasting. The specific contribution of sweet taste and metabolic hormones to this boosting effect should be tested more rigorously in sex-balanced designs in the future.


Translational Epidemiology: Genetic Ancestry in Breast Cancer: What Is the Role of Genetic Ancestry and Socioeconomic Status in Triple-Negative Breast Cancer?
Racial/ethnic and socioeconomic disparities seen in triple-negative breast cancer (TNBC) have prompted questions regarding the role of genetic ancestry in breast cancer (BC) subtype development, tumor biology, and ultimately prognosis. The causes of disparities in TNBC are influenced greatly by both sociopolitical factors and genetic ancestry, and now, the potential genomic underpinnings of social factors. To comprehensively understand disparities in TNBC, it is critical to take a translational epidemiologic approach that takes into account genomic and non-genomic factors. Understanding the interplay between genetic ancestry and social genomics and their proportional influence on outcomes can guide our priorities for screening, diagnosis, and interventions for this aggressive BC subtype.


Association between blood pressure and different antihypertensive drugs with outcome after ischemic stroke: A Mendelian randomization study.
Observational studies suggest an association between blood pressure (BP) and functional outcomes in ischemic stroke patients but whether this is causal or due to confounding is uncertain. We used Mendelian randomization (MR) to assess causality, and also explore whether particular classes of anti-hypertensives were associated with a better outcome after ischemic stroke. We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drugs from genome-wide association studies (GWAS) on 757,601 individuals. The primary outcome was 3-month dependence or death defined as a modified Rankin Scale (mRS) of 3-6. The secondary outcome was disability or death after 90 days defined as mRS 2-6. Cochran's Q statistic in the inverse variance weighted (IVW) model, the weighted median, MR-Egger regression, leave-one-single-nucleotide polymorphism (SNP)-out analysis, MR-Pleiotropy Residual Sum and Outlier methods were adopted as sensitivity analyses. To validate our primary results, we performed independent repeat analyses and Bi-directional MR analyses. Genetic predisposition to higher systolic and diastolic BP was associated with disability or death after ischemic stroke in univariable IVW MR analysis (odds ratio (OR) 1.29, 95% confidence interval (CI): 1.05-1.59, p = 0.014; OR 1.27, 95% CI: 1.07-1.51, p = 0.006, respectively). Pulse pressure was associated with both dependence or death and disability or death after ischemic stroke (OR = 1.05, 95% CI: 1.02-1.08, p = 0.002; OR = 1.04, 95% CI = 1.01-1.07, p = 0.009, respectively). Angiotensin-converting enzyme inhibitor (ACEI) and calcium channel blocker (CCB) were significantly associated with improved functional outcomes (dependence or death, OR 0.76, 95% CI: 0.62-0.94, p = 0.009; OR 0.89, 95% CI: 0.83-0.97, p = 0.005). Proxies for β-blockers, angiotensin receptor blockers (ARB), and thiazides failed to show associations with functional outcomes (p > 0.05). We provide evidence for an association of genetic predisposition to higher BP with a higher risk of 3-month functional dependence after ischemic stroke. Our findings support ACEI and CCB as promising antihypertensive drugs for improving functional outcomes in ischemic stroke.


Feyerabend, truth, and relativisms: Footnotes to the Italian debate.
There is a substantial literature on Feyerabend's relativism-including a few papers in this collection-but fewer specific studies of the ways that his writings and ideas have been taken up among the non-academic public. This is odd, given his obvious interest in the lives and concerns of persons who were not 'intellectuals'-a term that, for him, had a pejorative ring to it. It is also odd, given the abundance of evidence of how Feyerabend's relativism played a role in a specific national and cultural context-namely, contemporary Italian debates about relativism. This paper offers a study of how Feyerabend's ideas have been deployed by Italian intellectuals and cultural commentators-including the current Pope-and critically assesses them.


Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis.
The pathophysiology of sepsis may involve the activation of the NOD-type receptor containing the pyrin-3 domain (NLPR-3), mitochondrial and oxidative damages. One of the primary essential oxidation products is 8-oxoguanine (8-oxoG), and its accumulation in mitochondrial DNA (mtDNA) induces cell dysfunction and death, leading to the hypothesis that mtDNA integrity is crucial for maintaining neuronal function during sepsis. In sepsis, the modulation of NLRP-3 activation is critical, and mefenamic acid (MFA) is a potent drug that can reduce inflammasome activity, attenuating the acute cerebral inflammatory process. Thus, this study aimed to evaluate the administration of MFA and its implications for the reduction of inflammatory parameters and mitochondrial damage in animals submitted to polymicrobial sepsis. To test our hypothesis, adult male Wistar rats were submitted to the cecal ligation and perforation (CLP) model for sepsis induction and after receiving an injection of MFA (doses of 10, 30, and 50 mg/kg) or sterile saline (1 mL/kg). At 24 h after sepsis induction, the frontal cortex and hippocampus were dissected to analyze the levels of TNF-α, IL-1β, and IL-18; oxidative damage (thiobarbituric acid reactive substances (TBARS), carbonyl, and DCF-DA (oxidative parameters); protein expression (mitochondrial transcription factor A (TFAM), NLRP-3, 8-oxoG; Bax, Bcl-2 and (ionized calcium-binding adaptor molecule 1 (IBA-1)); and the activity of mitochondrial respiratory chain complexes. It was observed that the septic group in both structures studied showed an increase in proinflammatory cytokines mediated by increased activity in NLRP-3, with more significant oxidative damage and higher production of reactive oxygen species (ROS) by mitochondria. Damage to mtDNA it was also observed with an increase in 8-oxoG levels and lower levels of TFAM and NGF-1. In addition, this group had an increase in pro-apoptotic proteins and IBA-1 positive cells. However, MFA at doses of 30 and 50 mg/kg decreased inflammasome activity, reduced levels of cytokines and oxidative damage, increased bioenergetic efficacy and reduced production of ROS and 8-oxoG, and increased levels of TFAM, NGF-1, Bcl-2, reducing microglial activation. As a result, it is suggested that MFA induces protection in the central nervous system early after the onset of sepsis.


A new probe to monitor the effects of drugs on local field potentials.
We describe a new device with which microdialysis can be combined with bipolar local field potential (LFP) recordings. The device consists of a microdialysis probe with two ultra-thin electrical wires located within its tip. The device can be used to monitor LFPs with differential recording methods before, during, and after local application of drugs by reverse microdialysis, while concomitantly sampling biochemical constituents from the area of recording.


Determination of chymotrypsin in stool by a new photometric method.
A photometric method to determine chymotrypsin in stool, equivalent to the titrimetric analysis, was developed. The chymotrypsin concentrations found in healthy children and those with gastrointestinal and pancreatic disease permit the same clinical conclusions as the titrimetrically determined results. In view of its lower technical requirements, this method is suitable for the identification of maldigestion in pediatric and general practice.


Tripartite motif-containing protein 46 accelerates influenza A H7N9 virus infection by promoting K48-linked ubiquitination of TBK1.
Avian influenza A H7N9 emerged in 2013, threatening public health and causing acute respiratory distress syndrome, and even death, in the human population. However, the underlying mechanism by which H7N9 virus causes human infection remains elusive. Herein, we infected A549 cells with H7N9 virus for different times and assessed tripartite motif-containing protein 46 (TRIM46) expression. To determine the role of TRIM46 in H7N9 infection, we applied lentivirus-based TRIM46 short hairpin RNA sequences and overexpression plasmids to explore virus replication, and changes in type I interferons and interferon regulatory factor 3 (IRF3) phosphorylation levels in response to silencing and overexpression of TRIM46. Finally, we used Co-immunoprecipitation and ubiquitination assays to examine the mechanism by which TRIM46 mediated the activity of TANK-binding kinase 1 (TBK1). Type I interferons play an important role in defending virus infection. Here, we found that TRIM46 levels were significantly increased during H7N9 virus infection. Furthermore, TRIM46 knockdown inhibited H7N9 virus replication compared to that in the control group, while the production of type I interferons increased. Meanwhile, overexpression of TRIM46 promoted H7N9 virus replication and decrease the production of type I interferons. In addition, the level of phosphorylated IRF3, an important interferon regulatory factor, was increased in TRIM46-silenced cells, but decreased in TRIM46 overexpressing cells. Mechanistically, we observed that TRIM46 could interact with TBK1 to induce its K48-linked ubiquitination, which promoted H7N9 virus infection. Our results suggest that TRIM46 negatively regulates the human innate immune response against H7N9 virus infection.


Syringosubarachnoid shunt for treatment of syringomyelia.
The experiences with a series of 9 patients with syringomyelia treated by syringosubarachnoid shunt (SSS) are presented. All of the cases were evaluated by myelography, CT scan or MNR. The cases showed satisfactory results which consisted in stabilization of the symptoms (55%) or clinical improvement (44%). These results should be continuously evaluated, due to the short follow-up period and to the variable natural history of the illness. Treatment by SSS is a technique of low morbidity. It is recommended for patients with syringomyelia without significant descent of the tonsils or in those cases where posterior fossa operations have failed to obtain good results.


Axonal injury: a universal consequence of fatal closed head injury?
beta-Amyloid precursor protein immunostaining has recently been shown to be a reliable method for detecting the damage to axons associated with fatal head injury. In an attempt to compare the efficacy of this technique with conventional histological detection of axonal damage, we have reanalysed sections from a large well-characterised series of head-injured and control patients. The results indicate that the frequency of axonal injury has been vastly underestimated using conventional silver techniques, and that axonal injury may in fact be an almost universal consequence of fatal head injury.


Robot-assisted pyeloplasty and laparoscopic pyeloplasty in children: A comparison of single-port-plus-one and multiport surgery.
This study aimed to compare the effects of various trocar placements in robot-assisted and laparoscopic pyeloplasty involving children diagnosed with obstruction of the ureteropelvic junction (OUPJ). We retrospectively collected the data on 74 patients under 14 years of age who had been diagnosed with OUPJ; these patients underwent either robot-assisted or laparoscopic pyeloplasty in our hospital between January 2015 and November 2021. There were four groups, as follows: •Laparoscopic multiport pyeloplasty (LMPY),•Laparoscopic single-port pyeloplasty (LSPY),•Robotic-assisted multiport pyeloplasty (RMPY),•Robotic-assisted single-port-plus-one pyeloplasty (RSPY).Patients' characteristics as well as their perioperative and follow-up data were collected and evaluated. There was no significant difference in the data regarding patients' characteristics. These data included the grade of hydronephrosis according to the Society of Fetal Urology (SFU grade), anterior and posterior diameter of the renal pelvis and ureter (APDRPU), and the differential degree of renal function (DRF) at following time points: preoperative, postoperative, and comparison of preoperative and postoperative. There was no difference among these groups. During surgery, the time of trocar placement, urethroplasty time, and total operative time in the robotic groups (RMPY and RSPY) were longer than those in the laparoscopic groups (LMPY and LSPY). However, the ratio of the urethroplasty time and full operative time (UT/WT) in the robotic groups (RMPY and RSPY) was lower than that in the laparoscopic groups (LMPY and LSPY) (P = 0.0075). Also, the volume of blood loss was lower in the robotic groups (RMPY and RSPY) than that in the laparoscopic groups (LMPY and LSPY), although there was no statistical difference (P = 0.11). There were, however, significant differences in hospitalization days (P < 0.0001) and parents' cosmetic satisfaction scores (P < 0.001). There were no differences in fasting time, the length of time that a ureteral catheter remained in place, or the number of postoperative complications. Our study shows that both robotic multiple-port and single-port-plus-one approaches are comparable, with laparoscopic multiple-port and single-port approaches equally effective in resolving OUPJ in children. Robotic and single-port-plus-one approaches may be associated with some advantages in hospitalization time and cosmetic outcomes; therefore, these approaches may be useful in urologic surgery that requires precise suturing, especially in pediatric patients.


Plasma/Serum Leptin Levels in Patients with Systemic Lupus Erythematosus: A Meta-analysis.
Currently published data regarding the relationship between plasma/serum leptin levels and systemic lupus erythematosus (SLE) are contradictory. To derive a more precise evaluation of this relationship, a meta-analysis was performed. Published literature from PubMed, Embase and Cochrane Library were obtained. The study quality was assessed by the Newcastle-Ottawa scale. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effects or random-effect model analysis. Heterogeneity among studies was estimated using the Cochran Q and I(2) statistics. A total of 11 studies including 868 SLE patients and 591 controls were finally included in the meta-analysis. No significant differences in plasma/serum leptin levels was found between SLE patients and healthy controls when all studies were pooled into the meta-analysis (pooled SMD = 0.269, 95% CI = -0.188 to 0.726). However, subgroup analyses showed that SLE patients from an Asian population, age ≥40 years and BMI <25 had higher plasma/serum leptin levels when compared with controls. There is no significant difference in plasma/serum leptin levels between the entire group of SLE patients and controls. However, plasma/serum leptin levels are significantly higher in the subgroup of SLE patients from an Asian population ≥40 years of age and with a BMI <25.


Novel therapeutic strategies for recurrent SCLC.
Therapeutic options for patients with relapsed SCLC are limited, and the prognosis in this setting remains poor. While clinical outcomes for frontline treatment have modestly improved with the introduction of immunotherapy, treatment in the second-line setting persists almost unchanged. In this review, current treatment options and recent advances in molecular biology are described. Emerging therapeutic options in this setting, and potential strategies to improve clinical outcomes of these patients are also addressed.


Percentile-based averaging and skeletal muscle gauge improve body composition analysis: validation at multiple vertebral levels.
Skeletal muscle metrics on computed tomography (CT) correlate with clinical and patient-reported outcomes. We hypothesize that aggregating skeletal muscle measurements from multiple vertebral levels and skeletal muscle gauge (SMG) better predict outcomes than skeletal muscle radioattenuation (SMRA) or -index (SMI) at a single vertebral level. We performed a secondary analysis of prospectively collected clinical (overall survival, hospital readmission, time to unplanned hospital readmission or death, and readmission or death within 90 days) and patient-reported outcomes (physical and psychological symptom burden captured as Edmonton Symptom Assessment Scale and Patient Health Questionnaire) of patients with advanced cancer who experienced an unplanned admission to Massachusetts General Hospital from 2014 to 2016. First, we assessed the correlation of skeletal muscle cross-sectional area, SMRA, SMI, and SMG at one or more of the following thoracic (T) or lumbar (L) vertebral levels: T5, T8, T10, and L3 on CT scans obtained ≤50 days before index assessment. Second, we aggregated measurements across all available vertebral levels using percentile-based averaging (PBA) to create the average percentile. Third, we constructed one regression model adjusted for age, sex, sociodemographic factors, cancer type, body mass index, and intravenous contrast for each combination of (i) vertebral level and average percentile, (ii) muscle metrics (SMRA, SMI, & SMG), and (iii) clinical and patient-reported outcomes. Fourth, we compared the performance of vertebral levels and muscle metrics by ranking otherwise identical models by concordance statistic, number of included patients, coefficient of determination, and significance of muscle metric. We included 846 patients (mean age: 63.5 ± 12.9 years, 50.5% males) with advanced cancer [predominantly gastrointestinal (32.9%) or lung (18.9%)]. The correlation of muscle measurements between vertebral levels ranged from 0.71 to 0.84 for SMRA and 0.67 to 0.81 for SMI. The correlation of individual levels with the average percentile was 0.90-0.93 for SMRA and 0.86-0.92 for SMI. The intrapatient correlation of SMRA with SMI was 0.21-0.40. PBA allowed for inclusion of 8-47% more patients than any single-level analysis. PBA outperformed single-level analyses across all comparisons with average ranks 2.6, 2.9, and 1.6 for concordance statistic, coefficient of determination, and significance (range 1-5, μ = 3), respectively. On average, SMG outperformed SMRA and SMI across outcomes and vertebral levels: the average rank of SMG was 1.4, 1.4, and 1.4 for concordance statistic, coefficient of determination, and significance (range 1-3, μ = 2), respectively. Multivertebral level skeletal muscle analyses using PBA and SMG independently and additively outperform analyses using individual levels and SMRA or SMI.


Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues.
CD40 is a member of the tumor necrosis factor receptor family. We reveal here a correlation between CD40 expression and colon cancer differentiation. Upon CD40 ligand (CD40L) binding, CD40/CD40L signaling inhibited colon cancer proliferation, induced apoptosis, stalled cells at G0/G1, and influenced cell adhesion and metastasis. Clustering analysis identified the elevation of aryl hydrocarbon receptor repressor (AHRR) expression along with activation of CD40/CD40L signaling. Examination of clinical specimens revealed that both AHR and AHRR levels correlated with colon cancer histological grade. In addition, high expression of AHRR was associated with high expression of CD40 in tumor cells, with CD40L expression being particularly high in the tumor interstitium. Real-time PCR and western blotting analysis showed that AHRR expression in colon cancer cells was up-regulated by CD40L binding. The likely mediating signaling pathways for the effects of CD40 are described herein.


Secretory Carcinoma of Salivary Glands: A Case Series and Review of Literature.
Mammary analogue of secretory carcinoma is a recently described entity in WHO 2017 classification of head and neck tumours. It resembles secretory carcinoma of breast. It usually affects the salivary glands and has an indolent behaviour. We reviewed five cases of Mammary analogue of secretory carcinoma in our institute and compared our results with existing literature. All the patients underwent surgical resections and appropriate adjuvant treatment. Immunohistochemistry is an alternative cost effective tool as compared to genetic testing to differentiate secretory carcinoma from its mimickers. Surgery with adequate margins followed by adjuvant therapy is the treatment of choice.


Efficacy and safety of sodium hyaluronate in the treatment of Wilkes stage II disease.
To show whether an intra-articular (IA) infiltration of 1 mL sodium hyaluronate (SH) into the temporomandibular joint (TMJ) would significantly reduce pain and improve joint function in Wilkes stage II disease, compared with the oral administration of a combination of methocarbamol and paracetamol. Forty-one patients with Wilkes stage II disease were selected and randomly assigned to 2 groups. The experimental group received 1 IA infiltration of SH with assessments at days 14, 28, 56, and 84. The control group was given 2 tablets of a combination of methocarbamol 380 mg and paracetamol 300 mg every 6 hours for 4 weeks, with assessments at days 14 and 28. Forty-one patients were randomized into the study (SH: 20 patients, control drug: 21 patients). A statistically significant difference (P < . 05) was detected in favor of the SH group from day 56 onward for TMJ pain at rest, from day 14 onward for pain on jaw opening, and at days 28 and 56 for pain on mastication. The TMJ function was statistically significantly (P < .05) better in the test group at all follow-up visits. The global evaluation of efficacy by both, the patients and investigators, was better for the test group. No adverse reactions were detected with SH. An IA infiltration of SH showed better efficacy in reducing pain and improving joint function in Wilkes stage II disease, compared with the oral administration of methocarbamol-paracetamol tablets.


Adding and multiplying random matrices: a generalization of Voiculescu's formulas.
In this paper, we give an elementary proof of the additivity of the functional inverses of the resolvents of large N random matrices, using recently developed matrix model techniques. This proof also gives a very natural generalization of these formulas to the case of measures with an external field. A similar approach yields a relation of the same type for multiplication of random matrices.